title: Evaluation of novel acute urinary rat kidney toxicity biomarker for subacute toxicity studies in preclinical trials.
abstract: Novel urinary protein biomarkers for the detection of acute renal damage, recently accepted by the U.S. Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency (Japan), now have to be validated in practice. Limited data regarding the performance of these acute markers after subacute or subchronic treatment are publicly available. To increase the area of applicability of these markers, it is important to evaluate the ability to detect them after 28 days of treatment or even longer. Wistar rats were treated with three doses of cisplatin, vancomycin, or puromycin to induce renal damage. Twelve candidate proteins were measured by Luminex xMAP-based WideScreen assays, MesoScale Discovery-based MULTI-SPOT technology, or RENA-strip dipstick assay after 28 days. Treatment with all three model compounds resulted in a dose-dependent increase in urinary biomarkers, specific for the observed areas within the nephron, determined histopathologically. The most promising biomarkers in this study were NGAL, Kim-1, osteopontin, clusterin, RPA-1, and GSTYb1, detected by multiplexing technologies. The RENA-strip dipstick assay delivered good diagnostic results for vancomycin-treated but not for cisplatin- or puromycin-treated rats. Taken together, the data show that these new biomarkers are robust and measurable for longer term studies to predict different types of kidney toxicities.
authors.affiliation: Merck KGaA, Merck Serono, Toxicology, Darmstadt, Germany.
authors.forename: Tobias Christian
authors.initials: TC
authors.lastname: Fuchs
authors.forename: Katharina
authors.initials: K
authors.lastname: Frick
authors.forename: Barbara
authors.initials: B
authors.lastname: Emde
authors.forename: Stephanie
authors.initials: S
authors.lastname: Czasch
authors.forename: Friedrich
authors.initials: F
authors.lastname: von Landenberg
authors.forename: Philip
authors.initials: P
authors.lastname: Hewitt
mesh_terms: D000208:Acute Disease; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D015415:Biomarkers / Q000652:urine*; D002945:Cisplatin / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D008297:Male; D011691:Puromycin / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D059551:Toxicity Tests, Subacute / Q000379:methods*; D014640:Vancomycin / Q000633:toxicity; D015262:Xenobiotics / Q000633:toxicity*
chemical_list: D000900:Anti-Bacterial Agents; D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D015262:Xenobiotics; D011691:Puromycin; D014640:Vancomycin; D002945:Cisplatin