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Genetic and clinical predictors of age of ESKD in individuals with autosomal dominant tubulointerstitial kidney disease due to UMOD mutations

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posted on 2021-04-13, 09:14 authored by Kendrah Kidd, Petr Vylet'al, Céline Schaeffer, Eric Olinger, Martina Živná, Katerina Hodaňová, Victoria Robins, Emily Johnson, Abbigail Taylor, Lauren Martin, Claudia Izzi, Sofia C Jorge, Joaquim Calado, Rosa J Torres, Karl Lhotta, Dominik Steubl, Daniel P Gale, Christine Gast, Eva Gombos, Hannah C Ainsworth, Ying Maggie Chen, Jorge Reis Almeida, Cintia Fernandes de Souza, Catarina Silveira, Rita Raposeiro, Nelson Weller, Peter ConlonPeter Conlon, Susan Murray, Katherine BensonKatherine Benson, Gianpiero CavalleriGianpiero Cavalleri, Miroslav Votruba, Alena Vrbacká, Antonio Amoroso, Daniela Gianchino, Gianluca Caridi, Gian Marco Ghiggeri, Jasmin Divers, Francesco Scolari, Oliver Devuyst, Luca Rampoldi, Stanislav Kmoch, Anthony J Bleyer

Introduction: Autosomal dominant tubulo-interstitial kidney disease due to UMOD mutations (ADTKD-UMOD) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the UMOD gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD-UMOD and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival.

Methods: An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78, P < 0.001).

Results: The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected (P < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An in vitro score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD.

Conclusion: We report the clinical characteristics associated with 125 UMOD mutations. Male gender and a new in vitro score predict age of ESKD.


National Institutes of Health (NIH)–National Institute of Diabetes and Digestive and Kidney Diseases R21 DK106584.

Black-Brogan Foundation

NIH grants R01 DK105056A1, R03DK106451, and K08DK089015

The Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, Award Number W81XWH-19–1–0320

Ministry of Health of the Czech Republic (NV17–29786A)

Fonds National de la Recherche Luxembourg (6903109)

European Reference Network for Rare Kidney Diseases (ERKNet), project ID No. 739532

National Centre for Competence in Research Kidney CH program

Swiss National Science Foundation 310030–189044

Italian Society of Nephrology (SIN) under the “Adotta un progetto di ricerca” program

Ministry of Health of Italy (grant RF2010–2319394 and RF-2016–02362623), Soli Deo Gloria

Charles University in Prague (UNCE/MED/007 and PROGRES-Q26/LF1)

Telethon-Italy (GGP14263)



The original article is available at

Published Citation

Kidd K, Vylet'al P, Schaeffer C, Olinger E, Živná M, Hodaňová K, Robins V, Johnson E, Taylor A, Martin L, Izzi C, Jorge SC, Calado J, Torres RJ, Lhotta K, Steubl D, Gale DP, Gast C, Gombos E, Ainsworth HC, Chen YM, Almeida JR, de Souza CF, Silveira C, Raposeiro R, Weller N, Conlon PJ, Murray SL, Benson KA, Cavalleri GL, Votruba M, Vrbacká A, Amoroso A, Gianchino D, Caridi G, Ghiggeri GM, Divers J, Scolari F, Devuyst O, Rampoldi L, Kmoch S, Bleyer AJ. Genetic and clinical predictors of age of ESKD in individuals with autosomal dominant tubulointerstitial kidney disease due to UMOD mutations. Kidney International Reports. 2020;5(9):1472-1485.

Publication Date

3 July 2020

PubMed ID



  • Beaumont Hospital
  • Medicine
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Neurological and Psychiatric Disorders
  • Vascular Biology




  • Published Version (Version of Record)