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Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies

2010; Nature Portfolio; Volume: 28; Issue: 5 Linguagem: Inglês

10.1038/nbt.1623

1546-1696

Vishal S. Vaidya, Josef Ozer, Frank Dieterle, Fitz B. Collings, Victoria Ramírez, Sean P. Troth, Nagaraja Muniappa, Douglas T. Thudium, David Gerhold, Daniel Holder, Norma A. Bobadilla, Estelle Marrer, Elias Perentes, André Cordier, Jacky Vonderscher, Gerald Maurer, Peter L. Goering, Frank D. Sistare, Joseph V. Bonventre,

Muscle and Compartmental Disorders

Urinary kidney injury-1 (Kim-1) outperforms serum creatinine, blood urea nitrogen and urinary N-acetyl-β-D-glucosaminidase in detecting kidney damage induced in rats by a range of nephrotoxicants. Earlier detection of renal injury, enabled by monitoring levels of urinary Kim-1, should enable elimination of nephrotoxic candidates sooner in the drug development pipeline. 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-β-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.