title: Identification of metabolomic biomarkers for drug-induced acute kidney injury in rats.
abstract: Nephrotoxicity is a common side effect observed during both nonclinical and clinical drug development investigations. The present study aimed to identify metabolomic biomarkers that could provide early and sensitive indication of nephrotoxicity in rats. Metabolomic analyses were performed using capillary electrophoresis-time-of-flight mass spectrometry on rat plasma collected at 9 and 24 h after a single dose of 2-bromoethylamine or n-phenylanthranilic acid and at 24 h after 7 days of repeated doses of gentamicin, cyclosporine A or cisplatin. Among a total of 169 metabolites identified, 3-methylhistidine (3-MH), 3-indoxyl sulfate (3-IS) and guanidoacetate (GAA) were selected as candidate biomarkers. The biological significance and reproducibility of the observed changes were monitored over time in acute nephrotoxicity model rats treated with a single dose of cisplatin, with the glomerular filtration rate monitored by determination of creatinine clearance. Increased plasma levels of 3-MH and 3-IS were related to a decline in glomerular filtration due to a renal failure. In contrast, the decrease in plasma GAA, which is synthesized from arginine and glycine in the kidneys, was considered to reflect decreased production due to renal malfunction. Although definitive validation studies are required to confirm their usefulness and reliability, 3-MH, 3-IS and GAA may prove to be valuable plasma biomarkers for monitoring nephrotoxicity in rats.
authors.affiliation: Drug Developmental Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan; Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan; Department of Veterinary Pathology, Graduate School of Agriculture and Biological Science, Osaka Prefecture University, Izumisano, Osaka, Japan.
authors.forename: Takeki
authors.initials: T
authors.lastname: Uehara
authors.forename: Akira
authors.initials: A
authors.lastname: Horinouchi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Morikawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tonomura
authors.forename: Keiichi
authors.initials: K
authors.lastname: Minami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ono
authors.forename: Jyoji
authors.initials: J
authors.lastname: Yamate
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ohno
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Urushidani
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D003404:Creatinine / Q000097:blood; D023381:Endpoint Determination; D005189:False Positive Reactions; D019791:Guanidine / Q000097:blood; D007200:Indican / Q000097:blood; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008762:Methylhistidines / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
chemical_list: D015415:Biomarkers; D008762:Methylhistidines; D003404:Creatinine; D019791:Guanidine; C028118:3-methylhistidine; D007200:Indican
keywords: 3-indoxyl sulfate; 3-methylhistidine; acute kidney injury; guanidoacetate; metabolomics; nephrotoxicity; rat