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Perspective on Clinical Application of Biomarkers in AKI Chirag R. Parikh*†‡ and Sherry G. Mansour*† *Program of Applied Translational Research, Department of Medicine, and †Division of Nephrology, Department of Medicine, Yale University, School of Medicine, New Haven, Connecticut; and ‡Division of Nephrology, Department of Medicine, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
ABSTRACT Several biomarkers of renal injury have been identified but the utility of these biomarkers is largely confined to research studies, whereas widespread clinical applicability is limited. This is partly because the use of serum creatinine as the comparator has several limitations and restricts the full interpretation of biomarker performance. To highlight the potential for clinical application of biomarkers, the most pertinent biomarker data are summarized here, using clinically relevant scenarios in which biomarkers could assist with diagnostic and management dilemmas. The paradigms proposed in this review aim to enhance the clinical diagnosis, management, and prognosis of AKI through the combined use of available clinical markers and novel inflammatory, injury, and repair biomarkers. J Am Soc Nephrol 28: ccc–ccc, 2017. doi: 10.1681/ASN.2016101127
The field of nephrology has overcome many challenges since Dr. Homer Smith coined the term ARF in 1964.1 In 2002, there were .30 different definitions of ARF in the literature as described by the Acute Dialysis Quality Initiative (ADQI).2 A consensus on a definition was reached in 2004 with the introduction of the term AKI and the use of Risk, Assessment, Failure, Loss, and End Stage Renal Disease. Later, definitions were further refined with the advent of the Acute Kidney Injury Network (AKIN) criteria in 2009 and more recently the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. 3 –5 Although we have successfully achieved standardization in AKI screening, the field of nephrology still lacks a more comprehensive definition of AKI that incorporates other dimensions to improve specificity of type, etiology, and prognosis of AKI. Nephrology has yet to overcome its ultimate challenge of solely relying on serum creatinine and occasionally urine output to define J Am Soc Nephrol 28: ccc–ccc, 2017
AKI and its various causes (Table 1). The limitations of serum creatinine are well known and have been extensively explored in the literature.6–11 The lack of sensitivity of serum creatinine in the detection of AKI can be observed in protocol transplant kidney biopsy specimens, where there is substantial evidence of tubular injury without significant changes in serum creatinine.12 Even when there is a rise in serum creatinine, it occurs 48–72 hours after injury.13 In contrast, several novel biomarkers such as neutrophil gelatinase– associated lipocalin (NGAL) and IL-18 have been shown to increase within hours of injury.14 For this reason, in 2006 the Food and Drug Administration (FDA) released the Critical Path initiative in an effort to develop better evaluation tools such as biomarkers to further characterize diseases such as AKI.15 The FDA defined a “biomarker” as a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes,
pathogenic processes, or pharmacologic responses to therapeutic intervention. 16 Since commencement of the Critical Path biomarker initiative, there has been tremendous research interest in this area. Over 1000 manuscripts have been published investigating ideal biomarkers to predict early damage before creatinine rise as well as to indicate damage specific to kidney tissue (Figure 1). To date, several novel biomarkers of renal injury have been identified but are largely confined to research studies and have not been widely applied to clinical settings. This is partly due to the use of serum creatinine as the gold standard of AKI diagnosis, which limits the interpretation of biomarker performance to the confines of creatinine use. For example, a biomarker might rise in the setting of true injury but serum creatinine may remain unchanged in that setting due to volume of distribution or compensatory hyperfiltration, causing the biomarker to appear nonspecific. Or a biomarker might not rise as in prerenal azotemia (PRA), which is not true injury to kidney tissue but serum creatinine rises causing the biomarker to appear to lack sensitivity.
Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Chirag R. Parikh, Section of Nephrology, Yale University School of Medicine, 60 Temple Street, Suite 6C, New Haven, CT 06510. Email: [email protected] Copyright © 2017 by the American Society of Nephrology
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Table 1. Definitions of terms used in this review Term AKI Prerenal azotemia (PRA) Acute tubular injury (ATI)
Cardiorenal syndrome
Hepatorenal syndrome (HRS)
Definition A broad clinical syndrome encompassing various etiologies. In this review, the term AKI is used to identify a rise in creatinine as defined by AKIN or the KDIGO guidelines. Occasionally referred to as hemodynamic AKI. A rise in creatinine with minimal-to-no structural damage but rather a filtration dysfunction due to volume depletion, and hence it is reversible with volume resuscitation. Also known as acute tubular necrosis. This term indicates structural tubular damage/injury. Urine microscopy demonstrates granular casts and tubular epithelial cells. The rise in serum creatinine is usually not responsive to volume resuscitation and may be harmful. This syndrome is characterized by ineffective arterial circulation secondary to cardiac dysfunction and has activation to neurohormonal processes. It resembles PRA with afferent arteriole vasoconstriction, decreased GFR, sodium and water retention, and minimal structural damage, but is not reversible with volume resuscitation. This syndrome is characterized by ineffective arterial circulation secondary to splanchnic vasodilation and liver failure. It resembles PRA with afferent arteriole vasoconstriction, decreased GFR, sodium and water retention, and minimal structural damage, and is not reversible with volume resuscitation. It requires administration of splanchnic vasoconstrictors or liver transplantation to restore arterial circulation and renal blood flow.
Despite the limitations of serum creatinine, certain biomarkers were able to surface as complementary to established clinical markers in assessing patients with AKI. This is in part because novel biomarkers were associated with clinical outcomes such as dialysis and death, which helped address some of the limitations of using serum creatinine as the comparative gold standard.17,18 In an effort to highlight the potential for the clinical application of biomarkers to untangle the web of AKI etiologies and to identify meaningful AKI we will summarize the most pertinent biomarker data using four clinically relevant scenarios in
which biomarkers assist with diagnostic dilemmas (Table 2). SCENARIO 1: DISTINGUISHING PRA FROM ACUTE TUBULAR INJURY IN HOSPITALIZED PATIENTS Clinical Dilemma
Both nephrologists and internists frequently face the challenge of differentiating between PRA and acute tubular injury (ATI) when assessing hospitalized patients with AKI. This diagnostic conundrum has been further complicated
by the evolving definitions of the two conditions.19 The term PRA is usually used to indicate minimal-to-no structural damage and ATI to indicate true tubular injury. Thus, discerning between these two causes is important because it can alter patient management. If a diagnosis of PRA is made, intravenous fluids (IVF) and optimizing hemodynamics are the staple clinical therapies. In the case of ATI, however, a patient’s condition would not improve with IVFs and unnecessary fluid administration might actually cause harm.20 Often, the diagnosis is confirmed retrospectively rather than prospectively, because clinicians are able to differentiate between the two causes on the basis of the clinical course and duration of creatinine elevation, as well as response to fluids.21,22 Distinguishing between PRA and ATI becomes even more challenging in the setting of preexisting CKD. This scenario is clinically important because AKI superimposed on CKD is associated with worse clinical outcomes.23 Current Paradigm
Figure 1. Increasing trend in original papers published on renal biomarkers in AKI. The above search was conducted using PubMed (www.ncbi.nlm.nih.gov/pubmed). Mesh terms of AKI and biomarkers were used with the following filters: article type, observational studies, clinical trials; publication dates, 2006–2016 (each year was searched separately); restricted to humans and English language.
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Clinicians often rely on fractional excretion of sodium (FeNa) to diagnose PRA because it has been shown that FeNa,1% is diagnostic of PRA.24 However, many factors can affect the accuracy of FeNa measurement, because its measurement should be in the absence of diuretics, and precede any IVF administration.25 More so, urinary sodium is J Am Soc Nephrol 28: ccc–ccc, 2017
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Table 2. Current paradigm versus proposed paradigm in various clinical settings Clinical Dilemma
Setting
Proposed Paradigm
Current Paradigm
With Novel Markers
With Repurposing of Existing Markers
Hospitalized patients with AKI
PRA versus ATI
Clinical history Serum creatinine FeNa,1% Urine microscopy
Current paradigm + Novel biomarkers: IL-18, NGAL, KIM-1
Current paradigm + Urine microscopy score
AKI in cirrhosis
HRS versus PRA versus ATI
Serum creatinine ICA criteria
Current paradigm + Novel biomarkers: NGAL, LFABP, IL-18
Current paradigm + FeNa,0.1% Urine albumin
AKI in cardiorenal syndrome
Worsening renal function and diuretic management
Serum creatinine Serum BUN
Current paradigm + Novel biomarkers: NGAL, KIM-1, NAG
Current paradigm + Urine albumin Hematocrit Serum albumin Serum protein
AKI in deceased donors
Allocation and discard of kidneys
KDPI Kidney biopsy
Current paradigm + Novel injury biomarkers: NGAL, LFABP Novel repair biomarkers: YKL-40
ATI, acute tubular injury; FeNA, fractional excretion of sodium; IL-18, interleukin 18; NGAL, neutrophil gelatinase associated lipocalin; KIM-1, kidney injury molecule-1; HRS, hepatorenal syndrome; ICA, international club of ascites; LFABP, liver fatty acid binding protein; NAG, N-acetyl-b- D -glucosaminidase; KDPI, kidney donor profile index.
affected by multiple nonrenal factors and FeNa,1% has also been described in the setting of ATI.26 Aside from FeNa, urine microscopy findings have also been shown to be strongly diagnostic of ATI versus PRA. However, microscopy use is limited due to several factors such as availability of microscopes in hospital settings, and the fact that few academic clinicians aside from nephrologists are trained in urine microscopy.27 The performance of urine electrolytes and urine microscopy has not been evaluated in AKI etiologies superimposed on CKD. Proposed Paradigm
The addition of injury biomarkers to the clinical panel could potentially enhance clinician accuracy in distinguishing between PRA and ATI. Injured tubules in ATI elicit inflammatory responses and thus measuring proteins specific to the injured tubule or markers of kidneyspecific inflammation in urine would help distinguish ATI from PRA. Urine conJ Am Soc Nephrol 28: ccc–ccc, 2017
centrations of IL-18, which is a mediator of tubular apoptosis, are significantly higher in patients with ATI and longer duration of AKI compared with those with PRA, transient AKI, urinary tract infections, CKD, and healthy control participants.28–31 This protein is robust to sample processing, handling, and storage conditions and provides high discrimination for ATI.32 In addition to IL-18, urine NGAL measured in the emergency department has also been shown to reliably distinguish ATI from PRA.33 Using adjudicated cases of PRA and ATI, NGAL levels .104 mg/L were able to diagnose ATI with a likelihood ratio of 5.97.34 NGAL is released from renal tubules in response to injury, rises before creatinine, and is not affected by volume depletion or diuretics.35–38 In animal studies, NGAL, along with liver fatty acid binding protein (LFABP), was shown to rise only modestly in volume depletion without histologic damage, as compared with the model of ischemia reperfusion. 39 Lastly, kidney injury
molecule–1 (KIM-1) was extensively expressed in biopsy specimens of patients with ATI, and urine concentrations of KIM-1 distinguished ATI from other causes of AKI. 40 Once again, KIM-1 expression in renal tubules was dramatically increased after ischemia, demonstrating its biologic plausibility as a marker of true kidney injury.41 It has also been shown that urine NGAL improves the clinical model (consisting of multiple baseline characteristics including baseline eGFR, age, and history of diabetes) for predicting worsening AKI, defined as worsening AKIN stage and in-hospital death from an area under the curve (AUC) of 0.62–0.75, as compared with no improvement when adding FeNa to the model (AUC remained at 0.62).42 The use of IL-18, NGAL, LFABP, and KIM-1 in addition to the current paradigm would likely be able to distinguish between PRA and ATI, and ultimately help guide patient management. In addition, the repurposing of existing clinical markers such as urine microscopy Clinical Potential of Biomarkers in AKI
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could be used to differentiate ATI from PRA. For example, the urine microscopy score, which is calculated from the number of granular casts and tubular cells, has been found to be higher in patients with ATI compared with those with PRA and was highly correlated with the urinary levels of IL-18, NGAL, and KIM-1. Patients with a microscopy score $3 (on the basis of the number of granular casts and renal tubular epithelial cells present in urine sample) had 3.5 times the risk of AKI progression defined as worsening AKIN stage and inhospital mortality compared with those with microscopy scores of zero.42 Hence, in addition to novel biomarkers, clinically available biomarkers such as urine microscopy score could also be used to differentiate ATI from PRA. Lastly, biomarker performance improves for diagnosis of AKI in the background of CKD. Urine KIM-1 levels diagnosed AKI more accurately in those with eGFR,60 ml/min per m2 as compared with those with normal baseline kidney function.43 SCENARIO 2: DIFFERENTIAL DIAGNOSIS IN CIRRHOSIS Clinical Dilemma
The diagnostic task of identifying the cause of AKI becomes even more challenging as a patient’s concomitant medical history becomes more extensive. AKI is a common complication in patients with advanced cirrhosis and is associated with significant mortality. In the setting of cirrhosis, the differential diagnosis broadens to include hepatorenal syndrome (HRS) along with PRA and ATI. 44 The ability to make the distinction between HRS and ATI is critical, because treatments differ considerably. HRS may be reversed with restoration of renal perfusion, through vasoconstrictor therapy in addition to intravenous albumin treatment and subsequent liver transplantation. In contrast, patients with ATI should be treated with dialysis and considered for combined liver-kidney transplantation.45–48 4
Current Paradigm
The current criteria to diagnose HRS proposed by the International Club of Ascites (ICA) are presence of cirrhosis and ascites, serum creatinine .1.5 mg/dl without improvement after diuretic withdrawal and restoration of oncotic volume within 48 hours, absence of shock, lack of nephrotoxic agents, and absence of proteinuria, hematuria, and abnormal renal ultrasound.49 Notably, the ICA criteria rely heavily on the use of serum creatinine, but creatinine is especially unsuitable as a marker of kidney injury in the setting of cirrhosis because of low protein intake, loss of muscle mass, and decrease in synthesis secondary to hepatic injury.50 This will lead to false negative serum creatinine values and ultimately delay initiation of therapy. Many of the standard diagnostic tools, such as urine microscopy and FeNa,1%, have also traditionally been ineffective in this situation.51 Proposed Paradigm
In an effort to overcome the diagnostic limitations of serum creatinine, several biomarkers have been investigated in the setting of cirrhosis. Urine NGAL and IL-18 were able to discriminate between ATI and other causes of kidney impairment in patients with cirrhosis.52 The highest levels were found in patients with ATI, followed by HRS and PRA, respectively. 46,53 The combination of several biomarkers was also assessed in diagnosing the type of AKI in patients with cirrhosis.54 Using a cut-off value of 365 ng/ml for NGAL, 85 pg/ml for IL-18, and 25 ng/ml for LFABP, the diagnosis of ATI in patients with cirrhosis was evaluated. Patients with cirrhosis who had at least one biomarker above the cut-off level were five times as likely to have ATI and those with all markers positive were 13 times as likely to have ATI. Biomarker levels were also able to increase the post-test probability of having ATI; for example, having an NGAL level .365 ng/ml raised the pretest probability from 40% to a post-test probability of 76%.54 Fortunately, several clinically available tests have also demonstrated an
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ability to distinguish between HRS and ATI. FeNa has long been marginalized in the setting of cirrhosis as the clinical cutoff of ,1% is universal in these patients. However, its performance has recently been re-evaluated by multiple investigators.51,55,56 Although these studies have utilized different methods of diagnosing HRS, in all of their results, FeNa was significantly lower in cases of HRS than in cases of ATI. The median FeNa in patients with HRS across studies is remarkably uniform, averaging around 0.1%. In the study by Belcher et al., FeNa was lowest in patients with HRS (0.10% [interquartile range (IQR), 0.02–0.23]), and differed significantly from both levels in patients with PRA (0.27% [IQR, 0.13–0.58]), and levels in patients with ATI (0.31% [IQR, 0.12–0.65]).54 In the same study, spot albuminuria was investigated as an injury marker for ATI and was significantly higher in patients adjudicated with ATI (92 mg/dl [IQR, 44–254]) than it was in either PRA (21 mg/dl [IQR, 4–70]) or HRS (24 mg/dl [IQR, 13–129], P,0.001). The AUC identifying ATI at a cut-off of 44 mg/dl was 0.73 (IQR, 0.64–0.83). 54 Until additional markers become clinically available, clinicians should consider incorporating FeNa and proteinuria into their diagnostic and prognostic approaches to joint AKI-cirrhosis cases (Figure 2). Although using this proposed paradigm may help discriminate between ATI and HRS, distinguishing PRA from HRS may be less reliable. SCENARIO 3: MANAGEMENT DECISIONS IN CARDIORENAL SYNDROME Clinical Dilemma
There are further clinical challenges associated with patients with cardiorenal syndrome. Currently, diuretics remain the mainstay of treatment in acute decompensated heart failure.57 However, there exists a frequently vexing clinical scenario of continuing with diuretic use, ignoring a rise in creatinine to attain optimal decongestion and effective perfusion pressure, or decreasing diuretic J Am Soc Nephrol 28: ccc–ccc, 2017
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dose to avoid worsening renal function with diuresis. Current Paradigm
A creatinine rise of .0.3 mg/dl in the setting of decompensated heart failure has been associated with longer hospital stay, higher readmission rates, and mortality.58,59 These elevations in creatinine and BUN, commonly known as “worsening renal function” in the cardiology literature, are associated with aggressive diuresis that is required to restore cardiovascular hemodynamics.60,61 Unfortunately, both creatinine and possibly high diuretic doses are markers rather than drivers of poor outcomes. There is a tremendous lack of evidence to guide this clinical dilemma mainly because the clinical markers such as BUN, creatinine, and urine output do not measure true renal injury.62 This clinical scenario has been further complicated by recent data suggesting significantly lower longterm mortality in patients developing hemoconcentration secondary to more aggressive diuretic dosing, despite a rise in creatinine.63–65 Proposed Paradigm
It has been shown that in patients with chronic heart failure urine NGAL is elevated, indicating a possibility of tubular
damage.66 Similarly, urinary KIM-1 and N-acetyl-b-D-glucosaminidase were elevated in patients with chronic heart failure as compared with healthy controls despite a mean eGFR of 78 ml/min per m2, indicating the presence of tubular injury beyond that captured by creatinine.67 Therefore, low levels of NGAL, N-acetylb-D-glucosaminidase, and KIM-1 might aid in the decision to continue with intense diuretic regimens despite a rise in creatinine. These biomarkers could potentially be evaluated in future studies or in completed trials by examining banked samples such as those from the Diuretic Optimization Strategies Evaluation trial to evaluate renal injury in the setting of different intensities of diuresis.68 Clinically established markers such as urinary excretion of albumin (UAE) may reliably guide diuretic management in patients with decompensated heart failure.69 UAE as defined by 1+ proteinuria on dipstick was associated with greater decline in eGFR over 23 months in patients with moderateto-severe heart failure as compared with patients with negative protein on dipstick.69 In addition to UAE, the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial showed that markers of hemoconcentration were associated
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with worsening renal function (defined by decline in eGFR), but nonetheless lower mortality.63 Hemoconcentration was defined as an increase in at least two of the following: serum albumin, serum total protein, and hematocrit. Therefore, the application of existing clinical markers such as UAE, hematocrit, serum albumin, and serum protein, along with novel biomarkers, might generate a panel to distinguish between causes leading to creatinine rise with the potential for therapeutic diuretic success in decompensated heart failure. SCENARIO 4: ALLOCATION OF KIDNEYS FROM DECEASED DONORS Clinical Dilemma
Over 100,000 patients are awaiting kidney transplants in the United States and unfortunately the number of deceased donor transplants has plateaued around 11,000. This necessitates efforts to salvage all viable procured kidneys.70 Nevertheless, about 2500 procured kidneys from deceased donors are discarded each year. AKI kidneys are discarded at much higher rates secondary to risk of delayed graft function (DGF), risk of increased hospital stay post-transplantation, and concerns of long-term graft failure.71 However, it has been shown that donor AKI, especially in patients who later develop DGF, does not preclude favorable recipient allograft outcomes, and may in fact portend improved 6-month eGFR with increasing AKI severity using AKIN staging.72 Current Paradigm
Figure 2. Guided clinical management in patients with cirrhosis by phenotyping AKI via biomarkers. AKI in patients with cirrhosis with a broad differential including HRS, ATI, and PRA. The use of novel biomarkers along side clinical markers in joint AKI-cirrhosis cases may distinguish between these three etiologies, as well as help guide clinical management. J Am Soc Nephrol 28: ccc–ccc, 2017
To help address these shortcomings via better organ utilization, the national kidney allocation system was revised in December of 2014 to incorporate the kidney donor profile index.73 The kidney donor profile index comprises ten donor characteristics, which include terminal serum creatinine as well as donor age, height, weight, ethnicity, history of hypertension, history of diabetes, cause of death, hepatitis C status, and donation Clinical Potential of Biomarkers in AKI
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after circulatory death. These ten factors generate a score that is presented as percentage risk of graft failure compared with kidneys retrieved in the prior year. However, this panel has its limitations. For example, the use of terminal serum creatinine is especially restrictive around the time of death given that it is affected by multiple nonrenal factors such as altered creatinine kinetics, muscle injury, and administration of fluids, and a single value of creatinine does not fully account for the acute trajectory or chronicity of renal function. Wedge biopsy specimens of donor kidneys obtained at time of procurement are also not accurate, can overestimate the amount of glomerulosclerosis, and are suboptimal for the diagnosis of ATI.74 Consequently, there remains a compelling need for more reliable tools to assess donor kidney quality in the presence of AKI. Proposed Paradigm
To delineate which donor AKI kidneys will have poor versus favorable outcomes in recipients, both kidney injury and repair biomarkers have been evaluated in deceased donor urine. Two injury biomarkers, NGAL and LFABP, provided modest incremental value in predicting worse recipient 6-month eGFR, especially in those without DGF.75 On the contrary, a repair phase protein known as YKL-40 was associated with less DGF and better long-term eGFR.76 Preclinical studies on YKL-40 have generated strong support for its cytoprotective and reparative roles in the setting of kidney injury.77 Among those donor kidneys with clinically defined injury before transplantation, the ones with the greatest urinary YKL-40 levels have the best chance of successfully regaining function.76 The use of a recovery marker like YKL-40 in assessing deceased donor kidneys has immense potential, because it could increase the number of transplanted AKI kidneys by feasibly decreasing discard rates among AKI kidneys and providing more wait-listed patients with the opportunity to receive a viable kidney. 6
DISCUSSION Use of Biomarkers in Clinical Management
Although novel biomarkers can address diagnostic delay in AKI and differentiate between PRA and ATI, further research is needed to advance biomarkers to bedside. As a strategy, a recent clinical trial used plasma NGAL for enrollment of participants in the assessment of early versus late initiation of renal replacement therapy for AKI.78 In addition, the FDA approved the first AKI point-of-care biomarker device, NephroCheck. 79 It measures urinary levels of tissue inhibitor of metalloproteinase-2 and IGFbinding protein 7, which are cell cycle arrest biomarkers. Using NephroCheck, the positive predictive value to diagnose stage 2 or 3 AKI as defined by KDIGO is 49% and the negative predictive value is 97%.80–82 The effect of NephroCheck will be determined once it is adopted into clinical practice, but it does offer the ability to identify risk of imminent AKI in critically ill patients and potentially identify high-risk patients for enrollment in clinical trials. However, as emphasized by the ADQI, perhaps the combination of biomarkers of kidney damage and kidney function, rather than a biomarker representation of a single biologic process such as cell cycle arrest, will be needed to facilitate the diagnosis of AKI.83 This concept was validated in 345 children undergoing cardiopulmonary bypass, where the combination of functional (cystatin C) and damage (NGAL) biomarkers was superior than change in serum creatinine in predicting severity and persistence of AKI.84 More so, the use of biomarkers without proper clinical risk stratification will yield to suboptimal biomarker performance. To overcome this challenge, the renal angina index was established to risk-stratify patients with AKI on the basis of the severity of the clinical setting and the percentage change in creatinine clearance. This strategy was validated in a pediatric population where the incorporation of biomarkers into the renal angina index improved net reclassification of predicting AKI.85
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Conclusion and Future Direction
There may be successful biomarkers among the current candidates, but their full potential cannot be realized when they are compared with the confining indicator that is serum creatinine. It is also possible that AKI is a syndrome with each setting having a unique set of case-mix and pathophysiology with a distinctive set of clinical decisions, necessitating an individualized panel of biomarkers for each setting. In an effort to move away from the sole use of creatinine in diagnosing renal injury, the National Institutes of Health has initiated the Kidney Precision Medicine Project which is a mission toward obtaining and assessing kidney biopsy specimens to create a kidney tissue atlas and a movement toward tissue-driven definitions of renal injury and disease.86 After this hopeful transformation from creatinine-defined to tissue-defined renal injury, the field of nephrology will likely develop a deeper understanding of kidney injury biomarkers, which could lead physicians to incorporate them routinely into clinical practice and better personalize patient care.
ACKNOWLEDGMENTS C.R.P. is supported by National Institutes of Health (NIH) grants RO1HL085757 and K24DK090203. S.G.M. is supported by the T32 training grant (T32DK007276) from the NIH.
DISCLOSURES None.
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necrosis in mice. J Clin Invest 110: 1083– 1091, 2002 Nejat M, Pickering JW, Devarajan P, Bonventre JV, Edelstein CL, Walker RJ, Endre ZH: Some biomarkers of acute kidney injury are increased in pre-renal acute injury. Kidney Int 81: 1254–1262, 2012 Parikh CR, Butrymowicz I, Yu A, Chinchilli VM, Park M, Hsu CY, Reeves WB, Devarajan P, Kimmel PL, Siew ED, Liu KD; ASSESS-AKI Study Investigators: Urine stability studies for novel biomarkers of acute kidney injury. Am J Kidney Dis 63: 567–572, 2014 Nickolas TL, O’Rourke MJ, Yang J, Sise ME, Canetta PA, Barasch N, Buchen C, Khan F, Mori K, Giglio J, Devarajan P, Barasch J: Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med 148: 810–819, 2008 Singer E, Elger A, Elitok S, Kettritz R, Nickolas TL, Barasch J, Luft FC, Schmidt-Ott KM: Urinary neutrophil gelatinase-associated lipocalin distinguishes pre-renal from intrinsic renal failure and predicts outcomes. Kidney Int 80: 405–414, 2011 Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P: Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 14: 2534–2543, 2003 Mori K, Lee HT, Rapoport D, Drexler IR, Foster K, Yang J, Schmidt-Ott KM, Chen X, Li JY, Weiss S, Mishra J, Cheema FH, Markowitz G, Suganami T, Sawai K, Mukoyama M, Kunis C, D’Agati V, Devarajan P, Barasch J: Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemiareperfusion injury. J Clin Invest 115: 610– 621, 2005 Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P: Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 365: 1231– 1238, 2005 Mori K, Nakao K: Neutrophil gelatinaseassociated lipocalin as the real-time indicator of active kidney damage. Kidney Int 71: 967– 970, 2007 Doi K, Katagiri D, Negishi K, Hasegawa S, Hamasaki Y, Fujita T, Matsubara T, Ishii T, Yahagi N, Sugaya T, Noiri E: Mild elevation of urinary biomarkers in prerenal acute kidney injury. Kidney Int 82: 1114–1120, 2012 Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV: Kidney injury molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury. Kidney Int 62: 237– 244, 2002 Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, Sanicola M: Kidney injury molecule-1 (KIM-1), a putative epithelial cell
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adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem 273: 4135–4142, 1998 Hall IE, Coca SG, Perazella MA, Eko UU, Luciano RL, Peter PR, Han WK, Parikh CR: Risk of poor outcomes with novel and traditional biomarkers at clinical AKI diagnosis. Clin J Am Soc Nephrol 6: 2740–2749, 2011 Endre ZH, Pickering JW, Walker RJ, Devarajan P, Edelstein CL, Bonventre JV, Frampton CM, Bennett MR, Ma Q, Sabbisetti VS, Vaidya VS, Walcher AM, Shaw GM, Henderson SJ, Nejat M, Schollum JBW, George PM: Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function. Kidney Int 79: 1119–1130, 2011 Martín-Llahí M, Guevara M, Torre A, Fagundes C, Restuccia T, Gilabert R, Solá E, Pereira G, Marinelli M, Pavesi M, Fernández J, Rodés J, Arroyo V, Ginès P: Prognostic importance of the cause of renal failure in patients with cirrhosis. Gastroenterology 140: 488–496.e4, 2011 Velez JC, Kadian M, Taburyanskaya M, Bohm NM, Delay TA, Karakala N, Rockey DC, Nietert PJ, Goodwin AJ, Whelan TP: Hepatorenal acute kidney injury and the importance of raising mean arterial pressure. Nephron 131: 191–201, 2015 Dobre M, Demirjian S, Sehgal AR, Navaneethan SD: Terlipressin in hepatorenal syndrome: A systematic review and metaanalysis. Int Urol Nephrol 43: 175–184, 2011 Nassar Junior AP, Farias AQ, D’ Albuquerque LA, Carrilho FJ, Malbouisson LM: Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: A systematic review and meta-analysis. PLoS One 9: e107466, 2014 Nadim MK, Genyk YS, Tokin C, Fieber J, Ananthapanyasut W, Ye W, Selby R: Impact of the etiology of acute kidney injury on outcomes following liver transplantation: Acute tubular necrosis versus hepatorenal syndrome. Liver Transpl 18: 539–548, 2012 Wong F, Nadim MK, Kellum JA, Salerno F, Bellomo R, Gerbes A, Angeli P, Moreau R, Davenport A, Jalan R, Ronco C, Genyk Y, Arroyo V: Working party proposal for a revised classification system of renal dysfunction in patients with cirrhosis. Gut 60: 702–709, 2011 Davenport A: Difficulties in assessing renal function in patients with cirrhosis: Potential impact on patient treatment. Intensive Care Med 37: 930–932, 2011 Verna EC, Brown RS, Farrand E, Pichardo EM, Forster CS, Sola-Del Valle DA, Adkins SH, Sise ME, Oliver JA, Radhakrishnan J, Barasch JM, Nickolas TL: Urinary neutrophil gelatinaseassociated lipocalin predicts mortality and identifies acute kidney injury in cirrhosis. Dig Dis Sci 57: 2362–2370, 2012
52. Puthumana J, Ariza X, Belcher JM, Graupera I, Ginès P, Parikh CR: Urine interleukin 18 and lipocalin 2 are biomarkers of acute tubular necrosis in patients with cirrhosis: A systematic review and meta-analysis [published online ahead of print December 22, 2016]. Clin Gastroenterol Hepatol doi:10.1016/j. cgh.2016.11.035 53. Fagundes C, Pépin MN, Guevara M, Barreto R, Casals G, Solà E, Pereira G, Rodríguez E, Garcia E, Prado V, Poch E, Jiménez W, Fernández J, Arroyo V, Ginès P: Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis. J Hepatol 57: 267–273, 2012 54. Belcher JM, Sanyal AJ, Peixoto AJ, Perazella MA, Lim J, Thiessen-Philbrook H, Ansari N, Coca SG, Garcia-Tsao G, Parikh CR; TRIBEAKI Consortium: Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury. Hepatology 60: 622–632, 2014 55. Ariza X, Solà E, Elia C, Barreto R, Moreira R, Morales-Ruiz M, Graupera I, Rodríguez E, Huelin P, Solé C, Fernández J, Jiménez W, Arroyo V, Ginès P: Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis. PLoS One 10: e0128145, 2015 56. Fagundes C, Barreto R, Guevara M, Garcia E, Solà E, Rodríguez E, Graupera I, Ariza X, Pereira G, Alfaro I, Cárdenas A, Fernández J, Poch E, Ginès P: A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis. J Hepatol 59: 474–481, 2013 57. Wang DJ, Gottlieb SS: Diuretics: Still the mainstay of treatment. Crit Care Med 36 [Suppl]: S89–S94, 2008 58. Krumholz HM, Chen YT, Vaccarino V, Wang Y, Radford MJ, Bradford WD, Horwitz RI: Correlates and impact on outcomes of worsening renal function in patients . or =65 years of age with heart failure. Am J Cardiol 85: 1110–1113, 2000 59. Smith GL, Vaccarino V, Kosiborod M, Lichtman JH, Cheng S, Watnick SG, Krumholz HM: Worsening renal function: What is a clinically meaningful change in creatinine during hospitalization with heart failure? J Card Fail 9: 13–25, 2003 60. Weinfeld MS, Chertow GM, Stevenson LW: Aggravated renal dysfunction during intensive therapy for advanced chronic heart failure. Am Heart J 138: 285–290, 1999 61. Knight EL, Glynn RJ, McIntyre KM, Mogun H, Avorn J: Predictors of decreased renal function in patients with heart failure during angiotensin-converting enzyme inhibitor therapy: Results from the studies of left ventricular dysfunction (SOLVD). Am Heart J 138: 849–855, 1999 62. Leier CV: Renal roadblock in managing low output heart failure. Crit Care Med 32: 1228– 1229, 2004
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63. Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP: Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation 122: 265–272, 2010 64. van der Meer P, Postmus D, Ponikowski P, Cleland JG, O’Connor CM, Cotter G, Metra M, Davison BA, Givertz MM, Mansoor GA, Teerlink JR, Massie BM, Hillege HL, Voors AA: The predictive value of short-term changes in hemoglobin concentration in patients presenting with acute decompensated heart failure. J Am Coll Cardiol 61: 1973–1981, 2013 65. Greene SJ, Gheorghiade M, Vaduganathan M, Ambrosy AP, Mentz RJ, Subacius H, Maggioni AP, Nodari S, Konstam MA, Butler J, Filippatos G; EVEREST Trial investigators: Haemoconcentration, renal function, and post-discharge outcomes among patients hospitalized for heart failure with reduced ejection fraction: Insights from the EVEREST trial. Eur J Heart Fail 15: 1401–1411, 2013 66. Damman K, van Veldhuisen DJ, Navis G, Voors AA, Hillege HL: Urinary neutrophil gelatinase associated lipocalin (NGAL), a marker of tubular damage, is increased in patients with chronic heart failure. Eur J Heart Fail 10: 997–1000, 2008 67. Damman K, Van Veldhuisen DJ, Navis G, Vaidya VS, Smilde TD, Westenbrink BD, Bonventre JV, Voors AA, Hillege HL: Tubular damage in chronic systolic heart failure is associated with reduced survival independent of glomerular filtration rate. Heart 96: 1297– 1302, 2010 68. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O’Connor CM; NHLBI Heart Failure Clinical Research Network: Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 364: 797–805, 2011 69. Anand IS, Bishu K, Rector TS, Ishani A, Kuskowski MA, Cohn JN: Proteinuria, chronic kidney disease, and the effect of an angiotensin receptor blocker in addition to an angiotensin-converting enzyme inhibitor in patients with moderate to severe heart failure. Circulation 120: 1577–1584, 2009 70. United Network for Organ Sharing: Available at: http://www.unos.org/data/transplanttrends/. Accessed September 16, 2016 71. Ali T, Dimassi W, Elgamal H, Alabassi A, Aleid H, Altalhi M, Shoukri M, Almeshari K: Outcomes of kidneys utilized from deceased donors with severe acute kidney injury. QJM 108: 803–811, 2015 72. Hall IE, Schröppel B, Doshi MD, Ficek J, Weng FL, Hasz RD, Thiessen-Philbrook H, Reese PP, Parikh CR: Associations of deceased donor kidney injury with kidney
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discard and function after transplantation. Am J Transplant 15: 1623–1631, 2015 Gandolfini I, Buzio C, Zanelli P, Palmisano A, Cremaschi E, Vaglio A, Piotti G, Melfa L, La Manna G, Feliciangeli G, Cappuccilli M, Scolari MP, Capelli I, Panicali L, Baraldi O, Stefoni S, Buscaroli A, Ridolfi L, D’Errico A, Cappelli G, Bonucchi D, Rubbiani E, Albertazzi A, Mehrotra A, Cravedi P, Maggiore U: The Kidney Donor Profile Index (KDPI) of marginal donors allocated by standardized pretransplant donor biopsy assessment: Distribution and association with graft outcomes. Am J Transplant 14: 2515– 2525, 2014 Muruve NA, Steinbecker KM, Luger AM: Are wedge biopsies of cadaveric kidneys obtained at procurement reliable? Transplantation 69: 2384–2388, 2000 Reese PP, Hall IE, Weng FL, Schröppel B, Doshi MD, Hasz RD, Thiessen-Philbrook H, Ficek J, Rao V, Murray P, Lin H, Parikh CR: Associations between deceased-donor urine injury biomarkers and kidney transplant outcomes. J Am Soc Nephrol 27: 1534–1543, 2016 Puthumana J, Hall IE, Reese PP, Schröppel B, Weng FL, Thiessen-Philbrook H, Doshi M, Rao V, Lee CG, Elias JA, Cantley LG, Parikh CR: YKL-40 associated with renal recovery in deceased donor kidney transplantation. J Am Soc Nephrol 28: 389–393, 2017 Schmidt IM, Hall IE, Kale S, Lee S, He CH, Lee Y, Chupp GL, Moeckel GW, Lee CG, Elias JA, Parikh CR, Cantley LG: Chitinase-like protein Brp-39/YKL-40 modulates the renal response
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to ischemic injury and predicts delayed allograft function. J Am Soc Nephrol 24: 309–319, 2013 Zarbock A, Kellum JA, Schmidt C, Van Aken H, Wempe C, Pavenstädt H, Boanta A, Gerß J, Meersch M: Effect of early vs delayed initiation of renal replacement therapy on mortality in critically Ill patients with acute kidney injury: The ELAIN randomized clinical trial. JAMA 315: 2190–2199, 2016 FDA news release: FDA allows marketing of the first test to assess risk of developing acute kidney injury, 2014. Available at: http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm412910.htm. Accessed December 27, 2016 Kidney Disease Improving Global Outcomes: KDIGO clinical practice guideline for acute kidney injury. Section 2: AKI Definition. Kidney Int Suppl 2012. Available at: http:// www.kdigo.org/clinical_practice_guidelines/ pdf/KDIGO%20AKI%20Guideline.pdf. Accessed December 27, 2016 Hoste EA, McCullough PA, Kashani K, Chawla LS, Joannidis M, Shaw AD, Feldkamp T, Uettwiller-Geiger DL, McCarthy P, Shi J, Walker MG, Kellum JA; Sapphire Investigators: Derivation and validation of cutoffs for clinical use of cell cycle arrest biomarkers. Nephrol Dial Transplant 29: 2054–2061, 2014 Bihorac A, Chawla LS, Shaw AD, Al-Khafaji A, Davison DL, Demuth GE, Fitzgerald R, Gong MN, Graham DD, Gunnerson K, Heung M, Jortani S, Kleerup E, Koyner JL, Krell K, Letourneau J, Lissauer M, Miner J, Nguyen
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HB, Ortega LM, Self WH, Sellman R, Shi J, Straseski J, Szalados JE, Wilber ST, Walker MG, Wilson J, Wunderink R, Zimmerman J, Kellum JA: Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication. Am J Respir Crit Care Med 189: 932–939, 2014 Endre ZH, Kellum JA, Di Somma S, Doi K, Goldstein SL, Koyner JL, Macedo E, Mehta RL, Murray PT: Differential diagnosis of AKI in clinical practice by functional and damage biomarkers: Workgroup statements from the tenth Acute Dialysis Quality Initiative Consensus Conference. Contrib Nephrol 182: 30–44, 2013 Basu RK, Wong HR, Krawczeski CD, Wheeler DS, Manning PB, Chawla LS, Devarajan P, Goldstein SL: Combining functional and tubular damage biomarkers improves diagnostic precision for acute kidney injury after cardiac surgery. J Am Coll Cardiol 64: 2753–2762, 2014 Menon S, Goldstein SL, Mottes T, Fei L, Kaddourah A, Terrell T, Arnold P, Bennett MR, Basu RK: Urinary biomarker incorporation into the renal angina index early in intensive care unit admission optimizes acute kidney injury prediction in critically ill children: A prospective cohort study. Nephrol Dial Transplant 31: 586–594, 2016 National Institutes of Diabetes and Digestive and Kidney Diseases: Kidney Precision Medicine Project (KPMP), 2016. Available at: https:// www.niddk.nih.gov/research-funding/researchprograms/Documents/KPMP_Diagram_508. pdf. Accessed September 30, 2016
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Perspective on Clinical Application of Biomarkers in AKI Chirag R. Parikh*†‡ and Sherry G. Mansour*† *Program of Applied Translational Research, Department of Medicine, and †Division of Nephrology, Department of Medicine, Yale University, School of Medicine, New Haven, Connecticut; and ‡Division of Nephrology, Department of Medicine, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
ABSTRACT Several biomarkers of renal injury have been identified but the utility of these biomarkers is largely confined to research studies, whereas widespread clinical applicability is limited. This is partly because the use of serum creatinine as the comparator has several limitations and restricts the full interpretation of biomarker performance. To highlight the potential for clinical application of biomarkers, the most pertinent biomarker data are summarized here, using clinically relevant scenarios in which biomarkers could assist with diagnostic and management dilemmas. The paradigms proposed in this review aim to enhance the clinical diagnosis, management, and prognosis of AKI through the combined use of available clinical markers and novel inflammatory, injury, and repair biomarkers. J Am Soc Nephrol 28: ccc–ccc, 2017. doi: 10.1681/ASN.2016101127
The field of nephrology has overcome many challenges since Dr. Homer Smith coined the term ARF in 1964.1 In 2002, there were .30 different definitions of ARF in the literature as described by the Acute Dialysis Quality Initiative (ADQI).2 A consensus on a definition was reached in 2004 with the introduction of the term AKI and the use of Risk, Assessment, Failure, Loss, and End Stage Renal Disease. Later, definitions were further refined with the advent of the Acute Kidney Injury Network (AKIN) criteria in 2009 and more recently the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. 3 –5 Although we have successfully achieved standardization in AKI screening, the field of nephrology still lacks a more comprehensive definition of AKI that incorporates other dimensions to improve specificity of type, etiology, and prognosis of AKI. Nephrology has yet to overcome its ultimate challenge of solely relying on serum creatinine and occasionally urine output to define J Am Soc Nephrol 28: ccc–ccc, 2017
AKI and its various causes (Table 1). The limitations of serum creatinine are well known and have been extensively explored in the literature.6–11 The lack of sensitivity of serum creatinine in the detection of AKI can be observed in protocol transplant kidney biopsy specimens, where there is substantial evidence of tubular injury without significant changes in serum creatinine.12 Even when there is a rise in serum creatinine, it occurs 48–72 hours after injury.13 In contrast, several novel biomarkers such as neutrophil gelatinase– associated lipocalin (NGAL) and IL-18 have been shown to increase within hours of injury.14 For this reason, in 2006 the Food and Drug Administration (FDA) released the Critical Path initiative in an effort to develop better evaluation tools such as biomarkers to further characterize diseases such as AKI.15 The FDA defined a “biomarker” as a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes,
pathogenic processes, or pharmacologic responses to therapeutic intervention. 16 Since commencement of the Critical Path biomarker initiative, there has been tremendous research interest in this area. Over 1000 manuscripts have been published investigating ideal biomarkers to predict early damage before creatinine rise as well as to indicate damage specific to kidney tissue (Figure 1). To date, several novel biomarkers of renal injury have been identified but are largely confined to research studies and have not been widely applied to clinical settings. This is partly due to the use of serum creatinine as the gold standard of AKI diagnosis, which limits the interpretation of biomarker performance to the confines of creatinine use. For example, a biomarker might rise in the setting of true injury but serum creatinine may remain unchanged in that setting due to volume of distribution or compensatory hyperfiltration, causing the biomarker to appear nonspecific. Or a biomarker might not rise as in prerenal azotemia (PRA), which is not true injury to kidney tissue but serum creatinine rises causing the biomarker to appear to lack sensitivity.
Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Chirag R. Parikh, Section of Nephrology, Yale University School of Medicine, 60 Temple Street, Suite 6C, New Haven, CT 06510. Email: [email protected] Copyright © 2017 by the American Society of Nephrology
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Table 1. Definitions of terms used in this review Term AKI Prerenal azotemia (PRA) Acute tubular injury (ATI)
Cardiorenal syndrome
Hepatorenal syndrome (HRS)
Definition A broad clinical syndrome encompassing various etiologies. In this review, the term AKI is used to identify a rise in creatinine as defined by AKIN or the KDIGO guidelines. Occasionally referred to as hemodynamic AKI. A rise in creatinine with minimal-to-no structural damage but rather a filtration dysfunction due to volume depletion, and hence it is reversible with volume resuscitation. Also known as acute tubular necrosis. This term indicates structural tubular damage/injury. Urine microscopy demonstrates granular casts and tubular epithelial cells. The rise in serum creatinine is usually not responsive to volume resuscitation and may be harmful. This syndrome is characterized by ineffective arterial circulation secondary to cardiac dysfunction and has activation to neurohormonal processes. It resembles PRA with afferent arteriole vasoconstriction, decreased GFR, sodium and water retention, and minimal structural damage, but is not reversible with volume resuscitation. This syndrome is characterized by ineffective arterial circulation secondary to splanchnic vasodilation and liver failure. It resembles PRA with afferent arteriole vasoconstriction, decreased GFR, sodium and water retention, and minimal structural damage, and is not reversible with volume resuscitation. It requires administration of splanchnic vasoconstrictors or liver transplantation to restore arterial circulation and renal blood flow.
Despite the limitations of serum creatinine, certain biomarkers were able to surface as complementary to established clinical markers in assessing patients with AKI. This is in part because novel biomarkers were associated with clinical outcomes such as dialysis and death, which helped address some of the limitations of using serum creatinine as the comparative gold standard.17,18 In an effort to highlight the potential for the clinical application of biomarkers to untangle the web of AKI etiologies and to identify meaningful AKI we will summarize the most pertinent biomarker data using four clinically relevant scenarios in
which biomarkers assist with diagnostic dilemmas (Table 2). SCENARIO 1: DISTINGUISHING PRA FROM ACUTE TUBULAR INJURY IN HOSPITALIZED PATIENTS Clinical Dilemma
Both nephrologists and internists frequently face the challenge of differentiating between PRA and acute tubular injury (ATI) when assessing hospitalized patients with AKI. This diagnostic conundrum has been further complicated
by the evolving definitions of the two conditions.19 The term PRA is usually used to indicate minimal-to-no structural damage and ATI to indicate true tubular injury. Thus, discerning between these two causes is important because it can alter patient management. If a diagnosis of PRA is made, intravenous fluids (IVF) and optimizing hemodynamics are the staple clinical therapies. In the case of ATI, however, a patient’s condition would not improve with IVFs and unnecessary fluid administration might actually cause harm.20 Often, the diagnosis is confirmed retrospectively rather than prospectively, because clinicians are able to differentiate between the two causes on the basis of the clinical course and duration of creatinine elevation, as well as response to fluids.21,22 Distinguishing between PRA and ATI becomes even more challenging in the setting of preexisting CKD. This scenario is clinically important because AKI superimposed on CKD is associated with worse clinical outcomes.23 Current Paradigm
Figure 1. Increasing trend in original papers published on renal biomarkers in AKI. The above search was conducted using PubMed (www.ncbi.nlm.nih.gov/pubmed). Mesh terms of AKI and biomarkers were used with the following filters: article type, observational studies, clinical trials; publication dates, 2006–2016 (each year was searched separately); restricted to humans and English language.
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Clinicians often rely on fractional excretion of sodium (FeNa) to diagnose PRA because it has been shown that FeNa,1% is diagnostic of PRA.24 However, many factors can affect the accuracy of FeNa measurement, because its measurement should be in the absence of diuretics, and precede any IVF administration.25 More so, urinary sodium is J Am Soc Nephrol 28: ccc–ccc, 2017
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Table 2. Current paradigm versus proposed paradigm in various clinical settings Clinical Dilemma
Setting
Proposed Paradigm
Current Paradigm
With Novel Markers
With Repurposing of Existing Markers
Hospitalized patients with AKI
PRA versus ATI
Clinical history Serum creatinine FeNa,1% Urine microscopy
Current paradigm + Novel biomarkers: IL-18, NGAL, KIM-1
Current paradigm + Urine microscopy score
AKI in cirrhosis
HRS versus PRA versus ATI
Serum creatinine ICA criteria
Current paradigm + Novel biomarkers: NGAL, LFABP, IL-18
Current paradigm + FeNa,0.1% Urine albumin
AKI in cardiorenal syndrome
Worsening renal function and diuretic management
Serum creatinine Serum BUN
Current paradigm + Novel biomarkers: NGAL, KIM-1, NAG
Current paradigm + Urine albumin Hematocrit Serum albumin Serum protein
AKI in deceased donors
Allocation and discard of kidneys
KDPI Kidney biopsy
Current paradigm + Novel injury biomarkers: NGAL, LFABP Novel repair biomarkers: YKL-40
ATI, acute tubular injury; FeNA, fractional excretion of sodium; IL-18, interleukin 18; NGAL, neutrophil gelatinase associated lipocalin; KIM-1, kidney injury molecule-1; HRS, hepatorenal syndrome; ICA, international club of ascites; LFABP, liver fatty acid binding protein; NAG, N-acetyl-b- D -glucosaminidase; KDPI, kidney donor profile index.
affected by multiple nonrenal factors and FeNa,1% has also been described in the setting of ATI.26 Aside from FeNa, urine microscopy findings have also been shown to be strongly diagnostic of ATI versus PRA. However, microscopy use is limited due to several factors such as availability of microscopes in hospital settings, and the fact that few academic clinicians aside from nephrologists are trained in urine microscopy.27 The performance of urine electrolytes and urine microscopy has not been evaluated in AKI etiologies superimposed on CKD. Proposed Paradigm
The addition of injury biomarkers to the clinical panel could potentially enhance clinician accuracy in distinguishing between PRA and ATI. Injured tubules in ATI elicit inflammatory responses and thus measuring proteins specific to the injured tubule or markers of kidneyspecific inflammation in urine would help distinguish ATI from PRA. Urine conJ Am Soc Nephrol 28: ccc–ccc, 2017
centrations of IL-18, which is a mediator of tubular apoptosis, are significantly higher in patients with ATI and longer duration of AKI compared with those with PRA, transient AKI, urinary tract infections, CKD, and healthy control participants.28–31 This protein is robust to sample processing, handling, and storage conditions and provides high discrimination for ATI.32 In addition to IL-18, urine NGAL measured in the emergency department has also been shown to reliably distinguish ATI from PRA.33 Using adjudicated cases of PRA and ATI, NGAL levels .104 mg/L were able to diagnose ATI with a likelihood ratio of 5.97.34 NGAL is released from renal tubules in response to injury, rises before creatinine, and is not affected by volume depletion or diuretics.35–38 In animal studies, NGAL, along with liver fatty acid binding protein (LFABP), was shown to rise only modestly in volume depletion without histologic damage, as compared with the model of ischemia reperfusion. 39 Lastly, kidney injury
molecule–1 (KIM-1) was extensively expressed in biopsy specimens of patients with ATI, and urine concentrations of KIM-1 distinguished ATI from other causes of AKI. 40 Once again, KIM-1 expression in renal tubules was dramatically increased after ischemia, demonstrating its biologic plausibility as a marker of true kidney injury.41 It has also been shown that urine NGAL improves the clinical model (consisting of multiple baseline characteristics including baseline eGFR, age, and history of diabetes) for predicting worsening AKI, defined as worsening AKIN stage and in-hospital death from an area under the curve (AUC) of 0.62–0.75, as compared with no improvement when adding FeNa to the model (AUC remained at 0.62).42 The use of IL-18, NGAL, LFABP, and KIM-1 in addition to the current paradigm would likely be able to distinguish between PRA and ATI, and ultimately help guide patient management. In addition, the repurposing of existing clinical markers such as urine microscopy Clinical Potential of Biomarkers in AKI
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could be used to differentiate ATI from PRA. For example, the urine microscopy score, which is calculated from the number of granular casts and tubular cells, has been found to be higher in patients with ATI compared with those with PRA and was highly correlated with the urinary levels of IL-18, NGAL, and KIM-1. Patients with a microscopy score $3 (on the basis of the number of granular casts and renal tubular epithelial cells present in urine sample) had 3.5 times the risk of AKI progression defined as worsening AKIN stage and inhospital mortality compared with those with microscopy scores of zero.42 Hence, in addition to novel biomarkers, clinically available biomarkers such as urine microscopy score could also be used to differentiate ATI from PRA. Lastly, biomarker performance improves for diagnosis of AKI in the background of CKD. Urine KIM-1 levels diagnosed AKI more accurately in those with eGFR,60 ml/min per m2 as compared with those with normal baseline kidney function.43 SCENARIO 2: DIFFERENTIAL DIAGNOSIS IN CIRRHOSIS Clinical Dilemma
The diagnostic task of identifying the cause of AKI becomes even more challenging as a patient’s concomitant medical history becomes more extensive. AKI is a common complication in patients with advanced cirrhosis and is associated with significant mortality. In the setting of cirrhosis, the differential diagnosis broadens to include hepatorenal syndrome (HRS) along with PRA and ATI. 44 The ability to make the distinction between HRS and ATI is critical, because treatments differ considerably. HRS may be reversed with restoration of renal perfusion, through vasoconstrictor therapy in addition to intravenous albumin treatment and subsequent liver transplantation. In contrast, patients with ATI should be treated with dialysis and considered for combined liver-kidney transplantation.45–48 4
Current Paradigm
The current criteria to diagnose HRS proposed by the International Club of Ascites (ICA) are presence of cirrhosis and ascites, serum creatinine .1.5 mg/dl without improvement after diuretic withdrawal and restoration of oncotic volume within 48 hours, absence of shock, lack of nephrotoxic agents, and absence of proteinuria, hematuria, and abnormal renal ultrasound.49 Notably, the ICA criteria rely heavily on the use of serum creatinine, but creatinine is especially unsuitable as a marker of kidney injury in the setting of cirrhosis because of low protein intake, loss of muscle mass, and decrease in synthesis secondary to hepatic injury.50 This will lead to false negative serum creatinine values and ultimately delay initiation of therapy. Many of the standard diagnostic tools, such as urine microscopy and FeNa,1%, have also traditionally been ineffective in this situation.51 Proposed Paradigm
In an effort to overcome the diagnostic limitations of serum creatinine, several biomarkers have been investigated in the setting of cirrhosis. Urine NGAL and IL-18 were able to discriminate between ATI and other causes of kidney impairment in patients with cirrhosis.52 The highest levels were found in patients with ATI, followed by HRS and PRA, respectively. 46,53 The combination of several biomarkers was also assessed in diagnosing the type of AKI in patients with cirrhosis.54 Using a cut-off value of 365 ng/ml for NGAL, 85 pg/ml for IL-18, and 25 ng/ml for LFABP, the diagnosis of ATI in patients with cirrhosis was evaluated. Patients with cirrhosis who had at least one biomarker above the cut-off level were five times as likely to have ATI and those with all markers positive were 13 times as likely to have ATI. Biomarker levels were also able to increase the post-test probability of having ATI; for example, having an NGAL level .365 ng/ml raised the pretest probability from 40% to a post-test probability of 76%.54 Fortunately, several clinically available tests have also demonstrated an
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ability to distinguish between HRS and ATI. FeNa has long been marginalized in the setting of cirrhosis as the clinical cutoff of ,1% is universal in these patients. However, its performance has recently been re-evaluated by multiple investigators.51,55,56 Although these studies have utilized different methods of diagnosing HRS, in all of their results, FeNa was significantly lower in cases of HRS than in cases of ATI. The median FeNa in patients with HRS across studies is remarkably uniform, averaging around 0.1%. In the study by Belcher et al., FeNa was lowest in patients with HRS (0.10% [interquartile range (IQR), 0.02–0.23]), and differed significantly from both levels in patients with PRA (0.27% [IQR, 0.13–0.58]), and levels in patients with ATI (0.31% [IQR, 0.12–0.65]).54 In the same study, spot albuminuria was investigated as an injury marker for ATI and was significantly higher in patients adjudicated with ATI (92 mg/dl [IQR, 44–254]) than it was in either PRA (21 mg/dl [IQR, 4–70]) or HRS (24 mg/dl [IQR, 13–129], P,0.001). The AUC identifying ATI at a cut-off of 44 mg/dl was 0.73 (IQR, 0.64–0.83). 54 Until additional markers become clinically available, clinicians should consider incorporating FeNa and proteinuria into their diagnostic and prognostic approaches to joint AKI-cirrhosis cases (Figure 2). Although using this proposed paradigm may help discriminate between ATI and HRS, distinguishing PRA from HRS may be less reliable. SCENARIO 3: MANAGEMENT DECISIONS IN CARDIORENAL SYNDROME Clinical Dilemma
There are further clinical challenges associated with patients with cardiorenal syndrome. Currently, diuretics remain the mainstay of treatment in acute decompensated heart failure.57 However, there exists a frequently vexing clinical scenario of continuing with diuretic use, ignoring a rise in creatinine to attain optimal decongestion and effective perfusion pressure, or decreasing diuretic J Am Soc Nephrol 28: ccc–ccc, 2017
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dose to avoid worsening renal function with diuresis. Current Paradigm
A creatinine rise of .0.3 mg/dl in the setting of decompensated heart failure has been associated with longer hospital stay, higher readmission rates, and mortality.58,59 These elevations in creatinine and BUN, commonly known as “worsening renal function” in the cardiology literature, are associated with aggressive diuresis that is required to restore cardiovascular hemodynamics.60,61 Unfortunately, both creatinine and possibly high diuretic doses are markers rather than drivers of poor outcomes. There is a tremendous lack of evidence to guide this clinical dilemma mainly because the clinical markers such as BUN, creatinine, and urine output do not measure true renal injury.62 This clinical scenario has been further complicated by recent data suggesting significantly lower longterm mortality in patients developing hemoconcentration secondary to more aggressive diuretic dosing, despite a rise in creatinine.63–65 Proposed Paradigm
It has been shown that in patients with chronic heart failure urine NGAL is elevated, indicating a possibility of tubular
damage.66 Similarly, urinary KIM-1 and N-acetyl-b-D-glucosaminidase were elevated in patients with chronic heart failure as compared with healthy controls despite a mean eGFR of 78 ml/min per m2, indicating the presence of tubular injury beyond that captured by creatinine.67 Therefore, low levels of NGAL, N-acetylb-D-glucosaminidase, and KIM-1 might aid in the decision to continue with intense diuretic regimens despite a rise in creatinine. These biomarkers could potentially be evaluated in future studies or in completed trials by examining banked samples such as those from the Diuretic Optimization Strategies Evaluation trial to evaluate renal injury in the setting of different intensities of diuresis.68 Clinically established markers such as urinary excretion of albumin (UAE) may reliably guide diuretic management in patients with decompensated heart failure.69 UAE as defined by 1+ proteinuria on dipstick was associated with greater decline in eGFR over 23 months in patients with moderateto-severe heart failure as compared with patients with negative protein on dipstick.69 In addition to UAE, the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial showed that markers of hemoconcentration were associated
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with worsening renal function (defined by decline in eGFR), but nonetheless lower mortality.63 Hemoconcentration was defined as an increase in at least two of the following: serum albumin, serum total protein, and hematocrit. Therefore, the application of existing clinical markers such as UAE, hematocrit, serum albumin, and serum protein, along with novel biomarkers, might generate a panel to distinguish between causes leading to creatinine rise with the potential for therapeutic diuretic success in decompensated heart failure. SCENARIO 4: ALLOCATION OF KIDNEYS FROM DECEASED DONORS Clinical Dilemma
Over 100,000 patients are awaiting kidney transplants in the United States and unfortunately the number of deceased donor transplants has plateaued around 11,000. This necessitates efforts to salvage all viable procured kidneys.70 Nevertheless, about 2500 procured kidneys from deceased donors are discarded each year. AKI kidneys are discarded at much higher rates secondary to risk of delayed graft function (DGF), risk of increased hospital stay post-transplantation, and concerns of long-term graft failure.71 However, it has been shown that donor AKI, especially in patients who later develop DGF, does not preclude favorable recipient allograft outcomes, and may in fact portend improved 6-month eGFR with increasing AKI severity using AKIN staging.72 Current Paradigm
Figure 2. Guided clinical management in patients with cirrhosis by phenotyping AKI via biomarkers. AKI in patients with cirrhosis with a broad differential including HRS, ATI, and PRA. The use of novel biomarkers along side clinical markers in joint AKI-cirrhosis cases may distinguish between these three etiologies, as well as help guide clinical management. J Am Soc Nephrol 28: ccc–ccc, 2017
To help address these shortcomings via better organ utilization, the national kidney allocation system was revised in December of 2014 to incorporate the kidney donor profile index.73 The kidney donor profile index comprises ten donor characteristics, which include terminal serum creatinine as well as donor age, height, weight, ethnicity, history of hypertension, history of diabetes, cause of death, hepatitis C status, and donation Clinical Potential of Biomarkers in AKI
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after circulatory death. These ten factors generate a score that is presented as percentage risk of graft failure compared with kidneys retrieved in the prior year. However, this panel has its limitations. For example, the use of terminal serum creatinine is especially restrictive around the time of death given that it is affected by multiple nonrenal factors such as altered creatinine kinetics, muscle injury, and administration of fluids, and a single value of creatinine does not fully account for the acute trajectory or chronicity of renal function. Wedge biopsy specimens of donor kidneys obtained at time of procurement are also not accurate, can overestimate the amount of glomerulosclerosis, and are suboptimal for the diagnosis of ATI.74 Consequently, there remains a compelling need for more reliable tools to assess donor kidney quality in the presence of AKI. Proposed Paradigm
To delineate which donor AKI kidneys will have poor versus favorable outcomes in recipients, both kidney injury and repair biomarkers have been evaluated in deceased donor urine. Two injury biomarkers, NGAL and LFABP, provided modest incremental value in predicting worse recipient 6-month eGFR, especially in those without DGF.75 On the contrary, a repair phase protein known as YKL-40 was associated with less DGF and better long-term eGFR.76 Preclinical studies on YKL-40 have generated strong support for its cytoprotective and reparative roles in the setting of kidney injury.77 Among those donor kidneys with clinically defined injury before transplantation, the ones with the greatest urinary YKL-40 levels have the best chance of successfully regaining function.76 The use of a recovery marker like YKL-40 in assessing deceased donor kidneys has immense potential, because it could increase the number of transplanted AKI kidneys by feasibly decreasing discard rates among AKI kidneys and providing more wait-listed patients with the opportunity to receive a viable kidney. 6
DISCUSSION Use of Biomarkers in Clinical Management
Although novel biomarkers can address diagnostic delay in AKI and differentiate between PRA and ATI, further research is needed to advance biomarkers to bedside. As a strategy, a recent clinical trial used plasma NGAL for enrollment of participants in the assessment of early versus late initiation of renal replacement therapy for AKI.78 In addition, the FDA approved the first AKI point-of-care biomarker device, NephroCheck. 79 It measures urinary levels of tissue inhibitor of metalloproteinase-2 and IGFbinding protein 7, which are cell cycle arrest biomarkers. Using NephroCheck, the positive predictive value to diagnose stage 2 or 3 AKI as defined by KDIGO is 49% and the negative predictive value is 97%.80–82 The effect of NephroCheck will be determined once it is adopted into clinical practice, but it does offer the ability to identify risk of imminent AKI in critically ill patients and potentially identify high-risk patients for enrollment in clinical trials. However, as emphasized by the ADQI, perhaps the combination of biomarkers of kidney damage and kidney function, rather than a biomarker representation of a single biologic process such as cell cycle arrest, will be needed to facilitate the diagnosis of AKI.83 This concept was validated in 345 children undergoing cardiopulmonary bypass, where the combination of functional (cystatin C) and damage (NGAL) biomarkers was superior than change in serum creatinine in predicting severity and persistence of AKI.84 More so, the use of biomarkers without proper clinical risk stratification will yield to suboptimal biomarker performance. To overcome this challenge, the renal angina index was established to risk-stratify patients with AKI on the basis of the severity of the clinical setting and the percentage change in creatinine clearance. This strategy was validated in a pediatric population where the incorporation of biomarkers into the renal angina index improved net reclassification of predicting AKI.85
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Conclusion and Future Direction
There may be successful biomarkers among the current candidates, but their full potential cannot be realized when they are compared with the confining indicator that is serum creatinine. It is also possible that AKI is a syndrome with each setting having a unique set of case-mix and pathophysiology with a distinctive set of clinical decisions, necessitating an individualized panel of biomarkers for each setting. In an effort to move away from the sole use of creatinine in diagnosing renal injury, the National Institutes of Health has initiated the Kidney Precision Medicine Project which is a mission toward obtaining and assessing kidney biopsy specimens to create a kidney tissue atlas and a movement toward tissue-driven definitions of renal injury and disease.86 After this hopeful transformation from creatinine-defined to tissue-defined renal injury, the field of nephrology will likely develop a deeper understanding of kidney injury biomarkers, which could lead physicians to incorporate them routinely into clinical practice and better personalize patient care.
ACKNOWLEDGMENTS C.R.P. is supported by National Institutes of Health (NIH) grants RO1HL085757 and K24DK090203. S.G.M. is supported by the T32 training grant (T32DK007276) from the NIH.
DISCLOSURES None.
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