Urine NGAL Predicts Severity of Acute Kidney Injury After Cardiac Surgery: A Prospective Study

Background and objectives: The authors have previously shown that urine neutrophil gelatinase-associated lipocalin (NGAL), measured by a research ELISA, is an early predictive biomarker of acute kidney injury (AKI) after cardiopulmonary bypass (CPB). In this study, whether an NGAL immunoassay developed for a standardized clinical platform (ARCHITECT analyzer®, Abbott Diagnostics Division, Abbott Laboratories, Abbott Park, IL) can predict AKI after CPB was tested.Design, setting, participants, & measurements: In a pilot study with 136 urine samples (NGAL range, 0.3 to 815 ng/ml) and 6 calibration standards (NGAL range, 0 to 1000 ng/ml), NGAL measurements by research ELISA and by the ARCHITECT® assay were highly correlated (r = 0.99). In a subsequent study, 196 children undergoing CPB were prospectively enrolled and serial urine NGAL measurements obtained by ARCHITECT® assay. The primary outcome was AKI, defined as a ≥50% increase in serum creatinine.Results: AKI developed in 99 patients (51%), but the diagnosis using serum creatinine was delayed by 2 to 3 d after CPB. In contrast, mean urine NGAL levels increased 15-fold within 2 h and by 25-fold at 4 and 6 h after CPB. For the 2-h urine NGAL measurement, the area under the curve was 0.95, sensitivity was 0.82, and the specificity was 0.90 for prediction of AKI using a cutoff value of 100 ng/ml. The 2-h urine NGAL levels correlated with severity and duration of AKI, length of stay, dialysis requirement, and death.Conclusions: Accurate measurements of urine NGAL are obtained using the ARCHITECT® platform. Urine NGAL is an early predictive biomarker of AKI severity after CPB.Cardiopulmonary bypass (CPB) surgery is the most frequent major surgical procedure performed in hospitals worldwide, with well over a million operations undertaken each year in adults alone (1). Acute kidney injury (AKI), previously referred to as acute renal failure, is a frequent and serious complication encountered in 30% to 50% of subjects after CPB (2,3). AKI requiring dialysis occurs in up to 5% of these cases, in whom the mortality rate approaches 80%, and is the strongest independent risk factor for death after CPB, with an odds ratio of 7.9 (4). Even minor degrees of postoperative AKI, as manifest by only a 0.2 to 0.3 mg/dl rise in serum creatinine from baseline, predict a significant increase in short-term mortality (5,6). AKI after cardiac surgery is also associated with a number of adverse outcomes, including prolonged intensive care and hospital stay, dialysis dependency, diminished quality of life, and increased long-term mortality (7–9).Clinical investigations have identified several risk factors associated with the development of AKI after CPB, the majority related to either impaired renal perfusion or decreased renal reserve, and have resulted in the development of clinical scoring systems for the prediction of AKI (10–13). However, these tools have not been validated across medical centers, and have focused primarily on identifying the small number of high-risk, dialysis-requiring subjects. Concomitant advances in the basic sciences have illuminated the pathogenesis of AKI and have paved the way for successful therapeutic approaches in animal models (14). However, translational research efforts for the identification of effective therapeutic strategies in humans with AKI have yielded disappointing results (2,15). A major reason for the failure to find an effective treatment in patients is the paucity of early biomarkers for AKI, akin to troponins in acute myocardial disease (16). The availability of effective biomarkers may lead to improved efforts at ameliorating the course of AKI or preventing further renal injury. However, in current clinical practice, the gold standard for identification and classification of AKI is dependent on serial serum creatinine measurements (17), which are especially unreliable during acute changes in kidney function (15,16).We used a genome-wide interrogation strategy to identify kidney genes that are induced very early after AKI in animal models, whose protein products might serve as novel early biomarkers. We identified neutrophil gelatinase-associated lipocalin (NGAL) as one of the most upregulated genes in the kidney soon after ischemic injury (18–20). NGAL protein was also markedly induced in kidney tubule cells and easily detected in the plasma and urine in animal models of ischemic and nephrotoxic AKI (18–22). The expression of NGAL protein was also dramatically increased in kidney tubules of humans with ischemic, septic, and post-transplant AKI (23,24). Importantly, NGAL in the urine was found to be an early predictive biomarker of AKI in a variety of acute clinical settings (25). In a cohort of 20 subjects who developed AKI 2 to 3 d after cardiac surgery, urine NGAL measured by a research enzyme-linked immunosorbent assay (ELISA) was elevated within 2 to 6 h after CPB (16,26). Preliminary results using the research-based assay also suggest that urine NGAL measurements can predict AKI following contrast administration (27), kidney transplantation (28), hemolytic-uremic syndrome (29), lupus nephritis (30), and in critically ill subjects (31). The availability of a standardized clinical platform for NGAL measurements could revolutionize renal diagnostics, especially in intensive care situations (32). Therefore, the first objective of the present study was to determine whether an NGAL immunoassay developed for a standardized clinical platform (ARCHITECT® analyzer, Abbott Diagnostics) correlates with the research-based assay. The second objective was to determine the utility of the standardized NGAL immunoassay as a predictive biomarker of AKI after CPB in a large prospective cohort.     

Arterial stiffness and matrix metalloproteinases: A correlation study in hypertensive type 2 diabetic subjects

International Journal of Diabetes in Developing Countries - Matrix metalloproteinases (MMP’s) and tribbles 3 human homolog (Trb3) are implicated in atherosclerosis. Changes in the...