Identification of metabolomic biomarkers for drug-induced acute kidney injury in rats

Takeki Uehara, Akira Horinouchi, Yuji Morikawa, Yutaka Tonomura, Keiichi Minami, Atsushi Ono, Jyoji Yamate, Hiroshi Yamada, Yasuo Ohno, Tetsuro Urushidani

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29 Citations (Scopus)

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 24h after a single dose of 2-bromoethylamine or n-phenylanthranilic acid and at 24h after 7days 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.

Original languageEnglish
Pages (from-to)1087-1095
Number of pages9
JournalJournal of Applied Toxicology
Volume34
Issue number10
DOIs
Publication statusPublished - Oct 2014
Externally publishedYes

Keywords

  • 3-indoxyl sulfate
  • 3-methylhistidine
  • Acute kidney injury
  • Guanidoacetate
  • Metabolomics
  • Nephrotoxicity
  • Rat

ASJC Scopus subject areas

  • Toxicology

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  • Cite this

    Uehara, T., Horinouchi, A., Morikawa, Y., Tonomura, Y., Minami, K., Ono, A., Yamate, J., Yamada, H., Ohno, Y., & Urushidani, T. (2014). Identification of metabolomic biomarkers for drug-induced acute kidney injury in rats. Journal of Applied Toxicology, 34(10), 1087-1095. https://doi.org/10.1002/jat.2933