title: Evaluation of the relative performance of 12 urinary biomarkers for renal safety across 22 rat sensitivity and specificity studies.
abstract: Novel urinary kidney safety biomarkers have been identified recently that may outperform or add value to the conventional renal function biomarkers, blood urea nitrogen (BUN) and serum creatinine (SCr). To assess the relative performance of the growing list of novel biomarkers, a comprehensive evaluation was conducted for 12 urinary biomarkers in 22 rat studies including 12 kidney toxicants and 10 compounds with toxicities observed in organs other than kidney. The kidney toxicity studies included kidney tubular toxicants and glomerular toxicants. The 12 urinary biomarkers evaluated included Kim-1, clusterin, osteopontin, osteoactivin, albumin, lipocalin-2, GST-α, β2-microglobulin, cystatin C, retinol binding protein 4, total protein, and N-acetyl-β-D-glucosaminidase. Receiver operator characteristic (ROC) curves were generated for each biomarker and for BUN and SCr to compare the relative performance of the 12 biomarkers in individual animals against the microscopic histomorphologic changes observed in the kidney. Among the kidney toxicity biomarkers analyzed, Kim-1, clusterin, and albumin showed the highest overall performance for detecting drug-induced renal tubular injury in the rat in a sensitive and specific manner, whereas albumin showed the highest performance in detecting drug-induced glomerular injury. Although most of the evaluated kidney biomarkers were more sensitive in detecting kidney toxicity compared with BUN and SCr, all biomarkers demonstrated some lack of specificity, most notably NGAL and osteopontin, illustrating the need for caution when interpreting urinary biomarker increases in rat samples when organ toxicity is unknown.
authors.affiliation: Department of Safety Assessment and Laboratory Animal Resources, Merck Research Laboratories, West Point, PA 19486.
authors.forename: Katerina
authors.initials: K
authors.lastname: Vlasakova
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Erdos
authors.forename: Sean P
authors.initials: SP
authors.lastname: Troth
authors.forename: Kathleen
authors.initials: K
authors.lastname: McNulty
authors.forename: Valérie
authors.initials: V
authors.lastname: Chapeau-Campredon
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mokrzycki
authors.forename: Nagaraja
authors.initials: N
authors.lastname: Muniappa
authors.forename: Yi-Zhong
authors.initials: YZ
authors.lastname: Gu
authors.forename: Daniel
authors.initials: D
authors.lastname: Holder
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Bailey
authors.forename: Frank D
authors.initials: FD
authors.lastname: Sistare
authors.forename: Warren E
authors.initials: WE
authors.lastname: Glaab
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000652:urine*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000652:urine*; D057230:Limit of Detection; D008297:Male; D012372:ROC Curve; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018675:Toxicity Tests
chemical_list: D015415:Biomarkers
keywords: Kim-1; albumin.; clusterin; kidney biomarkers; renal toxicity