Neutrophil gelatinase associated lipocalin in acute kidney injury.

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Neutrophil Gelatinase Associated Lipocalin in Acute Kidney Injury

W. Frank Peacock IV, MD 1,2 Alan Maisel, MD 3 Jieun Kim, MD 4 Claudio Ronco, MD 5 Baylor College of Medicine, Houston, TX; 2Ben Taub General Hospital, Houston, TX; 3Department of Cardiology, VA San Diego Healthcare System, San Diego, CA; 4Department of Emergency Medicine, The Cleveland Clinic, Cleveland, OH; 5 Department of Nephrology, Dialysis, and Transplantation, International Renal Research Institute, San Bortolo Hospital, Vicenza, Italy 1

DOI: 10.3810/pgm.2013.11.2715

Abstract

Background: Neutrophil gelatinase-associated lipocalin (NGAL) is a member of the lipocalin family of proteins. Usually, NGAL is produced and secreted by kidney tubule cells at low levels, but the amount produced and secreted into the urine and serum increases dramatically after ischemic, septic, or nephrotoxic injury of the kidneys. The purpose of our review article is to summarize the role of NGAL in acute kidney injury (AKI), emergent, and intensive care. Methods: A PubMed search was performed (only English-language articles concerning human subjects were considered) using each of the following search term combinations: neutrophil gelatinase-associated lipocalin OR NGAL and acute kidney injury OR AKI; cardiac surgery; heart failure OR cardiology; intensive care; emergency department OR emergency medicine; nephropathy OR nephrotoxicity and transplantation. Results: The results of our search yielded 339 articles. Of the 339 articles, 160 were eligible for review based on the predefined criteria for inclusion. Conclusion: Based on the evidence reviewed, it is clear that patient NGAL level is an appropriate, sensitive, and specific early biomarker of AKI caused by a variety of different etiologies. It is advised that a multidisciplinary group of experts come together to make recommendations and propose a consensus of clinical procedures to advance the most efficacious NGAL monitoring protocol for early detection and treatment of patients with AKI. Keywords: acute kidney injury; neutrophil gelatinase-associated lipocalin; renal failure; renal dysfunction

Background

Correspondence: W. Frank Peacock IV, MD, Ben Taub General Hospital, 1504 Taub Loop Road, Houston, TX 77030. Tel: 713-873-2626 E-mail: [email protected]

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Neutrophil gelatinase-associated lipocalin (NGAL) is a member of the lipocalin family of proteins. Generally, NGAL is produced and secreted by kidney tubule cells at low levels, but the amount produced and secreted into the urine and serum increases dramatically after ischemic, septic, or nephrotoxic injury of the kidneys.1–7 Evidence from experimental and human studies indicate that urinary NGAL is derived from increased synthesis and release from the distal nephron in the setting of a rapid response to acute kidney injury (AKI), previously referred to as acute renal failure.4–7 Currently, there is no method or laboratory test that detects kidney injury close to the time of onset.8 The detection of worsening renal function is usually achieved by serial measurements of patient serum creatinine levels, even though rising trends may occur late in the process of end organ dysfunction.9 Hence, elevated serum creatinine level is an insensitive and late marker for AKI.10 Locating noninvasive parameters that can be used for monitoring active lesions and predicting long term prognosis would potentially be beneficial for individual intervention and therapy establishment.11

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NGAL in Acute Kidney Injury

Identifying underlying AKI early in its course may prevent the development of worsening renal function,9 and the use of NGAL level to detect early pathophysiologic processes, previously undetectable by conventional markers, could be of considerable clinical importance.9 After the onset of AKI, patient urine and plasma NGAL levels increase rapidly—in as little as 2 hours preceding a detectable increase in serum creatinine level of 12 to 24 hours.7,12,13 Increased NGAL level at hospitalization has been found to be highly predictive of patient subsequent development of AKI.14 The use of NGAL level as a novel serum or urine biomarker of AKI has been studied in the setting of postcardiac surgery,7 cardiac catheterization, after contrast-induced nephropathy (CIN),6 hemolytic uremic syndrome, kidney transplantation,7,15–19 chronic kidney disease (CKD), secondary to autoimmune disease,20 and polycystic and proteinuric diseases.21–23 In these fields, patient NGAL level has been shown to be a useful, sensitive, specific, noninvasive, and highly predictive biomarker for AKI.

Methods

On May 14, 2012, a PubMed search was performed (only English-language articles concerning human subjects were considered) using the each of the following search term combinations: neutrophil gelatinase-associated lipocalin OR NGAL and acute kidney injury OR AKI; cardiac surgery; heart failure OR cardiology; intensive care; emergency department OR emergency medicine; nephropathy OR nephrotoxicit and transplantation. The abstract of each article was reviewed to determine whether it contained the words NGAL or neutrophil gelatinase associated lipocalin, and that the studies were only clinical trials (not reviews) with $ 50 human patients (no animal studies), and used a defined standard diagnostic criteria for renal injury (eg, estimated glomerular filtration rate [eGFR], creatinine, pulmonary arterial hypertension, or inulin clearance, risk, injury, failure, loss, and end-stage kidney disease [RIFLE] criteria). As might be expected, some articles were found to fall into multiple categories. To avoid redundancy, manuscripts that were found in multiple categories are discussed in the categories where they seem most appropriate; this decision was based on the authors’ judgment and not according to any specific a priori criteria. When the results of searches yielded , 5 eligible articles, each article was briefly detailed. When the results of searches yielded $ 5 eligible articles, they were summarized collectively.

Results

The results of our search yielded 339 articles: 103 NGAL and acute kidney injury OR AKI; 41 NGAL and cardiac surgery;

20 NGAL and heart failure OR cardiology; 24 NGAL and intensive care; 5 NGAL and emergency department OR emergency medicine; 123 NGAL and nephropathy OR nephrotoxicity; and 22 NGAL and transplantation. Of the 339 articles, 160 were unique articles that were eligible for review based on the predefined criteria for inclusion in our review (Table 1). A total of 56 studies were related to NGAL and acute kidney injury OR AKI8,9,12,14,17,19,24–73; 31 related to NGAL and cardiac surgery7,16,19,31,33,35,45,47–51,54,55,57,58,62,64,74–86; 8 related to NGAL and cardiology or heart failure9,52,61,87–91; 18 related to NGAL and intensive care14,28,29,36–39,42,46,48,49,57,76,78–80,82,84; 4 related to NGAL and emergency department OR emergency medicine8,14,39,92; 25 related to NGAL and nephropathy/nephrotoxicity6,17,22,23,27,30–32,53,56,59,60,62,63,65,93–102; and 18 related to NGAL and transplantation.15,33,34,40,41,43,44,53,74,103–111

Discussion Acute Kidney Injury

Acute kidney injury, characterized by an acute decline in kidney function, often occurs in hospitalized patients. Although it is sometimes reversible, AKI is associated a higher incidence of morbidity and mortality due to increased risk of sepsis, bleeding, and cardiac events, as well as prolonged hospital stay and need for dialysis. The results of our search of the literature identified 56 clinical trials investigating the role of patient NGAL level as an early biomarker in the detection of AKI.8,9,12,14,17,19,24–73,112 Neutrophil gelatinase–associated lipocalin has been shown to be an early marker of AKI in a wide spectrum of clinical conditions,12,24–30,66,67,112 including postcardiac catheterization,31 cardiac surgery, and cardiopulmonary bypass (CPB)17,19,33,35,45,47,50,51,54,55,57,58,60,62,64,70,71; coronary artery disease (CAD)52,61; heart failure9,52; treatment in an intensive care unit (ICU)38,42,46; in trauma patients8,14,68; patients with toxic AKI and CIN17,31,36,39,60,63; CKD32,53,56,59; renal allograft and transplantation36,44,53; post liver transplantation40,106,110; and post heart and lung transplantation.33,41,74 Moreover, patient NGAL level has been shown to be an early predictor of clinical outcomes in AKI,12,25,34,37,43,67–69,72,73 enabling the clinician to distinguish AKI from other conditions, and it is quantitatively correlated with the severity of AKI.48,49,65

Intensive Care

Study findings show that sepsis contributes from 30% to 50% of all AKI encountered in critically ill patients113–117 and is an important causative factor of AKI.118 Patients with septic AKI typically have a poorer prognosis, with lower survival rates compared with AKI of nonseptic origin.115,119–121 In an


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attempt to elucidate early biomarkers of AKI in sepsis and other intensive care conditions, the role of NGAL has been investigated.38,39,42,46,122,123 Early detection and treatment of patients with AKI may reduce the need for renal replacement therapy (RRT).84,124 In our search of the literature, we identified 18 clinical trials in which the role of NGAL was investigated as an early biomarker in the detection of AKI in critically ill patients. Several studies have been conducted to estimate the diagnostic accuracy of plasma NGAL level for early detection of AKI and the need for RRT in adult ICU patients.38,42,79,84 The studies demonstrated that patient peak plasma NGAL concentrations increased with worsening AKI severity. Plasma NGAL level was also found to be a useful early marker for AKI when the timing of renal insult was largely unknown, and it allowed the diagnosis of AKI # 48 hours prior to a clinical diagnosis based on AKI consensus definitions.38 Urinary and plasma NGAL levels were higher at enrollment among patients who developed AKI within 48 hours compared with those who did not.46 Additionally, patient urinary and plasma NGAL levels predicted the need for RRT and correlated with AKI severity, the extent of systemic inflammation, and 28-day mortality.36–38,42,79,84 In a study of 632 consecutive patients,122 the development of AKI based on RIFLE classification during the first week of ICU stay was predicted, similar to serum creatininederived eGFR, when plasma and urine NGAL levels were measured on admission to the ICU. The authors found that patient plasma and urine NGAL levels at ICU admission were significantly related to AKI severity.122 Table 1. Literature Search Results Search Terms

Total Studies Found

Unique Studies That Met Criteria for Review Inclusion

NGAL and acute kidney injury or AKI

103

56

NGAL and cardiac surgery

41

31

NGAL and heart failure or cardiology

20

8

NGAL and intensive care

24

18

NGAL and emergency department or emergency medicine

5

4

NGAL and nephropathy or nephrotoxicity

123

26

NGAL and transplantation

22

18

Total

339

160

Abbreviations: AKI, acute kidney injury; NGAL, neutrophil gelatinaseassociated lipocalin.

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In a study of 83 critically ill patients with AKI,39 it was noted that patients with septic AKI had a higher incidence of comorbid diseases and that septic AKI was associated with higher patient serum NGAL and urinary NGAL levels at enrollment compared with patients with nonseptic AKI. Plasma NGAL level showed fair discrimination for AKI progression and RRT. Patients with septic AKI had higher detectable plasma and urine NGAL levels compared with patients with nonseptic AKI. These differences in NGAL levels in septic AKI have diagnostic and clinical relevance, as well as pathogenetic implications. Similar results were also noted in a study of 143 critically ill children with systemic inflammatory response syndrome or septic shock.28 Our review of the published studies indicate that patient NGAL level is highly predictive of AKI, severity of AKI, the potential need for RRT, and mortality in patients in the ICU.14,36–39,42,46,48,49,57,76,78–80,82,84,122

Emergency Medicine or Emergency Department

The use of patient NGAL level as a marker of AKI has been explored in the field of emergency medicine as patients in the emergency department (ED) represent a population whose illnesses are often uncharacterized, and for whom kidney injury is often evolving.8 It has been determined that NGAL testing in the ED is feasible.8 The results of our search of the literature identified 4 clinical trials in which the role of patient NGAL level was investigated as an early biomarker in the detection of AKI in emergent patients.8,14,39,92 One prospective consecutive enrollment study of 635 patients who presented to the ED showed that patient NGAL levels most accurately differentiated AKI from pre-renal azotemia, CKD, and patients with normal kidney function compared with measures of patient creatinine level and several other potential renal injury markers.14 Emergency department differentiation of renal risk using patient NGAL levels would allow better therapeutic strategies to be initiated much earlier than if patient creatinine levels are used as the determinate. In a second point-of-care, serum NGAL ED study, 661 patients with serial creatinine levels, obtained as a part of an evaluation of potential sepsis, patient NGAL level was considerably more sensitive than creatinine level in the identification of subsequent renal failure or death.8 Other studies offer physiologic support that early NGAL measurement may be useful in patients at presentation to the ED. In a pilot study of 100 cardiac surgery patients who were at increased risk of postoperative acute renal dysfunction,




treatment with sodium bicarbonate infusion was performed to attenuate postoperative increases in serum creatinine level.92 Neutrophil gelatinase-associated lipocalin and urinary creatinine levels were sampled before induction of anesthesia at 6 hours and at 24 hours after the commencement of CPB. The study found NGAL measurements to be useful as a novel indicator of AKI and as a potential novel indicator of efficacy of therapy.92 Bagshaw et al39 endeavored to determine if there were detectable differences in serum and urinary NGAL concentrations in patients with sepsis-induced AKI compared with nonsepsis-induced AKI. Patients (N = 83) had blood and urine specimens collected at enrollment, 12, 24, and 48 hours to measure plasma and urine NGAL levels. Results showed that septic AKI was associated with significantly higher plasma and urine NGAL levels at enrollment compared with patients who had nonseptic AKI. The authors concluded that differences in patient NGAL levels in septic AKI may have diagnostic and clinical relevance, as well as pathogenetic implications.39

Cardiology or Heart Failure

Increased NGAL levels in patients have been associated with insulin resistance, atherogenesis,90,125,126 and atherosclerotic plaques,127 and the increase in NGAL correlates with risk factors of atherosclerosis.128 Tubular damage, as indicated by increased NGAL concentrations, N-acetylβ-D-glucosaminidase and kidney injury molecule 1 are common in patients with chronic heart failure (CHF) and mildly reduced GFR.87 In addition, the presence of renal tubular injury (indicated by elevated plasma NGAL levels) is associated with increased risk of subsequent development of worsening renal function in patients admitted with acute decompensated heart failure.9,91 Worsening renal function during admissions for acute decompensated heart failure has been directly associated with poor patient prognosis.9 Patients with CHF frequently exhibit the combination of reduced GFR, increased urinary albumin excretion, and structural tubular damage.89 Damman et al89 have shown that structural tubular damage, measured by increased urinary concentrations of NGAL, is highly prevalent in patients with CHF. Across the spectrum of heart failure and healthy controls, patient NGAL levels are not only associated with different indices of renal dysfunction, but also positively associated with increased levels of N-terminal proB-type natriuretic peptide. Because heart failure and other cardiac pathologies often exist as comorbidities and share common pathophysiologies, NGAL level has been investigated to determine its

role as a potential indicator of AKI in patients with various cardiac disorders. We identified 9 clinical trials with $ 50 patients in which the role of NGAL was investigated using the keywords cardiology or heart failure.6,7,9,52,87–89,129,130 Zografos et al88 measured plasma NGAL levels in 73 consecutive patients who underwent first-time angiography for suspected CAD, and their associations with angiographic indexes of the severity of CAD (ie, number of diseased vessels and modified Gensini score) were estimated. Median plasma NGAL levels in patients with angiographically confirmed CAD were significantly higher than those in patients without CAD. Statistically significant correlations were observed between plasma NGAL level and the number of diseased vessels and modified Gensini score. Through multivariate analysis, plasma NGAL level was independently associated with the presence and severity of CAD. Based on the results of their study, Zografos et al88 found that plasma NGAL levels were significantly higher in patients with CAD and correlated with the severity of CAD. The results were similar to those of other studies.61 Poniatowski et al52 assessed whether NGAL level could represent a novel, sensitive marker of kidney function in adult patients with CHF due to stable CAD whose serum creatinine level was within normal range. They also studied the possible relationship between serum and urinary NGAL levels, serum cystatin C level, and eGFR in patients with CAD in regard to New York Heart Association class. Their results showed that both patient serum and urinary NGAL levels increased parallel to the New York Heart Association class. The findings of these and other studies61,90 indicate that NGAL level may be a useful and sensitive early biomarker for the presence of AKI association in patients with various coronary disease and heart failure processes.

Cardiac Surgery

Acute renal dysfunction is a common and serious postoperative complication of cardiac surgery, and CPB may affect 25% to 50% of patients.76,86,131–133 Acute kidney injury occurs frequently after CPB and cardiac surgery and is associated with increased patient morbidity, mortality, and duration of intensive care treatment.76,134–137 Moreover, it has been postulated that all patients subject to CPB experience ischemia/ reperfusion injury characterized by proximal tubular dysfunction, and that downstream pathways of the renal response to ischemia/reperfusion injury may be as important to the development of AKI as the initial stressor.138 In patients undergoing cardiac surgery, postoperative increases in serum creatinine levels of 20% to 25% from


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preoperative baseline are associated with increased morbidity and mortality.139–142 Even minimal increases in patient serum creatinine level are associated with an increase in mortality.140,143 In response, clinical prediction tools have been developed to evaluate and estimate patient risk of AKI after cardiac surgery.79–82,84,86,144–146 Elevated serum creatinine levels that reflect the development and severity of AKI do not occur until days after renal tubular injury has begun.147,148 Moreover, serum creatinine level is a poor marker of renal function in the immediate postoperative period due to hemodilution resulting from CPB.45,149 Investigations of patient NGAL levels have been performed to determine its role as a potential indicator of AKI in the pericardiac surgery arena.76,77,81,85 The results of our search of the literature identified 31 clinical trials that met our entry criteria in investigating the role of patient NGAL level in cardiac surgery.67–73,86,91,150–171 In an effort to determine the utility of NGAL and cystatin C levels as measures of kidney injury, Koyner et al172 prospectively collected plasma and urine from 72 adults undergoing elective cardiac surgery. Acute kidney injury was defined as a $ 25% increase in plasma creatinine level or RRT within the first 72 hours following surgery. The investigators found that both urinary cystatin C and NGAL levels were elevated in the 34 patients who later developed AKI, compared with those patients with no injury. In addition, patient NGAL level at the time of ICU arrival—and the urinary cystatin C level 6 hours after ICU admission—were most useful for predicting AKI. The authors concluded that urinary cystatin C and NGAL levels were superior to conventional and novel plasma markers in the early diagnosis of AKI following adult cardiac surgery. These results are similar to those of other studies.74 In another study of 50 consecutive adult patients undergoing cardiac surgery,54 postoperative AKI was defined as a serum creatinine level increase from baseline . –0.5 mg/dL (ie, 0.44 µmol/L), consistent with the definition of the 2003 Acute Renal Failure Consensus Conference.173 Patient urine was collected through a urinary catheter preoperatively and 2 hours after completion of surgery, and venous blood was collected preoperatively and 2 hours after completion of CPB. A sandwich enzyme-linked immunosorbent assay was used to measure patient NGAL levels in the urine and blood. Ultimately, 9 patients developed AKI, 2 of whom developed postoperative acute renal dysfunction that required continuous venovenous hemodialysis and filtration. In this group of adult cardiac surgery patients, NGAL levels were markedly increased within 2 hours of CPB, and the level of NGAL could be used to predict a group of patients who developed 86

postoperative AKI.54 Wagener et al19 similarly found that NGAL level measurement is useful in the early diagnosis of AKI in adults after cardiac surgery. Mishra et al7 demonstrated in children undergoing cardiac surgery that NGAL levels increased in patient serum and urine within 2 hours post-CPB, preceding the serum creatinine level elevation, in those children who went on to develop AKI. There was no increased NGAL levels in children with stable perioperative renal function.7,64 The results of these trials indicate that both patient plasma and urinary NGAL levels represent a novel specific biomarker for the early identification of AKI after cardiac surgery.7,19,31,33,35,47,50,51,54,55,57,58,62,75,78,79,172 Moreover, immediately following surgery, patient NGAL and cystatin C levels correlated with and were independent predictors of duration and severity of AKI, as well as duration of ICU stay after adult cardiac surgery.48,49,57

Nephropathy or Nephrotoxicity

Throughout the literature, patient NGAL level has been shown to be an early marker of nephropathy/nephrotoxicity in a wide spectrum of clinical conditions, including renal tubular disease,23,65,101 systemic lupus erythematosus,94,96 acute renal impairment,97 CKD,32,53,95,100 HIV-associated nephropathy,27 sickle cell nephropathy,102 kidney cancer,93 and CIN.6,22,56,59,62,138,174,175 Contrast-induced nephropathy, often defined as an increase in patient serum creatinine level by 25% to 50% above baseline and generally occurring within the first 24 hours after contrast exposure (in the absence of other causes), has become the third leading cause of nosocomial AKI.176 The reported incidence of CIN ranges from 0 to 50%, depending on the absence or presence of risk factors.177 Approximately half the cases of CIN are patients undergoing cardiac catheterization and angiography and about one-third of patient cases follow exposure to computed tomography.178 In addition, the number of percutaneous coronary intervention (PCI) procedures performed by interventional cardiologists each year is increasing.179 Contrast-induced nephropathy is a potentially serious complication of PCI.179 As the utility of patient NGAL level has been established in detecting AKI, it has also been investigated to determine its usefulness as an early marker of AKI associated with CIN.62,138,174,175 Patient NGAL level has been investigated to determine its role as a potential indicator of nephropathy or nephrotoxicity.22,56,59 We identified 26 clinical trials meeting our inclusion criteria that investigated the role of NGAL level in nephropathy or nephrotoxicity.102,151,180–203




In a study by Ling et al,60 patients undergoing coronary angiography with low osmolar contrast medium were enrolled and followed for $ 17 months. Urine samples were collected before coronary angiography and 24 hours afterward. Interleukin-18 (IL-18) and NGAL levels were measured by using an enzyme-linked immunosorbent assay kit. Contrast-induced nephropathy was diagnosed in 13 (ie, the CIN group) of 150 (8.7%) patients, whereas 27 patients without CIN served as a control group. At 24 hours post procedure, urinary IL-18 and NGAL levels were significantly increased in patients with CIN, but not in the control group (P , 0.05). Both IL-18 and NGAL levels proved to be good indicators in early diagnosis of CIN compared with serum creatinine levels; the authors concluded that either urinary IL-18 or NGAL level could be an early CIN biomarker. Bachorzewska-Gajewska et al17 conducted a study in 60 nondiabetic patients with normal serum creatinine levels who underwent elective PCI to assess whether NGAL and cystatin C levels could predict CIN. An evaluation of cystatin C and NGAL levels had been performed before PCI and 2, 4, 8, 24, and 48 hours after PCI, using commercially available tests. Patient serum creatinine level was assessed before PCI and 24 and 48 hours after PCI.17 The authors found a significant rise in plasma NGAL level after 2, 4, and 8 hours, and in urinary NGAL level 4, 8, and 24 hours after PCI. The results of their study demonstrated that NGAL level could predict CIN in patients undergoing PCI with good sensitivity and specificity—much earlier than serum creatinine or cystatin C levels. The findings have important implications for the clinical management of patients undergoing PCI because the window of opportunity to prevent CIN is short and the time to introduce proper treatment after the initiating insult is limited, particularly when patients are discharged within 24 to 48 hours after the procedure. Bolignano et al99 also found patient NGAL level to be a useful early biomarker in the development and progression of diabetic nephropathy. Malyszko et al31 investigated whether or not NGAL level, along with other biomarkers, could represent early indicators of CIN in patients with and without diabetes who had normal serum creatinine levels undergoing cardiac catheterization. Patients were evaluated before and 2, 4, 8, 24, and 48 hours after cardiac catheterization, using commercially available kits. In both groups, the authors found a significant rise in patient NGAL level after 2, 4, and 8 hours and in IL-18 level 4, 8, and 24 hours after cardiac catheterization. Contrast-induced nephropathy was similarly prevalent in both diabetic and nondiabetic patients undergoing cardiac catheterization. The authors concluded that patient NGAL

level was a potential early marker for nephrotoxicity and a predictor of CIN. The results are consistent with those of other toxicity studies.21 In a similar study, Bachorzewska-Gajewska et al63 explored whether NGAL could represent an early biomarker of CIN in 100 patients with normal serum creatinine levels undergoing PCI. They assessed patient serum and urinary NGAL levels in relation to cystatin C level, eGFR, and serum and urinary creatinine levels, measuring urinary and plasma NGAL levels before and 2, 4, 8, 24, and 48 hours after PCI. They found a significant rise in plasma NGAL level at 2, 4, and 8 hours after PCI, and in urinary NGAL levels at 4, 8, and 24 hours after PCI procedure. Likewise, cystatin C levels rose significantly 24 hours after the procedure. Overall, the prevalence of CIN in this cohort was 11%. Patient NGAL levels were significantly higher 2 hours after PCI (plasma NGAL level) or 4 hours after PCI (urinary NGAL level), whereas the cystatin C levels were higher only 8 and 24 hours after PCI in patients with CIN. Evidence presented in the trial indicated that patient NGAL level represented a sensitive early biomarker of renal impairment after PCI. Thus, results of these trials seem to indicate that patient NGAL level is an effective early biomarker for the identification of AKI after CIN.17,21,31,60,63

Transplantation

Kidney damage often occurs in patients who have undergone organ transplant or allograft procedures. Although it is sometimes reversible, kidney damage is clearly associated with high patient morbidity and mortality. According to our entry criteria, we identified 18 clinical trials investigating patient NGAL level as an early biomarker in the detection of AKI secondary to organ transplant.15,33,34,40,41,43,44,53,74,103–111 In our article, patient NGAL level has been shown to be an early marker of AKI and kidney function in a wide spectrum of organ transplant situations,34,105,107,108 including renal transplant,15,43,103,109,111 renal allograft,44,53,104 liver transplant,40,106,110 and heart and lung transplant.33,41,74 Patient serum and urine NGAL levels are both elevated earlier than serum creatinine level in the setting of delayed graft function following kidney transplantation.16,83 Our review of these published studies indicates that patient NGAL level is highly predictive of kidney injury secondary to a variety of organ transplant procedures.

Conclusion

Based on the evidence reviewed in our article, it is clear that patient NGAL level is an appropriate, sensitive, and specific


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early biomarker of AKI that is caused by a variety of different etiologies. Some authors have suggested that AKI diagnosis criteria may be expanded to incorporate the use of biomarkers such as NGAL.204 Although the results of our literature search are generally in agreement with and supportive of each other, there were factors that limited our ability to make direct comparisons of the results. Studies reviewed in our article have used varying definitions of AKI and different cutoff points to indicate patient NGAL levels predictive of AKI. Moreover, there has been variation in the frequency and timing used to monitor both serum and urinary NGAL levels. It remains unclear what cutoff values are the most informative as early indicators of AKI in various disease states. Likewise, it is unclear how often NGAL levels should be monitored and if the frequency should vary based upon the etiology of the suspected presentation. These all represent areas for future investigation. It is also advisable that a multidisciplinary group of experts come together to make recommendations and propose a consensus of clinical procedures to advance the most efficacious NGAL monitoring protocol for early detection and treatment of patients with AKI. With these developments, it is expected that the clinical utility and role of patient NGAL level in the early detection, prevention, and treatment of AKI will increase and continue to evolve.

Acknowledgments

This study was supported by an unrestricted educational grant from Comprehensive Research Associates, LLC, Chagrin Falls, OH. The authors would like to thank Dr Richard Pistolese for his assistance in the preparation and review of this manuscript.

Conflict of Interest Statement

W. Frank Peacock IV, MD, has received honoraria for lectures from Abbott Laboratories, Alere Inc, PDL BioPharma, and The Medicines Company. He has served as a consultant for Abbott Laboratories, Alere Inc, Beckman-Coulter Inc, Otsuka America Pharmaceutical Inc, and The Medicines Company; and he has received support in the form of research grants from Abbott Laboratories, BAS, Biosite Diagnostics Inc, B·R·A·H·M·S GmbH, Heartscape Technologies Inc, Inovise Medical Inc, Inverness Medical Innovations Inc, PDL BioPharma, and The Medicines Company. Alan Maisel, MD, has received honoraria for lectures from Abbott Laboratories and Alere Inc. He has served as a consultant for Abbott Laboratories, Alere Inc, and 88

B·R·A·H·M·S Gmbh; and he has received support in the form of research grants from Abbott Laboratories, Alere Inc, Critical Diagnostics, Otsuka America Pharmaceutical Inc, Gilead, Siemens Health, Nanosphere, and B·R·A·H·M·S GmbH. Jieun Kim, MD, declares no conflicts of interest. Claudio Ronco, MD, has received honoraria for lectures from Gambro, Alere Inc, and Abbott Laboratories.

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Urinary neutrophil gelatinase-associated lipocalin predicts graft loss after acute kidney injury in kidney transplant.

Neutrophil Gelatinase Associated Lipocalin (NGAL) in Leptospirosis Acute Kidney Injury: A Multicenter Study in Thailand.

Evaluation of serum neutrophil gelatinase-associated lipocalin in predicting acute kidney injury in critically ill patients.

Diagnostic accuracy of urinary neutrophil gelatinase-associated lipocalin in patients with septic acute kidney injury.

Urinary neutrophil gelatinase-associated lipocalin is an early predictor of acute kidney injury in premature infants.

Whole blood neutrophil gelatinase-associated lipocalin predicts acute kidney injury in burn patients.

Urine neutrophil gelatinase-associated lipocalin in septic patients with and without acute kidney injury.

Role of neutrophil gelatinase-associated lipocalin for early detection of acute kidney injury.

Neutrophil gelatinase-associated lipocalin (NGAL) predicts the occurrence of malaria-induced acute kidney injury.

Postoperative neutrophil gelatinase-associated lipocalin predicts acute kidney injury after pediatric cardiac surgery*.

Urinary neutrophil gelatinase-associated lipocalin (NGAL) distinguishes sustained from transient acute kidney injury after general surgery.

Amelioration of cisplatin-induced acute kidney injury by recombinant neutrophil gelatinase-associated lipocalin.

Neutrophil gelatinase-associated lipocalin in kidney transplantation: A review.

Plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) in dogs with acute kidney injury or chronic kidney disease.

Neutrophil gelatinase-associated lipocalin as early predictor of acute kidney injury after cardiac surgery in adults with chronic kidney failure.

Value of plasma neutrophil gelatinase-associated lipocalin (NGAL) in distinguishing between acute kidney injury (AKI) and chronic kidney disease (CKD).

Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as prognostic markers in idiopathic membranous nephropathy.

Neutrophil Gelatinase-Associated Lipocalin as an Early Sign of Diabetic Kidney Injury in Children.

Diagnostic value of neutrophil gelatinase-associated lipocalin for early diagnosis of cardiac surgery-associated acute kidney injury: a meta-analysis.

Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) and proteinuria predict severity of acute kidney injury in Puumala virus infection.

Neutrophil Gelatinase-Associated Lipocalin as a Biomarker of Acute Kidney Injury in Patients with Morbid Obesity Who Underwent Bariatric Surgery.

Plasma and urine neutrophil gelatinase-associated lipocalin in the diagnosis of new onset acute kidney injury in critically ill patients.

Role of urine neutrophil gelatinase-associated lipocalin in the early diagnosis of amphotericin B-induced acute kidney injury.

Plasma Neutrophil Gelatinase Associated Lipocalin Ratio Is a Sensitive and Specific Marker of Subclinical Acute Kidney Injury in Mice.