Prediction of Drug Induced Nephrotoxicity Using Traditional Markers and Urinary Biomarkers in Sprague Dawley Rats
Loading...
Date
2019
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Department of Biochemistry and Biochemical Engineering Jacob School of Biotechnology and Bioengineering Sam Higginbottom University of Agriculture, Technology And Sciences, Allahabad-211007 (U.P.) India
Abstract
Consistent, sensitive biomarkers of acute kidney injury in animal models and humans have
historically represented a poorly met need for investigators and clinicians. This research work
was undertaken to evaluate novel renal markers use in identifying acute kidney injury (AKI)
compared to traditional serum biomarkers which show changes when 30-40% of kidney is
damaged in experimentally induced nephrotoxicity in male Sprague Dawley rats. Cisplatin
and Gentamicin, a known nephrotoxicant is used at 2.5 and 5 mg/kg dose (single dose,
intraperitoneal) and 30 and 100 mg/kg/day (subcutaneous) level for 7 consecutive days,
respectively. On day 4 and day 8 post treatment, serum and urine samples from these rats were
analysed for traditional (serum: blood urea nitrogen and creatinine, urine: protein, albumin and
micro albumin (mALB) and novel biomarkers [Clusterin, kidney injury molecule-1 (Kim-1),
Lipcalin-2/ Neutrophil gelatinase associated lipocalin (NGAL) and Cystatin C], light and
electron (transmission and scanning) microscopic evaluation of kidneys were carried out.
Further immunohistochemical localization of Kim-1 was carried out on day 4 and 8 kidney
samples as well.
Urinary biomarkers were increased several folds as compared to traditional markers at both
doses of cisplatin and gentamicin treated rats and were duration and dose dependent.
Histological and electron microscopic changes seen on Day 4 and Day 8 were of minimal to
mild and moderate to severe in nature at both doses, respectively. Current experimental data
suggests urine Clusterin and IP 10 are highly sensitive biomarkers of detecting nephrotoxicity
with Cisplatin and Gentamicin in Sprague Dawley rats. Similarly, Kim-1 is also considered
highly sensitive renal biomarker for Cisplatin and Gentamicin (only at 100 mg/kg) as the levels
increased on day 4 that persisted until day 8 too. Urinary Kim-1 level, immunoreactivity and
histological changes further confirms to several published reports and FDA and EMA
recommendation that Kim-1 is highly sensitive biomarker for detecting drug induced acute
renal injury.
The results indicated that the novel urinary biomarkers are sensitive than traditional biomarkers
in identifying kidney damage. Kim-l level and immunohistochemical localization
demonstrated the correlation of the renal injury. Renal biomarkers is useful in identifying early
kidney damage and thus assessing adversity in toxicology studies. In addition, this noninvasive
method is useful in diagnosing acute kidney damage in patients when the renal damage is less
than 30% which is not detected using traditional biomarkers.
Description
Ph.D. Thesis
Keywords
null