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Consensus development in acute renal failure: the Acute Dialysis Quality Initiative

John A. Kelluma, Claudio Roncob, Ravindra Mehtac and Rinaldo Bellomod

Purpose of review Although acute renal failure is both common and highly lethal in the intensive care unit, our understanding of the epidemiology and pathophysiology of acute renal failure is limited, and treatment for acute renal failure is extremely variable around the world. The general lack of consensus with regard to definitions, prevention, and treatment of acute renal failure has limited progress in this field. Recent findings Consensus in acute renal failure requires establishing a framework in which intensivists, nephrologists, pharmacologists, and others who care for critically ill patients with or at risk for acute renal failure can reach consensus and develop evidence-based practice guidelines. The Acute Dialysis Quality Initiative seeks to provide an objective, dispassionate distillation of the literature and description of the current state of practice of dialysis and related therapies as they are applied to acutely ill patients. The purposes of Acute Dialysis Quality Initiative are first, to develop a consensus of opinion, with evidence where possible, on best practice; and second, to articulate a research agenda to focus on important unanswered questions. Summary Broad consensus in the diagnosis and management of acute renal failure and in the use of blood purification in nonrenal critical illness is achievable. Standardization of definitions, practice, and research methodology is urgently needed, and specific proposals have been made by an international, interdisciplinary group. Keywords acute renal failure, acute tubular necrosis, consensus conference, definitions, dialysis, kidney, nomenclature, renal replacement therapy
Curr Opin Crit Care 11:527 532. 2005 Lippincott Williams & Wilkins.
a Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; bDepartment of Nephrology, St Bortolo Hospital, Vicenza, Italy; c Division of Nephrology, University of California at San Diego, San Diego, California, USA; and dDepartment of Intensive Care, Austin Hospital, Melbourne, Australia

Abbreviations ADQI ARF CRRT ICU RIFLE RRT Acute Dialysis Quality Initiative acute renal failure continuous renal replacement therapy intensive care unit risk, injury, failure, loss, and end-stage kidney disease renal replacement therapy

2005 Lippincott Williams & Wilkins. 1070-5295

Acute renal failure (ARF) is one of the most common and life-threatening conditions seen among the critically ill and injured. The presence of renal dysfunction, whether severe enough to warrant renal replacement therapy (RRT) [1] or defined only by small changes in creatinine [2] or urine output [3], dramatically increases the risk of death in the hospital. ARF primarily occurs in the setting of multi-organ failure as a consequence of sepsis or polytrauma and rarely occurs in the absence of other organ failures [4]. Our understanding of the epidemiology and pathophysiology of ARF is limited, however. Furthermore, treatment for ARF is extremely variable around the world. The limitations imposed by a lack of consensus and the absence of a standard definition for ARF have made it very difficult to determine the effectiveness of treatments or to judge the risks accurately. Available evidence strongly suggests that standardization of medical practice saves money and improves outcome [5,6]. Although guidelines for the medical management of end-stage renal disease already exist [7], the focus of these initiatives has largely been on chronic or at least established renal failure. Consequently, there is little that is standard about the care of patients with ARF. We have previously suggested that one explanation for this lack of standards is the nature of the disease itself [8]. Most ARF in the intensive care unit (ICU) occurs not in isolation but as part of the multiple organ failure syndrome [4]. Standardizing the care of patients with multiple organ failure will be difficult and will require the joint efforts of intensivists and medical and surgical subspecialists. In addition, the management of ARF is primarily supportive, and supportive therapies have not traditionally been viewed as having a significant impact on patient outcomes. Indeed, the claim that patients die with renal failure, rather than of renal failure is still occasionally made. For these reasons, we have decided to undertake a process seeking consensus and evidence-based guidelines for the

Correspondence to John A. Kellum, MD, Clinical Research, Investigation, and Systems Modeling of Acute Illness Laboratory, Department of Critical Care Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261, USA Tel: 412 647 6966; fax: 412 647 3791; e-mail: kellumja@ccm.upmc.edu Current Opinion in Critical Care 2005, 11:527 532

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diagnosis and management of ARF. The name of this process is the Acute Dialysis Quality Initiative (ADQI). The intent of ADQI is to provide an objective, dispassionate distillation of the literature and description of the current state of practice of dialysis and related therapies as they are applied to acutely ill patients. The purposes of ADQI are first, to develop a consensus of opinion, with evidencewhere possible, on best practice; and second, to articulate a research agenda to focus on important unanswered questions. Acute Dialysis Quality Initiative consensus conferences have focused on RRT [9], research in ARF [10], blood purification in nonrenal disease [11], and, most recently, prevention of ARF. Results of these conferences have been published on the internet (www.ADQI.net) and subsequently summarized in peer-reviewed journals. In this review, we summarize the main results of the first three conferences.

methodology [15]. A series of summary statements are then developed through a series of breakout sessions in which individual work group members are required to identify key issues for which guidelines are needed and to classify current state of consensus and identify supporting evidence for each issue. Workgroup members are then required to present their findings to the entire group, revising each statement as needed until a final version is agreed on. The responsibility for presenting the findings of the work group to the rest of the participants is shared by each member on a rotating basis. A writing committee assembles the individual reports from the work groups, and each report is edited to conform to a uniform style and for length. The final reports are posted on the internet (www.ADQI.net) and mailed to each participant for comment and revision. Finally, international consultants are identified, and reports are sent to them for comment. Once final reports are completed, the writing committee summarizes the individual reports into a final conference document.

Acute Dialysis Quality Initiative conference methodology

The methodology used for this process combines both expert panel and evidence appraisal and was chosen to achieve the best of both methods. We recognize that the expert panel in absence of the literature can lead to statements at odds with high-quality research and that evidence appraisal without expert input to question the framework can lead to erroneous interpretation [12]. Furthermore, this combined approach has led to important practice guidelines with wide acceptance and adoption into clinical practice [13]. We further recognize that additional research will be needed and that the development of a research agenda will also be fostered by this approach [14]. The activities for ADQI conference are divided into three phases: preconference, conference, and after conference. In the preconference phase, the work groups are assembled and assigned to specific topics. Each group identifies a list of key questions, conducts a systematic literature search, and generates a bibliography of key studies. Studies are identified via MEDLINE search, bibliographies of review articles, and participants personal files. Searches are limited to English language articles. Articles written in other languages are used when identified and presented by members of the group, however [15]. The conference itself is divided into breakout sessions, where work groups address the issues in their assigned topic area, and plenary sessions, where their findings are presented, debated, and refined. Each work group is composed of three members, one of whom serves as the group facilitator. Conference directors circulate between the breakout groups and also serve as facilitators and moderators for plenary sessions. Evidence is classified according to levels per standard evidence-based medicine

Focus of Acute Dialysis Quality Initiative

Management of ARF is primarily supportive, and the elements of renal support include RRT, fluid and hemodynamic management, nutritional support, and alterations in drug dosing and selection [16]. Prevention of ARF in the ICU is also of prime importance, as is the use of blood purification in nonrenal disease. These six general areas are the primary focus of ADQI. ADQI conferences, dates, locations, and topics are shown in Table 1.

First Acute Dialysis Quality Initiative conference: continuous renal replacement therapy
The first ADQI conference was devoted to the subject of continuous RRT (CRRT). The reason for this choice was that CRRT is now being used at ever increasing rates worldwide. More than one-quarter of all patients with ARF are treated with CRRT [17]. Despite the increasing use, however, there were no published standards for the application of this therapy, and practice patterns varied widely between individual centers and across geographic regions [18]. Results from recent clinical trials on selection of dialysis membranes [19,20] and dialysis dose [21]
Table 1. Acute Dialysis Quality Initiative (ADQI) conferences. Conference ADQI I: 2000 ADQI II: 2002 ADQI III: 2003 ADQI IV: 2004 Venue New York, New York Vicenza, Italy Miami Beach, Florida Vicenza, Italy Topic Continuous renal replacement therapy Research in acute renal failure Blood purification in non-renal critical illness Prevention of acute renal failure

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provided strong yet conflicting evidence to guide therapy. Other areas of uncertainty had not been sufficiently addressed by clinical studies, and directives for future research were needed. Finally, the success of multicentered clinical trials in supportive care in the ICU (transfusion thresholds [22] and ventilator management [23]) intensified and renewed interest in the study of supportive care methods as major targets for future research. These developments set the stage for the first ADQI conference, which was held in New York in August 2000. Forty-six questions were considered by the ADQI panel, and there was consensus for 20 of them. Five questions were found to have existing, relevant evidence but could not be answered with consensus. These questions included whether synthetic dialysis membranes were superior to cellulose-based membranes. The group recommended statistical meta-analysis, which demonstrated that synthetic membranes were associated with lower mortality [24]. The question of whether CRRTwas superior to intermittent hemodialysis was also addressed by meta-analysis [25], but insufficient evidence is available to establish whether one modality is indeed superior. Thus, the group recommended a large multi-center clinical trial. A large clinical trial was also recommended to address the question of dialysis dose in ARF . This recommendation led to the design of a 28-center randomized trial currently underway in the United States [26] and the design of a upcoming multi-center study in Australia and New Zealand. The group also recommended a systematic review to address questions related to dialysis catheter design and access location, but this has not yet been conducted. ADQI also reviewed ample evidence that appeared to support the use of ultrasound for the placement of catheters. No consensus was reached among the group about its use, however [9]. For the remaining 21 questions there was insufficient evidence, and recommendations for future research were made [9]. These recommendations included the development of a standard set of criteria for the definition and classification of ARF and the conduct of large international observational studies on the use of RRT. These recommendations led to the second ADQI conference [10]. These recommendations also led to the design and conduct of the Beginning and Ending Supporting Therapy for the Kidney (BEST Kidney) Study [27,28,29], which examined the care of patients with ARF in 54 centers (23 countries) around the world. The results of this important study are gradually becoming available. The study found that the period prevalence of ARF (severe enough to warrant RRT) in the ICU is between 56% all over the world [29]. Despite this uniformity in the prevalence, however, the therapy for ARF and the resulting survival (078%) varies significantly between centers. One source of variation in treatment comes from the use of diuretics [27], which are used in approximately 70% of patients. Results

of an earlier observational study suggested a potential for harm [30], and although this could not be confirmed by the BEST Kidney study, there was no evidence of benefit either and the authors concluded that sufficient equipoise is present to recommend a clinical trial [27]. Understanding the reasons for variation in outcome in the treatment of ARF is further limited by our tools. Measures of severity of illness are limited when applied to patients with ARF, and none of the scoring systems currently available have sufficient discrimination or calibration to predict mortality for patients with ARF [28].

Second Acute Dialysis Quality Initiative conference: research in acute renal failure
Given the results of the first ADQI conference, the second conference was devoted to research. The conference set out to create a working definition of ARF; to address clinical and physiologic endpoints for clinical trials; and to evaluate animal models, methods for accessing fluid management, and information technology needs [10]. Consensus was reached on a broad list of questions, the most controversial of which was the definition. The clinical syndrome known as ARF has never been universally defined. Indeed, more than 30 definitions are in use in the literature today [31]. The definitions used in clinical studies are important determinants of the large variation in the reported occurrence rate (131%) [3234] and associated mortality (1983%) [3436] of ARF. Indeed, the lack of a uniform definition for ARF is believed to be a major impediment to research in the field [37]. Generally, ARF is defined as an abrupt and sustained decrease in renal function. Until recently, however, there has not been a consensus on how best to assess renal function, on which renal functions should be assessed, and on what cut-offs should be used to define ARF [38]. Controversy even exists about whether the syndrome should be classified as failure in the first place, because some of the clinical abnormalities in renal function are thought to be adaptive [39,40]. For example, decrease in the glomerular filtration rate in response to an insult (usually referred to as prerenal failure) could well be the adaptive mechanism to maintain medullary oxygen balance [39]. Therefore, to encompass the entire range of acute abnormalities in kidney function, the terms acute renal dysfunction or acute kidney injury might be more appropriate. To establish a uniform definition for ARF (acute renal dysfunction or acute kidney injury), the ADQI group proposed the RIFLE classification. The acronym RIFLE defines three grades of increasing severity of ARF (risk, injury, and failure, respectively R, I, and F), and two outcome variables (loss, and end-stage kidney disease, respectively L and E; Table 2). A unique feature of the RIFLE classification is that it provides for three grades of severity of renal dysfunction on basis of a change in serum creatinine or urine output from the baseline

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Table 2. RIFLE classification. GFR criteria Risk Injury Failure Urine output criteria

ultrafiltration, plasma therapies, and liver assist therapy for the treatment of nonrenal organ failure. Extra-corporeal therapies designed to remove substances from the circulation now include hemodialysis, hemofiltration, hemoadsorption, plasma filtration, cell-based therapies, and combinations of any of these. In recent years, there have been considerable advances in our understanding and technical capabilities, but consensus over the optimal way and under what conditions to use these therapies does not exist. In general, these therapies have been adapted to nonrenal organ failure from nephrologybased therapy (hemofiltration and hemoadsorption) or from hematology-based therapy (plasma exchange). Although this wider approach to blood purification in nonrenal organ failure seems logical and promising and opens new perspectives, many questions still remain unanswered, including the timing, duration, and frequency of these therapies in the clinical setting [43]. Although there is already evidence that these techniques are usually well tolerated and are effective in clearing mediators from the plasma [44], often improving physiologic parameters [45], large multi-center trials evaluating their efficacy to improve clinical outcomes (i.e. survival or organ function), rather than surrogate markers such as plasma mediator clearance or transient improvement in physiologic variables, are required to define their precise roles. Given the available data, it is possible to speculate that immunomodulation using either high-volume hemofiltration or hemoadsorption or both will be most useful in the early stages of severe sepsis and septic shock when high levels of inflammatory mediators appear in the circulation [46,47], while plasma therapies will be most useful later in the course of illness when thrombotic microangiopathy and endothelial injury begin to emerge [48]. For heart failure, management of volume coupled with solute and possibly even mediator removal can be effected with existing hemofiltration technology. The next challenge is to scale these systems to be as minimally invasive as possible [49]. For liver assistance, the most effective system is still in dispute but will likely be a bio-artificial system that combines both detoxification and replacement of some synthetic function [50]. In the future, the most effective blood purification strategy may well be the careful deployment of all of these therapies at right time [47,51,52].

Loss End-stage kidney disease

UO < 0.5 mL/kg/hr 3 6 h Serum creatinine 3 1.5 UO < 0.5 mL/kg/hr 3 12 h Serum creatinine 3 2 Serum creatinine 3 3 UO < 0.3 mL/kg/hr 3 24 h or serum creatinine or anuria 3 12 h $4 mg/dL with an acute rise >0.5 mg/dL Persistent acute renal failure = complete loss of kidney function > 4 weeks End-stage kidney disease > 3 months

RIFLE (risk, injury, failure, loss, end-stage kidney disease) class is determined based on the worst of either glomerular filtration (GFR) criteria or urine output criteria. GFR criteria are calculated as an increase of serum creatinine above the baseline serum creatinine level.

condition. This allows classification of patients with ARF into one of the three RIFLE severity classes. RIFLE represents a new classification system, so the clinical characteristics and prognostic importance of the different classes are not known. Several studies now suggest, however, that RIFLE is a valid predictor of clinical outcomes [3,41] and correlates with existing biomarkers of ARF [42].

Third Acute Dialysis Quality Initiative conference: blood purification in nonrenal disease
The third ADQI conference was devoted to the use of extracorporeal blood purification for treatment of critically ill patients without renal failure [11]. While the first ADQI conference concluded that so-called renal dose CRRT should not be used for treatment of nonrenal disease outside clinical trials, there are numerous other types of blood purification, including high-volume hemofiltration and plasma therapies, that have been used in the treatment of many different diseases. Blood purification offers a unique treatment option for nonrenal organ failure. Failure of the cardiovascular, hepatic, coagulation, and immune systems is characterized by loss of auto-regulation leading to multi-organ failure. Although the pathogenesis of each organ failure is complex and variable, brought about by a variety of underlying conditions, the potential to improve patient outcomes by simultaneously targeting multiple pathways can perhaps best be realized by blood purification. Unlike drug strategies, which are usually limited to one component of these complex networks, blood purification is, by its very nature, broad-spectrum and selfregulating. For example, as the concentration of mediators or toxins increases, so does the rate of removal. Furthermore, given the many failed trials of specific therapy, the recent focus of immunomodulatory therapy in sepsis has shifted to nonspecific methods of influencing the entire inflammatory response without suppressing it. The focus of the third ADQI international consensus conference was on the application of hemofiltration,

Consensus in the diagnosis and management of ARF and in the use of blood purification in nonrenal critical illness is achievable. It requires establishing a framework where intensivists, nephrologists, pharmacologists, and others who care for critically ill patients with or at risk for ARF can reach consensus and develop evidence-based practice guidelines. Prior to ADQI, there was little agreement on how much, when, and how renal support should be

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provided, and significant practice variation still exists. Remarkable progress is possible with the concerted efforts of those with an active interest in this rapidly growing area of medicine, however.

18 Silvester W. Prospective study of renal replacement therapy for acute renal failure in 21 hospitals in state of Victoria, Australia. Blood Purif 1997; 15: 147 152. 19 Himmelfarb J, Tolkoff-Rubin N, Chandran P, et al. A multicenter comparison of dialysis membranes in the treatment of acute renal failure requiring dialysis. J Am Soc Nephrol 1998; 9:257 266. 20 Jorres A, Gahl GM, Dobis C, et al. Haemodialysis-membrane biocompatibility and mortality of patients with dialysis-dependent acute renal failure: a prospective randomised multicentre trial. International Multicentre Study Group. Lancet 1999; 354:1337 1341. 21 Ronco C, Bellomo R, Homel P, et al. Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet 2000; 356:26 30. 22 Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340:409 417. 23 Brower RG, Matthay MA, Morris A, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342:1301 1308. 24 Subramanian S, Venkataraman R, Kellum JA. Influence of dialysis membranes on outcomes in acute renal failure: a meta-analysis. Kidney Int 2002; 62: 1819 1823. 25 Kellum JA, Angus DC, Johnson JP, et al. Continuous versus intermittent renal replacement therapy: a meta-analysis. Intensive Care Med 2002; 28: 29 37. 26 National Institutes of Health Clinical Trials. 2005. Available at: http://www. clinicaltrials.gov/ct/show/NCT00076219. 6-30-0005. 7-9-2005 [Accessed 18 August 2005].

The ADQI leadership acknowledges the numerous industrial partners who have generously provided support for ADQI consensus conferences. In particular, we thank Baxter, Bellco, B. Braun, Fresenius Medical Care, Gambro Renal Care, Immunocept, Kimal, Medica, Nextrom Med Tech, NxStage Medical, MedaSorb Technologies, and the Renal Research Institute.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 635). 1 Metnitz PG, Krenn CG, Steltzer H, et al. Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 2002; 30:2051 2058. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality: a cohort analysis. JAMA 1996; 275:1489 1494. Hoste E, Clermont G, Kersten A, et al. Clinical evaluation of the new RIFLE criteria for acute renal failure [abstract]. Crit Care 2004; 8:81. Tran DD, Oe PL, de Fijter CW, et al. Acute renal failure in patients with acute pancreatitis: prevalence, risk factors, and outcome. Nephrol Dial Transplant 1993; 8:1079 1084. Roberts RR, Zalenski RJ, Mensah EK, et al. Costs of an emergency departmentbased accelerated diagnostic protocol vs hospitalization in patients with chest pain: a randomized controlled trial. JAMA 1997; 278:1670 1676. Chassin MR, Galvin RW. The urgent need to improve health care quality. Institute of Medicine National Roundtable on Health Care Quality. JAMA 1998; 280:1000 1005. National Kidney Foundation. Kidney Disease Outcomes Quality Initiative. 2000. Available at: http://www.kdoqi.org [Accessed 18 August 2005]. Kellum JA, Mehta RL, Ronco C. Acute dialysis quality initiative (ADQI). Contrib Nephrol 2001; 132:258 265. Kellum JA, Mehta R, Angus DC, et al., for the ADQI Workgroup. The First International Consensus Conference on Continuous Renal Replacement Therapy. Kidney Int 2002; 62:1855 1863.

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42 Herget-Rosenthal S, Marggraf G, Husing J, et al. Early detection of acute renal failure by serum cystatin C. Kidney Int 2004; 66:1115 1122. Comparison of cystatin C with RIFLE criteria in patients with ARF. Cystatin C appears to predict the development of ARF defined by RIFLE, 1 to 2 days earlier. 43 Kellum JA, Venkataraman R. Application of blood purification to non-renal organ failure. Int J Artif Organs 2005; 28:445 449. A review of the use of blood purification in nonrenal disease. 44 Kellum JA, Song M, Venkataraman R. Hemoadsorption removes TNF, IL-6 and IL-10, reduces NFB DNA binding and improves short-term survival in lethal endotoxemia. Crit Care Med 2004; 32:801 805. 45 Cole L, Bellomo R, Journois D, et al. High-volume haemofiltration in human septic shock. Intensive Care Med 2001; 27:978 986.

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