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Genetic and Clinical Predictors of Age of ESKD in Individuals With Autosomal Dominant Tubulointerstitial Kidney Disease Due to UMOD Mutations

2020; Elsevier BV; Volume: 5; Issue: 9 Linguagem: Inglês

10.1016/j.ekir.2020.06.029

2468-0249

Kendrah Kidd, Petr Vyleťal, Céline Schaeffer, Eric Olinger, Martina Živná, Kateřina Hodaňová, Victoria Robins, Emily Johnson, Abbigail Taylor, Lauren Martin, Claudia Izzi, Sofía Jorge, Joaquim Calado, Rosa J. Torres, Karl Lhotta, Dominik Steubl, Daniel P. Gale, Christine Gast, Eva C. Gombos, Hannah C. Ainsworth, Ying Maggie Chen, Jorge Reis Almeida, Cintia Fernandes Souza, Catarina Silveira, Rita Raposeiro, Nelson Weller, Peter J. Conlon, Susan Murray, Katherine A. Benson, Gianpiero L. Cavalleri, Miroslav Votruba, Alena Vrbacká, Antonio Amoroso, Daniela Gianchino, Gianluca Caridi, Gian Marco Ghiggeri, Jasmin Divers, Francesco Scolari, Olivier Devuyst, Luca Rampoldi, Stanislav Kmoch, Anthony J. Bleyer,

Chronic Kidney Disease and Diabetes

IntroductionAutosomal 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.MethodsAn 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).ResultsThe 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.ConclusionWe report the clinical characteristics associated with 125 UMOD mutations. Male gender and a new in vitro score predict age of ESKD.