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Manuscript Number: Title: Acute Kidney Injury: Epidemiology and Diagnostic Criteria Article Type: Review Article Corresponding Author: Dr John Kellum, MD Corresponding Author's Institution: University of Pittsburgh First Author: Eric A Hoste, MD, PhD Order of Authors: Eric A Hoste, MD, PhD; John Kellum, MD

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Acute Kidney Injury: Epidemiology and Diagnostic Criteria Eric AJ Hoste,1,2 MD, PhD; John A Kellum,2 MD.

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Intensive Care Unit, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium.

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The Clinical Research, Investigation, and Systems Modeling of Acute Illness

(CRISMA) Laboratory, Department of Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh PA.

Address for correspondence: John A. Kellum, MD Room 608 Scaife Hall Department of Critical Care Medicine University of Pittsburgh 3550 Terrace Street Pittsburgh, PA 15261 Tel: (412) 647 6966 Fax: (412) 647 8060 Email: [email protected]

Word Count: 2869

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Abstract Recently published consensus criteria for the definition of acute kidney injury (AKI) have lead to significant changes in how we think about this disorder. Studies from around the world, both in and out of the ICU, have shown a dramatic incidence of AKI and high associated mortality. This review considers these new findings and their historical context and attempt to shed new light on this old problem.

Key Words: Acute renal failure; Acute kidney injury; RIFLE criteria.

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Introduction For most clinicians working in intensive care and nephrology, the notion of acute renal failure (ARF) is that of severe organ dysfunction. For research and even reimbursement purposes, ARF is often defined by the need for artificial support, termed renal replacement therapy (RRT). However, this narrow concept of ARF may be far too limiting and mounting evidence suggests that acute dysfunction of kidney manifest by changes in urine output and blood chemistries portend serious clinical consequences[1].

The term acute renal failure is relatively new in the medical lexicon. Eknoyan reminds us that the first description of ARF, then termed ischuria renalis, was by William Heberden in 1802 [2*]. At the beginning of the 20th century, ARF, then named Acute Bright’s disease, was well described in William Osler’s ‘Textbook for Medicine’ (1909), as a consequence of toxic agents, pregnancy, burns, trauma or operations on the kidneys. During the first World War the syndrome was named ‘War Nephritis’[3], and was reported in several publications. The syndrome was forgotten until the second world war, when Bywaters and Beall published their classical paper on crush syndrome [4]. It was Homer W. Smith who is credited for the introduction of the term ‘Acute Renal Failure’, in a chapter on ‘Acute renal failure related to traumatic injuries’, in his textbook ‘The kidney-structure and function in health and disease’ (1951). The same year a whole issue of the Journal of Clinical Investigation was dedicated to ARF [5].

In most reviews and textbooks chapter [6,7], the concept of acute kidney dysfunction still emphasizes the most severe forms with severe azotemia and often with oliguria or anuria.

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It is only in the past few years that moderate decreases of kidney function are recognized as important, e.g. by the SOFA score [8] and in studies on radiocontrast-induced nephropathy [9].

Moreover, until very recently there was no consensus on the diagnostic criteria or clinical definition of ARF resulting in multiple different definitions. A recent survey revealed the use of at least 35 definitions in literature [10]. Apart from differences in patient characteristics, this is probably one of the main reasons that there is such a wide variation in the reported incidence and outcome of ARF (incidence ranges between 1 and 31% [11,12], and mortality between 28% and 82% [12,13]). Obviously if one study defines ARF as a 25% or greater rise in serum creatinine and while another study defines ARF only as the need for RRT, the two studies will not describe the same cohort of patients. There is even a linear correlation between the degree of kidney dysfunction and the outcome of acute kidney dysfunction. The more strict the definition of ARF the greater the mortality (figure 1) [10].

Another element that has emerged in recent years is the observation that small decreases in kidney function are important. For example, Levy et al. [9] found that a 25% increase of serum creatinine after administration of radiocontrast was associated with a worse outcome compared to those who did not experience a 25% or greater increase. Chertow et al. [14*] defined hospital acquired acute kidney dysfunction as an increase of serum creatinine of >0.3 mg/dL and found that this was independently associated with mortality.

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Similarly, Lassnig et al.[15] saw, in a cohort of patients who underwent cardiac surgery, that acute kidney dysfunction, defined as an increase of serum creatinine ≥ 0.5 mg/dL or a decrease greater than 0.3 mg/dL was associated with worse survival. The reasons why small alterations in renal function lead to increases in hospital mortality are unclear. Possible explanations include the untoward effects of acute kidney dysfunction such as volume overload, retention of uremic compounds, acidosis, electrolyte disorders, increased risk for infection, and anemia [16*]. Although, acute kidney dysfunction could simply be colinear with unmeasured variables that lead to increased mortality, multiple attempts to control for known clinical variables has lead to the consistent conclusion that renal dysfunction is independently associated with outcome. Furthermore, more severe renal dysfunction tends to be associated with even worse outcome compared to milder abnormalities.

Acute Kidney Injury and the RIFLE criteria Recognizing that early and/or milder forms of renal dysfunction have clinical importance and that staging (mild to severe) is desirable in order to better describe the syndrome, the Acute Dialysis Quality Initiative (ADQI), a group of experts in acute kidney dysfunction, consisting of nephrologists and intensivists, proposed the RIFLE criteria to acute kidney dysfunction (http://www.ccm.upmc.edu/adqi/ADQI2/ADQI2g1.pdf) [17**]. The acronym RIFLE stands for the increasing severity classes Risk, Injury and Failure, and the 2 outcome classes Loss and End Stage Kidney Disease. The 3 severity grades are defined on the basis of the changes in serum creatinine or urine output (figure 2) where

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the worst of each criterion is used. The 2 outcome criteria, Loss and End Stage Kidney Disease, are defined by the duration of loss of kidney function.

The RIFLE criteria were published as a workgroup document on the ADQI website in June 2003, and published online May 2004, and in print August 2004 [17**]. Since then a number of papers have been published at the time this article was written that use the RIFLE criteria [18*,19,20*,21*,22*,23*,24**,25**,26*,27*,28] (table 1). Most of the studies were published in 2005-2006. In addition, the Acute Kidney Injury Network (AKIN) organized two conferences endorsed by the different critical care and nephrology societies. The aim of these conferences was to come to a broader consensus on the definitions and terminology for ARF. In particular this group has proposed the term Acute Kidney Injury (AKI) to define the entire spectrum of acute renal dysfunction from its earliest and mildest forms to the need for RRT. We will therefore adopt this term, as we have previously [1,24**].

Use of the RIFLE criteria In table 1 an overview of the papers that used the RIFLE criteria for AKI is presented. All studies used the severity grading criteria Risk, Injury and Failure, but only two studies [19,20*] also used the outcome criteria Loss, and End Stage Kidney Disease. Both studies that used the outcome criteria were in a cohort of AKI patients defined by the need for RRT. Only Bell et al.[20*] classified both severity grades and outcome classes. All patients included in this study were treated with CRRT for AKI. They had therefore severe AKI, and there is rationale to classify these as Failure, according to the

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adaptations made to the RIFLE criteria after the first AKIN conference (personal communication). Severity grading was performed according to the RIFLE criteria on creatinine and urine output criteria in 7 out of the 10 studies that reported on severity grading [20*,21*,22*,23*,24**,26*,28]. However, Lin et al. [26*], used different urine output criteria cut offs compared to those of RIFLE. The 3 remaining studies defined severity of AKI on a change of serum creatinine level, and not on urine output [18,25**,27*]. The reasons for this were diverse. Herget-Rosenthal compared assessment of GFR by serum creatinine and Cystatin C levels. Uchino retrospectively evaluated hospital-wide cases, which prevented assessment of urine output [25**]. In addition, the study by Heringlake was a large prospective study on practice patterns in cardiac surgery in German cardiovascular centers [27*]. Presumably the study coordinators chose to keep the questionnaire as compact as possible in order to get a large enough response.

Interestingly, one group chose to use the Cockcroft-Gault equation for assessment of GFR, rather than use a change in serum creatinine levels as all other authors did [21*]. When baseline serum creatinine level is unknown in a patient without a history of chronic kidney insufficiency, ADQI proposed the use of a baseline creatinine based upon the Modification of Diet in Renal Disease (MDRD) equation assuming a GFR >75 mL/min/1.73m2 [17**]. This was done in only 3 studies [24**,25**,26*]. Kuitunen also used the MDRD formula, however, not for assessment of a baseline creatinine level, but for assessment of GFR [22*].

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Most studies used the RIFLE criteria to assess the occurrence rate of AKI in specific cohorts of patients. However, 2 studies used the RIFLE criteria for other means than this. Herget-Rosenthal evaluated whether a serum level of Cystatin C is a better marker for GFR than a serum creatinine level [18*] and Hoste used the RIFLE outcome criteria as a secondary outcome parameter in a study on the impact of bloodstream infection in AKI patients treated with RRT [19].

Occurrence rate of AKI defined by the RIFLE criteria The occurrence rate of AKI defined by RIFLE criteria in the different cohorts ranged from 15.4% to 78.3% (table 1). This is higher as it is generally accepted when the classic terminology of ARF is used. The large study by Uchino demonstrated that almost 18% of hospitalized patients in a large tertiary care hospital had an episode of AKI defined by RIFLE on GFR criteria [25**]. This, is much higher as the incidence of 7.2% reported in a hallmark study on data from 1996 [29], and 4.9% in the same hospital on data from 1979 [30]. Although the definition of AKI used in that study differs from the RIFLE criteria, the sensitivity seems comparable. Hou and Nash defined AKI as a rise in serum creatinine >0.5mg/dL for patients with a baseline 1.0 mg/dL for patients with a baseline between 2 and 4.9 mg/dL, and >1.5 mg/dL for patients with serum creatinine level >5.0 mg/dL. An explanation for this can be that RIFLE criteria are more sensitive, especially for patients with acute on chronic disease, alternatively, the 3 cohorts can also have different baseline characteristics, and/or different comorbidities. The trend of increasing incidence for the same definition in the same institute suggests that the latter explanation seems more plausible. Increasingly, patients are now older, suffer from

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more comorbidity such as diabetes or cardiovascular disease, and more patients are exposed to diagnostic and therapeutic procedures with potential harm for kidney function. The 2 large studies in cardiac surgery patients indicate that the incidence of AKI after cardiac surgery is about 15-20% [22*,27*]. This is a considerably higher incidence compared to the incidence of ARF of