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  • Review Article
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Uromodulin: from physiology to rare and complex kidney disorders

Nature Reviews Nephrology volume 13, pages 525–544 (2017)Cite this article

Subjects

Key Points

  • Uromodulin — the most abundant urinary protein — is exclusively produced by renal epithelial cells; in the tubular lumen uromodulin forms high-molecular weight filaments that constitute the matrix of hyaline casts

  • Important functions of uromodulin include regulation of ion transport in the thick ascending limb, immunomodulation and protection against urinary tract infections and kidney stones

  • Levels of uromodulin in the urine and in the blood, where it is present in lower amounts, are valuable biomarkers for tubular mass and renal function

  • Rare mutations in UMOD cause autosomal dominant tubulointerstitial kidney disease; these mutations lead to retention of mutant uromodulin in the endoplasmic reticulum of tubular cells, tubulointerstitial damage and decreased levels of urinary uromodulin

  • Common variants in the UMOD promoter are associated with risk of chronic kidney disease (CKD) and hypertension; the unusually high prevalence of UMOD risk alleles suggests pathogen-driven selective pressure

  • UMOD represents a paradigm as a continuum of genetic disease risk, from rare mutations in Mendelian disease to common variants associated with complex traits including CKD and hypertension

Abstract

Uromodulin (also known as Tamm-Horsfall protein) is exclusively produced in the kidney and is the most abundant protein in normal urine. The function of uromodulin remains elusive, but the available data suggest that this protein might regulate salt transport, protect against urinary tract infection and kidney stones, and have roles in kidney injury and innate immunity. Interest in uromodulin was boosted by genetic studies that reported involvement of the UMOD gene, which encodes uromodulin, in a spectrum of rare and common kidney diseases. Rare mutations in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), which leads to chronic kidney disease (CKD). Moreover, genome-wide association studies have identified common variants in UMOD that are strongly associated with risk of CKD and also with hypertension and kidney stones in the general population. These findings have opened up a new field of kidney research. In this Review we summarize biochemical, physiological, genetic and pathological insights into the roles of uromodulin; the mechanisms by which UMOD mutations cause ADTKD, and the association of common UMOD variants with complex disorders.

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Figure 1: Segmental expression and biochemical characteristics of uromodulin.
Figure 2: Evolution of the UMOD gene.
Figure 3: Proposed physiological roles of uromodulin.
Figure 4: Genetic variants of uromodulin that are associated with kidney diseases.
Figure 5: Pathophysiology of autosomal dominant tubulointerstitial kidney disease (ADTKD)-UMOD.
Figure 6: Involvement of UMOD in a spectrum of diseases.

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Acknowledgements

O.D. is supported by grants from the European Community's Seventh Framework Programme (305608 EURenOmics), the Swiss National Centre of Competence in Research Kidney Control of Homeostasis (NCCR Kidney.CH) programme, the Swiss National Science Foundation (31003A_169850) and the Rare Disease Initiative Zürich (Radiz), a clinical research priority programme of the University of Zürich, Switzerland. E.O. is supported by the Fonds National de la Recherche Luxembourg (6903109), and the University Research Priority Programme “Integrative Human Physiology, ZIHP” of the University of Zürich. L.R. is supported by grants from Telethon-Italy (TCR08006, GGP14263), the Italian Ministry of Health (RF-2010-2319394) and Fondazione Cariplo (2014–0827). We are grateful to Gregor Weiss (ETH, Zurich) for providing EM pictures of uromodulin, to Céline Schaeffer (San Raffaele, Milan) for reviewing the UMOD mutations and to Sonia Youhanna (UZH, Zurich) for helpful assistance in deglycosylation experiments.

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Authors and Affiliations

  1. Institute of Physiology, University of Zurich, Winterthurerstrasse 190, Zürich, CH-8057, Switzerland

    Olivier Devuyst & Eric Olinger

  2. Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Via Olgettina 58, Milan, 20132, Italy

    Luca Rampoldi

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  1. Olivier Devuyst
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  2. Eric Olinger
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  3. Luca Rampoldi
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O.D., E.O. and L.R. researched the data, discussed the article content and wrote, edited and approved the manuscript before submission.

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Correspondence to Olivier Devuyst.

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Devuyst, O., Olinger, E. & Rampoldi, L. Uromodulin: from physiology to rare and complex kidney disorders. Nat Rev Nephrol 13, 525–544 (2017). https://doi.org/10.1038/nrneph.2017.101

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