title: Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs.
abstract: As kidney is a major target organ affected by drug toxicity, early detection of renal injury is critical in preclinical drug development. In past decades, a series of novel biomarkers of drug-induced nephrotoxicity were discovered and verified in rats. However, limited data regarding the performance of novel biomarkers in non-rodent species are publicly available. To increase the applicability of these biomarkers, we evaluated the performance of 4 urinary biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), clusterin, total protein, and N-acetyl-β-D-glucosaminidase (NAG), relative to histopathology and traditional clinical chemistry in beagle dogs with acute kidney injury (AKI) induced by gentamicin. The results showed that urinary NGAL and clusterin levels were significantly elevated in dogs on days 1 and 3 after administration of gentamicin, respectively. Gene expression analysis further provided mechanistic evidence to support that NGAL and clusterin are potential biomarkers for the early assessment of drug-induced renal damage. Furthermore, the high area (both AUCs=1.000) under receiver operator characteristics (ROC) curve also indicated that NGAL and clusterin were the most sensitive biomarkers for detection of gentamicin-induced renal proximal tubular toxicity. Our results also suggested that NAG may be used in routine toxicity testing due to its sensitivity and robustness for detection of tissue injury. The present data will provide insights into the preclinical use of these biomarkers for detection of drug-induced AKI in non-rodent species.
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176, China; Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Zhou
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176, China.
authors.forename: Ben
authors.initials: B
authors.lastname: Ma
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Lin
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Qu
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huo
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176, China.
authors.forename: Jufeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176, China; Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730, China. Electronic address: libo@nifdc.org.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
mesh_terms: D000209:Acute-Phase Proteins / Q000652:urine; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis / Q000652:urine*; D051152:Clusterin / Q000097:blood / Q000652:urine; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005839:Gentamicins / Q000633:toxicity*; D054834:Lipocalins / Q000097:blood / Q000652:urine; D008297:Male; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000652:urine; D011897:Random Allocation
chemical_list: D000209:Acute-Phase Proteins; D000900:Anti-Bacterial Agents; D015415:Biomarkers; D051152:Clusterin; D005839:Gentamicins; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; C000589991:neutrophil gelatinase-associated lipocalin protein, dog
keywords: Beagle dogs; Biomarkers; Clusterin; Nephrotoxicity; Neutrophil gelatinase-associated lipocalin; Preclinical study