Evaluation of the relative performance of 12 urinary biomarkers for renal safety across 22 rat sensitivity and specificity studies

• Published in: Toxicological sciences 2014-03, Vol.138 (1), p.3-20
• Main Authors: Vlasakova, Katerina, Erdos, Zoltan, Troth, Sean P, McNulty, Kathleen, Chapeau-Campredon, Valérie, Mokrzycki, Nathalie, Muniappa, Nagaraja, Gu, Yi-Zhong, Holder, Daniel, Bailey, Wendy J, Sistare, Frank D, Glaab, Warren E
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers - urine; Enzyme-Linked Immunosorbent Assay; Female; Kidney - drug effects; Kidney - pathology; Kidney Diseases - blood; Kidney Diseases - chemically induced; Kidney Diseases - pathology; Kidney Diseases - urine; Limit of Detection; Male; Rats; Rats, Sprague-Dawley; Rats, Wistar; ROC Curve; Toxicity Tests
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kft330

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.