Urinary clusterin, cystatin C, beta2-microglobulin and total protein as markers to detect drug-induced kidney injury.
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.
Dieterle
Frank
F
Novartis Institutes for BioMedical Research, Novartis, Basel, Switzerland. frank.dieterle@novartis.com
Perentes
Elias
E
Cordier
André
A
Roth
Daniel R
DR
Verdes
Pablo
P
Grenet
Olivier
O
Pantano
Serafino
S
Moulin
Pierre
P
Wahl
Daniel
D
Mahl
Andreas
A
End
Peter
P
Staedtler
Frank
F
Legay
François
F
Carl
Kevin
K
Laurie
David
D
Chibout
Salah-Dine
SD
Vonderscher
Jacky
J
Maurer
Gérard
G
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*
D054316:Biomarkers, Pharmacological; D051152:Clusterin; D055316:Cystatin C; D001613:beta 2-Microglobulin; D003404:Creatinine
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