ArticlesNeutrophil gelatinase-associated lipocalin (NGAL) as a biomarker 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.
Section snippets
Patients
This investigation was approved by the institutional review board of the Cincinnati Children's Hospital Medical Center. All children undergoing cardiopulmonary bypass for surgical correction of congenital heart disease between January, 2004, and November, 2004, were prospectively enrolled. We obtained written informed consent from the legal guardian of every child before enrolment. Exclusion criteria included pre-existing renal insufficiency, diabetes mellitus, peripheral vascular disease, and
Results
100 children were considered for participation in the study. 29 were excluded because of nephrotoxin use (ibuprofen, angiotensin-converting-enzyme inhibitors, gentamicin, vancomycin) before or soon after surgery. Thus, 71 children were included in the study.
Acute renal injury occurred in 20 children (28%) within a 3-day period. Of these, serum creatinine rose 24–48 h after cardiopulmonary bypass in eight, but in the other 12 the increase happened 48–72 h after the procedure. Thus, the diagnosis
Discussion
We have shown that the concentration of NGAL in urine and serum is strikingly raised in children with acute renal failure after cardiopulmonary bypass.
Human NGAL is a 25 kDa protein covalently bound to gelatinase from human neutrophils.23 It is generally expressed at very low concentrations in several human tissues, including kidney, trachea, lungs, stomach, and colon.24 NGAL expression is induced in injured epithelia; for example, concentrations are raised in the serum of patients with acute
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These authors contributed equally to this work