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Urinary biomarkers trefoil factor 3 and albumin enable early detection of kidney tubular injury

Nature Biotechnology volume 28, pages 470–477 (2010)Cite this article

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Abstract

The capacities of urinary trefoil factor 3 (TFF3) and urinary albumin to detect acute renal tubular injury have never been evaluated with sufficient statistical rigor to permit their use in regulated drug development instead of the current preclinical biomarkers serum creatinine (SCr) and blood urea nitrogen (BUN). Working with rats, we found that urinary TFF3 protein levels were markedly reduced, and urinary albumin were markedly increased in response to renal tubular injury. Urinary TFF3 levels did not respond to nonrenal toxicants, and urinary albumin faithfully reflected alterations in renal function. In situ hybridization localized TFF3 expression in tubules of the outer stripe of the outer medulla. Albumin outperformed either SCr or BUN for detecting kidney tubule injury and TFF3 augmented the potential of BUN and SCr to detect kidney damage. Use of urinary TFF3 and albumin will enable more sensitive and robust diagnosis of acute renal tubular injury than traditional biomarkers.

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Figure 1: Cisplatin kidney toxicity study.
Figure 2: Gentamicin kidney toxicity study.
Figure 3: Carbapenem A kidney toxicity study.
Figure 4: Genipin liver toxicity study and isoproterenol muscle and heart toxicity study.
Figure 5: ROC curves for TFF3 and for albumin compared to those for BUN, and creatinine.
Figure 6: Determination of the renal source of Tff3 mRNA by in situ hybridization.

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Acknowledgements

The authors wish to thank the participants in the Nephrotoxicity Predictive Safety Testing Consortium and the Merck Kidney Biomarker Working Group. We thank J. Mardi, J. Flor, A. Smith and D. Harner for photographic and editorial assistance in assembling the histopathology supplement.

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

    Yan Yu, Hong Jin, Josef S Ozer, Shu Shi, Ming Su, Wendy Bailey, Amy G Aslamkhan, Douglas Thudium, Frank D Sistare & David L Gerhold

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

    Daniel Holder

  3. Department of Integrative Systems Neuroscience, Merck Research Laboratories, West Point, Pennsylvania, USA

    Stephanie Villarreal & Paul Shughrue

  4. Department of Clinical Oncology, GlaxoSmithKline, Collegeville, Pennsylvania, USA

    David J Figueroa

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

    Holly Clouse

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

    Nagaraja Muniappa & Sean P Troth

  7. Preclinical Services, Charles River Laboratories–Redfield, Redfield, Arkansas, USA

    John Seng

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Contributions

Y.Y., D.H., J.S.O., P.S., S.P.T., W.B., A.G.A., F.D.S. and D.L.G. designed and analyzed experiments. Y.Y., H.J., S.V., D.J.F., H.C., M.S., J.S., N.M., S.P.T. and S.S. performed experiments. Y.Y., D.H., J.S.O., P.S., A.G.A., D.T., F.D.S. and D.L.G. wrote and edited the manuscript.

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Correspondence to David L Gerhold.

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All authors are employees of Merck, with the exception of J.S., who works for Charles River Laboaratories.

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Supplementary Tables 1–3, Supplementary Fig. 1, Supplementary Data, Supplementary Assay Validation and Supplementary Results (PDF 34182 kb)

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Yu, Y., Jin, H., Holder, D. et al. Urinary biomarkers trefoil factor 3 and albumin enable early detection of kidney tubular injury. Nat Biotechnol 28, 470–477 (2010). https://doi.org/10.1038/nbt.1624

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