Neutrophil gelatinase-associated lipocalin as a biomarker of acute kidney injury--where do we stand today?

Abstract

Neutrophil gelatinase-associated lipocalin (NGAL) is the first member of a new generation of diagnostics called ‘renal biomarkers’ that may be just a few steps away from entering clinical practice. What does this new test measure? Is this the new ‘troponin for the kidney’? What are the most important conclusions from clinical studies on NGAL? What are their limitations? How will NGAL affect clinical practice? Nephrologists will soon encounter these questions more frequently. Hence, in this editorial, we will attempt to briefly summarize the current state of the NGAL field. NGAL, a small 25-kDa protein of the lipocalin family, was discovered through a genome-wide analysis of kidney genes that are induced in response to experimental acute kidney injury (AKI) in animals [1]. NGAL was among the top upregulated genes in damaged kidneys and fulfilled the criteria of a promising biomarker of tubular damage since it was a secreted tubular protein that entered both urine and serum rapidly after the onset of AKI. Markedly, increased levels of NGAL in blood and urine could be detected following ischaemia-reperfusion injury in mice [1]. The early preclinical studies prompted a large and rapidly expanding body of clinical trials that addressed the utility of NGAL in diagnosing AKI. Studies in patients undergoing cardiopulmonary bypass revealed marked increases of plasma and urinary NGAL levels as early as 2 h after surgery in patients that developed AKI [2,3]. This increase in NGAL preceded the increase in serum creatinine by 24–48 h. Similar increases in NGAL levels were observed in other clinical settings, including contrast-induced AKI, sepsisassociated AKI and AKI following kidney transplantation [4–7]. Furthermore, several studies suggested that elevated NGAL levels are predictive of poor clinical outcomes in AKI, including dialysis initiation and mortality, even when adjusted for conventional predictors, such as creatinine levels [2,8–10]. Based on findings in mice and patients, a model of NGAL trafficking along the nephron was developed (Figure 1) which supported the concept of urinary or serum NGAL levels as biosensors of kidney damage [11]. NGAL messenger RNA and protein expression are markedly induced in tubules of the damaged kidney, resulting in elevated urinary and plasma levels of NGAL. In addition, circulating NGAL is filtered in the glomerulus but undergoes rapid and effective proximal tubular reabsorption unless the proximal tubule uptake machinery is damaged [12]. As a