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

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.

Author information

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.

Correspondence to David L Gerhold.

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Competing interests

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

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Supplementary Text and Figures

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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