The Year in Renal Medicine, Volume 1

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THE YEAR IN RENAL MEDICINE VOLUME 1

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THE YEAR IN

RENAL MEDICINE VOLUME 1

EDITED BY

JEREMY LEVY Department of Renal Medicine, Hammersmith Hospital, London, UK

CLINICAL PUBLISHING OX F O R D   

             

  .  .   . , 

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Clinical Publishing an imprint of Atlas Medical Publishing Ltd Oxford Centre for Innovation Mill Street, Oxford OX2 0JX, UK Tel:

+44 1865 811116

Fax:

+44 1865 251550

Web: www.clinicalpublishing.co.uk Distributed by: Taylor & Francis Ltd 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487, USA E-mail: [email protected] Taylor & Francis Ltd 23–25 Blades Court Deodar Road London SW15 2NU, UK E-mail: [email protected] © Atlas Medical Publishing Ltd 2005 First published 2005 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Clinical Publishing or Atlas Medical Publishing Ltd Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention A catalogue record for this book is available from the British Library ISBN 1 904392 39 3 ISSN 1742-3082 The publisher makes no representation, express or implied, that the dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publisher do not accept any liability for any errors in the text or for the misuse or misapplication of material in this work Project manager: Rosemary Osmond Typeset by Footnote Graphics Limited, Warminster, Wiltshire, UK Printed by T G Hostench SA, Barcelona, Spain

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Contents Contributors vii Foreword xi

Part I

Chronic renal failure 1.

Diabetic nephropathy 3 Merlin Thomas, Mark Cooper

2.

Peritoneal dialysis 23 Edwina Brown

3.

Anaemia in chronic renal failure 43 Iain Macdougall

4.

Cardiovascular disease 69 Robert Foley

Part II

Acute renal failure 5.

Prevention of acute radiocontrast nephropathy 91 Norbert Lameire

6.

Renal support in and treatment of acute renal failure 115 Frank Liu, Ravindra Mehta

7.

Glomerulonephritis 143 Gerald Appel, Alice Appel

8.

Vasculitis and lupus nephritis 165 David Jayne

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CONTENTS

Part III

End-stage renal disease 9.

Progression of chronic renal failure 193 Jonathan Fox, Bruce Mackinnon

10.

Haemodialysis 211 Ken Farrington

11.

Mineral metabolism and renal bone disease 233 Simon Steddon, Stanley Fan

12.

Transplantation 259 John Forman, Mohamed Sayegh

13.

Interstitial and tubular diseases 281 Jérome Rossert, Evelyne Fischer

Part IV

New developments 14.

Inherited renal disease 301 Marie Hogan, Vicente Torres

15.

Renal physiology: acid-base, potassium, calcium and blood pressure 327 Robert Unwin, Pedro Cutillas, Giovambattista Capasso

16.

Ethnicity and renal disease 343 Jeremy Levy

List of abbreviations 359 Index of papers reviewed 363 General index 377

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Editor and contributors Editor Jeremy Levy, MA, PhD, ILTM, FRCP Consultant Nephrologist, Department of Renal Medicine, Hammersmith Hospitals Trust, London, UK

Contributors Alice Sue Appel, PhD Research Associate, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York, USA Gerald B Appel, MD Professor of Clinical Medicine, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York, USA Edwina A Brown, DM, FRCP Professor of Renal Medicine and Consultant Nephrologist, Imperial College London, Charing Cross Hospital, Fulham Palace Road, London, UK Giovambattista Capasso, MD Professor of Nephrology, Chair of Nephrology, Second University of Naples, Italy Mark E Cooper, MB BS, PHD, FRACP Professor of Medicine and Director, Danielle Alberti Memorial Centre for Diabetes Complications, Baker Medical Research Institute, Melbourne, Victoria, Australia Pedro Cutillas, PhD Research Associate, Proteomics Unit, Ludwig Institute for Cancer Research, University College London, UK Ken Farrington, MD, FRCP Consultant Nephrologist, Lister Hospital, Stevenage, Hertfordshire, UK Stanley L-S Fan, MRCP Consultant Nephrologist, Department of Renal Medicine and Transplantation, Bart’s and The London Hospital, London, UK

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CONTRIBUTORS

Evelyne Fischer, MD, PhD Research Associate, Unit of Gene Expression and Disease/CNRS URA 1644, Department of Developmental Biology, Pasteur Institute, Paris, France Robert N Foley, MB, MSC, FRCPC, FRCPI Director, Nephrology Analytical Services, Minneapolis Medical Research Foundation, Minneapolis, Minnesota; and Associate Professor, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA John P Forman, MD Instructor of Medicine, Harvard Medical School, Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA Jonathan G Fox, BSc, MD, FRCP Consultant Nephrologist, Renal Unit, Glasgow Royal Infirmary, Glasgow, UK Marie Hogan, MB, BCH, MRCP Consultant, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota, USA David Jayne, MD, FRCP Consultant in Nephrology and Vasculitis, Renal Unit, Addenbrooke’s Hospital, Cambridge, UK Norbert Lameire, MD, PhD Chief of the Renal Division, Department of Medicine, University Hospital, Ghent, Belgium Jeremy Levy, MA, PhD, ILTM, FRCP Consultant Nephrologist, Department of Renal Medicine, Hammersmith Hospitals Trust, London, UK Frank Liu, MD Fellow, Division of Nephrology, Department of Medicine, University of California at San Diego, California, USA Iain C Macdougall, BSc, MD, FRCP Consultant Nephrologist and Honorary Senior Lecturer, Department of Renal Medicine, King’s College Hospital, London, UK Bruce Mackinnon, BSc, MRCP(UK) Specialist Registrar in Nephrology, Renal Unit, Glasgow Royal Infirmary, Glasgow, UK Ravindra L Mehta, MD, FACP Professor of Clinical Medicine, Division of Nephrology, Department of Medicine, University of California at San Diego Medical Center, San Diego, California, USA

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CONTRIBUTORS

IX

Jérome Rossert, MD, PhD Professor of Nephrology and Consultant Nephrologist, Georges Pompidou European Hospital, INSERM U652, and Pierre and Marie Curie University, Paris, France Mohamed H Sayegh, MD, FAHA, FASN Professor of Medicine and Pediatrics, Transplantation Medicine Chair, Harvard Medical School; Director, Transplantation Research Center, Brigham and Women’s Hospital & Children’s Hospital Boston, Boston, Massachusetts, USA Simon Steddon, MRCP Specialist Registrar, Department of Renal Medicine and Transplantation, Bart’s and The London Hospital, London, UK Merlin C Thomas, MB CHB, PhD, FRACP Don Jacquot Research Fellow, Danielle Alberti Memorial Centre for Diabetes Complications, Baker Medical Research Institute, Melbourne, Victoria, Australia Vicente Torres, MD, PhD Professor of Medicine, Division Chair, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota, USA Robert Unwin, BM, PhD, FRCP Professor of Nephrology and Physiology (St. Peter’s Chair of Nephrology), Centre for Nephrology, Royal Free and University College Medical School, University College, London, UK

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Foreword AJAY K SINGH MB MRCP(UK) Clinical Director, Renal Division, Brigham and Women’s Hospital Associate Professor of Medicine, Harvard Medical School, Boston, USA

This yearbook brings you the latest advances in kidney disease over the past year. The contributing authors utilize their extraordinary scientific knowledge to update us on progress in their respective fields, and in their efforts have covered all the main areas of nephrology. Two areas deserve particular mention. We are at the 50th anniversary of the first kidney transplant performed by a team led by Dr Joseph Murray at the Brigham and Women’s Hospital, for which he was awarded the Nobel Prize in Medicine. In 1954, Dr Murray could have hardly believed that his important accomplishments would herald the transplantation of virtually every organ, or that the discovery of more targeted drugs to suppress the immune system as it applies to transplantation would lead to more effective treatment of glomerulonephritis. Also, ninety years ago, Abel, Rowntree and Turner devised an apparatus for the dialysis of blood, and sixty years have elapsed since Willem Kolff, a young physician, built the first clinically usable dialyzer. Kolff’s machine, a huge rotating drum with a 40-metre cellulose acetate sausage skin membrane in a large liquid bath, was the precursor for modern dialysis. Chronic dialysis emerged in the 1970s and has since transformed itself into a big business with multiple chains that cross international borders to provide hundreds of thousands of people with kidney support treatment. Transplantation and dialysis represent important changes in nephrology, but one could scarcely discuss advances in nephrology without discussing advances in physiology, epidemiology, molecular nephrology, and glomerulonephritis. Dr Levy should be commended for recruiting a ‘who’s who’ of contributors to provide a timely update for practising nephrologists, researchers, trainees and students, and in particular to review their own field and comment on the most important papers over the last year.

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Part I Chronic renal failure

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1 Diabetic nephropathy MERLIN THOMAS, MARK COOPER

Introduction Diabetic nephropathy is one of the most important causes of both chronic kidney disease and end-stage renal failure (ESRF). In the USA and much of Europe, diabetes is the commonest cause of ESRF, and in many regions is increasing in incidence with the increasing prevalence of obesity and an ageing population of individuals from ethnic minorities with a strong predisposition to the development of diabetes. Over the last few years we have learned much about the natural history of diabetic nephropathy and the risks of progression from normal kidney structure and function to overt nephropathy and proteinuria, frequently leading to renal failure, and associated with hugely increased risks of cardiovascular morbidity and mortality. More recently, this has been associated with high-quality trial data on interventions that can reduce the risk of progression of diabetic kidney disease. There already exists a large literature on the benefits of using inhibitors of angiotensin-converting enzyme (ACE) in patients with type 1 diabetes to reduce the progression of renal impairment and reduce cardiovascular events. In addition, a number of trials have been reported using angiotensin receptor antagonists in patients with type 2 diabetes and microalbuminuria, and in those with overt nephropathy, demonstrating respectively significant reductions in progression to proteinuria and in worsening of renal function (using losartan, irbesartan and valsartan). These effects seemed to be independent of the lowering of blood pressure itself, since the use of other agents to achieve equivalent blood pressure control is not associated with similar risk reduction. To this end, these studies point towards the ultimate goal of being able to reduce significantly the rate of renal complications of diabetes. In this chapter we will look first at some recent work on the natural history of diabetic renal disease, then some experimental data on the possible mechanisms for renal damage in diabetes, and finally the benefits of various therapeutic interventions.

Natural history of diabetic nephropathy Diabetic nephropathy has generally been thought of in three phases: microalbuminuria (urinary albumin excretion 30–300 mg/day [20–200 µg/min]); macroalbuminuria or © Atlas Medical Publishing Ltd

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proteinuria (>300 mg/day [>200 µg/min]); and end-stage renal disease (ESRD). Microalbuminuria is the first clinical sign of diabetic damage to the kidney and is thought of as a harbinger of progressive kidney damage. Microalbuminuria also reflects a higher risk of cardiovascular disease and premature mortality. It is generally suggested that many (if not most) patients with microalbuminuria will progress to nephropathy, which will be followed by an inexorable decline in renal function. This may not be true.

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Regression of microalbuminuria in type 1 diabetes Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS. N Engl J Med 2003; 348: 2285–93

B A C K G R O U N D . Perkins et al. reported, in a study based at the Joslin Clinic, Boston, the phenomenon of regression of microalbuminuria in type 1 diabetes. In 386 type 1 diabetic patients with persistent microalbuminuria followed over 6 years, the frequency of regression of microalbuminuria was examined. Regression was arbitrarily deﬁned as a 50% reduction in urinary albumin excretion from one 2-year period to the next. I N T E R P R E T A T I O N . The researchers noted that regression of microalbuminuria occurred in over half of all patients, with a 6-year cumulative incidence of 58%. Only a minority of patients (19%) progressed to overt nephropathy (Table 1.1). Major factors linked to regression included a young age, a short duration of diabetes, good glycaemic control (glycated haemoglobin [HbA1c] <8%), low systolic blood pressure (systolic <115 mmHg) and low lipid levels (cholesterol <5.1 mmol/l), the last three variables being amenable to intervention. Patients with salutary levels of all modiﬁable factors had a hazard ratio for regression of 3.0 (95% conﬁdence interval [CI] 1.5–6.0) compared with patients with no salutary levels of any modiﬁable factor. Notably, regression appeared to be independent of the use of ACE inhibitors during the observation period.

Comment Much of the work in diabetic nephropathy has been rooted in the paradigm that elevated albumin excretion leads inexorably to overt nephropathy. The findings in this cohort that only one in five patients progressed and that many reverted to normoalbuminuria directly opposes this view. Not surprisingly, this report has sparked much controversy. However, the phenomenon of transient microalbuminuria has been reported in up to 30% of adolescents with type 1 diabetes 1,2. This figure is significantly less than that described in the Perkins et al. study, although both studies clearly demonstrate the phenomenon. Nevertheless, the concept of persistent microalbuminuria needs to be revisited. Indeed, it may be necessary to consider stricter criteria for the definition of persistent microalbuminuria by using a longer duration of monitoring to exclude transient increases in urinary albumin excretion. However, this kind of selection may be associated with its own inherent bias. Although it has been established by large clinical studies that the risk of adverse renal and cardio-

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Table 1.1 Prevalence of microalbuminuria and proteinuria in patients over a 6-year period Status*

Initial evaluation period†

1st follow-up period

2nd follow-up period

3rd follow-up period

n (%) Proteinuria Microalbuminuria Normal albumin excretion

– 386 (100) –

24 (7) 191 (54) 136 (39)

37 (13) 141 (49) 110 (38)

Total

386 (100)

351 (100)‡

288 (100)‡

33 (15) 99 (45) 88 (40) 220 (100)‡

* The lower limits of the albumin excretion rate for microalbuminuria and proteinuria were 30 and 300 g per minute, respectively. † The initial evaluation period was the ﬁrst two-year period during which microalbuminuria was present. Microalbuminuria was present initially in 287 patients (the prevalence cohort) and developed during a later period in 99 (the incidence cohort). In the incidence cohort, the initial evaluation period took place after two years in 62 patients and after four years in 37. ‡ After adjustment for the short length of potential follow-up in the incidence cohort, the completeness of follow-up was 91%, 83%, and 77% in the ﬁrst, second, and third periods, respectively. Source: Perkins et al. (2003).

vascular outcomes in diabetes is strongly correlated with the level of proteinuria (even within the normoalbuminuric range), the fate of patients who spontaneously regress to normoalbuminuria is unknown. Whether this represents recovery of glomerular integrity, as demonstrated after isolated pancreas transplantation, is yet to be determined 3. It is possible that under unfavourable conditions, such as deteriorated metabolic control or increasing blood pressure, these patients may still progress to overt nephropathy. Indeed, intermittent insults may be more damaging than persistent ones. Equally, regression may indicate a less aggressive or fulminant pathogenic process. Interestingly, the factors that promote regression identified in the Joslin Clinic study are similar to those that influence progression to overt proteinuria, further emphasizing the importance of blood pressure and glycaemic control in the natural history and evolution of diabetic nephropathy. Although ACE inhibitors were not associated with regression at the Joslin, this may reflect a selection bias in their use. Clearly, blockade of the renin–angiotensin system (RAS) has an important part in the management of patients with microalbuminuria.

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Renal insufﬁciency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus Kramer HJ, Nguyen QD, Curhan G, Hsu C-Y. JAMA 2003; 289: 3273–7

B A C K G R O U N D . Kramer et al. performed a cross-sectional analysis of a sample of type 2 diabetic subjects aged 40 years or older from the third National Health and

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Nutrition Examination Survey to determine the prevalence of renal impairment in the absence of classical markers of microvascular disease or diabetic glomerulosclerosis (retinopathy and albuminuria respectively). Out of 1197 type 1 diabetic subjects, 13% had a calculated glomerular ﬁltration rate (GFR) below 60 ml/min/1.73 m2. I N T E R P R E T A T I O N . Within this group with impaired renal function, 30% of subjects did not have microalbuminuria, macroalbuminuria or retinopathy. The authors concluded that a signiﬁcant number of diabetic patients with chronic renal impairment do not have classical diabetic glomerulosclerosis and that screening for this condition will require an assessment of GFR independent of monitoring albumin excretion and retinal status.

Comment Barring vascular accident, the majority of patients who develop macroalbuminuria will progress further to develop renal impairment. This pattern of progression leads logically to the ‘protein toxicity’ or Remuzzi hypothesis of pathogenesis, whereby protein leak causes progressive renal damage due to exposure of tubular elements to toxic concentrations of filtered serum proteins 4. Certainly albuminuria is correlated with structural changes in the kidney, including basement membrane thickness and collagen deposition 5. In addition, all therapies that slow disease progression reduce proteinuria. This paradigm is challenged by the comparative paucity of injury in minimal-change nephropathy and the findings that renal impairment may occur in some patients with diabetes in the absence of proteinuria. In this study, Kramer et al. demonstrate that 30% of patients with type 2 diabetes and renal impairment have no evidence of microvascular disease. It has been suggested that kidney disease in type 2 diabetes may be more heterogeneous, with a shorter course than that in patients with type 1 diabetes, as many patients present with already established nephropathy and hypertension. It is possible that renal impairment in patients without albuminuria is not directly due to diabetic nephropathy, since the majority of patients also have obesity, hypertension, atherosclerotic vascular disease and advancing age, all of which may be associated with progressive renal injury. It remains to be determined if these subjects have a lower rate of progression of renal disease, or if they have another explanation for their renal impairment, and if they respond in a similar manner to renoprotective interventions such as agents that interrupt the RAS.

Mechanisms of damage in diabetic nephropathy Although the classical histopathological features of diabetic nephropathy include glomerulosclerosis and basement membrane thickening, the precise mechanisms for the development of proteinuria remain poorly defined. Much data has been generated on the role of advanced glycation end-products (AGEs) in driving tissue damage in diabetes in general, and in the kidney. Several studies have addressed the mechanisms involved in the loss of glomerular permselectivity, including the role

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of glomerular basement membrane components. However, the central role of the podocyte slit diaphragm in maintaining the size-selective barrier of the glomerulus has been defined only relatively recently, and includes proteins such as nephrin, CD2-associated protein, podocin and -actinin-4. Whether changes in these proteins play a role in diabetic nephropathy is not well defined, and neither are the effects of hyperglycaemia, the RAS and AGEs.

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Nephrin expression is reduced in human diabetic nephropathy Doublier S, Salvidio G, Lupia E, et al. Diabetes 2003; 52: 1023–30

B A C K G R O U N D . Over the last few years there has been increasing interest in the role of the glomerular epithelial cell, the podocyte, in the pathogenesis of proteinuria and in particular in the progression of diabetic nephropathy. This ﬁeld has been greatly stimulated not only by the identiﬁcation of changes in podocyte numbers and density in human diabetic renal disease but also by the marked increase in our understanding of the ultrastructural changes of the podocyte in renal injury and the molecular characterization of these changes. Speciﬁcally, the identiﬁcation of the protein nephrin in the slit diaphragm of the podocyte and its link to the pathogenesis of proteinuria has opened up this ﬁeld. In this study the distribution of nephrin was examined semi-quantitatively in renal biopsies from patients with diabetes and nephrotic syndrome or microalbuminuria, and the effects of angiotensin II and glycated albumin on cultures of human podocytes in vitro were investigated. I N T E R P R E T A T I O N . The expression of nephrin was signiﬁcantly reduced in renal biopsies from diabetic patients with varying degrees of renal disease, and changed in its appearance from a linear to a granular pattern. The in vitro studies on human cultured podocytes demonstrated that glycated albumin and angiotensin II reduced nephrin expression.

Comment This study provides important evidence linking the podocyte and proteins (such as nephrin) that are present in the slit diaphragm to the pathogenesis of proteinuria in diabetes. Such proteins appear pivotal in the maintenance of the glomerular filtration barrier, as their absence is associated with heavy proteinuria and fulminant nephropathy. Changes in nephrin expression in the diabetic kidney have been reported previously in experimental studies 6. This study translates these findings to a clinical setting, showing that nephrin immunostaining in kidneys from diabetic subjects with both overt nephropathy and microalbuminuria is reduced (Fig. 1.1). In addition, there appear to be changes in the distribution of nephrin expression in these kidneys when compared with those from control subjects. However, it remains controversial whether the changes in nephrin expression are purely a manifestation of glomerular ultrastructural damage rather than being involved directly. Indeed, recent papers

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Fig. 1.1 Semi-quantitative analysis of nephrin expression as detected by immunoﬂuorescence staining in glomeruli of control subjects, patients with type 1 diabetes and nephrotic syndrome, patients with type 2 diabetes and nephrotic syndrome, the patient with type 1 diabetes and microalbuminuria, and patients with type 2 diabetes and microalbuminuria. **P <0.001 versus control subjects. Source: Doublier et al. (2003).

show that changes in podocyte structure and density occur in the early stages of diabetic nephropathy and might contribute to increasing albuminuria in type 2 diabetic patients 7. In this context, reduced nephrin density may reflect reduced podocyte density. This study goes on to examine the possible mechanisms leading to the downregulation of nephrin expression. Again, previous experimental studies have demonstrated that renoprotective therapies such as ACE inhibitors are able to restore nephrin expression in the diabetic kidney, correlating with improvements in albuminuria. In this study, Doublier et al. show that both angiotensin II and glycated albumin directly down-regulated nephrin expression. This finding is in contrast to other studies showing increased expression of nephrin following a continuous infusion of angiotensin II 8. A clear picture of the factors leading to loss of nephrin expression in diabetes is yet to be obtained. It is predicted that this will be a research area of ongoing interest that may ultimately lead to novel therapies that modulate urinary albumin excretion in diabetes.

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Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy Forbes JM, Cooper ME, Thallas V, et al. Diabetes 2003; 51: 3274–82

B A C K G R O U N D . Advanced glycation is a biochemical process involving a non-enzymatic reaction between glucose and proteins, lipids or nucleic acids that generates AGEs. The role of these AGEs in diabetic nephropathy has been characterized primarily by exploring the renal effects of agents that interfere with the formation of AGEs, thereby reducing renal AGE accumulation. AGEs are also known to be associated with oxidative stress, a key component in the development of diabetic complications. Forbes et al. examined the potential in vivo effect of the ACE inhibitor ramipril on renal AGE accumulation and compared it with that of a known AGE formation inhibitor, aminoguanidine. Markers of oxidative stress were also examined. I N T E R P R E T A T I O N . In diabetic rats, ramipril signiﬁcantly reduced renal AGE accumulation (assessed by immunohistochemistry), correlating with its renoprotective effect. The effect of ramipril was similar to that of the known AGE inhibitor aminoguanidine (Fig. 1.2). This occurred in association with a reduction in renal oxidative stress, as assessed by renal nitrotyrosine accumulation. The authors concluded that ACE inhibitors reduce renal AGE accumulation, possibly via a reduction in oxidative stress.

Comment Along with the RAS, AGEs have been shown to be pivotal mediators of diabetic nephropathy in both experimental and clinical diabetes. The findings by Forbes et al. provide an important link between these two pathogenic pathways. Previous studies by Huang et al. in NRK-49F cells found that AGEs increased collagen synthesis in a dose- and time-dependent manner, and that this effect could be inhibited by the ACE inhibitor captopril. It was suggested that blockade of the RAS may have reduced the expression of the receptor for AGE and the activity of its downstream mediators 9. Forbes et al. now demonstrate that ACE inhibition may also have important effects on AGEs in vivo. It remains to be established whether this effect is mediated directly by blockade of the RAS or simply through renoprotection in this model. Indeed, both ACE inhibitors and angiotensin receptor antagonists have the added ability to prevent the formation of AGEs in vitro, i.e. in the absence of a functioning RAS. It has been hypothesized that RAS blockade decreases the production of reactive carbonyl species by interfering with the formation of carbon-centred radicals and hydroxyl radicals, possibly by metal chelation and the scavenging of reactive oxygen species 10. This article demonstrates that blockade of the RAS in vivo also reduces the formation of reactive oxygen species, predominantly generated by NAD(P)H oxidase in diabetic nephropathy. The biochemical site of action of the ACE inhibitor remains to be delineated.

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Fig. 1.2 (a) Renal AGE ﬂuorescence corrected for protein content. *P <0.001 versus diabetic; †P <0.05 versus control. (b) Morphometric analysis of immunostaining for renal AGEs. *P <0.001 for control versus diabetic; †P <0.01 versus diabetic. C, control; CACEi, control plus ACE inhibitor; CAG, control plus aminoguanidine; D, diabetic; DACEi, diabetic plus ACE inhibitor; DAG, diabetic plus aminoguanidine. Source: Forbes et al. (2003).

Therapeutic intervention in diabetic nephropathy There has been a flurry of reports in the last couple of years on clinical interventions which might slow the progression of renal disease in patients with diabetes. These are important both for the individual with diabetes and for health economies, since even small increases in the time to develop ESRD have marked effects on quality of life and the cost of healthcare. Especially important have been the studies on angiotensin

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receptor antagonists in type 2 diabetes. In the last year further analyses of these studies have looked especially at cardiovascular end-points. Additionally, there is increasing evidence for the utility of both ACE inhibitors and angiotensin receptor blockers (ARBS), as well as for multifactorial interventions.

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Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes Gæde P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pedersen O. N Engl J Med 2003; 348: 383–93

B A C K G R O U N D . Gæde et al. reported the 8-year follow-up of the STENO-2 study, a targeted, intensiﬁed multifactorial intervention in type 2 diabetic patients with microalbuminuria compared with standard treatment. The primary end-point of this open parallel trial was a composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, revascularization and amputation. The importance of this study is its attempt to modify multiple factors simultaneously rather than targeting one alone. I N T E R P R E T A T I O N . In this study, which included 80 subjects in each group, intensiﬁed treatment, including aggressive reduction of hyperglycaemia, routine ACE inhibition (with captopril ﬁrst-line or losartan), lipid-lowering treatment, antioxidants and aspirin, was compared with conventional treatment according to Danish national guidelines. Not surprisingly, the group given intensiﬁed treatment had lower HbA1c levels, blood pressure and lipid levels as well as reduced urinary albumin excretion. The major ﬁnding was the reduction of more than 50% in cardiovascular disease in those treated intensively (Fig. 1.3). In addition, there was a decrease of less than 50% in nephropathy, retinopathy and autonomic neuropathy. The authors concluded that a target-driven, long-term intensiﬁed, multifactorial intervention reduces both macro- and microvascular events by ~50% in microalbuminuric, type 2 diabetic subjects.

Comment These findings extend the previous report by the STENO-2 investigators at the 4-year time point that showed the benefit of this multifactorial intervention strategy on microvascular end-points. The 8-year time point now shows an additional benefit on cardiovascular end-points. This is of great clinical relevance as cardiovascular disease is the major factor responsible for the increased morbidity and mortality in the diabetic population. However, the intensive regimen that was instituted consumed considerable resources and was not without significant cost. The findings of the STENO-2 study clearly emphasize the importance of treating modifiable risk factors in diabetes. Unfortunately, the design and power of the study does not allow us to determine which of the interventions was the most useful or cost-effective, and which, if any, were of minimal clinical utility. It is likely that ACE inhibition rather than antioxidants was more useful in reducing vascular events. Furthermore, statin

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Fig. 1.3 (a) Kaplan–Meier estimates of the composite end-point of death from cardiovascular causes, non-fatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, non-fatal stroke, amputation or surgery for peripheral atherosclerotic artery disease in the conventional therapy group and the intensive therapy group. (b) Relative risk of the development or progression of nephropathy, retinopathy and autonomic and peripheral neuropathy during the average follow-up of 7.8 years in the intensive therapy group compared with the conventional therapy group. Source: Gæde et al. (2003).

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therapy probably contributed to reduced cardiovascular events and, in particular, death in the intensively treated arm. STENO-2 provides important evidence for organizations linked to the healthcare system and health outcomes, to provide the infrastructure and resources to allow the medical profession and related healthcare workers to implement the sort of broad-brush interventions described. The challenge is to ensure that this experience is widely adopted in clinical practice.

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Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. JAMA 2003; 290: 2159–67

B A C K G R O U N D . The Diabetes Control and Complications Trial (DCCT) demonstrated the beneﬁts of intensiﬁed glycaemic control in type 1 diabetes for a range of microvascular end-points, including nephropathy. Subsequently, the same intensively and conventionally treated groups from the DCCT cohort were followed for a further 8 years without any further speciﬁc interventions to determine the effects of the relatively short period of intensive glucose control on long-term outcomes. I N T E R P R E T A T I O N . Notably, during the 8-year follow-up period, the DCCT groups that received intensiﬁed and conventional treatment had similar levels of glycaemic control. Nevertheless, the rate of development of microalbuminuria or overt albuminuria remained signiﬁcantly lower in those who had been treated with the intensive regimen 8 years previously (Fig. 1.4). In addition, fewer subjects from this (intensive) cohort developed hypertension or an elevated serum creatinine concentration (>170 mol/l). The authors concluded that, if subjects had been previously treated during the DCCT with intensiﬁed insulin therapy, the beneﬁt in delaying progression of diabetic nephropathy was maintained, even though glycaemic control had returned to standard treatment levels. Hence, even relatively short periods of good glycaemic control may have long-term beneﬁts.

Comment The Epidemiology of Diabetes Interventions and Complications (EDIC) study provides important evidence for a sustained benefit arising from intensive glycaemic control, even if that control is not sustained. These patients did not simply ‘revert to type’ at the end of the DCCT study, despite the restoration of ‘standard’ levels of glycaemic and blood pressure control. However, it must be appreciated that by the end of the DCCT study the conventional group already showed evidence of accelerated renal injury and elevated levels of urinary albumin excretion. Consequently, it comes as little surprise that these patients did worse than those starting the EDIC

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Fig. 1.4 Prevalence and incidence of albuminuria at the end of the DCCT and EDIC studies. Source: Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group (2003).

study in better condition after a period of intensive glycaemic control. Indeed, this is already apparent when one looks at the median albumin excretion rate (AER) and the prevalence of subjects with an AER greater than 28 and 208 g/min respectively at the baseline of the EDIC study. Although this difference in baseline characteristics constitutes a lead-time bias for the interpretation of the study, it is important to know that in the 8 years since the DCCT the difference between control and intensive arms can be sustained. This issue of persistent improvement in renal parameters as well as other features of vascular injury in type 1 diabetic subjects many years after cessation of the intensified glycaemic control intervention has led many investigators to suggest that ‘metabolic memory’ or imprinting may play a major role in sustained end-organ protection. The mechanism of this effect is the subject of ongoing research; however, it is likely that early damage will be amplified, even after initiation of more rigorous control. Equally, early protection (rigorous control) will have a long-term effect. These findings should encourage all clinicians to achieve and maintain glycaemic control as early as possible and for as long as possible, to maximally reduce the risk of complications. The DCCT/EDIC investigators should be commended for their ongoing commitment to this study. The follow-up findings continue to be of major interest and ultimately clinical relevance.

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Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy Rossing K, Jacobsen P, Pietraszek L, Parving H-H. Diabetes Care 2003; 26: 2268–74

B A C K G R O U N D . Despite the proven beneﬁt of RAS blockade by either ACE inhibitors or angiotensin receptor antagonists, previous clinical studies have found that such treatment slows but does not completely arrest the progression of renal disease. The objective of the present study was to evaluate the renoprotective effects of dual blockade of the RAS, as reﬂected by short-term changes in albuminuria, by adding an ARB at a maximally effective dose to treatment with maximally recommended doses of an ACE inhibitor in patients with type 2 diabetes and nephropathy. Rossing et al. studied 20 hypertensive patients with type 2 diabetes and overt proteinuria. Subjects were randomized in a cross-over design to either placebo or the angiotensin receptor antagonist candesartan 16 mg, which was added to their conventional therapy, which included an ACE inhibitor (40 mg lisinopril, 40 mg enalapril or 150 mg captopril). I N T E R P R E T A T I O N . Dual blockade led to a 28% decrease in albuminuria in association with a modest reduction in blood pressure (3/2 mmHg (Table 1.2)). Changes in albumin excretion did not correlate with the fall in blood pressure. These ﬁndings provide further evidence of a potential renoprotective role of dual blockade of the RAS in diabetic nephropathy.

Table 1.2 Effect of adding candesartan 16 mg od. to maximal recommended doses of ACE inhibitor (enalapril/lisinopril 40 mg daily) on kidney function and ABP in 20 patients with type 2 diabetes and diabetic nephropathy ACE inhibitor placebo Albuminuria (mg/24 h)† 24-h blood pressure (mmHg) GFR ml/min–1/1.73 m–2 Plasma creatinine (µmol/l) Plasma potassium (mmol/l) HbA1c (%) Cholesterol (mmol/l)

ACE inhibitor candesartan 16 mg

706 (349–1219) 508 (228–909) 138 (3)/72 (2) 135 (3)/70 (2) 77 (6) 121 (10)

74 (5) 123 (10)

Mean difference (95% CI)*

P-value*

28 (17–38) 3 (–2 to 8)/ 2 (–2 to 5) 4 (–1, 9) 2 (–7 to 10)

<0.001 0.21/0.38 0.10 0.66

4.0 (0.1)

4.2 (0.1)

–0.13 (–0.3 to 0.1)

0.13

7.9 (0.2) 4.5 (0.2)

8.1 (0.2) 4.6 (0.2)

–0.1 (–0.1 to 0.4) –0.1 (–0.2 to 0.4)

0.31 0.60

* Mean difference of (ACEI + placebo)–(ACEI + candesartan 16 mg). † Geometric mean (IQR). Source: Rossing et al. (2003).

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Comment This study confirms what had been suggested in the initial CALM (Candesartan And Lisinopril Microalbuminuria) study: that a further reduction in blood pressure is achievable using the combination of candesartan and lisinopril in type 2 diabetic patients. In addition, it demonstrates that dual blockade may also reduce albuminuria significantly further. Although ACE inhibitors are clearly renoprotective on their own, the acute reduction in plasma angiotensin II which follows their administration leads to withdrawal of angiotensin’s negative feedback inhibition of renal renin release. This results in an increase in plasma renin and consequently increased formation of angiotensin I and then II, the so-called angiotensin escape phenomenon 11. This rise in angiotensin II may overcome the competitive inhibition of the ACE enzyme. In addition, increased metabolism of angiotensin II via alternative pathways, such as serine chymases, may also contribute to angiotensin escape following ACE inhibition 12. These effects probably explain the findings that, during chronic administration of ACE inhibitors, plasma angiotensin and aldosterone levels tend to revert to normal 13. The addition of selective blockade of the angiotensin receptor has the potential to provide for a more complete blockade of the RAS than could be conferred following ACE inhibition alone 14. This and subsequent studies by the STENO group confirm the utility of dual blockade in both type 1 and type 2 diabetes with either early (microalbuminuria) or overt (proteinuria) nephropathy. Although these short-term studies have not been able to show unequivocal effects to delay or prevent end-stage renal failure, the Combination treatment of angiotensin-II receptor blocker and angiotensin-converting enzyme inhibitor in non-diabetic renal disease (COOPERATE) study has shown an effect of such a combination on hard renal end-points, such as renal function (serum creatinine). Furthermore, this combination remains under intensive investigation for its potential cardiac and vasoprotective effects.

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Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy Berl T, Hunsicker LG, Lewis JB, et al.; Irbesartan Diabetic Nephropathy Trial, Collaborative Study Group. Ann Intern Med 2003; 138: 542–9

B A C K G R O U N D . In the initial report of the Irbesartan Diabetic Nephropathy Trial (IDNT), most emphasis was placed on the primary, predominantly renal end-points when comparing the effects of irbesartan, amlodipine and placebo in a large cohort of type 2 diabetic subjects with proteinuria. The primary outcomes of the IDNT were doubling of serum creatinine levels, ESRD and death from any cause. To add to this data, Berl et al. now describe the cardiovascular outcomes from that study. I N T E R P R E T A T I O N . In this randomized, double-blind, placebo-controlled trial, which included 1715 subjects with impaired renal function (creatinine <266 mol/l) and

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proteinuria (>0.9 g/day), no difference could be detected in a composite of cardiovascular events regardless of treatment with irbesartan or amlodipine (Fig. 1.5). However, treatment with irbesartan was associated with a 28 and 35% decrease in congestive heart failure when compared to placebo- and amlodipine-treated subjects respectively.

Comment Although there is clear evidence that drugs that block the RAS are superior to other antihypertensive approaches in terms of renoprotective effects in diabetes, the data regarding cardiovascular risk are less clear. In the IDNT study, regardless of the intervention, lowering the blood pressure produced an equivalent reduction in cardiovascular risk. These findings should be considered in the context of the results from the Reduction of End-points in NIDDM (non-insulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) study, which shared many similarities in design and outcomes, although it did not directly compare a calcium channel blocker with an angiotensin receptor antagonist 15. Notably, the RENAAL study also showed no evidence of the superiority of an angiotensin receptor antagonist (in this case, losartan) over placebo in terms of major cardiovascular end-points. Nevertheless, the benefits seen with respect to renal end-points, including postponement of end-stage renal failure and heart failure, provide enough evidence for this class of antihypertensive agent to be considered first-line in the management of a diabetic patient with, or at high risk of, vascular complications. In addition, both the

Fig. 1.5 Time to ﬁrst composite cardiovascular end-point. Source: Berl et al. (2003).

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IDNT and RENAAL studies demonstrated a reduction in the risk of heart failure, an important cause of morbidity in patients with diabetes and advanced renal disease.

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Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study Bakris GL, Weir MR, Shanifar S, et al. Arch Intern Med 2003; 163: 1555–65

B A C K G R O U N D . The RENAAL study clearly demonstrated the renoprotective role of the angiotensin receptor antagonist losartan in type 2 diabetic patients with overt nephropathy and impaired renal function. Bakris et al. have now re-analysed the data from the RENAAL study, focusing on the impact of baseline blood pressure on primary outcomes in the study (doubling of serum creatinine, ESRD or death). Furthermore, the authors explored the potential implications of dihydropyridine calcium channel blockers as concurrent therapy for composite and renal outcomes. The study comprised 1513 participants with established nephropathy and hypertension associated with type 2 diabetes. I N T E R P R E T A T I O N . Notably, for every 10 mmHg increase in baseline systolic blood pressure, the risk of ESRD or death increased by 6.7% (P 0.007), with a signiﬁcantly increased risk for renal outcomes at all systolic blood pressure levels above 140 mmHg. However, there was no signiﬁcant change in risk of a renal end-point at any level of baseline diastolic blood pressure. Indeed, using a multivariate model, after adjusting for other variables, a 10-mmHg increase in diastolic blood pressure reduced the risk by 10.9% (P 0.01). A similar decrease in the primary end-point was observed in losartan-treated patients in the presence and absence of dihydropyridine calcium channel blockers.

Comment This study emphasizes that systolic blood pressure is a major modifiable risk factor for the progression of diabetic nephropathy. At any level of systolic blood pressure greater than 140 mmHg, there was significant risk of renal disease progression compared with levels below 130 mmHg. Diastolic blood pressure had little or no effect on outcome. This probably relates to the importance of pulse pressure, not only for cardiovascular but also renal disease. However, diastolic blood pressure may be correlated with renal outcomes in younger patients with type 1 diabetes and was strongly linked to age and duration of diabetes in the RENAAL study. Consequently, this negative association between outcome and diastolic blood pressure may reflect the prolonged nature of disease in patients with low diastolic blood pressure rather than a direct effect. The controversy about whether dihydropyridine calcium channel blockers are deleterious, neutral or protective for the kidney remains unresolved. The RENAAL study indicates that this class of antihypertensive agent is not deleterious to the diabetic kidney if administered with an angiotensin receptor antagonist. This is an important finding because, in order to achieve the low systolic blood pressure levels

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suggested by the findings described in this chapter and outlined in many national and international guidelines, a combination of antihypertensive agents, including dihydropyridine calcium channel blockers, is almost always required.

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Prevention of incipient diabetic nephropathy by high dose thiamine and benfotiamine Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ. Diabetes 2003; 52: 2110–20

B A C K G R O U N D . Recent seminal in vitro studies in endothelial cells have identiﬁed a range of biochemical abnormalities induced by hyperglycaemia, which are postulated to play a critical role in the genesis of diabetic vascular complications. These include accumulation of triosephosphate glycolytic intermediates that trigger ongoing biochemical perturbations that then lead to end-organ injury. The thiamine monophosphate derivative benfotiamine stunts these triosephosphate glycolytic

Fig. 1.6 Effect of high-dose (a) thiamine and (b) benfotiamine therapy on renal function (urinary albumin) in STZ diabetic rats and controls. , controls; , control 70 mg/kg thiamine or benfotiamine; , diabetic; , diabetic 7 mg/kg thiamine or benfotiamine; , diabetic 70 mg/kg thiamine or benfotiamine. Data are means standard errors (n = 5–9). Source: Babaei-Jadidi et al. (2003).

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intermediates via the pentose phosphate pathway, thereby reducing the accumulation of triosephosphates. Although benfotiamine has been used for the management of patients with diabetes in Eastern countries for many years, its efﬁcacy in nephropathy has not been tested. Babaei-Jadidi et al. examine the effect of benfotiamine as well as high-dose thiamine administered to diabetic rats. I N T E R P R E T A T I O N . Babaei-Jadidi et al. found that the onset of albuminuria could be prevented in diabetic animals treated with high-dose thiamine or benfotiamine for 24 weeks, and this was associated with a reduction in hyperﬁltration. In addition, this renal effect occurred in the context of reduced activation of various biochemical pathways implicated in diabetic complications, including protein kinase C, AGE accumulation and oxidative stress. Diabetic animals also appeared to have lower levels of plasma thiamine and transketolase expression, providing a rationale for supplementation in the context of diabetes. The authors concluded that the use of benfotiamine could be a novel strategy for the prevention of diabetic nephropathy.

Comment This is an interesting animal study that provides the important pre-clinical data to implicate a renoprotective role of benfotiamine in diabetic nephropathy. However, it should be noted that the study was performed in animals with early renal disease. Therefore one must be very cautious in extrapolating the findings to man, particularly in subjects with established nephropathy. Nonetheless, benfotiamine has also proved to be retinoprotective in the context of experimental diabetes 16 and also has useful effects in diabetic neuropathy 17. This inexpensive approach, with few side effects, may provide an important adjunct to the management of nephropathy in the future. The results of the planned clinical trials are keenly awaited.

Conclusion The last year has seen greater understanding of some of the mechanisms underlying the nephropathy seen in diabetes, and also of the treatments available. It is clear that a multifactorial approach reaps the greatest dividends, including an ACE inhibitor or angiotensin receptor antagonist. Drugs of the latter type certainly improve renal outcomes but may not affect cardiovascular events. Novel approaches also look likely to be in clinical use in the very near future.

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References 1. Rudberg S, Dahlquist G. Determinants of progression of microalbuminuria in IDDM

adolescents. Diabetes Care 1996; 19: 369–71. 2. Dahlquist G, Stattin EL, Rudberg S. Urinary albumin excretion rate and glomerular

filtration rate in the prediction of diabetic nephropathy; a long-term follow-up study of childhood onset type 1 diabetic patients. Nephrol Dial Transplant 2001; 16: 1382–6. 3. Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M. Reversal of lesions of dia-

betic nephropathy after pancreas transplantation. N Engl J Med 1998; 339: 69–75. 4. Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med 1998;

339: 1448–56. 5. Osterby R, Schmitz A, Nyberg G, Asplund J. Renal structural changes in insulin-

dependent diabetic patients with albuminuria. Comparison of cases with onset of albuminuria after short or long duration. APMIS 1998; 106: 361–70. 6. Cooper ME, Mundel P, Boner G. Role of nephrin in renal disease including diabetic

nephropathy. Semin Nephrol 2002; 22: 393–8. 7. Dalla Vestra M, Masiero A, Roiter AM, Saller A, Crepaldi G, Fioretto P. Is podocyte injury

relevant in diabetic nephropathy? Studies in patients with type 2 diabetes. Diabetes 2003; 52: 1031–5. 8. Langham RG, Kelly DJ, Cox AJ, Gow RM, Holthofer H, Gilbert RE. Angiotensin

II-induced proteinuria and expression of the podocyte slit pore membrane protein, nephrin. Nephrol Dial Transplant 2004; 19: 262–3. 9. Huang JS, Guh JY, Chen HC, Hung WC, Lai YH, Chuang LY. Role of receptor for

advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGEinduced collagen production in NRK-49F cells. J Cell Biochem 2001; 81: 102–13. 10. Miyata T, van Ypersele de Strihou C. Angiotensin II receptor blockers and angiotensin

converting enzyme inhibitors: implication of radical scavenging and transition metal chelation in inhibition of advanced glycation end product formation. Arch Biochem Biophys 2003; 419: 50–4. 11. Lakkis J, Lu WX, Weir MR. RAAS escape: a real clinical entity that may be important in

the progression of cardiovascular and renal disease. Curr Hypertens Rep 2003; 5: 408–17. 12. Brewster UC, Setaro JF, Perazella MA. The renin–angiotensin–aldosterone system:

cardiorenal effects and implications for renal and cardiovascular disease states. Am J Med Sci 2003; 326: 15–24. 13. van Hooft IM, Grobbee DE, Derkx FH, de Leeuw PW, Schalekamp MA, Hofman A. Renal

hemodynamics and the renin–angiotensin–aldosterone system in normotensive subjects with hypertensive and normotensive parents. N Engl J Med 1991; 324: 1305–11. 14. Johnston CI, Naitoh M, Burrell LM. Rationale and pharmacology of angiotensin II

receptor antagonists: current status and future issues. J Hypertens 1997; 15 (Suppl): S3–S6.

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15. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G,

Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–9. 16. Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 2003; 9: 294–9. 17. Stracke H, Hammes HP, Werkmann D, Mavrakis K, Bitsch I, Netzel M, Geyer J, Kopcke W, Sauerland C, Bretzel RG, Federlin KF. Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats. Exp Clin Endocrinol Diabetes 2001; 109: 330–6.

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2 Peritoneal dialysis EDWINA BROWN

Introduction Local health economics, nephrologist prejudice and the patient population are the predominant factors determining the use of peritoneal dialysis (PD) in the management of end-stage renal disease (ESRD). PD continues to be underused in many countries as it is seen to be second best to haemodialysis (HD). This is probably true if PD practice is suboptimal. It took many years for nephrologists to realize that the adequacy of PD depends on residual renal function, so the PD prescription needs to be increased if patients are to remain well as residual renal function declines. Both HD and PD have a role in the management of ESRD, both within a unit and for the individual patient. There are patients who definitely want either HD or PD for medical or social reasons. Results from the NECOSAD (Netherlands Cooperative Study into the Adequacy of Dialysis Treatment) randomized trial have shown that, in patients who are suitable for both modalities, outcomes from HD and PD are much the same. The choice of modality for such patients therefore rests on social issues. Wu et al. have published the results of detailed quality of life measurements when starting dialysis and 12 months later; these have shown important differences between HD and PD, thereby enabling patients to make an educated choice. What determines or predicts longer patient or technique survival remains a matter for debate. The ADEMEX (Adequacy of Peritoneal Dialysis in Mexico) study 1 showed that patient survival was independent of small solute clearance, at least in the range achievable on continuous ambulatory peritoneal dialysis (CAPD). Re-analysis of the CANUSA (Canada–USA) study had shown that peritoneal and renal clearances were not equivalent; patient survival within that study depended on baseline residual renal function 2. Preservation of residual renal function is therefore an important part of the management of patients on PD. The 2000 guidelines of the International Society of Peritoneal Dialysis (ISPD) for the management of peritonitis had therefore suggested that gentamicin should not be used if patients had residual renal function 3. This, however, has been shown not to be true by Baker et al.; appropriate dosing of gentamicin and blood monitoring enables gentamicin to be given safely in such patients. As in the pre-dialysis population, it makes sense to control blood pressure and block the angiotensin system to protect residual renal function. Results from a randomized controlled trial by Li et al. support the use © Atlas Medical Publishing Ltd

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of angiotensin-converting enzyme (ACE) inhibitors for this purpose in patients on PD. Patients on PD will eventually become anuric, and patients on HD with problematic vascular access also need to transfer to HD. The advent of automated peritoneal dialysis (APD) has enabled larger volumes of dialysate to be delivered, thereby enabling small solute clearance to be increased in patients who have become anuric. The European APD (automated PD) Outcomes Study (EAPOS), a prospective observational study in anuric patients, has shown that anuric patients can be maintained on APD with survival similar to that of HD and PD patients reported in other studies. Baseline ultrafiltration but not creatinine clearance (Ccrea) predicted survival. This failure to find that survival depended on small solute clearance agrees with the findings from ADEMEX 2, which was a large randomized, controlled trial comparing survival on CAPD of two groups of patients achieving different clearance targets. Further support for the concept that survival on PD is not dependent on solute removal comes from the study of Wang et al., which showed that poor survival is predicted by an inflammatory state and vascular comorbidity, not by dialysis parameters. The finding from EAPOS that ultrafiltration determined survival is important. Achieving good ultrafiltration enables better control of volume status and enables patients to eat better and thereby achieve better nutrition. The use of icodextrin for the overnight dwell in CAPD or the daytime dwell in APD enhances ultrafiltration. The results from a randomized controlled trial by Davies et al. have shown that this increase in ultrafiltration is clinically important and is accompanied by a reduction in weight and extracellular fluid volume. Peritonitis remains a major cause of technique failure in PD. Whatever antibiotics are used, treatment success has not improved beyond around 80%. Prevention of peritonitis, therefore, is key to prolonging time on PD. Regular use of mupirocin at the exit site has been shown in randomized trials to reduce the incidence of exit site infections and peritonitis due to Staphylococcus aureus 4,5. The long-term use of this regimen has been reported by Piraino et al., who showed continued dramatic reduction in S. aureus infections, with no change in Gram-negative infections. The risk of getting peritonitis is dependent on patient technique. The attention to detail required to maintain a sterile technique for a repetitive task is going to be affected by psychosocial factors. Often these are not reversible, but Troidle et al. have shown that depression is associated with peritonitis in long-term PD patients. This suggests that early detection and treatment of depression may improve technique survival in PD. The most dreaded complication of long-term PD is sclerosing encapsulating peritonitis, a reminder that the peritoneal membrane was not designed for years of exposure to bioincompatible dialysate. Time will tell whether the introduction of more biocompatible fluids will delay the onset of fibrosis and inflammation within the peritoneal membrane, leading to increasing membrane permeability and eventual peritoneal sclerosis. Meanwhile, there is increasing evidence, as presented by del Peso et al., that the use of tamoxifen in patients with peritoneal sclerosis is safe and well tolerated and prevents progression to full-blown encapsulating disease.

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Haemodialysis and peritoneal dialysis There has been fierce debate over the last decade between supporters of PD and HD about the relative merits of each modality of dialysis. There had been no prospective randomized comparisons, since it is difficult to find patients (or more commonly nephrologists) who would enter a trial in which the choice of dialysis was randomly allocated. For most patients, it is in reality better to suggest that the different modalities of dialysis represent a range of options from which patients can select the most appropriate one for a given stage of their disease (end-stage renal failure) and life (working, retired, social support, etc.). However, this holds true only if there really are no substantial disadvantages of one over the other (PD or HD). Recent data have improved our knowledge on this score, with a prospective randomized study (sadly underpowered and small, but surely the only one which will ever be done) and quality of life data from the two modalities.

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Effect of starting with haemodialysis compared with peritoneal dialysis in patients new on dialysis treatment: a randomized controlled trial Korevaar JC, Feith GW, Dekker FW, et al. for the NECOSAD Study Group. Kidney Int 2003; 64: 2222–8

B A C K G R O U N D . Until now, survival and health-related quality of life (HRQOL) of HD and PD patients have been compared only in observational studies and from registry data. These report small and opposing differences between both modalities. The aim of this study was to compare the outcome of HD and PD when used as the initial chronic dialysis treatment in a randomized controlled trial. All new dialysis patients from 38 dialysis centres in The Netherlands without indications against either modality were invited to take part. Patients who agreed were randomized to HD or PD. The primary outcome was mean quality-adjusted life year (QALY) score and the secondary outcome was survival. Quality of time spent on dialysis was obtained using the EuroQoL as a generic health assessment instrument, patients evaluating their own overall health on a visual analogue scale. The EuroQoL visual analogue scale score was repeated regularly over 2 years. The inclusion rate was very low and the trial was stopped prematurely after 38 patients had been randomized (18 to HD and 20 to PD). The mean QALY score in the ﬁrst 2 years was 59.1 (standard deviation [SD] 12) for HD versus 54.0 (SD 19) for PD patients; this small difference (5.1) was not signiﬁcant (95% conﬁdence interval [CI] –7.3 to 17.6). After 5 years of follow-up, nine HD and ﬁve PD patients had died (Fig. 2.1); this difference was signiﬁcant, with a hazard ratio (HR) of HD versus PD of 3.8 (95% CI 1.1–12.6). After adjustment for age, comorbidity and primary kidney disease, the HR was 3.6 (95% CI 0.8–15.4). I N T E R P R E T A T I O N . The small difference in QALY score between patients starting on HD and PD lends support to the hypothesis that the two modes of dialysis are equivalent. The

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signiﬁcant difference in longer-term survival, which favoured PD, could be used to propose that incident dialysis patients might beneﬁt from starting on PD.

Comment This is the first time that a proper randomized controlled trial has been attempted in order to compare the outcomes of HD and PD. Not surprisingly, it is extremely difficult to recruit patients to such a study as the differences between HD and PD have major impacts on lifestyle and most patients, after appropriate education, will select one or other modality. Thus, only 38 patients entered the study but the power calculations had suggested that 100 patients were needed to demonstrate equivalence between HD and PD. The study was therefore underpowered and it is not possible to exclude the possibility that prognostic factors at baseline were different for the two groups of patients. Despite these limitations, this is an important study and is unlikely ever to be repeated. The results suggest that at least the two modalities are equivalent; this is important information to give to patients starting on dialysis. Their choice of modality can then be determined by other considerations. The difference in long-term survival in favour of PD suggests that new dialysis patients, who are suitable for both HD and PD, might benefit from starting on PD.

Fig. 2.1 Survival of patients randomized to PD or HD. Source: Korevaar et al. (2003).

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Changes in quality of life during haemodialysis and peritoneal dialysis treatment: generic and disease speciﬁc measures Wu AW, Fink NE, Marsh-Manzi JVR, et al. J Am Soc Nephrol 2004; 15: 743–53

B A C K G R O U N D . This paper gives the results from the CHOICE (Choices for Healthy Outcomes in Caring for ESRD) study. Despite more than 20 years of use of HD and PD, relative differences between them in HRQOL are not clearly known. The aim of this study was to compare self-reported HRQOL and overall health status for HD and PD patients at the start of dialysis treatment and 1 year later. Incident ESRD patients were enrolled over a 3-year period from 81 dialysis units in the USA. Six hundred and ninety-eight HD and 230 PD patients completed a baseline CHOICE Health Experience Questionnaire. Of these 928 patients who completed the baseline questionnaire, 585 also completed the 1-year questionnaire; 101 died, 55 received a kidney transplant and 88 moved to a different dialysis facility. PD patients were slightly younger, were more likely to be white, well educated, employed and married; they also had less comorbidity and higher haematocrit. Unadjusted baseline scores showed better HRQOL for PD patients in both generic and ESRD domains (bodily pain, travel, diet restrictions and dialysis access [P <0.05]). At 1 year, SF-36 (short-form health survey with 36 questions) scores improved, with variable changes in ESRD domains. HD patients had greater improvements in two SF-36 domains (physical functioning and general health perception) than PD patients, but results were mixed for ESRD domains (PD was better for ﬁnances, HD was better for sleep and overall quality of life). HD and PD patients did not differ in change in overall health status and both were associated with similar HRQOL outcomes at 1 year. I N T E R P R E T A T I O N . This study shows that although PD provides a better quality of life at the start of dialysis, by 1 year quality of life is equivalent for PD and HD. In general, for some domains, patients on HD may have maintained their general health status to a greater extent than PD patients. However, each modality has distinct advantages and disadvantages. These differences should be explored with all patients who are making the choice between HD and PD.

Comment Analyses of many observational studies and registry data have failed to show any major differences between outcomes on HD and PD. Thus, the patient’s choice of dialysis modality depends mostly on psychosocial factors. Evidence on which to base information about these factors has been very limited. The North Thames Dialysis Study suggested that the quality of life of elderly people on dialysis was independent of dialysis modality 6; however, this observation was based only on a generic measure, the SF-36. This study has explored several domains of both generic and health status domains. Health and general well-being improve during the first year of dialysis for both HD and PD patients, with distinct advantages and disadvantages to each modality. Using the evidence provided from this study, it is possible to discuss

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with patients the effect of each modality on their quality of life—patients on PD find it easier to work and may have less pain and problems with diet, while patients on HD may have less problems with sleep or sexual functioning. This information should empower patients to make the appropriate choice of modality.

Residual renal function in peritoneal dialysis The importance of residual renal function for patient survival and well-being on PD cannot be underestimated. It is therefore crucial not to jeopardize this with any interventions undertaken during PD, and to consider therapeutic strategies that will maximize residual function.

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Empirical aminoglycosides for peritonitis do not affect residual renal function Baker RJ, Senior H, Clemenger M, Brown EA. Am J Kidney Dis 2003; 41: 670–5

B A C K G R O U N D . With the increasing emphasis on preserving residual renal function, there has been concern about the nephrotoxic potential of aminoglycosides when used for the treatment of peritonitis. The 2000 ISPD guidelines therefore recommended that aminoglycosides should not be used in patients with residual renal function, and that ceftazidime be used instead. In response to the 1996 ISPD guidelines, the authors had changed their peritonitis regimen from vancomycin and ciproﬂoxacin to cefazolin and gentamicin. Using urine and dialysis clearance measurements made every 6 months, pre-peritonitis and post-peritonitis residual renal function (using the mean of 24-hour urea and Ccrea) were determined for 70 peritonitis episodes treated with the aminoglycoside-based regimen (group A), 61 episodes treated without aminoglycosides (group B) and 74 control patients without peritonitis (group C). There was no statistical difference in the rate of decline in residual renal function between the three groups: group A, –0.08 0.50 ml/min/month compared with –0.17 0.27 ml/min/month in group B and –0.20 0.39 ml/min/month in group C (see Fig. 2.2). There was also no difference in the rate of decline in urine output between the three groups. In addition, an analysis was performed on a subgroup from group A of 16 patients who had been treated with a prolonged course of aminoglycosides (>5 days); again there were no signiﬁcant differences between this group and any other. I N T E R P R E T A T I O N . This study failed to show any evidence of an accelerated decline in residual renal function when using an empirical antibiotic regimen containing aminoglycosides for the treatment of peritonitis. It is therefore reasonable to recommend the continued use of these drugs in peritonitis regimens, even in patients with signiﬁcant residual renal function.

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Comment This is important evidence on which to base guidelines for the management of peritonitis. It should be noted that the dose of gentamicin used was adjusted according to residual renal function and that blood levels were monitored in patients receiving gentamicin for more than 3 days to maintain plasma levels in the range of 3–4 g/ml. The initial dose of gentamicin (given intraperitoneally) was 1.5 mg/kg for a daily urine output greater than 500 ml/24 h and 0.6 mg/kg for urine output less than 500 ml/24 h.

Fig. 2.2 Decline in estimated glomerular ﬁltration rate (GFR) according to use of aminoglycosides and absence of peritonitis. The horizontal line shows the mean value in each group. Source: Baker et al. (2003).

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Effects of an angiotensin-converting enzyme inhibitor on residual renal function in patients receiving peritoneal dialysis: a randomized, controlled study Li PKT, Chow KM, Wong TYH, Leung CB, Szeto CC. Ann Intern Med 2003; 139: 105–12

B A C K G R O U N D . It is well recognized that residual renal function is an important determinant of mortality and morbidity in patients receiving PD. Residual renal function is preserved longer in patients on PD than in those on HD, but few studies have evaluated therapeutic approaches to the preservation of residual renal function after starting PD. Retrospective and observational studies have suggested various factors, such as ACE inhibitors, that may affect the rate of decline of residual renal function. This is the ﬁrst randomized, controlled study to determine whether ACE inhibitors can slow the decline of residual renal function after starting PD. Sixty patients were enrolled from one centre and were randomly assigned to ramipril (5 mg/day) or no treatment. Target blood pressure was 135/85 or less. The rate of decline in residual GFR and the development of complete anuria were compared among groups. Baseline median residual GFR was 3.27 (2.00–7.87) ml/min in the ramipril group and 3.61 (2.01–7.67) ml/min in the control group. Patients were followed for 12 months. Blood pressure control was similar in both groups (average follow-up blood pressure was 143/78 in ramipril group and 141/81 in control group). As shown in Fig. 2.3, average residual GFR declined by 2.07 ml/min/1.73 m2 in the ramipril group versus 3.00 ml/min/1.73 m2 in the control group (P 0.03). Fourteen patients in the ramipril group and 22 in the control group developed anuria. At 12 months, the adjusted hazard ratio for developing anuria was 0.58 (CI 0.36–0.94) for the ramipril group compared with the control group. The rates of death from any cause, duration of hospitalization and cardiovascular events did not differ signiﬁcantly between the groups. I N T E R P R E T A T I O N . Although the trial was small and therefore had limited ability to exclude effects of potential confounding factors, the data do suggest that ramipril (and probably, therefore, other ACE inhibitors) may reduce the rate of decline of residual renal function in patients starting on PD.

Comment It is not surprising that ACE inhibitors slow the rate of decline of renal function after starting PD, just as they do in patients at earlier stages of renal disease. Blood pressure control was similar in the two groups, suggesting that the effect is due to inhibition of the renin–angiotensin system and not to differences in blood pressure. Preservation of residual renal function is a major advantage of PD, yet often little attention is paid to slowing the rate of decline of residual GFR in patients on dialysis. Before extrapolating the results of this study to clinical practice, the limitations of the study need to be considered. The study was small, most of the patients were hypertensive and blood pressure control was far from ideal (average blood pressure was greater than 140/80) compared with the UK Renal Association standard of 130/80. Despite these limita-

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Fig 2.3 Mean residual GFR at baseline and follow-up in the ramipril and control groups. Source: Li et al. (2003).

tions, this study can be added to the growing evidence of renoprotection provided by ACE inhibitors and angiotensin receptor blockers. Such drugs should therefore be used for blood pressure control in patients on PD unless there are contraindications, such as renovascular disease or hyperkalaemia.

Factors affecting outcome in peritoneal dialysis Having considered the potential place for PD compared with HD and factors affecting residual renal function, we can now look at other factors which play a role in determining outcome in PD, from the intrinsic (C-reactive protein [CRP] at the start of PD) to purely dialytic (choice of fluid), and those affecting patient survival and technique survival (e.g. infection and depression).

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Survival of functionally anuric patients on automated peritoneal dialysis: the European APD Outcome Study Brown EA, Davies SJ, Rutherford P, et al. on behalf of the EAPOS group. J Am Soc Nephrol 2003; 14: 2948–57

B A C K G R O U N D . Anuric patients are a difﬁcult group to dialyse effectively using CAPD. APD provides a means whereby solute removal and ultraﬁltration can be increased by the use of rapid exchanges overnight, yet there is considerable doubt whether adequate

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clearances and successful clinical outcomes can be achieved in anuric patients. The EAPOS was a 2-year prospective multicentre study of the feasibility and clinical outcomes of APD in anuric patients. A total of 177 patients were enrolled, with a median age of 54 years (range 21–91 years). Previous median total time on dialysis was 38 months (range 1.6–259 months), and 36% of patients had previously been on HD for more than 90 days. Diabetes and cardiovascular disease were present in 17 and 46% of patients respectively. The APD prescription was adjusted at the physician’s discretion to aim for Ccrea ≥60 l/week/1.73 per m2 and ultraﬁltration ≥750 ml/24 h during the ﬁrst 6 months. Baseline solute transport status (dialysate/plasma creatinine [D/P]) was determined with a peritoneal equilibration test. At 1 year, 78 and 74% achieved Ccrea and ultraﬁltration targets respectively: median drained dialysate volume was 16.2 l/24 h, with 50% of patients using icodextrin. Baseline D/P was not related to ultraﬁltration achieved at 1 year. At 2 years, patient survival was 78% and technique survival was 62% (see Fig. 2.4). Baseline predictors of poor survival were age (>65 years; P 0.006), nutritional status (Subjective Global Assessment grade C; P 0.009), diabetic status (P 0.008) and ultraﬁltration (<750 ml/24 h; P 0.47). Time-averaged analyses showed that age, Subjective Global Assessment grade C and diabetic status predicted patient survival, with ultraﬁltration the next most signiﬁcant variable (risk ratio, 0.5/l/day; P 0.097). Baseline Ccrea, time-averaged Ccrea and baseline D/P had no effect on patient or technique survival. I N T E R P R E T A T I O N . The survival of anuric patients on APD is similar to that of other patients on PD. Furthermore, the poor prognosis of CAPD patients with high peritoneal solute transport does not apply to patients on APD. By using APD (with icodextrin for the long day dwell as needed), it is possible to achieve sufﬁcient small solute clearance and ultraﬁltration to treat even anuric patients successfully. This is important not just for patients who are already on PD, but also for patients who are on HD, particularly those who no longer have vascular access. Finally, this study demonstrates the important role of ultraﬁltration in contrast to small solute clearance as an outcome parameter in patients on PD.

Comment The 2-year patient survival of 78% and technique survival in this study are identical to those reported from NECOSAD (HD and PD) 7. The results from EAPOS differ from those of the only other prospective study of anuric patients on PD 8, in which outcome was determined by small solute clearance. Mean Ccrea in that study was only 43.7 l/week/1.73 m2 and patient survival was lower, at 68.8% at 2 years. Thus, although Ccrea was not a determinant of survival in EAPOS, there is a threshold that needs to be reached to avoid uraemia-related deaths; a further increase in small solute clearance above this threshold has no survival advantage, at least in the range of clearances achievable by current dialysis techniques. This concept is supported by the ADEMEX study 1, in which uraemia-related deaths did occur in the low clearance group, although there was no overall survival difference between the low and higher clearance groups. A striking finding from this study is the association between poor ultrafiltration and reduced survival. Baseline ultrafiltration rate, unlike Ccrea, was shown to be a

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Fig. 2.4 Kaplan–Meier curve showing patient survival according to baseline ultraﬁltration of >750 ml/day (solid line) and <750 ml/day (dashed line); P 0.048. Source: Brown et al. (2003).

significant predictor of survival by both univariate and multivariate analyses. The reason that these patients did so poorly cannot be determined with certainty from this study, as fluid status in an individual patient is determined as much by fluid intake as the ultrafiltration achieved. This study, though, does suggest that clinicians need to pay close attention to APD patients who consistently achieve low ultrafiltration volumes.

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Is a single time point C-reactive protein predictive of outcome in peritoneal dialysis patients? Wang AYM, Woo J, Lam CWK, et al. J Am Soc Nephrol 2003: 14; 1871–9

B A C K G R O U N D . CRP is an inﬂammatory marker and has been shown to predict mortality in HD patients, but it remains uncertain whether a single CRP level has similar prognostic signiﬁcance in PD patients. A single high-sensitivity CRP (hs-CRP) level was measured in 246 CAPD patients without active infections at study baseline. Dialysis adequacy, echocardiography (left ventricular mass index, left ventricular dimensions and ejection fraction), nutrition markers (serum albumin, dietary intake and Subjective Global Assessment) and biochemical parameters (haemoglobin, lipids, calcium and phosphate) were also measured. The patients were then followed up prospectively for a median of 24 months (range 2–34 months). Fifty-nine patients died (36 from

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cardiovascular causes). Patients were stratiﬁed into tertiles according to baseline hs-CRP. Those with higher hs-CRP (≥5.55 mg/l) were signiﬁcantly older, had greater body mass index, a greater prevalence of coronary artery disease and a greater left ventricular mass index. One-year overall mortality was 3.9% (lower) vs 8.8% (middle) vs 21.3% (upper tertile) (P <0.0001). Cardiovascular death rate was 2.7% (lower) vs 5.2% (middle) vs 16.2% (upper tertile) (P <0.0001). Other signiﬁcant predictors for all-cause mortality included age, atherosclerotic vascular disease, left ventricular mass index and residual renal function. I N T E R P R E T A T I O N . The study demonstrates the usefulness of a single random CRP in predicting all-cause and cardiovascular mortality, independent of other cardiovascular, echocardiographic, dialysis, biochemical and nutritional parameters in PD patients. Cox regression analysis showed that the predictors of poor survival were higher hs-CRP, higher age, male sex, vascular comorbidity, increased left ventricular mass index, a history of heart failure and lower residual renal function. Small solute clearance was not a signiﬁcant predictor of survival in this model. Determination of CRP by a highly sensitive assay should be considered in all PD patients without active infections and would enhance risk stratiﬁcation.

Comment ADEMEX and EAPOS, as discussed earlier in this chapter, have both shown that survival on PD is not determined by small solute clearance. This study confirms that observation and suggests that the predictors of poor survival are evidence of inflammation and vascular comorbidity. Whether therapeutic manoeuvres to lower CRP would improve outcome needs to be determined by further studies.

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Icodextrin improves the ﬂuid status of peritoneal dialysis patients: results of a double-blind randomized controlled trial Davies SJ, Woodrow G, Donovan K, et al. J Am Soc Nephrol 2003; 14: 2338–44

B A C K G R O U N D . Worsening ﬂuid balance results in reduced technique and patient survival in PD. Under these conditions, the glucose polymer icodextrin is known to enhance ultraﬁltration in the long dwell. A multicentre, randomized, double-blind, controlled trial was undertaken to compare icodextrin versus 2.27% glucose to establish whether icodextrin improves ﬂuid status. Fifty patients with urine output <750 ml/day, high solute transport, and either treated hypertension or untreated blood pressure >140/90 mmHg, or a requirement for the equivalent of all 2.27% glucose exchanges were randomized to either 7.5% icodextrin or 2.27% glucose for the long dwell exchange, with stratiﬁcation for centre/country, dialysis modality (CAPD or APD) and the presence of cardiovascular disease. Patients were then evaluated at 1, 3 and 6 months. Members of the icodextrin group lost weight, whereas the control group gained weight; the difference between groups was 2.3 kg (P 0.036) at 6 months

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(shown in Fig. 2.5). The difference in weight change was reﬂected in changes in the total body water, as estimated by multifrequency bioimpedance and as measured independently by deuterium dilution. The differences were largely explained by reduced extracellular ﬂuid volume in those receiving icodextrin, who also achieved better ultraﬁltration and total sodium losses at 3 months (P <0.05) and had better maintenance of urine volume at 6 months (P 0.039). I N T E R P R E T A T I O N . This study has shown that patients with above-average solute transport, treated or untreated hypertension, or excessive dependence on hypertonic dialysate and a urine volume of <750 ml will beneﬁt from icodextrin in their ﬂuid management. Within 1 month of commencement of icodextrin, there is improved ﬂuid removal and ﬂuid status; this effect is sustained for 6 months without harmful effects on residual renal function.

Comment This is the first randomized, double-blind, controlled trial in PD patients in which manipulation of achieved ultrafiltration is linked to a clinically relevant end-point: specifically, the fluid status of the patient. Although it is well known that the use of icodextrin in the long dwell will enhance ultrafiltration, it does not necessarily follow that this will translate into improved fluid status as patients may simply drink more. Therefore, the observation from this study – that the use of icodextrin improves fluid status – is therefore clinically very important and suggests that icodextrin should be used proactively in patients with above-average solute transport, hypertension, excessive dependence on hypertonic dialysate and declining urine output.

Fig. 2.5 Changes in drained body weight (mean SEM) from baseline for patients randomized to icodextrin or 2.27% glucose. Source: Davies et al. (2003).

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Staphylococcus aureus prophylaxis and trends in Gram-negative infections in peritoneal dialysis patients Piraino B, Bernadini J, Florio T, Fried L. Perit Dial Int 2003; 23: 456–9

B A C K G R O U N D . Following several randomized controlled trials, the most recent practice guidelines of the ISPD for the management of PD-related infections recommend the use of S. aureus prophylaxis with daily mupirocin at the exit site. The aim of this study was to determine whether this practice increases Gram-negative infections by examining rates of Gram-negative exit site infection and peritonitis before and after the implementation of S. aureus prophylaxis in PD patients. Infection data were reviewed from two renal centres from 1 January 1982 for 19 years. Various methods of S. aureus prophylaxis had been used. In 1990, rifampicin, 600 mg daily for 5 days, was prescribed to all patients with a positive nose culture. In 1992, a randomized trial was started comparing rifampicin for 5 days every 3 months to prophylaxis with daily mupirocin ointment. Since completion of the trial in 1994, all S. aureus carriers on nose cultures used daily exit site mupirocin. In 1999, all patients started using exit site mupirocin. Six hundred and sixty-three incident patients were included in this survey. Staphylococcus aureus exit site infection and peritonitis rates ﬂuctuated without signiﬁcant trends during the ﬁrst decade (without prophylaxis). Results are shown in Fig 2.6. Contrasting the period of 1988–1989 (just before the institution of prophylaxis) to the era with prophylaxis (1990–2000), the decreases in S. aureus peritonitis and catheter infections were impressive (relative risk [RR] 0.83/year, 95% CI 0.78–0.87, P <0.0001; RR 0.81, 95% CI 0.75–0.88, P <0.0001, respectively). During 2000, S. aureus infection rates were 0.02/year for catheter infections and zero for peritonitis. Methicillin-resistant S. aureus infections have also been very infrequent during the prophylaxis era (ﬁve episodes of peritonitis and only two exit site infections since 1991). In contrast, Gram-negative infections declined towards the end of the 1980s, probably as a result of the implementation of better connectology. There were no signiﬁcant changes in Gram-negative infections since 1994. There was also little change in Pseudomonas aeruginosa infections over the entire period, but this is now the most common cause of catheter infection and catheter-related peritonitis. I N T E R P R E T A T I O N . Prophylaxis against S. aureus is highly effective in reducing the rate of S. aureus infections but has no effect on Gram-negative infections. Pseudomonas aeruginosa is now the most serious cause of catheter-related peritonitis. This is due to the decline in S. aureus infections and not to an increase in Pseudomonas infections.

Comment The failure to show an increase in Gram-negative infections is very reassuring as there has been concern that routine mupirocin prophylaxis would have the opposite effect. These data also show that the protection provided by daily mupirocin is seen when it is used as routine clinically as well as with selected patients in a clinical trial. The other reason for failure to implement a protocol of routine use of daily mupirocin is concern about the development of resistance to mupirocin. This was not evaluated in this study as the methods to evaluate mupirocin resistance are not

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Fig. 2.6 Staphylococcus aureus (upper panel) and Gram-negative (lower panel) infections in PD patients. Source: Piraino et al. (2003).

available in the USA. The continued effectiveness of mupirocin, however, suggests that little resistance developed. When considering the risk of mupirocin resistance, it is important to realize that the dramatic reduction in S. aureus (including methicillin-resistant S. aureus) reduces the use of vancomycin and cephalosporins. Resistance to these two antibiotics emerging in a unit would be of much greater concern than resistance to mupirocin.

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Depression and its association with peritonitis in long-term peritoneal dialysis patients Troidle L, Wartnick S, Wuerth DB, Gorban-Brennan N, Kliger AS, Finkelstein FO. Am J Kidney Dis 2003; 42: 350–4

B A C K G R O U N D . Peritonitis remains the leading cause of technique failure in patients on PD. Depression is the most common psychological disorder among patients with

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ESRD and has been associated with increased mortality in patients with a variety of medical illnesses. There are, however, very few studies looking at the relationship between clinical depression and medical outcomes in patients with ESRD. This prospective study was designed to examine the relationship between depression and peritonitis. All patients dialysing in the renal unit of the authors (Hospital of St Raphael, New Haven, CT, USA) over 5 years completed a Beck Depression Inventory (BDI) assessment at 6-month intervals. BDI scores were analysed in two ways. First, patients were placed into either group I (BDI score <10) or group II (BDI score ≥11; suggestive of depression) and were reclassiﬁed on the basis of subsequent scores. Secondly, multivariable analysis was performed looking at the initial BDI score as a risk factor for peritonitis, adjusting for age older than 65 years, diabetes, coronary artery disease and ethnicity. Two hundred and eighty-one individual BDI assessments were completed by 162 patients. There were 102 patients in group I (161 BDI assessments) and 83 patients in group II (120 BDI assessments). As shown in Table 2.1, there were 24 episodes of peritonitis in group I (peritonitis rate 1/23.4 patient months) and 35 episodes in group II (peritonitis rate 1/11.5 patient months) (P <0.05); this difference was due to Gram-positive infections (1/37.4 patient months in group I and 1/18.4 patient months in group II; P <0.05). There was no signiﬁcant difference in Gram-negative infections between the two groups. Using Cox regression, only a BDI score of 11 or greater was associated with the development of peritonitis (HR 2.7, 95% CI 1.23–6.03) and not age ≥65 years, diabetes, coronary artery disease or ethnicity. I N T E R P R E T A T I O N . Both analyses conﬁrm the association between peritonitis and depressive symptoms. Given the high incidence of depression among patients on PD, and the potential risk for peritonitis shown by this study, it is important that depression be recognized as a potentially treatable condition associated with the development of peritonitis. Further studies need to be done to determine whether treatment of depression can reduce the rate of peritonitis.

Comment This is an important study, as peritonitis remains the major cause of technique failure in PD. Depression has been associated with increased mortality and morbidity in a variety of disease states. This is the first prospective study to suggest that the presence of depression increases the risk of acquiring peritonitis, possibly by a reduction in the patient’s attention to detail, or because of the impairment in immunity that Table 2.1 Peritonitis rates (episodes per patient month) for patients with depression scores of <10 (group 1) or >11 (suggestive of depression; group 2) Type

Group 1

Group 2

P

No. of episodes Overall Gram-positive Gram-negative

24 1/23.4 1/37.4 1/112.2

35 1/11.5 1/18.4 1/57.7

<0.05 <0.05 >0.05

Source: Troidle et al. (2003).

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has been found with depression. Whether treatment of any depression will lower the risk of peritonitis remains to be determined by future studies. Meanwhile it would appear to be important to detect depression in patients on PD and consider medical and pharmacological interventions.

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Clinical experience with tamoxifen in peritoneal ﬁbrosing syndromes del Peso G, Bajo MA, Gil F, et al. Adv Perit Dial 2003; 19: 32–5

B A C K G R O U N D . Prolonged PD causes the peritoneal membrane to thicken due to sclerosis and ﬁbrosis. In some patients this progresses to encapsulating peritoneal sclerosis (EPS), which has a high mortality. As the condition is rare, most reports of successful therapy have been anecdotal and have been based on the use of various immunosuppressive agents or tamoxifen, which is an antiﬁbrotic agent and has also been used in the treatment of retroperitoneal ﬁbrosis. The purpose of this study was to establish whether treatment with tamoxifen in PD patients has a beneﬁcial effect on peritoneal sclerosis. This was a retrospective survey of 450 patients who had been on PD since 1980; 23 had been diagnosed with peritoneal sclerosis. Of these 23, nine were treated with tamoxifen (20 mg twice a day) for a mean period of 14.5 months (range 6–30 months). The other 14 patients received no treatment and were considered the control group. Both groups were similar in demography and PD history. Follow-up was longer in the control group (47 months vs 29 months in the tamoxifen group), but the difference did not reach statistical signiﬁcance. The use of tamoxifen caused mild thrombocytopenia in one patient, but there were no other toxic effects. In the control group, four patients developed EPS and died, three of them during the ﬁrst 6 months after diagnosis (Fig. 2.7). No patient treated with tamoxifen developed EPS. Overall

Fig. 2.7 Comparison of mortality rate in controls and tamoxifen-treated patients. Source: del Peso et al. (2003).

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mortality was signiﬁcantly higher in the control group (71% vs 22% in the tamoxifen group, P 0.03). I N T E R P R E T A T I O N . Treatment with tamoxifen of patients diagnosed with peritoneal scleroses reduces the related complications and signiﬁcantly reduces mortality, at least in the short to medium term. A prospective therapeutic trial is required to conﬁrm the results.

Comment EPS is a devastating complication of long-term PD. This study shows the importance of being able to detect the early stages of peritoneal sclerosis and fibrosis. This should be suspected in patients with high membrane transport and poor ultrafiltration; abdominal pain is common and peritoneal calcification with thickened bowel walls are noted on abdominal CT scan. In advanced cases with the full-blown EPS, obstruction of the small bowel occurs. This study is retrospective but is suggestive that tamoxifen is safe to use in these patients, has minimal side effects, and may prevent the progression of peritoneal sclerosis. This is hopeful for this rare condition. A prospective study is needed to confirm the results.

Conclusion This review of current clinical research in PD has focused on the role of PD within a model of integrated care for the renal patient. There is now sufficient evidence about survival on PD that the choice facing patients starting on dialysis is not HD or PD but how HD or PD would fit into their lifestyle. It is also becoming increasingly apparent that survival on dialysis is dependent on non-dialysis factors, such as vascular comorbidity, nutritional and inflammatory state. Increasing solute removal alone has no impact on survival as long as adequate dialysis is delivered to avoid uraemic symptoms. The good news is that even when patients have lost all their residual renal function and have become anuric, APD enables patients to remain on their chosen modality—and it also offers an alternative modality to HD patients struggling with vascular access. Finally there is light on the horizon to suggest that it may be possible to improve technique survival on PD; recent evidence suggests that residual renal function may be maintained longer with the use of ACE inhibitors, and that the risk of peritonitis can be reduced by the regular use of prophylactic mupirocin at the exit site and perhaps also with treatment of depression. The increasing use of biocompatible fluids that has been occurring during 2003 and 2004 may also protect the peritoneal membrane from the functional and structural changes that limit technique survival. We shall, however, have to wait for future years to see whether this is confirmed by improvement in patient outcomes.

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References 1. Paniagua R, Amato D, Vonesh E, Correa-Rotter R, Ramos A, Moran J, Mujais S. Effects

2.

3.

4.

5.

6.

7.

8.

of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol 2002; 13: 1307–20. Bargman JM, Thorpe KE, Churchill DN, for CANUSA study group. Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: a reanalysis of the CANUSA study. J Am Soc Nephrol 2001; 12: 2158–62. Keane WF, Bailie Gr, Boeschoten E, Gokal R, Golper TA, Holmes CJ et al. Adult peritoneal dialysis-related peritonitis treatment recommendations: 2000 update. Perit Dial Int 2000; 20: 396–411. Bernardini J, Piraino B, Holley J, Johnston J, Lutes R. A randomized trial of Staphylococcus aureus prophylaxis in peritoneal dialysis patients: mupirocin calcium ointment 2% applied to the exit site versus cyclic oral rifampin. Am J Kidney Dis 1996; 27: 695–700. Thodis E, Bhaskaran S, Pasadiakis P, Bargman JM, Vas SI, Oreopoulos DG. Decrease in Staphylococcus aureus exit-site infections and peritonitis in CAPD patients by local application of mupirocin ointment at the catheter exit site. Perit Dial Int 1998; 18: 261–70. Lamping DL, Constantinovici N, Roderick P, Normand C, Henderson L, Harris S, Brown E, Gruen R, Victor C. Clinical outcomes, quality of life, and costs in the North Thames Dialysis Study of elderly people on dialysis: a prospective cohort study. Lancet 2000; 356: 1543–50. Van Manen JG, Korevaar JC, Dekker FW, Boeschoten EW, Bossuyt PM, Krediet RT. How to adjust for comorbidity in survival studies in ESRD patients: a comparison of different indices. Am J Kidney Dis 2002; 40: 82–9. Szeto CC, Wong TY, Chow KM, Leung CB, Law MC, Wang AY, Lui SF, Li PK Impact of dialysis adequacy on the mortality and morbidity of anuric Chinese patients receiving continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 2001; 12: 355–60.

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3 Anaemia in chronic renal failure IAIN MACDOUGALL

Introduction The management of anaemia in chronic renal failure represents a technological triumph spanning the last two decades. It has long been recognized that the major cause of this condition was a relative deficiency of circulating erythropoietin from the diseased kidneys 1, but the manufacture of therapeutic erythropoietin eluded scientists until the advent of recombinant DNA technology. Human erythropoietin had already been isolated and purified from patients with aplastic anaemia in the late 1970s, but the isolation and cloning of the gene for this glycoprotein hormone in the early 1980s 2 opened the door to the large-scale manufacture of genetically engineered erythropoietin as a therapeutic agent. Clinical trials in the late 1980s confirmed its efficacy in treating the anaemia of renal failure, and the vast majority of patients with this condition no longer have to rely on repeated blood transfusions. Recombinant human erythropoietin therapy (epoetin) became widely used in the early 1990s, and for over 10 years this was regarded as a safe and highly effective treatment. Up to 90% of patients responded well, and adverse effects were few and easily manageable. This unconcerned, almost blasé, attitude to epoetin therapy continued until 2 years ago. In February 2002, Professor Casadevall published a report describing a cohort of 13 patients who had developed pure red cell aplasia induced by antierythropoietin antibodies (see discussion of the paper by Casadevall et al. below). As further cases came to light, nephrologists began to ask why this was happening: was it more common with one preparation of epoetin than another? Was the route of administration important? Was the formulation of the drug important? The dust has not fully settled, but it has become apparent in recent times that epoetin-induced pure red cell aplasia is much more common with one particular brand of epoetin alfa (Eprex; Erypo) 3. The formulation of the product does indeed seem to be important, and this has heightened awareness among the drug regulatory authorities of potential problems with antigenicity from all therapeutic proteins. The biopharmaceutical industry has also been massively affected, and several companies which were preparing to enter the rat race of manufacturing generic epoetin decided to axe their clinical development programmes. Despite all this, epoetin alfa and epoetin beta still exist as therapeutic agents, and in some other countries epoetin delta and epoetin omega are used. All of these are, in effect, recombinant human erythropoietin preparations. A © Atlas Medical Publishing Ltd

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second-generation erythropoietic agent has also been licensed for the treatment of renal anaemia, called darbepoetin alfa. This contains two extra N-linked glycosylation chains attached to the protein backbone, which also required five amino acids to be substituted in order to insert the extra carbohydrate moieties. This modification resulted in a molecule which remained biologically active in stimulating erythropoiesis, but which had a three-fold longer elimination half-life in vivo compared with conventional epoetin 4. A third-generation erythropoietic agent, called Continuous Erythropoiesis Receptor Activator (CERA), is also in the pipeline, currently in Phase III of its clinical development programme, and the Phase I and II results seem promising 5. There is increasing realization that chronic inflammation and immune activation associated with chronic renal failure may also contribute to the anaemia of this condition, and the consequences of inflammation can potentially cause a very profound resistance to erythropoietic therapy. The treatment of renal anaemia is a dynamic and developing field in clinical nephrology and the lessons learned by nephrologists have implications for specialists in other clinical disciplines with an interest in anaemia. The aim of this chapter is to review the most pertinent references related to the topic of renal anaemia within the last year or so.

Route of administration for erythropoietin therapy The initial clinical trials of recombinant human erythropoietin were in haemodialysis patients, who had ready access to the circulation, and in whom the intravenous route was therefore practical. Even in this population of patients, however, it became apparent after a few years that the use of the subcutaneous route may allow lower doses of erythropoietin to be used 6, and this had important implications in terms of reducing the potential costs of this expensive therapy. Many of the studies which supported the use of the subcutaneous route, however, were small and uncontrolled, and indeed not all of them showed a benefit. A large, adequately powered, randomized controlled study was required, and this was undertaken by the Veterans Affairs Cooperative Study Group in the late 1990s 7. This is unarguably the most scientifically rigorous of all the studies that have been conducted, and the study protocol ensured that patients were titrated down to the lowest effective dose of erythropoietin to maintain their haemoglobin concentration before switching to the comparator route of administration. This study confirmed the findings of some of the earlier uncontrolled studies, suggesting that a dose saving of approximately 32% could be gained when the drug was administered subcutaneously. Within the last year, a meta-analysis has been conducted to examine this issue.

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Meta-analysis of subcutaneous versus intravenous epoetin in maintenance treatment of anemia in hemodialysis patients Besarab A, Reyes CM, Hornberger J. Am J Kidney Dis 2002; 40: 439–46

B A C K G R O U N D . Clinical and pharmacokinetic studies have shown that target haemoglobin or haematocrit levels can be maintained using a reduced recombinant erythropoietin dosage by switching from intravenous to subcutaneous administration. A meta-analysis of comparative studies of epoetin administered intravenously versus subcutaneously was conducted to assess the relative costs of these administration routes. Twenty-seven prospective clinical studies involving 916 patients were included in the analysis. The average difference between intravenous and subcutaneous doses of epoetin and the average difference in drug costs between administration routes were determined. I N T E R P R E T A T I O N . The average reduction in dose in patients treated with subcutaneous versus intravenous epoetin was 48 IU/kg/week (P <0.001), representing an average annual cost saving with subcutaneous administration of US$1761 1080 (standard deviation [SD]) per patient (Fig. 3.1). The difference between subcutaneous and intravenous doses was similar in both parallel- and cross-over-design studies. A retrospective US survey showed a dose reduction of 26 IU/kg/week (P <0.001) with subcutaneous administration, translating to an annual saving of US$946 per patient. This study indicates that the cost of epoetin is reduced substantially when administered

Fig. 3.1 Comparison of intravenous and subcutaneous dose distributions over all reviewed studies. The mean subcutaneous dose was 113 43 IU/kg/week and the mean intravenous dose was 161 46 IU/kg/week. Source: Besarab et al. (2002).

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subcutaneously in comparison with intravenously. Recommendations of current US and European guidelines, which encourage the use of subcutaneous administration, not only have a sound rationale in terms of efﬁcacy and safety but also have a sound economic basis.

Comment At the time this meta-analysis was conducted, there were quite a number of published studies comparing the use of subcutaneous versus intravenous epoetin administration, and 27 such prospective clinical studies were included in this analysis. Unfortunately, many of these were small and uncontrolled, and this should be taken into account when interpreting the conclusions of this meta-analysis. Furthermore, the conclusions were heavily influenced by the results of the large randomized Veterans Affairs Study 7, described earlier, which contributed no fewer than 208 patients to this meta-analysis. Nevertheless, this was a very useful addition to the literature on this subject because there was previously much debate about whether subcutaneous administration really resulted in lower dose requirements. A further large randomized controlled study examining this issue would be useful, but with the advent of newer erythropoietic agents this will probably never be conducted.

Epoetin-induced pure red cell aplasia Another major factor affecting the selection of the route of administration for epoetin was the recent discovery that a small number of patients treated with epoetin developed pure red cell aplasia associated with anti-erythropoietin antibodies. This caused an even more severe anaemia, resulting in the use of regular blood transfusions. It has generally been realized that this condition occurs almost exclusively with the use of the subcutaneous route, and is not a problem with intravenous administration. While this is not a major handicap for haemodialysis patients, intravenous epoetin administration is completely impractical for use in patients receiving peritoneal dialysis and those not yet requiring renal replacement therapy. The subcutaneous administration of epoetin, however, is only one of the factors that may have contributed to the development of pure red cell aplasia, and product formulation has also assumed much greater importance and attention. New data are emerging all the time.

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Pure red cell aplasia and anti-erythropoietin antibodies in patients treated with recombinant erythropoietin Casadevall N, Nataf J, Viron B, et al. N Engl J Med 2002; 346: 469–75

B A C K G R O U N D . Within a period of 3 years, 13 patients were identiﬁed in whom pure red cell aplasia developed during treatment with recombinant human erythropoietin. The

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immunological basis for the anaemia was investigated in these patients. Serum samples from the 13 patients with pure red cell aplasia were tested for neutralizing antibodies that could inhibit erythroid colony formation by normal bone marrow cells in vitro. The presence of anti-erythropoietin antibodies was identiﬁed by means of binding assays with the use of radiolabelled intact, deglycosylated or denatured epoetin. I N T E R P R E T A T I O N . Serum from all 13 patients blocked the formation of erythroid colonies by normal bone marrow cells. The inhibition was reversed by epoetin (Fig. 3.2). Antibodies from 12 of the 13 patients bound only conformational epitopes in the protein moiety of epoetin; serum from the remaining patient bound to both conformational and linear epitopes in erythropoietin. In all the patients, the antibody titre slowly decreased after the discontinuation of treatment with epoetin. Neutralizing anti-erythropoietin antibodies and pure red cell aplasia can develop in patients with the anaemia of chronic renal failure during treatment with epoetin.

Comment This was the paper that shocked the nephrological world and made us aware of a new and important issue in the management of renal anaemia. Although this was a small series of patients, subsequent publications have confirmed that this is a real phenomenon, which has stimulated much research and attention over the last couple of years. It has also had a major impact on the biopharmaceutical industry, resulting in

Fig. 3.2 Inhibition of erythroid-colony formation by serum from one patient. Erythroid cells in normal bone marrow were stimulated with 1 U of epoetin per millilitre in the presence of 20% pooled control serum; with 1, 10, 50 or 100 U of epoetin per millilitre in the presence of 20% serum from Patient 1; or with 1 U of epoetin per millilitre in the presence of 20% serum from Patient 1 in which immunoglobulin G (IgG) had been depleted with protein G Sepharose or in the presence of 100 µg of puriﬁed IgG per millilitre from Patient 1. Erythroid colonies were scored after 7 days of culture. The results are expressed as percentages of colonies formed in the presence of control serum and 1 U of epoetin per millilitre. Source: Casadevall et al. (2002).

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many companies abolishing their clinical development programmes for manufacturing generic recombinant erythropoietins once the patent expires. For nephrologists, recognition of this ‘new’ condition has resulted in many haemodialysis patients being switched from subcutaneous to intravenous administration, despite the fact that higher doses may have to be given (see above).

Target haemoglobin concentration Ever since nephrologists had the ability to raise the haemoglobin concentration in their patients with renal failure by using epoetin therapy, target haemoglobin has been the most hotly debated topic in the management of such patients. The evidence strongly supports increasing the haemoglobin from below 9–10 g/dl up to at least 11–12 g/dl, but it has always been recognized that the latter target range is still below that of normal non-uraemic individuals. The largest randomized controlled study to address this issue was published in the New England Journal of Medicine in 1998 8, and the overall conclusion was that there was no benefit in increasing the haemoglobin to around 14 g/dl compared with around 10 g/dl in haemodialysis patients. Although an excellent, scientifically robust study, it did have a number of limitations, notably that all the patients included in the study were high-risk cardiac patients who had to have evidence of ischaemic heart disease or congestive cardiac failure in order to satisfy the inclusion criteria. Although not statistically proved, there was a suggestion that raising the haemoglobin to normal levels in this patient population may be detrimental in terms of both mortality and morbidity (including increased vascular access thrombosis) 8. However, the implications of this study for patients on peritoneal dialysis and those not yet requiring dialysis remain uncertain.

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A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients Furuland H, Linde T, Ahlmen J, Christensson A, Strombom U, Danielson BG. Nephrol Dial Transplant 2003; 18: 353–61

B A C K G R O U N D . Partial correction of renal anaemia with erythropoietin improves quality of life. Four hundred and sixteen Scandinavian patients with renal anaemia (pre-dialysis, haemodialysis and peritoneal dialysis) were randomized to reach a normal haemoglobin of 13.5–16.0 g/dl (n 216) or a subnormal haemoglobin of 9–12 g/dl (n 200) with or without epoetin alfa, to examine if normalization of haemoglobin with epoetin alfa in pre-dialysis and dialysis patients further improves quality of life and is safe. Study duration was 48–76 weeks. Quality of life was measured using Kidney Disease Questionnaires (KDQs) in 253 Swedish dialysis patients. Safety was examined in all patients. I N T E R P R E T A T I O N . Quality of life improved, measured as a decrease in physical symptoms (P 0.02), fatigue (P 0.05), depression (P 0.01) and frustration

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(P 0.05) in the Swedish dialysis patients when haemoglobin was normalized. In pre-dialysis patients, diastolic blood pressure was higher in the normal compared with the subnormal haemoglobin group after 48 weeks. However, the progression rate of chronic renal failure was comparable. In the normal haemoglobin group, 51% had at least one serious adverse event compared with 49% in the subnormal haemoglobin group (P 0.32). The incidence of thrombovascular events and vascular access thrombosis in haemodialysis patients did not differ. The mortality rate was 13.4% in the normal haemoglobin group and 13.5% in the subnormal haemoglobin group (P 0.98). Mortality decreased with increasing mean haemoglobin in both groups. Normalization of haemoglobin improved quality of life in the subgroup of dialysis patients (Table 3.1), appears to be safe, and can be considered in many patients with end-stage renal disease (ESRD).

Comment The conclusions of this randomized controlled study were slightly different from those of the US study mentioned above. First, this study was conducted in European patients, who have a much higher incidence of native fistulae than their US counterparts. Secondly, the study included representation from all three modalities of renal replacement therapy, in contrast to the US study, which included only haemodialysis patients. The Scandinavian study, however, was not adequately powered to show a difference in mortality between the two groups, even though there were no safety concerns. The quality-of-life improvements were somewhat modest, given the massively increased costs of targeting full correction of anaemia. Table 3.1 Quality of life in dialysis patients Normal-Hb (n 129)

Subnormal-Hb (n 124)

KDQ week 0 Main physical symptoms Fatigue Depression Frustration Relations

n 115 3.83 (1.67–7.00) 4.67 (1.17–7.00) 5.40 (1.40–7.00) 6.00 (3.00–7.00) 5.17 (1.83–6.67)

n 111 4.00 (1.00–7.00) 5.00 (1.00–7.00) 5.60 (1.60–7.00) 6.00 (1.00–7.00) 5.00 (1.17–6.83)

Change in KDQ from week 0 to week 48 Physical symptoms Fatigue Depression Frustration Relations

n 55 0.66 (–1.17–3.00) 0.16 (–2.50–2.34) 0.00 (–4.00–2.60) 0.00 (–1.67–2.34) 0.00 (–2.66–2.67)

n 62 0.25 (–1.17–2.66) –0.33 (–3.17–2.00) –0.40 (–2.40–2.20) 0.00 (–2.00–2.00) 0.00 (–2.67–2.33)

P-value* 0.02 0.05 0.01 0.05 0.19

Values are given as median (min–max). Values ranges from 1 to 7, where 1 is a ‘severe problem’ and 7 is ‘no symptoms’. KDQ, Kidney Disease Questionnaire. * Wilcoxon rank sum test. Source: Furuland et al. (2003).

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Haemoglobin and haematocrit targets for the anaemia of chronic renal disease Strippoli GF, Manno C, Schena FP, Craig JC. Cochrane Database Syst Rev 2003; 1: CD003967

B A C K G R O U N D . Anaemia affects 60–80% of patients with renal impairment, reduces quality of life, and is a risk factor for early death. Treatment options are blood transfusion, erythropoietin alfa or beta, and darbepoetin alfa. Recently, higher haemoglobin and haematocrit targets have been widely advocated because of positive data from observational studies. However, higher targets may lead to access thrombosis and hypertension, and are costly. This review assessed the beneﬁts and harms of low (haemoglobin ≤10 g/dl or haematocrit ≤30%) and high (haemoglobin >10 g/dl or haematocrit >30%) targets in pre- and post-dialysis patients receiving any treatment for anaemia. The Cochrane Renal Group specialized register (September 2002), Cochrane Controlled Trials Register (The Cochrane Library, Issue 3, 2002), MEDLINE (1966–September 2002), EMBASE (1988–September 2002), and reference lists of retrieved articles were searched. Randomized controlled trials and quasi-randomized controlled trials comparing low haemoglobin/haematocrit targets (haemoglobin ≤10 g/dl) with high haemoglobin/haematocrit targets (haemoglobin >10 g/dl) in patients with anaemia of chronic renal disease were selected for this analysis. Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and the results were expressed as relative risk for dichotomous outcomes and weighted mean difference for continuous outcomes, with 95% conﬁdence intervals (CIs). I N T E R P R E T A T I O N . Fifteen trials were identiﬁed in which 2096 patients were included. Twelve trials (673 patients) compared placebo with erythropoietin, and three trials (1423 patients) compared two doses of erythropoietin. Haemoglobin values of 10 g/dl (obtained with low erythropoietin doses) were associated with lower mortality compared with haemoglobin values of 14 g/dl or more (obtained with high erythropoietin doses) in the population with chronic renal disease and cardiovascular impairment (two trials, 1379 patients: relative risk [RR] 0.82; 95% CI 0.68–0.99). Lower targets obtained with a placebo resulted in an increased risk of seizures (four trials, 219 patients; RR 5.25; 95% CI 1.13–24.34) compared with higher targets reached with erythropoietin treatment. Finally, there was a reduced risk of hypertensive episodes when lower haemoglobin targets were reached with a placebo compared with higher targets reached with erythropoietin (six trials, 387 patients; RR 0.50; 95% CI 0.33–0.76). Quality of life was not adequately evaluated in the studies. Lower haemoglobin targets of 10 g/dl were associated with a lower risk of death in the population with cardiovascular impairment and chronic renal disease, compared with a haemoglobin of 14.0 g/dl. Lower haemoglobin targets (haemoglobin <10 g/dl) were also signiﬁcantly associated with an increased risk of seizures and a reduced risk of hypertension compared with haemoglobin greater than 10 g/dl. There is a need for more adequately powered and well-designed trials in this area. In particular, randomized controlled trials comparing the beneﬁts and harms of low (haemoglobin <10g/dl) versus intermediate (haemoglobin 13.0 g/dl) and high (haemoglobin 14.0 g/dl) haemoglobin in the pre-dialysis population with chronic renal disease are necessary.

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Comment This was a useful Cochrane Review, which was begging to be done at some point. Unfortunately, as with the meta-analysis comparing intravenous with subcutaneous administration described above, and as the authors of this review comment, there are not enough good-quality studies of sufficient power to provide answers to nephrologists’ questions. This Cochrane analysis was totally swamped by the data from the US study, which numerically contributed 98% of the total patient population. Thus, in effect the conclusions are the same as in the US Normal Haematocrit Study, but one must be careful not to extrapolate the results of this study to other patient populations not included in this trial, such as peritoneal dialysis, pre-dialysis, and haemodialysis patients with a low cardiac risk. Perhaps the main message from this Cochrane Review is the deficiency of quality trials in this area.

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The cost-effectiveness of maintaining higher hemoglobin targets with erythropoietin in hemodialysis patients Tonelli M, Winkelmayer WC, Jindal KK, Owen WF, Manns BJ. Kidney Int 2003; 64: 295–304

B A C K G R O U N D . There is uncertainty regarding the appropriate target haemoglobin level in haemodialysis patients treated with erythropoietin. The authors sought to determine the incremental cost-effectiveness of prescribing erythropoietin to maintain different target haemoglobin levels, by incorporating the impact of erythropoietin on health-related quality-of-life issues and adopting the perspective of the healthcare purchaser. They evaluated the prescription of erythropoietin to maintain target haemoglobin levels of 11.0–12.0, 12.0–12.5 and 14.0 g/dl compared with 9.5–10.5 g/dl. Model outputs were quality-adjusted life expectancy, and costs. I N T E R P R E T A T I O N . The base case analysis estimated intravenous erythropoietin requirements to be 3523, 5078, 6097 and 9341 units three times per week to maintain targets of 9.5–10.5, 11.0–12.0, 12.0–12.5 and 14.0 g/dl, respectively. The cost per quality-adjusted life year (QALY) gained for the 11.0–12.0 g/dl target versus 9.5–10.5 g/dl was US$55 295. For the 12.0–12.5 g/dl target, compared with 11.0–12.0 g/dl and 14.0 g/dl targets, the costs per QALY gained were US$613 015 and $828 215 respectively. In sensitivity analysis, clinically implausible reductions in hospitalization or erythropoietin requirements associated with the two higher haemoglobin targets were required to make their incremental cost per QALY gained
Comment This is a pharmacoeconomic analysis comparing the cost-effectiveness of maintaining different haemoglobin target levels in haemodialysis patients. There are

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limitations to this study but the overall conclusion is that normalization of haemoglobin in this patient population costs very much more than a lower haemoglobin, and that, in terms of maximum quality-adjusted life expectancy, a target of between 11 and 12 g/dl appears to be optimal. On a population basis, this is probably true, but it does not answer the nephrologist’s question that, if a patient happens to achieve a target haemoglobin of between 13 and 14 g/dl on a minimal dose of erythropoietin, should they be kept at this level or reduced to a lower target haemoglobin of 11–12 g/dl? A large, randomized outcome-based study would be required to answer this important question.

Iron management Good iron management remains critical to the management of patients with renal anaemia, and there has been a plethora of papers published on this topic over the last decade. It has become established that adequate iron availability is necessary in order to optimize the response to erythropoietic therapy, and often oral iron is insufficient to achieve this. Intravenous iron supplementation has therefore become increasingly used, and several randomized controlled trials have shown enhanced efficacy compared with oral iron 9,10. Many of these trials, however, were conducted using iron dextran, which was the main preparation available in the USA and much of Europe at the time. The major problem with iron dextran is the risk of life-threatening anaphylaxis, and this has resulted in increased interest in the use of other intravenous iron preparations, such as iron sucrose and iron gluconate. There is now evidence that such preparations are safer 11–13. There has also been a concern that intravenous iron may increase a patient’s susceptibility to infection and also increase oxidative stress. Although there is much in vitro data to support these concerns, clinical data are conflicting and robust scientific studies are lacking.

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High-dose parenteral iron sucrose depresses neutrophil intracellular killing capacity Deicher R, Ziai F, Cohen G, Mullner M, Horl WH. Kidney Int 2003; 64: 728–36

B A C K G R O U N D . Iron is essential for the formation of haemoglobin. During long-term treatment with human recombinant erythropoietin, most ESRD patients will not respond adequately to erythropoietin unless substituted with intravenous iron. However, concern exists about possible detrimental effects of parenteral iron on cellular host defence and iron-mediated increments of oxidative stress. Phagocytic function of polymorphonuclear leucocytes (PMNs) was analysed from 20 ESRD patients on peritoneal dialysis in response to 300 mg of iron sucrose or placebo administered intravenously over 2 h in a randomized double-blind manner. Fc R-dependent phagocytosis and killing (the primary outcome variable) of opsonized Escherichia coli, Fc R-dependent oxidative burst capacity, and complement receptor 3/tumour necrosis factor- (TNF-)-mediated

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release of bactericidal lactoferrin before administration, during administration and 1 h and 2 days after administration were evaluated. I N T E R P R E T A T I O N . The absolute count and the percentage of E. coli killed by PMNs of iron sucrose-treated peritoneal dialysis patients decreased signiﬁcantly over time in comparison with placebo-treated patients (P 0.008 and P 0.006, respectively) (Fig. 3.3). All secondary outcome variables were not different between the two groups over time. Killing capacity of PMNs isolated from ESRD patients decreased in response to high-dose parenteral iron sucrose, possibly explaining in part the reported higher hospitalization rates and lower survival rates of dialysis patients receiving frequent and high-dose parenteral iron.

Fig. 3.3 (a) Median number of killed E. coli/PMNs and (b) median killed E. coli as a percentage of the total number of phagocytosed E. coli/PMNs; at t 0, 30, 120 and 180 minutes and 48 h after parenteral administration of 300 mg of iron sucrose () or placebo (). Bars indicate the corresponding 95% CIs. Source: Deicher et al. (2003).

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Comment This study shows very elegantly the potential detrimental effects that high-dose intravenous iron may have in ESRD patients. The results are highly statistically significant compared with placebo, and it is likely that this is a real effect. The major limitation of this study is whether the parameters measured ex vivo actually matter to the patient in terms of increasing their susceptibility to infection. Unfortunately, this study cannot answer this question.

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Intravenous iron administration does not signiﬁcantly increase the risk of bacteremia in chronic hemodialysis patients Hoen B, Paul-Dauphin A, Kessler M. Clin Nephrol 2002; 57: 457–61

B A C K G R O U N D . Correction of iron deﬁciency is critical in chronic haemodialysis patients, and intravenous administration is superior to the oral route in this goal. Recently, concern was raised that intravenous iron administration might promote infection in dialysis patients. Data from a recent prospective study of 985 patients were reviewed in which no link between iron therapy and bacteraemia had been found. The potential roles of the administration route of the iron (intravenous versus oral), the weekly amount of iron administered, and the administration rate were tested with respect to the risk of bacteraemia in these patients. I N T E R P R E T A T I O N . In the subgroup of intravenous iron-treated patients, signiﬁcant risk factors for bacteraemia were found. Iron was not given more frequently intravenously in bacteraemic compared with non-bacteraemic patients. Among patients treated with intravenous iron, the frequency of iron administration and the amount of iron administered were signiﬁcantly higher in those who developed bacteraemia than in those who did not. In patients receiving intravenous iron, there was an increased risk of bacteraemia associated with concurrent administration of erythropoietin, which was not observed in patients receiving iron orally. This study failed to demonstrate a signiﬁcant association between intravenous iron administration and the risk of bacteraemia in dialysis patients. However, there may be a slightly increased risk of bacteraemia in patients given high-frequency, high-dose intravenous iron.

Comment This study suggests a note of caution, but the major conclusion from the authors was that there was no significant association between intravenous iron administration and the risk of bacteraemia in dialysis patients. The nephrologist is therefore left with the dilemma of whether or not to use intravenous iron to support erythropoiesis. The benefits are substantial and proven in terms of increasing haemoglobin and reducing erythropoietin dose requirements, and this has to be weighed against the slight risks to the patient. This latest study is a useful addition to the literature, but further similar analyses are needed before firm recommendations can be made on this issue.

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The effects of intravenous iron treatment on oxidant stress and erythrocyte deformability in haemodialysis patients Cavdar C, Temiz A, Yenicerioglu Y, et al. Scand J Urol Nephrol 2003; 37: 77–82

B A C K G R O U N D . It is well known that free iron causes oxidant stress to increase. However, data concerning whether maintenance doses of iron administered intravenously give rise to increased oxidant stress and disturbed erythrocyte deformability (EDEF) in haemodialysis patients is lacking. In the present study, the effects of intravenous iron on oxidant stress and EDEF were measured. Thirteen haemodialysis patients given intravenous iron were included in the study. All patients underwent three consecutive haemodialysis sessions. The ﬁrst session was performed without iron administration (Group 1), whereas in the subsequent sessions the same patients were given 20 mg (Group 2) and 100 mg (Group 3) iron sucrose intravenously at the end of the dialysis session. During the study periods, seven blood samples were taken from each patient: before dialysis, at the end of dialysis and 15, 30, 60, 90 and 120 min after each dialysis session. EDEF and plasma malondialdehyde (MDA) were measured from all samples. I N T E R P R E T A T I O N . Compared with the session without iron administration, there was no correlation between MDA and EDEF. MDA levels at 90 and 120 min were signiﬁcantly higher than those immediately before and just after the haemodialysis session (P <0.05). EDEF at 60, 90 and 120 min was found to be worse than before and just after the haemodialysis session (P <0.05). After 20 mg of iron, EDEF did not signiﬁcantly change, but MDA levels were found to be signiﬁcantly higher after 60 min into the haemodialysis session (P <0.05). With 100 mg of iron, the MDA level was increased after 30 min onwards, but EDEF was improved at 90 and 120 min. MDA levels after 100 mg of intravenous iron were signiﬁcantly lower than those after 20 mg of iron (P <0.05). Intravenous iron administered at doses of 20 and 100 mg did not cause an additional detrimental effect on oxidant stress, and EDEF was even improved by the administration of intravenous iron.

Comment As with the previous study on oxidative stress reported above, it is important to critically review the significance of ex vivo data generated from patients receiving intravenous iron. In this particular study (one of the latest to be published), however, there was no detrimental effect of intravenous iron on oxidative stress at the doses given, and there may possibly have been improvements in EDEF. There are many reasons why data on this issue are so conflicting. First, different doses of intravenous iron have been administered (in the study by Deicher et al. reported above, the dose of iron sucrose given was 300 mg, whereas in this study the doses used were 20 and 100 mg). Secondly, different methods were used to assess oxidative stress, and this is one of the critical problems with studies of this nature; the most appropriate investi-

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Fig. 3.4 Plasma MPA levels before and after dialysis sessions in which patients received no iron or 20 or 100 mg iron intravenously. Source: Cavdar et al. (2003).

gation for assessing oxidative stress is not clear. This confuses researchers and makes comparisons among studies problematic.

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Labile iron in parenteral iron formulations and its potential for generating plasma non-transferrin-bound iron in dialysis patients Esposito BP, Breuer W, Slotki I, Cabantchik ZI. Eur J Clin Invest 2002; 32 (Suppl 1): 42–9

B A C K G R O U N D . Labile plasma iron (LPI) associated with iron supplementation has been implicated in complications found in dialysis patients. As LPI can potentially catalyse oxygen radical generation, we determined the presence of labile iron in the parenteral preparations and the frequency of occurrence of LPI in dialysis patients. The capacity to donate iron to apotransferrin or to the chelator desferrioxamine was measured with ﬂuorescein-Tf and F1-DFO respectively. These probes undergo quenching upon binding to iron. Iron-catalysed generation of oxidant species was determined with dihydrorhodamine. Plasma non-transferrin-bound iron was determined by mobilization of iron from low-afﬁnity binding sites with oxalate followed by its quantiﬁcation with F1-Tf in the presence of Gallium (Ga) III. I N T E R P R E T A T I O N . Normal individuals and most (80%) dialysis patients, analysed at least 1 week after iron supplementation, showed no detectable LPI. However, approximately 20% of the patients (n 71) showed signiﬁcant LPI levels, in some cases weeks after iron administration. LPI levels correlated best with transferrin saturation. The iron preparations contained 2–6% low molecular weight and redox-active iron, most of which is chelated by transferrin. Parenteral iron formulations contain a small but signiﬁcant fraction of redox-active iron, most of which is scavenged by apotransferrin within 1 h.

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Therefore, oxidant stress associated with intravenous iron administration is likely to be transient. The bulk of the polymeric iron is apparently inaccessible to apotransferrin. Although LPI might return to normal within 2 h of intravenous iron infusion, the long-term persistence of low-level LPI in up to 20% of ESRD patients indicates that complete clearance of the intravenous iron may be more protracted than originally estimated.

Comment There is much debate and controversy among the experts regarding the methodology of measuring non-transferrin-bound iron. If one accepts the methods used in this paper, a small but significant number of ESRD patients may experience persistence of low levels of LPI after the administration of intravenous iron, although the vast majority do not seem to show this. It is also reassuring that the small but significant fraction of redox iron in intravenous iron preparations is largely scavenged by apotransferrin within 1 h. This could mean that any detrimental effect of intravenous iron on oxidative stress is short-lived, and again the potential benefits of this clinical practice have to be considered.

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Impairment of transendothelial leukocyte migration by iron complexes Sengoelge G, Kletzmayr J, Ferrara I, Perschl A, Horl WH, Sunder-Plassmann G. J Am Soc Nephrol 2003; 14: 2639–44

B A C K G R O U N D . Although iron sucrose and iron gluconate are generally well tolerated in patients treated for renal anaemia, recent clinical studies and cell culture experiments have suggested signiﬁcant toxicity and long-term side effects arising from the use of these iron complexes. Because of the possible role of iron in infection or cardiovascular disease, it was theorized that parenteral iron compounds inﬂuence endothelial and PMN interaction in vitro. A well-established double-chamber method was used to assess the effect of different concentrations of iron sucrose and iron gluconate on the transendothelial migration of PMN. I N T E R P R E T A T I O N . Pre-incubation of PMNs and endothelial cells as well as pre-incubation of PMNs alone with iron resulted in a signiﬁcant decrease in PMN migration. In contrast, after incubation of the endothelial cells alone with iron, no reduction in the transendothelial migration of PMNs was observed. Pre-incubation of PMNs and/or endothelial cells with 1 g/ml iron did not lead to any decrease in the rate of migrated PMNs. The only signiﬁcant change in experiments with 1 g/ml was an increase in PMN migration after pre-incubation of endothelial cells and PMNs with iron gluconate. A four-way analysis of variance showed signiﬁcant effects on PMNs diapedesis of the iron concentration (P <0.000001), of the type of iron complex (P <0.005), of the pre-incubation of endothelial cells (P <0.001) and of the pre-incubation of PMNs with iron (P <0.000001). It is concluded that iron sucrose and iron gluconate cause signiﬁcant inhibition of transendothelial migration of PMNs.

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Comment This is further in vitro evidence suggesting a potential detrimental effect of iron sucrose and iron gluconate administered intravenously. This study generated results of high statistical significance, about which there can be little debate. As before, however, the main limitation of this study is whether a transient impairment of transendothelial PMN migration is detrimental to the patient, weighed against the known adverse consequences of inadequately correcting the anaemia in such patients. Such in vitro data are of undoubted interest, but the relevance to clinical practice remains unclear.

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Effect of iron treatment on circulating cytokine levels in ESRD patients receiving recombinant human erythropoietin Weiss G, Meusburger E, Radacher G, Garimorth K, Neyer U, Mayer, G. Kidney Int 2003; 64: 572–8

B A C K G R O U N D . Anaemia in patients with ESRD is treated with recombinant human erythropoietin, often in combination with iron. However, iron catalyses the formation of toxic radicals that might promote vascular damage, is a nutrient for micro-organisms and negatively affects immune pathways, thus increasing the risk of severe infections. Twenty-eight patients on chronic haemodialysis were randomized to receive either erythropoietin alone (n 15) or erythropoietin in combination with intravenous iron (n 13) for a period of 12 weeks. Iron therapy-associated changes in cytokine patterns and endogenous radical formation were analysed. I N T E R P R E T A T I O N . TNF- levels were increased in ESRD patients at study entry and then decreased signiﬁcantly over time in subjects receiving additional iron, whereas they increased with erythropoietin alone. In contrast, serum concentrations of the antiinﬂammatory cytokine interleukin-4 (IL-4) increased with iron therapy. A signiﬁcant negative correlation between iron availability, as determined by transferrin saturation and TNF- levels (P 0.008), and a positive correlation between transferrin saturation and IL-4 (P 0.02) pointed to the potential role of iron in inducing immunological changes. Interestingly, iron therapy resulted in a slight decrease in the amounts of endogenous peroxides, which may be referred to reduced TNF- concentrations, since peroxide concentrations were positively correlated to TNF- levels (P 0.046) and negatively to transferrin saturation (P 0.02). Iron supplementation in ESRD patients down-regulates pro-inﬂammatory immune effector pathways and stimulates the expression of the anti-inﬂammatory cytokine IL-4. Such a condition is detrimental for the host response to invading pathogens. However, tissue damage by radicals such as endogenous peroxides may be reduced in this condition as a result of impaired TNF- formation.

Comment It is increasingly recognized that ESRD is a condition causing enhanced immune activation and propagation of pro-inflammatory cytokines. Some of these changes

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Fig. 3.5 Association between iron status and cytokine levels in ESRD patients. (a) Correlation between transferrin saturation (TfS) as a marker of iron availability and TNF- levels in ESRD patients at the end of the study period (r, correlation coefﬁcient; P, signiﬁcance value after Bonferroni correction). The regression line and the 95% CI are shown. (b) Association between transferrin saturation and circulating levels of the anti-inﬂammatory cytokine IL-4 at the end of the study period. Source: Weiss et al. (2003).

may be beneficial and protective for the patient, while others may be detrimental. This study examined whether the addition of intravenous iron to erythropoietin therapy was beneficial or detrimental to such patients, and both positive and negative effects were found. The reduction in TNF- may be beneficial, while the increase in IL-4 may be detrimental. In contrast to other reports, this study suggests that there may be a reduction in oxidative stress after intravenous iron, mediated by a decrease in TNF-. Although this is a fascinating study, it further confuses the nephrologist regarding whether intravenous iron is detrimental to the patient in terms of increasing the risk of infection or oxidative stress.

Responsiveness to erythropoietic therapy In addition to iron supplementation, other factors may affect responsiveness to erythropoietic therapy and some of these may be targets for therapeutic manipulation. However, by far the main cause of anaemia in chronic renal failure is a relative deficiency of erythropoietin, which generally responds well to therapeutic epoetin administration. It is also increasingly recognized that chronic inflammation antagonizes the cellular response to erythropoietin, probably mediated via pro-inflammatory cytokines, particularly TNF- and interferon- 14. Thus, to some extent, the anaemia of renal failure is also partly an anaemia of chronic disease. In most patients this inflammatory resistance can be easily overcome by exogenous erythropoietin,

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but in some patients it results in quite pronounced resistance to erythropoietic therapy. In the absence of iron deficiency, blood loss and other known causes of anaemia, chronic inflammation is probably the commonest cause of a suboptimal response to erythropoietic therapy in renal failure.

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Increased expression of erythropoiesis inhibiting cytokines (IFN-gamma, TNF-alpha, IL-10, and IL-13) by T cells in patients exhibiting a poor response to erythropoietin therapy Cooper AC, Mikhail A, Lethbridge MW, Kemeny DM, Macdougall IC. J Am Soc Nephrol 2003; 14: 1776–84

B A C K G R O U N D . Resistance to recombinant human erythropoietin occurs in a small but important proportion of haemodialysis patients. This may be due to increased immune activation because pro-inﬂammatory cytokines inhibit erythropoiesis in vitro. Using FACScan ﬂow cytometry, the proportion of PMA/ionomycin-stimulated T cells expressing cytokines ex vivo was compared in 18 poor responders to erythropoietin, 14 good responders to erythropoietin and 14 normal controls. I N T E R P R E T A T I O N . CD4+ T cells from poor responders expressed more interferon- (19 6%) compared with good responders (11 6%; P <0.001) and controls (12 6%; P <0.01). Similarly, CD4+ T cells from poor responders expressed more TNF- (poor responders 51 19%) than good responders (27 15%; P <0.01) and controls (30 19%; P <0.01). CD4+ expression of IL-10 was also enhanced, as was CD4 expression of IL-13. CD8+ T cells from poor responders also showed increased expression of cytokines. These data indicate that T cells from poor responders are in an enhanced activation state, possibly as a result of chronic inﬂammation. In the absence of any other cause (such as iron deﬁciency), the overproduction of cytokines may account for hyporesponsiveness to erythropoietic therapy in patients with renal failure.

Comment Ex vivo evidence that propagation of pro-inflammatory cytokines may affect responsiveness to erythropoietic therapy is reported. The mechanism of this effect was not investigated in the study, but there is evidence from other studies that TNF- and interferon- are important inhibitors of erythroid progenitor cell growth. Interferon-, in particular, is a pro-apoptotic cytokine which may antagonize the anti-apoptotic effect of erythropoietin on primitive red cells. At present, the strategies for counteracting this inflammatory effect are unsatisfactory, but this process may be therapeutically modifiable in the future.

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Fig. 3.6 (a) Percentage of CD4+ T cells that express IL-10 in normal controls, good responders and poor responders to recombinant human erythropoietin. (b) Percentage of CD8+ T cells that express IL-10 in normal controls, good responders and poor responders to recombinant human erythropoietin. Horizontal bars indicate the mean percentage values. Source: Cooper et al. (2003).

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Randomized prospective comparison between erythropoietin and androgens in CAPD patients Navarro JF, Mora C, Macia M, Garcia J. Kidney Int 2002; 61: 1537–44

B A C K G R O U N D . Anaemia and malnutrition are signiﬁcant complications in peritoneal dialysis patients. Previous studies in haemodialysis have shown that androgens are

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effective as a therapy for anaemia; however, this has not been tested in a randomized prospective trial in peritoneal dialysis patients. Furthermore, the anabolic properties of androgens may exert additional beneﬁts with respect to the nutritional status in this population. Twenty-seven stable male patients over 50 years of age who were receiving continuous ambulatory peritoneal dialysis (CAPD) were randomized to receive recombinant human erythropoietin (n 14) or nandrolone decanoate (200 mg/week intramuscularly; n 13) as therapy for anaemia. The evolution of haematological parameters and the effects on both nutritional anthropometric and biochemical variables were evaluated after 6 months of treatment. I N T E R P R E T A T I O N . Both haemoglobin and haematocrit showed similar increases in both groups. At the end of the study, only weight and body mass index signiﬁcantly increased in the erythropoietin-treated group. In contrast, both anthropometric (weight, body mass index, triceps skinfold thickness, mid-arm circumference and mid-arm muscle circumference) were signiﬁcantly increased in patients treated with nandrolone decanoate. In this group, serum urea nitrogen, urea net excretion and protein equivalent of nitrogen appearance decreased signiﬁcantly. These facts, together with an increase in serum creatinine and no changes in dietary intake during the study, suggest a rise in muscle mass related to an anabolic effect of nandrolone decanoate. Interestingly, serum levels of insulin-like growth factor type 1 (IGF-1) increased in patients in the androgen group compared with subjects treated with erythropoietin. Moreover, there was a positive and signiﬁcant correlation between the rise in IGF-1 concentrations and the increase in haemoglobin, haematocrit, mid-arm circumference and mid-arm muscle circumference. In conclusion, androgen therapy improved the anaemia in elderly male CAPD patients in a similar manner to that observed with erythropoietin. Furthermore, compared with erythropoietin, androgen administration was associated with beneﬁcial effects on nutritional status. The mechanism of action of androgens on haematological and nutritional parameters might be mediated, at least in part, by IGF-1.

Comment This prospective randomized controlled study suggests that androgen therapy was at least as good, if not better, than erythropoietin therapy alone. In addition to increasing the haemoglobin concentration, nandrolone decanoate also appeared to give a number of nutritional benefits, which did not occur with erythropoietin therapy. The main problem with androgens, however, is not only their need for parenteral therapy (intramuscular administration in this study), which is impractical for longterm use, but also the side-effect profile, which is unacceptable (compared with erythropoietin therapy) in the long term. Virilization, hirsutism, liver toxicity and possibly an increased risk of prostatic malignancy may all occur with androgen therapy, whereas erythropoietin avoids all of these problems. Nevertheless, given the high cost of erythropoietin therapy, there are undoubtedly areas of the world where androgens are used to treat the anaemia of renal failure, either on their own or as adjuvant therapy with erythropoietin. Studies such as the one described here provide additional evidence for this practice.

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Darbepoetin alfa therapy Darbepoetin alfa is a second-generation erythropoietic agent. This novel molecule was created out of a realization that the sialic acid-containing carbohydrate chains on recombinant human erythropoietin were critical for its metabolic stability in vivo. About a decade ago, scientists working in the USA discovered that the greater the amount of sialic acid residues on the erythropoietin molecule, the longer the circulating half-life in vivo. Darbepoetin alfa was therefore synthesized using site-directed mutagenesis, which inserted an additional two N-linked glycosylation chains onto the protein backbone of erythropoietin. This increased the elimination half-life of the new molecule to over 25 h after a single intravenous dose, compared with 8.5 h for a similar dose of epoetin alfa 4. Phase II and Phase III clinical trials followed, and the product became licensed for clinical use in 2001. Several of these studies have been published recently.

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Randomized controlled trial of darbepoetin alfa for the treatment of anemia in hemodialysis patients Nissenson AR, Swan SK, Lindberg JS, et al. Am J Kidney Dis 2002; 40: 110–18

B A C K G R O U N D . Darbepoetin alfa is a new erythropoiesis-stimulating protein with a three-fold longer terminal half-life than recombinant human erythropoietin in patients with chronic kidney disease. The purpose of this randomized, double-blind, non-inferiority study was to determine whether darbepoetin alfa is as effective as epoetin for the treatment of anaemia in haemodialysis patients when administered at a reduced dosing frequency. Patients receiving epoetin therapy were randomized to continue epoetin administered intravenously three times weekly (n 338) or to change to darbepoetin alfa administered intravenously once weekly (n 169). The dose of darbepoetin alfa or epoetin was individually titrated to maintain haemoglobin concentrations within 1.0–1.5 g/dl of the patients’ baseline values and within a range of 9–13 g/dl for up to 28 weeks. The primary end-point was the change in haemoglobin between baseline and the evaluation period. I N T E R P R E T A T I O N . Mean changes in haemoglobin levels from baseline to the evaluation period were 0.24 0.10 g/dl in the darbepoetin alfa group and 0.11 0.07 g/dl in the epoetin group, a difference of 0.13 g/dl. This difference was not statistically signiﬁcant or clinically relevant despite the reduced frequency of darbepoetin alfa administration. The safety proﬁle of darbepoetin alfa was similar to that of epoetin, and no antibody formation to either treatment was detected. In conclusion, darbepoetin alfa maintained haemoglobin concentrations as effectively and safely as epoetin in patients with chronic kidney disease, but with a reduced dosing frequency.

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Comment This is the first large US study showing that darbepoetin alfa was effective in maintaining correction of anaemia in patients already receiving epoetin therapy. The main hypothesis tested in this study, as in most other darbepoetin alfa studies, was that this could be achieved with a reduced dose frequency because of its longer circulating half-life. There were also no safety concerns with this new erythropoietic agent.

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Randomized trial of darbepoetin alfa for treatment of renal anemia at a reduced dose frequency compared with rHuEPO in dialysis patients Vanrenterghem Y, Barany P, Mann JF, et al. Kidney Int 2002; 62: 2167–75

B A C K G R O U N D . This study aimed to determine whether darbepoetin alfa was as effective and well tolerated as recombinant human erythropoietin (rHuEPO) for treating renal anaemia in dialysis patients when administered at a reduced dose frequency. A total of 522 European and Australian haemodialysis and peritoneal dialysis patients receiving stable rHuEPO therapy by either the intravenous or the subcutaneous route were randomized in an open-label fashion to continue rHuEPO or to receive an equivalent dose of darbepoetin alfa at a reduced dose frequency. Patients receiving erythropoietin once weekly changed to darbepoetin alfa once every other week, and those receiving erythropoietin two or three times weekly changed to once-weekly darbepoetin alfa. The doses of erythropoietin and darbepoetin alfa were titrated to maintain the haemoglobin close to the patient’s baseline level for up to 52 weeks. The primary end-point was the change in haemoglobin between baseline and the evaluation period at weeks 25–32 of treatment. I N T E R P R E T A T I O N . The mean change in haemoglobin from baseline to the evaluation period was similar in the darbepoetin alfa (–0.03 g/dl) and rHuEPO (–0.06 g/dl) groups, and the difference between the two treatments was not statistically signiﬁcant or clinically relevant, despite the reduced frequency of darbepoetin alfa administration (Fig. 3.7). At the end of the evaluation period, 95% of patients had their haemoglobin successfully maintained on their assigned dose frequency for darbepoetin alfa (once weekly and once every other week) and rHuEPO (once, twice and three times weekly). The safety proﬁles of darbepoetin alfa and rHuEPO were similar, and no antibodies to either treatment were detected. In conclusion, darbepoetin alfa maintains haemoglobin as effectively as rHuEPO, but with a reduced dose frequency.

Comment This study was very similar to the one by Nissenson et al. described above. The conclusions were the same, and the major difference in the present study was that this was conducted in European and Australian (rather than US) patients, and that peritoneal dialysis patients were also included in this study (receiving treatment subcutaneously). As before, however, the main conclusion of the study was that

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Fig. 3.7 Mean ( 2 SD) haemoglobin over time. , darbepoetin alfa (n 347); , recombinant human erythropoietin (rHuEPO; n 175). Whiskers denote the standard deviation. Source: Vanrenterghem et al. (2002).

darbepoetin alfa could maintain haemoglobin concentrations in a very similar manner to epoetin therapy, but with a reduced dosing frequency.

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Correction of anaemia with darbepoetin alfa in patients with chronic kidney disease receiving dialysis Macdougall IC, Matcham J, Gray SJ, on behalf of the NESP 960245/246 Study Group. Nephrol Dial Transplant 2003; 18: 576–81

B A C K G R O U N D . Darbepoetin alfa is a new recombinant erythropoietic protein with a three-fold longer half-life than recombinant human erythropoietin. The optimal starting dose and frequency of administration of this new agent were investigated for treating renal anaemia in dialysis patients. Two multicentre, sequential dose-escalation studies examined the intravenous route of administration of darbepoetin alfa in haemodialysis patients (n 75) and the subcutaneous route in peritoneal dialysis patients (n 47). Patients were randomized to receive darbepoetin alfa at doses ranging from 0.075 to 0.75 g/kg/week, administered by injection either once weekly or three times weekly. Patients achieving the primary end-point of an increase in haemoglobin of 1 g/dl or more after 4 weeks continued darbepoetin alfa for up to 52 weeks. Safety was assessed by adverse event reports, changes in laboratory values and vital signs, and antibody screening. I N T E R P R E T A T I O N . Darbepoetin alfa produced dose-related increases in haemoglobin over the ﬁrst 4 weeks of treatment in both studies. Two dose levels (0.45 and 0.75 g/kg/week) increased haemoglobin by at least 1 g/dl in 60–80% of patients, and no difference between once-weekly and three-times-weekly dosing was apparent. For

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patients who continued treatment up to 52 weeks, haemoglobin was maintained between 10 and 13 g/dl from mean baseline values of 8.4 and 8.7 g/dl. The adverse event proﬁle was similar to that associated with rHuEPO therapy, and no antibodies to darbepoetin alfa were detected. In conclusion, darbepoetin alfa is safe and effective for the treatment of anaemia in dialysis patients. The optimal weekly starting dose is 0.45–0.75 g/kg and once-weekly dosing is possible for both the subcutaneous and intravenous routes of administration.

Comment In contrast to the two previous studies reported above, this paper reports the results of two correction-phase studies in haemodialysis patients (treated with intravenous darbepoetin alfa) and peritoneal dialysis patients (treated with subcutaneous darbepoetin alfa). In both patient groups, there was a dose-dependent increase in haemoglobin, and there were no safety concerns. The study was not powered adequately to compare intravenous with subcutaneous administration (also, the population of patients was different—intravenous for haemodialysis patients and subcutaneous for peritoneal dialysis patients), but the preliminary data suggested that a once-weekly dosing regimen might be appropriate for both routes of administration.

Conclusion Treating the anaemia associated with renal failure has a massive impact on the overall well-being of patients, increasing their quality of life, exercise capacity and cardiac function. We have come a long way since the early clinical trials of intravenous epoetin in haemodialysis patients nearly two decades ago, and some of the most recent data are reported here. However, this remains a growing area of interest, with newer data emerging on the cause of epoetin-induced pure red cell aplasia, and also the development of novel erythropoietic agents. The next addition to the therapeutic repertoire is likely to be CERA, which has recently begun its Phase III clinical development programme 5. Preliminary results suggest that it may be possible to give this new agent even less frequently than darbepoetin alfa, perhaps once every 3–4 weeks. In short, new data and developments concerning the management of renal anaemia are appearing at a rapid rate and will probably continue to do so for the foreseeable future.

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References 1. Caro J, Brown S, Miller O, Murray T, Erslev AJ. Erythropoietin levels in uremic nephric

and anephric patients. J Lab Clin Med 1979; 93: 449–58. 2. Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F,

3.

4.

5.

6.

7.

8.

9. 10.

11.

12. 13. 14.

Stabinsky Z, et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA 1985; 82: 7580–4. Macdougall IC. Pure red cell aplasia with anti-erythropoietin antibodies occurs more commonly with one formulation of epoetin alfa than another. Curr Med Res Opin 2004; 20: 83–6. Macdougall IC, Gray SJ, Elston O, Breen C, Jenkins B, Browne J, Egrie J. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol 1999; 10: 2392–5. Macdougall IC, Bailon P, Tare N, Pahlke W, Pill J. CERA (Continuous Erythropoiesis Receptor Activator) for the treatment of renal anemia: an innovative agent with unique receptor binding characteristics and prolonged serum half-life. J Am Soc Nephrol 2003; 14: 769A. Bommer J, Barth HP, Zeier M, Mandelbaum A, Bommer G, Ritz E, Reichel H, Novack R. Efficacy comparison of intravenous and subcutaneous recombinant human erythropoietin administration in hemodialysis patients. Contrib Nephrol 1991; 88: 136–43. Kaufman JS, Reda DJ, Fye CL, Goldfarb DS, Henderson WG, Kleinman JG, Vaamonde CA. Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. Department of Veterans Affairs Cooperative Study Group on Erythropoietin in Hemodialysis Patients. N Engl J Med 1998; 339: 578–83. Besarab A, Kline Bolton W, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339: 584–90. Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 1995; 26: 41–6. Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int 1996; 50: 1694–9. Van Wyck DB, Cavallo G, Spinowitz BS, Adhikarla R, Gagnon S, Charytan C, Levin N. Safety and efficacy of iron sucrose in patients sensitive to iron dextran: North American clinical trial. Am J Kidney Dis 2000; 36: 88–97. Bastani B, Rahman S, Gellens M. Lack of reaction to ferric gluconate in hemodialysis patients with a history of severe reaction to iron dextran. ASAIO J 2002; 48: 404–6. Fishbane S. Safety in iron management. Am J Kidney Dis 2003; 41 (5 Suppl): 18–26. Means RT, Krantz SB. Progress in understanding the pathogenesis of the anemia of chronic disease. Blood 1992; 80: 1639–47.

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4 Cardiovascular disease ROBERT FOLEY

Introduction Chronic kidney disease has a dramatic effect on cardiac structure and function. Until recently, most observational studies were confined to dialysis patients, possibly because these are a captive population. Clearly, cardiovascular disease is a problem of epidemic size in end-stage renal disease (ESRD). More than half of all new dialysis patients have had a previous, overt episode of cardiovascular disease. This appears to be an international problem and registry studies from elsewhere do not suggest that respite is near at hand. Definitive trials in dialysis populations are few and far between, and have been historically disappointing. There has been a growing suspicion that intervening at ESRD may be too late. The last year produced yet another definitive trial that proved to be negative, the HEMO (haemodialysis) trial. This study, and a previous study in peritoneal dialysis patients (Adequacy of Peritoneal Dialysis in Mexico) 1, challenges the concept that an ever-increasing dialysis urea clearance target improves survival. Interventions that maintain residual renal function, even at the stage of dialysis dependency, may achieve more, as suggested by a provocative study by Li and colleagues using an angiotensin-converting enzyme (ACE) inhibitor in peritoneal dialysis patients. At least two smaller randomized trials showed mortality reductions (those of Lok et al., Cice et al. and Tepel et al.); while none of these studies were (simultaneously) large, multicentre trials with mortality as the primary outcome, the mere observation that dialysis mortality could be reduced in a trial setting was grounds for optimism. Importantly, interventions the efficacy of which has been proved in the general population to reduce cardiovascular disease are rarely used in patients with chronic kidney disease, often because these very patients were excluded from the initial studies. One promising, if imperfect, avenue of inquiry is to mine existing trial data for subgroups with chronic kidney disease; the study of Tonelli and colleagues is an example of this approach, applied to a statin. Another study (Holdaas et al.) used the more conventional approach of generating primary evidence specific to patients with renal disease, in this case using another statin in renal transplant patients. This study was negative for the primary outcome, but positive for some of the components making up this outcome, possibly because of inadequate power (even though it involved more than 2000 patients followed for more than 5 years). © Atlas Medical Publishing Ltd

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Last year has seen a profusion of studies examining the association between individual serological tests (often called ‘biomarkers’) and mortality in dialysis. The utility of single biomarkers is often questionable, especially in renal failure, where abnormalities of multiple metabolic pathways are so common. In particular, it is often difficult to separate the prognostic associations from intrinsic renal function, malnutrition, inflammation and previous cardiovascular disease, which are closely interrelated. Thus, the clinical utility of several of these markers is usually unknown, with the exception of cardiac muscle enzymes, which are among the best-studied and have clear clinical relevance in the diagnosis of myocardial infarction in dialysis patients. The study of McCullough and colleagues further illuminates this complex area with the use of cardiac biomarkers in the diagnosis of myocardial infarction in patients with varying degrees of renal impairment. In this chapter, I will first discuss my perspective on the HEMO study, then discuss a number of studies using individual therapeutic agents in patients with endstage renal failure (ESRF), before looking at cardiovascular outcomes in patients with chronic kidney disease.

Improving outcomes in end-stage renal disease

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Effect of dialysis dose and membrane ﬂux in maintenance hemodialysis Eknoyan G, Beck GJ, Cheung AK, et al; Hemodialysis (HEMO) Study Group. N Engl J Med 2002; 347: 2010–19

B A C K G R O U N D . This was a landmark study, using an open-label, randomized, controlled trial design. The intent of the study was to compare, simultaneously, mortality effects in haemodialysis patients of equilibrated Kt/V values of 1.05 versus 1.45 (approximately equivalent to urea reductions of 65 versus 75%) and low- versus high-ﬂux dialysis membranes, deﬁned as 2-microglobulin clearance less than 10 ml/min for low ﬂux and 2-microglobulin clearance greater than 20 ml/min with an ultraﬁltration coefﬁcient greater than 14 ml/min/mmHg for high ﬂux. Eligibility criteria included age 18–80 years, receipt of haemodialysis three times weekly for at least 3 months, residual urea clearance <1.5 ml/35 l of urea, serum albumin >26 g/l, and achievement of an equilibrated Kt/V >1.30 within 4.5 h during two or three consecutive dialysis sessions when target Kt/V was high. In practice, this meant that only 3% of patients in the study weighed more than 100 kg. A total of 2677 patients were screened, of whom 69% entered the trial, the ﬁrst and last patients entering between March 1995 and October 2000. All-cause mortality was the primary outcome, and follow-up was censored at transplantation. The sample size assumptions called for 900 patients to be randomized during the initial 1.5 years of the study, with all dropouts (from death, transplant or transfer to a non-participating dialysis unit) to be replaced until the last year of the trial. Conservatively, power was estimated at 84% to detect a 25% mortality reduction for each intervention.

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I N T E R P R E T A T I O N . The randomization process was successful with regard to the equality of known, pre-speciﬁed baseline characteristics. Thirty-ﬁve per cent had diabetes mellitus. It was notable, however, that approximately 56% were female, 63% were African–American, 80% had cardiac disease, and the average prior dialysis duration was approximately 3.7 years. The study was highly effective in terms of implementing interventions, in terms of targets of equilibrated Kt/V and dialysis ﬂux. Equilibrated Kt/V rose by 31.8%, from 1.16 in the low dose to 1.53 in the high-dose group. The increase in Kt/V appeared to be equally reﬂective of changes in the rate of urea clearance (a relative difference of 15.1%) and changes in dialysis duration (a relative difference of 15.3%). All-cause mortality was the primary outcome. The death rates, expressed as percentage mortality per year, were 16.6, 17.1, 17.1 and 16.2% in the low-dose, high-dose, low-ﬂux and high-ﬂux groups respectively, with all comparisons non-signiﬁcant from the standpoint of statistical and clinical signiﬁcance (Fig. 4.1). Similarly, no differences were found in terms of the main secondary outcomes: cardiac hospitalization or death, infectious hospitalization or death, a 15% drop, from baseline, in serum albumin drop or death, and non-access hospitalization. Several other analyses were performed, which were not considered main secondary outcomes, and two statistically signiﬁcant differences were found: a reduction in death from cardiac causes with high-ﬂux membranes, and a reduction in the combined outcome of ﬁrst hospitalization for cardiac causes or death from cardiac causes. Finally, interactions between the seven baseline characteristics of the study population, the two interventions and the primary study outcome were presented. Functionally, this was not too dissimilar to 14 subgroup analyses and should be viewed with a healthy degree of caution. Interactions were found between gender and dose, and between ﬂux and time on dialysis. Females had lower mortality rates with a high Kt/V target, whereas males had higher mortality. Those with follow-up greater than 3.7 years had lower mortality rates with the high-ﬂux dialysis membranes, whereas mortality comparisons were similar in those with shorter dialysis vintage.

Comment This was a very well-designed and superbly implemented trial. The proportion of African–American patients was much higher than expected, and patients had been on dialysis therapy for approximately 4 years. Consequently, it is likely that residual renal clearance was very low. The authors suggest that the high dose ‘most likely represents the maximal practical difference under conditions of thrice-weekly dialysis, as currently practiced in the United States’. While this may well be the case, the average treatment duration in the high-dose group was 219 min or 3.65 h which would not be considered dramatically long in most other countries. Not unexpectedly, there has been speculation that intervention at such a late stage and the failure to use much longer treatment durations may have accounted for some of the negative findings. The discussion in the paper suggests that the findings support current practice guidelines which recommend a single-pool Kt/V of 1.2. However, as this was a negative trial, this statement may not be wholly correct since no gold standard has yet to be established showing demonstrable superiority in the setting of a randomized trial. The study cannot rule out the unlikely possibility that an even lower Kt/V might

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be superior. It should be remembered that the original concept that Kt/V values lower than 1 were associated with bad outcomes was derived from a post hoc analysis of the National Cooperative Dialysis Study 2, which showed no differences in mortality with longer dialysis duration and lower blood urea nitrogen targets 3. Similarly, because a true gold standard has yet to be established, it remains possible that a much

Fig. 4.1 Survival curves for the treatment groups. Source: Eknoyan et al. (2002).

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higher threshold level of dialysis delivery may be needed to reduce mortality in longterm haemodialysis patients. How should we interpret the secondary analyses? A purist might suggest that a trial has one primary outcome, and one alone, and that secondary analyses should be discounted. The authors rightly point out that the secondary analyses should be interpreted with caution as multiple comparisons could very easily produce outcome differences simply by chance. The number of non-primary analyses was large, and difficult to track within the paper. Subgroup analyses can lead to specious conclusions. For example, one secondary outcome analysis showed that patients using high-flux membranes had lower cardiac mortality rates. Even if we ignore the fact that rating the cause of death is notoriously inaccurate in dialysis patients, it is worth remembering that total mortality rates were the same. Thus, finding lower cardiac death rates must imply higher rates of death from non-cardiac causes with high-flux membranes. In general, cause-specific mortality analyses are controversial, as death from a cause other than the index cause is usually analysed as a censoring event, not as a failure. Large, definitive randomized trials are few and far between in dialysis patients, and it is unlikely that studies to confirm each of the hypothesis-generating outcomes uncovered in the HEMO trial will be performed in the near future.

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Effect of ﬂuvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomized, placebo-controlled trial Holdaas H, Fellström B, Jardine AG, et al. on behalf of the Assessment of Lescol in Renal Transplantation (ALERT) Study Investigators. Lancet 2003; 361: 2024–31

B A C K G R O U N D . The intent of the study was to determine the effect of ﬂuvastatin on rates of major cardiac events in renal transplant patients. A ‘major cardiac event’ was deﬁned as the ﬁrst occurrence of any of the following: cardiac death, deﬁnite non-fatal myocardial infarction, probable non-fatal myocardial infarction, or coronary revascularization. Eligibility criteria were broad and included age between 30 and 75 years, renal transplantation for at least 6 months, cyclosporin use, total cholesterol between 4.0 and 7.0 mmol/l and non-occurrence of myocardial infarction within the preceding 6 months. The number of patients screened was not recorded, so that generalizability could not be accurately quantiﬁed. This being said, the patient proﬁles were not atypical for a European transplant population. The ﬁrst and last of the 2102 patients entered the trial between June 1996 and October 1997. The sample size assumed a 5-year duration of follow-up, a 25% placebo event rate, and a 25% effect size with active treatment, and was initially set at 1800, giving a power estimate of 83%. Another 250 patients were added when the actual placebo event rate was projected to be 22.5% over 5 years. In addition, a doubling of the ﬂuvastatin dose was introduced after 2 years, and two of the three planned interim analyses were dropped, suggesting that statistical power was an ongoing issue in this study.

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I N T E R P R E T A T I O N . The randomization process was successful with regard to equality of known, pre-speciﬁed baseline characteristics. The mean age was approximately 50 years, and about 12% had diabetic nephropathy. In addition to cyclosporin, which was used in all patients, approximately 81% used prednisolone, 65% azathioprine and 16% mycophenolate mofetil. Baseline total and LDL (low-density lipoprotein) cholesterol levels were 6.5 and 4.1 mmol/l, respectively. Fluvastatin reduced cholesterol levels by approximately 25%, equivalent to 1 mmol/l of LDL, an effect that was maintained throughout the follow-up interval. There was no statistically signiﬁcant difference in the primary outcome by assigned treatment (Fig. 4.2). However, rates of two of the components, cardiac death and deﬁnite myocardial infarction, were statistically signiﬁcantly lower, albeit at borderline levels of 0.031 and 0.051 respectively. The intervention was well tolerated and appeared to be safe. A post hoc analysis relating the

Fig. 4.2 Cumulative rates for primary composite end-points. Analyses by intention-to-treat. Source: Holdaas et al. (2003).

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primary outcome, as well as the individual components of the primary outcome, to the LDL cholesterol achieved (irrespective of randomized group) showed a signiﬁcant relationship, similar to that seen in adequately powered trials in the general population.

Comment This study appeared to be somewhat underpowered. P-values of 0.03 and 0.05 would not survive intact, with regard to null hypothesis rejection, if the number of analyses performed were taken into account. The study did show quite convincingly that fluvastatin was safe in transplant patients. The findings of this study will have to remain in the category ‘hypothesis-generating’; however, when the extreme cardiovascular risk is balanced against simplicity and safety, my approach would be to adopt the intervention, until definitive evidence becomes available.

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Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy: a prospective, placebocontrolled trial Cice G, Ferrara L, D’Andrea A, et al. J Am Coll Cardiol 2003; 41: 1438–44

B A C K G R O U N D . Dilated cardiomyopathy is a characteristic abnormality in dialysis patients, as is sympathetic overload. This placebo-controlled study of 114 dialysis patients with dilated cardiomyopathy evaluated the effect of carvedilol in addition to standard therapy. The primary outcome, change in left ventricular function on echocardiography, was found to be improved by carvedilol in an initial study 4. The present study extended the follow-up from 1 to 2 years. One hundred and thirty-two haemodialysis patients with dilated cardiomyopathy entered the initial study between February 1996 and December 1998. Sixty-eight per cent had prior ischaemic heart disease, and all had New York Heart Association (NYHA) class II to III, symptomatic of heart failure. Major exclusion criteria were NYHA class IV heart failure, bradycardia or heart block rate, prior ventricular tachycardia, hypotension, and other medical conditions where -blockers were clearly indicated or clearly contraindicated. I N T E R P R E T A T I O N . The study involved a provisional entry phase, during which all patients received carvedilol (3.125 mg twice a day) for 2 weeks in order to identify intolerant patients; 13.6% of all patients were carvedilol-intolerant. Tolerant patients were assigned placebo or carvedilol (1:1 randomization) in double-blind fashion. The dose of drug was doubled every 2 weeks, as tolerated, to a maximum of 25 mg twice a day. Echocardiography, which was performed at baseline and 1, 6 and 12 months after enrolment, showed that carvedilol improved echocardiographic morphology and function. In the present study, follow-up was extended by a further 12 months on the initial therapy. Two-year echocardiographic data showed smaller cavity diameters and higher ejection fractions in the active treatment group. Mortality rates were 51.7 vs 73.2% in the carvedilol and placebo groups, respectively (Fig. 4.3). Rates of cardiovascular death, hospital admissions, fatal myocardial infarctions, fatal strokes, and hospital admissions for worsening heart failure were also lowered by carvedilol.

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Fig. 4.3 Kaplan–Meier curves for all-cause mortality during the 24-month follow-up. Source: Cice et al. (2003).

Comment It is important to point out that this study used a run-in phase to identify patients who were intolerant of low-dose carvedilol. Many triallists frown on this type of design. With classic trial designs, in which randomization is performed without a run-in phase, these patients might be considered to have major drug-related side effects. The proportion of patients with major symptoms (13.6% at the initial dose of carvedilol) was considerable. One approach, using the intention-to-treat philosophy, is to handle these subjects as dropouts, who would ultimately develop each major event being studied. Finding a benefit under such conditions would be more persuasive evidence in favour of carvedilol. This study was designed primarily to look at echocardiographic changes. The proportion of patients that had to be screened was not described. Nevertheless, this was a provocative study, using an intervention with an attractive underlying hypothesis, and with considerable supportive controlled evidence in non-renal populations. As with most trials in dialysis populations, definitive hypothesis testing is awaited.

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The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure: a randomized, controlled trial Tepel M, van der Giet M, Statz M, Jankowski J, Zidek W. Circulation 2003; 107: 992–5

B A C K G R O U N D . Excessive oxidative stress, a characteristic feature of ESRD, is associated with higher mortality in haemodialysis patients. A previous trial showed that high-dose vitamin E reduced cardiovascular events in haemodialysis patients with symptomatic cardiac disease 5. The objective of this study was to determine whether acetylcysteine, a thiol-containing antioxidant given orally at a dose of 600 mg twice daily, reduces cardiovascular events in haemodialysis patients. The primary end-point of the study was a composite of fatal and non-fatal myocardial infarction, death from cardiovascular disease, coronary angioplasty, coronary bypass surgery, ischaemic stroke, peripheral vascular disease with amputation, or the need for angioplasty. The only eligibility requirements for the study were receipt of dialysis therapy for at least 3 months and absence of acetylcysteine allergy. The sample size calculation assumed a composite end-point incidence rate of 0.30 over 24 months in the control group, with a 40% reduction with acetylcysteine; a sample size of 126 gave a power value of 0.9 under these assumptions. One hundred and thirty-four patients entered the study, which ran between 1 October 1999 and 30 September 2001. The mean age was 62 years and the mean duration of dialysis therapy was 3 years. Diabetes mellitus, coronary artery disease and peripheral vascular disease were present in about one-third, one-ﬁfth and one-tenth of the subjects respectively. I N T E R P R E T A T I O N . A total of 51 primary end-points occurred over a median follow-up of 14 months, 33 in the control group, and 18 in the acetylcysteine group, a 40% relative risk reduction (P 0.03). No major side effects were observed with acetylcysteine; ﬁve patients (8%) experienced gastrointestinal discomfort. Haemodialysis patients were randomly assigned either to receive acetylcysteine (600 mg twice daily) or placebo (control group). The primary end-point was a composite variable consisting of cardiac events that included fatal and non-fatal myocardial infarction, cardiovascular disease death, the need for coronary angioplasty or coronary bypass surgery, ischaemic stroke, peripheral vascular disease with amputation, the need for angioplasty. As shown in Fig. 4.4, a relative risk reduction of 0.60 (95% conﬁdence interval [CI] 0.38–0.95), P 0.03 was observed.

Comment This was a very provocative study, and seems to partly confirm the previous SPACE (Secondary Prevention with Antioxidants of Cardiovascular Disease in End-stage Renal Disease) study with vitamin E. Antioxidants have generally been disappointing in controlled trials in non-renal populations at high cardiovascular risk. Ideally, large, confirmatory trials should be performed to confirm the effectiveness of this simple intervention.

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Fig. 4.4 Kaplan–Meier survival curves from primary end-points. Source: Tepel et al. (2003).

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Hemodialysis infection prevention with Polysporin ointment Lok CE, Stanley KE, Hux JE, Richardson R, Tobe SW, Conly J. J Am Soc Nephrol 2003; 14: 169–79

B A C K G R O U N D . There has been a growing realization that dialysis with catheters is associated with much higher cardiovascular morbidity and mortality. Most of this association appears to be driven by the intermediate outcome of bacteraemia/ septicaemia, a state of intense inﬂammatory activation. It would therefore be of interest if interventions to reduce infections could reduce cardiovascular mortality. The primary outcome of this 6-month randomized clinical trial was to determine whether a topical antibiotic ointment, Polysporin, would reduce the incidence of catheter-related infections, adjudicated in a blind fashion. Infection consisted of exit site infections, tunnel infections and bacteraemia. The only major inclusion criterion was a cuffed internal jugular dialysis line for haemodialysis. A sample size of 72 patients in each treatment group was required to detect a 50% difference between the treatment and placebo groups with 80% power, assuming a normal infection rate of 0.7 infections per patient per year, the rate observed in the two participating institutions in the year before the study. Secondary outcomes in this study included each individual component of the composite outcome and death.

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I N T E R P R E T A T I O N . The ﬁnal sample size was 169 patients. The median age of the study population was 66 years; 31% had underlying diabetic renal disease, 59% had coronary artery disease and the mean duration of dialysis therapy was 1.9 years. The comparative rates of infection (the primary study outcome) were 34% in the antibiotic group and 12% in the control group (P 0.0013). The incidence rates of bacteraemia per 1000 catheter days were 2.48 and 0.63 respectively (P 0.0004) and, as shown in Fig. 4.5, the numbers of deaths were 13 and 3 respectively (P 0.0041).

Comment This was a very well-performed study. It clearly needs replication in a larger multicentre setting. Death was a secondary outcome in this study, so that the provocative finding that a relatively simple intervention can reduce death rates in a dialysis setting requires confirmation. The findings also underscore the close ties between inflammation (albeit of the macro-inflammatory variety), cardiovascular disease and death and the huge cardiovascular risk associated with dialysis lines.

Fig. 4.5 Percentage of patients alive in each the two groups. Source: Lok et al. (2003).

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Effects of an angiotensin-converting enzyme inhibitor on residual renal function in patients receiving peritoneal dialysis; a randomized, controlled study Li PK, Chow KM, Wong TY, Leung CB, Szeto CC. Ann Intern Med 2003; 139: 105–12

B A C K G R O U N D . ACE inhibitors are a cornerstone of the management of established cardiac disease and also slow progression of chronic kidney disease. Loss of renal function is associated with dramatically heightened cardiovascular risk. Thus, interventions that maintain glomerular ﬁltration rate (GFR) should lower cardiovascular risk, even in those starting renal replacement therapy. The intent of this single-centre study from Hong Kong was to determine the impact of an ACE inhibitor, ramipril, on residual renal function in peritoneal dialysis patients. Residual GFR was the average of 24-hour urinary urea and creatinine clearances. Secondary outcomes included changes in urinary protein excretion, death, hospitalization and cardiovascular events. Major eligibility criteria included residual GFR >2 ml/min/1.73 m2, blood pressure greater than 120/70, and absence of ACE inhibitor use within the preceding 6 months, congestive heart failure, recent myocardial infarction, valvular heart disease, malignant hypertension and renal artery stenosis. I N T E R P R E T A T I O N . Two hundred and seventeen patients were screened and the ﬁnal sample size was 60 (28%). It was anticipated that the sample size of 60 would achieve an 83% power to detect a difference of GFR decline of 0.15 ml/min/1.73 m2 per month, a 50% reduction. After randomization, the groups were reasonably well matched on measured characteristics. The mean age was approximately 58 years, body mass index approximately 23 kg/m2, and diabetes mellitus was the principal cause of kidney failure. Over 12 months, residual GFR declined by 2.07 ml/min/1.73 m2 in the ramipril group, compared with 3.00 ml/min/1.73 m2 in the control group (Fig. 4.6), a statistically signiﬁcant difference in the primary outcome measure. Approximately twice as many control patients developed complete anuria.

Comment This was a small study with an intuitively obvious hypothesis. Because the sample was small, involving a single centre, generalizability remains in doubt, and even though measured characteristics were reasonably similar in both groups, a more important issue that cannot be addressed is differences in major unmeasured characteristics. In addition, the measure of GFR was based on creatinine and urea clearance. The study would be more credible with a definitive measurement technique, such as isotope GFR. Also, hard clinical outcomes, such as death and cardiovascular events, need evaluation in the setting of a much larger trial. Nevertheless, the study provides yet another reason to consider ACE inhibitors strongly in dialysis patients without hypotension.

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Fig. 4.6 Unadjusted mean GFR at baseline and follow-up in the ramipril and control groups. Source: Li et al. (2003).

Improving cardiovascular outcomes before end-stage renal disease The studies discussed so far have all involved interventions aiming to reduce cardiovascular mortality and morbidity in patients who already have established ESRF. However, it is well established that the excess of cardiovascular disease begins before patients develop ESRF, beginning while they have early chronic kidney disease. The remaining studies will all address these patients; they will discuss the level of cardiovascular risk that chronic kidney disease imparts, and the diagnosis and prevention of cardiovascular events.

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Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community Manjunath G, Tighiouart H, Ibrahim H, et al. J Am Coll Cardiol 2003; 41: 47–55

B A C K G R O U N D . Several recent studies have shown that the presence of chronic kidney disease is associated with mortality rates higher than expected, both in the setting of

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controlled trials and among those with symptomatic congestive heart failure and myocardial infarction. Other studies, most notably the third National Health and Nutrition Examination Survey (NHANES III), have shown cross-sectional associations between declining kidney function and cardiovascular disease. An obvious strength of NHANES is the fact that it represents a random sample of the general population of the USA; an obvious weakness is its inability to demonstrate the temporal sequence of the observed association. Thus, it is impossible to know whether kidney disease came before cardiovascular disease or vice versa. This study examined, prospectively, potential associations between the level of kidney function and atherosclerotic cardiovascular disease in the Atherosclerosis Risk in Communities (ARIC) study, using estimated GFR as a measure of kidney function. ARIC was a community-based study of coronary heart disease and stroke in 15 792 individual persons, aged 45 to 64 years. GFR was estimated using the Modiﬁcation of Diet in Renal Disease (MDRD) formula, based on serum creatinine, age, ethnicity and gender. The analysis included only subjects with estimated GFR between 15 and 150 ml/min/1.73 m2. The mean GFR and range at baseline was 92 and 16–149 ml/min/1.73 m2 respectively. Of the population, 2.8% had estimated GFR between 15 and 59 ml/min/1.73 m2, while almost half (49.9%) had GFR estimates between 60 and 89 ml/min/1.73 m2. The mean age was 54.2 years, 45% were male, 26% were African–Americans and 11.6% had diabetes mellitus. Five per cent had coronary heart disease and 4.8% had baseline cerebrovascular disease. I N T E R P R E T A T I O N . The average duration of follow-up in this study was 6.2 years. Five per cent of the cohort died, with a proportion of 22.4% dying from atherosclerotic cardiovascular disease; 6.3% experienced a cardiovascular event, with myocardial infarction approximately four times more common than stroke. After adjusting for traditional cardiovascular risk factors, rates of atherosclerotic cardiovascular disease were higher in those with lower estimated GFR levels. Overall, a decrement of 10 ml/ ml/min/1.73 m2 in estimated GFR was associated with a 5% increase in adjusted risk (Fig. 4.7).

Comment This study is convincing evidence that renal dysfunction is an independent risk factor for atherosclerotic heart disease in middle-aged subjects. Clearly, cause-and-effect relationships cannot be established. It is equally plausible that renal disease could cause cardiovascular disease, and vice versa, even within a single individual, a typical vicious circle (or lethal synergy) scenario. In a sense, knowing which came first, cardiovascular or renal disease, is almost a moot point. The most practical information may be that moderate degrees of renal dysfunction identify a group at high cardiovascular risk. Most population guidelines necessitate a more aggressive approach in higher risk groups where effective treatments are available. This study was carefully performed. However, some questions remain. It is unknown whether the patients identified had progressive kidney dysfunction. It is possible that lower GFR can be present without overt metabolic, immunological or haemodynamic attack. Congenital low nephron mass is an example of such a state. Urinary albumin excretion rates were not available, which might have clarified this

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issue. Similarly, GFR was not measured formally with a highly accurate technique, such as the relatively impractical technique of inulin clearance, or other techniques, such as isotope GFR. Intuitively, anthropometric estimates reflect both GFR and nutritional status. These imperfections, however, are typical, even in the best observational studies. Studies that jointly inform cardiologists and nephrologists, like this one, must be a cause of optimism.

Fig. 4.7 (a) Kaplan–Meier survival analysis for atherosclerotic cardiovascular disease stratiﬁed by level of GFR. (b) Kaplan–Meier survival analysis for all-cause mortality stratiﬁed by level of GFR. Source: Manjunath et al. (2003).

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Performance of multiple cardiac biomarkers measured in the emergency department in patients with chronic kidney disease and chest pain McCullough PA, Nowak RM, Foreback C, et al. Acad Emerg Med 2002; 9: 1389–96

B A C K G R O U N D . Diagnosis of myocardial infarction is difﬁcult in chronic kidney disease, in part because electrocardiographic abnormalities are so prevalent. The situation is compounded in haemodialysis patients by electrolyte ﬂux. Several studies have found false-positive elevations in cardiac troponin T, creatine kinase (CK), myoglobin, and CK-MB in patients with chronic kidney disease. The objective of this study was to evaluate several markers of myocyte injury, tested at the bedside in patients with a broad spectrum of renal dysfunction who were being evaluated for chest pain. The patient population was 1024 consecutive patients with possible acute myocardial infarction at a single centre in the USA in 1999. Patients entered the study if the emergency physician suspected possible myocardial infarction. Patients with advanced renal disease, including several dialysis patients, were approached. Patients receiving thrombolysis or emergency angioplasty were excluded. GFR was estimated with the MDRD formula. Rapid, point-of-care testing was performed to evaluate CK-MB, myoglobin and cardiac troponin I (cTnI). The gold standard deﬁnition of acute myocardial infarction included at least one central laboratory (as opposed to point-of-care CK-MB) value above 9 ng/ml plus at least one of the following items: characteristic chest pain; ischaemic electrocardiogram ﬁndings in temporal association with the CK-MB changes. Electrocardiograms were interpreted blindly by a cardiologist. I N T E R P R E T A T I O N . The quartiles of estimated GFR in the 757 patients without ESRF were 99.4, 72.7 and 47.0 ml/min. Another 51 patients had ESRD and were receiving haemodialysis. Nearly all the patients were admitted for observation. Myoglobin levels and CK-MB levels were both negatively correlated with estimated GFR levels. In contrast, cTnI levels were not associated with GFR levels. Using multiple receiver operating characteristic curve testing, with an adjudicated diagnosis of myocardial infarction as the gold standard, TnI showed a high degree of accuracy, with high sensitivity and speciﬁcity across all levels of renal function, including dialysis patients.

Comment This study was not primarily designed to address the issue of myocardial infarction diagnosis in chronic kidney disease. The prospective design, a priori definitions, blinded interpretation of subjective tests, and scope and range of the study sample make this a very useful addition that has clear clinical relevance.

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Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufﬁciency Tonelli M, Moyé L, Sacks FM, Kiberd B, Curhan G, for the Cholesterol and Recurrent Events (CARE) Trial Investigators. Ann Intern Med 2003; 138: 93–104

B A C K G R O U N D . This was a subgroup analysis of a well-known trial, including patients with mild chronic kidney disease. The parent study was a double-blind, placebocontrolled trial in men and post-menopausal women with recent myocardial infarction and total cholesterol levels less than 6.21 mmol/l (<240 mg/dl). The major exclusion criteria were dipstick proteinuria of 2 or more, and creatinine greater than 1.5 times the upper limit of normal at the central study laboratory. The MDRD Study formula was used to estimate GFRs. The present study selected patients with estimated GFR less than 75 ml/min/1.73 m2. Intervention consisted of 40 mg of pravastatin per day, or placebo. The primary end-point was a composite of death from coronary disease or a symptomatic non-fatal myocardial infarction. Forty-one per cent of the original cohort had mild chronic renal insufﬁciency, yielding a ﬁnal sample size of 1711. Table 4.1 Effect of pravastatin use on incidence of cardiovascular events in participants with chronic renal insufﬁciency, as deﬁned by creatinine clearance of 75 ml/min or less Event

Participants Participants in the in the placebo pravastatin group group† n (%)

Adjusted hazard ratio with pravastatin (95% CI)

P-value‡

Death from CHD or non-fatal MI§ Major coronary event Total mortality Fatal MI or conﬁrmed non-fatal MI CABG or PTCA Unstable angina Stroke

126 (14.5)

89 (10.5)

0.72 (0.55–0.95)

0.02

234 (27.0) 111 (12.8) 90 (10.4)

171 (20.3) 86 (10.2) 65 (7.7)

0.72 (0.59–0.88) 0.81 (0.61–1.08) 0.73 (0.52)–1.01)

0.001 0.14 0.06

153 (17.6) 142 (16.4) 46 (5.3)

105 (12.4) 133 (15.8) 29 (3.4)

0.65 (0.50–0.83) 0.93 (0.73–1.18) 0.62 (0.39–1.00)

0.001 >0.2 0.051

* All models were based on complete data for 1711 participants (867 in the placebo group and 844 in the pravastatin group). Hazard ratios and P-values were derived from Cox proportional hazards models. Patient-speciﬁc data were used to compute P-values and conﬁdence intervals. CABG, coronary artery bypass grafting; CHD, coronary heart disease; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty. † Percentages are cumulative incidents. ‡ Adjusted for age; sex; history of hypertension; smoking at baseline; diabetes mellitus; previous congestive heart failure; use of ACE inhibitors, calcium-channel blockers, -adrenergic blockers, and aspirin; proteinuria; systolic and diastolic blood pressure; baseline high-density lipoprotein and LDL cholesterol levels; baseline triglyceride levels; serum albumin levels; body surface area; and pravastatin use. § This combined variable was the speciﬁed primary end-point. Source: Tonelli et al. (2003).

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I N T E R P R E T A T I O N . Pravastatin reduced the primary end-point by 28% over nearly 5 years of follow-up (Table 4.1). In addition, major coronary events were reduced by 28% and coronary revascularization by 35%, although mortality rates were not statistically reduced. Tests for interaction suggested that beneﬁts were independent of the severity of renal insufﬁciency. Side effects were rare, similar in frequency to those in subjects with normal kidney function.

Comment This study can be criticized because it examines a subgroup after the fact. Yet again, purists can argue that this study merely generates another hypothesis that needs to be proved. It could also be argued that the patient sample would be atypical for most nephrology practices. A counter-argument, which is in vogue currently, is that this is exactly the type of patient that nephrologists should be seeing. Ideally, it would be useful to carry out definitive trials in patients with more advanced renal disease, in terms of both renal function and protein excretion rates. While this may be the case, few controlled trials in nephrology have enrolled such a large sample. The safety of the intervention was comforting, mirroring many other statin trials. While definitive, renal-specific trials are awaited, studies like this suggest that a proactive approach to cholesterol management may be beneficial.

Conclusion There is increasing evidence that cardiovascular disease begins early in chronic renal failure, and therefore that renal patients are at high risk of early morbidity and mortality. Fortunately, evidence (even if not gold standard evidence) is also accumulating that these patients, and those already on dialysis, respond as well to interventions to reduce their risk, much as in the general population. Whether changes to dialysis itself can influence the cardiovascular risks remains unclear.

References 1. Paniagua R, Amato D, Vonesh E, Correa-Rotter R, Ramos A, Moran J, Mujais S; Mexican

Nephrology Collaborative Study Group. Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol 2002; 13: 1307–20. 2. Gotch FA, Sargent JA. A mechanistic analysis of the National Cooperative Dialysis Study (NCDS). Kidney Int 1985; 28: 526–34.

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3. Lowrie EG, Laird NM, Parker TF, Sargent JA. Effect of the hemodialysis prescription of

patient morbidity: report from the National Cooperative Dialysis Study. N Engl J Med 1981; 305: 1176–81 4. Cice G, Ferrara L, Di Benedetto A, Russo PE, Marinelli G, Pavese F, Iacono A. Dilated cardiomyopathy in dialysis patients—beneficial effects of carvedilol: a double-blind, placebo-controlled trial. J Am Coll Cardiol 2001; 37: 407–11. 5. Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, Knecht A, Weissgarten Y, Brunner D, Fainaru M, Green MS. Secondary Prevention with Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE): randomised placebo-controlled trial. Lancet 2000; 356: 1213–18.

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Part II Acute renal failure

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5 Prevention of acute radiocontrast nephropathy NORBERT LAMEIRE

Introduction The definition of acute renal failure (ARF), especially ARF induced by radiocontrast media, is highly variable. In most studies the change in serum creatinine has been followed; this parameter is very sensitive to changes in urine flow rate and, more importantly, is influenced not only by changes in glomerular filtration rate but also by changes in the tubular secretion of creatinine. Many different definitions of radiocontrast nephropathy (RCN) appear in the literature, but it is commonly defined as an acute decline in renal function from 24 to 48 hours after the intravascular administration of contrast material in the absence of other causes. A definition such as a rise in serum creatinine greater than 25 or 50% above the baseline value is often used. Serum creatinine generally peaks at 3–5 days and returns to the baseline value by 7–10 days 1. The acute renal failure is non-oliguric in most cases. Urinalysis often reveals granular casts, tubular epithelial cells and minimal proteinuria, but in many cases may be entirely bland. Most, but not all, patients exhibit low fractional excretion of sodium. The diagnosis of RCN is frequently obvious if the typical course of events follows the administration of contrast. However, other causes of acute renal failure, including atheromatous embolic disease, ischaemia and other nephrotoxins, should always be considered. Most patients in whom RCN develops have risk factors; 90% of such nephropathy occurs in patients with pre-existing renal failure 2. The risk of RCN will therefore increase over the coming decades. Other risk factors include diabetes mellitus, volume depletion, congestive heart failure, the dose of the contrast agent and the concurrent use of other nephrotoxic drugs 1,2. RCN is the third leading cause of ARF in patients admitted to hospital 3. Despite its overall benign prognosis, in selected subgroups of patients, such as those with preexisting renal insufficiency or diabetes mellitus, up to 7% require transient dialysis or progress to end-stage renal disease. The occurrence of RCN has also been associated with increased mortality both in hospital and in the long term, with extended hospital admission times and increased healthcare costs 4. The incidence and prognostic implications of ARF are not clearly defined in patients undergoing percutaneous coronary intervention. Although ARF in these patients is © Atlas Medical Publishing Ltd

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multifactorial, a recent analysis of the Mayo Clinic Percutaneous Coronary Intervention Registry revealed that the risk of ARF was higher among diabetic than nondiabetic patients, whereas among those with a baseline creatinine concentration greater than 2.0 mg/dl all had a significant risk of ARF. In multivariate analysis, ARF was associated with baseline serum creatinine, acute myocardial infarction, shock, and the volume of contrast medium administered. Twenty-two per cent of patients with ARF died during the index hospitalization compared with only 1.4% of patients without ARF and, after adjustment, ARF remained strongly associated with death 5. For at-risk patients, clinicians must use their judgement to determine if imaging modalities that do not involve contrast media are an acceptable alternative to contrast studies. In many cases, however, such alternatives do not exist. Moreover, RCN occurs in patients without obvious risk factors. Thus, strategies for reducing the incidence of RCN include not just risk factor identification but also the modification of these risk factors, such as choosing contrast media less likely to cause RCN and the administration of therapeutic agents that further reduce the risk of RCN.

Pathogenesis of radiocontrast nephropathy The pathogenesis of the acute fall in glomerular filtration rate is due to a combination of transient renal vasoconstriction and the direct nephrotoxic effects of the contrast agent 1. In the early 1990s, the role of outer medullary hypoxia in the pathogenesis of both ischaemic and nephrotoxic acute renal failure including contrast mediainduced acute nephropathy, was defined. 6. Two important vasoconstrictors play a role in the renal vasoconstriction induced by radiocontrast media: adenosine and endothelin 1. In animals, significant increases in both plasma and urinary endothelin levels have been observed during and after intravenous radiocontrast administration. Furthermore, endothelin receptor antagonists have been found to prevent renal vasoconstriction in animal models of radiocontrast nephrotoxicity. Adenosine has been shown to reduce renal blood flow and glomerular perfusion pressure by means of A1 receptor-mediated renal afferent arteriolar vasoconstriction and A2 receptormediated efferent arteriolar vasodilatation. The administration of contrast in human subjects is known to be associated with the production of endogenous intrarenal adenosine, and adenosine antagonists like theophylline have been investigated as a means of reducing the risk of RCN 7–9. Figure 5.1 summarizes the pathogenesis of contrast media-induced nephropathy 10. Studies in humans and animals have also indicated that reactive oxygen species contribute to radiocontrast-induced nephrotoxicity 11. Several animal experiments have shown that RCN is accompanied by the increased production of reactive oxygen species and their inhibition by allopurinol, or that the removal of reactive oxygen species by superoxide dismutase attenuated the radiocontrast-induced decline in glomerular filtration rate. Several approaches to the prevention of nephropathy induced by contrast medium have been reported, of which vigorous hydration may be the most important 12,13.

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Fig. 5.1 Pathogenesis of contrast media-induced nephropathy. ATP, adenosine triphosphate; GFR, glomerular filtration rate. Source: Erley (2001) 10.

The most quoted paper on the prevention of contrast nephropathy has been one by Solomon et al. 14. In patients with chronic renal insufficiency who were undergoing cardiac angiography, hydration with half-normal saline (0.45%) administered at 75 ml/hour, beginning 12 hours before and ending 12 hours after the procedure, provided better protection against acute decreases in renal function induced by radiocontrast agents than does hydration with 0.45% saline plus mannitol or furosemide 1. Oral protocols require ingestion of 1000 ml of water during the 10 hours prior to the procedure, followed by intravenous half-normal saline at 300 ml/hour for 30–60 minutes and continued for a total of 6 hours after the procedure. Large clinical studies and meta-analyses have previously indicated that the use of low-osmolar contrast medium substantially reduces the risk of nephropathy in highrisk patients compared with the use of high-osmolar contrast medium 15–17 (see later). However, a meta-analysis that pooled data from 31 different trials concluded that a statistically significant benefit of low-osmolar contrast agents in terms of renal function could be shown only among patients with pre-existing renal dysfunction in whom the contrast material was administered intra-arterially 18. In contrast, no benefit was found among patients with normal renal function (with or without diabetes) or among those in whom the contrast material was administered intravenously. Some medications, such as diuretics, mannitol, dopamine, atrial natriuretic peptide, calcium channel blockers 19, endothelin receptor antagonists, theophylline,

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fenoldopam and prostaglandin, have been tried without major success. When these medications were added to a protocol of adequate hydration, no additional benefit of these drugs could be demonstrated. Recently the role of acetylcysteine has become prominent in the prevention of RCN. The first prospective study was performed in 83 patients with chronic renal insufficiency (serum creatinine concentration 2.4 1.3 mg/dl) who were undergoing computed tomography with a non-ionic, low-osmolality contrast agent 20. Patients were randomly assigned either to receive acetylcysteine (600 mg orally twice daily) and 0.45% saline intravenously, before and after administration of the contrast agent, or to receive placebo and saline. An increase of at least 0.5 mg/dl in the serum creatinine concentration 48 hours after administration of the contrast agent was observed in only one of the 41 patients in the acetylcysteine group (2%) and in nine of the 42 patients in the control group (21%). In the acetylcysteine group, the mean serum creatinine concentration decreased significantly from 2.5 1.3 to 2.1 1.3 mg/dl 48 hours after the administration of the contrast medium, whereas in the control group the mean serum creatinine concentration increased non-significantly from 2.4 1.3 to 2.6 1.5 mg/dl (P 0.001 for the comparison between groups). A number of other studies in recent years have shown the renoprotective effects of acetylcysteine in contrast nephropathy, but others were not able to confirm these results (see Alonso et al. and Birck et al., reviewed below).

Hydration protocols

✍

Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty Mueller C, Buerkle G, Buettner HJ, et al. Arch Intern Med 2002; 162: 329–36

B A C K G R O U N D . Despite the fact that many agents have been suggested for the prevention of contrast media-associated nephropathy, including hydration, furosemide, mannitol, dopamine hydrochloride, aminophylline, atrial natriuretic peptide, acetylcysteine, alprostadil and captopril, only hydration with hypotonic or isotonic sodium chloride is uniformly accepted and used in clinical practice. The optimal infusion for hydration (isotonic or hypotonic), however, has not been evaluated. Most authorities recommend hydration with half-normal isotonic sodium chloride 12 hours before and after the administration of radiocontrast 1,14,21. The choice of half-isotonic saline was based upon the desire to produce both volume expansion and a large volume of diluted urine. Volume expansion would reset the renal vasoactive tone towards a renal vasodilatory state; the concomitant water diuresis would dilute the concentration of the contrast medium in the urine 1. This was a prospective, randomized, controlled, open-label study in which patients scheduled for elective or emergency coronary angioplasty were randomly assigned to

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receive isotonic (0.9% saline) or half-isotonic (0.45% sodium chloride plus 5% glucose) hydration, beginning on the morning of the procedure for elective interventions and immediately before emergency interventions. An increase in serum creatinine of at least 0.5 mg/dl (44 mol/l) within 48 hours was defined as contrast media-associated nephrotoxicity. A total of 1620 patients were assigned to receive isotonic (n 809) or half-isotonic (n 811) hydration. Primary end-point analysis was possible in 1383 patients. Contrast media-associated nephropathy was significantly reduced with isotonic (0.7%; 95% confidence interval [CI] 0.1%–1.4%) versus half-isotonic (2.0%; 95% CI 1.0%–3.1%) hydration (P 0.04). Three predefined subgroups benefited in particular from isotonic hydration: women, persons with diabetes, and patients receiving 250 ml or more of contrast. The incidence of cardiac (isotonic 5.3% versus half-isotonic 6.4%; P 0.59) and peripheral vascular (isotonic 1.6% versus half-isotonic 1.5%, P 0.93) complications was similar between the two hydration groups. I N T E R P R E T A T I O N . Isotonic hydration is superior to half-isotonic hydration in the prevention of contrast media-associated nephropathy in all groups, but especially those with diabetes and those receiving large contrast loads.

Comment The key finding of this study was that the incidence of contrast media-associated nephropathy was significantly reduced with isotonic hydration. This is the largest trial ever performed in the field of the prevention of acute radiocontrast-induced nephropathy. Sodium load seems to be crucial for the preventive effect of hydration. More potent intravascular volume expansion and inhibition of the renin–angiotensin pathway may be achieved by higher sodium concentration with isotonic sodium

Fig. 5.2 Incidence of contrast media-associated nephropathy, mortality, and peripheral vascular complication (vascular). Source: Mueller et al. (2002).

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chloride solution. Some caution should, however, be exercised in the interpretation of this study. First, all patients had only mild chronic renal failure and it is therefore difficult to extrapolate the beneficial effects to patients with more severe pre-existing chronic kidney disease. Secondly, all patients were exposed to low-osmolarity nonionic radiocontrast media, which differ in various aspects from high-osmolarity ionic agents.

Selection of the contrast media Many studies have indicated that the use of low-osmolar contrast medium substantially reduces the risk of nephropathy in high-risk patients compared with the use of high-osmolar contrast medium 15–18,21–26. Third-generation non-ionic contrast agents reduce osmolality further by creating a dimer, linking two molecules of contrast agent together through a common sidechain and thereby increasing the size of the molecule in solution. Iodixanol is the first dimeric contrast agent in this class and is iso-osmolar. Until the publication of the study that will be discussed, a definite benefit of this structure over that of non-ionic monomers, in terms of either overall toxicity or nephrotoxicity, had yet to be shown, except in the reduction of pain when iodixanol is injected into small-calibre arteries for peripheral arteriography. One disadvantage of the dimeric structure, however, is a substantial increase in viscosity that renders the contrast material more difficult to inject with the use of small arteriographic catheters 23.

Iso-osmolar contrast media

✍

Nephrotoxic effects in high-risk patients undergoing angiography Aspelin P, Aubry P, Fransson S-G, Strasser R, Willenbrock R, Berg KJ, for the NEPHRIC Study Investigators. N Engl J Med 2003; 348: 491–9

B A C K G R O U N D . Iodixanol, a non-ionic, dimeric contrast medium, is iso-osmolar to blood at all concentrations, and its degree of toxicity is lower than that of low-osmolar contrast media. Two small studies previously found no differences in renal toxicity between iodixanol and low-osmolar contrast media used in angiography in patients without diabetes who had renal failure, and one study had shown a reduced incidence of nephropathy with iodixanol in patients with renal impairment (one-third of whom had diabetes) 26. This study was a randomized, double-blind, prospective, multicentre study comparing the nephrotoxic effects of an iso-osmolar, dimeric, non-ionic contrast medium, iodixanol, with those of a low-osmolar, non-ionic, monomeric contrast medium, iohexol. The study involved 129 patients with diabetes with serum creatinine concentrations of 1.5–3.5 mg/dl who underwent coronary or aortofemoral angiography. The primary end-point was the peak increase from baseline in the creatinine concentration during the 3 days after angiography.

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Other end-points were an increase in the creatinine concentration of 0.5 mg/dl or more, an increase of 1.0 mg/dl or more, and a change in the creatinine concentration from day 0 to day 7. The results showed that the creatinine concentration increased significantly less in patients who received iodixanol. From day 0 to day 3, the mean peak increase in creatinine was 0.13 mg/dl in the iodixanol group and 0.55 mg/dl in the iohexol group (P 0.001). Two of the 64 patients in the iodixanol group (3%) had an increase in the creatinine concentration of 0.5 mg/dl or more, compared with 17 of the 65 patients in the iohexol group (26%) (P 0.002). No patient receiving iodixanol had an increase of 1.0 mg/dl or more, but 10 patients in the iohexol group (15%) did. The mean change in the creatinine concentration from day 0 to day 7 was 0.07 mg/dl in the iodixanol group and 0.24 mg/dl in the iohexol group (P 0.003). I N T E R P R E T A T I O N . Nephropathy induced by contrast medium may be less likely to develop in high-risk, diabetic patients when iodixanol, an isotonic agent, is used rather than a low-osmolar, non-ionic contrast medium.

Comment The results of this study are very encouraging and the authors have tried as much as possible to eliminate the many confounding factors that are often associated with the occurrence of acute radiocontrast nephropathy. However, the criterion used in the study to define acute renal dysfunction (the peak increase in the patient’s serum creatinine concentration during the first 3 days after the procedure) is similar to but somewhat more stringent than the criterion for acute renal dysfunction used by most other authors (a 50% increase in the serum creatinine concentration or an absolute increase of 1 mg/dl [88.4 µmol/litre]).

Fig. 5.3 Differences in nephrotoxicity between iodixanol and iohexol. The bars show the number of patients with a maximal increase in the serum creatinine concentration between day 0 and day 3 of at least 0.5 mg per decilitre and at least 1.0 mg per decilitre, which are the two most common increments used to define nephropathy. Source: Aspelin et al. (2003).

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Gadolinium Gadolinium-based contrast formulations are non-iodinated contrast agents that are predominately infused intravenously during vascular imaging with magnetic resonance angiography (MRA). Intravenous gadolinium-based contrast medium is safe and well-tolerated, with no nephrotoxicity when given within recommended dosages. Prospective studies have evaluated the safety of gadolinium but have been criticized because of relatively small sample sizes. Patients in several of these studies received a much lower dose of gadolinium (0.1 mmol/kg) than is commonly infused during routine clinical MRA. Two recent reports of renal failure after intra-arterial infusion of gadolinium have led to new questions regarding its clinical safety.

✍

Safety of gadolinium contrast angiography in patients with chronic renal insufficiency Sam AD II, Morasch MD, Collins J, Song G, Chen R, Pereles FS. J Vasc Surg 2003; 38: 313–18

B A C K G R O U N D . In an attempt to identify the incidence of gadolinium-induced nephropathy and to identify the risk factors that may predispose to this complication, this study is relevant to real clinical practice. In a single-centre retrospective study from December 1999 to January 2001, 218 inpatients underwent MRA and 42 inpatients underwent conventional digital subtraction angiography, with gadolinium as the sole contrast agent. Patient comorbid conditions, indications for vascular imaging, contrast dose, urine output, baseline and post-procedure serum creatinine concentration, and outcome were recorded for all patients in whom gadolinium-induced renal failure developed. Of 260 patients who received gadolinium-based contrast agents, at a dose of 0.25 mmol/kg or more, 195 (75%) had pre-test baseline chronic renal insufficiency. In seven of 195 patients (3.5%) acute renal failure developed after gadolinium-based contrast medium administration, for MRA (n 153) in three patients (1.9%) and digital subtraction angiography (n 42) in four patients (9.5%). Average baseline creatinine clearance in the 195 patients with chronic renal insufficiency was 38.2 1.6 ml/min per 1.73 m2, and in the seven patients in whom acute renal failure developed it was 32.5 7.8 ml/min per 1.73 m2 (P 0.33). Acute renal failure did not develop in any of 65 patients with normal baseline clearance. I N T E R P R E T A T I O N . From this study it is clear that, despite reports of negligible nephrotoxicity, gadolinium-based contrast agents can, rarely, cause acute renal failure in patients with underlying chronic renal insufficiency. Estimation of creatinine clearance alone does not enable prediction of which patients are likely to have acute renal failure. Patients at high risk should be identified and prophylactic measures should be taken to reduce the risk of nephrotoxicity when they have to undergo a gadolinium-based radiological examination.

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Comment This is the first study on a large number of patients who were challenged with gadolinium. Because MRA is increasingly supplanting angiography for pre-operative vascular evaluation and many of these patients also suffer from chronic kidney disease with or without diabetes, this study should be kept in mind. From the study it also appears that the nephrotoxicity of gadolinium is dose-dependent, which is not surprising since its elimination is by glomerular filtration and the plasma half-life has been reported to increase in relation to the degree of renal insufficiency. The half-life increases to 30 hours in patients with renal failure, yet there is no toxic degeneration of the gadolinium chelate. Doses greater than 0.4 mmol/kg should not be used, but in this study nephrotoxicity was observed already with a dose of 0.27 mmol/kg. The drawbacks of this study are its retrospective nature and, more importantly, the lack of a control group. Although gadolinium-based contrast agents are certainly safer than iodinated agents in patients with pre-existing chronic kidney disease, a prospective study is needed to better define the true incidence of nephrotoxicity and the major risk factors associated with it.

Drugs used in the prevention of radiocontrast nephropathy Fenoldopam Fenoldopam mesylate is a specific dopamine-1 receptor agonist that produces systemic, peripheral and renal arterial vasodilatation. Fenoldopam has been shown to increase renal plasma flow in patients with and without chronic renal insufficiency and to prevent the reduction in glomerular filtration rate that occurs in dogs after contrast administration 27. In humans, fenoldopam preserves or increases renal plasma flow after iodinated contrast, which is otherwise markedly reduced. Single and multicentre registry (retrospective) experiences with this agent as a prophylactic measure to reduce contrast-induced nephropathy have been favourable. Recently there has been another prospective, placebo-controlled, double-blind, multicentre randomized trial with fenoldopam in which serial serum creatinine levels were measured at baseline and there was a follow-up of up to 30 days (see Stone et al., reviewed below).

✍

Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial Stone GW, McCullough PA, Tumlin JA, et al. JAMA 2003; 290: 2284–91

B A C K G R O U N D . Serial serum creatinine levels were measured at baseline and 1, 24, 48 and 72–96 hours after study drug administration and in a 30-day clinical

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follow-up. Between March 2001 and July 2002, 315 patients with a creatinine clearance of less than 60 ml/min at 28 centres in the US were randomized to receive fenoldopam mesylate (n 157) or placebo (n 158). Patients were hydrated and randomized to receive intravenous fenoldopam (0.05 g/kg per minute titrated to 0.10 g/kg per minute) versus matching placebo, starting 1 hour prior to angiography and continuing for 12 hours. Contrast-induced nephropathy was defined as an increase of 25% or more in serum creatinine level within 96 hours after the procedure. Mean SD patient age was 70 11 years, and 49% had diabetes mellitus. The baseline creatinine clearance was 29.0 1 ml/minute (range 7.5–56.8 ml/minute) and 157 108 ml of contrast was administered during the procedures. The primary end-point of contrast-induced nephropathy occurred in 33.6% of patients assigned to receive fenoldopam versus 30.1% assigned to receive placebo (relative risk 1.11; 95% CI 0.79–1.57). There were no significant differences in the 30-day rates of death (2.0 versus 3.8%; P 0.50), dialysis (2.6% versus 1.9%) or rehospitalization (17.6 and 19.9%) in patients randomized to fenoldopam and placebo respectively (Table 5.1).

Table 5.1 Primary and secondary end points Fenoldopam mesylate

Placebo

P value

137 46 (33.6) 20 (20.4)

146 44 (30.1) 18 (16.5)

.61 .48

39 (28.5) 0.32 (0.53)

35 (24.0) 0.26 (0.45)

.42 .86

153 16 (10.5) 15 (9.7)‡

156 16 (10.3) 15 (9.6)

>.99 >.99

3 (2.0) 4 (2.6)‡ 5 (3.3) 27 (17.6) 36 (23.4)‡

6 (3.8) 3 (1.9) 3 (1.9) 31 (19.9) 36 (23.1)

.50 .72 .50 .66 >.99

Renal function deterioration within 96 hours No. of patients Serum creatinine increase by ≥ 25%, No. (%) 2 consecutive 25% increases in serum creatinine, No. (%)* Serum creatinine increase by ≥ 0.5 mg/dl, No. (%) Maximum serum creatinine change, mean (SD), mg/dl† Clinical end point, No. (%) No. of patients Repeat angiography and/or angioplasty Coronary artery bypass graft surgery 30-day adverse events, No. (%) Death Dialysis Myocardial infarction Rehospitalization Composite of death, dialysis, myocardial infarction, or rehospitalization

* Denominator = 98 for the fenoldopam group and 109 for the placebo group † From baseline value to the peak value within 96 hours after study drug administration ‡ Denominator = 154 (1 patient lost to 30-day follow-up required dialysis and 1 required bypass surgery before hospital discharge). Source: Stone et al. (2003).

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I N T E R P R E T A T I O N . The selective dopamine-1 agonist fenoldopam mesylate does not prevent further renal function deterioration after contrast administration in patients with chronic renal insufficiency.

Comment Although this study has been well performed, there are some drawbacks. The amount of fluid that was administered in the protocol could have been higher, but there was no impact of the degree of hydration on the outcome; also in each group (fenoldopam and controls) approximately one-third of the patients also received acetylcysteine. In any case, one should agree with the authors that, at present, fenoldopam does not add a beneficial effect in the prevention of RCN in patients at risk of this complication. This study also illustrates the importance of completing adequately powered, prospective studies before active therapies are definitely adopted in routine clinical practice.

Acetylcysteine N-acetylcysteine (NAC) is a simple and inexpensive water-soluble molecule that contains a sulphhydryl residue. Its well-documented protective effect on several causes of liver damage has traditionally been attributed to the restoration of intracellular glutathione levels. NAC may also attenuate the course of hepatorenal syndrome, a renal vasoconstrictive response of indeterminate nature that develops during advanced liver failure. However, direct renal protective mechanisms may also play a role and recent studies suggest that NAC may increase intracellular glutathione and ameliorate renal ischaemia–reflow injury 28. NAC has been reported recently to prevent radiocontrast nephropathy in high-risk patients 20. NAC-related organ protection is attributed primarily to scavenging oxygen free radicals, either directly or through increasing intracellular glutathione concentrations, but other protective mechanisms may also play a role. Following the first successful clinical trial with acetylcysteine in the prevention of RCN 20, numerous other trials have been performed with this drug. To summarize results of these trials, which have not been uniformly positive, the three major meta-analyses that have been published recently should be consulted (see below).

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N-acetylcysteine ameliorates renal microcirculation: studies in rats Heyman SN, Goldfarb M, Shina A, Karmeli F, Rosen S. Kidney Int 2003; 63: 634–41

B A C K G R O U N D . This study was designed to explore the effect of NAC on renal microcirculation in an animal model of RCN and to determine whether this could be attributed to improved glomerular haemodynamics or to the prevention of hypoxic

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tubular damage via restoration of altered renal microcirculation. Blood pressure, total renal blood flow and selective regional cortical and outer medullary blood flow were monitored continuously in anaesthetized rats with ultrasonic and laser-Doppler probes during the infusion of NAC (60 mg/kg). In control intact rats blood pressure and renal microcirculation were unaffected by NAC. By contrast, following renal

Fig. 5.4 Haemodynamic effects of NAC in animals subjected to radiocontrast. NAC (60 mg/kg over 3 min) was injected to anaesthetized rats 15 mins after the administration of iothalamate meglumine 60% (CM, 4 ml/kg IV, n 11). , determined blood pressure and flows; , calculated vascular resistance; *P 0.01 vs baseline, one-way ANOVA. Source: Heyman et al. (2003).

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vasoconstriction induced by the radiocontrast agent iothalamate meglumine, NAC decreased total, cortical and medullary vascular resistance by 7–10% (P 0.05). NAC also reduced renal vascular resistance by 16% when given during angiotensin II infusion (P 0.05). Altered renal microcirculation, induced by the cyclooxygenase inhibitor indomethacin, by the nitric oxide synthase inhibitor nomeganitro-L-arginine (L-NAME), or with their combination, was partially restored by NAC. Nevertheless, NAC administration failed to attenuate renal function and morphology in a rat model of acute renal failure with selective outer medullary hypoxic injury, induced by indomethacin, L-NAME and iothalamate. NAC therefore ameliorates renal vasoconstriction, an effect that seems to be mediated by mechanisms that do not involve prostaglandins and nitric oxide. I N T E R P R E T A T I O N . This study clearly shows that the commonly accepted explanation of the protective effect of acetylcysteine – that it is due to its scavenging properties – is not completely true. Acetylcysteine is also a potent anti-vasoconstrictive agent when the kidney is challenged by angiotensin or contrast media. However, NAC was not able to attenuate renal function and morphology in a rat model of acute renal failure with selective outer medullary hypoxaemia.

Comment This is an interesting experimental study that provides an alternative explanation, namely renal vasodilation, for the protective action of NAC in RCN. On the other hand, the results also indicate that an improvement in renal microcirculation is not necessarily sufficient to alter the medullary oxygen balance, which is compromised in both experimental and probably also clinical acute renal failure. This study also provides an additional explanation for some of the negative clinical trials that have been obtained with NAC in the prevention of clinical RCN (see later).

Clinical studies

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Prevention of radiocontrast nephropathy with N-acetylcysteine in patients with chronic kidney disease: a meta-analysis of randomized, controlled trials Alonso A, Lau J, Jaber BL, Weintraub A, Sarnak MJ. Am J Kidney Dis 2004; 43: 1–9

B A C K G R O U N D . Results of several studies using NAC for the prevention of RCN have yielded conflicting results. The authors performed a meta-analysis of group data extracted from previously published studies to assess the effect of NAC on the prevention of RCN in patients with pre-existing chronic kidney disease. Ovid’s multidatabase search for Medline, the Cochrane Central Registry of Controlled Trials, the Cochrane Database of Systematic Reviews and HealthSTAR were used to identify candidate articles. Blinded and unblinded randomized controlled trials performed in

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humans 18 years and older with pre-existing chronic kidney disease, defined by a mean baseline serum creatinine level of 1.2 mg/dl or greater (≥106.1 mol/l) or creatinine clearance less than 70 ml/min (1.17 ml/s) were screened. The overall risk ratio for the development of RCN was computed using a random-effects model. Eight randomized controlled trials (n 885 patients) published in full-text articles were included in the primary analysis. In the control group, the overall rate of RCN was 18.5% (95% CI 15–22). In the primary analysis, overall risk ratio for RCN associated with the use of NAC was 0.41 (95% CI 0.22–0.79; P 0.007). In a sensitivity analysis that included four additional randomized controlled trials published in abstract form, the risk ratio remained significant at 0.55 (95% CI 0.34–0.91; P 0.020).

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Acetylcysteine for prevention of contrast nephropathy: meta-analysis Birck R, Krzossok S, Markowetz F, Schnulle P, Van Der Woude FJ, Braun C. Lancet 2003; 362: 598–603

B A C K G R O U N D . A meta-analysis of randomized controlled trials comparing acetylcysteine and hydration with hydration alone for preventing contrast nephropathy in patients with chronic renal insufficiency was performed. The trials were identified through a combined search of BIOSIS/RRM, Medline, Web of Science, Current Contents Medizin and the Cochrane Library databases. The incidence of contrast nephropathy 48 hours after administration of radiocontrast media was used as an outcome measure. Seven trials including 805 patients were eligible and analysed. The overall incidence of contrast nephropathy varied between 8% and 28%. Since significant heterogeneity was indicated by the Q statistics (P 0.016), a random effects model was used to combine the data. Compared with hydration alone, administration of acetylcysteine and hydration significantly reduced the relative risk of contrast nephropathy by 56% (0.435; 95% CI 0.215–0.879; P 0.02) in patients with chronic renal insufficiency. Meta-regression revealed no significant relationship between the relative risk of contrast nephropathy and the volume of radiocontrast medium administered or the degree of chronic renal insufficiency before the procedure.

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Meta-analysis of randomized clinical trials on the usefulness of acetylcysteine for prevention of contrast nephropathy Isenbarger DW, Kent SM, O’Malley PG. Am J Cardiol 2003; 92: 1454–8

B A C K G R O U N D . A third meta-analysis of the seven randomized clinical trials published in the peer-reviewed English language literature, involving 805 study subjects, that assessed the impact of prophylactic oral NAC for the prevention of contrast nephropathy at 48 hours demonstrated a large and statistically significant

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Fig. 5.5 Relative risk of occurrence of contrast nephropathy (a) for all seven trials, and (b) after exclusion of Tepel trial. Data are calculated by either a random-effects model (upper) or a fixed-effects model (lower). Boxes are relative risk, lines are 95% CI. Areas of boxes are proportional to the respective study weight within the corresponding pooled analysis (see also weight values on the right). The pooled treatment estimate and its 95% CI are shown as a diamond with a dotted vertical line indicating the pooled estimate value at the bottom of each plot. The vertical solid line indicates no treatment effect; values of less than 1 indicate treatment benefit. Source: Birck et al. (2003).

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risk reduction in the treatment group. Mean serum creatinine levels also decreased significantly in the NAC arm, although the magnitude was not large. Somewhat surprisingly, meta-regression analysis found no significant impact of baseline creatinine, contrast volume or the percentage of diabetics on the overall effect size. This is in contrast with the many epidemiological studies that have consistently documented associations of these and other factors with RCN. The studies in this meta-analysis, however, included only patients with increased risk at baseline. Further distinguishing factors were difficult to discern among this uniformly higher-risk group. I N T E R P R E T A T I O N . The three meta-analyses conclude that, compared with peri-procedural hydration alone, oral acetylcysteine with hydration significantly reduces the risk of contrast nephropathy in patients with chronic renal insufficiency. The relative risk of contrast nephropathy was not related to the amount of radiocontrast medium given or to the degree of chronic renal insufficiency before the procedure. One should, however, take into account that negative studies were found in every meta-analysis, that acetylcysteine without adequate hydration is not sufficient, and that in some of these studies the individual contribution of acetylcysteine is difficult to delineate. The definition of RCN was different in many of these studies, so that the absolute data on the incidence of RCN are variable. Also, the hydration protocols were not uniform.

Comment Although the weight of evidence favours the use of NAC, which is inexpensive and safe, the optimal dose, duration and route of administration of NAC for the indication of contrast nephropathy have not been established. Oral regimens initiated the day before contrast exposure pose logistic challenges for elective cases and are not applicable in emergencies. A striking result in many of the studies suggesting a favourable effect of oral acetylcysteine is that some of the difference is accounted for by the reduction in creatinine concentration in the NAC-treated group rather than a pure reduction in the incidence of RCN. Changes in serum creatinine may not always reflect changes in glomerular filtration rate since drugs may interfere with the tubular secretion of creatinine. Formal studies of the effect of NAC on tubular transport of creatinine have not been performed This factor should be kept in mind in the interpretation of the many studies that show an apparent protective effect by inducing a decrease in serum creatinine in the treated group rather than by a true decline in the incidence of RCN. A very recent study 29 investigated whether there are effects of NAC on serum creatinine levels that are independent of alterations in glomerular filtration rate. Volunteers received NAC at oral doses of 600 mg every 12 hours for a total of four doses. There was a significant decrease in the mean serum creatinine concentration and a significant increase in the calculated glomerular filtration rate 4 hours after the last dose of NAC, while the cystatin C concentrations did not change significantly (Fig. 5.6). Before the renoprotective effects of NAC against contrast agent-induced nephropathy are definitely accepted, the direct effects of NAC on creatinine levels, urea levels and truly measured glomerular filtration rate should be assessed.

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Fig. 5.6 Surrogate markers of renal function. Renal function was assessed with serum creatinine levels and estimated GFR (eGFR) (a) and cystatin C levels (b), determined before (baseline) and 4 and 48 h after the last administration of N-acetylcysteine (NAC). *P 0.05; **P 0.02, compared with baseline concentrations. Source: Hoffmann et al. (2004) 29.

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A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study Baker CS, Wragg A, Kumar S, De Palma R, Baker LR, Knight CJ. J Am Coll Cardiol 2003; 41: 2114–18

B A C K G R O U N D . One of the drawbacks of the current oral acetylcysteine protocols is to preclude prophylaxis of same-day or emergency patients owing to the need for prolonged pre-treatment. Therefore, a recent study has tested whether more rapid preparation of the patient before the administration of radiocontrast material would be equally effective. This study was designed to test a rapid protocol of intravenous acetylcysteine for prevention of RCN. The authors prospectively randomized 80 patients with stable renal dysfunction undergoing cardiac catheterization/ intervention to a rapid protocol of intravenous NAC (150 mg/kg in 500 ml N/saline over 30 minutes immediately before contrast followed by 50 mg/kg in 500 ml N/saline over 4 hours) or intravenous hydration (1 ml/kg per hour N/saline for 12 hours before

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and after contrast). RCN occurred in two of the 41 patients in the NAC group (5%) and in eight of the 39 patients in the hydration group (21%; P 0.045; relative risk 0.28; 95% CI 0.08–0.98). In the NAC group, mean serum creatinine fell from 1.85 0.59 to 1.77 0.73 and 1.79 0.73 mg/dl 48 hours and 4 days after contrast (P 0.02 and 0.023 versus baseline, respectively). In the hydration group, serum creatinine increased from 1.75 0.41 to 1.81 0.6 48 hours and 1.80 0.50 mg/dl 4 days after contrast (P 0.99 and 0.23, respectively). NAC infusion was ceased after the bolus in three patients (7%) due to flushing, itching, or a transient rash. I N T E R P R E T A T I O N . According to this study, administration of intravenous acetylcysteine should be considered in all patients at risk of RCN before contrast exposure when time constraints preclude adequate oral or intravenous hydration prophylaxis, provided the patient is able to tolerate this degree of volume loading.

Comment The rapid intravenous acetylcysteine protocol used by the authors showed efficacy similar to that seen in other trials using more prolonged, lower-dose oral regimens. The contrast dose used was relatively high but the degree of pre-existing kidney impairment was only moderate. Although the rationale for the trial was to test a regimen applicable in emergencies, the patients were not selected from such a population. In addition, patients who were unstable because of hypotension or heart failure were excluded. Furthermore, the safety of intravenous NAC has not been adequately tested; in addition, the study was terminated following the interim analysis after the first 80 patients had been randomized, while the planned enrolment was 160 patients.

Fig. 5.7 Changes in serum creatinine before and after radiocontrast exposure. Source: Baker et al. (2003).

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As discussed above, the difference between the control and the test group was to some extent due to the decrease in the serum creatinine level in the NAC group. The results from this study support the growing body of evidence favouring the use of NAC and extend our knowledge of its dosage and route of administration. Costs should be favourable compared with more prolonged saline administration. The protocol tested in this trial would be most applicable to ambulatory programmes for stable patients; caution should be observed in unstable patients because of the risk of pulmonary oedema.

Haemodialysis after contrast administration It has been shown that in patients with impaired renal function the half-lives of contrast media are increased severalfold because most contrast media are excreted in the urine. Haemodialysis removes contrast media effectively and therefore might prevent radiocontrast nephropathy. One study, which compared the prophylactic effect of haemodialysis with conservative management 30, found that haemodialysis removed contrast media but had no significant effect on the incidence of radiocontrast nephropathy. The study was limited to 15 patients in the dialysis group and patients with only moderate renal insufficiency (serum creatinine level 1.4 mg/dl) were included in the study. However, two larger studies in which prophylactic haemodialysis was started immediately after the administration of a contrast agent in patients with reduced renal function also demonstrated no net benefit 31,32. In contrast to haemodialysis, haemofiltration is a continuous form of renal replacement therapy that constitutes an alternative strategy for the prevention of contrast agent-induced nephropathy in high-risk patients. Haemofiltration is theoretically associated with a number of advantages. First, since peri-procedural hydration has been proved to be an efficacious and well-tolerated strategy (see above), the potential benefit of haemofiltration can be markedly amplified by administering a volume of fluid per hour that is 10–15 times that delivered by standard hydration but without an associated risk of fluid overload and lung congestion. Secondly, like glomerular filtration, haemofiltration is able to remove contrast agents from the circulation. This mechanism, along with the dilution of contrast agents through the infusion of replacement fluid, lowers the concentration of the contrast agent in the blood and may reduce the exposure of the kidneys to the nephrotoxic effects of these agents. Consequently, a recent prospective, randomized study compared haemofiltration with saline hydration for the prevention of RCN in a large number of patients with moderately to severely impaired renal function who were to undergo elective percutaneous coronary interventions.

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The prevention of radiocontrast-agent-induced nephropathy by hemofiltration Marenzi G, Marana I, Lauri G, et al. N Engl J Med 2003; 349: 1333–40

B A C K G R O U N D . The authors studied 114 consecutive patients with chronic renal failure (serum creatinine concentration 2 mg/dl) who were undergoing coronary interventions. The patients were randomly assigned to either haemofiltration in an intensive care unit (58 patients, with a mean SD serum creatinine concentration of 3.0 1.0 mg/dl) or isotonic saline hydration at a rate of 1 ml/kg of body weight per hour, given in a step-down unit (56 patients with a mean serum creatinine concentration of 3.1 1.0 mg/dl). Haemofiltration (fluid replacement rate 1000 ml/hour without weight loss) and saline hydration were initiated 4–8 hours before the coronary intervention and were continued for 18–24 hours after the procedure was completed. An increase in the serum creatinine concentration of more than 25% from the baseline value after the coronary intervention occurred less frequently among the patients in the haemofiltration group than among the control patients (5 versus 50%; P 0.001). Temporary renal replacement therapy (haemodialysis or haemofiltration) was required in 25% of the control patients and in 3% of the patients in the haemofiltration group. The rate of in-hospital events was 9% in the haemofiltration group and 52% in the control group (P 0.001). In-hospital mortality was 2% in the haemofiltration group and 14% in the control group (P 0.02), and the cumulative 1-year mortality was 10 and 30%, respectively (P 0.01). I N T E R P R E T A T I O N . In patients with chronic renal failure who are undergoing percutaneous coronary interventions, peri-procedural haemofiltration given in an intensive care unit appears to be effective in preventing the deterioration of renal function due to contrast agent-induced nephropathy and is associated with improved in-hospital and long-term outcomes.

Comment This is a remarkable study with very impressive results. The differences in both RCN and the need for renal replacement between the control and the haemofiltration groups are important; furthermore, even the long-term survival was importantly reduced in the patients treated with prophylactic haemofiltration. The high incidence of RCN in the control group (52%) was explained by the authors by the administration of relatively high amounts of contrast material and by the relatively poor renal function of the patients before the intervention (mean creatinine clearance was 26 ml/minute). A limitation of haemofiltration delivered in the intensive care unit is its relatively high cost compared with that of saline infusion delivered in less intensive treatment settings. However, it must be emphasized that these positive results were obtained in a group of patients at very high risk who were undergoing multiple interventions and requiring a larger volume of contrast agent than that used during simple diagnostic radiographic procedures. Therefore, these patients represent a population in which a

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Fig. 5.8 Serum creatinine concentration, blood urea nitrogen concentration, and urine output before the percutaneous coronary intervention, at the end of treatment (day 1), on the following two days (days 2 and 3), and at hospital discharge. For the interaction between time and treatment in terms of the serum creatinine concentration, F statistic 45.5 (P 0.001). Changes from baseline in the serum creatinine concentration were significant (P 0.01) before the procedure and on days 1, 2, and 3 in the haemofiltration group and at day 2, day 3, and discharge in the control group; the difference between the two groups was significant beginning on day 1. For the interaction between time and treatment in terms of the blood urea nitrogen concentration, F statistic 53.6 (P 0.001). Changes from baseline in the blood urea nitrogen concentration were significant (P 0.01) before the procedure and on days 1, 2, and 3 in the haemofiltration group and beginning on day 1 in the control group; the differences between the two groups were significant beginning on day 1. For the interaction between time and treatment in terms of urine output, F statistic 13.5 (P 0.001). Changes from baseline in the urine output were significant (P 0.01) on day 2 and day 3 in the control group but at no time-point in the haemofiltration group; the differences between the two groups were significant on day 2 and day 3. To convert values for creatinine to micromoles per litre, multiply by 88.4. To convert values for urea nitrogen to millimoles per litre, multiply by 0.357. Source: Marenzi et al. (2003).

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preventive strategy with haemofiltration appears to be justified and cost-effective, given the high risk of contrast agent-induced nephropathy, with its attendant high medical costs. However, as pointed out by the authors, the results of this study are not directly applicable to all high-risk patients who are exposed to contrast agents for simpler procedures.

Conclusion The use of iodinated contrast media continues to be a common cause of hospitalacquired acute renal failure, and its development increases in-hospital mortality significantly. Many preventive protocols have been tested and only adequate hydration, oral acetylcysteine and, in emergency contrast examinations, intravenous acetylcysteine pre-treatment have proved to be effective. However, before acetylcysteine can definitely be accepted as an easy and effective preventive drug, the effects of this drug on tubular creatinine handling should be further explored. In high-risk patients peri-procedural haemofiltration can apparently reduce the incidence of acute radiocontrast nephropathy, but its application must be balanced by its relatively high cost compared with the less expensive treatments, such as acetylcysteine and adequate hydration of the patient at risk.

References 1. Solomon R. Contrast-medium-induced acute renal failure. Kidney Int 1998; 53: 230–42. 2. Murphy SW, Barrett BJ, Parfrey PS. Contrast nephropathy. J Am Soc Nephrol 2000; 11:

177–82. 3. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002;

39: 930–6. 4. Gruberg L, Mintz GS, Mehran R, Gangas G, Lansky AJ, Kent KM, Pichard AD, Satler LF,

Leon MB. The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency. J Am Coll Cardiol 2000; 36: 1542–8. 5. Rihal CS, Textor SC, Grill DE, Berger PB, Ting HH, Best PJ, Singh M, Bell MR, Barsness GW, Mathew V, Garratt KN, Holmes DR Jr. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002; 105: 2259–64. 6. Heyman SN, Reichman J, Brezis M. Pathophysiology of radiocontrast nephropathy: a role for medullary hypoxia. Invest Radiol 1999; 34: 685–91.

05 YIRen Med I 089-114 FINAL

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Page 113

PREVENTION OF ACUTE RADIOCONTRAST NEPHROPATHY

113

7. Abizaid AS, Clark CE, Mintz GS, Dosa S, Popma JJ, Pichard AD, Satler LF, Harvey M,

8.

9.

10. 11. 12.

13. 14.

15.

16.

17.

18. 19.

20.

21. 22.

Kent KM, Leon MB. Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with pre-existing renal insufficiency. Am J Cardiol 1999; 83: 260–3, A5. Erley CM, Duda SH, Rehfuss D, Scholtes B, Bock J, Muller C, Osswald H, Risler T. Prevention of radiocontrast-media-induced nephropathy in patients with pre-existing renal insufficiency by hydration in combination with the adenosine antagonist theophylline. Nephrol Dial Transplant 1999; 14: 1146–9. Kapoor A, Kumar S, Gulati S, Gambhir S, Sethi RS, Sinha N. The role of theophylline in contrast-induced nephropathy: a case–control study. Nephrol Dial Transplant 2002; 17: 1936–41. Erley CM. Acute renal failure associated with radiocontrast agents. In: Molitoris BA, Finn WF (eds). Acute Renal Failure. Philadelphia, PA: WB Saunders, 2001; 29: 376–82. Katholi RE, Woods WT Jr, Taylor GJ, Deitrick CL, Womack KA, Katholi CR, McCann WP. Oxygen free radicals and contrast nephropathy. Am J Kidney Dis 1998; 32: 64–71. Morcos SK, Thomsen HS, Webb JA. Contrast Media Safety Committee, European Society of Urogenital Radiology (ESUR). Contrast-media-induced nephrotoxicity: a consensus report. Eur Radiol 1999; 9: 1602–13. Katzberg RW. Urography into the 21st century: new contrast media, renal handling, imaging characteristics, and nephrotoxicity. Radiology 1997; 204: 297–312. Solomon R, Werner C, Mann D, D’Elia J, Silva P. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med 1994; 331: 1416–20. Rudnick MR, Goldfarb S, Wexler L, Ludbrook PA, Murphy MJ, Halpern EF, Hill JA, Winniford M, Cohen MB, VanFossen DB. Nephrotoxicity of ionic and non-ionic contrast media in 1196 patients: a randomized trial. The Iohexol Cooperative Study. Kidney Int 1995; 47: 254–61. Taliercio CP, Vlietstra RE, Ilstrup DM, Burnett JC, Menke KK, Stensrud SL, Holmes DR Jr. A randomized comparison of the nephrotoxicity of iopamidol and diatrizoate in highrisk patients undergoing cardiac angiography. J Am Coll Cardiol 1991; 17: 384–90. Wang A, Holcslaw T, Bashore TM, Freed MI, Miller D, Rudnick MR, Szerlip H, Thames MD, Davidson CJ, Shusterman N, Schwab SJ. Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int 2000; 57: 1675–80. Barrett BJ, Carlisle EJ. Meta-analysis of the relative nephrotoxicity of high- and lowosmolality iodinated contrast media. Radiology 1993; 188: 171–8. Wang YX, Jia YF, Chen KM, Morcos SK. Radiographic contrast media induced nephropathy: experimental observations and the protective effect of calcium channel blockers. Br J Radiol 2001; 74: 1103–8. Tepel M, van Der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343: 180–4. Oliveira DB. Prophylaxis against contrast-induced nephropathy. Lancet 1999; 353: 1638–9. Parfrey PS, Barrett BJ. High-osmolality and low-osmolality contrast agents. N Engl J Med 1992; 327: 204–5.

05 YIRen Med I 089-114 FINAL

114

19/4/05 3:46 pm

Page 114

II . A C U T E R E N A L F A I L U R E

23. Sandler CM. Contrast-agent-induced acute renal dysfunction—is iodixanol the answer?

N Engl J Med 2003; 348: 551–3. 24. Davidson CJ, Laskey WK, Hermiller JB, Harrison JK, Matthai W Jr, Vlietstra RE, Brinker

25.

26. 27. 28.

29.

30.

31.

32.

JA, Kereiakes DJ, Muhlestein JB, Lansky A, Popma JJ, Buchbinder M, Hirshfeld JW Jr. Randomized trial of contrast media utilization in high-risk PTCA: the COURT trial. Circulation 2000; 101: 2172–7. Carraro M, Malalan F, Antonione R, Stacul F, Cova M, Petz S, Assante M, Grynne B, Haider T, Palma LD, Faccini L. Effects of a dimeric versus a monomeric non-ionic contrast medium on renal function in patients with mild to moderate renal insufficiency: a double-blind, randomized clinical trial. Eur Radiol 1998; 8: 144–7. Chalmers N, Jackson RW. Comparison of iodixanol and iohexol in renal impairment. Br J Radiol 1999; 72: 701–3. Bakris GL, Lass NA, Glock D. Renal hemodynamics in radiocontrast medium-induced renal dysfunction: a role for dopamine-1 receptors. Kidney Int 1999; 56: 206–10. Pincemail J, Defraigne JO, Detry O, Franssen C, Meurisse M, Limet R. Ischemia– reperfusion injury of rabbit kidney: comparative effects of desferrioxamine and N-acetylcysteine as antioxidants. Transplant Proc 2000; 32: 475–6. Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK. The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol 2004; 15: 407–10. Lehnert T, Keller E, Gondolf K, Schaffner T, Pavenstadt H, Schollmeyer P. Effect of haemodialysis after contrast medium administration in patients with renal insufficiency. Nephrol Dial Transplant 1998; 13: 358–62. Vogt B, Ferrari P, Schonholzer C, Marti HP, Mohaupt M, Wiederkehr M, Cereghetti C, Serra A, Huynh-Do U, Uehlinger D, Frey FJ. Prophylactic hemodialysis after radiocontrast media in patients with renal insufficiency is potentially harmful. Am J Med 2001; 111: 692–8. Huber W, Jeschke B, Kreymann B, Hennig M, Page M, Salmhofer H, Eckel F, Schmidt U, Umgelter A, Schweigart U, Classen M. Haemodialysis for the prevention of contrastinduced nephropathy: outcome of 31 patients with severely impaired renal function, comparison with patients at similar risk and review. Invest Radiol 2002; 37: 471–81.

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6 Renal support and treatment of acute renal failure FRANK LIU, RAVINDRA MEHTA

Introduction Despite the many advances made in both basic science and clinical medicine over the last decades, the understanding and successful treatment of acute renal failure (ARF) has lagged far behind the diseases of other major organ systems. For example, while the in-hospital mortality of acute myocardial infarction has been reduced from approximately 50% to just 7% 1 in the last 20 years, the in-hospital mortality of ARF has remained mostly unchanged over that same period of time. In particular, despite improved dialytic technology, including continuous modalities that can provide both renal support and unprecedented control of haemodynamics and volume, the mortality rate associated with a diagnosis of ARF in intensive care unit patients has persisted at around an unacceptable 50–70% 2. In attempting to improve outcomes in ARF, it may be useful to study the evolution of the treatment of acute myocardial infarction as a model—why has it been such a success? Clearly, progress has been the result of developments in every step of the treatment process, from the quick and accurate diagnosis of a firmly defined disease state to enhanced understanding of the underlying pathophysiology, and then finally to effective interventions that can, in many cases, reverse or lessen the consequences of the ischaemic event. Diagnosis has been greatly aided by new biochemical markers of myocyte injury (including troponin, myoglobin, creatine kinase and its MB fraction). In conjunction with cardiac markers, the clinical history and electrocardiographic criteria can establish the diagnosis of myocardial infarction within minutes to hours of the inciting event and set in motion a defined treatment algorithm, including adjunctive pharmacological therapies based on understanding of the underlying pathophysiology, and ultimately mechanical intervention. In contrast, the treatment of ARF has been thwarted by deficiencies in all of the steps described above. Unequivocally, the most important step in the treatment of a disease is correct and timely diagnosis of the disorder. However, in comparison with cardiologists, nephrologists have few clinically available tools to help make a proper diagnosis of ARF, and even these tools are easily confounded. For example, while the serum creatinine concentration may be a useful indicator of glomerular filtration © Atlas Medical Publishing Ltd

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rate in the steady state, it is at best a fickle marker of renal function in the acute setting, due to several factors. There is often a slow rise in creatinine even in cases of complete renal shutdown; rates of production vary widely in patients of different ages, genders and races; and the serum concentration is influenced by total body water, which may fluctuate drastically. A drop in urine output can also be a sign of renal failure, but is similarly unreliable in many types of ARF. Moreover, even if creatinine and urine output were reliable indicators of renal function, there are enough conflicting definitions of the state of ARF that there is no true accepted definition 3. The lack of a well-defined disease state often leads to delayed recognition of the disorder, delayed attempts at treating the disorder, and possibly worsened outcomes. In addition, the optimal timing of intervention and the tracking of treatment efficacy are difficult because there are no clear definitions of the natural history of ARF. For example, when someone suffers an insult that causes ARF, when is the best time to institute non-dialytic or dialytic treatment? If treatment is instituted, how does the care team assess the effectiveness of that treatment, and how long should one wait before changing tactics? The choice of a specific intervention is unclear because previous clinical trials have all used different definitions of the disease and varying inclusion and exclusion criteria. It is evident that ARF is a far more complex pathological state than acute myocardial infarction (MI), which is the result of an isolated event—plaque rupture and vascular occlusion. As every medical student and resident is taught, ARF can come in three general flavours: pre-renal, intrinsic and obstructive. This simple classification is on the surface reassuring, but unfortunately encompasses several states that are overwhelmingly complex and poorly understood, especially in the case of sepsis and resulting multi-organ failure. Given that current markers of renal failure are merely descriptive and may not provide any information about the underlying pathophysiology, even were it understood, finding effective treatment is made even more difficult. Lastly, though many advances have been made in the actual treatment of ARF, the modalities that are currently widely available remain at best supportive in nature, and at worst they are of questionable benefit or possible detriment. Non-dialytic measures have been tried in the past and have met with varying, if any, success. These include diuretic agents 4, renal-dose dopamine 5, atrial natriuretic peptide 6,7, insulin-like growth factor-1 8 and endothelin receptor antagonists 9. None of these has been proved to be effective in any significant trial, and have in some cases even been deemed harmful. This has left nephrologists with a limited number of evidencebased non-dialytic treatment options for ARF: i.e. intravenous fluids for pre-renal and a Foley catheter or nephrostomy tube for obstructive causes of renal failure. Although dialysis remains the most reliable treatment for renal failure of all causes, it is also fraught with unanswered questions in the setting of ARF regarding membranes, dose and modality (i.e. traditional intermittent haemodialysis, peritoneal dialysis, daily haemodialysis, or the several types of continuous renal replacement). Moreover, dialysis as it exists currently is only supportive, and has not been shown to reverse the disease in any sense other than by buying time for the natural healing process in the kidney to take place.

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Despite the grim picture offered here, there is hope on the horizon. New diagnostic tools, including biochemical markers of tubular cell injury akin to cardiac markers, are being developed, which, in conjunction with a push towards establishing a widely accepted classification system for ARF, may enable clinicians to make the diagnosis of ARF more rapidly than was previously possible. Options for both renal support and for treatment are also being investigated, including optimization of current technologies and exciting emerging technologies that promise to modify the pathophysiology of the disease via cytokine removal and via replacement of the kidney’s intrinsic metabolic activities that are not currently provided by existing dialysis technology. This chapter will focus on some of the most prominent developments in this challenging field over the last 18 months.

Diagnosis

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Urinary measurement of Na/H exchanger isoform 3 (NHE3) protein as new marker of tubule injury in critically ill patients with ARF du Cheyron D, Daubin C, Poggioli J, et al. Am J Kidney Dis 2003; 42: 497–506

B A C K G R O U N D . The most commonly used clinical tools for the diagnosis of renal failure – a rise in creatinine and a decrease in urine output – are far from ideal biomarkers in that they are not sensitive or speciﬁc for ARF until well after the injurious event has happened. Much research has therefore been conducted to ﬁnd an appropriate molecule that can quickly and accurately diagnose renal injury (and give a clue to the pathogenesis) at an early stage of the natural history of ARF. In this paper, the authors report that Na+/H+ exchanger isoform 3 (NHE3), the most abundant apical sodium transporter in the renal tubule, may be useful in this respect. In the study, 54 intensive care unit (ICU) patients with ARF, deﬁned as a ‘sudden’ increase in serum creatinine level to 2 mg/dl or greater in patients without pre-existing chronic renal insufﬁciency (CRI) or an increase to a value 50% greater than the baseline creatinine in patients with CRI, were categorized into renal failure secondary to pre-renal azotaemia, acute tubular necrosis (ATN), and intrinsic ARF other than ATN. Pre-renal azotaemia was diagnosed if renal impairment improved rapidly after volume repletion or improved cardiac output. ATN was deﬁned as renal dysfunction that persisted after correction of pre-renal factors and that was not attributed to hepatorenal syndrome or vascular, interstitial or glomerular causes. Intrinsic ARF other than ATN was conﬁrmed with renal biopsy. Urinary NHE3 protein abundance was estimated from semiquantitative immunoblots of urine membrane fraction samples collected from patients. As illustrated in Fig. 6.1, they found that urinary NHE3 levels were increased in patients with pre-renal azotaemia (0.12 0.08), and were even more elevated in patients with ATN (0.78 0.36), without overlap between the two groups. Levels were detectable as early as 12 hours after the inciting event. Conversely, urinary NHE3 levels were undetectable

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Fig. 6.1 Immunoblots of urine membrane fractions from patients with normal renal function when admitted to the intensive care unit (ICU) who experienced septic shockinduced ARF (patients 1 and 2) and radiographic contrast agent-induced ARF (patient 3); from patients who underwent renal transplantation (patient 4); and (bottom right) typical blots of speciﬁc subtypes of ARF. Cont, controls; pre-renal, pre-renal azotaemia; d and H, time in days and hours between ICU admission and sampling, respectively. To convert serum creatinine in mg/dl to mol/l, multiply by 88.4. Source: Du Cheyron et al. (2003).

in control patients without renal failure and in patients with intrinsic ARF other than ATN. NHE3 levels normalized to creatinine correlated positively with serum creatinine level in patients with ATN. Moreover, urinary NHE3 levels dropped in concert with recovery of renal function and had disappeared within 48 hours when the insult was clearly deﬁned (e.g. contrast nephropathy). I N T E R P R E T A T I O N . In patients with ARF, urinary NHE3 abundance may represent a novel biomarker of renal tubular damage that has the potential to discriminate between pre-renal azotaemia, ATN and intrinsic ARF other than ATN.

Comment While urinary NHE3 appears to be a promising marker for ARF – its aetiology as well as its presence – important limitations of this study include the small sample size, the lack of biopsy confirmation of the clinical diagnosis of ATN, and the timeand labour-intensive manner in which NHE3 is measured. Nevertheless, because increased natriuresis is one of the hallmarks of ATN, the appearance of NHE3 in the urine in ATN is mechanistically intuitive, and therefore all the more compelling. Furthermore, the finding that NHE3 is sloughed into the urine just hours after the

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presumed injury, persists throughout the maintenance period and disappears after recovery, implies that NHE3 may one day be used not only to diagnose ARF but also to track the progress (or lack thereof) of any treatment efforts. NHE3 is just one of several molecules being studied for the diagnosis of ARF. Muramatsu et al. found that cysteine-rich protein 61 (CYR61), a heparin-binding protein thought to be involved in tissue repair and growth, is induced in the kidney within 1 hour after ischaemic injury in a mouse model. Furthermore, CYR61 was detected in the urine 3–6 hours after ischaemia but was not detected in volumedepleted or control mice 10. Similarly, Han et al. found in a small preliminary human study that high urinary levels of kidney injury molecule-1 (KIM-1) may discriminate between ischaemic ATN, other forms of ARF (pre-renal or non-ischaemic intrinsic ARF), and chronic renal disease 11. While these markers may still be in the early stages of study, they promise one day to provide nephrologists with the ability to make a rapid diagnosis of renal injury and potentially to limit the extent of that injury by quick intervention 12.

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Signiﬁcance of the fractional excretion of urea in the differential diagnosis of acute renal failure Carvounis CP, Nisar S, Guro-Razuman S. Kidney Int 2002; 62: 2223–9

B A C K G R O U N D . In the treatment of ARF, one of the ﬁrst diagnostic steps is the differentiation between volume-related causes of ARF and intrinsic causes of ARF, such as ATN. This has traditionally been accomplished with the help of the fractional excretion of sodium (FENa), which essentially measures the kidney’s ability to appropriately reabsorb salt. However, this test is often confounded by the extensive use of salt-wasting diuretics. In this paper, Carvounis et al. tested the hypothesis that the fractional excretion of urea (FEurea) is superior to FENa in differentiating pre-renal ARF from ATN, especially in the setting of diuretic use. ARF was deﬁned as rapidly rising blood urea nitrogen (BUN) and creatinine (BUN >30 mg/dl and creatinine >1.5 mg/dl) with or without oliguria, or an increase in serum creatinine of >0.5 mg/dl in the preceding 2 days. Patients were divided into three groups: those with pre-renal azotaemia not treated with diuretics, those with pre-renal azotaemia treated with diuretics, and those judged to have ATN. Pre-renal azotaemia was diagnosed on the basis of rapid improvement in serum creatinine value and urine output after appropriate treatment of volume. ATN was diagnosed on the basis of clinical history, the persistence of ARF despite correction of pre-renal factors, and a urinary sediment consistent with ATN (muddy brown granular casts). The authors found that using FEurea ≤35% as a cut-off was highly sensitive and speciﬁc for the diagnosis of pre-renal azotaemia both in the absence and presence of diuretics (Fig. 6.2). The FEurea was greatly increased in patients with ATN (58.6 3.6%) but was <35% in pre-renal states. Moreover, the FEurea was as sensitive and speciﬁc as FENa in diagnosing pre-renal azotaemia without diuretics and ARF secondary to ATN, but was greatly superior to FENa in diagnosing pre-renal azotaemia in the setting of diuretic therapy (sensitivity 89 and 48% respectively).

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Fig. 6.2 Sensitivity of the three major indices for patients with pre-renal situations with or without diuretic use, and patients with ATN. The units shown on the vertical axis represent percentage. Please note that while all three indices are equally effective in patients with pre-renal situations who did not use diuretic therapy, only FEUN retains its high sensitivity even in pre-renal patients who use diuretics. Source: Carvounis et al. (2002).

I N T E R P R E T A T I O N . A FEurea value 35% is a sensitive and speciﬁc index in differentiating between ARF due to pre-renal azotaemia and that due to ATN, and is superior to FENa, especially in cases where diuretics have been administered previously.

Comment Because it is often difficult to judge volume status in patients with ARF, particularly when there has been prior diuretic use, a simple urine test to help discriminate between pre-renal azotaemia and ATN is of great clinical utility. Traditionally, FENa has been used as a clinical tool in discriminating pre-renal from intrinsic renal dysfunction in ARF. However, because FENa is reliant on an unadulterated sodium reabsorption mechanism to differentiate between salt-avid pre-renal states and saltwasting ATN, it is not very useful in the setting of diuretic therapy. FEurea offers a new method to assess functional change in the kidney in ARF and appears to be unaffected by diuretic use. The test is simple and practical, and requires only that urine urea nitrogen be sent in addition to the routine panel of urine electrolytes.

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Detection of inﬂammation following renal ischaemia by magnetic resonance imaging Jo SK, Hu X, Kobayashi H, et al. Kidney Int 2003; 64: 43–51

B A C K G R O U N D . Although the mechanism of ARF in humans remains a mystery, some animal models have shed light on the pathogenesis of ischaemic ATN. For example,

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ischaemic reperfusion injury and cisplatin-mediated ATN cause the release of inﬂammatory and cytotoxic mediators, inﬂux of inﬂammatory cells, and plugging of peritubular capillaries by inﬂammatory cells. In this paper, Jo et al. exploit the monocyte/macrophage inﬁltration of the kidney, using magnetic resonance imaging (MRI) to image ischaemic reperfusion injury in the kidney. Rats were subjected to 40 or 60 minutes of bilateral ischaemia (by clamping of the renal pedicles) or injection of mercuric chloride, which causes pure nephrotoxic and non-inﬂammatory ARF in rats. They were then injected with ultrasmall superparamagnetic iron oxide particles (USPIO), which are internalized by monocyte/macrophages and therefore cause a decrease in MRI signal intensity in areas of heavy macrophage inﬁltration. Coronal images of both kidneys were obtained before and 24 hours after injection of USPIO. The injection of the iron particles caused a black band to appear in the outer medulla 48, 72 and 120 hours after ischaemia (Fig. 6.3). The band was not detected in normal animals, 24 hours after ischaemia, or 48 hours after mercuric chloride injection. The degree of change in signal intensity did correlate with change in serum creatinine (r 0.78) or with the number of cells with internalized USPIO per high-power ﬁeld as conﬁrmatory renal pathology (r 0.96). I N T E R P R E T A T I O N . USPIO-enhanced MRI could detect monocyte/macrophage-induced inﬂammation 48 hours after 40 or 60 minutes of renal ischaemia in rats. There was no change in signal intensity within the kidneys in normal rats or in rats given mercuric chloride, a non-inﬂammatory model of renal failure.

Comment Jo et al. have presented compelling data that renal inflammation is a component of ischaemia–reperfusion injury in ARF and can be imaged by MRI. Furthermore, the change in MRI signal intensity correlated with serum creatinine, suggesting that the degree of inflammatory infiltration may be responsible for, or at least correlated with, the degree of renal injury. Although the study was done in rats and the high dose of iron used could probably not be used in humans, this study delivers a promise that MRI might be used to image renal injury non-invasively. Furthermore, though the authors did not follow the scans past 120 hours, there was some suggestion that the change in signal intensity began to recede as time passed after the renal insult, perhaps mirroring recovery from ARF. If this imaging technique could be optimized for human use, it might also be used to follow the natural history of ARF as well as its response to treatment.

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Fig. 6.3 Time course of MRI after ferumodextran-10 ultrasmall superparamagnetic iron oxide (USPIO) injection in ischaemic ARF. Rats were subjected to 60 minutes of bilateral ischaemia, and ferumodextran-10 USPIO particles were injected at days 0, 1, 2 and 4 after ischaemia. MRI images were obtained 24 hours after USPIO injection. (a) Ischaemia/ reperfusion at 24 hours (n 2). (b) Ischaemia/reperfusion at 48 hours (n 4). (c) Ischaemia/reperfusion at 72 hours (n 2). (d) Ischaemia/reperfusion at 120 hours (n 9). (e) Mean signal intensity change in the outer medulla was measured at different time-points after ischaemia. Source: Jo et al. (2003).

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Non-dialytic management of ARF

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Diuretics, mortality, and non-recovery of renal function in acute renal failure Mehta RL, Pascual MT, Soroko S, Chertow GM. JAMA 2002; 288: 2547–53

B A C K G R O U N D . Oliguria has been recognized as a proxy for the severity of ARF and the likelihood of requiring dialysis. Therefore, in addition to being given to decrease extracellular volume overload, diuretics are often given to patients with ARF to convert oliguric ARF to non-oliguric ARF. However, there is scant, if any, evidence that such a diuretic-induced conversion actually leads to improved clinical outcomes. In this study, Mehta et al. studied 552 ICU patients with ARF who received nephrology consultation to determine whether diuretic use was associated with a difference in all-cause hospital mortality and/or non-recovery of renal function. For patients with a prior history of renal disease, ARF was deﬁned by a BUN level of ≥40 mg/dl or a serum creatinine of ≥2.0 mg/dl, whereas in patients with prior renal disease ARF was deﬁned by a sustained rise in serum creatinine levels of ≥1 mg/dl compared with baseline. Propensity scores were used to adjust for the likelihood of requiring diuretics and severity of illness scores for the underlying patient characteristics. After correction for these factors, they found that diuretic use was associated with a signiﬁcant increase in the risk of death or non-recovery of renal function (odds ratio 1.77; 95% conﬁdence interval [CI] 1.14–2.76). Moreover, among patients who ultimately required dialysis for renal support, those who received diuretics had a longer median time from consultation to ﬁrst dialysis (median difference, 1–2 days; P <0.01). In further analysis, they separated the patients into groups on the basis of diuretic responsiveness, using a cutoff ratio of 1 mg furosemide equivalent per millilitre of urine produced to determine diuretic responsiveness. Using this index of diuretic sensitivity, they found that patients who were insensitive to diuretic therapy (with a mg furosemide/ml urine produced ratio ≥1.0) were largely responsible for the increased mortality found in diuretic-treated patients (Fig. 6.4). I N T E R P R E T A T I O N . The use of high-dose diuretics in critically ill patients with ARF was associated with an increased risk of death and non-recovery of renal function. This difference was mostly accounted for by patients who were relatively unresponsive to diuretics.

Comment Because this study was observational, it is difficult to assign a causative role to diuretics for worse outcomes. There are several interpretations that may explain these results. First, diuretic resistance may merely be a sign that the renal injury is very severe, and thus patients do worse purely on that basis. It is also conceivable that diuretics may be somehow directly toxic in this clinical setting. An additional possibility is that diuretics are neither intrinsically harmful nor beneficial. Rather, the worse outcomes found in this study may be related to another nebulous area of treat-

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Fig. 6.4 Time to death or dialysis from the day of consultation in the intensive care unit. Groups are stratiﬁed by day 1 status. For patients who were diuretic-resistant (mg furosemide equivalent per millilitre ratio 1.0), the numbers at risk for days 1, 2, 3 and 5 were 35, 19, 10 and 3, respectively. Analysis included 411 of the 416 patients who survived at least 7 days after nephrology consultation in the intensive care unit. Data were excluded for ﬁve patients who died at an unknown time. Source: Mehta et al. (2002).

ment of ARF: when to institute definitive renal supportive therapy, i.e. dialysis. In this scenario, waiting for diuretics to take effect in resistant patients might have no effect other than to delay dialysis in critically ill patients, thereby exposing these patients to a uraemic internal milieu for longer than if dialysis had been started immediately. Indeed, if diuretics are administered for ARF early in the hospital course, they might also cause a delay in asking for a nephrology consultation, which has been shown by the authors to lead to increased mortality and morbidity in ICU patients with ARF. However, without a blinded and randomized prospective trial to guide therapy, it is difficult to decide the true role of diuretics in treatment of ARF. Nevertheless, in the interim it seems justified to assert that if patients become increasingly resistant to diuretic therapy, diuretic therapy is unlikely to be of further benefit and more definitive therapy should be administered.

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Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice Miyaji T, Hu X, Yuen PS, et al. Kidney Int 2003; 64: 1620–31

B A C K G R O U N D . Other than supportive volume resuscitation, vasopressors and antibiotics, there remains little in the way of effective medical therapy for limiting the morbidity and mortality of septic shock. Ethyl pyruvate, which may preserve mucosal histology in mesenteric ischaemia/reperfusion injury 13, scavenge reactive oxygen species, downregulate pro-inﬂammatory cytokines, and decrease the activation of nuclear factor-B among other mediators of sepsis, has shown some ability to decrease tissue injury and mortality in animal models of sepsis 14–16. To see if ethyl pyruvate could inhibit renal and other organ injury in septic mice, the authors used a caecal ligation puncture (CLP) model to induce sepsis and multiple organ failure. Mice were subjected to laparotomy, after which the caecum was ligated and then punctured twice with a 21-gauge needle to expose the peritoneum to faecal material. Mice were then given imipenem as well as intravenous saline to mimic a fully-treated septic state at 6 and 18 hours after surgery. In addition, the mice were given a single dose of 0.4 ml Ringer’s lactate (control) or ethyl pyruvate 0, 6 or 12 hours after CLP surgery. The authors found that mice subjected to CLP developed functional and histological ARF and multiple organ damage, whereas sham-operated mice did not. Furthermore, when the animals were killed 24 hours after CLP surgery and blood was drawn, treatment with ethyl pyruvate was associated with decreased serum creatinine (0.14 0.02 vs 0.33 0.07 mg/dl) (Fig. 6.5), reduced histological tubular damage score in both the outer medulla and cortex, and decreased multiple organ injury (based on creatine kinase, hepatic transaminases and amylase concentrations for muscle, liver and pancreatic injury respectively) compared with animals treated with Ringer’s lactate. This effect was persistent even if ethyl pyruvate was given up to 12 hours after the CLP insult. Moreover, when compared with controls, treated animals had lower plasma levels of tumour necrosis factor (TNF-), lower kidney mRNA levels of inﬂammatory mediators such as TNF-, tissue factor, and plasminogen activator-1, and increased level of mRNA for urokinase-like plasminogen activator. I N T E R P R E T A T I O N . A single dose of ethyl pyruvate can inhibit functional and histological renal and other organ damage in a mouse model of sepsis and ARF, and may modulate the inﬂammatory and coagulation pathways associated with sepsis. This treatment appears to be effective even when given 12 hours after the initial insult.

Comment This study highlights some key issues that have not been well understood previously. First, animal models of ARF have often used a single ischaemic or nephrotoxic event to incite injury and do not correspond to the human experience. The CLP sepsis model using aged mice corresponds more to the clinical manifestations of ARF, as it involves appropriate antibiotics and volume repletion, treatments that are commonly used in humans, and hence makes the findings much more relevant. The

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Fig. 6.5 Time course of acute renal failure (ARF) after antibiotic- and volume-resuscitated caecal ligation puncture (CLP) sepsis in aged mice. Animals were killed at the indicated times for measurement of serum creatinine by picric acid (a) or high-performance liquid chromatography (HPLC) (c), and blood urea nitrogen (BUN) (b). *P <0.05 vs 0 hour. Source: Miyaji et al. (2003).

study also used the CYR61 marker and demonstrated that renal injury preceded any elevation in serum creatinine, thus highlighting the low sensitivity of changes in creatinine in reflecting underlying renal injury. The use of ethyl pyruvate provides a unique opportunity to use a relatively simple molecule to influence several downstream events in the inflammatory and coagulation cascades. The effects of ethyl pyruvate are manifested not only in the renal functional changes but also in changes

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in renal histology, supporting the concept that the injury can not only be prevented but can also be ameliorated. Finally, the efficacy of the intervention several hours after the insult makes it much more feasible to use as a therapeutic alternative to treat clinical ARF. We hope that these initial animal experiments will be quickly followed up with clinical trials testing the safety and efficacy of this molecule in humans.

Dialytic management of ARF One of the major unknowns in the management of ARF is the ‘dose’ of dialysis that will produce the best outcomes. Dialytic modalities for ARF range from low-dose therapies such as peritoneal dialysis to supranormal dosing of continuous renal replacement therapies (CRRT) as advocated by Ronco et al. 17 Intuitively, it would seem that a higher dose would prove beneficial, but there is no clear evidence that this is the case. Indeed, a meta-analysis conducted by Kellum et al. on 13 trials comparing intermittent haemodialysis with CRRT showed no difference in mortality (relative risk 0.93 [CI 0.79–1.09]; P 0.29), although some benefit from CRRT was extracted when adjusting for study quality and severity of illness 18. Similarly, a meta-analysis performed by Tonelli et al. on six randomized trials comparing intermittent haemodialysis with CRRT in ICU patients with ARF demonstrated no significant difference in mortality or renal recovery (Fig. 6.6) 19. On the other hand,

Fig. 6.6 Relative risk of death for intermittent haemodialysis: primary analysis (randomized trials). Source: Tonelli et al. (2002) 19.

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Schiffl et al. reported that daily intermittent dialysis therapy led to a decreased mortality rate when compared with an alternate-day dialysis regimen 20. Supporting these results are several studies demonstrating that increased solute clearance leads to better clinical outcomes. Even within modalities, there is no true consensus on what the proper dose might be. Adding to this debate are several studies that have emerged in the past year suggesting that dose may be an important factor in improving outcomes in ARF.

Dose comparisons

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Hemoﬁltration and peritoneal dialysis in infection-associated acute renal failure in Vietnam Phu NH, Hien TT, Mai NT, et al. N Engl J Med 2002; 347: 895–902

B A C K G R O U N D . In countries with limited healthcare resources, peritoneal dialysis (PD) is often used for renal support in critically ill patients with ARF because it is less expensive than haemoﬁltration techniques and because it offers better haemodynamic control than intermittent haemodialysis. However, its relative efﬁcacy in comparison with continuous venovenous haemoﬁltration (CVVH) is unknown. Therefore, the authors conducted an open, randomized comparison of CVVH and PD in 70 critically ill patients with infection-associated ARF in Vietnam. Though the authors did not speciﬁcally deﬁne ARF, any patient in whom urgent renal replacement therapy was indicated to treat ARF was eligible for the study. PD was carried out through a rigid PD catheter, using an open drainage system. Two-litre exchanges were used with a 30-minute dwell time in the abdomen for a total of approximately 70 litres per day. For CVVH, industry-produced lactate-based haemoﬁltration ﬂuid was used, with the amount of haemoﬁltrate set at approximately 25 litres/day. The authors found a marked difference between the groups, with a mortality rate of 47% in the PD-treated patients compared with 15% in the CVVH group (P 0.005) (Fig. 6.7). Furthermore, in patients assigned to CVVH, the rates of resolution of acidosis and of decline in the serum creatinine concentration were more than twice those in the group assigned to PD. In a multivariate analysis, the odds ratio for death was 5.1 (95% CI 1.6–16) and for the need for future dialysis it was 4.7 (95% CI 1.3–17). Cost-effectiveness was also superior in the CVVH-treated group. I N T E R P R E T A T I O N . In critically ill patients with infection-associated ARF, CVVH produces signiﬁcantly better outcomes in terms of correction of metabolic abnormalities, survival and cost-effectiveness when compared with PD.

Comment This study compares two modalities of continuous renal replacement, CVVH and PD for managing ARF in critically ill patients. The study population is not the typical type of patient that would be seen in developed countries as 69% of the patients had severe malaria. As defined in the accompanying editorial, the solute clearance characteristics for PD and CVVH generally reflect the product of the effluent volume and

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Fig. 6.7 Kaplan–Meier plots of time to death (a) and time to the end of the ﬁrst session of renal replacement therapy (b). In (b), arrows indicate censoring of data on patients who died during the ﬁrst session of renal replacement therapy. P values were derived by the log-rank test. Source: Phu et al. (2002).

the sieving coefficient (effluent/plasma concentration of solute). For PD the effluent saturation is estimated to be about 35–40% for urea and 15–20% for creatinine, while for CVVH it is 100% at the settings used in this study. Thus, although the effluent volume for PD was higher than that for CVVH, the creatinine clearance was probably double for CVVH which is supported by the finding that the serum creatinine level decreased much more quickly in the CVVH group than in the PD

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group. While creatinine may be only a fair marker for global solute removal, it seems similarly reasonable to assume that at least part of the impressive comparative benefit of CVVH was due to improved acid–base balance, as acidosis was corrected within 24 hours in most of the patients in the CVVH group but not in the PD group. This study therefore extends the notion that, even in the critical care setting, increased adequacy of solute clearance may lead to improved clinical outcome, as it does in chronic haemodialysis patients. Furthermore, it establishes haemofiltration-based techniques as the clear continuous modality of choice in the treatment of ARF in the critically ill. PD may still be of value in paediatric patients, in whom the small body surface area and relatively lower GFR requirements can be met with PD clearances.

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Effect of ﬁltration volume of continuous venovenous hemoﬁltration in the treatment of patients with acute renal failure in intensive care units Brause M, Neumann A, Schumacher T, Grabensee B, Heering P. Crit Care Med 2003; 31: 841–6

B A C K G R O U N D . In chronic haemodialysis, urea clearance, calculated to assess dialysis quality, has been shown to be an important determinant of morbidity and mortality. However, in the ICU setting therapeutic dose is often guided by laboratory data without any measurement of dialysis quality. Though data from Ronco et al. imply that higher doses may be more effective, especially in sepsis, many patients are prescribed relatively low doses, with a standard ﬁltration rate of 1 litre/hour. The authors therefore undertook to compare mortality, the need for further dialysis, urea clearance, and acid–base balance in a prospective trial comparing 56 ICU patients with ARF treated with a CVVH ﬁltration volume of either 1 litre/hour (group 1) or 1.5 litre/hour (group 2). Anticoagulation was achieved with heparin, and lactate-based substitution ﬂuid was used. ARF was diagnosed if (i) diuresis was not adequate despite diuretics, and a volume overload occurred; (ii) the serum creatinine increased to >265 mol (3 mg/dl); and (iii) serum potassium was >5.9 mmol/l. At the end of the trial, they found that the KT/V for urea was indeed signiﬁcantly greater (P <0.001) in group 2 (0.80 0.09) than in group 1 (0.53 0.007). In addition, pH correction was more rapid in group 2 than in group 1; group 2 had normalized their blood pH by 24 hours after the start of therapy, whereas even after 4 days of therapy group 1 could not reach a normal blood pH. This difference in correction of acidosis was attributed to rapid correction of pH in non-septic patients; ﬁltration volume did not seem to inﬂuence the rate of correction of acidosis in septic patients. Moreover, there were no differences between groups in terms of the clinical course or patient survival (mortality rate 73% in group 1, 69% in group 2; P ns). I N T E R P R E T A T I O N . Higher ﬁltration volumes lead to greater urea clearance in ICU patients with ARF. In addition, acidosis was more quickly corrected in non-septic patients prescribed the higher ﬁltration volume. There was no difference in mortality between the two groups.

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Comment Though there was no mortality difference between the groups, the study does establish the benefit of higher filtration volume for an important intermediate end-point in the treatment of ARF: improvement of acidosis and solute clearance. Considering that a filtration volume of 1.5 litres/hour would still be considered a low dose if compared with the high volumes shown by Ronco et al. to improve mortality in ARF, the results of this trial are not surprising. What this trial does establish, however, is that a standard prescribed filtration rate of 1 litre/hour is inadequate even to accomplish an intermediate end-point. Compounding this problem are the many technical obstacles in actually delivering even a low prescribed dose. Venkataraman et al. recently reported that, in their tertiary care facility, the mean prescribed flow rate was 1.36 0.31 litres/hour, but at least in part because patients were dialysed for an average of only 16.1 hours/day, the actual delivered dose was only two-thirds of the prescribed dose 21. The combination of low prescribed dose and the logistical challenges inherent in CRRT may therefore mean that these critically ill patients, especially those with sepsis, may be getting a woefully inadequate amount of renal replacement. Consequently, the results of these studies highlight the need for further research into optimal dialysis dosing for the disparate ARF populations as well as into methods to improve CRRT system life.

Hybrid dialytic therapies As the pathophysiology of sepsis is uncovered step by step, the role of inflammatory cytokines as central figures in determining the natural history of the illness has become accepted. Initial plasma concentrations of cytokines such as TNF- and interleukin (IL)-6, for example, have been correlated with patient outcome 22,23. This paradigm has led investigators to attempt removal of the offending factors from the circulation as a possible method to short-circuit the spiralling cycle of sepsis. Acute renal failure associated with sepsis is often compensated for with dialysis; however, culprit cytokines and other toxins that are at the core of the underlying physiology may be very poorly cleared by dialysis because they are too large to pass through the membrane pores 24. Therefore, dialysis as it exists today remains in large part a supportive modality in the ICU setting. Initially, adsorption of inflammatory mediators to a haemofilter during continuous haemofiltration was thought to be a viable strategy. However, saturation of the membrane occurs very quickly 25,26, making any substantial change in plasma cytokine concentrations unlikely with current technology. Consequently, other methods, including coupled plasmafiltration–adsorption (CPFA) systems, haemofiltration with highly permeable membranes, and even cell-based therapies have recently received attention.

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Hemodynamic response to coupled plasmaﬁltration–adsorption in human septic shock Formica M, Olivieri C, Livigni S, et al. Intensive Care Med 2003; 29: 703–8

B A C K G R O U N D . Because any putative harmful cytokines reside in the plasma partition of the blood, plasma exchange has been considered a possible method to short-circuit the pro-inﬂammatory cascade that characterizes septic shock. In this paper, the authors used continuous plasmaﬁltration in parallel with a hydrophobic sorbent (to adsorb cytokines) and in series with a haemoﬁlter (Fig. 6.8) in an effort to overcome the low cytokine sieving coefﬁcients seen in conventional CRRT. Twelve patients with septic shock, as deﬁned by the American College of Chest Physicians criteria, were enrolled in a prospective but non-randomized and non-controlled trial. Of the 12 patients enrolled, four had ARF (not deﬁned by the authors) as part of their sepsis syndrome. The procedure was performed on a three-pump, modular extracorporeal blood puriﬁcation system consisting of a plasmaﬁlter (polyethersulfone with a size cut-off of 800 kDa), a hydrophobic resin cartridge (70 g with a surface of about 700 m2/g), and a synthetic, high-permeability polyethersulfone haemoﬁlter. Sorbent cartridges were changed every 3 hours in accordance with previously published in vitro data so as to maximize cytokine adsorption. Patients received a median of ten sessions (range 4–18), lasting approximately 10 hours each, with an unspeciﬁed amount of time between treatments. The authors then measured clinical variables such as mean arterial pressure (MAP), cardiac index, systemic vascular index (SVR), PO2/FiO2 and vasopressor requirement, as well as Creactive protein (CRP) as a measure of systemic inﬂammation. They found that MAP, cardiac index, SVR, PO2/FiO2 and vasopressor requirement all improved signiﬁcantly when individual post-treatment values were compared with pre-treatment values (P <0.001 for all variables). Furthermore, there was a sharp decline in CRP level from before the ﬁrst treatment until after the last treatment; the level decreased from 29.3 7.3 to 7.9 4.8 mg/l; P <0.0001). When two patients were excluded from the

Fig. 6.8 Scheme of coupled plasmaﬁltration–adsorption. Source: Formica et al. (2003).

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analysis (one of whom was transferred to another hospital 1 day after enrolment, and one of whom died from surgical complications after two treatments), they found survival was 90% at day 28 and 70% at day 90. Some technical problems occurred in 21% of the sessions but were mostly related to software failure or circuit coagulation; this improved over the treatment period, the last 70 treatments only having six technical failures. There were no apparent untoward clinical effects during the treatments. I N T E R P R E T A T I O N . Coupled plasmaﬁltration-adsorption was a feasible and safe extracorporeal treatment and exerted a remakable improvement in the haemodynamics, the pulmonary function, and the outcome in septic shock patients with or without concomitant ARF.

Comment There are many limitations to this study beyond even its non-randomized and noncontrolled nature and its small sample size. First, no indication is given of why the patients had widely ranging numbers of treatments. Secondly, it is not clear how much time elapsed between the treatments and whether the time between treatments was standardized. Thirdly, though the decrease in CRP is impressive and implies that the inflammatory state was diminished by the treatments, this decrease may be confounded by the fact that CRP was only approximately 100 kDa and was therefore probably itself cleared by the treatment. Nevertheless, this study brings to light several important concepts. Though it is unclear exactly how the treatment was administered, it was associated with a survival rate of 90% at 28 days, which is greater (but not necessarily significantly so) than the 60% rate predicted by the patients’ mean APACHE II score. In addition, the treatment was observed to be safe and probably did improve haemodynamics and pulmonary function. Since the intervention was performed on some patients without ARF and there were no adverse consequences, it seems plausible that it might be implemented early in sepsis to interrupt cytokine-mediated damage, thereby possibly even preventing ARF. Two other recent papers have advanced plasma exchange as a possible treatment for septic shock with ARF. Using a similar CPFA system in a small cohort of ICU patients with sepsis and ARF, Ronco et al. demonstrated haemodynamic benefit and improved leucocyte function in CPFA-treated patients compared with patients treated with conventional continuous venovenous haemodiafiltration 27. Furthermore, Stegmayr et al., in a retrospective study of 76 ICU patients with sepsis, multi-organ failure including ARF, and disseminated intravascular coagulation (DIC), found that plasma exchange (by centrifugation), performed until DIC was reversed, led to a survival rate of 82% 28. Despite the uncontrolled, unrandomized and very lengthy duration of the study (more than 18 years), a mortality rate of only 18% in a patient population that would be expected to have a mortality rate of >80% establishes plasma exchange as a very promising therapy in this setting. Though these technologies (especially CPFA) are in their infancy in the ICU setting, these small studies strongly suggest that plasma exchange with or without added cytokine adsorption may be a viable strategy for the treatment and possibly prevention of ARF in sepsis.

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Intermittent high permeability hemoﬁltration in septic patients with acute renal failure Morgera S, Rocktaschel J, Haase M, et al. Intensive Care Med 2003; 29: 1989–95

B A C K G R O U N D . Conventional haemoﬁltration membranes have a pore diameter that allows only molecules under 30–50 kDa to be ﬁltered. Unfortunately, many of the inﬂammatory cytokines thought to be involved in the initiation and maintenance of septic shock are larger than this, and therefore cannot be eliminated from the circulation by conventional haemoﬁltration. High-permeability haemoﬁltration (HP-HF), which uses membranes with larger pores so as to allow the ﬁltration of these cytokines, has been studied in an animal model of Staphylococcus aureus sepsis, and was found to have some survival advantage compared with conventional haemoﬁltration 29. Encouraged by this positive animal data, the authors sought to demonstrate the clinical safety of such a procedure in humans, as well as the efﬁcacy with which the procedure could clear two inﬂammatory cytokines: TNF- and IL-6. Sixteen patients with multiple organ failure due to septic shock were enrolled in the study, although the authors did not specify which organs were affected. For the study period of 5 days, all patients were given the same treatment, which consisted of 12 continuous hours of HP-HF alternating with 12 hours of conventional haemoﬁltration (CVVH). HP-HF was performed with a specially developed polyamide haemoﬁlter that was highly permeable to substances with a weight up to 60 kDa. CVVH was performed with a standard high-ﬂux polyamide membrane with a permeability cut-off of roughly 30 kDa. Filtration was set at the low rate of 1 litre/hour because the haemodynamic consequences of HP-HF were unknown at the time the experiment was designed. The authors found that HP-HF did not seem to alter haemodynamics signiﬁcantly, as measured by cardiac output, mean arterial pressure or central venous pressure. Furthermore, they found that the sieving coefﬁcient for IL-6 approached 1, which resulted in a decrease in the plasma IL-6 burden, as estimated by the area under the curve for plasma IL-6. The calculated clearance of IL-6 was roughly 15 ml/minute over the study period. Severity of illness scores trended towards an improvement during HP-HF treatment but the result was non-signiﬁcant (P 0.09). However, HP-HF was associated with a signiﬁcant 12-hour transmembrane protein loss of 7.6 g and necessitated colloid replacement of 140 ml of colloid (human albumin or plasma) over the study period. Moreover, elimination of TNF- was so poor that the authors did not calculate a sieving coefﬁcient and clearance rate. I N T E R P R E T A T I O N . HP-HF as prescribed in this study did not have a signiﬁcant effect on haemodynamics but was associated with signiﬁcant transmembrane protein loss that required colloid replacement. It was able to decrease plasma levels of IL-6 but was ineffective in removing TNF- from the circulation.

Comment Probably more important than the actual degree of cytokine reduction is the proof of concept presented here that HP-HF is well tolerated and was able to decrease the plasma burden of an inflammatory cytokine in humans. The results of this study,

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coupled with a corollary study by the same group which demonstrated improved peripheral blood mononuclear cell proliferation in the HP-HF group 30, suggest that cytokine removal by HP-HF may be a promising technology for the treatment of ARF and sepsis. Nevertheless, no true clinical conclusions can be drawn from these studies as there were no clinical end-points measured (ICU/hospital stay, mortality, etc.). Because HP-HF is non-specific in that it may remove anti- as well as proinflammatory cytokines, the authors acknowledge that it is conceivable that systemic inflammation is worsened as a result of greater removal of anti-inflammatory cytokines. That an important harmful mediator such as TNF- was left behind in the circulation highlights the notion that there may be some unintended specificity of HP-HF (even if based just on size) that could sway the balance towards worsened inflammation. This possibility does seem unlikely, given the success of HP-HF in the animal model, but does require further study for clarification.

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Cell therapy with a tissue-engineered kidney reduces the multiple-organ consequences of septic shock Humes HD, Bufﬁngton DA, Fissell WH. Critical Care Med 2003; 31: 2421–8

B A C K G R O U N D . Though dialysis technology has improved and is effective in substituting for the small solute clearance ability of the kidney, it does not replace many metabolic activities normally carried out by the tubular cells. Given that ARF associated with sepsis occurs mostly as a result of necrosis of the proximal tubule cells in response to endotoxin and ischaemia, the return of essential functions of these cells (such as ammoniagenesis and glutathione reclamation), endocrine activity (such as vitamin D3 activation) and cytokine homeostasis might provide additional physiological replacement activities to change the current natural history of this disease process 31. To test this hypothesis, the authors employed a novel tissue-engineered bioartiﬁcial kidney consisting of a conventional haemoﬁltration cartridge in series with a renal tubule assist device containing 109 cultured porcine renal proximal tubule cells in an animal model of Gram-negative sepsis (Fig. 6.9). After establishing appropriate vascular access, 100 ml of broth containing large amounts of Escherichia coli was instilled into the peritoneal cavities of 14 adult pigs. Conventional continuous venovenous haemodiaﬁltration (CVVHDF) was then instituted along with a sham or cell renal tubule assist device (RAD). The pigs were then resuscitated identically with 80 ml/kg crystalloid and 80 ml/kg of colloid. No animals received vasopressor or inotropic agents. Collected at periodic intervals were haemodynamic data, blood for measurement of endotoxin levels and several other cytokines, and peripheral mononuclear cells for the level of endotoxin-induced IL-6 secretion. Animals were observed until no arterial waveform could be detected, at which time the experiment was terminated and the kidneys were removed for histological analysis. Septic shock resulted in histological ATN within hours in the kidneys of all animals. Pigs treated with the RAD had signiﬁcantly higher cardiac outputs and renal blood ﬂow and lower IL-6 and interferon- than sham-treated animals. Peripheral blood mononuclear cells isolated from RAD-treated animals were able to produce signiﬁcantly greater amounts of IL-6 in

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Fig. 6.9 Schematic diagram of the blood ﬂow circuit (dark lines) and ultraﬁltrate circuit (light lines) of the bioartiﬁcial kidney. RAD, renal tubule assist device. Source: Humes et al. (2003).

response to endotoxin than cells from sham-treated animals. In total, the improvement in haemodynamics and cytokine levels led to nearly a doubling of survival time (about 5 hours vs about 9 hours; P <0.005, exact ﬁgures not given) in the RAD-treated group compared with the sham-treated group. There was no difference between groups in the plasma levels of TNF-, IL-1, IL-2, IL-4, IL-6, IL-8 or IL-10. I N T E R P R E T A T I O N . Renal cell therapy ameliorates cardiac and vascular dysfunction, can alter systemic cytokine abnormalities, and improves survival time in an animal model of severe Gram-negative septic shock.

Comment This exciting technology emphasizes the complex role of the kidney not only in clearance of solutes but also in far-reaching immunomodulatory activities. Although the authors used an animal model and thus could not necessarily extrapolate the results of the study to humans, this report is just one of several pilot studies in several different models using this technology, all of which have been positive. The authors have previously shown in vitro that the cells within the RAD retain differentiated transport properties, metabolic processes and other important endocrinological activity 32. Furthermore, the RAD–CVVH system was able to replace filtration, transport, metabolic and endocrinological functions of the kidney in acutely uraemic dogs, both in non-septic 33 and septic 34 settings. Early-stage human clinical trials are currently under way; if they show as much promise as did the animal models, nephrologists may soon have an important new tool for the more comprehensive replacement of kidney function.

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Emerging areas of research Even as dialytic technology advances, as described above, there is still the hope that we may some day be able to harness the body’s own reparative mechanisms in a directed manner, thereby obviating the need for what may be, by then, considered primitive renal replacement modalities. While we are still far from this lofty goal, ongoing stem and precursor cell research may one day deliver this promise.

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Bone marrow stem cells contribute to repair of the ischaemically injured renal tubule Kale S, Karihaloo A, Clark PR, Kashgarian M, Krause DS, Cantley LG. J Clin Invest 2003; 112: 42–9

B A C K G R O U N D . Recovery from ATN is traditionally thought to occur when surviving cells local to the injured area dedifferentiate into a more primitive, mesenchymal phenotype, and then migrate to the denuded region to re-establish an intact epithelium. However, efforts to use growth factors to encourage these dedifferentiated local progenitor cells to act in the treatment of ATN in humans have met with only moderate success. Recent studies have shown, however, that the plasticity of bone marrow-derived stem cells (BMSCs) can allow them to cross lineage boundaries and participate in the repair of other tissues, such as those of the heart, liver and brain 35–37. Kale et al. demonstrate in this study that BSMCs may actually contribute to tubular repair in ATN, contrary to traditional teaching. Mice were given a sublethal dose of radiation to eliminate endogenous bone marrow cells. They were then transplanted with bone marrow from Rosa26 mice, which constitutively express -galactosidase via a transgenic bacterial lacZ gene. To see if BSMCs might be actively involved in the repair of the tubule, ischaemic necrosis was induced by ischaemia/reperfusion injury in one kidney and the animal was killed for histological analysis. The outer medulla of control and non-injured kidneys had only 2.4–3.0% -galactosidase-positive cells, consistent with the above results; however, in the outer medulla of the ischaemic kidney, 20.9% of the previously necrotic tubules had cells positive for -galactosidase activity (Table 6.1). Subsequently, they found that stem cell transplantation (SCT) after bone marrow ablation allowed mice to recover renal function (measured by serum BUN) after 7 days, whereas without SCT the mice did not recover renal function over the same period of time. I N T E R P R E T A T I O N . In mice, BSMCs are mobilized into the circulation by transient renal ischaemia and home speciﬁcally to injured regions of the renal tubule. There, they differentiate into tubular epithelial cells and are responsible in large part for the re-establishment of an intact epithelial surface. Stem cell transplants after bone marrow ablation seemed to limit the degree of ARF and allow recovery within 7 days.

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Table 6.1 Quantitation of -galactosidase–positive tubules Cortex (+ for BMSCs/total counted)

%

Outer medulla (+ for BMSCs/ total counted)

%

19/256 7/247 14/242 5/231 15/217 11/196

3.5 2.8 5.7 2.2 6.9 5.6 Average = 4.5 ± 0.8

43/225 40/225 55/225 41/233 54/198 39/203

19.1 17.8 24.4 17.6 27.3 19.2 Average = 20.9 ± 1.6

Contralateral kidney 11/213 11/269 12/239 10/225 10/200 9/225

5.2 4.1 5.0 4.4 5.0 4.0 Average = 4.6 ± 0.2

9/255 8/247 6/230 7/225 6/200 5/194

3.5 3.2 2.6 3.1 3.0 2.6 Average = 3.0 ± 0.1

3.8 2.2 3.4 5.7 3.9 Average = 3.8 ± 0.6

5/208 1/202 4/251 8/215 9/225

2.4 0.5 1.6 3.7 4.0 Average = 2.4 ± 0.7

Ischaemia reflow Ischaemic kidney

Control 8/209 5/230 8/236 12/209 8/205

Mice undergoing whole BMT were subjected 15 weeks later to unilateral 1/R (n = 6) or sham operation (control, n = 5), followed by 1 week of recovery and quantitation of the number of ß-galactosidase–positive tubules in the cortex and outer medulla of kidney sections. For each animal, between 194 and 269 tubules were counted from four random fields and scored for the presence or absence of blue cells. Data are presented as ± SEM. Source: Kale et al. (2003).

Comment The impressive results from this very elegant study suggest that the repair of the tubule after ischaemic ATN may be secondary to mobilization of BMSCs from the bone marrow into the peripheral blood and finally to the area of injury. Though the mechanisms by which one might harness and augment this phenomenon to treat human ATN are entirely unknown at this early stage, these results provide a very important theoretical basis and proof of concept that may act as a springboard for further research.

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Conclusion Advances continue to be made in the diagnosis and management of ARF. It is evident that we have a lot to learn about this disease and its effects. We believe that, in addition to the areas highlighted, a focus on the timing of interventions to specific timepoints in the course of the disease will be required. Future research in defining the natural (albeit modified by concomitant therapy for the underlying diseases) history of ARF and correlating time-points for targeted intervention is desperately needed if we are to make headway in reducing the burden of the disease. Given the increasing interest in ARF research, we are confident that progress will continue to be made and further evidence to support new therapeutic strategies will be obtained.

References 1. Canto JG, Every NR, Magid DJ, Rogers WJ, Malmgren JA, Frederick PD, French WJ,

2.

3. 4. 5.

6.

7.

8.

Tiefenbrunn AJ, Misra VK, Kiefe CI, Barron HV. The volume of primary angioplasty procedures and survival after acute myocardial infarction. National Registry of Myocardial Infarction 2 Investigators. N Engl J Med 2000; 342: 1573–80. Liano F, Junco E, Pascual J, Madero R, Verde E. The spectrum of acute renal failure in the intensive care unit compared with that seen in other settings. The Madrid Acute Renal Failure Study Group. Kidney Int Suppl 1998; 66: S16–S24. Mehta RL, Chertow GM. Acute renal failure definitions and classification: time for change? J Am Soc Nephrol 2003; 14: 2178–87. Venkataram R, Kellum JA. The role of diuretic agents in the management of acute renal failure. Contrib Nephrol 2001; 132: 158–70. Denton MD, Chertow GM, Brady HR. ‘Renal-dose’ dopamine for the treatment of acute renal failure: scientific rationale, experimental studies, and clinical trials. Kidney Int 1996; 50: 4–14. Allgren RL, Marbury TC, Rahman SN, Weisberg LS, Fenves AZ, Lafayette RA, Sweet RM, Genter FC, Kurnik BR, Conger JD, Sayegh MH. Anaritide in acute tubular necrosis. Auriculin Anaritide Acute Renal Failure Study Group. N Engl J Med 1997; 336: 828–34. Lewis J, Salem MM, Chertow GM, Weisberg LS, McGrew F, Marbury TC, Allgren RL. Atrial natriuretic factor in oliguric acute renal failure. Anaritide Acute Renal Failure Study Group. Am J Kidney Dis 2000; 36: 767–74. Hirschberg R, Kopple J, Lipsett P, Benjamin E, Minei J, Albertson T, Munger M, Metzler M, Zaloga G, Murray M, Lowry S, Conger J, McKeown W, O’Shea M, Baughman R, Wood K, Haupt M, Kaiser R, Simms H, Warnock D, Summer W, Hintz R, Myers B, Haenftling K, Capra W, et al. Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure. Kidney Int 1999; 55: 2423–32.

06 YIRenMed I 115-141 FINAL

140

19/4/05 3:47 pm

Page 140

II . A C U T E R E N A L F A I L U R E

9. Wang A, Holcslaw T, Bashore TM, Freed MI, Miller D, Rudnick MR, Szerlip H, Thames

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20. 21.

22.

23.

MD, Davidson CJ, Shusterman N, Schwab SJ. Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int 2000; 57: 1675–80. Muramatsu Y, Tsujie M, Kohda Y, Pham B, Perantoni AO, Zhao H, Jo SK, Yuen PS, Craig L, Hu X, Star RA. Early detection of cysteine rich protein 61 (CYR61, CCN1) in urine following renal ischaemic reperfusion injury. Kidney Int 2002; 62: 1601–10. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 2002; 62: 237–44. Mehta RL, McDonald B, Gabbai F, Pahl M, Farkas A, Pascual MT, Zhuang S, Kaplan RM, Chertow GM. Nephrology consultation in acute renal failure: does timing matter? Am J Med 2002; 113: 456–61. Sims CA, Wattanasirichaigoon S, Menconi MJ, Ajami AM, Fink MP. Ringer’s ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats. Crit Care Med 2001; 29: 1513–18. Ulloa L, Ochani M, Yang H, Tanovic M, Halperin D, Yang R, Czura CJ, Fink MP, Tracey KJ. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci USA 2002; 99: 12351–6. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ. HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999; 285: 248–51. Yang R, Gallo DJ, Baust JJ, Uchiyama T, Watkins SK, Delude RL, Fink MP. Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock. Am J Physiol Gastrointest Liver Physiol 2002; 283: G212–21. Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca G. Effects of different doses in continuous venovenous hemofiltration on outcomes of acute renal failure: a prospective randomized trial. Lancet 2000; 355: 26–30. Kellum JA, Angus DC, Johnson JP, Leblanc M, Griffin M, Ramakrishnan N, LindeZwirble WT. Continuous versus intermittent renal-replacement therapy: a meta-analysis. Intensive Care Med 2002; 28: 29–37. Tonelli M, Manns B, Feller-Kopman D. Acute renal failure in the intensive care unit: a systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis 2002; 40: 875–85. Schiffl H, Lang SM, Fischer R. Daily hemodialysis and the outcome of acute renal failure. New Engl J Med 2002; 346: 305–10. Venkataraman R, Kellum JA, Palevsky P. Dosing patterns for continuous renal-replacement therapy at a large, academic medical center in the United States. J Crit Care 2002; 17: 246–50. Pinsky MR, Vincent JL, Deviere J, Alegre M, Kahn RJ, Dupont E. Serum cytokine levels in human septic shock; relation to multiple-system organ failure and mortality. Chest 1993; 103: 565–76. Damas P, Reuter A, Gysen P, Demonty J, Lamy M, Franchimont P. Tumor necrosis factor and interleukin-1 serum levels during severe sepsis in humans. Crit Care Med 1989; 17: 975–8.

06 YIRenMed I 115-141 FINAL

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Page 141

RENAL SUPPORT AND TREATMENT OF ARF

141

24. Van Deuren M, van der Meer JW. Hemofiltration in septic patients is not able to alter the 25. 26. 27.

28.

29.

30.

31. 32.

33.

34.

35. 36. 37.

plasma concentration of cytokines therapeutically. Intensive Care Med 2000; 26: 1176–8. Silvester W. Mediator removal with CRRT: complement and cytokines. Am J Kidney Dis 1997; 30: 38–43. Goldfarb S, Golper T. Proinflammatory cytokines and hemofiltration membranes. J Am Soc Nephrol 1994; 5: 228–32. Ronco C, Brendolan A, Lonnemann G, Bellomo R, Piccinni P, Digito A, Dan M, Irone M, La Greca G, Inguaggiato P, Maggiore U, De Nitti C, Wratten ML, Ricci Z, Tetta C. A pilot study of coupled plasma filtration with adsorption in septic shock. Crit Care Med 2002; 30: 1250–5. Stegmayr BG, Banga R, Berggren L, Norda R, Rydvall A, Vikerfors T. Plasma exchange as rescue therapy in multiple organ failure including acute renal failure. Crit Care Med 2003; 31: 1730–6. Lee PA, Weger GW, Pryor RW, Matson JR. Effects of filter pore size on efficacy of continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine. Crit Care Med 1998; 26: 730–7. Morgera S, Haase M, Rocktaschel J, Bohler T, von Heymann C, Vargas-Hein O, Krausch D, Zuckermann-Becker H, Muller JM, Kox WJ, Neumayer HH. High permeability haemofiltration improves peripheral blood mononuclear cell proliferation in septic patients with acute renal failure. Nephrol Dial Transplant 2003; 18: 2570–6. Humes HD. Bioartificial kidney for full renal-replacement therapy. Semin Nephrol 2000; 20: 71–82. Humes HD, MacKay SM, Funke AJ, Buffington DA. Tissue engineering of a bioartificial renal tubule assist device: In vitro transport and metabolic characteristics. Kidney Int 1999; 55: 2502–14. Humes HD, Buffington DA, MacKay SM, Funke AJ, Weitzel WF. Replacement of renal function in uremic animals with a tissue-engineered kidney. Nat Biotechnol 1999; 17: 451–5. Fissell WH, Lou L, Abrishami S, Buffington DA, Humes HD. Bioartificial kidney ameliorates gram-negative bacteria-induced septic shock in uremic animals. J Am Soc Nephrol 2003; 14: 454–61. Eglitis MA, Mezey E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 1997; 94: 4080–5. Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, Henegariu O, Krause DS. Liver from bone marrow in humans. Hepatology 2000; 32: 11–16. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 2001; 98: 10344–9.

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7 Glomerulonephritis GERALD APPEL, ALICE APPEL

Introduction Although the clinical manifestations of glomerular diseases are limited, damage to the glomeruli of the kidney can occur through many different mechanisms. In some primary renal diseases the process is limited to the kidney while in others it is part of a generalized systemic process. Some recent papers addressing glomerulonephritis deal specifically with the underlying mechanisms of glomerular damage. For example, studies in animal models have clarified the pathogenic role of the circulating antibody ANCA (anti-neutrophil cytoplasmic antibody) in patients with microscopic polyangiitis and Wegener’s granulomatosis. Other studies have defined the significance of receptors for the immunoglobulin A (IgA) molecule in patients with IgA nephropathy or the role of a permeability factor in focal segmental glomerulosclerosis. Still others have better defined the clinical presentation and course of newly defined forms of glomerular disease, such as fibrillary glomerulonephritis, or have dealt with newer classification and epidemiological prognostic factors in lupus nephritis. Finally, many important efforts focus on newer, potentially more effective and safer treatment regimens of glomerular disease, including lupus, rapidly progressive glomerulonephritis, membranous nephropathy, and others. This review will discuss a number of important recent papers dealing with these issues.

Lupus nephritis Defining newer effective and safe regimens for the treatment of lupus nephritis has been a challenging area for nephrologists, rheumatologists and other clinicians. Older studies, while documenting the superior efficacy of intravenous cyclophosphamide compared with corticosteroids, did not show superiority over oral regimens. Side effects of prolonged or repeated courses of cyclophosphamide include alopecia, amenorrhoea, bladder haemorrhage and the risk of serious infections, and malignancies in the long term. Moreover, older studies were complicated by methodological flaws. Several recent studies document an adverse effect on outcome in certain racial groups, such as African-Americans. While it is unclear whether this is related to © Atlas Medical Publishing Ltd

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socio-economic or biological factors, treatment regimens in the USA must include significant numbers of blacks and they must be equally stratified. The histological definitions of the patterns of lupus according to the World Health Organization (WHO) classification are neither accurate nor precise by modern standards, and have led to some confusion. A revised uniformly accepted classification would be of great value in both treating the individual patient and performing and comparing treatment studies from different areas, and a recent consensus publication may have achieved this.

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Sequential therapies for proliferative lupus nephritis Contreras G, Pardo V, Leclercq B, et al. N Engl J Med 2004; 350: 971–80

B A C K G R O U N D . Data from a number of small studies have suggested that AfricanAmerican patients may respond poorly to conventional therapy for lupus nephritis. There is also significant concern about the best maintenance therapy to offer patients, especially those perceived to be at highest risk of relapse. This study attempted to address both these issues by enrolling a high-risk group of patients, treating all with the same induction therapy and subsequently randomizing them to continuing cyclophosphamide (a conventional approach for high-risk patients), oral azathioprine (as a less toxic long-term immunosuppressive agent) or mycophenolate mofetil (which has shown significant benefit in one controlled trial in a potentially lower-risk population). This was an open-label, randomized controlled trial of 59 patients with lupus nephritis who received induction therapy with intravenous cyclophosphamide and maintenance therapy with one of three regimens: intravenous cyclophosphamide pulses continued every third month (0.5–1.0 g/m2), oral azathioprine (0.5–3.0 mg/kg per day) or oral mycophenolate mofetil (0.5–3 g per day), all with low dose prednisolone (<0.5 mg/kg per day). Patients with WHO Classes III, IV or V lupus nephritis received induction therapy with four to seven monthly pulses of 0.5–1.0 g/m2 intravenous cyclophosphamide plus oral prednisone. I N T E R P R E T A T I O N . At the end of the induction phase 83% of patients were in remission. During maintenance therapy, five patients died (four in the cyclophosphamide group and one in the mycophenolate mofetil group), and chronic renal failure developed in five (three in the cyclophosphamide group and one each in the azathioprine and mycophenolate mofetil groups). Patient survival and time free of death or chronic renal failure (at 72 months) was better for the mycophenolate mofetil and azathioprine groups than for the intravenous cyclophosphamide group (P = 0.05 and 0.009 respectively; Fig. 7.1). Time free of relapse was best for the mycophenolate mofetil group. Infections, hospitalization days, nausea, vomiting and amenorrhoea were lower for the two oral regimens than for cyclophosphamide.

Comment This study included a significant number of African-Americans with lupus nephritis, a group with a poor renal and overall prognosis. It demonstrated a very high success rate after initial induction therapy. Even more importantly, it showed that switching

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Fig. 7.1 Kaplan–Meier estimates of patient survival (upper panel) and event-free survival (lower panel). Source: Contreras et al. (2004).

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to less toxic regimens for maintenance therapy can be effective, with fewer side effects. This study will have a major impact on the treatment of lupus nephritis patients in the USA. It is unclear, however, whether it is relevant to Caucasian patients, who may already be receiving less intensive induction and maintenance regimens with less toxicity. Moreover, it does not show clear superiority between the two oral maintenance regimens of azathioprine (which is available as a generic agent and is far less expensive) and the newer agent mycophenolate mofetil.

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The classification of glomerulonephritis in systemic lupus erythematosus revisited Weening JJ, D’Agati VD, Schwartz MM, et al. Kidney Int 2004; 65: 521–30

B A C K G R O U N D . The WHO classification of lupus nephritis reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathological studies have suggested a need for improved categorization and terminology. This is a critical issue for patient care, for the comparison of outcomes and for therapeutic trials. A consensus among pathologists is imperative to standardize biopsy interpretation and reporting. I N T E R P R E T A T I O N . This paper describes a revised classification scheme (Table 7.1). This revised classification restricts Class I and Class II to pure mesangial involvement (Class I with no hypercellularity but with mesangial immune deposits, Class II with mesangial hypercellularity as well). Class III, focal glomerulonephritis, involves fewer than 50% of the total glomeruli and is divided into active and chronic lesions. Class IV, diffuse glomerulonephritis, involves over 50% of the total glomeruli on the biopsy and is divided into lesions that involve parts of the glomerulus (segmental, IV-S) and those involving the whole glomerulus global (IV-G) as well as into active and chronic forms. Class V is membranous lupus and Class VI is an advanced sclerosing glomerular disease. A biopsy may show Class V membranous plus a proliferative lesion, and would then be classified as Class V + III or Class V + IV.

Comment This classification, developed by a large group of international expert nephropathologists with clinical nephrology and rheumatology advice, has several advantages over the older WHO classification first used in 1982. It provides a clear, uniform description of each lesion, allowing comparison between the biopsies of an individual and allowing precise classification for inclusion in treatment trials. By using the terms ‘active’ and ‘chronic’ after ‘proliferative lesions’, it serves as a guide to therapy. Chronic sclerosing lesions, as opposed to active inflammatory lesions, would be untreatable by immunosuppressive regimens. It separates pure membranous lupus with its unique prognosis from those biopsies with superimposed proliferative lesions. In the older classification, a VC or VD membranous biopsy was really one with a proliferative lesion superimposed and actually deserved therapy aimed at the prolifera-

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Table 7.1 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification of lupus nephritis (2003) Class I

Minimal mesangial lupus nephritis Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence

Class II

Mesangial proliferative lupus nephritis Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy, with mesangial immune deposits A few isolated subepithelial or subendothelial deposits may be visible by immunofluorescence or electron microscopy, but not by light microscopy

Class III

Focal lupus nephritis* Active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations Active lesions: focal proliferative lupus nephritis Active and chronic lesions: focal proliferative and sclerosing lupus nephritis Chronic inactive lesions with glomerular scars: focal sclerosing lupus nephritis

Class III (A) Class III (A/C) Class III (C) Class IV

Diffuse lupus nephritis† Active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving ≥ 50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations. This class is divided into diffuse segmental (IV-S) lupus nephritis when ≥ 50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) lupus nephritis when ≥ 50% of the involved glomeruli have global lesions. Segmental glomerulonephritis is defined as a glomerular lesion that involves less than half of the glomerular tuft. This class includes cases with diffuse wire loop deposits but with little or no glomerular proliferation Class IV-S (A) Active lesions: diffuse segmental proliferative lupus nephritis Class IV-G (A) Active lesions: diffuse global proliferative lupus nephritis Class IV-S (A/C) Active and chronic lesions: diffuse segmental proliferative and sclerosing lupus nephritis Class IV-G (A/C) Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritis Class IV-S (C) Chronic inactive lesions with scars: diffuse segmental sclerosing lupus nephritis Class IV-G (C) Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis Class V

Membranous lupus nephritis Global or segmental subepithelial immune deposits or their morphological sequelae by light microscopy and by immunofluorescence or electron microscopy, with or without mesangial alterations Class V lupus nephritis may occur in combination with Class III or IV, in which case both will be diagnosed. Class V lupus nephritis may show advanced sclerosis

Class VI

Advanced sclerotic lupus nephritis ≥ 90% of glomeruli globally sclerosed without residual activity

Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, severity of arteriosclerosis or other vascular lesions. * Indicate the proportion of glomeruli with active and with sclerotic lesions. † Indicate the proportion of glomeruli with fibrinoid necrosis and/or cellular crescents. Source: Weening et al. (2004)

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tive lesion. There remain some limitations even in this classification. Although vascular and tubulointerstitial changes are to be noted in the biopsy report, they are, as in the older classification, relegated to a step-down role despite their importance in some individuals. The value of separating segmental and global diffuse proliferative biopsies (Class IV-S and Class IV-G) will have to be confirmed in future studies.

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Prognosis in proliferative lupus nephritis: the role of socio-economic status and race/ethnicity Barr RG, Seliger S, Appel GB, et al. Nephrol Dial Transplant 2003; 18: 2039–46

B A C K G R O U N D . Studies of proliferative lupus nephritis have suggested that AfricanAmerican patients have a poorer prognosis than whites. No previous study has examined socio-economic status simultaneously. This retrospective cohort study of 128 patients in New York City with proliferative lupus nephritis evaluated the rate of progression of proliferative lupus nephritis (the time to doubling of serum creatinine) among a tri-ethnic population and correlated this with clinical, racial/ethnic and socio-economic features using individual and census-based neighbourhood data. I N T E R P R E T A T I O N . At 5 years 67% and at 10 years 59% of patients had not progressed to doubling of their serum creatinine. By multivariate analysis, elevated serum creatinine and hypertension at biopsy correlated with a poor renal outcome, as did living in a neighbourhood with high poverty (Fig. 7.2), and public rather than private insurance. Residence in a poor

Fig. 7.2 Progression of proliferative lupus nephritis over time, stratified by proportion in poverty. Source: Barr et al. (2003).

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neighbourhood remained associated with progression of disease even after adjustment for age, sex, creatinine, hypertension and race/ethnicity (relative risk 3.5; 95% confidence interval 1.2–11; P = 0.03). Although African-Americans and Hispanics fared worse than Caucasians, much of this was related to socio-economic factors. After adjustment for poverty the relative risk for African-Americans was reduced from 3.5 to 2.7. Poverty is therefore an important risk factor for progression of proliferative lupus nephritis.

Comment A number of studies from several regions of the USA and the National Institutes of Health have found that African-Americans with lupus nephritis have a worse prognosis than non-blacks. This is the first study to examine the influence of both race and socio-economic status on the outcome of patients with lupus nephritis. It clearly shows the large impact of poverty as an influence on renal survival over time. It does not, however, show the reasons for this effect. Poor compliance, inability to afford medications, distrust of physicians and fear of experimentation are all among the reasons why impoverished patients have a poor outcome. It does confirm that all studies in the USA must stratify for African-Americans and others who have a worse prognosis. It also raises the question of different treatment regimens based on these data; for example, the use of intravenous cyclophosphamide as opposed to oral regimens ensures the patient is taking the medicines.

Rapidly progressive glomerulonephritis Rapidly progressive glomerulonephritis is a very important cause of acute renal failure with many potential causes. These are often treatable if diagnosed early. The pathophysiology of these conditions is increasingly understood, and treatment regimens are often now stratified by disease severity and the precise cause. Long-term treatments are often required, and these must balance treatment efficacy and toxicity.

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Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice Xiao H, Heeringa P, Hu P, et al. J Clin Invest 2002; 110: 955–63

B A C K G R O U N D . Over 80% of patients with rapidly progressive glomerulonephritis and a crescentic picture on renal biopsy have ANCA. Although the presence of these autoantibodies is associated with renal disease in most individuals and the titres of the ANCA correlate to some extent with the course of the patients, their pathogenicity remains uncertain. No models of ANCA-associated disease have been described so far.

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I N T E R P R E T A T I O N . The most common form of ANCA is directed against myeloperoxidase (MPO). MPO knock-out mice (MPO –/–) were immunized with mouse MPO and subsequently developed anti-MPO ANCA. Splenocytes or immunoglobulin from these mice or control mice were injected into mice which lacked functioning B lymphocytes and T lymphocytes. All mice receiving splenocytes developed glomerular lesions (mostly mild), but only the mice injected with splenocytes from MPO-immunized mice developed a severe necrotizing and crescentic glomerulonephritis as well as granulomatous inflammation and vasculitis. Anti-MPO antibodies injected into the immune-deficient and normal mice produced necrotizing and crescentic glomerulonephritis without immune deposits. As expected, mice developed renal failure, as manifested by rising urea and creatinine, and proteinuria (Fig. 7.3).

Comment This animal model provides strong support for the pathogenicity of ANCA. Glomerular lesions of necrotizing and crescentic glomerulonephritis, identical to those seen in microscopic polyangiitis and Wegener’s granulomatosis, were reproduced in immune-incompetent animals by splenocyte transfer. In both immuneincompetent and normal mice, antibody transfer of specific anti-MPO antibodies produced the same lesion. This study provides good evidence that ANCA is not an epiphenomenon. It gives support to the clinical efforts of trying to suppress ANCA titres in patents and monitoring ANCA levels as a marker and cause of disease activity. It does not show why some patients develop ANCA in the first place and why some patients’ disease activity correlates less well with ANCA titres.

Fig. 7.3 Mean blood urea nitrogen (BUN) and serum creatinine in Rag2–/– mice 13 days after they had received 1 108, 5 107 or 1 107 anti-MPO splenocytes, anti-bovine serum albumin (BSA) splenocytes or non-immunized control splenocytes. The normal mouse assay reference range was 18–29 mg/dl for BUN and 0.2–0.8 mg/dl for serum creatinine. Source: Xiao et al. (2002).

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A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic antibodies Jayne D, Rasmussen N, Andrassy K, et al. N Engl J Med 2003; 349: 36–44

B A C K G R O U N D . Both Wegener’s granulomatosis and microscopic polyangiitis are associated with pauci-immune rapidly progressive glomerulonephritis and the presence of ANCA. While a combination of cyclophosphamide and corticosteroids has become a widely used and highly effective induction therapy for this disease, continued use of this regimen carries significant long-term toxicity. Previous data, though, had demonstrated good control of disease with continued use of cyclophosphamide. I N T E R P R E T A T I O N . This study examined whether a less toxic regimen of oral azathioprine was as effective as and less toxic than continued cyclophosphamide in preventing relapses of the vasculitic process. One hundred and forty-four out of 155 patients entering remission (93%) after cyclophosphamide/prednisolone induction (for 3 months) were randomized to receive either continued cyclophosphamide (1.5 mg/kg per day) or azathioprine (2 mg/kg per day) for a further 12 months. Thereafter, all patients received azathioprine and steroids. The rate of relapse over 18 months was not different between the two regimens (13.7% for cyclophosphamide and 15.5% for azathioprine; P = 0.65; Fig. 7.4) and neither was the

Fig. 7.4 Kaplan–Meier analysis of the time to first relapse in the azathioprine and cyclophosphamide groups. Source: Jayne et al (2003).

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occurrence of serious adverse side effects during the remission phase (10% for cyclophosphamide and 11% for azathioprine). The relapse rate was lower for patients with microscopic polyangiitis than for those with Wegener’s granulomatosis. Azathioprine is thus as effective as cyclophosphamide in maintaining remission and is likely to induce fewer longterm side effects.

Comment This study follows the general trend of attempting to reduce the side effects and toxicity of immunosuppressive regimens in patients who have successfully been induced into remission. It shows that the group treated with the clearly less toxic agent azathioprine fared equally well in terms of maintaining remission and without increasing unexpected side effects. The study is large and well powered, utilizing the resources of the European Vasculitis Study Group. Its shortcoming is the 18-month follow-up. Some events, such as chronic renal failure and other chronic organ damage, may develop only after many years. Continued follow-up of these patients will be necessary to prove the long-term equality of the regimens.

Focal segmental glomerulosclerosis The incidence of focal segmental glomerulosclerosis is increasing in the USA, both among all biopsied patients and among those with idiopathic nephrotic syndrome. Focal segmental glomerulosclerosis remains a histological diagnosis with many aetiologies. Major progress is being made in establishing the cause of secondary forms of the disease, whether due to genetic defects or associated with other entities such as obesity. Progress in understanding the aetiology of the idiopathic form of the disease deals with permeability factor(s), found in certain patients, which allow the urinary leakage of albumin.

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Serial estimates of serum permeability activity and clinical correlates in patients with native kidney focal segmental glomerulosclerosis Cattran D, Neogi T, Sharma R, McCarthy E, Savin V, for the North American Nephrotic Syndrome Group. J Am Soc Nephrol 2003; 14: 448–53

B A C K G R O U N D . One of the mechanisms of induction of proteinuria in focal segmental glomerulosclerosis is thought to be an as yet unidentified permeability factor present in patients’ serum which induces glomerular protein leakage. Some studies have demonstrated that patients with disease relapsing after transplantation have high titres of this factor, but it has not been demonstrated whether this factor is found in all patients, and if and how it changes over time and with treatment.

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I N T E R P R E T A T I O N . This study determined the in vitro permeability factor (Palb) of the serum of patients with idiopathic focal segmental glomerulosclerosis before, during, and after 24 weeks of therapy with either cyclosporin or placebo. Pre-treatment Palb was 0.36 and not different between the two groups. There was no difference between the treatment groups during or at the end of treatment (Table 7.2). There was no association between the level of Palb and remission or relapse.

Comment In idiopathic focal and segmental glomerulosclerosis the presence of a permeability factor, Palb, has been measured in vitro by placing patients’ plasma over isolated glomeruli in vitro and recording the degree of swelling of the glomeruli in response to changes in oncotic pressure. The presence of this factor causes proteinuria in experimental animals and has been correlated with the early recurrence of proteinuria and the recurrence of focal glomerulosclerosis in the transplant allograft. A serial study of Palb in patients over time has not yet been performed. This study analyses serial Palb values in two groups of patients who were part of the North American Nephrotic Syndrome Group. The regimens were part of a randomized, controlled, blinded trial of nephrotic patients with focal segmental glomerulosclerosis in which the cyclosporin arm gave greater total and partial remission of the nephrotic syndrome than did placebo. Moreover, in the original study the cyclosporin group had less decline in renal function over several years than did the placebo group. While the results are disappointing in that there were no positive correlations found, they are not surprising. The majority of the patients experienced partial remission with cyclosporin in this study, not complete remission. This may relate largely to haemodynamic changes and other antiproteinuric effects of the medication rather than to the immunological effects, which might correlate with disappearance of the permeability factor. Moreover, although the group appeared to have idiopathic disease and was uniform in histology, it is unclear whether some subgroups may have a high level of Palb while others have different mechanisms for their urinary albumin leakage. Table 7.2 Changes in laboratory parameters before and after treatment Cyclosporin

Creatinine (mg/dl)* Creatinine clearance (ml/min per 1.73 m2) Proteinuria (g/day)‡ Palb

Placebo

Pre-treatment

Post-treatment

Pre-treatment Post-treatment

1.2 ± 0.4† 72 ± 24

1.4 ± 0.6 54 ± 24

1.1 ± 0.6 66 ± 30

7.2 (3.6 to 14.4) 3.1 (0.2 to 14.5) 0.31 ± 0.23 0.46 ± 0.28

* To change to SI: 88.4. † ± values are SD. ‡ Median (range). Source: Cattran et al. (2003).

1.4 ± 0.8 60 ± 36

9.5 (4 to 22.4) 7.4 (1.2 to 20.0) 0.41 ± 0.21 0.36 ± 0.25

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NPHS2 mutations in late-onset focal and segmental glomerulosclerosis: R229Q is a common disease-associated allele Tsukaguchi H, Sudhakar A, Le TC, et al. J Clin Invest 2002; 110: 1659–66

B A C K G R O U N D . Mutations in a number of proteins making up the slit processes of the glomerular basement membrane have now been described in families with various congenital and inherited nephrotic syndromes. Defects in the NPHS1 alleles (encoding nephrin) cause congenital nephrosis of the Finnish type. NPHS2 encodes podocin, and mutations here are associated with recessive childhood steroidresistant nephrotic syndrome. I N T E R P R E T A T I O N . In steroid-resistant childhood focal segmental glomerulosclerosis, genetic mutations in the NPHS2 gene have been identified. This study screened the adults in 30 families for NPHS2 mutations, families in which multiple patients had focal glomerulosclerosis. In nine of the 30 families, mutations of NPHS2 appeared to be responsible for the disease. In six of the nine families, the affected individuals were compound heterozygotes for an R229Q amino acid substitution. In vitro, the effect of this amino acid substitution led to abnormal binding of the substituted podocin to nephrin. Among the adults, 91 individuals with idiopathic focal glomerulosclerosis were screened and 6% had at least one abnormal R229Q allele, an incidence significantly higher than in the general population. Two of the patients with the R229Q defect were discovered to have a previously documented genetic abnormality of podocin in their second allele, suggesting compound heterozygosity as the cause of their disease.

Comment In families in which multiple members have idiopathic focal segmental glomerulosclerosis, some will be found to have genetic defects in structural proteins of the visceral epithelial cell podocytes. These include podocin, nephrin, actinin 4 and CD2AP protein. All are involved in the structure of the visceral epithelial cell foot process or the slit diaphragm along the glomerular basement membrane. These genetic defects have been associated with steroid resistance and progressive renal disease. In studies of children and young adults with sporadic non-familial focal glomerulosclerosis, some patients have now been found with a similar genetic defect. This study has found a specific defect in the NPHS2 podocin gene in familial disease and shows that the defect translates into abnormal protein interaction in vitro among the structural proteins involved in the integrity of the glomerular capillary wall barrier to the passage of albumin. Moreover, it documents an increased incidence of the abnormal podocin gene in adults with sporadic focal glomerulosclerosis. Since several patients had podocin defects in each of their alleles, compound heterozygosity for podocin defects may explain some cases of steroid-resistant focal sclerosis in adults. The major significance of all the genetic studies in this area is that they focus attention on the visceral epithelial cell podocyte and its relationship to the slit

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diaphragm as a cause of focal glomerulosclerosis. Acquired abnormalities of structural visceral epithelial cell proteins may underlie the urinary protein leakage in the non-genetic forms of focal sclerosis, or an acquired defect may be superimposed on a genetic background (heterozygote abnormality of podocin, etc.) that leads to the disease process.

Membranous nephropathy Membranous nephropathy is the most common pattern of idiopathic nephrotic syndrome in Caucasians. Although most patients with the disease are labelled idiopathic without a known aetiology, there are many diseases associated with ‘secondary’ forms of membranous nephropathy. These include collagen diseases, such as systemic lupus erythematosus, viral diseases such as hepatitis B and C, and medications, including the non-steroidal anti-inflammatory drugs. Treatment remains controversial, especially the timing and place of immunosuppression. Both membranous glomerulopathy and acute interstitial nephritis have been reported to occur after treatment with non-steroidal anti-inflammatory drugs. Markowitz et al. report the first cases of membranous glomerulopathy and acute interstitial nephritis following treatment with celecoxib (Celebrex), a selective cyclooxygenase 2 (COX-2) inhibitor. The rapid and complete resolution of both conditions following discontinuation of Celebrex strongly implicates this agent in disease pathogenesis. These cases enlarge the spectrum of potential renal toxicities of the COX-2-specific non-steroidal anti-inflammatory drugs.

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Membranous glomerulopathy and acute interstitial nephritis following treatment with celecoxib Markowitz GS, Flakowitz DC, Isom R, et al. Clin Nephrol 2003; 59: 137–42

B A C K G R O U N D . Both membranous nephropathy and acute interstitial nephritis have been reported to occur following the use of non-steroidal anti-inflammatory drugs. This has not been reported previously with COX-2-specific inhibitors. I N T E R P R E T A T I O N . Two patients are described who developed renal lesions associated with the use of the COX-2 inhibitor celecoxib. The first patient had been on the non-steroidal drug for 7 months when she developed the nephrotic syndrome with proteinuria of almost 5 g daily. Biopsy showed membranous nephropathy which resolved when the celecoxib was discontinued. The second patient developed acute interstitial nephritis in association with the use of celecoxib. This resolved with steroid treatment.

Comment This paper documents the occurrence of membranous nephropathy in association with COX-2 inhibitor use for the first time. Both minimal-change nephrotic syndrome

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and membranous nephropathy are known to occur in association with the use of nonspecific, non-steroidal anti-inflammatory drugs. COX-2 inhibitors have most of the renal side effects seen with non-specific agents of this class of medication. The association with membranous nephropathy here depends upon the occurrence during drug usage and the rapid remission with discontinuation of the drug. The prolonged use of the drug prior to the onset of nephrotic syndrome is typical of non-steroidalassociated nephrotic syndrome. The second case illustrates the more common lesion of acute interstitial nephritis, which may or may not be associated with minimalchange nephrotic syndrome with non-steroidal drugs. Subsequent papers document other cases of nephrotic syndrome with COX-2 inhibitors, and these drugs should be considered as potential but rare causes of the nephrotic syndrome.

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Rituximab in idiopathic membranous nephropathy: a one-year prospective study Ruggenenti P, Chiurchiu C, Brusegan V, et al. J Am Soc Nephrol 2003; 14: 1851–7

B A C K G R O U N D . The cause of idiopathic membranous nephropathy is not known, but the disease is undoubtedly immune-mediated, and glomeruli contain deposits of immunoglobulins and complement. Agents that limit or prevent B-cell production of potentially nephritogenic immunoglobulin might block the early pathogenic events in this disease. The monoclonal antibody rituximab binds to the B-cell surface antigen CD20 and inhibits B cells – specifically their production of antibody – although patients are not rendered immunoglobulin-deficient. I N T E R P R E T A T I O N . This prospective 1-year observational study evaluated the effects of rituximab on eight patients with idiopathic membranous nephropathy and persistent proteinuria (>3.5 g/day for 6 months). Rituximab was given as four once-a-week infusions of 375 mg/m2. Proteinuria decreased from a mean of 8.6 g/day to 4.3 g/day by 3 months and 3.0 g/day by 12 months (Fig. 7.5). Cholesterol decreased from 236 to 184 mg/dl by 1 year and serum albumin rose from 2.7 to 3.5 g/dl. Serum creatinine remained stable. Two and three patients respectively had complete and partial remission of the nephrotic syndrome. There were no major drug-related side effects.

Comment Idiopathic membranous nephropathy is an immune complex disease in which immunoglobulins and complement localize to subepithelial electron-dense deposits in the glomeruli. Although many immunosuppressive treatment regimens have been proposed, many patients fare well without therapy. Patients with persistent proteinuria have done worse in all studies. Here, looking at such a population, the authors have used the specific anti-B-cell antibody rituximab to induce remission of the nephrotic syndrome which will presumably translate into improved long-term renal function. Although this is an uncontrolled pilot project, the remissions are impres-

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Fig. 7.5 Time course of serum creatinine concentration and 24-h urinary protein excretion rate in eight patients with idiopathic membranous nephropathy (IMN) from 6 months before rituximab administration to the end of the study (month 12). Source: Ruggenenti et al. (2003).

sive in this resistant population. However, risk factors other than persistent proteinuria have also been thought to be associated with an adverse renal outcome in patients with membranous nephropathy. Older patients, males and those with elevated serum creatinine all fare worse. The patients in this study were in a lower risk group being more commonly young females with normal serum creatinine. Five of the eight treated patients were female and some in their twenties often with normal serum creatinine levels. These patients might be expected to do well even without therapy over time. A controlled randomized trial will be necessary to define the role of rituximab in membranous nephropathy, as in other glomerular diseases.

Immunoglobulin A nephropathy Immunoglobulin A nephropathy remains the most common form of idiopathic glomerulonephritis world-wide. The disease is defined by the presence of immune complex deposits containing IgA in the mesangial and other regions of the glomerulus. These are associated with an inflammatory and sclerosing process that leads to progressive renal failure in some patients. The mechanism(s) responsible for both the IgA1 deposition and the subsequent inflammatory process of the disease remain to be defined. A lack of knowledge of the pathogenesis of the disease has impeded treatment studies. Moreover, such studies have been hampered by the fact that many

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patients do not have a decline in kidney function over decades and others progress only slowly over many years. Despite numerous studies which have focused on treatment of the subset of patients likely to have progressive disease, the appropriate therapy for many patients is still unclear.

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Mycophenolate mofetil in IgA nephropathy: results of a 3 year prospective placebo controlled randomized study Maes BD, Oyen R, Claes K, et al. Kidney Int 2004; 6: 1842–9

B A C K G R O U N D . Humoral immunity is thought to play a pivotal role in the pathogenesis of IgA nephropathy, characterized by the predominant deposition of IgA1 in the glomerular mesangium. Mycophenolate mofetil selectively inhibits the proliferation of B and T lymphocytes and the production of antibodies, and may also have other anti-inflammatory properties. This was a prospective placebo-controlled trial of mycophenolate mofetil in patients with IgA nephropathy. I N T E R P R E T A T I O N . Thirty-four patients with biopsy-proven IgA nephropathy were randomized to receive mycophenolate mofetil 2 g/day or placebo for 3 years. All patients received a low-salt diet and angiotensin-converting enzyme (ACE) inhibitors. At the end of the study period there was no difference between the groups in the percentage of patients with a decrease of 25% or more in insulin clearance or an increase in serum creatinine of over 50%. There was no difference in the change in serum creatinine, blood pressure, or any other renal parameter.

Comment This is a negative study with certain limitations, the biggest of which is the small number of patients enrolled. It would require at least 100 and probably more patients to show significant differences between the treatment groups here. This is in part due to the slow, progressive nature of the disease, but in part also to the effectiveness of using blockers of the renin–angiotensin system in this disease. Although many immunosuppressive regimens, including corticosteroids and cytotoxic drugs, have been advocated, none has yet proved effective in a large, blinded, randomized trial. Likewise, the use of fish oils in IgA nephropathy has been successful in some but not other trials. The use of ACE inhibitors or angiotensin II receptor blockers has been beneficial in reducing proteinuria and slowing the decline in renal function over time in virtually every study of glomerular disease patients, including those with IgA nephropathy. As there was an effective agent in both arms of the study, a small number of patients, and only 3 years of follow-up, the results of this trial are not unexpected. A marker of inflammation, the C-reactive protein level, was significantly reduced in the mycophenolate arm of this study, suggesting the need for a much larger randomized controlled trial. Such a study is now under way in the USA.

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Fig. 7.6 Insulin clearance (a) (mean ± SEM), serum creatinine (b) (mean ± SEM) and annualized rate of change in serum creatinine (c) in patients with IgA nephropathy treated with mycophenolate mofetil (MMF) or placebo (PLA). Source: Maes et al. (2004).

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Disease associated with fibril deposition in the glomeruli: amyloid, fibrillary, and immunotactoid glomerulopathy Amyloid fibril of many different proteins can precipitate in the kidney and cause progressive renal damage. Although both AA amyloid and hereditary amyloids may involve the kidney, AL amyloid due to the deposition of light chains is most common and leads to major treatment problems. Fibrillary and immunotactoid glomerulonephritis are both idiopathic glomerular diseases with the deposition of fibrils in the glomerular basement membrane. The fibrils are larger than amyloid fibrils and in most patients there is no associated plasma cell dyscrasia. Debate exists on the clinical features, course, treatment and distinctness of these two entities, which are being reported more frequently now that renal biopsies routinely include electron microscopic evaluation.

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High-dose intravenous melphalan with autologous stem cell transplantation in AL amyloidosis-associated end-stage renal disease Casserly LF, Fadia A, Sanchorawala V, et al. Kidney Int 2003; 63: 1051–7

B A C K G R O U N D . Patients with AL amyloid commonly have renal involvement and progressive renal dysfunction, leading to end-stage renal disease (ESRD), and survival of these patients is poor. High-dose immunoablative therapies are increasingly used for patients with myeloma and plasma cell dyscrasias, including high-dose melphalan and autologous stem-cell transplantation for patients with AL amyloidosis. This has proved successful in inducing remission in a significant proportion of such patients. The efficacy and tolerability of high-dose treatments in patients with AL amyloidosis causing ESRD are unknown. I N T E R P R E T A T I O N . This study examined the results of high-dose melphalan and stem-cell transplantation in 15 patients with AL amyloidosis-related ESRD treated at a single centre. Patients were treated with high-dose intravenous melphalan (70–200 mg/m2) and autologous peripheral blood stem-cell transplantation. Eight of the 15 patients had a haematological response and two died in the peritransplant period (Table 7.3). AL amyloid patients with ESRD undergoing stem-cell transplantation required more transfusions and had a greater incidence of mucositis than patients with non-ESRD amyloid transplant. For the ESRD AL amyloid transplant patients with a haematological response, median survival was 4.5 years. Five of the patients have undergone or are awaiting renal transplantation.

Comment Recent and increasing numbers of studies have shown that the use of high-dose chemotherapy and autologous stem-cell transplantation may induce remission in

Non-CR CR Not available CR Non-CR CR CR Non-CR Not available CR Not available Not available CR CR CR

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Dead/26 months Alive/73 months Dead/9 months Alive/65 months Dead/13 months Alive/64 months Dead/58 months Dead/17 months Dead/0 months Alive/50 months Dead/0.4 months Dead/11 months Dead/17 months Alive/37 months Alive/34 months

Survival status/ follow-up

Waiting list

Waiting list

Yes

Yes

Yes

Renal transplantation

Pulmonary failure Sudden death Arrhythmia

Haemorrhagic CVA Pulmonary/renal failure and infection Arrhythmia

Anaphylaxis to cyclosporin

Sudden death

Arrhythmia

Cause of death

No Yes Yes

No Yes Yes

No

Yes

Yes

Death attributed to amyloid

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CR, haematological complete response; non-CR, haematological non-complete response; CVA, cerebrovascular accident. * Classified as ‘Not available’ if death occurred before 1 year. Source: Casserly et al. (2003).

Haematological response at 12 months*

Patient

Table 7.3 Treatment outcomes in patients with end-stage renal disease

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some AL amyloid patients. This may be the treatment of choice for young patients with AL amyloid and limited organ system involvement. Few patients with ESRD due to amyloid have received this therapy. This is therefore a retrospective look at the potential benefits and risks of such therapy. Because this study was performed at a major centre with much clinical experience of stem-cell transplantation in amyloid patients, it is not clear whether similar results can be expected at other centres. Moreover, the results are not overwhelmingly impressive in terms of patient survival. On the other hand, this is a progressive disease with a uniformly bad long-term outcome. More data will be necessary in order to differentiate which AL amyloid patients in general, and specifically those with ESRD, will benefit from stem-cell therapy.

HIV-associated nephropathy HIV-associated nephropathy (HIVAN) is a specific form of collapsing focal segmental glomerulosclerosis characterized by a predilection for blacks, heavy proteinuria and the nephrotic syndrome, and a rapid course to renal failure. The glomerular pathology shows collapse of the glomerular capillary loops, proliferation of visceral epithelial cells, tubular microcosmic dilatation and the presence of tubuloreticular endothelial cell inclusions. Suggested treatments have included highly active antiretroviral therapy (HAART), ACE inhibitors or angiotensin receptor antagonists, and, in some selected patients, immunosuppressive agents. However, no treatment has been documented to be effective in a controlled randomized trial.

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Long-term renal survival in HIV-associated nephropathy with angiotensin-converting enzyme inhibition Wei A, Burns G, Williams BA, Mohammed NB, Visintainer P, Sivak SL. Kidney Int 2003; 64: 1462–71

B A C K G R O U N D . HIVAN is the most common cause of ESRD in HIV-infected patients in many centres, especially in the USA. ACE inhibitors have shown short-term benefit in patients with HIVAN but long-term benefits have not been established. I N T E R P R E T A T I O N . This is a single-centre prospective study of 44 biopsy-proven cases of HIVAN without severe renal insufficiency (serum creatinine <2.0 mg/dl). Twenty-eight patients received the ACE inhibitor fosinopril at 10 mg/day and 16 did not. Patients not receiving fosinopril had refused for various reasons (including worries over an experimental therapy and the risk of hyperkalaemia or renal impairment). The patient groups were similar in age, exposure to antiviral regimens, initial serum creatinine concentration, and CD4 lymphocyte counts. Median renal survival was 480 days for the treated patients and 147 days for the controls (Fig. 7.7). All untreated patients progressed to ESRD but only one treated patient did. Patient survival was 88% in the treated versus 21% in the untreated groups. The risk of progression to ESRD was markedly reduced in the group treated with ACE inhibitor (P <0.0001).

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Fig. 7.7 Kaplan–Meier survival estimate of renal failure in the two groups. Source: Wei et al. (2003).

Comment This study supports previous smaller uncontrolled trials showing a benefit for ACE inhibition in the HIVAN population. It is not a randomized controlled trial. Moreover, it does not detract from the potential benefits of HAART in the HIVAN population. It strongly supports the early use of blockers of the renin–angiotensin system in patients with this pattern of glomerular disease. A caveat that will apply is that some HIV-infected patients, whether through elevations of their serum creatinine or through hyperkalaemia, will not tolerate these medications.

Hepatitis C

✍

Influence of antiviral therapy in hepatitis C virus-associated cryoglobulinemic MPGN Alric L, Plaisier E, Thebault S, et al. Am J Kidney Dis 2004; 43: 617–23

B A C K G R O U N D . A number of treatments have emerged for patients with hepatitis C. The role of these treatments specifically in patients with hepatitis C and renal disease, often secondary to cryoglobulinaemia, is unclear. There have been concerns over drug dosing, toxicity and the potential risks and benefits of immunosuppression for a disease induced by a virus.

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I N T E R P R E T A T I O N . This study documents the course of 25 patients with membranoproliferative glomerulonephritis, the nephrotic syndrome, mixed cryoglobulinaemia and hepatitis C virus (HCV) infection treated with antiviral therapy. All patents were initially treated with prednisone, diuretics and plasmapheresis. In 18 patients standard or pegylated interferon alone with ribaviron therapy was then used for a mean duration of 18 ± 10 months. Seven patients who did not receive the antiviral therapy served as controls. HCV clearance was achieved in twelve of the 18 treated patients. Those patients with a sustained virological response had a decrease in proteinuria at the end of antiviral therapy and at follow-up (2.8 vs 1.0 vs 0.4 g/day), and cryoglobulin levels fell progressively. Serum creatinine levels remained constant regardless of the response to treatment.

Comment This is the first study of any significant number of patients receiving antiviral therapy for hepatitis C glomerulonephritis. It is complicated by the fact that the majority of patients received plasmapheresis and many received corticosteroids as well. On the other hand, it shows that these forms of therapy may be used successfully in this population The patients treated with antivirals with a virological response (twothirds of those treated) had improvements in proteinuria and serum albumin and serum cryoglobulins. Antiviral therapy should be considered for all patients with HCV-related membranoproliferative glomerulonephritis, probably after initial stabilization of renal function with plasmapheresis and immunosuppressive agents.

Conclusion Progress in glomerulonephritis stems in part from a better understanding of the mechanisms of glomerular damage. There have been studies showing that ANCA are not epiphenomenal but part of the disease process in microscopic polyangiitis and Wegener’s granulomatosis, studies of the permeability factor in focal sclerosis, studies showing the distribution of IgA receptors on mesangial cells, and studies better defining the course of events in experimental anti-glomerular basement membrane (GBM) disease. Each of these studies enhances not only our knowledge of a single disease entity but also of the more general nature of the glomerular response to various forms of damage. Better definition of the epidemiology and histology of diseases such as lupus nephritis will lead to uniformity in the design of controlled studies and thus to better and more effective treatment strategies. Treatments for many glomerular diseases include the use of immunosuppressive medications. Defining the safest induction or maintenance regimen for one disease will often lead to extension of its use in other glomerular diseases. Studies of the use of azathioprine or mycophenolate in lupus nephritis and rapidly progressive glomerulonephritis complement each other. Studies with rituximab in membranous nephropathy will lead to trials in other diseases. Recent papers have thus led to progress in many areas of glomerular disease which hopefully will translate into better patient care.

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8 Vasculitis and lupus nephritis DAVID JAYNE

Introduction Vasculitis and systemic lupus erythematosus (SLE) are multisystem autoimmune diseases, responsive to therapy yet associated with poor long-term outcomes 1. Renal involvement is common in both groups and is an adverse predictor for endstage renal disease (ESRD) and mortality 2. In renal vasculitis, 1-year mortality is 20%, while in lupus nephritis a review of cohort studies from the last decade shows ESRD and mortality rates of over 10% at 5 years and 25% at 10 years 3. Combination therapy with high-dose prednisolone and an immunosuppressive agent, usually cyclophosphamide, remains the standard approach to therapy but directly contributes to poor outcomes through a high rate of early infections and the consequences of cumulative drug exposure 4,5. Several important factors contribute to the difficulties in the management of vasculitis and lupus and thus their poor outcomes. These include a lack of good epidemiological studies, a complex classification that is often poorly understood, diagnostic delay, heterogeneous presentations, and an absence of planned healthcare. Furthermore, the aetiology of vasculitis and lupus is not understood, although evidence supports the contribution of both polygenic inheritance and environmental exposures. In order to improve outcomes there is a need for earlier diagnosis, before renal injury when remission induction treatment is more effective, for safer induction regimens and for more effective prevention of relapsing–remitting disease 2. The availability of serological testing, antinuclear antibodies in lupus and antineutrophil cytoplasm antibodies (ANCA) in vasculitis has facilitated earlier diagnosis, yet many patients are still diagnosed in advanced renal failure. Greater awareness of the disease based on better epidemiological data is important; Mahr et al. report the first study of the prevalence of systemic vasculitis in France. ANCA has also been helpful in the classification of vasculitis, in which the pattern of renal disease is remarkably similar between patients and mainly differs only in severity 6. For lupus nephritis the position is more complex because of the multiple pathogenetic mechanisms and differing, but overlapping, histological appearances. The World Health Organization (WHO) facilitated a classification of lupus nephritis over 20 years ago on which to base studies of prognosis and to guide therapy 7. Intrinsic problems with its design © Atlas Medical Publishing Ltd

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and differences over interpretation have necessitated an updated version, which is described by Weening et al. Microarray analysis of messenger ribonucleic acid (RNA) in autoimmunity has been viewed as generating rather than proving hypotheses. However, in both lupus and vasculitis there is evidence of immune dysregulation of circulating leucocytes, so assessing their transcriptome is particularly likely to be fruitful and results can be compared with existing knowledge or concepts of pathogenesis. Enthusiasts have also predicted gene profiles or ‘fingerprints’ that will revise disease classification and direct therapy. Although this science is at an immature stage, results are already appearing that change views of these disorders (see Bennett et al. and Yang et al.). In vasculitis, the European Vasculitis Study Group (EUVAS) have proposed a subgrouping of disease severity and extent at presentation, in order to guide therapy 8. Although focused on the major vasculitic diagnostic subgroup, ANCA-associated vasculitis (Wegener’s granulomatosis and microscopic polyangiitis [MPA]), the conclusions from the EUVAS studies can be generalized to other forms of systemic vasculitis. The first randomized trail from the EUVAS group has now reported its findings in detail (see Jayne et al., below). This trial found that a sequential approach to therapy, withdrawing cyclophosphamide at remission and using the safer azathioprine in its place was as effective as long-term cyclophosphamide. Success with a very similar approach in a smaller study was also reported in lupus nephritis (see Contreras et al., below). The results from both studies support the early withdrawal of cyclophosphamide which will minimize the late complications of cyclophosphamide, such as infertility and bladder cancer, that have been major concerns associated with this drug 5,9,10. However, current protocols are ineffective in the long-term prevention of disease relapse; a protracted, relapsing disease course with high cumulative exposure to corticosteroids and immunosuppressant agents with increasing disease and drug-induced incapacity remains the outlook for too many patients. There is a clear need for newer therapeutic agents to reduce toxicity and improve long-term disease control, and there is currently a rapid expansion of interest in newer medications, both from investigators and the pharmaceutical industry. Several studies have found mycophenolate mofetil (Roche, UK) effective in lupus nephritis and Contreras et al. also reported its efficacy in remission maintenance in lupus nephritis. Deoxyspergualin (Nippon Kyaku, Japan), a newer immunosuppressant with a poorly understood mechanism of action, appeared very promising in a preliminary study of refractory Wegener’s granulomatosis by Birck et al. The most promising recent innovation in autoimmunity has been depletion of B cells with the chimeric anti-CD20 monoclonal antibody rituximab (Roche, UK). This induces sustained disease remission in rheumatoid arthritis, lupus and vasculitis and is causing intense interest 11,12. Much of the late morbidity and mortality of vasculitis and lupus relates to a greatly increased risk of cardiovascular disease 13. With interest in the contribution of vascular inflammation to the pathogenesis of atheromatous vascular disease, a focus is falling on chronic inflammatory disorders of the vasculature. The endothelium is the target tissue in vasculitis and previous studies have found evidence of endothelial

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disease by measurement of von Willebrand factor or anti-endothelial cell antibodies 14,15. More recently, endothelial dysfunction in vasculitis has been correlated with disease activity and C-reactive protein 16. Using a sensitive technique to detect circulating endothelial cells, Woywodt et al. have reported greatly increased levels of these cells in the blood of vasculitis patients. In addition to their role in reducing cholesterol levels, statins have anti-inflammatory properties and modulate ANCAinduced neutrophil activation in vitro 17. It is likely that study of the vasculature in vasculitis and lupus will lead to new insights into the pathogenesis and therapy of the more common vascular diseases.

Epidemiology

✍

Prevalences of polyarteritis nodosa, microscopic polyangiitis, Wegener’s granulomatosis, and Churg–Strauss syndrome in a French urban multiethnic population in 2000: a capture–recapture estimate Mahr A, Guillevin L, Poissonnet M, Ayme S. Arthritis Rheum 2004; 51: 92–9

B A C K G R O U N D . Vasculitis is more common than previously thought, although whether this reflects increasing incidence or improved diagnosis is unclear. Following landmark incidence studies by Scott and Watts in the East of England, this French study used capture–recapture analysis to calculate the prevalence of the major vasculitis syndromes in a multiethnic community to the north-east of Paris 18. The incidence of vasculitis seems remarkably consistent in different European countries, although the distribution of the various subgroups varies, with Wegener’s granulomatosis more common in the north and MPA more common in the south of Europe. There is little hard evidence of ethnic differences in vasculitis, although these have long been suspected. I N T E R P R E T A T I O N . This study estimated the prevalences of polyarteritis nodosa (PAN), MPA, Wegener’s granulomatosis and Churg–Strauss syndrome (CSS) in a northeastern suburb of Paris, which has 1 093 515 adults (>15 years), 28% of whom are of nonEuropean ancestry. The study period encompassed the entire calendar year 2000. Cases were identified by general practitioners, the departments of all the public hospitals and two large private clinics, and the national health insurance system. The Chapel Hill nomenclature was used to diagnose MPA and American College of Rheumatology criteria to diagnose Wegener’s granulomatosis and CSS; PAN was diagnosed based on clinical laboratory, histological and/or angiographic findings. Three-source capture–recapture analysis was performed to correct for incomplete case ascertainment. A total of 75 cases were retained and capture–recapture analysis estimated that 23.8 cases had been missed by any one of the three sources. Accordingly, prevalences per million adults (95% confidence interval [CI]) were estimated to be 30.7 (95% CI 21–40) for PAN, 25.1 (95% CI 16–34) for MPA, 23.7

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(95% CI 16–31) for Wegener’s granulomatosis and 10.7 (95% CI 5–17) for CSS. The overall prevalence was 2.0 times higher for subjects of European ancestry than for non-Europeans (P = 0.01). This study provides the first prevalence estimates for these four vasculitides for a multiethnic urban population. The significantly higher prevalence observed for Europeans may indicate a genetic susceptibility of Caucasians. Compared with previous estimates based mostly on rural populations, the higher frequency of PAN and the lower frequency of Wegener’s granulomatosis might suggest specific environmental aetiological factors.

Comment The authors found a cumulative prevalence of 90 per million population of the four vasculitis subtypes studied (Table 8.1). Their highest rate was for PAN. They found a significantly lower incidence of vasculitis in non-Caucasian communities, which was similar to the results of earlier cohort studies 1. This study was limited by a short duration (1 year), whereas there is known to be considerable year-to-year variability in the presentation of these diseases. Also, it was difficult to control for movements in and out of the study population when studying an area integrated with a large metropolis. Overall, the rates are almost half those found in preliminary studies from Norwich, UK, and from Sweden. The high rate for PAN is surprising as this is now rarely diagnosed in the UK, following the Chapel Hill consensus classification statements 19. This may reflect referral bias to a group with international expertise in this area. The data on ethnic variation are important and require further study. This may lead to genetic clues to susceptibility.

Table 8.1 Prevalence estimates for PAN, MPA, WG and CSS for the total adult population and stratified for geographic origin*

Overall population PAN MPA WG CSS Total Geographic origin Europeans Non-Europeans

Prevalence per 1 000 000 adults

95 % CI

30.7 25.1 23.7 10.7 90.3

21–40 16–34 16–31 5–17 74–106

104.7† 52.5†

85–125 30–76

* PAN, polyarteritis nodosa; MPA, microscopic polyangiitis; WG, Wegener’s granulomatosis; CSS, ChurgStrauss syndrome; 95% CI, 95% confidence interval. † Relative risk 2.0 (95% CI 1.2–3.4; P = 0.01 as assessed with a chi-square test, 2 = 6.60). Source: Mahr et al. (2004).

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Classification

✍

The classification of glomerulonephritis in systemic lupus erythematosus revisited Weening JJ, D’Agati VD, Schwartz MM, et al. J Am Soc Nephrol 2004; 15: 241–50

B A C K G R O U N D . The classification of lupus nephritis is important because renal outcomes vary widely and treatment is toxic, so therapy needs to be measured against the likely prognosis. The WHO system for the classification of lupus nephritis has been widely cited and used but often poorly understood. Many experienced nephropathologists have been calling for a revision, and this has now been undertaken by an international group, the Renal Pathology Forum. Problems with the previous system were (i) the focus on proliferative glomerulonephritis; (ii) the classification of patients with both membranous and proliferative features was confusing (there was inconsistency in the classification of patients whose biopsies showed features of both proliferative and membranous glomerulonephritis); and (iii) the lack of consideration of segmental ischaemic lesions, or glomerulosclerosis. Despite these drawbacks the old system was broadly predictive of renal outcome, although different studies have documented different results, particularly for old Class V lupus nephritis, reflecting variation in its interpretation 20. This issue is particularly important in the evaluation of newer, more specific therapies that are more likely to have differential effects on the various pathogenetic mechanisms. For example, anti-inflammatory approaches may target glomerular proliferation; anti-immune strategies may target immune complex deposition; antithrombotic agents may target glomerular microthrombosis; and antifibrotic drugs may target glomerular and tubulo-interstitial scarring, which is the final common pathway of injury. I N T E R P R E T A T I O N . The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathological studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the WHO and subsequent clinicopathological data, we propose that Classes I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); Class III for focal glomerulonephritis (involving <50% of the total number of glomeruli) with subdivisions for active and sclerotic lesions; Class IV for diffuse glomerulonephritis (involving ≥50% of total number of glomeruli) either with segmental (Class IV-S) or global (Class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; Class V for membranous lupus nephritis; and Class VI for advanced sclerosing lesions. Combinations of membranous and proliferative glomerulonephritis (i.e. Class III and V or Class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal

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Table 8.2 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification of lupus nephritis (2003) Class I

Minimal mesangial lupus nephritis Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence Class II Mesangial proliferative lupus nephritis Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy, with mesangial immune deposits A few isolated subepithelial or subendothelial deposits may be visible by immunofluorescence or electron microscopy, but not by light microscopy Class III Focal lupus nephritis* Active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations Class III (A) Active lesions: focal proliferative lupus nephritis Class III (A/C) Active and chronic lesions: focal proliferative and sclerosing lupus nephritis Class III (C) Chronic inactive lesions with glomerular scars: focal sclerosing lupus nephritis Class IV Diffuse lupus nephritis† Active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving ≥ 50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations. This class is divided into diffuse segmental (IV-S) lupus nephritis when ≥ 50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) lupus nephritis when ≥ 50% of the involved glomeruli have global lesions. Segmental glomerulonephritis is defined as a glomerular lesion that involves less than half of the glomerular tuft. This class includes cases with diffuse wire loop deposits but with little or no glomerular proliferation Class IV-S (A) Active lesions: diffuse segmental proliferative lupus nephritis Class IV-G (A) Active lesions: diffuse global proliferative lupus nephritis Class IV-S (A/C) Active and chronic lesions: diffuse segmental proliferative and sclerosing lupus nephritis Class IV-G (A/C) Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritis Class IV-S (C) Chronic inactive lesions with scars: diffuse segmental sclerosing lupus nephritis Class IV-G (C) Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis Class V Membranous lupus nephritis Global or segmental subepithelial immune deposits or their morphological sequelae by light microscopy and by immunofluorescence or electron microscopy, with or without mesangial alterations Class V lupus nephritis may occur in combination with Class III or IV, in which case both will be diagnosed. Class V lupus nephritis may show advanced sclerosis Class VI Advanced sclerotic lupus nephritis ≥ 90% of glomeruli globally sclerosed without residual activity Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, severity of arteriosclerosis or other vascular lesions. * Indicate the proportion of glomeruli with active and with sclerotic lesions. † Indicate the proportion of glomeruli with fibrinoid necrosis and/or cellular crescents. Source: Weening et al. (2004)

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description of the various lesions and classes of lupus nephritis, allowing better standardization and providing a basis for further clinicopathological studies. It is hoped that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.

Comment A new consensus has been reached but the revision is not as radical or inclusive as it might have been. The definitions of Classes I and II, immune deposits with or without mesangial lesions, remain unchanged (Table 8.2). Proliferative lesions, Classes III and IV, now include an assessment of both activity and chronicity. This reflects the reality of practice, especially of follow-up biopsies after treatment, and should be easy to assess and report. Class IV is further subdivided according to the proportion of each glomerulus that is affected—segmental or global. Class V still represents membranous lesions. But whereas previously patients with both membranous and proliferative lesions were classified as Class V subtypes (a–d), they are now separated and reported as having both Class III/IV and Class V. The new system also requires statements on the presence of tubulo-interstitial or vascular lesions but does not include them in the core system. It will now be important for pathologists and clinical researchers to confirm which system they are using. Also, a study of the new system in practice would be helpful to expose its weaknesses in a rational manner. But of most importance will be a demonstration of the association of specific histological features with long-term renal prognosis. Only then will this system be able to influence therapeutic decisions in a rational way.

Post-genomics: messenger RNA microarrays

✍

Circumvention of normal constraints on granule protein gene expression in peripheral blood neutrophils and monocytes of patients with antineutrophil cytoplasmic autoantibody-associated glomerulonephritis Yang JJ, Pendergraft WF, Alcorta DA, et al. J Am Soc Nephrol 2004; 15: 2103–14

B A C K G R O U N D . Current technology allows the quantification of transcribed mRNA for all genes in the human genome. Subsequent analysis has yielded patterns or profiles that associate with disease prognosis and drug response in malignancies. This technology is now being applied to autoimmunity, typically using unsorted peripheral blood mononuclear cells as the substrate. Current studies in vasculitis and lupus should be regarded as preliminary and their results need confirmation by other groups.

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I N T E R P R E T A T I O N . Granulopoiesis-related genes are distinctively upregulated in peripheral leucocytes of patients with ANCA-associated glomerulonephritis. Affymetrix microarrays identified the upregulation of nine neutrophilic primary granule genes, including myeloperoxidase (MPO) and proteinase 3 (PR3), plus five secondary granule genes. Coordinate expression of the granulocyte maturation marker CD35, measured by TaqMan PCR, and positive in situ staining for PR3 transcripts in polymorphic neutrophils and monocytes indicate that these genes are expressed in ‘mature’ cells. Increased transcripts correlated with disease activity and absolute neutrophil values but not with ‘left shift’, drug regimen, cytokine levels, haematuria, proteinuria, ANCA titre, serum creatinine, gender or age. Upregulation of PR3 and MPO transcripts was specifically associated with ANCA disease (n = 56) as these changes were not detected in patients with ESRD (n = 25) or SLE (n = 17), as determined by TaqMan PCR. This is the first report of this phenomenon in non-neoplastic cells. The data raise the hypothesis that, in addition to the presence of anti-MPO or anti-PR3 autoantibodies, a second critical component in the cause of this disease is the reactivation of once-silenced genes, leading to increased antigen availability.

Comment The study by Yang et al. in ANCA-associated vasculitis reports the upregulation of neutrophil genes not usually expressed in mature cells, and did not find this phenomenon in other disease states associated with neutrophil activation (Fig. 8.1). This is the first clear evidence that neutrophil behaviour is uniquely perturbed in vasculitis and is likely to open new avenues for investigation. The observations are consistent with preliminary reports from other laboratories, and the upregulated genes include those coding for neutrophil proteases. It is unclear how this dysregulation fits into current theories of ANCA induced pathogenesis. It is also unclear whether the mRNA for the neutrophil autoantigens PR3 and MPO is translated into protein. The consistency of the observations indicates that this approach is likely to yield more useful information in the future.

✍

Interferon and granulopoiesis signatures in systemic lupus erythematosus blood Bennett L, Palucka AK, Arce E, et al. J Exp Med 2003; 197: 711–23

B A C K G R O U N D . Several small studies have been performed in SLE looking at gene expression profiling, and, perhaps surprisingly for such a heterogeneous disease, consistent patterns in mRNA expression have been found in comparison with controls. I N T E R P R E T A T I O N . SLE is a prototype systemic autoimmune disease characterized by flares of high morbidity. Using oligonucleotide microarrays, the authors showed that active SLE can be distinguished by a remarkably homogeneous gene expression pattern with overexpression of granulopoiesis-related and interferon (IFN)-induced genes. Using the most

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Fig. 8.1 PR3 and MPO gene expression is not due to high neutrophil values or to a left-shift phenomenon. (a) Comparison of the levels of PR3 and MPO transcripts in patients with ANCA versus patients who have high neutrophil values with a left shift. TaqMan PCR analysis shows that the levels of PR3 and MPO gene expression are significantly higher in the ANCA patient group (P <0.05). (b) TaqMan PCR analysis of maturation markers CD68 (normally expressed in bone marrow myeloblasts and promyelocytes) and CD35 (normally expressed on mature cells) indicates no statistical differences among the groups tested. Source: Yang et al. (2004).

stringent statistical analysis (Bonferroni correction), 15 genes were found to be highly upregulated in SLE patients; 14 of the genes are targets of IFN and one, defensin DEFA3, is a major product of immature granulocytes. A more liberal correction (Benjamini and Hochberg correction) yielded 18 additional genes, 12 of which are IFN-regulated and four granulocyte-specific. Indeed, immature neutrophils were identified in a large fraction of SLE patients’ white blood cells. High-dose glucocorticoids, a standard treatment of disease flares, shuts down the IFN signature, further supporting the role of this cytokine in SLE. The expression of ten genes correlated with disease activity according to the SLEDAI (Systemic

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Lupus Erythematosus Disease Activity Index). The most striking correlation (P <0.001; r = 0.55) was found with the formyl peptide receptor-like 1 protein, which mediates chemotactic activities of defensins. Therefore, while the IFN signature confirms the central role of this cytokine in SLE, microarray analysis of blood cells reveals that immature granulocytes may be involved in the pathogenesis of SLE.

Comment In the study by Bennett et al., 30 children with SLE were compared with healthy controls and a disease control group with juvenile arthritis. They found overexpression of IFN-- and granulopoiesis-related genes (Fig. 8.2). The IFN ‘signature’ has been reported previously and accords with elevated levels of IFN protein in serum and in affected tissues. The source of IFN appears to be monocytes and lymphocytes, and its effects on antigen presentation and on the innate immune system contribute to the breakdown of tolerance to self-antigens. The increase in granulocyte-specific transcripts was reflected by the presence of immature granulocyte precursors in the circulation and may represent a downstream result of immune activation that is of direct relevance to tissue injury. There are intriguing comparisons between data emerging in SLE and in vasculitis. Both studies reported perturbation in granulocyte lineage cells, with the presence of mRNA usually restricted to neutrophil development and not expected in circulating cells. These studies need to be expanded to larger study populations and to include comparisons with different disease manifestations, disease stage and treatments. The current data suggest that this technology will be a productive tool for the investigation of pathogenesis and may well develop into a routine method for evaluating disease activity and extent, and drug response.

Conventional therapies Moderate and severe forms of vasculitis and lupus have been treated with combinations of corticosteroids and an immunosuppressive agent for over 30 years. Cyclophosphamide has been the preferred immunosuppressive agent, but its use is associated with a high rate of leucopenia and infection, infertility and late malignancy 5. Efforts to reduce this toxicity have investigated intravenous pulses, in place of daily tablets and the switch from cyclophosphamide to a different immunosuppressive agent once disease control has been obtained. Several studies in SLE, particularly by the US National Institutes of Health, have popularized the intravenous route and suggested that therapy for up to 2 years is necessary 4. In vasculitis, EUVAS advocated daily oral tablets in a 1995 consensus report, but a more recent critical analysis of published evidence found no difference between the intravenous and oral routes for the hard end-points of death and renal failure 21,22. This subject is being addressed in an ongoing study by this group 8.

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Fig. 8.2 Correlation of gene expression and disease activity as measured by SLEDAI. Two IFN-induced genes (Cig49 and phospholipid scramblase 1) and a granulocyte-related gene (F2RPA) correlate significantly with SLEDAI. These particular genes are selected to illustrate different families. By comparison, there is no correlation of serum levels of anti-double-stranded DNA antibodies with disease activity. Source: Bennett et al. (2003).

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Treatment of polyarteritis nodosa and microscopic polyangiitis with poor prognosis factors: a prospective trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in sixty-five patients Guillevin L, Cohen P, Mahr A, et al. Arthritis Rheum 2003; 49: 93–100

B A C K G R O U N D . The French Vasculitis Collaborative Study Group has performed many clinical studies in vasculitis over the last 15–20 years. They have gone on to pool data from their trials to make important conclusions on prognosis and patient subgroupings 23. This most recent paper reports the results from a subgroup of patients entered into the ongoing CHUSPAN trial. It concerns patients with PAN or MPA and at least one adverse prognostic indicator as defined by the ‘five factor score’ 23. From diagnosis patients are randomized to receive either six or twelve pulses of intravenous cyclophosphamide, at monthly intervals, with remission and relapse as the primary end-points. I N T E R P R E T A T I O N . Because the optimal cyclophosphamide treatment duration for severe PAN without virus infection and MPA has not been established, we conducted a trial to compare the effectiveness of six versus twelve cyclophosphamide pulses given in combination with corticosteroids. Sixty-five previously untreated patients (18 PAN, 47 MPA) were randomized to receive twelve (n = 34) or six (n = 31) cyclophosphamide pulses combined with corticosteroids. PAN and MPA were histologically proven or met American College of Rheumatology criteria. All patients presented at least one factor of severity according to the five factor score. Cyclophosphamide pulses were administered every 2 weeks for 1 month, then every 4 weeks. The end-point of the study was the number of events (relapses and/or deaths) occurring in each group, analysed according to an intentionto-treat strategy. The outcome was evaluated by Cox proportional hazards analysis. The baseline characteristics were similar for both groups. The mean (± SD) follow-up was 32 ± 21 months. Survival analysis showed a significantly lower relapse probability (P = 0.02; hazard ratio [HR] = 0.34) and higher event-free survival (P = 0.02; HR = 0.44) for the twelve cyclophosphamide-pulse group while the mortality rates were not significantly different (P = 0.47). These results suggest that six cyclophosphamide pulses are less effective than twelve pulses in treating severe PAN and MPA, particularly with respect to the risk of relapses.

Comment The results showed that over 85% of patients achieved remission by 6 months but the longer cyclophosphamide course led to fewer relapses without a significant increase in toxicity (Table 8.3). Because vasculitis is a more fulminant disease than lupus nephritis, for which the monthly interval was originally chosen, there is a danger of underdosing patients, thereby delaying remission. Current studies by the EUVAS use a shorter interval between cyclophosphamide pulses, of 2 weeks for the first three pulses, then 3 weeks 8. No remission maintenance protocol was used and in the absence of ongoing treatment it is no surprise that a longer cyclophosphamide course

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Table 8.3 Outcome of 65 patients with PAN and MPA and poor prognostic factors according to the treatment regimen* 12 CY pulses Parameter Complete remission Deaths Relapses Event (relapses and/or deaths) Event occurring after the end of CY

6 CY pulses

MPA (n = 28)

PAN (n = 6)

Total (n = 34)

MPA (n = 19)

PAN (n = 12)

24 (86)

6 (100)

30 (88)

14 (74)

12 (100) 26 (84)

6 (21) 6 (21) 11 (39)

0 1 (17) 1 (17)

6 (18) 7 (21) 12 (35)

6 (26) 7 (37) 13 (68)

6/27 (22)

1/6 (17)

7/27 (26)

10/15 (67)

2 (17) 6 (50) 7 (58) 7/12 (58)

Total (n = 31)

P 0.73†

8 (26) 13 (42) 20 (65)

0.47‡ 0.02‡ 0.02‡

17/27 (63)

0.06‡

* Values are number (%). PAN, polyarteritis nodosa; MPA, microscopic polyangiitis; CY, cyclophosphamide. † According to Fisher’s exact test. ‡ According to Cox hazards proportional methods. Source: Guillevin et al. (2003).

led to more sustained remission. A problem with evaluating immunosuppressive agents in a vasculitis trial is variation in concomitant steroid dosing; in this trial steroid doses were high and were a major contributor to adverse effects. An important aspect of this trial was the inclusion of patients with PAN, who are typically excluded from trials of ANCA-associated vasculitis. This study will be the most authoritative evidence for the treatment of PAN for some time and will directly influence clinical practice. It clearly demonstrated the higher relapse rate of MPA compared with PAN, with either protocol, where only 55% survived to 3 years without disease relapse.

‘Sequential’ therapy of vasculitis and lupus nephritis

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A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies Jayne D, Rasmussen N, Andrassy K, et al. N Engl J Med 2003; 349: 36–44

B A C K G R O U N D . Although more effective than previous treatments, long courses of cyclophosphamide have been accompanied by high levels of irreversible toxicity, including malignancy, infertility and opportunistic infections. This study and that by

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Contreras et al. have promoted alternative regimens, whereby cyclophosphamide is replaced after 3–6 months with a safer immunosuppressive agent, either azathioprine or mycophenolate mofetil. Such sequential designs acknowledge the long-term relapsing nature of lupus and vasculitis, in which the cumulative exposure to therapy may cause as much or more damage than the disease itself. There is much experience of long-term azathioprine and mycophenolate mofetil from solid organ transplantation that supports their safety compared with cyclophosphamide. This approach also reflects the understanding that large doses of cyclophosphamide do not cure the disease—in fact cyclophosphamide dosing should be minimized. I N T E R P R E T A T I O N . The primary systemic vasculitides usually associated with autoantibodies to neutrophil cytoplasmic antigens include Wegener’s granulomatosis and MPA. The authors investigated whether exposure to cyclophosphamide in patients with generalized vasculitis could be reduced by substitution of azathioprine at remission. The patients studied had a new diagnosis of generalized vasculitis and a serum creatinine concentration of 5.7 mg/dl (500 mol/l) or less. All patients received at least 3 months of therapy with oral cyclophosphamide and prednisolone. After remission, patients were randomly assigned to continued cyclophosphamide therapy (1.5 mg/kg of body weight per day) or a substitute regimen of azathioprine (2 mg/kg per day). Both groups continued to receive prednisolone and were followed for 18 months from study entry. Relapse was the primary end-point. Of 155 patients studied, 144 (93%) entered remission and were randomly assigned to azathioprine (71 patients) or continued cyclophosphamide (73 patients). There were eight deaths (5%), seven of them during the first 3 months. Eleven relapses occurred in the azathioprine group (15.5%) and ten occurred in the cyclophosphamide group (13.7%; P = 0.65). Severe adverse events occurred in 15 patients during the induction phase (10%), in eight patients in the azathioprine group during the remission phase (11%), and in seven patients in the cyclophosphamide group during the remission phase (10%; P = 0.94 for the comparison between groups during the remission phase). The relapse rate was lower among the patients with MPA than among those with Wegener’s granulomatosis (P = 0.03). In patients with generalized vasculitis, the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the rate of relapse. Thus, the duration of exposure to cyclophosphamide may be safely reduced.

Comment The randomized trial by the European Vasculitis Study group found no difference in relapse rates between a short (3 months) and a conventional (12 months) course of cyclophosphamide in 156 vasculitis patients (Fig. 8.3). The short follow-up of 18 months precludes any statements of the effects on long-term relapse rates. Retrospective studies have indicated that when treatment is withdrawn relapse rates are higher in those who have received less cyclophosphamide. The implication is therefore that if shorter courses of cyclophosphamide are used, long-term therapy with an alternative immunosuppressive agent will be required. How long this therapy should continue is not known and will probably vary dependent on the diagnostic subgroup and the presence of persisting ANCA. The real value of this trial is to demonstrate the feasibility of large trials in vasculitis and to provide a benchmark against which to test newer drugs.

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Fig. 8.3 Kaplan–Meier analysis of the time to first relapse in the azathioprine and cyclophosphamide groups. Source: Jayne et al. (2003).

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Sequential therapies for proliferative lupus nephritis Contreras G, Pardo V, Leclercq B, et al. N Engl J Med 2004; 350: 971–80

B A C K G R O U N D . Long-term therapy with cyclophosphamide enhances renal survival in patients with proliferative lupus nephritis; however, the beneficial effect of cyclophosphamide must be weighed against its considerable toxic effects. I N T E R P R E T A T I O N . Fifty-nine patients with lupus nephritis (twelve in WHO Class III, 46 in Class IV and one in Class Vb) received induction therapy consisting of a maximum of seven monthly boluses of intravenous cyclophosphamide (0.5–1.0 g/m2 of body surface area) plus corticosteroids. Subsequently, the patients were randomly assigned to one of three maintenance therapies: quarterly intravenous injections of cyclophosphamide, oral

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azathioprine (1–3 mg/kg of body weight per day) or oral mycophenolate mofetil (500–3000 mg/day) for 1–3 years. The baseline characteristics of the three groups were similar, with the exception that the chronicity index was 1.9 points lower in the cyclophosphamide group than in the mycophenolate mofetil group (P = 0.009). During maintenance therapy, five patients died (four in the cyclophosphamide group and one in the mycophenolate mofetil group) and chronic renal failure developed in five (three in the cyclophosphamide group and one each in the azathioprine and mycophenolate mofetil groups). The 72-month event-free survival rate for the composite end-point of death or chronic renal failure was higher in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group (P = 0.05 and P = 0.009, respectively). The rate of relapse-free survival was higher in the mycophenolate mofetil group than in the cyclophosphamide group (P = 0.02). The incidence of hospitalization, amenorrhoea, infections, nausea and vomiting was significantly lower in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group. For patients with proliferative lupus nephritis, short-term therapy with intravenous cyclophosphamide followed by maintenance therapy with mycophenolate mofetil or azathioprine appears to be more efficacious and safer than long-term therapy with intravenous cyclophosphamide.

Comment The Contreras study was much smaller than the preceding trial in patients with vasculitis, and randomized patients with lupus nephritis into continued cyclophosphamide, azathioprine or mycophenolate. These two immunosuppressive agents are both antiproliferative drugs influencing purine metabolism. Mycophenolate mofetil is superior to azathioprine in renal transplantation for the prevention of rejection, when combined with ciclosporin. There have been few good trials of mycophenolate mofetil in autoimmunity, although interest from physicians is high. In this study, analysis of the azathioprine and mycophenolate mofetil groups together found superiority both in relapse rates and safety when compared with continued cyclophosphamide. The magnitude of the difference was surprising and may be an artefact of the sample size (Fig. 8.4). The sample size was too small to investigate a difference between azathioprine and mycophenolate mofetil. These preliminary results are encouraging for larger studies of early cyclophosphamide withdrawal in SLE. Mycophenolate mofetil is expensive and clear superiority needs to be demonstrated over established, cheaper treatments before its use can be widely recommended.

Newer therapies Deoxyspergualin The role of immunosuppressants in the therapy of vasculitis and lupus has been discussed above, as has the introduction of mycophenolate mofetil into therapeutic regimens. Alternative immunosuppressive agents, including azathioprine, metho-

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Number at risk

Fig. 8.4 Kaplan–Meier estimates of patient survival. Source: Contreras et al. (2004).

trexate and ciclosporin, have also been studied previously. Deoxyspergualin is a novel immunosuppressive agent licensed in Japan for the treatment of steroid-resistant kidney transplant rejection.

✍

15-Deoxyspergualin in patients with refractory ANCA-associated systemic vasculitis: a six-month open-label trial to evaluate safety and efficacy Birck R, Warnatz K, Lorenz HM, et al. J Am Soc Nephrol 2003; 14: 440–7

B A C K G R O U N D . Deoxyspergualin is a synthetic analogue of a protein from Bacillus laterosporus that is known to bind to heat-shock proteins. It has antiproliferative effects on myeloid and immune cells and reduces surface MHC expression, interleukin 2 release and activation of the NFB pathway. It has recently been shown to inhibit intracellular kinases, such as Akt kinase, of relevance to ANCA signal transduction. This was the first study in vasculitis and the majority of a group of patients with refractory or frequently relapsing Wegener’s granulomatosis achieved good disease control.

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I N T E R P R E T A T I O N . The combination of cyclophosphamide and oral corticosteroids is effective in the majority of patients with ANCA-associated vasculitis, but it carries substantial risk of drug-related morbidity and mortality. New regimens are desired, especially in refractory cases. The immunosuppressant 15-deoxyspergualin is effective in experimental autoimmune disease and transplantation as well as in acute kidney transplant rejection in humans. To assess the efficacy and safety of deoxyspergualin, an open-label multicentre trial was conducted in patients with antibody-associated vasculitis who were either unresponsive or had contraindications for standard immunosuppressants. Included were 19 cases of Wegener’s granulomatosis and one case of MPA. Nine of them had received cyclophosphamide shortly before study entry without apparent therapeutic success. Deoxyspergualin (0.5 mg/kg per day) was given for 2–3 weeks until the white blood-cell count dropped to 3000/l followed by a rest, until at least a white blood-cell count of at least 4000/l was reached again. This was repeated for up to six cycles. During the study, no other immunosuppressants besides steroids were allowed. Disease improvement during treatment with deoxyspergualin was achieved in 70% of cases (six cases of complete remission, eight cases of partial remission). Leucopenia occurred in each patient in a regular pattern during the cycles and was transient without exception. No mortality or septicaemia was observed. Mild to moderate infections were observed, mainly in the respiratory tract, but resolved under adequate treatment without sequel. It is concluded that treatment with deoxyspergualin is successful in patients with refractory Wegener’s granulomatosis under careful monitoring of the white blood-cell count.

Comment The study patients had disease that was difficult to treat and the high rate of response was encouraging (Table 8.4). Leucopenia was very frequent but rapidly reversible on discontinuation of deoxyspergualin. This has led to a regimen of periods of daily drug administration followed by washout periods. Despite the frequency of leucopenia, the infection rate was low, possibly indicating a preferential effect on neutrophils compared with lymphocytes and monocytes. If the efficacy of deoxyspergualin is borne out in future studies, this relative safety compared with cyclophosphamide and the presumed absence of any late or cumulative toxicity will be important. Direct randomized comparison to cyclophosphamide and the evaluation of deoxyspergualin in lupus and other severe autoimmune diseases is now required.

B-cell depletion with rituximab B cells have been considered an important component in the pathogenesis of both vasculitis and lupus, in which there are pathogenic autoantibodies. In addition to their role in antibody production, B cells can present antigen, provide costimulation to T cells and secrete cytokines. Experimental data point to a crucial role of lymphocytes in animal models of diabetes, arthritis and SLE. Very limited previous data point to a clinical role of B-cell depletion in vasculitis and lupus using rituximab 11,12.

6 6 6 6 6

6 2 6 2 6

7 9 10 11 12

13 15 17 19

20

PR/CR

CR/CR PR/PR PR/PR CR/REL

PR/CR PR/CR PR/PR PR/PR CR/REL

CR/CR CR/CR CR/CR PR/REL

7/na

5/na 3/na 5/na 3/na

4/na 4/na 10/na 5/na 1/na

0/na 6/na 3/na 7/na

MP 6/0

PRED 6/6 PRED 6/4 PRE 10/5 PRE 10

PREL 10/7.5 PREL 20/5 PRED 3/3 MP 6/4 PRE 5

MP 8/3 MP 4/2 PRE 7.5/5 PREL 4

Maintenance with DSG Maintenance with DSG Maintenance with DSG Maintenance with DSG: PREL could be tapered off completely; relapse in month 6; switch to CYC and high-dose steroids Maintenance with OCS Maintenance with AZA Maintenance with AZA Maintenance with MTX Maintenance therapy with AZA, after 2 mo severe renal relapse; switch to CYC and high-dose steroids; then fatal pneumocystis carinii pneumonia Maintenance with MTX Maintenance with MTX Maintenance with AZA Maintenance with AZA, MMF; relapse after 6 mo; switch to CYC and high-dose steroids Maintenance with AZA

Therapy during the 6 mo follow-up after study termination

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* PR, partial remission; CR, complete remission; REL, relapse; OCS, oral steroids; PRE, prednisone; PREL, prednisolone; PRED, prednylidene; CYC, cyclophosphamide; AZA, azathioprine; MTX, methotrexate; MMF, mycophenolate mofetil; DSG, 15-deoxyspergualin; na, not applicable. Source: Birck et al. (2003).

6 6 6 6

OCS (mg/d)

Clinical

(n)

BVAS

Outcome at study termination/6 mo later

Cycles treated

1 2 5 6

Patient

Table 8.4 Treatment and outcomes in responders*

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B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab Looney RJ, Anolik JH, Campbell D, et al. Arthritis Rheum 2004; 50: 2580–9

B A C K G R O U N D . Rituximab is a chimeric monoclonal antibody that depletes B cells by binding to CD20 and engaging Fc receptors, resulting in antibody-dependent cellular cytotoxicity. It has been licensed since 1997 for the treatment of nonHodgkin’s lymphoma and appears safe without an increase in the risk of infection. The study by Looney et al. provides further data in a dose-escalation study involving 17 patients with SLE. I N T E R P R E T A T I O N . A phase I/II dose-escalation trial of rituximab added to ongoing therapy in SLE was conducted. Rituximab was administered as a single infusion of 100 mg/m2 (low dose), a single infusion of 375 mg/m2 (intermediate dose) or as four infusions (1 week apart) of 375 mg/m2 (high dose). CD19+ lymphocytes were measured to determine the effectiveness of B-cell depletion. The Systemic Lupus Activity Measure (SLAM) score was used as the primary outcome for clinical efficacy. Rituximab was well tolerated in this patient population, most of them experiencing no significant adverse effects. Only three serious adverse events, which were thought to be unrelated to rituximab administration, were noted. Most patients (eleven of 17) had profound B-cell depletion (to <5 CD19+ B cells/l). In these patients, the SLAM score was significantly improved at 2 and 3 months compared with baseline (P = 0.0016 and P = 0.0022, respectively, by paired t-test). This improvement persisted for 12 months despite the absence of a significant change in levels of anti-double-stranded DNA antibody and complement. Six patients developed human antichimeric antibodies (HACA) at a level of 100 ng/ml or higher. These HACA titres were associated with African-American ancestry, higher baseline SLAM scores, reduced B-cell depletion and lower levels of rituximab 2 months after the initial infusion. Rituximab therapy appears to be safe for the treatment of SLE and holds significant therapeutic promise, at least for the majority of patients experiencing profound B-cell depletion. Based on these results, controlled trials of rituximab appear to be warranted.

Comment The authors found that B-cell depletion correlated with the dose of rituximab and doses similar to those used in lymphoma were required for reliable depletion. They also found that the disease response was related to B-cell depletion(Fig. 8.5). Interestingly, they failed to observe a correlation between complement and autoantibody levels and disease response, suggesting that rituximab was working through mechanisms other than the inhibition of autoantibody production. There were no serious adverse events directly attributable to rituximab, but a high incidence of an antiglobulin response to rituximab was found. This was higher in those given lower doses that failed to deplete B cells. The clinical significance of HACA is not known but they have the potential to cause infusion reactions on repeated rituximab dosing or to interfere with its action. It is uncertain whether rituximab should be combined

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Fig. 8.5 Systemic Lupus Activity Measure (SLAM) scores in patients with complete versus incomplete B-cell depletion. In the depleters, differences from baseline were significant 1, 2 and 3 months after infusion. Source: Looney et al. (2004).

with an immunosuppressant, both to optimize the therapeutic effect and to reduce the HACA frequency. The duration of action of rituximab is also uncertain. B-cell recovery was not necessarily accompanied by disease relapse and few patients have received multiple doses. The real potential of rituximab, or other B-cell depleting antibodies, is the induction of sustained remission without the need for long-term immunosuppressants. This will be a real advance and this strategy is the most exciting new therapy for autoimmunity directly available to patients.

Vascular disease Lupus predominantly affects young people and is associated with greatly increased risk of heart disease and stroke unrelated to classical cardiovascular risk factors 13. A similar phenomenon has been observed in rheumatoid arthritis and has led to the concept that prolonged inflammation accelerates vascular disease. This accords with observations of the association of C-reactive protein with cardiovascular risk. Lupus and vasculitis have a predilection for vascular inflammation and the study of vascular inflammation and injury in these conditions is attracting attention. For example, endothelial function in conduit vessels unaffected by vasculitis is impaired in vasculitis in proportion to vasculitic severity 24. Also, in vasculitis, a direct correlation

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has been shown between C-reactive protein and endothelial function, and reversal of impaired endothelial function has occurred with the tumour necrosis factor inhibitor infliximab 16,25.

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Circulating endothelial cells as markers for ANCA-associated small-vessel vasculitis Woywodt A, Streiber F, de Groot K, Regelsberger H, Haller H, Haubitz M. Lancet 2003; 361: 206–10

B A C K G R O U N D . A current model of vasculitis involves ANCA-induced activation of cytokine-primed neutrophils, resulting in neutrophil-mediated endothelial cytotoxicity 26. This sequence has been observed in vitro and in histological sections, and this study by Woywodt et al. sought further evidence for endothelial disease by looking for circulating endothelial cells and examining their viability. I N T E R P R E T A T I O N . Histological findings in small-vessel vasculitis associated with ANCA suggest that damaged endothelial cells undergo necrosis and detachment from the basement membrane. The authors postulated that isolation of these cells from peripheral blood might provide a novel marker of the disease and elucidate pathogenetic events. Eighteen patients with active ANCA-associated vasculitis, 20 patients in remission, 20 healthy controls, 12 patients with infection and 12 patients with glomerular disease not associated with ANCA were studied. Endothelial cells were isolated from peripheral blood by the use of Dynabeads coated with antibodies against CD146, and were stained for von Willebrand factor, CD31 and Ulex europaeus lectin 1. Tissue-factor immunocytochemistry and assays for markers of apoptosis and necrosis were also done. Few circulating endothelial cells were seen in healthy controls (0–20 cells/ml, median 5 cells/ml), patients with infection (0–16 cells/ml, median 8 cells/ml), and patients with non-ANCA glomerulonephritis (0–21 cells/ml, median 4 cells/ml). By contrast, large numbers of circulating endothelial cells were detected in patients with active vasculitis (20–5700 cells/ml, median 136 cells/ml; P <0.0001 compared with healthy controls). Cell numbers fell substantially during 6 months of successful immunosuppressive treatment among those with active disease. Patients in remission had moderately raised cell numbers (0–60 cells/ml, median 16 cells/ml). Eighty-four per cent of cells obtained from patients with active disease stained positive for annexin/propidium iodide and 86% stained positive for tissue factor, indicating a necrotic and procoagulant phenotype. Circulating endothelial cells are a novel marker of active ANCA-associated small-vessel vasculitis. The clinical use of this tool and the pathogenic mechanisms leading to these findings require further investigation.

Comment The authors found that circulating endothelial cells were detectable in greatly increased numbers in the sera of patients with vasculitis and that these cells were largely necrotic (Fig. 8.6). Numbers of cells correlated with levels of disease activity. This confirmed the endothelium as an important cellular target in vasculitis and suggested that vasculitis results in necrosis and shedding of endothelial cells. This is likely to be a

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Fig. 8.6 Cell numbers in patients with active and quiescent ANCA-associated vasculitis, healthy controls, patients with glomerular disease not associated with ANCA, and patients with infection. Data are ranges, interquartile ranges (white rectangles) and medians (horizontal lines within white rectangles). Source: Woywodt et al. (2003).

result of exposure to prothrombotic subendothelial structures promoting luminal thrombosis and distal infarction. Although it is unlikely that the assays used in this study will be used routinely for the assessment of vasculitis activity, better monitoring tools are required and immunoassays for endothelial components may be a future possibility. Increased levels of circulating endothelial cells have also been shown after myocardial infarction or ischaemia 27. Furthermore, therapeutic use of endothelial progenitors in heart disease has led to functional improvement 28. Further study of the mechanisms underlying endothelial damage, shedding and repair in vasculitis will have much wider implications.

Conclusion The studies reviewed above show increasing speed in the discovery of advances relevant to patient care. Treatment and outcomes have been stubbornly resistant to revolutionary change for several decades, but the next decade will see rapid change. The epidemiology of vasculitis and lupus is becoming understood and this will result in their recognition by healthcare services with new initiatives in integrating health-

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care delivery, which is currently fragmented. Consensus groups, particularly between America and Europe, have optimized disease classification based on our current understanding of the diseases. This has allowed the emergence of multicentre clinical trials run by collaborative study groups, and the harmonization of approaches to disease management. Previous pathogenetic studies have focused largely on animal models, with only limited advances in understanding of the human disease. Post-genomic approaches appear capable of important contributions, both in the mechanisms of disease and in the development of new assays to aid patient care. Several new therapies are under investigation that have the potential to overthrow current treatment paradigms and to be of real benefit to patients. The existence of collaborative study groups will expedite their evaluation and introduction to routine care. Despite improvements in treatment, the legacy of these diseases will remain and a better understanding of their impact on the vasculature may permit preventative strategies for cardiovascular disease to be introduced in these patient groups. Of greater significance will be the lessons that can be learnt in vasculitis and lupus that will be of relevance to vascular disease in general.

References 1. Booth AD, Almond MK, Burns A, Ellis P, Gaskin G, Neild GH, Plaisance M, Pusey CD,

2. 3. 4. 5.

6.

7. 8.

Jayne DR; Pan-Thames Renal Research Group. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis 2003; 41: 776–84. Jayne D. Current attitudes to the therapy of vasculitis. Kidney Blood Press Res 2003; 26: 231–9. Trager J, Ward MM. Mortality and causes of death in systemic lupus erythematosus. Curr Opin Rheumatol 2001; 13: 345–51. Austin HA, Balow JE. Treatment of lupus nephritis. Semin Nephrol 2000; 20: 265–76. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, Fauci AS. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992; 116: 488–98. Vergunst CE, van Gurp E, Hagen EC, van Houwelingen HC, Hauer HA, Noel LH, Waldherr R, Ferrario F, van der Woude FJ, Bruijn JA, Bajema IM; EC/BCR Project for ANCA-Assay Standardisation. An index for renal outcome in ANCA-associated glomerulonephritis. Am J Kidney Dis 2003; 41: 532–8. Donadio JV Jr, Hart GM, Bergstralh EJ, Holley KE. Prognostic determinants in lupus nephritis: a long-term clinicopathologic study. Lupus 1995; 4: 109–15. Jayne DR, Rasmussen N. Treatment of antineutrophil cytoplasm autoantibody-associated systemic vasculitis: initiatives of the European Community Systemic Vasculitis Clinical Trials Study Group. Mayo Clin Proc 1997; 72: 737–47.

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9. Boumpas DT, Austin HA, Vaughan EM, Yarboro CH, Klippel JH, Balow JE. Risk for

10.

11. 12. 13.

14.

15.

16.

17.

18. 19.

20.

21.

22.

23.

sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann Intern Med 1993; 119: 366–9. Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, Lau CS, Wong AK, Tong MK, Chan KW, Lai KN. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong–Guangzhou Nephrology Study Group. N Engl J Med 2000; 343: 1156–62. Leandro MJ, Edwards JC, Cambridge G, Ehrenstein MR, Isenberg DA. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 2002; 46: 2673–7. Specks U, Fervenza FC, McDonald TJ, Hogan MC. Response of Wegener’s granulomatosis to anti-CD20 chimeric monoclonal antibody therapy. Arthritis Rheum 2001; 44: 2836–40. Bessant R, Hingorani A, Patel L, MacGregor A, Isenberg DA, Rahman A. Risk of coronary heart disease and stroke in a large British cohort of patients with systemic lupus erythematosus. Rheumatology 2004; 43: 924–9. Chan TM, Frampton G, Jayne DR, Perry GJ, Lockwood CM, Cameron JS. Clinical significance of anti-endothelial cell antibodies in systemic vasculitis: a longitudinal study comparing anti-endothelial cell antibodies and anti-neutrophil cytoplasm antibodies. Am J Kidney Dis 1993; 22: 387–92. Frampton G, Jayne DR, Perry GJ, Lockwood CM, Cameron JS. Autoantibodies to endothelial cells and neutrophil cytoplasmic antigens in systemic vasculitis. Clin Exp Immunol 1990; 82: 227–32. Booth AD, Wallace S, McEniery CM, Yasmin, Brown J, Jayne DR, Wilkinson IB. Inflammation and arterial stiffness in systemic vasculitis: a model of vascular inflammation. Arthritis Rheum 2004; 50: 581–8. Choi M, Rolle S, Rane M, Haller H, Luft FC, Kettritz R. Extracellular signal-regulated kinase inhibition by statins inhibits neutrophil activation by ANCA. Kidney Int 2003; 63: 96–106. Watts RA, Scott DG. Classification and epidemiology of the vasculitides. Baillieres Clin Rheumatol 1997; 11: 191–217. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, Hagen EC, Hoffman GS, Hunder GG, Kallenberg CG. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37: 187–92. Schwartz MM, Bernstein J, Hill GS, Holley K, Phillips EA. Predictive value of renal pathology in diffuse proliferative lupus glomerulonephritis. Lupus Nephritis Collaborative Study Group. Kidney Int 1989; 36: 891–6. European Community Study Group on Clinical Trials in Systemic Vasculitis ECSYSVASTRIAL. European therapeutic trials in ANCA-associated systemic vasculitis: disease scoring, consensus regimens and proposed clinical trials. Clin Exp Immunol 1995; 101 (Suppl 1): 29–34. de Groot K, Adu D, Savage CO; EUVAS (European Vasculitis Study Group). The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review. Nephrol Dial Transplant 2001; 16: 2018–27. Guillevin L, Lhote F, Gayraud M, Cohen P, Jarrousse B, Lortholary O, Thibult N, Casassus P. Prognostic factors in polyarteritis nodosa and Churg–Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore) 1996; 75: 17–28.

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24. Bacon PA, Stevens RJ, Carruthers DM, Young SP, Kitas GD. Accelerated atherogenesis in

autoimmune rheumatic diseases. Autoimmun Rev 2002; 1: 338–47. 25. Booth AD, Jayne DR, Kharbanda RK, McEniery CM, Mackenzie IS, Brown J, Wilkinson

IB. Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation. Circulation 2004; 109: 1718–23. 26. Hewins P, Savage CO. ANCA and neutrophil biology. Kidney Blood Press Res 2003; 26: 221–5. 27. Mutin M, Canavy I, Blann A, Bory M, Sampol J, Dignat-George F. Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells. Blood 1999; 93: 2951–8. 28. George J, Goldstein E, Abashidze S, Deutsch V, Shmilovich H, Finkelstein A, Herz I, Miller H, Keren G. Circulating endothelial progenitor cells in patients with unstable angina: association with systemic inflammation. Eur Heart J 2004; 25: 1003–8.

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Part III End-stage renal disease

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9 Progression of chronic renal failure JONATHAN FOX, BRUCE MACKINNON

Introduction This chapter considers key studies of progression of chronic renal failure. No major new concepts have emerged from in vitro studies or animal experiments over the period from January 2003 to April 2004. Rather, it has been a time of consolidation of ideas about mechanisms and treatments. There have been a few important new studies in man but re-analyses of data from previously published studies have also contributed to a clearer understanding of therapeutic options and goals. The focus here will be on those reports that are of most relevance to the progression of chronic renal failure of any cause rather than those concerned with a specific disease state. So, for instance, the issue of glycaemic control in diabetes is not covered, nor are immunosuppressive regimens in microscopic polyangiitis. However, some studies conducted in patients with specific nephropathies are included, either because of the importance of the conditions concerned or because it was felt that their general principles might be applicable to patients with other conditions. Only studies addressing the decline of glomerular filtration rate (GFR) or markers of it, such as serum creatinine, are considered, rather than those concerned only with changes in surrogates, such as proteinuria.

Hypertension and proteinuria It has long been a source of frustration to nephrologists and, even more, to their patients, that, once established, chronic renal failure tends to progress even when the initial cause has been removed or controlled. This is generally true of both experimental and human renal diseases. The progressive decline in renal function is usually accompanied by systemic hypertension and proteinuria. Intraglomerular hypertension, resulting from the adaptive response to reduction in nephron mass, has long been accepted as a major factor in the progressive damage but, more recently, tubulointerstitial inflammation and scarring, probably resulting from the downstream effects of proteinuria, have also been recognized to be important 1. Given that there are, as yet, no evidence-based interventions in humans to ameliorate this kind of © Atlas Medical Publishing Ltd

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tubulointerstitial damage specifically, the main aims in the management of progressive chronic renal failure are to reduce intraglomerular pressure and to reduce proteinuria. Angiotensin-converting enzyme (ACE) inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduce intraglomerular pressure both by reducing systemic blood pressure and also by more specific effects on the glomerular vasculature. Each class of agent has been shown to reduce the rate of progression of renal failure in a wide variety of animal models and in numerous human nephropathies, but it remains uncertain if one class is superior to the other in man. For example, there is good evidence that ACEIs are beneficial in nephropathy due to type 1 diabetes mellitus and that ARBs are beneficial in nephropathy due to type 2 diabetes mellitus in humans, but head-to-head comparisons have not been performed as they would have to be extremely large to have adequate statistical power, given the similar magnitudes of the benefits afforded by these agents. Attention has instead turned to the possibility of an additive or even synergistic effect of combining these two classes of agent.

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Combination treatment of angiotensin-II receptor blocker and angiotensin-converting enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Lancet 2003; 361: 117–24

B A C K G R O U N D . Present ACEI treatment fails to prevent the progression of non-diabetic renal disease. This study assessed the efficacy and safety of combined treatment with an ACEI and an angiotensin-II receptor blocker, and monotherapy with each drug at its maximum dose, in patients with non-diabetic renal disease. Three hundred and thirty-six patients with non-diabetic renal disease were enrolled from one renal outpatient department in Japan. After screening and an 18-week run-in period, 263 patients were randomly assigned angiotensin-II receptor blocker (losartan, 100 mg daily), ACEI (trandolapril, 3 mg daily) or a combination of both drugs at equivalent doses. Survival analysis compared the effects of each regimen on the combined primary end-point of time to doubling of serum creatinine concentration or end-stage renal disease. Analysis was by intention to treat. Seven patients discontinued or were otherwise lost to follow-up. Ten (11%) of 85 patients on combination treatment reached the combined primary end-point compared with 20 (23%) of 85 on trandolapril alone (hazard ratio [HR] 0.38; 95% confidence interval [CI] 0.18–0.63; P 0.018) and 20 (23%) of 86 on losartan alone (0.40; 0.17–0.69; P 0.016). Covariates affecting renal survival were combination treatment (HR 0.38; 95% CI 0.18–0.63; P 0.011), age (1.30; 1.03–2.29; P 0.009), baseline renal function (1.80; 1.02–2.99; P 0.021), change in daily urinary protein excretion rate (0.58; 0.24–0.88; P 0.022), use of diuretics (0.80; 0.30–0.94; P 0.043) and antiproteinuric response to trandolapril (0.81; 0.21–0.91; P 0.039).

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The frequency of side effects with combination treatment was the same as with trandolapril alone. I N T E R P R E T A T I O N . Combination treatment safely retards the progression of non-diabetic renal disease compared with monotherapy. However, since some patients reached the combined primary end-point on combined treatment, further strategies for complete management of progressive non-diabetic renal disease need to be researched.

Comment This study showed that, in patients with non-diabetic renal disease and persistent proteinuria (0.3 g/24 hours), a combination of trandolapril (an ACEI) and losartan (an ARB) was better than monotherapy with either agent in reducing the rate of progression to the combined primary end-point of doubling of serum creatinine or end-stage renal disease (see Fig. 9.1). By the standards of most studies in renal disease, this study was quite large (336 patients) and was double-blind and placebo-controlled. Follow-up was for 3 years. Blood pressure control was comparable between the groups. The patients who benefited had a greater reduction in proteinuria. The study included a single-blind 18-week run-in period in which all patients were given trandolapril alone in increasing doses. During this period, the authors established that, in their patients, maximum proteinuria reduction was achieved at a dose of

Number at risk

Fig. 9.1 Proportion of patients reaching an end-point when treated with losartan, trandolapril or both. Source: Nakao et al. (2003).

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3 mg, which was the dose chosen for the rest of the study. Also, 9% of patients had side effects of trandolapril and 4% showed poor adherence to the study medication; all these patients were excluded from the rest of the study. These results have been supported by two other recent studies. In a small, shortterm, cross-over study in 24 patients with non-diabetic chronic nephropathies, Campbell et al. showed that a combination of half-doses of benazepril (an ACEI) and valsartan (an ARB) reduced proteinuria more than either agent alone 2. They found that the combination caused a 56% reduction in proteinuria compared with full-dose benazepril (45.9%) or valsartan (41.5%), with comparable blood pressure reduction. The combination was well tolerated for the 8-week study period. Similar results were obtained in a small study in patients with diabetic nephropathy 3. The combination of ACEI and ARB appears an attractive option for patients with progressive chronic renal failure and proteinuria. However, further larger and longer-term studies are required to confirm the efficacy and safety of this therapy. Unfortunately, even if the benefits of the COOPERATE study are confirmed, it should be noted that 11% of patients reached the end-points over the 3-year followup period despite the combination therapy.

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Retarding progression of chronic renal disease: the neglected issue of residual proteinuria Ruggenenti P, Perna A, Remuzzi G; GISEN Group Investigators. Kidney Int 2003; 63: 2254–61

B A C K G R O U N D . Findings that early changes in proteinuria independently predict long-term GFR decline (GFR) would highlight proteinuria as a major determinant of progression in chronic renal disease. This study investigated whether percentage changes (3 months versus baseline) in proteinuria (adjusted for concomitant changes in GFR) and residual proteinuria at 3 months, predicted GFR (over a median [interquartile range] follow-up of 31.3 [24.5–50.3] months) in 273 patients with proteinuric chronic nephropathies enrolled in the Ramipril Efficacy In Nephropathy (REIN) study. Short-term changes and residual proteinuria (r –0.23; P 0.0001 for both) significantly correlated with GFR and, in multivariate analyses, independently predicted GFR ( –0.23; P 0.0002 and –0.21; P 0.0004, respectively). For comparable levels of residual proteinuria, patients with greater short-term reduction had slower GFR (–0.28 0.04 versus –0.53 0.07 ml/minute per 1.73 m2 per month; P 0.04). On ramipril and conventional treatment, short-term changes in proteinuria (–18.2 3.5% and 24.2 6.7% respectively; P <0.0001) were associated with significantly different GFRs. However, similar changes in proteinuria resulted in a difference in GFR (ramipril, 0.39 0.07 ml/minute per 1.73 m2 per month; conventional therapy, 0.74 0.11 ml/minute per 1.73 m2 per month; P <0.01) that was sevenfold higher (0.35 versus 0.05 ml/minute per 1.73 m2 per month) in patients with basal proteinuria ≥ 3 g/24 hours than in those with basal proteinuria 1–3 g/24 hours

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(ramipril, 0.25 0.06 ml/minute per 1.73 m2 per month; conventional therapy, 0.30 0.07 ml/minute per 1.73 m2 per month; P value not significant). I N T E R P R E T A T I O N . Regardless of blood pressure control and treatment randomization, short-term changes in proteinuria and residual proteinuria reliably predict long-term disease progression. Reducing proteinuria is renoprotective, particularly in nephrotic patients. As for arterial hypertension, proteinuria should be a specific target for renoprotective treatment.

Comment Several small studies have indicated that the magnitude of reduction in proteinuria early after starting antihypertensive therapy predicts the subsequent reduction in the rate of progression of renal failure. Ruggenenti et al. therefore re-analysed the data from the REIN study and confirmed this observation in a fairly large group of patients with non-diabetic proteinuric nephropathies treated either with the ACEI ramipril or with conventional antihypertensive therapy (i.e. without ACEI or ARB). However, they found an even stronger relationship between the absolute level of residual proteinuria at 3 months and GFR decline. They concluded that reduction in proteinuria should be a specific goal of therapy as well as blood pressure reduction. The proteinuria target suggested was 0.5 g/24 hours.

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A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease Bianchi S, Bigazzi R, Caiazza A, Campese VM. Am J Kidney Dis 2003; 41: 565–70

B A C K G R O U N D . Chronic kidney diseases, particularly if presenting with significant proteinuria, are commonly associated with substantial alteration of serum lipid levels. Experimental evidence suggests that lipid abnormalities may contribute to the progression of kidney disease. However, studies in humans on the subject are scarce. In a prospective, controlled open-label study, the authors evaluated the effects of 1 year of treatment with atorvastatin, a 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor, versus no treatment, on proteinuria and the progression of kidney disease in 56 patients with chronic kidney disease. Before randomization, all patients had already been treated for 1 year with ACEIs or ARBs and other antihypertensive drugs. By the end of 1 year of treatment, urine protein excretion decreased from 2.2 0.1 to 1.2 1.0 g/24 hours (P 0.01) in patients treated with atorvastatin in addition to ACEIs and ARBs. By contrast, urinary protein excretion decreased only from 2.0 0.1 to 1.8 0.1 g/24 hours (P value not significant) in patients who did not receive atorvastatin in addition to ACEI or ARBs. During this time, creatinine clearance decreased only slightly and not significantly (from 51 1.8 to 49.8 1.7 ml/minute) in patients treated with atorvastatin. By contrast, during the same period of observation, creatinine clearance decreased from 50 1.9 to 44.2 1.6 ml/minute (P <0.01) in patients who did not receive atorvastatin.

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I N T E R P R E T A T I O N . This study has shown that treatment with atorvastatin in addition to a regimen with ACEIs or ARBs may reduce proteinuria and the rate of progression of kidney disease in patients with chronic kidney disease, proteinuria and hypercholesterolaemia. The benefits appear to occur in addition to those of treatment with ACEIs and ARBs.

Comment Chronic renal disease is often associated with abnormalities of the plasma lipids; this is particularly true of the nephrotic syndrome. There is a considerable body of experimental work in animals suggesting a beneficial effect of HMG-CoA reductase inhibitors (statins) on both proteinuria and renal failure progression. In the rather few human studies, treatment with statins has had a variable effect on proteinuria but no single previous study has shown a significant effect on progression of renal failure. A meta-analysis of 13 small controlled studies did show a modest improvement in progression (1.9 ml/minute per year) 4. The study of Bianchi et al. considered here is the first single randomized study to show that treatment with a statin can slow the rate of progression of chronic renal failure in humans. All the patients in both treatment and placebo groups were also taking ACEIs and/or ARBs, so the benefit of the statin was in addition to the effect of these agents. Over the 12 months of the study, creatinine clearance declined from 50.8 to 49.8 ml/minute in the atorvastatin-treated patients compared with 50.0 to 44.2 ml/minute in the controls. Figure 9.2 shows the percentage decrease in creatinine clearance (CrCL) in patients treated with atorvastatin (Group A) and those not treated (Group B).

Fig. 9.2 The bars indicate the percentage decrease in creatinine clearance (CrCL) in patients treated with atorvastatin (Group A) and those not treated (Group B). The percentage decline in creatinine clearance was significantly greater in patients treated with atorvastatin than in those not treated (P 0.01). Source: Bianchi et al. (2003).

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Despite being the largest study of its kind to date, this study is still very small, involving only 28 patients in each group. It is also weakened by being an open-label rather than a double-blind placebo-controlled study. Nevertheless, it suggests that treatment with a statin may reduce the rate of progression of chronic renal failure. Interestingly, as in a previous study, there was no correlation between changes in plasma lipids and proteinuria, suggesting that the effects of statins on the kidney may be not be mediated via lipid lowering.

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Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease Tonelli M, Moyé L, Sacks FM, Cole T, Curhan GC, for the Cholesterol and Recurrent Events (CARE) Trial Investigators. J Am Soc Nephrol 2003; 14: 1605–13

B A C K G R O U N D . Limited data suggest that HMG-CoA reductase inhibitors (statins) may slow the loss of renal function in individuals with chronic renal insufficiency. This study was conducted to determine whether pravastatin reduced rates of loss of renal function in people with moderate chronic renal insufficiency. This was a post hoc subgroup analysis of a randomized double-blind placebo-controlled trial. Data were analysed from the CARE study (a randomized trial of pravastatin versus placebo in 4159 participants with previous myocardial infarction and total plasma cholesterol 240 mg/dl). Participants with GFR (estimated by the method of the Modification of Diet in Renal Disease [MDRD] study) 60 ml/minute per 1.73 m2 body surface area at baseline were considered to have moderate chronic renal insufficiency. Multivariate regression was used to calculate rates of decline in MDRD-GFR for individuals receiving pravastatin and placebo, controlling for prospectively determined covariates that might influence rates of renal function loss. Change in renal function could be calculated in 3384 individuals, of whom 690 (20.4%) had MDRD-GFR 60 ml/minute per 1.73 m2 and were eligible for inclusion. Among all individuals with MDRD-GFR 60 ml/minute per 1.73 m2, the MDRD-GFR decline in the pravastatin group was not significantly different from that in the placebo group (0.1 ml/minute per 1.73 m2 per year slower; 95% CI –0.2 to 0.4; P 0.49). However, there was a significant stepwise inverse relation between MDRD-GFR before treatment and slowing of renal function loss with pravastatin use, with more benefit in those with lower MDRD-GFR at baseline (P 0.04). Rate of change in MDRD-GFR in the pravastatin group was 0.6 ml/minute per 1.73 m2 per year slower than placebo (95% CI –0.1 to 1.2 slower; P 0.07) in those with MDRD-GFR 50 ml/minute, and 2.5 ml/minute per 1.73 m2 per year slower (95% CI 1.4 to 3.6 slower; P 0.0001) in those with MDRD-GFR 40 ml/minute per 1.73 m2 per year. Pravastatin also reduced rates of renal loss to a greater extent in participants with than without proteinuria at baseline (P 0.006). I N T E R P R E T A T I O N . Pravastatin may slow renal function loss in individuals with moderate to severe kidney disease, especially those with proteinuria. These findings require confirmation by a large randomized trial conducted specifically in people with chronic renal insufficiency.

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Comment This was a re-analysis of a previous randomized controlled study of pravastatin versus placebo in over 4000 patients with previous myocardial infarction and normal or near-normal renal function (serum creatinine ≤1.5 times the upper limit of normal for the study laboratory). Changes in GFR over the median follow-up of 5 years were calculated in the 690 patients whose GFR, estimated by MDRD-GFR, was less than 60 ml/minute per 1.73 m2 at the start of the study. In this group as a whole, there was no significant effect of pravastatin on progression of renal failure, but when the groups with lower levels of MDRD-GFR (40 ml/minute per 1.73 m2) or with proteinuria (≥ 2 on dipstick) at the start of the study were analysed, those taking pravastatin had significantly lower rates of progression (see Fig. 9.3).

Fig. 9.3 Adjusted effect of pravastatin on rate of renal function loss, stratified by baseline renal function. The figure shows the annualized rate of change in renal function in pravastatin recipients compared with subjects receiving placebo. The effect of pravastatin on loss of renal function tended to be more beneficial in those with lower levels of renal function at baseline. Negative values reflect rates of change that were more rapid than for placebo. Bars represent 95% CI. Source: Tonelli et al. (2003).

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No effect of enalapril on progression in autosomal dominant polycystic kidney disease van Dijk MA, Breuning MH, Duiser R, van Es LA, Westendorp RG. Nephrol Dial Transplant 2003; 18: 2314–20

B A C K G R O U N D . ACEIs are capable of reducing proteinuria and microalbuminuria with preservation of renal function in diabetic and non-diabetic renal disease. This study was designed to investigate the effect of enalapril on the protection of renal

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function in autosomal dominant polycystic kidney disease. Sixty-one normotensive and 28 hypertensive patients with autosomal dominant polycystic kidney disease were studied. The normotensive group participated in a randomized, double-blind, placebo-controlled study, using enalapril. The hypertensive group was randomized for open-label treatment with enalapril or the blocker atenolol. The follow-up was 3 years, and renal function was established repetitively by measuring the clearance of inulin. In the normotensive group, renal function at baseline was 112 3 ml/minute and decreased by –8 2 ml/minute (P 0.001). The loss of renal function in the patients treated with enalapril or placebo was similar (–7 3 versus –9 1 ml/minute; P 0.4). Although blood pressure decreased significantly with enalapril treatment, it had no effect on microalbuminuria. In the hypertensive group, renal function at baseline was 89 2 ml/min. The mean decline in renal function was –12 2 ml/minute (P 0.001), and was equal in patients treated with enalapril and those treated with atenolol. The patients treated with atenolol required more additional treatment to control blood pressure, but no difference in the effect on microalbuminuria was observed between the two treatments. I N T E R P R E T A T I O N . This study was unable to detect a beneficial effect of ACE inhibition on loss of renal function in patients with autosomal dominant polycystic kidney disease.

Comment This study is included here to remind readers that ACE inhibition has not been shown to reduce the rate of progression of renal failure in all nephropathies. The study was small, involving only a total of 89 patients. In the normotensive group of 61 patients, it was a double-blind trial of enalapril versus placebo. In the hypertensive group of 28 patients, it was an open label comparison of enalapril with atenolol. In all patients, renal function was measured repetitively by the gold-standard method of inulin clearance over 3 years. In the normotensive patients, there was no significant difference in the rate of progression of renal failure despite a significantly lower blood pressure in the enalapril-treated patients. In the hypertensive patients, there was also no difference in progression rate. This study must be interpreted cautiously, given the small numbers of patients involved and the fact that it was not double-blind in the hypertensive patients, but it does illustrate the general principle that ACE inhibition is more effective in conditions characterized by proteinuria rather than in conditions where proteinuria is usually mild or absent, such as autosomal dominant polycystic kidney disease.

Other factors affecting progression of chronic kidney disease Although blood pressure control and reduction of proteinuria, with or without angiotensin blockade, are the factors with the best evidence for slowing progression of progressive kidney failure, there is increasing evidence for a range of other factors which can affect progression, some of which are modifiable.

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Environmental exposure to lead and progression of chronic renal diseases: a four-year prospective longitudinal study Yu C-C, Lin J-L, Lin-Tan D-T. J Am Soc Nephrol 2004; 15: 1016–22

B A C K G R O U N D . Previous retrospective research suggests that low-level environmental lead exposure is associated with an acceleration of age-related impairment of renal function. To elucidate the long-term relationship between low-level environmental lead exposure and progression of chronic renal diseases in patients without diabetes, 121 patients who had chronic renal insufficiency, a normal body lead burden (BLB) and no history of exposure to lead were observed prospectively for 48 months. Associations of both BLB and blood lead level (BLL) with renal function were evaluated, with reference to other covariates. The primary end-point was an increase in the serum creatinine level to double the baseline value. Sixty-three patients had BLB of at least 80 g and less than 600 g (high-normal group), and 58 patients had BLB less than 80 g (low-normal group). The primary end-point occurred in 17 patients. Fifteen of them had high-normal BLB, whereas two patients had low-normal BLB (HR 1.01; 95% CI 1.00–1.01 for each increment of 1 g; P 0.002). The BLB and BLL at baseline were the most important risk factors to predict progression of renal insufficiency. Each increase of 10 g in the BLB or 1 g/dl in the BLL reduced the GFR by 1.3 (P 0.002) or 4.0 ml/minute (P 0.01) during the study period. I N T E R P R E T A T I O N . Low-level environmental lead exposure is associated with accelerated deterioration of renal insufficiency. Even at levels far below the normal ranges, both increased BLL and BLB predict accelerated progression of chronic renal diseases.

Comment This study built on a previous study by the same group suggesting that low-level environmental lead exposure may be associated with the progression of renal failure in patients without known lead exposure and that repeated chelation therapy may slow the rate of progression 5. In the study considered here, 121 patients with no history of exposure to lead were observed prospectively for 4 years. Both BLB (see Fig. 9.4), measured by an EDTA chelation test, and BLL were associated with an increased risk of reaching the primary end-point of a doubling of the baseline serum creatinine level. In fact, these were the two most important risk factors to predict progression exceeding in magnitude all the traditional risk factors, such as hypertension and proteinuria, in their multivariate analysis. It should be noted, however, that patients with poorly controlled hypertension were excluded from the study and that their population had a very low prevalence of heavy proteinuria (only 4/121 patients had proteinuria in the nephrotic range). Nevertheless, this study suggests that the influence of low-level lead exposure as a contributor to progression of chronic renal failure may have been underestimated in the past. The mechanism of chronic lead

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Fig. 9.4 Kaplan–Meier plots of the primary end-point (cumulative survival) for subjects with low-normal and high-normal lead burden, showing that significantly more patients with high-normal body lead burden (BLB) reached the primary end-point (P 0.001). Source: Yu et al. (2004).

nephrotoxicity remains unclear. Chronic lead exposure is known to cause hypertension with increased production of reactive oxygen species and decreased excretion of nitric oxide, and it may be that these effects remain important in the kidney even when systemic hypertension is treated.

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High urine volume and low urine osmolality are risk factors for faster progression of renal disease Hebert LA, Greene T, Levey A, Falkenhain ME, Klahr S. Am J Kidney Dis 2003; 41: 962–71

B A C K G R O U N D . Increased fluid intake slows renal disease progression in animal models. The relevance of these findings to human renal disease is not clear, although increased fluid intake often is recommended to patients with chronic renal insufficiency. This study tested the hypothesis that urine volume, urine osmolality (Uosm) or both are significantly associated with decline in GFR in patients with chronic renal insufficiency. This was a retrospective analysis of MDRD study A patients with (n 139) and without (n 442) polycystic kidney disease (PKD). The key outcome measure was GFR slope in relation to mean 24-hour urine volume and Uosm during follow-up in study A (mean 2.3 years). The regression of GFR slope on mean follow-up 24-hour urine volume (adjusted for body surface area and MDRD diet and blood pressure group) showed that the greater the urine volume, the faster the GFR decline in patients both with and without PKD. For example, the difference in GFR slope for those with a mean follow-up 24-hour urine volume of

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2.4 versus 1.4 litres was –1.01 ml/minute per year (CI –0.27 to –1.75) for patients without PKD and –1.20 ml/minute per year (CI –0.06 to –2.34) for those with PKD. A similar but inverse relationship was shown between GFR decline and mean 24-hour Uosm in patients with (P 0.01) and without PKD (P 0.001). These associations remained significant after adjustment for 13 relevant baseline and follow-up covariates. I N T E R P R E T A T I O N . Sustained high urine volume and low Uosm are independent risk factors for faster GFR decline in patients with chronic renal insufficiency. Thus, high fluid intake does not appear to slow renal disease progression in humans. This suggests that, until better evidence becomes available, patients with chronic renal insufficiency should generally let their thirst guide fluid intake. The advice to avoid ‘pushing fluids’ might be particularly important for patients with PKD.

Comment It is traditional to advise patients with chronic renal failure to maintain a high fluid intake. This advice appears to have stemmed from early studies showing that urea clearance in man is increased by increased urine flow rates, with a consequent reduction in blood urea levels in patients with chronic renal failure. There is also some animal evidence suggesting that a high fluid intake may ameliorate renal injury in

Fig. 9.5 Relationship between GFR slope and mean 24-hour urine volume (arranged in quartiles) in patients without (open symbols) and with (closed symbols) PKD during follow-up in the MDRD study (mean follow-up 2.3 years). GFR slope was significantly associated with urine volume. The higher the urine volume, the greater the GFR decline in patients with (P 0.04) and without PKD (P 0.007). Source: Hebert et al. (2003).

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some models. There has been no prospective study in man, so this study, albeit a retrospective reanalysis of the MDRD study, is of interest. The authors analysed the relationship between rate of change of MDRD-GFR and mean 24-hour urine volume and urine osmolality over a median follow-up period of 2.3 years in 139 patients with PKD and 442 patients without PKD in cohort A of the MDRD study. Rather than finding any suggestion of a protective effect of high fluid intake, they found that the greater the urine volume (see Fig 9.5) and the lower the urine osmolality, the faster the decline in renal function in both groups. The authors speculate on the nature of this association, suggesting either that it could represent an adverse effect of high urine volume/ low urine osmolality on progression, or that faster progression causes high urine volume/low urine osmolality, either because of greater tubular injury or by directly increasing thirst. From their findings, they argue that the former is more likely; that is, that high fluid intake may promote progressive renal damage, perhaps by increasing intratubular stretch forces, which can induce fibrogenic mechanisms.

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Risk factors for chronic kidney disease: a prospective study of 23 534 men and women in Washington County, Maryland Haroun MK, Jaar BG, Hoffman SC, Comstock GW, Klag MJ, Coresh J. J Am Soc Nephrol 2003; 14: 2934–41

B A C K G R O U N D . Chronic kidney disease (CKD) is an increasing cause of morbidity and mortality in the US. Prospective data on risk factors for CKD are limited to men, and few studies examine the importance of smoking. The authors performed a community-based, prospective observational study of 20 years’ duration to examine the association between hypertension and smoking in relation to the future risk of CKD in 23 534 men and women in Washington County, Maryland. CKD was identified as end-stage renal disease in the Health Care Financing Administration database, or kidney disease listed on the death certificate. All cases were confirmed as CKD by medical chart review. Adjusted relative hazards of CKD were modelled using Cox proportional hazards regression including age as the time variable and baseline blood pressure, cigarette smoking, gender, and diabetes status as risk factors. The adjusted HR (95% CI) of developing CKD among women was 2.5 (0.05–12.0) for those with normal blood pressure, 3.0 (0.6–14.4) for those with high-normal blood pressure 3.8 (0.8–17.2) for stage 1 hypertension, 6.3 (1.3–29.0) for stage 2 hypertension, and 8.8 (1.8–43.0) for stage 3 or 4 hypertension, compared with individuals with optimal blood pressure. In men, the relationship was similar but somewhat weaker than in women, with corresponding HRs of 1.4 (0.2–12.1), 3.3 (0.4–25.6), 3.0 (0.4–22.2), 5.7 (0.8–43.0) and 9.7 (1.2–75.6). Current cigarette smoking was also significantly associated with the risk of CKD in both men and women (HR 2.9; 95% CI 1.7–5.0 in women and 2.4; 95% CI 1.5–4.0 in men). A large proportion of the attributable risk of CKD in this population was associated with stage 1 hypertension (23%) and cigarette smoking (31%).

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I N T E R P R E T A T I O N . The risk of CKD shows strong graded relationships to blood pressure, diabetes and current cigarette smoking. These relationships are at least as strong in women as in men.

Comment This community-based observational study examined the risk of developing CKD in 23534 adults who were part of a 20-year cancer screening study. In addition to the usual risk factors of hypertension and diabetes, there was a strong association between cigarette smoking and the development of CKD (HR 2.4 for men, 2.9 for women). The magnitude of this risk was similar to that for mild hypertension but less than that for more severe hypertension or diabetes.

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Cigarette smoking and increased urine albumin excretion are interrelated predictors of nephropathy progression in Type 2 diabetes Chuahirun T, Khanna A, Kimball K, Wesson DE. Am J Kidney Dis 2003; 41: 13–21

B A C K G R O U N D . Increased urine albumin excretion (UAE) predicts nephropathy progression in type 2 diabetes, whereas improved blood pressure control and ACE inhibition ameliorate both albuminuria and nephropathy progression. Cigarette smoking predicts nephropathy progression in patients with type 2 diabetes despite improved blood pressure control and ACE inhibition. The authors tested the hypothesis that cigarette smoking and increased UAE are interrelated predictors of nephropathy progression in patients with type 2 diabetes undergoing improved blood pressure control and ACE inhibition. Plasma creatinine levels and UAE as albumin–creatinine ratio were followed for 63.9 0.6 months in 84 patients with type 2 diabetes undergoing blood pressure control with regimens including ACEIs. Despite ACE inhibition and mean blood pressure reduction from 113.7 1.8 to 92.3 0.6 mmHg (P 0.001), plasma creatinine increased (1.03 0.02 to 1.25 0.04 mg/dl [91.1 1.8 to 110.5 3.5 mol/litre]; P 0.001) during follow-up. Regression analysis showed that entry albumin–creatinine ratio, but not cigarette smoking, predicted nephropathy progression when considering both factors together, but cigarette smoking predicted progression only when the albumin–creatinine ratio was excluded. Nephropathy progression was minimal for lower albumin–creatinine ratios at entry, but increased progressively for levels greater than 300. The increment in albumin–creatinine ratio during follow-up directly correlated with nephropathy progression (r2 0.307; P 0.001) and was greater in smokers than non-smokers (1878 346 versus 553 214; P 0.001). I N T E R P R E T A T I O N . These data show that cigarette smoking and increased UAE are interrelated predictors of nephropathy progression in patients with type 2 diabetes, and smoking increases UAE in these patients despite improved blood pressure control and ACE inhibition.

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Comment This prospective observational study examined the baseline characteristics predicting the progression of renal failure in 89 patients with type 2 diabetes mellitus undergoing blood pressure treatment including ACE inhibition over a mean follow-up period of 68 months. The level of albuminuria at the start was positively correlated with increased rate of progression. Cigarette smoking was associated with an increased rate of progression only if albuminuria was excluded from the model. The authors concluded that cigarette smoking and albuminuria are interrelated predictors of progression and that cigarette smoking increases albuminuria in these patients. In another, more recent, study from the same group, cessation of cigarette smoking in patients with type 2 diabetes mellitus reduced renal excretion of transforming growth factor beta (TGFB), which they considered to be a marker of renal injury 6. Previous studies in both diabetic and non-diabetic renal disease have shown that smoking is associated with increased renal injury. The studies considered in this chapter lend further support to this association and emphasize that smoking cessation should be an integral part of the therapy of patients with progressive chronic renal failure, for both cardiovascular and renal protection. There are several possible mechanisms for the damaging effect of smoking on the kidney, including activation of the sympathetic nervous and pressor systems, leading to systemic hypertension and renal vasoconstriction, endothelial damage, and perhaps also direct toxic effects on the renal tubular cells.

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Corticosteroid effectiveness in IgA nephropathy: long-term results of a randomized, controlled trial Pozzi C, Andrulli S, Del Vecchio L, et al. J Am Soc Nephrol 2004; 15: 157–63

B A C K G R O U N D . Proteinuria plays a causal role in the progression of IgA nephropathy (IgAN). A previous controlled trial showed that steroids are effective in reducing proteinuria and preserving renal function in patients with IgAN. The objective of this study was to evaluate the long-term effectiveness of steroids in IgAN, examine the trend of proteinuria during follow-up (starting from the hypothesis that the degree of reduction in proteinuria may influence IgAN outcome), and evaluate how histological scores can influence steroid response. A secondary analysis of a multicentre, randomized, controlled trial of 86 adult IgAN patients who were receiving supportive therapy or intravenous methylprednisolone plus oral prednisone for 6 months was conducted. Ten-year renal survival was significantly better in the steroid group than in the control group (97 versus 53%; log-rank test P 0.0003). In the 72 patients who did not reach the end-point (doubling in baseline serum creatinine), median proteinuria significantly decreased (1.9 g/24 hours at baseline, 1.1 g/24 hours after 6 months, and 0.6 g/24 hours after a median of 7 years). In the 14 progressive patients, proteinuria increased from a median of 1.7 g/24 hours at baseline to 2.0 g/24 hours after 6 months and 3.3 g/24 hours after

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a median of 5 years. Steroids were effective in every histological class. Cox multivariate regression analyses showed that, in addition to steroids, a low baseline histological score, a reduction in proteinuria after 6 months and no increase in proteinuria during follow-up were all independent predictors of a beneficial outcome. I N T E R P R E T A T I O N . Steroids significantly reduce proteinuria and protect against renal function deterioration in IgAN. The histological picture and proteinuria during early and late follow-up improve the prediction of outcome, but considerable variability remains outside the model.

Comment In this study, Pozzi and colleagues report on the results of long-term follow-up of patients in a study of corticosteroid treatment for immunoglobulin A (IgA) nephropathy, first reported in 1999 7. Until then, IgA nephropathy was generally regarded as not being amenable to specific therapy but, in the 1999 report, patients with biopsy-proven IgA nephropathy and plasma creatinine levels of 132 mol/litre or less and proteinuria of 1–3.5 g/24 hours treated with high-dose corticosteroid for 6 months had a significantly lower risk of a doubling of plasma creatinine after 5 years of follow-up than patients given placebo. Corticosteroid-treated patients had a significant decrease in mean urine protein excretion at 1 year that persisted throughout follow-up. The present study demonstrated that 10-year renal survival was also much improved in the corticosteroid-treated patients (97 versus 53%) (see Fig. 9.6). The issue of immunosuppressive treatment for IgA nephropathy has recently been the subject of a Cochrane Review 8. The conclusions were that the randomized controlled trials identified were ‘small, of sub-optimal methodological quality and tended only to report favourable and surrogate outcomes without a thorough reporting of treatment harms’. However, they did accept that ‘all outcomes favour the use of immunosuppressive interventions, with steroids appearing the most promising’. They suggested that further trials were needed to identify which patients were most likely to benefit from these interventions. The study of Pozzi et al. shows that, in appropriate patients with IgA nephropathy, a relatively short course (6 months) of high-dose corticosteroid treatment may offer long-term protection against the progression of renal disease. It further increases the hope, encouraged particularly by studies in idiopathic membranous nephropathy and also by the findings of studies in focal and segmental glomerulosclerosis, that short-term treatment may beneficially affect the long-term outcome in a wide variety of different forms of chronic glomerulonephritis.

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Fig. 9.6 Renal survival estimated on the basis of an increase in plasma creatinine concentrations to 100% above baseline values for patients treated with or without steroids. Source: Pozzi et al. (2004).

Conclusion It is now clear that in patients with progressive chronic renal failure and proteinuria, interventions that reduce proteinuria also tend to reduce the rate of renal functional decline. Proteinuria may simply be a marker of glomerular injury but it appears very likely that it also has additional toxicity through tubulointerstitial damage. Where possible, the aim should first be to ameliorate the initiating cause, for example by immunosuppressive treatment of glomerulonephritis. In addition, general measures to reduce proteinuria by combining strategies such as treatment with ACEIs, ARBs or both, lipid lowering and the cessation of smoking may be highly beneficial in ameliorating renal injury. This is the basis of the relatively new concept of ‘renoprotection’ 9. Unfortunately, even with early and aggressive deployment of all available renoprotective therapies, some patients will continue to progress to end-stage renal failure. In a proportion of patients this will be due to persistent activity of the original disease process, and in some it will be due to the failure of renoprotective measures to abolish maladaptive renal compensatory mechanisms. Studies such as those suggesting an influence of low-level lead exposure or high fluid intake on the progression of renal failure make it likely that there are further mechanisms of damage which have not yet received adequate attention.

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References 1. Brenner BM. Retarding the progression of renal disease. Kidney Int 2003; 64: 370–8. 2. Campbell R, Sangalli F, Perticucci E, Aros C, Viscarra C, Perna A, Remuzzi A, Bertocchi F,

3.

4. 5. 6.

7. 8.

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Fagiani L, Remuzzi G, Ruggenenti P. Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int 2003; 63: 1094–103. Rossing K, Christensin P, Jensen B, Parving H. Dual blockade of the renin–angiotensin system in diabetic nephropathy. A randomised double-blind crossover study. Diabetes Care 2001; 25: 95–100. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int 2001; 59: 260–9. Lin J-L, Lin-Tan D-T, Hsu K-H, Yu C-C. Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N Engl J Med 2003; 348: 277–86. Chuahirun T, Simoni J, Hudson C, Seipel BS, Khanna A, Harrist RB, Wesson DE. Cigarette smoking exacerbates and its cessation ameliorates renal injury in Type 2 diabetes. Am J Med Sci 2004; 327: 57–67. Pozzi C, Bolasco PG, Fogazzi GB, Andrulli S, Altieri P, Ponticelli C, Locatelli F. Corticosteroids in IgA nephropathy: a randomised controlled trial. Lancet 1999; 353: 883–7. Samuels JA, Strippoli GFM, Craig JC, Schena FP, Molony DA. Immunosuppressive agents for treating IgA nephropathy (Cochrane Review). In: The Cochrane Library, Issue 1. Chichester, UK: John Wiley & Sons, 2004. Schiepatti A, Remuzzi G. The future of renoprotection: frustrations and promises. Kidney Int 2003; 64: 1947–55.

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10 Haemodialysis KEN FARRINGTON

Introduction This has been a momentous period in haemodialysis research. It has been dominated by the publication of the results of the haemodialysis (HEMO) study. This is the first major randomized controlled trial in dialysis adequacy since the National Cooperative Dialysis Study 1,2 (NCDS) which established Urea Kinetic Modelling as the standard means of quantifying and monitoring the dialysis dose. In retrospect, the NCDS can be considered to have defined the lowest small solute clearance compatible with avoidance of short-term morbidity. The NCDS also found no significant independent benefit of time spent on dialysis (used as a surrogate for middle molecule clearance). Since then, many observational studies have suggested that outcome on haemodialysis continues to improve as the delivered dose is increased. Taking such studies into account, most guidelines suggest that the minimum delivered singlepool Kt/V (normalized urea clearance) (spKt/V) should be at least 1.2 (approximating to equilibrated Kt/V [eKt/V] 1.0 to 1.05) 3. Retrospective data also suggest that use of high-flux membranes to increase middle molecule clearance may improve survival. The HEMO study addressed the issues of dialysis dose (small solute clearance) and flux. Three papers generated by this study have been included here, together with other relevant contributions to the adequacy debate. The bones of the NCDS have been regularly picked through since it was first reported and there is little doubt that the findings of the HEMO study will be examined as painstakingly over the forthcoming years. The HEMO study may ultimately come to be seen as the study responsible for defining the limitations of three times weekly haemodialysis. Over the last few years there has been a resurgence of interest in dialysis regimens incorporating more frequent dialysis, sessions often taking place daily—so-called quotidian dialysis. There have been impressive reports relating to outcomes of daily or almost daily treatments delivered by high-efficiency means in short hours 4 or more slowly overnight 5. I have therefore included papers detailing outcomes from the London Daily/ Nocturnal Haemodialysis study, which is the first study to report prospective controlled comparative data from patients receiving short daily, long nocturnal or conventional haemodialysis. It was widely construed that such intensive treatment © Atlas Medical Publishing Ltd

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may only be applicable to fit, independent, low-risk patients, but this review details the successful use of the technique in patients with significant extrarenal comorbidity. The use of such techniques places even greater emphasis on the importance of adequate vascular access, which in many settings is difficult enough to achieve and maintain in order to support even our current conventional programmes. In recognition of the critical role of vascular access creation and maintenance for the continued well-being of haemodialysis patients, I have included comparative data from the Dialysis Outcomes and Practice Patterns Study relating to the creation, usage and maintenance of arteriovenous fistulas and a report of a randomized controlled trial of access flow surveillance. Much has been written about the potential use of serial measurements of access flow rates 6 and other techniques in this setting, most of them based on observational data and much in the wake of technological developments. Data from controlled sources are welcome. Cardiovascular disease is the major cause of the excess mortality in the dialysis population and hypertension is a major contributor. Removal of the surplus of salt and water that accumulates between haemodialysis sessions is vital in controlling blood pressure but is fraught with difficulty, especially in short-hours dialysis. Insufficient removal of salt and water during dialysis results in hypertension. Removal of too much fluid or fluid removal at too rapid a rate results in symptomatic hypotension on and after dialysis. Both these unwanted conditions are often achieved in the same individual at the same time. Technological advances, such as relative blood volume (RBV) monitoring, may have a role in optimizing intradialytic fluid removal, though knowledge of how to use these technologies in clinical situations often lags far behind the development of the technology. One of the papers reviewed investigates the potential role of RBV monitoring in hypotension-prone patients. Another investigates the predictive value of parameters derived from 24-hour ambulatory blood pressure monitoring with respect to long-term morbidity and mortality. Our understanding of the importance of abnormalities of mineral metabolism in dialysis patients has recently undergone a paradigm shift, the focus switching from bone to calcifying blood vessels. The finding of severe coronary artery calcification in young dialysis patients 7 related to the duration of dialysis, serum phosphate levels, calcium phosphate product and the use of calcium-based phosphate binders has induced a sense of foreboding. Perhaps our use of calcium as a phosphate binder has not only failed to control phosphate levels adequately but has also provided the raw material for soft tissue and vascular calcification. Adynamic bone, resulting from oversuppressed parathyroids, cannot act as a calcium sump like hyperparathyroid bone. The arrival on the scene of calcimimetics may be timely. These agents target the calciumsensing receptor in the parathyroid gland and lower parathyroid hormone levels without increasing calcium and phosphate levels. Studies in haemodialysis patients have been very promising, but will be discussed in the section on renal bone disease. The haemodialysis population is expanding rapidly. An increasing proportion of incident patients are elderly, frail and dependent. The outcome of dialysis in such patients is very poor 8. Non-dialytic management may have a role in some such patients, an issue addressed in the final paper reviewed.

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Dialysis adequacy

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Effect of dialysis dose and membrane flux in maintenance hemodialysis Eknoyan G, Beck GJ, Cheung AK, et al. N Engl J Med 2002; 347: 2010–19

B A C K G R O U N D . The HEMO study was devised to test the following hypotheses: that an increase in the dose of dialysis above the currently recommended K/DOQI (Kidney Disease Outcomes Quality Initiative) standards would improve survival and that the use of high-flux membranes would confer a survival benefit compared with the use of low-flux membranes. A randomized trial was carried out in 1846 patients receiving three times weekly dialysis. Using a two-by-two factorial design, patients were randomly assigned to a standard or high dose of dialysis and to a low-flux or high-flux dialyser. In the standard-dose group the urea reduction ratio was 66.3 ± 2.5%, the spKt/V 1.32 ± 0.09 and the eKt/V 1.16 ± 0.08; in the high-dose group the values were 75.2 ± 2.5%, 1.71 ± 0.11 and 1.53 ± 0.09 respectively. In the low-flux group 2-microglobulin clearance was 3 ± 7 ml/minute versus 34 ± 11 ml/minute in the high-flux group. The primary outcome, death from any cause, was not significantly influenced by the dose or flux assignment (Fig. 10.1): the relative risk of death in the high-dose group versus the standard-dose group was 0.96 (95% confidence interval [CI] 0.84–1.10; P = 0.53). The relative risk of death in the high-flux group versus the low-flux group was 0.92 (95% CI 0.81–1.05; P = 0.23). The main secondary outcomes (first hospitalization for cardiac causes or death from any cause, first hospitalization for infection or death from any cause, first 15% decrease in the serum albumin level or death from any cause, and all hospitalizations not related to vascular access) also did not differ significantly between either the dose groups or the flux groups. Possible benefits of the dose or flux interventions were suggested in two of seven pre-specified subgroups of patients. I N T E R P R E T A T I O N . Patients undergoing haemodialysis three times weekly appear to derive no major benefit from a higher dialysis dose than that recommended by current US guidelines or from the use of a high-flux membrane.

Comment The study can be interpreted as providing support for the continued use of current US standards of adequacy. However, the huge excess mortality in the haemodialysis population continues to spell out that current practice cannot be regarded as providing adequate replacement of renal function. Some would suggest that definitions of adequacy based solely on small solute clearance will always be inadequate, and that the concept of adequacy needs to be broadened. Others would suggest that increments in adequacy sufficient to affect survival can only be achieved by increasing the frequency of the treatments. Both have a point. As far as flux is concerned, there has already been a huge shift in usage from low- to high-flux membranes such that high-

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Fig. 10.1 Survival curves for the different treatment arms. Source: Eknoyan et al. (2002).

flux is now the major treatment in the US. It is likely that this shift will continue. The findings in subgroup analysis coupled with some aspects of study design also suggest that some caution is needed in interpreting this study. In the high-dose group the risk of death in women was 19% lower than that in the standard-dose group (P 0.01). In the high-flux group the risk of death was 32% lower than in the low-flux group

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among patients who had dialysed for more than 3.7 years before randomization, whereas in patients who had dialysed for a shorter period flux assignment had no impact (P 0.005). Some confounding or at least obscuring effects may have been produced by the use of prevalent patients (mean duration of dialysis before randomization was 3.7 years), 60% of whom had used high-flux dialysers prior to randomization, the exclusion of patients with serious comorbid conditions and those with severe hypoalbuminaemia, and the effective exclusion of very large patients. There is a strong association between sex and body size, so could an association between dose and body size account for the apparent benefits of higher doses in women? Could carryover effects from the use of high-flux membranes in the majority of patients before randomization have protected those subsequently assigned to receive low-flux treatments? These and other aspects are further addressed in the following two papers.

✍

Effects of high-flux hemodialysis on clinical outcomes: results of the HEMO study Cheung AK, Levin NW, Greene T, et al. J Am Soc Nephrol 2003; 14: 3251–63

B A C K G R O U N D . In the HEMO study, chronic high-flux dialysis did not significantly affect the primary outcome of the all-cause mortality (ACM) rate or the main secondary composite outcomes, including the rates of first cardiac hospitalization or ACM, first infectious hospitalization or ACM, first 15% decrease in serum albumin levels or ACM, or all non-vascular access-related hospitalizations. The high-flux intervention, however, seemed to be associated with reduced risks of specific cardiac-related events. The relative risks for the high-flux arm, compared with the low-flux arm, were 0.80 (95% CI 0.65–0.99) for cardiac death and 0.87 (95% CI 0.76–1.00) for the composite of first cardiac hospitalization or cardiac death. Also, the effect of high-flux dialysis on ACM seemed to vary depending on the duration of prior dialysis. When patients were stratified into a short-duration group and a long-duration group on the basis of the mean duration of dialysis of 3.7 years before randomization, in the long-duration subgroup randomization to high-flux dialysis was associated with lower risks of ACM (relative risk [RR] 0.68; 95% CI 0.53–0.86; P = 0.001), the composite of first albumin level decrease or ACM (RR 0.74; 95% CI 0.60–0.91; P = 0.005) and cardiac deaths (RR 0.63; 95% CI 0.43–0.92; P = 0.016) compared with low-flux dialysis. The trends for beneficial effects of high-flux dialysis on ACM rates were considerably weakened when the number of years of dialysis during the follow-up phase were combined with the number of pre-study years of dialysis in the analysis. For the short-duration subgroup, assignment to high-flux dialysis had no significant effect on any of the clinical outcomes that were examined. I N T E R P R E T A T I O N . High-flux dialysis might have a beneficial effect on cardiac outcomes, though results derived from multiple statistical comparisons must be interpreted with caution. The subgroup results that demonstrate that patients with different durations of dialysis are affected differently by high-flux dialysis are interesting and require further study for confirmation.

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Comment The potential reduction in the high-flux group in cardiac death and in ACM in patients dialysed for more than 3.7 years prior to randomization are of great potential interest and echo the findings of previous observational studies. The findings should not be over-interpreted since they arise from multiple statistical comparisons and since support for the interaction of flux and pre-study duration tended to weaken on further analysis. The criticism relating to carryover effects from the use of highflux membranes in patients prior to randomization potentially protecting those subsequently assigned to receive low-flux treatments was not overcome. Indeed, the findings in this paper that the benefits of high-flux assignment in patients dialysed for more than 3.7 years prior to randomization appeared to be confined to those that had been receiving low-flux treatments at the time of randomization would tend to sustain it. What does this mean for the prescription of flux? That the question might now reasonably be ‘why not high-flux?’ rather than ‘why high-flux?’ is worthy of note 9 while we await the reporting of the Membrane Permeability Outcome Study 10.

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Dialysis dose and the effect of gender and body size on outcome in the HEMO Study Depner T, Daugirdas J, Greene T, et al. Kidney Int 2004; 65: 1386–94

B A C K G R O U N D . Gender and body size have been associated with survival in haemodialysis populations. In recent observational studies, overall mortality was similar in men and women and higher in small patients. The effect of dialysis dose in each of these subgroups has not been tested in a clinical trial. The HEMO study was a controlled trial of dialysis dose and membrane flux. We examined the effect of dialysis dose on mortality and on selected secondary outcomes in subgroups of patients. Adjusting for age only, overall mortality was lower in patients with higher body weight (P <0.001), higher body mass index (BMI) (P <0.001) and higher body water content determined by the Watson formula (Vw) (P <0.001), but was not associated with gender (P = 0.27). The relative risk of mortality comparing the highdose with the standard-dose group was related to gender (P = 0.014). Women randomized to the high dose had a lower mortality rate than women randomized to the standard dose (RR = 0.81; P = 0.02), while men randomized to the high dose had a non-significant trend for a higher mortality rate than men randomized to the standard dose (RR = 1.16; P = 0.16). Analysis of both genders combined showed no overall dose effect (RR = 0.96; P = 0.52), as reported previously. Vw was >35 litres in 84% of men compared with 17% of women. However, the relative risk of mortality for the high versus standard dose remained lower in women than in men after adjustment for the interaction of dose with Vw or with other size parameters, including weight and BMI. Conversely, the dose effect was not significantly related to size parameters after controlling for the relationship of the dose comparison with gender.

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I N T E R P R E T A T I O N . The data suggest that mortality and morbidity might be reduced by increasing the dialysis dose above the current standard in women but not in men. This effect was not explained by differences between men and women in age, race, or several indices of body size. Because multiple comparisons were considered in this analysis, the role of gender in the effect of dialysis dose is suggestive and invites further study.

Comment The interaction between gender and dialysis dose has survived this analysis in spite of concerted attempts to attribute it in whole or in part to body size (Table 10.1). The borderline level of significance, arising from multiple statistical comparisons, suggests but does not prove a gender effect. Nevertheless modification of recommendations for the minimum delivered dialysis dose in women needs to be considered. Table 10.1 Effect of gender on the mortality response to dialysis dose, modulated by size Size parameter used to control the effect of gender

Effect of gender on response to high dose controlling for size parameter Ratio of RR

P value

None Weight kg Height cm Vw L Modelled V L Body surface area m2 BMI kg/m2 Black race

0.71 0.73 0.69 0.70 0.74 0.70 0.75 0.74

0.014 0.023 0.039 0.047 0.052 0.019 0.037 0.032

Shown in the second column are the ratios of relative mortality risk (RR) in the high- vs standard-dose groups in women compared with men after adjustment for the interaction of dose group with the specified size parameter. Ratios of RR <1 indicate a greater trend towards a benefit of the high dose in women than in men. All RRs were adjusted for the other six pre-specified baseline covariates. P values are not adjusted for multiple comparisons. Source: Depner et al. (2004).

✍

Effects of body size and body composition on survival in hemodialysis patients Beddhu S, Pappas LM, Ramkumar N, Samore M. J Am Soc Nephrol 2003; 14: 2366–72

B A C K G R O U N D . High BMI is associated with better outcomes in haemodialysis patients, in contrast to the general population. However BMI does not distinguish between muscle mass and adipose tissue, so it is unclear which confers the survival advantage. Twenty-four-hour urinary creatinine (UCr) excretion was used as a

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measure of muscle mass. The outcomes of haemodialysis patients with high BMI and normal or high muscle mass (inferred low body fat) and high BMI and low muscle mass (inferred high body fat) were studied to investigate the effects of body composition on outcomes. In 70 028 patients who initiated haemodialysis in the US between January 1995 and December 1999 with measured creatinine clearances reported in the Medical Evidence form, all-cause and cardiovascular mortalities were examined in Cox and parametric survival models. When compared with the group with normal BMI (18.5–24.9 kg/m2), patients with high BMI (≥25 kg/m2) had a lower hazard of death (hazard ratio [HR] 0.85; P <0.001). However, when compared with normal BMI patients with UCr above the 25th percentile (0.55 g/day), high-BMI patients with UCr >0.55 g/day had a lower hazard of all-cause death (HR 0.85; P <0.001) and cardiovascular death (HR 0.89; P <0.001), and high-BMI patients with UCr ≤ 0.55 g/day had a higher hazard of all-cause death (HR 1.14; P <0.001) and cardiovascular death (HR 1.19; P <0.001). I N T E R P R E T A T I O N . Both BMI and body composition are strong predictors of death. The protective effect conferred by high BMI is limited to patients with normal or high muscle mass. High-BMI patients with inferred high body fat have increased and not decreased mortality.

Comment These findings help resolve the risk factor paradox posed by the improved survival of haemodialysis patients with high BMI. The effect appears to be limited to patients with normal or high muscle mass. Obese patients (high BMI, low muscle mass) have increased and not decreased mortality, in accordance with intuition. A question mark remains about the validity of 24-hour UCr excretion at dialysis initiation as an adequate marker of muscle mass. This is well addressed in the discussion. The huge sample size adds to validity.

✍

Relative contribution of residual renal function and different measures of adequacy to survival in hemodialysis patients: an analysis of the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)-2 Termorshuizen F, Dekker FW, Van Manen JG, Korevaar JC, Boeschoten EW, Krediet RT; NECOSAD Study Group. J Am Soc Nephrol 2004; 15: 1061–70

B A C K G R O U N D . A delivered Kt/V(urea) (dKt/V(urea)) of 1.2 (single pool) is advocated in the US National Kidney Foundation Dialysis Outcomes Quality Initiative guidelines on haemodialysis adequacy, irrespective of the presence of residual renal function. Dialysis adequacy in patients treated by peritoneal dialysis includes the contribution made by residual renal function, which is an important determinant of patient survival. Therefore the contribution of treatment adequacy and residual renal function to patient survival in haemodialysis patients was investigated. The

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Netherlands Cooperative Study on the Adequacy of Dialysis is a prospective multicentre study that includes incident end-stage renal disease (ESRD) patients older than 18 years. The longitudinal data on the residual renal function and dialysis adequacy of patients who were treated with haemodialysis 3 months after the initiation of dialysis (n = 740) were analysed. The mean renal Kt/V(urea) (rKt/V(urea)) at 3 months was 0.7/week (SD 0.6) and the dKt/V(urea) at 3 months was 2.7/week (SD 0.8). Both components of urea clearance were associated with better survival (for each increase of 1/week in rKt/V(urea), RR of death = 0.44 [P <0.0001]; dKt/V(urea), RR of death = 0.76 [P <0.01]). However, the effect of dKt/V(urea) on mortality was strongly dependent on the presence of rKt/V(urea), low values for dKt/V(urea) of <2.9/week being associated with significantly higher mortality in anuric patients only. Furthermore, an excess of ultrafiltration in relation to interdialytic weight gain was associated with an increase in mortality independent of dKt/V(urea). I N T E R P R E T A T I O N . Residual renal clearance is an important predictor of survival in haemodialysis patients, and the dKt/V(urea) should be tuned appropriately to the presence of renal function. Further studies are required to substantiate the important role of fluid balance in haemodialysis adequacy.

Comment The role of residual renal function in haemodialysis patients is often neglected but these findings demonstrate that the presence of residual renal function, even at a low level, is associated with a lower mortality risk in haemodialysis patients too. We need to review the practice of prescribing the same dialysis dose to patients soon after initiation, when many have considerable residual renal function, and to patients many years later, when residual renal function has long been lost. It should be remembered, though, that there is considerable inter-patient variability in the rate of decline of residual renal function on both peritoneal dialysis (PD) and haemodialysis, so if residual renal function is to be taken into account in dialysis prescription it must be measured regularly, not assumed. Assuming a mean rate of decline risks the development of underdialysis.

Quotidian dialysis

✍

Patient quality of life on quotidian hemodialysis Heidenheim AP, Muirhead N, Moist L, Lindsay RM. Am J Kidney Dis 2003; 42(1 Suppl): 36–41

B A C K G R O U N D . Previous studies have shown that changing from conventional three times weekly haemodialysis treatment to more frequent regimes is associated with improvement in many parameters, including control of blood pressure, anaemia,

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mineral homeostasis, and quality of life. The London Daily/Nocturnal Haemodialysis Study is the first to provide prospective controlled comparative data from patients receiving short daily (n = 11), long nocturnal (n = 12 ) or conventional (n = 22) haemodialysis. All patients completed three sets of quality-of-life assessment tools: (i) a locally developed renal disease-specific questionnaire that assessed dialysis symptoms, uraemic symptoms, psychosocial stress and social-leisure activity; (ii) the generic Medical Outcomes Survey 36-Item Short Form (SF-36); and (iii) the global Health Utilities Index (HUI). As a supplement to the HUI, a subset of patients was asked to complete the Time Trade-Off assessment. Overall, the reduction in symptoms shows better fluid management because quotidian haemodialysis patients reported experiencing fewer and less severe cramping during dialysis, fewer headaches, less hypotension, fewer episodes of dizziness, decreased fluid restrictions, fewer blood pressure problems, decreased interdialytic weight gains, fewer episodes of shortness of breath, and a reduction in the sensation of easily feeling cold. HUI results showed that quotidian haemodialysis patients maintained functionality throughout the study period, whereas control patients showed a significant loss. Given the choice, all patients chose to remain on quotidian haemodialysis therapy after switching from conventional haemodialysis therapy. The Time Trade-Off analysis indicated that study patients were willing to trade far less time on quotidian haemodialysis therapy and much more time on conventional haemodialysis therapy in exchange for ‘perfect’ health. I N T E R P R E T A T I O N . As more studies focus on improved patient outcomes and appropriate funding mechanisms are established, more frequent home haemodialysis treatment should become a standard treatment option for patients with ESRD.

Comment Though previous studies have demonstrated improved quality of life in either daily short-hours dialysis or nocturnal dialysis in relation to conventional three times weekly treatment, this study is unique in comparing all three. The most remarkable finding of the study is not referred to in the abstract. The mean time to recover from a dialysis session (Table 10.2) was dramatically reduced in both daily short-hours treatment (range 16–67 minutes) and in nocturnal treatments (2–17 minutes) compared with conventional haemodialysis (397–459 minutes). The effect persisted throughout the 18-month follow-up period and is a dramatic commentary on the inadequacy of three times weekly treatments, in spite of some biochemical views to the contrary.

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Adequacy of quotidian hemodialysis Suri R, Depner TA, Blake PG, Heidenheim AP, Lindsay RM. Am J Kidney Dis 2003; 42(1 Suppl): 42–8

B A C K G R O U N D . Quotidian haemodialysis is increasing in popularity. Quotidian regimes are assumed to provide greater clearances than conventional treatments, though this has not formally been demonstrated. In the London Daily/Nocturnal Haemodialysis Study, dosing and adequacy of quotidian haemodialysis regimens,

Controls

symptoms

8.4 ± 3.8 (22)

10.2 ± 5.4 (13)

9.5 ± 5.1 (10)

327.0 ± 203.2 (10)

4.6 ± 2.0 (22)

5.3 ± 3.4 (12)

5.0 ± 3.0 (10) 3.8 ± 2.1 (21)

2.8 ± 2.9* (9)

2.3 ± 2.2* (9)

20.0 ± 36.9* (12)

16.7 ± 33.9* (9)

67.0 ± 128.2* (10) 36.7 ± 57.7* (9)

4.3 ± 2.8 (22)

4.8 ± 4.3 (12)

2.7 ± 1.3* (10)

9

4.3 ± 11.3 (7)

16.0 ± 24.9* (10)

4.1 ± 2.4 (19)

2.9 ± 2.8* (7)

3.1 ± 3.1* (10)

12

2.1 ± 5.7 (7)

34.0 ± 32.0* (10)

3.6 ± 2.3 (19)

3.0 ± 3.5 (7)

3.2 ± 3.2* (10)

15

7.5 ± 15.0 (4)

29.8 ± 44.1* (10)

3.9 ± 2.4 (13)

3.8 ± 3.0 (4)

3.4 ± 2.8* (10)

18

7.8 ± 4.5 (22)

7.1 ± 3.7* (12)

4.9 ± 3.8* (10) 8.3 ± 5.0 (22)

7.5 ± 5.5 (12)

4.1 ± 2.9* (10) 7.5 ± 4.3* (21)

5.4 ± 4.3* (9)

3.8 ± 3.2* (9)

7.3 ± 4.6* (19)

4.7 ± 4.2* (7)

4.8 ± 4.5* (10)

8.2 ± 4.8 (19)

3.9 ± 4.6* (7)

5.2 ± 4.5* (10)

8.0 ± 4.2 (13)

7.3 ± 8.3 (4)

6.0 ± 4.7* (10)

419.8 ± 414.7 (22) 459.8 ± 512.8 (22) 423.3 ± 399.0 (21) 442.1 ± 428.2 (19) 459.0 ± 466.5 (19) 396.9 ± 394.9* (13)

5.0 ± 17.3* (12)

22.0 ± 30.4* (10)

5.0 ± 2.8 (22)

4.0 ± 2.7 (12)

2.9 ± 2.3* (10)

6

Values expressed as mean ± SD (number of patients). Number of patients varies because of open study enrolment and availability of collected data at a given time. * P <0.05 compared with baseline. Source: Heidenheim et al. (2003)

Nocturnal HD

disease

375.0 ± 460.9 (22)

recover from Controls

Daily HD Nocturnal HD

Minutes to

Daily HD

Controls

symptoms

dialysis

Nocturnal HD

of dialysis

3

19/4/05 4:00 pm

Number of

647.5 ± 584.4 (12)

Daily HD

Number

0

Months

Group

Indicator

Table 10.2 Renal disease–specific quality-of-life indicators

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both short daily (n = 11) and long nocturnal (n = 12), were compared with conventional three times weekly haemodialysis (n = 22) using several models. Urea clearance was computed by percentage reduction in urea, kinetic modelling (spKt/V), Daugirdas rate equation (eKt/V) and Gotch standardized Kt/V (stdKt/V). Nocturnal haemodialysis patients maintained a mean single-session spKt/V of 1.64 throughout the study, similar to that of conventional haemodialysis patients (1.73), whereas daily haemodialysis patients showed a significant decrease in mean single-session spKt/V (0.93) compared with baseline (t(0)) values. Mean weekly spKt/V values increased from t(0) for both quotidian haemodialysis groups (9.08 for nocturnal haemodialysis, 5.55 for daily haemodialysis) and were higher in both quotidian haemodialysis groups compared with conventional haemodialysis patients. Weekly eKt/V, stdKt/V and normalized protein equivalent of nitrogen appearance values showed similar trends. Comparison of the three adequacy models showed an increase in weekly haemodialysis doses for both quotidian haemodialysis regimens compared with conventional haemodialysis; however, percentages of increases from t(0) to follow-up differed according to the model used (Fig. 10.2). The calculated efficiency of dose delivery at the 10-month follow-up comparing daily haemodialysis with conventional haemodialysis was 257 ± 26 versus 306 ± 17 minutes per stdKt/V unit delivered, respectively, amounting to almost 1 dialysis-hour saved per stdKt/V unit delivered for daily haemodialysis. I N T E R P R E T A T I O N . These results show that both quotidian haemodialysis regimens are more effective than conventional haemodialysis in improving weekly urea clearance measured by spKt/V, stdKt/V and eKt/V.

Comment Quotidian regimes improved small solute clearance irrespective of the kinetic measure employed. There is debate about the best measure to employ when comparing the adequacy of very different techniques. stdKt/V was developed to permit the explicit

Fig. 10.2 Comparison among the three adequacy models. For the nocturnal haemodialysis group, the percentage change differed depending on the adequacy model employed (P <0.05 for all comparison). For the daily haemodialysis group, the percentage of change in weekly spKt/V was significantly greater than those in weekly eKt/V and weekly stdKt/V (P <0.05). Source: Suri et al. (2003).

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comparison of any combination of intermittent and continuous dialysis treatment and is the current gold standard, though verification by direct dialysis quantification techniques is awaited. Whether the marked increases in weekly clearance (20% in short hours and almost double in nocturnal dialysis [Fig. 10.2]) will translate into improved survival remains to be seen, though the proven benefits for blood pressure, anaemia, mineral homeostasis and quality of life augur well.

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Long-term study of high-comorbidity ESRD patients converted from conventional to short daily hemodialysis Ting GO, Kjellstrand C, Freitas T, Carrie BJ, Zarghamee S. Am J Kidney Dis 2003; 42: 1020–35

B A C K G R O U N D . Conventional haemodialysis is associated with suboptimal clinical outcomes and high mortality rates. Daily haemodialysis (DHD) has been reported to improve outcomes and quality of life, predominantly in self-care or home dialysis populations. The effect of short DHD on patients with ESRD with high comorbidities has not been established. This prospective study compared clinical outcomes and quality of life in high-comorbidity patients with ESRD converted from conventional haemodialysis to short DHD while maintaining the same total weekly dialysis time. Study patients had 4.0 ± 1.7 major comorbid conditions in addition to ESRD. Standard dialysis parameters, antihypertensive and erythropoietin requirements, Kidney Disease Quality of Life (KDQOL) measurements, vascular access problems and hospitalization rates were compared while on short DHD therapy versus the previous 12 months on conventional haemodialysis therapy. Forty-two patients were studied on short DHD therapy for 793 patient-months during a 72-month period. During short DHD, standard Kt/V increased by 31%, hospitalization days decreased significantly by 34%, and vascular access problems did not increase. Cumulative survival was 33% at 6 years. In the 20 patients who remained on short DHD therapy for 12 months, after 1 year we found significant improvements in KDQOL scores, a 69% reduction in antihypertensive medications with stable blood pressure, and a 45% reduction in erythropoietin requirements with stable haematocrits. We hypothesize that these improvements are the result of the less extreme solute and fluid fluctuations and greater dialysis dose provided by short DHD, even when weekly dialysis time is unchanged. I N T E R P R E T A T I O N . High-comorbidity patients with ESRD converted to short DHD therapy had significantly improved clinical outcomes and quality of life and decreased hospitalizations, with no increase in vascular access problems.

Comment This is the first substantial study to examine the benefits of short-term daily dialysis in high-risk patients with high comorbid loads. Improved outcome measures included better control of blood pressure and anaemia and improved quality of life. However it was essentially a pilot study, lacking controls rigorous enough to allow conclusions about survival, though the quoted median survival of almost 3 years compares favour-

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ably with that of high-risk patients quoted elsewhere 8,11. More work is clearly required, but if these findings are confirmed the proportion of the dialysis population that might potentially benefit from this form of therapy is clearly considerable.

Vascular access

✍

Creation, cannulation and survival of arteriovenous fistulae: data from the Dialysis Outcomes and Practice Patterns Study Rayner HC, Pisoni RL, Gillespie BW, et al. Kidney Int 2003; 63: 323–30

B A C K G R O U N D . An arteriovenous (A-V) fistula is the optimal vascular access for haemodialysis. The National Kidney Foundation Dialysis Outcomes Quality Initiative (DOQI) recommends that fistulas should mature for at least 1 month before cannulation, but this recommendation is not evidence-based. If fistulas are created prior to ESRD and cannulation is possible earlier without compromising fistula survival, the need for temporary catheters would be reduced. Prospective observational data were analysed for a random sample (n = 3674) of incident patients at the time of initiating haemodialysis, haemofiltration or haemodiafiltration in 309 facilities in France, Germany, Italy, Japan, Spain, the UK and the US who were taking part in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Although the proportion of patients who had pre-dialysis care by a nephrologist differed little between countries, there were large variations in the proportion of patients who commenced haemodialysis via an A-V fistula, A-V graft or central venous catheter (Fig. 10.3). The usual time interval between referral and creation of A-V fistulas also differed greatly between countries. For new haemodialysis patients initiating haemodialysis with an A-V fistula (n = 894) the following results were observed: (i) median time to first cannulation varied greatly between countries: 25 and 27 days for Japan and Italy; 42 days for Germany; 80 and 86 days for Spain and France; and 96 and 98 days for the UK and the US; (ii) no association was found between cannulation at 28 days or less versus more than 28 days for patient characteristics of age, gender and 15 classes of patient comorbid factors; (iii) the risk of A-V fistula failure was increased for incident patients who had a prior temporary access (RR = 1.81; P = 0.01) or who were female (RR = 1.52; P = 0.02); (iv) cannulation 14 days or less after creation was associated with a 2.1-fold increased risk of subsequent fistula failure (P = 0.006) compared with fistulas cannulated more than 14 days; (v) no significant difference in A-V fistula failure was seen for fistulas cannulated in 15–28 days compared with 43–84 days. I N T E R P R E T A T I O N . Significant differences in clinical practice currently exist between countries regarding the creation of A-V fistulas prior to starting haemodialysis and the timing of initial cannulation. Cannulation within 14 days of creation is associated with reduced long-term fistula survival. Fistulas should ideally be left to mature for at least 14 days before first cannulation.

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Fig. 10.3 Proportion of incident patients who commenced haemodialysis via an arteriovenous (A-V) fistula, A-V graft and catheter (either cuffed or uncuffed) in participating countries (n = 3674). Analysis included incident patients who entered DOPPS within 5 days of their first dialysis treatment. Source: Rayner et al. (2003).

Comment Two main themes emerge from this paper. The first relates to the optimal timing of first cannulation of an A-V fistula, which from this observational study appears to be at least 14 days. The second is that there are important differences between countries in the clinical pathway along which patients are prepared for dialysis. The proportion of patients initiating dialysis with an A-V fistula is significantly lower in the UK (48%) and USA (15%) in spite of similar nephrology referral patterns. Proportionately more patients in these countries begin dialysis with central venous catheters, predisposing to subsequent fistula failure. Furthermore, waiting times for access creation (from surgical referral to access creation) are much longer in the UK than elsewhere, 60% of patients waiting more than 1 month. These differences exist in spite of universal agreement that the A-V fistula is the optimal access. Clearly there is a need to redesign patient pathways, especially in the UK and US, and to direct appropriate resource to improving timely fistula provision. One would anticipate an improvement in patient survival.

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A randomized controlled trial of blood flow and stenosis surveillance of hemodialysis grafts Ram SJ, Work J, Caldito GC, et al. Kidney Int 2003; 64: 272–80

B A C K G R O U N D . It is widely accepted that haemodialysis graft surveillance combined with correction of stenosis reduces thrombosis and prolongs graft survival. Nevertheless, few randomized controlled trials have evaluated this approach. In this randomized controlled trial, 101 patients were assigned to control, flow (Qa) or stenosis groups, and were followed for up to 28 months. All patients had monthly Qa measured by ultrasound dilution and quarterly percentage stenosis measured by duplex ultrasound. Referral for angiography was based on the following criteria: (i) control group (n = 34), clinical criteria; (ii) flow group (n = 32), Qa <600 ml/minute or clinical criteria; and (iii) stenosis group (n = 35), stenosis >50% or clinical criteria. Stenosis of at least 50% during angiography was corrected by pre-emptive percutaneous transluminal angioplasty (PTA). The pre-emptive PTA rate in the control group (0.22/patient-year) was two-thirds the rate in the flow group (0.34/patient-year), and was highest in the stenosis group (0.65/patient-year; P <0.01). The percentage of grafts that thrombosed was similar in the control (47%) and flow groups (53%), but reduced in the stenosis group (29%; P = 0.10). Two-year graft survival was similar in the control (62%), flow (60%) and stenosis groups (64%) (P = 0.89). I N T E R P R E T A T I O N . Qa and stenosis surveillance were not associated with improved graft survival, although thrombosis was reduced in the stenosis group. The most important factors in this result may be that monthly Qa and quarterly stenosis measurements were not accurate or timely indicators of the risk of thrombosis or progressive stenosis. This study does not support the concept that Qa or stenosis surveillance is superior to aggressive clinical monitoring.

Comment This is the first randomized controlled trial of the influence of access blood flow surveillance on graft survival and the first to compare access blood flow surveillance and stenosis surveillance. Neither improved graft survival in comparison with the control group, in which surveillance was by clinical observation. These findings contrast with claims arising from many earlier uncontrolled studies. Two caveats: first, this is a small study and so cannot exclude a modest benefit on fistula survival related to either of these surveillance methods: secondly, the intervention rate was high and graft survival relatively long in the control group, suggesting enthusiastic clinical surveillance was being carried out. This might be difficult to replicate. Nevertheless, in a setting of constrained resources, a drive to improve timely A-V fistula creation rather than extend access monitoring programmes might achieve the best balance. It should be pointed out that there are no similar data relating to A-V fistula.

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Blood pressure

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Characteristics of hypotension-prone haemodialysis patients: is there a critical relative blood volume? Barth C, Boer W, Garzoni D, et al. Nephrol Dial Transplant 2003; 18: 1353–60

B A C K G R O U N D . Intradialytic morbid events (IME, mostly hypotension), mainly due to ultrafiltration-induced hypovolaemia, are still the most frequent complication during haemodialysis. This study was performed to test the hypothesis that there is an individual critical RBV (RBV(crit)) in IME-prone haemodialysis patients. In this prospective international multicentre study, 60 IME-prone patients from nine dialysis centres were observed during up to 21 standard haemodialysis sessions without trial-specific intervention. The RBV was monitored continuously by an ultrasonic method (blood volume monitor). Also, the ultrafiltration rate was registered continuously. Blood pressure was measured at regular intervals, and more frequently during IME. All IME and specific therapeutic interventions were noted. In total, 537 IME, some with more than one symptom, were documented during 585 haemodialysis sessions. The occurrence of IME increased up to ten-fold from the start to the end of the haemodialysis session. RBV(crit) showed a wide inter-individual range, varying from 71 to 98%. However, the intra-individual RBV limit was relatively stable, with an SD of less than 5% in three-quarters of the patients. In patients with congestive heart failure, cardiac arrhythmia, advanced age, low ultrafiltration volume and low diastolic blood pressure, the authors observed higher values of RBV(crit). While all correlations between RBV(crit) and patient characteristics alone were found to be of weak or medium strength, the combination of diastolic blood pressure, ultrafiltration volume and age resulted in a strong correlation with RBV(crit): the linear equation with these parameters allows an estimation of RBV(crit) in patients not yet monitored with a blood volume monitor. I N T E R P R E T A T I O N . An individual RBV limit exists for nearly all patients. In most IME-prone patients, these RBV values were stable with only narrow variability, thus making it a useful indicator to mark the individual window of haemodynamic instabilities.

Comment Haemodynamic instability on haemodialysis is a major problem. It accounts for significant intra- and interdialytic morbidity and compromises the achievement of optimal fluid balance. Continuous monitoring of RBV during dialysis has been clinically available for some time but we are still learning how best to use it. It has been postulated that there is an individual limit of RBV below which a patient will develop symptomatic hypotension, the so-called crash-crit (RBV(crit)). This study demonstrates that a crash-crit can be defined for most hypotension-prone patients and that it varies greatly across the whole patient group (Fig. 10.4), but that it is generally

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Fig. 10.4 Individual RBVcrit of all patients with intradialytic morbid events (IME). RBVcrit was calculated as the average of all RBV measurements during IME of individual patients (n = 58). Source: Barth et al. (2003).

stable with limited variability in individuals. It may therefore be potentially useful as a guide to ultrafiltration. One wonders whether even this degree of variability will limit its clinical usefulness in those patients with comorbidities whose RBV(crit) is relatively high, in whom it would potentially be of the most use. Prospective studies will tell.

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Non-dipping is a potent predictor of cardiovascular mortality and is associated with autonomic dysfunction in haemodialysis patients Liu M, Takahashi H, Morita Y, et al. Nephrol Dial Transplant 2003; 18: 563–9

B A C K G R O U N D . Lack of nocturnal blood pressure fall (non-dipping) is common among haemodialysis patients, but little is known regarding its association with cardiovascular (CV) disease morbidity and mortality. Eighty haemodialysis patients initially underwent 24-h ambulatory blood pressure monitoring (ABPM), and then they were defined as either ‘dippers’ (n = 24, nocturnal blood pressure fall ≥ 10%) or ‘non-dippers’ (n = 56, fall <10%). Coronary angiography was performed when clinically indicated. Twenty-four-hour ambulatory ECG was recorded in 20 dippers and 20 non-dipper haemodialysis patients, and in 20 normal subjects. All patients were followed for up to 5.8 years (33.0 ± 19.1 months). The outcome events studied were the hospitalizations due to CV diseases and CV death. Compared with dippers, non-dippers initially had a higher incidence of coronary artery stenosis (P <0.05)

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along with left ventricular asynergy (P <0.01 in both cases). The circadian rhythm of autonomic function was impaired in non-dippers. The incidences of CV events and CV deaths were 3.5 and 9 times higher in non-dippers than in dippers. The cumulative CV event-free survival and CV survival rates were lower in non-dippers than in dippers (P = 0.02 and P = 0.005, respectively). Based on Cox analysis, non-dipping was associated positively with CV events and CV mortality (HR 2.46; 95% CI 1.02–5.92; P = 0.038 and HR 9.62; 95% CI 1.23–75.42; P = 0.031, respectively). Meanwhile, nocturnal systolic blood pressure fall, diurnal systolic blood pressure and diurnal pulse pressure were negatively associated with CV event/death. The clinic blood pressure was not associated with CV event/death. I N T E R P R E T A T I O N . The non-dipping phenomenon is closely related to a high incidence of CV diseases, poor long-term survival and profound autonomic dysfunction. ABPM is useful in predicting long-term CV prognosis in haemodialysis patients.

Comment This study, with an impressive follow-up, demonstrates the association of the phenomenon of non-dipping on 24-hour ambulatory blood pressure profiles with cardiovascular disease and autonomic dysfunction in haemodialysis patients. It is highly predictive of cardiovascular death and may be a useful screening tool. But can you treat it?

Selection for dialysis

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Choosing not to dialyse: evaluation of planned non-dialytic management in a cohort of patients with end-stage renal failure Smith C, Silva-Gane M, Chandna S, Warwicker P, Greenwood R, Farrington K. Nephron Clin Pract 2003; 95: c40–6

B A C K G R O U N D . An increasing proportion of incident haemodialysis patients are elderly, frail and dependent. The outcome of dialysis in such patients is very poor. Non-dialytic management may have a role in the management of some of these patients. This was a cohort study in 321 patients (mean age ± SD, 61.5 ± 15.4 years, 57% male, 30% diabetic) approaching end-stage renal failure who were referred to a renal unit and underwent multidisciplinary assessment and counselling about treatment options. The aim was to study factors influencing the recommendation for palliative (non-dialytic) treatment and to study the subsequent outcome in patients choosing not to dialyse. Recruitment was over 54 months and follow-up ranged from 3 to 57 months. Renal replacement therapy was recommended in 258 patients and palliative therapy in 63 (19.6%). Patients recommended for palliative therapy were more functionally impaired (modified Karnofsky scale), older and more likely to have diabetes. The comorbidity severity score was not an

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independent predictor. Thirty-four patients eventually died during palliative treatment, 26 of them from renal failure. Ten patients recommended for palliative treatment opted for and were treated by dialysis. Median survival after dialysis initiation in these patients (8.3 months) was not significantly longer than survival beyond the putative date of dialysis initiation in palliatively treated patients (6.3 vs 8.3 months [see Fig. 10.5]). Sixty-five per cent of deaths occurring in dialysed patients took place in hospital compared with 27% in palliatively treated patients (P = 0.001). I N T E R P R E T A T I O N . In high-risk, highly dependent patients with renal failure, the decision to dialyse or not has little impact on survival. Dialysis in such patients risks unnecessary medicalization of death.

Comment Some patients presenting at or near end-stage renal failure are elderly, highly dependent and frail, with multiple extrarenal comorbid conditions. Dialysis may be invasive, demanding, often painful and ultimately futile in some of these patients, in whom palliative (non-dialytic) therapy may be a reasonable option. Palliative treatment should include access to full medical support, including the use of erythropoietin and ongoing support by the multidisciplinary team in liaison with community and hospice services. It should be included as an option when therapeutic possibilities are discussed. This study suggests that dialysis may confer little survival advantage in such patients, though the numbers studied are small.

Fig. 10.5 Kaplan–Meier survival curves in palliative dialysed, palliative non-dialysed and all other dialysed patients. Source: Smith et al. (2003).

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Conclusion The last year has seen a number of highly significant publications in the field of haemodialysis, some of which will provide a focus for much discussion over the coming years. Fundamental questions remain relating to the quantification of dialysis adequacy, the determination of optimal dialysis dose, and the roles played by different factors such as time on dialysis, small solute clearance and biocompatibility. HEMO study has perhaps shown us the maximum that can be achieved by three times weekly dialysis. Where it is available, many patients might benefit from daily dialysis. The importance of quality of life must also be considered in any discussion about the potential benefits of dialysis in patients with extensive comorbidities; some of these patients may not be best served by starting dialysis.

References 1. Lowrie EG, Laird NM, Parker TF, Sargent JA. Effect of the hemodialysis prescription of

2. 3. 4. 5. 6. 7.

8.

9.

patient morbidity: report from the National Cooperative Dialysis Study. N Engl J Med 1981; 305: 1176–81. Gotch FA, Sargent JA. A mechanistic analysis of the National Cooperative Dialysis Study (NCDS). Kidney Int 1985; 28: 526–34. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Haemodialysis Adequacy: Update 2000. Am J Kidney Dis 2001; 37(Suppl 1): S7–S64. Traeger J, Sibai-Galland R, Delawari E, Arkouche W. Daily versus standard hemodialysis: one-year experience. Artif Organs 1998; 22: 558–63. Pierratos A, Ouwendyk M, Francoeur R, Vas S, Raj DS, Ecclestone AM, Langos V, Uldall R. Nocturnal hemodialysis: three-year experience. J Am Soc Nephrol 1998; 9: 859–68. III. NKF-K/DOQI Clinical Practice Guidelines for Vascular Access: Update 2000. Am J Kidney Dis 2001; 37: S137–81. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342: 1478–83. Chandna SM, Schulz J, Lawrence C, Greenwood RN, Farrington K. Is there a rationale for rationing chronic dialysis? A hospital based cohort study of factors affecting survival and morbidity. Br Med J 1999; 318: 217–23. Levin N, Greenwood R. Reflections on the HEMO study: the American viewpoint. Nephrol Dial Transplant 2003; 18: 1059–60.

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10. Locatelli F, Hannedouche T, Jacobson S, La Greca G, Loureiro A, Martin-Malo A,

Papadimitriou M, Vanholder R. The effect of membrane permeability on ESRD: design of a prospective randomized multicentre trial. J Nephrol 1999; 12: 85–8. 11. Khan IH, Catto GR, Edward N, Fleming LW, Henderson IS, MacLeod AM. Influence of coexisting disease on survival on renal-replacement therapy. Lancet 1993; 341: 415–18.

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11 Mineral metabolism and renal bone disease SIMON STEDDON, STANLEY FAN

Mineral metabolism: a modifiable cardiovascular risk factor? Introduction Renal osteodystrophy remains a virtually ubiquitous problem within the chronic kidney disease (CKD) population. Historically, attention has mainly focused on the prevention and treatment of secondary and autonomous hyperparathyroidism. More recently, the growing realization that the aberrant skeletal and mineral metabolism of uraemia has potential relevance to cardiovascular morbidity and mortality in these patients has caused a paradigm shift in the way renal bone disease is perceived and treated. It is now recognized that the excessive use of both calcium-based phosphate binders and active vitamin D analogues may contribute to the development of adynamic bone, the clinical consequences of which are only starting to be appreciated. A landmark study demonstrating a link between mortality and the serum concentrations of calcium, phosphorus and parathyroid hormone (PTH) was published in 1998 1. In this study, a random sample of 7096 prevalent haemodialysis patients, excluding those that had started dialysis within the previous 12 months, was drawn from two large US databases. After adjustment for age, race, sex, the presence of diabetes, smoking, AIDS and cancer, serum phosphorus was found to be an independent determinant of mortality risk (6% higher mortality risk for each 1 mg/dl increment in serum phosphorus). Serum calcium alone was not predictive of the risk of mortality (though serum calcium results were only available for approximately 50% of patients), but calcium phosphorus product (Ca P) was, the highest quintile (73–132 mg2/dl2) exhibiting a relative mortality risk 1.34 times that of the quintile range 43–52 mg2/dl2 (Table 11.1). Serum PTH concentration (available for analysis in approximately one-third of patients) was a significant predictor of mortality when considered as a continuous variable, though not when considered in quintiles. In addition, results from an even larger cohort of US dialysis patients (see Block et al., © Atlas Medical Publishing Ltd

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Table 11.1 Relative mortality risk by serum concentrations of calcium, phosphorus and PTH Quintiles

Phosphorus Calcium Ca P PTH

1st

2nd

3rd

4th

5th

1.00 0.96 1.06 0.92

1.00 1.05 1.00 1.00

1.02 1.00 1.08 1.00

1.18* 0.95 1.13 0.95

1.39** 0.91 1.34* 1.18

*P <0.05, ** P <0.0001. Source: Block et al. (1998) 1.

below) have recently been published. An important criticism of the original study is that it does not correct mortality risk for the duration of dialysis. This issue has recently been addressed by Stevens et al.

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Calcium, phosphate, and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality: evidence for the complexity of the association between mineral metabolism and outcomes Stevens LA, Djurdjev O, Cardew S, Cameron EC, Levin A. J Am Soc Nephrol 2004; 15: 770–9

B A C K G R O U N D . Current literature suggests an association between abnormal mineral metabolism (MM) and cardiovascular disease within the dialysis population, though the link is yet to be unequivocally established. In this study, prevalent dialysis patients (515) from British Columbia and Canada were followed prospectively between 2000 and 2002. I N T E R P R E T A T I O N . After adjustment for dialysis type, dialysis adequacy, serum concentrations of haemoglobin and albumin and demographic differences, serum phosphate predicted mortality (risk ratio [RR] 1.56 per 1 mmol/l increase; 95% conﬁdence interval [CI] 1.15–2.12; P <0.004). When combinations of parameters were modelled (overall P <0.003), the combinations of high serum phosphate and calcium with high PTH (RR 3.71; 95% CI 1.53–9.03; P <0.004) or low PTH (RR 4.30; 95% CI 2.01–9.22; P <0.001) were associated with the highest mortality risk. A high PTH with normal serum calcium and phosphate had the lowest mortality risk. These effects varied across different strata of dialysis duration.

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Mineral metabolism, mortality, and morbidity in maintenance hemodialysis Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. J Am Soc Nephrol 2004; 15: 2208–18

B A C K G R O U N D . Data concerning 40 538 haemodialysis patients who had undergone at least one determination of serum phosphorus and calcium concentration during the last 3 months of 1997 were analysed. Unadjusted, case mix-adjusted and multivariable-adjusted relative risks of death were calculated for selected categories of serum phosphorus, calcium, Ca P and intact PTH using proportional hazards regression. I N T E R P R E T A T I O N . After adjustment for case mix and laboratory variables, serum phosphorus concentrations >5.0 mg/dl were associated with an increased relative risk of death (1.07, 1.25, 1.43, 1.67 and 2.02 for serum phosphorus 5.0–6.0, 6.0–7.0, 7.0–8.0, 8.0–9.0 and >9.0 mg/dl). High adjusted serum calcium concentrations were also associated with an increased risk of death (Fig. 11.1), as was moderate to severe hyperparathyroidism (PTH concentrations 600 pg/ml).

Fig. 11.1 Relative risk of death for varying serum calcium concentrations adjusted for serum albumin. Source: Block et al. (2004).

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Comment Both studies confirm that high serum concentrations of serum phosphorus, Ca P and PTH are significantly associated with mortality. In addition, the study by Stevens et al. confirms the important influence of dialysis duration, while this report by Block et al. establishes an association between incremental increases in serum calcium concentration and the risk of death. Whether such relationships are causal remains to be seen. This type of observational data has provided the impetus behind the development of guidelines containing therapeutic targets for PTH, phosphorus and calcium at the various stages of CKD (Table 11.2, 2,3). The National Kidney Foundation have published the Kidney Disease Outcome Quality Initiative (K/DOQI) recommendation for serum calcium that is significantly lower than that previously advocated and may well prove elusive with existing treatments. In the case of PTH, the target concentration is close to normal in patients with CKD up to stage 3. In CKD stages 4 or 5, however, the target PTH level is three to five times the upper limit of normal, reflecting a body of evidence suggesting that moderate elevations in PTH are more likely to be associated with normal bone turnover. The validation of such targets and, in particular, whether therapeutically moving a patient from ‘out of target’ to ‘within target’ results in risk reduction will require further study. These caveats notwithstanding, it is clear that what constitutes best practice with regard to renal bone disease requires a thorough re-evaluation. Over the last few years there has been a shift in the prevalent form of renal osteodystrophy. Historically, the predominant histological type of renal osteodystrophy was osteitis fibrosa cystica and mixed uraemic osteodystrophy but the incidence of adynamic bone disease is rising rapidly 4,5. One of the consequences of low bone turnover is the reduced accretion of bone calcium. It has been suggested that this can result in an increased incidence of hypercalcaemia and hyperphosphataemia with consequent soft tissue and vascular calcification. This potential link is explored in the next section.

Table 11.2 Comparison of different targets set by professional bodies Target calcium (mM) Target phosphorus (mM)

Target PTH (pg/ml)

CKD 3–4

CKD 3–4

CKD 5

85–170 35–110

<4 upper limit of normal 85–170 150–300

CKD 5

UK Renal – 2.2–2.6 Association Europe 2.2–2.75 2.2–2.75 K/DOQI ‘normal’ 2.2–2.38

CKD 3–4

CKD 5 <1.8

0.8–1.47 0.96–1.47

1.47–1.79 1.12–1.76

Source: Gal-Moscovici and Popovtzer (2002) 4 and Sherrard et al. (1993) 5.

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Vascular calcification Cardiovascular disease remains the principal cause of mortality in patients with endstage kidney disease. Over the last few years there has been a growing appreciation that vascular calcification, hitherto considered a relatively benign phenomenon, might predict, or even contribute directly to, uraemic cardiovascular risk 6. Advances in radiological techniques and, in particular, the availability of electron-beam computed tomography (EBCT) have assisted in the identification and quantification of vascular calcification. Consequently, many observational studies have emerged that attest to the scale of the problem in CKD 7. Very broadly speaking, there are two types of arterial calcification: ● ●

intimal calcification, occurring mainly within atherosclerotic plaques; medial calcification, involving the medial wall or tunica media (otherwise known as Mönckeberg’s sclerosis).

Arterial calcification in CKD occurs in both the intima and media of the vessel, making its pathogenesis and clinical relevance complex and heterogeneous. In subjects without kidney disease, a positive EBCT scan (calcium in at least one vessel) correlates with the presence of atherosclerotic plaque. The greater the amount of coronary calcification, the greater the probability of obstructive disease 8. Vascular calcification in dialysis patients is common and tends to be medial as well as intimal, and therefore may not relate solely to atherosclerotic lesions; however, the calcium content of atherosclerotic plaques from patients on haemodialysis is greater than in age-matched controls with normal kidney function 9. Despite these differences, and in the absence of any direct evidence in uraemic patients, it is generally implied that coronary artery calcification equates to occlusive atherosclerosis 10. On this background, the diagnostic utility of EBCT for defining obstructive disease in haemodialysis patients was studied by Sharples et al. (see below).

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Coronary artery calciﬁcation measured with electron-beam computerized tomography correlates poorly with coronary artery angiography in dialysis patients Sharples EJ, Pereira D, Summers S, et al. Am J Kidney Dis 2004; 43: 313–19

B A C K G R O U N D . Coronary artery calciﬁcation (CAC) measured by EBCT correlates with plaque burden and vessel stenosis and is predictive of future cardiac events in the general population. This study compares the predictive value of CAC as assessed by EBCT with coronary angiography. Eighteen patients (72 vessels) were studied for angiographic evidence of stenotic disease, and this was correlated with individual vessel calciﬁcation score. There was no signiﬁcant correlation between the degree of vessel stenosis and calciﬁcation score for individual vessels in patients with positive

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calcium scan. Speciﬁcity was 48% and the positive predictive value was 53%. However, a calciﬁcation score of less than 20 strongly correlated with the absence of signiﬁcant luminal narrowing, and a calciﬁcation score of 0 had a negative predictive value of 87.5%. I N T E R P R E T A T I O N . CAC measured by EBCT is not an accurate marker of the degree of vessel stenosis in coronary artery disease in uraemic patients and should not be used as a single screening test for atherosclerotic coronary disease.

Comment Although some studies of subjects without renal failure have shown a strong correlation between the calcification score and vessel stenosis on an artery or artery segment basis 8, the American Heart Association Writing Group concluded in 1996 that there is a poor site-by-site correlation between calcification seen on EBCT and the severity of the obstructive atherosclerotic lesion. Nevertheless, in the general population, a high calcium score proved to be a consistent predictor of the atherosclerotic burden and future cardiovascular events (Fig. 11.2) 11. In this context, the results of the study by Sharples et al. (whilst the limitations imposed by a small sample size should be acknowledged) are not altogether surprising. It is probable that measurements of vascular calcification score by EBCT do not predict the precise anatomical location of obstructive atherosclerosis, but that they may be an important marker of

Fig. 11.2 Coronary artery calcium prevalence, 10-year event risk, and prevalence/risk ratio in asymptomatic men. Event risk and calcium prevalence are plotted against right axis, and prevalence/risk ratio is plotted against left axis. Source: Anderson et al. (1991) 11.

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cardiovascular risk. The association of vascular calcification, as determined by EBCT, with vascular dysfunction, as determined by pulse wave velocity (PWV), has been addressed by Haydar et al.

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Coronary artery calciﬁcation and aortic pulse wave velocity in chronic kidney disease patients Haydar AA, Covic A, Colhoun H, Rubens M, Goldsmith DJ. Kidney Int 2004; 65: 1790–4

B A C K G R O U N D . Many complications in end-stage renal disease (ESRD) patients are the result of the twin arterial pathologies of atherosclerosis and arteriosclerosis. Part of the latter process is calciﬁcation of the arterial media, which is thought to signiﬁcantly increase vascular stiffness. The aim of this study was to explore the relationship between measures of arterial stiffness: PWV and the extent of calciﬁcation in the coronary arteries. Over a 2-year period, 82 patients from a single centre were invited to participate in the study. Sixty-two agreed to undergo EBCT and in 55 (38 males and 17 females), PWV measurements were made. The mean age of the 55 patients was 56.4 years. The mean duration of dialysis was 65.4 months and the mean CAC score was 2551. The mean PWV was 9.13 m/s. PWV strongly correlated with total CAC even after correction for age, dialysis duration and time-averaged C-reactive protein (P 0.0001). This demonstrated that PWV is strongly correlated to the degree of EBCT-derived CAC score in chronic kidney disease patients. I N T E R P R E T A T I O N . Arterial stiffening, measured as aortic PWV, is independently predictive of the EBCT-derived CAC score in CKD patients.

Comment Although a link between vascular stiffness and calcification is suspected, there are few studies correlating arterial stiffness with calcification, particularly with sensitive techniques such as EBCT. In this study the correlation between CAC and PWV was independent of blood pressure after multivariate analysis. The study provides strong evidence to link conduit artery functional characteristics with the extent of accurately determined vascular calcification. The relationship was apparent after correcting for patient characteristics recognized as influencing both the calcification process and PWV: age, duration of dialysis, inflammation and the prescribed dose of calcium based phosphate binders. The association between bone turnover and vascular calcification has been supported by a study by London et al.

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Arterial calciﬁcations and bone histomorphometry in end-stage renal disease London G, Marty C, Marchais SJ, Guerin AP, Metivier F, de Vernejoul MC. J Am Soc Nephrol 2004; 15: 1943–51

B A C K G R O U N D . This study of 58 patients with end-stage renal disease on haemodialysis compared bone histomorphometry characteristics with arterial calciﬁcation (AC) scores (0–4) that were determined according to the number of arterial sites with calciﬁcations. I N T E R P R E T A T I O N . Patients with AC scores of 0 (no calciﬁcations) or 1 or 2 (mild calciﬁcations) had similar serum PTH levels and bone histomorphometry (more osteoclastic resorption, higher osteoclast numbers, and larger osteoblastic and double tetracycline-labelled surfaces) compared with patients with high AC scores (3 and 4). Multivariate analysis revealed that the AC score was positively associated with age (P <0.0001), daily dose of calcium-containing phosphate binders (P <0.009) and bone aluminium-stained surfaces (P <0.037). An inverse correlation was observed with osteoblastic surfaces (P <0.001). A high AC score was associated with the histomorphometric ﬁnding of low turnover or adynamic bone.

Comment This study completes a triangle of associations in uraemic patients: ● ● ●

mineral metabolism (serum PTH, calcium and phosphorus concentrations) and mortality vascular calcification and mortality bone turnover and vascular calcification.

Whilst these associations do not prove causality, a hypothesis emerges that the aberrant mineral metabolism of the uraemic milieu (and, indeed, its treatment) might contribute to vascular calcification, vascular dysfunction and eventually cardiovascular morbidity and mortality. It seems increasingly likely that vascular calcification is an active process that has an intimate relationship with bone turnover and proceeds under similar regulatory influences.

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Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels Moe SM, Duan D, Doehle BP, O’Neill KD, Chen NX. Kidney Int 2003; 63: 1003–11

B A C K G R O U N D . This group of researchers had previously demonstrated the expression of bone matrix proteins in calciﬁed arteries from dialysis patients. This observation

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suggested that vascular smooth muscle cells may transform to an osteoblastic phenotype. This study examined the expression of Cbfa1, an important transcriptional regulator of osteoblast differentiation. Sections of the inferior epigastric artery from uraemic patients were examined for the presence of Cbfa1, type I collagen and osteopontin by in situ hybridization and immunostaining. In complementary in vitro experiments, the effect of pooled uraemic sera from dialysis patients on Cbfa1 expression was assessed in bovine vascular smooth muscle cells. Cbfa1 and osteopontin were expressed in both the media and the intima in calciﬁed vessels, though staining in non-calciﬁed vessels was minimal. Pooled uraemic serum, when compared with pooled control serum, was able to induce the expression of Cbfa1 in bovine vascular smooth muscle cells by a time-dependent, non-phosphorus-mediated mechanism. I N T E R P R E T A T I O N . These results support the idea that Cbfa1 is a key regulatory factor in the vascular calciﬁcation observed in dialysis patients and is upregulated in response to many uraemic toxins.

Comment Identified players in the regulation of vascular smooth muscle cell calcification include phosphate, fetuin-A, matrix Gla-protein and osteopontin 12,13. Such discoveries yield potential therapeutic targets and bring the enticing prospect of future interventions that might prevent, or even reverse the process. The interested reader is pointed toward studies involving BMP-7 14 and paradoxically PTH 15 (and possibly circulating osteopontin 16) that are beyond the immediate remit of this chapter. Instead, we focus on the new therapies that have entered, or are about to enter, the clinical arena.

New therapies These include non-calcium-, non-aluminium-containing phosphate binders, ‘noncalcaemic’ analogues of vitamin D and the calcimimetic agent cinacalcet.

Non-calcium-containing phosphate binders Recent concerns regarding an elevated patient calcium burden have cast a cloud over calcium-based phosphate binders, particularly in the setting of concurrent vitamin D administration. Sevelamer hydrochloride is the first of a new generation of calciumand aluminium-free phosphate-binding agents; others, including lanthanum carbonate, are in the pipeline. The potential benefit of sevelamer must be balanced by its high cost when compared with other phosphate binders (Table 11.3), and the results of the Treat to Goal 17 and CARE (see Qunibi et al. below) studies have been greeted with much interest. The Treat to Goal study 17 randomized patients in the US to calcium acetate or sevelamer and patients in Europe (Germany and Austria) to calcium carbonate or sevelamer. The study was powered to detect a difference of 10 mg2/dl2 in the Ca P

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Table 11.3 Cost comparison of different phosphate binders available in the UK Phosphate binder (Renagel®

Sevelamer 800 mg) Calcium acetate (Phosex®) Calcium carbonate (Calcium-500) Calcium carbonate (Calcichew®) Aluminium hydroxide (Alu-cap®)

Daily dose

Cost

8.5 7.4 3.8–5.8 3.8–5.8 4

£5.87 £0.82 £0.39–£0.60 £0.36–£0.55 £0.13

Source: Based on the British National Formulary.

product. A 52-week treatment period involved dose titration of the binder and, when necessary, vitamin D analogues. Changes to the dialysate calcium concentration were permitted, as was the concurrent use of aluminium-based phosphate binders. The primary end-point (Ca P) was not significantly different in the two groups. However, the calcium group had: ●

greater suppression of PTH

●

lower use of vitamin D analogues higher use of aluminium greater increment in serum calcium (including an increased frequency of serum calcium >10.5 mg/dl).

● ●

In this study, the use of sevelamer did not lead to superior achievement of three of the four mineral metabolism targets set by K/DOQI (PTH, phosphorus and Ca P). It did, however, lead to fewer episodes of hypercalcaemia and attenuated the progression of coronary and aortic calcification.

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Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study) Qunibi WY, Hootkins RE, McDowell LL, et al. Kidney Int 2004; 65: 1914–26

B A C K G R O U N D . To determine whether calcium acetate or sevelamer hydrochloride best achieves the recently recommended treatment goals of phosphorus (≤5.5 mg/dl) and Ca P product (≤55 mg2/dl2), the authors conducted an 8-week randomized, double-blind study in 100 haemodialysis patients. I N T E R P R E T A T I O N . Comparisons of time-averaged concentrations (weeks 1–8) demonstrated that the calcium acetate recipients had lower serum phosphorus (1.08 mg/dl difference; P 0.0006), higher serum calcium (0.63 mg/dl difference; P <0.0001) and lower Ca P (6.1 mg2/dl2 difference; P 0.022) than the sevelamer recipients. At each week, the calcium acetate recipients were 20–24% more likely to attain

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goal phosphorus (odds ratio [OR] 2.37; 95% CI 1.28–4.37; P 0.0058) and 15–20% more likely to attain the Ca P goal (OR 2.16; 95% CI 1.20–3.86; P 0.0097). Transient hypercalcaemia occurred in eight of 48 (16.7%) calcium acetate recipients, all of whom received concomitant intravenous vitamin D. By regression analysis, hypercalcaemia was more likely with calcium acetate (OR 6.1; 95% CI 2.8–13.3; P <0.0001). Week-8 intact PTH levels were not signiﬁcantly different. Serum bicarbonate levels were signiﬁcantly lower with sevelamer hydrochloride treatment (P <0.0001).

Comment This study was a randomized double-blinded trial comparing calcium acetate with sevelamer over an 8-week period in 100 haemodialysis patients. After withdrawing all phosphate binders, patients were randomized and underwent weekly dose titration based on serum phosphorus concentration alone. The dose of concurrent vitamin D therapy and the dialysate calcium concentration were both held constant. Under this protocol, patients taking calcium acetate were more likely to attain the serum phosphorus and Ca P targets set by K/DOQI (<1.76 and <4.4 mmol/l respectively). Sevelamer-treated patients generally showed lower serum calcium concentrations (although the calcium acetate-treated patients had an average calcium concentration of 2.38 mmol/l, i.e. within the K/DOQI target) (Table 11.4). At the end of the trial, the mean doses of calcium acetate and sevelamer were 7.1 and 6.9 g/day respectively, giving a comparative daily cost (based on the British National Formulary) of £0.82 versus £5.87 respectively (Table 11.3). Nevertheless, the fact remains that high calcium loads have been linked to vascular calcification 18. It is possible that there are certain subgroups of patients who will gain particular benefit from sevelamer; for example, is the preferential use of sevelamer instead of calcium-based phosphate binders of greater benefit in patients with low turnover bone disease compared with other histogical subtypes of renal osteodystrophy?

‘Non-calcaemic’ vitamin D analogues The use of the active vitamin D analogues calcitriol and alfacalcidol to prevent and treat hyperparathyroidism secondary to renal failure is common. However, the calcaemic and phosphataemic effects of these agents can result in increments in Ca P, potentially accentuating cardiovascular risk. In addition, their direct and Table 11.4 Results of CARE study: mean concentration of serum phosphorus and calcium after 5–8 weeks of treatment with either sevelamer or calcium acetate Treatment

Phosphorus (mM)

Calcium (mM)

Ca P (mM2)

Calcium acetate Sevelamer P-value

1.76 2.05 0.38

2.40 2.25 <0.0001

4.22 4.58 0.42

Source: Quinibi et al. (2004).

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potent suppressive action on bone turnover has implicated them in the increasing incidence of adynamic bone. In the experimental setting the newer generation of vitamin D analogues have shown considerable therapeutic potential. Unfortunately, under the clinical spotlight none of these compounds have been shown to be truly non-calcaemic and such descriptions of them are misleading. Three are currently licensed for clinical use around the world: paricalcitol, doxercalciferol and 22-oxacalcitriol. Comparative studies against ‘conventional’ analogues are rare. A recent study by Sprague et al. 19 suggested that paricalcitol suppresses PTH faster than calcitriol but the frequency of hypercalcaemia and the mean calcium–phosphate product were the same. Teng et al. (see next paper) analysed retrospective data from the US-based haemodialysis facilities of Fresenius Medical Care, where both calcitriol and paricalcitol are regularly prescribed.

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Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. N Engl J Med 2003; 349: 446–56

B A C K G R O U N D . This study compared the 36-month survival rate among patients undergoing long-term haemodialysis who started to receive treatment with paricalcitol (29 021 patients) or calcitriol (38 378 patients) between 1999 and 2001. Crude and adjusted survival rates were calculated and stratiﬁed analyses were performed. I N T E R P R E T A T I O N . At 12 months, calcium and phosphorus levels had increased by 6.7 and 11.9% respectively in the paricalcitol group, compared with 8.2 and 13.9% respectively in the calcitriol group (P <0.001). The difference in survival was signiﬁcant at 12 months and increased with time (P <0.001). In the adjusted analysis, the mortality rate was 16% lower (95% CI 10–21%) among paricalcitol-treated patients than among calcitriol-treated patients.

Comment In this study, the survival rates at 36 months among 67 399 patients undergoing longterm haemodialysis who were treated with paricalcitol or calcitriol were compared. Target concentrations for Ca P and PTH were the same for all centres but the formulation of vitamin D prescribed was at the discretion of individual nephrologists. Patients receiving paricalcitol experienced a 16% (95% CI 10–21%) survival advantage even after adjustments for age, sex, race, diabetes status, duration of dialysis, dialysis access, baseline laboratory values and the standardized mortality rate associated with each dialysis centre (Fig. 11.3). Patients treated with paricalcitol also experienced lower increments in calcium and phosphorus but a greater reduction in PTH concentrations (Table 11.5). Of course, such a study has serious limitations – it is an uncontrolled, retrospective interrogation of a clinical database – but the results support the hypothesis that aberrant mineral metabolism and renal osteodystrophy

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Fig. 11.3 Survival of patients treated with either paricalcitol or calcitriol who received the same therapy for the duration of the follow-up. Source: Teng et al. (2003).

Table 11.5 Retrospective analysis of biochemical and patient outcome after treatment with vitamin D analogues (non-randomized)

N Calcium over 1 year (%) Phosphorus over 1 year (%) PTH over 1 year (%) Unadjusted mortality (OR compared with calcitriol) Adjusted mortality (OR compared with calcitriol)

Paricalcitriol

Calcitriol

29 021 6.7 11.9 –15 0.81 0.84

38 378 8.2 13.9 –5 95% CI 0.78–0.85 95% CI 0.79–0.90

Source: Teng et al. (2003).

are potentially modifiable cardiovascular risk factors. However, the overriding conclusion that can be drawn from this study is that a large, randomized, prospective and blinded study comparing newer analogues with more established compounds is badly needed.

Calcimimetics Phosphate binders (both calcium-based and non-calcium based) and vitamin D analogues (calcitriol and ‘non-calcaemic’ analogues) are currently the therapeutic cornerstones in the treatment of renal osteodystrophy. In practice these are effective,

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if imperfect, treatments. Hypercalcaemia and hyperphosphataemia frequently impede dose escalation or interrupt treatment with these agents. Moreover, the recently developed, and much more stringent, mineral metabolism targets (Table 11.2) are likely to place current best practice under increasing strain. Calcimimetics are allosteric modulators of the calcium-sensing receptor (CaSR); that is, they lower the threshold of CaSR activation by extracellular calcium. Small clinical trials have shown that the calcimimetic compound cinacalcet effectively suppresses PTH while being associated with decrements in serum calcium and phosphorus concentrations, presumably by reducing the action of PTH on bone, although a direct role of the CaSR at the bone cellular level has not been excluded 20,21.

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Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis Block GA, Martin KJ, de Francisco AL, et al. N Engl J Med 2004; 350: 1516–25

B A C K G R O U N D . Patients who were receiving haemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 to 180 mg to achieve intact PTH levels of 250 pg/ml or less. The primary end-point was the percentage of patients with values in this range during a 14-week efﬁcacy-assessment phase. I N T E R P R E T A T I O N . Forty-three per cent of the cinacalcet group reached the primary end-point compared with 5% of the placebo group (P <0.001). Overall, mean PTH values decreased by 43% in those receiving cinacalcet but increased by 9% in the placebo group (P <0.001). The serum Ca P product declined by 15% in the cinacalcet group and remained unchanged in the placebo group (P <0.001). Cinacalcet effectively reduced PTH levels independently of disease severity or changes in vitamin D sterol dose.

Comment The potential advantages of cinacalcet have been confirmed in this study by Block et al., reporting the combined results of two identical double-blind placebocontrolled phase II clinical trials. Haemodialysis patients with hyperparathyroidism (above the K/DOQI guideline of 300 pg/ml) were randomized to receive cinacalcet or placebo. After a 12-week dose titration phase, the efficacy of therapy over a 14-week period was assessed. Dose changes to vitamin D analogues and phosphate binders were permitted. During the efficacy phase, the mean reduction of PTH in the cinacalcet group was 43% compared with a rise of PTH in the control group of 9% (P <0.001; Table 11.6). Moreover, cinacalcet appeared to be equally effective in suppressing PTH irrespective of severity (approximately 60% of patients recorded at least 30% reduction of PTH). This is somewhat surprising, as nodular hyperplasia of the parathyroid glands is associated with decreased expression of both vitamin D

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Table 11.6 Effect of cinacalcet on mineral metabolism average during 14-week test phase Cinacalcet

Placebo

P-value

PTH Change (%) Value (pg/ml)

–43 374

9.0 693

<0.001 <0.001

Phosphorus Change (%) Value (pg/ml)

–8.4 1.79

0.2 1.92

<0.001 <0.001

Calcium Change (%) Value (pg/ml)

–6.8 2.30

0.4 2.48

<0.001 <0.001

Ca P Change (%) Value (pg/ml)

–14.6 4.1

0.5 4.8

<0.001 <0.001

Source: Block et al. (2004).

receptors and the CaSR. The former may partly explain why vitamin D analogues can appear ineffective in patients with severe hyperparathyroidism. There is recent evidence to suggest that calcimimetics might increase expression of CaSR in the parathyroid glands 22. If cinacalcet, or another calcimimetic, were to prove effective in patients with severe hyperparathyroidism without causing increments in serum calcium or phosphorus, they would represent an extremely important addition to the nephrologists’ armamentarium. Whilst cinacalcet might help achieve the standards set by K/DOQI and other consensus groups, it should be re-emphasized that it is yet to be proven that achieving such mineral metabolism targets will reduce cardiovascular risk. The half-life of cinacalcet action is short (maximal suppression of PTH occurs 2–4 hours after dosing 21) and PTH concentrations in the above trial were checked 24 hours after dosing. It is therefore possible that the effect of cinacalcet on PTH suppression is even more impressive than that reported thus far. The acute reduction of PTH may be particularly beneficial in patients with hyperparathyroidism as the PTH pulsatility is anabolic to bone 23. In the future, it may be possible to use calcimimetics to achieve and maintain different PTH concentrations determined by the particular clinical context of the patient.

Bone disease after kidney transplantation Whilst kidney transplantation may ameliorate many pathogenic factors that drive renal osteodystrophy, a large cohort of transplanted patients remains with CKD stage III–IV; these patients are thus at risk of developing secondary hyperparathyroidism and other manifestations of renal osteodystrophy. In addition, the immunosuppressive regimen adds a further burden to bone. During the last few years, there have

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been studies that have allowed us to refine the way we might protect and treat the bone disease of kidney transplant patients. However, the clinical studies conducted generally focus on bone quantity rather than bone quality. This is partly because it is easier to measure the former (bone mineral density [BMD] can be determined by a variety of techniques, of which dual-energy X-ray absorptiometry is generally considered the gold standard). This emphasis on BMD is perhaps unhelpful as it should be remembered that the term ‘osteoporosis’ has been recently redefined by the National Institutes of Health as ‘a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture’ 24; bone strength depends on several factors, including bone architecture, turnover, damage accumulation and the efficiency of repair (bone quality). Whilst accepting that changes in bone density do not represent the only attrition to the skeleton after transplantation, there is marked early loss of BMD. The reasons are multifactorial and include the detrimental effects of immunosuppression (predominantly glucocorticoids, although calcineurin inhibitors also have negative effects), persistent hyperparathyroidism, phosphaturia and immobility resulting from hospitalization. In the field of osteoporosis, bisphosphonates have been shown to have beneficial effects that include reducing the risk of fracture after corticosteroid use. It is therefore unsurprising that this therapy has been examined in the kidney transplant setting. An early small randomized controlled study 25 demonstrated the potential of two intravenous doses of pamidronate to retard bone loss when administered as prophylaxis (Fig. 11.4), but the design and size of the study meant that fracture risk, markers of bone turnover and bone histomorphometry were not measured. A larger study by Grotz et al. 26 was reported in 2001 and addressed some of the deficiencies of the original trial, showing that patients who received ibandronate (over a 9-month period) had higher BMD 1 year after transplantation than placebotreated recipients. Moreover, as a surrogate marker of fracture, the treated group suffered less loss of vertebral body height during the 1-year follow-up period. On this background, two important studies in this field were published in 2003: Haas et al. and Coco et al. both advanced our knowledge by providing bone biopsy data as well as biochemical surrogate markers of bone turnover.

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Zoledronic acid to prevent bone loss in the ﬁrst 6 months after renal transplantation Haas M, Leko-Mohr Z, Roschger P, et al. Kidney Int 2003; 63: 1130–6

B A C K G R O U N D . In a 6-month, randomized, placebo-controlled study, 20 kidney transplant recipients received either 4 mg zoledronic acid or placebo twice within 3 months after engraftment. At transplantation and after 6 months, mean trabecular calcium concentration and trabecular morphometry were measured in bone biopsies. BMD of the femoral neck and the lumbar spine were evaluated by dual-energy X-ray absorptiometry, and serum biochemical markers were determined monthly.

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Fig. 11.4 Early changes in BMD at femoral neck after kidney transplantation (a) without and (b) with Pamidronate prophylaxis. Source: Fan et al. (2000) 25.

I N T E R P R E T A T I O N . Trabecular calcium content increased signiﬁcantly in the zoledronic acid group but remained unchanged in the placebo group. BMD at the femoral neck showed no change in the zoledronic acid group but decreased in the placebo group. BMD of the lumbar spine was increased in the zoledronic acid group but showed no change in the placebo group. High-turnover bone disease resolved similarly in both groups, as evidenced by a signiﬁcant decrease in eroded bone surface, osteoclast and osteoblast surface. Serological markers of bone formation and resorption were signiﬁcantly lower in zoledronic acid-treated patients throughout the study. Kidney transplant function was stable after zoledronic acid therapy.

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Prevention of bone loss in renal transplant recipients: a prospective, randomized trial of intravenous pamidronate Coco M, Glicklich D, Faugere MC, et al. J Am Soc Nephrol 2003; 14: 2669–76

B A C K G R O U N D . A randomized, prospective, controlled, clinical trial was conducted using the bisphosphonate pamidronate intravenously in patients with new renal transplants. Treatment subjects (PAM) received pamidronate with vitamin D and calcium at baseline and at months 1, 2, 3 and 6. Control (CON) subjects received vitamin D and calcium only. During months 6–12, the subjects were observed without pamidronate treatment. Biochemical parameters of bone turnover were obtained monthly and BMD was obtained at baseline and months 6 and 12. Bone biopsies for mineralized bone histology were obtained at baseline and at 6 months in a subgroup of subjects who underwent scheduled living donor transplantation. I N T E R P R E T A T I O N . Pamidronate-treated patients preserved their bone mass at 6 and 12 months, as measured by bone densitometry (Fig. 11.5) and histomorphometry. Controls had decreased vertebral BMD at 6 and 12 months (4.8 0.08 and 6.1 0.09% respectively). Biochemical parameters of bone turnover were similar in both groups at 6 and 12 months. Bone histology revealed low-turnover bone disease in 50% of the patients at baseline. At 6 months, all the pamidronate-treated patients had adynamic bone disease, whereas 50% of the controls continued to have or developed decreased bone turnover (Fig 11.6). Pamidronate preserved vertebral BMD during treatment and 6 months after cessation of treatment. Pamidronate treatment was associated with the development of adynamic bone histology.

Comment These studies are all consistent in showing that BMD can be preserved using bisphosphonate prophylaxis. However, bone strength also depends on bone architecture and the ability to repair microfractures (related to bone turnover). By providing bone histomorphometry data, the studies by Haas and Coco are important. Although biochemical markers of bone turnover were reduced in the zoledronic acid-treated group, osteoid surface increased by 39% and the authors (Haas et al.) deduced that adynamic bone pathology was not a significant problem. The bone biopsies were performed without tetracycline double labelling, but instead bone mineralization density distribution measurement (BMDD) was performed on samples. This technique measures the mineral (calcium) content of the sample and is sensitive in the detection of small changes in mineralization. Increasing BMDD in zoledronic acid-treated patients argues against the development of significant osteomalacia. In the study by Coco et al. (in which the dose of pamidronate administered was higher than that administered in the study by Fan et al.: 180 mg over 6 months versus 1 mg/kg), 6-month bone histology from bisphosphonate treated patients all were consistent with the diagnosis of adynamic bone (Fig. 11.6). These results should

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Fig. 11.5 Percentage change in vertebral BMD after transplantation with and without pamidronate. Source: Coco et al. (2003).

Fig. 11.6 Changes in diagnosis of bone pathology after kidney transplantation with (solid) and without (dashed) pamidronate treatment. Source: Coco et al. (2003).

act as a counterpoint to the use of prolonged high doses of bisphosphonates in renal patients. Once incorporated into bone, bisphosphonates have prolonged biological effects and have the potential to cause focal demineralization defects and low bone turnover. In addition, pamidronate has been implicated in causing glomerular podocyte injury and perhaps it is prudent to limit the dose and duration of bisphosphonate prophylaxis to the minimum. With this in mind, the long-term follow-up data of the earlier bisphosphonate studies were of particular interest and were published recently.

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Long-term effects on bone mineral density of pamidronate given at the time of renal transplantation Fan SL, Kumar S, Cunningham J. Kidney Int 2003; 63: 2275–9

B A C K G R O U N D . The authors re-examined patients who had participated in the previously reported study 25, all of whom had been randomized to receive either placebo or pamidronate (0.5 mg/kg) at the time of transplantation and 1 month later. They now report 4-year BMD data from 17 of the 26 original cohorts. I N T E R P R E T A T I O N . The authors found that, without prophylaxis with pamidronate, bone loss at 4 years was substantial and signiﬁcant at the femoral neck (the mean loss was 12.3%) but was not signiﬁcant at the lumbar spine (the mean loss was 4.64%). Patients who received two doses of pamidronate experienced no statistically signiﬁcant bone loss at either the femoral neck or the lumbar spine. However, three of nine patients had a reduction of more than 10% in BMD over the 4 years despite the prophylactic treatments with bisphosphonate.

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Non-sustained effect of short-term bisphosphonate therapy on bone turnover three years after renal transplantation Schwarz C, Mitterbauer C, Heinze G, Woloszczuk W, Haas M, Oberbauer R. Kidney Int 2004; 65: 304–9

B A C K G R O U N D . A homogenous group of 20 de novo renal transplant recipients were equally randomized to two infusions of 4 mg of zoledronic acid (ZOL) or placebo at 2 weeks and 3 months after engraftment. Patients were followed up for 3 years by sequential determination of bone densitometry and speciﬁc biochemical markers. I N T E R P R E T A T I O N . From month 6 to 3 years after transplantation, both treatment groups exhibited an improvement in bone liberalization. Femoral neck BMD Z-scores (median, range) increased statistically signiﬁcantly from –1.3 (2.6) to –0.2 (3.6) in the placebo group and from –1.6 (2.9) to –1.2 (1.9) in the ZOL group. Biochemical parameters of osteoblast activity, such as osteocalcin and bone-speciﬁc alkaline phosphatase, did not increase signiﬁcantly in either group. Osteoprotegerin, a marker of osteoclast inhibition, was signiﬁcantly elevated over the ﬁrst 6 months in the ZOL group, but decreased to levels similar to those in the placebo group over the next 2.5 years. Other markers of osteoclast activity, such as the c-telopeptide of type 1 collagen, calcitonin and intact PTH, were not different between 6 months and 3 years in either group.

Comment Interpretation of the results from studies that include small numbers (17 and 20) must be guarded. Nevertheless, the results suggest that the early bone-sparing effect of bisphosphonates given at the time of transplantation confers little sustained bene-

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fit compared with placebo. Certainly, some patients continue to lose substantial bone mineral despite the prophylaxis given within the first few months of transplantation. This is to be expected as the transplant patients continue to be exposed to a variety of bone toxins, including corticosteroids and calcineurin inhibitors, and persisting hyperparathyroidism. Moreover, the recommendations set out by many national bodies, such as K/DOQI, for non-transplanted patients with CKD stages 3 and 4 that relate to the evaluation and treatment of disorders of calcium, phosphorus and PTH metabolism may be equally relevant, albeit frequently forgotten, in transplanted patients. It is perhaps becoming clear that it is difficult to define a ‘one size fits all’ strategy for the prevention of post-transplant bone disease. Instead, prophylaxis and treatment should be prescribed on an individual basis. A pragmatic approach (but one that has not been validated) is to give bone prophylaxis in the form of bisphosphonates but to exclude patients who have evidence of adynamic bone disease at the time of transplantation (based on PTH and surrogates of bone turnover, such as bone-specific alkaline phosphatase or osteocalcin). Further treatment will be needed for a significant subgroup of patients, although how these patients can be identified is not yet determined. Individualizing therapy according to risk stratification (including clinical predictors, bone mass, turnover, microarchitecture and microfracture) will require a greater degree of sophistication than is currently achievable.

Vitamin D to prevent post-transplant osteoporosis Although the role of bisphosphonates in preventing and treating post-transplant bone disease has been discussed, the potential of other therapies, such as vitamin D with adequate calcium supplementation, should not be forgotten. The study reported by De Sevaux et al. 27 in 2002 suggested that prophylaxis with 0.25 g of 1 -hydroxy-vitamin D3 and 1000 mg of elemental calcium prevented bone loss after kidney transplantation. This strategy avoids causing the mineralization defects that are a theoretical risk of bisphosphonates, although this has only been reported with the early, first-generation bisphosphonate etidronate and was not found in the study by Haas et al. It should be noted that 9% of the treatment group developed hypercalcaemia during follow-up, and of these 67% were treated with a bisphosphonate. Nonetheless, this protocol is attractive because the suppressive effect on bone turnover is short-lived compared with bisphosphonates. There has been no direct headto-head study comparing these alternative strategies of bone prophylaxis in the kidney transplant setting. However, Sambrook et al. (see next paper) has reported a study comparing these drugs in corticosteroid-induced osteoporosis.

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Prevention and treatment of glucocorticoid-induced osteoporosis: a comparison of calcitriol, vitamin D plus calcium, and alendronate plus calcium Sambrook PN, Kotowicz M, Nash P, et al. J Bone Miner Res 2003; 18: 919–24

B A C K G R O U N D . A randomized, multicentre, open-label trial was conducted to compare the efﬁcacies of alendronate, calcitriol and simple vitamin D in the prevention and treatment of glucocorticoid-induced bone loss. A total of 195 subjects (134 females and 61 males) commencing or already taking glucocorticoids were randomized to one of three groups: calcitriol 0.5–0.75 g/day; simple vitamin D (ergocalciferol) 30 000 IU weekly plus calcium carbonate 600 mg daily; or alendronate 10 mg/day plus calcium carbonate 600 mg daily. I N T E R P R E T A T I O N . Over 2 years, the mean change in lumbar BMD was 5.9% with alendronate, –0.5% with ergocalciferol and –0.7% with calcitriol (P <0.001). At the femoral neck, there was no signiﬁcant difference in BMD change between the treatments over 2 years (0.9% for alendronate, –3.2% for ergocalciferol and –2.2% for calcitriol). Lumbar bone loss varied according to whether patients were starting or receiving chronic glucocorticoids, and there was a signiﬁcant interaction between treatment and prior glucocorticoid use. Six of 66 calcitriol subjects, one of 61 ergocalciferol subjects and none of 64 alendronate subjects sustained new vertebral fractures.

Fig. 11.7 Changes in BMD at the lumbar spine in patients at risk of corticosteroidinduced osteoporosis after treatment with calcitriol (squares), ergocalciferol (circles) and alendronate (triangles). Source: Sambrook et al. (2003).

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Comment A drawback of this study includes the fact that corticosteroid-induced osteoporosis was studied, but the pathogenesis of bone disease after kidney transplantation is significantly more complex. Moreover, this study included patients initiating corticosteroids as well as patients already established on a maintenance dose of this drug. Extrapolation of results must be guarded against. With these provisos, the study showed that patients receiving calcitriol and ergocalciferol did not show any significant differences in BMD reduction at the lumbar spine over the 2-year study period. However, at this same site, the alendronate-treated patients were protected against further bone loss. At the femoral neck, there were no significant differences in the changes in BMD in patients allocated to the three different protocols. Whilst the comparison thus far has been between active vitamin D and bisphosphonate, perhaps the combination of active vitamin D, calcium and bisphosphonates warrants further investigation. Certainly, vitamin D and bisphosphonates have opposing actions on serum calcium levels and the combination might reduce the frequencies of hyper- and hypocalcaemia that have been reported when these agents are used as monotherapies.

Conclusion Over the last few years, new insights into the bone remodelling process and its relationship with arterial calcification have underlined the complex, heterogeneous nature of renal osteodystrophy and led to its emergence as a potentially modifiable cardiovascular risk factor. This, in turn, has provided the impetus behind the development of new, more stringent, therapeutic objectives—the achievement of which, it is hoped, will translate into improved patient survival. These consensus targets have set the scene for innovative therapeutic agents, including calcimimetics, designer vitamin D analogues and novel phosphate binders and it seems certain that these will be submitted to increasing scrutiny in clinical trials in the short and medium term. In the sphere of post-transplant bone disease, it is evident that the diversity of the problem requires a greater sophistication in assessment and treatment than currently available. The beneficial early effects of bisphosphonates may not be sustained and the indiscriminate use of such agents may actually prove detrimental in a significant proportion of patients. It has been an extremely exciting time in bone biology. Our understanding of the pathophysiology of many important skeletal disorders, including renal osteodystrophy, has advanced rapidly and encouraged the development of new therapeutic agents and strategies. It seems increasingly likely that the our day to day practice with respect to the diagnosis and management of the aberrant mineral metabolism of CKD will have changed significantly before the next edition of this yearbook appears.

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References 1. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus

and calcium phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998; 31: 607–17. 2. Eknoyan G, Levin A, Levin NW. Bone metabolism and disease in chronic kidney disease.

Am J Kidney Dis 2003; 42: 1–201. 3. The Standards and Audit Subcommittee of the Renal Association on behalf of the Renal

Association and the Royal College of Physicians. Treatment of adult patients with renal failure: recommended standards and audit measures. J R Coll Physicians Lond 1995; 29: 190–1. 4. Gal-Moscovici A, Popovtzer MM. Parathyroid hormone-independent osteoclastic

resorptive bone disease: a new variant of adynamic bone disease in haemodialysis patients. Nephrol Dial Transplant 2002; 17: 620–4. 5. Sherrard DJ, Hercz G, Pei Y, Maloney NA, Greenwood C, Manuel A, Saiphoo C, Fenton

SS, Segre GV. The spectrum of bone disease in end-stage renal failure—an evolving disorder. Kidney Int 1993; 43: 436–42. 6. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Arterial media

calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003; 18: 1731–40. 7. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J,

Emerick A, Greaser L, Elashoff RM, Salusky IB. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342: 1478–83. 8. Wexler L, Brundage B, Crouse J, Detrano R, Fuster V, Maddahi J, Rumberger J, Stanford

W, White R, Taubert K. Coronary artery calcification: pathophysiology, epidemiology, imaging methods, and clinical implications. A statement for health professionals from the American Heart Association Writing Group. Circulation 1996; 94: 1175–92. 9. Schwarz U, Buzello M, Ritz E, Stein G, Raabe G, Wiest G, Mall G, Amann K. Morphology

of coronary atherosclerotic lesions in patients with end-stage renal failure. Nephrol Dial Transplant 2000; 15: 218–23. 10. Kajinami K, Seki H, Takekoshi N, Mabuchi H. Coronary calcification and coronary

atherosclerosis: site by site comparative morphologic study of electron beam computed tomography and coronary angiography. J Am Coll Cardiol 1997; 29: 1549–56. 11. Anderson KM, Wilson PW, Odell PM, Kannel WB. An updated coronary risk profile; a

statement for health professionals. Circulation 1991; 83: 356–62. 12. Steitz SA, Speer MY, Curinga G, Yang HY, Haynes P, Aebersold R, Schinke T, Karsenty G,

Giachelli CM. Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ Res 2001; 89: 1147–54.

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13. Shanahan CM, Proudfoot D, Farzaneh-Far A, Weissberg PL. The role of Gla proteins in

vascular calcification. Crit Rev Eukaryot Gene Expr 1998; 8: 357–75. 14. Davies MR, Lund RJ, Hruska KA. BMP-7 is an efficacious treatment of vascular calcifica-

tion in a murine model of atherosclerosis and chronic renal failure. J Am Soc Nephrol 2003; 14: 1559–67. 15. Shao JS, Cheng SL, Charlton-Kachigian N, Loewy AP, Towler DA. Teriparatide (human

parathyroid hormone (1–34)) inhibits osteogenic vascular calcification in diabetic low density lipoprotein receptor-deficient mice. J Biol Chem 2003; 278: 50195–202. 16. Steitz SA, Speer MY, McKee MD, Liaw L, Almeida M, Yang H, Giachelli CM. Osteopontin

inhibits mineral deposition and promotes regression of ectopic calcification. Am J Pathol 2002; 161: 2035–46. 17. Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and

aortic calcification in hemodialysis patients. Kidney Int 2002; 62: 245–52. 18. Chertow GM, Raggi P, Chasan-Taber S, Bommer J, Holzer H, Burke SK. Determinants of

progressive vascular calcification in haemodialysis patients. Nephrol Dial Transplant 2004; 19: 1489–96. 19. Sprague SM, Llach F, Amdahl M, Taccetta C, Batlle D. Paricalcitol versus calcitriol in the

treatment of secondary hyperparathyroidism. Kidney Int 2003; 63: 1483–90. 20. Goodman WG, Hladik GA, Turner SA, Blaisdell PW, Goodkin DA, Liu W, Barri YM,

Cohen RM, Coburn JW. The Calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism. J Am Soc Nephrol 2002; 13: 1017–24. 21. Quarles LD, Sherrard DJ, Adler S, Rosansky SJ, McCary LC, Liu W, Turner SA, Bushinsky

DA. The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 2003; 14: 575–83. 22. Mizobuchi M, Hatamura I, Ogata H, Saji F, Uda S, Shiizaki K, Sakaguchi T, Negi S,

Kinugasa E, Koshikawa S, Akizawa T. Calcimimetic compound up-regulates decreased calcium-sensing receptor expression level in parathyroid glands of rats with chronic renal insufficiency. J Am Soc Nephrol 2004; 15: 2579–87. 23. Miller MA, Fox J. Daily transient decreases in plasma parathyroid hormone levels induced

by the calcimimetic NPS R-568 slows the rate of bone loss but does not increase bone mass in ovariectomized rats. Bone 2000; 27: 511–19. 24. Anonymous. Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement

2000; 17: 1–45. 25. Fan SL-S, Almond MK, Ball E, Evans K, Cunningham J. Pamidronate therapy as preven-

tion of bone loss following renal transplantation. Kidney Int 2000; 57: 684–90. 26. Grotz W, Nagel C, Poeschel D, Cybulla M, Petersen KG, Uhl M, Strey C, Kirste G,

Olschewski M, Reichelt A, Rump LC. Effect of ibandronate on bone loss and renal function after kidney transplantation. J Am Soc Nephrol 2001; 12: 1530–7. 27. De Sevaux RG, Hoitsma AJ, Corstens FH, Wetzels JF. Treatment with vitamin D and

calcium reduces bone loss after renal transplantation: a randomized study. J Am Soc Nephrol 2002; 13: 1608–14.

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12 Transplantation JOHN FORMAN, MOHAMED SAYEGH

Introduction It is widely accepted that kidney transplantation is preferred over continuation on dialysis, both in terms of morbidity and mortality, especially since the obstacle of acute rejection has largely been overcome. Chronic dysfunction of renal allografts continues to be a serious issue, however, and patients with chronic allograft dysfunction are increasingly joining the end-stage renal disease (ESRD) ranks and waiting lists for cadaveric transplantation. Therefore, basic and clinical research focusing upon the prevention and treatment of chronic allograft dysfunction is of paramount importance. We are limited in our understanding of chronic allograft dysfunction, in our ability to study it as an outcome in clinical trials, and in our ability to prevent it with current drug regimens. Currently, the Food and Drug Administration (USA) accepts only acute rejection as an end-point in clinical transplant trials. Other end-points that are germane to long-term allograft outcomes are needed. Possibilities include hard end-points, such as patient death, resumption of dialysis, and pre-emptive retransplantation. The costs, time, person-power and sample size that would be required to conduct a prospective trial using these hard long-term end-points are prohibitive. We are in need of surrogate end-points that can be measured easily and early and which reliably predict such hard outcomes as death and functional allograft failure. New immunosuppressive drug protocols, whether aimed at reducing non-immune allograft injury (e.g. eliminating calcineurin inhibitors) or alloimmune injury (e.g. by achieving tolerance) are a key component in minimizing chronic allograft dysfunction. In this chapter, we will examine significant clinical research developments in our understanding of chronic allograft dysfunction. Because of editorial restraints, we will review only a small selection of the many valuable papers published in this field. First, we will present work that highlights chronic allograft dysfunction as a ubiquitous and major clinical problem. Next, we will analyse papers that have studied potential surrogate markers of long-term allograft survival and papers that present highly novel means of predicting allograft outcomes. Finally, we will present studies of specific drug regimens that have particular relevance to long-term end-points and transplantation tolerance. In each case, the papers are critically reviewed, and in many cases problems with methodology and interpretation are identified. © Atlas Medical Publishing Ltd

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Chronic renal failure in transplant patients Chronic allograft dysfunction is the second leading cause of kidney transplant failure after death with a functioning allograft. Furthermore, after diabetes mellitus, allograft failure is now the second most common cause of ESRD in the USA, approximately 20% of transplants each year going to patients who have previously had one or more failed allografts. A number of studies have identified risk factors for poor long-term graft survival, and an episode of acute rejection has been reported to be among the most important adverse prognostic indicators. With the more potent immunosuppressive regimens used today, acute rejection has become much less common, but the burden of chronic allograft dysfunction persists.

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Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era Meier-Kriesche H, Schold JD, Srinivas TR, Kaplan B. Am J Transplant 2004; 4: 378–83

B A C K G R O U N D . One-year graft survival and projected graft half-life signiﬁcantly improved during the period from 1988 to 1996, an observation that was primarily attributed to a reduction in acute rejection rates with better immunosuppressive regimens 1. This study examined similar outcomes for recipients of kidney allografts from 1995 to 2000 using the Scientiﬁc Registry of Transplant Recipients, and demonstrated that improvements in long-term graft outcome have not occurred. Although rates of acute rejection have continued to decline steadily (the rate of rejection episodes in the ﬁrst 6 months was 43.7% in 1995 and 14.6% in 2000), 2-year graft survival for recipients of both living and cadaveric kidneys has reached a plateau (Table 12.1). Furthermore, the multivariate relative risk of death-censored graft loss has increased for recipients of cadaveric kidneys (Fig. 12.1). The authors then addressed the assumption that any acute rejection episode would reduce allograft survival. They compared graft survival in recipients without acute rejection with survival in those with acute rejection in whom estimated glomerular ﬁltration rate (GFR) returned to variable degrees of pre-rejection baseline. Multivariate Cox regression analysis showed that recipients with acute rejections and in whom GFR returned to within 15% of baseline had graft survival similar to that of those without acute rejection. The relative risk of death-censored graft loss was 2.7 if GFR returned to only 15–25% of baseline and 5.1 if GFR returned to <25% of pre-rejection baseline. I N T E R P R E T A T I O N . Despite further improvements in rates of acute rejection after 1995, graft survival has not continued to improve. The degree of renal function recovery from acute rejection is an important predictor of whether the rejection episode will affect graft survival.

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Table 12.1 Two-tier univariate overall graft survival rates for recipients with and without indications of acute rejection within 6 months after transplant by donation type No indication of acute rejection

Acute rejection

Year of transplant

Deceased donor

Living

Deceased donor

Living

1995 1996 1997 1998 1999 2000

91.3 91.3 91.5 92.1 91.5 88.9

95.5 95.3 96.0 95.6 94.9 93.8

90.2 90.4 91.0 90.7 90.7 89.0

93.9 94.2 94.6 94.9 95.7 95.6

Recipients used in calculations had a minimum 6-month follow-up period. Source: Meier-Kriesche et al. (2004).

Fig. 12.1 Relative risk of death-censored graft loss by donor type. Model corrected for induction, antiproliferative and inhibitor medication regiments at baseline, cold ischaemia time, panel reactive antibody (PRA) level, HLA-A, -B and -DR mismatches, recipient and donor gender, ethnicity, age, presence of delayed graft function, primary diagnosis and waiting time on dialysis. Source: Meier-Kriesche et al. (2004).

Comment This paper illustrates that projected gains in long-term allograft survival in the recent era are not being attained, and challenges the assumption that achieving even lower rates of acute rejection will translate into better overall graft outcomes. The authors provide an important follow-up to the previous work of Hariharan et al. 1 and propose that more study is warranted to explain this finding. The exact reasons for these observations are unclear. Possibly, new drugs are not inhibiting subclinical rejection,

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which could not be captured in their analysis and which may contribute to progressive loss of graft function. Other factors, such as extension of the donor pool and complications of more intense immunosuppression (like BK virus infection), may provide a partial explanation. Furthermore, the functional ramifications of acute rejection episodes should be integrated into future drug trials and outcome studies.

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The natural history of chronic allograft nephropathy Nankivell BJ, Borrows RJ, Fung CLS, O’Connell PJ, Allen RDM, Chapman JR. N Engl J Med 2003; 349: 2326–33

B A C K G R O U N D . Because chronically failed allografts typically show non-speciﬁc histology, the evolution of chronic allograft nephropathy has remained poorly understood. The authors took advantage of frequent protocol biopsies performed on a cohort of 120 diabetic recipients of kidney–pancreas (119) or kidney (1) transplants initially intended to evaluate diabetic nephropathy after kidney–pancreas transplantation. Of the 120 transplanted kidneys, 95.2% were still functioning at 10 years, and each patient underwent 8.0 4.4 (mean, standard deviation) protocol kidney biopsies. The median time from ﬁrst to last biopsy was 3.9 3.3 years. This study suggests that chronic allograft nephropathy evolved in their patients over two major phases. Generally speaking, phase 1 occurred during the ﬁrst year after transplant and was histologically characterized by acute inﬂammation (acute rejection and subclinical rejection) and acute tubular necrosis, with the development of Banff grade I or II chronic allograft nephropathy (deﬁned by the degree of interstitial ﬁbrosis and tubular atrophy). Despite good renal function at 1 year (mean serum creatinine 1.45 0.33 mg/dl), 94.2% of patients had Banff grade I chronic allograft nephropathy. The appearance of acute inﬂammation gradually diminished over phase 1, and was apparent in 17.7% of patients after the ﬁrst year. In a generalized estimating equation, signiﬁcant predictors of the severity of chronic allograft nephropathy at 1 year were acute tubular necrosis, an episode of steroid-resistant acute rejection, and subclinical rejection, while therapy with mycophenolate mofetil (MMF) decreased the severity of chronic allograft nephropathy. After the ﬁrst year, phase 2 was characterized by the appearance of arteriolar hyalinosis, vascular narrowing and progressive glomerulosclerosis, accompanied by further interstitial ﬁbrosis and tubular atrophy. At 10 years, all subjects had some degree of chronic allograft nephropathy, 58.4% of recipients had severe (Banff grade III) chronic allograft nephropathy, and 37.3% of glomeruli were completely sclerosed. Evidence of calcineurin inhibitor toxicity increased in prevalence and was ubiquitous at 10 years. Chronic rejection was evident in only 5.8% of subjects after the ﬁrst year. Early and late renal insults are summarized in Fig. 12.2. I N T E R P R E T A T I O N . The natural history of chronic allograft nephropathy is characterized by two major time-dependent patterns of injury. Potential immunological and nonimmunological insults also appear to be time-dependent.

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Fig. 12.2 Point prevalence of histologically deﬁned subclinical rejection in sequential biopsy specimens (a) and calcineurin-induced nephrotoxic effects (b). In (a), the solid parts of bars represent episodes of clinical acute rejection that occurred at or near the time of biopsy. The prevalence of this complication contrasts with that of calcineurin inhibitor nephrotoxicity, which was substantial and increased in concert with the time after transplantation (b). Source: Nankivell et al. (2003).

Comment The authors provide an important study that describes the histological progression of chronic allograft nephropathy over many years of follow-up. Because their study population was distinct from the general kidney transplant population (they were young Caucasian patients with type 1 diabetes, a low rate of delayed graft function, a high rate of acute rejection [71.4%], and all but one were kidney–pancreas transplants), their findings are not directly generalizable. Nevertheless, the absence of

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recurrent diabetic renal disease or other de novo renal disease allowed the observation of chronic allograft nephropathy development in kidneys in a setting where the potential insults (ischaemia, immunological, drug-induced) are, in fact, generalizable to all recipients. It is important to note that significant chronic allograft nephropathy was almost universal by the end of the first year, despite relatively normal renal function. Also, immunological injury, whether clinically apparent or subclinical, was both common and predictive of chronic injury. This argument, that immune injury plays an important role in chronic allograft nephropathy, is supported elsewhere in the literature 2. The authors report that calcineurin inhibitor toxicity became highly prevalent after the first year, and they claim that it was the primary cause of late injury. However, they defined calcineurin inhibitor toxicity as the appearance of striped fibrosis or arteriolar hyalinosis, which are non-specific findings that could potentially be caused by other insults. Furthermore, histological progression and loss of renal function could have other aetiologies, such as glomerular hyperfiltration, hypertension and other immunological injury. One potential interpretation of this paper is that more investigation is needed to find ways of preventing any immunological injury early on, while eliminating calcineurin inhibitors later after transplantation.

Predicting long-term outcomes Newer immunosuppressive regimens have virtually eliminated early (first year) graft loss. As previously discussed, improving long-term graft survival is now of paramount importance and there are significant potential public health benefits. A major roadblock to studies of long-term renal transplant outcome is presented by the time, the cost, and the large number of subjects required to conduct such trials; these hurdles essentially preclude prospective trials in which graft half-life, graft loss and patient death are the primary outcomes. Therefore, reliable, reproducible and highly predictive surrogate markers of long-term outcome are needed. Presented below are key studies that examine potential surrogates of long-term outcome, ranging in complexity from a serum creatinine measurement to a protocol biopsy. In addition, more complex immunological and genetic studies are presented in which the novel approaches described may serve as the basis for treatment decisions in future trials and thus become end-points in themselves.

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Post-transplant renal function in the ﬁrst year predicts long-term kidney transplant survival Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP. Kidney Int 2002; 62: 311–18

B A C K G R O U N D . Hariharan et al. had previously shown that 1-year graft survival and projected graft half-life increased from 1988 to 1996, when the year of transplantation

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was used as the primary exposure variable 1. In this paper, the authors attempted to explore this ﬁnding by analysing renal function in the ﬁrst year after transplant (which they deﬁned as creatinine concentrations at 6 and 12 months and the difference between the two values) as a predictor of graft survival and graft half-life in 105 742 adult renal transplants from 1988 to 1998 using the Scientiﬁc Registry of Transplant Recipients. Creatinine concentrations of >1.5 mg/dl at 6 months or 1 year, or a rise in creatinine of ≥0.3 mg/dl from 6 to 12 months, were associated with worse overall graft survival (Fig. 12.3). Likewise, incremental increases in 6-month and 12-month creatinine values and the change in creatinine values predicted incrementally lower graft half-life. In a multivariate regression model that controlled for both donor and recipient factors, every 1 mg/dl increase in the 1-year creatinine concentration was associated with a 63% increased risk of graft loss, while an incremental increase in change in creatinine from 6 months to 1 year was associated with an increase of 126% in the risk of graft loss. Of note, transplant year was only a predictor of graft loss if renal function was left out of the multivariate model. If included, transplant year no longer predicted graft loss, suggesting that transplant year and renal function during the ﬁrst year are surrogate markers. I N T E R P R E T A T I O N . Early renal function after transplantation is a useful marker to predict long-term outcomes, and may be potentially useful as a surrogate marker for use in research studies of transplantation. The earlier ﬁndings by these authors that transplant outcomes improved from 1988 to 1996 could be explained by improvements in early renal function over this same time frame.

Comment This study sought to investigate potential explanations for the earlier findings that transplant outcomes had improved from 1988 to 1996. The observation that transplant year no longer predicted improved graft survival after renal function was included in the multivariate model implies that improvements in early renal function are largely responsible for the improvements in overall graft survival. The finding that renal function at 1 year is highly predictive of long-term graft survival is not surprising; other authors have reported that the severity of chronic allograft nephropathy is inversely correlated with renal function at 1 year (see Nankivell et al. below, and 3). Therefore, the creatinine concentration in the first year reflects to some extent the degree of atrophy and fibrosis in the allograft. This paper is important because it provides evidence that 1-year creatinine concentrations may potentially be useful surrogate markers for long-term transplant outcome. Since many prospective trials of transplant recipients are far too underpowered and under-funded to analyse hard long-term outcomes, these findings are particularly relevant. Taken together, the Food and Drug Administration, which currently only considers acute rejection as an acceptable end-point in clinical transplant trials, should consider including renal function as an allowable end-point.

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Fig. 12.3 Kaplan–Meier estimates for graft survival after cadaveric renal transplantation according to 6-month (a), 1-year (b) and 6 to 12 month change in creatinine (c) concentration after transplantation. Source: Hariharan et al. (2002).

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The renal arterial resistance index and renal allograft survival Radermacher J, Mengel M, Ellis S, et al. N Engl J Med 2003; 349: 115–24

B A C K G R O U N D . These authors have expertise in performing Doppler ultrasound of renal arteries, and have previously shown that the resistive index in the kidney (the percentage decline in ﬂow velocity from peak systole to end-diastole in the renal parenchyma) predicts outcomes in patients with renal artery stenosis and other renal diseases. They measured the resistive index in 601 transplant patients at least 3 months after transplant, followed patients for a mean of more than 4 years, and determined whether a resistive index ≥80 predicted a 50% decline in estimated GFR, death-censored allograft failure (i.e. the need to resume dialysis), death, or a composite end-point of these three outcomes. They also correlated the resistive index to histological ﬁndings in a subset of 141 patients who underwent protocol biopsies. After controlling for multiple potentially confounding variables, a resistive index of ≥80 was associated with a 9.1-fold increased relative risk of the combined end-point (95% conﬁdence interval [CI] 6.6–12.7) compared with patients with a resistive index <80. The elevation in risk was also signiﬁcant when individual end-points of a decline of ≥50% in GFR (12.2; 8.2–18.2), the need for dialysis (8.8; 5.5–14.1) or death (7.2; 4.3–12.0) were analysed. Overall, the median graft survival was 2.5 years for patients with a resistive index ≥80 compared with 23.3 years for patients with a resistive index <80. In the 141 patients who underwent protocol kidney biopsy, the resistive index was not signiﬁcantly correlated with Banff scores for chronic allograft nephropathy, tubular atrophy or interstitial ﬁbrosis. I N T E R P R E T A T I O N . An elevated resistive index (80) is a negative prognostic indicator, associated with decline in renal function, allograft failure and death.

Comment This interesting paper proposes that a single non-invasive radiological test has enormous predictive power, an adverse finding by Doppler ultrasound being associated with a 9-fold higher risk of subsequent death, dialysis or loss of renal function. However, the findings of this study must be interpreted in the context of its design. First, the authors have special expertise in this technique, and it is certainly not clear that their findings could be replicated at other institutions with other radiologists. Secondly, precisely what functional or histological meaning the resistive index has in a transplanted kidney is unknown. Because the Doppler study and protocol biopsies were not simultaneous, a high resistive index may indicate a number of different processes, including active immunological rejection, tubular necrosis with oedema, severe vascular injury, functional effects of calcineurin inhibitors, etc. Finally, and most problematically, the specific statistical methods that the authors used leave room for significant false-positive results; furthermore, they did not appropriately adjust for potentially compounding factors. They used an automated program to build their multivariable models; in doing so, they eliminated from their final model

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many variables that could potentially have confounded the impact of the resistive index and nullified their findings. To elaborate: the first table in the paper shows that a resistive index 80 was significantly associated with recipient age, diabetes, higher blood pressure, increased cold ischaemia time, delayed graft function, more cadaveric donation, and serum CRP level. The authors next demonstrate that each one of these variables was (in univariate analysis) significantly associated with poor graft outcome. Therefore, each one of these factors met the very definition of a confounder, and should have been used to adjust the effect estimate of the resistive index. What the authors show instead are multivariable models selected by the computer, with different and sometimes counterintuitive variables included for the prediction of each outcome. For example, the authors found that a pulse rate >80 at the time of the Doppler study conferred a significant (40%) increase in the risk of the combined end-point. This counterintuitive result raises the concern about false-positive results. We are left not knowing whether resistive index is indeed an independent predictor of poor graft outcome, or rather a marker of age, diabetes, hypertension, cold ischaemia time, and delayed graft function. These problems are a classic example of the difficulties with automated statistical selection programmes and raise genuine concern about the interpretation of this study.

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Protocol core needle biopsy and histologic Chronic Allograft Damage Index (CADI) as a surrogate end point for long-term graft survival in multicenter studies Yilmaz S, Tomlanovich S, Mathew T, et al. J Am Soc Nephrol 2003; 14: 773–9

B A C K G R O U N D . These authors embarked on this study with the goal of deﬁning a surrogate marker for long-term graft outcome for potential use in future treatment studies. Within two large multicentre trials of mycophenolate mofetil (MMF), 388 subjects underwent protocol transplant renal biopsy at 1 year. These biopsies were reviewed at a single centre in a blinded fashion, and ascribed a Chronic Allograft Damage Index (CADI) score. The CADI score is derived from the study pathologists’ rating of six individual components: degree of inﬂammation, interstitial ﬁbrosis, tubular atrophy, glomerulosclerosis, vascular hyalinosis, and mesangial matrix increase. Because some of these subjects also had protocol biopsies at baseline and at 3 years, the authors were able to note a time-dependent increase in mean CADI score, from 1.3 at baseline to 3.3 at 1 year and 4.1 at 3 years. They divided subjects according to their CADI score at 1 year into three categories: low score (<2), elevated score (2–3.9) and high score (≥4). At 1 year, the mean creatinine concentration was similar in the low and elevated groups (1.4 and 1.5 mg/dl), but was higher in subjects with a score ≥4 (1.9 mg/dl). The 3-year allograft survival was 100% in the low CADI score group, 95% in the elevated CADI score group and 83% in the high CADI score group. In multivariate logistic regression analysis, the CADI score at 1 year was associated with 3-year graft loss (odds ratio 1.6; 95% CI 1.3–2.1). Independent clinical predictors of an elevated

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CADI score at 1 year were donor age and an episode of acute rejection in the ﬁrst year after transplant, while other risk factors for graft loss (i.e. cold ischaemia time, delayed graft function, HLA-DR mismatch, etc.) were not independently associated with an elevation of the CADI score. I N T E R P R E T A T I O N . The CADI score obtained from protocol transplant kidney biopsies 1 year after transplant may predict the long-term graft outcome, and may be useful as a surrogate marker for long-term graft survival in future clinical studies.

Comment This is an important paper because of the need for useful surrogate end-points of long-term graft survival. The authors have shown that protocol renal biopsies in transplant patients are feasible, and that the CADI score at 1 year is a significant predictor of 3-year graft outcome. The CADI score, first published in 1994, evaluates allograft biopsies on the basis of four possible severities of inflammation, interstitial fibrosis, glomerulosclerosis and mesangial matrix expansion, and vascular hyalinosis 4. The most widely used biopsy scoring system for chronic allograft injury is the Banff 97 score, which is based upon the severity of interstitial fibrosis and tubular atrophy alone; exclusion of glomerulosclerosis, mesangial matrix expansion and vascular hyalinosis from the Banff 97 chronic allograft nephropathy (CAN) score was intentional because interstitial fibrosis and tubular atrophy suffer the least from sampling error 5. Like the CADI score, the Banff 97 CAN score has been associated with graft survival 6. Several key points should be made regarding the interpretation of the 1-year CADI score and the relation to graft survival. First, the authors report that the CADI score at 1 year was associated with a 60% increase in the odds of 3-year graft loss, but nowhere in their paper do they cite how they examined this relationship. For example, if each increase of one point in CADI score predicted a 60% increase in the odds of loss, the overall impact of the CADI score would appear to be very large, whereas if they made an arbitrary cut-off point (e.g. comparing subjects with a CADI score 4 vs <4) the interpretation of their result would be completely different. This omission is important; indeed, the absolute difference in 3-year survival between the low and elevated groups (100 vs 95%) may not be clinically meaningful. Secondly, it is not clear if the CADI score provides a significant improvement in predictive power over other scoring systems, such as the Banff CAN index, which is more widely known. Finally, whether the CADI score has better predictive power than serum creatinine concentration at 1 year or a resistive index (as discussed above) has yet to be determined. A comparison between these two non-invasive measures and the CADI score (requiring biopsy) may be warranted before a decision is made about the optimal surrogate marker of long-term outcome for treatment studies.

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Regulatory CD25 T cells in human kidney transplant recipients Salama AD, Najaﬁan N, Clarkson MR, Harmon WE, Sayegh MH. J Am Soc Nephrol 2003; 14: 1643–51

B A C K G R O U N D . Salama et al. studied the alloreactivity of T cells obtained from the peripheral blood of 23 kidney transplant patients (15 with no prior history of acute rejection and eight with a history of acute rejection), using an ELISPOT (enzyme-linked immunospot) assay that detects interferon (IFN-) secretion by T cells. The authors had demonstrated previously in a separate cohort that allohyporesponsiveness (deﬁned by <60 T cells/million reacting to alloantigen by secreting IFN-) was signiﬁcantly more common in stable patients than in patients with a history of acute rejection. In this study, they sought to investigate the role of regulatory T cells as potential mediators of hyporesponsiveness to allogeneic peptides. Regulatory cells (which have a CD4+ CD25+ phenotype) were depleted from peripheral blood mononuclear cells; regulation was deﬁned for each patient as a signiﬁcant increase in alloresponsiveness after CD25+ cells had been depleted compared with that patient’s initial baseline assay. The chief ﬁnding of this paper was that evidence of regulation was found in 47% of assays that were initially hyporesponsive. The authors posited that anergy or clonal deletion of alloreactive T cells could explain the hyporesponsiveness in the other patients, or that regulation was missed because regulatory T cells may predominantly be found locally in the transplanted kidney and not in the circulation. I N T E R P R E T A T I O N . Immune hyporesponsiveness to transplanted alloantigens can be detected by a reproducible assay and may be, at least in some cases, actively mediated by regulatory T cells which suppress the function of alloreactive T cells.

Comment This is an important paper because those patients who are hyporesponsive to transplanted alloantigens and who have evidence of regulation may benefit from a reduction in their immunosuppression. The authors have previously demonstrated that a reproducible ELISPOT assay showing allohyporesponsiveness was more common in patients with stable renal function 7. In that study, they showed that in HLA-DRmismatched patients, an ELISPOT assay that detected fewer than 60 alloreactive T cells from the patients’ blood could distinguish ‘stable’ patients with no acute rejection (mean creatinine concentration 1.1 mg/dl) from ‘high-risk’ patients with past acute rejection (mean creatinine concentration 2.3 mg/dl). Here, they demonstrate that in a significant fraction of patients the observed hyporesponsiveness (detection of fewer than 60 alloreactive T cells in the ELISPOT assay) may be mediated by regulatory T cells. It is these patients who could potentially benefit from reduction of immunosuppression, thus decreasing the risk of calcineurin inhibitor toxicity and infection while maintaining a low level of alloreactivity. It should be noted that the assay in this study measured indirect alloreactivity (in which recipient

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T cells react to alloantigen that is shed from the allograft and presented by recipient cells) as opposed to direct alloreactivity (in which recipient T cells directly react to donor MHC on donor cells). Indeed, in the same issue of the Journal of the American Society of Nephrology, Game et al. found that regulatory T cells did not suppress direct alloreactivity 8. This is an important distinction, because the frequency of T cells that react in the direct pathway declines over time in transplant patients, and it is the indirect pathway that may be most responsible for mediating chronic rejection. Clearly, more studies and larger prospective series are required to confirm these exciting findings; whether or not an ELISPOT assay that demonstrates regulation will allow reduction of immunosuppression is a matter for a randomized prospective trial.

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Molecular heterogeneity in acute renal allograft rejection identiﬁed by DNA microarray proﬁling Sarwal M, Chua MS, Kambham N, et al. N Engl J Med 2003; 349: 125–38

B A C K G R O U N D . This study analysed whether acute rejection episodes that are indistinguishable by histological light microscopy have heterogeneous but recognizable patterns of gene expression, and whether these differences in gene expression have prognostic implications. The authors used DNA chip technology (whereby total RNA is extracted from biopsy specimens and the reverse transcriptase–polymerase chain reaction is used to produce cDNA, which is hybridized onto DNA chips, or microarrays) to analyse gene expression patterns in 62 biopsies from 50 patients. Four general clusters of gene expression were found (called clusters A–D), although there was still signiﬁcant heterogeneity within each cluster. All biopsies that were classiﬁed by light microscopy as normal fell into cluster D. All biopsies characterized histologically as showing chronic allograft nephropathy demonstrated a gene expression pattern of the cluster C type, and all those diagnosed clinically and histologically with drug toxicity had a gene expression pattern of the cluster B type. Twenty-ﬁve of the 50 patients had acute rejection that was basically identical by light microscopy – the gene expression patterns of these 25 were spread among clusters A, B and C. The authors analysed these 25 patients to determine if the gene expression pattern predicted outcome. They found that patients with acute rejection and a cluster A microarray proﬁle had signiﬁcantly more graft loss (nine of 11 grafts lost in a median of 11 months) than patients with acute rejection and different gene expression patterns (three of nine and none of ﬁve in a median of 13 months) (P 0.02). The authors noted that cluster A uniquely demonstrated B-cell gene signatures (e.g. CD20, immunoglobulin). They therefore stained the biopsies for CD20 (a B-cell marker) and found that patients with acute rejection whose biopsies were positive for CD20 had signiﬁcantly more graft loss (eight of nine at 13 months) than patients without CD20 staining (one of eleven at 10 months) (P <0.001). I N T E R P R E T A T I O N . Broad gene expression patterns can distinguish acute rejections that appear the same by light microscopy, and these patterns may have prognostic signiﬁcance. Also, the presence of B cells in acute rejection may be a key negative prognostic factor.

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Comment This is the first study to apply DNA microarray technology as a prognostic tool in the setting of acute kidney transplant rejection, and serves to encourage further study in this area. It is therefore of particular relevance. The clusters of gene expression that the authors found must be confirmed by other investigators, as must their prognostic significance; to facilitate this, the authors made public the details of their gene clusters on a website that is mentioned in the methods section of the paper. Perhaps the most immediately clinically useful finding is that CD20 was a highly significant predictor of graft loss after acute rejection. Staining for CD20 is relatively simple on most biopsy specimens, and could have important treatment implications should others duplicate the authors’ results. That the study did not have sufficient power to adjust the association between gene expression cluster or CD20 staining for other known risk factors for graft loss should raise some degree of caution in interpreting these findings.

Advances in immunosuppression and long-term allograft outcomes Numerous drug trials, most of them addressing only short-term graft and patient outcomes, have been published over the last several years. In general, we are now able to largely prevent acute rejection and to achieve very high 1-year allograft and patient survival. However, chronic allograft dysfunction is already a significant cause of ESRD and, as was discussed earlier, improvements in long-term graft survival appear to have reached a plateau. Chronic allospecific inflammation, subclinical rejection and calcineurin inhibitor toxicity may contribute to chronic allograft dysfunction. Addressing each of these problems may indeed lead to prolonged allograft survival. In addition, steps toward tolerance – the holy grail of organ transplantation – such that both the immune response and immunosuppression are minimized, may well have the greatest public health impact. Advances in immunosuppressive regimens and tolerizing regimens which have particular relevance for long-term outcomes are discussed below.

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Mycophenolate mofetil versus azathioprine therapy is associated with a signiﬁcant protection against long-term renal allograft function deterioration Meier-Kriesche HU, Steffen BJ, Hochberg AM, et al. Transplantation 2003; 75: 1341–6

B A C K G R O U N D . Studies have shown that MMF may be superior to azathioprine in the short term after transplantation. This study addressed whether MMF also had

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advantages on long-term outcomes. The authors examined medication use in 49 666 transplant patients in the United States Renal Data System. They included only subjects with at least 1 year of follow-up, and excluded subjects who were multiorgan recipients or paediatric patients, or if they switched drugs (MMF to azathioprine or azathioprine to MMF) during the ﬁrst 12 months after transplant. Use of MMF or azathioprine was identiﬁed by United Network for Organ Sharing case forms completed at discharge and 6, 12 and 24 months after transplant. The authors deﬁned worsening renal function as a 20% decline in the slope of 1/creatinine concentration after the ﬁrst transplant year, or by achieving a threshold creatinine level of ≥1.6 mg/dl some time after the ﬁrst transplant year. Using these end-points, 19% of patients who were on MMF had a 20% decline in 1/creatinine by 4 years, compared with 30% who were on azathioprine. If achieving a creatinine concentration of ≥1.6 mg/dl after the ﬁrst year was considered to be worsened renal function, then 20% of patients on MMF compared with 34% of patients on azathioprine had worsened renal function at 4 years. Similar results were found when the authors considered a combined end-point of worsened renal function, death or allograft loss. In multivariate proportional hazards models, MMF was associated with a 16% reduced risk of having worsened renal function (95% CI 9–22%) compared with azathioprine. I N T E R P R E T A T I O N . MMF may have advantages over azathioprine in terms of long-term graft function.

Comment The findings of this study imply that MMF is superior to azathioprine in the long term, reducing the risk of renal function decline. A recent report by Gonzalez Molina et al. suggests that MMF may modify the progression of chronic allograft nephropathy, thereby supporting the findings of this paper 9. It is also possible that MMF prevents late acute rejection or subclinical rejection 10. However, there may be other explanations for the findings of this paper. First, several publications show that treatment with MMF can allow reductions in cyclosporin dose with stabilization of renal function as the result 11,12. Therefore, patients on MMF may have had lower overall calcineurin inhibitor doses compared with patients on azathioprine. Secondly, because MMF is a superior antirejection drug, the baseline renal function at 1 year may have been different in the two groups, something that was not mentioned in the paper and could have affected the results. Finally, they could not take into account any centre effect, in which transplant centres with more experience and perhaps better overall outcomes may favour MMF while other centres may favour azathioprine. Nevertheless, these first two criticisms do not detract from the suggestion that MMF is superior in the long term. Even if the explanation is a tolerable reduction in calcineurin inhibitor dose or better 1-year renal function, it still implies that MMF is preferred.

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Long-term beneﬁts with sirolimus-based therapy after early cyclosporine withdrawal Kreis H, Oberbauer R, Campistol JM, et al. J Am Soc Nephrol 2004; 15: 809–17

B A C K G R O U N D . Because calcineurin inhibitors are associated with decline in renal function, hypertension and chronic allograft dysfunction, the authors conducted a trial in which Caucasian European transplant recipients who had initially been treated with cyclosporin (CSA), sirolimus and prednisone were randomized 3 months after transplantation to continue the same CSA-based regimen (CSA-SRL-ST group, with target sirolimus levels of >5 ng/ml) or CSA withdrawal (SRL-ST group, with target sirolimus levels of 20–30 ng/ml). The primary end-point was overall graft survival at 3 years and the secondary end-point was renal function and slope of GFR over time. At 36 months, graft loss was equivalent in the two groups (94% in the CSA-SRL-ST group vs 96% in the SRL-ST group; P 0.49). When the authors considered graft loss as including loss to follow-up, they found signiﬁcantly better graft survival in the CSA withdrawal group, reﬂecting fewer losses to follow-up in this group of patients. Calculated GFR was better in the SRL-ST group than in the CSA-SRL-ST group (Fig. 12.4) at 12, 24 and 36 months (e.g. the 36-month GFR was 59 ml/min in the SRL-ST group compared with 47 ml/min in the CSA-SRL-ST group). More favourable renal function with CSA withdrawal was robust; similar results were found in subjects with and without acute rejection, and with varying degrees of HLA mismatch. Discontinuation of

Fig. 12.4 Calculated glomerular ﬁltration rate in patients who completed 36 months of therapy. Source: Kreis et al. (2004).

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therapy and the overall number of adverse events were not different between the two groups, although the frequencies of certain speciﬁc side effects were different. I N T E R P R E T A T I O N . In Caucasian patients initially treated with CSA, sirolimus and prednisone, withdrawing CSA 3 months after transplantation while increasing the sirolimus dose offers equivalent 3-year graft survival and better renal function when compared with maintenance of the same CSA-based regimen.

Comment This report is the 3-year follow-up of the Rapamune Maintenance Regimen study, and demonstrates the feasibility (and potential superiority) of an immunosuppressive regimen in which calcineurin inhibitors are discontinued early after transplant. Several key concerns regarding the authors’ conclusions should be raised. First, the authors defined graft loss as a combination of death, dialysis and loss to follow-up. Assuming that loss to follow-up is equivalent to graft loss is flagrantly invalid, and thus their conclusion that CSA withdrawal is associated with better 3-year graft survival should be rejected. In fact, when graft loss was appropriately defined as death or dialysis, overall graft survival in the two groups was the same. This point also raises concern over their analysis of renal function because they assigned a GFR of zero to subjects with graft loss, again incorrectly assuming that subjects lost to follow-up have also lost their renal function. However, their results showing better renal function with CSA withdrawal were robust, even after analysing only those subjects for whom data were available. The major finding of this paper is that CSA withdrawal, along with an increase in sirolimus dose, was associated with better renal function 12, 24 and 36 months after transplant. Also, blood pressure was lower after CSA withdrawal (mean 131/76 vs 140/81, P 0.006). If one assumes that renal function translates into long-term allograft survival, then this feasible regimen, free from calcineurin inhibitors, may be advantageous.

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Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study Knechtle SJ, Pirsch JD, Fechner JH, et al. Am J Transplant 2003; 3: 722–30

B A C K G R O U N D . Profound depletion of T cells in non-human primates reduces the need for maintenance immunosuppression and, in some circumstances, induces tolerance 13,14. The combination of cyclosporin monotherapy and profound depletion of T cells, B cells and natural killer cells with Campath-1H, an anti-CD52 monoclonal antibody, was associated with transplant success in humans 15,16. Thus, the researchers treated 29 relatively low-risk transplant recipients (i.e. age <60 years, minimally sensitized, low cytomegalovirus risk, and no extended donors) with Campath-1H (20 mg intravenously on two successive days) and minimal maintenance immunosuppression (sirolimus only in 24 patients and sirolimus plus 2 weeks of prednisone in ﬁve patients). Subjects had protocol biopsies at 6 and 12 months and ﬂow cytometry monitoring of lymphocyte populations. Of the 29 patients, eight had an episode of acute rejection; ﬁve of these

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eight rejection episodes were acute humoral rejection. Seven of these eight subjects were converted to triple therapy with tacrolimus, MMF and prednisone after treatment of their rejection episode. One of the 29 patients lost their allograft to severe rejection. The mean 12-month serum creatinine concentration was 1.6 0.8 mg/dl in subjects without rejection and 2.0 0.5 mg/dl in subjects with rejection. Flow cytometry indicated that T and B lymphocytes remained profoundly depleted at 12 months (mean CD4 and CD8 counts at 1 year were 135 and 130 cells/l respectively). There were no systemic infections or malignancies. I N T E R P R E T A T I O N . The majority of patients treated with Campath-1H followed by sirolimus monotherapy had stable renal function and were free from acute rejection at 1 year. This treatment regimen may predispose to acute humoral rejection.

Comment This trial using Campath-1H induction demonstrates that immunosuppression minimization is feasible and relatively effective; 72% of subjects had stable renal function with no rejection at 12 months on sirolimus monotherapy, while no serious infections or malignancy seemed to result from profound and long-lasting T- and B-cell depletion. Although the authors do not state that their regimen was intended to induce transplant tolerance, potent induction regimens designed to halt alloimmunity at the time of engraftment (when immune attack is most likely) are important steps towards the reduction and possibly the elimination of maintenance immunosuppression, allowing immune regulation to take the place of pharmacological immune suppression. That 17% of subjects developed acute humoral rejection, typically an uncommon form of rejection, is intriguing and may reflect diminished capacity of the T cells that regulate memory B cells. The high rate of humoral rejection may also reflect bias in the methods, as the authors stained for C4d fragments in every biopsy, which is not typically performed. Whether monotherapy maintenance will continue to be successful in the 72% of rejection-free subjects in the long term remains to be seen, and enthusiasm for this regimen’s safety and efficacy should be restrained until that time. Nevertheless, this paper represents an important step towards the minimization of immunosuppression and possibly the induction of tolerance.

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Tolerogenic immunosuppression for organ transplantation Starzl TE, Murase N, Abu-Elmagd K, et al. Lancet 2003; 361: 1502–10

B A C K G R O U N D . The authors recruited 82 eligible patients awaiting organ transplantation at a single centre (50 of the patients were kidney recipients) to undergo a trial of immunosuppression minimization and elimination. All subjects were treated just before the transplant operation with 5 mg/kg of intravenous thymoglobulin and 1–2 g of methylprednisolone. After transplant, subjects received tacrolimus monotherapy and after 4 months attempts were made to wean the tacrolimus. In 35 of the 82 subjects (when available), donor bone marrow cells were infused at the time of transplantation. Other immunosuppressive agents were used only to treat acute

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rejection, or when the clinicians caring for the subjects chose to violate the study protocol. Of the 50 kidney recipients, 40 received cadaveric transplants, and 10 of these were combined kidney–pancreas transplants. Donor bone marrow cells were infused in 20 of the 40 cadaveric transplant operations. One recipient died as a complication of surgery and two lost their grafts in the ﬁrst year. Of the remaining 47 kidney recipients, 39 were weaned from tacrolimus, starting 3.9–11.9 months after transplant. Follow-up of these subjects has ranged from 14 to 17 months from the time of transplantation. At the end of follow-up, 25 of these 39 subjects continued to be on intermittent doses of tacrolimus monotherapy, including every other day (n 1), three times per week (n 6), twice per week (n 11) and once per week (n 7). In some of these subjects, weaning had been temporarily interrupted. The failure to wean tacrolimus in the remaining 14 subjects was due to a progressive decline in renal function (in kidney-alone recipients) or an increase in lipase concentration (in kidney–pancreas recipients). The mean creatinine concentration of the 47 kidney recipients with functional grafts at the end of follow-up was 1.8 mg/dl. No difference between those who did and did not receive donor bone marrow cells was noted. Acute rejection occurred in 67% of subjects in the ﬁrst month and 18–33% of subjects between months 2 and 10, and declined to 9% in month 12. Acute rejection was treated by intensiﬁcation of immunosuppression with other agents on a temporary basis, and return to tacrolimus monotherapy thereafter. At the end of follow-up, 83% of kidney recipients were on monotherapy and 53% were on intermittent dosing. I N T E R P R E T A T I O N . Monotherapy maintenance is a feasible goal in kidney transplantation, and in some recipients maintenance immunosuppression may potentially be almost eliminated, indicating some degree of tolerance.

Comment This study, like that by Knechtle et al. (2003), is an important step towards developing tolerizing treatment regimens. The principle – that elimination of the initial immunological attack with a potent T-cell depleting agent, while later allowing regulatory T cells to establish tolerance – was again tested. The authors allowed variability in their maintenance treatment protocol, generally tailoring therapy to the individual while working to the overall goal of eliminating immunosuppression. They found that more than 50% of kidney recipients required minimal doses of maintenance immunosuppression by the end of follow-up, thereby establishing that tolerance can be achieved in some subjects and providing proof of principle. Several intriguing findings of their research should be mentioned. In ex vivo experiments on a subset of the recipients, lymphocytes derived from peripheral blood maintained alloreactivity, even among the patients who had stable renal function on only intermittent tacrolimus. This finding suggests that tolerance resulted from regulation of the alloimmune response rather than deletion of alloreactive lymphocytes. In eleven of the 16 biopsies where the donor and recipient were of different gender, lymphoid aggregates contained both donor-derived and recipient-derived lymphocytes. These chimeric aggregates may be important in establishing tolerance, but this point is not clear. In summary, this paper is very exciting, providing evidence that transplant tolerance may be attainable in some patients. Long-term follow up of these patients is

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required, however, and new efforts should be made to identify immunological or clinical conditions that could predict successful weaning and withdrawal of immunosuppression. Most importantly, it will be critical to define the immunological phenotype of ‘tolerant’ patients in order to design specific strategies to induce transplant tolerance in humans.

Conclusion Kidney transplantation is the optimal treatment for ESRD, but transplant recipients typically suffer from progressive chronic renal failure progressing to death or ESRD. The papers presented include studies of drug regimens to minimize chronic allograft dysfunction or induce tolerance, and studies of potential surrogate markers of longterm graft survival. It would seem prudent for future trials to analyse renal function at 1 year and, if acute rejection develops, whether renal function returns to baseline. Measuring serum creatinine is easy and reproducible. It is not clear that using Doppler ultrasound to identify the resistive index or performing a protocol biopsy adds additional prognostic information to the renal function and other recipient or donor characteristics. Although the ELISPOT and DNA microarray assays are relatively new technologies and require further testing, it is not hard to imagine their potential utility in describing the phenotype of a tolerant recipient, or in identifying the recipient in whom immunosuppression should be intensified or minimized. It seems clear that MMF has advantages over azathioprine, not only during the first year after transplantation but also in later years. Substitution of calcineurin inhibitors with other immunosuppressive drugs (e.g. sirolimus) may also have benefits in the long term, but this requires further study. What seems most exciting is the observation that some patients become tolerant to their allografts after initial intense T-cell depletion, as reflected in their minimal requirement for immunosuppression at later time-points. Achieving tolerance has perhaps the greatest potential for ameliorating chronic allograft dysfunction, simultaneously preventing alloantigen-dependent and certain alloantigen-independent factors that contribute to the failing allograft.

References 1. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved

graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000; 342: 605–12.

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2. Shishido S, Asanuma H, Nakai H, Mori Y, Satoh H, Kamimaki I, Hataya H, Ikeda M,

Honda M, Hasegawa A. The impact of repeated subclinical acute rejection on the progression of chronic allograft nephropathy. J Am Soc Nephrol 2003; 14: 1046–52. 3. Krieger NR, Becker BN, Heisey DM, Voss BJ, D’Alessandro AM, Becker YT, Odorico JS,

Kalayoglu M, Pirsch JD, Sollinger HW, Knechtle SJ. Chronic allograft nephropathy uniformly affects recipients of cadaveric, nonidentical living-related, and living-unrelated grafts. Transplantation 2003; 75: 1677–82. 4. Isoniemi H, Taskinen E, Hayry P. Histological chronic allograft damage index accurately

predicts chronic renal allograft rejection. Transplantation 1994; 58: 1195–8. 5. Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MC, Cavallo T, Croker BP, Demetris

AJ, Drachenberg CB, Fogo AB, Furness P, Gaber LW, Gibson IW, Glotz D, Goldberg JC, Grande J, Halloran PF, Hansen HE, Hartley B, Häyry PJ, Hill CM, Hoffman EO, Hunsicker LG, Lindblad AS, Yamaguchi Y. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55: 713–23. 6. Freese P, Svalander CT, Molne J, Norden G, Nyberg G. Chronic allograft nephropathy –

biopsy findings and outcome. Nephrol Dial Transplant 2001; 16: 2401–6. 7. Najafian N, Salama AD, Fedoseyeva EV, Benichou G, Sayegh MH. Enzyme-linked

immunosorbent spot assay analysis of peripheral blood lymphocyte reactivity to donor HLA-DR peptides: potential novel assay for prediction of outcomes for renal transplant recipients. J Am Soc Nephrol 2002; 13: 252–9. 8. Game DS, Hernandez-Fuentes MP, Chaudhry AN, Lechler RI. CD4CD25 regulatory

T cells do not significantly contribute to direct pathway hyporesponsiveness in stable renal transplant patients. J Am Soc Nephrol 2003; 14: 1652–61. 9. Gonzalez Molina M, Seron D, Garcia del Moral R, Carrera M, Sola E, Jesus Alferez M,

Gomez Ullate P, Capdevila L, Gentil MA. Mycophenolate mofetil reduces deterioration of renal function in patients with chronic allograft nephropathy; a follow-up study by the Spanish Cooperative Study Group of Chronic Allograft Nephropathy. Transplantation 2004; 77: 215–20. 10. Knoll GA, MacDonald I, Khan A, Van Walraven C. Mycophenolate mofetil dose reduc-

tion and the risk of acute rejection after renal transplantation. J Am Soc Nephrol 2003; 14: 2381–6. 11. Weir MR, Anderson L, Fink JC, Gabregiorgish K, Schweitzer EJ, Hoehn-Saric E, Klassen

DK, Cangro CB, Johnson LB, Kuo PC, Lim JY, Bartlett ST. A novel approach to the treatment of chronic allograft nephropathy. Transplantation 1997; 64: 1706–10. 12. Weir MR, Ward MT, Blahut SA, Klassen DK, Cangro CB, Bartlett ST, Fink JC. Long-term

impact of discontinued or reduced calcineurin inhibitor in patients with chronic allograft nephropathy. Kidney Int 2001; 59: 1567–73. 13. Knechtle SJ, Vargo D, Fechner J, Zhai Y, Wang J, Hanaway MJ, Scharff J, Hu H, Knapp L,

Watkins D, Neville DM Jr. FN18-CRM9 immunotoxin promotes tolerance in primate renal allografts. Transplantation 1997; 63: 1–6. 14. Thomas JM, Neville DM, Contreras JL, Eckhoff DE, Meng G, Lobashevsky AL, Wang PX,

Huang ZQ, Verbanac KM, Haisch CE, Thomas FT. Preclinical studies of allograft tolerance in rhesus monkeys: a novel anti-CD3-immunotoxin given peritransplant with donor bone marrow induces operational tolerance to kidney allografts. Transplantation 1997; 64: 124–35.

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15. Calne R, Friend P, Moffatt S, Bradley A, Hale G, Firth J, Bradley J, Smith K, Waldmann H.

Prope tolerance, perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients. Lancet 1998; 351: 1701–2. 16. Calne R, Moffatt SD, Friend PJ, Jamieson NV, Bradley JA, Hale G, Firth J, Bradley J, Smith KG, Waldmann H. Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation 1999; 68: 1613–16.

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13 Interstitial and tubular diseases JEROME ROSSERT, EVELYNE FISCHER

Introduction This chapter will focus on new developments in: ● ● ● ●

the identification of genes responsible for congenital tubulointerstitial kidney diseases the pathogenesis of interstitial fibrosis the renal consequences of exposure to metals such as lead and lithium immunoallergic acute interstitial nephritis induced by proton pump inhibitors.

Recent advances in the pathogenesis, treatment and prevention of acute tubular necrosis and the pathogenesis and treatment of cystic kidney diseases will be discussed in other chapters.

Identification of genes responsible for congenital tubulointerstitial nephritis Nephronophthisis and medullary cystic kidney diseases are the most frequent genetic diseases responsible for end-stage kidney disease in children and young adults. They constitute a group of tubulointerstitial diseases that are characterized by a renal histological triad of (i) tubular basement membrane disintegration, including extreme thinning and attenuation but also layering and thickening; (ii) tubular atrophy with cysts development; and (iii) interstitial fibrosis. While nephronophthisis is transmitted as an autosomal recessive trait, medullary cystic kidney diseases are transmitted in an autosomal dominant manner. Recent data show that there is unexpected genetic heterogeneity for these diseases. While NPHP1, the gene responsible for juvenile nephronophthisis, had been identified in Hildebrandt’s laboratory in 1997, three additional genes responsible for nephronophthisis and one gene responsible for medullary cystic kidney disease have been identified in 2002 and 2003.

© Atlas Medical Publishing Ltd

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Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left–right axis determination Otto EA, Schermer B, Obara T, et al. Nat Genet 2003; 34: 413–20

B A C K G R O U N D . The kidney phenotype of the infantile form of nephronophthisis (NPHP2) combines clinical features of nephronophthisis, including tubular basement membrane disruption and interstitial fibrosis, with features reminiscent of autosomal dominant polycystic kidney disease, such as enlarged kidneys and widespread cyst development with the presence of cysts outside the medullary region. A locus associated with infantile nephronophthisis (NPHP2) has been mapped, and the gene for inversin (INVS) has been shown to be localized in the NPHP2 critical genetic interval 1. Since introduction of a null mutation in the mouse gene encoding inversin causes renal cyst formation in enlarged kidneys, situs inversus and pancreatic islet cell dysplasia 2, the inversin gene was considered as being a very good candidate for infantile nephronophthisis. I N T E R P R E T A T I O N . Analysis of exons of the inversin gene in nine affected individuals from seven different families with early onset of nephronophthisis showed recessive mutations in all subjects. Seven mutations were truncating mutations and two were missense ones, all of them causing disruption of functional domains of the protein. Thus, mutations in the inversin gene are responsible for infantile nephronophthisis, and NPHP2 and inversin correspond to the same gene. It is of note that, in zebrafish, disruption of the inversin orthologue also resulted in the appearance of cysts in the pronephros, which is the functional kidney in this species. Analysis of the inversin protein showed that it associates with nephrocystin, both in renal cells lines and in vivo. Nephrocystin is the product of NPHP1, mutations in which cause juvenile nephronophthisis (NPHP1). Furthermore, inversin appears to be colocalized with -tubulin, which is a constituent of the primary cilium, and to functionally interact with this protein.

Comment These data show that mutations in the inversin gene are responsible for NPHP2. They also suggest that inversin is involved in the function of the primary cilium. Since functional abnormalities of this cilium play a central role in the pathogenesis of polycystic kidney disease 3, this may explain the polycystic kidney disease-like renal cystic phenotype of human NPHP2.

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Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto–retinal degeneration and hepatic fibrosis Olbrich H, Fliegauf M, Hoefele J, et al. Nat Genet 2003; 34: 455–9

B A C K G R O U N D . Adolescent nephronophthisis (NPHP3) and juvenile nephronophthisis (NPHP1) share the same characteristic renal morphology, but patients with NPHP3 reach end-stage renal disease (ESRD) significantly later, with a median age of 19 years 4. Thus, NPHP3 is the recessive cystic kidney disease with the latest onset of ESRD. Hildebrandt’s group have previously localized the locus associated with NPHP3 on chromosome 3 (3q21–q22) 4. Furthermore, subsequent linkage analysis showed that a locus associated with Senior–Løken syndrome, in which nephronophthisis associated with Leber congenital amaurosis, also maps to the NPHP3 region 5. However, the gene that is mutated in patients with NPHP3 has not been identified. I N T E R P R E T A T I O N . By mutational screening in unrelated families affected by adolescent nephronophthisis, the authors have identified a new gene, NPHP3. Mutations in NPHP3 were found in families with isolated nephronophthisis, but also in families with nephronophthisis associated with hepatic fibrosis or tapetoretinal degeneration. NPHP3 mutations mostly consist of missense mutations involving conserved amino acids. Renal pathology in adolescent nephronophthisis resembles the cystic kidney disease observed in mice harbouring the pcy mutation 6. Analysis of the pcy locus showed that the mutated gene is the mouse orthologue of the human NPHP3 gene. Pcy mice carry a homozygous mutation in the Nphp3 gene that is absent in 22 other mouse strains, including the one in which the spontaneous pcy mutation initially arose. This mutation predicts the exchange of a conserved amino acid. In situ hybridization analysis of Nphp3 showed that, in adult kidney, expression is restricted to distal tubules at the corticomedullary region, which corresponds to the site of cyst formation. Furthermore, during embryogenesis Nphp3 is expressed in kidney tubules, but also in retina, lung and liver, which fits with associated tapetoretinal degeneration or hepatic fibrosis in individuals with mutations in NPHP3. Biochemical analysis of nephrocystin 3, the NPHP3 protein, showed that it interacts with nephrocystin. This latter protein is encoded by NPHP1, which is the gene mutated in juvenile nephronophthisis (NPHP1).

Comment The gene underlying NPHP3 has been identified. It encodes a protein named nephrocystin 3. Nephrocystin 3 and nephrocystin are probably involved in a common pathway, which explains the phenotypic similarities between NPHP3 and NPHP1.

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The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin Mollet G, Salomon R, Gribouval O, et al. Nat Genet 2002; 32: 300–5. Erratum in Nat Genet 2002; 32: 459

A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution Otto E, Hoefele J, Ruf R, et al. Am J Hum Genet 2002; 71: 1161–7

B A C K G R O U N D . So far, the only gene known to be responsible for the juvenile form of nephronophthisis has been NPHP1. Recently, a second locus associated with this form of the disease was mapped to chromosome 1 7. Subsequently, two groups carried out haplotype analyses of families affected with nephronophthisis that were not linked to the three loci previously identified (NPHP1–3), in order to identify NPHP4. I N T E R P R E T A T I O N . Analyses conducted in families with juvenile nephronophthisis not linked to mutations in NPHP1 led to the identification of the NPHP4 gene. Interestingly, mutations in NPHP4 were also identified in a patient with Cogan syndrome (nephronophthisis with ocular motor apraxia) and in two families with nephronophthisis associated with retinitis pigmentosa. NPHP4 encodes a protein called nephrocystin 4/nephroretinin, which is expressed in kidney, testis, skeletal muscle, heart and liver, and to a lesser extent in brain and lung. This protein does not have significant sequence similarities with nephrocystin, the product of NPHP1, but it interacts with nephrocystin.

Comment As for NPHP1, mutations in NPHP4 are responsible for juvenile nephronophthisis. This gene encodes a protein, nephrocystin 4/nephroretinin, that interacts with nephrocystin, which suggests that these two proteins participate in a common signalling pathway. The absence of mutation in additional families with nephronophthisis suggests further genetic locus heterogeneity for juvenile nephronophthisis.

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A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin Dahan K, Devuyst O, Smaers M, et al. J Am Soc Nephrol 2003; 14: 2883–93

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Familial juvenile hyperuricemic nephropathy: detection of mutations in the uromodulin gene in five Japanese families Kudo E, Kamatani N, Tezuka O, et al. Kidney Int 2004; 65: 1589–97

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Mutations of the uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains Wolf MT, Mucha BE, Attanasio M, et al. Kidney Int 2003; 64: 1580–7

B A C K G R O U N D . Medullary cystic kidney disease type 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) appear to represent two facets of the same disease 8,9. This autosomal dominant disorder is responsible for the progressive development of chronic interstitial nephritis with marked thickening of tubular basement membranes, which is associated with the abnormal tubular handling of urate responsible for hyperuricaemia during childhood (FJHN) and/or with the presence of small cysts in the renal medulla (MCKD2). Genetic analyses have identified mutations in the gene that encodes uromodulin/Tamm–Horsfall protein (Umod) as a cause of FJHN in three families and of MDCK2 in one family 9. Five additional mutations in UMOD were reported by 10 in five kindred of FJHN 10. I N T E R P R E T A T I O N . In these three papers, the authors report the identification of mutations in Umod in 16 families of FJHN and three of MCKD2. All mutations were localized in the highly conserved fourth exon of Umod. Nine mutations were missense mutations involving a cysteine residue, eight other mutations resulted in replacement of another residue, and two were in frame deletions. However, 16 families with MCKD2 did not have mutation in the exons of the Umod gene, which suggests some genetic heterogeneity of this disease. A more detailed analysis of affected patients was performed by Pirson’s group. It showed that there was a constant decrease in the urinary excretion of uromodulin, and that the protein excreted in the urine was the wild-type protein. Consistent with this result, immunohistochemical experiments performed on kidney biopsies of affected patients showed marked accumulation of uromodulin in a subset of tubules that appeared to have characteristics of the thick ascending limb of the Henle’s loop. Furthermore, these tubules sometimes appeared dilated, distorted or cystic.

Comment These studies clearly show that mutations in Umod are responsible for FJHN and MCKD2. However, the links between mutations in the Umod gene and cyst formation, interstitial fibrosis and abnormal urate handling remain elusive. Mutations in Umod appear to be responsible for the disruption of the tertiary structure of the molecule that results in decreased protein secretion. This could lead to global dysfunction of the cells of the ascending limb of the loop of Henle.

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A transcriptional network in polycystic kidney disease Gresh L, Fischer E, Reimann A, et al. EMBO J 2004; 23: 1657–68

B A C K G R O U N D . Despite the identification of different genes responsible for cystic kidney diseases, relatively little is known about the transcriptional networks that control epithelial differentiation of renal tubules. Hepatocyte nuclear factor 1 (HNF1) is a transcription factor expressed in the tubular epithelial cells of the kidney 11. Autosomal dominant mutations in this gene are associated with a particular form of diabetes mellitus called maturity onset diabetes of the young type 5 (MODY5), but some affected patients also present renal cysts 12. By analysing mice that do not express HNF1 in the kidney, Pontoglio’s group was able to identify a transcriptional network responsible for cyst formation. To do so, they had to use mice with kidney-specific inactivation of the gene, since null mice die at an early stage of embryogenesis, before kidney formation. I N T E R P R E T A T I O N . Kidney-specific inactivation of HNF1 leads to an early-onset polycystic kidney disease. One day after birth, several tubules are already dilated and at 8 days the kidneys of all mutant mice exhibit numerous cysts that disrupt the renal architecture. Interestingly, renal cyst formation is accompanied by a drastic defect in the transcriptional activation of Umod, Pkd2, Pkhd1 and polaris, four genes whose mutations are responsible for distinct cystic kidney syndromes. Consistent with this result, in vivo HNF1 binds to regulatory sequences in these genes.

Comment These results uncover a direct transcriptional hierarchy between HNF1 and genes whose mutations are responsible for cystic kidney diseases. Three of the four direct target genes are localized in the primary cilium, an intracytoplasmic organelle involved in the control of cellular proliferation. A paper recently published by Igarashi’s group has confirmed that HNF1 regulates the expression of the Pkhd1 gene both in vitro and in vivo 13.

Pathogenesis of interstitial fibrosis associated with chronic kidney diseases Regardless of the underlying renal disease, progression of chronic kidney diseases leads to a common histological end-point, the ‘end-stage kidney’, that is characterized by non-functional sclerotic glomeruli, atrophied tubules and a fibrotic interstitium. Two kinds of observations suggest that these tubulointerstitial lesions play a key role in the progression of chronic kidney diseases. First, for many renal diseases, there is a striking correlation between renal function at the time of biopsy and the severity of interstitial fibrosis. Secondly, the extent of interstitial fibrosis is the best

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histological prognostic marker of most renal diseases. However, the pathogenesis of tubulointerstitial lesions is still incompletely understood, even if the key role of transforming growth factor (TGF-) in promoting the accumulation of extracellular matrix has been established in many experimental models, and if an important role of proteinuria in promoting tubulointerstitial lesions has also been well established. In particular, the origin of interstitial fibroblasts has long been elusive and it is only recently that data showing the occurrence of epithelial–mesenchyme transition (EMT), i.e. the transdifferentiation of tubular cells into fibroblastic cells, have started to accumulate. Similarly, the occurrence of tubular hypoxia at very early stages of kidney diseases and its role in inducing tubulointerstitial lesions is only starting to be recognized.

Transdifferentiation of tubular cells into interstitial fibroblasts In 2002, pioneer work from Neilson’s laboratory clearly showed that EMT is essential for the generation of interstitial fibroblasts 14. Using transgenic reporter mice, Iwano et al. 14 showed that, in a mouse model of chronic interstitial fibrosis, a large proportion of interstitial fibroblasts arise by transdifferentiation of tubular epithelial cells. Of the many factors that can regulate EMT, TFG- is the most potent inducer that is capable of initiating and completing the entire course of EMT. TGF- is a soluble molecule that is secreted as pro-TGF- and cleaved from its propeptide in the extracellular space, giving rise to mature TGF-. Mature TGF- then associates with its propeptide and with other proteins to form latent complexes that have no biological activity and can be considered as storage forms of TGF-. After being dissociated from these complexes, through interactions with proteins such as thrombospondin 1 and integrin v6, TGF- binds to specific receptors which belong to the family of serine–threonine kinase receptors. Binding of TGF- to its receptors induces the phosphorylation of intracellular proteins of the Smad family: Smad2 and Smad3. This phosphorylation modifies the conformation of Smad2 and Smad3 and enables them to hetero-oligomerize with Smad4, which is another member of the Smad family of proteins. The Smad2–Smad4 and Smad3–Smad4 complexes are then translocated into the nucleus, where they bind to specific DNA sequences and act as transcription factors.

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Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction Sato M, Muragaki Y, Saika S, Roberts AB, Ooshima A. J Clin Invest 2003; 112: 1486–94

B A C K G R O U N D . It has been demonstrated clearly that upregulation of TGF- plays a key role in the pathogenesis of most fibrotic diseases, including renal fibrosis. To study the role of Smad3 in mediating the effects of TGF- during renal interstitial

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fibrosis, Sato et al. analysed interstitial fibrosis caused by unilateral ureteral obstruction (UUO) in mice lacking Smad3. UUO induces rapid accumulation of extracellular matrix within the interstitium, which leads to complete destruction of the obstructed kidney within a few weeks. I N T E R P R E T A T I O N . Analysis of Smad3-null mice showed that they are protected against interstitial lesions induced by UUO, as evidenced by abrogation of monocyte influx and collagen accumulation, thus confirming the key role of TGF- in the pathogenesis of interstitial fibrosis and illustrating Smad3 as a key effector in the downstream pathway. There was also a decrease in accumulation of TGF-, suggesting that this cytokine stimulates its own production through the Smad3 pathway, which creates a vicious circle. To study more precisely the role of Smad3 in mediating the effects of TGF- on tubular cells, primary renal tubular epithelial cells were cultured from wild-type and Smad3-null mice. Tubular epithelial cells from Smad3-null mice were protected against EMT induced by exogenous TGF- or by mechanical stretching, as well as against autoinduction of TGF-. Monocytes from wild-type mice, but not from Smad3-null mice, could induce EMT of cultured tubular cells, showing that Smad3 also mediates the induction of EMT by monocytes, possibly by enhancing the production of TGF- by these cells. Furthermore, in vivo, when monocytes were injected into the renal subcapsular space, mice transplanted with wild-type monocytes showed a higher number of monocytes infiltrating the renal cortex than did mice transplanted with Smad3-null monocytes. This suggests that Smad3 is also involved in the TGF--induced chemotaxis of inflammatory cells towards the renal cortex.

Comment These data demonstrate that the Smad3 pathway is central to the pathogenesis of the interstitial fibrosis induced by UUO. In particular, it appears to mediate EMT, infiltration of the renal cortex by monocytes, and increased production of TGF- itself by tubular cells and possibly by monocytes. Inhibitors of this pathway may thus prove useful in slowing the progression of chronic kidney diseases. However, it is important to keep in mind that lack of Smad3 can accelerate malignant progression in vivo, and impair T-cell activation and mucosal immunity 15,16.

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BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury Zeisberg M, Hanai J, Sugimoto H, et al. Nat Med 2003; 9: 964–8

B A C K G R O U N D . BMP-7 is a member of the TGF- superfamily that is expressed at high levels in kidney and that is indispensable for normal kidney development 17. Like TGF-, BMP-7 binds receptors that have a serine threonine kinase activity and activate the Smad pathway. Binding of BMP-7 to its receptors induces the phosphorylation of Smad1, Smad5 and Smad8, which can then associate with Smad4, enter the nucleus and activate transcription. Analysis of animal models of chronic renal injury shows that early treatment with BMP-7 can protect against renal

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failure and kidney fibrosis 18–20. This led Kalluri’s group to study the molecular pathways underlying the renoprotective effects of BMP-7, and in particular its effects on EMT. Under normal conditions, tubular cells are tightly connected to each other and form an integrated epithelial sheet, while during EMT epithelial cells lose polarity and adherens junctions. Suppression of E-cadherin expression, a well-characterized adhesion receptor found within adherens-type junctions, is one of the earliest changes observed during EMT. Thus, modulation of E-cadherin expression could play a key role in regulating EMT. I N T E R P R E T A T I O N . Analysis of a mouse model of chronic glomerulonephritis showed that, in vivo, treatment with BMP-7 can not only prevent the progression of chronic kidney disease, but also reverse already established chronic renal injury, with repair of existing interstitial lesions and improvement of renal function. Furthermore, analysis of E-cadherin expression showed that treatment with BMP-7 results in restoration of E-cadherin expression in previously damaged tubules. In vitro analysis of the mechanisms of action of BMP-7 showed that incubation of tubular epithelial cells with TGF- induces EMT, with a decrease in E-cadherin expression and loss of epithelial cell morphology, while incubation of mouse distal tubular epithelial cells with BMP-7 reverses TGF--induced EMT, in association with re-expression of E-cadherin and restoration of the epithelial phenotype. Analyses of mRNA levels of E-cadherin and transfection experiments suggest that TGF- directly inhibits the expression of the E-cadherin gene while BMP-7 has opposite effects. Over-expression of activated Smad3 or Smad5 proteins mimicked the effects of TGF- or BMP-7 on E-cadherin expression, respectively, showing that both cytokines exert their effects on the E-cadherin gene through the Smad pathway. Consistent with these results, in vivo, phosphorylated Smad2 and Smad3 accumulates in the nucleus of tubular cells with decreased expression of E-cadherin, while repaired tubules with re-expression of E-cadherin show accumulation of phosphorylated Smad1 in the nucleus.

Comment BMP-7 is able to inhibit TGF--mediated EMT, and this effect is mediated, at least in part, by regulation of the transcription of the E-cadherin gene through the Smad pathway. More importantly, in vivo, in a mouse model of renal chronic renal injury, systemic administration of BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury and improvement of renal function. BMP-7 could thus become a therapeutic agent able to reverse chronic renal injury.

Role of early hypoxia in induction of tubulointerstitial lesions The early events leading to tubular injury and interstitial fibrosis during the course of progressive kidney diseases are still incompletely identified. In 2003, several papers from Nangaku’s laboratory have shown that, in different models of chronic kidney disease, hypoxia is an early event and may contribute to the induction of tubulointerstitial lesions.

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Evidence of tubular hypoxia in the early phase in the remnant kidney model Manotham K, Tanaka T, Matsumoto M, et al. J Am Soc Nephrol 2004; 15: 1277–88

B A C K G R O U N D . Subtotal nephrectomy in the rat is a classic experimental model of progressive chronic kidney disease. In this model, the earliest response consists of glomerular hyperfiltration, which depends on activation of the renin–angiotensin system and eventually leads to glomerulosclerosis. However, subsequent progressive tubulointerstitial damage plays an essential role in the deterioration of renal function. The study described above shows that hypoxia of tubular cells occurs very early after subtotal nephrectomy, and it suggests that early hypoxia of tubular cells could play an important role in the pathogenesis of tubulointerstitial lesions. I N T E R P R E T A T I O N . After subtotal nephrectomy in rats, analysis of the remnant kidney showed that 4 and 7 days after nephron loss there are hypertrophic glomeruli and tubules but no histological evidence of tubulointerstitial damage. However, at that time there is already a marked increase in the number of hypoxic tubules, as demonstrated by (i) an increase in the number of tubules that could be stained by a marker of hypoxic cells, (ii) enhanced expression of HIF-1, which is the master hypoxia response regulator, and (iii) increased expression of hypoxia-responsive genes. In addition, while there is still no significant loss of peritubular capillaries, there are already morphological changes in peritubular capillaries, such as narrowing of capillary lumina, which may be related to poor tissue perfusion and hypoxia. Consistent with these data, decreased perfusion of tubular cells could be demonstrated. Interestingly, most of the changes described above were prevented by treatment with an angiotensin II receptor blocker, which suggests that they might be mediated, at least in part, by activation of the renin–angiotensin system.

Comment Subtotal nephrectomy is associated with early tubulointerstitial hypoxia, which precedes any pathological change in the corresponding region. Since hypoxia has been shown to favour EMT as well as the production of extracellular matrix, it probably plays a pathogenic role in the subsequent development of tubulointerstitial injury. Furthermore, hypoxia appears to be dependent on activation of the renin–angiotensin system and on haemodynamic alterations induced by nephron loss. Thus, some of the beneficial effects of ACE inhibitors or of angiotensin receptor blockers may be related to an improvement in interstitial perfusion and a subsequent decrease in tubular hypoxia.

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Hypoperfusion of peritubular capillaries induces chronic hypoxia before progression of tubulointerstitial injury in a progressive model of rat glomerulonephritis Matsumoto M, Tanaka T, Yamamoto T, et al. J Am Soc Nephrol 2004; 15: 1574–81

B A C K G R O U N D . To elucidate whether early tubular hypoxia participates in the progression of chronic kidney diseases, the authors focused on an experimental model of glomerulonephritis induced by uninephrectomy and repeated anti-Thy-1 antibody injections in rat. In this model, severe glomerulosclerosis is already present 2 weeks after antibody injection and persists at least 11 weeks. Tubulointerstitial injury and macrophage infiltration are mild during the first 2 weeks and then gradually get more severe. I N T E R P R E T A T I O N . Using a dye that specifically stains hypoxic cells, it was possible to show the presence of a large number of hypoxic tubular cells in rats that had been treated by uninephrectomy plus injections of anti-Thy-1 antibodies. These hypoxic tubules were widely distributed from the medulla to the outer cortex, and could be detected as soon as 1 week after nephrectomy. At that time, peritubular capillary loss around damaged tubules is limited, and hypoxia could be linked to haemodynamic phenomena responsible for decreased blood flow. In particular, blood flow in peritubular capillaries was decreased by approximately 40% in the disease group compared with the controls.

Comment In this model, alterations in blood flow in peritubular capillaries induced chronic hypoxia at an early stage, before the occurrence of progressive tubulointerstitial injury and the loss of peritubular capillaries. Thus, hypoxia may play a central role in the induction of tubulointerstitial lesions rather than acting only as an amplifier of already well established tubulointerstitial lesions. The mechanism of the impairment of blood flow in peritubular capillaries is probably multifactorial, involving narrowing of glomerular capillaries induced by mesangial matrix accumulation, but also an imbalance of vasoactive substances.

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Microvascular and tubulointerstitial injury associated with chronic hypoxia-induced hypertension Mazzali M, Jefferson JA, Ni Z, Vaziri ND, Johnson RJ. Kidney Int 2003; 63: 2088–93

B A C K G R O U N D . To support the role of hypoxia in the pathogenesis of tubulointerstitial lesions, it was important to show that chronic hypoxia can damage normal kidney.

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I N T E R P R E T A T I O N . Chronic hypoxia was induced in rats by placing them in a hypobaric chamber for up to 24 days. Chronic hypoxia induced endothelial cell swelling in arterioles and then thickening of the arterioles, as well as progressive and subtle tubular injury, interstitial fibrosis and inflammation.

Comment Both arteriolar disease and subtle interstitial inflammation and fibrosis occur early in hypoxic rats, and can thus be direct consequences of hypoxia.

✍

Transdifferentiation of cultured tubular cells induced by hypoxia Manotham K, Tanaka T, Matsumoto M, et al. Kidney Int 2004; 65: 871–80

B A C K G R O U N D . Recent studies suggest that interstitial fibroblasts derive from renal tubular cells that have undergone EMT (see above). However, while different studies suggest that tubular EMT can be induced by profibrotic cytokines, such as TGF-, the role of hypoxia in tubular EMT remains unclear. I N T E R P R E T A T I O N . When immortalized rat proximal tubular cells were cultured in normobaric hypoxia, they underwent EMT. It was characterized by morphological changes, expression of smooth muscle actin and production of increased amounts of type I collagen. Furthermore, cell motility assays also demonstrated that transformed cells had greater migratory capacity than normal tubular cells, which is consistent with a fibroblastic phenotype. The role of hypoxia in EMT is also supported by in vivo experiments. In rats, chronic ischaemic nephropathy was associated with strong expression of smooth muscle actin by tubular cells, suggesting the occurrence of transdifferentiation.

Comment This study shows that hypoxia can induce tubular EMT, which is an early event in renal interstitial fibrosis.

Section summary Taken together, these studies show that hypoxia of tubular cells occurs early during the course of different experimental kidney diseases, before tubulointerstitial lesions can be identified. Hypoxia of tubular cells could thus play an early role in the induction of tubulointerstitial lesions, along with proteinuria. Among the mechanisms by which hypoxia may induce tubulointerstitial damage are its ability to induce EMT and to increase the production of extracellular matrix by fibroblastic cells through events that are at least partly TGF--dependent. Furthermore, at later stages of chronic kidney diseases it is also clear that hypoxia participates in the destruction of

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tubules, with formation of atubular glomeruli. Since the early hypoxic events induced by subtotal nephrectomy could be reversed by blockage of the angiotensin II receptors, correction of interstitial hypoxia may be another pathway by which these drugs slow the progression of chronic kidney diseases.

The renal consequences of exposure to metals While many pathological conditions can be responsible for the occurrence of chronic tubulointerstitial nephritis, the major causes are exposure to drugs or heavy metals, metabolic disorders and urological diseases. During the last year, two papers drew our attention to the consequences of long-term exposure to low levels of lead or lithium.

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Environmental lead exposure and progression of chronic renal diseases in patients without diabetes Lin JL, Lin-Tan DT, Hsu KH, Yu CC. N Engl J Med 2003; 348: 277–86

B A C K G R O U N D . In humans, it has been known for decades that chronic lead poisoning can result in chronic tubulointerstitial nephritis, hypertension and gout, and such renal lesions can also be reproduced in rats chronically intoxicated with lead 21. However, it was unclear whether long-term exposure to low levels of environmental lead can be responsible for chronic kidney damage. Such a possibility had been suggested by epidemiological studies that showed an association between decreased glomerular filtration rate (GFR) and increased body lead burden. On the other hand, the causal relationship has been debated, since decreased renal function is probably responsible for decreased ability to clear lead. To clarify this point, Lin and colleagues studied 202 Taiwanese patients with chronic kidney disease and normal total-body lead burden. I N T E R P R E T A T I O N . Two hundred and two patients with chronic kidney disease and decreased GFR (serum creatinine level between 132 and 345 mol/l) who had a normal total-body lead burden (<600 g, as measured by the ethylenediamine tetraacetate [EDTA] mobilization test and 72-hour urine collection) and no history of exposure to lead were observed for 24 months. The primary end-point was an increase in the serum creatinine level to 1.5 times the baseline value or the need for dialysis. It occurred in 24 patients and the serum creatinine levels and body lead burden at baseline were the most important risk factors. Specifically, each increase of 100 g (0.5 mol) in the body lead burden led to a decrease in the estimated GFR of 0.3 ml/min per 1.73 m2 during the observation period, after adjustment for other factors (P <0.001). After the observation period, 64 subjects with a high-normal body lead burden (80–600 g of lead) and serum creatinine levels of less than 371 mol/l were randomly assigned to the chelation control groups in a 1:1 ratio. For 3 months, the patients in the chelation group received weekly lead chelation therapy with calcium disodium EDTA (intravenous infusions of 1 g over a period of 2 hours) unless the body lead burden fell below 60 g, and the control group received placebo. The change in

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the estimated GFR in the chelation group was 3.4 ± 4.4 ml/min per 1.73 m2 compared with –1.0 ± 3.7 ml/min per 1.73 m2 in the control group (P <0.001). During the ensuing 24 months, 19 patients in the chelation group received repeated lead chelation therapy because their body lead burden, assessed every 6 months during this period, exceeded 60 g. The estimated GFR improved from 29.5 ± 9.7 ml/min per 1.73 m2 before repeated chelation to 34.5 ± 11.6 ml/min per 1.73 m2 after repeated chelation (P <0.001). Overall, the estimated GFR improved significantly by the end of the 27-month intervention period in patients receiving chelation therapy: the mean (± SD) change in the estimated GFR in the patients in the chelation group was 2.1 ± 5.7 compared with –6.0 ± 5.8 ml/min per 1.73 m2 in the controls (P <0.001). The rate of decline in the estimated GFR in the chelation group was also lower than that in the controls during the 24-month period of repeated chelation therapy or placebo.

Comment This study suggests that low-level environmental lead exposure may accelerate the progression of renal insufficiency in patients with chronic kidney disease. Furthermore, it suggests that, in patients with a high-normal body lead burden (80–600 g of lead), repeated chelation therapy may improve renal function and slow the progression of renal insufficiency. However, it should be stressed that EDTA has many biochemical and cellular effects, besides its ability to chelate metals such as lead, iron and cadmium. Thus, this study does not prove that the favourable effects of the chelation therapy were due to lead removal.

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Lithium-induced nephropathy: rate of progression and prognostic factors Presne C, Fakhouri F, Noel LH, et al. Kidney Int 2003; 64: 585–92

B A C K G R O U N D . While chronic administration of lithium salts has been widely used by psychiatrists for more than 30 years, the spectrum of its renal side effects is not well defined. It is clear that lithium can impair renal concentrating ability, and polyuria and polydipsia due to nephrogenic diabetes insipidus occur in about 20% of the patients chronically treated with lithium. However, while the possibility of developing lithium-induced chronic tubulointerstitial nephritis has been strongly suggested by analyses of small series of patients, cross-sectional and longitudinal epidemiological studies have given conflicting results. Some of these studies have stressed how renal insufficiency was infrequent and mild in lithium-treated patients, while others have underlined the existence of confounding factors. Thus, so far, the natural history of lithium-induced nephritis is still not known. In particular, the ability of lithium to induce ESRD has been reported only rarely. This study shows that lithium therapy is a cause of ESRD that needs to be fully recognized. I N T E R P R E T A T I O N . Seventy-four patients were included in this study: 54 had lithium-induced renal failure and 20 were referred for systematic renal biopsy in 1980 while they were treated with lithium for at least 5 years. The mean annual loss of estimated GFR in

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the patients with lithium-induced nephropathy was 2.29 ml/min, and twelve reached ESRD at a mean age of 65 years. Estimated GFR at referral and at last follow-up was inversely related to the duration of lithium therapy in both univariate and multivariate analyses. The degree of interstitial fibrosis on renal biopsy was also related to the duration of lithium therapy and to the cumulative dose of lithium. It was predictive of final renal function. In addition to the study mentioned above, a survey of lithium-induced ESRD was conducted in French dialysis centres. The prevalence of lithium-related ESRD in France was estimated as 2 per 1000 dialysis patients. The average latency between the onset of lithium therapy and ESRD was 20 years.

Comment Lithium-induced chronic renal disease appears to be a clear entity and represents about 0.2% of all causes of ESRD in France. It is responsible for a slowly progressive decline in renal function, the rate of decline being related to the duration of lithium administration. Regular monitoring of estimated GFR is thus mandatory in patients receiving long-term lithium treatment.

Acute interstitial nephritis Drug-induced acute interstitial nephritis (AIN) is a relatively rare disease which has been occurring at a relatively stable rate over the years. However, the list of drugs responsible for AIN has increased considerably over the years. Methicillin was the leading cause of AIN in the 1980, but it has been replaced by other antibiotics and non-steroidal anti-inflammatory drugs. In recent years, analysis of case reports suggest that proton pump inhibitors are becoming an increasingly frequent cause of AIN.

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Drug-induced tubulo-interstitial nephritis secondary to proton pump inhibitors: experience from a single UK renal unit Torpey N, Barker T, Ross C. Nephrol Dial Transplant 2004; 19: 1441–6

B A C K G R O U N D . AIN is a rare cause of acute renal failure and is most often a result of hypersensitivity to drugs. However, the class of drugs responsible for AIN has changed over time. In the last few years anecdotal reports have suggested that proton pump inhibitors have become an important cause of AIN. I N T E R P R E T A T I O N . A single-centre retrospective analysis of renal biopsy performed in 296 consecutive patients between 1995 and 1999 shows that AIN was identified in 24 biopsies (8.1%). Interestingly, eight out of 14 cases with presumed drug-related AIN could be attributed to the proton pump inhibitors omeprazole and lansoprazole.

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Comment In the population studied, the drugs most commonly associated with interstitial nephritis were proton pump inhibitors. Nephrologists should be aware of the possibility that these drugs can induce acute renal failure.

Conclusion This review of the literature published in 2003 shows that important progresses have been made in understanding the pathogenesis of congenital tubulointerstitial diseases and in deciphering some of the mechanisms responsible for interstitial fibrosis and progression of chronic kidney diseases. In particular, the role of EMT and the harmful effects of hypoxia become more and more obvious. Furthermore, the attention of nephrologists has been drawn to the deleterious consequences of exposure to low levels of heavy metals.

References 1. Haider NB, Carmi R, Shalev H, Sheffield VC, Landau D. A Bedouin kindred with infantile

2.

3. 4.

5.

6.

7.

nephronophthisis demonstrates linkage to chromosome 9 by homozygosity mapping. Am J Hum Genet 1998; 63: 1404–10. Morgan D, Turnpenny L, Goodship J, Dai W, Majumder K, Matthews L, Gardner A, Schuster G, Vien L, Harrison W, Elder FF, Penman-Splitt M, Overbeek P, Strachan T. Inversin, a novel gene in the vertebrate left–right axis pathway, is partially deleted in the inv mouse. Nat Genet 1998; 20: 149–56. Erratum in: Nat Genet 1998; 20: 312. Calvet JP. Cilia in PKD—letting it all hang out. J Am Soc Nephrol 2002; 13: 2614–16. Omran H, Fernandez C, Jung M, Häffner K, Fargier B, Villaquiran A, Waldherr R, Gretz N, Brandis M, Rüschendorf F, Reis A, Hildebrandt F. Identification of a new gene locus for adolescent nephronophthisis on chromosome 3q22 in a large Venezuelan kindred. Am J Hum Genet 2000; 22: 118–27. Omran H, Sasmaz G, Haffner K, Volz A, Olbrich H, Melkaoui R, Otto E, Wienker TF, Korinthenberg R, Brandis M, Antignac C, Hildebrandt F. Identification of a gene locus for Senior-Loken syndrome in the region of the nephronophthisis type 3 gene. J Am Soc Nephrol 2002; 13: 75–9. Omran H, Haffner K, Burth S, Fernandez C, Fargier B, Villaquiran A, Nothwang HG, Schnittger S, Lehrach H, Woo D, Brandis M, Sudbrak R, Hildebrandt F. Human adolescent nephronophthisis: gene locus synteny with polycystic kidney disease in pcy mice. J Am Soc Nephrol 2001; 12: 107–13. Schuermann MJ, Otto E, Becker A, Saar K, Ruschendorf F, Polak BC, Ala-Mello S, Hoefele J, Wiedensohler A, Haller M, Omran H, Nurnberg P, Hildebrandt F. Mapping of

13 YIRenMed I 281-297 FINAL

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Page 297

INTERSTITIAL AND TUBULAR DISEASES

8.

9.

10.

11.

12.

13.

14. 15.

16. 17.

18.

19.

20.

21.

297

gene loci for nephronophthisis type 4 and Senior-Loken syndrome, to chromosome 1p36. Am J Hum Genet 2002; 70: 1240–6. Dahan K, Fuchshuber A, Adamis S, Smaers M, Kroiss S, Loute G, Cosyns JP, Hildebrandt F, Verellen-Dumoulin C, Pirson Y. Familial juvenile hyperuricemic nephropathy and autosomal dominant medullary cystic kidney disease type 2: two facets of the same disease? J Am Soc Nephrol 2001; 12: 2348–57. Hart TC, Gorry MC, Hart PS, Woodard AS, Shihabi Z, Sandhu J, Shirts B, Xu L, Zhu H, Barmada MM, Bleyer AJ. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 2002; 39: 882–92. Turner JJ, Stacey JM, Harding B, Kotanko P, Lhotta K, Puig JG, Roberts I, Torres RJ, Thakker RV. UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy. J Clin Endocrinol Metab 2003; 88: 1398–401. Lazzaro D, De Simone V, De Magistris L, Lehtonen E, Cortese R. LFB1 and LFB3 homeoproteins are sequentially expressed during kidney development. Development 1992; 114: 469–79. Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn BN, Lindner T, Yamagata K, Ogata M, Tomonaga O, Kuroki H, Kasahara T, Iwamoto Y, Bell GI. Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat Genet 1997; 17: 384–5. Hiesberger T, Bai Y, Shao X, McNally BT, Sinclair AM, Tian X, Somlo S, Igarashi P. Mutation of hepatocyte nuclear factor-1beta inhibits Pkhd1 gene expression and produces renal cysts in mice. J Clin Invest 2004; 113: 814–25. Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002; 110: 341–50. Yang X, Letterio JJ, Lechleider RJ, Chen L, Hayman R, Gu H, Roberts AB, Deng C. Targeted disruption of Smad3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J 1999; 18: 1280–91. Vijayachandra K, Lee J, Glick AB. Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model. Cancer Res 2003; 63: 3447–52. Luo G, Hofmann C, Bronckers AL, Sohocki M, Bradley A, Karsenty G. BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes Dev 1995; 9: 2808–20. Hruska KA, Guo G, Wozniak M, Martin D, Miller S, Liapis H, Loveday K, Klahr S, Sampath TK, Morrissey J. Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction. Am J Physiol Renal Physiol 2000; 279: F130–43. Morrissey J, Hruska K, Guo G, Wang S, Chen Q, Klahr S. Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function. J Am Soc Nephrol 2002; 13 (Suppl 1): S14–S21. Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Muller GA, Kalluri R. Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am J Physiol Renal Physiol 2003; 285: F1060–7. Sanchez-Fructuoso AI, Blanco J, Cano M, Ortega L, Arroyo M, Fernandez C, Prats D, Barrientos A. Experimental lead nephropathy: treatment with calcium disodium ethylenediaminetetraacetate. Am J Kidney Dis 2002; 40: 59–67.

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14 Inherited renal disease MARIE HOGAN, VICENTE TORRES

Introduction In recent years, advances in molecular genetics – specifically, positional cloning – have led to the discovery of new genes involved in renal disease. This process was brought about by the careful clinical follow-up and acquisition of detailed family histories in individuals with suspected inherited renal diseases. Analysis of linkage (the tendency of certain genes to be inherited together) and haplotype mapping studies using genetic markers have facilitated the study of the genetic basis of these diseases in affected members of these families. Haplotype analysis examines and specifies the genetic information descending through a pedigree, providing a way to visualize gene flow and correlate this in affected individuals. Using these approaches, it may sometimes take years before wide genetic intervals can be narrowed down and candidate gene loci identified. This process has been accelerated by the availability of more genetic markers that can be located precisely on the human physical map due to the availability of human genome sequences in publicly available bioinformatics databases, such as GenBank at the National Center for Biotechnology Information 1. Additionally, gene expression data are publicly available for many of these candidate genes by searching databases of expressed sequence tags (ESTs; these are short sequences of cDNA), electronic expression profile databases (Genecards™) and gene array data 2. Also, comparative genetic maps from the mouse, rat and other model organisms have provided scientists with a way to confirm their findings and permit further investigation of candidate gene expression. Detailed transcript maps for critical genetic regions in the mouse and the human are providing very powerful tools to identify human kidney disease genes. Comparative maps enable the identification of conserved (and thus functionally important) regions of sequence and can provide the basis for evaluating the non-coding regions close to these genes, which also have the potential to undergo alterations in sequence and may be involved in disease pathogenesis. Increasingly, scientists are also using animal models of human kidney diseases to help identify genes implicated in monogenic human kidney diseases and to localize other genetic modifier genes. With the identification of these genes, data are now emerging about the genotype–phenotype correlations of major kidney diseases. We summarize the results from some of these studies in this chapter. © Atlas Medical Publishing Ltd

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Nephrologists are aware of the clinical heterogeneity of genetic diseases that present in the renal clinic. For example, autosomal dominant polycystic kidney disease can be asymptomatic or can present with brain or aortic aneurysm; Alport syndrome may present without sensorineural hearing loss; and tuberous sclerosis may present without the typical skin lesions or neurological findings. Molecular genetic testing is likely to have an increasing impact on clinical nephrology practice over the next few years as the pace of discovery gathers momentum and technological advances become available to practising nephrologists. These technologies will provide nephrologists with new disease biomarkers to add to the traditional methods of kidney biopsy interpretation, and will also assist nephrologists in the evaluation and identification of living related kidney transplant donors in the detection of preclinical inherited kidney disease. As more genetic tests become clinically available, it is likely that molecular diagnostics will transform the clinical evaluation process. As the technology is now available, clinical nephrologists should become aware of the online public databases that are both up to date and peer-reviewed, and are useful in the clinic, such as GeneTests 3. This database provides helpful clinical diagnostic information for genetic disorders and keeps an up-to-date list of places where molecular diagnostics for clinical and research testing are available worldwide.

Glomerular disease Glomerular disease is the third leading cause of end-stage renal disease (ESRD). Focal segmental glomerulosclerosis (FSGS) is the underlying pathological entity in 5% of adults and 20% of children with ESRD. Its prevalence is probably understated as many patients present with ESRD without having undergone renal biopsy. In the last 4 years, multiple novel genes encoding proteins involved in the pathogenesis of steroid-resistant nephrotic syndrome have been identified – mostly in cases of FSGS. The proteins they encode are primarily located at the glomerular slit diaphragm. Since the basic molecular mechanisms behind most glomerular diseases remain to be elucidated, the identification of these new genes will probably provide a high yield of information in the coming years as we begin to discover their functional roles and discover yet more interacting partner proteins.

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Identiﬁcation of the ﬁrst gene locus (SSNS1) for steroid-sensitive nephrotic syndrome on chromosome 2p Ruf RG, Fuchshuber A, Karle SM, et al. J Am Soc Nephrol 2003; 14: 1897–900

B A C K G R O U N D . Little progress has been made in the identiﬁcation of novel genes involved in steroid-sensitive nephrotic syndrome (SSNS), which is by far the most common form of nephrotic syndrome seen in clinical nephrology practice (the lesions seen are minimal change [80%] and focal segmental glomerulosclerosis [20%]). This

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report highlights the identiﬁcation of the ﬁrst genetic locus implicated in the causation of steroid-sensitive nephrotic syndrome SSNS1 on chromosome 2p12-13.2. I N T E R P R E T A T I O N . The authors found linkage by studying three families using a whole genome scan approach. The most helpful pedigree contained three affected siblings from a consanguineous family (INS6). The authors narrow the genetic interval to 13 Mb (physical interval of 10.5 Mb) containing 58 known genes and another 23 predicted genes.

Comment The genes in this interval remain to be studied for their possible role in this disease. It also remains to be seen whether the gene(s) in this disease are mediating effects indirectly through the immune system or through defects of structural or functional components at the level of the podocyte (the visceral glomerular epithelial cell) in the kidney.

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NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele Tsukaguchi H, Sudhakar A, Le TC, et al. J Clin Invest 2002; 110: 1659–66

B A C K G R O U N D . FSGS is an important cause of ESRD, accounting for at least 2.5% of all cases of ESRD 4. It is reported that the incidence of this disease is rising and that about 50% of these individuals progress to ESRD by age 30; therefore, FSGS is a signiﬁcant clinical problem. Subtypes now recognized are primary (idiopathic or sporadic), secondary, familial and FSGS associated with congenital syndromes. While FSGS is most often considered to be sporadic in origin, there are multiple reports of inherited forms. In the last 4 years considerable progress has been made in the identiﬁcation of several disease-associated genes or loci using these families (Table 14.1). The genes identiﬁed so far include those coding for nephrin, podocin, CD2AP and -actinin; all of these proteins are found in the podocyte (the glomerular epithelial cell). When these structural proteins are missing or altered, mild to massive proteinuria and progressive renal interstitial ﬁbrosis and renal failure ensues in many patients. Recently studies have been done to establish whether mutations in some of these diseaseassociated genes are also found in individuals with (sporadic) primary FSGS. I N T E R P R E T A T I O N . To investigate if NPHS2 mutations might be responsible for milder adult-onset disease (adolescent or adult-onset disease), 30 families with FSGS and apparent autosomal recessive inheritance and 91 individuals with primary (sporadic) FSGS were subsequently studied. Mutation analysis of NPHS2 and some haplotype analysis was performed. Nine of these 30 families had NPHS2 mutations. Five of these were compound heterozygotes and one family had a homozygous change. Most convincing was the ﬁnding that one of these families had four affected individuals, all of whom were compound heterozygotes coded for the polymorphisms coding for R229Q and R291W amino acid changes in the NPHS2 gene (inherited in a recessive manner). The remaining three of these nine families were found to have one disease-associated allele. In the sporadic

Neph-/-

? ? ?

11q24 19q13.1 1p13.1

FSGS, focal segmental glomerulosclerosis.

Nephrotic syndrome in knockout mice (no human disease yet identiﬁed) No animal or human phenotype yet identiﬁed NEPH2 NEPH3/NLG1 KIAA1365

NEPH1

ACTN4 ? CD2AP

Nephrin-like protein Nephrin-like protein (ﬁltrin) Densin

Nephrin-like protein

-actinin 4 ? CD2-associated protein

Nephrin Podocin

Protein

? ? ?

Infancy 3 mo to 5 yr; later onset with missense mutations Any age Any age Adult (neonatal nephrotic syndrome in mice with homozygous deletion) At birth

Onset

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1q23.1

AD AD AD

19q13 11q 6p12

NPHS1 NPHS2

Gene

304

Increased susceptibility to FSGS

AR AR

19q13 1q25-31

Congenital nephrotic syndrome Steroid-resistant nephrotic syndrome Familial FSGS

Inheritance

Locus

Disorder

Table 14.1 Genetic and clinical features of nephrotic syndrome caused by inherited diseases of the podocyte

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FSGS cohort, 11 of 91 patients had R229Q (i.e. 6% allele frequency) compared with allele frequencies of 1.6–3% in control populations they screened. The differences in frequency of R229Q between these cohorts did not reach statistical signiﬁcance. Additional NPHS2 mutation analysis in these 11 sporadic cases identiﬁed an A284V change in two of these patients. The R229Q variant, which appears to be insufﬁcient alone to cause FSGS, may enhance susceptibility to renal injury in the compound heterozygous state when combined with a second mutant NPHS2 allele. It is still unclear if the R229Q is disease-causing or just a common polymorphism. Data from the in vitro nephrin-binding assay performed by the authors suggests that this amino acid change causes decreasing binding of podocin to nephrin and contributes to the clinical phenotype (Fig. 14.1).

Fig. 14.1 Nephrin-binding assay. (a) The bottom autoradiograph shows in vitro-translated and labelled mutant and wild-type (WT) podocin after incubation with puriﬁed nephrin, immunoprecipitation with an anti-nephrin antibody, transfer to nitrocellulose, and exposure to radiographic ﬁlm. Shown above is the result of Western analysis of the same blots using the anti-nephrin antibody for immunodetection. (b) Densitometry of the R229Q and R291W bands from repeated paired experiments. Intensity (with error bars indicating SEM) is given as a percentage of wild-type intensity, which is set by deﬁnition at 100%. Source: Tsukaguchi et al. (2002).

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Comment The hypothesis that the R229Q change in podocin is associated with disease needs to be further evaluated in large control populations and in larger numbers of patients with sporadic FSGS before it can be assigned as clearly associated with disease. It has not been fully determined whether R229Q is a disease-associated polymorphism or truly a disease-causing change. Whether the 50% reduction in binding is physiologically relevant, as the authors suggest, is not clear. The authors also propose that the phenotypic effect of the R229Q change in podocin may be facilitated by variants in other genes (e.g. NPHS1). Recently, Pereira et al. and others have reported that this R229Q functional variant is associated with a 2.77-fold increased risk of developing microalbuminuria in the general population when they investigated carrier status in 1577 individuals in Brazil 5. This study found 9 out of 61 individuals (14.8%) with the R229Q allele and microalbuminuria, compared with 59 out of 966 (6.1%) who had microalbuminura but did not have this polymorphism.

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Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome Ruf RG, Lichtenberger A, Karle SM, et al. J Am Soc Nephrol. 2004; 15: 722–3

B A C K G R O U N D . Nephrotic syndrome is one of the most common diagnoses in paediatric nephrology. Eighty per cent of the children with this condition are steroidsensitive (SSNS) and 20% are steroid resistant (steroid-resistant nephrotic syndrome, SRNS); 75% have histologic evidence of FSGS and 20% of SRNS children have minimal change nephrotic syndrome. NPHS2 is the gene that encodes podocin and is implicated in a recessive form of SRNS characterized by early-onset disease in childhood. Additionally, NPHS2 mutations have been associated with sporadic (i.e. non-familial) SRNS in 20–30% of cases 6. It would seem logical that, if there is a genetic/ non-immune mediated basis for the occurrence of the proteinuria in these patients (e.g. a defect in podocin), then nephrologists might consider avoidance of steroid-based therapy of the primary disease and need not be concerned about recurrent disease after kidney transplant. This paper examines these questions: (1) Do patients with NPHS2 mutations respond to standard steroid treatment? (2) Do they have the same risk of FSGS recurrence after kidney transplant? I N T E R P R E T A T I O N . NPHS2 mutational analysis was performed in 190 patients with SRNS from 165 families (Fig. 14.2) and in a control group of 124 patients with SSNS from 120 families. The median age of onset of nephrotic syndrome was 3.4 years. Forty-three families from 165 families (26%) with SRNS (56 of 190 patients, 29%) were found to have homozygous or compound heterozygous mutations in NPHS2. No NPHS2 mutations were observed in the 120 SSNS families. Thirty-three of 56 patients (59%) with NPHS2 mutations progressed to ESRD whereas 34 of 129 patients (26%) without NPHS2 mutations progressed to ESRD. None of the 29 patients with mutations in NPHS2 who were treated with cyclosporin A or cyclophosphamide showed complete remission of

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Fig. 14.2 NPHS2 mutations observed in 165 families with steroid-resistant nephrotic syndrome (SRNS). The schematic diagram depicts the eight NPHS2 exons. Missense mutations are indicated above the exon bar, as coloured circles. The amino acid change in the podocin gene is indicated above the circles. Splice site and frameshift mutations are shown below the exon bar and are symbolized as coloured bars, indicating the position of truncation. Mutations are colour-coded; novel mutations not previously described are red (E102K; P118L all three; K126N; R168H two; G257E; V268G []), previously reported mutations observed again in the 165 families with SRNS are orange (Exon 2-R138Q11; L169P; R229Q; V290M; R291W; E310V []), and mutations previously described by the authors are green []. The frequencies of the different mutations observed among the 165 families with SRNS are indicated by the different numbers of circles. Each circle or bar is equivalent to one mutation observed among 165 families with SRNS, corresponding to the data presented. Source: Ruf et al. (2004).

nephrotic syndrome. A partial response to these drugs was observed in ﬁve (17%), suggesting a complex extrarenal mechanism in the pathogenesis of this disease. Recurrent disease after renal transplant was seen in 7 of 20 patients with SRNS (35%) without NPHS2 mutations, but in only 2 of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2. The common polymorphism R229Q (coding for an arginine-to-glutamine amino acid substitution) was observed in 13 of 190 patients (7%) with SRNS, 6 of 124 patients with SSNS (6%) and 9 of 80 healthy controls (11%).

Comment Ruf et al. conclude in this study that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid treatment, and they found a reduced risk of the recurrence of FSGS in these individuals after renal transplantation. They confirm findings from a previous smaller study in which no children with familial SRNS had recurrence after renal transplantation 7.

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Contrary to the findings in this study, it should also be noted that other studies have demonstrated rates of recurrence of FSGS in patients with NPHS2 mutations similar to rates in those without NPHS2 mutations. This paper expands the spectrum of disease-causing mutations now reported for NPHS2 and also confirms some nucleotide changes to be polymorphisms (specifically R229Q). As this information may influence the long-term management of patients with NPHS2 mutations, the authors advocate molecular genetic testing for NPHS2 mutations at the time of initial evaluation, abrogating the need for future steroid trials if the patient fails the initial steroid trial. However, from this study there still remains a reduced risk in these patients of disease recurrence: 2 of 24 (8%) patients with homozygous or compound heterozygous mutations after renal transplantation.

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X-linked Alport syndrome: natural history and genotype–phenotype correlations in girls and women belonging to 195 families: a ‘European Community Alport Syndrome Concerted Action’ study Jais JP, Knebelmann B, Giatras I, et al. J Am Soc Nephrol 2003; 14: 2603–10

B A C K G R O U N D . Alport syndrome accounts for 1–2.5% of patients reaching ESRD in Europe and the USA. The commonest form is X-linked and is associated with mutations in the 5 chain of type IV collagen gene (COL4A5). It is characterized by progressive haematuric nephritis, progressive sensorineural hearing loss and frequently ocular abnormalities. The rate of progression to ESRD and deafness has been shown to be mutation-dependent in males. Large deletions, nonsense mutations, or small mutations changing the reading frame led to a 90% probability of developing ESRD before 30 years of age; in patients with missense or splice site mutation the corresponding risk was 50 and 70%. The renal disease has a much more variable course in females, remaining mild in most. Here, the European Community Alport Syndrome Concerted Action (ECASCA) group report the ﬁndings of the ﬁrst large study that examines the natural history of the disease in females and attempts to correlate phenotype with genotype. I N T E R P R E T A T I O N . The study examined 506 girls and women in a cohort of 195 X-linked families with identiﬁed COL4A5 mutations. Among these females, 95.5% had microscopic haematuria and 75% developed proteinuria. Follow-up in 288 females indicated that 34 (12%) had chronic renal failure and 51 (18%) had reached ESRD at last evaluation (Fig. 14.3). By comparison with males, all females had functioning kidneys at age 30 and only 12% had reached ESRD by 40. In the male group, 70% of men at age 30 and nearly 90% by age 40 had reached ESRD. There was some evidence for genotype–phenotype correlation, the lowest rate of progression being seen in females with missense mutations. Abnormally thin glomerular basement membrane was predominantly seen in females with a missense mutation, but there was no overall correlation between the type of mutation and ultrastructural changes in the glomerular basement membrane. The most ominous predictor of ESRD was the occurrence of proteinuria, and the risk of developing ESRD was also higher in females with hearing loss.

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Fig. 14.3 Probability of end-stage renal disease (ESRD) in 315 boys and men and 288 girls and women with COL4A5 mutation. In the third curve, girls and women with incomplete clinical data were added because they were not in ESRD at last follow-up. Source: Jais et al. (2003).

Comment The variability in severity of kidney disease seen in female heterozygotes with Alport syndrome may be explained by somatic inactivation. This study provides useful information for the practising nephrologist that will help in evaluating the risk of developing renal failure and deafness in female carriers of X-linked Alport syndrome. The course of the disease is less benign in females than previously thought, with the likelihood that ~30% of females have ESRD by age 60. The occurrence and severity of proteinuria is a reliable predictor of prognosis in females with the Alport mutation. The authors suggest that heterozygous females with asymptomatic haematuria, when older than 30–40 years, could be considered as potential kidney donors as they have a very low risk of developing renal failure. This remains controversial.

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Fabry disease: detection of undiagnosed hemodialysis patients and identiﬁcation of a ‘renal variant’ phenotype Nakao S, Kodama C, Takenaka T, et al. Kidney Int 2003; 64: 801–7

B A C K G R O U N D . Fabry disease is an X-linked recessive lysosomal storage disease resulting from deﬁcient -galactosidase A (-Gal-A) activity. The disease results in progressive accumulation of glycosphingolipids, predominantly globotriaosylceramide

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(GL-3) in the blood vessels, kidneys and heart. In the classical presentation of Fabry disease, renal disease is a major presenting feature in affected males. The ﬁrst renal signs may be proteinuria, microhaematuria and lipiduria. Patients may have a highly variable clinical presentation, which can include acroparaesthesias, angiokeratomas and hypohidrosis, and they may develop corneal and lenticular opacities by adolescence. The median age at diagnosis is 28.6 years 8. At tissue level, with advancing age there is progressive neutral glycosphingolipid accumulation (of lysosomal GL-3) in the vascular endothelium, which leads to renal failure and cardiac, vascular and brain complications in affected males and, to a lesser extent, in female carriers. Because the early clinical studies of enzyme replacement in Fabry disease have now demonstrated safety and efﬁcacy, it is important that affected individuals are detected as early as possible as genetic counselling and therapeutic intervention can then be initiated; this can lead to remarkable improvement in pain symptoms and in quality of life. Recently, a limited cardiac variant of Fabry disease has been identiﬁed which does not present until the sixth or seventh decade of life, with left ventricular hypertrophy or cardiomyopathy and proteinuria, but renal function, adjusted for age, is normal. In this paper, the authors identify a ‘renal variant’ Fabry disease and determine its prevalence in a Japanese population of haemodialysis patients. The clinical diagnosis must be conﬁrmed by determination of -Gal-A activity in leucocytes or plasma and/or detection of GL-3 deposition in tissue biopsies, and should be followed by molecular genetic analysis. I N T E R P R E T A T I O N . The authors screened 514 male haemodialysis patients for -Gal-A deﬁciency by assaying plasma -Gal-A activity and found six patients with low levels. These six patients had lymphocyte -Gal-A activity determined as well as plasma GL-3 levels, which were elevated in all. A control population of 43 healthy Japanese male subjects also had plasma -Gal-A activity levels determined. Mutation analysis of the -Gal-A gene conﬁrmed the diagnosis of Fabry disease in the six individuals with low enzyme activity (Fig. 14.4).

Comment In this study, the authors report that 6 (1.2%) of 514 consecutive male patients in a population of haemodialysis patients from Japan had deficient plasma -Gal-A activity. This study confirms that renal disease may be the only manifestation of Fabry disease. The prevalence of the renal variant phenotype was 5 patients in 514 (0.97%). One of the six patients was a misdiagnosed patient with classic Fabry disease, which was not detected despite an earlier renal biopsy with typical pathological changes of foamy inclusions in podocytes, consistent with glycosphingolipid deposits that had leached out during fixation. Subsequent osmium fixation and toluidine blue O staining demonstrated glycosphingolipid deposits in epithelial cells and in the capillary endothelial cells of the glomeruli. The population under study differs from that of patients seen in American or European dialysis units as 366 (71%) were classified as having chronic glomerulonephritis (with no renal biopsy performed to establish a diagnosis for renal disease) and only 16 (3.1%) of them had a renal biopsy. The figures reported in this study are higher than those for dialysis patients reported in European (0% in The Netherlands) and US (0.47%) studies 9,10. The prevalence of Fabry disease in haemodialysis units

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Fig. 14.4 Plasma -galactosidase A (-Gal A) activity in 89 normal healthy males and 514 males with end-stage renal disease (ESRD) on haemodialysis. Plasma activity of 2.5 U/ml was deﬁned as abnormally low. Source: Nakao et al. (2003).

in Austria was found to be 0.161%, significantly higher than that seen in the American and European Fabry disease registries (0.0188 and 0.0167% respectively) 11,12. Therefore, prevalence data from these studies should be interpreted with some caution, and it is likely that the prevalence reported in dialysis units depends to a great extent on how often proteinuric patients get kidney biopsies (which varies from site to site and country to country).

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The authors make a good case for screening all male patients with unclassified causes of renal disease (i.e. those with no renal biopsy) for Fabry disease by measurement of -Gal-A activity. This guideline could also be extended to women with unexplained renal disease as 12% women can also progress to ESRD, with the caveat that enzyme levels in women with the disease can lie within normal limits 11. In summary, the prevalence of Fabry disease in haemodialysis patients may be higher than previously estimated.

Hereditary tubulointerstitial kidney diseases Nephronophthisis is the most common genetic cause of chronic renal failure in children and is characterized by progressive tubulointerstitial kidney involvement, clinical symptoms of polyuria, growth retardation and deterioration of renal function during childhood and adolescence. Renal pathology is characterized by thickened basement membrane, interstitial fibrosis and medullary cysts in advanced stages. Although these disorders are historically categorized as cystic diseases, the most prominent pathological finding is renal fibrosis. In the last few years several genes associated with nephronophthisis have been identified (Table 14.2). Congenital hepatic fibrosis and retinitis pigmentosa may be associated in some cases.

Table 14.2 Classiﬁcation of the nephronophthisis/medullary cystic kidney disease complex Disease

Inheritance Locus

NPH1 AR (juvenile) NPH2 AR (infantile) NPH3 AR (adolescent) NPH4 AR (juvenile) MCKD1 AD MCKD2 AD and FJHN

Chromosome Gene product

Median age of ESRD

Extrarenal associations

NPHP1

2q12-q13

Nephrocystin

13 yr

Senior-Löken syndrome

NPHP2

9q22-q31

Inversin

1 to 3 yrs

NPHP3

3q21-q22

Nephrocystin-3

19 yrs

NPHP4

1p36

Nephrocystin-4/ 13 yrs nephroretinin ? 62 yrs

MCKD1 1q21 MCKD2 16p1

Uromodulin/ 32 yrs Tamm-Horsfall protein

Orthologous animal model

Inv-/- mouse Senior-Löken Pcy mouse syndrome Senior-Löken syndrome Gout, hyperuricaemia Gout, hyperuricaemia

AR, autosomal recessive; AD, autosomal dominant; ESRD, end-stage renal disease.

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Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left–right axis determination Otto EA, Schermer B, Obara T, et al. Nat Genet 2003; 34: 413–20

B A C K G R O U N D . Our understanding of the nephronophthisis/medullary cystic kidney disease complex has been considerably expanded in the last 2 years. NPHP2 encodes the protein inversin and mutations in this gene are responsible for an infantile form of nephronophthisis, which occurs with or without situs inversus. I N T E R P R E T A T I O N . Both polycystic kidney disease and nephronophthisis are now emerging as disorders of primary cilia. In 2003 Watanabe et al. showed that inversin is a component of the primary cilia and contributes to left–right determination, and is essential for normal node ﬂow 13. In this paper, Otto et al. identiﬁed inversin as the gene mutated in NPHP2 with and without situs inversus. They capitalized on the availability of the inv/inv mouse model, which has cystic kidneys, situs inversus and pancreatic islet cell dysplasia. They showed molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1, interaction of nephrocystin with -tubulin (a component exclusive to primary cilia) and colocalization of nephrocystin, inversin and -tubulin in primary cilia of renal tubular cells. Furthermore, they produced a polycystic kidney disease-like renal phenotype and randomization of heart looping by knockdown of invs expression in zebraﬁsh. They rescued the phenotype with injection of mouse Invs mRNA.

Comment This paper points to a shared mechanism in the pathogenesis of cysts in this disorder and polycystic kidney disease. Currently, it is thought that defects in cilial function can interfere with the ability of the renal epithelium to sense luminal flow rates, resulting in abnormal growth. A similar defect in the node is thought to explain the occurrence of situs inversus in these individuals.

Cystic kidney disease The cystic kidney diseases are a genetically diverse group of clinical syndromes. It is now 9 years since the PKD1 gene was cloned (defects in the PKD1 and PKD2 genes cause autosomal dominant polycystic kidney disease [ADPKD], which affects ~1 in 1000 adults worldwide). In the last 2 years new studies, mainly in animal models of the diseases, have added to a growing amount of evidence that suggests that cilial dysfunction underlies many, if not all, forms of inherited cystic renal and hepatorenal diseases. With the availability of these models, a number of novel therapeutic strategies have been tested with very promising results 14–16.

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Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH II. Nat Med 2004; 10: 363–4

B A C K G R O U N D . Autosomal dominant polycystic kidney disease is a major cause of ESRD and is characterized by mutations in either PKD1 or PKD2, which encode membrane proteins. Abnormalities in two major intracellular messengers, Ca2+ and cAMP, are also associated with this disease. In the last year, two genes that cause autosomal dominant polycystic liver disease have been identiﬁed (PKRCSH and SEC63) 17,18. Several proteins implicated in the pathogenesis of polycystic kidney disease have been localized to primary cilia (which extend into the lumen of collecting ducts and tubules) and implicated in mechanotransduction, and the polycystin complex has been shown to have a role in intracellular calcium homeostasis 19. OPC-31260, an antagonist of the vasopressin V2 receptor, the major cAMP agonist in the collecting duct, has been shown to be an effective therapy in two animal models of cystic kidney disease (autosomal recessive polycystic kidney disease [ARPKD]; the PCK rat) and nephronophthisis (the pcy mouse) 16. In rats, OPC-31260 blocks the antidiuretic action of arginine vasopressin (AVP) in a dose-dependent fashion. OPC-31260 blocks AVP-induced production of cAMP and aquaporin-2 water channel insertion into the luminal surface of the renal collecting tubule (AQP-2) 20. In this study the efﬁcacy of OPC-31260 was tested in an animal model of ADPKD. I N T E R P R E T A T I O N . OPC-31260 (0.05%), a vasopressin V2 non-peptide antagonist, was administered in the diet of Pkd–/tm1Som mice with a defect in a gene orthologous to human PKD2; these mice reliably develop polycystic kidney disease within 4 months of birth. This treatment was continued between 3 and 16 weeks of age and markedly reduced the renal accumulation of cAMP and diminished disease progression, as reﬂected by lower kidney/body weights, blood urea nitrogen, numbers of renal cysts and ﬁbrosis volumes, and mitotic and apoptotic indices (Fig. 14.5). The drug was well tolerated and there were no associated electrolyte abnormalities. It did not have an effect on liver cysts. This drug is probably speciﬁc as the V2 receptor it targets is located only in the kidneys and some endothelial cells.

Comment Recent studies have shown that cAMP plays a major role in kidney cystogenesis, stimulating fluid secretion in normal collecting ducts and in ADPKD cysts. Adenylyl cyclase agonists activate extracellular signal-regulated kinase (ERK) signalling and increase the proliferation of ADPKD cells while inhibiting the proliferation of kidney cortex cells. A similar change is induced in collecting duct cells when treated with Ca2+ channel blockers, suggesting an interplay between Ca2+ and the cAMP signalling pathways (Fig. 14.6). This study shows the potential of V2 receptor antagonists to markedly slow the progression of cystic disease. They have been shown to have a good safety profile in preclinical and clinical studies, in which they are being

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Fig. 14.5 Effects of OPC32160 on development of PKD in Pkd2 -/tm1Som mice. (a, b) Representative kidney sections at the same magniﬁcation, stained with H&E. (c, d) Gross appearance of whole kidneys from the most severely affected untreated (c) and OPC32160-treated (d) Pkd2 -/tm1Som mice. (e–g) Effect of OPC32160 on body weight (BW; e), kidney weight (f), renal cyst volume (g) and blood urea nitrogen (BUN) concentration (h) in Pkd2 -/tm1Som mice. *P <0.05 compared with control, by two-way ANOVA. Source: Torres et al. (2004).

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Fig. 14.6 Polycystin pathway can inﬂuence intracellular regulation of Ca 2 and cAMP in collecting-duct epithelial cells from polycystic kidneys. Polycystin-1 (PC-1) acts as a sensor for extracellular signals. Polycystin-2 (PC-2) is regulated by polycystin-1 and acts as a Ca 2 channel that can induce the release of Ca 2 from intracellular stores. Disruption of the polycystin pathway results in reduced [Ca 2 ]i, which in turn stimulates adenylyl cyclase VI (AC VI), inhibits cAMP-dependent phosphodiesterases (PDE) and results in increased levels of intracellular cAMP. ER, endoplasmic reticulum; RyR, ryanodine receptor; R, G-protein-coupled receptor; PLC, phospholipase C; AQP-2, aquaporin-2; N, nucleus; PKA, protein kinase A; CREB, cAMP-responsive element binding protein. Source: Torres et al. (2003).

evaluated for treatment of hyponatraemia and disorders of water retention, such as congestive heart failure. The major adverse effect is likely to be the increased free water diuresis associated with the use of these drugs, though this may be averted by titration of drug dosage; this will be evaluated in future human clinical trials.

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Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome Ansley SJ, Badano JL, Blacque OE. Nature 2003; 425: 628–33. Epub 2 September 2003

B A C K G R O U N D . Bardet–Biedl syndrome (BBS) is a rare genetic syndrome characterized by retinal dystrophy (leading to blindness), obesity, polydactyly, renal

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abnormalities, hypogonadism, diabetes mellitus and learning disability. Renal structural or functional abnormalities are reported to be almost universal in these patients and constitute an important contributor to death 21. These abnormalities comprise calyceal abnormalities, hypertension, defects in urinary concentrating ability, renal tubular acidosis and chronic renal insufﬁciency, leading to ESRD. The disease is genetically heterogeneous, with eight loci mapped to date, and could be regarded as lying somewhere between a monogenic and a polygenic disorder. After the discovery of the ﬁrst three BBS genes, it was shown that three mutations at two different BBS loci are required for pathogenesis in some families 22. Understanding of the function of the BBS proteins has so far been limited. I N T E R P R E T A T I O N . Ansley et al. identify the sixth BBS gene (BBS8) and implicate defective basal bodies in the pathogenesis of pleiotropic BBS. Basal bodies are modiﬁed centrioles that sit at the base of cilia and ﬂagella. The authors identiﬁed a novel sequence that contained a region of similarity to the previously known BBS4 protein sequence. On screening this sequence for mutations in BBS patients, they found mutations in three affected individuals from these families. The predicted protein sequence had similarity with the prokaryotic protein encoded by the gene pilF, which is found in primitive hairlike structures called pili in Escherichia coli; these are involved in bacterial twitching. Also, since the authors had observed one individual in a BBS8 family with situs inversus, which is known to be caused by dysfunction of the nodal cilium, they hypothesized that the BBS proteins are involved in cilial function and studied this in human cell lines and tissues. They demonstrated that BBS8 protein localizes to ciliated structures in human tissues. Next, using Caenorhabditis elegans, a well-characterized eukaryotic model organism used in the study of cilia and intraﬂagellar transport, they established whether BBS8 has a role in ciliary biogenesis/function. After identifying the C. elegans BBS8 homologue (bbs-8) and also all the other known BBS homologues (bbs-1, bbs-2, bbs-7) and osm-5 (the homologue of TG737, the mouse gene for polycystic kidney disease) in C. elegans, they showed localization to the basal body of ciliated cells of all of these proteins in this organism. They propose that these proteins may be involved in the same cellular function, which is important in development. These proteins may mediate communication between the cilium and the rest of the cell.

Comment The findings of Ansley et al. that the BBS proteins localize to the basal body of ciliated cells (in C. elegans) suggest that BBS results from a defect in ciliary function. Defects in primary cilia have also been associated with the proteins involved in ADPKD (polycystin-1 and polycystin-2), ARPKD (fibrocystin) and nephronophthisis (nephrocystin and inversin). The identification of the BBS8 gene and the role of the protein in basal bodies are likely to provide insights into our understanding the molecular basis of the clinical components of BBS, including hypertension, renal abnormalities and obesity. In the future we may find proof that several of the BBS proteins function in the same pathway.

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Nephrolithiasis Kidney stones affect about 12% of males and about 5% of females in the Western world and are familial in 45% of patients. They are most commonly associated with hypercalciuria. The prevalence of kidney stones varies not just with race and sex, but also strongly with geographical location, indicating both genetic and environmental influences in the pathogenesis of the disease. Several of these diseases have been shown to have monogenic inheritance and have led to advances in understanding of the molecular basis of the associated metabolic defects in these disorders.

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Evidence for genetic heterogeneity in Dent’s disease Hoopes RR Jr, Raja KM, Koich A, et al. Kidney Int 2004; 65: 1615–20

B A C K G R O U N D . Dent’s disease, (also known as X-linked nephrolithiasis and X-linked recessive hypophosphataemic rickets) is an inherited Fanconi syndrome associated with loss-of-function mutations in the hCLCN5 gene encoding chloride channel (ClC)-5 voltage-gated chloride channel. ClC-5 is highly expressed in all three segments (S1-S3) of the proximal tubule (PT) and in intercalated cells of the distal tubule of the rat kidney. The channel has been shown to be involved in transepithelial solute transport (e.g. the receptor-mediated endocytic pathway of the PT cells). Heterologous expression in Xenopus oocytes of the mutant hCLC-5s associated with Dent’s disease has been shown to abolish or markedly decrease chloride conductance. These patients have low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, renal failure, hypophosphataemia of renal origin, or aminoaciduria. The basic unit of ClCs is a dimer of identical proteins, each of which forms a pore on its own. In addition, ClC proteins may associate with accessory -subunits (e.g. barttin), a small protein that is necessary for the proper function of ClC-K channels. Currently there exist many more chloride channels than genes known to encode these channels. I N T E R P R E T A T I O N . Hoopes et al. performed mutation analysis on patients with a clinical diagnosis of Dent’s disease. This was based on (1) the presence of LMW proteinuria (2) hypercalciuria (deﬁned as >4 mg/kg in a 24-hour collection or >0.25 mg calcium per mg creatinine on a spot urine sample) (3) at least one of the following: nephrocalcinosis, nephrolithiasis, haematuria, hypophosphataemia, or renal insufﬁciency. Probands from 35 unrelated families met the inclusion criteria for the study. Mutation analysis led to 16 mutations being identiﬁed—only two of which have been previously reported. Ten were missense mutations. Four nonsense mutations and two frameshift mutations were identiﬁed (Table 14.3). Thirteen subjects had normal coding sequence and no mutations in the promoter could be identiﬁed.

Comment The study increases the number of mutations now detected in the CLCN5 gene. In this study, nine of the ten missense mutations cluster within or near transmembrane domains of the chloride channel protein 5. The T657 mutation occurs in

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Table 14.3 Mutations in 19 patients with Dent’s disease Patient

Base change

Mutation

Helix

Restriction enzyme

Missense mutations 1 TGTCGT 2 TCGTTG 3 TCGTTG 4 TCGTTG 5 GAAGCA 6 AGCGGC 7 GGTGAT 8 GGGAGG 9 CGGTGG 10 AGCAAC 11 AAGGAG 12 ACTAGT

C221R S244L S244L S244L E267A S270G G462D G513R R516W S545N K546E T657S

F G G G H H-to-I loop N O O-to-P loop Q Q C-terminal loop

Btg I – – – Ear I Alu I SfaN I Aar I Hinf I – – –

Nonsense mutations 13 TGGTAG 14 TGTTGA 15 CGATGA 16 CGATGA 17 CGATGA

W45X C221X R347X R718X R718X

Frameshift mutations 18 CCCCC– 19 ACATACA

C del 687fs T ins 694fs

Sau96 I Dde I – Hph I Hph I

Source: Hoopes et al. (2004).

the C-terminal cytoplasmic domain within ten amino acids of a PY domain that appears to be an internalization signal that interacts with ubiquitin–protein ligases. The implications of this mutation will need to be studied in functional studies. Recently, the X-ray crystal structures of two bacterial ClCs have been established, allowing derivation of a three-dimensional model for hClC-5 and permitting the mapping of human ClC-5 mutations and prediction of the functional implications of these mutations 23. Ninety per cent of missense mutations occur at the interface of the interaction of the homodimer and lead to a loss of or great reduction in channel activity. The L200R mutation has been shown to lead to loss of Cl– conductance. This study reveals the first suggestive evidence of genetic heterogeneity in Dent’s disease; 13 families of 32 were found not to have any mutation in CLCN-5, suggesting that there must be other proteins involved in the regulation, processing or trafficking of ClC-5 in normal kidney tubule reabsorption, or perhaps another chloride channel is involved. Since the risk of developing renal insufficiency in adult life is elevated for this type of nephrolithiasis, the correct diagnosis could potentially modify the natural history of the disease by preventing the evolution towards uraemia. The current availability of molecular genetic diagnostics in Dent’s disease may therefore be helpful to the practising nephrologist.

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Inherited renal neoplasia Renal cell tumours are divided into benign and malignant neoplasms. Although most cases of renal cancer are sporadic, it is the familial cases of renal cancer that have provided the greatest insights into our understanding of renal cancer. Many of the genes causing familial renal cancer have now been identified (Table 14.4) and confer a germ-line predisposition to renal cancer. Finding the functions of these genes will be invaluable in understanding the cellular and molecular pathogenesis of renal cell cancer and identifying targets for novel therapeutic strategies.

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Rheb promotes cell growth as a component of the insulin/TOR signaling network Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA. Nat Cell Biol 2003; 5: 566–71

B A C K G R O U N D . Tuberous sclerosis is an autosomal dominant condition of high penetrance and is characterized by the development of hamartomas in multiple organs. It affects up to one in 6000 people and is associated with renal angiomyolipomas and cysts. A subset of patients develop severe polycystic kidney disease. Affected individuals have mutations of either TSC1 or TSC2, the genes encoding the protein products TSC1 (tuberin) and TSC2 (hamartin), which form a heterodimer. Studies in mammalian systems and Drosophila have shown that the TSC1/2 complex functions to inhibit cell growth and cell proliferation, thus correlating with the ﬁnding of giant cells observed in hamartomas of tuberous sclerosis patients. The mammalian target of rapamycin protein signalling (mTOR) has been shown to be antagonized by the TSC1/2 complex. The role of TSC1/2 in the mTOR pathway was proposed ﬁrst in genetic studies in Drosophila that suggested that TSC1/2 functions as a suppressor of growth, mediating its effects through its coupling to the insulin signalling pathway and TOR. I N T E R P R E T A T I O N . In a genetic screen for novel regulators of cell growth in Drosophila, Saucedo et al. identify Rheb (Ras homologue expressed in brain), a member of the Ras GTPase superfamily, as having a role in the regulation of cell growth by identifying mutant ﬂies with an enlarged eye phenotype. From sequence alignment comparisons they identiﬁed the causative gene as rheb and cloned it. They then made transgenic ﬂies that overexpressed rheb, which partially rescued the ﬂies from a growth-impaired state. Again, using Drosophila, these rheb transgenic ﬂies that they generated had increased levels of Rheb protein leading to larger ﬂies and altered cell cycle kinetics (accelerating G1–S transition) in multiple tissues with the implication being that rheb is promoting cell growth. Overexpression of Rheb increased phosphorylation of S6K, the p70 ribosomal protein involved in translation and an effector of TOR-mediated growth. Rheb appears to be negatively regulated by the tuberin/hamartin complex, which functions as a GTPase-activating protein (Fig. 14.7).

VHL, 3p25

c-MET, 7q31 FH, 1q42–43 BHD, 17p11.2

TSC1 and TSC2, 9q34, 16p13 Unknown, ?VHL, chromosome 3 Unknown Unknown Unknown, 1q21

von Hippel-Lindau disease

Hereditary papillary renal cancer

Hereditary leiomyomatosis renal cancer

Birt-Hogg-Dubé syndrome

Tuberous sclerosis

Constitutional chromosome 3 translocation

Familial clear cell renal cancer

Familial renal oncocytoma

Papillary thyroid neoplasia

Unknown

Unknown

Unknown

Unknown

Hamartin, tuberin (tumour suppressors)

Folliculin (? tumour suppressor)

Fumarate hydratase (tumour suppressor)

HGF-R (oncogene)

pVHL (tumour suppressor)

Protein (function)

?PRCC and oncocytomas; papillary thyroid cancer, nodular thyroid disease

Multiple, bilateral oncocytomas

CCRCC

Multiple, bilateral CCRCC

Multiple, bilateral angiomyolipomas (and other RCC?); cortical tubers, ependymal nodules; adenoma sebaceum; subungual ﬁbromas; retinal hamartomas

Hybrid oncocytic renal tumours, ChRCC, CCRCC, oncocytomas. ?PRCC; cutaneous nodules (ﬁbrofolliculomas); lung cysts, spontaneous pneumothorax

PRCC non-type I; uterine leiomyomas and leiomyosarcomas; cutaneous nodules (leiomyomas)

Multiple, bilateral PRCC type I

Multiple, bilateral CCRCC and renal cysts; retinal and CNS hemangioblastomas; pheochromocytomas; pancreatic cysts and neuroendocrine tumours; endolymphatic sac tumours; epididymal and broad ligament cystadenoumas

Manifestations

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CCRCC, conventional renal cell carcinoma (also known as ‘clear cell renal cell carcinoma’); ChRCC, chromophobe renal cell carcinoma; PRCC, papillary renal cell carcinoma. Source: Pavlovich et al. (2003) 24 .

Causative gene, location

Syndrome

Table 14.4 Genetic syndromes associated with hereditary renal cancer

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Fig. 14.7 Proposed model for Rheb regulation of nutrient import and its relationship with Tsc1/Tsc2 and two possible relationships with how Rheb signals to TOR. Source: Saucedo et al. (2003).

Comment More than 70% of human disease genes are also found in Drosophila 25. This paper is an example of how powerful a genetic system Drosophila can be when used to study the molecular mechanisms involved in these diseases. This work furthers advances made in 2001, when several groups of researchers reported that Tsc1 and Tsc2 inhibit cell growth in Drosophila 26–28. These functions of TSC1/TSC2 are mediated by the inhibition of mTOR. This work provides further insight into the molecular basis for TSC1/TSC2 in insulin signalling and tumour suppressor functions and in the inhibition of cell growth. A clinical trial in tuberous sclerosis patients with angiomyolipomas associated with rapamycin therapy (sirolimus), an inhibitor of mTOR, a drug that is widely used in organ transplantation and has a safe clinical profile, is under way, sponsored by the Tuberous Sclerosis Alliance (http://www.tsalliance.org/) and the National Cancer Institute in the USA.

Conclusion In this chapter, we provide a sample of recent important advances in molecular genetics research relevant to understanding the molecular basis of inherited kidney diseases. These should serve to increase the clinical nephrologist’s awareness of progress made in the metabolic and genetic diseases encountered in clinical practice and of promising therapies currently at the clinical trial stage (rapamycin for tuberous sclerosis and vasopressin antagonists for polycystic kidney disease). Several of these

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studies also highlighted the importance of animal models (Drosophila fruit fly, worm and the mouse) as an experimental platform to investigate the fundamental processes involved in human disease and the power of comparative genomics (e.g. pilF, the E. coli domain that has homology to BBS8, a new human protein implicated in a subset of BBS patients; PilF, a component of pili or hairlike appendages in E. coli, provided the link that enabled the possible function of BBS8 to be found), which are increasingly providing the key to the discovery of gene and protein functions. As it was impossible to cover all recent developments in this subject area comprehensively, we have also highlighted a few useful web resources (see references in the Introduction). These may provide a starting point for nephrologists wanting to track down more detailed and up-to-date information relating to the genetic basis of kidney diseases when they are making diagnoses in patients with kidney disease. These web resources should also lead to more general background information, and they increasingly provide essential support that will give nephrologists the means to integrate their clinical findings with the available genomic and medical genetics resources available online, and to locate genetic referral centres and centres for molecular genetic testing.

References 1. NCBI. http://www.ncbi.nlm.nih.gov/. 2. GeneCards. http://bioinformatics.weizmann.ac.il/cards/. 3. GeneTests. National Institutes of Health. Health Resources and Services Administration,

US Department of Energy. http://www.genetests.org/. 4. USRDS. 2003 Annual Data Report, US Renal Data System: Atlas of End-Stage Renal Disease

in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2003. 5. Pereira AC, Pereira AB, Mota GF, Cunha RS, Herkenhoff FL, Pollak MR, Mill JG, Krieger

JE. NPHS2 R229Q functional variant is associated with microalbuminuria in the general population. Kidney Int 2004; 65: 1026–30. 6. Karle SM, Uetz B, Ronner V, Glaeser L, Hildebrandt F, Fuchshuber A. Novel mutations in

NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. J Am Soc Nephrol 2002; 13: 388–93. 7. Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC,

Niaudet P, Antignac C. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 2000; 24: 349–54. 8. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders.

JAMA 1999; 281: 249–54.

14 YIRenMed I 299-325 FINAL

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19/4/05 4:03 pm

Page 324

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9. Linthorst GE, Hollak CE, Korevaar JC, Van Manen JG, Aerts JM, Boeschoten EW. Alpha-

10. 11. 12.

13.

14. 15.

16.

17.

18.

19.

20.

21. 22.

23.

24.

galactosidase A deficiency in Dutch patients on dialysis: a critical appraisal of screening for Fabry disease. Nephrol Dial Transplant 2003; 18: 1581–4. Desnick R, et al. European Symposium on Fabry Disease, Athens, Greece. November 2002. Thadhani R, Wolf M, West ML, Tonelli M, Ruthazer R, Pastores GM, Obrador GT. Patients with Fabry disease on dialysis in the United States. Kidney Int 2002; 61: 249–55. Tsakiris D, Simpson HK, Jones EH, Briggs JD, Elinder CG, Mendel S, Piccoli G, dos Santos JP, Tognoni G, Vanrenterghem Y, Valderrabano F. Report on management of renal failure in Europe, XXVI, 1995: rare diseases in renal replacement therapy in the ERA-EDTA Registry. Nephrol Dial Transplant 1996; 11: S4–20. Watanabe D, Saijoh Y, Nonaka S, Sasaki G, Ikawa Y, Yokoyama T, Hamada H. The left– right determinant inversin is a component of node monocilia and other 90 cilia. Development 2003; 130: 1725–34. Sweeney WE, Chen Y, Nakanishi K, Frost P, Avner ED. Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int 2000; 57: 33–40. Sweeney WE Jr, Hamahira K, Sweeney J, Garcia-Gatrell M, Frost P, Avner ED. Combination treatment of PKD utilizing dual inhibition of EGF-receptor activity and ligand bioavailability. Kidney Int 2003; 64: 1310–19. Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med 2003; 9: 1323–6. Li A, Davila S, Furu L, Qian Q, Tian X, Kamath PS, King BF, Torres VE, Somlo S. Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease. Am J Hum Genet 2003; 72: 691–703. Davila S, Furu L, Gharavi AG, Tian X, Onoe T, Qian Q, Li A, Cai Y, Kamath PS, King BF, Azurmendi PJ, Tahvanainen P, Kaariainen H, Hockerstedt K, Devuyst O, Pirson Y, Martin RS, Lifton RP, Tahvanainen E, Torres VE, Somlo S. Mutations in SEC63 cause autosomal dominant polycystic liver disease. Nat Genet 2004; 36: 575–7. Epub 9 May 2004. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 2003; 33: 129–37. Thibonnier M, Coles P, Thibonnier A, Shoham M. The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists. Annu Rev Pharmacol Toxicol 2001; 41: 175–202. Parfrey PS, Davidson WS, Green JS. Clinical and genetic epidemiology of inherited renal disease in Newfoundland. Kidney Int 2002; 61: 1925–34. Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, Scambler PJ, Davidson WS, Beales PL, Lupski JR. Triallelic inheritance in Bardet–Biedl syndrome, a Mendelian recessive disorder. Science 2001; 293: 2256–9. Wu F, Roche P, Christie PT, Loh NY, Reed AA, Esnouf RM, Thakker RV. Modeling study of human renal chloride channel (hCLC-5) mutations suggests a structural–functional relationship. Kidney Int 2003; 63: 1426–32. Pavlovich CP, Schmidt LS, Phillips JL. The genetic basis of renal cell carcinoma. Urol Clin North Am 2003; 30(3): 437–54, vii.

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25. Reiter LT, Potocki L, Chien S, Gribskov M, Bier E. A systematic analysis of human disease-

associated gene sequences in Drosophila melanogaster. Genome Res 2001; 11: 1114–25. 26. Gao X, Pan D. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell

growth. Genes Dev 2001; 15: 1383–92. 27. Potter CJ, Huang H, Xu T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin

signaling in regulating cell growth, cell proliferation, and organ size. Cell 2001; 105: 357–68. 28. Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 2001; 105: 345–55.

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15 Renal physiology: acid-base, potassium, calcium and blood pressure ROBERT UNWIN, PEDRO CUTILLAS, GIOVAMBATTISTA CAPASSO

Introduction Renal physiology is still (perhaps) more about studying renal (excretory and hormonal) function in health and disease than about renal disease processes per se. However, developments in renal physiology now permeate almost all aspects of renal medicine as a result of the many recent, and often spectacular, advances in molecular genetics and their successful application to various familial forms of renal disease. Several of these have been to do with glomerular filtration and the filtration barrier, and with the renal tubule and its many transport functions. However, this exciting progress in our understanding of renal physiology did not come out of the blue, solely as a result of progress in molecular biology and genetics, but stemmed from a multifaceted and laboriously achieved foundation in renal physiology. Indeed, the breakthroughs in renal water handling (progress in understanding vasopressin’s cellular action and the identification of aquaporins) that led to the characterization of the now diverse forms of nephrogenic diabetes insipidus and the mechanistic details of electrolyte handling that underlie the distinctions between Gitelman’s and Bartter’s syndromes (which are still evolving), as well as the various forms of renal tubular acidosis, all had their origins in improved and established cellular models of fluid and electrolyte handling along the nephron. Without this prior knowledge, in renal tubular physiology at least, the molecular genetic advances would not have been so rapid or so dramatic. However, the enormous power and range of molecular tools now available to us and their application to rare clinical disorders of renal function have provided novel insights into aspects of renal function that were only guessed at, or not even suspected. Examples are Dent’s disease and new insights into the way in which the proximal tubule handles filtered proteins 1, magnesium losing nephropathy (with hypercalciuria and nephrocalcinosis) and the properties of the paracellular reabsorptive pathway for divalent cations 2 and, more recently, Gordon’s syndrome and the functions of as yet poorly understood novel ‘regulatory’ proteins in NaCl reabsorption and hypertension 3. There are also examples in between, © Atlas Medical Publishing Ltd

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where the underlying molecular defect was suspected and confirmed, but which in turn shed light on control mechanisms; for example, in pseudo-hypoaldosteronism type I and the renal epithelial sodium channel (ENaC), so important in fine-tuning whole-body sodium homeostasis 4. How can we make use of all this new information? An obvious next step is to try to relate a given molecular defect, in its various forms (mutations), to the clinical phenotype, and to see if more subtle defects, polymorphisms perhaps, are relevant to the wider ‘normal’ population; say, for example, in relation to pharmacogenetics and diuretic drug responses, or to common clinical problems such as renal stone disease. Attempts are being made to do this, but are limited by the rarity of many of these inherited tubular disorders (and the occasional disagreement over what constitutes the real phenotype, as originally described) on the one hand, and, on the other, access to well-defined patient populations in which familial patterns can be looked for, as well as the resources needed to do this. Finally, the production of transgenic animal (mainly mouse) models (‘knockouts’ in the case of loss of function gene mutations) is proving of great interest. Moreover, from the few published studies to date, these mouse models are also giving rise to some unexpected surprises and do not always seem to replicate closely the phenotype of their human equivalent. There is no doubt that the reciprocity arising from the study of normal renal function and clinical renal disorders is proving highly productive, and offers some exciting insights that may even extend beyond the kidney. Indeed, the renal tubule is beginning to compete, just a little, with the pre-eminence in clinical nephrology of the glomerulus! Nevertheless, to summarize research in renal physiology over the last 12 months is an almost impossible task, given what it can encompass and the enormous number of associated publications. Therefore, we have had to be highly selective and we have chosen articles that provide something of the flavour of current progress and directions in renal physiology—although our choices inevitably reflect some personal bias. The main theme of our selection is proteomics and ways in which new methods of protein detection and analysis are being applied to studies of renal physiology and pathophysiology.

The application of proteomics to renal physiology The subject known as proteomics, which follows on from genomics, is an important area of current and future progress in biological research. The proteome can be defined as the set of gene products (proteins) present in a biological specimen (a cell type, a tissue, an organ, or a biological fluid) under a defined set of conditions. In contrast to the genome, the proteome is dynamic, because gene expression changes during development and will vary within and between sources. The proteome of a tissue or biological fluid may also change under pathological conditions, potentially providing a basis for the early detection of disease. In a simple proteomic experiment, proteome patterns of healthy individuals (or control animals) can be compared with

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those of well-defined patient groups (or an animal model of disease). As long as consistent differences can be detected, these patterns might aid diagnosis as well as offering clues as to pathogenesis. Furthermore, if the genes that exhibit altered expression can be identified and shown to have an aetiological role in disease progression, their protein products may eventually prove to be suitable targets for drug development. The methodology of proteomics is not yet as well established as that of genomics, because at present different laboratories use different analytical techniques, which are themselves under constant development. Typically, the proteomes to be compared (e.g. urine from healthy subjects versus patients or controls versus an experimental model in the case of animal studies) are visualized using a method known as two-dimensional gel electrophoresis (2DE), which produces gel maps, and these can be compared using bioinformatics software. The identities of specific proteins detected as showing an altered level of expression can be determined by mass spectrometry (MS). However, several problems concerning reproducibility and bias of the 2DE approach have recently been identified 5 and other MS-based approaches have been developed. In one such method – liquid chromatography-tandem mass spectrometry (LC-MS/MS) – proteins are analysed directly without the need for gel electrophoresis. A problem with both these MS-based methods is that they are time-consuming and labour-intensive. A method known as surface-enhanced laserdesorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), in which proteins and peptides can be analysed directly by MS in a form compatible with highthroughput sample analysis, has recently been commercialized. We review first three papers that have each used one or other of the methods briefly outlined above to investigate the proteome of urine, and then four publications that have used an immunodetection approach to identify altered expression of specific and known proteins involved in renal salt and water transport. As it uses a readily available biological fluid, analysis of urine is the least intrusive method for the indirect study of renal function and disease. There is still little evidence that the ureter and/or lower urinary tract alter urine composition significantly, but there is growing evidence that urine itself may be biologically active and (as nephron tubular fluid) both reflect and affect renal function in health and in disease.

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Urine protein proﬁling with surface-enhanced laser-desorption/ionization time-of-ﬂight mass spectrometry Schaub S, Wilkins J, Weiler T, Sangster K, Rush D, Nickerson P. Kidney Int 2004; 65: 323–32

B A C K G R O U N D . Urine is a complex chemical mixture containing many organic and inorganic salts that interfere with protein analysis by conventional methods of MS, such as MALDI-TOF MS (matrix assisted laser desorption/ionization time-of-ﬂight MS). To get around this problem, proteins in urine can be desalted using several methods, including

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chromatography, in which proteins are retained in a solid support while the salts are washed away. Subsequently, proteins are eluted from the solid support material using an appropriate solvent. This process effectively separates proteins from other urinary constituents so that they can be analysed by MALDI-TOF MS. In a novel variation of MALDI-TOF MS, termed SELDI-TOF MS, the chromatographic material forms part of the hardware that is the mass spectrometer and this clean-up step can be done much faster and reproducibly, which are two important requirements for diagnosis and identiﬁcation of protein patterns that might reﬂect altered (patho-)physiological states. This paper by Schaub et al. investigated the effect of several parameters on the reproducibility and overall performance of urinary peptide analysis by SELDI-TOF MS. I N T E R P R E T A T I O N . Urinary protein proﬁles, which were reproducible even after urine storage and three freeze–thaw cycles, consisted of about 30 proteins. Protein patterns were similar in ﬁrst-void and midstream male urine specimens, whereas these patterns differed in females. Data are presented showing that the observed intensity (signal strength) of a protein in MS did not correlate with the concentration of this protein in the original sample.

Comment The approach of SELDI-TOF MS to obtain protein profiles is in principle an attractive one, since only a few microlitres of sample are normally needed for analysis. However, an important limitation of the technique is that it detects only a subset of proteins present in a sample. This report describes the detection of about 30 molecular weight values that might correspond to the same number of proteins, but this contrasts with other reports on the proteome of urine, which have shown that there are several hundred proteins in this biological fluid. Thus, using SELDI-TOF MS as a basis for renal disease diagnosis may only be possible if there is an alteration in the level of at least one of the 30 proteins identified in this way. Another limitation of SELDI-TOF MS is that it does not identify the nature of the proteins detected (only their molecular weight is reported). In contrast, other MS-based methods are capable of detecting and sequencing hundreds of peptides in a single analysis. Unfortunately, due to limited throughput, these methods (e.g. LC-MS/MS) may not be suitable for studies involving large sample numbers. More research on the technical aspects of proteomics is still needed to fully analyse and exploit the potential of urine as both a diagnostic tool and a means of studying renal function in vivo.

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Sodium loading changes urinary protein excretion: a proteomic approach Thongboonkerd V, Klein JB, Pierce WM, Jevans AW, Arthur JM. Am J Physiol Renal Physiol 2003; 284: F1155–63

B A C K G R O U N D . Thongboonkerd et al. tested the hypothesis that a physiological manipulation of a whole animal (the rat) such as a sodium (NaCl) load would alter its urinary proteome and that any changes in urine composition might reﬂect changes in

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renal tubular cell transporter protein expression (see later). Rats were given deionized water followed by 2.7% saline to drink for 28 h. Urine was collected before and after sodium loading and proteins isolated by ultracentrifugation. Previous studies had shown that ultracentrifugation of urine isolates a ‘membrane fraction’ in which several sodium transport proteins are enriched 6. Protein patterns were compared by 2DE and the identity of the proteins showing an altered level of excretion was determined by MALDI-TOF MS. I N T E R P R E T A T I O N . A total of 45 proteins showed an altered pattern of excretion after NaCl loading. Many of these corresponded to isoforms of the same gene product. Several proteins that form part of the cell cytoskeleton, such as actin and ezrin, were excreted in lower amounts, whereas others, such as albumin and calbindin, were present in higher amounts, in urine from NaCl-treated rats.

Comment This paper demonstrates the use of 2DE to explore the excretion of proteins after a physiological disturbance and/or adaptation. The changes observed in the excretion of proteins after NaCl loading probably do reflect altered expression of these proteins in renal tubular cells. However, although previous papers with a similar goal have used immunochemistry to identify sodium transporters in urine, these were not identified in this study; this may be due to an important limitation of this approach, which is that, because of their hydrophobicity, most membrane proteins do not enter the gels used for 2DE 7. Consequently, comprehensive proteomic analysis still requires methods that are complementary to 2DE.

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Detection and analysis of urinary peptides by on-line liquid chromatography and mass spectrometry: application to patients with renal Fanconi syndrome Cutillas PR, Norden AG, Cramer R, Burlingame AL, Unwin RJ. Clin Sci (Lond) 2003; 104: 483–90

B A C K G R O U N D . The renal Fanconi syndrome is characterized by a defect in the reuptake of several ﬁltered solutes in the proximal tubule, including small peptides and proteins, and is usually associated with progressive renal failure. Although the genetic causes of some of the conditions leading to the renal Fanconi syndrome are known at the molecular level, the mechanisms leading to kidney failure are still unclear. One working hypothesis is that bioactive low molecular weight peptides and proteins derived from plasma and present in the tubular ﬂuid might be the cause of this renal failure. In this paper, a combination of chromatography and MS was used to analyse the urinary proteome of renal Fanconi patients in order to explore which peptides might potentially have a role in this process. I N T E R P R E T A T I O N . Almost 200 different polypeptides were detected in the urine of renal Fanconi patients and in control subjects. Several cytokines (e.g. insulin-like growth

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factor [IGF]-I, IGF-II and bone morphogenic protein [BMP-1]) and chemokines (e.g. chemokines 3 and 15) were detected in Fanconi urine, but not in normal urine, when the analysis was standardized to creatinine content.

Comment Receptors for some of the peptides identified in these analyses (e.g. IGF-II) have been reported to be located at the apical membrane of tubular cells. In Fanconi patients, these receptors may be overstimulated, and this might contribute to a defect in normal regulation of cell signalling and gene expression. This paper identified some of the bioactive peptides with potential roles in this process and provides an example of a relatively comprehensive proteomic analysis that does not require gel electrophoresis. The limitation of this approach is that, by itself, it does not provide quantitative information, so that the analysis is really only qualitative. Nevertheless, this limitation may be overcome by combining this approach with isotopic labelling of proteins and peptides prior to their analysis by mass spectrometry, as has been demonstrated in other settings 8.

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Glomerular hyperﬁltration and the salt paradox in early type 1 diabetes mellitus: a tubulo-centric view Vallon V, Blantz RC, Thomson S. J Am Soc Nephrol 2003; 14: 530–7

B A C K G R O U N D . Diabetes mellitus is today the leading cause of end-stage renal disease. The pathogenesis of diabetic nephropathy is poorly understood, but it is recognized that glomerular hyperﬁltration and kidney growth are early events in diabetes and precede eventual glomerulosclerosis. Up to now, glomerular hyperﬁltration has been attributed to abnormalities of the glomerulus and preglomerular vasculature, although speciﬁc mechanisms have not been fully delineated 9. On the other hand, kidney enlargement, a feature of diabetes, is characterized by kidney growth due to hyperplasia and hypertrophy, mediated mainly by an increase in size and length of the proximal tubule 10. Glomerular hyperﬁltration and kidney growth are so closely associated that it is not possible to establish cause or effect. In this paper, the authors propose a unifying model: as the tubule grows, more of the glomerular ﬁltrate is reabsorbed and less reaches the macula densa cells, which then increases the glomerular ﬁltration rate (GFR) via the normal physiological mechanism of tubulo-glomerular feedback. I N T E R P R E T A T I O N . Using the renal micropuncture technique in streptozotocin (STZ)treated diabetic rats (a model of insulin-deﬁcient diabetes mellitus), the authors found that along the segments proximal (upstream of) the macula densa, there was an increase in fractional reabsorption. Such results suggest that an increase in reabsorption by the proximal nephron is a primary event, leading to glomerular hyperﬁltration. The underlying molecular mechanism that might be responsible for this effect is the upregulation of the 2 Na+-glucose cotransporters, SLGT1 and SLGT2 (sodium-dependent glucose transporters 1 and 2), which may be activated by the increase in ﬁltered glucose due to the hyperglycaemia of diabetes.

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Comment This is an important study and review for several reasons. It deals with a major clinical problem in renal medicine—diabetic nephropathy—a growing cause of endstage renal disease which is still poorly understood. Experimental evidence is cited showing that, in early insulin-dependent diabetes, there is a primary increase in fluid and electrolyte reabsorption along the proximal tubule, suggesting that this increase in reabsorption is not a consequence of glomerular hyperfiltration per se (by the mechanism known as glomerulo-tubular balance), but is present even after controlling for differences in GFR. Simply stated, glomerular hyperfiltration in early diabetes is caused by primary tubular hyper-reabsorption (therefore, the problem is tubular and not glomerular), which entrains a normal physiological response, the activation of tubulo-glomerular feedback, which in turn increases GFR (Fig. 15.1). The potential therapeutic implications thus depend on understanding why the proximal tubule hyper-absorbs in the first place and if this is linked in some way to its almost exclusive role in normal glucose reabsorption. One possibility is to block glucose absorption using inhibitors of the Na+-coupled glucose transporter SLGT to try and prevent the effect of hyperglycaemia and the associated increase in the filtered load of glucose from stimulating proximal tubule reabsorption. However, one criticism of this analysis is that other transporters (including transporters of glucose and Na+) that are also present upstream of the macula densa could be upregulated in early diabetes: examples are isoform 3 of the Na+/H+ exchanger (NHE3) and the bumetanide-sensitive Na+–K+–2Cl– cotransporter (NKCC2 or BSC1); recent findings seem to support this, as discussed next.

Fig. 15.1 Proposed model of glomerular hyperﬁltration in diabetes mellitus. (1) Primary increase in proximal tubule sodium and ﬂuid reabsorption. (2) Subsequent decrease in sodium and chloride delivery to the macula densa (MD). (3) Consequent increase in single-nephron GFR (SNGFR). Source: Vallon et al. (2003).

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Increased renal ENaC subunit and sodium transporter abundances in streptozotocin-induced type 1 diabetes Song J, Knepper MA, Verbalis JG, Ecelbarger CA. Am J Physiol Renal Physiol 2003; 285: F1125–37

B A C K G R O U N D . Uncontrolled diabetes mellitus can be associated with copious urinary losses of water and Na+, because of the osmotic diuretic effect of heavy glycosuria. The purpose of this study was to investigate possible adaptive (compensatory) changes in the protein abundance of Na+ and water transporters, and of channels, expressed along the renal tubule, which might limit the salt and water losses. Results were correlated with the severity of diabetes, as well as with the effect of corrective insulin treatment. The STZ rat model of diabetes was again used (see above). Sprague-Dawley rats were given an intraperitoneal injection of STZ (65 mg/kg). In the early phase (ﬁrst 4 days) of uncontrolled diabetes, there was a signiﬁcant increase in band densities for NHE3, the thiazide-sensitive NaCl cotransporter (NCC) and the ENaC subunits , and . A strong correlation was found between blood glucose levels and protein abundance of aquaporin 3 (AQP3), the bumetanide-sensitive Na+–K+–2Cl– cotransporter (NKCC2 or BSC1) and -ENaC. I N T E R P R E T A T I O N . Using a targeted proteomic (see above and later) approach, the authors found that the kidney can adapt to salt and water losses associated with diabetes by upregulation of speciﬁc Na+ and water transport proteins. These changes include upregulation of both proximally and distally (nephron) located Na+ transporters, including ENaC, most probably mediated by an increase in the activities of aldosterone and vasopressin. In addition, several other types of AQP were also upregulated. These changes are probably critical for the maintenance of extracellular ﬂuid balance in the face of large and osmotically driven ﬂuid and electrolyte losses.

Comment As noted, glycosuria, a defining feature of both type 1 and type 2 diabetes mellitus, can cause osmotic diuresis, leading to renal salt and water losses. In a widely used model of type 1 diabetes mellitus, the authors controlled for the potential renal toxicity of STZ by including a group of STZ-treated rats maintained relatively euglycaemic with insulin. Their results demonstrate that all the parameters they chose to measure, including urinary volume, osmolality, kidney size and the protein abundance of specific solute and water transporters, and channels, were not affected by STZ per se, and therefore any changes observed could be attributed to the state of uncontrolled diabetes. However, there was one exception: the expression of NHE3 in the early stages of diabetes seemed to increase, perhaps to eliminate STZ from the kidney. This is an interesting observation in itself. The second important finding of this study was the effect of diabetes on the renal abundance of the ENaC subunits. In general, all three subunits of ENaC were increased in diabetes. This might be explained by the associated increases in aldosterone and vasopressin activities, as a consequence of the

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salt and water losses. The most remarkable increase (>3-fold) in a Na+ transporter in diabetes was in NKCC2. However, these results are at odds with the study of Nejsum et al. 11, which reported no significant increase, but consistent with that of Kim et al. 12, who found a ~2-fold increase in NKCC2 abundance after 20 days of diabetes. Finally, the effect of STZ-induced diabetes on renal abundance of AQPs showed upregulation of both AQP2 and AQP3, changes expected to be an adaptive response to increased vasopressin levels to mitigate the fluid losses in diabetes.

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Altered expression of major renal Na transporters in rats with unilateral obstruction Li C, Wang W, Kwon T-H, Knepper MA, Nielsen S, Froklaer J. Am J Physiol Renal Physiol 2003; 284: F155–66

B A C K G R O U N D . It is well known that during recovery from urinary tract obstruction there is a marked reduction in the ability of the kidney to concentrate urine and to conserve salt, an effect that is probably due to a dysregulation of renal Na+ transport. In this study, changes in expression of the key renal Na+ transporters were examined in a rat model after 24 h of unilateral ureteric obstruction (UUO), to explore the molecular basis of the marked natriuresis occurring after release of obstruction. Urine collection after relief of UUO showed a signiﬁcant reduction in urine osmolality, solute-free water reabsorption (increased free water clearance) and marked natriuresis. Consistent with these ﬁndings, immunoblotting and immunocytochemical studies demonstrated signiﬁcant reductions in the abundance of the major renal Na+ transporters: NHE3; the ‘sodium pump’ (Na+,K+-ATPase); the type 2 Na+-phosphate cotransporter (NaPi-2); the type 1 bumetanide-sensitive Na+-K+-2Cl- cotransporter (NKCC2 or BSC1); and the thiazide-sensitive Na+–Cl– cotransporter (NCC). In the non-obstructed contralateral kidney, a signiﬁcant reduction in the abundance of the inner medullary Na+,K+-ATPase and cortical NaPT2a was also found. I N T E R P R E T A T I O N . Again, using their targeted proteomic approach (see earlier), these investigators have demonstrated that in rats with UUO, downregulation of the main renal Na+ transporters, including those critical to the countercurrent concentrating mechanism of the thick ascending limb of Henle’s loop, contributes to the impaired urinary concentrating ability and natriuresis that follows relief of renal obstruction. Moreover, the reduced levels of Na+,K+-ATPase and NaPi-2 in the contralateral non-obstructed kidney might be related to a compensatory increase in Na+ and water excretion during and after obstruction.

Comment Urinary tract obstruction has major effects on renal haemodynamics and tubular function, leading to significant fluid and electrolyte losses following its relief. This study demonstrates that in a rat model of UUO there is also impaired urinary concentrating ability and salt wasting in the obstructed kidney following release of the obstruction. At the same time, the expression of several key renal Na+ transporters

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(NHE3, NaPT2a, Na+,K+-ATPase, BSC1 and NCC) was significantly downregulated in the obstructed kidney, indicating that reduction in expression of these transport proteins is probably the basis for the functional changes observed (Fig. 15.2). Thus, reabsorption of Na+ was severely impaired along the nephron. Previous studies in this model have revealed that the main defects in renal tubular Na+ reabsorption are in the distal nephron: renal micropuncture studies have shown diminished net reabsorption of both Na+ and water between the loop of Henle and the beginning of the papillary collecting duct 13,14. But a novelty of this study is that changes in the proximal nephron (in NHE3 and NaPT2a), at least at the protein expression level, also occur. In the contralateral non-obstructed kidney, immunoblotting also revealed reduced expression of Na+,K+-ATPase in the inner medulla and reduced expression of NaPi-2a in the proximal tubule. Interestingly, this was associated with an increase in excretion of Na+ and of phosphate during and after release of UUO. These findings demonstrate nicely a correspondence between the expression of Na+-coupled transporters and altered renal function, and also that segmental changes in Na+ and phosphate transporter expression occur in both the obstructed and the non-obstructed kidney in UUO.

Fig. 15.2 Semiquantitative immunoblots of the bumetanide-sensitive Na+-K+-2Clcotransporter (BSC1) from UUO and sham-operated rats. Note that in obstructed kidneys there is a marked decrease in BSC1 abundance (a, b), while BSC1 abundance is unchanged in non-obstructed kidneys compared with sham-operated controls (c, d). Source: Li et al. (2003).

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Renal expression of sodium transporters and aquaporin-2 in hypothyroid rats Schmitt R, Klussmann E, Kahl T, Ellison DH, Bachmann S. Am J Physiol Renal Physiol 2003; 284: F1097–104

B A C K G R O U N D . Hypothyroidism is associated with signiﬁcant abnormalities in the renal handling of salt and water. To investigate the involvement of tubular transport proteins in these defects, rats were rendered pharmacologically hypothyroid and the abundance of major tubular transport proteins was assessed by immunoblot and immunohistochemistry. Hypothyroidism was associated with a signiﬁcant decrease in NHE3 and NaPT2a, while NKCC2 and the water channel AQP2 were unaltered in their total kidney abundance, despite markedly reduced renal mass. Indeed, the latter proteins showed enhanced immunostaining. On the other hand, the thiazide-sensitive Na+-Cl– cotransporter (NCC), the , and subunits of the epithelial Na+ channel (ENaC) and the 1 subunit of Na+,K+-ATPase showed a moderate decrease in total kidney abundance that was in keeping with the reduced kidney mass (Fig. 15.3). I N T E R P R E T A T I O N . This paper demonstrates that experimental hypothyroidism is associated with decreased abundance of renal Na+ entry pathways, along with a reduction in creatinine clearance (as a measure of GFR), increased fractional excretion of Na+, increased vasopressin excretion and polyuria. The reduction in NHE3 and NaPT2a is likely to be related to the low T3 (tri-iodothyronine) levels, as well as the reduced GFR, while the increases in NKCC2 and AQP2 probably reﬂect vasopressin-induced adaptation of the tubule to preserve Na+ and water balance. The changes observed were largely corrected by substitution of exogenous T3.

Comment Hypothyroidism is characterized by an impairment of renal function that includes a reduction in GFR, reduced diluting and concentrating ability, and exaggerated natriuresis in response to salt and water loading. In this study, it is shown that rats with methimazole-induced hypothyroidism have a major deficit in whole-body and kidney weight gain, reduced creatinine clearance, and a marked increase in urinary output, and fractional excretion, of Na+. This was accompanied by changes in the expression of proteins related to Na+ and water transport. In fact, NHE3 and NaPT2a were decreased while NKCC2 and AQP2 were unchanged (on immunoblot) or, more convincingly, increased (on immunostaining). The parallel reductions in NHE3 and NaPT2a along the proximal tubule are in agreement with previous findings 15 and this confirms earlier published data obtained by renal micropuncture 16. With respect to the increase in NKCC2 and AQP2, it is probably not related to T3 deficiency but rather to the enhanced secretion of vasopressin. This hormone can affect the expression of various Na+ transporters, including NKCC2, and regulates water channel abundance in the collecting duct. As the authors have measured

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Fig. 15.3 Abundance of various sodium transporters and water channels in control and methimazole-treated rats. Source: Schmitt et al. (2003).

urinary vasopressin excretion, they have avoided any potential errors from shortterm variations in plasma vasopressin concentration induced by stress and other experimental conditions. However, a surprising result of this study was the finding that the abundance of the 1-subunit of Na+,K+-ATPase was reduced in proportion to kidney size and unchanged immunohistochemically, whereas previous data from various models of experimental hypothyroidism have shown clearly that there is a reduction in Na+,K+-ATPase activity 16.

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Response of proximal tubule sodium transporters to acute injury-induced hypertension Yang LE, Leong PKK, Ye S, Campese VM, McDonough AA. Am J Physiol Renal Physiol 2003; 284: F313–22

B A C K G R O U N D . An acute injection of phenol into the lower pole of a kidney produces an immediate increase in noradrenaline secretion from the posterior hypothalamus, reﬂexly increasing renal sympathetic activity and provoking a rapid onset and persistent form of hypertension. This paper tried to determine if phenol injury provoked a redistribution of proximal tubule Na+ transporters from a cytosolic pool (inactive state) to the apical surface (active state), mediated by the sympathetic activation, and that this contributed to the generation and/or maintenance of the associated hypertension. To this end, rats were injected with 50 l of 10% phenol; the kidneys were then removed and renal cortical membranes fractionated into three pools containing, respectively, apical brush borders, dense apical tubes and intracellular membranes. The acute phenol injury increased blood pressure, which was associated with a redistribution of NHE3 from intracellular to apical membranes (Fig. 15.4). Such a change could be prevented by renal denervation prior to phenol injection. I N T E R P R E T A T I O N . The results of this study support the hypothesis that acute intrarenal phenol injection provokes a redistribution of proximal tubule NHE3 from a subapical endosomal pool to the apical brush border, and that this may contribute to the onset and persistence of phenol injury-induced hypertension.

Comment There is now a lot of evidence in support of a role for increased sympathetic nerve activity in ‘renal’ hypertension, e.g. in renal artery stenosis and in chronic renal failure 17. This has also been reinforced by the development of a rat model of renal injury leading to increased central noradrenaline secretion and enhanced renal sympathetic nerve activity and hypertension. The injury itself is not sufficiently destructive to severe renal injury and hypertension, because renal denervation before phenol injection can prevent the rise in blood pressure. However, the presence of the phenol-injected kidney is necessary for the development of chronic hypertension, since its removal at 4 weeks normalizes blood pressure, probably as a result of loss of renal afferent stimulation 18. The present study extends these observations by investigating potential underlying molecular mechanisms affecting proximal tubule Na+ transport, long known to be stimulated by increased renal sympathetic activity, in this model of neurogenic hypertension. Acute phenol injection provoked a rapid redistribution of NHE3 to apical membrane microvilli, a response that might contribute to the generation, or maintenance, of hypertension in this model. An important question that remains to be answered is whether the redistribution of NHE3, or other Na+ transporters (not examined in this study), along the proximal tubule is really associated with a significant increase in proximal tubule fluid reabsorption.

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Fig. 15.4 Redistribution of NHE3 to low-density membranes in response to phenol injection and inhibition by prior denervation. The membranes were pooled in three windows: 1 (fractions 3–5) is enriched in apical brush-border membranes; 2 (fractions 6–8) contains mixed membranes; 3 (fractions 9–11) is enriched in endosomal membranes. (a) Typical immunoblots for NHE3 of each fraction from saline vs phenol treated (injected animals) renal cortices. (b) A summary of NHE3 distribution in each window expressed as a percentage of the total signal. (c) Results of the experiments in which the left kidney was denervated before phenol injection. Source: Yang et al. (2003).

Indeed, in the present study, the hypertension caused by acute phenol injury did not cause a significant change in urine volume or in endogenous lithium clearance (an indirect measure of proximal tubule sodium, and therefore fluid, reabsorption). Moreover, the hypertension evoked by the acute phenol injection does not lead to the usual compensatory response known as ‘pressure natriuresis’, or to the large

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increase in lithium clearance seen during vasoconstrictive hypertension, suggesting that the normal renal response curve is in some way re-set 19.

Conclusion What is becoming clear is that methods of protein detection, so much more likely to be functionally relevant than corresponding mRNA levels, be it immunologically or by mass spectrometry, will, in the case of renal physiology, significantly advance our understanding of normal and abnormal adaptive changes in function, and identify new potential regulatory factors. The use of specific antibodies to monitor alterations in solute and water transporters along the nephron under various physiological or pathological conditions is best exemplified by the recent studies by Knepper 20. While this approach has great specificity, it depends on knowing in advance what to look at (and the panel of antibodies available and their properties), and at least some preconception of how nephron transport function might be integrated. In contrast, the MS-based approach can be applied blind to any biological sample, although the wealth of information that results now depends on comprehensive and sophisticated bioinformatics for analysis. However, these approaches are almost certainly complementary and will not only confirm and refine existing models of renal fluid and electrolyte transport and their regulation, but will also reveal their complexity and thereby improve our understanding 21.

References 1. Norden AG, Lapsley M, Igarashi T, Kelleher CL, Lee PJ, Matsuyama T, Scheinman SJ,

Shiraga H, Sundin DP, Thakker RV, Unwin RJ, Verroust P, Moestrup SK. Urinary megalin deficiency implicates abnormal tubular endocytic function in Fanconi syndrome. J Am Soc Nephrol 2002; 13: 125–33. 2. Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 1999; 285: 103–6. 3. Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP. Human hypertension caused by mutations in WNK kinases. Science 2001; 293: 1107–12. 4. Rotin D. Regulation of the epithelial sodium channel (ENaC) by accessory proteins. Curr Opin Nephrol Hypertens 2000; 9: 529–34.

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5. Gygi SP, Corthals GL, Zhang Y, Rochon Y, Aebersold R. Evaluation of two-dimensional

6. 7. 8.

9. 10. 11.

12.

13. 14. 15. 16. 17. 18.

19. 20. 21.

gel electrophoresis-based proteome analysis technology. Proc Natl Acad Sci USA 2000; 97: 9390–5. Mckee JA, Kumar S, Ecelbarger CA, Fernandez-Llama, P, Terris J, Knepper MA. Detection of Na+ transporter proteins in urine. J Am Soc Nephrol 2000; 11: 2128–32. Santoni V, Molloy M, Rabilloud T. Membrane proteins and proteomics: un amour impossible? Electrophoresis 2000; 21: 1054–70. Gygi SP, Rist B, Gerber SA, Turecek F, Gelb MH, Aebersold R. Quantitative analysis of complex protein mixtures using isotope-coded affinity tags. Nat Biotechnol 1999; 17: 994–9. Hostetter TH, Troy JL, Brenner BM. Glomerular hemodynamics in experimental diabetes mellitus. Kidney Int 1981; 19: 410–15. Rasch R, Dorup J. Quantitative morphology of the rat kidney during diabetes mellitus and insulin treatment. Diabetologia 1997; 40: 802–9. Nejsum LN, Kwon TH, Marples D, Flyvbjerg A, Knepper MA, Frokaer J, Nielsen S. Compensatory increase in AQP2, p-AQP2 and AQP3 expression in rats with diabetes mellitus. Am J Physiol Renal Physiol 2001; 280: F715–26. Kim GH, Ecelbarger CA, Mitchell C, Packer RK, Wade JB, Knepper MA. Vasopressin increases Na-K-2Cl cotransporter expression in thick ascending limb of Henle’s loop. Am J Physiol Renal Physiol 1999; 276: F96–103. Sonnenberg H, Wilson DR. The role of the medullary collecting duct in post-obstructive diuresis. J Clin Invest 1976; 57: 1564–74. Yarger WE, Aynedjian HS, Bank N. A micropuncture study of post-obstructive diuresis in the rat. J Clin Invest 1972; 51: 625–37. Cano A, Baum M, Moe OW. Thyroid hormone stimulates the renal Na/H exchanger NHE3 by transcriptional activation. Am J Physiol Cell Physiol 1999; 276: C102–8. Capasso G, De Santo NG, Kinne R. Thyroid hormones and renal transport: cellular and biochemical aspects. Kidney Int 1987; 32: 443–51. Grisk O, Rettig R. Interactions between the sympathetic nervous system and the kidneys in arterial hypertension. Cardiovasc Res 2004; 61: 238–46. Ye S, Zhong H, Yanamadala V, Campese VM. Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity. Am J Hypertens 2002; 15: 717–24. Guyton AC. Blood pressure control—special role of the kidneys and body fluids. Science 1991; 252: 1813–16. Knepper MA. Proteomics and the kidney. J Am Soc Nephrol 2002; 13: 1398–408. Cutillas P, Burlingame A, Unwin R. Proteomic strategies and their application in studies of renal function. News Physiol Sci 2004; 19: 114–19.

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16 Ethnicity and renal disease JEREMY LEVY

Introduction It has been recognized for some years in Europe, the USA and Australasia that populations of non-European origin have increased susceptibility to renal disease. With the increasing migration of ethnic minorities and the ageing of these populations, their prevalence of renal disease is increasing significantly, with huge implications for public health because of the cost of renal replacement therapy and of the associated cardiovascular morbidity. In developing countries a similar problem is related mostly to the epidemic of diabetes, the inability of poor countries to afford dialysis programmes, and hence the particular importance of preventing renal failure. The leading cause of the excess of renal disease in ethnic minorities is the massive increase in type 2 diabetes. In the UK, for example, in some cities 25% of the South Asian population over 65 years old now have type 2 diabetes. Similar (if not worse) figures are reported from Native Americans and Hispanics in the USA, Aborigines in Australia and Pacific Islanders. Some data also suggest that not only is diabetes increased in these populations, but the risk of end-stage renal failure in patients with diabetes is also greater than in Caucasians. However, it is not only diabetes which contributes to the excess of renal disease in ethnic minority populations. In London and Leicester (in the UK), for example, data from the 1980s showed that South Asian populations had a three-fold increased risk of non-diabetic end-stage renal failure. Australian Aborigines, too, have been well documented to have a large excess of both diabetic and non-diabetic disease causing end-stage renal failure. Differentiating genetic and environmental factors as the cause of this increased susceptibility has proved difficult. The public health challenge caused by the increased risk of renal disease in these populations is potentially enormous. End-stage renal failure increases with age in all populations, and many ethnic minorities currently consist of younger adults. Diabetes as the prime cause of end-stage renal disease (ESRD) is also increasing in prevalence with changing dietary habits, reduced exercise, etc. Outcomes for patients from ethnic minorities with established end-stage renal failure have been variable, with poorer survival reported in some countries, but not universally. In view of the high risk of renal disease in some populations, there has been much debate (but little data) © Atlas Medical Publishing Ltd

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on the potential value of screening for renal disease in selected groups of individuals, and the best approach. This last year has seen a number of exciting publications relating to these topics, from further epidemiology on the incidence and prevalence of renal disease in ethnic minority populations, differences in morbidity between different ethnic groups, data on the underlying potential causes of renal disease, and some early data on the potential value of screening and on the management of high-risk populations.

Epidemiology

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End-stage renal disease in Indo-Asians in the North-West of England Trehan A, Winterbottom J, Lane B, et al. QJM 2003; 96: 499–504

B A C K G R O U N D . In the UK the incidence of ESRD is increasing, and several retrospective studies have shown an increased incidence in people from South Asia. The South Asian population in the UK also has a high incidence of diabetes. This study looked prospectively at all patients starting dialysis in part of the UK with regard to their ethnic background and medical care prior to the need for dialysis, to determine to what degree the increasing demand for renal replacement therapy in the UK is due to Indo-Asian patients. The paper also aimed to study the presentation to renal services of Indo-Asian patients with ESRD and report any inequalities in initial treatment of Indo-Asian patients with ESRD compared with their white counterparts. I N T E R P R E T A T I O N . This was a prospective, inception cohort study. Consecutive adult patients with ESRD who started renal replacement therapy between 1 April 2000 and 31 December 2001 in all 14 renal units serving an area from North Cheshire to South Cumbria, including Greater Manchester and Lancashire, were recruited and interviewed. Of the 578 patients, 9.5% were Indo-Asian. The annual acceptance rate for renal replacement therapy was 342 per million population in Indo-Asians compared with 91 per million population in the white population (P <0.001). Table 16.1 shows the acceptance rates for renal replacement therapy in Asians and Caucasians compared to their populations and their age distribution. The acceptance rates for dialysis in the older patients were almost 10-fold higher in Indo-Asians, and the age distribution shows significantly fewer elderly Indo-Asians. Indo-Asian patients with ESRD were younger (median age 51 vs 60 years; P = 0.006) and more socially deprived (81 vs 36.5% in the fifth Carstairs quintile; P <0.001). A greater proportion of Indo-Asian patients with ESRD presented late to specialist renal services (31 vs 19%; P = 0.03). After adjustment for their younger age, atherosclerotic renovascular disease and/or hypertensive nephropathy was more prevalent in Indo-Asian patients (odds ratio [OR] 4.9; P = 0.03). There was no difference in the initial mode of maintenance dialysis or the perception of choice the patients felt they had, based on their ethnicity.

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Table 16.1 Age-specific acceptance for renal replacement therapy (RRT) and population by age and ethnic minority in Greater Manchester White

Indo-Asian

Age (years)

16–24 25–44

General population ( 1000)

239.1

Acceptance for RRT (per million)

54.4

45–64

65+

693.39 573.84 382.56 79.3

148.1

290.0

16–24 19.71 101.5

25–44 45–64 36.75

15.49

65+ 4.65

299.3 1032.9 1290.3

Source: Trehan et al. (2003).

Comment This study confirmed the silent epidemic of ESRD in Indo-Asian patients in the north-west of England, possibly vascular in aetiology, in which specialist intervention is late. This suggests that Indo-Asian patients should be prioritized for early intervention strategies to reduce the burden of ESRD. More importantly, it has shown that a greater proportion of these only come to medical attention with advanced renal failure compared with Caucasians. Opportunities for slowing the progression of chronic renal failure have therefore been lost, as have interventions to reduce the morbidity associated with chronic kidney disease (anaemia, hypertension, cardiac and bone disease), and a planned start to dialysis. This study reinforces the public health implications and the potential role for screening in this high-risk population. The demographic trends shown also predict a future increase in the rates of ESRD in Indo-Asians, since relatively few people in this study were elderly in whom the highest rates of renal failure were documented.

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Renal disease in relatives of Indo-Asian Type 2 diabetic patients with end-stage diabetic nephropathy Chandie Shaw PK, van Es LA, Paul LC, Rosendaal FR, Souverijn JHM, Vandenbroucke JP. Diabetologia 2003; 46: 618–24

B A C K G R O U N D . Many studies have demonstrated familial clustering of type 2 diabetes and, in some populations, a familial predisposition to diabetic nephropathy. The incidence of ESRD in diabetics has also been reported in many countries to be higher than expected in Asian patients. Indo-Asian immigrants in The Hague, The Netherlands, have a nearly 40-fold higher risk of end-stage diabetic nephropathy compared with the Caucasian population. This study aimed to find out if there was genetic susceptibility to nephropathy within the Indo-Asian population by investigating whether close relatives of patients with known type 2 diabetes had an increased incidence of nephropathy of any type. The Asian population in this study from Holland was mostly from Surinam.

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I N T E R P R E T A T I O N . The study compared the prevalence of nephropathy between two groups of first-degree relatives of Indo-Asian patients with type 2 diabetes. The first group (case relatives) consisted of 169 relatives of patients with end-stage diabetic nephropathy and the second group (control relatives) consisted of 161 relatives of diabetic patients who had no nephropathy. The case and control relatives were examined for diabetes, blood pressure, renal function, microalbuminuria and urine dipstick measurements. The mean age was 41 years and similar in the case and control relatives. Diabetes was distributed equally in the two family groups. Increased nephropathy was not found in first-degree relatives of Indo-Asian type 2 diabetic patients with end-stage diabetic nephropathy in comparison with the control relatives.

Comment This study could not detect genetic susceptibility for diabetic nephropathy within the Indo-Asian population in The Netherlands. The lack of familial clustering of renal disease in Indo-Asian diabetic patients pointed to a general genetic or environmental susceptibility for diabetic nephropathy in this population. A major problem with this study was the relatively high proportion of relatives who declined to participate or could not be contacted. Despite this, there was no difference in the prevalence of kidney disease in families of patients with type 2 diabetes with or without nephropathy, suggesting no specific genetic factor contributing to kidney disease specifically in this Asian population. However, since the overall risk of renal failure in Surinamese patients with diabetes is 40-fold higher than in Caucasians, this suggests that, overall, either the population as a whole has increased susceptibility to renal disease, or that environmental factors play a role. These results are different from those for other populations at high risk from renal disease and diabetes, such as the American Pima Indians.

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Ethnic differences among Chinese, Malay and Indian patients with type 2 diabetes mellitus in Singapore Hong CY, Chia KS, Hughes K, Ling SL. Singapore Med J 2004; 45: 154–60

B A C K G R O U N D . Ethnic differences exist in patients with diabetes mellitus, and Asian patients in many countries have been reported to be particularly susceptible to both diabetes and its complications. However, the term ‘Asian’ covers a huge geographic area and the populations so referred are not genetically, evolutionarily or environmentally homogeneous. The aim of the study was to determine ethnic differences among Chinese, Malay and Indian patients with type 2 diabetes mellitus in Singapore. I N T E R P R E T A T I O N . The study design was cross-sectional, involving 967 patients who were attending follow-up care for type 2 diabetes mellitus at a primary care clinic. Data collection was by patient interview and examination, and from case records. Blood and urine samples were collected for analysis of indicators of diabetic control and albuminuria. Malays had the highest mean body mass index after controlling for age, gender, duration of diabetes and exercise status. The adjusted mean body mass index was 27.4 kg/m2 for Malays, 25.7 kg/m2

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for Indians and 24.9 kg/m2 for Chinese (P <0.01). Haemoglobin A1c (HbA1c) levels were highest among Indians after controlling for age, duration of diabetes, body mass index and treatment. Adjusted mean HbA1c was 8.3% for Indians, 8.0% for Malays and 7.7% for Chinese (P <0.01). Compared with Chinese, Indians were more likely to have a positive family history of diabetes (prevalence rate ratio [PRR] 1.3; 95% confidence interval [CI] 1.0–1.7) but were less likely to have associated hypertension (PRR 0.7; 95% CI 0.5–1.0) and microalbuminuria and macroalbuminuria (PRR 0.6; 95% CI 0.4–1.0). Therefore, ethnic differences exist with regard to body mass index, diabetic control as reflected by HbA1c levels, family history of diabetes, the presence of associated hypertension and the severity of albuminuria. Indians, while having poorer control of diabetes, are less prone to hypertension and renal complications than Chinese.

Comment This study has shown a number of quite significant differences in the phenotypes and complications of patients with type 2 diabetes from three different Asian populations in Singapore. This sort of detailed analysis is important before considering public health interventions to try to reduce the problems associated with diabetes, and should also be considered when describing ethnic minority populations from around the world.

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Racial differences in diabetic nephropathy, cardiovascular disease, and mortality in a national population of veterans Young BA, Maynard C, Boyko EJ. Diabetes Care 2003; 26: 2392–9

B A C K G R O U N D . It has been reported previously that micro- and microvascular complications from diabetes occur with varying frequencies among different racial groups in the USA, but studies have often been confounded by socio-economic problems, access to healthcare, etc. This study examined a very large number of patients receiving care under the Veterans Affairs (VA), a large proportion of whom were African-American, but with equal access to healthcare through the VA service. Its aim was to determine racial differences in the prevalence of diabetic nephropathy and cardiovascular disease (CVD), and the risk of mortality in a national healthcare system. I N T E R P R E T A T I O N . This longitudinal cohort study was conducted in 429 918 veterans with diabetes. Racial minority groups were analysed for baseline differences in the prevalence of early diabetic nephropathy, diabetic ESRD and CVD, and longitudinal risk of mortality compared with Caucasians. The 429 918 patients identified with diabetes were of the following racial groups: Caucasian (56.2%), African-American (15.3%), Asian (0.5%), Native American (0.4%), and unknown race (21.4%). Minority individuals were, on average, younger and less likely to have CVD but were more likely to have renal disease than Caucasians. After adjustment for age, sex and economic status, African-Americans (adjusted OR 1.3; 95% CI 1.2–1.4) and Native Americans (OR 1.5; 95% CI 1.1–2.1) were more likely to have

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early diabetic nephropathy than Caucasians. Diabetic ESRD was more likely to be present in African-Americans (OR 1.9; 95% CI 1.9–2.0), Hispanics (OR 1.4; 95% CI 1.3–1.4), Asians (OR 1.8; 95% CI 1.5–2.1) and Native Americans (OR 1.9; 95% CI 1.5–2.3) than Caucasians. Concurrently, the adjusted OR of CVD in racial minority groups was 27–49% less than in Caucasians, whereas the 18-month risk of mortality among people from most racial minority groups was 7–12% lower than in Caucasians. Table 16.2 shows the odds ratios for renal and cardiovascular disease in the different racial groups. The authors concluded that, when access to care is comparable, microvascular complications, macrovascular disease and subsequent death occur with different frequencies among various racial groups.

Comment This study has included a huge number of patients and shows clear and interesting (but unexplained) differences in the complications from diabetes between Caucasians and African-Americans. However, the patients may have had a higher incidence of chronic ill health than the general population. These data may partly explain why mortality varies between racial groups with end-stage renal failure (often lower in African-Americans), and raise some suggestion of more rapid progression of chronic kidney disease in others.

Potential causes of renal disease in non-Caucasians

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Microalbuminuria is more frequent in South Asian than in European origin populations: a comparative study in Newcastle, UK Fischbacher CM, Bhopal R, Rutter MK, et al. Diabet Med 2003; 20: 31–6

B A C K G R O U N D . Microalbuminuria predicts renal failure in type 1 diabetes, probably in type 2 diabetes, and is an independent predictor of morbidity and mortality in patients with simple hypertension. Microalbuminuria predicts cardiovascular disease in populations of European origin, but evidence from the general population of South Asians is lacking. Mortality from coronary heart disease is 40–50% higher in UK South Asians than in the whole population, for reasons that are incompletely understood. Asian patients in the UK are at increased risk of both diabetic nephropathy and other renal diseases, the cause of which is unknown. This study examined urinary albumin excretion in non-diabetic South Asians compared with Europeans to see if differences in albumin excretion could partly explain the increased risk in Asians of renal disease. I N T E R P R E T A T I O N . Microalbuminuria was measured using the albumin–creatinine ratio in an age- and sex-stratified random sample of 1509 adults from European (n = 825), Indian (n = 259), Pakistani (n = 305) and Bangladeshi (n = 120) ethnic groups. Levels of urinary

1.0 1.5 (1.2–1.8) 2.0 (1.6–2.4)

1.0 2.4 (2.0–2.8) 3.4 (2.9–4.1)

1.0 1.5 (1.2–1.8) 1.8 (1.5–2.2)

1.0 1.3 (1.2–1.3) 0.7 (0.6–0.8) 0.8 (0.6–1.1) 1.4 (1.0–1.9)

Unadjusted

1.0 1.0 (0.8–1.2) (1.1 (0.8–1.3)

1.0 1.3 (1.2–1.4) 0.7 (1.6–1.8) 0.8 (0.5–1.1) 1.5 (1.1–2.1)

Adjusted*

Diabetic nephropathy

1.0 5.82 (5.35–6.31) 11.70 (10.78–12.70)

1.0 0.53 (0.52–0.54) 0.54 (0.53–0.56) 0.61 (0.56–0.67) 0.58 (0.53–0.64)

Unadjusted

1.0 3.99 (3.67–4.35) 7.14 (6.55–7.77)

1.0 0.51 (0.50–0.52) 0.58 (0.57–0.60) 0.67 (0.61–0.74) 0.73 (0.66–0.82)

Adjusted†

Cardiovascular disease

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Data are OR (95% CI). * Models adjusted for age, cardiovascular disease, hypertension, non-service connection, total number of visits, region, and sex. † Models adjusted for age, race, stroke, sex, presence of renal disease, COPD, hypertension, previous amputation, total number of visits, non-service connection, diabetic eye disease, and region. Source: Young et al. (2003).

1.0 1.9 (1.9–2.0) 1.4 (1.3–1.4) 1.8 (1.5–2.1) 1.9 (1.5–2.3)

1.0 1.9 (1.8–1.9) 1.2 (1.1–1.3) 1.8 (1.5–2.1) 1.5 (1.3–1.9)

Caucasian African American Hispanic Asian Native American Age category (years) <40 40–65 65–75

Adjusted*

Unadjusted

Covariate

ESRD

Table 16.2 Relative odds of diabetic nephropathy and cardiovascular disease by race and other covariates

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albumin excretion were substantially higher in South Asians (geometric mean albumin creatinine ratio 0.83; 95% CI 0.75–0.91) than in Europeans (0.55; 95% CI 0.51–0.60). Microalbuminuria was associated with older age, hypertension and diabetes, but independently of these risk factors urinary albumin excretion was higher in South Asians than Europeans.

Comment Urinary albumin excretion was higher and microalbuminuria more frequent in UK South Asians than in the majority ethnic population for individuals selected from the general population. The increased albumin excretion was not explained by hypertension or glucose intolerance. Whether this is a cause or consequence of the increased susceptibility to renal disease in South Asians is unknown, but suggests an important area for further investigation since microalbuminuria may be relevant to the causal pathways leading to the excess of cardiovascular mortality and possibly renal failure in UK South Asians.

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Kidney volume, blood pressure, and albuminuria: findings in an Australian aboriginal community Singh GR, Hoy WE. Am J Kidney Dis 2004; 43: 254–9

B A C K G R O U N D . Type 2 diabetes, hypertension and chronic kidney disease are now extremely common in Australian Aborigines, the precise cause being unknown. Renal disease is manifest initially as proteinuria. They also have high rates of low birth weight. One hypothesis is that low birth weight due to intra-uterine malnutrition may contribute to renal disease and hypertension by leading to nephron deficiency. This study examined kidney size (measured by ultrasound) in relation to blood pressure and albuminuria in this population at high risk for renal and cardiovascular disease. I N T E R P R E T A T I O N . Forty-three per cent (672 of 1560) of the population in a remote coastal Australian Aboriginal community aged 4.4–72.1 years participated in the study. Kidney size correlated closely with body size. Systolic blood pressure was correlated inversely with kidney length and kidney volume, after adjusting for age, sex and body surface area; a 1-cm increase in mean kidney length was associated with a 2.2-mmHg decrease in systolic blood pressure, and a 10-ml increase in mean kidney volume was associated with a 0.6-mmHg decrease in systolic blood pressure (P = 0.001). Figure 16.1 shows the inverse correlation of BP with kidney size in both adults and children. Mean kidney volume explained 10% of the variance in systolic blood pressure in a multivariate model containing age, sex and body surface area. In addition to higher systolic blood pressure, adults who had the lowest quartiles of kidney volume also had the highest levels of overt albuminuria (P = 0.044). Smaller kidneys predispose to higher blood pressure and albuminuria in this population. The lower volumes possibly represent kidneys with reduced nephron numbers, which might be related to an adverse intra-uterine environment. Susceptibility to renal disease could be a direct consequence of reduced nephron numbers; the higher blood pressures with which they are associated could also contribute to, as well as derive from, this association.

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Fig. 16.1 Systolic blood pressure and mean kidney volume, adjusted for age, sex, and body surface area in children and adults. Source: Singh and Hoy (2004).

Comment This study has shown that lower kidney volumes are correlated with higher blood pressure and overt albuminuria in Aboriginal adults. One of the difficulties is in accurately determining kidney volume by ultrasound, and relating this to overall body size. Lower kidney volumes are, however, undoubtedly associated with reduced nephron mass and probably number, but the link between this and progressive kidney failure and even hypertension is not fully elucidated. Previous studies in this population have shown that low birth weight is associated with smaller kidneys, so this study takes the link one stage further.

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C-reactive protein, cardiovascular risk, and renal disease in a remote Australian Aboriginal community McDonald S, Maguire G, Duarte N, Wang XL, Hoy W. Clin Sci 2004; 106: 121–8

B A C K G R O U N D . This study further examines the potential causes of the vast excess of chronic disease in the Australian Aboriginal community, especially cardiovascular disease. Traditional risk factors do not explain the excess morbidity and mortality. Inflammation has been recognized as an important marker of increased cardiovascular mortality, and higher CRP levels in general populations have been associated with increased cardiovascular disease and poor outcomes. This study

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examined the distribution of C-reactive protein (CRP) and other markers of inflammation and their relationships with cardiovascular risk markers and renal disease in a remote Australian Aboriginal community. I N T E R P R E T A T I O N . Two hundred and thirty-seven adults (58% of the adult population) in a remote Aboriginal community in the Northern Territory of Australia were included. Main outcome measures were CRP, fibrinogen and immunoglobulin G (IgG) concentrations, blood pressure, the presence of diabetes, lipids, albuminuria, seropositivity to three common microorganisms, and carotid intima–media thickness (IMT). Serum concentrations of CRP (median 7 mg/l, interquartile range 5–13 mg/l) were markedly increased and were significantly correlated with fibrinogen and IgG concentrations and inversely correlated with serum albumin concentration. Higher CRP concentrations were associated with IgG seropositivity to Helicobacter pylori and Chlamydia pneumoniae and higher IgG titre for cytomegalovirus. Higher CRP concentrations were associated with the following: the 45- to 54-year age group, female subjects, the presence of skin sores, higher body mass index, waist circumference, blood pressure, glycated haemoglobin and greater albuminuria. CRP concentrations increased with the number of cardiovascular risk factors, carotid IMT and albuminuria independently of other risk factors. Figure 16.2 shows the strong relationship between CRP and overall cardiovascular risk as measured by a simple scoring system. These CRP concentrations were markedly higher than described in other community settings and are probably related, in large part, to chronic and repeated infections. Their association with markers of cardiovascular risk and renal disease are compatible with the high rates of cardiovascular and renal disease in this community, and provide more evidence of strong links between these conditions, through a shared background of infection/inflammation. This suggests that a strong focus on the prevention and management of infections will be important in reducing these conditions, in addition to interventions directed at more traditional risk factors.

Fig. 16.2 CRP concentration by cardiovascular risk factor score. Values are geometric means ± 95% CI. Source: McDonald et al. (2004).

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Comment This study enrolled a huge proportion of a community population, and therefore has wide applicability in this setting. Although an Aboriginal population may not represent other ethnic groups, the study has widespread important implications. The differences from other populations are manifest, for example, in the much higher serum CRP levels measured here than have been documented in other studies, possibly because of a higher incidence of chronic infections (chest, skin and gastrointestinal). However, it is also possible that the higher CRP levels are a consequence of increased atherosclerotic disease. Overall, it is most likely that high CRP, caused by a variety of factors, is associated with the increased renal and cardiovascular morbidity without necessarily being the cause. Whether interventions specifically targeting CRP or its underlying cause will affect the incidence of renal and cardiovascular disease remains to be seen.

Management of high-risk populations

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Identification of persons at high risk for kidney disease via targeted screening: the NKF Kidney Early Evaluation Program Brown WW, Collins A, Chen S-C, et al. Kidney Int Suppl 2003; 83: S50–5

B A C K G R O U N D . Given the high prevalence of chronic kidney disease in the community (more than 340 000 individuals were receiving renal replacement therapy in the USA at the end of 1999; this number is projected to double by the year 2010) and the enormous cost, morbidity and mortality of ESRD, recent attention has focused on the potential value of screening populations for early kidney disease. Screening is not without risk, and it is important to establish the costs (not just financial) and the benefits that can be obtained. In general, there are no data that support widespread screening of healthy populations, but it may be that screening high-risk groups has more benefit. In the USA, almost half the patients with ESRD had a primary diagnosis of diabetes mellitus, and more than one-quarter a primary diagnosis of hypertension; in both these groups there are effective treatments which can prevent or delay the rate of progression of kidney disease and reduce morbidity and mortality. This study examined the US National Kidney Foundation’s pilot scheme for screening high-risk individuals. I N T E R P R E T A T I O N . In 1997, the National Kidney Foundation launched KEEP™ (Kidney Early Evaluation Program), a free community-based screening that targets first-order relatives of persons with hypertension, diabetes or kidney disease, and those with a personal history of diabetes or hypertension. Of the 889 individuals screened in the pilot study, 71.4% had at least one abnormality. Table 16.3 documents the number of individuals found to have abnormal results for either renal disease, hypertension or diabetes with or without a personal prior history of disease. The programme includes an educational component and referral to a physician for

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Table 16.3 Values outside the normal range for each screening test Single abnormal value—no prior history of disease Screening test

Abnormal value n of subjects

n of subjects

Percentage

Serum glucose Microalbuminuria Pyuria Haematuria Serum creatinine Diastolic hypertension Systolic hypertension Total

113 188 148 179 126 259 342

14 27 33 48 37 22 52 233

6.0 11.6 14.2 20.6 15.9 9.4 22.3 100.0

Source: Brown et al. (2003).

follow-up of abnormal values. Targeted screenings were an effective means of identifying persons at risk for kidney disease, and could identify individuals at risk early enough in the course of their disease to allow for effective intervention.

Comment This study has demonstrated an enormous pool of undiagnosed hypertension, renal disease and diabetes in high-risk individuals who might have been expected to have more education about the diseases since they all had a family or personal history. Overall, over 70% of screened individuals had some abnormality detected. A significant number of the screened individuals did go on to seek medical care, although a worrying factor was the high rate of non-confirmation by primary care physicians. Whether this represented the lack of appreciation of ‘mildly’ elevated blood pressure, or ‘minor’ urinary abnormalities is unclear since no data were obtained from the primary care physician. This pilot study has shown that screening high-risk individuals may be worthwhile, but it will require intervention or longer-term outcome studies to demonstrate any benefit from early detection. It also demonstrates the importance of education for primary care physicians who might be asked to see screened individuals for further management.

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Reduction in natural death and renal failure from a systematic screening and treatment program in an Australian Aboriginal community Hoy WE, Wang Z, Baker PR, Kelly AM. Kidney Int Suppl 2003; 83: S66–73

B A C K G R O U N D . Given the high incidence of cardiovascular and renal disease in the Australian Aboriginal population, is there a simple intervention achievable in remote areas which might affect morbidity and mortality? This is the first study in a general

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population to demonstrate the ability of a simple intervention (inhibitors of angiotensin-converting enzyme) to reduce mortality over a relatively short period of time. In November 1995, the authors introduced a renal and cardiovascular treatment programme into the Tiwi community, which has a 3- to 5-fold increase in death rates and a recent annual incidence of treated ESRD of 2760 per million. I N T E R P R E T A T I O N . People eligible for treatment were those with confirmed hypertension, diabetics with microalbuminuria or overt albuminuria, and people with overt albuminuria, regardless of blood pressure and diabetes. Treatment centred on the use of perindopril with additional agents as needed to reach defined blood pressure goals, attempts to control glucose and lipid levels, and health education. Two hundred and sixty-seven people (30% of the adult population) were enrolled, with a mean follow-up of 3.39 years. Rates of terminal end-points were compared on an intention-to-treat basis with those of 327 historical controls matched for baseline disease severity, who were followed for a mean of 3.18 years in the pre-treatment programme era, against a background of no treatment or inconsistent changing treatment. Terminal events occurred in 38 controls and 23 people in the treatment group. The estimated rate of natural deaths in the treatment group was 50% that of the controls (P = 0.012); the rate of renal deaths was 47% (P = 0.038) and the rate of non-renal deaths was 54% of that in the controls (P = 0.085). Survival benefit in the treatment group was observed at all levels of overt albuminuria, in non-diabetics and diabetics, in normotensive as well as hypertensive people, and in people who had been taking angiotensin-converting enzyme inhibitors in the pre-programme era, as well as those who had not. No benefit was detectable in people without overt albuminuria because of their low death, and questionable among people with glomerular filtration rate below 60 ml/min. The effect on overall death rates and new endstage renal failure is shown in Fig. 16.3. The number of people needed to be treated to avoid

Fig. 16.3 Average annual number of natural deaths ( adults. Source: Hoy et al. (2003).

) and new dialysis starts ( ) in Tiwi

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one terminal event of natural causes was calculated at only 11.6. Falling rates of deaths and renal failure in the whole community support marked benefit of the programme. Millions of dollars have been saved, based on the avoidance of dialysis alone, but the reduction in premature death is the greater benefit. Chronic disease programmes like this are enormously effective and should be introduced into to all high-risk communities as a matter of urgency.

Comment This study has shown a major impact on mortality and renal replacement therapy with the use of perindopril in people with either diabetes and microalbuminuria, hypertension or overt proteinuria in a programme essentially run by local health workers. Care was provided outside of clinics and using careful protocols and did not require significant input from nurses or doctors once established. Mortality was reduced by about 50% and renal failure by almost 60% over 3 years compared with historic controls. This benefit became apparent after only 2 years of treatment, and the number needed to be treated to prevent death was small, suggesting good cost– benefit. The strategy was successful partly because of its devolution to local communities and their ownership and control, rather than being thought to be imposed. This may well provide a model for the implementation of such care in remote communities in developing countries.

Conclusion The last decade has seen the description of the large excess of renal disease in ethnic minority patients in developed countries, resulting in part from diabetes and hypertension. The papers described here over the last year have begun to explore the potential underlying mechanisms for this, and the likely genetic or environmental contributions. The high risk for individuals from ethnic minorities in developed countries is, however, not constrained geographically, and with changes in diet, environment and living conditions in developing countries the incidence of renal failure is increasing exponentially. This has enormous implications for developing countries, where renal replacement therapy is not a viable option economically, hence the crucial importance of preventing renal failure. The data from Wendy Hoy has shown that renal failure and deaths can be prevented in high-risk individuals (Australian Aboriginals) by a relatively simple approach, where the local community is heavily involved, and without the need for intensive medical input. Finally, we are just embarking on a period when screening may be beneficial in high-risk populations to detect early renal disease, since we now have interventions which can slow or prevent renal failure.

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Further reading 1. Feehally J. Ethnicity and renal disease. Clin Med 2003; 3(6) 578–82. 2. Lightstone L, Rees AJ, Tomson C, Walls J, Winearls CG, Feehally J. High incidence of end3.

4. 5. 6.

stage renal disease in Indo-Asians in the UK. QJM 1995; 88: 191–5. Hoy WE, Wang Z, VanBuynder P, Baker PR, McDonald SM, Mathews JD. The natural history of renal disease in Australian Aborigines. Part 2: Albuminuria predicts a natural death and renal failure. Kidney Int 2001; 60: 249–56. Lightstone L. Preventing renal disease: the ethnic challenge in the United Kingdom. Kidney Int 2003; 63(Suppl 83): S135–8. Narva A. The spectrum of kidney disease in American Indians. Kidney Int 2003; 63(Suppl 83): S3–7. Lemley K. A basis for accelerated progression of diabetic nephropathy in Pima Indians. Kidney Int 2003; 63(Suppl 83): S38–42.