A panel of urinary biomarkers to monitor reversibility of renal injury and a serum marker with improved potential to assess renal function.
The Predictive Safety Testing Consortium's first regulatory submission to qualify kidney safety biomarkers revealed two deficiencies. To address the need for biomarkers that monitor recovery from agent-induced renal damage, we scored changes in the levels of urinary biomarkers in rats during recovery from renal injury induced by exposure to carbapenem A or gentamicin. All biomarkers responded to histologic tubular toxicities to varied degrees and with different kinetics. After a recovery period, all biomarkers returned to levels approaching those observed in uninjured animals. We next addressed the need for a serum biomarker that reflects general kidney function regardless of the exact site of renal injury. Our assay for serum cystatin C is more sensitive and specific than serum creatinine (SCr) or blood urea nitrogen (BUN) in monitoring generalized renal function after exposure of rats to eight nephrotoxicants and two hepatotoxicants. This sensitive serum biomarker will enable testing of renal function in animal studies that do not involve urine collection.
Ozer
Josef S
JS
Department of Investigative Laboratory Sciences, Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania, USA.
Dieterle
Frank
F
Troth
Sean
S
Perentes
Elias
E
Cordier
André
A
Verdes
Pablo
P
Staedtler
Frank
F
Mahl
Andreas
A
Grenet
Olivier
O
Roth
Daniel R
DR
Wahl
Daniel
D
Legay
François
F
Holder
Daniel
D
Erdos
Zoltan
Z
Vlasakova
Katerina
K
Jin
Hong
H
Yu
Yan
Y
Muniappa
Nagaraja
N
Forest
Tom
T
Clouse
Holly K
HK
Reynolds
Spencer
S
Bailey
Wendy J
WJ
Thudium
Douglas T
DT
Topper
Michael J
MJ
Skopek
Thomas R
TR
Sina
Joseph F
JF
Glaab
Warren E
WE
Vonderscher
Jacky
J
Maurer
Gérard
G
Chibout
Salah-Dine
SD
Sistare
Frank D
FD
Gerhold
David L
DL
D000818:Animals; D054316:Biomarkers, Pharmacological / Q000097:blood / Q000378:metabolism / Q000652:urine; D001806:Blood Urea Nitrogen; D015780:Carbapenems / Q000633:toxicity; D003404:Creatinine / Q000097:blood; D055316:Cystatin C / Q000097:blood*; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005839:Gentamicins / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000175:diagnosis*; D007677:Kidney Function Tests / Q000379:methods*; D008297:Male; D012372:ROC Curve; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D054316:Biomarkers, Pharmacological; D015780:Carbapenems; D055316:Cystatin C; D005839:Gentamicins; D003404:Creatinine
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