title: Comparative profile of commercially available urinary biomarkers in preclinical drug-induced kidney injury and recovery in rats.
abstract: We designed a study to provide reversibility and comparative injury data for several candidate urinary biomarkers of kidney injury in the United States Food and Drug Administration biomarker qualification process. The nephrotoxin gentamicin was given to rats once on each of three days and the animals were killed during dosing or over the following 42 days. Between days one and three, all biomarkers except albumin were elevated, peaked at day 7, and returned to control levels by day 10 (μ- and α-glutathione S-transferases, and renal papillary antigen-1) or day 15 (kidney injury molecule-1, lipocalin-2, osteopontin, and clusterin). All biomarkers performed better during injury than during recovery except osteopontin, which performed equally well in both time periods. During the evolution of injury, kidney injury molecule-1, renal papillary antigen-1, and clusterin best mirrored the histopathologic lesions. During injury resolution, kidney injury molecule-1, osteopontin, and blood urea nitrogen best reflected recovery. Based on histopathology, necrosis, or apoptosis scoring, kidney injury molecule-1 was the best biomarker of overall renal injury. Evaluation by regeneration score showed that renal papillary antigen-1 best reflected tubular and/or collecting duct regeneration, especially during recovery. Thus, these biomarkers performed with different effectiveness when evaluated by individual pathological processes such as necrosis, apoptosis, and regeneration.
authors.affiliation: Division of Applied Pharmacology Research, Office of Testing and Research, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA. Rodney.rouse@fda.hhs.gov
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Rouse
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Sharron R
authors.initials: SR
authors.lastname: Stewart
authors.forename: Barry A
authors.initials: BA
authors.lastname: Rosenzweig
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Espandiari
authors.forename: Nakissa K
authors.initials: NK
authors.lastname: Sadrieh
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000652:urine*; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood / Q000652:urine*; D015815:Cell Adhesion Molecules / Q000652:urine; D051152:Clusterin / Q000652:urine; D005839:Gentamicins; D005982:Glutathione Transferase / Q000652:urine; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D054834:Lipocalins / Q000652:urine; D008297:Male; D009336:Necrosis; D053495:Osteopontin / Q000652:urine; D011237:Predictive Value of Tests; D040901:Proteomics / Q000379:methods; D012372:ROC Curve; D051381:Rats; D017207:Rats, Sprague-Dawley; D011933:Reagent Kits, Diagnostic; D012038:Regeneration; D013997:Time Factors
chemical_list: D015415:Biomarkers; D015815:Cell Adhesion Molecules; D051152:Clusterin; D005839:Gentamicins; D005982:Glutathione Transferase; D054834:Lipocalins; D053495:Osteopontin; D011933:Reagent Kits, Diagnostic; C498500:Clu protein, rat; C110936:Havcr1 protein, rat; C506897:Spp1 protein, rat