Renal recovery

Goldstein et al. Critical Care 2014, 18:301 http://ccforum.com/content/18/1/301 VIEWPOINT Renal recovery Stuart L Goldstein1, Lakhmir Chawla2,3, Claudio Ronco4 and John A Kellum5,6* Abstract Acute kidney injury (AKI) research in the past decade has mostly focused upon development of a standard AKI definition, validation of early novel biomarkers to predict AKI prior to serum creatinine rise and predict AKI severity, and assessment of aspects of renal replacement therapies and their impact on survival. Given the independent association between AKI and mortality in the acute phase, such focus makes imminent sense. More recently, the recognition that AKI is associated with subsequent development of chronic kidney disease and end-stage renal disease, with the attendant increase in mortality, has led to interest in the clinical epidemiology and the mechanistic understanding of renal recovery after an AKI episode in critically ill patients. We review the current knowledge surrounding renal recovery after an AKI episode, including renal replacement therapy initiation timing and modality impact, biomarker assessment and mechanistic targets to guide potential future clinical trials. Background The field of acute kidney injury (AKI) in the critically ill patient population has been subject to a significant research focus over the past decade. Hallmarks of this research progress include development and validation of standardized multidimensional AKI definitions [1,2], which help assessment of AKI outcomes, discovery of novel biomarkers to detect AKI development and predict AKI severity earlier [3], and prospective randomized trials enabling assessment of potentially modifiable aspects of AKI supportive care, namely the timing and intensity of renal replacement therapy delivery [4,5]. The realization that patients are dying from, and not just * Correspondence: 5 Center for Critical Care Nephrology, CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Center, Pittsburgh, PA 15621, USA 6 Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15621, USA Full list of author information is available at the end of the article © 2014 BioMed Central Ltd. with, AKI [6] has driven the effort to alter the course of AKI. By reducing rates of 'kidney attack' [7,8], thereby preventing or at least mitigating AKI, patient mortality and morbidity should likewise be lessened. A natural extension of 'peri-AKI' epidemiological research would expand the focus to patients who survive an AKI episode, and a reassessment of the long-term consequences of AKI. The fact that episodes of AKI are associated with more rapid progression to chronic kidney disease (CKD) in adult patients is a relatively recent observation [9]; the 2009 United States Renal Data System Report revealed that adults with an AKI episode during hospitalization have an approximately 10-fold greater risk of progressing to end-stage renal disease than patients who did not experience AKI [10]. Similar observations were also reported around the same time for cardiac surgery patients [11]. The goals of this review on renal recovery after AKI are to 1) provide a state of the art description of our current understanding of the epidemiology of AKI survivors, 2) describe the evolution of novel biomarkers in the AKI to CKD field and 3) describe potential risk factors for renal recovery versus non-recovery in AKI survivors. Renal recovery: the definition Serum creatinine-based definitions None of the advancements in AKI research would have occurred without development and validation of the first standardized multi-dimensional AKI definition, known as the RIFLE criteria (Risk, Injury, Failure, Loss, Endstage kidney disease) [1], and its subsequent recalibrations, pediatric RIFLE (pRIFLE) [12], the Acute Kidney Injury Network [2] and Kidney Disease Improving Global Outcomes (KDIGO) criteria [13]. Likewise, a standard definition of renal recovery is essential to provide an accurate account of post-AKI epidemiology. The Acute Dialysis Quality Initiative II work group provided the first such definition when they proposed the empiric RIFLE criteria, as the 'Loss' and 'End-stage kidney disease' strata ('L' and 'E') contained both estimated glomerular filtration rate (GFR) and time components in their metrics. Loss is defined as persistent complete loss of kidney Goldstein et al. Critical Care 2014, 18:301 http://ccforum.com/content/18/1/301 Page 2 of 7 function for greater than 4 weeks, and End-stage kidney disease is defined as complete loss of kidney function at 3 months after AKI development. The KDIGO AKI Workgroup proposed a refinement with the somewhat less severe concept of 'acute kidney disease' (AKD). AKD, defined as a GFR <60 ml/minute/1.73 m2 or evidence of structural kidney damage for less than 3 months, provides an operationally integrated bridge between AKI and CKD. The AKD concept, which incorporates the concept of partial renal recovery, should be used to raise awareness and engender the necessary clinical mechanisms to follow AKI survivors for progression to CKD, which has been recently highlighted as a missed opportunity for adequate transitions of care [14]. Prospective AKI trials in the critically ill have mostly focused upon patients who receive acute renal replacement therapy (RRT), since they are at the highest risk for mortality and RRT is one of the few aspects of the AKI episode that is modifiable. A more temporally proximal definition of renal recovery was utilized in the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) trial; patients with a 6 hour creatinine clearance >20 ml/minute were trialed off RRT, whereas patients with a creatinine clearance <12 ml/minute had RRT continued [4]. Thus, at the current time, the definition of renal recovery depends upon the time frame of interest, as depicted in Figure 1. The report from the 2011 NIDDK Workshop on Clinical Trial Design [15] recently proposed a composite endpoint of death, dialysis provision and incomplete renal recovery at 28 or 60 days. This concept had already been used in the evaluation of plasma neutrophil gelatinase-associated lipocalin (NGAL) as a predictor of renal recovery defined by the composite of mortality, persistence of RIFLE-F or need for RRT [16] and was subsequently operationalized as Major Adverse Kidney Events at Day 30 in a study of novel AKI biomarker prediction of AKI and outcomes [17]. Future prospective interventional trials aimed at promoting renal recovery should consider incorporating at least one of these definitions as an outcome. An important consequence of these composite endpoints is that the issue of competing risk between persistent renal dysfunction, RRT and death is obviated by combining these outcomes into a single endpoint. In addition, they are perhaps more patientcentered since kidneys that recover in patients that (...truncated)