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

Abstract

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.

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Figure 1: Correlation of Kim-1 mRNA and protein levels in the kidney and urine, and comparison of urinary Kim-1 levels with SCr, BUN and urinary NAG with severity grades of histopathology following a dose response and time course in ten Novartis rat toxicology studies.
Figure 2: ROC analysis for Novartis studies.
Figure 3: Correlation of BUN, SCr, urinary Kim-1 and urinary NAG with severity grades of histopathologic change after gentamicin treatment in the Merck study.
Figure 4: Correlation of BUN, SCr, urinary Kim-1 and urinary NAG with severity grades of histopathologic change after cisplatin nephrotoxicity treatment in the Merck study.
Figure 5: ROC analysis for Merck studies.
Figure 6: Comparison of Kim-1 with routinely used biomarkers as an early diagnostic indicator of kidney injury after 20-min bilateral I/R.

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Acknowledgements

Part of this work was presented at the American Society of Nephrology meeting in Philadelphia, November 7–11, 2005 and the Society of Toxicology meeting in Charlotte, North Carolina, March 4–9, 2007. This work was supported by National Institutes of Health grants ES016723 to V.S.V.; DK39773, DK72831 and DK74099 to J.V.B., and by research grants G34511M and CO1-40182A-1 from the Mexican Council of Science and Technology (CONACYT) and DGAPA IN208602-3 of National University of Mexico to N.A.B. We thank T.W. Forest, B. Sacre-Salem and T.E. Adams for providing histomorphologic readings for the Merck studies. The Novartis Biomarker CRADA team is acknowledged for contributing to the project, in particular D.R. Roth, A. Mahl, F. Staedtler, P. Verdes, D. Wahl, F. Legay, P. End and S.-D. Chibout. We thank P. Bernd for performing the protein homogenization. S. Leuillet and B. Palate from CIT are acknowledged for performing the Novartis in-life studies and the histopathology assessment. J. Mapes from Rules Based Medicine is acknowledged for the Kim-1 measurements of the Novartis studies. We thank D. Moor and P. Brodmann from Biolytix for the validation and measurements of the RT-PCR assays. We thank M. Topper, W. Bailey, G. Miller and P. Srinivasa for helpful comments on the manuscript. We thank K. Thompson from Center for Drug Evaluation and Research, US FDA for critically reviewing the manuscript.

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Authors

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V.S.V., J.S.O., N.A.B., F.D.S., F.D., J.V., G.M. and J.V.B. designed research; V.S.V., J.S.O., F.B.C., V.R., S.T., N.M., D.T., D.G., D.J.H., E.P. and A.C. performed research; V.S.V., J.S.O., S.T., D.J.H., N.A.B., F.D.S. and J.V.B. contributed new reagents/analytic tools; V.S.V., J.S.O., S.T., N.M., D.T., D.G., D.J.H., N.A.B., F.D.S., E.M., F.D. and J.V.B. analyzed data; and V.S.V., J.S.O., N.A.B., F.D.S., E.M., F.D., P.L.G. and J.V.B. wrote the paper.

Corresponding authors

Correspondence to Vishal S Vaidya, Josef S Ozer or Frank D Sistare.

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Competing interests

J.V.B. is an inventor on KIM-1 patents, which have been licensed by Partners Healthcare to Johnson & Johnson, Genzyme and BiogenIdec. J.S.O., S.T., N.M., D.T., D.G., D.J.H. and F.D.S. are employed by Merck. F.D., E.M. E.P. A.C. J.V. and G.M.are employed by Novartis.

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Supplementary Tables 1–7, Supplementary Figs. 1–3, Supplementary Methods and Supplementary Data (PDF 15206 kb)

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Vaidya, V., Ozer, J., Dieterle, F. et al. Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol 28, 478–485 (2010). https://doi.org/10.1038/nbt.1623

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