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A panel of urinary biomarkers to monitor reversibility of renal injury and a serum marker with improved potential to assess renal function


The Predictive Safety Testing Consortium's first regulatory submission to qualify kidney safety biomarkers revealed two deficiencies. To address the need for biomarkers that monitor recovery from agent-induced renal damage, we scored changes in the levels of urinary biomarkers in rats during recovery from renal injury induced by exposure to carbapenem A or gentamicin. All biomarkers responded to histologic tubular toxicities to varied degrees and with different kinetics. After a recovery period, all biomarkers returned to levels approaching those observed in uninjured animals. We next addressed the need for a serum biomarker that reflects general kidney function regardless of the exact site of renal injury. Our assay for serum cystatin C is more sensitive and specific than serum creatinine (SCr) or blood urea nitrogen (BUN) in monitoring generalized renal function after exposure of rats to eight nephrotoxicants and two hepatotoxicants. This sensitive serum biomarker will enable testing of renal function in animal studies that do not involve urine collection.

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Figure 1: For carbapenem A–treated rats, correlation of urinary ELISA and MesoScale Discovery biomarker levels with histomorphologic change.
Figure 2: Correlation of urinary MesoScale Discovery biomarker levels with histomorphologic change for carbapenem A-treated rats.
Figure 3: Correlation of urinary ELISA- and MesoScale Discovery-derived biomarker levels with histomorphologic change in gentamicin-treated rats.
Figure 4: ROC curves for the inclusion and exclusion analysis with eight different nephrotoxicant studies and two different hepatotoxicant studies from Novartis.
Figure 5: Levels of S-cystatin C, BUN and SCr observed in individual animals.
Figure 6: Levels of S-cystatin C, BUN and SCr observed in individual animals.


  1. Bonventre, J.V. et al. Next-generation biomarkers for detecting kidney toxicity. Nat. Biotechnol. 28, 436–440 (2010).

    Article  CAS  Google Scholar 

  2. Ferguson, M.A., Vaidya, V.S. & Bonventre, J.V. Biomarkers of nephrotoxic acute kidney injury. Toxicology 245, 182–193 (2008).

    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. Han, W.K. et al. Urinary biomarkers in the early diagnosis of acute kidney injury. Kidney Int. 73, 863–869 (2008).

    Article  CAS  Google Scholar 

  5. Yu, Y., Jin, H., Holder, D., Ozer, J.S. & Villarreal, S. Urinary biomarkers trefoil factor 3 and albumin enable early detection of kidney tubular injury. Nat. Biotechnol. 28, 470–477 (2010).

    Article  CAS  Google Scholar 

  6. Dieterle, F. et al. Urinary clusterin, cystatin C, β2-microglobulin and total protein as markers to detect drug-induced kidney injury. Nat. Biotechnol. 28, 463–469 (2010).

    Article  CAS  Google Scholar 

  7. Vaidya, V.S. et al. Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat. Biotechnol. 28, 478–485 (2010).

    Article  CAS  Google Scholar 

  8. 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 

  9. Razzaque, M.S. & Taguchi, T. Cellular and molecular events leading to renal tubulointerstitial fibrosis. Med. Electron Microsc. 35, 68–80 (2002).

    Article  CAS  Google Scholar 

  10. Westhuyzen, J. et al. Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrol. Dial. Transplant. 18, 543–551 (2003).

    Article  CAS  Google Scholar 

  11. 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 

  12. 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 

  13. Berger, T. et al. Lipocalin 2-deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury. Proc. Natl. Acad. Sci. USA 103, 1834–1839 (2006).

    Article  CAS  Google Scholar 

  14. Silkensen, J.R., Agarwal, A., Nath, K.A., Manivel, J.C. & Rosenberg, M.E. Temporal induction of clusterin in cisplatin nephrotoxicity. J. Am. Soc. Nephrol. 8, 302–305 (1997).

    CAS  PubMed  Google Scholar 

  15. Orlandi, A. et al. Modulation of clusterin isoforms is associated with all-trans retinoic acid-induced proliferative arrest and apoptosis of intimal smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 25, 348–353 (2005).

    Article  CAS  Google Scholar 

  16. Vaidya, V.S. & Bonventre, J.V. Mechanistic biomarkers for cytotoxic acute kidney injury. Expert Opin. Drug Metab. Toxicol. 2, 697–713 (2006).

    Article  CAS  Google Scholar 

  17. Hoffmann, W. Trefoil factors TFF (trefoil factor family) peptide-triggered signals promoting mucosal restitution. Cell. Mol. Life Sci. 62, 2932–2938 (2005).

    Article  CAS  Google Scholar 

  18. Mussap, M. & Plebani, M. Biochemistry and clinical role of human cystatin C. Crit. Rev. Clin. Lab. Sci. 41, 467–550 (2004).

    Article  CAS  Google Scholar 

  19. Takuwa, S., Ito, Y., Ushijima, K. & Uchida, K. Serum cystatin-C values in children by age and their fluctuation during dehydration. Pediatr. Int. 44, 28–31 (2002).

    Article  CAS  Google Scholar 

  20. Madero, M., Sarnak, M.J. & Stevens, L.A. Serum cystatin C as a marker of glomerular filtration rate. Curr. Opin. Nephrol. Hypertens. 15, 610–616 (2006).

    Article  CAS  Google Scholar 

  21. Dharnidharka, V.R., Kwond, C. & Stevens, G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am. J. Kidney Dis. 40, 221–226 (2002).

    Article  CAS  Google Scholar 

  22. Shlipak, M.G., Praught, M.L. & Sarnak, M.J. Update on cystatin C: new insights into the importance of mild kidney dysfunction. Curr. Opin. Nephrol. Hypertens. 15, 270–275 (2006).

    Article  CAS  Google Scholar 

  23. Herget-Rosenthal, S. et al. Early detection of acute renal failure by serum cystatin C. Kidney Int. 66, 1115–1122 (2004).

    Article  CAS  Google Scholar 

  24. Anonymous US Food and Drug Administration Agency 510(k) Substantial equivalence determination decision summary device only. (FDA, Rockville, Maryland, USA, 2007) <>.

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

    Article  CAS  Google Scholar 

  26. Hanley, J.A. & McNeil, B.J. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 143, 29–36 (1982).

    Article  CAS  Google Scholar 

  27. DeLong, E.R., DeLong, D.M. & Clarke-Pearson, D.L. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44, 837–845 (1988).

    Article  CAS  Google Scholar 

  28. Rosen, H. et al. Reduced immunotoxicity and preservation of antibacterial activity in a releasable side-chain carbapenem antibiotic. Science 283, 703–706 (1999).

    Article  CAS  Google Scholar 

  29. 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 

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S. Leuillet and B. Palate (Centre International de Toxicologie (CIT)) kindly performed Novartis studies and the histopathology assessment and J. Mapes (RBM) developed the S-cystatin C assay. We thank G. Miller and P. Srinivasa for helpful comments on the manuscript. Z.E., K.V. and W.E.G. kindly shared unpublished observations for GST alpha.

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

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Correspondence to David L Gerhold.

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All authors are present or past employees of Merck or Novartis.

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Supplementary Tables 1,2 and Supplementary Figs. 1–4 (PDF 655 kb)

Supplementary Data Set (XLS 315 kb)

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Ozer, J., Dieterle, F., Troth, S. et al. A panel of urinary biomarkers to monitor reversibility of renal injury and a serum marker with improved potential to assess renal function. Nat Biotechnol 28, 486–494 (2010).

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