Development of a Clinical Research Agenda for Acute Kidney Injury ...

Development of a Clinical Research Agenda for Acute Kidney Injury Using an International, Interdisciplinary, Three-Step Modified Delphi Process John A. Kellum,* Ravindra L. Mehta,† Adeera Levin,‡ Bruce A. Molitoris,§ David G. Warnock,储 Sudhir V. Shah,¶ Michael Joannidis,** and Claudio Ronco,†† for the Acute Kidney Injury Network (AKIN) *Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; †Department of Medicine, University of California at San Diego, San Diego, California; ‡Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; §Department of Medicine, Indiana University, Indianapolis, Indiana; 储 Department of Medicine, University of Alabama, Birmingham, Alabama; ¶Department of Medicine, University of Arkansas, Little Rock, Arkansas; **Department of Medicine, Medical University of Innsbruck, Innsbruck, Austria; and †† Department of Nephrology Dialysis and Transplantation, San Bortolo Hospital, Vicenza, Italy Background and objectives: Although acute kidney injury is common and significantly increases the risk for intensive care unit and hospital mortality, little is known about its true incidence or how it can be prevented. Furthermore, key unanswered questions remain about the optimal diagnosis and treatment of patients with acute kidney injury. An international, consensusbased, prioritized research agenda was sought to guide clinical and translational research in acute kidney injury. Design, setting, participants, & measurements: A three-step modified Delphi process involving 43 participants representing 19 professional societies, organizations, and multiple stakeholder groups ranging from clinical practice to basic science research was conducted. Results: Twenty research questions were generated across six focus groups. Overall, research priorities generated from nephrologists and intensivists were similar and highly correlated. The stakeholder groups included members from 15 countries. Results from adult and pediatric groups showed important differences, as did results from developing compared with developed countries; however the priority rankings from the developed and developing countries were significantly correlated. Top research priorities in acute kidney injury include determining optimal timing of renal replacement therapy and improving the understanding of the epidemiology of acute kidney injury around the world. Conclusions: Research recommendations that are highly consistent across various stakeholder groups and between developed and developing countries have been produced. It is hoped that these recommendations will prove valuable in guiding future clinical and translational research in this area. Clin J Am Soc Nephrol 3: 887-894, 2008. doi: 10.2215/CJN.04891107

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apid deterioration in kidney function in patients who become acutely ill, a syndrome known as acute kidney injury (AKI), is frighteningly common and dramatically increases the risk for intensive care unit and hospital mortality. In addition, AKI may increase the risk for chronic kidney disease and can occur outside hospital settings. The true incidence of AKI is not known. AKI occurs in approximately 13 to 20% of hospitalized pa-

Published online ahead of print. Publication date available at www.cjasn.org. Correspondence: Dr. John A. Kellum, The CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Laboratory, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Scaife Hall, Room 608, 3550 Terrace Street, Pittsburgh, PA 15261. Phone: 412-647-0740; Fax: 412-647-8060; E-mail: kellumja@ccm.upmc.edu Copyright © 2008 by the American Society of Nephrology

tients (1,2) and in as many as 67% of patients who are admitted to the intensive care unit (3). AKI may occur either in patients with normal baseline function or in those with chronic kidney disease. In hospitalized patients, AKI increases the risk for death in hospital by as much as four-fold (1), and even critically ill patients, who already have a high risk for death, have nearly twice that risk when they develop AKI (3). In addition to the massive burden that AKI places on patients and the health care system, it has become apparent that little is known about the syndrome and that further research is urgently needed. Furthermore, AKI is an international problem and one that, by its very nature, requires multidisciplinary input. An organized and integrated approach is needed. Although medical research traditionally has been organized ISSN: 1555-9041/303–0887

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along geopolitical and departmental lines, researchers and funding agencies are increasingly aware that the traditional divisions within medical research may in fact impede the pace of scientific discovery (4). Many funding agencies, including the National Institutes of Health (NIH), encourage the conduct of interdisciplinary research and have sought to reengineer the clinical research enterprise along multidisciplinary lines; however, research is expensive, and funding is limited. Acting on this need for collaborative and integrated approaches to AKI, the Acute Kidney Injury Network (AKIN) was established in Amsterdam in September 2005. The proposal to generate an international, multidisciplinary research network had been stimulated by the existence of other groups, such as the Acute Dialysis Quality Initiative (ADQI). AKIN activities were endorsed by all 18 of the world’s leading professional societies in adult and pediatric nephrology and critical care (5); however, the development of a robust research agenda that fulfills the needs of a broad scientific and clinical community requires careful attention to regional differences in health care delivery and disease frequencies. Thus, AKIN established an international collaboration of various stakeholder groups. Because the ultimate goal of the clinical research agenda is to generate evidence that will improve care, we chose to ensure the quality of the research agenda using criteria developed to assess quality of clinical practice guidelines (Appraisal of Guidelines Research and Evaluation [AGREE] collaboration) (6). Our aim was to achieve an international, consensus-based, prioritized research agenda that will serve to guide clinical and translational research in AKI.

Materials and Methods We assembled a multidisciplinary stakeholder committee that comprised representation from the 18 leading international professional societies of critical care and nephrology; a complete list of the participating societies is listed in Table 1. The committee included adult medicine and pediatrics, as well as representatives from basic science, translational and clinical research, policy development, and the NIH. We convened a series of organization meetings with members representing the major stakeholders and developed a program for the workshop. Participants were selected to represent the spectrum of international AKI experts and societies interested in AKI. We contacted each society individually and requested that they select delegates to send to a 3-d conference, held in Vancouver, British Columbia, Canada. Each society was required to finance the travel and accommodations for their delegates. Societies were not asked to review results of the research prioritization procedure. Additional members of the committee were then selected on the basis of expertise in specific areas not otherwise represented by the society delegates and to provide overall balance among disciplines, research expertise, and international representation. These additional members were invited to attend at their own expense, although limited travel stipends were available on a case-by-case basis. An overall research agenda was developed by the committee as an iterative process using a three-step modified Delphi procedure. This procedure consisted of a literature review phase, focus group interactions with presentations to the entire committee, and a ranking phase.

Focus Group Selection and Composition Preceding the conference, we organized the committee membership into six focus groups (Table 2), two in each of the following three

Clin J Am Soc Nephrol 3: 887-894, 2008

Table 1. Stakeholder groupsa Professional societies American College of Chest Physicians American Society of Nephrology American Society of Pediatric Nephrologists American Thoracic Society Asia Pacific Association of Critical Care Medicine Asian Pacific Society of Nephrology Australian and New Zealand Intensive Care Society Brazilian Intensive Care Society Canadian Critical Care Society Chinese Society of Nephrology European Dialysis and Transplant Society European Society of Intensive Care Medicine Indian Society of Nephrology International Pediatric Nephrology Association International Society of Nephrology National Kidney Foundation Sociedade Latino-Americana de Nefrologia e Hipertensão Société de Réanimation de Langue Française Society of Critical Care Medicine Guideline development organization and policy and funding agencies Acute Dialysis Quality Initiative Kidney Disease: Improving Global Outcomes National Institute of Diabetes and Digestive and Kidney Diseases Practitioners nephrology critical care medicine pediatrics Researchers basic science translational clinical

domains: Epidemiology, early evaluation and management, and renal replacement therapy (RRT). Domains were chosen by consensus with formal feedback provided over a series of conference calls with the chairs and executive committee of the conference. Once the topics for the focus groups were determined, we assigned each of the committee members to one of the six focus groups on the basis of expertise. Efforts were made to maintain balance among various stakeholder groups within each focus group. Two co-chairs were nominated to lead each focus group, and a facilitator with experience in consensus conferences and clinical practice guideline development was assigned to each domain (i.e., two focus groups).

Literature Review and Synthesis Before the conference, each of the co-chairs organized a systematic review of the literature that pertained to their focus group. Literature summaries will be published separately for each workgroup. Search strategies with search terms for each focus group are provided in Appendix 1. The purpose of the review was to identify key unanswered questions. A secure internet Web site was setup with FTP capability;


Research Agenda for AKI

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Table 2. Focus groupsa Domain

Epidemiology Evaluation and early management Renal replacement therapy a

Focus Group: Primary Question

Group Group Group Group Group Group

1: 2: 3: 4: 5: 6:

What is the worldwide incidence of AKI? How can AKI be studied in different environments? How/when should AKI be evaluated? How should AKI be managed? Indications/patient selection for RRT? Choice of therapy

AKI, acute kidney injury; RRT, renal replacement therapy.

group members were able to upload and download full-text articles, and through a number of iterative steps, a series of clinical questions were developed.

Focus Group Activities and Presentations In September 2006, we held a 3-d conference in Vancouver, British Columbia, Canada. The conference began with a series of brief presentations covering each of the three domains, presented by one of the co-chairs. At that time, questions from each of the six focus groups were presented to the entire committee. Feedback was provided, and during the subsequent 2 d, questions were refined by focus groups using published methods (7). The three facilitators provided input to improve quality of each research question using criteria developed by the AGREE collaboration (6).

Prioritization of Research Questions Once each focus group had developed a set of research questions with input from the entire committee, the final step in the Delphi process was to survey individually each of the members to determine the priority for each research question. This was done in real time at the conference. Prioritization was accomplished by asking each member to assign a value of 1 (highest priority) to 10 (lowest priority) to each of the research questions.

Analysis and Definitions Priority ranking was determined by calculating the mean score for each question and then ordering the list from highest to lowest priority. Because bias may be introduced because different raters could use only part of the absolute range, we also analyzed the individual scores after normalizing by the mean of scores for each rater. Next we compared priorities across different major stakeholder groups. We compared results from experts in nephrology with those from critical care. We also compared responses from North America with those from Europe, Asia, and South America. For purposes of analysis, we defined nephrologists and intensivist according to their main practice even when they were dual-boarded. We compared overall priority rankings across stakeholder groups using ANOVA, with individual pair-wise comparisons using Student-Newman-Keuls test. Rank correlation was determined using the Spearman coefficient. We considered a P ⬍ 0.05 as significant.

yielded a total of 20 research questions across all six focus groups (Table 3). The results of step 3, prioritization exercise, are also shown in Table 3 and are shown by the overall committee and separately by critical care and nephrology. Results were not statistically different between the raw scores and weighted scores, and the rankings that they produced were identical for the top 15 questions. Thus, additional analysis was performed using the raw scores only.

Differences across Major Stakeholder Groups Although the overall scores generated from nephrologists and intensivists were not statistically different (ANOVA), some differences in prioritization were seen (Table 3); however rankings from nephrologists and intensivist were highly correlated (r2 ⫽ 0.5, P ⫽ 0.0022). Individual scores for each question are shown in Figure 1. Pair-wise comparisons of scores for individual questions showed that only two questions received statistically different scores from nephrologists versus intensivists. The question, “When should RRT be withheld?” received a much lower raw score (6.21) from intensivists compared with nephrologists (4.29; P ⫽ 0.02); however, overall ranking was similar: 20th versus 17th. The question, “What dosage of RRT is required to maximize patient and renal survival?” received a mean score of 1.93 from intensivists but only a 3.25 from nephrologists (P ⫽ 0.04). This difference resulted in a considerable disparity in rankings: Second versus 10th. Only four pediatric specialists (three nephrologists and one intensivist) completed the entire exercise (three were from North America). There was significant variation in ratings within this group; however, the top-ranked question received very consistent ratings. Among the pediatricians, the question, “What dosage of RRT is required to maximize patient and renal survival?” was ranked first (mean score 1.5). The question, “How should RRT be dosed for different clinical situations?” was ranked third (mean score 2.3) among pediatricians although ranking only 11th overall.

Differences among Geographic Regions

Results Forty-six participants accepted invitations to attend the conference; three members could not attend because of unexpected schedule conflicts, and three additional members had to leave before the final prioritization exercise. This left 40 members who participated in the entire Delphi process. Steps 1 and 2

The stakeholder groups included members from 15 countries. Nine of the members came from developing countries in Asia and South America. Ratings from these members were different from those obtained from members from developed countries (P ⫽ 0.03), and the resultant rankings were considerably different (Table 4); however the priority rankings from developed

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Table 3. Research questionsa Priority Question

Raw Score All

When should RRT be initiated, and does timing affect outcome? Do other GFR markers predict clinical outcomes better than serum creatinine? Does AKI lead to CKD? Does severity of AKI predict renal and nonrenal clinical outcomes? What is the incidence of AKI? Are there biomarkers that predict severity and recovery in AKI? What ⬙dose⬙ of RRT is required to maximize patient and renal survival? What are the markers of kidney damage that predict the development and severity of AKI, as defined by low GFR with or without oliguria? What is the best measure to assess whether AKI is volume-responsive? What is the best measure to assess the optimal volume status in patients with AKI? How should RRT be dosed for different clinical situations? Is there a difference in prognosis between volume-responsive and volume-nonresponsive AKI? Does oliguria add to creatinine elevation to predict clinical outcomes (renal and nonrenal)? Can the presence or absence of biomarkers or imaging diagnose the prerenal component (prospective versus retrospective)? Are there differences in outcome between similar patients: With prerenal component AKI, with AKI without prerenal component, and without AKI? What is the economic cost of AKI? Does the timing of discontinuation of RRT in AKI influence renal recovery and patient outcomes? What is ⬙dose⬙ of RRT? When should RRT be withheld? Does modality of RRT affect outcome? a

Nephrology

CCM

2.1

1

1

1

2.58

2

3

5

2.63 2.68

3 4

2 5

8 3

2.77 2.8

5 6

8 6

4 6

2.83

7

10

2

3.08

8

4

12

3.25

9

7

14

3.25

10

9

10

3.3

11

12

7

3.72

12

11

15

3.8

13

15

9

3.9

14

13

11

4.22

15

14

18

4.25 4.25

16 17

16 18

16 17

4.65 4.9 4.97

18 19 20

19 17 20

19 20 13

CKD, chronic kidney disease; CCM, critical care medicine.

and developing countries were significantly correlated (r2 ⫽ 0.35, P ⫽ 0.01). It is interesting that rankings from different geographic regions within the developed countries were not correlated (e.g., North America and Europe: r2 ⫽ 0.006, P ⫽ 0.97). Table 4 shows differences between various regions for the top three research questions within each region.

Discussion Several studies have now demonstrated that AKI is a common and frequently lethal complication of critical illness (1–3); however, the incidence of AKI in various populations is unknown, and numerous unanswered questions arise regarding diagnosis, evaluation, and early management and RRT for this syn-


Figure 1. Histograms showing raw scores (1 ⫽ highest, 10 ⫽ lowest) for priority for each of the 20 research questions (see Table 3). Shown are raw scores for all members together (f) and for nephrology (䡺) and critical care medicine (CCM; u) separately. Questions 7 and 19 were significantly different comparing nephrologists with intensivists (P ⬍ 0.05).

drome. We assembled an international, multidisciplinary stakeholder group for the purpose of developing and prioritizing a research agenda for AKI. Our results indicate that top priorities for research in AKI involve the broad topics of epidemiology and RRT. Indeed, timing of initiation of RRT was consistently at or near the top of priorities for all stakeholder groups. This is perhaps not surprising given that there is no consensus on the indications for RRT in AKI. Like other aspects of RRT, the indications have generally been extrapolated from the endstage kidney disease experience. These indications have generally included refractory hyperkalemia, fluid overload that does not respond to diuretic therapy, severe persistent metabolic acidosis, and overt uremic symptoms (e.g., pericardial effusion, encephalopathy). Although there is little dispute regarding the necessity of RRT for these indications, there is no consensus on the degree of azotemia or on the duration of AKI that warrants initiation of therapy in the absence of these “absolute” indications. Many clinicians believe that waiting for “conventional” indications for initiation of RRT in patients with acute renal failure may be inappropriate and that the earlier RRT is provided, the better the outcome will be; however, many patients with AKI recover renal function without requiring any RRT. Early initiation therefore poses the risk of initiating therapy in patients who might never require RRT using a more conservative approach (8,9). Only a few clinical studies have tried to evaluate the effect of timing of initiation of RRT on clinical outcomes in AKI and have provided conflicting results (10,11). Thus, prospective studies to evaluate optimal timing of RRT for AKI are urgently needed. Both similarities and differences in results from various stakeholder groups are notable. First, results from nephrology and critical care were virtually identical. The only differences were in questions of withholding RRT, in which intensivists had less interest, and in the dosage of RRT. Whereas intensiv-


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ists still considered this question second on their priority list, nephrologists rated it only 10th. Awareness of ongoing clinical trials in this area was apparently not a factor, because both groups were equally aware. Neither intensivists nor nephrologists considered the question of RRT modality to be of high priority (13th and 20th, respectively). This is interesting given that it has been the subject of multiple clinical trials, including one recent trial (12), and the issue remains unsettled (13). Surprising, results from developing countries correlated with those from developed countries, whereas larger differences were seen between individual regions. Table 4 shows comparisons of the top three priorities by region and the corresponding rank in other regions. Although timing of RRT was consistently a top priority, other research questions were less universally accepted. For example, the question, “What is the best measure to assess whether AKI is volume responsive?” was rated highly in the Americas but in the lower half of priorities in Europe and Asia. Similarly evaluation of biomarkers was at the top of the priority list for Europe but only seventh in North America and 13th in Asia. Establishing the incidence of AKI was first in Asia and South America but was seventh and 12th in Europe and North America, respectively. These variations may reflect fundamental differences in the way health care is provided or in the spectrum of diseases seen in each region. Our committee had only small representation from pediatrics, mostly from North America; however, our results suggest that challenges that clinicians who deal with pediatric AKI face may be different from those seen in adult patients. In particular, the question of how RRT should be dosed in different clinical situations seems much more germane to pediatric AKI (third versus 11th overall). The need for representation from pediatrics in establishing a universal research agenda cannot be overstressed. This process and report have important limitations. At this stage, we have not involved nonphysician stakeholders, including patients, nurses, and other allied health professionals. We have not yet included other physician groups with an interest in AKI either (e.g., radiologists, cardiologists, surgeons). Hospital administrators and insurance providers are also relevant stakeholders, and funding agencies outside of the US-based NIH would also be appropriate to include. We intend to include these groups in the future; however, our current focus is on clinicians and investigators who have a primary interest in the care of patients with AKI. We recognize important limitations to our methods. Although we had representation from 15 countries, there may be at the local level important differences to which our sampling was not sensitive. Furthermore, although experts and society delegates came from different countries, they clearly cannot speak for those countries. Although we had participation of 43 experts, we do not suggest that these members speak for the entire clinical and scientific community with respect to AKI; however, our approach in assembling a nominal group to develop a research agenda has been used by others and found to result in recommendations consistent with the larger community (14). In AKI, a similar approach has also been used by ADQI to produce clinical practice and research recommendations that have been widely adopted (15,16). Fi-

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Table 4. Rankings for top three priorities across four geographic regions Question

North America

Europe

Asia

South America

Developing Countriesa

When should RRT be initiated, and does timing affect outcome? Do other GFR markers predict clinical outcomes better than serum creatinine? Does AKI lead to CKD? Does severity of AKI predict renal and nonrenal clinical outcomes? What is the incidence of AKI? Are there biomarkers that predict severity and recovery in AKI? What is the best measure to assess whether AKI is volume-responsive?

1

2

3

1

3

9

3

2

2

2

3 10

3 2

4 4

4 2

5 6

12 7

7 1

1 13

1 2

1 9

2

14

12

3

7

a

Combines data from developing countries in Asia and South America.

nally, our approach included only quality assessment as a guide to question development, and we did not attempt to evaluate quality of the final product. This was a pragmatic decision given that no validated methods of quality assessments for research agenda are available. Our approach to this complex area also has many strengths. First, by including all of the major international societies that represent critical care and nephrology, we were assured a broad range of views. To our knowledge, this is first time in history that such a conference has taken place. Second, by including stakeholders that represent different disciplines, research fields, countries, and heath care systems, we were able to compare views between stakeholder groups. Finally, by prioritizing our research agenda, we can provide recommendations as to research direction in AKI.

Conclusions AKIN has developed a research agenda using an international, multidisciplinary three-step modified Delphi process. We have produced recommendations that are highly consistent across different stakeholder groups and between developed and developing countries. Top research priorities in AKI include determining optimal timing of RRT and improving our understanding of the epidemiology of AKI around the world. We hope that these recommendations will prove valuable in guiding future clinical and translational research in this area.

Appendix 1: Literature Search Strategy The databases Medline (1966 through August 2006), EMBASE (1980 through 2006, week 36), CINAHL (1982 through August 2006), and PubMed were systematically searched. Articles in any language were considered. Four comprehensive search themes were used with individual searches under each group combined using the Boolean operator “OR.” The Boolean searches were performed by using the following medical subject headings (MeSH) and text word searches: 1. (“acute kidney failure”[All Fields] OR “kidney failure,

acute”[All Fields] OR (“acute kidney failure”[Text Word] OR “kidney failure, acute”[MeSH Terms] OR acute renal failure[Text Word]) OR “renal insufficiency, acute”[All Fields] OR (“renal insufficiency, acute”[MeSH Terms] OR acute renal insufficiency[Text Word])) OR (acute[All Fields] AND ((“kidney”[All Fields] NOT Medline[SB]) OR “kidney”[All Fields] OR ((“kidney”[TIAB] NOT Medline[SB]) OR “kidney”[MeSH Terms] OR renal[Text Word])) AND (“physiopathology”[All Fields] OR (“physiopathology”[Subheading] OR dysfunction[Text Word])) OR acute[All Fields] AND (“kidney”[All Fields] OR (“kidney”[MeSH Terms] OR kidney[Text Word])) AND ((“wounds and injuries”[TIAB] NOT Medline[SB]) OR “wounds and injuries”[MeSH Terms] OR injury[Text Word]) OR “acute kidney tubular necrosis”[All Fields] OR “kidney tubular necrosis, acute”[All Fields] OR (“acute kidney tubular necrosis”[Text Word] OR “kidney tubular necrosis, acute”[MeSH Terms] OR acute tubular necrosis[Text Word])) AND (“epidemiology”[All Fields] OR “epidemiology”[All Fields] OR (“epidemiology”[Subheading] OR “epidemiology”[MeSH Terms] OR epidemiology[Text Word])) 2. (“acute kidney failure”[All Fields] OR “kidney failure, acute”[All Fields] OR (“acute kidney failure”[Text Word] OR “kidney failure, acute”[MeSH Terms] OR acute renal failure[Text Word]) OR “renal insufficiency, acute”[All Fields] OR (“renal insufficiency, acute”[MeSH Terms] OR acute renal insufficiency[Text Word])) OR (acute[All Fields] AND ((“kidney”[All Fields] NOT Medline[SB]) OR “kidney”[All Fields] OR ((“kidney”[TIAB] NOT Medline[SB]) OR “kidney”[MeSH Terms] OR renal[Text Word])) AND (“physiopathology”[All Fields] OR (“physiopathology”[Subheading] OR dysfunction[Text Word])) OR acute[All Fields] AND (“kidney”[All Fields] OR (“kidney”[MeSH Terms] OR kidney[Text Word])) AND ((“wounds and injuries”[TIAB] NOT Medline[SB]) OR “wounds and injuries”[MeSH Terms] OR injury[Text Word]) OR “acute kidney tubular necrosis”[All Fields] OR “kidney tubular necrosis, acute”[All Fields] OR (“acute kidney tubular necrosis”[Text Word] OR “kidney tubular necrosis, acute-


”[MeSH Terms] OR acute tubular necrosis[Text Word])) AND (“therapy”[Subheading] OR (“therapeutics”[TIAB] NOT Medline[SB]) OR “therapeutics”[MeSH Terms] OR treatment[Text Word]) AND Clinical Trial[ptyp] AND “humans”[MeSH Terms] 3. (“urinalysis”[MeSH Terms] OR Urinalysis[Text Word]) OR (((“urinary tract”[TIAB] NOT Medline[SB]) OR “urinary tract”[MeSH Terms] OR urinary[Text Word]) AND (“sodium”[MeSH Terms] OR sodium[Text Word])) OR (((“urinary tract”[TIAB] NOT Medline[SB]) OR “urinary tract”[MeSH Terms] OR urinary[Text Word]) AND ((“osmolar concentration”[TIAB] NOT Medline[SB]) OR “osmolar concentration”[MeSH Terms] OR osmolality[Text Word])) OR (fractional[All Fields] AND excretion[All Fields] AND (“sodium”[MeSH Terms] OR sodium[Text Word])) OR (fractional[All Fields] AND excretion[All Fields] AND (“urea”[MeSH Terms] OR urea[Text Word])) OR ((“urine”[Subheading] OR “urine”[MeSH Terms] OR urine[Text Word]) AND (“specific gravity”[MeSH Terms] OR specific gravity[Text Word])) OR ((“urine”[Subheading] OR “urine”[MeSH Terms] OR urine[Text Word]) AND (“microscopy”[MeSH Terms] OR microscopy[Text Word])) OR (((“urinary tract”[TIAB] NOT Medline[SB]) OR “urinary tract”[MeSH Terms] OR urinary[Text Word]) AND ((“biologic markers”[TIAB] NOT Medline[SB]) OR “biologic markers”[MeSH Terms] OR biomarkers[Text Word])) OR (“KIM-1 protein, rat”[Substance Name] OR kidney injury molecule-1[Text Word]) OR ((“cystatin C”[TIAB] NOT Medline[SB]) OR “cystatin C”[Substance Name] OR cystatin C[Text Word]) OR (((“sodium-hydrogen antiporter”[TIAB] NOT Medline[SB]) OR “sodium-hydrogen antiporter”[MeSH Terms] OR sodium-hydrogen exchanger[Text Word]) AND ((“protein isoforms”[TIAB] NOT Medline[SB]) OR “protein isoforms”[MeSH Terms] OR isoform[Text Word]) AND (“phase iii clinical trials”[Text Word] OR “clinical trials, phase iii”[MeSH Terms] OR 3;[Text Word])) OR (((“neutrophils”[TIAB] NOT Medline[SB]) OR “neutrophils”[MeSH Terms] OR neutrophil[Text Word]) AND gelatinase-associated[All Fields] AND lipocalin[All Fields]) AND NGAL[All Fields] OR B2-microglobulin[All Fields] OR ((“kallikreins”[TIAB] NOT Medline[SB]) OR “kallikreins”[MeSH Terms] OR kallikrein[Text Word]) OR Tamm-Horsfall[All Fields] OR (((“urinary tract”[TIAB] NOT Medline[SB]) OR “urinary tract”[MeSH Terms] OR urinary[Text Word]) AND (“retinol-binding proteins”[MeSH Terms] OR retinol binding protein[Text Word])) OR enzymuria[All Fields] OR aminoaciduria[All Fields] AND Clinical Trial[ptyp] AND “humans”[MeSH Terms] 4. (“acute kidney failure”[All Fields] OR “kidney failure, acute”[All Fields] OR (“acute kidney failure”[Text Word] OR “kidney failure, acute”[MeSH Terms] OR acute renal failure[Text Word]) OR “renal insufficiency, acute”[All Fields] OR (“renal insufficiency, acute”[MeSH Terms] OR acute renal insufficiency[Text Word])) OR (acute[All Fields] AND ((“kidney”[All Fields] NOT Medline[SB]) OR “kidney”[All Fields] OR ((“kidney”[TIAB] NOT Medline[SB]) OR “kidney”[MeSH Terms] OR renal[Text Word])) AND (“physiopathology”[All Fields] OR (“physiopathology”[Subheading] OR dysfunction[Text Word])) OR acute[All Fields] AND (“kidney”[All Fields]


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OR (“kidney”[MeSH Terms] OR kidney[Text Word])) AND ((“wounds and injuries”[TIAB] NOT Medline[SB]) OR “wounds and injuries”[MeSH Terms] OR injury[Text Word]) OR “acute kidney tubular necrosis”[All Fields] OR “kidney tubular necrosis, acute”[All Fields] OR (“acute kidney tubular necrosis”[Text Word] OR “kidney tubular necrosis, acute”[MeSH Terms] OR acute tubular necrosis[Text Word])) AND ((“dialysis”[MeSH Terms] OR dialysis[Text Word]) OR (hemodialysis[Text Word] OR (“renal dialysis”[TIAB] NOT Medline[SB]) OR “renal dialysis”[MeSH Terms] OR hemodialysis[Text Word]) OR (hemodialysis[Text Word] OR (“renal dialysis”[TIAB] NOT Medline[SB]) OR “renal dialysis”[MeSH Terms] OR hemodialysis[Text Word]) OR (hemofiltration[Text Word] OR “hemofiltration”[MeSH Terms] OR hemofiltration[Text Word]) OR (hemodiafiltration[Text Word] OR “hemodiafiltration”[MeSH Terms] OR hemodiafiltration[Text Word]) OR (hemodiafiltration[Text Word] OR “hemodiafiltration”[MeSH Terms] OR hemodiafiltration[Text Word]) OR (“renal replacement therapy”[MeSH Terms] OR renal replacement therapy[Text Word])) AND Clinical Trial[ptyp] AND “humans”[MeSH Terms]

Acknowledgments The following societies provided support for their members to travel to the meeting: American College of Chest Physicians, American Society of Nephrology, American Society of Pediatric Nephrologists, American Thoracic Society, Asia Pacific Association of Critical Care Medicine, Asian Pacific Society of Nephrology, Australian and New Zealand Intensive Care Society, Associaçaõ de Medicina Intensiva Brasileira, Canadian Critical Care Society, Chinese Society of Nephrology, European Dialysis and Transplant Society, European Society of Intensive Care Medicine, Indian Society of Nephrology, International Pediatric Nephrology Association, International Society of Nephrology, National Kidney Foundation, Sociedade Latino-Americana de Nefrologia e Hipertensaõ, Socie´te´ de Reánimation de Langue Française, and Society of Critical Care Medicine. Additional funding was provided in the form of educational grants to the National Kidney Foundation and the American Society of Nephrology: Amgen, Eli Lilly and Co, and Biosite. AKIN Participants were as follows: Bagga Arvind, MD, All India Institute of Medical Sciences; Joseph Bonventre, MD, PhD, Harvard University, Boston, MA; Catherine S.C. Bouman, MD, Amsterdam, Netherlands; Emmanuel A. Burdmann, MD, Sao Jose Rio Preto Medical School, Saõ Paulo, Brazil; Jorge Cerda, MD, Albany Medical College, Albany, NY; Andrew Davenport, MD, Royal Free Hospital, London, UK; Prasad Devarajan, MD, Cincinnati Children’s Hospital, Cincinnati, OH; Vincent D’Intini, MD; Geelong Hospital, Geelong, Victoria, Australia; Kai-Urie Eckardt, MD, University of Erlangers, Nurenberg, Germany; Paul W. Eggers, PhD, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; R.T. Noel Gibney, MD, University of Alberta, Edmonton, AB, Canada; Stuart L. Goldstein, MD, Baylor University, Houston, TX; Stefan Herget-Rosenthal, MD, University Duisburg-Essen, Essen, Germany; Jonathan Himmelfarb, MD, Maine Medical Center, Portland, ME; Eric Hoste, MD, PhD, Ghent, Belgium; Michael Joannidis, MD, Innsbruck, Austria; John A. Kellum, MD, University of Pittsburgh, Pittsburgh, PA; Vijay Kher, MD, DM, Fortis Hospital, Delhi, India; Ashok L. Kirpalani, MD, Bombay Hospital, Institute of Medicine, Mumbai, India; Franco Laghi, MD; Loyola University, Chicago, IL; Norbert Lameire, MD, Ghent University, Ghent, Belgium; Andrew S. Levey, MD, New England Medical Center, Boston, MA; Adeera Levin, MD, St. Paul’s Hos-

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pital, Vancouver, BC, Canada; Suzand M. Ajeje Lobo, MD, Sao Jose Rio Preto Medical School, Saõ Paulo, Brazil; Raul Lombardi, MD, Impasa, Montevideo, Uruguay; Ravi Mehta, MD, University of California, San Diego, San Diego, CA; Bruce A. Molitoris, MD, Indiana University, Indianapolis, IN; Patrick Murray, MD, University of Chicago, Chicago, IL; Mark D. Okusa, MD, University of Virginia, Charlottesville, VA; Paul M. Palevsky, MD, VA Pittsburgh Health System, Pittsburgh, PA; Neesh Pannu, MD, University of Alberta, Edmonton, AB, Canada; Chirag Parikh, MD, PhD, Yale University, Newhaven, CT; Richard C. Prielipp, MD, Mayo Clinic, Minneapolis, MN; Claudio Ronco, MD, Vicenza, Italy; Miet Schetz, MD, PhD, University Hospital, Leuven, Belgium; Sudhir Shah, MD, University of Arkansas, Little Rock, AK; Peter Skippen, MBBS, British Columbia Children’s Hospital, Vancouver, BC, Canada; Patrick S.K. Tan, MBBS, Kuala Lumpur, Malaysia; Ashita Tolwani, MD, University of Alabama at Birmingham, Birmingham, AL; Shigehiko Uchino, MD, Saitama Medical Center, Saitama, Japan; Ravindran Viswanathan, Kuala Lumpur, Malaysia; Hai Wang, MD, Peking University, Beijing, China; David G. Warnock, MD, University of Alabama at Birmingham, Birmingham, AL. J.A.K., R.L.M., A.L., B.A.M., D.G.W., S.V.S., M.J., and C.R. participated in study concept and design and drafting/reviewing of the manuscript; and J.A.K., R.L.M., and A.L., participated in data acquisition and analysis and in interpretation of the data.

Disclosures Each of the participating societies and organizations paid for travel for each of their representatives. Funding for travel stipends for nonsociety participants and for activities related to the meeting were provided through unrestricted educational grants from Amgen, Eli Lilly and Co, and BioSite as targeted donations to the American Society of Nephrology and the National Kidney Foundation, which in turn provided logistical support. Industry donors were not permitted to provide any input on the selection of committee members or on their activities; neither did they attend the meeting.

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