Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Nature Biotechnology volume 28, pages 478–485 (2010)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Chertow, G.M., Burdick, E., Honour, M., Bonventre, J.V. & Bates, D.W. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J. Am. Soc. Nephrol. 16, 3365–3370 (2005).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Vaidya, V.S., Ramirez, V., Ichimura, T., Bobadilla, N.A. & Bonventre, J.V. 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).

    Article  CAS  Google Scholar 

  4. Liangos, O. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Emeigh Hart, S.G. Assessment of renal injury in vivo. J. Pharmacol. Toxicol. Methods 52, 30–45 (2005).

    Article  CAS  Google Scholar 

  7. Price, R.G. 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).

    PubMed  Google Scholar 

  8. Bonventre, J.V., Vaidya, V.S., Schmouder, R., Feig, P. & Dieterle, F. Next-generation biomarkers for detecting kidney toxicity. Nat. Biotechnol. 28, 436–440 (2010).

    Article  CAS  Google Scholar 

  9. Ichimura, T. 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).

    Article  CAS  Google Scholar 

  10. Ichimura, T. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Zhou, Y. 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).

    Article  CAS  Google Scholar 

  15. Han, W.K., Bailly, V., Abichandani, R., Thadhani, R. & Bonventre, J.V. Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int. 62, 237–244 (2002).

    Article  CAS  Google Scholar 

  16. van Timmeren, M.M. 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).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Ichimura, T., Hung, C.C., Yang, S.A., Stevens, J.L. & Bonventre, J.V. Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am. J. Physiol. Renal Physiol. 286, F552–F563 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Carson, R.T. & Vignali, D.A. Simultaneous quantitation of 15 cytokines using a multiplexed flow cytometric assay. J. Immunol. Methods 227, 41–52 (1999).

    Article  CAS  Google Scholar 

  21. Mattes, W.B. & Walker, E.G. Translational toxicology and the work of the predictive safety testing consortium. Clin. Pharmacol. Ther. 85, 327–330 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Harrell, F.E. Regression Modeling Strategies, edn. 1. (Springer, New York; 2001).

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

    Article  Google Scholar 

  26. Pencina, M.J., D'Agostino, R.B. Sr., D'Agostino, R.B. Jr. & Vasan, R.S. 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).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Sing, T., Sander, O., Beerenwinkel, N. & Lengauer, T. ROCR: visualizing classifier performance in R. Bioinformatics 21, 3940–3941 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

  1. Josef S Ozer

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

Authors and 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. Vishal S Vaidya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Josef S Ozer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frank Dieterle
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fitz B Collings
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Victoria Ramirez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sean Troth
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nagaraja Muniappa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Douglas Thudium
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David Gerhold
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Daniel J Holder
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Norma A Bobadilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Estelle Marrer
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Elias Perentes
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. André Cordier
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jacky Vonderscher
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Gérard Maurer
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Peter L Goering
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Frank D Sistare
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Joseph V Bonventre
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding authors

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

Ethics declarations

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.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing