Rat Urinary Osteopontin and Neutrophil Gelatinase-Associated Lipocalin Improve Certainty of Detecting Drug-Induced Kidney Injury

Abstract

Traditional kidney biomarkers are insensitive indicators of acute kidney injury, with meaningful changes occurring late in the course of injury. The aim of this work was to demonstrate the diagnostic potential of urinary osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL) for drug-induced kidney injury (DIKI) in rats using data from a recent regulatory qualification submission of translational DIKI biomarkers and to compare performance of NGAL and OPN to five previously qualified DIKI urinary biomarkers. Data were compiled from 15 studies of 11 different pharmaceuticals contributed by Critical Path Institute's Predictive Safety Testing Consortium (PSTC) Nephrotoxicity Working Group (NWG). Rats were given doses known to cause DIKI or other target organ toxicity, and urinary levels of the candidate biomarkers were assessed relative to kidney histopathology and serum creatinine (sCr) and blood urea nitrogen (BUN).OPN and NGAL outperformed sCr and BUN in identifying DIKI manifested as renal tubular epithelial degeneration or necrosis. In addition, urinary OPN and NGAL, when used with sCr and BUN, increased the ability to detect renal tubular epithelial degeneration or necrosis. NGAL and OPN had comparable or improved performance relative to Kim-1, clusterin, albumin, total protein, and beta-2 microglobulin. Given these data, both urinary OPN and NGAL are appropriate for use with current methods for assessing nephrotoxicity to identify and monitor DIKI in regulatory toxicology studies in rats. These data also support exploratory use of urinary OPN and NGAL in safety monitoring strategies of early clinical trials to aid in the assurance of patient safety.

Usefulness of urinary biomarkers for nephrotoxicity in cynomolgus monkeys treated with gentamicin, cisplatin, and puromycin aminonucleoside

“…The usefulness of NGAL to detect the damage of the renal tubules has been reported in rats (Han et al, 2012;Phillips et al, 2016) and dogs (Kai et al, 2013;Zhou et al, 2014). After renal ischemia or nephrotoxicity, intrarenal NAGL synthesis is dramatically upregulated at protein levels.…”

Acute biomarker panel changes associated with amphotericin B nephrotoxicity in female Sprague-Dawley rats

“…In this 10 day study, AmpB (3 mg/kg/day) was used as a prototype kidney toxicant to induce experimental nephrotoxicity in female SD rats. The findings described here are anticipated to provide the basis for the inclusion of both male and female rats as needed in studies designed to detect DIKI in preclinical toxicology studies (EMA, 2009;Phillips et al, 2016).…”

“…Microscopic examination of the H&E-stained slides was initially performed by a molecular pathologist with full knowledge of the treatment group and any in-life study information that would improve the diagnostic accuracy of the study, excluding the novel biomarker results. Histopathology lesion grading followed the recommended histopathology best practices in the context of rat novel kidney biomarker qualification studies from the PSTC NWG (Phillips et al, 2016). The kidney lesion severity grading scores were characterized as minimal, mild (slight), moderate, marked and severe.…”

“…The normal ranges and variability of these biomarkers in male and female Sprague-Dawley rats have been described (Gautier et al, 2014a). Pharmaceutical companies have continued to integrate DIKI biomarkers in rat toxicology studies (Hoffmann et al, 2010;Burt et al, 2014;Phillips et al, 2016). Yet, relative performances of the qualified DIKI biomarkers have been evaluated mostly in male SD rats and male Han-Wistar rats (Vlasakova et al, 2014).…”

Serum Neutrophil Gelatinase-Associated Lipocalin Levels In Early Detection Of Contrast-Induced Nephropathy

“…Padhy et al reported that NGAL peaked at 4 th hour and returned to normal by 48 th hour in CIN after coronary angiography [14]. In a recent paper, Philipps et al demonstrated that NGAL was a good marker of drug-induced acute renal injury [15].…”