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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 detectionmore » 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. - Highlights: • Urinary NGAL, clusterin and NAG levels were significantly elevated in canine AKI. • NGAL and clusterin gene expression were increased following treatment with gentamicin. • NGAL and clusterin have high specificity and sensitivity for detection of AKI.« less

Authors:
 [1];  [2]; ; ; ; ;  [1];  [1];  [2]
  1. 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)
  2. (China)
Publication Date:
OSTI Identifier:
22439845
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 280; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BEAGLES; BIOLOGICAL MARKERS; CHEMISTRY; DETECTION; DRUGS; ENZYMES; GENES; INJURIES; KIDNEYS; NEUTROPHILS; RATS; SENSITIVITY; SPECIFICITY; TOXICITY; UREA

Citation Formats

Zhou, Xiaobing, Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730, Ma, Ben, Lin, Zhi, Qu, Zhe, Huo, Yan, Wang, Jufeng, Li, Bo, E-mail: libo@nifdc.org.cn, and Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730. Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2014.07.002.
Zhou, Xiaobing, Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730, Ma, Ben, Lin, Zhi, Qu, Zhe, Huo, Yan, Wang, Jufeng, Li, Bo, E-mail: libo@nifdc.org.cn, & Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730. Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs. United States. doi:10.1016/J.TAAP.2014.07.002.
Zhou, Xiaobing, Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730, Ma, Ben, Lin, Zhi, Qu, Zhe, Huo, Yan, Wang, Jufeng, Li, Bo, E-mail: libo@nifdc.org.cn, and Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730. Wed . "Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs". United States. doi:10.1016/J.TAAP.2014.07.002.
@article{osti_22439845,
title = {Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs},
author = {Zhou, Xiaobing and Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730 and Ma, Ben and Lin, Zhi and Qu, Zhe and Huo, Yan and Wang, Jufeng and Li, Bo, E-mail: libo@nifdc.org.cn and Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730},
abstractNote = {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. - Highlights: • Urinary NGAL, clusterin and NAG levels were significantly elevated in canine AKI. • NGAL and clusterin gene expression were increased following treatment with gentamicin. • NGAL and clusterin have high specificity and sensitivity for detection of AKI.},
doi = {10.1016/J.TAAP.2014.07.002},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 280,
place = {United States},
year = {Wed Oct 01 00:00:00 EDT 2014},
month = {Wed Oct 01 00:00:00 EDT 2014}
}