Performance of novel kidney biomarkers in preclinical toxicity studies.
The kidney is one of the main targets of drug toxicity, but early detection of renal damage is often difficult. As part of the InnoMed PredTox project, a collaborative effort aimed at assessing the value of combining omics technologies with conventional toxicology methods for improved preclinical safety assessment, we evaluated the performance of a panel of novel kidney biomarkers in preclinical toxicity studies. Rats were treated with a reference nephrotoxin or one of several proprietary compounds that were dropped from drug development in part due to renal toxicity. Animals were dosed at two dose levels for 1, 3, and 14 days. Putative kidney markers, including kidney injury molecule-1 (Kim-1), lipocalin-2 (Lcn2), clusterin, and tissue inhibitor of metalloproteinases-1, were analyzed in kidney and urine using quantitative real-time PCR, ELISA, and immunohistochemistry. Changes in gene/protein expression generally correlated well with renal histopathological alterations and were frequently detected at earlier time points or at lower doses than the traditional clinical parameters blood urea nitrogen and serum creatinine. Urinary Kim-1 and clusterin reflected changes in gene/protein expression and histopathological alterations in the target organ in the absence of functional changes. This confirms clusterin and Kim-1 as early and sensitive, noninvasive markers of renal injury. Although Lcn2 did not appear to be specific for kidney toxicity, its rapid response to inflammation and tissue damage in general may suggest its utility in routine toxicity testing.
Hoffmann
Dana
D
Department of Toxicology, University of Würzburg, Würzburg, Germany.
Adler
Melanie
M
Vaidya
Vishal S
VS
Rached
Eva
E
Mulrane
Laoighse
L
Gallagher
William M
WM
Callanan
John J
JJ
Gautier
Jean C
JC
Matheis
Katja
K
Staedtler
Frank
F
Dieterle
Frank
F
Brandenburg
Arnd
A
Sposny
Alexandra
A
Hewitt
Philip
P
Ellinger-Ziegelbauer
Heidrun
H
Bonventre
Joseph V
JV
Dekant
Wolfgang
W
Mally
Angela
A
D000818:Animals; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016133:Polymerase Chain Reaction; D012372:ROC Curve; D051381:Rats; D017208:Rats, Wistar; D018675:Toxicity Tests
D015415:Biomarkers; D017931:DNA Primers