Using NGAL as an Early Diagnostic Test of Acute Kidney Injury

Abstract

Neutrophil gelatinase-associated lipocalin (NGAL) has generated great interest as a novel biomarker for the timely detection of acute kidney injury (AKI). Despite the enthusiasm surrounding NGAL, the research so far details and attempts to minimize a host of limitations that substantially preclude its use as a valuable diagnostic biomarker to detect AKI and guide clinical treatment. In our review of the current research, obvious drawbacks such as variable sensitivity and specificity, even among similar patient populations were discovered. Furthermore, there are not well-defined cutoff values among various patient populations which would permit use of NGAL as a positive or negative diagnostic marker similar to troponin in cardiac injury. Moreover, due to the wide variation in baseline concentration of NGAL among patients, the added requirement of serial measurements, that may not even be accurate in at-risk or chronic kidney injury populations, further degrades the benefit of early detection.     

Urine Neutrophil Gelatinase-Associated Lipocalin Moderately Predicts Acute Kidney Injury in Critically Ill Adults

Urine neutrophil gelatinase-associated lipocalin (uNGAL) has shown promise as a biomarker for the early detection of acute kidney injury (AKI) in fixed models of injury, but its ability to predict AKI and provide prognostic information in critically ill adults is unknown. We prospectively studied a heterogeneous population of 451 critically ill adults, 64 (14%) and 86 (19%) of whom developed AKI within 24 and 48 h of enrollment, respectively. Median uNGAL at enrollment was higher among patients who developed AKI within 48 h compared with those who did not (190 versus 57 ng/mg creatinine, P < 0.001). The areas under the receiver operating characteristic curves describing the relationship between uNGAL level and the occurrence of AKI within 24 and 48 h were 0.71 (95% Confidence Intervals [CI]: 0.63 to 0.78) and 0.64 (95% CI: 0.57 to 0.71), respectively. Urine neutrophil gelatinase-associated lipocalin remained independently associated with the development of AKI after adjustment for age, serum creatinine closest to enrollment, illness severity, sepsis, and intensive care unit (ICU) location, although it only marginally improved the predictive performance of the clinical model alone. A Cox proportional hazards model using time to first dialysis, adjusted for APACHE II score, suggested that uNGAL independently predicts severe AKI during hospitalization [HR 2.60, 95% CI:1.55 to 4.35]. In summary, although a single measurement of uNGAL exhibited moderate predictive utility for the development and severity of AKI in a heterogeneous ICU population, its additional contribution to conventional clinical risk predictors appears limited.Despite advances in the provision of hospitalized care, the incidence of acute kidney injury (AKI) is increasing and remains an independent predictor of morbidity and mortality.^1–3 An impediment toward improving outcomes has been continued reliance on belated and unreliable markers of injury.⁴ Recent efforts directed toward discovery of biomarkers with early predictive and prognostic potential have yielded several candidates including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1),⁵ cystatin C,^6,7 Na⁺/H⁺ exchanger isoform 3 (NHE3),⁸ and IL-18 (IL-18).^9–12NGAL is a 25-kD protein of the lipocalin family, whose structure is defined by a calyx that modulates local iron channeling and serves as a growth and differentiation factor for renal tubular epithelia.^13–15 Increased expression in the proximal renal tubular epithelia during ischemic injury has provided a rationale for its use as an early biomarker of AKI.¹⁶ Performance testing of urine NGAL (uNGAL) has yielded particular promise in patient settings with temporally defined mechanisms of injury including both pediatric and adult patients undergoing cardiopulmonary bypass,^17,18 postrenal transplantation,¹⁹ diarrhea-associated hemolytic-uremic syndrome,²⁰ and in a cohort of pediatric patients requiring mechanical ventilation.²¹We assessed the ability of uNGAL to predict both the development and severity of AKI in a mixed adult ICU cohort subject to heterogeneous patterns, timing, and causes of injury. The added and conjoint predictive ability of uNGAL beyond a panel of a priori selected clinical predictors for AKI was also quantified. Data were obtained from subjects enrolled in the ongoing NIH-sponsored Validation of biomarkers in Acute Lung Injury Diagnosis (VALID) study, a single-center, multi-ICU prospective cohort whose primary purpose is to investigate panels of new and existing plasma, serum, or urine protein biomarkers to both diagnose Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) in at-risk patients and identify patients with ALI/ARDS early who are at highest risk for adverse clinical outcomes (Figure 1).Open in a separate windowFigure 1.VALID study scheme.     

Efficacy of N-Acetylcysteine in Preventing Acute Kidney Injury After Cardiac Surgery: A Meta-Analysis Study

Purpose: To evaluate whether perioperative N-acetylcysteine (NAC) administration reduces the risk of cardiac surgery associated acute kidney injury (CSA-AKI). Materials and Methods: A systematic literature review (Medline, PubMed, Cochrane, Biomedical central, Google Scholar) identified 10 studies (1391 patients; 695 NAC and 696 placebo) that compared the efficacy and adverse effects of perioperative NAC administration for CSA-AKI prevention in adults undergoing elective cardiac surgery. Meta-analysis was performed using Comprehensive Meta-Analysis statistical software. Results: Patients in the NAC-treated and placebo groups had similar rate of CSA-AKI occurrence, change in creatinine levels, as well as the in-hospital mortality rate (RR = 0.841, 95% CI = 0.691 to 1.023, p = 0.083; pooled difference in means = ?0.328, 95% CI = ?0.712 to 0.056, p = 0.094; RR = 0.741, 95% CI = 0.388 to 1.418, p = 0.366, respectively). Conclusions: Our study does not support perioperative NAC administration as a mean to reduce the risk of CSA-AKI.     

心脏术后尿中性粒细胞明胶酶相关脂质运载蛋白和白细胞介素18与急性肾损伤的关系

目的 探讨接受体外循环心脏手术患者尿中性粒细胞明胶酶相关脂质运载蛋白（NGAL）和尿白细胞介素18（IL-18）与急性肾损伤（AKI）的关系。 方法 根据AKI的诊断标准，将33例体外循环心脏手术的患者分为AKI组及非AKI组，分别留取术前及术后不同时间点的血液和尿液标本，测定Scr、尿NGAL和IL-18水平。 结果 33例中有9例发生AKI，发生率为27.27%。AKI组Scr升高峰值出现在12～48 h内。与术前相比， AKI组术后2 h、4 h尿NGAL及IL-18水平升高，差异有统计学意义（P < 0.01）。与非AKI组比较，AKI组术后各时间点的尿NGAL水平、术后2 h及4 h的尿IL-18水平都较高，差异有统计学意义（P < 0.01）。经尿肌酐（Ucr）校正后，相应时间点的NGAL/Ucr和IL-18/Ucr差异仍有统计学意义（P < 0.01）。术后2 h尿NGAL和尿NGAL/Ucr的界定（cutoff） 值分别在250 µg/L和250 µg/mmol时；术后2 h尿IL-18和尿IL-18/Ucr的界定值分别在1800 ng/L和1800 ng/mmol时，体现出较好的敏感性和特异性。 AKI组术后12 h Scr水平与术后2 h尿NGAL水平呈正相关（r = 0.638，P < 0.05）。结论 体外循环下接受心脏手术的患者AKI发生率较高；术后2 h尿NGAL和NGAL/Ucr、术后2 h尿IL-18和尿IL-18/Ucr当达到一定界定值时，均可作为体外循环下心脏手术后AKI发生的早期诊断参考指标，其中术后2 h尿NGAL/Ucr为250 µg/mmol时更敏感。     

Effect of 6% hydroxyethyl starch 130/0.4 on kidney and haemostatic function in cardiac surgical patients: a randomised controlled trial

Whether third-generation hydroxyethyl starch solutions provoke kidney injury or haemostatic abnormalities in patients having cardiac surgery remains unclear. We tested the hypotheses that intra-operative administration of a third-generation starch does not worsen postoperative kidney function or haemostasis in cardiac surgical patients compared with human albumin 5%. This triple-blind, non-inferiority, clinical trial randomly allocated patients aged 40–85 who underwent elective aortic valve replacement, with or without coronary artery bypass grafting, to plasma volume replacement with 6% starch 130/0.4 vs. 5% human albumin. Our primary outcome was postoperative urinary neutrophil gelatinase-associated lipocalin concentrations, a sensitive and early marker of postoperative kidney injury. Secondarily, we evaluated urinary interleukin-18; acute kidney injury using creatinine RIFLE criteria, coagulation measures, platelet count and function. Non-inferiority (delta 15%) was assessed with correction for multiple comparisons. We enrolled 141 patients (69 starch, 72 albumin) as planned. Results of the primary analysis demonstrated that postoperative urine neutrophil gelatinase-associated lipocalin (median (IQR [range])) was slightly lower with hydroxyethyl starch (5 (1–68 [0–996]) ng.ml⁻¹) vs. albumin (5 (2–74 [0–1604]) ng.ml⁻¹), although not non-inferior [ratio of geometric means (95%CI) 0.91 (0.57, 1.44); p = 0.15] due to higher than expected variability. Urine interleukin-18 concentrations were reduced, but interleukin-18 and kidney injury were again not non-inferior. Of 11 individual coagulation measures, platelet count and function, nine were non-inferior to albumin. Two remaining measures, thromboelastographic R value and arachidonic acid-induced platelet aggregation, were clinically similar but with wide confidence intervals. Starch administration during cardiac surgery produced similar observed effects on postoperative kidney function, coagulation, platelet count and platelet function compared with albumin, though greater than expected variability and wide confidence intervals precluded the conclusion of non-inferiority. Long-term mortality and kidney function appeared similar between starch and albumin.