Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery

Summary

Background

The scarcity of early biomarkers for acute renal failure has hindered our ability to launch preventive and therapeutic measures for this disorder in a timely manner. We tested the hypothesis that neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for ischaemic renal injury after cardiopulmonary bypass.

Methods

We studied 71 children undergoing cardiopulmonary bypass. Serial urine and blood samples were analysed by western blots and ELISA for NGAL expression. The primary outcome measure was acute renal injury, defined as a 50% increase in serum creatinine from baseline.

Findings

20 children (28%) developed acute renal injury, but diagnosis with serum creatinine was only possible 1–3 days after cardiopulmonary bypass. By contrast, urine concentrations of NGAL rose from a mean of 1·6 μg/L (SE 0·3) at baseline to 147 μg/L (23) 2 h after cardiopulmonary bypass, and the amount in serum increased from a mean of 3·2 μg/L (SE 0·5) at baseline to 61 μg/L (10) 2 h after the procedure. Univariate analysis showed a significant correlation between acute renal injury and the following: urine and serum concentrations of NGAL at 2 h, and cardiopulmonary bypass time. By multivariate analysis, the amount of NGAL in urine at 2 h after cardiopulmonary bypass was the most powerful independent predictor of acute renal injury. For concentration in urine of NGAL at 2 h, the area under the receiver-operating characteristic curve was 0·998, sensitivity was 1·00, and specificity was 0·98 for a cutoff value of 50 μg/L.

Interpretation

Concentrations in urine and serum of NGAL represent sensitive, specific, and highly predictive early biomarkers for acute renal injury after cardiac surgery.

Introduction

Acute renal failure represents a very important and potentially devastating disorder in clinical medicine.1, 2, 3, 4, 5 Its prevalence varies from 5% of all patients admitted to hospital to 30–50% of those in intensive-care units. Despite substantial technical improvements in treatments, mortality and morbidity associated with acute renal failure remain dismally high.

Renal ischaemia-reperfusion injury is the leading cause of acute renal failure in the native and transplanted kidney. Advances in basic science research have highlighted the pathogenesis of such injury and have paved the way for successful therapeutic approaches in animal models. However, translational research efforts in patients have yielded disappointing results. A major reason for the failure to find an effective treatment in patients is the scarcity of early biomarkers for acute renal failure, akin to troponins in acute myocardial disease, and hence an unacceptable delay in initiating any treatment regimens.1, 2, 3, 4, 5, 6, 7, 8, 9 Indeed, work done in patients has established that the earlier the intervention, the better the chance of ameliorating the renal dysfunction.⁶

In current clinical practice, acute renal failure is typically diagnosed by measuring serum creatinine. Unfortunately, creatinine is an unreliable indicator during acute changes in kidney function.¹⁰ First, serum creatinine concentrations might not change until about 50% of kidney function has already been lost. Second, serum creatinine does not accurately depict kidney function until a steady state has been reached, which could take several days. However, work in animals has shown that although acute renal failure due to ischaemia can be prevented, treated, or both by several techniques, these must be started very early after the renal injury.1, 2, 3

Acute renal dysfunction occurs in up to 40% of adults after cardiac surgery, with 1–5% needing dialysis, in whom the mortality rate approaches 80%.11, 12, 13 Pathophysiological mechanisms include diminished renal blood flow, loss of pulsatile flow, hypothermia, atheroembolism, and a generalised inflammatory response. Various clinical algorithms have been proposed for prediction of acute renal failure needing dialysis, based on preoperative risk factors,12, 13, 14, 15 but no methods are available for the early diagnosis of lesser degrees of renal injury. Acute renal failure also complicates up to 10% of cardiac surgical procedures in infants and children with congenital heart disease.¹⁶ This population is especially vulnerable to development of acute renal failure since many children need multiple surgical procedures for step-by-step repair of complex congenital anomalies. However, these children are unique in that comorbid conditions such as advanced age, atherosclerotic disease, and diabetes are usually absent, making them an ideal group for investigation of biomarkers as predictors of early ischaemic renal injury.

We have previously used a genome-wide interrogation strategy to identify kidney genes that are induced very early after ischaemia in animal models, whose protein products might serve as novel biomarkers for the initiation phase of acute renal failure.¹⁷ We identified neutrophil gelatinase-associated lipocalin (NGAL) as one of the most strikingly upregulated genes (HUGO-approved gene name LCN2) and overexpressed proteins in the kidney after ischaemia.17, 18, 19 NGAL was easily detected in urine early after ischaemia in mouse and rat models.¹⁸ We therefore tested the hypothesis that NGAL represents an early biomarker of ischaemic renal injury in children undergoing cardiac surgery.