Acute Kidney Injury

Acute Kidney Injury – Scientiﬁc Evidence Driving Change in Patient Management Guest Editors Rinaldo Bellomo, Heidelberg...

Author: Rinaldo Bellomo | Joseph Bonventre

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Acute Kidney Injury – Scientiﬁc Evidence Driving Change in Patient Management Guest Editors

Rinaldo Bellomo, Heidelberg, Vic. Joseph Bonventre, Boston, Mass.

19 figures, 4 in color, and 12 tables, 2008

Basel • Freiburg • Paris • London • New York • Bangalore • Bangkok • Shanghai • Singapore • Tokyo • Sydney

S. Karger Medical and Scientific Publishers Basel • Freiburg • Paris • London New York • Bangalore • Bangkok Shanghai • Singapore • Tokyo • Sydney

Disclaimer The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the journal is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.

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Vol. 109, No. 4, 2008

Contents

c181 Introduction Bellomo, R. (Heidelberg, Vic.); Bonventre, J. (Boston, Mass.)

e109 Antioxidants. Do They Have a Place in the Prevention

or Therapy of Acute Kidney Injury?

c182 Definition and Classification of Acute Kidney Injury Kellum, J.A. (Pittsburgh, Pa.); Bellomo, R. (Melbourne, Vic.); Ronco, C. (Vicenza) c188 The Epidemiology of Severe Acute Kidney Injury:

p80 Distant-Organ Changes after Acute Kidney Injury Feltes, C.M.; Van Eyk, J.; Rabb, H. (Baltimore, Md.)

from BEST to PICARD, in Acute Kidney Injury: New Concepts

p85 Emerging Therapies for Extracorporeal Support Bouchard, J.; Khosla, N.; Mehta, R.L. (San Diego, Calif.)

Pisoni, R.; Wille, K.M.; Tolwani, A.J. (Birmingham, Ala.)

e118 The Bioartificial Kidney and Bioengineered Membranes in Acute Kidney Injury

c192 Biomarkers for the Diagnosis of Acute Kidney Injury Waikar, S.S.; Bonventre, J.V. (Boston, Mass.) c198 Imaging Techniques in Acute Kidney Injury Sharfuddin, A.A.; Sandoval, R.M.; Molitoris, B.A. (Indianapolis, Ind.)

Ding, F. (Ann Arbor, Mich./Shanghai); Humes, H.D. (Ann Arbor, Mich.) c217 Outcome Prediction for Patients with Acute Kidney

Injury Uchino, S. (Tokyo)

p55 Cardiac Surgery-Associated Acute Kidney Injury:

Putting Together the Pieces of the Puzzle Shaw, A.; Swaminathan, M.; Stafford-Smith, M. (Durham, N.C.) e95

Koyner, J.L. (Chicago, Ill.); Sher Ali, R. (New York, N.Y.); Murray, P.T. (Chicago, Ill.)

c224 Acute Kidney Injury: New Concepts, Renal Recovery Bell, M. (Solna/Stockholm)

Septic Acute Kidney Injury: New Concepts Bellomo, R.; Wan, L.; Langenberg, C.; May, C. (Melbourne, Vic.)

p61 Radiocontrast-Induced Acute Kidney Injury McCullough, P.A. (Royal Oak, Mich.) p73 Acute Kidney Injury: New Concepts. Hepatorenal

Syndrome: The Role of Vasopressors Moreau, R.; Lebrec, D. (Clichy) e102 Inflammation in Acute Kidney Injury Kinsey, G.R.; Li, L.; Okusa, M.D. (Charlottesville, Va.) c206 New Insights on Intravenous Fluids, Diuretics and

Acute Kidney Injury Townsend, D.R.; Bagshaw, S.M. (Edmonton, Alta.)

© 2008 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/nef_issues

c229 Author Index Vol. 109, No. 4, 2008 c230 Subject Index Vol. 109, No. 4, 2008

c231 Author Index Vol. 109, 2008 c234 Subject Index Vol. 109, 2008 after c236 Contents Vol. 109, 2008

Nephron Clin Pract 2008;109:c181 DOI: 10.1159/000142925

Published online: September 18, 2008

Introduction

The field of acute nephrology has seen significant changes in recent times. These changes go to the core of many significant clinical issues. They affect the definition and classification of acute kidney dysfunction, our understanding of its epidemiology, our ability to make earlier diagnoses, our ability to use novel imaging modalities to understand its pathogenesis, and our insight into why acute kidney injury (AKI) might occur under different clinical circumstances including cardiac surgery, septic shock, radiocontrast agent exposure, liver disease and various toxins. Advances in our understanding have affected our strategies for intervention which have been directed toward the modulation of inflammation, improvement in fluid therapy, administration of antioxidants, optimization of dialytic technique, and development of new dialytic paradigms with the introduction of bio-assist devices. Finally, new pathophysiological insights have enabled us to better appreciate how to predict outcome in these patients as well as understand the significance of renal recovery and the factors that modulate it. In this issue of Nephron, we have gathered experts in each of the above areas of acute nephrology to offer readers a condensation of many major advances in this field. The title itself summarizes an important change from the concept of acute renal failure to that of acute kidney injury. This is a key conceptual change [1] supported by consensus opinion [2, 3]. This term has been proposed and accepted because it deals with the full spectrum of the syndrome of kidney involvement in a variety of acute diseases and emphasizes that even minor changes in renal function which may be dismissed clinically carry an independent association with an increased risk of mortality [2, 3]. Using this conceptual framework, new definitions © 2008 S. Karger AG, Basel 1660–2110/08/1094–0181$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nec

and classifications have been developed and one, the RIFLE classification, has now been studied and found robust in 1250,000 patients. Armed with a definition and a classification system and with the understanding that even minor subclinical injury to the kidney may matter, we have been able to emphasize the need to develop early biomarkers of such injury [4] and appreciate the role of inflammation [5] in inducing injury. Through sufficiently early diagnosis, a better classification system and a clearer understanding of the pathogenesis, these steps promise, for the first time in a long while, to deliver novel and effective therapies for patients. Clinicians need to keep abreast of these evolutions if they wish to continue to deliver the best care to their patients. We believe this issue of Nephron goes a long way in making this possible. Rinaldo Bellomo, Heidelberg, Vic. Joseph Bonventre, Boston, Mass.

References 1 Kellum JA: Acute kidney injury. Crit Care Med 2008; 36(suppl):S141– S145. 2 Bellomo R, Ronco C, Kellum JA, et al: Acute renal failure: definition, outcome measures, animal models, fluid therapy and information technology needs. The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204–R212. 3 Mehta RL, Kellum JA, Shah SV, et al: Acute kidney injury network: report of an initiative to improve outcome in acute kidney injury. Crit Care 2007;11:R31. 4 Vaidya VS, Ferguson MA, Bonventre JV: Biomarkers of acute kidney injury. Annu Rev Pharmacol Toxicol 2008;48:463–493. 5 Bonventre JV: Pathophysiology of acute kidney injury: roles of potential inhibitors of inflammation. Contrib Nephrol. Basel, Karger, 2007, vol 156, pp 39–46.

Prof. Rinaldo Bellomo Department of Intensive Care Austin Hospital Heidelberg, Vic. 3084 (Australia) Tel. +61 3 9496 5992, Fax +61 3 9496 3932, E-Mail [email protected]

Nephron Clin Pract 2008;109:c182–c187 DOI: 10.1159/000142926

Published online: September 18, 2008

Definition and Classification of Acute Kidney Injury John A. Kellum a Rinaldo Bellomo b Claudio Ronco c a

The Clinical Research, Investigation, and Systems Modeling of Acute illness (CRISMA) Laboratory, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pa., USA; b Department of Intensive Care and Department of Medicine, Austin Hospital and University of Melbourne, Heidelberg, Melbourne, Vic., Australia; c Department of Nephrology, Ospedale San Bortolo, Vicenza, Italy

Key Words Acute kidney injury ⴢ Acute renal failure ⴢ RIFLE criteria ⴢ Epidemiology ⴢ Hemodialysis ⴢ Hemofiltration ⴢ Kidney disease ⴢ Critical illness

Abstract Changes in urine output and glomerular filtration rate are neither necessary nor sufficient for the diagnosis of renal pathology. Yet no simple alternative for the diagnosis currently exists. Until recently, there has been no consensus as to diagnostic criteria or clinical definition of acute renal failure. Depending on the definition used, acute renal failure has been reported to affect from 1 to 25% of ICU patients and has led to mortality rates from 15 to 60%. The RIFLE criteria were developed to standardize the diagnosis of acute renal failure and in the process the term acute kidney injury (AKI) has been proposed to encompass the entire spectrum of the syndrome from minor changes in renal function to requirement for renal replacement therapy. Thus, AKI is not acute renal failure but a more general description. Small changes in kidney function in hospitalized patients are important and are associated with significant changes in short and possibly long-term outcomes. The RIFLE criteria provide a uniform definition of AKI and have now been validated in numerous studies. Copyright © 2008 S. Karger AG, Basel

© 2008 S. Karger AG, Basel 1660–2110/08/1094–0182$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nec

Acute Organ Distress

The presence of, or risk for, acute dysfunction of vital organs is a defining aspect of critical illness. Indeed, the purpose of critical care is to provide life-sustaining organ support (e.g. mechanical ventilation) and to rapidly intervene to save organ function (e.g. opening of coronary arteries). For most vital organs, injury and reduced function are tightly correlated. For some organs injury can be severe before decreased function is apparent – for example as much as 80% of the liver can be damaged be before clinical symptoms are manifest. For other organs dysfunction may be greater than what is produced by irreversible injury (e.g. stunned or hibernating myocardium). However, the kidney may be unique in that the earliest clinical manifestations of injury are also consistent with ‘perfect’ function. Under stress, for example that occurs with acute hemorrhage, a perfectly functioning kidney responds to the fall in blood pressure and rise in vasopressin by reducing urine output and glomerular filtration rate (GFR). Indeed, a ‘normal’ urine output and GFR in the face of volume depletion could only be viewed as renal dysfunction. Thus, changes in urine output and GFR, while they are the hallmarks of kidney failure, are neither necessary nor sufficient for the diagnosis of renal pathology [1, 2]. John A. Kellum, MD Department of Critical Care Medicine, University of Pittsburgh, School of Medicine Room 608 Scaife Hall, 3550 Terrace Street Pittsburgh, PA 15261 (USA) Tel. +1 412 647 6966, Fax +1 412 647 8060, E-Mail [email protected]

Screat criteria* Risk

Urine output criteria

Increased creatinine ×1.5 x1.5 (Or (or increase Increasecreatine creatineof of ≥0.3mg/dl) ≥0.3 mg/dl)

UO <0.5 < .5ml/kg/h ml/kg/h x 6 hhr ×6

Increased creatinine ×2 x2

UO <0.5 < .5ml/kg/h ml/kg/h x 12 hhr ×12

Injury

Failure

Increase creatinine ×3 x3 UO <0.3 < .3ml/kg/h ml/kg/h or creatinine ≥4mg/dl ≥4 mg/dl ×24 x 24 hhroror (Acuterise (acute riseof of ≥0.5 mg/dl) Anuria x×12 12 hhrs

Loss ESKD

Oligu ria

Of course, there are differences between a normally functioning, but stressed, kidney and one that is diseased or injured. For example, in the face of severe extracellular fluid depletion, GFR is reduced. This reduction is sometimes called ‘single-nephron’ GFR to distinguish it from the loss of nephrons that occurs in renal disease (e.g. diabetic nephropathy) but it actually refers to all nephrons. The reduced GFR means that a greater fraction of salt and water can be absorbed and thus less will enter the tubules. Of course, less tubular filtrate means less urine and less nitrogen excretion. This form of azotemia is commonly called ‘prerenal’ to indicate that the cause lies outside, specifically ‘before’ the kidney. However, it is often very difficult to separate so-called prerenal from ‘intra-renal’ azotemia and in certain situations (e.g. sepsis) classical tools such as urine chemistries may be misleading [3, 4]. Furthermore, while the prerenal concept may be useful to understand the physiology it may also be problematic clinically. Indeed, it is quite temping to extrapolate the prerenal/renal paradigm to a benign and malignant azotemia. As we have argued elsewhere [3–5], pure prerenal physiology is unusual in hospitalized patients and its effects are not necessary benign.

Persistent AKI = Complete complete loss lossof of renal function >4 > 4weeks weeks End End-stage Stage kidney Kindeydisease Disease

Fig. 1. The RIFLE criteria for AKI (used with permission [12]). Screat = Serum creatinine concentration; UO = urine output. * All serum creatinine references are based on changes from baseline values. The Risk criteria include the modifications recommended by AKIN [13].

Acute Renal Failure

Like many diagnostic problems in medicine, time is an ally – when we can afford it. In time, ‘acute kidney distress’ will either resolve or lead to pathology. But even here there is still room for debate. Both the hepatorenal and cardiorenal syndromes are forms of, for lack of better term, ‘chronic prerenal states’. Thus, it seems, the kidney is a hard organ to pin down. Given the difficulties in separating renal function from dysfunction, it is perhaps not too surprising that precise biochemical or clinical criteria for diagnosis of acute renal failure have been elusive. Although the term ‘acute renal failure’ dates back to Homer Smith who first introduced it in a chapter on ‘Acute renal failure related to traumatic injuries’, in his textbook ‘The kidney-structure and function in health and disease’ (1951), a precise biochemical definition of the term was never proposed. Until recently there was no consensus on the diagnostic criteria or clinical definition of acute renal failure resulting in multiple different definitions. A recent survey revealed the use of at least 35 definitions in literature [6]. This state of confusion has given rise to wide variation in reported incidence and clinical significance of acute renal failure. Depending on the definition used, acute renal Definition and Classification of AKI

failure has been reported to affect from 1 to 25% of ICU patients and has led to mortality rates from 15 to 60% [7–9] – making the term, from an epidemiologic perspective, almost useless.

RIFLE Criteria

Over the last few years we have repeatedly made the case for a consensus definition and a classification system for acute renal failure [10, 11]. The major aim of such a system would be to bring one of the major intensive care syndromes to a standard of definition and a level of classification similar to that achieved by two other common ICU syndromes (sepsis and ARDS). Furthermore, the need to classify the severity of the syndrome rather than only consider the most severe form was emphasized. Following such advocacy and through the persistent work of the Acute Dialysis Quality Initiative (ADQI) group, such a system was developed through a broad consensus of experts [12]. The characteristics of this system are summarized in figure 1. The acronym RIFLE stands for the increasing severity classes R isk, Injury and Failure, and the 2 outcome classes Loss and End-Stage Kidney Disease. Nephron Clin Pract 2008;109:c182–c187

c183

The 3 severity grades are defined on the basis of the changes in serum creatinine or urine output where the worst of each criterion is used. The 2 outcome criteria, Loss and End-Stage Kidney Disease, are defined by the duration of loss of kidney function. The term acute kidney injury (AKI) has been proposed to encompass the entire spectrum of the syndrome from minor changes in renal function to requirement for renal replacement therapy (RRT) [13]. Thus, the concept of AKI, as defined by RIFLE, creates a new paradigm. AKI is not just acute renal failure; it encompasses the entire spectrum from severe to less severe conditions. Importantly, when we focus exclusively on patients with renal failure or on those who receive dialysis, we overlook the strong association of AKI with hospital mortality even when only a minority of patients receives renal replacement therapy. In a study by Hoste et al. [14], only 14% of patients reaching RIFLE ‘F’ received renal replacement therapy, yet these patients experienced a hospital mortality more than 5 times that of the same ICU population without AKI. Such evidence demands that we change the way we think about this disorder. Is renal support underutilized or delayed? Are there other supportive measures that should be employed for these patients?

RIFLE Version 1.2

Concern was initially raised about RIFLE, over the use of very small alterations in serum creatinine and urine output; furthermore, some objected to the use of an acronym instead of the numerical stages used in chronic kidney disease. Interestingly, others were concerned that a 50% increase in serum creatinine was too conservative and sought to demonstrate that even smaller changes were important [15]. However, the original publication of the RIFLE criteria has now been accessed more than 100,000 times [16] and RIFLE has become the most widely used definition of acute renal failure in both the critical care and nephrology literature [17–21]. The total number of patients included in studies validating RIFLE now exceeds 200,000. Thus, the goal of standardizing a definition and classification system for one of the most common ICU syndromes would appear to have been realized. However, standards do not mean complacency and efforts to include more recent evidence has led the AKI Network (AKIN), a somewhat larger, multi-disciplinary, international group, to propose some small modifications to the RIFLE criteria [13]. These modifications can be summac184

Nephron Clin Pract 2008;109:c182–c187

rized as follows: (a) broadening of the ‘Risk’ category of RIFLE to include an increase in serum creatinine of at least 0.3 mg/dl even if this does not reach the 50% threshold; (b) setting a 48-hour window on the first documentation of any criteria, and (c) categorizing patients as ‘Failure’ if they are treated with renal replacement therapy regardless of what their serum creatinine or urine output is at the point of initiation. AKIN also proposed that stages 1, 2 and 3 be used instead of R, I and F – no doubt an important upgrade to the system. These differences between ADQI-RIFLE and AKIN stages might therefore appear quite modest, but indeed, that was precisely the intent. Furthermore, a recent study by Bagshaw et al. [22] has show that the changes are even more trivial than they might seem. As expected, by broadening the criteria for ‘Risk’ (stage 1) there is increased sensitivity (more individuals are classified as having AKI). However, this difference affects only 1% of patients. Moreover, since the data available to Bagshaw and colleagues was only from day 1 of the ICU stay, a large proportion of the 1% of patients would likely have been classified, ultimately, as having AKI by RIFLE anyway. Unfortunately, this study cannot address the other two modifications to RIFLE. This may not ultimately matter very much, however, since the proposal to classify patients treated with RRT as stage 3 only applies to their maximum stage and does not preclude investigators from reporting the stage of AKI just prior to RRT. Other studies will need to explore whether the proposed 48-hour time window for reaching at least stage 1 criteria excludes patients that should be included in the AKI diagnosis. ADQI also included GFR in the original RIFLE criteria but with the understanding that it would only be used as a rough ‘guide’ since few patients will have GFR measured and a non-steady-state GFR is of limited value in any case. Another recommendation from ADQI was how to handle the absence of a baseline creatinine. The ADQI group recommended using the MDRD equation to back-estimate a baseline creatinine using a low normal value for GFR (75 ml) [23]. This approach was first operationalized by Hoste et al. [14] who used the lowest of the following as the baseline when no true baseline was available: hospital admission creatinine; ICU admission creatinine; MDRD estimated creatinine. By using the lowest of these three, the authors insured that a subject admitted with a low creatinine would have that information included (and thus a higher maximum RIFLE class if the creatinine increased) while a subject admitted with a high creatinine and no history of CKD Kellum /Bellomo /Ronco

would be classified based on a change from a theoretical baseline estimated from MDRD. Although logical, this approach has yet to be validated and may still over- or underestimate the degree of renal impairment on admission. The study by Bagshaw et al. [22] used the estimated baseline criteria from the MDRD equation for both RIFLE and AKIN staging. However, the authors also estimated the change in GFR from the MDRD equation for RIFLE but not for AKIN staging. This resulted in a few more cases classified as stage 3 instead of stage 2 but was otherwise inconsequential. Thus, RIFLE criteria are, pending more specific biomarkers of kidney injury, the new gold standard.

Epidemiology of Acute Kidney Injury

One of the earliest studies evaluating the epidemiology of AKI was by Abosaif et al. [24] who studied 247 patients admitted to ICU with a serum creatinine 1150 ␮mol/l. The investigators found that the ICU mortality was greatest among patients classified as RIFLE F with a 74.5% mortality compared to 50% among those classified as I and 38.3% in those classified as R. In a significantly larger single-center multi-ICU study, Hoste et al. [14] studied 5,383 critically ill patients. They found that AKI occurred in 67% of patients with 12% achieving a maximum class of R, 27% I, and 28% F. Of the 1,510 patients who reached R, 56% progressed to either I or F. Patients with a maximum score of R had a mortality rate of 8.8%, compared to 11.4% for I and 26.3% for F. On the other hand, patients who had no evidence of AKI had a mortality rate of 5.5%. Furthermore, RIFLE I (hazard ratio of 1.4) and RIFLE F (hazard ratio of 2.7) were independent predictors of hospital mortality after controlling for other variables known to predict outcome in critically ill patients. Uchino and colleagues focused on the predictive ability of the RIFLE classification in a cohort of 20,126 patients admitted to a teaching hospital for 124 h over a 3year period [25]. The authors used serum creatinine from an electronic laboratory database to classify patients into RIFLE R, I and F and followed them to hospital discharge or death. Nearly 10% of patients achieved a maximum RIFLE R, 5% I and 3.5% F. There was a nearly linear increase in hospital mortality with increasing RIFLE class with patients at R having more than 3 times the mortality rate of patients without AKI. In multivariate regression class R carried an odds ratio of hospital mortality of 2.5, I of 5.4 and F of 10.1. Definition and Classification of AKI

In the first population-based study of AKI, Ali et al. [26] studied the incidence of AKI in Northern Scotland, a geographical population base of 523,390. The incidence of AKI was 2,147 per million population. Sepsis was a precipitating factor in 47% of patients. RIFLE classification was useful for predicting recovery of renal function (p ! 0.001), requirement for renal replacement therapy (p ! 0.001), length of hospital stay for survivors (p ! 0.001), and in-hospital mortality (p = 0.035). A recent study by Ostermann and Chang [20] analyzed 41,972 patients admitted to 22 intensive care units in the United Kingdom and Germany between 1989 and 1999 as part of the Riyadh Intensive Care Program database. AKI defined by RIFLE occurred in 15,019 (35.8%) patients: 7,207 (17.2%) with R, 4,613 (11%) I, and 3,199 (7.6%) with F. Hospital mortality rates were RIFLE R 20.9%, I 45.6%, and F 56.8%, compared with 8.4% among patients without AKI. Finally, in the largest study to date, Bagshaw and colleagues studied 120,123 patients admitted to one of 57 intensive care units across Australia for at least 24 h from January 2000 to December 2005. In striking similarity to the study by Ostermann, AKI occurred in 36.1%, with a maximum category R in 16.3%, I in 13.6%, and F 6.3%. AKI, defined by any RIFLE category, was associated with an increase in hospital mortality (OR 3.29, 95% CI 3.19– 3.41, p ! 0.0001). The crude hospital mortality by RIFLE category was 17.9% for R, 27.7% for I, and 33.2% for F. By multivariable analysis, each RIFLE category was independently associated with hospital mortality (OR: R 1.58, I 2.54, and F 3.22).

Beyond RIFLE

In the future, the use of functional makers (urine output and serum creatinine) will hopefully be replaced or augmented by injury biomarkers. Several potential serum and urinary markers have been identified and reviewed elsewhere [27]. These markers include neutrophil gelatinase-associated lipocalin (NGAL) [28], kidney injury molecule-1 (KIM-1) [29], cysteine-rich protein 61 [30], spermidine/spermine N(1)-acetyltransferase [31], cystatin C [32], and urine IL-18 [33, 34]. In the future, markers of cellular injury in the kidney will likely define AKI and offer the potential to diagnose the disorder before functional decline. Until then, the ‘tried and true’ markers of urine output and serum creatinine, disciplined by RIFLE criteria, will be the best we can provide. Nephron Clin Pract 2008;109:c182–c187

c185

Complications

AKI Normal

Increased risk

Damage

↓ GFR

Kidney failure

Death

Antecedents

Fig. 2. AKI conceptual model developed

AKI Stage

by AKIN (the Acute Kidney Injury Network) at the Vancouver Summit 2006 (www.akinet.org).

Outcomes

Conclusion

Small changes in kidney function in hospitalized patients are important and associated with significant changes in short- and possibly long-term outcomes. The RIFLE classification for AKI is already quite analogous to KDOQI chronic kidney disease (CKD) staging, which is well known to correlate disease severity with cardiovascular complications and other morbidities [35]. CKD stages also have been linked to specific treatment recommen-

dations, which have proved extremely useful in managing this disease [35]. As the epidemiology of AKI becomes clearer and as treatments emerge (both made all the more possible by standard criteria for diagnosis and classification), RIFLE classifications will undoubtedly be used to reference recommendations for prevention and treatment. Now that we have one uniform classification system, it’s time to concentrate on making this a reality. Figure 2 shows a conceptual model of AKI developed by AKIN for the purpose of furthering research in this field.

References 1 Kellum JA: Acute kidney injury. Crit Care Med 2008;36:S141–S145. 2 Thurau K, Boylan JW: Acute renal success: the unexpected logic of oliguria in acute renal failure. Am J Med 1976;61:308–315. 3 Bagshaw SM, Langenberg C, Wan L, May CN, Bellomo R: A systematic review of urinary findings in experimental septic acute renal failure. Crit Care Med 2007;36:1592–1598. 4 Bagshaw SM, Langenberg C, Bellomo R: Urinary biochemistry and microscopy in septic acute renal failure: a systematic review. Am J Kidney Dis 2006;48:695–705. 5 Kellum JA: Prerenal azotemia: still a useful concept? Crit Care Med 2007;35:1630–1631. 6 Kellum JA, Levin N, Bouman C, Lameire N: Developing a consensus classification system for acute renal failure. Curr Opin Crit Care 2002;8:509–514. 7 Liano F: Epidemiology of acute renal failure: a prospective, multicenter, communitybased study. Madrid Acute Renal Failure Study Group. Kidney Int 1996;50:811–818.

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8 Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ: Acute renal failure in intensive care units: causes, outcome, and prognostic factors of hospital mortality; a prospective, multicenter study. French Study Group on Acute Renal Failure. Crit Care Med 1996;24:192–198. 9 Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C: Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294:813–818. 10 Bellomo R, Kellum JA, Ronco C: Acute renal failure: time for consensus. Intensive Care Med 2001;27:1685–1688. 11 Kellum JA, Mehta RL, Ronco C: Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol. Basel, Karger, 2001, vol 132, pp 258–265.

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12 Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P: Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8:R204– R212. 13 Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A: Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. 14 Hoste EA, Clermont G, Kersten A, Venkataram R, Angus DC, De Bacquer D, Kellum JA: RIFLE criteria for acute kidney injury is associated with hospital mortality in critical ill patients: a cohort analysis. Crit Care 2006; 10:R73.

Kellum /Bellomo /Ronco

15 Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW: Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005; 16: 3365–3370. 16 http://ccforum.com/mostviewedalltime. 523-2007. 17 Bellomo R, Kellum JA, Ronco C: Defining and classifying acute renal failure: from advocacy to consensus and validation of the RIFLE criteria. Intensive Care Med 2006. 18 Hoste EA, Kellum JA: Acute kidney injury: epidemiology and diagnostic criteria. Curr Opin Crit Care 2006;12:531–537. 19 Himmelfarb J, Ikizler TA: Acute kidney injury: changing lexicography, definitions, and epidemiology. Kidney Int 2007; 71: 971– 976. 20 Ostermann M, Chang RW: Acute kidney injury in the intensive care unit according to RIFLE. Crit Care Med 2007;35:1837–1843. 21 Bagshaw SM, George C, Dinu I, Bellomo R: A Multi-centre evaluation of the rifle criteria for early acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008; 23: 1203–1210. 22 Bagshaw SM, George C, Bellomo R: A comparison of the RIFLE and AKIN criteria for acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008;Epub ahead of print.

Definition and Classification of AKI

23 Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, and the ADQI workgroup: acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204–R212. 24 Abosaif NY, Tolba YA, Heap M, Russell J, El Nahas AM: The outcome of acute renal failure in the intensive care unit according to RIFLE: model application, sensitivity, and predictability. Am J Kidney Dis 2005; 46: 1038–1048. 25 Uchino S, Bellomo R, Goldsmith D: An assessment of the RIFLE criteria for acute renal failure in hospitalized patients. Crit Care Med 2006;34:1913–1917. 26 Ali T, Khan I, Simpson W, Prescott G, Townend J, Smith W, Macleod A: Incidence and outcomes in acute kidney injury: a comprehensive population-based study. J Am Soc Nephrol 2007; 18:1292–1298. 27 Venkataraman R, Kellum JA: Defining acute renal failure: the RIFLE criteria. J Intensive Care Med 2007;22:187–193. 28 Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P: Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365:1231– 1238. 29 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;62:237–244.

30 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 ischemic reperfusion injury. Kidney Int 2002;62:1601–1610. 31 Zahedi K, Wang Z, Barone S, Prada AE, Kelly CN, Casero RA, Yokota N, Porter CW, Rabb H, Soleimani M: Expression of SSAT, a novel biomarker of tubular cell damage, increases in kidney ischemia-reperfusion injury. Am J Physiol Renal Physiol 2003; 284: F1046–F1055. 32 Ahlstrom A, Tallgren M, Peltonen S, Pettila V: Evolution and predictive power of serum cystatin C in acute renal failure. Clin Nephrol 2004;62:344–350. 33 Parikh CR, Jani A, Melnikov VY, Faubel S, Edelstein CL: Urinary interleukin-18 is a marker of human acute tubular necrosis. Am J Kidney Dis 2004;43:405–414. 34 Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL: Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol 2005;16:3046–3052. 35 Levin A, Stevens LA: Executing change in the management of chronic kidney disease: perspectives on guidelines and practice. Med Clin North Am 2005;89:701–709.

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Nephron Clin Pract 2008;109:c188–c191 DOI: 10.1159/000142927

Published online: September 18, 2008

The Epidemiology of Severe Acute Kidney Injury: from BEST to PICARD, in Acute Kidney Injury: New Concepts Roberto Pisoni a Keith M. Wille a Ashita J. Tolwani a Department of Medicine, University of Alabama at Birmingham, Birmingham, Ala., USA

Key Words Acute renal failure ⴢ Acute kidney injury ⴢ BEST ⴢ PICARD

Abstract Various definitions of acute kidney injury (AKI) exist, making comparisons among studies difficult. Despite this, significant changes have occurred in the epidemiology of AKI during the last decade. Recent studies, including PICARD and BEST, have examined the epidemiology of ICU-related AKI in the USA and worldwide, respectively, and found that AKI remains a major cause of morbidity and mortality. The incidence of AKI has increased, most likely due to a trend toward older, more severely and chronically ill patients admitted to the hospital. Sepsis and multi-organ system failure continue to be strongly associated with AKI, as well as pre-morbid chronic kidney disease. The proportion of patients with AKI requiring dialysis is high. The mortality of ICU-related AKI, although still very elevated, may be decreasing. Understanding these changes, in the context of standardized definitions, will be essential for the design of successful interventional studies. Copyright © 2008 S. Karger AG, Basel

Introduction

Characterizing the epidemiology of acute renal failure (ARF) has been problematic due to variations in the definition of ARF, differences in the causes and settings of © 2008 S. Karger AG, Basel 1660–2110/08/1094–0188$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nec

ARF, and dissimilarities among patients developing ARF. Of these, the major obstacle to research in this area has been the lack of a uniform definition, which has led to conflicting reports in the literature. Because of this lack of standardization, in 2002, the Acute Dialysis Quality Initiative (ADQI) workgroup proposed a consensus definition of ARF categorized into three grades of increasing severity: Risk (defined as oliguria more than 6 h or a serum creatinine increase of at least 50%), Injury, and Failure (both defined by a greater increase in serum creatinine, or duration and severity of oliguria, compared to the ‘Risk’ group). These categories – R, I, and F – were associated with two clinical outcomes: renal loss and endstage renal disease (ESRD) [1]. Loss and ESRD were defined by the need for renal replacement therapy (RRT) for 1 4 weeks and 13 months, respectively. These criteria were identified by the acronym RIFLE. The ADQI workgroup, together with representatives from three nephrology societies and the European Society of Intensive Care Medicine, formed the Acute Kidney Injury Network (AKIN) [2]. The AKIN proposed a similar system comprised of three stages of increasing severity of renal dysfunction (corresponding to the risk, injury, and failure categories of RIFLE); however, to emphasize the emerging data that even small alterations in renal function may lead to adverse outcomes [3], the term acute kidney injury (AKI) was used instead of acute renal failure. Additionally, a lower creatinine threshold (60.3 mg/ dl increase in serum creatinine) was employed for stage 1 Dr. Ashita Tolwani ZRB 604 1530 3rd Avenue S Birmingham, AL 35294-0007 (USA) Tel. +1 205 975 2021, Fax +1 205 996 2156, E-Mail [email protected]

AKI, with a time limit of 48 h to reach this threshold. Multiple studies are beginning to validate the utility of these criteria to various populations, showing a correlation between more severe RIFLE stages and worse clinical outcomes [4]. This review summarizes the results of two pivotal multicenter cohort studies of severe AKI, BEST and PICARD.

Epidemiology

The incidence of AKI and its associated mortality vary by patient setting, and are lower in the general population and higher in critically ill patients admitted to the intensive care unit (ICU). AKI is less common in the community setting, with a reported incidence ranging from 17 per million/year for adults !50 years up to 620 per million/year for those between 80 and 89 years. AKI accounts for 1% of hospital admissions in the United States [5]. The incidence of hospital-acquired AKI is 5–7%, exceeding that of community-acquired AKI by 5- to 10fold, and has nearly doubled over the last two decades [6]. Acute tubular necrosis (ATN) remains the most common cause of hospital-acquired AKI and is often multifactorial (sepsis, postsurgical, contrast agents, medications). In the ICU, 5–20% of patients, many of which have multiorgan failure, develop AKI [7]. The incidence of ICUrelated AKI has also increased over the last few decades. This is probably related to the rising incidence of sepsisrelated hospital admissions, increased prevalence of risk factors for AKI, including chronic kidney disease (CKD), diabetes mellitus, and congestive heart failure, and expanded use of intravenous radiocontrast agents. ICU patients with AKI have higher morbidity, mortality, and health care costs compared to ICU patients without AKI [8].

the median Simplified Acute Physiology Score (SAPS II) was 48. Approximately 30% of patients had impaired kidney function at baseline. About two-thirds of patients who developed AKI received RRT. Septic shock, present in 47.5%, was the most common contributing factor to AKI, followed by major surgery (34.3%), cardiogenic shock (26.9%), hypovolemia (25.6%), potentially drug-induced (19%), hepatorenal syndrome (5.7%), and obstructive uropathy (2.6%) [9]. Patients with septic AKI had higher rates of non-renal organ failure, and a greater need for mechanical ventilation and vasoactive medications compared to non septic AKI patients [10]. The overall hospital mortality rate in the BEST study was 60.3% but varied widely among centers (ranging between 50.5 and 76.8% among countries contributing more than 100 patients) [9]. Septic AKI had a higher inhospital mortality rate than nonseptic AKI (70.2 vs. 51.8%, p ! 0.001), even after adjusting for relevant covariates [10]. Study center, older age, time between hospital admission and study inclusion, SAPS II score, use of mechanical ventilation, and vasopressor use were significant independent risk factors for mortality. Most survivors (86%) were dialysis-independent at discharge. Median lengths of ICU and hospital stay were 10 and 22 days, respectively. As expected, baseline CKD increased the risk of RRT dependence (22.6 vs. 6.9%, p ! 0.001). There was a trend toward less need for RRT at discharge in septic versus nonseptic AKI patients; however, this was mostly related to a lower rate of CKD in patients with septic AKI.

Program to Improve Care in Acute Renal Disease (PICARD)

The largest prospective study of severe AKI was conducted on 29,269 critically ill adults admitted to the ICUs of 54 centers in 23 countries over 15 months beginning in September 2000 (Beginning and Ending Supportive Therapy for the Kidney: BEST Kidney) [9]. AKI was defined by oliguria (urine output !200 ml in 12 h) and/or BUN 184 mg/dl (130 mmol/l). The period prevalence of AKI was 5.7%, ranging from 1.4–25.9% across all study centers. Median age was 67 years; 63.6% were male and

The PICARD group conducted a prospective observational study from 1999 to 2001 involving 618 patients with ICU-related AKI at 5 academic medical centers in the United States [11]. AKI was defined by an increase in serum creatinine 60.5 mg/dl if the baseline creatinine was !1.5 mg/dl (new-onset AKI) or an increase 61.0 mg/dl if the baseline creatinine was between 1.5 and 4.9 mg/dl (AKI on CKD). This study demonstrated that comorbidities are now more common than in previous studies of patients developing AKI in the ICU. Thirty percent of patients had CKD, 37% had coronary artery disease, 29% had diabetes mellitus, and 21% had chronic liver disease. Of note, comorbidity rates varied significantly by site. The need for RRT was similar to that in the BEST Study, with 64% requiring dialysis. AKI was associ-

AKI Epidemiology

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ated with extrarenal organ system failure in most patients. The mean age of patients enrolled was 59.5 years, and the majority was white. The most common causes of AKI were ischemic ATN, which included sepsis and hypotension, followed by AKI related to unresolved prerenal factors, nephrotoxicity, cardiac disease, liver disease, and multifactorial causes. In-hospital mortality was 37%, with important variations by site. Interestingly, patients with AKI superimposed on CKD had a lower mortality rate than those with new-onset AKI (31 vs. 41%, p = 0.03). This finding, not observed in the BEST Study, has also been reported in other large database studies, as well as in studies examining predictors of mortality following AKI [8, 12, 13]. Subsequent epidemiological studies using the PICARD cohort have aimed to derive prediction rules for mortality related to AKI and to explore the associations between dialysis modality, timing of initiation, and survival [8].

Administrative Database Studies

Retrospective analyses of large administrative databases have recently shown a significant change in the incidence and the mortality associated with severe AKI [8, 14]. In a national representation of hospital discharges, the incidence of severe AKI (defined by AKI requiring dialysis) from 1988 to 2002 has increased from 4 to 27 per 100,000 population. In-hospital mortality, while still high, has decreased from 41.3 to 28.1% (p ! 0.001) [8]. A progressive 2.8% annual increase in the incidence of AKI and a progressive 3.8% annual decrease in AKI associated mortality (95% CI: –4.7 to –2.12; p ! 0.001), which interestingly was not observed in ICU patients without AKI, was documented from 1996–2005 in a large database of ICU patients in Australia and New Zealand [15]. The reasons for improvements in mortality are unclear and need to be investigated in future prospective studies.

Conclusion

References

Knowledge of the true incidence of and risk factors for ARF is essential for driving efforts to detect and treat this problem at the earliest possible opportunity. Previously, the epidemiology of ARF has been poorly defined due to a lack of common standards for diagnosis and classification, thereby hampering the study of ARF and improvement in patient outcomes. Recognizing this, and the fact that even small changes in serum creatinine are associc190

ated with increased morbidity, mortality, and cost, two new uniform standards for diagnosing and classifying ARF have been proposed: RIFLE and AKI. Whether these definitions become more widely accepted depends on their utility and validity. Thus far, several studies have examined the incidence and prognosis of ARF associated with the different RIFLE stages and found a correlation between worse outcomes and more severe RIFLE stages. Two large prospective observational studies have provided new insight into the epidemiology of severe AKI: BEST and PICARD. They have demonstrated that AKI is common in the ICU setting and associated with a striking impact on morbidity and mortality. The incidence of ICU-related AKI has increased, likely related to several factors: a trend toward older, more severely and chronically ill patients admitted to the hospital; an increased incidence of sepsis-related hospital admissions, and an expanded use of invasive procedures. Both BEST and PICARD found sepsis to be the most common contributing factor to ICU-related AKI. BEST showed that patients with septic AKI have more severe illness with higher rates of multiorgan failure and mortality, compared to nonseptic AKI. In addition to sepsis, other independent predictors of in-hospital mortality included advanced age and delayed onset of AKI (time between hospital admission and study inclusion). An important percentage of patients developing severe AKI had baseline CKD. These patients seem to have a lower in-hospital mortality rate but yet worse outcomes, requiring long-term RRT more frequently. Despite the increased incidence of severe AKI, the associated mortality rate, while still high, has not increased and in some studies has decreased. It is unknown if this is due to improved ICU and/or nephrology care, or to other factors. Of note, there is a wide variation across centers in patient characteristics and outcome, requiring the need of additional multicenter and interventional studies in AKI.

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1 Bellomo R: Defining, quantifying, and classifying acute renal failure. Crit Care Clin 2005;21:223–237. 2 Molitoris BA, Levin A, Warnock DG, et al: Improving outcomes of acute kidney injury: report of an initiative. Nat Clin Pract Nephrol 2007;3:439–442. 3 Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW: Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005; 16: 3365–3370.

Pisoni /Wille /Tolwani

4 Ricci Z, Cruz D, Ronco C: The RIFLE criteria and mortality in acute kidney injury: a systematic review. Kidney Int 2008; 73: 538– 546. 5 Kaufman J, Dhakal M, Patel B, Hamburger R: Community-acquired acute renal failure. Am J Kidney Dis 1991;17:191–198. 6 Lameire N, Van Biesen W, Vanholder R: The changing epidemiology of acute renal failure. Nat Clin Pract Nephrol 2006; 2: 364– 377. 7 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.

AKI Epidemiology

8 Waikar SS, Liu KD, Chertow GM: Diagnosis, epidemiology and outcomes of acute kidney injury. Clin J Am Soc Nephrol 2008;3:844– 861. 9 Uchino S, Kellum JA, Bellomo R, et al: Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294: 813–818. 10 Bagshaw SM, Uchino S, Bellomo R, et al: Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol 2007; 2:431–439. 11 Mehta RL, Pascual MT, Soroko S, et al: Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Int 2004;66:1613–1621.

12 Chertow GM, Soroko SH, Paganini EP, et al: Mortality after acute renal failure: models for prognostic stratification and risk adjustment. Kidney Int 2006;70:1120–1126. 13 Chertow GM, Christiansen CL, Cleary PD, Munro C, Lazarus JM: Prognostic stratification in critically ill patients with acute renal failure requiring dialysis. Arch Intern Med 1995;155:1505–1511. 14 Xue JL, Daniels F, Star RA, et al: Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol 2006;17:1135–1142. 15 Bagshaw SM, George C, Bellomo R: Changes in the incidence and outcome for early acute kidney injury in a cohort of Australian intensive care units. Crit Care 2007; 11:R68.

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Nephron Clin Pract 2008;109:c192–c197 DOI: 10.1159/000142928

Published online: September 18, 2008

Biomarkers for the Diagnosis of Acute Kidney Injury Sushrut S. Waikar Joseph V. Bonventre Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass., USA

Key Words Acute kidney injury ⴢ Acute renal failure ⴢ Biomarker ⴢ Diagnosis

Abstract The identification of acute kidney injury relies on tests like blood urea nitrogen and serum creatinine that were identified and incorporated into clinical practice several decades ago. This review summarizes clinical studies of newer biomarkers that may permit earlier and more accurate identification of acute kidney injury. The urine may contain sensitive and specific markers of kidney injury that are present due to either impaired tubular reabsorption and catabolism of filtered molecules or release of tubular cell proteins in response to ischemic or nephrotoxic injury. Many potential markers have been studied. Promising injury markers in the urine include N-acetyl-␤- D glucosaminidase, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and interleukin-18. New biomarkers of kidney injury hold the promise of substantially improving the diagnostic approach to acute kidney injury. Adequately powered clinical studies of multiple biomarkers are needed to qualify the biomarkers before they can be fully adopted in clinical practice. Once adopted, more sensitive biomarkers of acute kidney injury hold the potential to transform the care of patients with renal disease. Copyright © 2008 S. Karger AG, Basel

Introduction

Acute renal failure, now termed acute kidney injury (AKI), is an increasingly common and devastating complication in hospitalized patients. The current diagnostic

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tests for AKI include serum creatinine (SCr) and blood urea nitrogen (BUN), two biomarkers that were identified and incorporated into clinical practice several decades ago. It is now widely appreciated that SCr and BUN are suboptimal markers for AKI, and that more sensitive, specific, and early biomarkers are needed. This review sets out to cover recent developments in the field of AKI biomarker validation in clinical studies. Injury versus Failure: Towards a Troponin for the Kidney

The new term ‘acute kidney injury’ instead of ‘acute renal failure’ – by its replacement of the word ‘injury’ for ‘failure’ – hints towards a paradigm shift in nephrology. The diagnosis of ‘failure’ refers to the kidney’s inability to perform one of its major functions, namely glomerular filtration. The diagnosis of glomerular filtration failure is made only after endogenous filtration markers (BUN or SCr) have accumulated in the blood, typically hours or even days after an inciting event. The diagnosis of ‘injury’, by contrast, does not presuppose a reduction in glomerular filtration. Newer biomarkers are needed to identify correlates of cellular (typically tubular) injury, which may be present well before or in the absence of a reduction in GFR. The analogy to cardiology may be instructive: clinicians diagnosing acute myocardial infarction do not wait until a reduction in cardiac output, but rather make the diagnosis of myocardial injury on the basis of elevations of tissuespecific biomarkers in the serum. The biological response of kidney tissue to ischemic or nephrotoxic injury may be utilized as early indicators of

Sushrut S. Waikar, MD, MPH Brigham and Women’s Hospital, MRB-4 75 Francis Street Boston, MA 02115 (USA) Tel. +1 617 732 6020, Fax +1 617 732 6392, E-Mail [email protected]

AKI. Urine is readily accessible and has been proposed to be a more promising biological fluid than serum or plasma to identify the earliest markers of kidney injury. Time honored tests like urinary microscopy, urine osmolality, and fractional excretion of sodium or urea are nonspecific and insensitive, although careful and large prospective studies have not been conducted [1]. The urine may contain more sensitive and specific markers of kidney injury that are present due to impaired tubular reabsorption and catabolism of filtered molecules, release of enzymes or exosomes from tubular cells, and as a response of tubular cells to ischemic or nephrotoxic injury. This review will focus on several promising urinary biomarkers under investigation.

Tubular Enzymes and Markers of Tubular Dysfunction

The apical surface of proximal tubular epithelial cells contains numerous microvilli that form the brush border and contain proteins with enzymatic functions to carry out the specialized tasks of the proximal tubule. Intracellular enzymes can be released into the urine with injury [2] either by exocytosis or leakage. The proteins can exist in the free form or may be membrane-encased as exosomes. Several different classes of enzymes can be found: lysosomal proteins, such as N-acetyl-␤-D-glucosaminidase (NAG), brush border enzymes including gamma-glutamyl transferase (GGT) and alkaline phosphatase, as well as cytosolic proteins such as ␣-glutathione S-transferase (␣-GST). Furthermore, when proximal tubular epithelial cells are injured, they may not metabolize cystatin C properly, and filtered intact cystatin C may appear in the urine. Similarly, injured cells may not completely reabsorb low-molecularweight proteins that are freely filtered into the urinary space, such as ␣1- and ␤2-microglobulin. Westhuyzen et al. [3] compared the predictive value of a number of tubular enzymes for the subsequent development of AKI, defined as a 50% rise in serum creatinine to at least 1.7 mg/dl. Four of 26 subjects developed AKI; baseline levels of GGT, AP, NAG, ␣-GST and ␲-GST were higher in those who developed AKI, compared to those who did not. ␣-GGT and ␲-GST had the best predictive value on their own, with areas under the receiver-operating characteristic curve (AUC-ROC) of 0.95 (95% CI 0.79–1.0) and 0.93 (95% CI 0.74–1.0), respectively. Changes in enzyme levels preceded detectable changes in timed creatinine clearance. However, when the authors attempted to develop cutpoints based on this small study and tested the generalizability of their results in a test population of 19 patients (4 of whom developed AKI), the sensitivity and specificity of these biomarkers were significantly reduced.

Biomarkers for the Diagnosis of AKI

Several investigators have examined the ability of tubular enzymes to predict adverse clinical outcomes. Herget-Rosenthal et al. [4] risk-stratified patients with nonoliguric AKI (defined as a doubling in creatinine from a baseline concentration of !106 ␮mol/l to at least 115 ␮mol/l) using tubular enzymes as biomarkers. They identified 73 subjects who met prespecified criteria for AKI; 26 of these individuals subsequently required dialysis. They measured urinary excretion of cystatin C, ␣1- and ␤2-microglobulin, ␣-GST, NAG, retinol-binding protein (RBP), GGT and lactate dehydrogenase on the day of study enrollment. Cystatin C and ␣1-microglobulin (markers of abnormal proximal tubule function) had the best predictive value for the need for dialysis, with AUC-ROC curves of 0.92 and 0.86, respectively. Of the tubular enzymes studied, NAG had the best predictive value, with an AUC-ROC of 0.81. In another study, Chew et al. [5] found that levels of NAG and tissue non-specific alkaline phosphatase were higher in AKI patients with poor outcomes (defined as need for dialysis or death). Liangos et al. [6] recently performed a study of NAG and kidney injury molecule-1 (KIM-1, a tubular injury marker, discussed below) in 201 patients with established AKI. They found that elevated NAG levels portended poor clinical outcomes, with the odds of death or dialysis requirement increased over fivefold in patients with the highest versus lowest quartiles or urinary NAG levels, even after careful multivariable adjustment for disease severity and comorbidity. The predictive power of KIM-1 levels in this study will be discussed below. Tubular enzymes present in the urine have long been studied as markers of AKI, but they have not been adopted in widespread clinical use either as early diagnostic tests, prognostic indicators, or surrogate endpoints for interventional studies. Some authors have suggested that tubular enzymes are overly sensitive, because they tend to rise after injuries such as cardiopulmonary bypass without an associated rise in SCr [7, 8]. Investigators should exercise caution, however, in interpreting performance characteristics of new biomarkers against a gold standard like SCr that has poor specificity and sensitivity: cardiac troponin would appear to be nonspecific against earlier (and now discredited) cardiac biomarkers like lactate dehydrogenase.

Neutrophil Gelatinase-Associated Lipocalin (NGAL)

NGAL is one of the best-studied urinary biomarkers of AKI to date. Also known as lipocalin-2 or siderocalin, NGAL was first discovered as a protein in granules of hu-

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man neutrophils; animal studies showed its promise as an early marker of ischemic and nephrotoxic kidney injury [9]. Mishra et al. [10] prospectively obtained serial urine and serum samples from 71 children undergoing cardiopulmonary bypass for surgical correction of congenital heart disease. Twenty children developed AKI, defined as a 50% increase in SCr. Urinary NGAL at just 2 h following CPB almost perfectly predicted which patients would go on to develop AKI (AUC-ROC 0.998). Serum NGAL was inferior to urinary NGAL for the identification of AKI. As encouraging as these results were, it should be noted that 29% of eligible patients were excluded due to perioperative use of ibuprofen, angiotensin-converting enzyme inhibitors, gentamicin, or vancomycin. A larger follow-up study of 120 children (using similar exclusion criteria) by Dent et al. [11] showed that 2-hours postoperative serum NGAL was predictive of AKI (AUC-ROC 0.96) and correlated with postoperative change in SCr, duration of AKI, and length of stay. Wagener reported less sanguine results on urinary NGAL in 81 adult patients undergoing cardiac surgery; the only exclusion criterion was pre-existing end-stage renal disease [12]. Sixteen patients developed AKI, defined as a 50% increase in SCr. Urinary NGAL levels were consistently higher immediately postoperatively and at 1, 3, 18, and 24 h postoperatively in patients who went on to develop AKI. Substantial overlap, however, was noted between patients who did and did not develop AKI. The AUC-ROC for NGAL ranged from 0.67 (immediately after surgery) to 0.80 (18 h following surgery). The salient differences between the pediatric and adult cardiac surgery cohorts included patient age, comorbidity, and exclusion criteria. Parikh et al. [13] studied urinary NGAL in 53 consecutive patients undergoing living or deceased donor kidney transplantation. NGAL levels (normalized to urine creatinine concentration) were significantly higher in deceased donor recipients with delayed graft function (DGF) (n = 10, median 3,306 ng/mg creatinine) than prompt graft function (n = 20, median 756 ng/mg creatinine). A cutoff value of 1,000 ng/mg creatinine had 90% sensitivity and 83% specificity for the identification of DGF; the AUCROC was 0.90. Zappitelli et al. [15] studied urinary NGAL in 140 children admitted to the intensive care unit requiring mechanical ventilation. Urine was collected daily for 4 days. The authors found on cross-sectional analysis that mean and peak urinary NGAL levels were higher in patients with worsening degrees of AKI (as judged by the pediatric RIFLE criteria). At 48 h prior to the development of AKI,

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urinary NGAL had an AUC-ROC of 0.79 for the subsequent development of AKI. Urinary NGAL has also been studied as a surrogate marker of kidney injury from aprotinin, a nephrotoxic fibrinolytic used in cardiac surgery. Wagener et al. [36] found that postoperative levels of urinary NGAL were almost 20 times higher in patients who received aprotinin compared to epsilon amino-caproic acid, lending support to the suggestion of aprotinin’s nephrotoxicty. Urinary NGAL was also found to be higher after coronary angiography in 13 patients with AKI than in 27 controls without AKI [17].

Interleukin-18

IL-18 was found to potentiate ischemic AKI and to be detectable in the urine of mice subjected to ischemic kidney injury [18]. Urinary IL-18 has been studied by Parikh and coworkers in a variety of clinical settings, including delayed graft function [14], cardiac surgery [19], acute respiratory distress syndrome [20], and cross-sectionally in patients with and without kidney disease [21]. The first AKI study of urinary IL-18 in humans was a cross-sectional comparison of patients with ATN (n = 14), pre-renal azotemia (n = 8), UTI (n = 5), CKD (n = 12), transplant recipients (n = 22), and healthy controls (n = 11) [21]. The highest levels of urinary IL-18 were observed in patients with ATN and delayed graft function, with relatively little overlap from patients with pre-renal azotemia, urinary tract infections, and CKD. The AUC-ROC from this cross-sectional cohort (for the identification of ATN, including delayed graft function) was 0.95, with a sensitivity of 85% and specificity of 88% at a cutoff of 500 pg IL18/mg creatinine. The NIH sponsored Acute Respiratory Distress Syndrome Network trial of low versus high tidal volume ventilation was the source of urine samples in a subsequent study of urinary IL-18 [20]. Parikh and colleagues performed a prospective, nested, case-control study in 138 of the 861 patients enrolled; exclusion criteria included a baseline SCr 11.2 mg/dl. They found that urinary IL-18 levels were higher in those patients who developed AKI (defined as a 50% increase in SCr within 6 days of enrollment), and that higher levels were predictive of mortality. The AUC-ROC for IL-18 (not normalized to urine creatinine) was 0.73 at 24 h prior to AKI diagnosis; this value does not compare favorably with the AUC-ROC of 0.95 from the cross-sectional study of urinary IL-18. Parikh et al. [20] also measured IL-18 in urine samples collected in the pediatric cardiac surgery cohort used to

Waikar/Bonventre

study NGAL. They measured IL-18 in all 20 cases of AKI and in 35 of the 51 non-AKI cases (matched according to race, gender, and age to AKI cases). Compared to NGAL, which increased 25-fold within 2 h and declined after 6 h of CPB, IL-18 increased at 4–6 h and remained elevated up to 48 h following CPB. The reported AUC-ROCs for IL-18 were 0.61 at 4 h, 0.75 at 12 h, and 0.73 at 24 h, substantially lower than the 0.998 reported by Mishra for NGAL at 2 h following CPB. IL-18 was also studied by Washburn et al. [14] in critically ill children requiring mechanical ventilation (identical cohort as studied by Zappitelli et al. [15] for NGAL). They found on cross-sectional analysis that peak urinary IL-18 levels were higher in patients with worsening degrees of AKI (as judged by the pediatric RIFLE criteria). However, in prospective analysis IL-18 demonstrated no ability to predict the subsequent development of AKI (AUC-ROC 0.54). Not surprisingly for a pro-inflammatory cytokine that plays an important role in sepsis, urinary IL-18 was significantly higher in patients with sepsis than in those without, and limited its diagnostic ability for the early identification of AKI in this cohort. Urinary IL-18 has also been studied as a biomarker of contrast nephropathy with mixed results. Ling et al. [17] found higher urinary levels in 13 patients who developed AKI following coronary angiography than in 27 non-AKI controls (p ! 0.01), whereas Bulent et al. [22] found no difference in a similar number of patients with and without AKI.

Kidney Injury Molecule-1 (KIM-1)

NHE3 is the most abundant sodium transporter in the renal tubule and is responsible for proximal reabsorption of up to 70% of filtered sodium and bicarbonate. Du Cheyron et al. [23] performed a cross-sectional study of 68 patients admitted to the ICU. They isolated membrane fractions from the urine and measured NHE3 concentrations using semiquantitative immunoblotting. NHE3 protein was undetectable in patients without AKI (n = 14), detectable at relatively low levels in patients with pre-renal azotemia (n = 17) and post-renal obstruction (n = 3), and was significantly elevated in ATN (n = 17; 6.6-fold higher than in pre-renal azotemia). The same investigators also measured urinary retinol-binding protein (RBP), the primary plasma transport protein for vitamin A which is filtered by the glomerulus and then reabsorbed by the proximal tubule. Urinary RBP was significantly higher in patients with ATN than normal controls, but significant overlap was noted, particularly with pre-renal azotemia.

Kidney injury molecule-1 (‘KIM-1’ in humans, or ‘Kim-1’ in rodents) was identified as the single most upregulated gene in postischemic rat kidney using a PCR-based technique [24]. KIM-1 encodes a type I cell membrane glycoprotein containing, in its extracellular portion, a novel sixcysteine immunoglobulin-like domain and a threonine/ serine and proline-rich domain characteristic of mucinlike O-glycoslyated proteins, suggesting its potential involvement in cell-cell and/or cell-matrix interactions [25]. After proximal tubular kidney injury, the ectodomain of KIM-1 protein is shed from cells into the urine in rodents and in humans. In both ischemia-reperfusion and cisplatin-induced nephrotoxicity models in the rat, urinary Kim-1 is a sensitive and specific indicator of proximal tubular kidney injury and is increased earlier than any of the conventional biomarkers, e.g. plasma creatinine, blood urea nitrogen, glycosuria, proteinuria, and urinary NAG [26]. In recently completed studies of 8 mechanistically different proximal tubule nephrotoxicants and 2 different hepatotoxicants in rats, Kim-1 had an AUC-ROC of 0.99 for proximal tubular toxicity, using histopathology as the gold standard; of 21 urinary markers studied, Kim-1 was found to be to have the highest sensitivity and specificity [27]. Human studies have begun to confirm the promise of urinary KIM-1 for the diagnosis of AKI. Han et al. [28] demonstrated marked expression of KIM-1 in kidney biopsy specimens from 6 patients with acute tubular necrosis (ATN), and found elevated urinary levels of KIM-1 in 7 patients with ischemic ATN; urinary levels of KIM-1 were significantly lower in contrast nephropathy (n = 7), although the levels did correlate with severity of contrastinduced injury. Levels of urinary KIM-1 were lower in AKI not due to ATN (n = 9), CKD (n = 9), and were below limits of detection in normal subjects (n = 8) [28]. KIM-1 is also highly expressed in the setting of renal cell carcinoma (RCC), as shown by Han et al. [29]. KIM-1 was detectable in the urine of patients with RCC, suggesting a potential role for early non-invasive diagnosis. Lin et al. [30] studied KIM-1 protein expression in a large series of 480 neoplasms and found KIM-1 expression in papillary, clear cell, and metastatic RCC but not chromophobe RCC. They also demonstrated KIM-1 staining in 15 of 16 cases of clear cell carcinoma of the ovary. Van Timmeren et al. [31] stained for KIM-1 protein in tissue specimens from 102 patients who underwent kidney biopsy for a variety of kidney diseases and 7 patients who underwent nephrectomy for renal cell carcinoma. No tissue KIM-1 was found in patients with minimal change disease or in the

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tumor-free samples of renal cell carcinoma. In all other disease conditions, KIM-1 protein was identified in dedifferentiated proximal tubular cells and correlated with tubulointerstitial fibrosis and inflammation. In the subset of patients who underwent urine collection near the time of biopsy, urinary KIM-1 levels correlated with tissue expression of KIM-1. Urinary KIM-1 may therefore hold promise as a non-invasive assessment of the activity and prognosis of a variety of acute and chronic kidney diseases. The diagnostic and prognostic role of KIM-1 in kidney transplant recipients was evaluated by Zhang et al. [32] in 25 protocol biopsies, 25 biopsies of patients with active tubular injury, and 12 patients with acute cellular rejection. Focal KIM-1 expression was found in 28% of protocol biopsies despite the absence of conventional histologic evidence of tubular cell injury. Proximal tubule KIM-1 expression was found in all patients with histologic evidence of tubular cell injury, and higher KIM-1 staining correlated with improved renal outcomes at 18 months. Van Timmeren et al. [33] studied 24-hour urinary KIM-1 excretion in 145 stable renal transplant recipients who were subsequently followed for 4 years. Higher KIM-1 excretion was associated with significantly higher risk of graft loss over the follow-up period. High KIM-1 excretion was also associated with proteinuria, low creatinine clearance, and high donor age, but was independently associated with graft loss after multivariate adjustment for these variables. Liangos et al. [6] studied urinary KIM-1 (and NAG, see above) at the time of nephrology consultation in 201 patients with established AKI. Because non-AKI controls were not included in this study, diagnostic performance characteristics like sensitivity, specificity, or the area under the receiver operating characteristics curve were not reported. KIM-1 demonstrated prognostic significance: elevated levels were significantly associated with the clinical composite endpoint of death or dialysis requirement, even after adjustment for disease severity or comorbidity. How KIM-1 and other markers will compare to other predictive markers and clinical scoring systems is the subject of extensive ongoing studies.

Other Markers

Keratinocyte-derived chemokine was found by Molls et al. [34] in a mouse model of renal ischemia-reperfusion injury to be elevated in serum and urine 3 h following injury. These investigators measured urinary levels of a structurally homologous molecule in humans, termed human growth-related oncogene- ␣ (Gro- ␣), in a small c196

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pilot study of patients (n = 17) undergoing kidney transplantation, and found markedly higher levels among those with DGF following deceased donor transplantation. Zhou et al. [35] have focused on urinary exosomes (small excreted vesicles which contain membrane and cytosolic proteins) as a potential source of novel AKI biomarkers. Exosomal fetuin-A was identified in preclinical rodent models of ischemic and cisplatin-induced AKI; a small pilot study in 9 humans showed exosomal fetuin-A to be present in the urine of ICU patients with AKI but not in healthy volunteers or ICU patients without AKI [35].

Conclusion

New biomarkers under clinical investigation will likely perform differently with respect to disease specificity (e.g. sepsis vs. nephrotoxic versus postoperative AKI), time course (early vs. late markers), and prognostic characteristics (markers of incipient AKI vs. markers of prognosis in established AKI). Establishing the optimal test(s) for a given clinical scenario will require prospective validation in large numbers of patients with a variety of causes of AKI, preferably with measurement of numerous candidate biomarkers for the purpose of efficiency. The possibility that new biomarkers may be superior to SCr for the identification of AKI will require investigators to test the creatinineindependent associations between biomarker levels and exposures (e.g. cardiopulmonary bypass time, dose of nephrotoxin administration) and outcomes (e.g. not only AKI as defined by creatinine but also length of stay, need for dialysis, and mortality). Early and accurate diagnosis of AKI will allow interventional studies to be performed in a timely fashion, which is a prerequisite for the future development of effective prevention and therapeutic strategies that have eluded nephrology for years.

References

1 Bagshaw SM, Langenberg C, Bellomo R: Urinary biochemistry and microscopy in septic acute renal failure: a systematic review. Am J Kidney Dis 2006;48:695–705. 2 D’Amico G, Bazzi C: Urinary protein and enzyme excretion as markers of tubular damage. Curr Opin Nephrol Hypertens 2003;12: 639–643. 3 Westhuyzen J, Endre Z, Reece G, Reith D, Saltissi D, Morgan T: Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrol Dial Transplant 2003; 18:543– 551.

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4 Herget-Rosenthal S, Poppen D, Husing J, Marggraf G, Pietruck F, Jakob H-G, Phillipp T, Kribben A: Prognostic value of tubular proteinuria and enzymuria in nonoliguric acute tubular necrosis. Clin Chem 2003; 50: 552–558. 5 Chew SL, Lins RL, Daelemans R, Nuyts GD, De Broe ME: Urinary enzymes in acute renal failure. Nephrol Dial Transplant 1993; 8: 507–511. 6 Liangos O, Perianayagam MC, Vaidya VS, Han WK, Wald R, Tighiouart H, MacKinnon RW, Li L, Balakrishnan VS, Pereira BJ, Bonventre JV, Jaber BL: Urinary N-acetylbeta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol 2007;18:904–912. 7 Eijkenboom JJ, van Eijk LT, Pickkers P, Peters WH, Wetzels JF, van der Hoeven HG: Small increases in the urinary excretion of glutathione S-transferase A1 and P1 after cardiac surgery are not associated with clinically relevant renal injury. Intensive Care Med 2005;31:664–667. 8 Hamada Y, Kanda T, Anzai T, Kobayashi I, Morishita Y: N-acetyl-beta-D-glucosaminidase is not a predictor, but an indicator of kidney injury in patients with cardiac surgery. J Med 1999;30:329–336. 9 Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P: Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003; 14:2534–2543. 10 Mishra J, Dent C, Tarabishi R, et al: Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365:1231–1238. 11 Dent CL, Ma Q, Dastrala S, Bennett M, Mitsnefes MM, Barasch J, Devarajan P: Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study. Crit Care 2007;11:R127. 12 Wagener G, Jan M, Kim M, Mori K, Barasch JM, Sladen RN, Lee HT: Association between increases in urinary neutrophil gelatinaseassociated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology 2006; 105:485–491. 13 Parikh CR, Jani A, Mishra J, Ma Q, Kelly C, Barasch J, Edelstein CL, Devarajan P: Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation. Am J Transplant 2006; 6: 1639–1645. 14 Washburn KK, Zappitelli M, Arikan AA, Loftis L, Yalavarthy R, Parikh CR, Edelstein CL, Goldstein SL: Urinary interleukin-18 is an acute kidney injury biomarker in critically ill children. Nephrol Dial Transplant 2008;23:566–572.

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15 Zappitelli M, Washburn KK, Arikan AA, Loftis L, Ma Q, Devarajan P, Parikh CR, Goldstein SL: Urine neutrophil gelatinaseassociated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study. Crit Care 2007; 11:R84. 16 Shaw AD, Stafford-Smith M, White WD, et al: The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008;358:784–793. 17 Ling W, Zhaohui N, Ben H, Leyi G, Jianping L, Huili D, Jiaqi Q: Urinary IL-18 and NGAL as early predictive biomarkers in contrastinduced nephropathy after coronary angiography. Nephron Clin Pract 2008; 108:c176– c181. 18 Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, Schrier RW, Edelstein CL: Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest 2001;107:1145–1152. 19 Parikh CR, Mishra J, Thiessen-Philbrook H, Dursun B, Ma Q, Kelly C, Dent C, Devarajan P, Edelstein CL: Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int 2006;70:199– 203. 20 Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL: Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol 2005;16:3046–3052. 21 Parikh CR, Jani A, Melnikov VY, Faubel S, Edelstein CL: Urinary interleukin-18 is a marker of human acute tubular necrosis. Am J Kidney Dis 2004;43:405–414. 22 Bulent Gul CB, Gullulu M, Oral B, Aydinlar A, Oz O, Budak F, Yilmaz Y, Yurtkuran M: Urinary IL-18: a marker of contrast-induced nephropathy following percutaneous coronary intervention? Clin Biochem 2008;41: 544–547. 23 du Cheyron D, Daubin C, Poggioli J, Ramakers M, Houillier P, Charbonneau P, Paillard M: Urinary measurement of Na+/H+ exchanger isoform 3 (NHE3) protein as new marker of tubule injury in critically ill patients with ARF. Am J Kidney Dis 2003; 42: 497–506. 24 Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, Sanicola M: Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem 1998;273:4135–4142. 25 Bailly V, Zhang Z, Meier W, Cate R, Sanicola M, Bonventre JV: Shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration. J Biol Chem 2002;277:39739–39748.

26 Vaidya VS, Ramirez V, Ichimura T, Bobadilla NA, Bonventre JV: Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am J Physiol Renal Physiol 2006;290: F517–F529. 27 Dieterle F, Staedtler F, Grenet O, et al: Qualification of biomarkers for regulatory decision making: a kidney safety biomarker project (abstract, Society of Toxicology). Toxicologist 2007; 96:383. 28 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;62:237–244. 29 Han WK, Alinani A, Wu CL, Michaelson D, Loda M, McGovern FJ, Thadhani R, Bonventre JV: Human kidney injury molecule-1 is a tissue and urinary tumor marker of renal cell carcinoma. J Am Soc Nephrol 2005;16:1126– 1134. 30 Lin F, Zhang PL, Yang XJ, Shi J, Blasick T, Han WK, Wang HL, Shen SS, Teh BT, Bonventre JV: Human kidney injury molecule-1 (hKIM-1): a useful immunohistochemical marker for diagnosing renal cell carcinoma and ovarian clear cell carcinoma. Am J Surg Pathol 2007; 31:371–381. 31 van Timmeren MM, van den Heuvel MC, Bailly V, Bakker SJ, van Goor H, Stegeman CA: Tubular kidney injury molecule-1 (KIM1) in human renal disease. J Pathol 2007;212: 209–217. 32 Zhang PL, Rothblum LI, Han WK, Blasick TM, Potdar S, Bonventre JV: Kidney injury molecule-1 expression in transplant biopsies is a sensitive measure of cell injury. Kidney Int 2008;73:608–614. 33 van Timmeren MM, Vaidya VS, van Ree RM, Oterdoom LH, de Vries AP, Gans RO, van Goor H, Stegeman CA, Bonventre JV, Bakker SJ: High urinary excretion of kidney injury molecule-1 is an independent predictor of graft loss in renal transplant recipients. Transplantation 2007;84:1625–1630. 34 Molls RR, Savransky V, Liu M, Bevans S, Mehta T, Tuder RM, King LS, Rabb H: Keratinocyte-derived chemokine is an early biomarker of ischemic acute kidney injury. Am J Physiol Renal Physiol 2006; 290:F1187– F1193. 35 Zhou H, Pisitkun T, Aponte A, et al: Exosomal fetuin-A identified by proteomics: a novel urinary biomarker for detecting acute kidney injury. Kidney Int 2006; 70: 1847– 1857. 36 Wagener G, Gubitosa G, Wang S, Borregaard N, Kim M, Lee HT: Increased incidence of acute kidney injury with aprotinin use during cardiac surgery detected with urinary NGAL. Am J Nephrol 2008;28:576–582.

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Nephron Clin Pract 2008;109:c198–c204 DOI: 10.1159/000142929

Published online: September 18, 2008

Imaging Techniques in Acute Kidney Injury Asif A. Sharfuddin Ruben M. Sandoval Bruce A. Molitoris Division of Nephrology, Department of Medicine, Indiana Center for Biological Microscopy, Indiana University School of Medicine, Indianapolis, Ind., USA

Key Words Multi-photon microscopy ⴢ Ultrasound ⴢ MRI ⴢ Acute kidney injury ⴢ Ischemia ⴢ Sepsis

Abstract Multi-photon microscopy, along with advances in other imaging modalities, allows investigators the opportunity to study dynamic events within the functioning kidney. These emerging technologies enable investigators to follow complex heterogeneous processes in organs such as the kidney with improved spatial and temporal resolution, and sensitivity. Furthermore, the ability to obtain volumetric data (3-D) makes quantitative 4-D (time) analysis possible. Finally, use of up to three fluorophores concurrently in multi-photon microscopy allows for three different or interactive processes to be observed simultaneously. Therefore, this approach complements existing molecular, biochemical, pharmacologic and radiologic techniques by advancing data analysis and interpretation to subcellular levels for molecules without the requirement for fixation. Its use in acute kidney injury is in its infancy but offers much promise for unraveling the complex interdependent processes known to contribute to cell injury and organ failure. Also, recent advances in other imaging techniques offer potential clinical diagnostic tools to study acute kidney injury in animal models and in patients. Copyright © 2008 S. Karger AG, Basel

© 2008 S. Karger AG, Basel 1660–2110/08/1094–0198$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nec

Introduction

Developments in kidney imaging over the last decade have provided researchers new and tremendously indepth insights into complex yet highly interdependent processes. A significant advance in these developments has been the emerging technology of studying cells within their natural living environment, rather than in isolated ex vivo controlled settings. This gives the unique opportunity of analyzing cellular pathophysiology and the effects of potential treatments in the context of an intact functioning organ. It also offers hope for additional diagnostic tools for diagnosis, stratification and prognostic purposes. The purpose of this review is to emphasize newer imaging techniques that have application to preclinical and potentially clinical studies.

Multi-Photon Microscopy

The potential to image deeper, with far less phototoxicity, into biological tissue was accomplished by utilizing multi-photon microscopy where increased penetration (up to 200 ␮m in the kidney) occurs from the unique photophysics of multi-photon fluorescence excitation, in which fluorescence is stimulated by the simultaneous absorption of two low-energy photons by a fluorophore [1– 3]. It also allows for utilization of multiple fluorescent Bruce A. Molitoris, MD Division of Nephrology, Indiana University School of Medicine 950 W. Walnut Street, R2-202 Indianapolis, IN 46202 (USA) Tel. +1 317 274 5287, Fax +1 317 274 8575, E-Mail [email protected]

probes simultaneously, enabling labeling of different physiological compartments. Distinguishing these fluorescent emissions from endogenous or auto-fluorescence is also easier and enhanced in multi-photon fluorescence microscopy, as compared to confocal microscopy, as the fluorescence excitation occurs only at the focal point of the excitation beam. Therefore, out of focus fluorescent excitation is eliminated [2]. Table 1 lists the possible types of data that can be acquired using multi-photon imaging of the kidneys. Figure 1 shows renal cortical images under physiological states (fig. 1a) and during acute kidney injury in a rat model of sepsis (fig. 1b). Reduced glomerular filtration, proximal tubule cell injury, apoptosis, reduced PTC endocytosis, reduced RBC flow rates, and increased WBC adhesion have been visualized in models of acute renal injury. Migration of WBC out of the microvasculature has not been seen up to 24 h after injury. Yu et al. [4] have developed a quantitative ratiometric approach using a generalized polarity (GP) concept that was implemented to analyze the multidimensional data obtained from multi-dextran infusion experiments, the concept being the comparison of relative intensities of two fluorescent dyes. Ratiometric-imaging methods are relatively independent of the amount of fluorescent probes injected, the excitation power and the depth of field being imaged. These properties are particularly advantageous for the quantitative imaging of animals where there is variability in the quantity of dyes injected, the appropriate levels of laser power used, and imaging depth. In addition, using ratiometric techniques also minimizes spatial variations of the fluorescence signals across the field of view due to detector/sample nonuniformity. Finally, these investigators were able to quantify GFR based upon the disappearance (filtration) of a small molecular weight dextran, compared to a nonfiltered fluoroscopy dextran, over time.

Table 1. Investigational uses for multi-photon microscopy

Glomerular Size/volume Permeability/filtration Fibrosis/sclerosis Microvasculature RBC flow rate Endothelial permeability WBC adherence/rolling Vascular diameter Cellular uptake Cell type-specific uptake Site – apical vs. basolateral membrane Mechanism – endocytosis vs. carrier/transporter mediated Cellular trafficking Intracellular organelle distribution Cytosol localization Cellular metabolism Fluorescence decay over time Cell toxicity Cell injury in necrosis, apoptosis Surface membrane/blebbing Mitochondrial function Glomerular filtration rate determination

Intracellular organelles such as mitochondria and lysosomes can be studied in acute injury states by specific labeling of these organelles and quantifying individual number and fluorescence potential of respective organelles. DNA fluorescent markers can help identify specific cell types based on their nuclear morphology (e.g. nuclei of podocytes are characteristically bean shaped, while endothelial cells have characteristic flattened elongated morphology). It also permits evaluation of intranuclear uptake of other fluorescent compounds in disease and therapeutic states, and analysis of necrosis and apoptosis [5].

Intracellular – Endocytosis, Trafficking, Transcytosis Intracellular uptake, distribution and metabolism can be studied and quantified once the fluorescent probe has entered the cell. Using multi-photon microscopy it is now possible to observe and quantify endocytosis occurring across the apical membrane of the proximal tubule cells [1]. Furthermore, it is possible to follow the intracellular accumulation and subcellular distribution over time in the same animal, and to undertake repeated observations in the same animal at varying intervals over days to weeks. Such experiments are particularly useful in understanding drug delivery for acute kidney injury states.

Glomerular Permeability Glomerular permeability and filtration of different sized compounds across glomerular capillaries can be quantified and visualized using Munich-Wistar rats with surface glomeruli (100 ␮m in diameter). Areas of interest can be defined and isolated and fluorescence intensities measured to obtain quantitative date. By using the change in GP or ratiometric methods, it is possible to quantify glomerular permeability by measuring relative change intensities of dyes in the bloodstream or within the Bowman’s space [4]. Filtration and clearance of smaller size molecules is typically faster than larger-size molecules. By using two different-sized fluorescent dextrans, it is thus possible to measure glomerular filtration fraction by

Kidney Imaging

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* *

*

a

Fig. 1. Intravital kidney imaging showing endothelial and epithelial cells dysfunction during sepsis. a A rat under physiologic con-

ditions was given a large 500-kDa amount of fluorescein dextran (green) to label the microvasculature, Hoechst 33342 (cyan) to label nuclei systemically, and a small 3-kDa amount of rhodmaine dextran (red). Circulating red blood cells (RBCs) within the microvasculature appear as black streaks as the 500-kDa dextran (green) fills the plasma space but remains excluded from the RBCs. Proximal tubule cells with early endosomes incorporating the small 3-kDa dextran (red) are easily distinguished from distal tubules (center) that do not internalize the small dextran but incorporate higher intensity of the nuclear dye. Note the lack of flux

measuring the changes in concentration in the bloodstream over time of each dextran. Proximal Tubule (PT) Reabsorption Since many acute kidney injury states affect the PTs, it is very important to be able to study the reabsorptive profile of the tubular epithelium and its recovery with or without therapeutic intervention. It is possible to evaluate the reabsorptive properties of the PT by: (1) direct observation of the epithelial cells and lumen of the PT, (2) luminal GP changes in the PT, and (3) comparing the change in GP values from within PT lumen with those from within the Bowman’s capsule [1–4]. Red Blood Cell Flow Rates Multiphoton microscopy can also be utilized to study and quantify red blood cell (RBC) flow rates in the microvasculature. It is possible to image and differentiate the motion of RBCs in the renal cortex microvasculature. RBCs exclude the nonfilterable fluorescent dye used to label the circulating plasma and consequently appear as dark, nonfluorescent objects on the images. The acquisition of repetitive scans along the central axis of a capilc200

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b

of the 500-kDa dextran into the interstitial space under physiologic conditions (arrowheads). b A rat kidney 24 h after cecal ligation and puncture to induce sepsis. Alterations in the RBC flow can be seen as nucleated white blood cells (arrows) which obstruct and hinder flow. Also noticeable is the flux of the 500-kDa dextran (green) into the interstitial space between the microvasculature and tubules (arrowheads). Proximal tubule cell accumulation of the 3-kDa dextran (red) is minimal and seen as cytosolic staining. Also distinguishable is the appearance of apoptotic nuclei (asterisk) and increased nuclear fluorescence associated with nuclear condensation. Bar = 20 ␮m.

lary (line-scan method) gives the flow of RBCs, which leaves dark striped bands in the images, where the slope of the bands is inversely proportional to the velocity; the more shallow the slope, the faster the flow rate [6]. Using standardized vessel length, diameter and angles, it is possible to calculate the RBC flow rates in different states, e.g. ischemia, sepsis, and response to specific treatments [7–11]. Inflammation and Leukocytes Inflammation is being increasingly recognized as an important and central process in the initiation, maintenance and progression of acute and chronic kidney injury. Hence, understanding the dynamic roles and functions of different leukocytes and their interactions with soluble and endothelial cell factors is key to develop and test preventive and therapeutic strategies. Multi-photon microscopy provides the opportunity to observe these crucial processes in vivo. The most effective method to image leukocytes in the kidney involves direct fluorescent labeling of specific WBC lineages. Fluorescent agents such as rhodamine 6G, acridine red or orange are preferentially concentrated in WBC and allow intravascular Sharfuddin/Sandoval/Molitoris

detection. The DNA dye Hoechst, used to label all nuclei, also permits detection of WBC and differentiation of RBCs in the vascular space. Various markers are available for B lymphocytes, CD8+ T lymphoblasts, macrophages, naïve T cells, etc. [9]. Vascular Pathology Acute kidney injury resulting from ischemia is associated with microvascular permeability defects and this is eventually linked with microvascular drop-out [11]. Various other pathological conditions affect the vascular space especially the glomerular vasculature. Apart from studying flow rates as mentioned above, using mixtures of different-sized fluorescent labeled dextrans, we can now examine the effect of injury on the microvasculature by observing and measuring the extravasation of these dextrans into the interstitium as elegantly demonstrated by Sutton et al. [12]. Furthermore, using multiple fluorescent labeling there is also the opportunity study the effect of injury on the intricate and dynamic interaction of the endothelium with the matrix proteins such as metalloproteinases [13]. It also allows for correlation and further quantification of the relationship between the endothelial permeability and alterations in blood flow rates. The regulation of glomerular hemodynamics is dependent on the interplay between the microvasculature, tubule and the juxtaglomerular apparatus (JGA). Peti-Peterdi and colleagues [14] have now extended their studies into actually being able to quantify renin content of the JGA in vivo in anesthetized Munich-Wistar rats using quinacrine tagging of the renin-secreting granules. They have also been able to measure the diameters of the afferent and efferent arterioles as well as glomerular volume. Fluorescence microscopy application also extends its application to gene transfer into specific targets, e.g. tubular or endothelial cells. Green fluorescent protein (GFP) linked with the protein of interest, e.g. actin, that is cloned into an adenovirus vector, can be delivered into the urinary Bowman’s space, proximal tubule lumen or superficial efferent arteriole by micropuncture techniques. The expression of these fluorescent labeled proteins is an invaluable tool in studying dynamic changes in the cell in various disease models [15].

minimal invasion. Yamamoto et al. [16] initially utilized a small pencil-lens video microscope in ischemic rat kidneys to study changes in peritubular capillaries by directly opposing the capsule with a 1-mm tipped video microscope. The peri-glomerular microvasculature can be evaluated as well with a small incision in the capsule permitting access to the deeper tissues. The line-shift method calculation of RBC flow in these capillaries can determine the renal microvascular blood flow in ischemic as well as reperfusion states. These studies were recently extended to the human scenario by using high magnification videoendoscopy in a similar manner in human renal transplantation. This method demonstrated diminished peritubular flow occurring after reperfusion and this correlated with reductions in creatinine clearance [17].

Infra-Red Imaging

Other novel imaging techniques utilized in ischemiareperfusion include infra-red (IR) imaging. Kirk and colleagues [18] used an advanced digital IR camera to image local temperature gradients simultaneously across the entire transplanted kidney by passively detecting IR emission. Infrared re-warming time was correlated with the subsequent return of renal function as well as a negative correlation with the regression slope of creatinine and the regression slope of BUN. The advantages of this method include providing a global whole kidney image of reperfusion instead of measurements of a single region, as well as giving information about regional defects. It can also provide valuable real-time intra-operative data and imaging which can assist surgeons in complicated surgeries and making instant therapeutic manipulations.

MRI Studies in AKI

Recent refinement of intravital videomicroscopy, combined with sophisticated image analysis, has permitted researchers to monitor microcirculation in vivo with

Dendrimers can be polymerized to form nanoparticles of precise size that can be readily chelated to imaging agents such as gadolinium. Particle size is extremely important as the body handles specific size nanoparticles very differently. For instance, 2-nm particles are handled very similarly to low-molecular-weight contrast agents, but the kidney demonstrates significantly decreased renal excretion when it is 6-nm particles, and virtually no renal excretion for 11-nm particles [19]. In a rat model of tubular nephrotoxicity caused by cis-platinum, Kobaya-

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shi et al. [20] observed loss of the normal outer stripe in the medulla. The loss of the normal renal architecture after the G-4 dendrimer was proportional to the degree of renal damage. Thus, dendrimer-based MR could be used to monitor specific outer medullary damage caused by nephrotoxic events such as drugs, ischemia, infection, and obstruction. Star et al. [21] have shown, in a mouse model, that dendrimer-enhanced MRI can distinguish sepsis-induced ARF from prerenal azotemia and renal failure due to ischemia-reperfusion or cisplatin. Furthermore, the injury could be detected as early as 6 h before serum creatinine was elevated, track the response to therapy, and provide prognostic information. However, the recent link of gadolinium-based contrast agents with nephrogenic systemic fibrosis may limit its use in human clinical studies of AKI. USPIO Magnetic resonance angiography utilizes ultra-small particles of iron oxide (USPIO) that have been developed as macromolecular agents based on iron. USPIO are 20to 30-nm dextrans coated in a formulation chemically known as ferumoxtran-10 and are not filterable across the glomerulus. These agents circulate intravascularly and might be used to evaluate renal blood volume, flow and dynamic intravascular blood flow measurements. By 24 h, macrophages and monocytes phagocytose almost all circulating USPIO and then travel to the lymph nodes and areas of inflammation [19]. In acute ischemia-reperfusion injury, USPIO-laden macrophages accumulate in the outer medulla, corresponding to an inflammatory infiltrate induced by the ischemia [22], whereas others have demonstrated that, in renal transplant models of allograft rejection, uptake of USPIO corresponds with the loss of signal in the renal parenchyma and the degree of lymphocytic infiltration. Thus, USPIO could serve as a marker to detect early acute kidney injury. BOLD-MRI Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) is a noninvasive method to assess tissue oxygen bioavailability, using deoxyhemoglobin as an endogenous contrast agent [23]. Oxyhemoglobin is a diamagnetic molecule that creates no magnetic moment as oxygen molecules are bound to iron, while deoxyhemoglobin is a paramagnetic molecule that generates magnetic moments by its unpaired iron electrons. Higher levels of deoxyhemoglobin result in increased magnetic spin dephasing of blood water protons and decreased signal intensity on T2*-weighted MR imaging sequences. Inc202

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creased R2* or decreased intensity on T2-weighted images imply increased deoxyhemoglobin (decreased oxyhemoglobin) and decreased partial pressures of oxygen (PaO2) in tissues. Therefore, the technique can be used to determine intrarenal oxygen bioavailability and has been used to investigate human and experimental models of kidney disease including radiocontrast nephropathy, acute allograft dysfunction, acute ischemic kidney injury, and unilateral ureteral obstruction [24]. This form of noninvasive imaging is desirable as it uses an endogenous marker and thus is free from exogenous agents and their potentially harmful side effects. Other MR techniques recently being studied to image ATN and differentiate it from other causes of renal failure involve 23Na MRI. The maintenance of the corticomedullary sodium gradient, an indicator of normal kidney function, is presumably lost early in the course of ATN. In rat kidneys at 6 h after the induction of ATN, the sodium images revealed that the sham-controlled kidney exhibited a linear increase in sodium concentration along the corticomedullary axis as compared to the ATN kidney where the cortico-outer medullary sodium gradient was reduced by 21% and the inner medulla to cortex sodium ratio was decreased by 40%. This was inversely correlated with small but significant rise in plasma creatinine and very limited outer medullary histologic ATN. Thus, it is possible that 23Na MRI may non-invasively detect corticomedullary sodium gradient abnormalities to identify evolving ATN when morphologic tubular injury is still focal and limited [25]. Electron Paramagnetic Resonance Imaging Oxidative stress plays a role in acute kidney injury and as this role is further defined, the importance of investigating the kinetics of reactive oxygen species (ROS) or related substances in vivo will be needed. One method to detect and study oxidative stress is electron paramagnetic resonance (EPR) imaging which is a technique to detect unpaired electrons. In the ischemia-reperfusion model, EPR imaging by Hirayama and Nagase [26] has shown significantly impaired renal radical-reducing activity in the early post-reperfusion state and only partial recovery of this radical-reducing activity even after serum markers have normalized. Other models of acute kidney injury such as LPS and puromycin nephrosis have also been investigated using EPR imaging. Positron Emission Tomography Positron emission tomography (PET) allows generation of images with higher resolution and absolute quanSharfuddin/Sandoval/Molitoris

tification of biological processes such as transport activities and enzyme activities and its correlation with renal blood flow and glomerular filtration rate. Its value is further enhanced when its functional information is combined with computerized tomographic data. Using new PET tracers, it is possible that qualitative and quantitative assessments of in vivo hypoxia, apoptosis, endothelial dysfunction, signal transduction and organic cation transport can be performed [27]. Contrast-Enhanced Ultrasonography Sonographic imaging of the kidneys is a routine procedure in clinical practice; however, conventional 2-D sonography has limitations due to the limited sensitivity of color Doppler ultrasonography (CDUS) for the detection of intracortical capillaries and deep pedicular vessels, and also the poor contrast of B-mode imaging for parenchymal disease [28]. Microbubble ultrasound contrast agents overcome these limitations allowing much improved assessment of the complete vascular supply of native or transplanted kidneys. After intravenous administration, microbubbles simply travel in through the renal microvasculature, but do not pass through the Bowman’s capsule. Hence, they remain in the renal blood pool without sticking to the capillary walls, are not phagocytosed, do not reach the interstitial compartment, and are not excreted into the collecting system. Thus, their pharmacokinetics is strongly different from iodinated contrast agents and gadolinium chelates. It does have the advantage of repeated administration of microbubble contrast agents in patients with renal injury and there no toxicity has yet been reported [28].

Contrast-enhanced sonography (CES) has a much higher sensitivity and specificity and might be considered the modality of choice for the detection of infarction and cortical necrosis, particularly in ischemic renal transplants. CES provides quantitative information on microvascular perfusion of the renal allografts and offers improved diagnostic significance compared with CDUS for the detection of chronic allograft nephropathy. In contrast to conventional CDUS resistance and pulsatility indices, renal blood flow estimated by CES was highly significant related to serum creatinine in kidney allografts. Perirenal hematoma, ATN and vascular rejection are associated with characteristic changes of the time intensity curve of CES. Quantitative determination of arterial arrival of an US contrast medium in the early phase after kidney transplantation has been studied and this may identify acute rejection earlier than conventional techniques [29]. Further research, which is ongoing, into the role of CES in other disease states will be needed to establish its place in the diagnosis of acute kidney injury.

Conclusion

In summary, recent advances in imaging techniques, especially in intravital multi-photon microscopy, has now enabled investigators to employ and develop unique, tailor-made techniques to visualize the functioning kidney and analyze, in a dynamic fashion, the cellular and subcellular processes that occur in various acute kidney injury states and the response to therapy. Application of some of these techniques to patients is close at hand and will add to the diagnostic repertoire of the clinician.

References 1 Molitoris BA, Sandoval RM: Pharmacophotonics: utilizing multi-photon microscopy to quantify drug delivery and intracellular trafficking in the kidney. Adv Drug Deliv Rev 2006;58:809–823. 2 Dunn KW, Sandoval RM, Molitoris BA: Intravital imaging of the kidney using multiparameter multiphoton microscopy. Nephron Exp Nephrol 2003; 94:e7–e11. 3 Dunn KW, Sandoval RM, Kelly KJ, Dagher PC, Tanner GA, Atkinson SJ, Bacallao RL, Molitoris BA: Functional studies of the kidney of living animals using multicolor twophoton microscopy. Am J Physiol Cell Physiol 2002;283:C905–C916.

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4 Yu W, Sandoval RM, Molitoris BA: Quantitative intravital microscopy using a Generalized Polarity concept for kidney studies. Am J Physiol Cell Physiol 2005; 289:C1197– C1208. 5 Kelly KJ, Plotkin Z, Vulgamott SL, Dagher PC: P53 mediates the apoptotic response to GTP depletion after renal ischemia-reperfusion: protective role of a p53 inhibitor. J Am Soc Nephrol 2003; 14:128–138. 6 Kleinfeld D, Mitra PP, Helmchen F, Denk W: Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex. Proc Natl Acad Sci USA 1998; 95: 15741– 15746.

7 Molitoris BA, Sandoval RM: Intravital multiphoton microscopy of dynamic renal processes. Am J Physiol Renal Physiol 2005;288: F1084–F1089. 8 Kang JJ, Toma I, Sipos A, McCulloch F, PetiPeterdi J: Quantitative imaging of basic functions in renal (patho)physiology. Am J Physiol Renal Physiol 2006;291:F495–F502. 9 Atkinson SJ: Functional intravital imaging of leukocytes in animal models of renal injury. Nephron Physiol 2006;103:p86–p90. 10 Sandoval RM, Molitoris BA: Quantifying endocytosis in vivo using intravital twophoton microscopy. Methods Mol Biol 2008; 440:389–402.

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11 Sutton TA, Horbelt M, Sandoval RM: Imaging vascular pathology. Nephron Physiol 2006;103:p82–p85. 12 Sutton TA, Mang HE, Campos SB, Sandoval RM, Yoder MC, Molitoris BA: Injury of the renal microvascular endothelium alters barrier function after ischemia. Am J Physiol Renal Physiol 2003;285:F191–F198. 13 Sutton TA, Kelly KJ, Mang HE, Plotkin Z, Sandoval RM, Dagher PC: Minocycline reduces renal microvascular leakage in a rat model of ischemic renal injury. Am J Physiol Renal Physiol 2005;288:F91–F97. 14 Kang JJ, Toma I, Sipos A, McCulloch F, PetiPeterdi J: Imaging the renin-angiotensin system: an important target of anti-hypertensive therapy. Adv Drug Deliv Rev 2006; 58: 824–833. 15 Ashworth SL, Tanner GA: Fluorescent labeling of renal cells in vivo. Nephron Physiol 2006;103:p91–p96. 16 Yamamoto T, Tada T, Brodsky SV, Tanaka H, Noiri E, Kajiya F, Goligorsky MS: Intravital videomicroscopy of peritubular capillaries in renal ischemia. Am J Physiol Renal Physiol 2002;282:F1150–F1155.

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17 Hattori R, Ono Y, Kato M, Komatsu T, Matsukawa Y, Yamamoto T: Direct visualization of cortical peritubular capillary of transplanted human kidney with reperfusion injury using a magnifying endoscopy. Transplantation 2005;79:1190–1194. 18 Gorbach A, Simonton D, Hale DA, Swanson SJ, Kirk AD: Objective, real-time, intraoperative assessment of renal perfusion using infrared imaging. Am J Transplant 2003; 3: 988–993. 19 Choyke PL, Kobayashi H: Functional magnetic resonance imaging of the kidney using macromolecular contrast agents. Abdom Imaging 2006;31:224–231. 20 Kobayashi H, Kawamoto S, Jo SK, Sato N, Saga T, Hiraga A, Konishi J, Hu S, Togashi K, Brechbiel MW, Star R: Renal tubular damage detected by dynamic micro-MRI with a dendrimer-based magnetic resonance contrast agent. Kidney Int 2002;61:1980–1985. 21 Dear JW, Kobayashi H, Jo SK, Holly MK, Hu X, Yuen PS, Brechbiel MW, Star RA: Dendrimer-enhanced MRI as a diagnostic and prognostic biomarker of sepsis-induced acute renal failure in aged mice. Kidney Int, 2005;67:2159–2167. 22 Jo SK, Hu X, Kobayashi H, Lizak M, Miyaji T, Koretsky A, Star RA: Detection of inflammation following renal ischemia by magnetic resonance imaging. Kidney Int 2003; 64: 43–51.

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23 Mason RP: Non-invasive assessment of kidney oxygenation: a role for BOLD MRI. Kidney Int 2006;70:10–11. 24 Prasad PV: Evaluation of intra-renal oxygenation by BOLD MRI. Nephron Clin Pract 2006;103:c58–c65. 25 Maril N, Margalit R, Rosen S, Heyman SN, Degani H: Detection of evolving acute tubular necrosis with renal 23Na MRI: studies in rats. Kidney Int 2006;69:765–768. 26 Hirayama A, Nagase S: Electron paramagnetic resonance imaging of oxidative stress in renal disease. Nephron Clin Pract 2006; 103:c71–c76. 27 Haufe SE, Riedmuller K, Haberkorn U: Nuclear medicine procedures for the diagnosis of acute and chronic renal failure. Nephron Clin Pract 2006;103:c77–c84. 28 Correas JM, Claudon M, Tranquart F, Hélénon AO: The kidney: imaging with microbubble contrast agents. Ultrasound Q 2006; 22:53–66. 29 Schwenger V, Hinkel UP, Nahm AM, Morath C, Zeier M: Real-time contrast-enhanced sonography in renal transplant recipients. Clin Transplant 2006;20(suppl)17:51–54.

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Nephron Physiol 2008;109:p55–p60 DOI: 10.1159/000142937

Published online: September 18, 2008

Cardiac Surgery-Associated Acute Kidney Injury: Putting Together the Pieces of the Puzzle Andrew Shaw Madhav Swaminathan Mark Stafford-Smith Division of Cardiothoracic Anesthesia and Critical Care Medicine, Duke University Medical Center, Durham, N.C., USA

Key Words Acute kidney injury ⴢ Cardiac surgery ⴢ Dialysis

Abstract Background: Acute kidney injury (AKI) is a common problem in the context of cardiac surgery. There are both similarities and differences with AKI occurring in other clinical scenarios. In this paper, we discuss those aspects of AKI that are particular to cardiac surgery-associated AKI (CSA-AKI), with emphasis on recent advances in the field. Methods: We summarize the recent literature relating to CSA-AKI, focusing on epidemiology, pathophysiology, risk prediction and prevention. Results: The Acute Kidney Injury Network (AKIN) criteria for the diagnosis and severity of AKI are a useful framework within which future epidemiological studies of AKI may be considered. Percent change in serum creatinine remains a sensitive and clinically relevant continuous measure of declining kidney function. New biomarkers of diagnosis are currently being validated, while biomarkers of prognosis are lacking. Notably, intraoperative antifibrinolytic therapy effects invalidate ‘tubular proteinuria’ biomarkers. Better characterization of genetic predisposition to CSA-AKI may enhance risk prediction, since currently available clinical models lack precision, particularly for the important clinical endpoint of new renal replacement therapy.

© 2008 S. Karger AG, Basel 1660–2137/08/1094–0055$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nep

Conclusions: CSA-AKI remains a clinically relevant problem for 5–10% of cardiac surgery patients and is associated with adverse clinical outcomes. Small changes in serum creatinine are important and should not be ignored. The overall incidence of new dialysis after cardiac surgery remains low. Copyright © 2008 S. Karger AG, Basel

Introduction

Acute kidney injury (AKI), characterized by a rapid decline in glomerular filtration rate and accumulation of nitrogenous waste products (blood urea nitrogen and creatinine), remains a common, serious complication of cardiac surgery [1]. Multiple etiologies have been proposed, including nephrotoxins, atheroembolism, ischemia-reperfusion, and cardiopulmonary bypass (CPB)induced activation of inflammatory pathways. Renal failure requiring dialysis occurs in up to 5% of cardiac surgery patients [2], while an additional 8–15% have moderate kidney injury (e.g. 11.0 mg/dl rise in serum creatinine). Lesser renal injuries are even more common (in some series as many as 50% of patients undergoing cardiac surgery have a 25% postoperative rise in serum creatinine). The temporal pattern of the creatinine rise is dependent on the specific operation performed (fig. 1), Andrew Shaw Division of Cardiothoracic Anesthesia and Critical Care Medicine Duke University Medical Center Durham, NC 27710 (USA) Tel. +1 919 681 6752, Fax +1 919 681 4978, E-Mail [email protected]

Color version available online

Patterns of acute kidney injury after cardiac surgical procedures 110

90

(~50% reduction in GFR) Average peak Daily average (baseline to postop day 10)

%⌬Cr

70

50

30

10

–10 n = 134

n = 214

n = 87

n = 411

n = 4,421

n = 8,358

n = 1,331

n = 1,091

n = 879

n = 64

n = 158

Aortic PortAcc

Mitral PortAcc

Mitral mdn st

OPCAB

CABG 1º nonemergent

All CABG

All valve

Aortic mdn st

CABG + valve

ht txplt

dbl lung txplt

serum creatinine values, relative to preoperative, for the first ten days after different cardiac surgery procedures. Average peak values always considerably exceed the highest average daily value since creatinine peaks on different days among patients. %⌬Cr = Peak fractional serum creatinine rise; aortic PortAcc = minimally invasive parasternotomy aortic valve replacement;

PortAcc = port access mitral valve surgery; mdn st = median sternotomy mitral valve surgery; OPCAB = off-pump coronary artery bypass surgery; CABG = coronary artery bypass surgery; 1° = primary; aortic mdn st = median sternotomy aortic valve replacement; ht txplt = heart transplant; dbl lung txplt = double lung transplant; postop = postoperative. Use with permission from Stafford-Smith et al. [21].

and within each general pattern different patients will experience greater or lesser peaks depending on their individual clinical circumstances. In many settings, including cardiac surgery, AKI is independently associated with in-hospital mortality, even after adjustment for comorbid diseases and other complications. All degrees of AKI are associated with increased mortality and other adverse outcomes [3]. The grave prognosis associated with this complication may be due, at least in part, to the distant effects of AKI on other organ functions. Unfortunately, the characteristics typical of individuals presenting for cardiac sur-

gery (such as advanced age and history of atherosclerotic vascular disease) make these patients a group at high ‘renal risk’. Our group has recently investigated the changing epidemiology of AKI after heart surgery [2], a complication of cardiac surgery that appears to be occurring increasingly often, despite more general advances in perioperative healthcare delivery. This is most probably due to a relaxation of the criteria required for the diagnosis of AKI, accompanying the more widely appreciated importance of small reductions in renal function for overall outcome [4].

Fig. 1. Average daily (diamonds) and unadjusted peak (triangles)

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Pathophysiology

AKI in the setting of cardiac surgery has etiological features that are both common to other types of AKI, and peculiar to itself. Rather than discuss each pathophysiological mechanism individually, here we summarize the approach developed by Bellomo et al. [5] in the summary document from the recent Acute Dialysis Quality Initiative consensus meeting on CSA-AKI, held in Italy in 2007. These authors considered a number of different pathophysiological mechanisms occurring in a sequence of insults to the kidney that together lead to an overall reduction in function that manifests as a rise in serum creatinine level. These mechanisms include: (1) exogenous and endogenous toxins, (2) metabolic factors, (3) ischemiareperfusion, (4) neurohormonal activation, (5) inflammation, and (6) oxidative stress. Each of these mechanisms is important for CSA-AKI, but not all at the same time. For example, aprotinin is clearly important in the intraoperative phase (see below) but rarely in the pre- and postoperative phase. Likewise, preexisting kidney disease is important preoperatively since its severity defines the landscape on which further renal insults exert their influence on residual (postoperative) kidney function. There has recently been considerable interest in the role of different antifibrinolytic drugs in heart surgery, and this is reviewed in more detail below since it has not been dealt with in detail in the nephrology literature elsewhere. Antifibrinolytic drugs are used in the course of heart surgery to reduce bleeding, avoid blood transfusion and prevent reoperation (‘take-back’) procedures, since these are all known to increase mortality after cardiac surgery. Exposure of the circulation to the cardiopulmonary bypass machine leads to widespread intravascular thrombin generation (even in the presence of systemic heparin anticoagulation) and this in turn leads to increased fibrinolysis once the patient is weaned from CPB and the heparin anticoagulation is reversed with protamine. Increased fibrinolysis leads to bleeding, particularly in the setting of complex operations (e.g. revision procedures) and is associated with higher chest tube output, more blood transfusion and a higher reoperation rate. Antifibrinolytic drugs such as aprotinin, aminocaproic acid and tranexamic acid are given in order to reduce the severity of this complication. Aminocaproic acid and tranexamic acid are both known to be effective antifibrinolytic agents, and have a very good safety record. Curiously, they block reuptake of small filtered proteins in the proximal tubule, resulting Cardiac Surgery-Associated Acute Kidney Injury

in ‘tubular proteinuria’ that resolves as soon as they are withdrawn [6]. For many years, the greater blood-sparing effect of aprotinin led people to believe that aprotinin was superior to both of these agents, and that there were no specific safety issues relating to its use. In 2006, Mangano et al. [7] published a report that questioned both the efficacy and safety of this drug. This report generated much debate and was followed by a series of reports of the safety and efficacy of aprotinin from both multicenter [8] and single-center groups [9]. In November 2007, the US FDA requested marketing of the drug be suspended after a multicenter randomized trial of antifibrinolytic therapy in high-risk cardiac surgery patients was stopped early by their safety monitoring board due to excess mortality in the aprotinin arm. The future of this drug is uncertain at time of writing, but from a renal perspective what is clear is that its use is definitely associated with a rise in serum creatinine, and also possibly a higher incidence of new dialysis after heart surgery. These adverse renal effects have not been seen with the other agents however.

Diagnosis

There have been reports of acute kidney injury occurring in the setting of heart surgery for as long as there have been cardiac surgery operations performed [10]. Until recently there has been no consensus on what constitutes renal failure, what constitutes renal dysfunction, how best to measure these phenomena, and which diagnostic criteria are the most sensitive and specific. The preferred term for newly reduced kidney function is ‘acute kidney injury’ as opposed to ‘acute renal failure’, and this term recognizes the spectrum of dysfunction that is known to occur in acutely injured/damaged kidneys. Recently, consensus diagnostic criteria for AKI have been published [11] that will enable researchers to organize their efforts such that progress may be made in this condition. These criteria define three stages of injury (1, 2 and 3) based on increasingly severe reductions of kidney function (50% rise in serum creatinine or at least 0.3 mg/dl; 100% rise in serum creatinine, and 200% rise or any dialysis, respectively). The percentage rise concept is important since it allows for a variable baseline, and there is additionally a requirement for the rise to occur within a window of 48 h. There are also criteria based on urine output, but it is unclear how robust these are in the setting of heart surgery during which routine manipulation of urine output is the rule rather than the exception. Nephron Physiol 2008;109:p55–p60

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Table 1. Clinical risk factors for CSA-AKI

Advanced age African-American ethnicity Increased body weight Hypertension Peripheral vascular disease Diabetes mellitus (and metabolic syndrome) Reduced left ventricular function Chronic obstructive pulmonary disease Revision surgery Aortic valve surgery Operations involving circulatory arrest Prolonged cardiopulmonary bypass

We believe that a continuous measure of declining kidney function, namely maximum percentage rise in serum creatinine level relative to baseline, is particularly useful in CSA-AKI, since it permits the use of more powerful statistical techniques (linear regression rather than logistic regression for example) when modeling risk factors for development of CSA-AKI (see below) and has consistently been associated with major increases in adverse outcomes including mortality. This has now been accepted by the mainstream medical literature [9]. Accompanying this epidemiological advance are new biomarkers of acute kidney injury. Specifically, neutrophil gelatinase-associated lipocalin (NGAL) is a novel marker of renal injury that is present in high levels in both the urine and plasma of patients with AKI, and especially in the setting of heart surgery, when it has been shown to increase almost immediately in patients who go on to develop a rise in serum creatinine [12]. Other markers such as interleukin-18 and kidney injury molecule-1 have also shown promise for earlier detection of CSAAKI, and may offer the ability to differentiate ischemiareperfusion from inflammatory AKI. What we do not have currently are biomarkers of disease progression, to dialysis or chronic kidney disease (CKD) for example. This is an important issue, since without them we are unable to conduct appropriately stratified studies of preventive therapies. In recognition of the need for well-characterized biomarkers of AKI diagnosis and progression, there are now several multicenter consortia conducting prospective studies with the aim of discovering and validating novel biochemical markers in both the urine and plasma of heart surgery patients at risk for both AKI and new dialysis in the setting of cardiac surgery. p58

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Risk Prediction

Clinical Risk Factors Many risk factors have been identified since the first report of acute renal failure after cardiac surgery [10]. More recent studies evaluating intermediate renal injuries in large cohorts of cardiac surgery patients with the full range of baseline renal functions have helped identify more subtle effects. Even though a wide variety of patient and procedural factors have been shown to affect the risk of renal impairment (table 1), and elegant preoperative risk stratification algorithms have been developed [13], unfortunately these have little use as clinical tools for cardiac surgery. For patients with normal renal function, the current paradigm relies heavily on patient characteristics and does not discriminate effectively between low- and high-risk patients. Known risk factors for postoperative renal impairment are shown in table 1. Generally speaking, these account for less than 10% of the variation in postoperative creatinine levels relative to baseline. Knowledge of baseline renal function (serum creatinine) can explain a further 30% of any given creatinine rise, but this improvement is simply due to the nonlinear response of creatinine with different starting creatinine values. However, due to their proximity to the threshold for new renal replacement therapy, patients with pre-existing renal dysfunction are at much greater risk for dialysis. Despite this, they are not at greater risk for renal impairment relative to their baseline [14]. The role of anemia and blood transfusion is particularly relevant for CSA-AKI since both are risk factors for AKI. Most cardiac anesthesiologists will not allow onpump hematocrit to drop below 20% since this significantly increases the risk of kidney impairment in the postoperative period [15], but in patients with pre-existing anemia this may not be possible without allogeneic blood transfusion. Perfusion techniques such as continuous rapid autologous priming may reduce the hemodilution from the pump prime that occurs at the onset of cardiopulmonary bypass, but some degree of anemia is unavoidable in patients who do not begin the procedure with a normal red cell mass. Genetic Risk Factors Although many preoperative and procedural predictors and biologic markers have been identified, risk stratification based on these factors explains only a small part of the variability in post-cardiac surgery renal dysfunction [16]. In addition, little is known regarding the relaShaw/Swaminathan/Stafford-Smith

tionship of the several known polymorphisms associated with altered activation of the renal paracrine and/or inflammatory pathways with AKI following CABG surgery. To date, studies have focused on only a few genetic polymorphisms (apolipoprotein E (ApoE) 448C (␧4) [17] and IL-6 –174G/C [18]) and have not taken into account other important pathways/proteins or interactions between potentially synergistic insults. In an earlier report we showed that genetic variants of inflammatory and paracrine pathways at multiple loci are associated with susceptibility to AKI after cardiac surgery [19]. In the age of the genome-wide association study, it is likely that many variants will be shown to be associated with both the continuous and dichotomous measures of declining kidney function described earlier. Finding variants with significant p values is not the problem – discerning those variants that are truly important for risk prediction and identifying the populations in which they are most helpful is the current focus of groups working in this area. It is highly unlikely that there will be a specific CSA-AKI gene, since this is not a Mendelian phenotype. Nevertheless, CSA-AKI occurs as a response to stress in the setting of a controlled traumatic insult, and this response does have evolutionary correlates (i.e. the physiological response to injury, blood loss and trauma) and thus it is feasible that variants in conserved genomic regions may play a role in its manifestation.

Prevention of CSA-AKI

translated none of this success into humans. In part, this has reflected a lack of consensus on what the disease entity under study actually is (see above, ‘Diagnosis’). This is also a reflection of our use of models that focus on individual pathophysiological mechanisms, such as ischemia-reperfusion, rather than on models which faithfully reproduce the clinical situation. These two problems have now been addressed – the AKIN criteria addressing the diagnostic heterogeneity issue, and the use of animal models of CSA-AKI by our group and others addressing the second – such that the future is bright for novel preventive agents of CSA-AKI. For an in-depth review of the literature relating to prevention of CSAAKI, readers are referred to the recent paper by Schetz et al. [20].

Conclusions

Cardiac surgery-associated AKI represents a particular type of AKI since it has special etiological and temporal components. We know that there are specific types of insults that occur (atheroembolism, aprotinin, circulatory arrest) and most importantly (from the prevention perspective), we know when the insult occurs. We anticipate that the recent advances in epidemiology and biomarker discovery, together with the use of more clinically relevant animal models, means that we are on the brink of some important advances in the care of patients with this serious problem.

After more than 40 years of animal research in the field of AKI, we know exactly how to prevent experimental AKI in rats. Unfortunately, we have collectively

References 1 Conlon PJ, Stafford-Smith M, White WD, Newman MF, King S, Winn MP, Landolfo K: Acute renal failure following cardiac surgery. Nephrol Dial Transplant 1999;14:1158– 1162. 2 Swaminathan M, Shaw AD, Phillips-Bute BG, McGugan-Clark PL, Archer LE, Talbert S, Milano CA, Patel UD, Stafford-Smith M: Trends in acute renal failure associated with coronary artery bypass graft surgery in the United States. Crit Care Med 2007; 35:2286– 2291.

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3 Stafford-Smith M: In Newman MF (ed): 2003 Society of Cardiovascular Anesthesiologists Monograph – Perioperative Organ Protection. Baltimore, Lippincott Williams & Wilkins, 2003, pp 89–124. 4 Lassnigg A, Schmid ER, Hiesmayr M, Falk C, Druml W, Bauer P, Schmidlin D: Impact of minimal increases in serum creatinine on outcome in patients after cardiothoracic surgery: do we have to revise current definitions of acute renal failure? Crit Care Med 2008; 36:1129–1137.

5 Bellomo R, Auriemma S, Fabbri A, D’Onofrio A, Katz N, McCullough PA, Ricci Z, Shaw A, Ronco C: The pathophysiology of cardiac surgery-associated acute kidney injury (CSAAKI). Int J Artif Organs 2008;31:166–178. 6 Stafford-Smith M: Antifibrinolytic agents make alpha1- and beta2-microglobulinuria poor markers of post cardiac surgery renal dysfunction. Anesthesiology 1999; 90: 928– 929. 7 Mangano DT, Tudor IC, Dietzel C: The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353–365.

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8 Schneeweiss S, Seeger JD, Landon J, Walker AM: Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med 2008;358:771–783. 9 Shaw AD, Stafford-Smith M, White WD, Phillips-Bute B, Swaminathan M, Milano C, Welsby IJ, Aronson S, Mathew JP, Peterson ED, Newman MF: The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008;358:784–793. 10 Doberneck RC, Reiser MR, Lillehei CW: Acute renal failure after open-heart surgery utilizing extracorporeal circulation and total body perfusion. J Thor Cardiovasc Surg 1962;43:441–452. 11 Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A: Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. 12 Wagener G, Gubitosa G, Wang S, Borregaard N, Kim M, Lee HT: Increased incidence of acute kidney injury with aprotinin use during cardiac surgery detected with urinary NGAL. Am J Nephrol 2008;28:576–582.

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13 Thakar CV, Arrigain S, Worley S, Yared JP, Paganini EP: A clinical score to predict acute renal failure after cardiac surgery. J Am Soc Nephrol 2005;16:162–168. 14 Andersson LG, Ekroth R, Bratteby LE, Hallhagen S, Wesslen O: Acute renal failure after coronary surgery: a study of incidence and risk factors in 2009 consecutive patients. Thorac Cardiovasc Surg 1993;41:237–241. 15 Stafford-Smith M, Newman MF: What effects do hemodilution and blood transfusion during cardiopulmonary bypass have on renal outcomes? Nat Clin Pract Nephrol 2006; 2:188–189. 16 Ostermann ME, Taube D, Morgan CJ, Evans TW: Acute renal failure following cardiopulmonary bypass: a changing picture. Intensive Care Med 2000;26:565–571. 17 MacKensen GB, Swaminathan M, Ti LK, Grocott HP, Phillips-Bute BG, Mathew JP, Newman MF, Milano CA, Stafford-Smith M: Preliminary report on the interaction of apolipoprotein E polymorphism with aortic atherosclerosis and acute nephropathy after CABG. Ann Thorac Surg 2004;78:520–526.

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18 Gaudino M, Di Castelnuovo A, Zamparelli R, Andreotti F, Burzotta F, Iacoviello L, Glieca F, Alessandrini F, Nasso G, Donati MB, Maseri A, Schiavello R, Possati G: Genetic control of postoperative systemic inflammatory reaction and pulmonary and renal complications after coronary artery surgery. J Thorac Cardiovasc Surg 2003;126:1107–1112. 19 Stafford-Smith M, Podgoreanu M, Swaminathan M, Phillips-Bute B, Mathew JP, Hauser EH, Winn MP, Milano C, Nielsen DM, Smith M, Morris R, Newman MF, Schwinn DA: Association of genetic polymorphisms with risk of renal injury after coronary bypass graft surgery. Am J Kidney Dis 2005;45: 519–530. 20 Schetz M, Bove T, Morelli A, Mankad S, Ronco C, Kellum JA: Prevention of cardiac surgery-associated acute kidney injury. Int J Artif Organs 2008;31:179–189. 21 Stafford-Smith M, Patel UD, Phillips-Bute BG, Shaw AD, Swaminathan M: Acute kidney injury and chronic kidney disease after cardiac surgery. Adv Chron Kid Dis 2008;15: 257–277.

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Nephron Exp Nephrol 2008;109:e95–e100 DOI: 10.1159/000142933

Published online: September 18, 2008

Septic Acute Kidney Injury: New Concepts Rinaldo Bellomo Li Wan Christoph Langenberg Clive May Department of Intensive Care and Department of Medicine, Austin Health, and Howard Florey Institute, University of Melbourne, Melbourne, Vic., Australia

Key Words Acute renal failure ⴢ Vasodilatation ⴢ Nitric oxide ⴢ Apoptosis ⴢ Glomerulus ⴢ Tubule ⴢ Afferent arteriole ⴢ Efferent arteriole ⴢ Glomerular filtration rate

Abstract Acute kidney injury (AKI) is a serious condition that affects many ICU patients. The most common causes of AKI in ICU are severe sepsis and septic shock. The mortality of AKI in septic critically ill patients remains high despite of our increasing ability to support vital organs. This is partly due to our poor understanding of the pathogenesis of sepsis-induced renal dysfunction. However, new concepts are emerging to explain the pathogenesis of septic AKI, which challenge previously held dogma. Throughout the past half century, septic AKI has essentially been considered secondary to kidney ischemia. However, recent models of experimental sepsis have challenged this notion by demonstrating that, in experimental states, which simulate the hemodynamic picture most typically seen in man (e.g. hyperdynamic sepsis) renal blood flow, actually increases as renal vascular resistance decreases. These experimental observations provide proof of concept that septic AKI can occur in the setting of renal hyperemia and that ischemia is not necessary for loss of glomerular filtration rate (GFR) to occur. They also suggest that similar hemodynamic event may occur in man. In addition, preliminary studies in septic sheep show that,

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when ATP is measured using an implanted phosphorus coil and magnetic resonance technology, renal bioenergetics are preserved in the setting of advanced septic shock. While these findings need to be confirmed, they challenge established paradigms and offer a new conceptual framework of reference for further investigation and intervention in man. Copyright © 2008 S. Karger AG, Basel

Introduction

Severe acute kidney injury requiring acute renal replacement therapy affects approximately 5% of all ICU patients [1]. When recently published consensus criteria (RIFLE criteria) are used to define AKI [2], this condition can be shown to occur in almost 8% of hospital patients [3] and in 150% of ICU patients [4]. Thus, AKI is a major clinical problem in modern hospitals and ICUs. In addition, there is strong evidence that sepsis and septic shock are the most important cause of AKI in critically ill patients and account for 50% or more of cases of AKI in ICU [1, 5]. Despite our increasing ability to support vital organs and resuscitate patients, the incidence and mortality of septic AKI remain high [1, 5, 6]. A possible explanation of why, despite treatment, AKI is so common in severe sepsis and septic shock and why mortality has remained high might relate to our limited understanding of septic AKI and its pathogenesis. It is therefore very imProf. Rinaldo Bellomo Department of Intensive Care, Austin Health Heidelberg, Vic. 3084 (Australia) Tel. +61 3 9496 5992, Fax +61 3 9496 3932, E-Mail [email protected]

Temp 42°C RR: 50 breaths/min

baseline (before dashed vertical line) following a bolus of intravenous E. coli (after dashed vertical line). The x-axis represents time in minutes. HR = Heart rate in beats/ min; CO = cardiac output in liters/min; MAP = mean arterial pressure in mm Hg. The y-axis on the left reports the numerical values for HR and MAP, the y-axis on the right reports the numerical values for CO. The animals had a high temperature and a fast respiratory rate (RR) as reported in the top right corner.

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portant for critical care physicians and nephrologists to have an appreciation of new concepts, which have recently emerged and continue to emerge in this field of medicine.

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[7], these animal models have been mostly based on ischemia-reperfusion injury or drug-induced injury. These models are not relevant to septic AKI and information obtained from such models may be misleading when applied by clinicians to interpret what might be happening to a septic patient who is developing AKI in the ICU or ward.

Pathogenesis

Our understanding of the pathogenesis of human AKI in general is markedly affected by the lack of histopathological information of what happens to the human kidney as glomerular filtration rate decreases and oliguria develops in a variety of clinical settings. This lack of information stems from the risks associated with renal biopsy (especially repeated renal biopsy). These risks make it ethically unjustifiable to obtain tissue from patients who do not have suspected parenchymal disorders. In the absence of such information, we rely on indirect assessments of what might be happening to the kidney. Such assessments are based on blood tests and urine tests and force us to ‘guess’ what might be happening to kidney. It is not surprising, therefore, that our understanding of septic human AKI has advanced little in the last 50 years. To overcome such limitations, animal models of ARF have been developed that enable more sophisticated and invasive measurements to be made. Unfortunately, as recently highlighted e96

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The Primacy of Renal Blood Flow

A major paradigm that has been derived from observations in animals and humans with hypodynamic shock (hemorrhagic, cardiogenic or even septic) is that AKI is due to renal ischemia. This construct implies that restoration of adequate renal blood flow should therefore be the primary means of renal protection in critically ill patients. Whether, in presence of a normal or increased cardiac output, renal blood flow (RBF) actually decreases significantly or remains stable or even increases, however, remains controversial and not well studied. Accordingly, the dogma that most AKI (septic or otherwise) is ‘ischemic’ remains inadequately tested. In several experimental studies of septic ARF, global renal blood flow declines after induction of sepsis or endotoxemia [8, 9]. This may result not only in a reduction in glomerular filtration rate (GFR) but also, if hypoperfuBellomo/Wan/Langenberg/May

E. coli i.v. bolus

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sion is severe and prolonged, in metabolic deterioration and diminished contents of high-energy phosphates, possibly causing cells death, ATN and established acute renal failure. On the other hand, other studies show that the renal circulation participates in the systemic vasodilatation seen during severe sepsis/septic shock, so that renal blood flow does not diminish and the development of septic AKI occurs not in the setting of renal hypoperfusion but of adequate and even increased renal perfusion. Ravikant and Lucas [10], for example, studied a pig model of sepsis and showed that during hyperdynamic sepsis, there was an increase in global RBF and an increase in medullary blood flow. Brenner et al. [11] developed and studied a percutaneously placed thermodilution renal blood flow catheter in eight critically ill patients. They demonstrated that sepsis-induced acute renal dysfunction occurred despite normal values of total renal blood flow. Furthermore, during human sepsis, patients typically show a hyperdynamic state. Observations in hyperdynamic models of sepsis may, therefore, be much more relevant to human septic shock. Indeed, the reason why the results of experimental studies are so different in terms of renal perfusion may be entirely related to the animal models (including animal type and type of insult), different methods of measurement, the time and frequency of

measurements and, more importantly, the state of the systemic circulation (hypodynamic or hyperdynamic state). In fact, the consistent observation is that, once a hyperdynamic state exists, global renal hypoperfusion/ ischemia is not the norm. We recently performed a comprehensive review of electronic reference libraries, using sepsis and acute renal failure as the key words and limiting it to animal models [12]. We found approximately 160 original articles. Of these, only a minority reported both cardiac output and renal blood flow. We found that the changes in RBF depended very much on the model and that once the model was hyperdynamic (high CO) RBF was either preserved or increased. On multivariate analysis, CO was the only significant predictor of RBF (p ! 0.01). To further study septic AKI, we developed a sheep model of severe sepsis we simulated sepsis as seen in man (fever, tachycardia, tachypnea, elevated lactate, hypotension, increased cardiac output) by administering live Escherichia coli intravenously in sheep (fig. 1). In this model, we obtained continuous information on cardiac output and renal blood flow by means of chronically implanted transit-time flow probes. In multiple experimental studies, we have repeatedly and consistently demonstrated that once hyperdynamic sepsis is initiated, RBF increases, often by more than 100% (papers 13–18) (fig. 2). We

New Concepts in Septic AKI

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Normal glomerulus

Fig. 3. Possible mechanisms behind the loss of GFR in hyperdynamic vasodilated sepsis despite increased renal blood. The septic glomerulus displays afferent and efferent arteriolar vasodilatation but greater efferent vasodilation as shown by the larger vertical arrow. RBF increases as shown by the larger red horizontal arrows, but GCP is low, GFR is also low and urine output falls (smaller yellow arrow).

have also shown that such renal hyperemia is associated with renal vasodilatation but that, despite such hyperemia and vasodilatation, oliguria develops and creatinine clearance decreases (AKI). These observations provide strong experimental evidence that, in the short term (6 h), AKI can occur in the setting of renal hyperemia.

Intrarenal Hemodynamic Changes

It is possible that, even though there is preserved or increased global renal blood flow in hyperdynamic sepsis, internal redistribution of blood flow favoring may occur. Unfortunately, no studies have looked at medullary and cortical blood flow in hyperdynamic sepsis with technology that allows continued measurement over time. A recent investigation by our group used laser Doppler flowmetry to continuously monitor medullary and cortical flow in hyperdynamic septic sheep [19]. We found that both flows remain unchanged and that the administration of vasopressor therapy (norepinephrine) induced a significant increase in such flows. These observations further challenge the view that the medulla is ischemic during hyperdynamic sepsis but simultaneously highlight that hemodynamic factors are indeed at work, which can be modified by interventions which affect systemic blood pressure and cardiac output. Thus, intrarenal hemodynamic events do occur which might affect function. However, their favorable modifie98

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Glomerulus in sepsis

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cation by vasoconstrictor therapy further challenges widely held view of what is optimal renal resuscitation in sepsis.

A Model of Sustained Septic AKI

The above observation, while important only related to a short-term model of septic AKI (6 h). It was unknown whether RBF would remain elevated if hyperdynamic sepsis was sustained for a longer period. In order to address this important issue of great relevance to human sepsis, we developed a long-term model (48 h) of septic AKI achieved by the continuous intravenous infusion of live E. coli as a dose carrying limited lethality (20%). In this model, we were able to maintain a high cardiac output, low blood pressure state for 48 h. At 48 h, we stopped the infusion and administered intravenous gentamicin. The findings of this model were even more striking than those seen in the short-term model [20]. We found that cardiac output CO increased threefold over time and that RBF increased at almost exactly the same rate as mirror image of the CO. This increase in RBF was associated with a decrease in renal vascular resistance which was similar in magnitude such that almost all of the increase in RBF could be accounted for by renal vasodilatation. As RBF increased by 300%, however, urinary output progressively declined to near anuria and creatinine clearance (our marker for GFR) decreased by 80%. The serum creatinine increased fourBellomo/Wan/Langenberg/May

efferent arteriolar tone, such vasodilatation should, however, increase GFR, not decrease it, as GCP would be increased by the increased flow. The only logical mechanism by which RBF can increase and, simultaneously, GCP decrease and GFR also decrease, is based on the simultaneous dilatation of both arterioles but with greater efferent than afferent dilatation such that GCP decreases and GFR also decreases. This is a situation similar to that seen with the administration of angiotensin-converting enzyme inhibitors (fig. 3). If this were true, the administration of angiotensin II should restore GFR while decreasing RBF in sepsis. Preliminary experiments in our laboratory (not yet published) have recently confirmed this hypothesis. What remains unknown is whether this mechanism is operative in man. Fig. 4. Photograph of implanted phosphorus coil around sheep

kidney. This pre-experiment implantation is necessary to obtain high-quality renal ATP signals by MRI during septic shock in vivo.

Renal Bioenergetics

fold. Clearly, these animals had developed severe AKI with marked loss of GFR in the setting of marked hyperemia. Interestingly, during this 48-hour period all markers of tubular function indicated overall preservation of tubular activity providing suggestive evidence that GFR was lost in the absence of tubular necrosis [20]. We were then able to study their recovery from such severe septic AKI. During recovery, we saw the same changes seen during sepsis but in reverse [21]. RBF returned to normal over 48 h as did cardiac output and renal vascular resistance. The information obtained from this model and the information obtained from the short-term model provided clear proof of the concept that oliguric AKI can develop in the presence of marked hyperemia. This observation calls for some reflection of how this might happen. GFR is dependent upon the pressure that drives ultrafiltration across the glomerular membrane (the glomerular capillary pressure – GCP). This pressure is affected by oncotic pressure but, more markedly, by the relationship between the afferent and efferent glomerular arterioles. These arterioles are the major controllers or renal blood flow as 190% of such flow is delivered to the glomeruli. For RBF to increase and renal vascular resistance to decrease, the afferent arterioles must dilate. However, such dilatation is needed but not sufficient. The efferent arterioles must also dilate. If such dilatation maintains the normal relationship between afferent and

The observation that RBF is increased in hyperdynamic sepsis does not necessarily mean that ‘relative’ ischemia can be ‘ruled out’ as a mechanism of renal injury. In sepsis, RBF may be markedly increased and, with it, renal oxygen delivery may also be markedly increased. However, renal oxygen consumption may be so great during sepsis that demand for oxygen might still exceed supply. In this state of relative or cryptic ischemia, renal ATP would become deplete despite markedly increased RBF. In order to test this hypothesis, it is necessary to perform the measurement of ATP in vivo in a septic animal. This, in turn, requires the preliminary implantation of a phosphorus coil around the kidney in order to obtain an adequate ATP signal using magnetic resonance technology (fig. 4). We have recently reported the findings of such ATP measurements with or without the use of a magnetic resonance compatible transit-time flow probe to simultaneously measure RBF and ATP in septic shock [16, 17]. We found that, despite severe hypotensive septic shock and anuria, our animals had increased or preserved RBF and unchanged ATP. We were also able to calculate renal pH using the phosphorus signal and found no significant change in renal pH despite severe septic shock. These observations support the view that bioenergetic failure is unlikely to occur at least in the first few hours of septic AKI. Such observations are logical as decreased GFR leads to decreased solute delivery to the tubules. As solute transport is responsible for most of the oxygen consumption by the tubules, decreased GFR provides a natural protection (so-called acute renal success) from any form of bioenergetic stress.

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Conclusions

As discussed above, a growing body of experimental data has accumulated over the last 5 years to demonstrate that septic AKI can occur in the setting of marked hyperemia and vasodilatation and that renal ischemia is not necessary for the loss of GFR to occur in sepsis. Furthermore, evidence is accumulating that maldistribution of

intrarenal blood flow is unlikely to account for the loss of GFR seen in septic AKI. Moreover, renal ATP levels are maintained during the first hours of severe septic AKI. These observations challenge the notion that septic AKI is secondary to ischemia. Studies of renal blood flow in septic man are now needed to confirm or refute these experimental studies.

References 1 Uchino S, Kellum J, Bellomo R, et al: Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294: 813–818. 2 Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; the ADQI Workgroup: Acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the ADQI Group. Critical Care 2004;8:R204–R212. 3 Uchino S, Bellomo R, Goldsmith D, Bates S, Ronco C: An assessment of the RIFLE criteria for acute renal failure in hospitalized patients. Crit Care Med 2006;34:1913–1917. 4 Hoste EA, Clermont G, Kersten A, et al: RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crti Care 2006; 10:R73–R80. 5 Silvester W, Bellomo R, Cole L: Epidemiology, management, and outcome of severe acute renal failure of critical illness in Australia. Crit Care Med 2001;29:1910–1915. 6 Bagshaw SM, Uchino S, Bellomo R, et al: Septic acute kidney injury in critically ill patients: clinical characteristics and outcome. Clin J Am Soc Nephrol 2007; 2:431–439. 7 Heyman SN, Lieberthal W, Rogiers P, Bonventre JV: Animal models of acute tubular necrosis. Curr Opin Crit Care 2002; 8: 526– 534.

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8 Badr KF, Kelley VE, Rennke HG, Brenner BM: Roles for thromboxane A 2 and leukotrienes in endotoxin-induced acute renal failure. Kidney Int 1986;30:474–480. 9 Kikkeri D, Pennell JP, Hwang KH, Jacob AI, Richman AV, Bourgoignie JJ: Endotoxemic acute renal failure in awake rats. Am J Physiol 1986;250:F1098–F1106. 10 Ravikant T, Lucas TE: Renal blood flow distribution in septic hyperdynamic pigs. J Surg Res 1977;22:294–298. 11 Brenner M, Schaer GL, Mallory DL, Suffredini AF, Parrillo JE: Detection of renal blood flow abnormalities in septic and critically ill patients using a newly designed indwelling thermodilution renal vein catheter. Chest 1990;98:170–179. 12 Langenberg C, Bellomo R, May C, Wan L, Egi M, Morgera S: Renal blood flow in sepsis. Crit Care 2005;9:R363–R374. 13 Di Giantomasso D, May C, Bellomo R: Vital organ blood flow in hyperdynamic sepsis. Chest 2003;124:1053–1059. 14 Di Giantomasso D, May C, Bellomo R: Norepinephrine and organ blood flow in sepsis. Intensive Care Med 2003;29:1774–1781. 15 Wan L, Bellomo R, May C: The effect of normal saline resuscitation on vital organ blood flow in septic sheep. Intensive Care Med 2006;32:1238–1242.

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16 May C, Wan L, Williams J, Wellard MR, Pell G, Jackson G, Bellomo R: A technique for the measurements of renal ATP in a large animal model of sepsis. In J Artif Organs 2005; 28: 16–21. 17 May C, Wan L, Williams J, Wellard MR, Pell G, Langenberg C, Bellomo R: A technique for the simultaneous measurement of renal ATP, blood flow and pH in a large animal model of septic shock. Crit Care Resusc 2007;9:30– 33. 18 Di Giantomasso D, Bellomo R, May CN: The haemodynamic and metabolic effects of epinephrine in experimental hyperdynamic septic shock. Intensive Care Med 2005; 31: 454–462. 19 Di Giantomasso D, Morimatsu H, May CN, Bellomo R: Intra-renal blood flow distribution in hyperdynamic septic shock: effect of norepinephrine. Crit Care Med 2003; 31: 2509–2513. 20 Langenberg C, Wan L, Egi M, May CN, Bellomo R: Renal blood flow in experimental septic acute renal failure. Kidney Int 2006; 69:1996–2002. 21 Langenberg C, Wan L, Egi M, May CN, Bellomo R: Renal blood flow and function during recovery from experimental septic acute kidney injury. Intensive Care Med 2007; 33: 1614–1618.

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Nephron Physiol 2008;109:p61–p72 DOI: 10.1159/000142938

Published online: September 18, 2008

Radiocontrast-Induced Acute Kidney Injury Peter A. McCullough Divisions of Cardiology, Nutrition, and Preventive Medicine, William Beaumont Hospital, Royal Oak, Mich., USA

Key Words Acute kidney injury ⴢ Iodinated contrast ⴢ Chronic kidney disease ⴢ Cardiovascular disease ⴢ Porphylaxis ⴢ Osmolality

Abstract Many radiographic studies and procedures use iodinated contrast media and consequently pose the risk of contrastinduced acute kidney injury (AKI). This is an important complication, which accounts for a significant number of cases of hospital-acquired renal failure associated increased hospital length of stay and increased mortality. Sustained reductions in renal blood flow, hypoxic injury, direct cellular toxicity by the contrast media, and superimposed organ injury are all believed to play a role in this form of AKI. Avoidance of dehydration and multimodality prevention measures may reduce rates of this problem in patients at risk. Contrast-induced AKI is likely to remain a significant challenge for specialists in the future since the patient population is aging, chronic kidney disease and diabetes are coming more common, and use of iodinated contrast is growing. Copyright © 2008 S. Karger AG, Basel

© 2008 S. Karger AG, Basel 1660–2137/08/1094–0061$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nep

Introduction

Contrast-induced acute kidney injury (AKI) is an important complication in the use of iodinated contrast media which accounts for a significant number of cases of hospital-acquired AKI [1–3]. This iatrogenic complication has been a subject of concern to physicians in recent years because of its adverse effect on prognosis and addition to healthcare costs. At the same time, many hospitalized patients have compromised renal function [4, 5] which is the most important risk factor for contrast-induced AKI. This paper highlights conclusions from the Contrast-Induced Nephropathy (CIN) Consensus Working Panel, an international multidisciplinary group convened to address the challenges of contrast-induced AKI whose findings were published in 2006 [6–12].

Evaluating the Literature on Contrast-Induced AKI

The CIN Consensus Working Panel comprised two radiologists, two cardiologists and two nephrologists practicing in Europe and the United States. At the first meeting in November 2004, the overall scope and strategy for the project were agreed and at the second in September 2005, the Working Panel reviewed and discussed all the evidence and developed a series of consensus statements. A systematic search of the literature was underPeter A. McCullough, MD, MPH Divisions of Cardiology, Nutrition, and Preventive Medicine William Beaumont Hospital, 4949 Coolidge Highway Royal Oak, MI 48073 (USA) Tel. +1 248 655 5948, Fax +1 248 655 5901, E-Mail [email protected]

Table 1. Consensus statements concerning contrast-induced AKI,

adapted from McCullough et al. [13] Consensus statement 1 Contrast-induced AKI is a common and potentially serious complication following the administration of contrast media in patients at risk for acute renal injury Consensus statement 2 The risk of contrast-induced AKI is elevated and of clinical importance in patients with chronic kidney disease (particularly when diabetes is also present), recognized by an estimated glomerular filtration rate <60 ml/min/1.73 m2 Consensus statement 3 When serum creatinine or estimated glomerular filtration rate is unavailable, then a survey may be used to identify patients at higher risk for contrast-induced AKI than the general population Consensus statement 4 In the setting of emergency procedures, where the benefit of very early imaging outweighs the risk of waiting, the procedure can be performed without knowledge of serum creatinine or eGFR Consensus statement 5 The presence of multiple contrast-induced AKI risk factors in the same patient or high-risk clinical scenarios can create a very high risk (⬃50%) for contrast-induced AKI and (⬃15%) acute renal failure requiring dialysis after contrast exposure Consensus statement 6 In patients at increased risk for contrast-induced AKI undergoing intra-arterial administration of contrast, ionic high-osmolality agents pose a greater risk for contrast-induced AKI than lowosmolality agents; current evidence suggests that for intra-arterial administration in high-risk patients with chronic kidney disease, particularly those with diabetes mellitus, nonionic, iso-osmolar contrast is associated with the lowest risk of contrast-induced AKI Consensus statement 7 Higher contrast volumes (>100 ml) are associated with higher rates of contrast-induced AKI in patients at risk; however, even small (⬃30 ml) volumes of iodinated contrast in very-high-risk patients can cause contrast-induced AKI and acute renal failure requiring dialysis, suggesting the absence of a threshold effect Consensus statement 8 Intra-arterial administration of iodinated contrast appears to pose a greater risk of contrast-induced AKI above that with intravenous administration Consensus statement 9 Adequate intravenous volume expansion with isotonic crystalloid (1.0–1.5 ml/kg/h) for 3–12 h before the procedure and continued for 6–24 h afterwards can lessen the probability of contrastinduced AKI in patients at risk; the data on oral as opposed to intravenous volume expansion as a contrast-induced AKI prevention measure are insufficient Consensus statement 10 No adjunctive medical or mechanical treatment has been proven to be efficacious reducing the risk of AKI after exposure to iodinated contrast; prophylactic hemodialysis or hemofiltration has not been validated as an effective strategy

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taken to identify all references relevant to the subject of contrast-induced AKI, as a result of which 865 potentially relevant papers were identified and reviewed. The results of the literature search were used to compile reviews covering the epidemiology and pathogenesis of AKI, baseline renal function measurement, risk assessment, identification of high-risk patients, contrast medium use and preventive strategies [6–12]. After reviewing all the evidence, a series of consensus statements was developed and has been published elsewhere (table 1) [13].

Epidemiology and Prognostic Implications of Contrast-Induced AKI

The reported incidence of contrast-induced AKI varies widely across the literature, depending on the patient population and the baseline risk factors. Moreover, as with any clinical event, the incidence also varies depending on the criteria by which it is defined. Contrast-induced AKI is typically defined in the recent literature as an increase in serum creatinine (Cr) occurring within the first 24 h after contrast exposure and peaking up to 5 days afterwards. In most instances, the rise in serum Cr is expressed either in absolute terms (0.5–1.0 mg/dl) or as a proportional rise in serum Cr of 25 or 50% above the baseline value. The most commonly used definition in clinical trials is a rise in serum Cr of 0.5 mg/dl or a 25% increase from the baseline value, assessed at 48 h after the procedure. The European Society of Urogenital Radiology defines contrast-induced AKI as impairment in renal function (an increase in serum Cr by 10.5 mg/dl or 125% within 3 days after intravascular administration of contrast medium) without an alternative etiology [14]. The Acute Kidney Injury Network definition is a rise in serum Cr 60.3 mg/dl with oliguria which is compatible with previous definitions and is a new standard to follow for the critical care physician. Fortunately, the frequency of contrast-induced AKI has decreased over the past decade from a general incidence of ⬃15 to ⬃7% of patients [15]. This is due to a greater awareness of the problem, better risk prevention measures, and improved iodinated contrast media with less renal toxicity. However, many cases of contrast-induced AKI continue to occur because of the ever-increasing numbers of procedures requiring contrast. Nash et al. [3] reported that radiographic contrast media were the third commonest cause of hospital-acquired renal failure (after decreased renal perfusion and nephrotoxic medications) and were responsible for 11% of cases. McCullough

It has been recognized for some time that mortality is increased in patients developing contrast-induced AKI whether or not dialysis is required [16–20]. In a large retrospective study of over 16,000 hospitalized patients undergoing procedures requiring iodinated contrast, a total of 183 subjects developed contrast-induced AKI (defined as a 25% increase in serum Cr) [21]. The risk of death during hospitalization was 34% in subjects who developed contrast-induced AKI compared with 7% in matched controls who had received contrast medium but did not develop contrast-induced AKI. Even after adjusting for comorbid disease, patients with contrast-induced AKI had a 5.5-fold increased risk of death [21]. The high risk of in-hospital death associated with contrast-induced AKI was also documented in a retrospective analysis of 7,586 patients, of whom 3.3% developed contrast-induced AKI after exposure to iodinated contrast. Among those who developed contrast-induced AKI, the in-hospital death rate was 22% compared with 1.4% in patients who did not develop AKI [22]. The mortality rates at 1 and 5 years after development of contrast-induced AKI were 12.1 and 44.6%, respectively, compared to 3.7 and 14.5% in patients who were free of renal injury (p ! 0.001). A further study confirmed the high mortality in patients who develop contrast-induced AKI, especially in those who require dialysis: the hospital mortality was 7.1% in contrast-induced AKI patients and 35.7% in patients who required dialysis. By 2 years, the mortality rate in patients who required dialysis was 81.2% [17]. Contrast-induced AKI (defined as an increase 625% in serum Cr) occurred in 37% of 439 patients with renal impairment (baseline serum Cr 61.8 mg/dl) undergoing percutaneous coronary intervention (PCI) [23]. In this group, the hospital mortality rate was 14.9% compared with 4.9% in patients without contrast-induced AKI (p = 0.001). The cumulative 1-year mortality rates were 37.7 and 19.4%, respectively. The 1-year mortality was 45.2% for patients with contrast-induced AKI requiring dialysis and 35.4% for those with contrast-induced AKI not requiring dialysis [23]. In patients undergoing primary PCI for myocardial infarction (MI), contrast-induced AKI is independently associated with short- and long-term mortality rates and were also significantly higher in those who developed contrast-induced AKI [24–26]. As well as an increased risk of death, contrast-induced AKI is also associated with other adverse outcomes including late cardiovascular events after PCI. In one registry of 5,967 PCI patients, the development of contrastinduced AKI was associated with an increased incidence of MI and target vessel revascularization at 1 year [26].

Another large PCI study documented the link between contrast-induced AKI, postprocedural increases in creatine kinase-myocardial band (CK-MB) subfraction, and the risk of late cardiovascular events [27]. In a group of 5,397 patients, a postprocedural rise in serum Cr was a more powerful predictor of late mortality than CK-MB. Creatinine increases were associated with a 16% rate of death or MI at 1 year, rising to 26.3% when CK-MB levels were also elevated after the procedure [27]. More in-hospital events such as bypass surgery, bleeding requiring transfusion and vascular complications were observed in patients who developed contrast-induced AKI, both in those with previous renal dysfunction and those with previously normal renal function. At 1 year, the cumulative rate of major adverse cardiac events was significantly higher in patients who had developed contrast-induced AKI (p ! 0.0001 for patients with and without chronic kidney disease – CKD) [28]. However, others have observed no difference in the rates of MI and target vessel revascularization in patients with contrast-induced AKI [23]. Contrast-induced AKI leads to increased hospital length of stay, regardless of baseline renal function [28]. In a series of 200 patients undergoing PCI for acute MI, patients who developed contrast-induced AKI had a longer hospital stay, a more complicated clinical course, and a significantly increased risk of death compared to those without contrast-induced AKI [25]. A recent economic analysis of the direct costs associated with contrast-induced AKI showed that the average additional cost was USD 10,345 for the hospital stay and USD 11,812 for 1 year [29]. The major determinant of the increased costs associated with contrast-induced AKI was the cost of the longer initial hospital stay. While most cases of contrast-induced AKI reflect mild transient impairment of renal function, dialysis is needed in a small proportion of patients. The need for dialysis after contrast-induced AKI varies according to patients’ underlying risks at the time of contrast administration but is generally less than 1% [17, 30, 31], although it was considerably higher in some older studies with high-osmolal contrast media (HOCM) [32, 33]. In contemporary studies, contrast-induced AKI requiring dialysis developed in almost 4% of patients with underlying renal impairment [34] and 3% of patients undergoing primary PCI for acute coronary syndromes (ACS) [25]. Although contrast-induced AKI requiring dialysis is relatively rare, the impact on patient prognosis is considerable, with high hospital and 1-year mortality rates [17, 23].

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Reduced nephron mass vulnerable to injury Associated factors: diabetes, poor renal perfusion, others Contrast enters renal vasculature Endothelium-independent transient vasodilation (minutes) Adenosine release from macula densa (tubulo-glomerular feedback)

Endothelin release

Decreased nitric oxide synthesis/release

Fig. 1. Postulated pathophysiology of con-

trast-induced AKI. In the presence of a reduced nephron mass, the remaining nephrons are vulnerable to injury. Iodinated contrast, after causing a brief (minutes) period of vasodilation, cause sustained (hours to days) intrarenal vasoconstriction and ischemic injury. The ischemic injury sets off a cascade of events largely driven by oxidative injury causing death of renal tubular cells. If a sufficient mass of nephron units are affected, then a recognizable rise in serum creatinine will occur.

Sustained intrarenal vasoconstriction (h) Prolonged contrast transit time in kidneys Increased contrast exposure to renal tubular cells Contrast direct cellular injury and death

Pathophysiology of Contrast-Induced AKI

CKD is both necessary and sufficient for the development of contrast-induced AKI. In patients with CKD, identified by an estimated glomerular filtration rate (eGFR) !60 ml/min/1.73 m2 (which roughly corresponds in the elderly to a serum Cr 11.0 mg/dl in a woman and 11.3 mg/dl in a man), there is a considerable loss of nephron units and the residual renal function is vulnerable to declines with renal insults (iodinated contrast, cardiopulmonary bypass, renal-toxic medications, atheroembolism, etc.). Thus, the pathophysiology of contrast-induced AKI assumes baseline reduced nephron number, with superimposed acute vasoconstriction caused by the release of adenosine, endothelin, and other renal vasoconstrictors triggered by iodinated contrast. After a very brief increase in renal blood flow, via the above mechanisms, there is an overall ⬃50% sustained reduction in renal blood flow lasting for several hours (fig. 1). There is a concentration of iodinated contrast in the renal tubules and collecting ducts, resulting in a persistent nephrogram on fluoroscopy. This stasis of contrast in the kidney allows for direct cellular injury and death to renal tubular cells. The degree of cytotoxicity to renal tubular cells is directly related to the length of exposure those cells have to iodinated contrast; hence, the importance of high urinary flow rates before, during and after contrast procep64

Prostaglandin dysregulation

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Medullary hypoxia

Ischemic injury and death

Oxidative stress, inﬂammation, other organ injury processes

Acute kidney injury

dures. The sustained reduction in renal blood flow to the outer medulla leads to medullary hypoxia, ischemic injury, and death of renal tubular cells. By these two mechanisms, it is believed that other organ injury processes including oxidative stress and inflammation may play a further role. Any superimposed insult such as sustained hypotension in the catheterization laboratory, microshowers of atheroembolic material from catheter exchanges or the use of intra-aortic balloon counterpulsation, or a bleeding complication can amplify the injury processes occurring in the kidney. Pathophysiologic factors related to contrast-induced AKI are presented in table 2. A detailed review of pathophysiology is outside the scope of this paper and the reader is referred to a published review for further information [9].

Baseline Renal Function

Virtually every report describing risk factors for contrast-induced AKI lists abnormal baseline serum Cr, low GFR, or CKD as risk factors. Almost every multivariate analysis has shown that CKD is an independent risk predictor for contrast-induced AKI [1, 15, 22, 30, 34, 35]. The risk of contrast-induced AKI is increased in patients with an eGFR !60 ml/min/1.73 m2 (stage 3–5 CKD), and special precautions should be taken in these patients. These McCullough

Radiocontrast-Induced AKI

70

Diabetes No diabetes

60

50

AKI (%)

statements apply to stable renal function. In critically ill patients, renal function may be dynamic and compromised (due to cardiogenic shock, heart failure, drug-induced injury, etc.), making the risk state greater, and, thus, clinical judgment must be applied to the assessment of baseline renal function. It is important to assess renal function before administration of contrast medium to ensure that appropriate steps are taken to reduce the risk. Since serum Cr alone does not provide a reliable measure of renal function, the National Kidney Foundation Kidney Disease Outcome Quality Initiative (KDOQI) recommends that clinicians should use an eGFR calculated from the serum Cr as an index of renal function rather than using serum Cr [36] in stable patients. For outpatient radiology studies, where renal function data are unavailable, a simple survey or questionnaire may be used to identify outpatients at higher risk for AKI in whom appropriate precautions should be taken [37–39]. A brief seven item survey inquires on the following: (1) history of renal disease; (2) prior renal surgery; (3) proteinuria; (4) diabetes mellitus (DM); (5) hypertension; (6) gout; (7) use of nephrotoxic drugs (nonsteroidal anti-inflammatory agents, etc.). The majority of patients with CKD would have one or more positive responses to these questions. For inpatients undergoing any exposure to iodinated contrast, the serum Cr should be available before contrast is given. In the setting of emergency procedures, where the benefit of very early imaging outweighs the risk of waiting for the results of a blood test (trauma, shock, etc.), it may be necessary to proceed without serum Cr assessment or GFR estimation [8]. It is suggested that a baseline blood sample is taken prior to the emergency procedure to enable monitoring afterwards even if the initial result is not immediately known. However, where possible, an indication should be obtained of the likelihood that the patient has impaired renal function that may increase the risk of AKI, to enable suitable precautions to be taken. In addition to CKD, other risk markers include DM [26, 28], volume depletion [40], nephrotoxic drugs, hemodynamic instability [27, 41] and other comorbidities. Importantly, DM is neither necessary nor sufficient as a determinant for contrast-induced AKI. However, DM appears to act as a risk multiplier, meaning that in a patient with CKD it amplifies the risk of contrast-induced AKI (fig. 2). Several large series of PCI patients have shown an association between contrast-induced AKI and indicators of hemodynamic instability such as periprocedural hypotension and use of an intra-aortic balloon pump [26, 28]. It is not surprising that hypotension increases the risk of contrast-induced AKI since it increases the likeli-

40

30

20

10

0 0

20

40 60 80 100 Estimate of renal ﬁltration function eGFR or CrCl (ml/min)

120

Fig. 2. Risk of contrast-induced AKI according to baseline renal function (eGFR or creatinine clearance in milliliters per minute) modeled from published data. Contrast-induced AKI was defined as serum creatinine increase of 25% and/or 0.5 mg/dl and is shown separately for patients with (solid circles) and without (open circles) diabetes. Data adapted from McCullough [12].

Table 2. Factors that predispose to contrast-induced AKI

Reduced remnant nephron mass vulnerable to injury (eGFR or CrCl <60 ml/min) – Increases reabsorptive workload in proximal tubule – Structural changes in the renal vasculature Defective protective mechanisms – Altered vasodilation due to diabetes, hypertension, aging, hyperlipidemia, atherosclerosis – Altered renal prostaglandin synthesis due to aging or NSAIDs Enhanced systemic vasoconstrictive stimuli – Volume depletion – Cirrhosis Reduced oxygen delivery – Volume depletion – Anemia – Low cardiac output Superimposed or pre-existing acute organ injury – Sepsis – Atheroembolism – Drug toxicity (aminoglycosides, amphotericin)

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Contrast-induced acute kidney injury rate (%)

18 16

IOCM LOCM

p = 0.003

14 12 10

p = 0.001

8 6

NS p < 0.001

4 2

NS

NS

NS

0 CKD (–) CKD (–) CKD (+) CKD (+) CKD (–) CKD (+) DM (–) DM (+) DM (–) DM (+)

RRR (%) for IOCM

42.2

70.6

54.5

80.4

47.4

68.8

Total 61.5

Fig. 3. Rates of contrast-induced AKI (rise in serum creatinine 1 0.5 mg/dl) in a meta-analysis of 16 head-to-head trials comparing IOCM to LOCM. Relative risk reductions (RRR) are for IOCM compared to LOCM. CKD = Baseline chronic kidney disease defined as an estimated creatinine clearance !60 ml/min. Data adapted from McCullough et al. [47].

hood of renal ischemia and is a significant risk factor for acute renal failure in acutely ill patients. Anemia has also been reported as a predictor of contrast-induced AKI and may compound hypoxic injury by further limiting oxygen delivery [42]. The effect of risk factors is additive and the likelihood of contrast-induced AKI rises sharply as the number of risk factors increases [17, 41]. A similar pattern of additive risk has been documented for AKI requiring dialysis [30]. The additive nature of risk has allowed the development of prognostic scoring schemes [15, 41]. Since none of the published schemes has been adequately studied or prospectively validated in different populations beyond cardiovascular procedures, it is not appropriate to recommend routine use of any particular risk scoring in clinical practice. However, the concept is that in a patient with CKD, DM, and other comorbidities, predicted risks of contrast-induced AKI and emergency dialysis can approach ⬃50 and ⬃15%, respectively. Critical Care and Risks of Iodinated Contrast

Many clinical situations may arise in which the risk of contrast-induced AKI is increased with the most common scenario in the catheterization laboratory being cardiogenic shock [6]. While, in general, the benefits of rep66

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vascularization outweigh the risks of the procedure, in the setting of shock requiring the placement of an intraaortic balloon pump, considerably higher rates of contrast-induced AKI can be expected. A common scenario in complicated patients is repeated exposure to iodinated contrast over a period of a few days. While there are no studies on the ideal interim ‘rest’ period for the kidneys, the general principal is that if additional contrast is given in the setting of AKI, outcomes are likely to worsen. Most clinical trials have used an interim period of 10 days from a prior procedure to be sure the patient has not incurred AKI from the first procedure. Because of the added insult of cardiopulmonary bypass, the risk of contrast-induced AKI in patients undergoing emergency coronary artery bypass surgery following angiography is increased. Finally, the published literature on the risk of contrast-induced AKI in heart or renal transplant recipients is inconsistent and clinicians should be conservative and consider them at high risk [6].

Differences in Iodinated Contrast

Iodinated contrast media packages iodine atoms, which are radiopaque, on carbon-based molecules which are water-soluble. Contrast media is classified according to osmolality, which reflects the total particle concentration of the solution (the number of molecules dissolved in a specific volume). Contrast media can be categorized according to osmolality (high-osmolal [HOCM] ⬃2,000 mosm/kg, low-osmolal [LOCM] 600–800 mosm/kg, and isosmolal [IOCM] 290 mosm/kg) [7]. Over the past 40 years, the osmolalities of available CM have been gradually decreased to physiological levels. In the 1950s, only HOCM (e.g. diatrizoate) with osmolality 5–8 times that of plasma were used. In the 1980s, LOCM agents such as iohexol, iopamidol, and ioxaglate were introduced having osmolality 2–3 times greater than that of plasma. In the 1990s, iso-osmolar nonionic iodixanol with the same physiologic osmolality as blood was developed. Red blood cell deformation, systemic vasodilation, intrarenal vasoconstriction, as well as direct renal tubular toxicity are all more common in contrast agents with osmolality greater than that of blood. In a meta-analysis of studies before 1992, the pooled odds ratio for the incidence of contrastinduced AKI events (rise in serum Cr of 10.5 mg/dl) in 25 trials was 0.61, 95% CI 0.48–0.77, indicating a significant reduction in risk with LOCM compared to HOCM [43]. Studies published since this meta-analysis generally support these findings [44]. Most studies comparing difMcCullough

the baseline level of eGFR in ml [55]. This means for patients with significant CKD reasonable goals would be: !30 ml for diagnostic cardiac catheterization and !100 ml for PCI, CT, and other intravascular studies. The risk of contrast-induced AKI is generally higher following intra-arterial than after intravenous injection [56, 57]. However, in CT studies, where a comparatively large volume of contrast medium is given as a compact intravenous (80–120 ml) bolus rather than an infusion, the risk of AKI may be increased.

ferent LOCM agents have been small trials that have not shown clinically relevant variation within this class [7]. Iodixanol has been shown to have the lowest risk for contrast-induced AKI in patients with CKD and DM [45–46]. In a pooled analysis of 16 head-to-head, randomized trials (2,727 patients) of intra-arterial contrast medium, the incidence of contrast-induced AKI was significantly lower with iodixanol than with LOCM (fig. 3) [47]. A systematic review by Solomon [48] also demonstrated the lowest risk of contrast-induced AKI with iodixanol. This study included a total of 17 prospective clinical trials (1,365 patients), but only two of these trials were randomized head-to-head comparisons of iodixanol versus LOCM and the other data came from the placebo arms of 13 trials of preventive strategies for contrastinduced AKI and the LOCM arms of 2 trials comparing LOCM and HOCM. Finally, a meta-analysis of the renal tolerability of another IOCM, iotrolan 280 (not approved for intravascular use), provides further evidence that IOCM are associated with a lower-risk contrast-induced AKI [49]. In this analysis of 14 double-blind studies, it was found that iotrolan had less effect on renal function that the LOCM with which it was compared (iopamidol, iohexol, iopromide). A recent, head-to-head randomized trial showed a significantly lower rate of contrast-induced AKI with iodixanol compared with LOCM in high-risk patients undergoing coronary angiography [50]. In lower-risk patients undergoing CT, where contrast is given intravenously, the rates of contrast-induced AKI were similar with iodixanol and LOCM [51]. In addition, in very-low-risk patients given intracoronary administration of contrast, no difference has been shown between iodixanol and LOCM [52]. The American College of Cardiology/American Heart Association guidelines for the management of ACS patients with CKD listed the use of IOCM as a class I, level of evidence A recommendation [53]. The National Kidney Foundation KDOQI guidelines have also recommended use of IOCM in renal dialysis patients to minimize the chances of volume overload and complications prior to the next dialysis session [7]. Most other societies concur with these recommendations for intra-arterial administration and allow the use of LOCM in lower-risk patients and intravenous administration. Most multivariate analyses have shown that contrast volume is an independent predictor of contrast-induced AKI [17, 26, 30, 41]. Even small volumes (⬃30 ml) of contrast medium can have adverse effects on renal function in patients at particularly high risk [54]. As a general rule, the volume of contrast received should not exceed twice

Volume expansion and treatment of dehydration has a well-established role in the prevention of contrast-induced AKI, although few studies address this theme directly. There are limited data on the most appropriate choice of intravenous fluid, but the evidence indicates that isotonic crystalloid (saline or bicarbonate solution) is probably more effective than half-normal saline [58]. Additional confirmatory trials with sodium bicarbonate [59] are needed since the largest trial to date showed no benefit of sodium bicarbonate over normal saline [60]. There is also no clear evidence to guide the choice of the optimal rate and duration of infusion. However, good urine output (1150 ml/h) in the 6 h after the procedure has been associated with reduced rates of AKI in one study [61]. Since not all of the intravenously administered isotonic crystalloid remains in the vascular space, in order to achieve a urine flow rate of at least 150 ml/h, 61.0– 1.5 ml/kg/min of intravenous fluid has to be adminis-

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Nephrotoxic Drugs

While there are no withdrawal studies in this area, it is reasonable practice to hold NSAIDS, calcineurin inhibitors, high-dose loop diuretics, aminoglycosides, and other nephrotoxic agents for several days, if possible, prior to contrast exposure. It is routine practice to hold metformin prior to all contrast procedures not because metformin itself is nephrotoxic, but because in the setting of AKI if metformin is continued, lactic acidosis can develop leading to systemic complications and death. In the setting of accidental administration of metformin in a patient with AKI, the metformin can be cleared from the body with dialysis. As a general rule, metformin should not be restarted until the clinician is confident that the patient has not incurred AKI.

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tered for 3–12 h before and 6–12 h after contrast exposure. Oral volume expansion may have some benefit, but there is not enough evidence to show that it is as effective as intravenous volume expansion [62].

Dialysis and Hemofiltration

Iodinated contrast is water soluble and removed by dialysis, but there is no clinical evidence that prophylactic dialysis reduces the risk AKI, even when carried out within 1 h or simultaneously with contrast administration. Hemofiltration, however, performed 6 h before and 12–18 h after contrast deserves consideration given reports of reduced mortality and need for hemodialysis in the postprocedure period in very-high-risk patients (serum Cr 3.0–4.0 mg/dl, eGFR 15–20 ml/min/1.73 m2) [63, 64]. Hemofiltration works to ensure adequate intravascular volume, reduce uremic toxins which may worsen AKI, and provides stability to the high-risk patient after the procedure reducing the risks of oliguria, volume overload, and electrolyte imbalance that are associated with short-term mortality. Under the direction of a nephrologist, a double-lumen catheter is placed in a jugular or femoral vein for blood withdrawal and reinfusion and connected with an extracorporeal circuit. Blood is driven through the circuit by means of a peristaltic pump (e.g. prisma hemofiltration pump) at a rate of 100 ml/min. Isotonic replacement fluid (postdilution hemofiltration) is set at a rate of 1,000 ml/h, and is matched with the rate of ultrafiltrate production so that no net fluid loss occurs. The cardiologist should be aware that hemofiltration calls for a 5,000-IU heparin bolus before initiation followed by a continuous heparin infusion of 500–1,000 IU/h through the inflow side of the catheter. At the time of the cardiac procedure, the hemofiltration treatment should be stopped, and the circuit temporarily filled with a saline solution and short-circuited to exclude the patient without interruption of the flow. Immediately after the procedure the hemofiltration should be restarted. This approach should be considered only in the veryhighest-risk patient in conjunction with nephrology consultation and dialysis planning.

Pharmacologic Prophylaxis

There are no currently approved pharmacological agents for the prevention of AKI. With iodinated contrast, the pharmacological agents tested in small trials p68

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that deserve further evaluation include the antioxidants ascorbic acid and N-acetylcysteine (NAC), statins, aminophylline/theophylline, and prostaglandin E1 [10]. Of these agents, only ascorbic acid has been tested in a multicenter, blinded, placebo-controlled trial (n = 231) and been shown to reduce rates of contrast-induced AKI. The dose of ascorbic acid (vitamin C over the counter) used in this trial was 3 g p.o. the night before and 2 g p.o. b.i.d. after the procedure [65]. Although popular, NAC has not been consistently shown to be effective. To date, 11 meta-analyses have been published on this subject [66–76], seven of these reports found a net benefit for NAC in the prevention of CIN. However, a recent review by Bagshaw et al. [77] found marked heterogeneity in study results in 10 of the 11 meta-analyses. Importantly, only in those trials where NAC reduced serum Cr below baseline values because of decreased skeletal muscle production, did renal injury rates appear to be reduced. Thus, NAC appears to falsely lower Cr and not fundamentally protect against AKI. However, NAC as an antioxidant has been shown to lower rates of AKI and mortality after primary PCI in one trial [78]. The recently published Renal Insufficiency following Contrast Media Administration Trial suggested that the use of volume supplementation with sodium bicarbonate together with NAC was more effective than NAC alone in reducing the risk of AKI [79]. Dosing of NAC has varied in the trials; however, the most successful approach has been with 1,200 mg p.o. b.i.d. on the day before and after the procedure. Fenoldopam, dopamine, calcium-channel blockers, atrial natriuretic peptide and L-arginine have not been shown to be effective in the prevention of contrast-induced AKI. Furosemide, mannitol and an endothelin receptor antagonist are potentially detrimental [10]. In general, cardiovascular patients undergoing procedures with iodinated contrast have either high risk for atherosclerosis or have the anatomic presence of disease. Therefore, the vast majority of patients should be on statin therapy with a common low-density lipoprotein cholesterol (LDL-C) target of !70 mg/dl. It has been demonstrated that patients continued on statins during cardiovascular procedures including PCI and CABG have lower rates of AKI [80]. Small randomized trials published to date support this concept as well [81, 82]. Preservation of endothelial function at the level of the glomerulus and reductions in systemic inflammatory factors are postulated mechanisms by which statins may have renoprotective effects [82]. Thus, statins should be a standard of care for patients undergoing these procedures for a variety of reaMcCullough

Calculate eGFR or CrCl Assess contrast-induced AKI risk

eGFR <30 ml/min Start/continue statin Discontinue NSAIDs, other nephrotoxic drugs, metformin

• Hospital admission • Other strategies as for eGFR 30–59 • Nephrology consultation* • Consider hemoﬁltration preand postprocedure

• Serum Cr before discharge and/or 24–96 h after • Expectant care

eGFR 30–59 ml/min Start/continue statin Discontinue NSAIDs, other nephrotoxic drugs, metformin

• i.v. isotonic (NaCl/NaHCO3) • 1.0–1.5 ml/kg/h 3–12 h pre and 6–24 post • Ensure urine ﬂow rate >150 ml/h • Iso-osmolal contrast • DM, ACS, other added risks • Low osmolal contrast • No other added risks • Limit contrast volume • <30 ml diagnostic • <100 ml diagnostic + intervention • Consider adjunctive medications† • Antioxidants • NAC 1,200 mg p.o. b.i.d. pre- and postprocedure or • Ascorbic acid 3 g p.o. pre2 g p.o. b.i.d. postprocedure

eGFR ≥60 ml/min Discontinue metformin

Good clinical practice

* Plans should be made in case AKI occurs and dialysis is required † Potentially beneﬁcial agents (NAC, ascorbic acid, aminophylline, PGE1); none approved for this indication

Fig. 4. Advanced algorithm for the management of patients receiving iodinated contrast media.

sons started at baseline and continued over the long-term course of care provided they are well-tolerated (without skeletal muscle or liver adverse effects). This administration should be continued during periods of intensive care, provided there are no contra-indications.

96 h after discharge. Rehospitalization is reasonable for uremic symptoms, hyperkalemia, and volume overload in the setting of AKI.

Biomarkers for Contrast-Induced AKI

Figure 4 presents an integrated advanced algorithm for the management of contrast-induced AKI. It should be noted that there are no approved pharmaceutical agents for the prevention of this complication, thus the practitioner should be cautious with the use of any of the drugs suggested. Importantly, all patients at risk for contrast-induced AKI should have follow-up Cr and electrolyte monitoring daily while in hospital, and then at 48–

Serum Cr is both an indirect and insensitive marker of baseline kidney function and of AKI. Thus, there is considerable interest in developing blood and urine biomarkers for AKI analogous to troponin for acute MI. Neutrophil gelatinase-associated lipocalin (NGAL), a member of the lipocalin family, is readily excreted and detected in urine, due to its small molecular size (25 kDa) and resistance to degradation. NGAL is highly accumulated in the human kidney cortical tubules, blood and urine, after nephrotoxic and ischemic injuries such as ex-

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Multimodality Prevention

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posure to iodinated contrast. Thus, whole blood NGAL might represent an early, sensitive, biomarker for AKI being developed for point-of-care use in the catheterization laboratory [83, 84]. Finally, cystatin C is a serum protein that is filtered out of the blood by the kidneys and that serves as a measure of kidney function. Cystatin C is produced steadily by all types of nucleated cells in the body. Its low molecular mass allows it to be freely filtered by the glomerular membrane in the kidney. Its concentration in blood correlates with the glomerular filtration rate. The levels of cystatin C are independent of weight and height, muscle mass, age, and sex. Measurements can be made and interpreted from a single random sample. Cystatin C is a better marker of the glomerular filtration rate and kidney function than Cr and is cleared for use by the United States Food and drug administration. It is expected that this marker will replace serum Cr in the future as the blood marker of renal filtration function.

dration using a balancing pump with marked elevations of urine output to reduce the transit time of iodinated contrast in the renal tubules, systemic cooling, and novel, hopefully less toxic forms of radiopaque contrast agents. Another approach may involve coronary sinus withdrawal of blood and contrast after intracoronary injection, thus reducing the volume of contrast delivered downstream to the kidneys [85, 86]. If procedures using iodinated contrast could be performed with no risk of AKI, it is expected that major medical complications and death could be appreciably reduced. Thus, future clinical trials should position a composite of clinically meaningful outcomes as the primary endpoint, and the rise of serum Cr and other biomarkers as the secondary endpoint. Taking this approach, investigators will not only be able to test new approaches to improve outcomes, but solve the mystery of how a transient rise in Cr can lead to disparate catastrophic developments over the short and longer term.

Future Approaches Conclusion

Because contrast-induced AKI has a timed injury to the body, it is one of the most amenable forms of AKI for clinical trials. Future approaches include large planned studies of oral and intravenous antioxidants (including a potent oral antioxidant, deferiprone), intrarenal infusions of renal vasodilators using flow directed catheters in the procedural suite or intensive care unit, forced hy-

Contrast-induced AKI is predictable and may be partially preventable. Reasonable steps should be taken to minimize risk. Novel diagnostic and therapeutic approaches are needed to manage the ever-increasing numbers of vulnerable patients undergoing procedures using iodinated contrast media.

References 1 McCullough PA, Soman SS: Contrast-induced nephropathy. Crit Care Clin 2005; 21: 261–280. 2 Gleeson TG, Bulugahapitiya S: Contrast-induced nephropathy. AJR Am J Roentgenol 2004;183:1673–1689. 3 Nash K, Hafeez A, Hou S: Hospital-acquired renal insufficiency. Am J Kidney Dis 2002; 39:930–936. 4 Chew DP, Astley C, Molloy D, et al: Morbidity, mortality and economic burden of renal impairment in cardiac intensive care. Intern Med J 2006;36:185–192. 5 Bagshaw SM, Mortis G, Doig CJ, et al: Oneyear mortality in critically ill patients by severity of kidney dysfunction: a populationbased assessment. Am J Kidney Dis 2006;48: 402–409.

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6 Becker CR, Davidson C, Lameire N, et al: High-risk situations and procedures. Am J Cardiol 2006;98:37K–41K. 7 Davidson C, Stacul F, McCullough PA, et al: Contrast medium use. Am J Cardiol 2006;98: 42K–58K. 8 Lameire N, Adam A, Becker CR, et al: Baseline renal function screening. Am J Cardiol 2006;98:21K–26K. 9 McCullough PA, Adam A, Becker CR, et al: Risk prediction of contrast-induced nephropathy. Am J Cardiol 2006; 98:27K–36K. 10 Stacul F, Adam A, Becker CR, et al: Strategies to reduce the risk of contrast-induced nephropathy. Am J Cardiol 2006; 98:59K–77K. 11 Tumlin J, Stacul F, Adam A, et al: Pathophysiology of contrast-induced nephropathy. Am J Cardiol 2006;98:14K–20K. 12 McCullough PA, Adam A, Becker CR, et al: Epidemiology and prognostic implications of contrast-induced nephropathy. Am J Cardiol 2006;98:5K–13K.

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13 McCullough PA, Stacul F, Davidson C, et al: Overview. Am J Cardiol 2006; 98:2K–4K. 14 Thomsen HS: Guidelines for contrast media from the European Society of Urogenital Radiology. AJR Am J Roentgenol 2003; 181: 1463–1471. 15 Bartholomew BA, Harjai KJ, Dukkipati S, et al: Impact of nephropathy after percutaneous coronary intervention and a method for risk stratification. Am J Cardiol 2004; 93: 1515–1519. 16 Hou SH, Bushinsky DA, Wish JB, et al: Hospital-acquired renal insufficiency: a prospective study. Am J Med 1983;74:243–248. 17 McCullough PA, Wolyn R, Rocher LL, et al: Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med 1997;103:368–375.

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18 Iakovou I, Dangas G, Mehran R, et al: Impact of gender on the incidence and outcome of contrast-induced nephropathy after percutaneous coronary intervention. J Invasive Cardiol 2003;15:18–22. 19 Polena S, Yang S, Alam R, et al: Nephropathy in critically Ill patients without preexisting renal disease. Proc West Pharmacol Soc 2005;48:134–135. 20 Haveman JW, Gansevoort RT, Bongaerts AH, et al: Low incidence of nephropathy in surgical ICU patients receiving intravenous contrast: a retrospective analysis. Intensive Care Med 2006;32:1199–1205. 21 Levy EM, Viscoli CM, Horwitz RI: The effect of acute renal failure on mortality: a cohort analysis. JAMA 1996;275:1489–1494. 22 Rihal CS, Textor SC, Grill DE, et al: Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002;105:2259–2264. 23 Gruberg L, Mintz GS, Mehran R, et al: 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; 36:1542–1548. 24 Sadeghi HM, Stone GW, Grines CL, et al: Impact of renal insufficiency in patients undergoing primary angioplasty for acute myocardial infarction. Circulation 2003; 108: 2769–2775. 25 Marenzi G, Lauri G, Assanelli E, et al: Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004; 44:1780–1785. 26 Lindsay J, Apple S, Pinnow EE, et al: Percutaneous coronary intervention-associated nephropathy foreshadows increased risk of late adverse events in patients with normal baseline serum creatinine. Catheter Cardiovasc Interv 2003;59:338–343. 27 Lindsay J, Canos DA, Apple S, et al: Causes of acute renal dysfunction after percutaneous coronary intervention and comparison of late mortality rates with postprocedure rise of creatine kinase-MB versus rise of serum creatinine. Am J Cardiol 2004;94:786–789. 28 Dangas G, Iakovou I, Nikolsky E, et al: Contrast-induced nephropathy after percutaneous coronary interventions in relation to chronic kidney disease and hemodynamic variables. Am J Cardiol 2005; 95: 13–19. 29 Subramanian S, Tumlin J, Bapat B, et al: Economic burden of contrast-induced nephropathy: implications for prevention strategies. J Med Econ 2007;10:119–134. 30 Freeman RV, O’Donnell M, Share D, et al: Nephropathy requiring dialysis after percutaneous coronary intervention and the critical role of an adjusted contrast dose. Am J Cardiol 2002; 90:1068–1073.

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31 Birck R, Krzossok S, Markowetz F, et al: Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet 2003; 362: 598–603. 32 Martin-Paredero V, Dixon SM, Baker JD, et al: Risk of renal failure after major angiography. Arch Surg 1983;118:1417–1420. 33 Gomes AS, Baker JD, Martin-Paredero V, et al: Acute renal dysfunction after major arteriography. AJR Am J Roentgenol 1985; 145: 1249–1253. 34 Nikolsky E, Mehran R, Turcot DB, et al: Impact of chronic kidney disease on prognosis of patients with diabetes mellitus treated with percutaneous coronary intervention. Am J Cardiol 2004;94:300–305. 35 Davidson CJ, Hlatky M, Morris KG, et al: Cardiovascular and renal toxicity of a nonionic radiographic contrast agent after cardiac catheterization. A prospective trial. Ann Intern Med 1989;110:119–124. 36 K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 suppl 1):S1–S266. 37 Tippins RB, Torres WE, Baumgartner BR, et al: Are screening serum creatinine levels necessary prior to outpatient CT examinations? Radiology 2000;216:481–484. 38 Choyke PL, Cady J, DePollar SL, et al: Determination of serum creatinine prior to iodinated contrast media: is it necessary in all patients? Tech Urol 1998;4:65–69. 39 Olsen JC, Salomon B: Utility of the creatinine prior to intravenous contrast studies in the emergency department. J Emerg Med 1996;14:543–546. 40 Krumlovsky FA, Simon N, Santhanam S, et al: Acute renal failure: association with administration of radiographic contrast material. JAMA 1978;239:125–127. 41 Mehran R, Aymong ED, Nikolsky E, et al: A simple risk score for prediction of contrastinduced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004; 44: 1393–1399. 42 Nikolsky E, Mehran R, Lasic Z, et al: Low hematocrit predicts contrast-induced nephropathy after percutaneous coronary interventions. Kidney Int 2005;6:706–713. 43 Barrett BJ, Carlisle EJ: Meta-analysis of the relative nephrotoxicity of high- and low-osmolality iodinated contrast media. Radiology 1993;188:171–178. 44 Rudnick MR, Goldfarb S, Wexler L, et al: Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. The Iohexol Cooperative Study. Kidney Int 1995;47:254–261. 45 Aspelin P, Aubry P, Fransson SG, et al: Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med 2003; 348: 491–499. 46 Chalmers N, Jackson RW: Comparison of iodixanol and iohexol in renal impairment. Br J Radiol 1999; 72: 701–703.

47 McCullough PA, Bertrand ME, Brinker JA, et al: A meta-analysis of the renal safety of isosmolar iodixanol compared with low-osmolar contrast media. J Am Coll Cardiol 2006;48:692–699. 48 Solomon R: The role of osmolality in the incidence of contrast-induced nephropathy: a systematic review of angiographic contrast media in high risk patients. Kidney Int 2005; 68:2256–2263. 49 Clauss W, Dinger J, Meissner C: Renal tolerance of iotrolan 280: a meta analysis of 14 double-blind studies. Eur Radiol 1995; 5: S79–S84. 50 Jo SH, Youn TJ, Koo BK, et al: Renal toxicity evaluation and comparison between visipaque (iodixanol) and hexabrix (ioxaglate) in patients with renal insufficiency undergoing coronary angiography: the RECOVER study: a randomized controlled trial. J Am Coll Cardiol 2006; 48:924–930. 51 Barrett BJ, Katzberg RW, Thomsen HS, et al: Contrast-induced nephropathy in patients with chronic kidney disease undergoing computed tomography: a double-blind comparison of iodixanol and iopamidol. Invest Radiol 2006;41:815–821. 52 Solomon RJ, Natarajan MK, Doucet S, et al: Cardiac Angiography in Renally Impaired Patients (CARE) study: a randomized double-blind trial of contrast-induced nephropathy in patients with chronic kidney disease. Circulation 2007;115:3189–3196. 53 Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B: ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction-Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/ Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007;50:652–726. 54 Manske CL, Sprafka JM, Strony JT, et al: Contrast nephropathy in azotemic diabetic patients undergoing coronary angiography. Am J Med 1990;89:615–620.

Nephron Physiol 2008;109:p61–p72

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55 Laskey WK, Jenkins C, Selzer F, Marroquin OC, Wilensky RL, Glaser R, Cohen HA, Holmes DR Jr, NHLBI Dynamic Registry Investigators: Volume-to-creatinine clearance ratio: a pharmacokinetically based risk factor for prediction of early creatinine increase after percutaneous coronary intervention. J Am Coll Cardiol 2007; 50:584–90. Epub 2007 Jul 30. 56 Campbell DR, Flemming BK, Mason WF, et al: A comparative study of the nephrotoxicity of iohexol, iopamidol and ioxaglate in peripheral angiography. Can Assoc Radiol J 1990;41:133–137. 57 Moore RD, Steinberg EP, Powe NR, et al: Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial. Radiology 1992; 182:649–655. 58 Mueller C, Buerkle G, Buettner HJ, et al: Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med 2002;162:329–336. 59 Merten GJ, Burgess WP, Gray LV, et al: Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA 2004; 291: 2328– 2334. 60 Brar S: A randomized controlled trial for the prevention of contrast induced nephropathy with sodium bicarbonate vs. sodium chloride in persons undergoing coronary angiography (the MEENA trial). Abstract 209-9. 56th Annual Scientific Session of the American College of Cardiology, New Orleans, 2007, pp 24–27. 61 Stevens MA, McCullough PA, Tobin KJ, et al: A prospective randomized trial of prevention measures in patients at high risk for contrast nephropathy: results of the P.R.I.N.C.E. study. J Am Coll Cardiol 1999; 33:403–411. 62 Taylor AJ, Hotchkiss D, Morse RW, et al: PREPARED: Preparation for Angiography in Renal Dysfunction: a randomized trial of inpatient vs outpatient hydration protocols for cardiac catheterization in mild-to-moderate renal dysfunction. Chest 1998; 114: 1570–1574. 63 Marenzi G, Marana I, Lauri G, et al: The prevention of radiocontrast-agent-induced nephropathy by hemofiltration. N Engl J Med 2003;349:1333–1340. 64 Marenzi G, Lauri G, Campodonico J, Marana I, Assanelli E, De Metrio M, Grazi M, Veglia F, Fabbiocchi F, Montorsi P, Bartorelli AL: Comparison of two hemofiltration protocols for prevention of contrast-induced nephropathy in high-risk patients. Am J Med 2006;119:155–162.

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65 Spargias K, Alexopoulos E, Kyrzopoulos S, Iokovis P, Greenwood DC, Manginas A, Voudris V, Pavlides G, Buller CE, Kremastinos D, Cokkinos DV: Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation 2004;110:2837–2842. 66 Birck R, Krzossok S, Makowetz F, Schnulle P, van der Woude F, Braun C: Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet 2003;362:598–603. 67 Isenbarger D, Kent S, O’Malley P: Metaanalysis of randomized clinical trials on the usefulness of acetylcysteine for prevention of contrast nephropathy. Am J Cardiol 2003;92: 1454–1458. 68 Alonso A, Lau J, Jaber B, Weintraub A, Sarnak M: Prevention of radiocontrast nephropathy with N-acetylcysteine in patients with chronic kidney disease: a meta-analysis of randomized, controlled trials. Am J Kidney Dis 2004;43:1–9. 69 Kshirsagar A, Poole C, Mottl A, Shoham D, Franceschini N, Tudor G, Agrawal M, DenuCiocca C, Magnus Ohman E, Finn WF: N-acetylcysteine for the prevention of radiocontrast induced nephropathy: a metaanalysis of prospective controlled trials. J Am Soc Nephrol 2004;15:761–769. 70 Pannu N, Manns B, Lee H, Tonelli M: Systematic review of the impact of N-acetylcysteine on contrast nephropathy. Kidney Int 2004;65: 1366–1374. 71 Guru V, Fremes S: The role of N-acetylcysteine in preventing radiographic contrast-induced nephropathy. Clin Nephrol 2004; 62: 77–83. 72 Bagshaw S, Ghali WA: Acetylcysteine for prevention of contrast-induced nephropathy: a systematic review and meta-analysis. BMC Med 2004;2:38. 73 Misra D, Leibowitz K, Gowda R, Shapiro M, Khan I: Role of N-acetylcysteine in prevention of contrast-induced nephropathy after cardiovascular procedures: a meta-analysis. Clin Cardiol 2004;27:607–610. 74 Nallamothu BK, Shojania KG, Saint S, Hofer TP, Humes HD, Moscucci M, Bates ER: Is acetylcysteine effective in preventing contrast-related nephropathy? A meta-analysis. Am J Med 2004;117:938–947. 75 Liu R, Nair D, Ix J, Moore D, Bent S: Nacetylcysteine for prevention of contrast-induced nephropathy: a systematic review and meta-analysis. J Gen Intern Med 2005; 20: 193–200.

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76 Duong M, MacKenzie T, Malenka D: N-acetylcysteine prophylaxis significantly reduces the risk of radiocontrast-induced nephropathy. Catheter Cardiovasc Interv 2005; 64: 471–479. 77 Bagshaw SM, McAlister FA, Manns BJ, Ghali WA: Acetylcysteine in the prevention of contrast-induced nephropathy: a case study of the pitfalls in the evolution of evidence. Arch Intern Med 2006;166:161–166. 78 Marenzi G, Assanelli E, Marana I, Lauri G, Campodonico J, Grazi M, De Metrio M, Galli S, Fabbiocchi F, Montorsi P, Veglia F, Bartorelli AL: N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med 2006;354:2773–2782. 79 Briguori C, Airoldi F, D’Andrea D, et al: Renal insufficiency following contrast media administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies. Circulation 2007;115:1211–1217. 80 Khanal S, Attallah N, Smith DE, Kline-Rogers E, Share D, O’Donnell MJ, Moscucci M: Statin therapy reduces contrast-induced nephropathy: an analysis of contemporary percutaneous interventions. Am J Med 2005; 118:843–849. 81 Chello M, Barbato R, Patti G, Goffredo C, di Sciasco G, Covino E: Prevention of postoperative acute renal failure by statin therapy in patients undergoing cardiac surgery. J Am Coll Cardiol 2007; in press. 82 McCullough PA, Rocher LR: Statin therapy in renal disease: harmful or protective. Curr Atheroscler Rep 2007;9:18–24. 83 Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, Malyszko JS, Dobrzycki S: Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions. Am J Nephrol 2006; 26: 287– 92. Epub 2006 Jun 13. 84 Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P: Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365:1231– 1238. 85 Movahed MR, Wong J, Molloi S: Removal of iodine contrast from coronary sinus in swine during coronary angiography. J Am Coll Cardiol 2006;47:465–467. 86 Michishita I, Fujii Z: A novel contrast removal system from the coronary sinus using an adsorbing column during coronary angiography in a porcine model. J Am Coll Cardiol 2006;47:1866–1870.

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Nephron Physiol 2008;109:p73–p79 DOI: 10.1159/000142939

Published online: September 18, 2008

Acute Kidney Injury: New Concepts Hepatorenal Syndrome: The Role of Vasopressors

Richard Moreau Didier Lebrec INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, and Service d’Hépatologie, Hôpital Beaujon, Clichy, France

Key Words Cirrhosis ⴢ Ascites ⴢ Portal hypertension ⴢ Hepatorenal syndrome ⴢ Vasoconstrictors

Abstract Type 1 hepatorenal syndrome (HRS) is prerenal failure specific to decompensated cirrhosis. In patients with HRS, there is marked splanchnic/systemic vasodilation resulting in arterial hypotension, arterial baroreceptor unloading, overstimulation of the sympathetic nervous and renin-angiotensin systems. This reflex neurohumoral hyperactivity via endogenous vasoconstrictors/vasopressors such as angiotensin II and noradrenaline induces arterial vasoconstriction in different extrasplanchnic vascular beds (including preglomerular arteries in the kidneys). Decreased arterial pressure (i.e. low renal perfusion pressure) and preglomerular vasoconstriction are thought to play a major role in the decline of the glomerular filtration rate (GFR). Nonrandomized studies in patients with HRS have shown that the administration of a splanchnic vasoconstrictor (vasopressin analogue or ␣1-adrenoceptor agonist), usually combined with intravenous albumin, causes increases in arterial pressure, arterial baroreceptor uploading, decreased neurohumoral activity, decreased renal vascular resistance, and increased GFR. Randomized clinical trials have shown that treatment with a combination of the vasopressin analogue terlipressin and intravenous albumin improves renal function in patients with

© 2008 S. Karger AG, Basel 1660–2137/08/1094–0073$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

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type 1 HRS. Vasopressor therapy with terlipressin plus intravenous albumin is the medical treatment of choice for type 1 HRS. Copyright © 2008 S. Karger AG, Basel

Introduction

Acute kidney injury (AKI) is common in patients with decompensated cirrhosis (i.e. patients with ascites and/or variceal hemorrhage) [1, 2]. AKI is very rare in patients with compensated cirrhosis [1]. The factors causing AKI are prerenal, intrarenal and postrenal, with prerenal factors being more common than the others (60, 39 and 1%, respectively) [3]. Interestingly, most intrarenal causes of AKI are due to ischemic acute tubular necrosis [3]. In other words, renal hypoperfusion is the main mechanism of AKI in patients with decompensated cirrhosis. Prerenal factors range from obvious renal hypoperfusion in patients with intravascular volume depletion (caused by hemorrhage, vomiting or diarrhea) to more subtle renal hypoperfusion, such as that seen in patients with type 1 (acute) hepatorenal syndrome (HRS specific for decompensated cirrhosis) [1]. The diagnosis of type 1 HRS is mainly based on the exclusion of other expected causes of AKI in patients with decompensated cirrhosis [4]. It should be kept in mind that patients with decompensated cirrhosis may also have chronic HRS, called type 2 HRS Dr. R. Moreau INSERM U773, Hôpital Beaujon FR–92118 Clichy (France) Tel. +33 1 40 87 55 13, Fax +33 1 47 30 94 40, E-Mail [email protected]

[4]. In the present review, unless specified otherwise, the term type 1 HRS will be replaced by HRS. At diagnosis of HRS, patients have liver failure indicated by a high Child-Pugh score (110) and a model of end-stage liver disease (MELD) score (120) [3, 5]. Mean arterial pressure is below 80 mm Hg [5]. Serum creatinine levels and creatinine clearance are above 2.8 mg/dl (250 ␮mol/l) and below 20 ml/min, respectively [1]. In this case, renal failure is not responsive to intravenous albumin administration (e.g. 60–80 g/day for 2 days) [6]. In HRS, there is no spontaneous improvement of glomerular filtration rate (GFR) [7]. HRS is a life-threatening complication of cirrhosis [2, 3, 7]; in untreated patients, the spontaneous probability of survival at 1 month is very low (25%) [7]. In this review, two different aspects of the term ‘vasopressor’ will be examined successively: first, the role endogenous vasopressors in the pathophysiology of HRS, and, second, the role of vasopressor therapy in the medical treatment of HRS.

Role of Endogenous Vasopressors in HRS Pathophysiology

In the ‘classical’ model of the pathophysiology of HRS, splanchnic and systemic vasodilation play a crucial role in the cascade of events leading to HRS. The ‘classical’ model can be summarized as follows: In early cirrhosis, the development of portal hypertension is associated with arteriolar vasodilation in the splanchnic circulation due to the local production (in the arterial walls) of nitric oxide and other vasorelaxant substances [8, 9]. As the disease progresses, splanchnic arterial vasodilation increases and the systemic circulation becomes hyperdynamic, i.e. characterized by high cardiac output and low systemic vascular resistance [10]. It should be noted that the decrease in splanchnic arterial tone plays a crucial role in the development of systemic vasodilation [10]. The consequences of systemic vasodilation are a decrease in effective arterial blood volume and arterial pressure [10]. Arterial hypotension results in arterial baroreceptor unloading, reflex stimulation of the renin-angiotensin and sympathetic nervous systems, vasopressin secretion, sodium and water retention and the formation of ascites [11]. At this stage of decompensated cirrhosis, there is marked neurohumoral hyperactivity and arterial pressure depends on arterial reactivity to the vasoconstrictor action of endogenous vasopressors, i.e. angiotensin-II, noradrenaline, and arginine vasopressin [12]. Since the p74

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Splanchnic/systemic vasodilation

Decreased cardiopulmonary pressures

Arterial hypotension Arterial baroreceptor unloading

Low-pressure baroreceptor unloading

Increased activity of endogenous vasoconstrictor/vasopressor systems Arteriolar vasoconstriction Nonrenal, nonsplanchnic vascular beds

Renal circulation (preglomerular)

Decreased GFR

Fig. 1. In patients with HRS, there is marked splanchnic/systemic vasodilation which results in arterial hypotension, arterial baroreceptor unloading, overstimulation of the sympathetic nervous and renin-angiotensin systems. In addition, low-pressure baroreceptors may be unloaded. Reflex neurohumoral hyperactivity, via endogenous vasoconstrictors/vasopressors such as angiotensin II and noradrenaline, induces arterial vasoconstriction in different extrasplanchnic vascular beds (including preglomerular arteries in the kidneys). Decreased arterial pressure (i.e. low renal perfusion pressure) and preglomerular vasoconstriction play a major role in the decline of GFR.

splanchnic circulation is hyporeactive to the constrictor effect of angiotensin-II, noradrenaline, and vasopressin, due to the local overproduction of vasorelaxant substances [8], the maintenance of arterial pressure is due to vasoconstriction in extra-splanchnic vascular territories including the kidneys and brain [10]. HRS is a complication of end-stage cirrhosis with extreme deterioration in effective arterial blood volume and marked arterial hypotension. In this syndrome, the homeostatic neurohumoral overactivity is very intense leading to marked renal (preglomerular) vasoconstriction and an extreme decrease in renal blood flow. In addition, patients have low arterial pressure, high renal venous pressure (due to the accumulation of ascites) and thus low renal perfusion pressure. The combination of a marked decrease in renal blood flow and low renal perfusion pressure results in low GFR, azotemia and increased serum creatinine levels [1] (fig. 1). Results of recent hemodynamic studies have suggested that mechanisms other than systemic vasodilatation may be involved in the development of HRS [13]. Indeed, the development of this syndrome was found to be associated with significant reductions in both cardiopulmonary pressures [13]. Since decreases in these pressures induce Moreau/Lebrec

cardiopulmonary baroreceptor unloading resulting in increased neurohumoral vasoconstrictor activity, reductions in cardiopulmonary pressures may contribute to renal vasoconstriction in patients with HRS [13].

Vasopressor Therapy for HRS

Background Liver transplantation is the only treatment to cure end-stage cirrhosis [11, 14]. However, patients with HRS who are transplanted have a lower probability of postoperative survival and a higher probability of developing postoperative complications than patients without HRS [11, 14]. Therefore, measures to bridge the period when patients are waiting for liver transplantation are needed. In addition, treatment for HRS is also needed in patients who are not candidates for liver transplantation [14]. The ideal treatment of HRS would reverse HRS by decreasing serum creatinine levels to below 1.5 mg/dl (133 ␮mol/l) [15]. Splanchnic/systemic vasodilation and subsequent arterial hypotension play a crucial role in the mechanisms resulting in renal hypoperfusion in HRS [1]. Logically, it has been suggested that the administration of a powerful splanchnic/systemic vasoconstrictor should increase arterial pressure, upload arterial baroreceptors, decrease neurohumoral activity, decrease renal vascular tone and increase renal blood flow and GFR [1]. Vasoconstrictors/vasopressors evaluated in HRS include vasopressin analogues (i.e. the V1a vasopressin receptor agonists ornipressin and terlipressin) and ␣1-adrenoceptor agonists (midodrine and noradrenaline). Proof-of-Concept Vasopressin Analogues Acute administration of vasopressin analogues induces vasoconstriction in splanchnic and systemic arterioles [16]. In acute hemodynamic studies of the effects of intravenous ornipressin administration (6 IU/h over a period of 4 h), the presence of splanchnic vasoconstriction was associated with a significant systemic vasopressor effect (i.e. increased mean arterial and pulmonary capillary wedged pressures) coupled with a significant decrease in endogenous renal vasoconstrictor system activity [16]. The latter may be explained in part by arterial and cardiopulmonary baroreceptor uploading due to the ornipressin-induced vasopressor effect. The overall response to ornipressin was associated with significant increases in renal plasma flow and GFR [16]. Acute ornipressin Acute Kidney Injury in Cirrhosis

administration decreases cardiac output response [16]. Administration of ornipressin for 1–2 weeks, in combination with albumin [17] or dopamine [18], results in increased GFR. However, ornipressin administration was found to induce severe ischemic adverse events that prevent the clinical use of this drug [17]. In nonazotemic cirrhotic patients, acute terlipressin administration increases arterial pressure and decreases portal pressure neurohumoral activity [19]. A 2-day intravenous administration of terlipressin induces an arterial vasopressor effect associated with significant decreases in plasma renin concentrations and significant increases in GFR [20]. Nonrandomized studies including 154 patients with HRS have evaluated the efficacy of long-term terlipressin administration combined with intravenous albumin [reviewed in ref. 1]. The dose of terlipressin ranged from 2 to 6 mg/day. Renal function improved in 25–80% of patients treated with this drug [1]. These findings suggest that terlipressin is beneficial in patients with HRS since renal function does not spontaneously improve in HRS. Alpha-Adrenoceptor Agonists Three nonrandomized pilot studies including 79 patients with HRS have evaluated a two-drug combined therapy with midodrine and octreotide [21–23]. This combination was used because midodrine per se induces systemic vasoconstriction and octreotide is known to inhibit the secretion of glucagon (a vasodilator which may play a role in cirrhosis-associated vasodilation) [8]. However, in patients with HRS, octreotide administration alone does not elicit any systemic vasoconstrictor/vasopressor effect and does not improve renal function [24]. In addition, intravenous albumin was administered. Interestingly, treatment doses were adjusted to achieve prespecified increases in arterial pressure [21–23], increases in central venous pressure [21], and decreases in plasma renin activity [21]. HRS reversal was achieved in 40–70% of patients [22, 23]. Tolerance to treatment was good. A pilot study has investigated the effects of continuous intravenous noradrenaline administration (at a mean dose of 0.8 mg/h for a mean duration of 10 days) in combination with intravenous albumin and furosemide in 12 patients [25]. Treatment doses were adjusted to achieve prespecified increases in arterial pressure, central venous pressure and urine volume. Combined therapy resulted in a significant vasopressor effect and decreases in plasma renin activity. HRS reversal occurred in 83% of the patients. Noradrenaline was well tolerated.

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Table 1. Characteristics of studies using vasoconstrictor therapy in patients with HRS Study characteristics

Solanki et al. [26]

Sanyal et al. [27]

Martín-Llahí et al. [28]

Patients with type 1 HRS, n

24

112

33

9

32

0

0

13

13

0

Patients with type 2 HRS, n

Alessandria et al. [29]

Sharma et al. [30]

Study design

single-blind, randomized, placebocontrolled; 12 patients assigned to terlipressin (1 mg/12 h i.v.), 12 patients assigned to placebo

double-blind, randomized, placebocontrolled; 56 patients assigned to terlipressin (1–2 mg/6 h i.v.), 56 patients assigned to placebo

open-label randomized; 23 patients assigned to terlipressin (1–2 mg/4 h i.v.) plus albumin, 23 patients assigned to albumin alone1

open-label, randomized; 12 patients assigned to terlipressin (1–2 mg/4 h i.v.), 10 patients assigned to noradrenaline (0.1–0.7 ␮g/kg ⴢ min i.v.)2

open-label, randomized; 16 patients assigned to terlipressin (0.5–2 mg/4–6 h i.v.), 16 patients assigned to noradrenaline (0.5–3.0 mg/h)

Concomitant i.v. albumin administration

all patients received albumin during follow-up (dose not specified)

all patients received albumin during followup (dose not specified)

all patients received albumin during followup (1 g/kg on day 1, then 20–40 g/day)

all patients received albumin during followup; terlipressin group: 46810 g/day3; noradrenaline group: 5684 g/day3

all patients received albumin during followup (20 g daily)

Study end point

HRS reversal

HRS reversal

HRS reversal

HRS reversal

HRS reversal

Proportion of patients reaching the end point of HRS reversal, %

terlipressin: 42; placebo: 0

terlipressin: 34; placebo: 13

terlipressin: 35; no treatment: 5

terlipressin: 83; noradrenaline: 70

terlipressin: 50; noradrenaline: 50

Proportion of patients with adverse events, %

25 (terlipressinrelated)

9 (terlipressin-related)

17 (terlipressin-related)

0 (in both groups)

terlipressin: 6; nordrenaline: 6

HRS = Hepatorenal syndrome: type 1 is the acute form of HRS and type 2 the ‘chronic’ form of HRS, according to the definition provided by the International Ascites Club [26–30]. Plus-minus values are means 8 SD. To convert values for creatinine to micromoles per liter, multiply by 88.4. 1 In the study by Martín-Llahí et al. [28], 14 patients (60%) with type 1 HRS were randomly assigned to receive terlipressin plus albumin and 19 patients (83%) with type 1 HRS were randomly assigned to albumin alone.

2 In the study by Alessandria et al. [29], 4 patients (42%) with type 1 HRS were randomly assigned to receive terlipressin and 4 patients (40%) with type 1 HRS were randomly assigned to receive noradrenaline. 3 HRS reversal was defined by reduction of serum creatinine levels to <1. 5 mg/dl (133 ␮mol/l).

Randomized Trials Five randomized trials of terlipressin or noradrenaline have been performed in patients with HRS [26–30]. The results of four trials have been reported in full papers [26– 29] and the results of the fifth study have been presented in an international meeting [30]. There is no randomized trial with midodrine in HRS. Of the five randomized trials, only one was a doubleblind placebo-controlled design study [27]. However, the latter trial was also the largest [27]. All studies had one arm with terlipressin. In three studies, the terlipressin arm was compared to a placebo arm [26, 27] or an ‘untreated arm’ [28] and in the two other studies terlipressin was compared to noradrenaline [29, 30]. In the five trials, all patients received intravenous albumin to optimize ex-

tracellular fluid volume and also because a nonrandomized study has shown that renal function improves more frequently in patients treated with terlipressin and intravenous albumin than in those treated with terlipressin alone [31]. However, there is no randomized trial of a vasopressor alone versus vasopressor plus albumin. A total of 236 patients was enrolled, 210 (89%) with type 1 HRS. Terlipressin was administered to a total of 119 patients (102 (86%) had type 1 HRS) and the protocol for use was similar in the four studies. Noradrenaline was administered to 26 patients (20 (77%) with type 1 HRS) and the protocol for use was very similar in the two studies. Treatment was administered until the reversal of HRS (as defined earlier) or for two weeks. Terlipressin induced HRS reversal in 34–83% of the cases (table 1), confirming

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the effectiveness of this drug in patients with HRS. These results mainly apply to patients with acute HRS because terlipressin was used in a large number of patients with type 1 HRS. Noradrenaline therapy induced HRS reversal in 50–80% of cases (table 1), suggesting that this drug may be an alternative approach in the treatment of HRS. However, these results need to be confirmed because they were obtained in small series of patients. It should be emphasized that approaches to the medical treatment of HRS, other than vasopressor therapy, are either ineffective or still under evaluation [reviewed in refs. 1, 14]. Together, these findings indicate that, to date, terlipressin plus albumin is the medical treatment of choice for type 1 HRS. At least 50% of patients with type 1 HRS do not have improved renal function with vasopressor therapy (table 1). What are the reasons for this? HRS (like other causes of prerenal failure) and ischemic acute tubular necrosis represent a continuum, with the former leading to the latter when blood flow is sufficiently compromised to result in the death of tubular cells [1, 32]. Even if the International Ascites Club diagnostic criteria were used at enrollment in all studies [26–30], it may be difficult to distinguish patients with true HRS from patients who have already developed ‘HRS-induced’ ischemic acute tubular necrosis [6]. At enrollment, none of the studies [26– 30] measured markers of tubular damage. In other words, these studies may have enrolled patients with true ‘HRSinduced’ ischemic acute tubular necrosis. This is important because renal function may not improve in cirrhotic patients with ischemic acute tubular necrosis treated by vasoconstrictor/vasopressor therapy [6]. A post-hoc analysis [33] of the large randomized, double-blind, placebo-controlled trial of terlipressin for HRS [27], found that a predictive factor for improvement of renal function was lower serum creatinine levels at diagnosis (thus when treatment begins). This suggests that the earlier the treatment is started, the better the renal response. In the large, randomized, double-blind, placebocontrolled trial of terlipressin [27] treatment may have been started too late, at least in some patients. Indeed, in this study, an important criterion used to define type 1 HRS was a doubling of serum creatinine to 62.5 mg/dl (222 ␮mol/l) in less than 2 weeks [27]. In one randomized trial, terlipressin was given at fixed doses (1 mg every 8 h or 12 h) [26]. However, the effect of a dose of terlipressin may differ according to the degree of liver failure. The higher the Child-Pugh score, the greater the dose of terlipressin [31]. Interestingly, other studies used goal-directed terlipressin therapy [27–29];

terlipressin was initially given at a dose of 0.5 mg/4 h and increased in a stepwise fashion every 3 days to 1 and 2 mg/4 h if a significant reduction in serum creatinine (of at least 1 mg/dl (88 ␮mol/l)) was not obtained. Although a 3-day delay is reasonable for obtaining a 1 mg/dl decrease in serum creatinine, it may be too long and favor a shift from ‘terlipressin-sensitive’ functional renal failure to ‘terlipressin-resistant’ tubular necrosis. The impact of more rapid increases in doses of terlipressin according to goals other than a 3-day decrease in serum creatinine levels has not yet been studied. In HRS, the vasopressor-induced improvement in renal function is thought to be mediated by the splanchnic and systemic hemodynamic response to this drug [6]. This hemodynamic response may not occur in some patients with HRS. For example, when terlipressin administration does not elicit an increase in arterial pressure in patients the probability of obtaining a terlipressin-induced improvement of renal function is low [27, 34]. Theoretically, the following mechanisms may explain the lack of systemic vasopressor response to terlipressin or noradrenaline. First, the vasopressor response may not occur in patients with severe liver failure, even when maximum doses of vasopressors are used. Indeed, severe liver failure is known to induce splanchnic and systemic arterial hyporeactivity to the administration of vasoconstrictors/vasopressors [8]. Interestingly, a high ChildPugh score [3] or a high MELD score [27] are predictive of failure of terlipressin to improve renal function. Second, vasopressor therapy may cause a reduction in cardiac output by mechanisms other than physiological baroreceptor-mediated bradycardia, e.g. by inducing coronary vasoconstriction [35] responsible for left ventricular dysfunction. Nevertheless, in nonrandomized [reviewed in ref. 6] and randomized trials (table 1), the safety profile of vasopressors was relatively good. It has been suggested that the intrarenal production of vasoconstrictors such as endothelin-1 or prostanoids may play a role in renal vasoconstriction in HRS [reviewed in ref. 1, 14]. The impact of vasopressor therapy on intrarenal production of endothelin-1 and/or prostanoids is unknown. Studies are needed.

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Survival In the large randomized, double-blind, placebo-controlled trial of terlipressin, survival did not significantly differ between the terlipressin group and the placebo group [27]. However, in this study, survival was significantly higher in patients with HRS reversal than in patients without [27]. A large retrospective study of terp77

lipressin therapy for HRS also found that survival was better in patients with improved renal function than in those without [3]. Improvement of renal function and lower Child-Pugh score (or MELD score) were independent predictors of survival [3, 27].

Conclusions

HRS is a type of prerenal failure that is specific to decompensated cirrhosis. In patients with HRS, there is marked splanchnic/systemic vasodilation which results in arterial hypotension, arterial baroreceptor unloading, overstimulation of the sympathetic nervous and reninangiotensin systems. This reflex neurohumoral hyperactivity, via endogenous vasoconstrictors/vasopressors such as angiotensin II and noradrenaline, induces arterial vasoconstriction in different extrasplanchnic vascu-

lar beds (including the preglomerular arteries in the kidneys). Decreased arterial pressure (i.e. low renal perfusion pressure) and preglomerular vasoconstriction play a major role in the decline of glomerular filtration rate (GFR). Pilot studies in patients with HRS have shown that the administration of a splanchnic vasoconstrictor (vasopressin analogue or ␣1-adrenoceptor agonist), most often combined with intravenous albumin, caused increases in arterial pressure, arterial baroreceptor uploading, decreased neurohumoral activity, decreased renal vascular resistance, and increased GFR. Randomized clinical trials have shown that treatment with a combination of the vasopressin analogue terlipressin and intravenous albumin improved renal function in patients with type 1 HRS. Vasopressor therapy with terlipressin plus intravenous albumin is the medical treatment of choice for type 1 HRS.

References 1 Moreau R, Lebrec D: Acute renal failure in patients with cirrhosis: perspectives in the age of MELD. Hepatology 2003;37:233–243. 2 Thabut D, Massard J, Gangloff A, Carbonell N, Francoz C, Nguyen-Khac E, Duhamel C, Lebrec D, Poynard T, Moreau R: Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure. Hepatology 2007; 46:1872–1882. 3 Moreau R, Durand F, Poynard T, et al: Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology 2002; 122: 923–930. 4 Arroyo V, Ginès P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, Reynolds TB, RingLarsen H, Schölmerich J: Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996;23:164–176. 5 Alessandria C, Ozdogan O, Guevara M, et al: MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology 2005; 41: 1282–1289. 6 Moreau R, Lebrec D: The use of vasoconstrictors in patients with cirrhosis: type 1 HRS and beyond. Hepatology 2006; 43: 385– 394. 7 Ginès A, Escorsell A, Ginès P, Salo J, Jimenez W, Inglada L, Navasa M, Claria J, Rimola A, Arroyo V, Rodes J: Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 1993; 105:229–236.

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8 Moreau R, Lebrec D: Endogenous factors involved in the control of arterial tone in cirrhosis. J Hepatol 1995; 22:370–376. 9 Gadano AC, Sogni P, Heller J, Moreau R, Bories PN, Lebrec D: Vascular nitric oxide production during the development of two experimental models of portal hypertension. J Hepatol 1999;30:896–903. 10 Fernandez-Seara J, Prieto J, Quiroga J, Zozaya JM, Cobos MA, Rodriguez-Eire JL, Garcia-Plaza A, Lela J: Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure. Gastroenterology 1989; 97: 1304–1312. 11 Ginès P, Guevara M, Arroyo V, Rodés J: Hepatorenal syndrome. Lancet 2003; 362:1819– 1827. 12 Gaudin C, Braillon A, Poo JL, Moreau R, Hadengue A, Lebrec D: Regional sympathetic activity, severity of liver disease and hemodynamics in patients with cirrhosis. J Hepatol 1991;13:161–168. 13 Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Gines P, Moreira V, Milicua JM, Jiménez W, Arroyo V: Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005;42:439–447. 14 Moreau R: Hepatorenal syndrome in patients with cirrhosis. J Gastroenterol Hepatol 2002;17:739–747. 15 Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V: Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310–1318.

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16 Lenz K, Hortnagel H, Druml W, Reither H, Schmid R, Schneeweiss B, Laggner A, Grimm G, Gerbes AL: Ornipressin in the treatment of functional renal failure in decompensated cirrhosis: effects on renal hemodynamics and atrial natriuretic factor. Gastroenterology 1991;101:1060–1067. 17 Guevara M, Ginès P, Fernandez-Esparrach G, Sort P, Salmeron JM, Jimenez W, Arroyo V, Rodès J: Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion. Hepatology 1998; 27:35–41. 18 Gülberg V, Bilzer M, Gerbes AL: Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamin. Hepatology 1999;30:870–875. 19 Gadano A, Moreau R, Vachiery F, Soupison T, Yang S, Cailmail S, Sogni P, Hadengue A, Durand F, Valla D, Lebrec D: Natriuretic response to the combination of atrial natriuretic peptide and terlipressin in patients with cirrhosis and refractory ascites. J Hepatol 1997;26:1229–1234. 20 Hadengue A, Gadano A, Moreau R, Giostra E, Durand F, Valla D, Erlinger S, Lebrec D: Beneficial effects of the two-day administration of terlipressin in patients with cirrhosis and hepatorenal syndrome. J Hepatol 1998; 29:565–570. 21 Angeli P, Volpin R, Gerunda G, Craighero R, Roner P, Merenda R, Amodio P, Sticca A, Caregaro L, Maffei-Faccioli A, Gatta A: Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 1999;29:1690–1697.

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22 Wong F, Pantea L, Sniderman K: Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology 2004; 40:55–64. 23 Esrailian E, Pantangco ER, Kyulo NL, Hu KQ, Runyon BA: Octreotide/midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome. Dig Dis Sci 2007;52:742–748. 24 Pomier-Layrargues G, Paquin SC, Hassoun Z, Lafortune M, Tran A: Octreotide in hepatorenal syndrome: a randomized, doubleblind, placebo-controlled, crossover study. Hepatology 2003; 38:238–243. 25 Duvoux C, Zanditenas D, Hezode C, Chauvat A, Monin JL, Roudot-Thoraval F, Mallat A, Dhumeaux D: Effects of noradrenalin and albumin in patients with type 1 hepatorenal syndrome: a pilot study. Hepatology 2002; 36:374–380. 26 Solanki P, Chawla A, Garg R, Gupta R, Jain M, Sarin SK: Beneficial effects of terlipressin in hepatorenal syndrome: a prospective, randomized placebo-controlled clinical trial. J Gastroenterol Hepatol 2003; 18:152–156.

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27 Sanyal AJ, Boyer T, Garcia-Tsao G, Regenstein F, Rossaro L, Appenrodt B, Blei A, Gülberg V, Sigal S, Teuber P: A randomized prospective double blind placebo controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology 2008; in press. 28 Martín-Llahí M., Pépin MN, Guevara M, Díaz F, Torre A, Monescillo A, Soriano G, Terra C, Fábrega E, Arroyo V, Rodés J, Ginès P: Terlipressin and albumin versus albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology 2008; in press. 29 Alessandria C, Ottobrelli A, Debernardi-Venon W, Todros L, Cerenzia MT, Martini S, Balzola F, Morgando A, Rizzetto M, Marzano A: Noradrenalin versus terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study. J Hepatol 2007;47:499–505. 30 Sharma P, Kumar A, Sharma BC, Sarin SK: Noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome: a randomized controlled trial. Hepatology 2006;44(suppl 1):449A. 31 Ortega R, Ginès P, Uriz J, Cardenas A, Calahorra B, De Las Heras D, Guevara M, Bataller R, Jiménez W, Arroyo V, Rodés J: Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology 2002; 36:941–948.

32 Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl J Med 1996; 334: 1448– 1460. 33 Sanyal AJ, Boyer TD, Teuber P: Prognostic factors for hepatorenal syndrome (HRS) reversal in patients with type 1 HRS enrolled in a randomized, double-blind, placebocontrolled trial. Hepatology 2007; 46(suppl 1):564A. 34 Colle I, Durand F, Pessione F, Rassiat E, Bernuau J, Barrière E, Lebrec D, Valla DC, Moreau R: Clinical course, predictive factors and prognosis in patients with cirrhosis and type 1 hepatorenal syndrome treated with terlipressin: a retrospective analysis. J Gastroenterol Hepatol 2002;17:882–888. 35 Medel J, Boccara G, Van de Steen E, Bertrand M, Godet G, Coriat P: Terlipressin for treating intraoperative hypotension: can it unmask myocardial ischemia? Anesth Analg 2001;93:53–55.

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Nephron Exp Nephrol 2008;109:e102–e107 DOI: 10.1159/000142934

Published online: September 18, 2008

Inflammation in Acute Kidney Injury Gilbert R. Kinsey Li Li Mark D. Okusa Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Va., USA

Key Words Innate immunity ⴢ Adaptive immunity ⴢ Leukocytes ⴢ Acute renal failure

Abstract Ischemia-reperfusion injury (IRI) is one of the major causes of acute kidney injury (AKI) and evidence supporting the involvement of both innate and adaptive immunity in renal IRI has accumulated in recent years. In addition to leukocytes, kidney endothelial cells promote inflammation after IRI by increasing adhesion molecule expression and vascular permeability. Kidney tubular epithelial cells increase complement binding and upregulate toll-like receptors, both of which lead to cytokine/chemokine production in IRI. Activation of kidney resident dendritic cells, interferon- ␥ -producing neutrophils, infiltrating macrophages, CD4+ T cells, B cells and invariant natural killer T cells are all implicated in the pathogenesis of AKI. The complex interplay between innate and adaptive immunity in renal IRI is still not completely understood, but major advances have been made. This review summarizes these recent advances to further our understanding of the immune mechanisms of acute kidney injury. Copyright © 2008 S. Karger AG, Basel

© 2008 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nee

Introduction

Acute kidney injury (AKI) is associated with a high degree of morbidity and mortality and the incidence remains unacceptably high. Ischemia-reperfusion injury (IRI) is one of the major causes of AKI. Currently, no pharmacological agents have proven to prevent AKI and the mortality rate of patients with severe AKI has not declined in recent decades [1]. Ischemia and/or reperfusion initiate changes in vascular endothelial cells, tubular epithelial cells and leukocytes that result in the loss of immune system homeostasis in the kidney [2–6]. The ensuing inflammation leads to kidney parenchymal cell death and in severe cases AKI. The inflammatory response can be mediated by two different, but related, arms of the immune system: innate and adaptive immunity. The innate immune system is activated very early in infectious or inflammatory states in a non-antigen-specific fashion and is comprised of neutrophils, monocytes/macrophages, dendritic cells (DCs), natural killer (NK) cells and natural killer T (NKT) cells. In contrast, the adaptive immune system becomes responsive to specific antigens (from pathogens or dead self cells) over the course of several days and includes DC maturation and antigen presentation, CD4 and CD8 T lymphocyte proliferation and activation, and T to B lymphocyte interactions. LeukoMark D. Okusa, MD Division of Nephrology Box 800133, University of Virginia Health System Charlottesville, VA 22908 (USA) Tel. +1 434 924 2187, Fax +1 434 924 5848, E-Mail [email protected]

cytes such as DCs and macrophages play key roles in both types of immunity by producing pro-inflammatory cytokines and presenting antigen to lymphocytes. Evidence supporting the involvement of both innate and adaptive immunity in renal IRI has accumulated in recent years. This review will highlight some of the new concepts in the immunologic mechanisms of ischemiainduced AKI.

Renal Vascular Endothelium

One of the early events in renal IRI is activation of the endothelium leading to an increase in vascular permeability [7] which promotes extravasation of leukocytes into the kidney. Brodsky et al. [8] showed that after renal IRI, there was loss of endothelial cells from afferent arterioles and interruption of endothelial cell contacts, an effect reversed through transfer of endothelial cells [8] or through treatment with a sphingosine-1-phosphate analog prodrug, FTY-720 [9]. In addition to changes in the integrity of the endothelial cell layer of the renal vasculature, IRI upregulates the expression of adhesion molecules that facilitate leukocyte-endothelial cell interactions. The expression of intracellular adhesion molecule 1 (ICAM-1) increases in the kidney by 1 h after IRI and mice lacking ICAM-1 are protected from renal IRI [4]. Leukocyte adhesion to endothelial cells leads to inflammation and extension of cellular injury. Additionally, renal endothelial cells upregulate the expression of CX3CL1 (fractalkine), a ligand for the CX3CR1 receptor highly expressed on macrophages that mediates macrophage recruitment in the inflamed kidney, and pretreatment with a neutralizing CX3CR1 mAb reduced the severity of AKI [10]. Therefore, the endothelium plays an important early role in the inflammatory response to kidney damage by promoting the accumulation of leukocytes.

tive role for proximal tubular Crry expression, mice deficient in Crry are more susceptible to kidney IRI [2]. Complement activation, by the alternative pathway, is required for the production of the pro-inflammatory chemokines macrophage inflammatory factor-2 (MIP-2) and keratinocyte-derived chemokine (KC) by the renal tubular epithelium after IRI [11]. These chemokines attract neutrophils and macrophages to the injured kidney. Another recent study demonstrated that toll-like receptor 4 (TLR4) is upregulated in TECs after IRI and deficiency of TLR4 on kidney parenchymal cells was more effective at preventing kidney IRI than TLR4 deficiency on bone marrow-derived cells [12]. TLRs are a family of pattern recognition receptors that detect motifs of pathogens and host material released during injury that are important for activation of innate immunity. TLR4 deficiency blunted the IRI-induced production of pro-inflammatory cytokines and chemokines and inhibited macrophage and neutrophil accumulation [12]. A similar study showed, using bone marrow chimeras, that lack of TLR2 expression on kidney parenchymal cells also inhibited renal IRI and kidney pro-inflammatory cytokine production was reduced in TLR2–/– mice compared to wild-type controls [13]. Molecules such as high-mobility group B1 (HMGB1), heat shock proteins, hyaluronan and biglycan released from damaged tissues activate TLRs and lead to downstream activation of transcription factors that regulate the expression of survival genes or proinflammatory cytokines and chemokines. TLRs expressed on endothelial cells and epithelial cells are involved in kidney IRI via both MyD88-dependent and independent pathways [14]. These studies highlight the important role for renal endothelial and epithelial cells in the inflammation of AKI.

Neutrophils

Several studies have demonstrated that tubular epithelial cells (TECs) play a pro-inflammatory role in kidney IRI. Normally, the epithelial cells lining the proximal tubules of the kidney express the complement inhibitor Crry preferentially on the basolateral membrane [2]. After renal IRI, Crry is redistributed away from the basolateral surface of the cell, which permits the deposition of C3 on the tubular epithelium [2]. In support of a protec-

Neutrophils rapidly respond to injury and are important mediators of innate immunity. Adherence of neutrophils to the vascular endothelium is a crucial early process in the initiation of damage to ischemic tissues. Neutrophils respond to invading pathogens either by phagocytosis or releasing granules containing proteases and other enzymes, which generate reactive oxygen species. In inflammatory states, neutrophil degranulation can lead to the destruction of normal self cells in the inflamed tissue. One of the hallmarks of renal IRI, in mouse models, is neutrophil accumulation in the postischemic kidney [3, 4, 12] and depletion of neutrophils

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prevents AKI [4]. Our laboratory has demonstrated that blocking upstream activation of invariant NKT (iNKT) cells (see below) prevents renal accumulation of IFN-␥producing neutrophils and kidney dysfunction after IRI in mice [3]. These studies suggest the involvement of neutrophils in the pathogenesis of kidney dysfunction in the widely used murine model of IRI-induced AKI. Furthermore, neutrophil activation and infiltration may be governed by other leukocytes, such as iNKT cells. In contrast, studies in other species (rabbit and rat) have not reported extensive neutrophil accumulation or protective effects of neutrophil depletion in mild or severe renal IRI [15].

Macrophages

Macrophages are derived from monocytes in the blood and are named for their role as phagocytes. In addition to phagocytosis, macrophages produce pro-inflammatory cytokines that can stimulate the activity of other leukocytes [Li and Okusa, unpubl. data; 16]. Macrophages infiltrate the injured kidney shortly after neutrophils (within 1 h of reperfusion), and this infiltration is mediated by CCR2 [Li and Okusa, unpubl. data] and CX3CR1 signaling pathways [10]. These macrophages have a distinct F4/80lowLy6ChighGR-1+CX3CR1low ‘inflamed’ phenotype [Li and Okusa, unpubl. data; 16]. Depletion of kidney and spleen macrophages, using liposomal clodronate, prior to renal IRI prevented AKI and adoptive transfer of macrophages reconstituted AKI [5]. Intracellular cytokine staining of kidney infiltrating macrophages by flow cytometry demonstrated that these leukocytes are significant producers of the cytokines IL-1␣, IL-6, IL-12p40/70 and TNF-␣ [Li and Okusa, unpubl. data]. Another study identified IL-6 expression in renal outer medulla interstitial macrophages by in situ hybridization 4 h after IRI [16]. The increased abundance of IFN-␥ from iNKT cells and neutrophils provides potent stimulation for macrophage activation early in IRI.

Dendritic Cells

DCs are an important link between innate and adaptive immunity and their role in AKI is not completely understood. CD11c+ MHC class II+ DCs are the most abundant leukocyte subset in the normal mouse kidney suggesting an important role in renal immunity and inflammation. Upon stimulation, DCs can convert to a mae104

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ture cell type characterized by high levels of class II major histocompatibility complex (MCH class II) and co-stimulatory molecules and low phagocytic capacity. Mature DCs are specialized in T cell activation. However, DCs are also important in the innate immune response by releasing pro-inflammatory factors, interacting with NKT cells via CD40–CD40L and presenting glycolipids via the CD1d molecule to activate iNKT cells. Dong et al. [17] demonstrated that after IRI renal DCs produce the proinflammatory cytokines/chemokines TNF, IL-6, MCP-1 and RANTES, and that depletion of DCs prior to IRI significantly reduced the kidney levels of TNF produced after IRI. IL-12 and its new family member IL-23 are mainly produced from activated DCs and macrophages, and their downstream cytokines IFN-␥ and IL-17, associated with macrophage activation and neutrophil recruitment, may amplify the immune response following kidney reperfusion. These results suggest a role for the innate response of DCs in AKI. In a separate study, DCs were shown to traffic to the renal draining lymph nodes after IRI and induce T cell proliferation in an antigen-specific fashion, implicating renal DCs in the adaptive immune response to IRI [18]. While these studies strongly suggest that DCs play an important role in ischemia-induced AKI, additional studies are needed to determine the effect of specific-DC depletion in IRI-induced AKI. The use of a genetically engineered mouse in which the DCspecific surface protein CD11c is conjugated to the human diphtheria toxin receptor (CD11c-DTR mouse) should facilitate DC depletion studies and offer more insight into the role of renal DCs in IRI.

Lymphocytes

Lymphocytes are the major mediators of adaptive immunity. Antigen presentation by APCs, in the presence of sufficient co-stimulation, causes expansion and activation of T cells with a T cell receptor (TCR) specific for the presented antigen. B cells do not require antigen presentation; rather, they recognize soluble antigens that they engulf and process to present to T cells with a TCR specific for the same antigen. The interaction of the B and T cell stimulates the B cell to generate antibodies specific for the antigen. Other antigens can induce antibody production in the absence of T cell participation. A role for T cells in the pathogenesis of kidney IRI has been established in different mouse models lacking certain types of lymphocytes [6, 19]. In nu/nu mice (which lack CD4 and CD8 T cells), IRI measured Kinsey/Li/Okusa

by serum creatinine levels and renal histology was significantly reduced compared to wild-type controls [19]. Reconstitution of nu/nu mice with CD4+ T cells alone and not CD8+ T cells alone restores kidney injury after IRI [19]. Additionally, RAG-1–/– mice (lacking both B and T cells) are also protected from IRI and adoptive transfer of CD4+ T cells from wild-type mice reconstitutes injury [6]. Importantly, transfer of CD4+ T cells from IFN-␥–/– mice failed to re-establish injury in this model [6]. These results suggest that CD4+ T cells, and specifically IFN-␥ produced by these cells, mediate the early phase of IRI. Mice deficient in B cells (␮MT mice) are also protected from IRI [20]. The adoptive transfer of purified B cells back into these mice, however, does not restore kidney injury after ischemia [20]. On the other hand, transfer of serum from wild-type mice does result in higher serum creatinine values after IRI compared to the ␮MT mice without serum transfer [20]. The authors suggest that lack of a circulating factor, possibly an immunoglobulin, may be responsible for the protection observed in B celldeficient mice. Other investigators have reported a lack of protection from IRI in RAG-1–/– mice [21, 22]. Burne-Taney et al. [22] reported that while RAG-1–/– mice were not protected from IRI, RAG-1–/– mice reconstituted with either T or B cells alone were protected. The reasons for the discrepancy between laboratories in results using the RAG1–/– mice are unclear at present and cannot be explained by strain differences [21, 22]. It is possible that in some models, combined T and B cell deficiency leads to increased innate immune responses [22].

Invariant Natural Killer T Cells

Ischemia-reperfusion

Bone marrowderived cells

Renal Endothelial dendritic cells cells

Epithelial cells

iNKT

PMN

MØ

Inﬁltration Activation Cytokine production

Vascular permeability Adhesion molecule expression

Antigen presentation in dLN Cytokine production

Complement deposition TLR2/4 expression Chemokine production

Acute kidney injury

Fig. 1. Inflammatory role of bone marrow-derived and kidney

cells in AKI. Ischemia-reperfusion induces changes in leukocytes, endothelial cells and tubular epithelial cells that result in kidney inflammation and mediate AKI. Bone marrow derived cells such as iNKT cells [3], neutrophils (PMN [3, 4, 12]) and macrophages (MØ [16]) accumulate in the kidney, are activated and produce pro-inflammatory cytokines (i.e. IFN-␥ production by iNKT cells and PMNs [3]). Endothelial cells are damaged by IRI leading to increased vascular permeability [8, 9] and expression of adhesion molecules such as ICAM-1 [4] and fractalkine [10]. These changes facilitate the accumulation of leukocytes in the kidney. Renal dendritic cells produce cytokines and chemokines [17] and traffic to the renal draining lymph node and present antigens to T cells [18]. Tubular epithelial cells exhibit increased complement deposition [2] and upregulate the expression of tolllike receptors (TLRs [12, 13]), both of which mediate chemokine and cytokine production in the injured kidney [11–13]. Changes in each cell type directly or indirectly influence the other cells involved to promote inflammation after renal IRI. These interactions between kidney and bone marrow derived cells and between innate and adaptive immunity demonstrate the complex nature of the inflammation associated with AKI.

Several studies have demonstrated that CD4+ T cells are involved in renal IRI (see above). However, conventional CD4+ T cells are thought to play a role in antigenspecific, adaptive immunity that requires 2–4 days for T cell processing, a time course that cannot explain the rapid, innate immune response following IRI. NKT cells are a unique subset of T lymphocytes with surface receptors and functional properties shared with conventional T cells and NK cells. Invariant NKT cells posses a conserved invariant TCR (V␣14/J␣18 and V␤8.2,V␤2 or V␤7) together with the NK cell marker NK1.1. In contrast to conventional T cells, the NKT cell TCR does not interact with peptide antigen presented by classical MHCclass I or II, rather it recognizes glycolipids presented by

the class I-like molecule, CD1d. A glycolipid, ␣-galactosylceramide, is the most efficient activator for iNKT cells. The most remarkable property of iNKT cells is their ability to rapidly produce large amounts of cytokines, including Th1-type (IFN-␥, TNF) and Th2-type (IL-4, IL-13) at the same time within 1–2 h. The rapid response by iNKT cells following activation can amplify and regulate the

Inflammation in AKI

Nephron Exp Nephrol 2008;109:e102–e107

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function of DCs, regulatory T cells, NK and B cells, as well as conventional T cells, and thus links innate and adaptive immunity. A recent finding from our laboratory is that early IRI (30 min following reperfusion) leads to an increase in activated CD4+CD69+ cells and the number of IFN-␥-producing iNKT cells in the kidney is significantly increased by 3 h of reperfusion compared to sham-operated mice [3]. At this time point, there is also a significant increase in IFN-␥+ neutrophil recruitment in the IRI kidney. Blockade of NKT cell activation with the anti-CD1d mAb, NKT cell depletion with an antiNK1.1 mAb in wild-type mice, or use of iNKT cell-deficient mice (J␣18–/–) inhibited the accumulation of IFN␥-producing neutrophils after IRI and prevented AKI [3]. Given that (1) there is a major disconnect between the timing of the protection seen in CD4+ T cell-deficient mice and the timing of conventional T cell activation, (2) IFN-␥–/– CD4+ T cells do not reconstitute injury in RAG-1–/– mice, and (3) the mouse CD4+ T cell population contains iNKT cells that can be activated within hours, the current findings suggest that iNKT cells are the major early-acting CD4+ cell type in renal IRI. CD1drestricted NKT cells include type I NKT (iNKT) cells and type II NKT cells; the role of type II NKT cells in kidney IRI has not been examined.

Conclusions

Over the past decade many new concepts in the role of inflammation in AKI have emerged (fig. 1). Among them are pro-inflammatory changes in the endothelial and epithelial cells of the kidney. Additionally, complement, TLRs and numerous cytokines and chemokines are clearly involved in amplifying the immune response to kidney injury. The complex interplay between innate and adaptive immunity in renal IRI is still not completely understood but advances have been made in this area. Critical early roles for neutrophils, macrophages, and T and B and NKT cells have been established in mouse models of AKI. Finally, these new concepts may lead to new targets for development of clinically relevant treatment strategies for AKI.

Acknowledgements This work was supported by grants from the National Institutes of Health RO1 DK56223, RO1 DK62324, and RO1 DK06595.

References 1 Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl J Med 1996; 334: 1448– 1460. 2 Thurman JM, Ljubanovic D, Royer PA, Kraus DM, Molina H, Barry NP, Proctor G, Levi M, Holers VM: Altered renal tubular expression of the complement inhibitor crry permits complement activation after ischemia/reperfusion. J Clin Invest 2006; 116: 357–368. 3 Li L, Huang L, Sung SS, Lobo PI, Brown MG, Gregg RK, Engelhard VH, Okusa MD: NKT cell activation mediates neutrophil IFNgamma production and renal ischemia-reperfusion injury. J Immunol 2007;178:5899– 5911. 4 Kelly KJ, Williams WW Jr, Colvin RB, Meehan SM, Springer TA, Gutierrez-Ramos JC, Bonventre JV: Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest 1996; 97: 1056–1063.

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5 Day YJ, Huang L, Ye H, Linden J, Okusa MD: Renal ischemia-reperfusion injury and adenosine 2a receptor-mediated tissue protection: role of macrophages. Am J Physiol Renal Physiol 2005;288:F722–F731. 6 Day YJ, Huang L, Ye H, Li L, Linden J, Okusa MD: Renal ischemia-reperfusion injury and adenosine 2a receptor-mediated tissue protection: the role of CD4+ T cells and IFNgamma. J Immunol 2006;176:3108–3114. 7 Sutton TA, Mang HE, Campos SB, Sandoval RM, Yoder MC, Molitoris BA: Injury of the renal microvascular endothelium alters barrier function after ischemia. Am J Physiol Renal Physiol 2003;285:F191–F198. 8 Brodsky SV, Yamamoto T, Tada T, Kim B, Chen J, Kajiya F, Goligorsky MS: Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells. Am J Physiol Renal Physiol 2002; 282:F1140– F1149. 9 Awad AS, Ye H, Huang L, Li L, Foss FW Jr, Macdonald TL, Lynch KR, Okusa MD: Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney. Am J Physiol Renal Physiol 2006;290:F1516–F1524.

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10 Oh DJ, Dursun B, He Z, Lu L, Hoke TS, Ljubanovic D, Faubel S, Edelstein CL: Fractalkine receptor (CX3CR1) inhibition is protective against ischemic acute renal failure in mice. Am J Physiol Renal Physiol 2008; 294: F264–F271. 11 Thurman JM, Lenderink AM, Royer PA, Coleman KE, Zhou J, Lambris JD, Nemenoff RA, Quigg RJ, Holers VM: C3a is required for the production of CXC chemokines by tubular epithelial cells after renal ishemia/reperfusion. J Immunol 2007;178:1819–1828. 12 Wu H, Chen G, Wyburn KR, Yin J, Bertolino P, Eris JM, Alexander SI, Sharland AF, Chadban SJ: TLR4 activation mediates kidney ischemia/reperfusion injury. J Clin Invest 2007;117:2847–2859. 13 Leemans JC, Stokman G, Claessen N, Rouschop KM, Teske GJ, Kirschning CJ, Akira S, van der Poll T, Weening JJ, Florquin S: Renalassociated TLR2 mediates ischemia/reperfusion injury in the kidney. J Clin Invest 2005;115:2894–2903.

Kinsey/Li/Okusa

14 Shigeoka AA, Holscher TD, King AJ, Hall FW, Kiosses WB, Tobias PS, Mackman N, McKay DB: TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways. J Immunol 2007;178:6252–6258. 15 Thornton MA, Winn R, Alpers CE, Zager RA: An evaluation of the neutrophil as a mediator of in vivo renal ischemic-reperfusion injury. Am J Pathol 1989; 135:509–515. 16 Kielar ML, John R, Bennett M, Richardson JA, Shelton JM, Chen L, Jeyarajah DR, Zhou XJ, Zhou H, Chiquett B, Nagami GT, Lu CY: Maladaptive role of IL-6 in ischemic acute renal failure. J Am Soc Nephrol 2005; 16: 3315–3325.

Inflammation in AKI

17 Dong X, Swaminathan S, Bachman LA, Croatt AJ, Nath KA, Griffin MD: Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury. Kidney Int 2007;71:619–628. 18 Dong X, Swaminathan S, Bachman LA, Croatt AJ, Nath KA, Griffin MD: Antigen presentation by dendritic cells in renal lymph nodes is linked to systemic and local injury to the kidney. Kidney Int 2005; 68: 1096– 1108. 19 Burne MJ, Daniels F, El Ghandour A, Mauiyyedi S, Colvin RB, O’Donnell MP, Rabb H: Identification of the CD4(+) T cell as a major pathogenic factor in ischemic acute renal failure. J Clin Invest 2001; 108: 1283–1290.

20 Burne-Taney MJ, Ascon DB, Daniels F, Racusen L, Baldwin W, Rabb H: B cell deficiency confers protection from renal ischemia reperfusion injury. J Immunol 2003; 171:3210–3215. 21 Park P, Haas M, Cunningham PN, Bao L, Alexander JJ, Quigg RJ: Injury in renal ischemia-reperfusion is independent from immunoglobulins and T lymphocytes. Am J Physiol Renal Physiol 2002;282:F352–F357. 22 Burne-Taney MJ, Yokota-Ikeda N, Rabb H: Effects of combined T- and B-cell deficiency on murine ischemia reperfusion injury. Am J Transplant 2005;5:1186–1193.

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Nephron Clin Pract 2008;109:c206–c216 DOI: 10.1159/000142930

Published online: September 18, 2008

New Insights on Intravenous Fluids, Diuretics and Acute Kidney Injury Derek R. Townsend a, b Sean M. Bagshaw a a

Division of Critical Care Medicine, Faculty of Medicine and Dentistry, and b Department of Anesthesiology and Pain Medicine, University of Alberta Hospital, University of Alberta, Edmonton, Alta., Canada

Key Words Acute kidney injury ⴢ Acute renal failure ⴢ Volume overload ⴢ Hydroxyethylstarch ⴢ Loop diuretic ⴢ Furosemide ⴢ Oliguria ⴢ Fluid therapy ⴢ Resuscitation

Abstract Acute kidney injury (AKI) is commonly and increasingly encountered in patients with critical illness. Fluid therapy is the cornerstone for the prevention and management of critically ill patients with AKI. New data have emerged that have raised concern that specific types of fluid (i.e. hydroxyethylstarch) may either contribute to or exacerbate AKI. Additional data have accumulated to indicate that the unnecessary accumulation of fluid and volume overload can negatively impact clinical outcomes. This finding may be further compounded in patients with oliguric AKI where solute and free water elimination are impaired. Diuretic therapy in AKI remains controversial. However, diuretic use is common, despite a paucity of evidence to show improved clinical outcomes. There are few therapeutic interventions proven to impact the clinical course and outcome of critically ill patients with established AKI. Current management strategies center largely on supportive care, with rapid resuscitation, removal of the stimulus contributing to AKI, judicious avoidance of complications, and allowing time for recovery. In this

© 2008 S. Karger AG, Basel 1660–2110/08/1094–0206$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nec

review, we explore recent insights on intravenous fluid therapy, volume overload, and diuretic therapy in the context of the critically ill patients with AKI. Copyright © 2008 S. Karger AG, Basel

Introduction

Critically ill patients frequently present with or develop acute kidney injury (AKI). Recent studies would suggest the incidence is far greater than previously appreciated. Observational data have shown that AKI occurs in an estimated 36–67% of all ICU patients [1–3], while AKI severe enough to warrant commencement of renal replacement therapy (RRT) occurs in 4–6% [4–6]. Moreover, numerous investigations have now shown the incidence of AKI continues to rise [7–9]. This high and increasing burden of AKI also remains associated with an unacceptably high morbidity and mortality [5, 6, 8–12]. Fluid therapy represents an essential stratagem for the prevention and/or the management of critically ill patients with AKI. New data have emerged that have raised concern that specific types of fluid (i.e. hydroxyethylstarch; HES) may either contribute to or exacerbate AKI [13]. In addition, there is accumulating evidence that the unnecessary accumulation of fluid can negatively impact Dr. Sean M. Bagshaw Division of Critical Care Medicine, University of Alberta Hospital 3C1.12 Walter C. Mackenzie Centre, 8440-112 Street Edmonton, Alta. T6G 2B7 (Canada) Tel. +1 780 407 6755, Fax +1 780 407 1228, E-Mail [email protected]

clinical outcomes, in particular in oliguric patients with established AKI [14–16]. Finally, diuretic therapy in AKI remains controversial. Yet, diuretics are extensively used in critically ill patients despite a lack of definitive evidence of effectiveness for improved clinical outcomes and concern for harm [17]. Overall, there are very few therapeutic interventions proven to impact the clinical course and outcome of ICU patients with established AKI [18–20]. Rather, management of the ICU patient with AKI is largely supportive and predicated on timely resuscitation, removal of the stimulus contributing to AKI, judicious avoidance of complications, and allowing time for recovery. In this review, we explore recent insights on intravenous fluid therapy, volume overload, and diuretic therapy in the context of the ICU patients with AKI.

Intravenous Fluids in AKI

There is broad consensus on the importance of fluid therapy in the acute resuscitation of critically ill patients [21]. Moreover, administration of fluid therapy is common and it is likely that all ICU patients receive some intravenous fluid therapy during an episode of critical illness. Fluid therapy also represents a central cornerstone for the prevention and/or the management of critically ill patients with AKI. Of the numerous strategies evaluated to date for prevention of AKI, only fluid therapy has been shown to be consistently effective [22]. However, there is no evidence fluid therapy will reverse AKI once established. There are several fluid types commercially available for use in ICU patients. These are broadly categorized as either crystalloid solutions (i.e. 0.9% normal saline or balanced Ringer’s lactate), and colloid solutions (i.e. starch, dextran, gelatin, albumin). There remains, however, considerable debate and controversy, along with conflicting data, about which type of fluid (i.e. crystalloid vs. colloid) should ideally be used during the acute resuscitation of critically ill patients [23–25]. The majority of critically ill patients likely receive some combination of crystalloids, colloids and/or blood products during an episode of critical illness [26]; however, large surveys of resuscitation and fluid therapy practice are currently lacking [27]. No randomized trials have definitively proven a beneficial effect on survival with a particular fluid type across a range of critically ill populations [28, 29] (table 1). Rather, more recent data have raised concern that specific synthetic colloids are associated with adverse clinical effects, New Insights on Intravenous Fluids, Diuretics and Acute Kidney Injury

including either contributing to or exacerbating AKI [13, 30–34]. In a recent systematic review of 113 clinical studies, Barron et al. [35] found that use of HES was associated with higher rates of anaphylactic reactions, pruritis, coagulopathy and clinical important episodes of bleeding when compared with albumin. Of more concern is the accumulating data of HES contributing to adverse kidney effects. In a multicenter, randomized trial comparing 6% HES with 3% fluid-modified gelatin for acute resuscitation in severe sepsis, use of HES resulted in a higher rate of AKI, oliguria and a higher peak serum creatinine when compared with gelatin [34]. These authors suggest that volume expansion with starch was an independent precipitant of AKI in severe sepsis. In a multicenter European study of septic critically ill patients, Sakr et al. [36] showed HES was associated with higher crude rates of RRT (11 vs. 9%, p = 0.006); however, this was not evident after adjustment in multi-variable analysis. The Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial, a randomized comparison of crystalloid (Ringer’s lactate) versus pentastarch (10% HES) resuscitation in 537 critically ill patients with severe sepsis, has recently been reported [13]. Those allocated to HES received a median cumulative volume of 70.4 ml/kg during the study period. A higher cumulative volume of HES administered was found to have a significant doseresponse correlation with both severe AKI necessitating RRT (p ! 0.001) and 90-day mortality (p = 0.001). This has raised speculation that septic states may induce greater sensitivity to the adverse effects of HES used for resuscitation due to differences in systemic inflammation [37]. Moreover, the observed adverse effects associated with HES in sepsis are perhaps not evident in other critical care settings (i.e. major surgery, cardiopulmonary bypass, trauma) [38, 39]. However, HES has also been associated with declines in kidney function in settings other than critical illness [30–33]. In a small randomized trial, use of HES in the first week after kidney transplant was associated with a higher mean serum creatinine (145 vs. 312 ␮mol/l, p = 0.009) and a greater need for RRT (33 vs. 5%, p = 0.03) compared with those allocated to gelatin-only fluids [30]. Legendre et al. found evidence of osmotic-nephrosis-like lesions in 80% of patients after cadaveric kidney transplantation in those having received HES; however, no adverse effects on graft function were evident at 3 and 6 months after transplant [33]. While fluid resuscitation may be context specific, there is no evidence at present that HES has clinical suNephron Clin Pract 2008;109:c206–c216

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Table 1. Summary of randomized clinical studies reporting increased risk of AKI associated with HES administration

Study, ref.

Brunkhorst [13] McIntyre [104] Schortgen [34] Cittanova [30]

Year

2008 2008 2001 1996

Number of patients

Study population

Starch fluid (MW/MS)

537 41 129 47

severe sepsis/septic shock septic shock severe sepsis/septic shock brain dead kidney donors

HES (200/0.50) HES (200/0.45) HES (200/0.60) HES (200/0.62)

Received RRT incidence, %

risk ratio, 95% CI

31 14 20 33

1.66 (1.2–2.3) 2.86 (0.3–25.2) 1.16 (0.6–2.4) 6.67 (0.9–48.5)

MW = Molecular weight; MS = molar substitution; RRT = renal replacement therapy.

periority or is associated with improved survival. Instead, HES would appear associated with a higher risk of adverse effects when compared with albumin or crystalloid solutions, in particular severe AKI requiring RRT. There is debate whether these adverse effects correlate with specific characteristics of the starch solution such as concentration, molecular weight, and degree of molar substitution [37]. However, there are little clinical data available, in particular in critically ill patients, to guide clinicians on this issue [40]. Accordingly, given these observations, along with the fact these colloids are expensive alternatives to crystalloids, HES should be used sparingly and only in the context of comparative clinical trials.

Fluid Overload and Oliguria

Fluid therapy is a clear priority in the acute resuscitative phase of critical illness to restore effective circulating volume and preserve tissue perfusion [41]. Fluid therapy given early and targeted to physiologic end points such a cardiac output, preload, stroke volume, mean arterial pressure, central venous pressure and/or urine output have been shown to improve clinical outcomes [42, 43]. In all patients, fluid therapy should be goal-directed and titrated in response to changes in hemodynamics and volume status. Fluid therapy is also often context specific, with varying end points for resuscitation across different critically ill populations. Monitoring volume status in critically ill patients, in particular those at risk for or with AKI, is an essential clinical issue [41]. Recent evidence highlights the lack of value of more traditional ventricular preload indicators (i.e. right atrial pressure, pulmonary artery occlusion pressure, right ventricular end diastolic volume) as predictors of fluid responsiveness, in terms of improved cardiac output or stroke volume, in ICU patients [44]. In a recent systematic review, Michard c208

Nephron Clin Pract 2008;109:c206–c216

et al. [44] found that 28–60% of all critically ill hemodynamically unstable patients failed to respond to fluid therapy when using these preload indicators. This has clinical relevance, as an increasing number of clinical studies have shown an association between volume overload and adverse clinical outcomes [14–16, 45–50]. Moreover, the judicious monitoring of volume status in critically ill patients with AKI, with or without oliguria, may be even more relevant due to impaired capacity for solute and free water elimination. Oliguria in AKI, in the absence of clear hypovolemia, is not necessarily an indication for a fluid challenge. The distinction is important. In the context of hypovolemia and/or reduced effective circulating volume, fluid therapy would appear appropriate. However, there is no clear evidence to support a fluid challenge in the resuscitated ICU patient with oliguric AKI. While such a fluid challenge may indeed temporarily increase urine flow, there is no data to suggest it attenuates the severity of AKI or improves clinical outcome. Instead, the liberal use of fluid therapy in these circumstances may exacerbate fluid overload and lead to harm [14–16, 46– 50] (table 2). In a small cohort of critically ill patients with sepsis-induced AKI, Van Biesen et al. [16] found that, despite apparent optimal hemodynamics, restored intravascular volume and an already high use of diuretic therapy, additional fluid therapy not only failed to improve kidney function but lead to unnecessary volume overload, impaired gas exchange and pulmonary edema. Several observational studies in pediatric critically ill patients have consistently shown a positive cumulative fluid balance (i.e. percentage fluid overload) at the time of initiation of RRT independently predicted worse clinical outcome [46–49]. Similar findings in adult observational studies of a positive cumulative fluid balance independently predicting hospital mortality have been shown [14, 50, 51]. Townsend /Bagshaw

Table 2. Summary of clinical studies showing an association between fluid balance and clinical outcome

Study, ref.

Year

Number of Design patients

Population

Intervention

Outcome

Simmons [50]

1987

113

P, C

ARDS

N/A

mortality associated with positive daily/ cumulative fluid balance and weight gain

Schuller [45]

1991

89

R, C

ALI/ARDS

N/A

mortality associated with higher positive fluid balance >1 l over 36 h (50 vs. 26%, p < 0.05) along with longer duration of MV and ICU/hospital stay

Goldstein [48]

2001

21

R, C

pediatric AKI

N/A

mortality associated with higher %FO at RRT initiation (34 vs. 16.4%, p = 0.03)

Brandstrup [52]

2003

172

RCT

elective colorectal surgery

restrictive vs. stan- restrictive strategy reduced post-operative dard peri-operative weight gain and complications (33 vs. 51%, p = 0.003) fluid strategy

Foland [46]

2004

113

R, C

pediatric AKI

N/A

mortality associated with higher %FO at RRT initiation (15.5 vs. 9.2%, p = 0.01)

Gillespie [47]

2004

77

R,C

pediatric AKI

N/A

mortality associated with higher %FO at RRT initiation (>10%, RR 3.02, p = 0.002)

Goldstein [49]

2005

116

R, C

pediatric AKI

N/A

mortality associated with higher %FO at RRT initiation (25.4 vs. 14.2%, p = 0.03)

Sakr [14]

2005

393

P, C

ALI/ARDS

N/A

mortality associated with positive cumulative fluid balance (+4.4 vs. –3.0 l, OR 1.5, p = 0.003)

Uchino [51]

2006

331

P, NR

critically ill

N/A

mortality associated with positive fluid balance (OR 1.0002 per each ml/day, p < 0.01)

Wiedemann [15] 2006

1,000

RCT

ALI/ARDS

conservative vs. liberal fluid strategy

conservative strategy had lower cumulative 7-day fluid balance (0.13 vs. 6.9 l, <0.001), improved gas exchange, shorter time on ventilator and ICU stay, no difference in rate of RRT or mortality

P = Prospective; R = retrospective; C = cohort; RCT = randomized clinical trial; NR = nonrandomized; ALI = acute lung injury; ARDS = acute respiratory distress syndrome; N/A = not applicable; %FO = percentage fluid overload; RR = risk ratio; MV = mechanical ventilation.

The ARDS Clinical Trials Network performed a large multicenter randomized comparison of conservative versus liberal fluid management strategies in 1,000 mostly septic critically ill patients with acute lung injury [15]. While there was no difference in 60-day mortality between the two strategies (25.5% for conservative vs. 28.4 for liberal, p = 0.3), there were other notable findings from this study. The liberal group received more fluid and had lower urine output during each of the first 7 days compared with the conservative group, resulting in a higher cumulative fluid balance (6.99 vs. –0.13 l, p ! 0.0001). The conservative strategy, when compared with

the liberal strategy, showed improvements in gas exchange and had more ventilator-free days (14.6 vs. 12.1 days, p ! 0.001), more ICU-free days (13.4 vs. 11.2 days, p ! 0.001) and a trend for lower need of RRT (10 vs. 14%, p = 0.06) without increasing non-pulmonary organ dysfunction or hemodynamic instability [15]. Similar improvements in outcome, along with reduced peri-operative complications, have also been shown with the use of a conservative fluid strategy in patients undergoing major abdominal surgery [52, 53]. These data extend considerably that of prior studies showing a therapeutic strategy of reducing net fluid bal-

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Nephron Clin Pract 2008;109:c206–c216

c209

Table 3. Summary of available diuretic agents commonly used in the management of volume overload, oliguria and AKI in critically

ill patients (adapted from Mehta et al. [89]) Diuretic class

Site of action

Chemical nature

Prototypic drug

Dose range

Carbonic anhydrase inhibitor Osmotic Loop Distal convoluted tubule Potassium-sparing

PCT PCT, LOH PCT, TAL, LOH DCT CD

sulfonamide polysaccharide sulfonamide benzothiadiazine steroid

acetazolamide mannitol furosemide hydrochlorothiazide spironolactone

5 mg/kg p.o./i.v. 25–100 g (0.5–1.0 g/kg) i.v. 20–120 mg p.o./i.v. 12.5–50 mg p.o. 25–200 mg p.o.

PCT = Proximal convoluted tubule; LOH = loop of Henle; TAL = thick ascending loop; DCT = distal convoluted tubule; CD = collecting tubule.

ance is safe and can lead to improved clinical outcomes. Moreover, these data should also be considered in the context of oliguric AKI, along with recent shifts in clinical practice that have occurred in critical care over the last 10 years [21, 43, 54]. In particular, the process of early-goal directed therapy has been a major advance in the approach to resuscitation of critically ill septic patients [43]. In the trial by Rivers et al. [43], those allocated to early-goal directed therapy received approximately 5 liters of total fluid therapy within the first 6 h and over 13 liters by 72 h. Unfortunately, cumulative fluid balance, urine output, diuretic therapy and kidney outcomes were not reported, but notably, serum creatinine values were elevated at enrolment. At minimum this would suggest that most, if not all, of these septic patients had evidence of AKI. Rapid and large volume resuscitation of early septic shock, as performed in this trial and largely endorsed by the Surviving Sepsis Campaign Guidelines [21], may have the potential to precipitate complications, such as those related to volume overload, at a much earlier point in patients with oliguria and established AKI. The inference of the accumulated data is that volume overload is an important clinical problem, and that coupled with the rising incidence of AKI will likely increase in modern ICU practice. There are few therapeutic options available for volume overloaded critically ill patients with oliguric AKI short of earlier initiation of RRT or a trial of diuretic therapy.

Diuretic Therapy in AKI

The use of diuretic therapy in critically ill patients with volume overload, oliguria and/or AKI is a common and long-standing practice [16, 17, 55, 56] (table 3). By far c210

Nephron Clin Pract 2008;109:c206–c216

the most common class of diuretic agents routinely used are loop diuretics, in particular the sulfonamide drug furosemide [17, 55, 56]. In a retrospective study involving 552 ICU patients with AKI, Mehta et al. found that 59% had received diuretic therapy prior to consultation with a nephrologist [55]. Of diuretic agents that had been given, 62% had received furosemide with a median (IQR) single dose of 80 mg (20–320). In another multicenter observational study of 1,743 ICU patients with AKI, Uchino et al. [56] showed that 70% had received diuretic agents at the time of study enrolment with furosemide being the primary diuretic used in 98%. Similarly, in a small singlecenter prospective evaluation of patients with sepsis-induced AKI, Van Biesen et al. [16] found that 72% had received diuretic therapy, mostly with furosemide. Clearly, most ICU clinicians are familiar with the administration, pharmacology and adverse effects of furosemide [17]. A recent survey of nephrology and ICU clinicians confirmed furosemide was the most common diuretic agent used [17]. Moreover, in ICU patients, furosemide is near universally given by the intravenous route, and dosing is generally titrated to achieve a urine output goal in the range of 0.5–1.0 ml/kg/h. Yet, regrettably, despite the common use of furosemide in clinical practice, its role in the management of ICU patients with AKI remains, by and large, poorly understood and controversial. Loop diuretics, such as furosemide, have weak vasodilatory properties and act at the medullary thick ascending loop of Henle to inhibit the Na+/K+/Cl– pump on the luminal cell membrane surface and can theoretically reduce renal tubular cell oxygen demand [57–59]. Recent experimental data in a rat model of ischemia/reperfusion-induced AKI have shown that low-dose furosemide can reduce injury by improving renal hemodynamics and attenuation of ischemia-induced apoptosis and reTownsend /Bagshaw

Table 4. Summary of randomized clinical studies of loop diuretics in the management of AKI

Study, ref.

Year

Number of Loop diuretics protocol patients

Comment

Clinical outcomes

Toxicity

Cantarovich [71]

1971

47

furosemide 100–3,200 mg i.v. fixed/progressive daily

all were receiving RRT at enrolment

no difference in mortality (p = 0.75)

tinnitus*

Karayannopoulos [76]

1974

20

furosemide 1,000–3,000 mg i.v. daily

not critically ill

reduced need for RRT with furosemide (p = 0.02)

none reported

Kleinknecht [77]

1976

66

furosemide 3 mg/kg i.v. load, 1.5–6.0 mg/kg i.v. q4h

not critically ill, co-interventions (MA), most already on RRT

no differences in duration of AKI (p > 0.1), duration of RRT (p > 0.1) or mortality (p = 1.0)

tinnitus, deafness, vertigo*

Brown [69]

1981

56

furosemide 2 mg/min i.v. or 1,000 mg q8h p.o.

not critically ill, furosemide given to both

no differences in need for RRT (p = 1.0), duration of RRT, or mortality (p = 0.78)

deafness (n = 2)

Shilliday [82]

1997

92

furosemide or torasemide 3 mg/kg i.v. q6h

co-interventions (DA, MA)

no differences in need for RRT (p = 0.87), renal recovery (p = 0.56), or mortality (p = 0.24)

deafness (n = 1)

Cantarovich [73]

2004

330

furosemide 25 mg/kg/day i.v. or 35 mg/kg/day p.o.

all were receiving RRT at enrolment

no difference in mortality (p = 0.36), duration of RRT (p = 0.21) or renal recovery (p = 0.51)

deafness (n = 4)

DA = Dopamine; MA = mannitol; RRT = renal replacement therapy; ICU = intensive care unit. * Rates of toxic effect were not reported. In these studies, ototoxicity may have been confounded by concomitant use of aminoglycosides. Symptoms were reported to occur temporally within a few hours after furosemide administration. No long-term sequelae were reported.

lated gene transcription [60, 61]. While these findings add credibility to the theoretical benefit for furosemide to attenuate kidney injury, additional experimental studies have been contradictory [62–66]. Thus, at least theoretically, the timely administration of furosemide might attenuate and/or reduce the severity of kidney injury, however, it should be emphasized that this has yet to be proven in human clinical studies. More pragmatically, for the ICU patient with AKI, furosemide likely plays an important role as a tool for preventing and/or managing volume overload by augmenting natriuresis and diuresis, for maintaining acid-base and potassium homeostasis, and for aiding in delivery of adequate nutritional support.

There is an abundance of clinical studies that have evaluated loop diuretics for the management of AKI [67– 85] (table 4). Regrettably, the majority of these studies have shortcomings and also have not shown the use of loop diuretics leads to improved clinical outcomes. More recently, the controversy has been highlighted by two large observational studies presenting discordant arguments on the potential impact of loop diuretics on mortality and renal recovery in ICU patients with AKI [55, 56]. Both studies estimated risk ratios for mortality 11.0 with loop diuretics, implying an increase in mortality with their use in AKI. The study by Mehta et al. [55] was performed at four academic hospitals from 1989 to 1995 and enrolled a total of 552 ICU patients with AKI. This study suggested an increased risk of death and/or

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nonrecovery of kidney function with the use of loop diuretics. Of note, this study included only those patients having had a nephrology consultation while admitted to ICU, excluded patients with ‘hypovolemia’, failed to report the proportion requiring RRT, and included data on only 64% of potentially eligible ICU patients from the entire cohort (n = 851). These issues could predispose to significant selection and/or observation bias. Likewise, these issues also question to generalizability of these findings to broader ICU practice worldwide [86]. The study by Uchino et al. [56] was performed at 54 ICUs across 23 countries and enrolled 1,743 ICU patients with AKI, defined by having received RRT or fulfilling predefined criteria for AKI. While the risk ratio estimate for mortality with loop diuretic use was 11.0 in this study, it was nonsignificant after adjustment by multivariable analysis that included controlling for potential residual confounding by propensity analysis and compensation of collinearity in model variables. Neither of these studies can definitively conclude that any observed association between loop diuretics and mortality is causal. In addition to the obvious limitations in study design, neither of these studies integrated additional aspects of clinical management that may have influenced survival and/or renal recovery such as temporal relationship between onset of AKI and diuretic use, fluid resuscitation, severity of AKI and changes over time (i.e. transition between RIFLE categories) and the relative timing of initiation of RRT when indicated. These issues are complex and are not ideally captured by a retrospective cohort study design or by analysis of secondary hypotheses from study databases. Additional clinical studies have suggested that loop diuretics might attenuate the severity of kidney injury by converting ‘oliguric’ to ‘nonoliguric’ AKI. Yet, this may be false reassurance, as conversion of oliguria to a state of adequate diuresis may only suggest a milder degree of AKI. While this may allow for better management of complications of AKI (i.e. volume overload, hyperkalemia), it may also contribute to delay in definitive supportive therapy such as RRT and worse clinical outcome [55, 56, 87]. Small clinical trials have also suggested loop diuretics may shorten the duration of AKI, improve the rate of renal recovery, and perhaps delay or ameliorate need for RRT [71, 72, 76, 77, 84]. However, it should be emphasized again that clear improvements in survival and/or renal recovery have not been shown in modern ICU practice for patients with AKI with high-quality evidence. In a meta-analysis of furosemide for prevention and management of AKI, Ho et al. [88] concluded that furosec212

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mide was not associated with clinical benefit but rather increased the risk of harm and adverse effects. This analysis, however, included trials where furosemide was administered to both prevent and treat AKI and one study where furosemide was given to both the treatment and the control groups. Further, it included duplicated control data from one study with three treatment groups and provided approximated or estimated rates of toxicity in another. This study did confirm that there is no high-quality data to suggest that the prophylactic use of furosemide will prevent AKI in susceptible patients [89]. Overall, inferences from this analysis would appear limited. Sampath et al. [90] also performed a systematic review and Bayesian evidence synthesis of 13 randomized and nonrandomized studies on diuretic use in AKI. This study calculated an estimate of the probability that loop diuretics were associated with a risk ratio for mortality 11.0. The authors found an 83% probability of a risk ratio 11.0 for mortality with loop diuretics. Another meta-analysis assessing loop diuretics for treatment of AKI, with a focus on ICU patients, included five randomized trials enrolling 555 patients [91]. This study found loop diuretics has no significant impact on mortality or renal recovery, however, their use was associated with a shorter duration of RRT, a shorter time to spontaneous decline in surrogate measures of kidney function (i.e. serum creatinine) and a greater increase in urine output from baseline. This study was not able to comment on whether loop diuretics had any impact on acid-base status, duration of mechanical ventilation, secondary organ dysfunction, hospital length of stay or health costs due to inadequate data. More importantly, however, Bagshaw and coworkers highlighted the poor overall trial quality and the lack of generalizability of this evidence to modern ICU patients with AKI. For example, the trials in this analysis, along with those from prior analyses [88, 90], were generally small, confounded by co-interventions (i.e. mannitol, dopamine), and typically characterized by delayed or late intervention defined by either prolonged periods of oligo-anuria or already on RRT at the time of enrolment [72, 73, 76, 77, 82]. The latter point should be stressed, as any delays to appropriate therapy in AKI have been found to contribute to increased mortality and reduced likelihood of renal recovery [92–94]. Similarly, in all these trials, furosemide was often given by large intravenous bolus doses, where no specific titration of therapy to physiologic end points such as urine output was performed. Finally, many of these trials often did not include ICU patients, thus greatly limiting their applicability and generalizability to the modern ICU patients with AKI. AccordTownsend /Bagshaw

ingly, there is continued debate and controversy as to whether loop diuretics can impact clinical outcomes and should be used in ICU patients with AKI [95–99]. Interestingly, the evidence summarized in these systematic reviews largely forms the basis for the prevailing view on whether loop diuretics have any benefit in AKI. Despite this, evidence from surveys and observational studies indicate that clinicians routinely administer loop diuretics in AKI, but not in a manner consistent with how they were administered in these trials. Thus, one naturally asks: Are nephrology and ICU clinicians mistaken to use loop diuretics altogether or is the evidence on the effectiveness of loop diuretics misleading? The practical limitations identified with the currently available literature on loop diuretics coupled with the apparent practice malalignment would strongly indicated evidence of clinical equipoise for additional investigations evaluating loop diuretics in ICU patients with AKI. There is a need for a high-quality suitably powered randomized trial of loop diuretics in critically ill patients with early AKI either identified by RIFLE category – RISK [100] or by novel urinary biomarkers of AKI such as neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18) or kidney injury molecule-1 (KIM-1) [101–103]. Such a trial should also incorporate clinically-relevant and patient-centered outcomes, such as progression of AKI, need for RRT or renal recovery, as well as important secondary outcomes focused on issues of harm, dose-response and physiologic end points (i.e. fluid balance).

Conclusions

AKI is common and increasingly encountered in ICU patients. Fluid therapy is the cornerstone for the prevention and management of critically ill patients developing AKI. New data have emerged that show evidence of harm with use of HES in critically ill patients, in particular a dose-response increase in the risk of AKI requiring RRT. Whether this increased risk is correlated with explicit characteristics of the HES solution (i.e. concentration, molecular weight, degree of molar substitution) remains to be determined. Data have also emerged to indicate volume overload and a positive cumulative fluid balance can contribute to worse clinical outcomes in critically ill patients. Those with oliguric AKI may be less able to accommodate fluid accumulation due to impaired solute and free water elimination. These critically ill patients with AKI may need initiation of RRT and/or a trial of diuretic therapy earlier in the course after development of AKI. Diuretic therapy in AKI remains controversial due to concern for harm and a lack of definitive effectiveness in clinical trials; its use, however, remains common. It remains unclear what drives this practice but raises the important question: Are clinicians mistaken to use diuretic therapy in AKI or is the evidence on the effectiveness of diuretic therapy misleading? This paradoxical observation between clinical practice and available evidence would suggest there is equipoise and urgent need for higher-quality evidence on this issue.

References 1 Hoste EA, Clermont G, Kersten A, Venkataraman R, Angus DC, De Bacquer D, Kellum JA: RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care 2006;10:R73. 2 Bagshaw SM, George C, Dinu I, Bellomo R: A multi-centre evaluation of the RIFLE criteria for early acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008; 23:1203–1210. 3 Ostermann M, Chang RW: Acute kidney injury in the intensive care unit according to RIFLE. Crit Care Med 2007;35:1837–1843. 4 Guerin C, Girard R, Selli JM, Perdrix JP, Ayzac L: Initial versus delayed acute renal failure in the intensive care unit: a multicenter prospective epidemiological study. Rhone-Alpes Area Study Group on Acute Renal Failure. Am J Respir Crit Care Med 2000;161:872–879.

New Insights on Intravenous Fluids, Diuretics and Acute Kidney Injury

5 Bagshaw SM, Laupland KB, Doig CJ, Mortis G, Fick GH, Mucenski M, Godinez-Luna T, Svenson LW, Rosenal T: Prognosis for longterm survival and renal recovery in critically ill patients with severe acute renal failure: a population-based study. Crit Care 2005; 9: R700–R709. 6 Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C: Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294:813–818. 7 Bagshaw SM, George C, Bellomo R: Changes in the incidence and outcome for early acute kidney injury in a cohort of Australian intensive care units. Crit Care 2007; 11:R68. 8 Waikar SS, Curhan GC, Wald R, McCarthy EP, Chertow GM: Declining mortality in patients with acute renal failure, 1988 to 2002. J Am Soc Nephrol 2006;17:1143–1150.

9 Xue JL, Daniels F, Star RA, Kimmel PL, Eggers PW, Molitoris BA, Himmelfarb J, Collins AJ: Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol 2006; 17:1135–1142. 10 Mehta RL, Pascual MT, Soroko S, Savage BR, Himmelfarb J, Ikizler TA, Paganini EP, Chertow GM: Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Int 2004;66:1613–1621. 11 Metnitz PG, Krenn CG, Steltzer H, Lang T, Ploder J, Lenz K, Le Gall JR, Druml W: Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 2002;30:2051–2058. 12 Morgera S, Kraft AK, Siebert G, Luft FC, Neumayer HH: Long-term outcomes in acute renal failure patients treated with continuous renal replacement therapies. Am J Kidney Dis 2002;40:275–279.

Nephron Clin Pract 2008;109:c206–c216

c213

13 Brunkhorst FM, Engel C, Bloos F, MeierHellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K: Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125–139. 14 Sakr Y, Vincent JL, Reinhart K, Groeneveld J, Michalopoulos A, Sprung CL, Artigas A, Ranieri VM: High tidal volume and positive fluid balance are associated with worse outcome in acute lung injury. Chest 2005; 128: 3098–3108. 15 Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL: Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354: 2564–2575. 16 Van Biesen W, Yegenaga I, Vanholder R, Verbeke F, Hoste E, Colardyn F, Lameire N: Relationship between fluid status and its management on acute renal failure (ARF) in intensive care unit (ICU) patients with sepsis: a prospective analysis. J Nephrol 2005;18: 54–60. 17 Bagshaw SM, Delaney A, Jones D, Ronco C, Bellomo R: Diuretics in the management of acute kidney injury: a multinational survey. Contrib Nephrol 2007; 156:236–249. 18 Abel RM, Beck CH Jr, Abbott WM, Ryan JA Jr, Barnett GO, Fischer JE: Improved survival from acute renal failure after treatment with intravenous essential L-amino acids and glucose: results of a prospective, doubleblind study. N Engl J Med 1973; 288: 695– 699. 19 Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca G: Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet 2000;356:26–30. 20 Schiffl H, Lang SM, Fischer R: Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002;346:305–310. 21 Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296–327. 22 Venkataraman R, Kellum JA: Prevention of acute renal failure. Chest 2007;131:300–308. 23 Bellomo R: Fluid resuscitation: colloids vs. crystalloids. Blood Purif 2002;20:239–242. 24 Vincent JL: Fluid resuscitation: colloids vs. crystalloids. Acta Clin Belg Suppl 2007:408– 411.

c214

25 Vincent JL: The pros and cons of hydroxyethyl starch solutions. Anesth Analg 2007; 104:484–486. 26 McIntyre LA, Fergusson D, Cook DJ, Nair RC, Bell D, Dhingra V, Hutton B, Magder S, Hebert PC: Resuscitating patients with early severe sepsis: a Canadian multicentre observational study. Can J Anaesth 2007; 54: 790– 798. 27 McIntyre LA, Hebert PC, Fergusson D, Cook DJ, Aziz A: A survey of Canadian intensivists’ resuscitation practices in early septic shock. Crit Care 2007;11:R74. 28 Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R: A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350: 2247–2256. 29 Perel P, Roberts I: Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2007: CD000567. 30 Cittanova ML, Leblanc I, Legendre C, Mouquet C, Riou B, Coriat P: Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant recipients. Lancet 1996;348:1620–1622. 31 Cittanova ML, Mavre J, Riou B, Coriat P: Long-term follow-up of transplanted kidneys according to plasma volume expander of kidney donors. Intens Care Med 2001; 27: 1830. 32 Dickenamm MJ, Filipovic M, Schneider MC, Brunner FP: Hydroxyethylstarch-associated transient acute renal failure after epidural anaesthesia for labour analgesia and Caesarean section. Nephrol Dial Transplant 1998; 13:2706. 33 Legendre C, Thervet E, Page B, Percheron A, Noel LH, Kreis H: Hydroxyethylstarch and osmotic-nephrosis-like lesions in kidney transplantation. Lancet 1993;342:248–249. 34 Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, Hemery F, Lemaire F, Brochard L: Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001; 357:911–916. 35 Barron ME, Wilkes MM, Navickis RJ: A systematic review of the comparative safety of colloids. Arch Surg 2004;139:552–563. 36 Sakr Y, Payen D, Reinhart K, Sipmann FS, Zavala E, Bewley J, Marx G, Vincent JL: Effects of hydroxyethyl starch administration on renal function in critically ill patients. Br J Anaesth 2007;98:216–224. 37 Kellum JA, Cerda J, Kaplan LJ, Nadim MK, Palevsky PM: Fluids for prevention and management of acute kidney injury. Int J Artif Organs 2008;31:96–110. 38 Gan TJ, Bennett-Guerrero E, Phillips-Bute B, Wakeling H, Moskowitz DM, Olufolabi Y, Konstadt SN, Bradford C, Glass PS, Machin SJ, Mythen MG: Hextend, a physiologically balanced plasma expander for large volume use in major surgery: a randomized phase III clinical trial. Hextend Study Group. Anesth Analg 1999;88:992–998.

Nephron Clin Pract 2008;109:c206–c216

39 Wiesen P, Canivet JL, Ledoux D, Roediger L, Damas P: Effect of hydroxyethylstarch on renal function in cardiac surgery: a large scale retrospective study. Acta Anaesthesiol Belg 2005;56:257–263. 40 Blasco V, Leone M, Antonini F, Geissler A, Albanese J, Martin C: Comparison of the novel hydroxyethylstarch 130/0.4 and hydroxyethylstarch 200/0.6 in brain-dead donor resuscitation on renal function after transplantation. Br J Anaesth 2008;100:504– 508. 41 Pinsky MR, Brophy P, Padilla J, Paganini E, Pannu N: Fluid and volume monitoring. Int J Artif Organs 2008;31:111–126. 42 Lin SM, Huang CD, Lin HC, Liu CY, Wang CH, Kuo HP: A modified goal-directed protocol improves clinical outcomes in intensive care unit patients with septic shock: a randomized controlled trial. Shock 2006; 26: 551–557. 43 Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368–1377. 44 Michard F, Teboul JL: Predicting fluid responsiveness in ICU patients: a critical analysis of the evidence. Chest 2002; 121: 2000– 2008. 45 Schuller D, Mitchell JP, Calandrino FS, Schuster DP: Fluid balance during pulmonary edema: is fluid gain a marker or a cause of poor outcome? Chest 1991; 100: 1068– 1075. 46 Foland JA, Fortenberry JD, Warshaw BL, Pettignano R, Merritt RK, Heard ML, Rogers K, Reid C, Tanner AJ, Easley KA: Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis. Crit Care Med 2004; 32: 1771– 1776. 47 Gillespie RS, Seidel K, Symons JM: Effect of fluid overload and dose of replacement fluid on survival in hemofiltration. Pediatr Nephrol 2004; 19:1394–1399. 48 Goldstein SL, Currier H, Graf C, Cosio CC, Brewer ED, Sachdeva R: Outcome in children receiving continuous venovenous hemofiltration. Pediatrics 2001; 107: 1309– 1312. 49 Goldstein SL, Somers MJ, Baum MA, Symons JM, Brophy PD, Blowey D, Bunchman TE, Baker C, Mottes T, McAfee N, Barnett J, Morrison G, Rogers K, Fortenberry JD: Pediatric patients with multi-organ dysfunction syndrome receiving continuous renal replacement therapy. Kidney Int 2005;67:653– 658. 50 Simmons RS, Berdine GG, Seidenfeld JJ, Prihoda TJ, Harris GD, Smith JD, Gilbert TJ, Mota E, Johanson WG Jr: Fluid balance and the adult respiratory distress syndrome. Am Rev Respir Dis 1987;135:924–929.

Townsend /Bagshaw

51 Uchino S, Bellomo R, Morimatsu H, Sugihara M, French C, Stephens D, Wendon J, Honore P, Mulder J, Turner A: Pulmonary artery catheter versus pulse contour analysis: a prospective epidemiological study. Crit Care 2006;10:R174. 52 Brandstrup B, Tonnesen H, Beier-Holgersen R, Hjortso E, Ording H, Lindorff-Larsen K, Rasmussen MS, Lanng C, Wallin L, Iversen LH, Gramkow CS, Okholm M, Blemmer T, Svendsen PE, Rottensten HH, Thage B, Riis J, Jeppesen IS, Teilum D, Christensen AM, Graungaard B, Pott F: Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial. Ann Surg 2003; 238: 641– 648. 53 Nisanevich V, Felsenstein I, Almogy G, Weissman C, Einav S, Matot I: Effect of intraoperative fluid management on outcome after intra-abdominal surgery. Anesthesiology 2005;103:25–32. 54 Liu KD, Matthay MA, Chertow GM: Evolving practices in critical care and potential implications for management of acute kidney injury. Clin J Am Soc Nephrol 2006; 1: 869–873. 55 Mehta RL, Pascual MT, Soroko S, Chertow GM, Group PS: Diuretics, mortality, and nonrecovery of renal function in acute renal failure (see comment). JAMA 2002; 288: 2547–2553. 56 Uchino S, Doig GS, Bellomo R, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Nacedo E, Gibney N, Tolwani A, Ronco C, Kellum JA: Diuretics and mortality in acute renal failure. Crit Care Med 2004; 32: 1669– 1677. 57 De Torrente A, Miller PD, Cronin RE, Paulsin PE, Erickson AL, Schrier RW: Effects of furosemide and acetylcholine in norepinephrine-induced acute renal failure. Am J Physiol 1978;235:F131–F136. 58 Heyman SN, Brezis M, Reubinoff CA, Greenfeld Z, Lechene C, Epstein FH, Rosen S: Acute renal failure with selective medullary injury in the rat. J Clin Invest 1988; 82: 401– 412. 59 Kramer HJ, Schuurmann J, Wassermann C, Dusing R: Prostaglandin-independent protection by furosemide from oliguric ischemic renal failure in conscious rats. Kidney Int 1980;17:455–464. 60 Aravindan N, Aravindan S, Riedel BJ, Weng HR, Shaw AD: Furosemide prevents apoptosis and associated gene expression in a rat model of surgical ischemic acute renal failure. Ren Fail 2007;29:399–407. 61 Aravindan N, Shaw A: Effect of furosemide infusion on renal hemodynamics and angiogenesis gene expression in acute renal ischemia/reperfusion. Ren Fail 2006;28:25–35.

New Insights on Intravenous Fluids, Diuretics and Acute Kidney Injury

62 Costa MA, Loria A, Elesgaray R, Balaszczuk AM, Arranz C: Role of nitric oxide pathway in hypotensive and renal effects of furosemide during extracellular volume expansion. J Hypertens 2004;22:1561–1569. 63 Costa MA, Marchetti M, Balaszczuk AM, Arranz CT: Effects of L-arginine and furosemide on blood pressure and renal function in volume-expanded rats. Clin Exp Pharmacol Physiol 2001;28:528–532. 64 Croce M, Costa Manso E, Gato JJ, Cordoba H, Oehling A: Furosemide inhibits in vitro histamine release induced by antigens and anti-IgE. J Invest Allergol Clin Immunol 1992;2:205–210. 65 Oppermann M, Hansen PB, Castrop H, Schnermann J: Vasodilatation of afferent arterioles and paradoxical increase of renal vascular resistance by furosemide in mice. Am J Physiol Renal Physiol 2007;293:F279–F287. 66 Pedersen M, Vajda Z, Stodkilde-Jorgensen H, Nielsen S, Frokiaer J: Furosemide increases water content in renal tissue. Am J Physiol Renal Physiol 2007;292:F1645–F1651. 67 Beroniade V: Furosemide in acute and chronic renal failure. Dialysis Renal Transplant 1969;5:241–245. 68 Borirakchanyavat V, Vongsthongsri M, Sitprija V: Furosemide and acute renal failure. Postgrad Med J 1978;54:30–32. 69 Brown CB, Ogg CS, Cameron JS: High dose frusemide in acute renal failure: a controlled trial. Clin Nephrol 1981; 15:90–96. 70 Brown CB, Ogg CS, Cameron JS, Bewick M: High dose frusemide in acute reversible intrinsic renal failure: a preliminary communication. Scot Med J 1974;19(suppl 1):35–39. 71 Cantarovich F, Fernandez JC, Locatelli A, Perez Loredo J: Frusemide in high doses in the treatment of acute renal failure. Postgrad Med J 1971;47(suppl):13–17. 72 Cantarovich F, Galli C, Benedetti L, Chena C, Castro L, Correa C, Perez Loredo J, Fernandez JC, Locatelli A, Tizado J: High dose frusemide in established acute renal failure. Br Med J 1973;4:449–450. 73 Cantarovich F, Rangoonwala B, Lorenz H, Verho M, Esnault VL: High-dose furosemide for established ARF: a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Am J Kidney Dis 2004;44:402– 409. 74 Chandra M, Agarwal SS, Mitra MK, Tandon NN, Gupta NN: Some observations in the management of acute renal failure by massive intravenous frusemide therapy. J Assoc Physicians India 1975;23:415–422. 75 Chandra M, Agarwal SS, Mitra NK, Gupta NN: Massive intravenous frusemide therapy in acute renal failure. J Indian Med Assoc 1975;64:47–48. 76 Karayannopoulos S: High-dose frusemide in renal failure. Br Med J 1974;ii:278–279. 77 Kleinknecht D, Ganeval D, Gonzalez-Duque LA, Fermanian J: Furosemide in acute oliguric renal failure: a controlled trial. Nephron 1976;17:51–58.

78 Lucas CE, Zito JG, Carter KM, Cortez A, Stebner FC: Questionable value of furosemide in preventing renal failure. Surgery 1977;82: 341–320. 79 Lumlertgul D, Keoplung M, Sitprija V, Moollaor P, Suwangool P: Furosemide and dopamine in malarial acute renal failure. Nephron 1989;52:40–44. 80 Minuth AN, Terrell JB Jr, Suki WN: Acute renal failure: a study of the course and prognosis of 104 patients and of the role of furosemide. Am J Med Sci 1976;271:317–324. 81 Seedat YK: High dose frusemide in established acute renal failure. Br Med J 1973; 4: 784. 82 Shilliday IR, Quinn KJ, Allison ME: Loop diuretics in the management of acute renal failure: a prospective, double-blind, placebo-controlled, randomized study. Nephrol Dialy Transplant 1997;12:2592–2596. 83 Sirivella S, Gielchinsky I, Parsonnet V: Mannitol, furosemide, and dopamine infusion in postoperative renal failure complicating cardiac surgery. Ann Thorac Surg 2000;69:501– 506. 84 Vargas Hein O, Staegemann M, Wagner D, von Heymann C, Martin M, Morgera S, Spies C: Torsemide versus furosemide after continuous renal replacement therapy due to acute renal failure in cardiac surgery patients. Renal Fail 2005;27:385–392. 85 Zito J, Cortez A, Lucas CE, Stebner FC, Rosenberg IK, Jaanimagi JL: Distribution of renal blood flow after furosemide in critically ill patients. Surg Forum 1976;27:27–29. 86 Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Oudemans-van Straaten H, Ronco C, Kellum JA: Continuous renal replacement therapy: a worldwide practice survey. The Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Intens Care Med 2007;33:1563–1570. 87 Liangos O, Rao M, Balakrishnan VS, Pereira BJ, Jaber BL: Relationship of urine output to dialysis initiation and mortality in acute renal failure. Nephron Clin Pract 2005; 99: c56–c60. 88 Ho KM, Sheridan DJ: Meta-analysis of frusemide to prevent or treat acute renal failure. BMJ 2006;333:420. 89 Mehta RL, Cantarovich F, Shaw A, Hoste E, Murray P: Pharmacologic approaches for volume excess in acute kidney injury (AKI). Int J Artif Organs 2008;31:127–144. 90 Sampath S, Moran JL, Graham PL, Rockliff S, Bersten AD, Abrams KR: The efficacy of loop diuretics in acute renal failure: assessment using Bayesian evidence synthesis techniques. Crit Care Med 2007; 35: 2516– 2524. 91 Bagshaw SM, Delaney A, Haase M, Ghali WA, Bellomo R: Loop diuretics in the management of acute renal failure: a systematic review and meta-analysis. Crit Care Resusc 2007;9:68.

Nephron Clin Pract 2008;109:c206–c216

c215

92 Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Oudemans-van Straaten H, Ronco C, Kellum JA: Timing of renal replacement therapy and clinical outcomes in critically ill patients with severe acute kidney injury. J Crit Care 2008;23:in press. 93 Gettings LG, Reynolds HN, Scalea T: Outcome in post-traumatic acute renal failure when continuous renal replacement therapy is applied early vs. late. Intens Care Med 1999;25:805–813. 94 Liu KD, Himmelfarb J, Paganini EP, Ikizler A, Soroko S, Mehta RL, Chertow GM: Timing of initiation of dialysis in critically ill patients with acute kidney injury. CJASN 2006;1:915–919. 95 Kellum JA: Diuretics in acute renal failure: protective or deleterious. Blood Purif 1997; 15:319–322. 96 Kellum JA: Use of diuretics in the acute care setting. Kidney Int Suppl 1998; 66:S67– S70.

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97 Lameire N, Vanholder R, Van Biesen W: Loop diuretics for patients with acute renal failure: helpful or harmful? JAMA 2002; 288:2599–2601. 98 Noble DW: Acute renal failure and diuretics: propensity, equipoise, and the need for a clinical trial (comment). Crit Care Med 2004;32:1794–1795. 99 Schetz M: Should we use diuretics in acute renal failure? Best Pract Res Clin Anaesthesiol 2004;18:75–89. 100 Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P: Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204–R212. 101 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;62:237–244.

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102 Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P: Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365:1231–1238. 103 Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL: Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol 2005; 16: 3046– 3052. 104 McIntyre LA, Fergusson DA, Cook DJ, Rankin N, Dhingra V, Granton S: Fluid resuscitation in the management of early septic shock (FINESS): a pilot randomized controlled trial (abstract). Am J Respir Crit Care Med 2008;in press.

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Nephron Exp Nephrol 2008;109:e109–e117 DOI: 10.1159/000142935

Published online: September 18, 2008

Antioxidants Do They Have a Place in the Prevention or Therapy of Acute Kidney Injury?

Jay L. Koyner a Roshan Sher Ali b Patrick T. Murray a, c, d a Section of Nephrology, Department of Medicine, University of Chicago, Chicago, Ill., b Department of Internal Medicine, Rochester General Hospital, Rochester, New York, N.Y., and c Department of Anesthesia and Critical Care, and d Committee on Clinical Pharmacology, University of Chicago, Chicago, Ill., USA

Key Words Acute kidney injury ⴢ Oxidative stress ⴢ Free radicals ⴢ Reactive oxygen metabolites ⴢ Anti-oxidants

Abstract Over the past several years, advances in our understanding of the pathogenesis of acute kidney injury (AKI) have demonstrated the role of oxidant stress and reactive oxygen metabolites (ROM) in the development of AKI in a variety of clinical settings. This review serves to define the pathways that lead to the generation of ROM following a variety of insults, as well as to review the current literature concerning the role of antioxidant therapy in the prevention and treatment of AKI in several clinical settings. Investigators have explored the potential therapeutic role of anti-oxidants in both experimental animal models and human studies of AKI in several clinical settings, including cardiac and aortic occlusive surgeries, sepsis, drug nephrotoxicity (cisplatin and gentamicin), as well as rhabdomyolysis. While the experimental animal studies have generally been more successful, taken together this literature supports the hypothesis that oxidant stress-induced production of ROM plays a major role in the pathogenesis of many forms of AKI, and continues to suggest the potential utility of antioxidant therapy in human AKI. Ongoing trials in concert with improved diagnostic techniques will hopefully lead to improved outcomes in the setting of AKI through the prophylactic or early therapeutic use of antioxidant therapy. Copyright © 2008 S. Karger AG, Basel

© 2008 S. Karger AG, Basel 1660–2129/08/1094–0109$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nee

Acute kidney injury (AKI) is a devastating and common problem in clinical medicine. Depending on the definition used, the incidence of AKI may vary from 5% in hospitalized patients to 30–50% of patients in ICU. Over the past several years, it has become increasingly clear that reactive oxygen metabolites (ROM) are important mediators in the pathogenesis of ischemic and toxic kidney injury. In this review, we will discuss the role of oxidant stress, production of ROM, and the subsequent imbalance between the pro- and anti-oxidant systems in the development and treatment of ischemic and nephrotoxic AKI.

Oxidant Mechanism

Oxidants have been thought to play a role in inflammation and tissue injury for over 35 years [1]. While much work still needs to be done in order to allow for prophylactic and therapeutic interventions in the setting of AKI, much of the oxidant stress pathway has been well documented and its role in cell injury is becoming increasingly evident. Oxygen normally accepts four electrons and is converted directly to water. The partial reduction of oxygen occurs in a variety of physiologic settings, including ischemia and reperfusion, and results in the generation of partially reduced and potentially toxic reactive oxygen intermediates (superoxide anion, hydrogen peroxide, hydroxyl radical) [2]. Patrick T. Murray, MD Section of Nephrology, MC 5100, Room-511 University of Chicago Hospitals, 5841 South Maryland Avenue Chicago, IL 60637 (USA) Tel. +1 773 834 0374, Fax +1 773 702 5818, E-Mail [email protected]

Fe3+ O2 l Fe2+ O2 Fe2+ H2O2 l Fe3+ OH OH O2 H2O2 l O2 OH OH

Fig. 1. Haber-Weiss reaction. See text for details.

Oxygen (O2) ] superoxide (O2–) ] hydrogen peroxide (H2O2) ] hydroxyl radical (OH–) ] water (H2O)

These reactions do not occur in isolation, and require a variety of substrates in order to further reduce these oxygen species. For example, the metabolism of hydrogen peroxide (H2O2) by the enzyme myeloperoxidase generates additional toxic products such as hypochlorous acid (HOCl). Additionally, H2O2 and superoxide are catalyzed by metals (such as iron) to play a role in the production of additional reactive oxidants [3]. Through a variety of mechanisms, these molecules are converted into metabolic intermediates that result in protein nitrosylation and cell damage via oxidant injury [4]. Iron plays a key role in this process as well; it is readily oxidized and reduced and can worsen injury via the catalyzation of chemical reactions that generate powerful oxidant species such as the hydroxyl radical (this is commonly referred to as the metal-catalyzed Haber-Weiss reaction, as displayed above in fig. 1) [3]. Finally, iron plays a major role in the initiation and propagation of lipid peroxidation, which produces hydroxyl radicals and perferryl iron – both of which are powerful ROMs [3]. Since iron can participate in the formation of these ROM, it is not surprising that humans (and most species) have evolved a complex system of transport and storage proteins (transferrin and ferritin) for iron. This mechanism serves to limit the size and exposure of the intracellular iron pool. The role of iron in the pathogenesis of acute and chronic kidney injury is still not completely understood and the subject of much ongoing investigation [5]. While this topic will be covered separately in the main edition of Nephron, it should be noted that recent advances have led to the discovery of plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) as a viable early biomarker of AKI in a variety of settings, including cardiac surgery and cisplatin toxicity [6–9]. Additionally, the recent recognition that NGAL is capable of capturing and depleting siderophores (small iron-binding molecules) has led to the theory that NGAL serves as a mediae110

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tor of iron shuttling between the intracellular and extracellular spaces [10]. The concordance of these two functions of NGAL (cytoprotective iron binding while acting as a marker of renal tubular injury) has further served to generate interest in the role of ROMs and iron in AKI. Oxidant stress has been implicated in the pathogenesis of AKI in several experimental models of ischemic or nephrotoxic AKI. Limited clinical data have supported the hypothesis that oxidant stress is an important contributor to the pathogenesis of AKI in several clinical settings. However, definitive proof that antioxidant therapy can prevent or ameliorate clinical AKI is still lacking. AKI following Cardiac and Aortic Occlusive Surgeries It has been long known that ischemia-reperfusion of the myocardium leads to a tremendous generation of ROM and cellular injury [11]. As a result, several groups have attempted to study renal function in the setting of elective surgeries where the renal ischemia-reperfusion insult can be quantified prospectively (e.g. cardiopulmonary bypass (CPB) in cardiothoracic surgery, or suprarenal aortic cross clamp during abdominal aortic aneurysm repair). Additionally, these clinical settings allow for the investigation of a variety of therapeutic and prophylactic interventions to prevent or ameliorate renal ischemia-reperfusion injury in randomized controlled clinical trials. AKI after CPB is common and is associated with increased morbidity, length of stay in the ICU and hospital, and mortality [12]. While it is clear that the pathogenesis of CPB-related AKI is multifactorial, oxidant stress is an important mechanism of renal injury; and as a result several trials of potential prophylactic and therapeutic antioxidant agents have been conducted. Haase et al. [14] conducted a randomized multi-blind placebo-controlled phase II trial of high-dose, weight-adjusted N-acetylcysteine (NAC) (300 mg/kg in 5% glucose) in high-risk patients undergoing CPB. NAC can directly scavenge ROM and reduce oxidative stress during CPB; it also regenerates the glutathione pool that is depleted during times of oxidative stress. In this trial, 61 subjects who were at high risk for the development of AKI (age 170, insulin-dependent diabetes, repeat cardiac surgery, class 3 or 4 heart failure or the presence of CKD) were randomized to high-dose NAC or placebo, with the primary end point being absolute change in serum creatinine within the first 5 postoperative days. The study failed to demonstrate a difference in the serum creatinine in this early postoperative period. Additionally, there was no difference in the urine output for the first 48 h, levels Koyner /Sher Ali /Murray

of serum cystatin C (another GFR marker) in the first 5 postoperative days or any major clinical outcome (length of ventilation, length of ICU or hospital stay) [14]. It is a strength of this study that serum cystatin C was used in addition to serum creatinine to monitor renal function, since NAC has been shown to alter serum creatinine levels independent of GFR, probably by decreasing CPKmediated production of creatinine from muscle [15] (although a recent study calls this aspect of NACs physiologic activity into doubt) [16]. Unfortunately, the study was underpowered, and could simply have been a falsenegative trial. Similar to the Haase study, Lassnigg et al. [17] performed a randomized double-blind placebo-controlled trial investigating the role of intravenous vitamin E supplementation in reducing ischemia-reperfusion injury after elective cardiac surgery. While this study was designed to detect differences in a variety of biochemical markers of oxidative stress (malondialdehyde, creatine kinase, interleukin (IL) 6 in the presence of absence of 4 perioperative doses of 270 mg of vitamin E, it did not demonstrate any difference in these levels, nor did it demonstrate any difference in the rates of AKI [17]. Finally, mannitol has been investigated as a therapeutic option to decrease the ROM load following adult cardiac surgery. Mannitol was chosen in large part because of its free radical scavenging ability; as a polyol (sugar alcohol), mannitol readily donates a hydrogen ion and decreases ROMs. Larsen et al. [18] conducted a randomized, double-blind, controlled trial investigating the effect of mannitol in the cardioplegia fluid on serum malondialdehyde levels (a surrogate for ROMs) following cardiac surgery. They randomized 33 adults to receive standard therapy or mannitol (4 or 8 g/l) as part of their cardiopulmonary bypass regimen. While they were unable to show any statistically significant difference between the postoperative malondialdehyde levels in the three groups, there was a dose-dependent trend towards lower malondialdehyde levels in those subjects receiving the higher dose of mannitol [18]. Burns et al. [19] conducted a randomized, quadrupleblind placebo-controlled trial investigating the role of intravenous NAC in preserving renal function in high-risk adults undergoing cardiac bypass surgery with CPB. 295 study subjects were randomized to receive either 4 doses (2 intra-operatively, 2 postoperatively) of 600 mg of intravenous (i.v.) NAC or placebo. AKI was defined as an increase in serum creatinine of 10.5 mg/dl or a 625% increase from preoperative baseline within the first 5 postoperative days. This negative trial showed no difference

in the rate of AKI (NAC 29.7% vs. placebo 29.0%, p = 0.89). Additionally, there was no difference in postoperative morbidity (including need for RRT) or mortality (NAC 3.4% vs. placebo 2.4%; p = 0.99) [19]. Similarly, Ristikankare et al. [20] performed a small prospective randomized double-blind study to investigate the role of i.v. NAC in reducing the rate of CPB-induced AKI in patients with chronic kidney disease. This 80-subject study failed to demonstrate a difference between NAC and placebo, despite measuring several markers of renal function and injury including plasma creatinine, serum cystatin C, and urinary N-acetyl-␤-D-glucosaminidase (NAG). Finally, El-Hamamsy et al. [21] conducted a randomized doubleblind, placebo-controlled trial in 100 subjects to investigate the role of intravenous NAC in reducing the production of ROMs following adult cardiac surgery. The primary end point of this trial was the release of cardiac troponin T within the first 24 postoperative hours; additional end points included renal function, creatine kinase levels, arrhythmias and IL-6 production. The study found no difference in clinical outcomes (AKI) or biomarker activity (IL-6, troponin, etc.) between the two groups [21]. Prophylactic use of antioxidant therapies during aortic occlusive surgery has been similarly unsuccessful in clinical trials. Hynninen et al. [22] conducted a prospective, randomized, placebo-controlled, double-blind trial to study the effects of continuous i.v. NAC (24 h) for the prevention of AKI in patients undergoing abdominal aortic surgery. The primary end point of this study was AKI as measured by the urinary excretion of AKI markers NAG/urine creatinine ratio or the urine albumin/ urine creatinine. In this trial of 69 subjects (34 randomized to receive NAC, 35 to placebo), there was no difference in these urinary markers of AKI, as well as no difference in the plasma creatinine and serum cystatin C during the postoperative period. NAC did not offer any significant protection against AKI or any other postoperative clinical outcome. Similarly, Macedo et al. [23] conducted a randomized double-blind, placebo-controlled trial investigating the role of oral and i.v. NAC (1,200 mg p.o. b.i.d. the day prior to the operation and 600 mg i.v. b.i.d. for the first 48 postoperative hours) in preventing AKI (defined as a 625% increase in preoperative creatinine within the first 72 postoperative hours) following elective abdominal aortic aneurysm (AAA) repair. This trial studied 42 subjects and did not find a benefit of NAC when looking at AKI rates, mortality, peak creatine kinase level or length of ICU stay (p = NS for all). Moore et al. [24] were similarly unable to demonstrate any benefit when investigating the role of oral NAC in

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preventing AKI in a randomized controlled trial of 20 individuals undergoing elective endovascular AAA repair. In contrast to the results of Lassnigg et al. [17] in cardiac surgery, Wijnen et al. [25] found a decrease in serum levels of creatine kinase, aspartate aminotransferase and lipofuscine levels in individuals undergoing infrarenal AAA repair who received preoperative supplementation with multiple antioxidants (vitamins E and C, allopurinol, NAC and mannitol). In this small (n = 42) prospective randomized trial, they did not examine renal biomarkers or AKI, and the exact mechanism that led to the decrease in the oxidant stress biomarkers is unclear. While not tested in humans to date, there are compelling data from experimental animal models regarding the role of heme-oxygenase induction in preventing AKI and decreasing oxidant stress [26]. Briefly, heme-oygenase-1 is an enzyme that is capable of converting heme into carbon monoxide (CO), iron, and biliverdin (which is in turn reduced to bilirubin by biliverdin reductase) [26]. This degradation of heme into CO (which has the added benefit of inhibiting nitric oxide synthesis) and bilirubin is considered to be protective against oxidant stress and ROMs, and has led to exploration of its role in reducing the impact of ischemia-reperfusion-induced AKI [27]. Salom et al. [26] employed a rodent model of ischemia and demonstrated that the induction of heme oxygenase1 (via the use of cobalt chloride) 24 h prior to ischemic AKI led to a reduction in AKI, along with reduced oxidant stress as measured by NO and peroxynitrite levels, and these findings were reversed in the presence of a heme-oxygenase inhibitor (stannous mesoporphyrin). In summary, despite the conduct of several studies, no antioxidant drug has been shown to be of benefit for prevention or therapy of AKI in patients undergoing cardiac or aortic occlusive surgery.

Sepsis and Critically Ill Patients

While the role of ROMs have been long recognized as the potential source of injury in the setting of cardiac surgery-associated AKI, increasing evidence is pointing to the role of oxidative stress in the setting of septic and critical illness-related AKI. Starkopf et al. [28] measured lipid peroxidation products (thiobarbituric acid reactive substances and diene conjugates) and markers of blood antioxidant status (serum antioxidant capacity and red blood cell glutathione) in 12 cardiac surgery patients and 10 septic patients. They demonstrated that the increase in e112

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lipid peroxidation levels and decrease in serum antioxidative capacity induced by sepsis was comparable to that developing in patients undergoing cardiac surgery. Himmelfarb et al. [29] assayed the concentrations of a select group of oxidative stress biomarkers in the setting of AKI. In their retrospective analysis of PICARD study (Program to Improve Care in Acute Renal Disease) samples, they compared plasma levels of protein thiol (a marker for the ability to perform reduction reactions and a surrogate for total antioxidant capacity) and protein carbonyl (an index of oxidative injury) between patients with AKI, critically ill subjects without AKI, patients with end-stage renal disease (ESRD), and healthy controls. This landmark paper clearly demonstrated that thiol concentrations were significantly lower in those with AKI compared to those critically ill subjects without AKI (p ! 0.001). Similarly, plasma protein carbonyl was significantly elevated in the AKI group when compared to both the critically ill without AKI or healthy controls (p ! 0.001 for both). This paper was one of the first to clearly document the association of increased oxidative stress with the development and outcome of AKI in critically ill patients. To further investigate the role of oxidative stress in the pathogenesis and outcome of AKI, Perianayagam et al. [30] examined the effect of variability in oxidative stress genes on the development and severity of AKI. Recognizing that polymorphisms in the genes that code for NADPH oxidase p22phox and catalase have been shown to alter gene expression and enzyme activity, respectively, they sought to demonstrate the role of these variants in AKI patient outcomes. Through the prospective analysis of the DNA of 200 hospitalized subjects with AKI, they showed that those with a T allele at position +242 in the NADPH oxidase p22phox gene were at a 2-fold increased risk of requiring renal replacement therapy (RRT) or hospital death (p = 0.01). This association persisted even when controlling for age, race, gender and severity of illness scores (p = 0.01). Similarly, a T allele at position –262 in the catalase gene was associated with decreased wholeblood catalase activity (p ! 0.001) [30]. It should be noted that study limitations including the combined analysis of Caucasians and African-Americans, as well as the relatively small sample size (to dissect complex disease genetics), only underscore the need for larger studies to confirm these interesting findings. Cisplatin Cisplatin is an important anti-neoplastic drug for the treatment of solid tumors, but its clinical use is limited Koyner /Sher Ali /Murray

creased the concentrations of carbonylated proteins, and had cytoprotective properties in murine proximal tubular cells. Although another study reported similar renal protective effects in rats [36], this agent has been linked to the development of AKI following its use human studies treating stroke [37]. There is, however, one FDAapproved agent for the reduction of cumulative renal toxicity in patients receiving cisplatin, an organic thiophosphate called amifostine. Amifostine decreases nephrotoxicity by donating protective thiol groups; unfortunately, this agent’s use is limited by a variety of factors including its cost, side effect profile, and concerns that its use could interfere with the antitumor effects of cisplatin [38].

secondary to dose-dependent renal toxicity. Cisplatin nephrotoxicity involves oxidative stress, apoptosis, inflammation and fibrogenesis. Using a rodent model, Santos et al. [31] demonstrated that cisplatin induces mitochondrial dysfunction as measured by a decline in membrane electrochemical potential, as well as decreased mitochondrial calcium uptake. Additionally, cisplatin depleted the kidney’s antioxidant defense by decreasing levels of reduced glutathione and NADPH. Finally, cisplatin induced oxidative damage to mitochondrial lipids as demonstrated by an increase in the concentration of carbonylated proteins and a decrease in sulfhydryl protein concentrations [31]. Several animal models have attempted to utilize antioxidant strategies to attenuate cisplatin nephrotoxicity. Ajith et al. [32] conducted a comparative study of the effects of vitamin C (ascorbic acid) and vitamin E (␣-tocopherol) on cisplatin (10 mg/kg)-induced nephrotoxicity in mice. Both vitamins have known anti-oxidant properties, and the experiment was designed to expose the animals to high and low doses of both vitamins C and E (250 and 500 mg/kg of each). The vitamins were administered 1, 24 and 48 h after cisplatin injection. Higher doses of both vitamins were effective in protecting against oxidative renal damage, as measured by increasing superoxide dismutase (SOD) and reduced glutathione activity, with vitamin C outperforming vitamin E [32]. Similarly, Lynch et al. [33] demonstrated in a rodent model that cisplatin (16 mg/kg) nephrotoxicity could be attenuated by the use of allopurinol (xanthine oxidase inhibitor) and ebselen (seleno-organic drug, glutathione mimic and free radical scavenger). Their rat model demonstrated that the combination of allopurinol and ebselen outperformed each drug individually, and led to a significant decrease in post-cisplatin serum creatinine (p ! 0.05) and blood urea nitrogen (p ! 0.01) elevations when compared to those animals which received the cisplatin with vehicle [33]. Several other agents have been proposed as giving effective protection against cisplatin renal injury. Iron has been implicated in several models of tissue injury, including cisplatin toxicity, through the generation of hydroxyl radicals via the Haber-Weiss reaction (see fig. 1). In a rat model, the iron chelator deferoxamine has been shown to provide functional (as measured by blood urea nitrogen and creatinine) and histological protection against cisplatin-induced renal injury [34]. Edaravone, a free radical scavenger, has also been investigated as a potential prophylactic therapy for cisplatin nephrotoxicity. Satoh et al. [35] demonstrated that Edaravone attenuated the cisplatin-induced mitochondrial membrane potential loss, de-

Gentamicin-Induced Nephrotoxicity Aminoglycoside antibiotics are an integral therapeutic agent in the treatment of Gram-negative bacterial infections. Unfortunately, their use is somewhat limited by nephrotoxicity (which occurs in 10–15% of cases) and ototoxicity (in approximately 3–25% of patients) [39]. While gentamicin and other aminoglycosides have been studied extensively, the biochemical and cellular basis of their nephrotoxicity is not completely understood. It is evident that gentamicin leads to the disruption of the proximal convoluted tubule and interferes with critical cellular processes through several mechanisms, including oxidant injury. In vivo and in vitro, gentamicin enhances the generation of ROMs by altering mitochondria respiration, leading to the generation of H2O2 [40]. Additionally, gentamicin enhances the generation of superoxide anion and hydroxyl radical by renal cortical mitochondria. Finally, gentamicin induces the release of iron from these same renal cortical mitochondria; this causes lipid peroxidation in vitro, with iron serving as a potent catalyst for free radical formation [40]. Similar to cisplatin nephrotoxicity, many prophylactic and therapeutic experimental animal studies have demonstrated the ability to attenuate gentamicin-induced renal failure. Zurovsky and Haber [41] injected endotoxin and/or gentamicin into rats, and then subsequently administered vitamin E or dimethylthiourea (a potent scavenger of hydroxyl radicals); they demonstrated that both agents were effective in preserving renal function, as well as arresting the progressive renal damage associated with gentamicin toxicity. Kopple et al. [42] investigated the role L-carnitine, an anti-oxidant that prevents the accumulation of end products of lipid peroxidation, in the setting of a rat model of gentamicin-induced AKI. Using varying doses of gentamicin (50 and 80 mg/kg/day) and

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L-carnitine (40 or 200 mg/kg/day), they demonstrated that L-carnitine improved renal function and ameliorated the severity of renal pathologic findings in a dose-dependent manner [42]. Despite this success in experimental models, neither of these likely readily tolerable interventions have translated into a change in the clinical practice. Similarly, several more novel agents including kallikrein/kinin [43], Silymarin (the mixture of flavonolignans extracted from Silybum marianum) [44], Spirulina fusiformis (a blue-green algae with potent free radical scavenging properties) [45] and Ebselen [46] have shown promise in their ability to decrease gentamicin-induced AKI in animal models, but none has yet translated into successful human trials. Feldman et al. [47] conducted a prospective randomized controlled open label trial investigating the role of N-acetyl cysteine (NAC) to prevent gentamicin-induced hearing loss in the setting of ESRD. While the exact mechanism of ototoxicity is different from that of nephrotoxicity, it should be noted that their common pathogenesis includes oxidative stress and reactive oxygen species. The trial in 53 chronic hemodialysis patients demonstrated that giving NAC (600 mg by mouth twice a day) decreased the rate of ototoxicity at both 1 and 6 weeks (41.6% reduction p = 0.025). Similarly, although Mazzon et al. [48] demonstrated a renoprotective effect of NAC on gentamicin-induced nephrotoxicity in rats, to date there are no studies demonstrating decreased nephrotoxicity with NAC in humans. Finally, there are animal studies demonstrating benefits of iron chelation (deferoxamine) in the setting of aminoglycoside-induced ototoxicity [49], although these too have not translated into successful clinical trials.

Rhabdomyolysis Rhabdomyolysis is an important cause of AKI, especially in trauma patients; the renal injury stems from the toxicity of myoglobin and other intracellular molecules released from damaged myocytes, usually in combination with hypovolemia. Due to the inherent difficulty of performing a clinical trial in natural disaster and trauma victims, much of the research performed in this field uses animal models of myoglobinuric AKI. The most common in vivo model is induced by the intramuscular injection of hypertonic glycerol; this model has been shown to enhance the generation of hydrogen peroxide, associated with lipid peroxidation and depletion of reduced glutathione stores [50]. As a direct result of these pathophysiologic findings, several antioxidant agents have been studied in this model. e114

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Aydogdu et al. [51] investigated the potential utility of in a rat model of myoglobinuric AKI. They demonstrated that L-carnitine significantly decreased creatine phosphokinase (CPK) levels (p ! 0.05), serum creatinine (p ! 0.001), serum urea (p ! 0.001), and nitric oxide (p ! 0.001) levels compared to glycerol-induced AKI with placebo therapy. Additionally, histopathologically the L-carnitine-treated animals demonstrated less necrosis and cast formation (p ! 0.001 for both), as well as less iron accumulation (p ! 0.01) [51]. Similarly, Rodrigo et al. [52] investigated the role of natural anti-oxidants (flavonol-rich red wine) in preventing glycerol-induced AKI. In their rat model, they demonstrated that the antioxidant properties of red wine polyphenols led to a decrease in CPK levels, along with reductions in the expression of catalase, glutathione peroxidase and SOD [51]. While these studies have succeeded in animal models, they have yet to be translated into clinical trials or practice. The current standard of care for treating rhabdomyolysis, regardless of its cause (which can be quite varied), involves initial aggressive fluid resuscitation with saline, followed by forced urinary alkalinization once volume repletion is achieved. In the setting of a successful saline resuscitation, several studies have attempted to show an additional benefit of initiating forced urinary alkalinization. Through the administration mannitol-bicarbonate intravenous solutions, urine alkalinization may prevent the precipitation of the heme-pigment casts and thus prevent tubular obstruction and AKI. This effect is in part mediated by maintaining urinary flow and preventing tubular obstruction; but additional effects of myoglobin solubility and antioxidant effects are also likely important benefits of this approach. Urinary alkalinization increases the solubility of myoglobin, decreasing cast formation. As noted above, mannitol possesses antioxidant free radical scavenging activity, and it appears that sodium bicarbonate may similarly have antioxidant effects. Sodium bicarbonate has a pKa of 6.3, so it is often used to induce urinary alkalinization; it is also physiologically abundant and readily dissociable. There have been multiple reports of the anti-oxidant properties of bicarbonate, which is thought to play a role in the oxidant stress pathway, presumably due to its ability to catalyze the conversion of hydrogen peroxide (H2O2) into water and oxygen – a catalase-like reaction [53, 54]. In reality, these reports are tangential and relate to the bicarbonate anion’s ability to buffer the catalase-like reaction with a variety of elements (e.g. iron and manganese) capable of helping to convert hydrogen peroxide to oxygen and water withL-carnitine

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out the release of harmful ROMs [55]. Of additional relevance in protection against nephrotoxicity in rhabdomyolysis, it is thought that bicarbonate’s alkalinization helps to prevent the dissociation of free iron from myoglobin [56]. Animal models have shown that in the setting of experimental traumatic rhabdomyolysis, despite lowering systemic pH, a hypertonic combination of 0.9% saline, sodium bicarbonate and mannitol reduces tissue injury/ markers of oxidant stress (as measured by malondialdehyde (MDA) and glutathione levels) and restores renal blood flow better than 0.9% saline alone, or hypertonic (7.5%) saline. Additionally, while there was a significant decrease in the measures of oxidant stress in all three groups (0.9% saline/bicarbonate/mannitol, 0.9% saline alone and 7.5% hypertonic saline) compared to controls and shams, there was a further significant reduction in the MDA levels between the 0.9% saline/bicarbonate/ mannitol and both the 0.9% saline and 7.5% saline groups (p ! 0.05). This decreased measure of oxidant stress was found despite the combination treatment yielding a lower pH compared to the other fluid and control arms [57]. Unfortunately, these animal data have not been replicated in human studies. In a retrospective review of 382 trauma ICU admissions with abnormal creatine kinase levels, Brown et al. [58] did not find that bicarbonate and mannitol improved the AKI rate or mortality in patients with rhabdomyolysis (creatine kinase level greater than 5,000 unit/l). The use of these agents is additionally complicated by their multiple toxicities (worsening of hypocalcemia, hypokalemia, hyperosmolality). Unfortunately, despite compelling evidence from experimental models, the proposed additional benefits of urinary alkalinization or mannitol therapy beyond volume expansion with saline in the treatment of rhabdomyolysis remain unproven by comparative clinical trials. Further underscoring the important role of oxidant injury in the pathogenesis of myoglobinuric nephrotoxicity, animal models of rhabdomyolysis have demonstrated

References

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the role of heme oxygenase-1 in preventing AKI and reducing ROMs. In 1992, Nath et al. [59] used a rodent model of glycerol-induced rhabdomyolysis to demonstrate that the kidney responds to the overwhelming burden of heme via the induction of the heme oxygenase as well as the synthesis of ferritin. This was the first in vivo evidence that induction of heme oxygenase coupled to ferritin synthesis is a protective antioxidant response, suggesting a therapeutic strategy for populations at a high risk for rhabdomyolysis [59]. Unfortunately, this work has not yet been translated into clinical studies.

Conclusion

This review demonstrates that while the causative agent(s) in acute kidney injury may differ, oxidant stress has been shown to play a role in the development of the renal injury in a variety of experimental and clinical settings. Additionally, across several causes of AKI there is clear evidence pointing to the potential utility of antioxidants (free radical scavengers, iron chelators, or possibly even simple intravenous fluid with bicarbonate or mannitol) in the treatment and prevention of AKI. While there is a wealth of ‘positive’ studies in experimental animal models, they have not translated to success in therapeutic human trials. This failure is due, in part, to the lack of clinically useful biomarkers to diagnose the early presence and likely severity of AKI. It is our belief that the improved early diagnosis of AKI via NGAL (perhaps specifically) and other novel biomarkers will aid in the design and conduct of multiple prophylactic and early therapeutic clinical trials in human AKI. With further investigation, we anticipate that these trials will disclose more details regarding the roles of anti-oxidants in AKI, and will translate to success in preventing and treating AKI related to oxidant stress in a variety of clinical settings.

1 Shah SV, Baliga R, Rajapurkar M, et al: Oxidants in chronic kidney disease. J Am Soc Nephrol 2007; 18:16–28. 2 Fridovich I: The biology of oxygen radicals. Science 1978;201:875–880. 3 Halliwell B, Gutteridge J: Role of free radicals and catalytic metal ions in human disease: an overview. Meth Enzymol 1990; 186: 1–85.

4 Siegel NJ, Devarajan P: Pathogenesis of acute renal failure; in Avner HW, Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 1223–1232. 5 Swaminathan S, Shah SV: Novel approaches targeted toward oxidative stress for the treatment of chronic kidney disease. Curr Opin Nephrol Hypertens 2008; 17:143–148.

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6 Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, et al: Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions. Am J Nephrol 2006; 26:287–292. 7 Mishra J, Dent C, Tarabishi R, et al: Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005; 365: 1231– 1238. 8 Mishra J, Mori K, Ma Q, et al: Neutrophil gelatinase-associated lipocalin: a novel early urinary biomarker for Cisplatin nephrotoxicity. Am J Nephrol 2004; 24:307–315. 9 Parikh CR, Jani A, Mishra J, et al: Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation. Am J Transplant 2006; 6: 1639–1645. 10 Schmidt-Ott KM, Mori K, Li JY, et al: Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 2007; 18: 407– 413. 11 Hearse DJ, Humphrey SM, Bullock GR: The oxygen paradox and the calcium paradox: two facets of the same problem? J Mol Cell Cardiol 1978; 10:641–668. 12 Chertow G, Levy E, Hammermeister K, et al: Independent association between acute renal failure and mortality following cardiac surgery. Am J Med 1998;104:343–348. 13 Sucu N, Cinel I, Unlu A, et al: N-acetylcysteine for preventing pump-induced oxidoinflammatory response during cardiopulmonary bypass. Surg Today 2004; 34: 237–242. 14 Haase M, Haase-Fielitz A, Bagshaw SM, et al: Phase II, randomized, controlled trial of high-dose N-acetylcysteine in high-risk cardiac surgery patients. Crit Care Med 2007;35: 1324–1331. 15 Hoffmann U, Fischereder M, Kruger B, et al: The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol 2004;15:407–410. 16 Haase M, Haase-Fielitz A, Ratnaike S, et al: N-acetylcysteine does not artifactually lower plasma creatinine concentration. Nephrol Dial Transplant 2008;17:17. 17 Lassnigg A, Punz A, Barker R, et al: Influence of intravenous vitamin E supplementation in cardiac surgery on oxidative stress: a double-blinded, randomized, controlled study. Br J Anaesth 2003;90:148–154. 18 Larsen M, Webb G, Kennington S, et al: Mannitol in cardioplegia as an oxygen free radical scavenger measured by malondialdehyde. Perfusion 2002;17:51–55. 19 Burns KE, Chu MW, Novick RJ, et al: Perioperative N-acetylcysteine to prevent renal dysfunction in high-risk patients undergoing cabg surgery: a randomized controlled trial. JAMA 2005;294:342–350.

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20 Ristikankare A, Kuitunen T, Kuitunen A, et al: Lack of renoprotective effect of i.v. N-acetylcysteine in patients with chronic renal failure undergoing cardiac surgery. Br J Anaesth 2006;97:611–616. 21 El-Hamamsy I, Stevens LM, Carrier M, et al: Effect of intravenous N-acetylcysteine on outcomes after coronary artery bypass surgery: a randomized, double-blind, placebocontrolled clinical trial. J Thorac Cardiovasc Surg 2007;133:7–12. 22 Hynninen MS, Niemi TT, Pöyhiä R, et al: Nacetylcysteine for the prevention of kidney injury in abdominal aortic surgery: a randomized, double-blind, placebo-controlled trial. Anesth Analg 2006;102:1638–1645. 23 Macedo E, Abdulkader R, Castro I, et al: Lack of protection of N-acetylcysteine (NAC) in acute renal failure related to elective aortic aneurysm repair: a randomized controlled trial. Nephrol Dial Transplant 2006: 21: 1863–1869. 24 Moore NN, Lapsley M, Norden AG, et al: Does N-acetylcysteine prevent contrast-induced nephropathy during endovascular AAA repair? A randomized controlled pilot study. J Endovasc Ther 2006; 13:660–666. 25 Wijnen MH, Roumen RM, Vader HL, et al: A multiantioxidant supplementation reduces damage from ischaemia reperfusion in patients after lower torso ischaemia: a randomised trial. Eur J Vasc Endovasc Surg 2002;23:486–490. 26 Salom MG, Ceron SN, Rodriguez F, et al: Heme oxygenase-1 induction improves ischemic renal failure: role of nitric oxide and peroxynitrite. Am J Physiol Heart Circ Physiol 2007;293:H3542–H3549. 27 Akagi R, Takahashi T, Sassa S: Fundamental role of heme oxygenase in the protection against ischemic acute renal failure. Jpn J Pharmacol 2002;88:127–132. 28 Starkopf J, Zilmer K, Vihalemm T, et al: Time course of oxidative stress during open-heart surgery. Scand J Thorac Cardiovasc Surg 1995;29:181–186. 29 Himmelfarb J, McMonagle E, Freedman S, et al: Oxidative stress is increased in critically ill patients with acute renal failure. J Am Soc Nephrol 2004; 15:2449–2456. 30 Perianayagam MC, Liangos O, Kolyada AY, et al: NADPH oxidase p22phox and catalase gene variants are associated with biomarkers of oxidative stress and adverse outcomes in acute renal failure. J Am Soc Nephrol 2007; 18:255–263. 31 Santos NA, Catao CS, Martins NM, et al: Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Arch Toxicol 2007;81:495–504. 32 Ajith TA, Usha S, Nivitha V: Ascorbic acid and alpha-tocopherol protect anticancer drug cisplatin induced nephrotoxicity in mice: a comparative study. Clin Chim Acta 2007;375:82–86.

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33 Lynch ED, Gu R, Pierce C, et al: Reduction of acute cisplatin ototoxicity and nephrotoxicity in rats by oral administration of allopurinol and ebselen. Hear Res 2005;201:81–89. 34 Baliga R, Zhang Z, Baliga M, et al: In vitro and in vivo evidence suggesting a role for iron in cisplatin-induced nephrotoxicity. Kidney Int 1998;53:394–401. 35 Satoh M, Kashihara N, Fujimoto S, et al: A novel free radical scavenger, edarabone, protects against cisplatin-induced acute renal damage in vitro and in vivo. J Pharmacol Exp Ther 2003;305:1183–1190. 36 Iguchi T, Nishikawa M, Chang B, et al: Edaravone inhibits acute renal injury and cyst formation in cisplatin-treated rat kidney. Free Radic Res 2004;38:333–341. 37 Hishida A: Clinical analysis of 207 patients who developed renal disorders during or after treatment with edaravone reported during post-marketing surveillance. Clin Exp Nephrol 2007; 11:292–296. 38 Capizzi RL: Amifostine reduces the incidence of cumulative nephrotoxicity from cisplatin: laboratory and clinical aspects. Semin Oncol 1999;26(2 suppl 7):72–81. 39 Humes HD: Aminoglycoside nephrotoxicity. Kidney Int 1988;33:900–911. 40 Walker P, Barri Y, Shah S: Oxidant mechanisms in gentamicin nephrotoxicity. Renal Failure 1999;21:433–442. 41 Zurovsky Y, Haber C: Antioxidants attenuate endotoxin-gentamicin induced acute renal failure in rats. Scand J Urol Nephrol 1995; 29:147–154. 42 Kopple JD, Ding H, Letoha A, et al: L-Carnitine ameliorates gentamicin-induced renal injury in rats. Nephrol Dial Transplant 2002; 17:2122–2131. 43 Bledsoe G, Crickman S, Mao J, et al: Kallikrein/kinin protects against gentamicin-induced nephrotoxicity by inhibition of inflammation and apoptosis. Nephrol Dial Transplant 2006;21:624–633. 44 Varzi HN, Esmailzadeh S, Morovvati H, et al: Effect of silymarin and vitamin E on gentamicin-induced nephrotoxicity in dogs. J Vet Pharmacol Ther 2007;30:477–481. 45 Kuhad A, Tirkey N, Pilkhwal S, et al: Effect of Spirulina, a blue green algae, on gentamicin-induced oxidative stress and renal dysfunction in rats. Fundam Clin Pharmacol 2006;20:121–128. 46 Dhanarajan R, Abraham P, Isaac B: Protective effect of Ebselen, a selenoorganic drug, against gentamicin-induced renal damage in rats. Basic Clin Pharmacol Toxicol 2006; 99: 267–272. 47 Feldman L, Efrati S, Eviatar E, et al: Gentamicin-induced ototoxicity in hemodialysis patients is ameliorated by N-acetylcysteine. Kidney Int 2007;72: 359–363. 48 Mazzon E, Britti D, De Sarro A, et al: Effect of N-acetylcysteine on gentamicin-mediated nephropathy in rats. Eur J Pharmacol 2001; 424:75–83.

Koyner /Sher Ali /Murray

49 Mostafa BE, Tawfik S, Hefnawi NG, et al: The role of deferoxamine in the prevention of gentamicin ototoxicity: a histological and audiological study in guinea pigs. Acta Otolaryngol 2007;127:234–239. 50 Baliga R, Ueda N, Walker PD, et al: Oxidant mechanisms in toxic acute renal failure. Am J Kidney Dis 1997;29:465–477. 51 Aydogdu N, Atmaca G, Yalcin O, et al: Protective effects of L-carnitine on myoglobinuric acute renal failure in rats. Clin Exp Pharmacol Physiol 2006;33:119–124. 52 Rodrigo R, Bosco C, Herrera P, et al: Amelioration of myoglobinuric renal damage in rats by chronic exposure to flavonol-rich red wine. Nephrol Dial Transplant 2004; 19: 2237–2244.

Antioxidants

53 Merten GJ, Burgess WP, Gray LV, et al: Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA 2004; 291: 2328– 2334. 54 Bouzas-Mosquera A, Recio-Mayoral A: Sodium bicarbonate, N-acetylcysteine, and saline for the prevention of contrast-induced nephropathy. Am Heart J 2008; 155:e31. 55 Stadtman ER, Berlett BS, Chock PB: Manganese-dependent disproportionation of hydrogen peroxide in bicarbonate buffer. Proc Natl Acad Sci USA 1990;87:384–388.

56 Zager RA: Rhabdomyolysis and myohemoglobinuric acute renal failure. Kidney Int 1996;49:314–326. 57 Ozguc H, Kahveci N, Akkose S, et al: Effects of different resuscitation fluids on tissue blood flow and oxidant injury in experimental rhabdomyolysis. Crit Care Med 2005; 33: 2579–2586. 58 Brown CV, Rhee P, Chan L, et al: Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference? J Trauma 2004;56:1191–1196. 59 Nath KA, Balla G, Vercellotti GM, et al: Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat. J Clin Invest 1992;90:267–270.

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Nephron Physiol 2008;109:p80–p84 DOI: 10.1159/000142940

Published online: September 18, 2008

Distant-Organ Changes after Acute Kidney Injury Carolyn M. Feltes Jennifer Van Eyk Hamid Rabb Departments of Anesthesia and Critical Care Medicine, and Medicine, Johns Hopkins University School of Medicine, Baltimore, Md., USA

Key Words Kidney ⴢ Lung ⴢ Inflammation ⴢ Critical care ⴢ Cytokines ⴢ Leukocytes

Abstract Acute kidney injury (AKI) contributes significantly to morbidity and mortality in both adults and children. While clinical data suggest that AKI contributes to and exacerbates multiorgan failure, the physiologic and molecular mechanisms responsible for these interactions were previously unknown. New data linking AKI with distant-organ dysfunction includes evidence that inflammatory cascades are abnormal after organ injury. Leukocyte trafficking, cytokine expression, cell adhesion-molecule expression and membrane ion and water-channel expression in distant organs are deranged after kidney injury. The responses to oxidative stress after AKI are also altered, suggesting complex mechanisms of crosstalk between the injured kidney and distant organs. Novel methodologies, including genomics and proteomics, are now being employed to unravel interorgan communication to accelerate clinically meaningful discovery for this serious disease. Copyright © 2008 S. Karger AG, Basel

© 2008 S. Karger AG, Basel 1660–2137/08/1094–0080$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nep

Introduction

Acute kidney injury (AKI, as defined in [1]) occurs frequently in critically ill patients and is a crucial contributor to morbidity and mortality in both adults and children [2]. The severity of AKI is associated with increased ICU mortality and length of stay, as well as significantly higher levels of care involving invasive measures like mechanical ventilation [3, 4]. AKI rarely occurs in isolation, and often affects the patient with concomitant diseases or injuries. Patients with only modest rises in serum creatinine (!0.5 mg/dl change from baseline) have significant increases in 30-day mortality after cardiothoracic surgery compared to those patients with no renal injury; if the serum creatinine change is greater than 0.5 mg/dl, the mortality risk increases 18-fold [5]. After percutaneous cardiac catheterization, patients with AKI have higher complication rates, including myocardial infarction and increased long-term mortality [6]. In trauma patients, development of AKI after injury predicts worse outcome, and was in fact the only significant risk factor predictive of ICU and overall hospital mortality in one study [7]. Oliguria and increases in serum creatinine greater than 85% above baseline have also been associated with more difficult weaning from mechanical ventilation in an adult ICU setting [8]. While clinical data suggest that AKI contributes to the development and exacerbation of multiorgan failure, the H. Rabb, MD Ross 965, Johns Hopkins Hospital 720 Rutland Ave Baltimore, MD 21205 (USA) Tel. +1 410 502 1555, Fax +1 410 614 5129, E-Mail [email protected]

physiologic and molecular mechanisms responsible for these interactions were previously unknown. This brief review summarizes the new mechanistic data linking AKI with distant-organ dysfunction. We will provide a concise overview of the evidence concerning derangement of the immunologic and inflammatory cascades as well as the response to oxidative stress after AKI, and their potential roles in kidney – distant-organ crosstalk. Finally, we will discuss some novel methodologies and areas of investigation that could prove beneficial in future studies.

Leukocyte Activation and Trafficking

Several recent experimental studies using rodent renal ischemia-reperfusion injury (IRI) models have demonstrated that distant-organ leukocyte trafficking occurs after AKI. In experiments utilizing a 45-min unilateral renal IRI model in mice, flow cytometric analysis demonstrated neutrophil infiltration in the damaged kidney as well as in several nonischemic organs, including the contralateral kidney, liver and spleen, starting within 60 min of injury [9]. Intermediate T cells, which constitutively express IL-2R␤ and an intermediate density of the TCR-CD3 complex, allowing for potential forbidden clones showing self-reactivity, were also evaluated. Interestingly, increased numbers of intermediate T cells were found in the injured kidney as well as the liver, spleen and contra-lateral kidney within 3 h of injury. Within these intermediate T cell populations, there were increased percentages of forbidden clones compared with sham animals, as well as an increased percentage of cells expressing the Fas ligand. In a more recent study, AKI in several models (60 min bilateral IR, bilateral nephrectomy or bilateral pedicle ligation) induced pulmonary injury and neutrophil infiltration that was similar in nature (although to a lesser degree) to that induced by sepsis [10]. Using a permanent unilateral kidney vessel clamp model in rats, macrophage infiltration and cellular proliferation in distant organs after AKI has also been examined [11]. Kidney injury resulted in increased macrophage localization in both the contralateral kidney as well as the cardiac interstitium. In both kidney and heart, gene and protein expression of the macrophage chemokine osteopontin was also increased. The role of macrophages in the modulation of lung injury after AKI was directly elucidated in a 30-min bilateral IRI model in rats [12]. In these experiments, kidney injury caused significantly increased pulmonary vascular permeability as quantified by Evan’s AKI and Distant-Organ Injury

blue dye extravasation. Pretreatment of animals prior to renal injury with CNI-1493, a potent macrophage activation inhibitor, abrogated the pulmonary injury (despite no change in severity of the renal injury induced). In contrast to the deleterious role of inflammatory cells in distant organs after AKI, uremic neutrophils have been shown to attenuate acute lung injury [13]. In an elegant study, mice underwent 32 min of bilateral IRI or bilateral nephrectomy, with subsequent induction of acute lung injury by intratracheal HCl instillation and mechanical ventilation. In this model of severe, neutrophil-dependent lung injury, neutrophil-depleted mice were protected from pulmonary histologic injury; oxygenation impairment was also attenuated. Depletion of endogenous neutrophils from uremic mice with subsequent injection of nonuremic neutrophils (or vice versa) was then performed before induction of lung injury. Only mice that had received uremic neutrophils displayed resistance to histologic lung injury, with impaired neutrophil recruitment associated with downregulation of surface L-selectin expression on the uremic neutrophils. Clearly, the mechanisms by which AKI might initiate, affect or direct leukocyte activation and trafficking are complicated and only partially understood. One means may be by modulation of cytokines and chemokines.

Cytokines and Chemokines

Cytokines appear to be significantly altered by AKI, potentially resulting in systemic organ effects once released into circulation. In a rat model of bilateral IRI, serum IL-1 and TNF-␣ levels increased 1 h after injury [14]; at 6 h after injury, IL-1 and TNF-␣ were also increased in cardiac cells. 48 h later, cardiac myocytes had elevated levels of TUNEL staining, suggesting increased apoptosis. Echocardiograms obtained at 48 h after ischemia showed significant left ventricular dilatation as well as a significantly decreased shortening fraction in AKI animals compared to controls. A panel of cytokines and chemokines was measured in kidney and blood in a mouse AKI model, and the chemokine KC was found to be upregulated in urine, serum and kidney within 1–3 h of injury [15]. These studies were extended to humans, where Gro-␣ (the human KC analogue) was significantly increased in the urine of human kidney transplant recipients. Importantly, Gro-␣ levels in urine correlated with graft function and predicted the need for dialysis.

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Acute Kidney Injury

Cytokines/Chemokines Proinflammatory (IL-1, IL-6, KC) and Anti-inflammatory (IL-10)

Altered Response to Oxidative Stress HO-1, SOD, and catalase reduced after renal injury

Leukocyte Trafficking Neutrophil, T-cell, and macrophage migration

Changes in Sodium and Water Channels ENaC, Aquaporin-5 and Na,K-ATPase

Distant Organ Injury

Fig. 1. AKI leads to distant-organ injury via a variety of cellular and molecular pathways. AKI causes alterations in leukocyte trafficking to distant organs, leading to subsequent inflammatory damage. Cytokine and chemokine expression changes after renal injury in both serum and distant organs. AKI alters the expression levels of sodium and water channels in pulmonary tissue. Finally, AKI modifies responses to oxidative stress in distant organs.

Another study in a mouse model demonstrated that pro-inflammatory cytokines increased in the kidney and serum after kidney injury and appeared to mediate subsequent lung damage [16]. Comparison of 22-min unilateral clamp and bilateral clamp models with bilateral nephrectomy revealed that IL-6, IL-1␤, and IL-12 increased significantly in both serum and kidney after ischemia and nephrectomy, while serum KC and GM-CSF increased significantly after bilateral IRI. Lung histology 24 h after either bilateral nephrectomy or bilateral IRI showed histologic abnormalities; treating animals with IL-10 (an anti-inflammatory cytokine) just prior to nephrectomy ameliorated this damage. A recent study focused on the inflammatory pathogenesis of AKI-induced changes in brain. After 60 min of bilateral renal ischemia in mice, KC and G-CSF were increased in the cerebral cortex and hippocampus [17]. There was an increased number of pyknotic hippocampal cells as well as activated microglia (indicative of increased apoptosis and inflammation) in animals after kidney injury compared to control mice. The mice with AKI exhibited increased brain vascular permeability, demonstrated by Evan’s blue dye extravasation, indicating a breakdown of the blood-brain barrier function. p82

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Other nonkidney IR models have implicated cytokines and chemokines in post-IRI, distant-organ injury. In a supraceliac aortic-clamp model, mice had significant lung injury 2 and 4 h after IRI, as well as increases in liver enzymes [18]. Serum proinflammatory cytokines IL-6 and KC were increased, while lung tissue revealed increased IL-1␤ and KC. IRI was then performed in IL-10 knock-out mice, and while there appeared to be no difference in pro-inflammatory cytokine expression between wild-type and knockout mice, lung injury was worsened in the IL-10 knockouts. Treatment with IL-10 in knockout mice significantly attenuated this lung injury. ␣-Melanocyte-stimulating hormone (␣-MSH), another anti-inflammatory cytokine, may also be involved in lung injury after IRI [19]. In this series of experiments using a 40-min bilateral IRI model in mice, treatment with ␣-MSH just prior to clamp release led to decreased lung injury by histology, as well as decreased leukocyte infiltration, pulmonary TNF-␣ and ICAM-1 mRNA expression. However, ␣-MSH also reduced renal injury itself, thus some effects of ␣-MSH on lung injury could have been from reduced primary renal injury. One proposed molecular mechanism by which cytokine expression after kidney injury might be modulated is the I␬B␣ pathway. Phosphorylation of I␬B␣ leads to its destruction, which then allows NF␬B dimers to translocate to the nucleus and initiate transcription of many pro-inflammatory genes. In these ␣-MSH studies, renal ischemia caused phosphorylation of cytosolic I␬B␣ in both kidney and lung within 15–30 min after reperfusion [19].

Oxidative Stress

Induction of oxidative stress – and derangement of systemic responses – could also mediate AKI-induced distant-organ dysfunction. Heme-oxygenase-1 (HO-1), an enzyme that catalyzes the degradation of Heme, is responsive to ischemic, nephrotoxic and inflammatory stimuli and is known to modulate conditions like atherosclerosis, vasculopathies and acute ischemia. Its expression quenches oxidative stress, generates anti-inflammatory and anti-oxidant metabolites such as bilirubin, and upregulates cell cycle inhibitors such as p21. HO-1 may also suppress the expression of MCP-1, a potent chemoattractant for monocytes. Mice that are homozygous knockouts for HO-1 are more sensitive to kidney IRI, with subsequent increased BUN and creatinine, worsened GFR and increased mortality [20]. These HO-1 knockout mice Feltes/Van Eyk/Rabb

also display systemically increased IL-6 expression in serum, heart and lung compared to wild type mice after renal injury. In a separate study, unilateral renal IRI in mice led to decreased hepatic levels of superoxide dismutase, catalase and glutathione, suggesting that IRI might compromise the distant organ’s ability to cope with oxidative stress or damage [21]. This study also found increased cytokine and other inflammatory activity in the liver, similar to other studies in lung and heart, with increased levels of hepatic tissue myeloperoxidase (a measure of neutrophil and macrophage recruitment) and TNF-␣. Another study utilizing a unilateral IRI model in rabbits also found decreased levels of superoxide dismutase and catalase after injury, and found that pretreatment with DHEA (recently reported to possess antioxidant properties) reversed these effects [22]. These data suggest that the oxidative stress response may play a crucial role in distant-organ injury after renal IRI.

Future Directions

There are likely many other important pathways that participate in the distant-organ effects of AKI that have only been partially studied. Effective alveolar fluid clearance, crucial in the pathogenesis of acute lung injury, is impaired after experimental kidney injury. In a series of experiments utilizing a bilateral renal ischemia model in rats, mRNA levels of pulmonary epithelial sodium channel as well as aquaporin-5 were reduced 48 h after injury [23]. In addition, protein expression of aquaporin-5 and NaK-ATPase were markedly diminished in lung tissue after renal IRI, which may help explain the pulmonary edema so notable after AKI. There are new and exciting technologies emerging that may shed further light on these pathways and processes. For example, genomic analysis of lung tissue after renal IRI in a mouse model recently identified ischemiaspecific changes in the lung transcriptome that are distinguishable from those produced by uremia [24]. Relevant biological pathways potentially involved in kidney IRI-induced lung injury were then identified via gene ontology analysis, revealing that several inflammatory and cell signaling genes, including those involved in apoptosis and ubiquitination, were activated. Further gene array-based evaluation focused on distinct time and severity of injury-specific inflammatory transcriptomic responses in the kidney during AKI, and compared these to an inflammation-specific genomic AKI and Distant-Organ Injury

analysis of the lung [25]. Soluble inflammatory products related to the implicated genes identified included IL-6, levels of which were increased in the circulation during AKI and could serve as a link between intrarenal and distant-organ dysfunction. Global functional genomics analysis of validated candidate genes (Cd14, Socs3, Saa3, Lcn2, and Il1r2) showed that the major pathways deranged after renal injury were those involving IL-6 and IL-10 signaling [25]. The emerging field of proteomics is also well suited for this line of inquiry (reviewed in [26]). The proteome consists of all proteins expressed in a cell at any given time, including protein isoforms as well as co- and post-translationally modified forms. Unlike genomics, which presents information about gene transcription and therefore the theoretical status of cellular proteins, the proteome describes the concrete gene products (proteins) present. This is particularly important as there can often be discord between mRNA expression levels and functional protein expression. Proteomics also offers a more complex analysis of cellular and mechanistic events, as changes in protein modification, activation and degradation can be evaluated. Logistically, proteomics requires the isolation and resolution of the protein(s) of interest, usually via 2D gel electrophoresis or liquid chromatography, followed by digestion and detection of peptides via mass spectrometry. The pattern of peptide signals obtained is then compared with database entries for identification of the protein. Application of this as well as other novel techniques will potentially result in further understanding of the complex processes underlying distant-organ injury after kidney injury.

References

1 Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A: Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. 2 Hoste EA, Clermont G, Kersten A, Venkataraman R, Angus DC, De Bacquer D, Kellum JA: Rifle criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care 2006;10:R73. 3 Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL: Modified rifle criteria in critically ill children with acute kidney injury. Kidney Int 2007;71:1028–1035. 4 Metnitz PG, Krenn CG, Steltzer H, Lang T, Ploder J, Lenz K, Le Gall JR, Druml W: Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 2002;30:2051–2058.

Nephron Physiol 2008;109:p80–p84

p83

5 Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W, Bauer P, Hiesmayr M: Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol 2004; 15: 1597– 1605. 6 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: 2259–2264. 7 Ala-Kokko T, Ohtonen P, Laurila J, Martikainen M, Kaukoranta P: Development of renal failure during the initial 24 h of intensive care unit stay correlates with hospital mortality in trauma patients. Acta Anaesthesiol Scand 2006;50:828–832. 8 Vieira JM, Jr., Castro I, Curvello-Neto A, Demarzo S, Caruso P, Pastore L Jr, Imanishe MH, Abdulkader RC, Deheinzelin D: Effect of acute kidney injury on weaning from mechanical ventilation in critically ill patients. Crit Care Med 2007;35:184–191. 9 Miyazawa S, Watanabe H, Miyaji C, Hotta O, Abo T: Leukocyte accumulation and changes in extra-renal organs during renal ischemia reperfusion in mice. J Lab Clin Med 2002;139:269–278. 10 Kim do J, Park SH, Sheen MR, Jeon US, Kim SW, Koh ES, Woo SK: Comparison of experimental lung injury from acute renal failure with injury due to sepsis. Respiration 2006; 73:815–824. 11 Tokuyama H, Kelly DJ, Zhang Y, Gow RM, Gilbert RE: Macrophage infiltration and cellular proliferation in the non-ischemic kidney and heart following prolonged unilateral renal ischemia. Nephron Physiol 2007; 106: p54–p62.

p84

12 Kramer AA, Postler G, Salhab KF, Mendez C, Carey LC, Rabb H: Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability. Kidney Int 1999;55:2362–2367. 13 Zarbock A, Schmolke M, Spieker T, Jurk K, Van Aken H, Singbartl K: Acute uremia but not renal inflammation attenuates aseptic acute lung injury: a critical role for uremic neutrophils. J Am Soc Nephrol 2006; 17: 3124–3131. 14 Kelly KJ: Distant effects of experimental renal ischemia/reperfusion injury. J Am Soc Nephrol 2003;14:1549–1558. 15 Molls RR, Savransky V, Liu M, Bevans S, Mehta T, Tuder RM, King LS, Rabb H: Keratinocyte-derived chemokine is an early biomarker of ischemic acute kidney injury. Am J Physiol Renal Physiol 2006; 290:F1187– F1193. 16 Hoke TS, Douglas IS, Klein CL, He Z, Fang W, Thurman JM, Tao Y, Dursun B, Voelkel NF, Edelstein CL, Faubel S: Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury. J Am Soc Nephrol 2007;18:155–164. 17 Liu M, Liang Y, Chigurupati S, Lathia JD, Pletnikov M, Sun Z, Crow M, Ross CA, Mattson MP, Rabb H: Acute kidney injury leads to inflammation and functional changes in the brain. J Am Soc Nephrol 2008; 19: 1360– 1370. 18 Welborn MB 3rd, Moldawer LL, Seeger JM, Minter RM, Huber TS: Role of endogenous interleukin-10 in local and distant organ injury after visceral ischemia-reperfusion. Shock 2003;20:35–40.

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19 Deng J, Hu X, Yuen PS, Star RA: Alpha-melanocyte-stimulating hormone inhibits lung injury after renal ischemia/reperfusion. Am J Respir Crit Care Med 2004;169:749–756. 20 Tracz MJ, Juncos JP, Croatt AJ, Ackerman AW, Grande JP, Knutson KL, Kane GC, Terzic A, Griffin MD, Nath KA: Deficiency of heme oxygenase-1 impairs renal hemodynamics and exaggerates systemic inflammatory responses to renal ischemia. Kidney Int 2007;72: 1073–1080. 21 Serteser M, Koken T, Kahraman A, Yilmaz K, Akbulut G, Dilek ON: Changes in hepatic tnf-alpha levels, antioxidant status, and oxidation products after renal ischemia/reperfusion injury in mice. J Surg Res 2002; 107: 234–240. 22 Yildirim A, Gumus M, Dalga S, Sahin YN, Akcay F: Dehydroepiandrosterone improves hepatic antioxidant systems after renal ischemia-reperfusion injury in rabbits. Ann Clin Lab Sci 2003;33:459–464. 23 Rabb H, Wang Z, Nemoto T, Hotchkiss J, Yokota N, Soleimani M: Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int 2003;63:600–606. 24 Hassoun HT, Grigoryev DN, Lie ML, Liu M, Cheadle C, Tuder RM, Rabb H: Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy. Am J Physiol Renal Physiol 2007;293:F30–F40. 25 Grigoryev DN, Liu M, Hassoun HT, Cheadle C, Barnes KC, Rabb H: The local and systemic inflammatory transcriptome after acute kidney injury. J Am Soc Nephrol 2008; 19:547–558. 26 Matt P, Fu Z, Fu Q, Van Eyk JE: Biomarker discovery: Proteome fractionation and separation in biological samples. Physiol Genomics 2008;33:12–17.

Feltes/Van Eyk/Rabb

Nephron Physiol 2008;109:p85–p91 DOI: 10.1159/000142941

Published online: September 18, 2008

Emerging Therapies for Extracorporeal Support Josée Bouchard Nitin Khosla Ravindra L. Mehta University of California at San Diego, San Diego, Calif., USA

Key Words Acute kidney injury ⴢ Dialysis ⴢ Liver dialysis ⴢ Sepsis ⴢ Ultrafiltration

Abstract Dialytic therapies have undergone major technological developments in the last decade and emerging techniques are promoted not only for acute kidney injury, but also for sepsis, acute decompensated heart failure, and acute and acuteon-chronic liver failure. New devices specifically target the pathophysiological mechanisms involved in these conditions. In septic shock and sepsis, high-volume hemofiltration, coupled plasma filtration adsorption, cascade hemofiltration and high permeability hemofiltration enhance removal of pro-inflammatory mediators, while in liver failure, Molecular Adsorbents recycling System (MARS쏐) and Prometheus쏐 favor the elimination of albumin-bound toxins such as bilirubin. In acute decompensated heart failure, simplified ultrafiltration machines are used to reach negative fluid balance in a minimalist setting. In the context of limited resources and growing expansion in the availability of technologies, a critical assessment is required and the use of these devices needs to be put in perspective. This article reviews the mechanisms, advantages and limitations of these techniques along with the current evidence available regarding their influence on major clinical outcomes. Copyright © 2008 S. Karger AG, Basel

© 2008 S. Karger AG, Basel 1660–2137/08/1094–0085$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nep

Introduction

Intermittent and continuous dialysis techniques are commonly utilized for acute kidney injury (AKI); however, new therapies have emerged to improve the prognosis of sepsis and AKI, septic shock, liver failure and acute decompensated heart failure. This article presents an overview of the new techniques, describes the operational characteristics unique to each therapy, reviews the preliminary clinical results and provides a critical assessment to inform a judicious use of these therapies.

Enhanced Convection

High-Volume Hemofiltration (HVHF) HVHF is defined by delivering an ultrafiltration rate between 50 and 100 ml/kg/h, and requires higher blood flow rate, high flux membrane and larger filter surface area than conventional hemofiltration. This method has been used in treating selected intoxications, inborn errors of metabolism, and septic shock (table 1). The rationale of providing HVHF in septic shock relies on three leading concepts that enhance removal of pro-inflammatory molecules that induce hemodynamic collapse and organ damage [1]. The peak concentration hypothesis involves removal of inflammatory mediators from the blood compartment leading to reduced tissue levels of Ravindra L. Mehta, MD UCSD Medical Center 200 W. Arbor Drive, MC 8342 San Diego, CA 92103 (USA) Tel. +1 619 543 7310, Fax +1 619 543 7420, E-Mail [email protected]

Table 1. Comparison of the different techniques, mechanism and suggested clinical indications Technique

Abbreviation

Mechanism of action

Suggested clinical indications

High-volume hemofiltration/pulse high-volume hemofiltration

HVHF/ PHVHF

hemofiltration

septic shock and sepsis, some intoxications and inborn errors of metabolism

Cascade hemofiltration

–

hemofiltration + high permeability filter

septic shock

Sustained low efficiency dialysis/ extended daily dialysis

SLED/ EDD

sustained hemodialysis

AKI

Single-pass batch dialysis machine or genius system쏐

–

sustained hemodialysis

AKI

High permeability hemofiltration

HPHF

high permeability filter

cast nephropathy and septic AKI

Plasmapheresis (plasma filtration)

–

plasma filtration

–

Hemoperfusion

–

adsorption

sepsis

Coupled plasma filtration adsorption

CPFA

plasma filtration and plasma adsorption

severe sepsis and septic shock

Molecular Adsorbents in Recycling System

MARS쏐

adsorption and convection and/or dialysis of the albumin solution

acute and acute-on-chronic liver failure

Prometheus쏐 or fractionated plasma separation and adsorption

Prometheus쏐 or FPSA

adsorption of plasma and convection and/or dialysis of blood

acute and acute-on-chronic liver failure

Single pass albumin dialysis

SPAD

adsorption, convection and/or dialysis of blood

acute and acute-on-chronic liver failure

Isolated ultrafiltration

UF

ultrafiltration

acute decompensated heart failure

these substances, thus impairing further organ damage. In the threshold immunomodulation hypothesis, removal of inflammatory substances from the blood compartment not only decreases blood, interstitial and tissue levels of mediators, but also takes away pro-mediators thereby impairing their transformation into mediators and the following inflammatory cascade. The mediator delivery hypothesis proposes that the infusion of high amounts of substitution fluids enhances interstitial circulation of mediators from the intercellular space to the blood via the lymphatics. This interstitial wash-out could explain the absence of decrease in serum cytokine concentrations during hemofiltration despite documented cytokine removal. One nonrandomized trial treated 20 patients in severe hyperdynamic septic shock with 12 h of HVHF and found that it decreased norepinephrine requirements in 55% of patients. Although not primarily designed to evaluate mortality, hospital mortality was lower than expected (40 vs. 60%) [2]. Three other nonrandomized trials suggested that HVHF can be used as a salvage therapy in severe septic shock [3–5]. An ongoing trial in Europe, called the IVOIRE study (hIgh VOlume in Intensive caRE), is p86

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designed to compare the effect of UFR of 35 and 70 ml/ kg/h on mortality at 28 days in patients with sepsis and acute kidney injury. This study should bring more insight into this issue [1]. Due to the higher costs, increased blood flow rate requirements to avoid filter clotting and higher risk for fluid imbalances of HVHF, a variant of this technique has been described and named pulse high-volume hemofiltration (PHVHF). On a 24-hour schedule, HVHF is delivered for 6–8 h at an UFR of 85 ml/kg/h and then CVVH is performed at 35 ml/kg/h [6]. A preliminary uncontrolled study conducted in 15 patients found a reduction in vasopressor requirement shortly after treatment cessation. Despite the encouraging outcome of these studies, larger studies are necessary before HVHF can be recommended for routine clinical use in patients with AKI and sepsis or refractory septic shock. Cascade HVHF Cascade hemofiltration allows both highly efficient extraction of middle size molecules and restitution of small solutes by using sequential filters of different permeability (fig. 1a) [7]. The device includes a high permeBouchard/Khosla/Mehta

Return to patient Replacement ﬂuid Eﬄuent middle-sized molecules Low cut-oﬀ membrane

High cut-oﬀ membrane

Small and middle-sized molecules

Small molecules are returned to the patient (reinjection >75%)

a

Patient

Blood circuit

Secondary circuit Albumin 20% Low-ﬂux dialyzer

High-ﬂux dialyzer

Patient

Activated charcoal Anion exchange resin

b

Blood Plasma Albuﬂow

Adsorbing cartridges

Regular dialyzer

Fig. 1. a Cascade hemofiltration. b MARS. c Prometheus.

Emerging Therapies for Extracorporeal Support

c

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ability filter (cut-off 69 kDa) and a second filter of low permeability (5 kDa). Given the high permeability of the first filter, small and middle molecules are removed. This ultrafitrate then passes through the second filter and creates a new ultrafiltrate that contains just small molecules that is returned to the patient. The middle molecules are then discarded in the spent dialysate and replacement fluid is used to replace this volume. As the ultrafiltrate is reinfused, less replacement fluid is required than in HVHF. A small nonrandomized trial has found a decrease in the need of vasopressors with this technique in patients with septic shock [7].

Enhanced Diffusion

Sustained Low-Efficiency Dialysis (SLED) and Extended Daily Dialysis (EDD) The widespread availability and familiarity with conventional dialysis machines has led to attempts to modify these machines to mimic CRRT. Traditional dialysis machines have dialysate flow rates set at 500–800 ml/ min, whereas CRRT systems usually provide dialysate flow rates at 17–34 ml/min (1–2 liters/h). The Fresenius dialysis machines have been modified to allow a dialysate flow rate of 100 ml/min. With this technique, solute control and hemodynamic stability are similar to CRRT. No difference in mortality between hybrid therapy and CRRT has been found in an interim report on the first 481 patients from the Stuivenberg Hospital Acute Renal Failure (SHARF) study [8]. If these results are validated in a large prospective clinical trial, these modalities could be increasingly used due to their lower cost, reduced need in anticoagulation and similar solute removal [9]. Genius System or Single-Pass Batch Dialysis Machine The Genius system (Fresenius Medical Care, Bad Homburg, Germany) presents several unique characteristics compared to standard dialysis machines [10]. A batch dialysis of 75 liters is prepared in a large glass container. Blood and dialysate flow are generated by one two-sided pump; therefore both flows have an equal rate, up to 350 ml/min. Fresh and spent dialysate are stored in the same container and separation among the two layers is caused by the increased density of the spent dialysate due to its cooler temperature and higher solute content. This system has primarily been applied in chronic hemodialysis patients, although it has recently been recommended for daily use in critically ill patients with AKI. A p88

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daily 12-hour session proved to be as efficient as CRRT with a UFR at 30 ml/kg/h in regard to detoxification and hemodynamic stability in a small randomized trial [11]. The true benefit of this setup may rest in its lack of requirement for continuous water supply, allowing it to be rapidly deployed to treat life-threatening conditions such as hyperkalemia.

Increased Membrane Permeability

High Permeability Hemofiltration (HPHF) Pores from conventional high-flux filters allow substances with molecular cut-off of 10–20 kDa to cross the membrane [12], while high cut-off membranes (HCO) allow the passage of substances of 45–60 kDa. Given the higher molecular weight of inflammatory mediators (9– 54 kD) and free light chains (25–50 kDa), the use of HCO seems promising in sepsis and multiple myeloma with cast nephropathy. In septic patients undergoing continuous renal replacement therapy (CRRT), HCO have been shown to enhance clearance of IL-1ra and IL-6, proportionally to their initial serum concentrations [13]. Preliminary results in 10 septic patients with AKI have also found an increased in mean arterial pressure with their use. However, protein and albumin are also lost. These losses can be minimized with diffusion compared to convection [13]. The clinical consequences related to this enhanced permeability are unknown and larger studies are required before their use can be promoted. Moreover, according to the mediator delivery concept, HPHF has the potential to remove large amount of mediators in the blood compartment; however, its ability to remove mediators from interstitial and tissue levels is limited because it does not increase lymphatic flow. A reconciliation between proposed pathophysiological and treatment mechanisms would be of benefit to improve the efficacy of future devices. A preliminary study in 13 patients with multiple myeloma and AKI showed that daily extended hemodialysis using a filter with very large pores (Gambro HCO 1100, Hechingen, Germany) removes up to 5 times more free light chains compared to plasma exchange and may reduce dialysis dependence [12]. However, albumin losses (MW 65 kDa) need to be replaced and loss of immunoglobulins requires active surveillance for infections in these immunocompromised patients. More data are required before we can recommend its use.

Bouchard/Khosla/Mehta

Plasmapheresis Plasmapheresis can be used in sepsis to provide immunohomeostasis of pro- and anti-inflammatory cytokines and other sepsis mediators by targeting molecules with molecular weight up to 900 kDa [1]. One randomized controlled trial of a limited number of subjects revealed a trend toward fewer failing organs but no effect on mortality with continuous plasmapheresis using a hollow-fiber plasma filter [14]. Another randomized clinical trial of 106 patients with septic shock found an allcause mortality rate of 33.3% in the continuous flow plasmapheresis group and 53.8% in the control group, but imbalances in randomization favored the pheresis group [15]. Currently, there are insufficient data to recommend for or against this procedure in sepsis. The use of combined plasmapheresis and CRRT has also been reported but requires additional studies.

Adsorption

Hemoperfusion Polymyxin B-immobilized fiber (PMX-B) has been designed to adsorb endotoxin and has been mainly used in Japan and Europe in patients with sepsis or septic shock [16]. In a randomized, controlled study, 36 patients with severe sepsis or septic shock showed significant improvement in renal and hemodynamic status but no reduction on endotoxin levels. Another randomized trial has shown possible benefits on survival in early sepsis [17]. Further studies are needed to prove this effectiveness. Coupled Plasma Filtration Adsorption (CPFA) CPFA is aimed at reducing levels and activities of proand anti-inflammatory mediators to restore a normal immune function [18]. The device includes the combined use of a plasma filter (cut-off of 800 kDa) and a resin cartridge for adsorption. Plasma is filtered through the resin (30–40 ml/min) and then reinfused in the blood after efficient non-selective removal of mediators. Convection and/or diffusion can be combined with this technique for removal of small molecules and fluid if AKI is present. As a low flow of plasma is used, it allows a longer contact time of mediators with the sorbent and the cartridge is usually saturated after 10 h. Two small studies have shown that CPFA improves hemodynamic status and immune function in patients with severe sepsis and multiorgan dysfunction [19, 20]. Interestingly, changes in monocytes function and hemodynamics were achieved without any measurable effect on plasma levels of TNF and IL-10. Emerging Therapies for Extracorporeal Support

Liver Assist Systems or ‘Liver Dialysis’ Over the last decade, several different liver assist systems have been designed to treat liver failure by removing albumin-bound toxins, such as bilirubin and bile acids. These therapies are aimed at bridging the patient to transplantation. The most popular device is the Molecular Adsorbents Recirculating System (MARS쏐; GambroHospal, Mirandola, Italy). As a primary step, the free fraction of albumin-bound toxins diffuses against a 20% albumin dialysate in a closed circuit across a highly permeable high-flux membrane, which is impermeable to albumin (fig. 1b). The albumin solution, now carrying blood-bound toxins, is dialyzed in a renal circuit through a low-flux dialyzer and cleared from albumin-bound toxins in a closed circuit by two adsorptive columns. Hence, the term ‘albumin dialysis’ reflects the concept that it is the albumin solution and not the blood which is dialyzed [21]. This technique has been useful in treating hepatic encephalopathy and intractable cholestatic pruritus. In simple pass albumin dialysis, albumin is added to the dialysate to reach a concentration of 4 to 5%. As its name implies, the albumin solution is not recycled and therefore this technique is also costly and resource-consuming. Similar to MARS, the Prometheus쏐 system (Fresenius Medical Care, Bad Homburg, Germany) uses two circuits, a blood circuit including two filters, and an adjacent circuit with two adsorptive columns to facilitate the adsorption of albumin-bound substances (fig. 1c) [22]. The hydrophobic toxins pass the albumin-permeable filter between the two circuits and, therefore, a fraction of the patient’s plasma is filtered and the patient’s own albumin loads the second circuit. The plasma is later returned in the blood circuit to be dialyzed. This is similar to CPFA but in contrast to MARS where dialysis occurs in the albumin circuit. The two filters in the blood circuit produce greater resistance, enhancing the need for adequate anticoagulation, which seems feasible with citrate. This device causes a transitory decrease in albumin during the procedures, probably responsible for the drop in blood pressure within the first hour of treatment. Initial preliminary results showed comparable clinical efficacy of MARS and Prometheus. Major drawbacks to the use of these devices are their cost and the lack of data regarding survival, although there is a likelihood of decreased mortality in acute on chronic liver failure. Possible benefits also need to be assessed in regard to their impact on bridging to liver transplantation and on major complications, namely bleeding and infection. A large randomized trial, the HELIOS study, studying the effect of Prometheus on 1- and 3Nephron Physiol 2008;109:p85–p91

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month survival in acute-on-chronic liver failure, is expecting to publish its first results within a year [22]. Currently, these techniques should remain experimental and are contraindicated in the presence of uncontrolled coagulopathy, uncontrolled sepsis and severe gastrointestinal bleeding.

Isolated Ultrafiltration (UF)

The first reports of UF with hemodialysis machines in patients with congestive heart failure (CHF) were published in the 1980s. Over the last years, selected patients with decompensated heart failure have been treated with new ultrafiltration (UF) devices (Aquadex System 100, CHF Solutions, Minneapolis, Minn., USA) [23, 24]. These devices rely on the same underlying principle of fluid removal used in hemodialysis; however, they are smaller, do not require central venous access or specialized nursing and can be performed outside the ICU. Fluid removal rate ranges between 100 and 500 ml/h. Two recent randomized controlled trials have evaluated these devices in patients hospitalized for CHF. One demonstrated higher fluid removal at 24 h in the single 8-hour UF session group (4.6 liters) compared to the standard group treated with intravenous diuretics (2.8 liters) [23], but showed no difference in the primary endpoint of greater weight loss at 24 h. The largest trial, including 200 patients randomized within 24 h of hospitalization, found a significant decrease in their primary endpoint, weight loss at 48 h, in the UF group compared to the diuretic

group (5.0 8 3.1 vs. 3.1 8 3.5 kg) and rate of rehospitalization in UF group at 90 days (18 vs. 32%) [24]. Though it did not reach statistical significance, hypotension was twice as common in the UF group. Importantly, in these two trials, renal function did not seem to deteriorate more with UF, though patients with a creatinine 13 mg/ dl were excluded from the latter trial. These methods show a potential benefit for selected patients with CHF; however, additional data are required regarding efficacy compared to maximal doses of diuretics, use in patients with diastolic dysfunction or prone to hypotension, and cost-effectiveness before its use is promoted on a large scale.

Conclusion

Although several new extracorporeal support techniques are now available, they are still at the early stages of clinical testing. Initial studies appear promising and might provide significant advances for several different conditions associated with poor rates of survival. A solid proof of their efficacy and an assessment of their cost-effectiveness are needed before wider use is implemented.

Acknowledgement Josée Bouchard is a scholar of the Kidney Foundation of Canada.

References 1 Honore PM, Joannes-Boyau O, Gressens B: Blood and plasma treatments: The rationale of high-volume hemofiltration. Contrib Nephrol. Basel, Karger, 2007, vol 156, pp 387–395. 2 Cornejo R, Downey P, Castro R, Romero C, Regueira T, Vega J, Castillo L, Andresen M, Dougnac A, Bugedo G, Hernandez G: Highvolume hemofiltration as salvage therapy in severe hyperdynamic septic shock. Intensive Care Med 2006;32:713–722. 3 Honore PM, Jamez J, Wauthier M, Lee PA, Dugernier T, Pirenne B, Hanique G, Matson JR: Prospective evaluation of short-term, high-volume isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock. Crit Care Med 2000;28:3581–3587.

p90

4 Joannes-Boyau O, Rapaport S, Bazin R, Fleureau C, Janvier G: Impact of high volume hemofiltration on hemodynamic disturbance and outcome during septic shock. ASAIO J 2004;50:102–109. 5 Piccinni P, Dan M, Barbacini S, Carraro R, Lieta E, Marafon S, Zamperetti N, Brendolan A, D’Intini V, Tetta C, Bellomo R, Ronco C: Early isovolaemic haemofiltration in oliguric patients with septic shock. Intensive Care Med 2006;32:80–86. 6 Ratanarat R, Brendolan A, Piccinni P, Dan M, Salvatori G, Ricci Z, Ronco C: Pulse highvolume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival. Crit Care 2005;9:R294–R302.

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7 Wiesen PN, Monchi M, Dubois BE, Preiser JCE, Damas PP: Cascade high volume hemofiltration: preliminary data in septic shock patients. Blood Purif 2007;25:190. 8 Malbrain M, Elseviers M, Van der Niepen P, Damas P, Hoste E, Devriendt J, Lins R: Interim results of the SHARF4 study: outcome of acute renal failure with different treatment modalities. Crit Care 2004;8:153. 9 Berbece AN, Richardson RM: Sustained low-efficiency dialysis in the ICU: cost, anticoagulation, and solute removal. Kidney Int 2006;70:963–968. 10 Dhondt A, Eloot S, Wachter DD, Smet RD, Waterloos MA, Glorieux G, Lameire N, Verdonck P, Vanholder R: Dialysate partitioning in the genius batch hemodialysis system: effect of temperature and solute concentration. Kidney Int 2005;67:2470–2476.

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11 Kielstein JT, Kretschmer U, Ernst T, Hafer C, Bahr MJ, Haller H, Fliser D: Efficacy and cardiovascular tolerability of extended dialysis in critically ill patients: a randomized controlled study. Am J Kidney Dis 2004; 43: 342–349. 12 Hutchison CA, Cockwell P, Reid S, Chandler K, Mead GP, Harrison J, Hattersley J, Evans ND, Chappell MJ, Cook M, Goehl H, Storr M, Bradwell AR: Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies. J Am Soc Nephrol 2007; 18: 886– 895. 13 Morgera S, Slowinski T, Melzer C, Sobottke V, Vargas-Hein O, Volk T, ZuckermannBecker H, Wegner B, Muller JM, Baumann G, Kox WJ, Bellomo R, Neumayer HH: Renal replacement therapy with high-cutoff hemofilters: impact of convection and diffusion on cytokine clearances and protein status. Am J Kidney Dis 2004;43:444–453. 14 Reeves JH, Butt WW, Shann F, Layton JE, Stewart A, Waring PM, Presneill JJ: Continuous plasmafiltration in sepsis syndrome: plasmafiltration in sepsis study group. Crit Care Med 1999;27:2096–2104. 15 Busund R, Koukline V, Utrobin U, Nedashkovsky E: Plasmapheresis in severe sepsis and septic shock: a prospective, randomised, controlled trial. Intensive Care Med 2002;28: 1434–1439.

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16 Vincent JL, Laterre PF, Cohen J, Burchardi H, Bruining H, Lerma FA, Wittebole X, De Backer D, Brett S, Marzo D, Nakamura H, John S: A pilot-controlled study of a polymyxin B-immobilized hemoperfusion cartridge in patients with severe sepsis secondary to intra-abdominal infection. Shock 2005;23:400–405. 17 Nemoto H, Nakamoto H, Okada H, Sugahara S, Moriwaki K, Arai M, Kanno Y, Suzuki H: Newly developed immobilized polymyxin B fibers improve the survival of patients with sepsis. Blood Purif 2001; 19: 361–368; discussion 368–369. 18 Formica M, Inguaggiato P, Bainotti S, Wratten ML: Coupled plasma filtration adsorption. Contrib Nephrol. Basel, Karger, 2007, vol 156, pp 405–410. 19 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;30:1250–1255.

20 Formica M, Olivieri C, Livigni S, Cesano G, Vallero A, Maio M, Tetta C: Hemodynamic response to coupled plasmafiltration-adsorption in human septic shock. Intensive Care Med 2003;29:703–708. 21 Karvellas CJ, Gibney N, Kutsogiannis D, Wendon J, Bain VG: Bench-to-bedside review: current evidence for extracorporeal albumin dialysis systems in liver failure. Crit Care 2007;11:215. 22 Krisper P, Stauber RE: Technology insight: artificial extracorporeal liver support – how does Prometheus compare with MARS? Nat Clin Pract Nephrol 2007;3:267–276. 23 Bart BA, Boyle A, Bank AJ, Anand I, Olivari MT, Kraemer M, Mackedanz S, Sobotka PA, Schollmeyer M, Goldsmith SR: Ultrafiltration versus usual care for hospitalized patients with heart failure: the relief for acutely fluid-overloaded patients with decompensated congestive heart failure (rapid-CHF) trial. J Am Coll Cardiol 2005; 46: 2043– 2046. 24 Costanzo MR, Guglin ME, Saltzberg MT, Jessup ML, Bart BA, Teerlink JR, Jaski BE, Fang JC, Feller ED, Haas GJ, Anderson AS, Schollmeyer MP, Sobotka PA: Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007; 49: 675–683.

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Nephron Exp Nephrol 2008;109:e118–e122 DOI: 10.1159/000142936

Published online: September 18, 2008

The Bioartificial Kidney and Bioengineered Membranes in Acute Kidney Injury Feng Ding a, b H. David Humes a, 1 a b

Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, Mich., USA; Department of Nephrology, Huashan Hospital, Fudan University, Shanghai, PR China

Key Words Acute kidney injury ⴢ Cell therapy ⴢ Tubule cells ⴢ Tissue engineering ⴢ Inflammation ⴢ Nanotechnology

Abstract The treatment of severe acute kidney injury (AKI) with dialysis or hemofiltration remains suboptimal with high levels of morbidity and mortality. Current renal replacement therapies substitute for the small solute clearance function of the kidney but do not replace the lost reclamation, metabolic and endocrine functions of this organ. Cell therapy and tissue engineering offer hope of fuller replacement of kidney function in renal failure patients. A renal tubule assist device (RAD) that includes a conventional hemodialysis filter and a bioreactor containing living renal proximal tubule cells has been successfully engineered. Differentiated activity of these cells and survival advantages have been demonstrated in large-animal models of sepsis and AKI. Data from phase I/II and phase II clinical studies have shown that the addition of renal tubule cell therapy to conventional continuous renal replacement therapy (CRRT) treatment resulted in a signifi-

1 H.D.H. is a shareholder of Innovative BioTherapies, Inc., and Nephrion, Inc., biotechnology spin-out companies of the University of Michigan, Ann Arbor, Mich., USA.

© 2008 S. Karger AG, Basel 1660–2129/08/1094–0116$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nee

cant clinical impact on survival, and that RAD treatment demonstrated an acceptable safety profile. Another substantive advance for the treatment of AKI will be the development of nanofabrication technology to further improve the clearance function of the kidney to replicate glomerular permselectivity while retaining high rates of hydraulic permeability. New developments in this translational research area will improve the unmet medical needs of patients with renal failure. Copyright © 2008 S. Karger AG, Basel

Introduction

Acute renal failure (ARF) is generally defined as an abrupt and sustained decline in the glomerular filtration rate (GFR), which leads to accumulation of nitrogenous waste products and uremic toxins. The term ARF has recently been modified to acute kidney injury (AKI) to reflect the importance of even modest changes in renal function to morbidity and mortality. AKI affects 5–7% of hospitalized patients and up to 30% of patients in intensive-care settings. The mortality rate of patients with ARF remains greater than 50% in most studies, and exceeds 70% in intensive care units (ICUs). Novel therapeutic approaches need to be formulated to change this dismal prognosis for patients with AKI. Prof. H. David Humes, MD Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, 4520 MSRB I, SPC 5651, 1150 W. Medical Center Dr. Ann Arbor, MI 48109 (USA) Tel. +1 734 647 8018, Fax +1 734 763 4851, E-Mail [email protected]

Rationality of Renal Cell Therapy

Preclinical Studies of Bioartificial Kidney

Several limitations in current therapies for AKI exist. First, although current artificial renal replacement therapies, either intermittent or continuous, can administer substantive small- and middle-molecule solute and fluid clearance, they are not complete replacement therapies. In addition to its major role in maintaining the constant extracellular environment, the kidney has many other roles. It is regarded as an endocrine organ, responsible for the secretion of hormones that are critical in maintaining hemodynamics (renin, angiotension II, prostaglandins, nitric oxide, endothelin, and bradykinin), red blood cell production (erythropoietin), bone metabolism (1,25-dihydroxyvitamin D3 or calcitriol), and perhaps other asyet-undiscovered entities. The traditional renal replacement therapies, based on diffusion, convection, or absorption, provide only filtration; they do not replace these lost homeostatic, regulatory, metabolic, and endocrine functions of the kidney. Second, a growing body of evidence indicates that inflammation plays a major role in the pathophysiology of AKI, so that this disorder is, to some extent, an inflammatory disease [3]. Inflammatory cascades initiated by endothelial dysfunction can be augmented dramatically by the generation of several potent mediators by the ischemic proximal tubule. These are evidenced by recent human studies demonstrating that the levels of the proinflammatory cytokines IL-6 and IL-8 in the plasma predict mortality in patients with AKI [4]. Strategies that modulate the inflammatory response provide significant beneficial effects in experimental AKI [5]. The degree of inflammation in populations with end-stage renal disease (ESRD), which is clearly a pro-inflammatory state, has been highly correlated to mortality rates [6]. These data suggest that renal function, most likely renal tubule cell function, plays a critical immunomodulatory role in AKI. Renal epithelial cells are antigen-presenting cells that possess co-stimulatory molecules and that synthesize and process a variety of inflammatory cytokines. They also supply antioxidant by glutathione synthesis and glutathione peroxidase in the proximal tubule cell. In addition, low 1,25-dihydroxyvitamin D3 (1,25-(OH)2-Vit D3) levels in hospitalized patients appear to correlate with mortality [7], suggesting yet another influence of the kidney on immune competence. It can be suggested that the loss of renal tubule cells, rather than loss of filtration and clearance function, may be the cause of this inflammatory dysregulation. Replacement of renal cell function in renal failure may impact the natural history of patients suffering from renal failure.

A bioartificial tubule unit is clearly feasible when conceived as a combination of living cells supported on polymeric substrata acting as scaffolds for the cells. Renal tubule progenitor cells can be cultured on the biomatrixcoated hollow fiber membranes of a standard high-flux hemofilter. The membrane is both water- and solute-permeable, allowing for differentiated vectorial transport and metabolic and endocrine activity. Immunoprotection of cultured progenitor cells is achieved concurrent with long-term functional performance as long as conditions support tubule cell viability [9]. Large-animal studies using a renal tubule assist device (RAD) consisting of renal proximal tubule progenitor cells have demonstrated that this device replaces filtration, transport, metabolic, and endocrine functions of the kidney in acutely uremic dogs following bilateral nephrectomies [10–12]. A series of additional animal experiments investigated the impact of treatment with this device on the high mortality of sepsis complicated by AKI. Studies in both dogs and pigs have demonstrated that RAD treatment in a bioartificial kidney circuit improves cardiovascular performance associated with changes in cytokine profiles and confers a significant survival advantage in septic or endotoxin animal models [13–15]. To further evaluate the RAD’s influence on local inflammation in tissue and distant organ dysfunction, especially in the lungs, a recent study compared bronchoalveolar lavage (BAL) fluid from cell-RAD-treated and non-cell, sham-treated groups in a pig model with septic shock with AKI. The levels of total protein in BAL from sham control animals were significantly higher than in the RAD group (143 8 11 compared to 78 8 10 ␮g/ml, respectively; p ! 0.05). Pro-inflammation cytokines, including IL-6 and IL-8, were markedly elevated in the non-cell group. These results demonstrate an important role of renal epithelial cells in ameliorating multiorgan injury in sepsis by influencing microvascular injury and the local proinflammatory response [16].

Bioartificial Kidney and Bioengineered Membranes in AKI

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Phase I/II Clinical Studies of the Bioartificial Kidney

These encouraging preclinical animal data led to an FDA-approved phase I/II clinical trial to evaluate the safety and efficacy of this new system on ten critically ill patients with ARF and multiorgan dysfunction syndrome (MODS) receiving CVVH [17]. The predicted hospital e119

mortality rates for these patients, as assessed with Acute Physiology, Age, Chronic Health Evaluation (APACHE) III scores, averaged 185%. The devices used in this study were seeded with human renal proximal tubule cells isolated from kidneys donated for cadaveric transplantation but found to be unsuitable for transplantation due to anatomic or fibrotic defects. The RAD perfusion pump system was connected in series to a CVVH extracorporeal pump system, following the principle tested in the preclinical animal studies, but with a minor adaptation of the circuit to maintain the original CVVH prescription in terms of blood flow rate from the patient and UF rate from the hemofilter. The results of this clinical trial demonstrated that the experimental treatment could be delivered safely under study protocol guidelines for up to 24 h when used in conjunction with CVVH. The clinical data also indicate that the RAD maintains and exhibits viability, durability and functionality in this clinical setting. Cardiovascular stability of the patients was maintained, and increased native kidney function, as determined by elevated urine outputs, temporally correlated with RAD treatment. The device also demonstrated differentiated metabolic and endocrinologic activity, with glutathione reclamation and endocrinologic conversion of 25-OH-Vit D3 to 1,25(OH)2-Vit D3. All but one treated patient with more than a 3-day follow-up showed improvement, as assessed by acute physiologic scores. Six of the 10 treated patients survived past 28 days with kidney function recovery, although only 1 was expected to survive by the predicted mortality scoring system. Of interest, plasma cytokine levels suggested that RAD therapy produces dynamic and individualized responses in patients depending on their unique pathophysiologic conditions. For the subset of patients who had excessive proinflammatory levels, RAD treatment resulted in significant declines in granulocyte-colony stimulating factor, IL-6, IL-10 and especially IL-6/IL-10 ratios, suggesting a greater decline in IL-6 relative to IL-10 levels and a less proinflammatory state.

Phase II Clinical Studies of the Bioartificial Kidney

These favorable phase I/II trial results led to an FDAapproved, randomized, controlled, open-label phase II investigation at ten clinical sites to determine whether this cell therapy approach alters patient mortality [18]. Fifty-eight patients (age 18–80 years) with ARF requiring CRRT in the ICU were randomized (2: 1) to receive e120

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CVVH + RAD (n = 40) or CRRT alone (n = 18). The primary endpoints were all-cause mortality at days 28, 90, and 180, time to recovery of renal function, time to ICU and hospital discharge, and safety. Baseline demographics and clinical characteristics were well balanced between treatment groups. Mean SOFA renal organ dysfunction sub-scores were 2.9 and 2.7 in the RAD and CRRT groups, respectively. Acute physiology and chronic health evaluation (APACHE) II scores were slightly, but not significantly, higher in the CRRT-alone group. By most key clinical laboratory parameters, the RAD group had higher degrees of disease severity and multiple-organ failure than the CRRT-alone group (but no significant differences). A higher proportion of patients in the RAD group completed the study (21 of 40, 53%) compared to patients who received CRRT alone (4 of 18, 22%). Median time on RAD therapy was 35.9 h with a range of 1.8 to 72.1 h. At day 28, the mortality rate was 33% in the RAD group and 61% in the CRRT group (p = 0.082); these 28day results did not reach statistical significance. Survival through day 180, however, was significantly improved in the RAD group (p = 0.034), and the Cox hazard ratio indicated that the risk of death was approximately 50% of that observed in the CRRT-alone group. By day 28, 21 (53%) of the 40 patients in the RAD group had recovered renal function, 10 (25%) had died before renal recovery, 8 (20%) remained on renal support and 1 (3%) had withdrawn consent. In the CRRT-alone group, a lower proportion of patients had recovered renal function (5 of 18, 28%) by day 28, a higher proportion had died prior to recovery (9 of 18, 50%) and a similar proportion remained on renal support (4 of 18, 22%) compared to the RAD group. Subgroup analyses, including severity of illness (SOFA and APACHE scores), number of organ failures and presence of sepsis at study entry were evaluated. Consistently higher survival rates at 28 days were observed in the RAD group compared to the CRRT-alone group, regardless of the number of organ failures. The incidence of sepsis in the two groups was high, at 73 and 67% in RAD and CRRT-alone groups, respectively. RAD therapy decreased the mortality rate in the patients with sepsis from 67% in the CRRT-alone group to 34%. Of note, patients with five or more organs failure had a 60% mortality rate in the RAD group compared to a 100% rate in CRRT alone. Thus, it appears from these small sample sizes that RAD treatment effects may be more pronounced with greater illness severity at baseline. These promising data suggest that the addition of renal tubule cell therapy to CVVH results in a substantive clinical impact on survival, and that RAD treatment demonstrates an acceptDing /Humes

able safety profile. A pivotal phase III, randomized, multicenter trial is required to further evaluate this new therapeutic approach to AKI.

New Membranes in Acute Kidney Injury

Advances in the treatment of AKI will involve the tissue engineering of kidney nephronal units combined with use of an ultrafiltration source. Microelectromechanical systems (MEMS) are being used to develop novel membrane technology for ultrafiltration to better replicate glomerular filtration processes. Current polymer membranes for renal replacement are performance limited. In general, such membranes are fairly thick or employ a multilayer scaffold for mechanical support, and they have a distribution of pore sizes rather than a regular array of uniform pores. Pores in conventional polymer membranes tend to be either roughly cylindrical, have a round orifice terminating a larger channel, or have a structure resembling an opencell sponge. These structures may provide less than optimal geometries for membrane filtration for two reasons. First, a wide dispersion in pore sizes within a membrane leads to imperfect retention of molecules larger than the mean pore size of the membrane. Reducing the mean pore size of the membrane may partially solve this problem. This solution, however, has the undesired effect of reducing the hydraulic permeability of the membrane. Second, the round shape of conventional pores dictates a fourth-power dependence of hydraulic permeability on pore radius. On the contrary, a pore that is slit-shaped allows steric hindrance to solute passage dictated by the smallest critical dimension of the pore, while increasing hydraulic permeability by a factor of the long dimension of the pore. Consequently, it might be predicted that filtration structures with parallel slit-shaped pores might have superior performance when compared to structures with round pores. The glomerular filtration barrier im-

References

Bioartificial Kidney and Bioengineered Membranes in AKI

poses an electrostatic restriction on solute passage. This function has been variously attributed to the proteins within the slit diaphragm, the glomerular basement membrane, and the glycocalyx of the glomerular endothelial cell. From the viewpoint of electrostatic effects, the thickness of the electrical double layer is in the same order of magnitude as the nanometer-scale pore size itself and can contribute to the rejection of charged solutes by the pore. With these first-principle predictions in mind, novel silicon nanopore membranes with 10- to 100-nm ! 45␮m slit pores have been prototyped by an innovative process based on MEMS technology. Silicon chips bearing 1 ! 1-mm arrays of approximately 104 slit pores were fabricated via sacrificial layer techniques. The pore structure is defined by deposition and patterning of a polysilicon film on the silicon wafer. The critical submicron pore dimension is defined by the thickness of a sacrificial SiO2 layer, which can be grown with unprecedented control to within 81 nm. The oxide layer is etched away in the final processing step to create the porous polysilicon membrane. Preliminary data on the transport properties of MEMS membranes are encouraging. Measured hydraulic permeabilities correlated well with theoretical predictions for flow-through slit-shaped pipes, also knows as HeleShaw flows. The observed albumin sieving coefficient data provide encouragement that protein permselectivity is also feasible with this technology. Recent laboratory data have validated the possibilities of these membranes as scaffolding for a renal tubule cell bioreactor [19]. In summary, recent advances in biomaterials along with cell therapeutic applications may dramatically improve the approach to renal dialytic care by providing more physiologic replacement of lost kidney function. It is hoped that these advances will result in an improvement of the current dismal prognosis of patients suffering from AKI and ESRD.

1 Brady HR, Clarkson MR, Lieberthal W: Acute renal failure; in Brenner BM (ed): Brenner & Rector’s The Kidney. Philadelphia, Saunders, 2004, pp 1215–1292. 2 Waikar SS, Liu KD, Chertow GM: The incidence and prognostic significance of acute kidney injury. Curr Opin Nephrol Hypertens 2007;16:227–236.

3 Kelly KJ: Acute renal failure: much more than a kidney disease. Semin Nephrol 2006; 26:105–113. 4 Simmons EM, Himmelfarb J, Sezer MT, Chertow GM, Mehta RL, Paganini EP, Soroko S, Freedman S, Becker K, Spratt D, Shyr Y, Ikizler TA; PICARD Study Group: Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int 2004;65: 1357–1365.

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5 Okusa MD: The inflammatory cascade in acute ischemic renal failure. Nephron 2002; 90:133–138. 6 Bologa RM, Levine DM, Parker TS, Cheigh JS, Serur D, Stenzel KH, Rubin AL: Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients. Am J Kidney Dis 1998;32:107–114. 7 Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS: Hypovitaminosis D in medical inpatients. N Engl J Med 1998;338:777–783. 8 Gage FH: Cell therapy. Nature 1998;392(6679 suppl):18–24. 9 Nikolovski J, Gulari E, Humes HD: Design engineering of a bioartificial renal tubule cell therapy device. Cell Transplant 1999; 8: 351–364. 10 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;55:2502–2514.

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11 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: 451–455. 12 Humes HD, Fissell WH, Weitzel WF, Buffington DA, Westover AJ, MacKay SM, Gutierrez JM: Metabolic replacement of kidney function in uremic animals with a bioartificial kidney containing human cells. Am J Kidney Dis 2002;39:1078–1087. 13 Fissell WH, Dyke DB, Weitzel WF, Buffington DA, Westover AJ, MacKay SM, Gutierrez JM, Humes HD: Bioartificial kidney alters cytokine response and hemodynamics in endotoxin-challenged uremic animals. Blood Purif 2002;20:55–60. 14 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;14:454–461.

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15 Humes HD, Buffington DA, Lou L, Abrishami S, Wang M, Xia J, Fissell WH: Cell therapy with a tissue-engineered kidney reduces the multiple-organ consequences of septic shock. Crit Care Med 2003;31:2421–2428. 16 Humes HD, Buffington DA, Lou L, Wang M, Abrishami S: Renal cell therapy ameliorates pulmonary abnormalities in a large animal model of septic shock and acute renal injury. J Am Soc Nephrol 2007; 18:A382. 17 Weitzel WF, Bartlett RH, Swaniker FC, Paganini EP, Luderer JR, Sobota J: Initial clinical results of the bioartificial kidney containing human cells in ICU patients with acute renal failure. Kidney Int 2004; 66: 1578–1588. 18 Tumlin J, Wali R, Williams W, Murray P, Tolwani AJ, Vinnikova AK, et al: Efficacy and safety of renal tubule cell therapy for acute renal failure. JASN 2008; 19: 1034– 1040. 19 Fissell WH, Fleischman AJ, Humes HD, Roy S: Development of continuous implantable renal replacement: past and future. Transplant Res 2007;150:327–336.

Ding /Humes

Nephron Clin Pract 2008;109:c217–c223 DOI: 10.1159/000142931

Published online: September 18, 2008

Outcome Prediction for Patients with Acute Kidney Injury Shigehiko Uchino Intensive Care Unit, Department of Anesthesiology, Jikei University School of Medicine, Nishi-Shinbashi, Minato-ku, Tokyo, Japan

Key Words Acute kidney injury ⴢ Outcome prediction ⴢ Severity score ⴢ Creatinine ⴢ Sepsis

Abstract Background/Aims: To review the currently available severity scores to predict outcome of acute kidney injury (AKI) patients, to discuss the problems with such scores, and to provide information for the development of more accurate AKI severity scores in the future. Methods: Literature review and multivariate analysis using a large international database for AKI. Results: Although general severity scores have good discrimination and calibration abilities to predict outcome of critically ill patients, the accuracy of these systems for AKI patients has been questioned. To improve prediction ability, multiple AKI severity scores have been published in the literature. However, most of these scores were developed and tested in a single center, or if multicentric, they were confined to a single country. Seven variables (mechanical ventilation, bilirubin, age, oliguria, hypotension, sepsis and platelet count) are often found as common risk factors in these severity scores and should be included in future AKI severity scores. Although several studies have consistently reported that both low creatinine and high urea at the start of RRT are related to worse outcome in AKI patients, they might not improve prediction ability. Conclusion: Using available information and a large database collected internationally, a more accurate score for AKI is likely to be developed.

Introduction

Despite continuing progress in medical treatment, acute kidney injury (AKI) in critical illness carries a hospital mortality of more than 60% [1]. Several randomized controlled trials have been unsuccessfully conducted to decrease such mortality [2, 3]. One of the difficulties with the conduct of clinical trials of AKI is that there is no reliable scoring system to stratify patient selection and confirm balanced randomization. Firstly, I will review the currently available severity scores to predict outcome of AKI patients and the problems with such scores. Secondly, to provide information for the development of more accurate AKI severity scores in the future, I will discuss the major risk factors for hospital mortality in patients with AKI.

Limitations of General Illness Severity Scores

General illness severity scores, e.g. SAPS-II, APACHEII and APACHE-III, have been developed to evaluate new therapies, monitor resource utilization, and improve quality assessment [4–6]. In general, these scores have good discrimination and calibration abilities to predict outcome of critically ill patients and have been widely accepted and used in multicenter clinical trials to confirm successful randomization [7, 8].

Copyright © 2008 S. Karger AG, Basel © 2008 S. Karger AG, Basel 1660–2110/08/1094–0217$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nec

Shigehiko Uchino, MD Intensive Care Unit, Department of Anesthesiology Jikei University School of Medicine, 3-19-18, Nishi-Shinbashi, Minato-ku Tokyo 105-8471 (Japan) Tel. +81 3 3433 1111, Fax +81 3 5401 0454, E-Mail [email protected]

Table 1. Studies reporting AKI severity scores

Authors

Year

Region

Centers

Patients

Population

RRT, %

Mortality, %

Cioffi et al. [16] Bullock et al. [17] Rasmussen et al. [18] Lohr et al. [19] Schaefer et al. [20] Liano et al. [21] Barton et al. [22] Paganini et al. [23] Chertow et al. [24] Mehta et al. [25] SHARF II [26] PICARD [27]

1984 1985 1985 1988 1991 1993 1993 1996 1998 2002 2004 2006

USA USA Australia USA Germany Spain UK USA USA, Canada USA Belgium USA

1 1 1 1 1 1 1 1 48 4 8 5

65 462 148 126 134 328 250 512 256 605 293 618

surgical hospital hospital hospital ICU hospital ICU ICU hospital ICU ICU ICU

100 62 – 100 100 51 100 100 42 50 37 64

81 68 53 75 57 53 51 67 36 52 51 –

SHARF = Stuivenberg Hospital Acute Renal Failure; PICARD = program to improve care in acute renal disease.

However, the accuracy of these scores for AKI patients has been questioned [9–12]. Fiaccadori et al. [10] evaluated APACHE II [4], SAPS II [6] and MPM II [13] in 425 patients admitted to their department with AKI. The area under the receiver-operating characteristic curve (AUROC) of the three scores was 0.75, 0.77 and 0.85, respectively. Although MPM II had the highest AUROC, it consistently and significantly overestimated the observed mortality. They concluded that none of the scores provided sufficient confidence for the prediction of outcome in individual patients. Lima et al. [11] evaluated APACHE II, SAPS II and LODS in 324 patients that were admitted to the ICU and were referred to nephrologists for AKI management. The AUROCs of the three scores were 0.72, 0.77 and 0.68, respectively. All scores underestimated hospital mortality and had the Lemeshow-Hosmer test p ! 0.001. We also evaluated SAPS II and SOFA [15] in the BEST kidney database [12]. The BEST kidney study is an international multicenter observational study for AKI, including more than 1,700 patients from 54 centers in 23 countries [1]. In this database, both scores had an AUROC of less than 0.7 (SAPS II 0.645, SOFA 0.675), not different from a single measurement of serum lactate concentration at study inclusion (0.639). The reason why general severity scores do not work for AKI patients well is unclear, but it might be because only a small fraction of subjects with AKI were involved in the original databases.

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AKI-Specific Severity Scores

Multiple AKI severity scores have been published in the literature and are listed in table 1 [16–27]. Most of these scores were developed in a single center, or if multicentric, they were confined to a single country. Although one study was conducted in a multicenter setting [24], this study was originally conducted as a randomized controlled study of atrial natriuretic peptide for AKI [28] and the sample size was smaller than other more recently conducted studies [25–27]. The three AKI severity scores, which are based on larger samples than others and have been recently published, are discussed below. Mehta et al. [25] generated an AKI severity score using 605 patients who had a nephrology consultation for AKI in the ICU at four hospitals in Southern California, USA, between October 1989 and September 1995. AKI was defined either by a BUN 1 40 mg/dl or SCr 12 mg/dl for patients with no prior history of kidney disease. For patients with preexisting renal insufficiency, AKI was defined by a sustained rise in SCr 11 mg/dl compared with baseline. Multivariate logistic regression analysis was used to generate the score. Using their population, they compared the AUROC and Hosmer-Lemeshow goodness-of-fit of their score with several general severity scores and kidney specific severity scores [19, 20, 23, 24, 26, 29]. They found that their score had the best discrimination (AUROC of 0.832) and calibration ability among all scores they tested. The SHARF (Stuivenberg Hospital Acute Renal Failure) II score [26] was a modified version of the previousUchino

ano et al. [21] in 238 patients who received RRT in the ICU. The AUROC of these scores ranged from 0.63 to 0.78, with Liano’s score being the highest. The BEST kidney study [12] evaluated the scores by Liano et al. [21], Paganini et al. [23], Chertow et al. [24] and Mehta et al. [25] in 53 centers. All scores had the AUROC of less than 0.7 and Hosmer-Lemeshow test p ! 0.0001. Although the BEST study also found that Liano’s score had the best discrimination and calibration ability among the four scores, other studies found a very low AUROC for this score (0.63 [25] and 0.56 [27]). One of the major reasons why such difference exists between general and AKI severity scores is the size of population. General severity scores were based on multicenter, multinational databases including more than 5,000 patients. On the other hand, most of the AKI scores were generated from populations included in one center and none of them had more than 700 patients. Therefore, a large database collected in multiple centers of multiple nations would be required to generate more accurate scores for AKI.

ly published kidney-specific severity score [29]. Originally, these investigators generated a score based on data from 197 patients in a single center in Belgium from March 1996 to April 1997. AKI was defined as a SCr of more than 2 mg/dl or an increase of more than 50%, observed in patients with previous mild-to-moderate chronic renal failure. Data were collected at the study inclusion (T0) and 48 h later (T48) and two scores were generated for each data collection point (SHARF-I0 and SHARFI48). Both of these scores included the same 5 variables (age, albumin, prothrombin time, mechanical ventilation and heart failure). Both scores showed good discrimination (AUROC: 0.87 and 0.89) and good calibration (goodness-of-fit C p value: 0.83 and 0.28) in their population. However, when they re-evaluated the validation of these scores in 8 ICUs using the same inclusion criteria (from September 1997 to March 1998, 293 patients), they found that the discrimination ability of the original SHARF scores deteriorated (AUROC: 0.67 and 0.78, respectively). They also found that three additional variables were related to hospital mortality (bilirubin, sepsis and hypotension). The AUROC of these new scores improved significantly compared to the original ones (AUROC: 0.82 and 0.83, respectively). The PICARD (Program to Improve Care in Acute Renal Disease) score is the most recently published AKIspecific severity score and also the population to generate the score is the largest in the literature. This study was conducted in five centers in the USA from February 1999 to August 2001, including 618 patients [27]. AKI was defined as an increase in SCr 10.5 mg/dl with baseline SCr !1.5 mg/dl, or an increase in SCr 11.0 mg/dl with baseline SCr 11.5 mg/dl and !5.0 mg/dl. Patients with a baseline SCr 15.0 mg/dl were not included. Using multivariate logistic regression analysis, the investigators created three scores: at day of AKI diagnosis, day of consultation and day of first renal replacement therapy (RRT). Using their population, they compared the AUROC of their score with several general severity scores and AKI severity scores (Liano, Paganini and original SHARF I). Surprisingly, the AUROC of their score was only 0.68 at the day of consultation, which was lower than that of APACHE-III [5], SAPS-II [6] and SOFA [15] (all of these score had the AUORC of 0.70). Compared to general severity scores, AKI severity scores have not reached consistent high levels of performance. External validation studies have shown that no AKI severity scores have good outcome prediction ability [9–12]. Douma et al. [9] evaluated the scores by Rasmussen et al. [18], Lohr et al. [19], Schaefer et al. [20] and Li-

Because of different case mix, collected variables, sample size and statistical power in each study, reported risk factors for hospital mortality in patients with AKI are quite variable. To find out common and relevant risk factors, those used in more than two AKI severity scores are shown in table 2. The most frequently used risk factor is mechanical ventilation, followed by bilirubin, age, oliguria and hypotension. These risk factors are often included in general severity scores as well, except for sepsis. Sepsis has been reported to be a leading precipitant of AKI, with 50–70% of AKI being related to sepsis [1, 30]. However, only a few studies have looked at this relationship specifically. Neveu et al. [31] reported that AKI was of septic origin in 50% of the cases and associated with significantly higher hospital mortality than nonseptic AKI. Hoste et al. [32] observed 185 septic patients in a surgical ICU and found that 16.2% of these patients developed AKI and 70% of them required RRT. Therefore, sepsis is an important condition for both the development of AKI and hospital mortality. If generating a new AKI severity score is planned, it seems important to include sepsis as a variable. Although gender was included in five studies (table 2), two studies found female and three found male as a risk

Outcome Prediction for AKI

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Which Variables Should Be Included in Further Severity Scores?

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Table 2. Common variables in 12 AKI severity scores

Reference number 16 Mechanical ventilation Bilirubin Age Oliguria Hypotension Gender Acute myocardial infarction High urea/urea rise Sepsis Heart failure Platelet count Low creatinine Prothrombin time

* * * *

17

18

19

20

21

22

23

24

25

26

27

* * * *

*

*

*

* *

* * * *

* * *

* * * *

*

* * * * *

* *

*

* * * * * *

* * *

factor, suggesting that this factor depends on the patient population under study and is not a reliable risk factor. Although acute myocardial infarction (AMI), heart failure and prothrombin time are used in more than 3 severity scores, they are often just a ‘subvariable’ (e.g. Cioffi’s score had cardiac failure as a independent variable, which included low cardiac index, arrhythmias and AMI [16]). Therefore, only seven variables (mechanical ventilation, bilirubin, age, oliguria, hypotension, sepsis and platelet count) are common risk factors and should be included in future AKI severity scores.

Should Creatinine and Urea Be Included in Severity Scores?

The fact that both low creatinine and high urea are independent risk factors for AKI is not intuitively understandable (table 2). Therefore, careful discussion is needed if they should be used in a future AKI severity score. Serum creatinine concentration is known to be dependent of age, gender, race, muscle mass, nutritional status, dietary protein intake and fluid volume status [33]. Serum creatinine is included in general severity scores as one of independent variables [4]. Also, Cartin-Ceba et al. [34] looked at 11,291 patients in three ICUs and found that, even after adjusting for several confounding factors, low creatinine was associated with increased mortality in a dose-response manner. However, it has also been reported that a small creatinine rise was related to high c220

Nephron Clin Pract 2008;109:c217–c223

*

*

* *

* * * *

* *

* *

*

* * * *

* * *

*

* * * * *

Number of studies 11 8 7 7 6 5 4 4 4 3 3 3 3

mortality in various groups of patients [35, 36]. Coca et al. [36] systematically reviewed the literature and found that 0.5–0.9 mg/dl increase in serum creatinine from baseline had a relative risk (RR) of death of 6.2, and even a smaller increase (0.3–0.4 mg/dl) also had a RR of death of 2.3. Recently, to evaluate this apparent paradox, Cerdá et al. [33] included volume status, weight change between admission and continuous RRT (CRRT), serum albumin at start of CRRT, admission glomerular filtration rate calculated with the MDRD formula [37] and Liano’s score [21] in the multivariate logistic regression analysis for hospital mortality in patients with AKI requiring CRRT. Although including these variables eliminated the significance of creatinine, their final model still found that the odds ratio for creatinine was 1.302. Because their sample size was small (134 patients), the significance of their findings is unclear. Serum urea concentration is also affected by many factors, e.g. steroid usage, intestinal bleeding, fluid status, volume distribution, and so on. Nonetheless, urea has been used a marker of timing for starting RRT in several studies [38, 39]. These studies have shown that patients with higher urea at start of RRT had worse outcome than patients with lower urea and concluded that early start of RRT might have affected outcome of patients requiring RRT favorably. However, this assumption (low urea means early start of RRT) does not make sense because serum creatinine should also be low if RRT is started early and yet a low creatinine is related to worse outcome. Uchino

This point is important, because timing of starting RRT has been a matter of debate and further studies are necessary. When conducting such studies, serum urea or creatinine concentrations might not be good indicators in terms of defining the timing of starting RRT (early or late). To further investigate these problems, I have analyzed the BEST kidney database [40]. Eight hundred and eighty-two of 1,006 patients treated with CRRT had all the necessary variables to conduct multivariate logistic regression analysis for hospital mortality, i.e. the seven variables discussed above and four variables that possibly affected serum creatinine and urea concentrations (explanatory variables). Table 3 shows the result of the multivariate analysis. All common risk factors were found be significant factors for hospital mortality. Even after adjusting for these risk factors and explanatory variables, both creatinine and urea remained significant (creatinine: p ! 0.0001; urea: p = 0.015). However, creatinine and urea clearly have a strong colinearity. If creatinine is high, urea is usually also high. Therefore, even if both variables are independent factors for the prediction of outcome, it is uncertain whether including both variables in a severity score could improve the prediction ability of the score. Thus, to evaluate the impact of including creatinine and urea on outcome prediction ability, two multivariate analyses were conducted for hospital mortality and the AUROC for each analysis was calculated (fig. 1). The AUROC of the analysis without creatinine and urea was 0.730, which improved only slightly to 0.744 when including these two variables. Therefore, this result suggests that, although both creatinine and urea remain significant variables for predicting outcome even after excluding confounding factors, they might not improve prediction ability. This finding is important when generating future AKI severity scores.

Conclusions

Currently available severity scores have significant limitations. General severity scores do not reliably predict the outcome of patients with AKI, partly because data from only a few patients with AKI were collected when these scores were generated. AKI severity scores also contain problems and limitations, mainly due to being based on small populations. Seven variables (mechanical ventilation, bilirubin, age, oliguria, hypotension, sepsis and platelet count) are often found as comOutcome Prediction for AKI

Table 3. Multivariate logistic regression analysis for hospital mortality in the BEST kidney database

Independent variable

Odds ratio (95% CI)

p value

Creatinine, ␮mol/l Urea, mmol/l Common risk factors Mechanical ventilation Bilirubin, mmol/l Age, years Hypotension Sepsis Platelet count (103/␮l) Oliguria (<400 ml/day) Explanatory variables Fluid overload Body weight, kg Chronic kidney disease ICU-CRRT, day

0.998 (0.997–0.999) 1.019 (1.004–1.034)

<0.0001 0.015

2.072 (1.332–3.223) 1.003 (1.002–1.005) 1.029 (1.018–1.039) 1.644 (1.094–2.470) 1.816 (1.319–2.500) 0.997 (0.996–0.998) 1.504 (1.089–2.076)

0.0012 0.0004 <0.0001 0.017 0.0003 <0.0001 0.013

0.940 (0.683–1.295) 0.989 (0.980–0.999) 0.974 (0.683–1.390) 1.017 (0.988–1.047)

0.71 0.024 0.89 0.26

ICU-CRRT = Duration between ICU admission to start of CRRT.

1

0.8

0.6

0.4

Without creatinine/urea With creatinine/urea

0.2

0 0

0.2

0.4

0.6

0.8

1

Fig. 1. ROC curves for hospital mortality. The thin and bold lines

indicate the predicted mortality calculated with and without creatinine and urea, respectively. Including creatinine and urea, there was only small improvement in the area under the ROC curve (from 0.730 to 0.744).

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mon risk factors and should be included in future AKI severity scores. Although several studies have consistently reported that both low creatinine and high urea at start of RRT are related to worse outcome, their inclusion

might not improve prediction ability. Using such information and a large database collected internationally, it might be possible to generate a better illness severity score for AKI patients.

References 1 Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C, Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators: Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294:813–818. 2 Hirschberg R, Kopple J, Lipsett P, et al: Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure. Kidney Int 1999;55:2423– 2432. 3 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– 774. 4 Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. Crit Care Med 1985;13: 818–828. 5 Knaus WA, Wagner DP, Draper EA, et al: The APACHE III prognostic system: risk prediction of hospital mortality for critically ill hospitalized adults. Chest 1991;100:1619– 1636. 6 Le Gall J-R, Lemeshow S, Saulnier F: A new simplified acute physiology score (SAPS II) based on a European/North American multicentre study. JAMA 1993;270:2957–2963. 7 Metnitz PG, Lang T, Vesely H, Valentin A, Le Gall JR: Ratios of observed to expected mortality are affected by differences in case mix and quality of care. Intensive Care Med 2000;26:1466–1472. 8 Harrison DA, Brady AR, Parry GJ, Carpenter JR, Rowan K: Recalibration of risk prediction models in a large multicenter cohort of admissions to adult, general critical care units in the United Kingdom. Crit Care Med 2006;34:1378–1388. 9 Douma CE, Redekop WK, van der Meulen JH, van Olden RW, Haeck J, Struijk DG, Krediet RT: Predicting mortality in intensive care patients with acute renal failure treated with dialysis. J Am Soc Nephrol 1997; 8:111– 117. 10 Fiaccadori E, Maggiore U, Lombardi M, Leonardi S, Rotelli C, Borghetti A: Predicting patient outcome from acute renal failure comparing three general severity of illness scoring systems. Kidney Int 2000; 58: 283– 292.

c222

11 Lima EQ, Dirce MT, Castro I, Yu L: Mortality risk factors and validation of severity scoring systems in critically ill patients with acute renal failure. Ren Fail 2005; 27: 547– 556. 12 Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Doig GS, Oudemans van Straaten H, Ronco C, Kellum JA, Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators: External validation of severity scoring systems for acute renal failure using a multinational database. Crit Care Med 2005;33:1961–1967. 13 Lemeshow S, Teres D, Klar J, Avrunin JS, Gehlbach SH, Rapoport J: Mortality Probability Models (MPM II) based on an international cohort of intensive care unit patients. JAMA 1993;270:2478–2486. 14 Le Gall JR, Klar J, Lemeshow S, Saulnier F, Alberti C, Artigas A, Teres D: The logistic organ dysfunction system: a new way to assess organ dysfunction in the intensive care unit. ICU Scoring Group. JAMA 1996; 276: 802–810. 15 Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, Suter PM, Sprung CL, Colardyn F, Blecher S: Use of the SOFA score to assess the incidence of organ dysfunction/ failure in intensive care units: results of a multicenter, prospective study. Working group on ‘sepsis-related problems’ of the European Society of Intensive Care Medicine. Crit Care Med 1998;26:1793–1800. 16 Cioffi WG, Ashikaga T, Gamelli RL: Probability of surviving postoperative acute renal failure: development of a prognostic index. Ann Surg 1984;200:205–211. 17 Bullock ML, Umen AJ, Finkelstein M, Keane WF: The assessment of risk factors in 462 patients with acute renal failure. Am J Kidney Dis 1985;5:97–103. 18 Rasmussen HH, Pitt EA, Ibels LS, McNeil DR: Prediction of outcome in acute renal failure by discriminant analysis of clinical variables. Arch Intern Med 1985; 145: 2015– 2018. 19 Lohr JW, McFarlane MJ, Grantham JJ: A clinical index to predict survival in acute renal failure patients requiring dialysis. Am J Kidney Dis 1988;11:254–259. 20 Schaefer JH, Jochimsen F, Keller F, Wegscheider K, Distler A: Outcome prediction of acute renal failure in medical intensive care. Intensive Care Med 1991;17:19–24.

Nephron Clin Pract 2008;109:c217–c223

21 Liano F, Gallego A, Pascual J, et al: Prognosis of acute tubular necrosis: an extended prospectively contrasted study. Nephron 1993; 63:21–31. 22 Barton IK, Hilton PJ, Taub NA, Warburton FG, Swan AV, Dwight J, Mason JC: Acute renal failure treated by haemofiltration: factors affecting outcome. Q J Med 1993;86:81– 90. 23 Paganini EP, Halstenberg WK, Goormastic M: Risk modeling in acute renal failure requiring dialysis: the introduction of a new model. Clin Nephrol 1996; 46:206–211. 24 Chertow GM, Lazarus JM, Paganini EP, Allgren RL, Lafayette RA, Sayegh MH: Predictors of mortality and the provision of dialysis in patients with acute tubular necrosis. The Auriculin Anaritide Acute Renal Failure Study Group. J Am Soc Nephrol 1998;9:692– 698. 25 Mehta RL, Pascual MT, Gruta CG, Zhuang S, Chertow GM: Refining predictive models in critically ill patients with acute renal failure. J Am Soc Nephrol 2002; 13:1350–1357. 26 Lins RL, Elseviers MM, Daelemans R, Arnouts P, Billiouw JM, Couttenye M, Gheuens E, Rogiers P, Rutsaert R, Van der Niepen P, De Broe ME: Re-evaluation and modification of the Stuivenberg Hospital Acute Renal Failure (SHARF) scoring system for the prognosis of acute renal failure: an independent multicentre, prospective study. Nephrol Dial Transplant 2004;19:2282–2288. 27 Chertow GM, Soroko SH, Paganini EP, Cho KC, Himmelfarb J, Ikizler TA, Mehta RL: Mortality after acute renal failure: models for prognostic stratification and risk adjustment. Kidney Int 2006;70:1120–1126. 28 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: 828–834. 29 Lins RL, Elseviers M, Daelemans R, Zachée P, Zachée P, Gheuens E, Lens S, De Broe ME: Prognostic value of a new scoring system for hospital mortality in acute renal failure. Clin Nephrol 2000; 53:10–17.

Uchino

30 Bagshaw SM, Laupland KB, Doig CJ, Mortis G, Fick GH, Mucenski M, Godinez-Luna T, Svenson LW, Rosenal T: Prognosis for longterm survival and renal recovery in critically ill patients with severe acute renal failure: a population-based study. Crit Care 2005; 9: 700–709. 31 Neveu H, Kleinknecht D, Brivet F, Loirat P, Landais P: Prognostic factors in acute renal failure due to sepsis: results of a prospective multicentre study. The French Study Group on Acute Renal Failure. Nephrol Dial Transplant 1996;11:293–299. 32 Hoste EA, Lameire NH, Vanholder RC, Benoit DD, Decruyenaere JM, Colardyn FA: Acute renal failure in patients with sepsis in a surgical ICU: predictive factors, incidence, comorbidity, and outcome. J Am Soc Nephrol 2003;14:1022–1030. 33 Cerdá J, Cerdá M, Kilcullen P, Prendergast J: In severe acute kidney injury, a higher serum creatinine is paradoxically associated with better patient survival. Nephrol Dial Transplant 2007;22:2781–2784.

Outcome Prediction for AKI

34 Cartin-Ceba R, Afessa B, Gajic O: Low baseline serum creatinine concentration predicts mortality in critically ill patients independent of body mass index. Crit Care Med 2007;35:2420–2423. 35 O’Brien MM, Gonzales R, Shroyer AL, Grunwald GK, Daley J, Henderson WG, Khuri SF, Anderson RJ: Modest serum creatinine elevation affects adverse outcome after general surgery. Kidney Int 2002;62:585– 592. 36 Coca SG, Peixoto AJ, Garg AX, Krumholz HM, Parikh CR: The prognostic importance of a small acute decrement in kidney function in hospitalized patients: a systematic review and meta-analysis. Am J Kidney Dis 2007;50:712–720.

37 National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39(2 suppl 1):S1–S266. 38 Gettings LG, Reynolds HN, Scalea T: Outcome in post-traumatic acute renal failure when continuous renal replacement therapy is applied early vs. late. Intensive Care Med 1999;25:805–813. 39 Liu KD, Himmelfarb J, Paganini E, Ikizler TA, Soroko SH, Mehta RL, Chertow GM: Timing of initiation of dialysis in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol 2006;1:915–9. 40 Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Oudemans-van Straaten H, Ronco C, Kellum JA: Continuous renal replacement therapy: a worldwide practice survey. The beginning and ending supportive therapy for the kidney (BEST kidney) investigators. Intensive Care Med 2007;33:1563–1570.

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Nephron Clin Pract 2008;109:c224–c228 DOI: 10.1159/000142932

Published online: September 18, 2008

Acute Kidney Injury: New Concepts, Renal Recovery Max Bell Department of Anaesthesiology and Intensive Care, Karolinska University Hospital, Solna, and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

Key Words AKI ⴢ Epidemiology ⴢ Outcome ⴢ Renal recovery ⴢ Morbidity

Abstract Background/Aims: Long-term outcome after critical illness is important. After acute kidney injury (AKI) one measurement of such long-term outcome is assessment of renal recovery. Methods: A literature search was performed using the Medline database from 1960 to the present. The attempt was to include major clinical trials and other systematic reviews published in the field of renal recovery after critical illness. Results: More than 15 studies have covered the topic of renal outcome after intensive care, but the results are ambiguous. Studies from the mid-1990s showed that AKI survivors were at great risk of becoming dialysis dependent for life, with non-recovery reported at around 30%. Later investigations found lower risks, with non-recovery between 5 and 8% depending on the choice of continuous or intermittent renal replacement therapies. Conclusion: Continuous renal replacement therapies may be associated with better chances of renal recovery. Determining when and how to measure long-term renal outcome remains a matter of controversy. Copyright © 2008 S. Karger AG, Basel

© 2008 S. Karger AG, Basel 1660–2110/08/1094–0224$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nec

Background

Long-term outcome after critical illness is an overlooked but crucial measurement of treatment quality. The treating physician has an obligation to his or her current and future patients – and to their next of kin – to focus on more than short-term outcome. We need to optimize outcomes like mortality, morbidity and quality of life beyond the walls of the intensive care unit and hospital. A number of recent studies have elucidated one aspect of long-term outcome for the subgroup of patients with acute kidney injury (AKI): the measurement of renal recovery. In this paper, we define renal recovery as not being dialysis dependent. This is very blunt, but practical – and extremely few studies have investigated the long-term renal outcome, measured as glomerular filtration rate (GFR). Additionally, we lack consensus on what method to use in determining GFR. Nonetheless, we are aware of at least one study pointing to the fact that even mild renal dysfunction (and only slightly lowered GFR) is associated with increased long-term mortality [1]. If the research community decides to use the above definition of renal recovery another question arises as discussed below: when do we measure renal recovery? Some would argue that common sense is enough, but we also have hard data telling us that patients surviving Max Bell Department of Anaesthesiology and Intensive Care Karolinska University Hospital, F2:01, SE–171 76 Solna, Stockholm (Sweden) Tel. +46 8 5177 2066, Fax +46 8587 1000, E-Mail [email protected]

with or without the need for chronic dialysis therapy have differing quality of life. Health-related quality of life has been reported to be significantly impaired for patients on chronic dialysis therapy [2]. Moreover, the cost of lifelong dialysis is high, with annual expenses estimated at over USD 50,000 [3]. Furthermore, the overall mortality of patients with renal failure requiring dialysis is very high. Recent Swedish data from the Swedish Register of Active Uremia (SRAU) indicate a yearly mortality at 28.1% for patients on chronic dialysis [4]. This paper focuses on the current evidence regarding renal recovery after acute kidney injury. A literature search using terms as ‘acute kidney injury, acute renal failure, renal recovery, morbidity, outcome and long-term outcome’ was performed using the Medline database from 1960 to the present. The attempt was to include major clinical trials and other systematic reviews published in the field.

The Evidence

Reports from the early and mid-1990s indicate that survivors after acute kidney injury requiring renal replacement therapy (RRT) in the intensive care unit are at great risk of becoming dialysis dependent for life. Cosentino et al. [5] detail the risk for survivors to never recover their renal function at 34.3%. In a study from the same period of time, Chertow et al. [6] found 33% of the survivors to be dialysis dependent. Neither of these two studies focused specifically on renal recovery, but more concerning is the fact that they did not specify a time-frame for when renal recovery was determined. The Chertow study used hospital discharge as a cut-off, and the Cosentino study used ICU discharge. Both these research papers solely reported data on patients treated with intermittent hemodialysis (IHD). In a small retrospective study from 1991, Spurney et al. [7] reported that 23 of 26 surviving patients (88%) recovered their renal function. One study found that 16.2% of survivors after ARF remained dependent on long-term dialysis, and only a small decline in this number was seen 18 months after the ARF episode [8]. Even higher numbers of dialysis dependence were reported by Augustine et al. [9] in a randomized trial published in 2004. They defined renal recovery as the discontinuation of dialysis therapy before discharge from the hospital. Only 9 patients, 36% of the survivors, or 11% of the total population, were dialysis free at that time, 5 patients that had been on continuous therapy versus 4 on IHD. Less renal recovery was seen in patients with a AKI: New Concepts, Renal Recovery

greater decrease in median arterial pressure (MAP) and maintenance of urine output after dialysis was an independent predictor of renal recovery. Albright and co-workers analyzed patient survival and renal recovery after acute renal failure in randomized comparison between cellulose acetate (CA) and polysulfone membrane (PS) dialyzers [10]. Of the 37 survivors, only 27 (73%) patients recovered their renal function at 30 days. More recent studies tell a somewhat differing tale. In a Finnish study, 5 of 62 patients (8%) treated with continuous RRT – without end-stage renal disease prior to ICU admission – became dialysis dependent within 6 months after inclusion in the cohort [11]. All of these 5 patients did have ‘chronic diseases predisposing to renal failure’ (it is not clear from the paper what diseases the authors mean) at admission to the ICU. In Scotland, Ali et al. [12] reported the following data: of 474 patients with AKI full renal recovery (as defined by a serum creatinine below the thresholds for inclusion in the cohort, i.e. 1150 ␮mol/l in men or 1130 ␮mol/l in women) was achieved in 321 patients (68%) and 24 (5%) had partial recovery (serum creatinine remained over the threshold) and in 127 patients (27%) recovery could not be determined because the patient died in the acute phase. Recovery in the RIFLE F category was significantly lower, and only two patients remained on dialysis for 190 days. After exclusion of the 127 from the whole group of 474 patients, where recovery could not be determined, 92.5% had full recovery, 7% had partial recovery and 0.6% had no recovery. When the cohort was restricted to the 37 patients receiving RRT, the 2 patients remaining on dialysis (‘no recovery’) were found in that very group. This indicates that 5.4% of patients with severe AKI – requiring RRT – ended up in need of chronic dialysis. In Australia, Silvester et al. [13] followed 299 patients on RRT (the vast majority, 98%, were treated with continuous therapies) and reported that 25 of the 159 surviving patients (15.7%) developed the need for chronic dialysis. Of these 25 patients, 80% or 20 patients had preICU renal impairment. A single-center study from Sweden on patients with AKI on CRRT found that only 5 (4.8%) of 105 patients were permanently dialysis-dependent after their stay in the ICU. Four of these 5 started chronic RRT as soon as they left the ICU and a fifth patient was monitored by nephrologists, but was not started on RRT until ⬃3 years after the episode of critical illness [14].

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Color version available online

Jacka et al. [15] investigated the impact of continuous RRT versus intermittent hemodialysis in a nonrandomized single-center study. They found that, although seemingly sicker patients were treated with CRRT (as indicated by more acute lung injury, greater requirement of vasopressor, higher therapeutic intervention scale scores) the renal outcome was significantly better. Of 37 survivors, 24 were treated with CRRT and 21 regained their renal function (87.5%). Of the 14 survivors from the IHD group, only 5 (36%) regained their renal function. In 2002, a meta-analysis showed signs of an increased risk with a point-estimate of 1.66 (95% CI 0.78–3.52) for dialysis dependence after IHD as compared to CRRT [16]. Furthermore, a randomized controlled trial by Mehta et al. [17] showed benefits for CRRT regarding renal recovery. Chronic renal insufficiency at death or hospital discharge was diagnosed in 17% where therapy was IRRT versus only 4% of patients whose initial therapy was CRRT (p = 0.01). For patients receiving an adequate trial of monotherapy, recovery of renal function was 92% for CRRT versus 59% for IRRT (p ! 0.01). Lastly, a higher percentage of subjects crossing over from IRRT to CRRT recovered their renal function compared to patients crossing over in the opposite direction (45 vs. 7%, p ! 0.01). A recent multicenter, multinational study also focused on initial technique of renal replacement therapy (RRT) and the effect on patient – and kidney – survival in critically ill patients with acute kidney injury [18]. This was the third publication from the Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators Writing Committee. Enrolling 1,218 patients treated with continuous RRT (CRRT) or intermittent RRT (IRRT) for acute renal failure (ARF) in 54 ICUs in 23 countries, the investigators followed the patients to death or hospital discharge. Their findings were important: patients treated with CRRT (n = 1,006, 82.6%) had higher illness severity scores, required vasopressor drugs and mechanical ventilation more frequently compared to those receiving IRRT (n = 212, 17.4%). Also, the reasons for initiating RRT differed, for instance, sepsis was more common in the CRRT group. Considering the different patient categories the authors unsurprisingly found that unadjusted hospital survival was lower in the CRRT group. However, multivariable logistic regression showed that choice of RRT was not an independent predictor of c226

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Cumulative incidence of permanent renal failure (%)

Intermittent versus Continuous Renal Replacement Therapy and Renal Recovery 20 18 16 14 12 10 8 6 4 IHD CRRT

2 0 90 days

1

2

3

4 5 Time (years)

6

7

Fig. 1. From the SWING study [19]. Cumulative incidence of per-

manent renal failure with dialysis dependence among patients surviving 90 days.

hospital survival or dialysis-free hospital survival. Most importantly, the study showed that the choice of CRRT was a predictor of dialysis independence at hospital discharge among survivors (OR 3.3, 95% CI 1.8–6.0, p ! 0.0001). They conclude that worldwide, the choice of CRRT as initial therapy is not a predictor of hospital survival or dialysis-free hospital survival, but that it is an independent predictor of renal recovery among survivors. The authors speculate on the reasons for this, and whether hypotension plays a part. The numbers of reported hypotensive episodes were indeed significantly higher in the IRRT group than in the CRRT group (27.9 and 18.8%, respectively). The Swedish Intensive Care Nephrology Group (SWING) performed a study of 2,202 patients with ARF [19]. They were treated with either CRRT or IRRT in 32 Swedish intensive care units. Duration of follow-up ranged from 3 months to 10 years. SWING addressed the same issue as the BEST investigators [18], namely whether the ICU choice of treatment modality affects renal recovery. Within 90 days of initial dialysis, 1,100 patients had died. No association was found between dialysis modality and 90-day mortality. Among the 90-day survivors, 944 had received CRRT Bell

Table 1. Renal recovery after AKI in patients treated with RRT Study, number of patients and year of publication

Comments

Study design

Patients

Percentage of survivors with nonrecovery

Time when renal outcome was measured

Spurney [7] (n = 26), 1991

retrospective chart review

survivors of ARF on RRT >4 weeks

12

1 year

Cosentino [5] (n = 363), 1994

prospective

ARF on RRT (IHD)

34.3

ICU discharge

Chertow [6] (n = 132), 1995

retrospective chart review

ARF on RRT (IHD)

33

hospital discharge

Bhandari [8] (n = 1,095), 1996

a decline in number of patients with ESRD was seen after 18 months

retrospective

ARF, defined as Scr >600 ␮mol/l and/or requiring RRT

16

90 days–18 months

Albright [10] (n = 53), 2000

n = 66, but only 53 on RRT in the ICU, 37 patients survived to 30 days

prospective, comparing hemodialysis membranes

ARF on RRT (IHD only)

27

30 days

Korkeila [11] (n = 62), 2000

nonrecovery associated with premorbid risk factors

retrospective cohort study

ARF on RRT (CRRT)

8

6 months

Silvester [13] (n = 299), 2001

80% of survivors (n = 159) with multicenter national nonrecovery had pre-ICU cohort study renal impairment

ARF on RRT (98% on CRRT)

15.7

hospital discharge

prospective

ARF

11

90 days

64

hospital discharge

Metcalfe [20] (n = 34), 2002 Augustine [9] (n = 80), 2004

only 25 patients were alive at hospital discharge

RCT, IHD vs. CRRT

ARF on RRT (IHD and CRRT)

Bell [14] (n = 207), 2005

105 survivors at 30 days

retrospective cohort study

ARF on RRT (CRRT only)

Jacka [15] (n = 93), 2005

38 survivors, CRRT (24) vs. IHD (14)

retrospective chart review

ARF on RRT (CRRT and IHD)

12.5% in CRRT group and 64% in IHD group

hospital discharge

Ali [12] (n = 37), 2007

474 patients with AKI, only 37 on RRT, 21 died

retrospective cohort study

ARF on RRT (51% on IHD and 49% on CRRT)

12.5

90 days

Bell [19] (n = 2,202), 2007

32 ICUs contributed data, CRRT vs. IHD

multicenter national cohort study

ARF on RRT (CRRT and IHD)

8.3% in CRRT group and 16.5 % in IHD group

90 days (and up to 10 years)

4.8

up to 18 months

and 158 had received IRRT. The risk of end-stage renal disease (ESRD) requiring hemodialysis was considerably higher in 90-day survivors treated with IRRT than in those treated with CRRT (adjusted odds ratio 2.60, 95% CI 1.5–4.3). This finding was especially interesting considering the fact that more patients had diabetes (with an increased risk of ESRD) in the CRRT group. However, the trend towards a higher risk of ESRD with IRRT decreased with increasing duration of follow-up (fig. 1). Among the 90-day survivors who did develop ESRD, the risk of death was markedly higher in patients treated with IRRT than in those treated with CRRT (hazard ratio 2.3, 95% CI 1.3–4.1). A summary of studies dealing with long-term renal recovery is presented in table 1.

The intensive care research community is finally focusing on long-term outcome. Renal recovery is one important parameter, and the above-mentioned studies elucidate the fact that we can – that we must – look beyond ICU mortality. It is practical – and allows benchmarking – to define renal recovery as being free from a lifelong need of dialysis. As higher expenses associated with CRRT have been used in the debate regarding choice of modality, the down-stream costs of ESRD requiring chronic hemodialysis may have to be considered in future discussions. Seemingly, continuous renal replacement therapies are associated with better chances of renal

AKI: New Concepts, Renal Recovery

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Conclusions

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recovery. The introduction of slow low-efficiency daily dialysis (SLEDD) – a variant of intermittent hemodialysis – also needs to be evaluated in terms of renal recovery. Even though hospital discharge may be convenient, it is preferable (in order to be able to adequately compare outcome data) to measure renal outcome at a given time

point; we propose the use of 90 days, well aware that longer long-term follow-up also adds valuable information. In determining the optimal choice of critical care intervention for acute kidney injury, the issues of long-term mortality, long-term morbidity and quality of life should be paramount in future investigations.

References 1 Van Biesen W, De Bacquer D, Verbeke F, Delanghe J, Lameire N, Vanholder R: The glomerular filtration rate in an apparently healthy population and its relation with cardiovascular mortality during 10 years. Eur Heart J 2007;28 :478–483. 2 Gokal R: Quality of life in patients undergoing renal replacement therapy. Kidney Int suppl 1993; 40:S23–S27. 3 Lee H, Manns B, Taub K, Ghali WA, Dean S, Johnson D, Donaldson C: Cost analysis of ongoing care of patients with end-stage renal disease: the impact of dialysis modality and dialysis access. Am J Kidney Dis 2002; 40: 611–622. 4 Schon S, Ekberg H, Wikström B, Odén A, Ahlmén J: Renal replacement therapy in Sweden. Scand J Urol Nephrol 2004; 38:332– 339. 5 Cosentino F, Chaff C, Piedmonte M: Risk factors influencing survival in ICU acute renal failure. Nephrol Dial Transplant 1994; 9(suppl 4):179–182. 6 Chertow GM, Christiansen CL, Cleary PD, Munro C, Lazarus JM: Prognostic stratification in critically ill patients with acute renal failure requiring dialysis. Arch Intern Med 1995;155 :1505–1511. 7 Spurney RF, Fulkerson WJ, Schwab SJ: Acute renal failure in critically ill patients: prognosis for recovery of kidney function after prolonged dialysis support. Crit Care Med 1991; 19:8–11. 8 Bhandari S, Turney JH: Survivors of acute renal failure who do not recover renal function. Qjm 1996;89:415–421.

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9 Augustine JJ, Sandy D, Seifert TH, Paganini EP: A randomized controlled trial comparing intermittent with continuous dialysis in patients with ARF. Am J Kidney Dis 2004;44: 1000–1007. 10 Albright RC Jr, Smelser JM, McCarthy JT, Homburger HA, Bergstralh EJ, Larson TS: Patient survival and renal recovery in acute renal failure: randomized comparison of cellulose acetate and polysulfone membrane dialyzers. Mayo Clin Proc 2000; 75: 1141– 1147. 11 Korkeila M, Ruokonen E, Takala J: Costs of care, long-term prognosis and quality of life in patients requiring renal replacement therapy during intensive care. Intensive Care Med 2000;26:1824–1831. 12 Ali T, Khan I, Simpson W, Prescott G, Townend J, Smith W, Macleod A: Incidence and outcomes in acute kidney injury: a comprehensive population-based study. J Am Soc Nephrol 2007;18:1292–1298. 13 Silvester W, Bellomo R, Cole L: Epidemiology, management, and outcome of severe acute renal failure of critical illness in Australia. Crit Care Med 2001;29:1910–1915. 14 Bell M, Liljestam E, Granath F, Fryckstedt J, Ekbom A, Martling CR: Optimal follow-up time after continuous renal replacement therapy in actual renal failure patients stratified with the RIFLE criteria. Nephrol Dial Transplant 2005;20:354–360. 15 Jacka MJ, Ivancinova X, Gibney RT: Continuous renal replacement therapy improves renal recovery from acute renal failure. Can J Anaesth 2005;52:327–332.

Nephron Clin Pract 2008;109:c224–c228

16 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;40:875–885. 17 Mehta RL, McDonald B, Gabbai FB, Pahl M, Pascual MT, Farkas A, Kaplan RM; Collaborative Group for Treatment of ARF in the ICU: A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int 2001;60:1154–1163. 18 Uchino S, Bellomo R, Kellum JA, Morimatsu H, Morgera S, Schetz MR, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, OudemansVan Straaten HM, Ronco C; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators Writing Committee: Patient and kidney survival by dialysis modality in critically ill patients with acute kidney injury. Int J Artif Organs 2007; 30:281–292. 19 Bell M, SWING, Granath F, Schön S, Ekbom A, Martling CR: Continuous renal replacement therapy is associated with less chronic renal failure than intermittent haemodialysis after acute renal failure. Intensive Care Med 2007;33:773–780. 20 Metcalfe W, Simpson M, Khan IH, Prescott GJ, Simpson K, Smith WC, MacLeod AM; Scottish Renal Registry: Acute renal failure requiring renal replacement therapy: incidence and outcome. Q J Med 2002; 95: 579– 583.

Bell

Author Index Vol. 109, No. 4, 2008

Bagshaw, S.M. c206 Bell, M. c224 Bellomo, R. c181, c182, e95 Bonventre, J.V. c181, c192 Bouchard, J. p85

Okusa, M.D. e102 Pisoni, R. c188 Rabb, H. p80 Ronco, C. c182

Ding, F. e118 Feltes, C.M. p80 Humes, H.D. e118 Kellum, J.A. c182 Khosla, N. p85 Kinsey, G.R. e102 Koyner, J.L. e109

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Sandoval, R.M. c198 Sharfuddin, A.A. c198 Shaw, A. p55 Sher Ali, R. e109 Stafford-Smith, M. p55 Swaminathan, M. p55 Tolwani, A.J. c188 Townsend, D.R. c206

Langenberg, C. e95 Lebrec, D. p73 Li, L. e102

Uchino, S. c217

May, C. e95 McCullough, P.A. p61 Mehta, R.L. p85 Molitoris, B.A. c198 Moreau, R. p73 Murray, P.T. e109

Waikar, S.S. c192 Wan, L. e95 Wille, K.M. c188

Van Eyk, J. p80

c229

Subject Index Vol. 109, No. 4, 2008

Acute kidney injury c182, c188, c192, c198, c206, c217, c224, e109, e118, p55, p61, p85 – renal failure c182, c188, c192, c206, e95, e102 Adaptive immunity e102 Afferent arteriole e95 Anti-oxidants e109 Apoptosis e95 Ascites p73 BEST c188 Biomarker c192 Cardiac surgery p55 Cardiovascular disease p61 Cell therapy e118 Chronic kidney disease p61 Cirrhosis p73 Creatinine c217 Critical care p80 – illness c182 Cytokines p80 Diagnosis c192 Dialysis p55, p85 Efferent arteriole e95 Epidemiology c182, c224 Fluid therapy c206 Free radicals e109 Furosemide c206 Glomerular filtration rate e95 Glomerulus e95 Hemodialysis c182 Hemofiltration c182 Hepatorenal syndrome p73 Hydroxyethylstarch c206 Inflammation e118, p80 Innate immunity e102 Iodinated contrast p61 Ischemia c198

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Kidney p80 – disease c182 Leukocytes e102, p80 Liver dialysis p85 Loop diuretic c206 Lung p80 Morbidity c224 MRI c198 Multi-photon microscopy c198 Nanotechnology e118 Nitric oxide e95 Oliguria c206 Osmolality p61 Outcome c224 – prediction c217 Oxidative stress e109 PICARD c188 Portal hypertension p73 Prophylaxis p61 Reactive oxygen metabolites e109 Renal recovery c224 Resuscitation c206 RIFLE criteria c182 Sepsis c198, c217, p85 Severity score c217 Tissue engineering e118 Tubule e95 – cells e118 Ultrafiltration p85 Ultrasound c198 Vasoconstrictors p73 Vasodilatation e95 Volume overload c206

Author Index Vol. 109, 2008

Açıkgöz, Y. c168 Akiba, T. c100 Akimoto, T. c119 Akiyama, S. c49 Akizawa, T. c100 Ando, Y. c119 Aoki, A. c33 Asano, Y. c100 Aydin, F. c168 Aytekin, S. c168 Bagshaw, S.M. c206 Banas, B. c154 Bang, B.K. c127 Beecroft, J.M. c133 Beirão, I. c95 Bek, K. c168 Bek, Y. c168 Bell, M. c224 Bellomo, R. c181, c182 Berlyne, S. cI Böger, C.A. c154 Bonventre, J.V. c181, c192 Cabrita, A. c95 Cattran, D.C. c148 Chatzinikolaou, A. c55 Chen, Y.-M. c109 Chien, K.-L. c109 Chiu, Y.-L. c109 Choi, B.S. c127 Choi, Y.J. c127 Connell, J.M.C. c1 Costa, P.M.P. c95 Cox, C. c65 Dargie, H. c1 Davenport, A. c65, c173 Deighan, C.J. c40 Douroudos, I. c55 Doyle, A. c1 Dung, D.T.K. c25 Fatouros, I.G. c55 Ferrell, W.R. c40 Fonseca, I. c95 Foster, J. c1 Fox, J.G. c40, c148 Franco, M.F. c161 Fraser, E.P. c148 Fujisawa, M. c25 Fukuhara, S. c100

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Galal, A.Z. c140 Geddes, C.C. c148 Gohbara, M. c33 Gotoh, H. c49 Gotoh, T. c49 Gotoh, Y. c49 Götz, A.K. c154 Hamano, T. c72 Hanly, P.J. c133 Hao, D.D. c25 Hashimoto, T. c9 Hayashi, T. c72 Hien, M.T. c25 Higashi, T. c100 Hishida, A. c18 Hossain, M.A. c140 Huong, N.T. c25 Hursting, M.J. c80 Iio, K. c72 Imai, E. c72 Imai, R. c9 Imamura, S. c33 Inagaki, M. c49 Ishida, J. c18 Ito, C. c119 Ito, J. c25 Ito, T. c72 Iwamoto, M. c33 Iwatani, H. c72 Jardine, A. c1 J-DOPPS Research Group c100 Johnston, N. c1 Kato, A. c18 Kawabata, M. c25 Kawaguchi, T. c100 Kellum, J.A. c182 Kim, J.Y. c127 Kim, S.H. c127 Kim, Y.K. c127 Kim, Y.O. c127 Kim, Y.S. c127 Kimura, T. c72 Kitamura, K. c33 Kobayashi, H. c9 Kora, M.A.E. c140 Krämer, B.K. c154 Kurokawa, K. c100

Kusakari, M. c33 Kusano, E. c119 Lieu, D.T. c25 Lin, S.-L. c109 Lobato, L. c95 Mackinnon, B. c40, c148 Mark, P.B. c1 Mastroianni-Kirsztajn, G. c161 Meliton, G. c133 Michailidis, I. c55 Molitoris, B.A. c198 Moreira, L. c95 Morey, B. c173 Morio, Y. c49 Murray, P.T. c80 Muto, S. c119 Nagai, Y. c72 Nagasawa, Y. c72 Ngoc, N.T.B. c25 Ngoc, T.B. c25 Nishida, M. c9 Nishimura, M. c9 Oanh, L.T.K. c25 Odamaki, M. c18 Oguchi, K. c49 Okino, K. c9 Ono, T. c9 Ozkaya, O. c168 Padmanabhan, N. c1 Panagoutsos, S. c55 Pasadakis, P. c55 Pereira, A.B. c161 Pisoni, R. c188 Popal, M. c154 Porto, G. c95 Prasad, G.V.R. c133 Requião-Moura, L.R. c161 Ronco, C. c182 Saito, A. c100 Saito, O. c119 Sandoval, R.M. c198 Sanematsu, H. c33 Sattar, N. c40 Senturk, N. c168

c231

Sharfuddin, A.A. c198 Shirakawa, T. c25 Shoker, A. c140 Sivridis, D. c55 Sovatzidis, A. c55 Sugimoto, T. c33 Sumi, M. c33 Sumitsuji, S. c72 Suzuki, K. c33

Tolwani, A.J. c188 Townsend, D.R. c206 Tsai, T.-J. c109 Tsuji, M. c49 Turanli, A.Y. c168 Tuyen, D.G. c25

Takahashi, H. c9, c119 Takahashi, Y. c100 Takeda, S. c119 Takeda, Y. c72 Taxildaris, K. c55 Thuraisingham, R. c65 Tokoro, T. c9

Vargemezis, V. c55 Veras de S. Freitas, T. c161 Vinh, L.D. c25 Vuong, M.T. c25

Axelsson, J. e71 Ayala, E.R. e71

Kelly, D.J. e1 Kinsey, G.R. e102 Kitajikma, S. e29 Kööbi, P. e84 Koskela, J.K. e84 Koyner, J.L. e109

Bellomo, R. e95 Breborowicz, A. e71 Cook, H.T. e39 Cox, A. e1 Ding, F. e118

Uchino, S. c217 Urushidani, Y. c33

Gilbert, R.E. e1 Goldberg, H. e46 Hara, A. e29 Hayashi, K. e20 Heimburger, O. e71 Hishida, A. e57 Humes, H.D. e118 Ishiguro, K. e20 Ispanovic, E. e46 Itoh, H. e20 Kaneko, S. e29 Kapus, A. e46 Karavalakis, E. e84 Kawachi, H. e29

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Nephron Vol. 109, 2008

Yamasaki, K. c72 Yamazaki, S. c9, c100 Yang, C.W. c127 Yano, S. c33 Yokogi, H. c33 Yokoyama, H. c100 Yoon, H.E. c127 Zahran, A. c140 Zaltzman, J. c133

Wada, T. c100 Waikar, S.S. c192

Roufosse, C. e39 Ruskoaho, H. e84 Rysä, J. e84 Sakakima, M. e57 Sakamaki, Y. e20 Saruta, T. e20 Sasamura, H. e20 Shankland, S.J. e8 Sher Ali, R. e109 Shimizu, F. e29 Stenvinkel, P. e71 Styszynski, A. e71 Sugaya, T. e29

Lan, H.Y. e79 Langenberg, C. e95 Li, L. e102 Lindholm, B. e71

Eräranta, A. e84 Fujigaki, Y. e57 Furuichi, K. e29

Walker, R. c173 Washio, K. c49 Wille, K.M. c188 Wu, K.-D. c109

Matsushima, K. e29 May, C. e95 Mukaida, N. e29 Munk, S. e46 Murray, P.T. e109 Mustonen, J. e84

Thai, K. e1 Tokuyama, H. e1 Toyama, T. e29

Nangaku, M. e8 Narumi, S. e29 Niemelä, O. e84 Nikolic-Paterson, D.J. e1 Okumura, T. e29 Okusa, M.D. e102

Vehmas, T.I. e84 Wada, T. e8, e29 Wan, L. e95 Wang, H. e46 Whiteside, C. e46 Xia, L. e46

Pawlaczyk, K. e71 Pippin, J.W. e8 Pörsti, I. e84

Yamamoto, T. e57 Yao, Q. e71

Qian, J.Q. e71

Zhang, Y. e1

Author Index

The Abstracts of issue No. 3 have their own Author Index

Almeida, N.E. p1 Berl, T. p1 Bouchard, J. p85 Brown, L.M. p1 Capasso, J.M. p1 Chan, L. p1 Christians, U. p1 Feltes, C.M. p80

Kase, Y. p19 Kaye, M. p11 Khosla, N. p85 Klawitter, J. p1 Lebrec, D. p73 Leibfritz, D. p1 Maunsbach, A.B. p1 McCullough, P.A. p61 Mehta, R.L. p85 Moreau, R. p73

Petrovic, S. p29 Pihakaski-Maunsbach, K. p1 Rabb, H. p80 Rivard, C.J. p1 Shaw, A. p55 Stafford-Smith, M. p55 Sun, X. p29 Swaminathan, M. p55 Takeda, S. p19

Hattori, T. p19 Nishimura, H. p19

Author Index

Nephron Vol. 109, 2008

Van Eyk, J. p80

c233

Subject Index Vol. 109, 2008

Abdominal fat mass c18 Acute hepatitis A c127 – kidney injury c182, c188, c192, c198, c206, c217, c224 – renal failure c127, c182, c188, c192, c206 Adolescent c161 Amyloidosis c95 Anemia c9, c33, c95, c100 Antioxidant capacity c55 Antithrombin deficiency c80 Aorta c1 Argatroban c80 Arterial stiffness c18 Arteriosclerosis c1 Atherosclerosis c9 Audit, blood pressure control c65 BEST c188 Biocompatibility c100 Biomarker c192 Blood pressure c148 Cardiovascular disease c25, c109 Chronic kidney disease c25 – – – progression c109 Cockcroft-Gault glomerular filtration rate c140 Compliance, phosphate control c173 Coronary artery disease c9, c72 Creatinine c217 Critical illness c182 Cu/Zn superoxide dismutase c49 Diabetes c119 –, end-stage renal disease c65 Diabetic glomerulosclerosis c119 – nephropathy c72, c154 – retinopathy c119 Diagnosis c192 Dialysis c80, c100, c127 – membrane(s) c100, c154 Dialyzer biocompatibility c154 Dietitian c173 Dip-stick urine test c25 Distensibility c1 Endothelial function c40 End-stage renal disease c9, c72, c109, c133 Epidemiology c161, c182, c224 Erythropoietin c33, c95, c100

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ESRD c1 Estimated glomerular filtration rate c140 Exercise c55 Familial amyloid polyneuropathy c95 Fluid therapy c206 Furosemide c206 Glomerular disease c161 Glomerulonephritis c161 Haemodialysis, dietetic time c173 –, target blood pressure c65 Hematuria c119 Hemodialysis c18, c33, c55, c182 –, vitamin C supplementation c49 Hemofiltration c182 Heparin-induced thrombocytopenia c80 High-flux membranes c100 High-molecular-weight adiponectin c18 Hydroxyethylstarch c206 Hyperphosphataemia c173 Hypertension c33, c65 Hypotension c65 IgA nephropathy c148 Ischemia c198 Isotope glomerular filtration rate c140 Kidney disease c182 – transplantation c133 Laser Doppler iontophoresis c40 Lipid peroxidation c55 Loop diuretic c206 Magnetic resonance imaging c1 Malnutrition c9 Management system c25 Membrane flux c154 Modified diet in renal disease-isotope dilution mass spectrometry c140 Morbidity c224 MRI c198 Multidetector row computed tomography c72 Multi-photon microscopy c198 Nephrotic syndrome c119, c161 Nutrition c173

Resuscitation c206 Revascularization c9 RIFLE criteria c182

Oliguria c206 Outcome c148, c224 – prediction c217 Oxidative damage c55 – stress c49 Oxidized vitamin C c49 Periodic limb movements c133 Peritoneal dialysis c168 Phosphate c173 PICARD c188 Polysomnography c133 Progression c148 Proteinuria c40, c148

Target blood pressure c65 Transplant chronic kidney disease c140 Transthyretin c95 Ultrasound c198 Uremic pruritus c168

Renal amyloidosis c95 – dysfunction c80 – insufficiency c168 – recovery c224 – replacement therapy c80 – transplant c133 Restless legs syndrome c133

Vietnam c25 Virga glomerular filtration rate c140 Vitamin D c9 Volume overload c206

Acute kidney injury e109, e118 – renal failure e29, e95, e102 Adaptive immunity e102 Afferent arteriole e95 Angiogenesis e71 Angiotensin II e46 Anti-oxidants e109 Apoptosis e8, e95 Apoptosis-inducing factor e8 Arterial function e84 Autoradiography e57

Glomerular filtration rate e95 Glomerulus e95

Bone marrow e39 – marrow-derived stem cells e39

Leukocytes e102

High glucose e46 Inflammation e118 Innate immunity e102 Ischemia e29 Kidney disease e79 – failure e84

Macrophage migration inhibitory factor e79 Macrophages e79 Matrigel e46 Mesangial cells e1

Caspase-3 e8 Cell proliferation e1, e29 – therapy e118 Chemokines e29 Collagen e71

Nanotechnology e118 Native renal stem cells e39 Nitric oxide e95

Diabetic nephropathy e20 Dialysis solutions e71 Efferent arteriole e95 Embryonic stem cells e39 Endothelial-dependent vasodilation e84 Endothelin-1 e46 ERK1/2 e46 Fibrosis e39, e71 Free radicals e109

Subject Index

Sepsis c198, c217 Severity score c217 Standards, haemodialysis c65 Survival, end-stage diabetic nephropathy c154

Oxidative stress e109 Parathyroid hormone e84 Peritoneal dialysis rat model e71 Platelet-derived growth factor e1 Progenitor-like cell e57 Protein kinase-C e46 Proximal tubule e57

Nephron Vol. 109, 2008

c235

Reactive oxygen metabolites e109 Renal regeneration e39 Signal transduction e8 Spontaneously hypertensive rats e20 Stem cells e39 Streptozotocin e20 T cells e79 Tissue engineering e118

Acid-base balance p29 Acidosis p29 Acute kidney injury p55, p61, p85 Aging p11 Anion exchange p29 Anti-glomerular basement membrane nephritis p19 Ascites p73

Tranilast e1 Transient antihypertensive treatment e20 Tubule e95 – cells e118 Ultrafiltration e71 Vasodilatation e95 Vitamin D e84

Kidney p80 Leukocytes p80 Liver dialysis p85 Lung p80 Metabonomics p1 Nocturia p11

Bicarbonate transport p29 Osmolality p61 Cardiac surgery p55 Cardiovascular disease p61 Chloride transport p29 Chronic kidney disease p61 Circadian weight change p11 Cirrhosis p73 Corticosterone p19 Critical care p80 Cytokines p80 Dialysis p55, p85 Hepatorenal syndrome p73 Hypertonicity p1

Polyol pathway p1 Portal hypertension p73 Prophylaxis p61 Proteinuria p19 Proteomics p1 Saireito p19 Sepsis p85 Sodium excretion p11 Sorbitol p1 Ultrafiltration p85 Vasoconstrictors p73

IMCD3 cells p1 Inflammation p80 Iodinated contrast p61

c236

Nephron Vol. 109, 2008

Subject Index

Vol. 109, 2008

Editor-in-Chief L.G. Fine, Los Angeles, Calif. Administrative Editors S. Beesley, London B. Fine, Los Angeles, Calif.

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Contents Vol. 109, 2008

c72

Assessment of Coronary Stenosis by a 16-Slice MDCT Scanner in Asymptomatic Diabetic Patients Starting Dialysis Therapy Iio, K. (Izumisano/Suita); Nagasawa, Y. (Suita); Kimura, T. (Izumisano); Yamasaki, K. (Izumisano/Suita); Takeda, Y. (Izumisano); Hamano, T.; Iwatani, H. (Suita); Sumitsuji, S. (Izumisano/Suita); Nagai, Y. (Izumisano); Ito, T.; Imai, E. (Suita); Hayashi, T. (Izumisano)

c80

Argatroban Anticoagulation in Renal Dysfunction: A Literature Analysis

c95

Berlyne, S. (Brooklyn, N.Y.)

Low Erythropoietin Production in Familial Amyloidosis TTR V30M Is Not Related with Renal Congophilic Amyloid Deposition. A Clinicopathologic Study of Twelve Cases

Original Papers

Beirão, I.; Moreira, L.; Porto, G.; Lobato, L.; Fonseca, I.; Cabrita, A.; Costa, P.M.P. (Porto)

No. 1

Hursting, M.J. (Austin, Tex.); Murray, P.T. (Chicago, Ill.)

Obituary cI

Geoffrey Merton Berlyne (1931–2007)

c100 Biocompatibility and Permeability of Dialyzer Membranes c1

Aortic Stiffness and Diastolic Flow Abnormalities in End-Stage Renal Disease Assessed by Magnetic Resonance Imaging Doyle, A.; Mark, P.B.; Johnston, N.; Foster, J.; Connell, J.M.C.; Dargie, H.; Jardine, A.; Padmanabhan, N. (Glasgow)

c9

c18

Association of Insulin Resistance with de novo Coronary Stenosis after Percutaneous Coronary Artery Intervention in Hemodialysis Patients

Yokoyama, H. (Ishikawa); Kawaguchi, T. (Kyoto); Wada, T. (Kanazawa); Takahashi, Y. (Kyoto); Higashi, T. (Osaka); Yamazaki, S.; Fukuhara, S. (Kyoto); Akiba, T.; Akizawa, T. (Tokyo); Asano, Y. (Utsunomiya); Kurokawa, K. (Tokyo); Saito, A. (Isehara) for the J-DOPPS II Study

Nishimura, M.; Tokoro, T.; Nishida, M.; Hashimoto, T.; Kobayashi, H.; Yamazaki, S.; Imai, R.; Okino, K. (Kyoto); Takahashi, H. (Osaka); Ono, T. (Kyoto)

No. 3

Association of High-Molecular-Weight to Total Adiponectin Ratio with Pulse Wave Velocity in Hemodialysis Patients Kato, A.; Odamaki, M.; Ishida, J.; Hishida, A. (Hamamatsu)

c25

Impact and Perspective on Chronic Kidney Disease in an Asian Developing Country: A Large-Scale Survey in North Vietnam Ito, J. (Kobe); Dung, D.T.K.; Vuong, M.T.; Tuyen, D.G.; Vinh, L.D.; Huong, N.T.; Ngoc, T.B.; Ngoc, N.T.B.; Hien, M.T.; Hao, D.D.; Oanh, L.T.K.; Lieu, D.T. (Hanoi); Fujisawa, M.; Kawabata, M.; Shirakawa, T. (Kobe)

c33

Association between Erythropoietin Requirements and Antihypertensive Agents Yano, S.; Suzuki, K.; Iwamoto, M.; Urushidani, Y.; Yokogi, H.; Kusakari, M.; Aoki, A.; Sumi, M.; Kitamura, K.; Sanematsu, H.; Gohbara, M.; Imamura, S.; Sugimoto, T. (Shimane)

c40

Do Not Affect Anemia, Erythropoietin Dosage or Mortality in Japanese Patients on Chronic Non-Reuse Hemodialysis: A Prospective Cohort Study from the J-DOPPS II Study

Endothelial Function in Patients with Proteinuric Primary Glomerulonephritis Mackinnon, B.; Deighan, C.J.; Ferrell, W.R.; Sattar, N.; Fox, J.G. (Glasgow)

Original Papers c109 Outcomes of Stage 3–5 Chronic Kidney Disease before End-Stage Renal Disease at a Single Center in Taiwan Chiu, Y.-L.; Chien, K.-L.; Lin, S.-L.; Chen, Y.-M.; Tsai, T.-J.; Wu, K.-D. (Taipei)

c119 Microscopic Hematuria and Diabetic Glomerulosclerosis – Clinicopathological Analysis of Type 2 Diabetic Patients Associated with Overt Proteinuria Akimoto, T.; Ito, C.; Saito, O.; Takahashi, H.; Takeda, S.; Ando, Y.; Muto, S.; Kusano, E. (Shimotsuke)

c127 Acute Hepatitis A-Associated Acute Renal Failure in Adults Kim, S.H.; Yoon, H.E.; Kim, Y.K.; Kim, J.Y.; Choi, B.S.; Choi, Y.J.; Kim, Y.O.; Kim, Y.S.; Bang, B.K.; Yang, C.W. (Seoul)

c133 Improvement of Periodic Limb Movements following Kidney Transplantation Beecroft, J.M. (Calgary, Alta.); Zaltzman, J.; Prasad, G.V.R.; Meliton, G. (Toronto, Ont.); Hanly, P.J. (Calgary, Alta.)

No. 2

c140 Validation of the Virga GFR Equation in a Renal Transplant Population

Original Papers c49

Oral Vitamin C Supplementation in Hemodialysis Patients and Its Effect on the Plasma Level of Oxidized Ascorbic Acid and Cu/Zn Superoxide Dismutase, an Oxidative Stress Marker Washio, K. (Tokyo/Saitama); Inagaki, M.; Tsuji, M.; Morio, Y. (Tokyo); Akiyama, S.; Gotoh, H.; Gotoh, T.; Gotoh, Y. (Saitama); Oguchi, K. (Tokyo)

c55

c65

Zahran, A. (Menoufiya); Hossain, M.A. (Saskatoon, Sask.); Kora, M.A.E.; Galal, A.Z. (Menoufiya); Shoker, A. (Saskatoon, Sask.)

c148 Validation of the Toronto Formula to Predict Progression in IgA Nephropathy Mackinnon, B.; Fraser, E.P. (Glasgow); Cattran, D.C. (Toronto, Ont.); Fox, J.G.; Geddes, C.C. (Glasgow)

Acute Exercise May Exacerbate Oxidative Stress Response in Hemodialysis Patients

c154 Effect of Membrane Flux and Dialyzer Biocompatibility on Survival in End-Stage Diabetic Nephropathy

Fatouros, I.G. (Komotini); Pasadakis, P.; Sovatzidis, A. (Alexandroupolis); Chatzinikolaou, A. (Komotini); Panagoutsos, S.; Sivridis, D. (Alexandroupolis); Michailidis, I.; Douroudos, I.; Taxildaris, K. (Komotini); Vargemezis, V. (Alexandroupolis)

Götz, A.K.; Böger, C.A.; Popal, M.; Banas, B. (Regensburg); Krämer, B.K. (Regensburg/Bochum)

Blood Pressure Control and Symptomatic Intradialytic Hypotension in Diabetic Haemodialysis Patients: A Cross-Sectional Survey Davenport, A.; Cox, C.; Thuraisingham, R. (London)

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c161 Should Adolescents with Glomerulopathies Be Treated as Children or Adults? Requião-Moura, L.R.; Veras de S. Freitas, T.; Franco, M.F.; Pereira, A.B.; Mastroianni-Kirsztajn, G. (São Paulo)

c168 Characteristics of Pruritus in Children on Peritoneal Dialysis

No. 3

Senturk, N.; Ozkaya, O.; Aytekin, S.; Bek, K.; Açıkgöz, Y.; Aydin, F.; Bek, Y.; Turanli, A.Y. (Samsun)

c173 More Dietetic Time, Better Outcome? A Randomized Prospective Study Investigating the Effect of More Dietetic Time on Phosphate Control in End-Stage Kidney Failure Haemodialysis Patients

Minireview e79 Role of Macrophage Migration Inhibition Factor in Kidney Disease Lan, H.Y. (Hong Kong)

Morey, B.; Walker, R.; Davenport, A. (London)

Original Paper e84 Paricalcitol Treatment and Arterial Tone in Experimental Renal Insufficiency Karavalakis, E.; Eräranta, A.; Vehmas, T.I.; Koskela, J.K.; Kööbi, P.; Mustonen, J. (Tampere); Niemelä, O. (Tampere/Seinäjoki); Rysä, J.; Ruskoaho, H. (Oulu); Pörsti, I. (Tampere)

No. 1 Original Papers e1

e8

Tranilast Ameliorates Experimental Mesangial Proliferative Glomerulonephritis

No. 1

Tokuyama, H.; Kelly, D.J.; Cox, A.; Zhang, Y. (Melbourne, Vic.); Thai, K. (Toronto, Ont.); Nikolic-Paterson, D.J. (Clayton, Vic.); Gilbert, R.E. (Melbourne, Vic./Toronto, Ont.)

Original Papers p1

Dexamethasone’s Prosurvival Benefits in Podocytes Require Extracellular Signal-Regulated Kinase Phosphorylation

Klawitter, J. (Denver, Colo./Bremen); Rivard, C.J.; Brown, L.M.; Capasso, J.M.; Almeida, N.E. (Denver, Colo.); Maunsbach, A.B.; Pihakaski-Maunsbach, K. (Aarhus); Berl, T. (Denver, Colo.); Leibfritz, D. (Bremen); Christians, U.; Chan, L. (Denver, Colo.)

Wada, T. (Seattle, Wash./Tokyo); Pippin, J.W. (Seattle, Wash.); Nangaku, M. (Tokyo); Shankland, S.J. (Seattle, Wash.) e20

Differential Effects of Transient Treatment of Spontaneously Hypertensive Rats with Various Antihypertensive Agents on the Subsequent Development of Diabetic Nephropathy

p11

No. 2

IFN-Inducible Protein 10 (CXCL10) Regulates Tubular Cell Proliferation in Renal Ischemia-Reperfusion Injury Furuichi, K.; Wada, T.; Kitajikma, S.; Toyama, T.; Okumura, T.; Hara, A. (Kanazawa); Kawachi, H.; Shimizu, F. (Nigata); Sugaya, T. (Tokyo); Mukaida, N. (Kanazawa); Narumi, S.; Matsushima, K. (Tokyo); Kaneko, S. (Kanazawa)

Original Paper p19

No. 3

Minireview Stem Cells and Renal Regeneration Roufosse, C.; Cook, H.T. (London)

Original Paper p29 Increased Acid Load and Deletion of AE1 Increase Slc26a7 Expression Sun, X.; Petrovic, S. (Cincinnati, Ohio)

Original Papers e46

Regulation of Mesangial Cell Alpha-Smooth Muscle Actin Expression in 3-Dimensional Matrix by High Glucose and Growth Factors Whiteside, C.; Munk, S.; Ispanovic, E.; Wang, H.; Goldberg, H.; Kapus, A.; Xia, L. (Toronto, Ont.)

e57

A Distinct Population of Tubular Cells in the Distal S3 Segment Contributes to S3 Segment Regeneration in Rats following Acute Renal Failure Induced by Uranyl Acetate

Saireito and Saikosaponin D Prevent Urinary Protein Excretion via Glucocorticoid Receptor in Adrenalectomized WKY Rats with Heterologous-Phase Anti-GBM Nephritis Hattori, T.; Nishimura, H.; Kase, Y.; Takeda, S. (Ami-machi)

No. 2

e39

Aging, Circadian Weight Change, and Nocturia Kaye, M. (Montreal, Que.)

Ishiguro, K.; Sasamura, H.; Sakamaki, Y.; Hayashi, K.; Saruta, T.; Itoh, H. (Tokyo) e29

A Metabonomic and Proteomic Analysis of Changes in IMCD3 Cells Chronically Adapted to Hypertonicity

Abstracts p37

First Joint Meeting of the French Society of Nephrology, the UK Renal Association and the Nephrology Section of the Royal Society of Medicine Royal Society of Medicine, London, February 28–29, 2008 Guest Editors Philip Mason (Oxford); Peter Mathieson (Bristol); Pierre Ronco (Paris)

Sakakima, M.; Fujigaki, Y.; Yamamoto, T.; Hishida, A. (Hamamatsu) e71

The Role of the TGF/Smad Signaling Pathway in Peritoneal Fibrosis Induced by Peritoneal Dialysis Solutions Yao, Q. (Stockholm/Shanghai); Pawlaczyk, K. (Stockholm/Poznan); Ayala, E. R. (Stockholm); Styszynski, A.; Breborowicz, A. (Poznan); Heimburger, O. (Stockholm); Qian, J.Q. (Shanghai); Stenvinkel, P.; Lindholm, B.; Axelsson, J. (Stockholm)

Contents

Nephron Vol. 109, 2008

V

No. 4

e102 Inflammation in Acute Kidney Injury Kinsey, G.R.; Li, L.; Okusa, M.D. (Charlottesville, Va.)

Acute Kidney Injury – Scientific Evidence Driving Change in Patients Management

c206 New Insights on Intravenous Fluids, Diuretics and Acute

Guest Editors: Rinaldo Bellomo (Heidelberg, Vic.); Joseph Bonventre, (Boston, Mass.)

Kidney Injury Townsend, D.R.; Bagshaw, S.M. (Edmonton, Alta.) e109 Antioxidants. Do They Have a Place in the Prevention or Therapy

of Acute Kidney Injury? c181 Introduction Bellomo, R. (Heidelberg, Vic.); Bonventre, J. (Boston, Mass.) c182 Definition and Classification of Acute Kidney Injury Kellum, J.A. (Pittsburgh, Pa.); Bellomo, R. (Melbourne, Vic.); Ronco, C. (Vicenza) c188 The Epidemiology of Severe Acute Kidney Injury:

from BEST to PICARD, in Acute Kidney Injury: New Concepts Pisoni, R.; Wille, K.M.; Tolwani, A.J. (Birmingham, Ala.) c192 Biomarkers for the Diagnosis of Acute Kidney Injury Waikar, S.S.; Bonventre, J.V. (Boston, Mass.) c198 Imaging Techniques in Acute Kidney Injury Sharfuddin, A.A.; Sandoval, R.M.; Molitoris, B.A. (Indianapolis, Ind.) p55

Cardiac Surgery-Associated Acute Kidney Injury: Putting Together the Pieces of the Puzzle Shaw, A.; Swaminathan, M.; Stafford-Smith, M. (Durham, N.C.)

e95

Septic Acute Kidney Injury: New Concepts Bellomo, R.; Wan, L.; Langenberg, C.; May, C. (Melbourne, Vic.)

p61

Radiocontrast-Induced Acute Kidney Injury McCullough, P.A. (Royal Oak, Mich.)

p73

Koyner, J.L. (Chicago, Ill.); Sher Ali, R. (New York, N.Y.); Murray, P.T. (Chicago, Ill.) p80

Distant-Organ Changes after Acute Kidney Injury

p85

Emerging Therapies for Extracorporeal Support

Feltes, C.M.; Van Eyk, J.; Rabb, H. (Baltimore, Md.) Bouchard, J.; Khosla, N.; Mehta, R.L. (San Diego, Calif.)

e118 The Bioartificial Kidney and Bioengineered Membranes in Acute Kidney Injury Ding, F. (Ann Arbor, Mich./Shanghai); Humes, H.D. (Ann Arbor, Mich.) c217 Outcome Prediction for Patients with Acute Kidney Injury Uchino, S. (Tokyo) c224 Acute Kidney Injury: New Concepts, Renal Recovery Bell, M. (Solna/Stockholm) c229 Author Index Vol. 109, No. 4, 2008 c230 Subject Index Vol. 109, No. 4, 2008 c231 Author Index Vol. 109, 2008 c234 Subject Index Vol. 109, 2008

Acute Kidney Injury: New Concepts. Hepatorenal Syndrome: The Role of Vasopressors Moreau, R.; Lebrec, D. (Clichy)

VI

Nephron Vol. 109, 2008

Contents