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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

Nature Biotechnology volume 28, pages 486–494 (2010)Cite this article

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Abstract

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.

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Acknowledgements

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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Author notes

  1. Josef S Ozer & Jacky Vonderscher

    Present address: Present addresses: Pharmacokinetics, Dynamics, and Metabolism, PGRD, Pfizer, Andover Laboratories, Andover, Massachusetts, USA (J.S.O.) and Molecular Medicine Labs, Group Research, Hoffmann-La Roche, Basel, Switzerland (J.V.).,

  2. Josef S Ozer and Frank Dieterle: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Investigative Laboratory Sciences, Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania, USA

    Josef S Ozer, Zoltan Erdos, Katerina Vlasakova, Hong Jin, Yan Yu, Tom Forest, Spencer Reynolds, Wendy J Bailey, Douglas T Thudium, Michael J Topper, Thomas R Skopek, Joseph F Sina, Warren E Glaab, Frank D Sistare & David L Gerhold

  2. Translational Sciences, Novartis Institutes for BioMedical Research, Novartis, Basel, Switzerland.,

    Frank Dieterle, Elias Perentes, André Cordier, Pablo Verdes, Frank Staedtler, Andreas Mahl, Olivier Grenet, Daniel R Roth, Daniel Wahl, François Legay, Jacky Vonderscher, Gérard Maurer & Salah-Dine Chibout

  3. Department of Pathology, Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania, USA

    Sean Troth & Nagaraja Muniappa

  4. Department of Biometrics, Merck Research Laboratories, West Point, Pennsylvania, USA

    Daniel Holder

  5. Department of Exploratory Toxicology, Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania, USA

    Holly K Clouse

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Contributions

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.

Corresponding author

Correspondence to David L Gerhold.

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Competing interests

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). https://doi.org/10.1038/nbt.1627

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