title: Rat Urinary Osteopontin and Neutrophil Gelatinase-Associated Lipocalin Improve Certainty of Detecting Drug-Induced Kidney Injury.
abstract: Traditional kidney biomarkers are insensitive indicators of acute kidney injury, with meaningful changes occurring late in the course of injury. The aim of this work was to demonstrate the diagnostic potential of urinary osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL) for drug-induced kidney injury (DIKI) in rats using data from a recent regulatory qualification submission of translational DIKI biomarkers and to compare performance of NGAL and OPN to five previously qualified DIKI urinary biomarkers. Data were compiled from 15 studies of 11 different pharmaceuticals contributed by Critical Path Institute's Predictive Safety Testing Consortium (PSTC) Nephrotoxicity Working Group (NWG). Rats were given doses known to cause DIKI or other target organ toxicity, and urinary levels of the candidate biomarkers were assessed relative to kidney histopathology and serum creatinine (sCr) and blood urea nitrogen (BUN).OPN and NGAL outperformed sCr and BUN in identifying DIKI manifested as renal tubular epithelial degeneration or necrosis. In addition, urinary OPN and NGAL, when used with sCr and BUN, increased the ability to detect renal tubular epithelial degeneration or necrosis. NGAL and OPN had comparable or improved performance relative to Kim-1, clusterin, albumin, total protein, and beta-2 microglobulin. Given these data, both urinary OPN and NGAL are appropriate for use with current methods for assessing nephrotoxicity to identify and monitor DIKI in regulatory toxicology studies in rats. These data also support exploratory use of urinary OPN and NGAL in safety monitoring strategies of early clinical trials to aid in the assurance of patient safety.
authors.affiliation: *Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut 06877.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Phillips
authors.affiliation: Merck and Co, Inc, Summit, New Jersey 07901.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Holder
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania 19406.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ennulat
authors.affiliation: Sanofi, Vitry-sur-Seine, 94400 France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Gautier
authors.affiliation: Critical Path Institute, Tucson, Arizona 85718.
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Sauer
authors.affiliation: AbbVie, North Chicago, Illinois 60064.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Janssen Research and Development, San Diego, California 92116.
authors.forename: Eric
authors.initials: E
authors.lastname: McDuffie
authors.affiliation: Janssen Research and Development, San Diego, California 92116.
authors.forename: Manisha
authors.initials: M
authors.lastname: Sonee
authors.affiliation: Merck and Co, Inc, Summit, New Jersey 07901.
authors.forename: Yi-Zhong
authors.initials: YZ
authors.lastname: Gu
authors.affiliation: Merck and Co, Inc, Summit, New Jersey 07901.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Troth
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania 19406.
authors.forename: Karen
authors.initials: K
authors.lastname: Lynch
authors.affiliation: Eli Lilly and Company Indianapolis, Indiana 46285.
authors.forename: Diane
authors.initials: D
authors.lastname: Hamlin
authors.affiliation: Summit Therapeutics, Cambridge, Massachusetts 02142.
authors.forename: David G
authors.initials: DG
authors.lastname: Peters
authors.affiliation: Novartis Pharmaceuticals, Basel, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Brees
authors.affiliation: Critical Path Institute, Tucson, Arizona 85718 ewalker@c-path.org.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Walker
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis* / Q000652:urine; D000209:Acute-Phase Proteins / Q000652:urine*; D000818:Animals; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine*; D053495:Osteopontin / Q000652:urine*; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000652:urine*; D012372:ROC Curve; D051381:Rats; D015203:Reproducibility of Results; D016482:Urinalysis
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; C506897:Spp1 protein, rat; D053495:Osteopontin; D003404:Creatinine
keywords: drug development tool qualification; drug-induced kidney injury; letter of support.; neutrophil gelatinase-associated lipocalin (NGAL); osteopontin (OPN); urinary safety biomarker