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Improving outcomes of acute kidney injury:report of an initiativeBruce A Molitoris*, Adeera Levin, David G Warnock, Michael Joannidis, Ravindra L Mehta, John A Kellum,

Claudio Ronco and Sudhir V Shah on behalf of the Acute Kidney Injury Network working group

INTRODUCTION

Acute kidney injury (AKI) is a common clinicalproblem defined by an abrupt (within 48 h)increase in serum creatinine, resulting froman injury or insult that causes a functionalor structural change in the kidney. Recentepidemiological studies have detected widevariation in etiologies of, and risk factors asso-ciated with, AKI.14 This condition increases

hospital mortality rates, which further worsen ifdialysis is required.14 There is emerging recog-nition of the fact that even minor, short-termchanges in serum creatinine are associated withincreased mortality.59 Other important conse-quences of AKI are progression of pre-existingchronic kidney disease and even development ofend-stage renal disease.1012

A major limitation in improving outcomesof AKI has been the lack of common standardsfor diagnosis and classification of the condition.Recognizing that future clinical and translationalresearch into AKI will require the developmentof multidisciplinary collaborative networks ofinvestigators, a group representing membersof the Acute Dialysis Quality Initiative,13 andnephrology and critical care societies, recentlyestablished the Acute Kidney Injury Network(AKIN)14 in order to facilitate international,interdisciplinary and intersociety collaborationthat will ensure progress is made in the field ofAKI. The fundamental goal of AKIN is to ensurethe best outcomes for patients with, and those atrisk of developing, AKI. The first AKIN confer-ence, held in Amsterdam, The Netherlands, in

September 2005 (see Box 1 for a list of partici-pants), focused on developing uniform stan-dards for the definition and classification ofAKI. Key recommendations are summarizedbelow (the complete report has been publishedin Critical Care14).

UNIfORm STaNDaRDS fOR DefINITION

aND ClaSSIfICaTION Of aKI

Previous studies have used an assortment ofdefinitions for AKI, including those based on

Acute kidney injury (AKI) is a complex disorder comprising severaletiological factors and occurring in multiple settings. The disorder has a

variety of clinical manifestations that range from minimal elevation inserum creatinine level to anuric renal failure. We describe the formationof a multidisciplinary collaborative network focused on AKI. This AcuteKidney Injury Network has proposed uniform standards for diagnosingand classifying AKI. These proposed standards will need to be validated infuture studies, a process that will be facilitated by the Acute Kidney Injury

Network, which offers a forum that encourages acquisition of knowledge toimprove patient outcomes.

keywords acut nal failu, clinical tial, finitin, iagni, taging

BA Molitoris is Director of the Division of Nephrology in the Departmentof Medicine, Indiana University, Indianapolis, IN, USA. A Levin is Professorof Medicine in the Division of Nephrology, Director of the Kidney FunctionClinic, St Pauls Hospital, and Co-Director of the Clinical InvestigationProgram, University of British Columbia, Vancouver, BC, Canada.DG Warnock is Director of the Division of Nephrology in the Departmentof Medicine, University of Alabama, Birmingham, AL, USA. M Joannidis isDirector of the Medical Intensive Care Unit in the Department of Internal

Medicine, Medical University of Innsbruck, Innsbruck, Austria. RL Mehtais Professor of Clinical Medicine in the Department of Medicine, Universityof California San Diego Medical Center, San Diego, CA, USA. JA Kellumis Professor in the Department of Critical Care Medicine, University ofPittsburgh, Pittsburgh, PA, USA. C Ronco is Head of the Department of

Nephrology, Dialysis and Transplantation, San Bortolo Hospital, Vicenza,Italy. SV Shah is Professor of Internal Medicine and Director of the Divisionof Nephrology, University of Arkansas for Medical Sciences, and Chief ofthe Renal Section, Medical Service, John L McClellan Memorial VeteransHospital, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.

Corrspondnc*Indiana University School of Medicine, R2, Room 202, 950 West Walnut Street, Indianapolis,

IN 46202, USA

[email protected]

Rcid 17 May 2007 accptd 6 June 2007

www.nature.com/clinicalpractice

doi:10.1038/ncpneph0551

RevIew CRITeRIaThe PubMed database was searched for articles relevant to the definition, diagnosisand classification of acute kidney injury and acute renal failure.

SUMMArY

august 2007 vol 3 no 8 nAtUre clinicAl prActice nEPHRologY 439
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changes in serum creatinine, absolute levels ofserum creatinine, changes in urine output orblood urea nitrogen concentrations, or the needfor dialysis. The wide variation in definitions hasmade it difficult to compare information acrossstudies and populations.15 The diagnostic criteriafor AKI that were proposed by AKIN are shownin Box 2 and are based on three considerations.Firstly, the definition of AKI should be based on

parameters that are readily obtainable worldwide,and needs to be broad enough to accommodatevariations in clinical presentation between agegroups, locations and clinical situations. Secondly,serum creatinine and urine output are twomeasures commonly used to reflect renal function;however, they are both influenced by factors otherthan glomerular filtration rate, and do not provideinformation about the nature and site of kidneyinjury. Finally, there is currently a lack of sensitiveand specific markers of kidney injury available

for use in clinical practice (several kidney-specificbiomarkers are being developed).16

Selection of the absolute criteria for diagnosing

AKI that are presented in Box 2 was based onevidence that even small changes in serum creati-nine are associated with adverse outcomes in avariety of settings. These changes are associatedwith both short-term increases in morbidityand mortality, and with longer-term outcomes(e.g. 1-year mortality). The coefficient of varia-tion of serum creatinine levels measured usingmodern analysis methods is relatively small;therefore, changes of 26.4mol/l (0.3 mg/dl)or more are unlikely to be the result of assayerror.17 Urine output was included as a diag-nostic criterion because in intensive care patientsit often portends renal dysfunction before theonset of changes in serum creatinine level;hydration state, use of diuretics and presenceof obstruction can, however, influence urinevolume. A time constraint of 48 h for diagnosiswas proposed to ensure that the process beingdiagnosed is acute and representative of eventswithin a clinically relevant period.

Table 1 shows the staging system for AKI thatis proposed by AKIN. The system is intendedto define the degree of renal dysfunction at thetime of diagnosis, and to facilitate tracking of

the course of the disease over time. The RIFLE(Risk, Injury, Failure, Loss, End-stage renaldisease) criteria13 utilize changes in serum creati-nine and urine output to characterize three levelsof renal dysfunction. The staging system proposedhere retains the emphasis on changes in serumcreatinine and urine output, and correspondsto the Risk, Injury and Failure categories ofthe RIFLE classification, with the Stage 1 criteriarepresenting the new diagnostic criteria for AKI.The Loss and End-stage renal disease categories

Box 1Members of the AKIN working group.

Arvind Bagga

Aysin Bakkaloglu

Joseph V Bonventre

Emmanuel A Burdmann

Yipu Chen

Prasad DevarajanVince DIntini

Geoff Dobb

Charles G Durbin Jr

Kai-Uwe Eckardt

Claude Guerin

Stefan Herget-Rosenthal

Eric Hoste

Michael Joannidis

John A Kellum

Ashok Kirpalani

Andrea Lassnigg

Jean-Roger Le Gall

Adeera Levin

Raul Lombardi

William Macias

Constantine Manthous

Ravindra L Mehta

Bruce A Molitoris

Claudio Ronco

Miet Schetz

Frederique Schortgen

Sudhir V Shah

Patrick SK Tan

Haiyan Wang

David G Warnock

Steve Webb

Box 2 Proposed diagnostic criteria for AKI.

An abrupt (within 48 h) reduction in kidney function

defined as an absolute increase in serum creatinine

level of 26.4mol/l (0.3 mg/dl) OR a percentage

increase in serum creatinine level of 50% (1.5-

fold from baseline) OR a reduction in urine output

(documented oliguria of 6 h).These criteria should be applied in the context

of the clinical presentation and following adequate

fluid resuscitation when applicable. Permission

obtained from BioMed Central Mehta RL et al.

(2007) Crit Care11: R31.
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of the RIFLE system were removed from thestaging system as they are outcomes of AKI itself.The proposed diagnostic (Box 2) and staging(Table 1) criteria for AKI are designed to facili-

tate acquisition of knowledge and to validate theemerging concept that small alterations in kidneyfunction contribute to adverse outcomes. AKINrecognizes that these criteria might be overlysensitive; accordingly, there could be an increasein the number of false-positive diagnoses, suchthat some patients who receive a diagnosis of AKIwill not have the disease. It is evident that thesecriteria will require evaluation and validation,and eventually amendment, as new biomarkersemerge that might more accurately detect AKI.16

INTeRNaTIONal COllaBORaTIve

NeTwORK

Establishment of an international collaborativeresearch network could facilitate acquisitionof evidence through well-designed and well-conducted clinical trials, dissemination of infor-mation via multidisciplinary joint conferences andpublications, and translation of knowledge frompreclinical research. AKIN proposed to furtherdevelop their collaborative effort on the basis offour main principles. First, identifying the keyroles of each of the current participating societiesand groups to allow retention of their individual

identities and strengths, while exploiting oppor-tunities for collaboration. Second, defining thescope of collaboration. Third, determiningand developing the infrastructure needed forthe collaborative network. Fourth, identifyingunifying principles and initial projects that wouldform the basis of ongoing collaboration.14

CONClUSIONS

The AKIN conference attendees recognizedthat collaborative and integrated joint meetings

are essential to facilitating the disseminationof knowledge, clarifying clinical practice andenhancing research. The group described thefive key elements that should be addressed by

the professional communities involved in thecare of patients with AKI.14 These are evaluationof the global epidemiology of AKI, delineationof clinically meaningful outcomes, developmentand implementation of strategies to improveoutcomes, promotion of research studies toenhance knowledge, and assessment of theeffectiveness of these collaborative approaches.A follow-up conference was held in Vancouverin 2006 and the results will be published soon.

KeY POINTS

The large numbers of etiologies and risk

factors associated with acute kidney injury

(AKI) have led to the ad hoc development of a

wide range of definitions of this condition

The lack of common standards for diagnosis

and classification of AKI has hampered

study of the condition and improvement of

patient outcomes

At their first meeting in September 2005,

members of the Acute Kidney Injury

Network (AKIN) working group proposed

new standards based on RIFLE criteria and

recognition of the fact that small changes inserum creatinine level are associated with

increased mortality

The common standards for diagnosis and

classification of AKI proposed by AKIN will

require validation

AKIN recommends that a broader

international collaborative network be

established to facilitate progress in AKI

research, dissemination of knowledge, and

implementation of standards of patient care

Tb 1Proposed classification/staging system for acute kidney injury, based on modification of RIFLE criteria.

stag sum catinin citia Uin utput citia

1 Increase of 26.4mol/l (0.3 mg/dl) OR to 150200% of baseline(1.52.0-fold)

6 h

2 Increase to >200300% of baseline (>23-fold) 12 h

3a

Increase to >300% of baseline (>3-fold; or serum creatinine354mol/l [4.0 mg/dl] with an acute rise of at least 44mol/l[0.5 mg/dl])


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Rrncs

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4 Liangos O et al. (2006) Epidemiology and outcomes of

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Soc Nephrol16: 33653370

6 Lassnigg A et al. (2004) Minimal changes of serum

creatinine predict prognosis in patients after

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12 Mehta RL et al. (2002) Diuretics, mortality, and

nonrecovery of renal function in acute renal failure.

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acute kidney injury. Crit Care11: R31

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physiological principles. Intensive Care Med30:

3337

16 Han WK and Bonventre JV (2004) Biologic markers

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Opin Crit Care10: 476482

17 Perrone RD et al. (1992) Serum creatinine as an indexof renal function: new insights into old concepts. Clin

Chem38: 19331953

acknodgntsIn order to encourage

dissemination of the

information set out in this

paper, it is freely accessible

on the Nature Clinical

Practice Nephrology

website, and will also be

published in theAmerican

Journal of KidneyDiseases, Clinical Journal

of the American Society of

Nephrology,Journal

of the American Society of

Nephrology, and Kidney

International. This article

has not been formally

peer-reviewed.

Copting intrstsThe authors declared no

competing interests.
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