Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction. STUDY DESIGN: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines. SETTING & STUDY POPULATIONS: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms. SELECTION CRITERIA FOR STUDIES: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI. DATA EXTRACTION: Individual-study-data meta-analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis. ANALYTICAL APPROACH: Individual-study-data meta-analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses. RESULTS: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.79-0.81) and 0.86 (95% CI, 0.84-0.86). Cutoff concentrations at 95% specificity for urinary NGAL were>580ng/mL with 27% sensitivity for severe AKI and>589ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were>364ng/mL with 44% sensitivity and>546ng/mL with 26% sensitivity, respectively. LIMITATIONS: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies. CONCLUSIONS: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation.

Neutrophil Gelatinase-Associated Lipocalin as a Biomarker of Allograft Function After Renal Transplantation: Evaluation of the Current Status and Future Insights.

Neutrophil gelatinase-associated lipocalin (NGAL), a protein belonging to the lipocalin superfamily initially found in activated neutrophils, is expressed by several cell types, including kidney tubule. The increase in NGAL production and release from tubular cells in response to various insults has been proven to predict acute kidney injury (AKI). For this reason, it has emerged as a valuable noninvasive biomarker of AKI in clinical nephrology. Also in the renal transplant setting, different studies have indicated NGAL as a valuable tool, especially in the early postoperative period, since the currently available clinical and laboratory parameters remain poorly sensitive to monitor immediate posttransplant graft function. This is an analysis of the recent literature to assess the utility of plasma and urinary NGAL, exosomal mRNA for NGAL, and NGAL levels in the perfusate of machine-perfused kidneys for the prediction of graft function recovery in the early postsurgery phase after renal transplantation. We found that NGAL appears as a promising troponin-like biomarker to detect short-term impairment of graft function after renal transplant, but there are still some limitations in its clinical application, essentially related to its low specificity. Moreover, comparing NGAL assayed in serum, urine, machine-perfusate, or as exosomal mRNA, each one has shown limitations and benefits in terms of predictive performance for DGF, according to various existing studies, feasibly due to different cut-off levels, designs and patient sample sizes.

Neutrophil gelatinase-associated lipocalin (NGAL) in kidney injury - A systematic review.

BACKGROUND: Neutrophil Gelatinase Associated Lipocalin (NGAL) is a secretory protein of neutrophils that can be found both in plasma and urine. Previous works have demonstrated a valuable marker for the early detection of acute kidney injury. In this systematic review, we aimed to assess whether NGAL could be helpful in the diagnosis and prognosis of systemic diseases with kidney involvement. METHODS: MEDLINE, PubMed, and EMBASE databases were searched for NGAL, described as a human biomarker for diseases (total: 1690). Specifically, included studies describing the use of NGAL for determining kidney injury outcomes and other conditions associated with kidney dysfunction, including cardiovascular diseases, cardiac surgery, and critically ill systemic disorders. RESULTS: A total of 24 validated studies were included in the systemic review after applying the exclusion criteria. In all these studies, NGAL appeared to have a predictive value irrespective of age, from newborn to 78 years. The results indicate that NGAL levels can accurately predict the outcome and severity of acute kidney injury occur in several disease processes, including contrast-induced AKI during cardiac surgery, kidney transplant rejection, chronic heart failure, and systemic inflammation in critically ill patients, even though the significance of NGAL is highly variable across studies. Very high plasma NGAL levels were observed in the patients before the acute rejection of the kidney, indicating the prognostic potential of the NGAL. Specifically, the assays conducted before 72 hrs provided a significant predictive value. CONCLUSION: Urinary and serum NGAL appears to be an independent predictor of not only kidney complications but also cardiovascular and liver-related diseases. The kidney is also involved in pathogenesis.

Incidence, Risk Factors, the Role of Plasma NGAL and Outcome of Contrast-Induced Acute Kidney Injury in Critically Ill Children.

OBJECTIVES: To study the incidence of contrast-induced acute kidney injury (CI-AKI), evaluate its risk factors, study the role of plasma neutrophil gelatinase-associated lipocalin (NGAL) and evaluate the outcome of CI-AKI in critically ill children. METHODS: In this prospective cohort study, children aged 1 mo to 12 y who underwent contrast computed tomography (CECT) for various medical indications were included. Patients without renal function test before contrast administration, children with chronic kidney disease, children admitted for less than 48 h, and those with serum bilirubin more than 5 mg per dL were excluded. Serum creatinine and estimated-Glomerular filtration rate (e-GFR) were measured at admission, immediately before, and at 6, 24, 48 h after contrast. Plasma neutrophil gelatinase-associated lipocalin (NGAL) was measured before and 6 h after contrast. The incidence of CI-AKI by p-RIFLE (Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease) criteria, its risk factors, the diagnostic role of NGAL in CI-AKI, and outcomes [30 d unfavorable outcome (death, readmission) and renal recovery] were studied. RESULTS: One hundred children were enrolled. The indications for CECT were brain (58%) and respiratory pathology (20%). Incidence of CI-AKI was 35% (95% CI 26.4% to 44.8%); 71% in 'Risk,' and 29% in the 'Injury' stage. After multivariate logistic regression, age younger than 2 y was independently associated with CI-AKI. There was no significant difference in NGAL before (ROC-AUC 0.38, 95% CI 0.26 to 0.50) and 6 h after CECT scan (AUC 0.41, 95% CI 0.29 to 0.54) to predict CI-AKI. There were 7% deaths but no readmission at 30 d. Among 33 CI-AKI patients who survived, the operational definition of renal recovery was achieved in 51.5% (n = 17), complete renal recovery was achieved in 97% (n = 32), and partial renal recovery was achieved in 3% (n = 1) of patients at discharge, while none received renal supportive therapy. CONCLUSIONS: The incidence of contrast-induced acute kidney injury was 35% with age younger than two year being independently associated with CI-AKI. NGAL did not predict the CI-AKI.

The effect of early renal replacement therapy guided by plasma neutrophil gelatinase associated lipocalin on outcome of acute kidney injury: A feasibility study.

PURPOSE: The optimal time and the parameter utilized for decision to initiate renal replacement therapy (RRT) in acute kidney injury (AKI) are still controversial. Recently, high levels of plasma NGAL (pNGAL) has been strongly correlated with poor AKI outcome. This is a feasibility study conducted to test whether early RRT initiation guided by pNGAL could improve AKI outcome. MATERIAL AND METHODS: The study comprised of triage trial and interventional trial running subsequently. As a guide for triage to RRT, we measured pNGAL at the enrollment time. Forty patients with pNGAL≥400ng/mL (high pNGAL group) were randomized to 'early' or 'standard' group. Patients with pNGAL<400ng/mL (n=20) were defined as low pNGAL group. RESULTS: The triggering pNGAL selected AKI patients with more severity of illness and worse clinical outcome. However, in high pNGAL group, early RRT did not result in different 28-day mortality from the standard group. The median numbers of day free from mechanical ventilation were significantly higher in the early RRT group. CONCLUSIONS: Our finding suggested that it was feasible to use pNGAL to triage severe AKI patients. However, early initiation of RRT in this high risk group did not affect the 28-day mortality.

Is plasma neutrophil gelatinase-associated lipocalin a predictive biomarker for acute kidney injury in sepsis patients? A systematic review and meta-analysis.

PURPOSE: Neutrophil gelatinase-associated lipocalin (NGAL) is a useful biomarker for early diagnosis of acute kidney injury (AKI). However, the diagnostic value of NGAL for predicting AKI in sepsis patients is unclear. METHODS: MEDLINE, EMBASE, and Cochrane Library databases were searched to identify research publications. RESULTS: Twelve studies from 9 countries including a total of 1582 patients, of whom 315 (19.9%) developed AKI, were included in the study; plasma NGAL levels were significantly higher in adult sepsis patients with AKI than in those without AKI (mean difference, 274.65; 95% confidence interval [CI], 106.16-443.15; I(2) = 94%). Urine NGAL levels were not significantly different. The diagnostic odds ratio of plasma NGAL for predicting AKI in sepsis patients was 6.64 (95% CI, 3.80-11.58). The diagnostic accuracy of plasma NGAL was 0.881 (95% CI, 0.819-0.923) for sensitivity, 0.474 (95% CI, 0.367-0.582) for specificity, 0.216 (95% CI, 0.177-0.261) for positive predictive value and 0.965 (95% CI, 0.945-0.977) for negative predictive value. CONCLUSION: Plasma NGAL has a high sensitivity and a high negative predictive value for detection of AKI in adult sepsis patients. However, its low specificity and low positive predictive value could limit its clinical utility. The usefulness of urine NGAL was not revealed in this study.

Usefulness of plasma neutrophil gelatinase-associated lipocalin as an early marker of acute kidney injury after cardiopulmonary bypass in Korean cardiac patients: a prospective observational study.

OBJECTIVES: Development of acute kidney injury (AKI) after cardiopulmonary bypass (CPB) is relatively common and associated with increased mortality. Recently, plasma neutrophil gelatinase-associated lipocalin (NGAL) was used for the prediction of AKI. We evaluated the clinical usefulness of plasma NGAL. DESIGN AND METHODS: One hundred twelve adult patients undergoing cardiovascular surgery with CPB were included. Blood samples were obtained at baseline, at intensive care unit (ICU) admission, and 24h after ICU admission. The development of AKI, which is defined as an increase in serum creatinine by more than 50% within 3 postoperative days, was monitored. NGAL levels were analyzed by a Biosite Triage meter (Alere Medical, USA). Diagnostic performance of NGAL was analyzed using the area under the receiver operating characteristic curve. RESULTS: In AKI patients (n=13), plasma NGAL levels at ICU admission were significantly higher than those at baseline [177 (122-402) vs. 121 (74-158) ng/mL, median (interquartile range), p=0.028], whereas serum creatinine showed no significant change. The predictive value of NGAL at ICU admission was 0.812 [95% confidence interval (CI), 0.68 to 0.95] with a cut-off value of 168.5ng/mL (sensitivity, 61.5%; specificity, 88.9%). After the exclusion of 35 patients with preoperative decreased renal function, the predictive value was increased to 0.911 (95% CI, 0.82 to 1.00). CONCLUSIONS: This study showed that plasma NGAL may serve as a useful biomarker for the early detection of AKI in adult patients following CPB.