Acute Kidney Injury


DGF (which typically occurred two to four days later), with an AUC of 0.9.44


This has now been confirmed in a larger multicenter cohort, in which urine NGAL measured within six hours of kidney transplantation predicted subsequent DGF with an AUC of 0.81.45


A recent study of serial


urine NGAL measurements after deceased donor kidney transplants in 176 recipients demonstrated that day-one urine NGAL was independently associated with DGF, and predicted prolonged DGF (lasting over 14 days) with an AUC of 0.75.46


Importantly, the day-one


urine NGAL levels predicted DGF with an AUC of 0.744 even in a subset of patients with good urine output and decreasing serum creatinine values, in whom DGF was not clinically expected.46


Plasma NGAL


measurements have also been correlated with DGF following kidney transplantation from donors after cardiac death.47


However, the utility


of early and/or serial NGAL measurements for the prediction of subsequent clinical outcomes such as graft rejection and long-term graft survival remain to be fully explored.


An emerging application of NGAL is in the arena of human nephrotoxicities. For example, several investigators have examined the role of NGAL as a predictor of AKI following contrast administration.48–52 In a prospective study of children undergoing elective cardiac catheterization with contrast administration, both urine and plasma NGAL predicted contrast-induced nephropathy (defined as a 50% increase in serum creatinine from baseline) within two hours after contrast administration, with an AUC of 0.91–0.92.52


In several studies of


adults administered contrast, an early rise in both urine (four hours) and plasma (two to four hours) NGAL was documented, in comparison with a much later increase in plasma cystatin C levels (eight to 24 hours after contrast administration), providing further support for NGAL as an early biomarker of contrast nephropathy.48–51


A meta-analysis revealed an


overall AUC of 0.894 for prediction of AKI, when NGAL was measured within six hours after contrast administration and AKI was defined as a >25% increase in serum creatinine.42


In terms of other common


nephrotoxins, early urinary NGAL measurements have proved to be useful for the prediction of cisplatin-induced AKI,53


nephrotoxicity, and early cyclosporine-associated nephrotoxicity54


gentamicin-induced in


preliminary studies. Furthermore, subjects who developed AKI after aprotinin use during cardiac surgery displayed a dramatic rise in urine NGAL in the immediate post-operative period, attesting to the potential use of NGAL for the prediction of AKI associated with aprotinin.55


Urine and plasma NGAL measurements have been shown to represent early biomarkers of AKI in a heterogeneous pediatric intensive care setting, being able to predict this complication about two days prior to the rise in serum creatinine, with high sensitivity and AUCs of 0.68–0.78.56,57


NGAL levels in critically ill adult populations.58–66


Finally, in a study of adults in the emergency department setting, a single measurement of urine NGAL at the time of initial presentation predicted AKI with an AUC of 0.95, and reliably distinguished pre-renal azotemia from intrinsic AKI and from CKD.66


Thus, NGAL is a useful early


AKI marker that predicts development of AKI even in heterogeneous groups of patients with multiple comorbidities and with unknown timing of kidney injury. However, it should be noted that patients with septic AKI display the highest concentrations of both plasma and urine NGAL compared with those with non-septic AKI,63


a confounding factor that


may add to the heterogeneity of the results in critical care subjects. In addition, the diagnostic accuracy of both urine and plasma NGAL in this setting increased with increasing AKI severity, with AUCs improving from 0.77 to 0.88 depending on the RIFLE stage attained.60


Despite these


limitations inherent to a diverse critical care setting, a meta-analysis revealed an overall AUC-ROC of 0.73 for prediction of AKI, when NGAL was measured within six hours of clinical contact with critically ill subjects and AKI was defined as a >50% increase in serum creatinine.42


Because of its high predictive properties for AKI, NGAL is also emerging as an early biomarker in interventional trials. For example, a reduction in urine NGAL has been employed as an outcome variable in clinical trials demonstrating the improved efficacy of a modern hydroxyethyl starch preparation over albumin or gelatin in maintaining renal function in cardiac surgery patients.67–69


Similarly, the response of urine NGAL


In addition, urinary NGAL levels have been utilized to document the efficacy of a miniaturized cardiopulmonary bypass system in the preservation of kidney function compared with standard cardiopulmonary bypass.71


The approach of using NGAL as a trigger to


initiate and monitor novel therapies, and as a safety biomarker when using potentially nephrotoxic agents, is a logical next step. It is also hoped that the use of predictive and sensitive biomarkers such as NGAL as end-points in clinical trials will result in a reduction in required sample sizes, and hence the cost incurred.


Several studies have also examined plasma and urine Urine NGAL obtained on


In more mixed populations of all critical care admissions, the urine NGAL on admission has been somewhat less predictive of AKI, with an AUC ranging from 0.8859,60


admission predicted subsequent AKI in multi-trauma patients with an AUC of 0.98.58


to 0.71.61 In studies of adult intensive


care patients, early plasma NGAL concentrations also represented a predictive biomarker for development of AKI within the next two days, with AUC ranges of 0.77–0.92.60,62,64


transplantation, a single plasma NGAL level obtained within two hours of reperfusion was predictive of subsequent AKI with an AUC of 0.79.65


40 In subjects undergoing liver


Beyond the prediction of creatinine-based AKI, it is highly desirable for biomarkers to provide an early warning signal for impending adverse outcomes. In this respect, an increasing number of studies have demonstrated the utility of early NGAL measurements for predicting the severity and clinical outcomes of AKI. In children undergoing cardiac surgery, early post-operative plasma NGAL levels strongly correlated with duration and severity of AKI, length of hospital stay, and mortality.72 In a similar cohort, early urine NGAL levels highly correlated with duration and severity of AKI, length of hospital stay, dialysis requirement, and death.73


In a multicenter study of children with diarrhea-associated hemolytic uremic syndrome, urine NGAL obtained early during hospitalization predicted the severity of AKI and dialysis requirement with high sensitivity.74


Early urine NGAL levels were also predictive of


duration of AKI (AUC 0.79) in a heterogeneous cohort of critically ill pediatric subjects.56


In adults undergoing cardiopulmonary bypass, those who subsequently required renal replacement therapy were found to have the highest urine NGAL values soon after surgery.30–37 were documented in the adult critical care setting.58–66


published studies in critically ill subjects revealed an overall AUC of 0.78 for prediction of subsequent dialysis requirement, when NGAL was


US NEPHROLOGY


Similar results Collectively, the


was attenuated in adult cardiac surgery patients who experienced a lower incidence of AKI after sodium bicarbonate therapy compared with sodium chloride.70


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