Neutrophil Gelatinase-Associated Lipocalin: A Novel Early Urinary Biomarker for Cisplatin Nephrotoxicity

Abstract

Background: Cisplatin is one of the most widely used chemotherapeutic agents, but the risk of nephrotoxicity frequently hinders the use of higher doses to maximize its antineoplastic effects. The lack of early biomarkers has impaired our ability to initiate potential therapeutic or preventive interventions in cisplatin nephrotoxicity in a timely manner. In this study, we have explored the expression and urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) in a mouse model of cisplatin-induced nephrotoxic injury. Methods: Mice were subjected to intraperitoneal injections of 20 mg/kg (high dose) or 5 mg/kg (low dose) cisplatin. The expression of NGAL was measured in the kidney and urine by Western analysis and immunofluorescence, and compared to changes in serum creatinine and urinary N-acetyl-β-D-glucosaminidase (NAG). Results: Cisplatin resulted in tubule cell necrosis and apoptosis following the high dose, but not the low dose. By Western analysis, NGAL protein was rapidly induced in the kidney within 3 h of high-dose cisplatin. By immunofluorescence, NGAL was induced predominantly in proximal tubule cells in a punctate cytoplasmic distribution, reminiscent of a secreted protein. NGAL was easily detected in the urine by Western analysis within 3 h of cisplatin administration in a dose- and duration-dependent manner. By comparison, changes in urinary NAG or serum creatinine were not evident until 96 h after cisplatin. Using defined concentrations of purified recombinant NGAL, urinary NGAL excretion following cisplatin administration was quantified to be in the 20–80 ng/ml range. Conclusion: The results indicate that NGAL represents an early and quantitative urinary biomarker for cisplatin nephrotoxicity.

Evaluation of Renal Function Using the Level of Neutrophil Gelatinase-Associated Lipocalin is Not Predictive of Nephrotoxicity Associated with Cisplatin-Based Chemotherapy

“…The preclinical studies showed that urinary NGAL levels were increased based on the dose and duration during three-hour cisplatin infusion in the rat model of cisplatin-induced nephrotoxicity (Mishra et al, 2004). A previous clinical study evaluated the role of NGAL in the follow-up of cisplatin-induced renal damage.…”

“…There are some studies regarding NGAL use as an early indicator in acute renal failure associated with cardiac surgery, the use of contrast agent and renal transplantation (Parikh et al, 2006;Wagener et al, 2006;Ling et al, 2008). However, there are limited studies in its use in chemotherapeutic agent-induced acute renal failure (Mishra et al, 2004).…”

Neutrophil Gelatinase-Associated Lipocalin induces the expression of heme oxygenase-1 and superoxide dismutase 1, 2

“…NGAL is a 25-kDa glycoprotein that has initially been discovered in granules of human neutrophils and was later shown to be expressed by certain epithelial cells as well, especially during inflammation (Kubben et al 2007). In addition, NGAL is thought to be an acute phase protein whose expression is induced under harmful conditions such as intoxication, renal injury, burn injury, human cancers, inflammatory bowel disease, infection, and other forms of cellular stresses (Nielsen et al 1996, Seth et al 2002, Mishra et al 2003, Flo et al 2004, Mishra et al 2004, Vemula et al 2004, Tong et al 2005 Zhang et al 2007, Bauer et al 2008, Cho and Kim 2009, Katano et al 2009). …”

Evaluation of Urinary α-Glutathione-S-Transferase (α-GST) as a Marker of Early Cisplatin Induced Kidney Injury

“…We could found the incidence of kidney injury in these patients after cisplatin administration is around 20%. In more recent experience, incidences of 20-30% renal insufficiency have been reported using saline hydration and diuresis (9). Ronald et al studied the early clinical use of cisplatin and saw dose-related cisplatininduced acute renal failure in 14 to 100% of patients, with the incidence, varying with the cumulative dose.…”

“…Platinum compounds like cisplatin are very effective as chemotherapeutic agents but the risk of nephrotoxicity frequently hinders the use of its higher dose to maximise its antineoplastic effects. The lack of early biomarkers of AKI has impaired our ability to initiate the preventive interventions for the nephrotoxicity in a timely manner [9]. To improve the identification of patients at risk of AKI and their care, novel approaches for early diagnosis and risk stratification are needed.…”