N e u t ro p h i l g e l a t i n a s e associated lipocalin (NGAL) as a Biomarker for Early Acute Kidney Injury

Douglas Shemin,
KEYWORDS  NGAL  Acute kidney injury  Acute tubular necrosis
MD*,

Lance D. Dworkin,

MD

For many years, an acute and potentially reversible decline in the glomerular filtration rate (GFR) was termed acute renal failure (ARF); acute renal failure was classically thought to be attributable to prerenal factors (an actual or effective decline in the extracellular volume), postrenal factors owing to urinary obstruction, or intrarenal factors owing to a pathologic process occurring in 1 of the 4 loci in the nephron: the glomerulus, the renal vasculature, the interstitium, and the renal tubules.1 Although hundreds of causes of ARF have been described, in clinical observational studies, the vast majority of patients with ARF were found to have 1 of 2 etiologies: prerenal failure, and tubular injury owing to ischemic or nephrotoxic factors, or ATN.2,3 In the past several years, there have been 2 major changes in the description and definition of ARF. First, the term ARF itself has been discarded in the nephrology literature; the term for an acute and potentially reversible decline in the GFR is now called acute kidney injury (AKI). The term kidney more directly describes the location of the pathologic process than renal, and the term injury is more comprehensive than failure, and includes even small declines in the GFR. This terminology change is based on data that strongly suggest that even tiny increases in the serum creatinine level over baseline values are associated with clinically significant morbid and mortal outcomes, including progression to chronic kidney disease (CKD). In more than 80,000 elderly patients studied after a myocardial infarction, for example, patients whose serum creatinine levels rose by 0.1 mg/dL over the course of a hospitalization had a 14% higher mortality rate and a 45% higher rate of progression to end-stage renal disease (ESRD) than patients whose serum creatinine level did not change.4

The authors have nothing to disclose. Division of Kidney Diseases and Hypertension, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI 02903, USA * Corresponding author. E-mail address: Dshemin@lifespan.org Crit Care Clin 27 (2011) 379389 doi:10.1016/j.ccc.2010.12.003 criticalcare.theclinics.com 0749-0704/11/$ see front matter 2011 Elsevier Inc. All rights reserved.

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The second change has been in the definition of AKI, which historically had been defined in multiple different studies in multiple different ways. In 2002, a consensus panel devised the RIFLE classification, which divided declines in renal function over at least a 7-day period into 5 categories: Risk, Injury, Failure, Loss, and End Stage.5 The RIFLE criteria were further modified by another consensus panel, which devised the Acute Kidney Injury Network (AKIN) criteria, published in 2007. This defined AKI as an abrupt (within 48 hours) reduction in kidney function; reduction in kidney function was further defined either as an absolute increase in the serum creatinine by 0.3 mg/dL (25 mm/L), or by 50% of the baseline value, or oliguria, with a urine output less than 0.5 mL/kg/h for at least 6 hours in the setting of appropriate volume expansion. AKI is subdivided into 3 stages, according to severity.6 The AKIN criteria, like the RIFLE criteria and the many idiosyncratic criteria for AKI in the past, relies heavily on the serum creatinine level as a biochemical indicator of renal function. The change in the serum creatinine, however, cannot differentiate between changes in renal function owing to volume depletion, hemodynamic changes in renal perfusion, urinary obstruction, or actual renal injury, and there is also good evidence that the change in creatinine may not occur until hours or days after the onset of renal injury.7 The blood urea nitrogen (BUN) level is even less reliable than the serum creatinine level in diagnosis; it is dependent upon, among other factors, dietary protein intake, hepatic function, and renal tubular avidity for sodium. Urinary sodium, fractional excretion of sodium, and urinary microscopic findings do not reliably predict AKI.8
BIOMARKERS IN THE DIAGNOSIS OF AKI

These concerns about diagnostic accuracy in testing for AKI have led to efforts to identify reliable biomarkers for AKI, much as troponin is a biomarker for acute coronary syndrome. The ideal biomarker for AKI is one that can be objectively and reliably measured, is sensitive and specific in diagnosis of AKI, is able to detect AKI at or near the onset of injury, is predictive of severity, and can be used to monitor the effects of treatment.9 Of all of these characteristics, the most important is early detection; a large number of experimental therapies for AKI seem to be most beneficial when administered very early in the course of injury, before the onset of a rise in the serum creatinine.7 Based on studies in experimental models of AKI and in humans, a number of biomarkers have been proposed: cystatin C, soluble tumor necrosis factor (TNF) receptors, N-acetyl-beta-D-glucosaminidase, kidney injury molecule 1, isoform 3 of the sodium-hydrogen exchanger, interleukin (IL)-16, IL-18, matrix metalloproteinase-9, and neutrophil gelatinaseassociated lipocalin (NGAL).9 This review focuses on the biomarker NGAL and its potential utility in the diagnosis, prognosis, and treatment of AKI. NGAL is a 25-kD protein that was originally described covalently bound to matrix metalloprotein-9 (MMP-9) in animal neutrophils.10 It has a barrel-shaped structure with a hydrophobic calyx that binds small, lipid, and lipophilic molecules.11 NGAL is synthesized in renal tubular, intestinal, hepatic, and pulmonary tissue, and synthesis is markedly upregulated in tissue injury. NGAL synthesis is also increased in cancer: NGAL binds to MMP-9, preventing MMP degradation, and the resulting increase MMP-9 in activity promotes cancer progression.12 Under physiologic conditions, NGAL is expressed in low concentrations in kidney, lung, and gastrointestinal tissue. Circulating NGAL is filtered by the glomerulus, and reabsorbed in the proximal tubule. It is secreted in low concentrations by the thick ascending limb of the renal tubule and

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the normal urinary level of NGAL is very low (<5 ng/mL).13 In proximal tubular injury, NGAL synthesis is increased and reabsorption may decrease so that urinary levels increase.12 In distal tubular injury there is increased distal renal tubular expression and synthesis of NGAL and NGAL secretion increases, increasing urinary levels as well.14 NGAL is protease resistant15 and does not seem to be degraded or metabolized after synthesis and secretion into the tubule lumen. NGAL is synthesized by normal intestinal, hepatic, and pulmonary tissue and can be detected in the plasma; the normal plasma level, in healthy adults, is 50 to 90 ng/mL.16,17 The kidney is not considered to be a significant source for plasma NGAL. In one experimental study of unilateral renal ischemia, NGAL was not immediately present in the renal vein or the circulation, but was present in the ureter of the ischemic kidney.14 In AKI, plasma NGAL levels rise, either related to concomitant hepatic, pulmonary, or intestinal tissue injury, coupled with decreased glomerular filtration of NGAL.
NGAL AS A PREDICTOR OF THE DEVELOPMENT OF AKI

Beginning about 10 years ago, experimental studies demonstrated that NGAL gene expression was markedly and immediately upregulated after renal ischemia/reperfusion injury in mice,18 after ischemia/reperfusion injury and mercuric chloride administration in rats,19 after cisplatin-induced renal injury in mice,15 and in cultured human proximal tubular cells subjected to hypoxic injury.15 In both mouse and rat models of acute kidney injury, NGAL has been shown to be detectable within an hour after onset of injury, which precedes the urinary appearance of beta-2 microglobulin and many other markers of tubular injury.15 Clinical studies have confirmed these experimental findings. In 2005, a landmark trial by Mishra and colleagues13 examined 71 pediatric patients undergoing openheart surgery and cardiopulmonary bypass. Urinary and plasma samples of NGAL were sequentially measured, and their values were compared with conventional criteria for the diagnosis of AKI, defined as a 50% increase in the serum creatinine level. Twenty percent of the children developed conventional clinical evidence for AKI within 24 to 72 hours after cardiopulmonary bypass. Elevations of both the urine and plasma NGAL level correlated very strongly with the subsequent development of AKI. In those patients in whom 50% increases in serum creatinine eventually developed, urinary NGAL levels significantly rose (to values over 100 times the baseline value) and serum levels significantly rose, to values 10 times the baseline value, both within 2 hours of cardiopulmonary bypass. In addition to these data, there are now a large number of clinical trials that have examined the predictive value of NGAL in the urine and plasma, in pediatric and in adult populations, as correlated with the subsequent development of clinically evident AKI (usually defined, per the AKIN criteria, as a 50% increase in the serum creatinine level or an arithmetic increase of at least 0.3 mg/dL over a 48-hour period) in patients at risk for AKI. Rather than using a strict cutoff for an abnormal urinary or serum level of NGAL, these studies tend to measure sensitivity and specificity for a wide variety of threshold values with an area under the receiver operating characteristic curve (AUC ROC). An AUC ROC value of 0.90 to 1.00 may indicate excellent, 0.80 to 0.89 good, 0.70 to 0.79 fair, 0.60 to 0.69 poor, and 0.50 to 0.59 no useful performance for discrimination of an outcome being evaluated.20 The following tables summarize these studies on the predictive value of one NGAL measurement on the subsequent risk for AKI, using the AKIN or RIFLE criteria for AKI. Tables 1 and 2 list studies examining urinary NGAL levels; Table 1 in adult populations, and

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Table 1 Sensitivity and specificity of elevations in urinary NGAL levels in predicting development of AKI: adult populations References Wagener et al,21 2006 Parikh et al,22 2006 Koyner et al,23 2008 Xin et al,24 2008 Bennett et al,25 2008 Portilla et al,26 2008 Ling et al,27 2008 Nickolas et al,28 2008 Tuladhar et al,29 2009 Siew et al,30 2009 Makris et al,31 2009 McIllroy et al,32 2010 Hall et al,33 2010 Yang et al,34 2010 Martensson et al,35 2010 Clinical Setting Cardiothoracic surgery patients Kidney transplant recipients Cardiothoracic surgery Cardiothoracic surgery Cardiothoracic surgery Cardiothoracic surgery Cardiac catheterization Emergency room patients Cardiothoracic surgery Critically ill adults Multiple trauma Cardiothoracic surgery Kidney transplant recipients Hospitalized inpatients Patients with septic shock Number of Patients 81 63 72 33 196 40 40 635 50 451 31 426 91 256 65 Sensitivity 73% 90% 49% 71% 82% 100% 77% 90% 93% Not reported 91% 76% 77% 88% Not reported Specificity 78% 83% 79% 73% 90% 100% 71% 99% Not reported Not reported 95% 34% 74% 81% Not reported AUC ROC (95% CI) 0.80 (0.571.03) 0.90 (0.700.92) 0.69 (0.570.82) 0.88 0.93 1.00 0.73 (0.540.93) 0.95 (0.881.00) 0.96 (0.91.0) 0.71 (0.630.78) 0.98 (0.820.98) 0.61 (0.540.68) 0.81 (0.700.92) 0.88 0.67

Abbreviations: AKI, acute kidney injury; AUC ROC, area under the receiver operating characteristic curve; CI, confidence interval; NGAL, neutrophil gelatinase associated lipocalin.

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Table 2 Sensitivity and specificity of elevations in urinary NGAL in predicting development of AKI in a 48-hour period: pediatric studies References Mishra et al,13 2005 Hirsch et al,36 2007 Zappitelli et al,37 2007 Clinical Setting Pediatric cardiopulmonary bypass Pediatric cardiac catheterization Pediatric critical care Number of AUC ROC Patients Sensitivity Specificity (95% CI) 71 100% 98% 0.99

91 150

73% 77%

100% 72%

0.92 0.78 (0.620.95)

Abbreviations: AKI, acute kidney injury; AUC ROC, area under the receiver operating characteristic curve; CI, confidence interval; NGAL, neutrophil gelatinaseassociated lipocalin.

Table 2 in pediatric populations. Tables 3 and 4 list studies examining serum NGAL levels; Table 3 in adult populations and Table 4 in pediatric populations. Clinical data on the efficacy of urinary or plasma NGAL levels in prediction of AKI were recently summarized in a large meta-analysis.13 This analysis suggested that in critical care settings, urinary NGAL has a slightly higher predictive value than serum NGAL. Studies in pediatric patients seem to yield higher sensitivities, specificities, and AUC ROC values than studies in adults, and studies in which AKI resulted from a single

Table 3 Sensitivity and specificity of elevations in serum NGAL levels in predicting development of AKI in a 48-hour period: adult studies References Clinical Setting Number of Patients Sensitivity 72 100 80 Specificity AUC ROC (95% CI)

Koyner Cardiothoracic et al,23 2008 surgery Haase-Fielitz Cardiothoracic et al,38 2009 surgery Tuladhar Cardiothoracic et al,29 2009 surgery

Not Not 0.54 reported reported (0.400.67) 79% 80% 73% 78% 67% 100% 0.80 (0.630.96) 0.85 (0.730.97) 0.91

Malyszko Diabetics 91 et al,39 2009 undergoing cardiac catheterization Constantin Adult ICU patients et al,40 2009 Cruz et al,16 2010 Adult ICU patients 88 301 59 65 83

82% 73% 68%

97% 81% 80%

0.92 (0.85 0.97) 0.78 (0.650.90) 0.79

Niemann Liver transplant et al,41 2009 recipients Martensson Patients with septic et al,35 2010 shock Bagshaw Critically ill patients et al,42 2010

Not Not 0.67 reported reported Not Not 0.71 reported reported

Abbreviations: AKI, acute kidney injury; AUC ROC, area under the receiver operating characteristic curve; CI, confidence interval; ICU, intensive care unit; NGAL, neutrophil gelatinaseassociated lipocalin.

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Table 4 Sensitivity and specificity of elevations in serum NGAL levels in predicting development of AKI in a 48-hour period: pediatric studies References Mishra et al,13 2005 Dent et al,43 2007 Wheeler et al,17 2008 Clinical Setting Pediatric cardiopulmonary bypass Pediatric cardiothoracic surgery Pediatric critical care Number of Patients 71 Sensitivity 70% Specificity 94% AUC ROC (95% CI) 0.91

120

84%

94%

0.96 (0.940.99) 0.68 (0.560.79)

143

86%

39%

Abbreviations: AKI, acute kidney injury; AUC ROC, area under the receiver operating characteristic curve; CI, confidence interval; NGAL, neutrophil gelatinaseassociated lipocalin.

nephrotoxic injury (for example, hypotension during cardiopulmonary bypass) seem to show a higher predictive effect of urinary or serum NGAL than studies in which patients had multiple and prolonged nephrotoxic injury (for example, in intensive care units [ICUs] in the setting of septic shock). Urinary or serum NGAL values are most predictive when the diagnosis of AKI is based on more severe declines in the GFR. In one study, if AKI was defined as an increase in the serum creatinine of more than 25% above baseline, the mean AUC ROC value was 0.65; when AKI was defined as an increase in the serum creatinine of more than 50% above baseline, the mean AUC ROC was 0.79.38 In addition, and very importantly, the predictive value of an NGAL increase is greatest in patients whose kidney function is normal at baseline. In one large prospective trial of patients undergoing cardiac surgery, urinary NGAL did not significantly change in patients with stage III, IV, and V chronic kidney disease (CKD) and a baseline estimated GFR of lower than 60 mL/min, who developed AKI. In contrast, it changed significantly in patients who had a preoperative estimated GFR higher than 90 mL/min and developed AKI.32 In other series of patients with established CKD or chronic renal allograft dysfunction44 and in heart transplant recipients,45 the serum NGAL level inversely correlated with the GFR, confirming a high baseline level of NGAL in individuals with established CKD. There is some variability among these studies regarding the method used to measure the urinary or serum NGAL level. Most investigators use an enzyme-linked immunosorbent (ELISA) assay; a minority use an immunoblot technique. Individual studies varied in the level of NGAL that was associated with injury. With the ELISA tests, a urinary NGAL level of >150 ng/mL seemed to correlate best with the subsequent development of AKI, with a slightly lower cutoff (>150 ng/mL) for pediatric populations43; plasma levels of >100 ng/mL seemed to correlate with subsequent development of AKI.16 Finally, and as the above tables indicate, virtually all the studies examining NGAL as a marker for the development of AKI have been performed in critical care settings, particularly after cardiopulmonary bypass, or in the setting of intra-arterial contrast administration. There are a handful of exceptions: one small recently published study showed that urinary NGAL excretion predicted AKI in patients with solid tumors receiving cis platinum46 and another study showed that urinary NGAL levels predicted AKI in a multicenter cohort of children with diarrhea-associated hemolytic uremic syndrome.47 There is some evidence that NGAL might play an important role in the

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diagnosis of delayed graft function following renal transplantation. In a pediatric transplant study, an increase in NGAL expression in renal tissue detected within 1 hour of renal perfusion after implantation was strongly correlated with the subsequent elevation of the serum creatinine after transplantation and the clinical development of delayed graft function.48 Other studies confirm that urinary21,32 and plasma49 elevations in NGAL levels after renal transplantation correlate with the subsequent development of delayed graft function.
NGAL AS A PREDICTOR OF THE SEVERITY OF AKI

Most of the clinical trials summarized previously are inadequately powered to evaluate the predictive value of NGAL levels in determining the risk for requiring renal replacement therapy (RRT) or the risk of mortality associated with AKI; RRT rates and mortality rates are too low in these series. This caveat notwithstanding, it appears that there is a relationship between the magnitude of the elevation in NGAL levels and the severity of AKI. In 3 studies of plasma NGAL measurements, the initial plasma NGAL level directly predicted the severity of AKI, as assessed by the RIFLE and AKIN criteria.16,38,40 In a study of 301 adults admitted to a single ICU, mean peak plasma NGAL levels were 162 ng/mL in patients who did not develop AKI, and 230 ng/mL, 332 ng/mL, and 804 ng/mL in patients who met the criteria for risk, injury, and failure respectively in the RIFLE classification scheme.16 A study of 88 ICU patients showed that no patients with a preliminary plasma NGAL level of lower than 155 ng/mL needed RRT for AKI; 15% of patients with a plasma NGAL level higher than 155 ng/mL required RRT.40 A meta-analysis published in 2009 suggested that early urinary and plasma NGAL levels correlated directly with requirement for RRT in AKI and with inhospital mortality.43 Tables 5 and 6 summarize studies that have examined the relationship between NGAL levels in the plasma and urine, in patients who required RRT for AKI as compared with patients who did not require RRT, and in patients who died with AKI as compared with patients who survived.

Table 5 Mean urinary levels of NGAL and outcomes (RRT and death) in patients with AKI Study Bennett et al,25 2008 Clinical Setting 196 patients undergoing cardiothoracic surgery 451 critically ill adults NGAL Measurement Urine NGAL 2 hours after cardiopulmonary bypass Urine NGAL within 24 hours of admission to ICU Mean (or Median) NGAL Levels RRT data (in ng/mg creatinine) 5081 320 with RRT 1850 197 no RRT (P<.01) Mortality data: not reported RRT data (in ng/mg creatinine) 548 (IQR 1564665) with RRT 61 (IQR 17232) no RRT (P<.001) Mortality data: 223 (IQR 361074) dead 56 (IQR 16195) alive (P<.001) RRT data (in ng/mg creatinine) 423 (2471088) with RRT 143 (28283) no RRT (P<.03) Mortality data: 418 (2011068) dead 106 (30883) alive (P 5 .078)

Siew et al,30 2009

Bagshaw et al,42 2010

83 adults in intensive care units

Urine NGAL within 12 and 24 hours of admission to ICU

Abbreviations: AKI, acute kidney injury; ICU, intensive care unit; IQR, interquartile range; NGAL, neutrophil gelatinaseassociated lipocalin; RRT, renal replacement therapy.

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Table 6 Mean plasma levels of NGAL and outcomes (RRT and death) in patients with AKI Study Bagshaw et al,42 2010 Clinical Setting 83 adults in intensive care units NGAL Measurement Urine NGAL within 24 and 48 hours of admission to ICU Mean (or Median) NGAL Levels RRT data (in ng/mL) 445 (336869) with RRT 269 (133401) no RRT (P 5 .051) Mortality data: 496 (192750) dead 264 (122437 alive (P 5 .019)

Abbreviations: AKI, acute kidney injury; ICU, intensive care unit; NGAL, neutrophil gelatinaseassociated lipocalin; RRT, renal replacement therapy.

LIMITATIONS OF NGAL

A number of limitations to the value of NGAL as a predictor of AKI and its severity remain. As discussed previously, NGAL levels appear to be most sensitive and specific in predicting AKI in studies of homogeneous patients with single, acute, easily identifiable, and predictable nephrotoxic insults, such as cardiopulmonary bypass or intravenous contrast. NGAL appears to be less sensitive and specific in more heterogeneous cohorts with multifactorial causes for AKI. It is also unclear whether NGAL levels can differentiate potentially reversible causes of AKI such as prerenal azotemia from more severe kidney injury. NGAL levels seem to predict AKI in children with better accuracy than with adults, who make up the vast majority of patients with AKI. Plasma NGAL levels are also higher in patients with underlying CKD,32 and most of the clinical trials of NGAL discussed earlier excluded patients with CKD from analysis. This exclusion is an important confounding issue, because CKD is a major risk factor for AKI, particularly in the critical care setting. Of note, in a recent prospective study of more than 25,000 patients with AKI, over 30% had underlying CKD.50 Baseline plasma NGAL levels are higher in patients with malignancies and systemic bacterial infections and these may be confounding factors. Urinary NGAL levels may also be elevated in the setting of urinary tract infections, and in one study levels were even used to diagnose early urinary tract infections in the absence of AKI.51 Finally, most studies of NGAL have used research laboratorybased enzyme-linked immunosorbent assays (ELISAs) with variable and potentially lengthy turnaround times. Because NGAL elevations need to be detected early if they are to have any clinical benefit, assays need to provide results rapidly and in a point-of-care setting. Rapid, point-of-care assays for urinary and plasma NGAL are now available11 but have not been tested in large clinical trials.

SUMMARY

Based on the information to date, although limitations in the accuracy of NGAL in predicting AKI persist, the preponderance of published studies demonstrate that NGAL, when measured in the plasma and in the urine, is a reliable biomarker for the subsequent development of clinically apparent AKI, much as troponin is a biomarker for the development of acute coronary syndrome. Significant increases in NGAL levels above baseline antedate other clinical markers of AKI such as the rise in the serum creatinine level, by 24 to 48 hours. A less extensive data set suggests that the magnitude of the NGAL elevation, in the plasma and urine, correlates with the severity of AKI, with the eventual requirement for RRT, and the risk of mortality.

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Studies of NGAL in AKI need to be conducted in larger series involving multiple centers and in settings other than cardiothoracic ICUs. The NGAL assays need to be standardized assays and methods developed to provide results rapidly and at the point of care. Finally, early detection of AKI is only important and clinically relevant if it facilitates interventions that can improve outcomes. If very early detection of AKI, via the measurement of plasma or urinary NGAL, can be followed by effective treatment to abort the development or limit the severity of AKI, and therefore decrease the rate of RRT, length of hospitalization stay, and/or mortality risk, NGAL measurement will become a critically important diagnostic tool in critical care medicine, pediatrics, and surgery. Those trials have yet to be performed.
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