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 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.
Prediction of renal recovery
One set of current tools for potentially predicting renal recovery is encompassed in clinical severity of illness (SOI) scores. While these may seem attractive options initially, it is important to remember that SOI scores are used to characterize and stratify adult and pediatric critical illness [
32]. The initial SOI systems were developed to benchmark, or compare, critical care units against one another, to monitor resource use, evaluate therapies, and improve quality assessment. They were not intended to predict SOI in individual patients but, rather, to group patients together in strata of illness, which would allow group-wide mortality or SOI prediction. As an example, Uchino and colleagues [
33] tested two general illness severity scores (Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment (SOFA)), and four AKI-specific severity scores in 1,742 patients as part of the BEST Kidney Study. None of these scoring systems tested had a high level of discrimination or calibration to predict outcome for AKI patients. If systems do not perform well to predict AKI-associated mortality, it is no wonder that prediction of renal recovery has remained elusive as well [
34]. Although factors such as advanced age, male gender, presence of sepsis/septic shock, hypotension, respiratory failure, use of mechanical ventilation, presence of oliguria, and high serum bilirubin, low serum creatinine, and using vasoactive substances are risk factors for AKI [
35], we know far less about the clinical determinants of renal recovery. In a small study, a subset (n = 76) of the ATN study cohort [
4], Srisawat and colleagues found that age and underlying chronic disease predicted non-recovery of renal function (area under the curve (AUC) 0.74) following provision of RRT for AKI [
16]. Determinants of renal recovery may be influenced by etiology of AKI. The same authors studied recovery following severe AKI (RIFLE-F) in patients with community-acquired pneumonia and found that a model composed of age, creatinine on the first day of RIFLE-F, pneumonia severity index on admission, and maximum non-renal SOFA score yielded an AUC of 0.78 [
36].
Some recent work has demonstrated promise for clinical prediction for renal recovery with more specific markers. A systematic review of patients with hemolytic uremic syndrome revealed that renal replacement therapy provision and central nervous system involvement increased risk for end-stage renal disease [
37], although rates of renal recovery were not directly addressed. A recent assessment of AKI to stage 4 CKD progression in the US Veterans population developed and then validated three models to predict CKD risk, with increasing AKI severity by RIFLE score and in-hospital hypoalbuminemia providing the strongest prediction [
38]. Of note, each increase in RIFLE score was associated with an adjusted odds ratio of 4.43 for development of stage 4 CKD, which was higher than any other covariate except the need for RRT. Although these models require validation in other cohorts and should be tested longitudinally in a systematic assessment of patients at risk for AKI, they provide some clues as to which patients should be targeted for close follow-up and potentially therapeutic trials to slow CKD progression.
Although oliguria (urine output less than 400 ml/day) is a common event in the ICU and urine flow is one of the diagnostic and staging criteria for AKI, only a few studies have focused on the role of urine output as a prognostic renal biomarker. Oliguric patients without change in serum creatinine concentrations demonstrated increased mortality rates and dialysis requirements similar to patients with serum creatinine change-based AKI [
39]. A
post hoc analysis from the BEST kidney study revealed that the urine output area under the receiver operating characteristic curve for successful discontinuation of continuous RRT (CRRT) was 0.85, although it fell to 0.67 when diuretics were used. Urine output cutoffs of 436 ml/day and 2,330 ml/day for patients without and with diuretics, respectively, had the highest accuracy [
40].
Recently, some studies have begun to assess the ability of novel biomarkers to predict renal recovery and/or progression to CKD. NGAL has been extensively studied in the field of AKI [
41]. In the late phase of AKI, NGAL is believed to play a role as a growth and differentiation factor for restoring tubular epithelial function with the assistance of siderophore-iron complexes. However, most previous studies have tested plasma/urine NGAL as a marker for early diagnosis of AKI; only a few studies have examined plasma/urine NGAL as a prognosticate marker of clinical outcome, mostly with mortality and hospital length of stay as endpoints. In fact, a systematic review demonstrated similar mortality rates and length of stay for patients with 'NGAL-positive: creatinine-negative' AKI versus 'NGAL-negative: creatinine-positive' AKI [
42].
Two studies (also mentioned above) have assessed NGAL as a predictor of renal recovery [
16,
36]. Plasma NGAL was assessed in patients with community-acquired pneumonia on the first day they experienced severe AKI (defined as RIFLE-F), and recovery was defined as being alive and neither requiring RRT during hospitalization nor having a persistent RIFLE-F classification at hospital discharge [
36]. The investigators found that elevated plasma NGAL levels were associated with renal non-recovery with a 17% increase in predicting renal non-recovery. The second study, the Biological Markers of Recovery for the Kidney study [
16], was conducted as an ancillary to the ATN study [
4]. Urine samples were collected on days 1, 7, and 14 from 76 patients who developed AKI and received RRT in the ICU. For predicting recovery, decreasing urinary NGAL and urinary hepatocyte growth factor in the first 14 days was associated with greater odds of renal recovery.
Interestingly, animal models of AKI-to-CKD transition identify NGAL, as well as another novel AKI biomarker, Kidney injury molecule-1 (KIM-1), as two of the most upregulated genes and proteins in the kidney, revealing a possible role for these proteins as biomarkers [
43]. Furthermore, studies on urinary NGAL and KIM-1 in other renal diseases demonstrate higher NGAL concentrations are associated with more rapid progression of CKD [
44‐
49]. Coupling the animal data with the human data noted provides evidence that novel biomarkers can serve as early markers of ongoing renal injury, even in the setting of AKI. The clinical impact is potentially great in the setting of AKI, for even if a patient is undergoing dialysis, therapies directed at mitigating ongoing injury may have a role in AKI treatment and CKD prevention.
Competing interests
The authors declare that they have no competing interests.