title: Tissue Kim-1 and urinary clusterin as early indicators of cisplatin-induced acute kidney injury in rats.
abstract: The kidney is one of the main targets of drug toxicity, and early detection of renal damage is critical in preclinical drug development. A model of cisplatin-induced nephrotoxicity in male Sprague Dawley rats treated for 1, 3, 5, 7, or 14 days at 1 mg/kg/day was used to monitor the spatial and temporal expression of various indicators of kidney toxicity during the progression of acute kidney injury (AKI). As early as 1 day after cisplatin treatment, positive kidney injury molecule-1 (Kim-1) immunostaining, observed in the outer medulla of the kidney, and changes in urinary clusterin indicated the onset of proximal tubular injury in the absence of functional effects. After 3 days of treatment, Kim-1 protein levels in urine increased more than 20-fold concomitant with a positive clusterin immunostaining and an increase in urinary osteopontin. Tubular basophilia was also noted, while serum creatinine and blood urea nitrogen levels were elevated only after 5 days, together with tubular degeneration. In conclusion, tissue Kim-1 and urinary clusterin were the most sensitive biomarkers for detection of cisplatin-induced kidney damage. Thereafter, urinary Kim-1 and osteopontin, as well as clusterin immunostaining accurately correlated with the histopathological findings. When AKI is suspected in preclinical rat studies, Kim-1, clusterin, and osteopontin should be part of urinalysis and/or IHC can be performed.
authors.affiliation: Drug Safety Sciences, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium. pvinken@its.jnj.com
authors.forename: Petra
authors.initials: P
authors.lastname: Vinken
authors.forename: Sofie
authors.initials: S
authors.lastname: Starckx
authors.forename: Erio
authors.initials: E
authors.lastname: Barale-Thomas
authors.forename: Adriana
authors.initials: A
authors.lastname: Looszova
authors.forename: Manisha
authors.initials: M
authors.lastname: Sonee
authors.forename: Nick
authors.initials: N
authors.lastname: Goeminne
authors.forename: Loes
authors.initials: L
authors.lastname: Versmissen
authors.forename: Kristel
authors.initials: K
authors.lastname: Buyens
authors.forename: Ann
authors.initials: A
authors.lastname: Lampo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D051152:Clusterin / Q000652:urine*; D004195:Disease Models, Animal; D000072596:Hepatitis A Virus Cellular Receptor 1; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D053495:Osteopontin / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests / Q000379:methods*; D016482:Urinalysis
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; C495243:Clu protein, mouse; D051152:Clusterin; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; D053495:Osteopontin; D002945:Cisplatin