The Year in Renal Medicine, Volume 1

00 YIRenMed I

i-xi prel FINAL

19/4/05 3:41 pm

Page i

THE YEAR IN RENAL MEDICINE VOLUME 1

00 YIRenMed I

i-xi prel FINAL

19/4/05 3:41 pm

Page ii

00 YIRenMed I

i-xi prel FINAL

19/4/05 3:41 pm

Page iii

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   

             

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

00 YIRenMed I

i-xi prel FINAL

19/4/05 3:41 pm

Page iv

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

00 YIRenMed I

i-xi prel FINAL

22/4/05 2:49 pm

Page v

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

00 YIRenMed I

i-xi prel FINAL

19/4/05 3:41 pm

VI

Page vi

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

00 YIRenMed I

i-xi prel FINAL

19/4/05 3:41 pm

Page vii

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

00 YIRenMed I

VIII

i-xi prel FINAL

19/4/05 3:41 pm

Page viii

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

00 YIRenMed I

i-xi prel FINAL

19/4/05 3:41 pm

Page ix

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

00 YIRenMed I

i-xi prel FINAL

19/4/05 3:41 pm

Page x

00 YIRenMed I

i-xi prel FINAL

22/4/05 2:47 pm

Page xi

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.

00 YIRenMed I

i-xi prel FINAL

19/4/05 3:41 pm

Page xii

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 1

Part I Chronic renal failure

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 2

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 3

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

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 4

I.CHRONIC RENAL FAILURE

4

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.

✍

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-

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 5

5

DIABETIC NEPHROPATHY

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.

✍

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

01 YIRenMed I 001-022 FINAL

6

19/4/05 3:42 pm

Page 6

I.CHRONIC RENAL FAILURE

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

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 7

DIABETIC NEPHROPATHY

7

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.

✍

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

01 YIRenMed I 001-022 FINAL

8

19/4/05 3:42 pm

Page 8

I.CHRONIC RENAL FAILURE

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.

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 9

DIABETIC NEPHROPATHY

✍

9

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.

01 YIRenMed I 001-022 FINAL

10

19/4/05 3:42 pm

Page 10

I.CHRONIC RENAL FAILURE

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

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 11

DIABETIC NEPHROPATHY

11

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.

✍

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

01 YIRenMed I 001-022 FINAL

12

19/4/05 3:42 pm

Page 12

I.CHRONIC RENAL FAILURE

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).

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 13

DIABETIC NEPHROPATHY

13

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.

✍

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

01 YIRenMed I 001-022 FINAL

14

19/4/05 3:42 pm

Page 14

I.CHRONIC RENAL FAILURE

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.

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 15

15

DIABETIC NEPHROPATHY

✍

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).

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 16

I.CHRONIC RENAL FAILURE

16

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.

✍

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

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 17

DIABETIC NEPHROPATHY

17

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).

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 18

I.CHRONIC RENAL FAILURE

18

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.

✍

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

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 19

DIABETIC NEPHROPATHY

19

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.

✍

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).

01 YIRenMed I 001-022 FINAL

20

19/4/05 3:42 pm

Page 20

I.CHRONIC RENAL FAILURE

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.

01 YIRenMed I 001-022 FINAL

19/4/05 3:42 pm

Page 21

DIABETIC NEPHROPATHY

21

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.

01 YIRenMed I 001-022 FINAL

22

19/4/05 3:42 pm

Page 22

I.CHRONIC RENAL FAILURE

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.

02 YIRenMed I 023-041 FINAL

19/4/05 3:43 pm

Page 23

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

02 YIRenMed I 023-041 FINAL

24

19/4/05 3:43 pm

Page 24

I.CHRONIC RENAL FAILURE

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.

02 YIRenMed I 023-041 FINAL

19/4/05 3:43 pm

Page 25

PERITONEAL DIALYSIS

25

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.

✍

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

02 YIRenMed I 023-041 FINAL

26

19/4/05 3:43 pm

Page 26

I.CHRONIC RENAL FAILURE

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).

02 YIRenMed I 023-041 FINAL

19/4/05 3:43 pm

Page 27

PERITONEAL DIALYSIS

✍

27

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

02 YIRenMed I 023-041 FINAL

28

19/4/05 3:43 pm

Page 28

I.CHRONIC RENAL FAILURE

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.

✍

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.

02 YIRenMed I 023-041 FINAL

19/4/05 3:43 pm

Page 29

PERITONEAL DIALYSIS

29

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).

02 YIRenMed I 023-041 FINAL

Page 30

I.CHRONIC RENAL FAILURE

30

✍

19/4/05 3:43 pm

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-

02 YIRenMed I 023-041 FINAL

19/4/05 3:43 pm

Page 31

PERITONEAL DIALYSIS

31

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).

✍

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

02 YIRenMed I 023-041 FINAL

32

19/4/05 3:43 pm

Page 32

I.CHRONIC RENAL FAILURE

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

02 YIRenMed I 023-041 FINAL

19/4/05 3:43 pm

Page 33

PERITONEAL DIALYSIS

33

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.

✍

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

02 YIRenMed I 023-041 FINAL

19/4/05 3:43 pm

Page 34

I.CHRONIC RENAL FAILURE

34

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.

✍

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

02 YIRenMed I 023-041 FINAL

19/4/05 3:43 pm

Page 35

PERITONEAL DIALYSIS

35

(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).

02 YIRenMed I 023-041 FINAL

Page 36

I.CHRONIC RENAL FAILURE

36

✍

19/4/05 3:43 pm

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

02 YIRenMed I 023-041 FINAL

19/4/05 3:43 pm

Page 37

PERITONEAL DIALYSIS

37

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.

✍

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

02 YIRenMed I 023-041 FINAL

19/4/05 3:43 pm

Page 38

I.CHRONIC RENAL FAILURE

38

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).

02 YIRenMed I 023-041 FINAL

19/4/05 3:43 pm

Page 39

PERITONEAL DIALYSIS

39

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.

✍

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).

02 YIRenMed I 023-041 FINAL

40

19/4/05 3:43 pm

Page 40

I.CHRONIC RENAL FAILURE

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.

02 YIRenMed I 023-041 FINAL

19/4/05 3:43 pm

Page 41

PERITONEAL DIALYSIS

41

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.

02 YIRenMed I 023-041 FINAL

19/4/05 3:43 pm

Page 42

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 43

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

03 YIRenMed I 043-067 FINAL

44

19/4/05 3:44 pm

Page 44

I.CHRONIC RENAL FAILURE

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.

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 45

ANAEMIA IN CHRONIC RENAL FAILURE

✍

45

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).

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 46

I.CHRONIC RENAL FAILURE

46

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.

✍

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

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 47

ANAEMIA IN CHRONIC RENAL FAILURE

47

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).

03 YIRenMed I 043-067 FINAL

48

19/4/05 3:44 pm

Page 48

I.CHRONIC RENAL FAILURE

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.

✍

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

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 49

ANAEMIA IN CHRONIC RENAL FAILURE

49

(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).

03 YIRenMed I 043-067 FINAL

50

✍

19/4/05 3:44 pm

Page 50

I.CHRONIC RENAL FAILURE

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.

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 51

ANAEMIA IN CHRONIC RENAL FAILURE

51

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.

✍

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

03 YIRenMed I 043-067 FINAL

52

19/4/05 3:44 pm

Page 52

I.CHRONIC RENAL FAILURE

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.

✍

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

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 53

ANAEMIA IN CHRONIC RENAL FAILURE

53

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).

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 54

I.CHRONIC RENAL FAILURE

54

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.

✍

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.

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 55

ANAEMIA IN CHRONIC RENAL FAILURE

✍

55

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-

03 YIRenMed I 043-067 FINAL

56

19/4/05 3:44 pm

Page 56

I.CHRONIC RENAL FAILURE

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.

✍

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.

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 57

ANAEMIA IN CHRONIC RENAL FAILURE

57

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.

✍

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.

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 58

I.CHRONIC RENAL FAILURE

58

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.

✍

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

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 59

ANAEMIA IN CHRONIC RENAL FAILURE

59

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,

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 60

I.CHRONIC RENAL FAILURE

60

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.

✍

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.

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 61

ANAEMIA IN CHRONIC RENAL FAILURE

61

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).

✍

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

03 YIRenMed I 043-067 FINAL

62

19/4/05 3:44 pm

Page 62

I.CHRONIC RENAL FAILURE

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.

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 63

ANAEMIA IN CHRONIC RENAL FAILURE

63

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.

✍

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.

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 64

I.CHRONIC RENAL FAILURE

64

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.

✍

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

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 65

ANAEMIA IN CHRONIC RENAL FAILURE

65

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.

✍

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

03 YIRenMed I 043-067 FINAL

66

19/4/05 3:44 pm

Page 66

I.CHRONIC RENAL FAILURE

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.

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 67

ANAEMIA IN CHRONIC RENAL FAILURE

67

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.

03 YIRenMed I 043-067 FINAL

19/4/05 3:44 pm

Page 68

04 YIRenMed I 069-087 FINAL

19/4/05 3:45 pm

Page 69

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

04 YIRenMed I 069-087 FINAL

70

19/4/05 3:45 pm

Page 70

I.CHRONIC RENAL FAILURE

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

✍

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.

04 YIRenMed I 069-087 FINAL

19/4/05 3:45 pm

Page 71

CARDIOVASCULAR DISEASE

71

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

04 YIRenMed I 069-087 FINAL

72

19/4/05 3:45 pm

Page 72

I.CHRONIC RENAL FAILURE

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).

04 YIRenMed I 069-087 FINAL

19/4/05 3:45 pm

Page 73

CARDIOVASCULAR DISEASE

73

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.

✍

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.

04 YIRenMed I 069-087 FINAL

74

19/4/05 3:45 pm

Page 74

I.CHRONIC RENAL FAILURE

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).

04 YIRenMed I 069-087 FINAL

19/4/05 3:45 pm

Page 75

CARDIOVASCULAR DISEASE

75

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.

✍

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.

04 YIRenMed I 069-087 FINAL

76

19/4/05 3:45 pm

Page 76

I.CHRONIC RENAL FAILURE

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.

04 YIRenMed I 069-087 FINAL

19/4/05 3:45 pm

Page 77

CARDIOVASCULAR DISEASE

✍

77

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.

04 YIRenMed I 069-087 FINAL

78

19/4/05 3:45 pm

Page 78

I.CHRONIC RENAL FAILURE

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

✍

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.

04 YIRenMed I 069-087 FINAL

19/4/05 3:45 pm

Page 79

CARDIOVASCULAR DISEASE

79

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).

04 YIRenMed I 069-087 FINAL

Page 80

I.CHRONIC RENAL FAILURE

80

✍

19/4/05 3:45 pm

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.

04 YIRenMed I 069-087 FINAL

19/4/05 3:45 pm

Page 81

CARDIOVASCULAR DISEASE

81

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.

✍

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

04 YIRenMed I 069-087 FINAL

82

19/4/05 3:45 pm

Page 82

I.CHRONIC RENAL FAILURE

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

04 YIRenMed I 069-087 FINAL

19/4/05 3:45 pm

Page 83

CARDIOVASCULAR DISEASE

83

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).

04 YIRenMed I 069-087 FINAL

Page 84

I.CHRONIC RENAL FAILURE

84

✍

19/4/05 3:45 pm

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.

04 YIRenMed I 069-087 FINAL

19/4/05 3:45 pm

Page 85

85

CARDIOVASCULAR DISEASE

✍

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).

04 YIRenMed I 069-087 FINAL

19/4/05 3:45 pm

86

Page 86

I.CHRONIC RENAL FAILURE

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.

04 YIRenMed I 069-087 FINAL

19/4/05 3:45 pm

Page 87

CARDIOVASCULAR DISEASE

87

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.

04 YIRenMed I 069-087 FINAL

19/4/05 3:45 pm

Page 88

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 89

Part II Acute renal failure

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 90

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 91

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

05 YIRen Med I 089-114 FINAL

92

19/4/05 3:46 pm

Page 92

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

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.

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 93

PREVENTION OF ACUTE RADIOCONTRAST NEPHROPATHY

93

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,

05 YIRen Med I 089-114 FINAL

94

19/4/05 3:46 pm

Page 94

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

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

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 95

PREVENTION OF ACUTE RADIOCONTRAST NEPHROPATHY

95

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).

05 YIRen Med I 089-114 FINAL

96

19/4/05 3:46 pm

Page 96

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

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.

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 97

PREVENTION OF ACUTE RADIOCONTRAST NEPHROPATHY

97

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).

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 98

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

98

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.

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 99

PREVENTION OF ACUTE RADIOCONTRAST NEPHROPATHY

99

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

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

100

Page 100

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

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).

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 101

PREVENTION OF ACUTE RADIOCONTRAST NEPHROPATHY

101

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).

✍

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

05 YIRen Med I 089-114 FINAL

102

19/4/05 3:46 pm

Page 102

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

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).

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 103

PREVENTION OF ACUTE RADIOCONTRAST NEPHROPATHY

103

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

✍

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

05 YIRen Med I 089-114 FINAL

104

19/4/05 3:46 pm

Page 104

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

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).

✍

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.

✍

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

19/4/05 3:46 pm

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).

05 YIRen Med I 089-114 FINAL Page 105

PREVENTION OF ACUTE RADIOCONTRAST NEPHROPATHY 105

05 YIRen Med I 089-114 FINAL

106

19/4/05 3:46 pm

Page 106

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

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.

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 107

PREVENTION OF ACUTE RADIOCONTRAST NEPHROPATHY

107

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.

✍

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

05 YIRen Med I 089-114 FINAL

108

19/4/05 3:46 pm

Page 108

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

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).

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 109

PREVENTION OF ACUTE RADIOCONTRAST NEPHROPATHY

109

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.

05 YIRen Med I 089-114 FINAL

Page 110

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

110

✍

19/4/05 3:46 pm

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

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 111

PREVENTION OF ACUTE RADIOCONTRAST NEPHROPATHY

111

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).

05 YIRen Med I 089-114 FINAL

19/4/05 3:46 pm

Page 112

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

112

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

19/4/05 3:46 pm

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.

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 115

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

06 YIRenMed I 115-141 FINAL

116

19/4/05 3:47 pm

Page 116

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

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.

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 117

RENAL SUPPORT AND TREATMENT OF ARF

117

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

✍

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

06 YIRenMed I 115-141 FINAL

118

19/4/05 3:47 pm

Page 118

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

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

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 119

RENAL SUPPORT AND TREATMENT OF ARF

119

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.

✍

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).

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 120

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

120

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.

✍

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,

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 121

RENAL SUPPORT AND TREATMENT OF ARF

121

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.

06 YIRenMed I 115-141 FINAL

122

19/4/05 3:47 pm

Page 122

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

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).

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 123

RENAL SUPPORT AND TREATMENT OF ARF

123

Non-dialytic management of ARF

✍

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-

06 YIRenMed I 115-141 FINAL

124

19/4/05 3:47 pm

Page 124

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

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.

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 125

RENAL SUPPORT AND TREATMENT OF ARF

✍

125

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

06 YIRenMed I 115-141 FINAL

126

19/4/05 3:47 pm

Page 126

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

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

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 127

RENAL SUPPORT AND TREATMENT OF ARF

127

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.

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 128

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

128

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

✍

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

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 129

RENAL SUPPORT AND TREATMENT OF ARF

129

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

06 YIRenMed I 115-141 FINAL

130

19/4/05 3:47 pm

Page 130

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

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.

✍

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.

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 131

RENAL SUPPORT AND TREATMENT OF ARF

131

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.

06 YIRenMed I 115-141 FINAL

132

✍

19/4/05 3:47 pm

Page 132

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

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).

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 133

RENAL SUPPORT AND TREATMENT OF ARF

133

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.

06 YIRenMed I 115-141 FINAL

Page 134

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

134

✍

19/4/05 3:47 pm

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,

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 135

RENAL SUPPORT AND TREATMENT OF ARF

135

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.

✍

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

06 YIRenMed I 115-141 FINAL

136

19/4/05 3:47 pm

Page 136

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

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.

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 137

RENAL SUPPORT AND TREATMENT OF ARF

137

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.

✍

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.

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 138

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

138

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.

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 139

RENAL SUPPORT AND TREATMENT OF ARF

139

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

19/4/05 3:47 pm

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.

06 YIRenMed I 115-141 FINAL

19/4/05 3:47 pm

Page 142

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 143

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

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 144

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

144

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.

✍

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

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 145

GLOMERULONEPHRITIS

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

145

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 146

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

146

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.

✍

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-

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 147

GLOMERULONEPHRITIS

147

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)

07 YIRenMed I 143-164 FINAL

148

19/4/05 3:55 pm

Page 148

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

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.

✍

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).

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 149

GLOMERULONEPHRITIS

149

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.

✍

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.

07 YIRenMed I 143-164 FINAL

150

19/4/05 3:55 pm

Page 150

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

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).

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 151

GLOMERULONEPHRITIS

✍

151

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).

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 152

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

152

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.

✍

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.

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 153

GLOMERULONEPHRITIS

153

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

07 YIRenMed I 143-164 FINAL

Page 154

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

154

✍

19/4/05 3:55 pm

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

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 155

GLOMERULONEPHRITIS

155

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.

✍

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

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 156

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

156

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.

✍

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-

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 157

GLOMERULONEPHRITIS

157

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

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 158

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

158

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.

✍

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.

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 159

GLOMERULONEPHRITIS

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).

159

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 160

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

160

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.

✍

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

19/4/05 3:55 pm

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

07 YIRenMed I 143-164 FINAL Page 161

GLOMERULONEPHRITIS 161

07 YIRenMed I 143-164 FINAL

162

19/4/05 3:55 pm

Page 162

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

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.

✍

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).

07 YIRenMed I 143-164 FINAL

19/4/05 3:55 pm

Page 163

GLOMERULONEPHRITIS

163

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.

07 YIRenMed I 143-164 FINAL

164

19/4/05 3:55 pm

Page 164

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

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