title: Assessment of cisplatin-induced kidney injury using an integrated rodent platform.
abstract: Current diagnosis of drug-induced kidney injury (DIKI) primarily relies on detection of elevated plasma creatinine (Cr) or blood urea nitrogen (BUN) levels; however, both are indices of overall kidney function and changes are delayed with respect to onset of nephron injury. Our aim was to investigate whether early changes in new urinary DIKI biomarkers predict plasma Cr, BUN, renal hemodynamic and kidney morphological changes associated with kidney injury following a single dose of cisplatin (CDDP) using an integrated platform in rodent. Conscious surgically prepared male Han Wistar rats were given a single intraperitoneal dose of CDDP (15mg/kg). Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), urinalysis, DIKI biomarkers, CDDP pharmacokinetics, blood pressures, heart rate, body temperature and electroencephalogram (EEG) were measured in the same vehicle- or CDDP-treated animals over 72h. Plasma chemistry (including Cr and BUN) and renal tissues were examined at study termination. Cisplatin caused progressive reductions of GFR, ERPF, heart rate and body temperature from day 1 (0-24h). DIKI biomarkers including alpha-glutathione S-transferase (α-GST) significantly increased as early as 6h post-dose, which preceded significant declines of GFR and ERPF (24h), increased plasma Cr and BUN (72h), and associated with renal acute tubular necrosis at 72h post-dose. The present study adds to the current understanding of CDDP action by demonstrating that early increases in urinary excretion of α-GST predict DIKI risk following acute exposure to CDDP in rats, before changes in traditional DIKI markers are evident.
authors: Global Safety Assessment, AstraZeneca R&D Waltham, MA 02451, USA.
authors: Yafei
authors: Y
authors: Chen
authors: David
authors: D
authors: Brott
authors: Wenli
authors: W
authors: Luo
authors: Eric
authors: E
authors: Gangl
authors: Harriet
authors: H
authors: Kamendi
authors: Herbert
authors: H
authors: Barthlow
authors: David
authors: D
authors: Lengel
authors: James
authors: J
authors: Fikes
authors: Lewis
authors: L
authors: Kinter
authors: Jean-Pierre
authors: JP
authors: Valentin
authors: Russell
authors: R
authors: Bialecki
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000378:metabolism* / Q000633:toxicity*; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
chemical_list: D005978:Glutathione; D002945:Cisplatin