6-5 nephsap

Volume 6 Number 5 September 2007

Acute Kidney Injury andCritical Care NephrologyCo-Editors:Patrick T. Murray, MD, and Paul M. Palevsky, MD

Editor-in-Chief: Stanley Goldfarb, MD Deputy Editor: Jeffrey S. Berns, MD

NephSAPNephrology Self-Assessment Program

EDITOR-IN-CHIEFStanley Goldfarb, MDPhiladelphia, PA

DEPUTY EDITORJeffrey S. Berns, MDPhiladelphia, PA

MANAGING EDITORGisela Deuter, BSN, MSAWashington, DC

ASSOCIATE EDITORSRajiv Agarwal, MDIndianapolis, INGabriel M. Danovitch, MDLos Angeles, CASteven Fishbane, MDMinneola, NYRichard J. Glassock, MDLaguna Niguel, CAKevin J. Martin, MBBChSt. Louis, MORajnish Mehrotra, MDTorrance, CAPatrick T. Murray, MDChicago, ILPatrick H. Nachman, MDChapel Hill, NCPaul M. Palevsky, MDPittsburgh, PABiff F. Palmer, MDDallas, TXRichard H. Sterns, MDRochester, NYStephen C. Textor, MDRochester, MNRaymond R. Townsend, MDPhiladelphia, PAJohn P. Vella, MDPortland, ME

FOUNDING EDITORSRichard J. Glassock, MD, MACP

(Editor-in-Chief)Robert G. Narins, MD, MACP

PrefaceNephSAP is one of the three major publications of the American Society of Nephrology(ASN). Its primary goals are self-assessment, education, and the provision of ContinuingMedical Education (CME) credits and Maintenance of Certification (MOC) credits forindividuals certified by the American Board of Internal Medicine. At no additional cost,members of the ASN will receive NephSAP with their monthly issue of The Journal of theAmerican Society of Nephrology (JASN).EDUCATION: Medical and Nephrologic information continues to accrue at a blisteringpace. Continuously bombarded from all sides with demands on their time, busy practitio-ners, academicians, and trainees at all levels are increasingly challenged to digest andassimilate all this new material. As a provider of postgraduate education, the ASNcontinues to seek new methods for helping its members absorb this information in palatableways. At the Annual Meeting (Renal Week) and at our annual Board Review Course andUpdate, we provide novel sessions that summarize and integrate new clinical informationand translate emerging areas of science into data that is useful at the bedside. TheNephrology Quiz and Questionnaire and our association with Hypertension, Dialysis, andClinical Nephrology (HDCN) and UpToDate have extended our educational activities tothe Internet. The Editors of JASN, CJASN, and NephSAP will strive to achieve an efficientintegration of their respective publications, so that the sum of the parts is greater than thewhole.

Each bimonthly issue of NephSAP is dedicated to a specific theme, i.e., to a specificarea of clinical nephrology, hypertension, dialysis, and transplantation, and consists of anEditorial, a Syllabus, and Self-Assessment questions. Over the course of 18 months, allclinically relevant and key elements of our discipline will be reviewed and updated. Theauthors of each issue digest, assimilate, and interpret key publications from the previousissues of other years and integrate this new material with the body of existing information.

SELF-ASSESSMENT: Twenty-five single-best-answer questions will follow the 50 to 75 pagesof Syllabus text, and an answer sheet is enclosed. After returning the completed answer sheetto the ASN, those answering75% correctly will receive CME credit, and receive the answersto all the questions along with brief discussions and an updated bibliography. To help answerthe questions, readers may go to the ASN web site, where relevant material from UpToDate inNephrology will be posted. Thus, members will find a new area reviewed every 2 months, andthey will be able to test their understanding with our quiz. This format will help readers stayabreast of developing areas of clinical nephrology, hypertension, dialysis, and transplantation,and the review and update will support those taking certification and recertification examina-tions.

CONTINUING MEDICAL EDUCATION: Most state and local medical agencies as well ashospitals are demanding documentation of requisite CME credits for licensure and for staffappointments. Credits, obtainable by attending our Annual Board Review Course and Updateand by attending Renal Week, are also offered by NephSAP. We think that this publicationoffers a palatable, efficient, and entertaining way of satisfying this administrative demand. Inaddition, individuals certified by the American Board of Internal Medicine may obtain creditstowards Maintenance of Certification (MOC) by successfully completing the self-assessmentportion of NephSAP.

This paper meets the requirements of ANSI/NISO Z39.48-1921 (Permanence of Paper),effective with July 2002, Vol. 1, No. 1.

NephSAP (Print: 1536-836X; Online: 1934-3175)2007 by The American Society of Nephrology

NephSAP

Acute Kidney Injury and Critical Care Nephrology

Editorial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281From Acute Renal Failure to Acute Kidney Injury: Whats

Changed? Ravindra L. Mehta, John A. Kellum, and Adeera Levin

Syllabus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286Acute Kidney Injury and Critical Care Nephrology

Patrick T. Murray and Paul M. Palevsky

CME Self-Assessment Questions . . . . . . . . . . . . . . . . . . . . . 339Questions Linked to UpToDate in Green

CME Answer Sheet

CME Certification and Evaluation Form

Upcoming Issues

Chronic Kidney Disease and ProgressionJeffrey S. Berns and Steven Fishbane. . . . . . . . . . . . . .November 2007

TransplantationGabriel M. Danovitch and John D. Vella . . . . . . . . . . . . .January 2008

HypertensionStephen C. Textor and Raymond R. Townsend. . . . . . . . . . .March 2008

Glomerular, Vascular, and Tubulointerstitial DiseasesRichard J. Glassock and Patrick H. Nachman . . . . . . . . . . . .May 2008

Renal ImagingParvati Ramchandani . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .July 2008

NephSAP Volume 6, Number 5, September 2007

NephSAP Review Panel

Georgi Abraham, MDChennai, IndiaPablo H. Abrego, MD, FASNWausau, WIAnil K. Agarwal, MD, FACP, FASNColumbus, OHKamal E. Ahmed, MD, FASNYuma, AZVinod K. Bansal, MD, FASNMaywood, ILM. J. Barchman, MD, FASNGreenville, NCAdel E. Berbari, MDBeirut, LebanonBruce E. Berger, MDCleveland, OHPaul Bolin, MDGreenville, NCMauro Braun, MDWeston, FLCharles Carpenter, MDBoston, MALaurence E. Carroll, MD, FASNLancaster, PAJorge Cerda, MD, FACP, FASNAlbany, NYChokchai Chareandee, MD, FASNLa Crosse, WILakhmir Chawla, MDWashington, DCMahmoud El-Khatib, MDCincinnati, OHMichael Emmett, MDDallas, TXLynda A. Frassetto, MD, FASNSan Francisco, CAPedro Frommer, MDHouston, TX

Duvuru Geetha, MDBaltimore, MDRichard N. Hellman, MD, FACPIndianapolis, INJean L. Holley, MDCharlottesville, VAR. Morrison Hurley, MDVancouver, CanadaEkambaram Ilamathi, MD, FASNStony Brook, NYSharon L. Karp, MDIndianapolis, INPranay Kathuria, MD, FACP, FASNTulsa, OKQuresh T. Khairullah, MDDetroit, MIRamesh Khanna, MDColumbia, MOOliver Lenz, MD, FASNMiami, FLEdgar V. Lerma, MD, FACP, FASNChicago, ILPhilippe Madhoun, MDCharleroi, BelgiumJulanta Malyszko, MDBialystok, PolandHanna W. Mawad, FASNLexington, KYRajnish Mehrotra, MD, FACPTorrance, CAPascal Meier, MD, FASNLusanne, SwitzerlandJacob Mooij, MD, PhDTaif, Saudi ArabiaHenry Mroch, MD, FASNSpokane, WA

Mamiko Ohara, MD, FASNChiba, JapanPairach Pintavorn, MD, FACP, FASNAugusta, GAPaul H. Pronovost, MD, FASNWaterbury, CTNash Purohit, MDClearwater, FLMohammad A. Quasem, MD, FASNBinghamton, NYVenkat Ramanathan, MDBaylor, TXRobert Richardson, MDToronto, CanadaBijan Roshan, MDBoston, MAMohammad G. Saklayen, MDDayton, OHRamesh Saxena, MD, PhDDallas, TXGaurang M. Shah, MD, FACPLong Beach, CAKedar Shetye, MD, FASNCharleston, SCDomenic Sica, MDRichmond, VANeil E. Soifer, MD, FASNChicago, ILHarold Szerlip, MD, FACPAugusta, GANauman Tarif, MDRiyadh, Saudi ArabiaLuigi Vernaglione, MDManduria, ItalyAntonio R. Vilches, MD, PhDBuenos Aires, Argentina


Program Mission and ObjectivesThe mission of the Nephrology Self-Assessment Program (NephSAP) is to regularly provide a vehicle that will be useful for clinicalnephrologists who seek to renew and refresh their clinical knowledge and diagnostic and therapeutic skills. This Journal consists of aseries of challenging, clinically oriented questions based on case vignettes, a detailed Syllabus that reviews recent publications,and an Editorial on an important and evolving topic. Taken together, these parts should assist individual clinicians whowish to undertake a rigorous self-assessment of their strengths and weaknesses in the broad domain of nephrology.

Accreditation and Credit DesignationThe American Society of Nephrology is accredited by the Accreditation Council for Continuing Medical Education to provide continuingmedical education for physicians.

The ASN designates this educational activity for a maximum of 6.0 AMA PRA Category 1 Credits. Physicians should only claim creditcommensurate with the extent of their participation in the activity.

Continuing Medical Education (CME) Information

Date of Original Release: September 2007Date Examination Available Online: Monday, September 10, 2007

CME Credit Eligible Through: August 31, 2008Answers: Correct answers with explanations will be posted on the ASN website in September 2008 when the issue is archived.

UpToDate Links Active: September and October 2007

CME Credit: 6.0 AMA PRA Category 1 Credits

Target Audience: Nephrology Board and Recertification candidates, practicing nephrologists, and internists.

Method of Participation: Read the syllabus and complete the self-assessment examination in this issue, which issupplemented by original articles in the reference lists.

The information below addresses both methods of participationonline and paper (mail-in) submission: There is no fee for the online examination. However, the fee for processing the mail-in form continues to be

$15, with a waiver of the second mail-in submission. Each participant has two attempts to pass the examination. Online examinations will provide scores in real time,

whereas the turn-around time for mail-in forms is usually between two and three weeks.

Scoring: Answer >75% correct: Receive answers to the questions; full CME credit is provided on first submission. Answer

Instructions to Obtain American Board of Internal Medicine (ABIM) Maintenance of Certification(MOC) Credit: Respondents must be certified by ABIM in internal medicine and/or nephrology and must be enrolled in the

ABIMMOC program via the ABIM website (www.abim.org). Include your ABIM ID Certificate number and your date of birth. Pass the self-assessment examination within the timeframe specified in this issue of NephSAP.

Once these criteria are met, ASN will provide the information to ABIM for verification and awarding the 10 MOC creditstoward renewal of the internal medicine or nephrology certificate. Notice of issuance of ABIMMOC credits and theirexpiration dates will be sent to the candidate from ABIM directly.

MOC credit will be applied to only those ABIM candidates who have enrolled in the program. It is your responsibility tocomplete the ABIM MOC enrollment process before requesting MOC credit from ASN for completion of NephSAPexaminations. ASN will not contact you if your credits are not accepted by ABIM.

Instructions to access the ASN website, NephSAP, AND THE UpToDate LINK

The link to UpToDate provides an additional source of information that should help you to answer up to 5 selectedNephSAP questions from each issue. UpToDate will post these reviews on the ASNs website (asn-online.org), whereit will remain for the next 60 days. The link is free and can be used to supplement the information provided in theSyllabus. Correct and incorrect answers, along with references and a brief explanation, will be provided to subscribersafter they return their answer sheets and comment forms to the ASN offices. CME credit will remain available to thosecompleting their forms for up to one year after publication of the questions. The NephSAP Editorial Board and UpToDatewould appreciate receiving comments and suggestions regarding the value of this link as well as any other thoughts thatyou might have on how to further improve NephSAP.

1. The ASN website is optimized for Microsoft Internet Explorer 5.0 or higher but can also be viewed with the latest NetscapeNavigator or Opera browsers.

2. The ASN website cannot support legacy browsers, including Netscape 3.0 and 4.0. If you are using a legacy browser and wish todownload one this site supports, please use a browser below to begin the downloading process:Microsoft Internet Explorer 5.0: http://www.microsoft.com/windows/ie/downloads/default.aspNetscape 7.0: http://channels.netscape.com/ns/browsers/download.jspOpera 7.0: http://www.opera.com/download/

3. Go to www.asn-online.org.4. On the ASN home page, click on the NephSAP link (NephSAP cover) on the right side of the page.5. On the NephSAP page, click on the title of the issue for the UpToDate links.6. The links (in green) follow each selected question and multiple choice answers.


Editorial Board Disclosure InformationIt is policy at ASN for individuals who are in a position to control the content of an educational activity to disclose to thelearners all relevant financial relationships they have with any commercial interests that provide products or services thatmay be relevant to the content of the continuing medical education (CME) activity. For this purpose, we consider rela-tionships of the person involved in the CME activity to include financial relationships of a spouse or partner.The intent of this policy is not to prevent expert faculty with relevant relationship(s) with commercial interest(s) frominvolvement in CME, but rather to ensure that ASN CME activities promote quality and safety, are effective in improvingmedical practice, are based on valid content, and are independent of control from commercial interests and free of com-mercial bias. A peer-review process is conducted for all content. In addition, all faculty are instructed to provide bal-anced, scientifically rigorous, and evidence-based presentations.The editorial board and editorial authors have reported the listed financial relationships with commercial interests relatedto the content of this CME activity.Agarwal, RajivGrants or research support: Abbott, National Institutes of Health; Consultantships: Abbott, Astra-

Zeneca, Merck, Watson Pharma; Honoraria: Astra-Zeneca, Merck, Watson Pharma; Scientific advisor: WatsonPharma

Berns, JeffreyConsultantships: Amgen, Neose; Honoraria: AmgenDanovitch, Gabriel M.Grants or research support/scientific advisor : Astellas, RocheFishbane, StevenGrants or research support: Abbott, Amgen, Genzyme, Roche, Watson; Consultantships: Amgen,

Roche, Watson; Honoraria: Abbott, Amgen, Ortho Biotech, Roche, WatsonFuchs, Elissa (Medical Editor)noneGlassock, Richard J.Consultantship, scientific advisor: Aspreva, FibroGen, Genentech, Keryx, Novartis, Roche,

Scientific Partners, Quest Diagnostics, UpToDate; Advisory Board, Board of Directors: Aspreva, American RenalAssociates, Los Angeles Biomedical Institute, University of Kidney Associates

Goldfarb, StanleyConsultantship: Aetna, Amgen Inc., Bayer, GE Healthcare; Honoraria: GE Healthcare, Nabi; AdvisoryBoard: Glycad Pharmaceuticals

Martin, Kevin J.Honoraria: Abbott, Amgen, Shire; Advisory Board: Abbott, ShireMehrotra, RajnishGrants or research support: Amgen, Johnson & Johnson, Shire; Consultantship: Novartis, Shire;

Honoraria: Baxter Healthcare, GenzymeMurray, Patrick T.Grants or research support: Biosite, GlaxoSmithKline, NxStage Medical; Consultantship: Scios;

Honoraria: GE Healthcare; Advisory Board: NxStage Medical, Quantum BiotechnologiesNachman, Patrick H.Research support: AsprevaPalevsky, Paul M.nonePalmer, Biff F.Honoraria: Astellas, Boehringer, NorvartisSterns, Richard H.Honoraria/consultantship/scientific advisor: AstellasTextor, Stephen C.noneTownsend, Raymond R.Grants or research support: Novartis; Consultantship: Abbott, Ateor, GlaxoSmithKline,

UpToDate; Honoraria: Bristol-Myers Squibb, Merck, PfizerVella, John P.Grants or research support: Astellas, Wyeth; Scientific advisor: RocheEditorial Authors:Kellum, John A.noneLevin, AdeeranoneMehta, Ravindra L.none


Disclosure of Unapproved or Off-Label Usage:ASN requires all faculty to disclose any discussion of an investigational and/or off-label use of a pharmaceutical productor device within their manuscript. Participants should note that the use of products outside FDA-approved labeling shouldbe considered experimental and are advised to consult current prescribing information for approved indications.Editorial:None.

Syllabus:This educational activity contains discussions of off-label uses of the following:

Product Unapproved or Off-Label UsageN-acetylcysteineNesicitide

Prevention of contrast-induced nephropathyAdministered in patients undergoing cardiac surgery with cardiopulmonary bypass

Commercial Support for This Issue:None.


EditorialFrom Acute Renal Failure to Acute Kidney Injury: Whats Changed?

Ravindra L. Mehta,* John A. Kellum, and Adeera Levin*Department of Medicine, University of California San Diego, San Diego California;Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;and Department of Medicine, University of British Columbia, Vancouver, British Columbia,Canada

Acute renal failure (ARF), a common and dev-astating problem in clinical medicine, has been thefocus of extensive clinical and basic research efforts inthe past several decades. Unfortunately, despite thesignificant progress made in our understanding of thebiology and mechanism of the disease in animal mod-els, translation of this knowledge into improved man-agement and outcomes for patients has been limited. Avariety of factors contribute to the lack of success. Thedisease is encountered in a variety of settings (e.g.,pediatric and adult, inpatient and outpatient, intensivecare unit [ICU] and non-ICU), with varied clinicalmanifestations ranging from a minimal elevation inserum creatinine to anuric renal failure. Recent epide-miologic studies demonstrate the wide variation incauses and risk factors (14); describe the increasedmortality associated with this disease, particularlywhen dialysis is required (1,3,57); and suggest arelationship to the subsequent development of chronickidney disease and progression to dialysis dependence(1,5,6,810). The reported incidence of ARF varieswidely, because definitions for the disease range fromquantitative and qualitative alterations in serum creat-inine to alterations in urine output (UOP) and dialysisrequirement (1,9,1117). Similarly, clinical trials haveused varying criteria for diagnosing ARF and ascer-taining outcomes from the intervention. Recent evi-dence suggests that ARF is often underrecognized, andeven small alterations in serum creatinine are associ-ated with severe consequences (1824). The lack of auniversally recognized definition of ARF has posed asignificant limitation, contributing to the lack of clin-ical success (25). These findings highlight the need fora uniform standard for diagnosing and classifyingARF that can be easily implemented across multiple

settings. This would facilitate patient selection, helpclassify patients into prospectively defined categoriesand reduce variability in clinical trials, and ultimatelyenhance our ability to improve the treatment of thesepatients.

Recognizing the need for uniform standards, theAcute Dialysis Quality Initiative (ADQI) group in2002 proposed consensus recommendations of theRIFLE (risk, injury, failure, loss, and ESRD) criteriafor the definition and staging of ARF (24). The wideinterest sparked by the publication of these criteriademonstrated the additional need for multidisciplinarycollaborative efforts for clinical and translational re-search in this area. Consequently, the ADQI group andrepresentatives from three nephrology societiesAmerican Society of Nephrology, International Soci-ety of Nephrology, and National Kidney Foundationand critical care societiesEuropean Society ofIntensive Care Medicine and Society of Critical CareMedicineconvened a retreat in Vicenza, Italy, inSeptember 2004 and agreed to establish the AcuteKidney Injury Network (AKIN). AKIN is a collabo-rative network that is composed of experts that areselected by societies and organizations to representboth the area of expertise and their sponsoring orga-nization. The network is intended to facilitate thedevelopment and execution of initiatives in acute kid-ney injury (AKI) and ensure progress in the field ofAKI by sharing information and integrating basic,clinical, and outcome sciences; education; and imple-mentation processes. The fundamental goal is to en-sure the best outcomes for patients with AKI (26).

As an initial step to facilitate scientific inquiry inAKI, the AKIN group organized a 3-d conference inAmsterdam in September 2005 to review the medical

Nephrology Self-Assessment Program - Vol 6, No 5, September 2007

281

literature and formulate a consensus working defini-tion of AKI. Representatives from various interna-tional nephrology and critical care societies convenedand after 2 d of deliberations agreed on a terminologyfor the disease, developed interim diagnostic and stag-ing criteria, and proposed a framework for additionalAKIN activities (26). The group proposed the termacute kidney injury (AKI) to reflect the entire spec-trum of ARF. The terminology acknowledges thatalthough there are different causative factors, in mostinstances, an acute decline in kidney function is sec-ondary to an injury that leads to a functional orstructural change in the kidney. In addition, the wordfailure reflects only one end of the spectrum ofclinical conditions that are seen in this disease.

Diagnostic Criteria for AKIDiagnostic criteria are used to establish the pres-

ence of a disease, whereas staging criteria define theseverity of the disease process at any given time. Onemust establish a diagnosis of the disease before it canbe staged. Measures that define a disease should beresponsive to change, track the natural history ofdisease, and provide an assessment of the severity ofinjury. Most disease definitions rely on the presence ofspecific markers that are measurably altered in re-sponse to an injury, and the sensitivity and specificityof any definition depends on the criteria used. Theseresponse variables may appear at varying timepoints in the disease and help to define the course ofthe disease. Ideally, the magnitude and pattern ofchange of the response variable correlate with diseaseoutcomes. Serum creatinine levels and changes inUOP are the most commonly applied measures ofrenal function, although they each are influenced byfactors other than the GFR. In addition, neither serumcreatinine nor UOP provides any information on thenature and site of kidney injury. These concepts con-tributed to the development of the proposed diagnosticcriteria (Table 1) that were based on consideration ofthe following:

1. Recognition of AKI requires delineation of eas-ily measured criteria that can be widely applied.The definition needs to be broad enough to ac-commodate variations in clinical presentationacross age groups, locations, and clinical situa-tions.

2. Current clinical practice does not focus much

attention on small increments in serum creatinine,which are often attributed to laboratory variations.However, the coefficient of variation of serumcreatinine with modern analyzers is relativelysmall; therefore, increments of 0.3 mg/dl are un-likely to be due to assay variation (27).

3. Changes in volume status can influence serumcreatinine levels (28) and mask recognition ofchanges in renal function. Consequently, diagnos-tic criteria would be applied only after an optimalstate of hydration had been achieved. The amountand type of fluid to be administered were notdelineated because the amount of fluid resuscita-tion depends on the underlying clinical situation(29).

4. The need for including UOP as a diagnostic cri-terion is based on the knowledge of critically illpatients in whom this parameter often heraldsrenal dysfunction before serum creatinine rises. Itwas recognized that the hydration state, use ofdiuretics, and presence of obstruction can influ-ence the urine volume, hence the need to considerthe clinical context. In addition, accurate mea-surements of UOP may not be easily available inall cases, particularly in patients in non-ICU set-tings. Despite these limitations, it was believedthat the use of changes in UOP offers a sensitiveand easily discernible means of identifying pa-tients, but its value as an independent criterion fordiagnosis of AKI will need to be validated.

5. A time constraint of 48 h for diagnosis wasselected to ensure that the process was acute andrepresentative of events within a clinically rele-vant period. It was acknowledged that the criteria

Table 1. Definition and diagnostic criteria for AKIa

An abrupt (within 48 h) reduction in kidney functioncurrently defined as an absolute increase in serumcreatinine of either 0.3 mg/dl (25 mol/L) or apercentage increase of 50% or a reduction in UOP(documented oliguria of 0.5 ml/kg per h for 6 h)

aThese criteria include both an absolute and a percentage change in creatinineto accommodate variations related to age, gender, and body mass index and toreduce the need for a baseline creatinine but does require at least two creatininevalues within 48 h. The UOP criteria were included on the basis of the predictiveimportance of this measure but also recognizing that UOP may not be measuredroutinely in non-ICU settings. It is assumed that the diagnosis on UOP criteriaalone will require exclusion of urinary tract obstruction reducing UOP or othereasily reversible causes of reduced UOP. These criteria should be used in contextof the clinical presentation and after adequate fluid resuscitation when applicable.AKI, acute kidney injury. Adapted with permission from Mehta et al.: Report of anInitiative to Improve Outcomes in Acute Kidney Injury. Crit Care 11: R31, 2007.26

282 Nephrology Self-Assessment Program - Vol 6, No 5, September 2007

require two creatinine values to be availablewithin any 48-h time window.

6. The role of emerging sensitive and specific mark-ers for kidney injury that are not currently avail-able in clinical practice was considered. Severalgroups are working on developing and validatingbiomarkers of kidney injury that may be used inthe future for diagnosis and prognosis.

Staging/Classification for AKIThe goal of a staging system is to allow classi-

fication that supports accurate identification and prog-nostication and inform diagnostic or therapeutic inter-ventions. The group recognized that a number ofsystems for staging and classifying AKI are in use orhave been proposed (30). The RIFLE criteria (24)proposed by the ADQI group were developed by aninterdisciplinary, international consensus process andare now being validated by various groups worldwide(3134). However, since then, data suggesting thatsmaller changes in serum creatinine than considered inthe RIFLE criteria might be associated with adverseoutcomes (1823) have emerged. In addition, giventhe consensus definition for AKI (Table 1), RIFLEcriteria have been modified so that patients who meetthe definition for AKI could be staged (Table 2). Theproposed staging system retains the emphasis onchanges in serum creatinine and UOP but includes thefollowing principles:

1. Whereas diagnosis of AKI is based on changesover 48 h, staging occurs over a slightly longertime frame. One week was proposed by ADQIin the original RIFLE criteria (24).

2. There was a conscious decision not to include the

therapy for AKI (renal replacement therapy[RRT]) as a distinct stage because this constitutesan outcome of AKI.

3. The new staging system maps to the RIFLE stagesas follows:a. The risk category should have same criteria as

the diagnosis of AKI stage 1.b. Those who are classified in the injury and

failure categories map to stages 2 and 3 ofAKI.

c. The loss and ESRD categories were removedfrom the staging system and remain outcomes.

d. Given the variability inherent in commencingRRT and because of variability in resources indifferent populations and countries, patientswho receive RRT are to be included in stage 3(analogous to stage 5 chronic kidney disease,GFR 15, or dialysis).

Implications of Diagnostic and Staging CriteriaThe proposed criteria will need to be validated in

future studies; however, it is anticipated that theywould enhance our ability to improve the treatment ofthese patients. Validation studies will need to be de-signed to answer pertinent questions that are unclear.For instance, is the 48-h time window necessary,should fluid resuscitation be a requirement, and, if so,how much fluid needs to be administered; are the UOPcriteria robust, and will it be confounded by use ofdiuretics; and how can a baseline creatinine be esti-mated if one is not available? In addition, the AKINcriteria currently require an increment in serum creat-inine level as a measure of renal dysfunction, but itwould be relevant to know whether a decrease in

Table 2. Classification/staging system for AKIa

Stage Creatinine Criteria Urine Output Criteria1 Increase in serum creatinine of 0.3 mg/dl or

increase to 150 to 200% from baseline0.5 ml/kg per h for 6 h

2 Increase in serum creatinine to 200 to 300%from baseline

0.5 ml/kg per h for 12 h

3b Increase in serum creatinine to 300% frombaseline (or serum creatinine 4.0 mg/dlwith an acute rise of at least 0.5 mg/dl)

0.3 ml/kg per h 24 h or anuria 12 h

aThe staging system proposed is a highly sensitive interim staging system and based on recent data indicating that a small change in serum creatinine influencesoutcome. It is intended for use so that additional data will be gathered and research initiatives proposed before further refinement. Only one criterion (creatinine or UOP)has to be fulfilled to qualify for a stage. Adapted with permission from Mehta et al.: Report of an Initiative to Improve Outcomes in Acute Kidney Injury. Crit Care 11:R31, 2007.26

bGiven wide variation in indications and timing of initiation of RRT, individuals who receive RRT are considered to have met criteria for stage 3 irrespective of the stagethey are in at time of RRT.

Nephrology Self-Assessment Program - Vol 6, No 5, September 2007 283

serum creatinine of0.3 mg/dl has a similar influenceon outcomes and hence would qualify as a diagnosticcriterion for AKI.

While these validation studies are performed, itis worthwhile considering the various areas wherethese diagnostic and staging criteria would requirechange in practice. There is wide variation in thestandard of care for measuring serum creatinine inhospitalized patients. Whereas most ICUs incorporatea serum creatinine measurement as a standard labora-tory test every 24 h, non-ICU patients have a muchwider variation in the frequency of these measure-ments. This will obviously have an influence on thediagnostic and staging criteria. The proposed stagingcriteria build on existing knowledge and permit indi-viduals using current staging systems (e.g., RIFLE) totransition to the new system without loss of compara-bility. Appropriate drug dosing adjusted to the level ofrenal function is an important component for the careof hospitalized patients. Most common, dosage adjust-ments are done on the basis of estimated GFR from theCockroft-Gault formula and may need modification onthe basis of the AKI staging criteria. Similarly, alteredrenal function is a recognized adverse event in clinicaltrials and the Common Terminology Criteria for Ad-verse Events are commonly used for cancer trials. Theparameters that are used to stage the severity of renaldysfunction are somewhat different from the proposedAKI stages and consequently may require some ad-justments. It is also clear that as we learn more aboutthe natural history and course of AKI, we will beguided by emerging biomarkers, and these will need tobe incorporated into future versions of the diagnosticand staging criteria.

ConclusionsAKI continues to be a vexing problem that oc-

cupies a significant amount of time for clinicians andoffers numerous challenges to investigators. Standard-izing the diagnostic and staging criteria for this diseaseis a crucial step to understanding the natural historyand consequences of the disease. We believe that theAKIN initiative can serve as a catalyst to facilitateresearch initiatives in this field and to develop theevidence to support changes in practice. The multidis-ciplinary collaborations will greatly enhance our abil-ity to design prospective studies to evaluate potentialprevention and treatment strategies. We anticipate thatthe broad support and commitment obtained through

society involvement will significantly enhance theability to disseminate the results to the worldwidecommunity and to address one of the limitations ofconsensus recommendations that they are often notadopted. We envision that the AKIN will provide aneffective mechanism for facilitating efforts to improvepatient outcomes. In essence, AKI is not just ARFrenamed but represents a new era in our understandingof and approach to this global problem that requires aconcerted international, multidisciplinary effort tomake a difference.

References1. Mehta RL, Pascual MT, Soroko S, Savage BR, Himmelfarb J,

Ikizler TA, Paganini EP, Chertow GM: Spectrum of acute renalfailure in the intensive care unit: The PICARD experience. KidneyInt 66: 16131621, 2004

2. Waikar SS, Curhan GC, Wald R, McCarthy EP, Chertow GM:Declining mortality in patients with acute renal failure, 1988 to2002. J Am Soc Nephrol 17: 11431150, 2006

3. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, MorgeraS, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A,Ronco C: Acute renal failure in critically ill patients: A multina-tional, multicenter study. JAMA 294: 813818, 2005

4. Liangos O, Wald R, OBell JW, Price L, Pereira J, Jaber BL:Epidemiology and outcomes of acute renal failure in hospitalizedpatients: A national survey. Clin J Am Soc Nephrol 1: 4351, 2006

5. Clermont G, Acker CG, Angus DC, Sirio CA, Pinsky MR, JohnsonJP: Renal failure in the ICU: Comparison of the impact of acuterenal failure and end-stage renal disease on ICU outcomes. KidneyInt 62: 986996, 2002

6. Metnitz PG, Krenn CG, Steltzer H, Lang T, Ploder J, Lenz K, LeGall JR, Druml W: Effect of acute renal failure requiring renalreplacement therapy on outcome in critically ill patients. Crit CareMed 30: 20512058, 2002

7. Thakar CV, Worley S, Arrigain S, Yared JP, Paganini EP: Influenceof renal dysfunction on mortality after cardiac surgery: Modifyingeffect of preoperative renal function. Kidney Int 67: 11121119,2005

8. Druml W: Long term prognosis of patients with acute renal failure:Is intensive care worth it? Intensive Care Med 31: 11451147, 2005

9. Liano F, Junco E, Pascual J, Madero R, Verde E: The spectrum ofacute renal failure in the intensive care unit compared with that seenin other settings. The Madrid Acute Renal Failure Study Group.Kidney Int Suppl 66: S16S24, 1998

10. Mehta RL, Pascual MT, Soroko S, Chertow GM: Diuretics, mor-tality, and nonrecovery of renal function in acute renal failure.JAMA 288: 25472553, 2002

11. Lameire N, Van Biesen W, Vanholder R: Acute renal failure. Lancet365: 417430, 2005

12. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ: Acute renal failurein intensive care units: Causes, outcome, and prognostic factors ofhospital mortalityA prospective, multicenter study. French StudyGroup on Acute Renal Failure. Crit Care Med 24: 192198, 1996

13. Chertow GM, Lazarus JM, Christiansen CL, Cook EF, Hammer-meister KE, Grover F, Daley J: Preoperative renal risk stratification.Circulation 95: 878884, 1997

14. Mehta RL, McDonald B, Gabbai F, Pahl M, Farkas A, Pascual MT,Zhuang S, Kaplan RM, Chertow GM: Nephrology consultation inacute renal failure: Does timing matter? Am J Med 113: 456461,2002

15. Mehta RL, Pascual MT, Gruta CG, Zhuang S, Chertow GM:


Refining predictive models in critically ill patients with acute renalfailure. J Am Soc Nephrol 13: 13501357, 2002

16. Vincent JL: Incidence of acute renal failure in the intensive careunit. Contrib Nephrol 16, 2001

17. Hoste EA, Lameire NH, Vanholder RC, Benoit DD, DecruyenaereJM, Colardyn FA: Acute renal failure in patients with sepsis in asurgical ICU: Predictive factors, incidence, comorbidity, and out-come. J Am Soc Nephrol 14: 10221030, 2003

18. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW:Acute kidney injury, mortality, length of stay, and costs in hospi-talized patients. J Am Soc Nephrol 16: 33653370, 2005

19. Gruberg L, Mintz GS, Mehran R, Gangas G, Lansky AJ, Kent KM,Pichard AD, Satler LF, Leon MB: The prognostic implications offurther renal function deterioration within 48 h of interventionalcoronary procedures in patients with pre-existent chronic renalinsufficiency. J Am Coll Cardiol 36: 15421548, 2000

20. Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, DrumlW, Bauer P, Hiesmayr M: Minimal changes of serum creatininepredict prognosis in patients after cardiothoracic surgery: A pro-spective cohort study. J Am Soc Nephrol 15: 15971605, 2004

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24. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P: Acuterenal failure: Definition, outcome measures, animal models, fluidtherapy and information technology needs. The Second Interna-

tional Consensus Conference of the Acute Dialysis Quality Initiative(ADQI) Group. Crit Care 8: R204R212, 2004

25. Bellomo R, Kellum JA, Ronco C: Defining acute renal failure:Physiological principles. Intensive Care Med 30: 3337, 2004

26. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, WarnockDG, Levin A: Acute Kidney Injury Network (AKIN): Report of aninitiative to improve outcomes in acute kidney injury. Crit Care 11:R31, 2007

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30. Mehta RL, Chertow GM: Acute renal failure definitions and clas-sification: Time for change? J Am Soc Nephrol 14: 21782187,2003

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SyllabusAcute Kidney Injury and Critical Care Nephrology

Patrick T. Murray** and Paul M. Palevsky*Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago,Illinois; and Renal Section, VA Pittsburgh Healthcare System, and Department of Medicine,University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Learning Objectives1. To review recent advances in defining the

pathogenesis and pathophysiology of AKI.2. To foster a better understanding of current strat-

egies for the prevention and pharmacologic man-agement of AKI.

3. To analyze the evidence base regarding the man-agement of renal replacement therapy in AKI.

4. To examine recent advances in nonrenal aspectsof critical care medicine that affect the manage-ment of patients with acute and chronic kidneydisease.

This issue of NephSAP is an update to the threeprevious issues of NephSAP devoted to acute kidneyinjury (AKI), published in March 2003 (1), September2004 (2), and March 2006 (3). In this edition, on the basisof a survey of the literature published in the 18-mointerval from July 2005 to January 2007, we reviewrecent advances through the perspective of previous stud-ies. The reader should be aware that we have not pro-vided a comprehensive review of all aspects of AKI andshould refer to the three previous issues for more detailedcoverage of topics that are only briefly discussed in thisissue or have been omitted completely because of apaucity of recent advances.

This issue also examines recent advances incritical care medicine that affect the care of patientswith acute and chronic kidney disease. Critical careunits increasingly are a locus for nephrology care. It istherefore necessary for nephrologists to have an un-derstanding of the rapidly evolving practice of criticalcare medicine. Although this review is not encyclope-dic, we have included important issues that nephrolo-gists will frequently encounter while caring for criti-cally ill patients.

References1. Palevsky PM: Acute renal failure. NephSAP 2: 4185, 20032. Palevsky PM: Acute renal failure. NephSAP 3: 245284, 20043. Palevsky PM, Murray PT: Acute kidney injury and critical care

nephrology. NephSAP 5: 72120, 2006

Definition of Acute Kidney InjuryConceptually, acute kidney injury (AKI) is easily

defined as the loss of renal function, measured by adecline in GFR, that develops over a period of hours todays. Clinically, AKI is manifested by accumulationof creatinine, urea, and other metabolic waste productsthat are normally excreted by the kidney in blood andother body fluids. The actual change in solute concen-tration, however, is dependent on multiple factors,including not only the change in renal function butalso differences in the metabolic generation and vol-ume of distribution of these solutes, which can also bealtered during AKI. Furthermore, changes in func-tional parameters, such as serum creatinine and bloodurea nitrogen concentrations and urine volume, do notreflect the etiologic basis of kidney injury. Thus,similar changes in these parameters may be seen inpatients with hemodynamically mediated functionalprerenal azotemia, obstructive nephropathy, or theintrinsic renal injury of acute tubular necrosis.

Recent literature has emphasized the correlationbetween changes in renal function and clinical out-comes. As reviewed in the previous issues of Neph-SAP devoted to AKI, even small changes in serumcreatinine are associated with mortality risk. For ex-ample, Chertow et al. (1) described a progressive risein hospital mortality associated with increases in se-rum creatinine in a cohort of nearly 20,000 patientswho were hospitalized at a single urban academicmedical center during an 8-mo period. After multiva-riable modeling to adjust for demographic factors and

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comorbid disease, an increase in serum creatinine of0.3 to 0.4 mg/dl was associated with an adjusted oddsratio (OR) for death of 1.7 (95% confidence interval[CI] 1.2 to 2.6), an increase of 0.5 mg/dl with an ORof 6.5 (95% CI 5.0 to 8.5), and an increase in serumcreatinine of 1.0 mg/dl with an OR of 9.7 (95% CI7.1 to 13.2). When analyzed on the basis of relativechange in serum creatinine, increments of 25, 50,and 100% were associated with OR for death of 2.0,4.4, and 6.6, respectively.

As detailed in the previous issues of NephSAP,clinical studies of AKI have used multiple operationaldefinitions, making it difficult to compare epidemio-logic studies and to evaluate interventions for itsprevention and treatment. In May 2002, a workingconsensus definition of AKI was developed at theSecond International Consensus Conference of theAcute Dialysis Quality Initiative (ADQI) (2). Thisconsensus definition, referred to by the acronym RI-FLE, stratified AKI into three grades of severity ofrenal injury (risk, injury, and failure) on the basis ofchanges in serum creatinine or urine output (UOP) andtwo outcome criteria (loss and ESRD) on the basis ofthe duration of loss of kidney function (Table 1).

During the 18 mo covered by the literature re-view for this issue of NephSAP, a proliferation ofstudies validated the RIFLE criteria across a variety ofclinical settings (39). The majority of these studiesevaluated the relationship between the RIFLE severitygrades of risk, injury, and failure and mortality risk. Ina single-center, retrospective study at a university-affiliated Australian medical center, Uchino et al. (3)

evaluated 20,126 consecutive patients who were ad-mitted between January 2000 and December 2002.The overall hospital mortality was 8.0%. Using onlythe change in serum creatinine to assess severity ofAKI, 9.1% of patients were categorized in the RIFLEcategory of risk, 5.2% in the RIFLE category of injury,and 3.7% in the RIFLE category of failure. Hospitalmortality progressively increased with severity ofAKI, with OR for death after multivariate adjustmentfor demographic and clinical factors of 2.5, 5.4, and10.1 for patients who met the criteria of risk, injury,and failure, respectively, as compared with patientswho did not meet any of the RIFLE criteria.

Similarly, Hoste et al. (4) performed a retrospec-tive cohort study of patients who were admitted toseven intensive care units (ICU) at a single Americanacademic medical center between July 1, 2000, andJune 30, 2001. Using both the creatinine and UOPcriteria, 8.1% of the total cohort of 5383 patients metthe criteria for risk, 7.1% for injury, and 6.8% forfailure at the time of ICU admission. During thecourse of ICU care, 67% of the cohort met criteria forthe diagnosis of AKI, with 12% fulfilling the criteriafor a maximal RIFLE classification of risk, 27% amaximal classification of injury, and 28% a maximalclassification of failure. Only 14.2% of the patientswho met the criteria for failure were treated with renalreplacement therapy (RRT). As was seen in the studyby Uchino et al., mortality correlated with the maxi-mal RIFLE class attained, with hospital mortality ratesof 8.8% for risk, 11.4% for injury, and 26.3% forfailure compared with 5.5% for patients without cri-

Table 1. RIFLE and AKIN staging criteria for AKIa

RIFLEStage

AKINStage Serum Creatinine Criteria Urine Output Criteria

Riskb 1 Increase in serum creatinine of 1.5- to 2.0-foldfrom baseline (RIFLE and AKIN) or increase inserum creatinine of 0.3 mg/dl (AKIN)


Injury 2 Increase in serum creatinine of two- to three-foldfrom baseline


Failure 3 Increase in serum creatinine of more thanthree-fold from baseline or serum creatinine of4 mg/dl with an acute rise of 0.5 mg/dl

0.3 ml/kg per h for 24 h oranuria for 12 h

Lossc Persistent renal failure for 4 wkESRDc Persistent renal failure for 3 mo

aAKI, acute kidney injury; AKIN, Acute Kidney Injury Network; RIFLE, risk, injury, failure, loss, ESRD.bRIFLE risk and AKIN stage 1 criteria differ in the inclusion of an absolute increase in serum creatinine of 0.3 mg/dl in the AKIN criteria.cNo AKIN stages correspond to RIFLE loss or RIFLE ESRD.


teria for AKI. Hospital mortality in patients whoattained a maximal RIFLE class of failure on the basisof change in serum creatinine was 27.9% as comparedwith 21.9% (P 0.02) for patients who were classi-fied as meeting the failure criteria on the basis of UOP.Similar correlations between severity of AKI classi-fied using RIFLE criteria and outcomes have beendescribed in other studies across critically ill patients(5,6) as well as in specific populations such as thoseundergoing liver transplantation (7), cardiac surgery(8), and bone marrow transplantation (9).

As discussed in the editorial review by Mehta etal. that accompanies this issue, the Acute KidneyInjury Network (AKIN), a collaborative initiative ofglobal nephrology and critical care societies, has pro-posed modification of the RIFLE criteria (10). TheAKIN workgroup defined AKI as an abrupt (within48 h) reduction in kidney function as manifest by anincrease in serum creatinine of either 0.3 mg/dl or arelative increase of 50%, or a reduction in UOP to0.5 ml/kg per h for 6 h, corresponding to theRIFLE Risk criteria with the addition of the absolutechange in serum creatinine of 0.3 mg/dl. The AKINworkgroup retained the three RIFLE severity grades ofrenal injury (risk, injury and failure), renaming themstages 1, 2, and 3, but dropped the two RIFLE out-come criteria (loss and ESRD; Table 1). To date, thereare no published validation studies of these modifiedcriteria.

Although the original RIFLE criteria and themore recent modifications proposed by AKIN providea valuable framework for epidemiologic studies andclinical trials, the applicability of these criteria toindividual patient treatment remains less clear. Theobservation by Hoste et al. (4) that fewer than 15% ofpatients classified as RIFLE failure are started on RRTsuggests that although these criteria are sensitiveenough to identify increased mortality risks, they arenot specific enough to guide clinical care. In addition,the concordance between the serum creatinine andUOP criteria that define each of the stages of AKI andclinical outcomes has not been validated. For theclassification scheme to be valid, mortality risk andother outcomes should be the same whether a patientis classified as meeting the risk, injury, or failurecriteria on the basis of either changes in serum creat-inine or changes in UOP. However, in the studyreported by Hoste et al. (4), patients who were clas-sified as RIFLE Failure on the basis of the UOP

criteria had a significantly lower mortality risk thanpatients who were assigned to the same category onthe basis of change in serum creatinine.

Another fundamental weakness of the RIFLEand AKIN criteria is inherent in their reliance onfunctional parameters for the identification of kidneyinjury. Changes in serum creatinine and the develop-ment of oliguria cannot differentiate between hemo-dynamically mediated changes in renal function (pre-renal azotemia), obstructive disease, and intrinsic renalinjury (11). More important, these functional parame-ters often lag hours or days behind the onset ofstructural injury.

Recognition of the inherent insensitivity of anydefinition of AKI that is dependent solely on urineflow and common biochemical markers of renal func-tion, such as serum creatinine and urea, has led toefforts for the identification of other markers for thediagnosis of AKI. Cystatin C is a low molecularweight protein produced at a constant rate by allnucleated cells whose function is to inhibit cysteineproteases. Because of its low molecular weight, it isfreely filtered at the glomerulus and reabsorbed andcatabolized but not secreted by the renal tubule.Plasma levels correlate with GFR and, unlike creati-nine, are not significantly affected by age, gender,race, or muscle mass. Recently, Herget-Rosenthal etal. (12) compared cystatin C with creatinine for thediagnosis of AKI in a series of 85 patients. Increases inserum levels of cystatin C were detectable 1 to 2 dearlier than comparable changes in serum creatinineregardless of whether the threshold for increase inserum levels was at least 50%, 100%, or 200%. Sim-ilar results also were reported by Villa et al. (13) whenexamining a series of 50 critically ill patients whowere at high risk for the development of AKI. Al-though these data suggest that cystatin C may permitearlier detection of AKI, its utility in clinical treatmentof patients has not been established.

Biomarkers of renal tubular injury also havebeen proposed as potential tools for the rapid diagnosisof renal parenchymal injury (14). As reviewed byZhou et al. (14) in the editorial accompanying the lastissue of NephSAP focused on AKI, multiple candidatebiomarkers for the diagnosis of AKI have been iden-tified. These include N-acetyl--D-glucosaminidase,kidney injury molecule-1, isoform 3 of the sodium-hydrogen exchanger, neutrophil gelatinase-associatedlipocalin (NGAL), and IL-18. Recent published stud-


ies have focused primarily on the last two of thesecandidate biomarkers.

NGAL is a 25-kD protein, originally character-ized in neutrophils, that is bound to gelatinase. Thephysiologic role of NGAL in the kidney is unknown;however, it is believed to play a role in renal morpho-genesis. Expression of NGAL mRNA and protein inthe kidney is rapidly upregulated after renal ischemiain animal models. Its precise role in the mature kidneyalso is uncertain; it has been suggested, however, thatits expression after tubular injury may play a role inthe induction of repair and re-epithelialization (14,15).The relationship between NGAL and human ischemia-reperfusion injury is illustrated in a study of allograftkidney biopsy samples obtained within 1 h of vascularanastomosis after transplantation of 13 deceased-do-nor and 12 living-donor renal allografts (15). NGALstaining was significantly increased in the deceased-donor allografts as compared with the living-donorallografts, with a strong correlation between intensityof staining and both cold ischemia time and peakpostoperative serum creatinine.

Several clinical studies have suggested that urineNGAL expression may serve as an early marker ofAKI. In a clinical trial of 71 children who underwentcardiac surgery, urinary NGAL increased within 2 h ofcardiopulmonary bypass to a level of 50 g/L in all20 children who had an increase in serum creatinine of50% (RIFLE Risk) and in only one of the 51children who did not meet the definition of AKI (16).Although the sensitivity and specificity to predict thislevel of kidney injury of 100% and 98%, respectively,are impressive, giving an area under the receiveroperating characteristics (ROC) curve of 0.999, theclinical relevance for urinary NGAL is less certain,because none of the children who manifested thischange in kidney function progressed to severe AKI orrequired RRT.

Urinary NGAL also was evaluated in adult pa-tients who underwent cardiac surgery, with less im-pressive results (17). In a cohort of 81 such patients ata single institution, 16 developed AKI, as defined byan increase in serum creatinine of 50% (RIFLERisk). Preoperative urinary NGAL levels were com-parable among patients who did and did not developAKI and were not significantly different immediatelyafter surgery. However, within 1 h after surgery, theurinary NGAL concentration began dropping in pa-tients who did not develop AKI but continued to rise

in patients with AKI, peaking at 3 h and remainingelevated for 24 h. Peak concentrations in patients withAKI were 6000 7600 g/L, as compared with1800 3500 g/L in patients who did not developAKI. Using a threshold urine NGAL of 213 g/L, thearea under the ROC curve for prediction of a 50%increase in serum creatinine was 0.74 at 3 h and 0.8 at18 h. Although the majority of the 16 patients whodeveloped AKI did not manifest severe renal injury,five patients did require treatment with RRT.

IL-18 also has been considered as a candidatebiomarker for parenchymal renal injury. IL-18 is aproinflammatory cytokine generated by caspase-1mediated cleavage in injured proximal tubules andreleased into the urine (14). In animal models, IL-18has been shown to exacerbate tubular necrosis, andneutralizing antibodies to IL-18 reduce renal ischemicinjury in mice (14). Urinary IL-18 levels were mea-sured in 72 individuals, 14 with acute tubular necrosis,eight with prerenal azotemia, five with urinary tractinfections, 12 with chronic kidney disease, 22 whoreceived a kidney transplant, and 11 healthy controlsubjects (18). Patients with acute tubular necrosis hadsignificantly higher urinary IL-18 levels as comparedwith control subjects and patients with other forms ofkidney disease. Similarly, patients who underwenttransplantation and had delayed graft function hadhigher urinary IL-18 levels than patients with promptgraft function.

Using banked samples collected on days 0, 1,and 3 of the Acute Respiratory Distress Syndrome(ARDS) Network trial, urine IL-18 levels of 100pg/ml were associated with a 6.5-fold increased riskfor development of AKI, defined as an increase inserum creatinine of 50% (RIFLE Risk), in the sub-sequent 24 h (19). However, the sensitivity of urinaryIL-18 for detection of this level of renal injury in thesesamples was only 50%, with a specificity of 85%,giving positive and negative predictive values of 62and 78%, respectively, and an area under the ROCcurve of 0.73. Urinary IL-18 also was evaluated afterpediatric cardiac surgery, using samples from the samecohort in the NGAL study described previously (20).Urinary IL-18 increased 4 to 6 h after cardiopulmo-nary bypass, peaked with 25-fold increases overbaseline at 12 h, and remained elevated up to 48 h afterbypass in children who developed AKI (RIFLE Risk)but did not significantly increase in children withoutAKI. Thus, urinary NGAL and IL-18 seem to be


sequential markers, with NGAL peaking within 2 to4 h and IL-18 at 12 h. However, the sensitivity andspecificity of urinary IL-18 at 12 h were only 50 and94%, respectively, with an area under the ROC curveof 0.75, as compared with a sensitivity and specificityfor urinary NGAL at 2 h of 100 and 98%, respectively,and an area under the ROC curve of 0.99. Althoughthese data suggest that urinary IL-18 alone may not besufficient as a biomarker for AKI, it may be useful aspart of a panel of biomarkers, increasing the prognos-tic capability of an extremely sensitive marker, such asNGAL.

Further progress in the development and clinicalvalidation of biomarkers for detection of renal injury isnecessary to refine the clinical definition of AKI. Asthe development of troponin, by allowing more rapiddiagnosis of acute myocardial infarction, facilitatedmany of the recent advances in the management ofacute coronary syndromes, biomarkers for the earlydiagnosis of AKI may permit early targeted interven-tions to reverse or ameliorate tubular injury in AKI.

References1. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW:

Acute kidney injury, mortality, length of stay, and costs in hospi-talized patients. J Am Soc Nephrol 16: 33653370, 2005

2. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P: Acuterenal failure: Definition, outcome measures, animal models, fluidtherapy and information technology needsThe Second Interna-tional Consensus Conference of the Acute Dialysis Quality Initiative(ADQI) Group. Crit Care 8: R204R212, 2004

3. Uchino S, Bellomo R, Goldsmith D, Bates S, Ronco C: An assess-ment of the RIFLE criteria for acute renal failure in hospitalizedpatients. Crit Care Med 34: 19131917, 2006

4. Hoste EA, Clermont G, Kersten A, Venkataraman R, Angus DC, DeBacquer D, Kellum JA: RIFLE criteria for acute kidney injury areassociated with hospital mortality in critically ill patients: A cohortanalysis. Crit Care 10: R73, 2006

5. Bell M, Liljestam E, Granath F, Fryckstedt J, Ekbom A, MartlingCR: Optimal follow-up time after continuous renal replacementtherapy in actual renal failure patients stratified with the RIFLEcriteria. Nephrol Dial Transplant 20: 354360, 2005

6. Abosaif NY, Tolba YA, Heap M, Russell J, El Nahas AM: Theoutcome of acute renal failure in the intensive care unit according to

RIFLE: Model application, sensitivity, and predictability. Am JKidney Dis 46: 10381048, 2005

7. Guitard J, Cointault O, Kamar N, Muscari F, Lavayssiere L, Suc B,Ribes D, Esposito L, Barange K, Durand D, Rostaing L: Acute renalfailure following liver transplantation with induction therapy. ClinNephrol 65: 103112, 2006

8. Kuitunen A, Vento A, Suojaranta-Ylinen R, Pettila V: Acute renalfailure after cardiac surgery: Evaluation of the RIFLE classification.Ann Thorac Surg 81: 542546, 2006

9. Lopes JA, Jorge S, Silva S, de Almeida E, Abreu F, Martins C, doCarmo JA, Lacerda JF, Prata MM: An assessment of the RIFLEcriteria for acute renal failure following myeloablative autologousand allogeneic haematopoietic cell transplantation. Bone MarrowTransplant 38: 395, 2006

10. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, WarnockDG, Levin A: Acute Kidney Injury Network (AKIN): Report of aninitiative to improve outcomes in acute kidney injury. Crit Care 11:R31, 2007

11. Van Biesen W, Vanholder R, Lameire N: Defining acute renalfailure: RIFLE and beyond. Clin J Am Soc Nephrol 1: 13141319,2006

12. Herget-Rosenthal S, Marggraf G, Husing J, Goring F, Pietruck F,Janssen O, Philipp T, Kribben A: Early detection of acute renalfailure by serum cystatin C. Kidney Int 66: 11151122, 2004

13. Villa P, Jimenez M, Soriano MC, Manzanares J, Casasnovas P:Serum cystatin C concentration as a marker of acute renal dysfunc-tion in critically ill patients. Crit Care 9: R139R143, 2005

14. Zhou H, Hewitt SM, Yuen PS, Star RA: Acute kidney injurybiomarkers: Needs, present status, and future promise. NephSAP 5:6371, 2006

15. Mishra J, Ma Q, Kelly C, Mitsnefes M, Mori K, Barasch J,Devarajan P: Kidney NGAL is a novel early marker of acute injuryfollowing transplantation. Pediatr Nephrol 21: 856863, 2006

16. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, RuffSM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P:Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarkerfor acute renal injury after cardiac surgery. Lancet 365: 12311238,2005

17. Wagener G, Jan M, Kim M, Mori K, Barasch JM, Sladen RN, LeeHT: Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiacsurgery. Anesthesiology 105: 485491, 2006

18. Parikh CR, Jani A, Melnikov VY, Faubel S, Edelstein CL: Urinaryinterleukin-18 is a marker of human acute tubular necrosis. Am JKidney Dis 43: 405414, 2004

19. Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL: Urine IL-18is an early diagnostic marker for acute kidney injury and predictsmortality in the intensive care unit. J Am Soc Nephrol 16: 30463052, 2005

20. Parikh CR, Mishra J, Thiessen-Philbrook H, Dursun B, Ma Q, KellyC, Dent C, Devarajan P, Edelstein CL: Urinary IL-18 is an earlypredictive biomarker of acute kidney injury after cardiac surgery.Kidney Int 70: 199203, 2006

Epidemiology and PrognosisStudies of the epidemiology of acute kidney

injury (AKI) depend on the specific definition used forcase identification. For example, a study that relies ona relatively small increment in serum creatinine islikely to find a much higher incidence of AKI than astudy that defines AKI on the basis of need fordialysis. Similarly, studies that use disparate case def-initions are likely to find substantially different out-

Consensus criteria for the definition andstratification of AKI have been developedon the basis of changes in serum creati-nine and urine output. Although these cri-teria correlate with mortality risk and willfacilitate uniformity of definitions in clinicaltrials, there is still a need for sensitive andspecific biomarkers of renal injury.


comes, with higher mortality rates associated withmore stringent case definitions.

Recently, Uchino et al. (1) reported the results ofa multinational, prospective, observational study ofAKI in critically ill patients. Between September 2000and December 2001, a total of 29,269 critically illpatients were hospitalized in the participating inten-sive care units (ICU) of 54 hospitals in 23 countriesacross North and South America, Europe, Asia, andAustralia. With the use of a case definition for AKI ofa urine output of 200 ml in 12 h or a blood ureanitrogen concentration of 84 mg/dl, 1738 of thesepatients had AKI, for a period prevalence of 5.7%; ofthese, 1260 (72.5%) patients required renal replace-ment therapy (RRT). The major reason for ICU ad-mission was classified as medical in 58.9% of pa-tients and surgical for the remaining 41.1%. Septicshock was the most common contributing factor forthe development of AKI (47.5%), followed by majorsurgery (34.3%), cardiogenic shock (26.9%), hypovo-lemia (25.6%), and drug toxicity (19.0%). Approxi-mately 30% of patients had underlying chronic kidneydisease (CKD). ICU mortality was 52%, with anadditional 8% mortality in the hospital after ICUdischarge, for an overall hospital morality of 60.3%.Among surviving patients, 13.8% were still receivingRRT at the time of hospital discharge.

Several studies published during the intervalcovered by this issue of NephSAP attempted to analyzethe epidemiology and outcomes of AKI using largeadministrative databases (25). Liangos et al. (2) an-alyzed the 2001 National Hospital Discharge Survey(NHDS), identifying patients with AKI on the basis ofInternational Classification of Diseases, Ninth Revi-sion (ICD-9) codes. Among the approximately330,210 discharges included in the database, AKI wascoded as a discharge diagnosis with a frequency of19.2 per 1000 hospitalizations. This corresponds to anestimated 558,000 cases of AKI per year on the basisof a national estimate of slightly more than 29 millionhospital discharges annually. Approximately 7.5% ofpatients with AKI were identified as requiring RRT.There was a strong association between AKI andhospital mortality, with an overall hospital mortalityrate of 21.3% in patients who were coded as havingAKI as compared with only 2.3% in patients withoutAKI. AKI was more commonly coded for in olderpatients and in patients who were male or identified asblack race. Coding for AKI was also associated with

diagnoses of CKD, congestive heart failure, chroniclung disease, sepsis, and cardiac surgery. After multi-variate adjustment for age, gender, ethnic background,and payment source, AKI was associated with aneight-fold increased odds for death; the addition ofcoexisting conditions, acute hospital-related factors,and acute dysfunction of other organ systems to themultivariate model decreased the odds of death to 4.1(95% confidence interval 4.0 to 4.1). AKI also wasassociated with prolongation of hospital length of stay(LOS). When analyzed by single acute organ systemdysfunction, AKI was associated with a longer hospi-tal LOS (7 versus 3 d for patients without AKI) thanany other single organ system dysfunction. The pro-longation of LOS among patients who required dialy-sis was greater in patients who had AKI and did notrequire dialysis. On multivariate analysis, adjusting fordemographic factors and comorbidities, AKI was as-sociated with an estimated prolongation of hospitalLOS of 2 d, surpassed only by sepsis (2.6 d) andcardiac surgery (3.9 d). AKI also was associated witha two-fold increased odds for transfer to a short- orlong-term care facility after hospital discharge.

Xue et al. (3) performed a similar analysis usingthe Medicare 5% Sample Beneficiary Standard Ana-lytical File for the years 1992 through 2001. Duringthis 10-yr interval, the overall incidence rate of AKIwas 23.8 cases per 1000 discharges. However, therewas an approximately 11% per year increase in therate of AKI, rising from 14.6 cases per 1000 dis-charges in 1992 to 36.4 cases per 1000 discharges in2001. As was observed in the study by Liangos et al.(2), older age, male gender, and black race werestrongly associated with AKI risk. Hospital mortalitywas 32.9% in patients who had AKI and required RRTand 27.5% in patients who had AKI and did notrequire RRT, as compared with 4.6% in patients with-out AKI. Mortality rates also were higher amongpatients in whom AKI was coded as a secondarydiagnosis (32.6%) as compared with patients in whomAKI was the primary diagnosis (15.2%). AKI also wasassociated with an increased mortality in the first 90 dafter hospital discharge (34.5%) as compared withpatients who were discharged without an AKI diagno-sis (13.1%). Although these results are very similar tothose reported by Liangos et al. using the NHDScohort, the higher overall incidence of AKI observedby Xue et al. most likely reflects differences betweenthe two cohorts, with the greatest difference relating to


the ages of patients in the cohorts. As a result of theage dependence of Medicare eligibility, the medianage of patients in the Medicare 5% sample was sig-nificantly older as compared with the NHDS cohort.

In another analysis, Waikar et al. (4) analyzed athird database of hospitalized patients, the NationalInpatient Sample (NIS). The NIS is the largest all-payer administrative database of US hospitalizations.Examining data from 1988 to 2002, they observed anincrease in the percentage of annual discharges withAKI from 0.4% in 1988 to 2.1% in 2002. Correctingfor census data, they estimated that the US population-adjusted incidence of AKI increased from 61 per100,000 population in 1988 to 288 per 100,000 pop-ulations in 2002. When they limited the analysis toAKI that required RRT, the rates increased from0.03% of hospital discharges in 1988 to 0.20% in2002, corresponding to population-adjusted rates of 4per 100,000 population in 1988 to 27 per 100,000population in 2002. During this same period, theyobserved a decrease in hospital mortality from 40.4%in 1988 to 20.3% in 2002 for all patients with AKI anda corresponding decrease in mortality from 41.3% in1988 to 28.1% in 2002 among patients who had AKIand required renal support. Adjusting for demographicfactors, comorbidities, and other clinical parameters ina multivariable model, the odds ratio for in-hospitalmortality during the final 5-yr interval (1998 to 2002)was 0.40, as compared with the preceding 5-yr inter-val, for all patients with AKI and 0.47 for the subgroupof patients who required RRT.

Although these three studies provide importantinsight into the epidemiology of AKI, caution must betaken in interpreting epidemiologic studies that arebased on administrative data. In their study, Liangos etal. (2) conducted a validation of the ICD-9 diagnosesby comparing the ICD-9 codes for 13,412 patientswho were discharged from a single tertiary medicalcenter in 2001 with corresponding changes in serumcreatinine (2). Using a definition of AKI of an increasein serum creatinine of 0.5, 1.0, or 1.5 mg/dl from nadirvalues of 1.9, 2.0 to 4.9, and 5.0 mg/dl, respec-tively, the ICD-9 coding data identified only 304 of1584 patients with AKI and coded 43 patients who didnot meet clinical criteria as having AKI. Thus, thesensitivity and specificity of the ICD-9 coding was19.2 and 99.6%, respectively, with a positive predic-tive value (PPV) and negative predictive value (NPV)of 87.6 and 90.1%, respectively. Similarly, using a

case definition for AKI of a 100% increase in serumcreatinine (nadir to peak) during hospitalization,Waikar et al. (4) compared ICD-9 coding with clinicaldata from 7545 admissions to a single hospital inBoston in 1994 and 19,206 admission to two hospitalsin Boston in 2002. ICD-9 coding for AKI had 17.4%sensitivity, 98.7% specificity, 89.9% NPV, and 63.5%PPV in the 1994 cohort and 29.3% sensitivity, 97.4%specificity, 91.5% NPV, and 59.1% PPV in the 2002cohort.

In a third validation study, investigators fromboth groups validated ICD-9 codes for AKI againstserum creatininebased definitions for AKI in 97,705adult discharges from three academic medical centersin Boston in 2004 (6). Using as the definition of AKIan increase in serum creatinine of 0.5, 1.0, or 1.5mg/dl from nadir values of 1.9, 2.0 to 4.9, and 5.0mg/dl, respectively, the sensitivity, specificity, NPV,and PPV were 28.3, 99.0, 91.0, and 80.2%, respec-tively. When AKI was defined on the basis of a 100%increase in serum creatinine concentration, the sensi-tivity, specificity, NPV, and PPV were 35.4, 97.7,96.1, and 47.9%, respectively. Notably, there wassignificant interinstitution variability, with the sensi-tivity ranging between 32.2 and 47.6%. Coding forAKI that was treated using RRT was significantlymore reliable, with values of sensitivity, specificity,NPV, and PPV all 90%.

These validation data have several implications(7). First, estimates of AKI that are based on admin-istrative data significantly underestimate the true inci-dence of AKI. Second, reliability of coding is variablebetween institutions. Third, the reliability of codingseems to have increased over time, raising a questionas to whether the secular trends in the reported inci-dence of AKI are real or represent artifact in admin-istrative databases as the result of changes in codingpractice.

An additional study, using hospital case-mix datasets from 23 hospitals as reported by the Massachu-setts Division of Health Care Finance and Policyduring 1999 and 2000, attempted to analyze the costsand LOS of uncomplicated AKI, defined as AKI notassociated with nonrenal organ failure (5). The patientcohort in this study was restricted to 2252 adultswhose principle hospital diagnosis was AKI and whodid not receive care in an ICU or require mechanicalventilation. Patients with uncomplicated AKI incurredmedian direct hospital costs of $2600, had a median


hospital LOS of 5 d, and had a hospital mortality rateof 8%. These values all were greater than those asso-ciated with hospitalizations for heart failure, pneumo-nia, gastrointestinal hemorrhage, cellulitis, or bronchi-tis and asthma and were exceeded only byhospitalizations for circulatory disorders with acutemyocardial infarction and complications (direct hos-pital cost $3600; LOS 5 d; mortality 24%) and cere-brovascular disorders except transient ischemic attack(direct hospital cost $2700; LOS 4 d; mortality 11%).

The longer term outcomes of AKI have been lesswell characterized than hospital outcomes. Severalrecent studies examined these longer term outcomes(811). In a cohort of 425 patients who developedsevere AKI that required RRT but who had no previ-ous kidney disease, in-hospital mortality was 47% (8).At the time of hospital discharge, 57% of the survivingpatients had normal renal function, 33% had mild tomoderate renal impairment (serum creatinine 1.3 to3.0 mg/dl), and 10% had severe renal impairment(serum creatinine 3 mg/dl). No patients remaineddialysis dependent. One-year follow-up data wereavailable on 222 of the 226 patients who survivedhospital discharge. Seventy-six patients had died, foran overall 1-yr survival of 35%. Only one patient, anindividual with a serum creatinine at hospital dis-charge of 4.2 mg/dl, had progressed to ESRD. Thus, inthis cohort, 1% of surviving patients progressed torequiring long-term dialysis. Similar survival datawere reported by Lins et al. (9) in follow-up of 293patients who did not have known preexisting renaldisease and had been treated for AKI at eight centersin Belgium. A total of 145 (49.5%) patients survivedtheir index hospitalization; of these individuals, 32died during the first year after hospital discharge, for a1-yr mortality of 62%. Renal function 1 yr afterdischarge could be documented for 105 of the 113surviving patients. Mean serum creatinine in thesepatients was 1.96 mg/dl at hospital discharge and 1.94mg/dl at 1 yr. Fourteen patients had been dialysisdependent at hospital discharge; four of them recov-ered renal function and were able to discontinue dial-ysis, whereas three others required re-initiation ofdialysis during the follow-up period. Thus, at 1 yr,11.5% of surviving patients were dialysis dependent.

Similarly, Bagshaw et al. (10) analyzed the 1-yroutcomes of 240 patients who required RRT for AKIin the ICU of the Calgary Health Region between May1, 1999, and April 30, 2002. The 28-d, 90-d, and 1-yr

case-fatality rates were 61, 60, and 64%, respectively.Among surviving patients, 38% no longer requireddialysis at the time of ICU discharge, and 68% hadrecovered renal function at hospital discharge. Seven-ty-eight percent of the 87 patients who survived to atleast 1 yr did not require continued RRT, becomingdialysis independent after a median duration of 11 d;among the 19 patients who remained dialysis depen-dent, 12 (63%) had preexisting CKD, with a medianpremorbid serum creatinine of 2.6 mg/dl. Thus, al-though it has been suggested that AKI is a significantcontributor to the development of ESRD, these smallstudies do not support this contention. Differentiationmay be necessary between patients with acute onchronic disease and patients with de novo AKI. Longerterm follow-up of a larger population of patients withAKI will be required to ascertain the true impact ofAKI on the development and progression of CKD andESRD.

In an additional study, Noble et al. (11) evalu-ated long-term quality of life in a cohort of 16 patientswho had survived for a median of 14.5 yr after anepisode of AKI and respiratory failure that requiredRRT. These 16 individuals were the survivors of anoriginal cohort of 117 patients. Among this originalcohort, 79.4% died before hospital discharge. Eight ofthe 24 patients who survived to hospital dischargesubsequently died after a median of 5 yr (range 6 moto 15 yr). Quality of life was assessed using the SF-36in 12 of the 16 surviving patients. Scores for overallphysical health and seven of the eight domains (phys-ical functioning, role physical, bodily pain, generalhealth, vitality, social functioning, and role emotional)were significantly lower than population norms. Onlythe scores for overall mental health and the domainscore for mental health were not significantly differentfrom the general population.

Pediatric patients with AKI represent a specialpopulation. Askenazi et al. recently reported on the 3-to 5-yr longitudinal follow-up of 245 children who hadAKI and were treated at the Texas Childrens Hospitalbetween January 1998 and June 2001 (12). A total of174 (71%) survived to hospital discharge. An addi-tional 32 children died after discharge and 16 weredialysis dependent long term, leaving 126 potentialpediatric participants. Among this population, only 29could be located and evaluated, 17 (59%) of whomhad at least one sign of renal injury, including mi-croalbuminuria (n 9), hyperfiltration (n 9), de-


creased GFR (n 4), and hypertension (n 6). Thus,in the pediatric population, survivors of AKI have highrisks for ongoing renal injury and require long-termfollow-up.

References1. 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 multina-tional, multicenter study. JAMA 294: 813818, 2005

2. Liangos O, Wald R, OBell JW, Price L, Pereira BJ, Jaber BL:Epidemiology and outcomes of acute renal failure in hospitalizedpatients: A national survey. Clin J Am Soc Nephrol 1: 4351, 2006

3. Xue JL, Daniels F, Star RA, Kimmel PL, Eggers PW, Molitoris BA,Himmelfarb J, Collins AJ: Incidence and mortality of acute renalfailure in Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol17: 11351142, 2006

4. Waikar SS, Curhan GC, Wald R, McCarthy EP, Chertow GM:Declining mortality in patients with acute renal failure, 1988 to2002. J Am Soc Nephrol 17: 11431150, 2006

5. Fischer MJ, Brimhall BB, Lezotte DC, Glazner JE, Parikh CR:Uncomplicated acute renal failure and hospital resource utilization:A retrospective multicenter analysis. Am J Kidney Dis 46: 10491057, 2005

6. Waikar SS, Wald R, Chertow GM, Curhan GC, Winkelmayer WC,Liangos O, Sosa MA, Jaber BL: Validity of International Classifi-cation of Diseases, Ninth Revision, Clinical Modification Codes forAcute Renal Failure. J Am Soc Nephrol 17: 16881694, 2006

7. Lameire N, Van Biesen W, Vanholder R: The rise of prevalence andthe fall of mortality in patients with acute renal failure: What theanalysis of two databases does and does not tell us. J Am SocNephrol 17: 923925, 2006

8. Schiffl H: Renal recovery from acute tubular necrosis requiring renalreplacement therapy: A prospective study in critically ill patients.Nephrol Dial Transplant 21: 12481252, 2006

9. Lins RL, Elseviers MM, Daelemans R: Severity scoring and mor-tality 1 year after acute renal failure. Nephrol Dial Transplant 21:10661068, 2006

10. Bagshaw SM, Laupland KB, Doig CJ, Mortis G, Fick GH, Mucen-ski M, Godinez-Luna T, Svenson LW, Rosenal T: Prognosis forlong-term survival and renal recovery in critically ill patients withsevere acute renal failure: A population-based study. Crit Care 9:R700709, 2005

11. Noble JS, Simpson K, Allison ME: Long-term quality of life andhospital mortality in patients treated with intermittent or continuoushemodialysis for acute renal and respiratory failure. Ren Fail 28:323330, 2006

12. Askenazi DJ, Feig DI, Graham NM, Hui-Stickle S, Goldstein SL:35 year longitudinal follow-up of pediatric patients after acuterenal failure. Kidney Int 69: 184189, 2006

Pathobiology of Acute Kidney Injury: RecentInsights from Experimental Sepsis Models andDistant Effects of Renal Injury

This section updates and expands on the reviewof the pathophysiology of acute tubular necrosis in theprevious NephSAP issues (13). The majority of ex-perimental data concerning the pathophysiology andpathogenesis of acute kidney injury (AKI) previouslyassessed were derived from renal ischemia-reperfusion

models. In this edition, we focus on a review of thepathophysiology and pathogenesis of septic AKI (alsoreviewed separately as a clinical syndrome in thisissue), focusing on emerging data from current exper-imental sepsis models. These models have evolvedthroughout the years, attempting to replicate key as-pects of clinical human sepsis (4). Although endotoxinadministration remains a useful sepsis model, newermodels of infection that more closely resemble clinicalsepsis have been developed (5,6). Examples includececal ligation and puncture or intraperitoneal injectionof bacteria. Some models also include administrationof parenteral fluids and antibiotics and the use of agedmice, all to mirror more closely human sepsis (5).

It has been recognized for some time that exper-imental septic AKI can occur in the absence of hypo-tension (7). However, it also is known that inadequatefluid resuscitation masked with pressor use can causeAKI and multiple system organ failure (8). Further-more, the use of pressors (9) and inotropes (10) inexperimental sepsis can improve renal function. Renalvasoconstriction may play a role in the renal hypoper-fusion in septic shock, although increased renovascu-lar resistance with decreased renal blood flow is not aconsistent finding in experimental sepsis models(11,12). However, it also has been demonstrated re-peatedly that antagonism of increased renovascularresistance mediated by increased endothelin levels canimprove renal blood flow in endotoxemic animals; assuch, this phenomenon seems to be a robust observa-tion (13,14). Thus, although it is unclear whether renalhypoperfusion typically plays a role in causing septicAKI, improved perfusion can improve renal function,and under-resuscitation of septic animals increasesend-organ injury and death. There also has been agradually enhanced understanding of the role of im-paired endothelial function in the pathogenesis ofseptic organ failure (15). Wang et al. (16) demon-strated that knockout mice that were deficient in en-dothelial nitric oxide synthase were more susceptibleto endotoxemic AKI than were wild-type mice. AfterMcGirt et al. (17) found that the hepatic hydroxy-methyl glutarylCoA reductase inhibitor simvastatinincreased endothelial nitric oxide synthase expressionand improved endothelial function in hemorrhagicstroke, Merx et al. (18) showed that the same drugimproved survival in septic mice (cecal ligation andpuncture). Yasuda et al. (19) recently confirmed thatpretreatment (but not delayed administration) with


simvastatin improves survival in their sepsis model(cecal ligation and puncture in elderly mice receivingfluids and antibiotics), associated with improved renalfunction, evidence of better renal microvascular flow,and decreased systemic TNF levels. Thus, simvastatinseems to improve outcome and decrease organ dys-function by multiple mechanisms: A direct effect onrenal perfusion and also anti-inflammatory effects in-cluding decreased systemic TNF production. Otheremerging data similarly point to endothelial activationand dysfunction as important mediators of septic organinjury and mortality.

The successful use of activated protein C to treathuman sepsis was reviewed in the previous issue ofNephSAP devoted to AKI and critical care nephrology(3). This drug has both anticoagulant and anti-inflam-matory effects, and ongoing basic research seeks todetermine the mechanisms of benefit of this drug(6,20,21). Ganopolsky and Castellino (21) found thatheterozygous mice with protein C deficiency devel-oped more severe hypotension and AKI after cecalligation and puncture than did wild-type mice and hadhigher plasma cytokine levels and increased mortality.Gupta et al. (6) recently confirmed these findings in arat cecal ligation and puncture model; they found thatthe time course of development of AKI correlated withthe evolution of sepsis-induced protein C deficiency,and they determined that protein C supplementationcould ameliorate septic renal inflammation, injury, anddysfunction, suggesting a potential approach to pre-vention or early therapy of septic AKI.

There is abundant literature implicating endo-toxin, inflammatory cytokines, and other mediators ofthe inflammatory cascade in the pathogenesis of septicAKI, and emerging discourse is elucidating the path-ways involved. Some evidence suggests that the ef-fects of inflammatory mediators may be organ spe-cific. For example, Cunningham et al. (22) used anelegant transplant model to demonstrate that the sus-ceptibility to endotoxemic AKI in TNF receptor-1knockout mice traveled with the kidney, suggestingthat TNF acts to cause AKI by direct actions on thekidney mediated through the TNF-1 receptor. Theysubsequently showed that this renal injury is caused bysystemic TNF release stimulated by activation of Toll-like receptor-4 (23), one of a group of receptors thatrecognize pathogens and initiate the inflammatorycascade (24). Dear et al. (25) recently found thatmyeloid differentiation factor 88 (a molecule involved

in the signal transduction pathways of multiple Toll-like receptors) but not Toll-like receptor 4 was re-quired to cause septic AKI in their murine cecalligation and puncture model. They speculated thatToll-like receptor 4 is a receptor for endotoxin itselfand therefore more important in the endotoxemicmodel than in a polymicrobial cecal ligation and punc-ture model with a different array of inflammatorystimuli. Other evidence points to the potential role ofthe caspase enzyme cascade in causing septic AKI,including apoptosis induction (26) and decreased ILproduction (27). Finally, in addition to helping dissectthe mediators and signal transdu

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