Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies.
Kidney toxicity accounts both for the failure of many drug candidates as well as considerable patient morbidity. Whereas histopathology remains the gold standard for nephrotoxicity in animal systems, serum creatinine (SCr) and blood urea nitrogen (BUN) are the primary options for monitoring kidney dysfunction in humans. The transmembrane tubular protein kidney injury molecule-1 (Kim-1) was previously reported to be markedly induced in response to renal injury. Owing to the poor sensitivity and specificity of SCr and BUN, we used rat toxicology studies to compare the diagnostic performance of urinary Kim-1 to BUN, SCr and urinary N-acetyl-beta-D-glucosaminidase (NAG) as predictors of kidney tubular damage scored by histopathology. Kim-1 outperforms SCr, BUN and urinary NAG in multiple rat models of kidney injury. Urinary Kim-1 measurements may facilitate sensitive, specific and accurate prediction of human nephrotoxicity in preclinical drug screens. This should enable early identification and elimination of compounds that are potentially nephrotoxic.
Vaidya
Vishal S
VS
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. vvaidya@partners.org
Ozer
Josef S
JS
Dieterle
Frank
F
Collings
Fitz B
FB
Ramirez
Victoria
V
Troth
Sean
S
Muniappa
Nagaraja
N
Thudium
Douglas
D
Gerhold
David
D
Holder
Daniel J
DJ
Bobadilla
Norma A
NA
Marrer
Estelle
E
Perentes
Elias
E
Cordier
André
A
Vonderscher
Jacky
J
Maurer
Gérard
G
Goering
Peter L
PL
Sistare
Frank D
FD
Bonventre
Joseph V
JV
D000118:Acetylglucosaminidase / Q000652:urine; D000818:Animals; D054316:Biomarkers, Pharmacological / Q000378:metabolism / Q000652:urine*; D001806:Blood Urea Nitrogen; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism / Q000652:urine*; D002945:Cisplatin / Q000633:toxicity; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D005839:Gentamicins / Q000633:toxicity; D006651:Histocytochemistry; D007668:Kidney / Q000187:drug effects / Q000293:injuries; D007677:Kidney Function Tests / Q000379:methods* / Q000592:standards; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D012372:ROC Curve; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015427:Reperfusion Injury; D013853:Thioacetamide / Q000633:toxicity
D000118:Acetylglucosaminidase; D054316:Biomarkers, Pharmacological; D015815:Cell Adhesion Molecules; D002945:Cisplatin; D003404:Creatinine; D016572:Cyclosporine; D005839:Gentamicins; D013853:Thioacetamide; C110936:Havcr1 protein, rat
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