title: Time course of renal proximal tubule injury, reversal, and related biomarker changes in rats following cisplatin administration.
abstract: Cisplatin (CDDP) is known to produce renal proximal tubule injury. Various renal biomarkers have been related to CDDP nephrotoxicity in previous research, but the temporal and spatial relationship of these biomarkers to injury reversal has not been well defined. In this study, the progression and reversal of renal histopathology findings relative to serum and urinary biomarker changes were examined during a 4-week postdose period following single intraperitoneal administration of CDDP (1 mg/kg) or 0.9% saline. Degeneration, vacuolation, inflammation, and regeneration of the S3 segment of proximal tubules were evident 72 hours following CDDP administration. Tubular degeneration and regeneration were also observed at 1 and 1.5 weeks but at lower incidences and/or severity indicating partial reversal. Complete histologic reversal was observed by 2 weeks following CDDP administration. Urinary kidney injury molecule 1 (KIM-1), α-glutathione-S-transferase (α-GST), and albumin levels increased at 72 hours postdosing, concurrently with the earliest histologic evidence of tubule injury. Changes in urinary KIM-1 correlated with KIM-1 immunostaining in the proximal tubular epithelial cells. No significant changes in serum biomarkers occurred except for a minimal increase in urea nitrogen at 1.5 weeks postdosing. Of the novel renal biomarkers examined, urinary KIM-1, α-GST, and albumin showed excellent concordance with CDDP-induced renal injury progression and reversal; and these biomarkers were more sensitive than traditional serum biomarkers in detecting early, acute renal tubular damage confirmed by histopathology. Furthermore, urinary KIM-1, α-GST, and albumin outperformed other biomarkers in correlating with the time of maximum histologic injury.
authors.affiliation: Drug Safety Sciences, Janssen Research & Development, LLC, San Diego, CA, USA. jmcduffi@its.jnj.com
authors.forename: James Eric
authors.initials: JE
authors.lastname: McDuffie
authors.forename: Jing Ying
authors.initials: JY
authors.lastname: Ma
authors.forename: Marciano
authors.initials: M
authors.lastname: Sablad
authors.forename: Manisha
authors.initials: M
authors.lastname: Sonee
authors.forename: Lynn
authors.initials: L
authors.lastname: Varacallo
authors.forename: Calvert
authors.initials: C
authors.lastname: Louden
authors.forename: Antonio
authors.initials: A
authors.lastname: Guy
authors.forename: Jennifer
authors.initials: J
authors.lastname: Vegas
authors.forename: Xuejun
authors.initials: X
authors.lastname: Liu
authors.forename: David
authors.initials: D
authors.lastname: La
authors.forename: Sandra
authors.initials: S
authors.lastname: Snook
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood* / Q000652:urine*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage*; D051152:Clusterin / Q000652:urine; D005982:Glutathione Transferase / Q000378:metabolism; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000418:Albumins; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D002945:Cisplatin; D051152:Clusterin; D005982:Glutathione Transferase; D007527:Isoenzymes; C110936:Havcr1 protein, rat; C119995:glutathione S-transferase alpha
keywords: Sprague-Dawley rat; cisplatin; nephrotoxicity; reversal