Human neutrophil gelatinase associated lipocalin (NGAL), also known as neutrophil glucosaminidase-associated lipocalin, 24p3, oncogene 24p3, p25, migration stimulating factor inhibitor (MSFI), human neutrophil lipocalin (HNL), α1-microglobulin related protein, siderocalin, or uterocalin, is a 198 amino acid long secreted glycoprotein encoded by a gene located at the chromosome locus 9q34.11. The NGAL gene has seven exons that produce at least five functional transcripts, the most common of which encodes for a 198 amino acid secreted protein. NGAL expression is significantly up-regulated both in the tissues and in the body fluids in several benign conditions including inflammatory, ischemic and metabolic disorders.
In this context, NGAL has been shown to modulate the pathogenesis of several benign conditions particularly vascular diseases (e.g. atherosclerosis) and renal diseases. In atherosclerotic plaques, NGAL expression correlated with presence of inflammatory changes, and signs of plaque instability like intra-plaque hemorrhage and presence of a luminal thrombus. NGAL has been shown to associate with gelatinases, particularly matrix metalloproteinase-8 (MMP8) and 9 (MMP9). Through this association, it prolong the proteolytic activity of the MMPs.
Observations in metabolic disorders showed that NGAL levels were increased in human subjects upon a 26-hour continuous infusion of insulin suggesting that it is up-regulated in response to insulin. Serum NGAL levels were also higher in women with gestational diabetes and pre-eclampsia. Diabetes is associated with chronic inflammation and micro-vasculopathy. However, whether the increase in NGAL levels reflects a response or contributes to the pathogenesis of this disease is still being explored.
NGAL expression is rapidly up-regulated in response to renal injury and has proven to be a robust marker for acute kidney injury (AKI). NGAL was effective in the early diagnosis of AKI in several clinical settings, including perioperative AKI, contrast-induced AKI, sepsis-associated AKI, and AKI following kidney transplantation. Importantly, NGAL effectively discriminated patients in the emergency room with intrinsic AKI from those with other diagnoses including pre-renal AKI, CKD, and those who actually had normal renal function. Furthermore, several studies suggested that NGAL could be useful in the prediction of poor clinical outcomes in AKI. In these studies, serum and/or urine NGAL levels were determined using various techniques: automated e.g. turbidimetric assays in clinical chemistry analyzers or chemiluminescence immunoassays in immunoassay analyzers; manual e.g. ELISAs and multiplex platforms. Provocatively proposed as “the troponin of the kidney”, several reliable clues have now been gathered that the current assessment of NGAL by commercial methods is anything but specific for renal injury as yet. Undeniably, the introduction of NGAL brought valuable gains for early diagnosis of AKI, but yet this enigmatic protein is far from being considered “the” ideal biomarker. At variance with troponin testing, which is based on antibodies that specifically recognize the cardiospecific isoforms of both troponin I and T, the cocktail of antibodies used in the current NGAL immunoassays do not distinguish between the protein produced by the tubular cell from that synthesized by neutrophils (where it was first described as “ Neutrophil Gelatinase ”), cardiomyocytes, as well as that released from other sources including uterus, prostate, salivary glands, lung, liver, trachea, stomach and colon.
Further Reading: Chakraborty et al, Biochim Biophys Acta. 2012 Aug;1826(1):129-69 and Lippi et al, Clin Chem Lab Med. 2012 Published Online: 07/06/2012.