title: Urinary clusterin, cystatin C, beta2-microglobulin and total protein as markers to detect drug-induced kidney injury.
abstract: Earlier and more reliable detection of drug-induced kidney injury would improve clinical care and help to streamline drug-development. As the current standards to monitor renal function, such as blood urea nitrogen (BUN) or serum creatinine (SCr), are late indicators of kidney injury, we conducted ten nonclinical studies to rigorously assess the potential of four previously described nephrotoxicity markers to detect drug-induced kidney and liver injury. Whereas urinary clusterin outperformed BUN and SCr for detecting proximal tubular injury, urinary total protein, cystatin C and beta2-microglobulin showed a better diagnostic performance than BUN and SCr for detecting glomerular injury. Gene and protein expression analysis, in-situ hybridization and immunohistochemistry provide mechanistic evidence to support the use of these four markers for detecting kidney injury to guide regulatory decision making in drug development. The recognition of the qualification of these biomarkers by the EMEA and FDA will significantly enhance renal safety monitoring.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis, Basel, Switzerland. frank.dieterle@novartis.com
authors.forename: Frank
authors.initials: F
authors.lastname: Dieterle
authors.forename: Elias
authors.initials: E
authors.lastname: Perentes
authors.forename: André
authors.initials: A
authors.lastname: Cordier
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Roth
authors.forename: Pablo
authors.initials: P
authors.lastname: Verdes
authors.forename: Olivier
authors.initials: O
authors.lastname: Grenet
authors.forename: Serafino
authors.initials: S
authors.lastname: Pantano
authors.forename: Pierre
authors.initials: P
authors.lastname: Moulin
authors.forename: Daniel
authors.initials: D
authors.lastname: Wahl
authors.forename: Andreas
authors.initials: A
authors.lastname: Mahl
authors.forename: Peter
authors.initials: P
authors.lastname: End
authors.forename: Frank
authors.initials: F
authors.lastname: Staedtler
authors.forename: François
authors.initials: F
authors.lastname: Legay
authors.forename: Kevin
authors.initials: K
authors.lastname: Carl
authors.forename: David
authors.initials: D
authors.lastname: Laurie
authors.forename: Salah-Dine
authors.initials: SD
authors.lastname: Chibout
authors.forename: Jacky
authors.initials: J
authors.lastname: Vonderscher
authors.forename: Gérard
authors.initials: G
authors.lastname: Maurer
mesh_terms: D000818:Animals; D054316:Biomarkers, Pharmacological / Q000378:metabolism / Q000652:urine*; D016009:Chi-Square Distribution; D051152:Clusterin / Q000235:genetics / Q000378:metabolism / Q000652:urine*; D003404:Creatinine / Q000097:blood / Q000378:metabolism; D055316:Cystatin C / Q000235:genetics / Q000378:metabolism / Q000652:urine*; D020869:Gene Expression Profiling; D006651:Histocytochemistry; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D007674:Kidney Diseases / Q000175:diagnosis / Q000473:pathology; D007677:Kidney Function Tests / Q000379:methods*; D007678:Kidney Glomerulus / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000473:pathology; D008297:Male; D011379:Prognosis; D011507:Proteinuria / Q000652:urine; D012372:ROC Curve; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D001613:beta 2-Microglobulin / Q000235:genetics / Q000378:metabolism / Q000652:urine*
chemical_list: D054316:Biomarkers, Pharmacological; D051152:Clusterin; D055316:Cystatin C; D001613:beta 2-Microglobulin; D003404:Creatinine
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