Article | Published:

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

Nature Biotechnology volume 28, pages 478485 (2010) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , , & Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J. Am. Soc. Nephrol. 16, 3365–3370 (2005).

  2. 2.

    & Drug-associated renal dysfunction and injury. Nat. Clin. Pract. Nephrol. 2, 80–91 (2006).

  3. 3.

    , , , & Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am. J. Physiol. Renal Physiol. 290, F517–F529 (2006).

  4. 4.

    et al. Urinary N-acetyl-beta-(d)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J. Am. Soc. Nephrol. 18, 904–912 (2007).

  5. 5.

    et al. Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans. Clin. Transl. Sci. 1, 200–208 (2008).

  6. 6.

    Assessment of renal injury in vivo. J. Pharmacol. Toxicol. Methods 52, 30–45 (2005).

  7. 7.

    The role of NAG (N-acetyl-beta-D-glucosaminidase) in the diagnosis of kidney disease including the monitoring of nephrotoxicity. Clin. Nephrol. 38 Suppl 1, S14–S19 (1992).

  8. 8.

    , , , & Next-generation biomarkers for detecting kidney toxicity. Nat. Biotechnol. 28, 436–440 (2010).

  9. 9.

    et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J. Biol. Chem. 273, 4135–4142 (1998).

  10. 10.

    et al. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J. Clin. Invest. 118, 1657–1668 (2008).

  11. 11.

    et al. Identification of putative gene based markers of renal toxicity. Environ. Health Perspect. 112, 465–479 (2004).

  12. 12.

    et al. Shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration. J. Biol. Chem. 277, 39739–39748 (2002).

  13. 13.

    et al. Kidney injury molecule-1 is an early biomarker of cadmium nephrotoxicity. Kidney Int. 72, 985–993 (2007).

  14. 14.

    et al. Comparison of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury, and chromium. Toxicol. Sci. 101, 159–170 (2008).

  15. 15.

    , , , & Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int. 62, 237–244 (2002).

  16. 16.

    et al. High urinary excretion of kidney injury molecule-1 is an independent predictor of graft loss in renal transplant recipients. Transplantation 84, 1625–1630 (2007).

  17. 17.

    et al. Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity. Am. J. Physiol. Renal Physiol. 292, F131–F139 (2007).

  18. 18.

    , , , & Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am. J. Physiol. Renal Physiol. 286, F552–F563 (2004).

  19. 19.

    et al. Tubular kidney injury molecule-1 in protein-overload nephropathy. Am. J. Physiol. Renal Physiol. 291, F456–F464 (2006).

  20. 20.

    & Simultaneous quantitation of 15 cytokines using a multiplexed flow cytometric assay. J. Immunol. Methods 227, 41–52 (1999).

  21. 21.

    & Translational toxicology and the work of the predictive safety testing consortium. Clin. Pharmacol. Ther. 85, 327–330 (2009).

  22. 22.

    et al. Towards consensus practices to qualify safety biomarkers for use in early drug development. Nat. Biotechnol. 28, 446–454 (2010).

  23. 23.

    & Nonhepatic thioacetamide injury. II. The morphologic features of proximal renal tubular injury. Am. J. Pathol. 74, 575–590 (1974).

  24. 24.

    Regression Modeling Strategies, edn. 1. (Springer, New York; 2001).

  25. 25.

    A note on a general definition of the coefficient of determination. Biometrika 78, 691–692 (1991).

  26. 26.

    , , & Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat. Med. 27, 157–172 (2008).

  27. 27.

    et al. Kidney injury molecule-1 expression in transplant biopsies is a sensitive measure of cell injury. Kidney Int. 73, 608–614 (2008).

  28. 28.

    et al. A rapid urine test for early detection of kidney injury. Kidney Int. 76, 108–114 (2009).

  29. 29.

    , , & ROCR: visualizing classifier performance in R. Bioinformatics 21, 3940–3941 (2005).

  30. 30.

    & A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 148, 839–843 (1983).

Download references

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.

Author information

Author notes

    • Josef S Ozer

    Present address: Pharmacokinetics, Dynamics, and Metabolism, PGRD, Pfizer, Andover Laboratories, Andover, Massachusetts, USA.

Affiliations

  1. Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Vishal S Vaidya
    • , Fitz B Collings
    • , Victoria Ramirez
    •  & Joseph V Bonventre
  2. Department of Investigative Laboratory Sciences, Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania, USA.

    • Josef S Ozer
    • , Douglas Thudium
    • , David Gerhold
    •  & Frank D Sistare
  3. Translational Sciences, Novartis Institutes for BioMedical Research, Basel, Switzerland.

    • Frank Dieterle
    • , Estelle Marrer
    • , Elias Perentes
    • , André Cordier
    • , Jacky Vonderscher
    •  & Gérard Maurer
  4. Department of Pathology, Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania, USA.

    • Sean Troth
    •  & Nagaraja Muniappa
  5. Department of Biometrics, Merck Research Laboratories, West Point, Pennsylvania, USA.

    • Daniel J Holder
  6. Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.

    • Norma A Bobadilla
  7. Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.

    • Peter L Goering

Authors

  1. Search for Vishal S Vaidya in:

  2. Search for Josef S Ozer in:

  3. Search for Frank Dieterle in:

  4. Search for Fitz B Collings in:

  5. Search for Victoria Ramirez in:

  6. Search for Sean Troth in:

  7. Search for Nagaraja Muniappa in:

  8. Search for Douglas Thudium in:

  9. Search for David Gerhold in:

  10. Search for Daniel J Holder in:

  11. Search for Norma A Bobadilla in:

  12. Search for Estelle Marrer in:

  13. Search for Elias Perentes in:

  14. Search for André Cordier in:

  15. Search for Jacky Vonderscher in:

  16. Search for Gérard Maurer in:

  17. Search for Peter L Goering in:

  18. Search for Frank D Sistare in:

  19. Search for Joseph V Bonventre in:

Contributions

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.

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.

Corresponding authors

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

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1–7, Supplementary Figs. 1–3, Supplementary Methods and Supplementary Data

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nbt.1623

Further reading