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

摘要

IntroductionAutosomal dominant tubulo-interstitial kidney disease due toUMODmutations (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 theUMODgene, 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-UMODand 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. Anin?vitroscore 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 125UMODmutations. Male gender and a newin?vitroscore predict age of ESKD.