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Abstract: FR-PO808

Predictors of Age of ESRD in Autosomal Dominant Tubulointerstitial Kidney Disease due to UMOD Mutations

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Bleyer, Anthony J., Wake Forest University School of Medicine, Winston-Salem, United States
  • Rampoldi, Luca, San Raffaele Scientific Institute, MILAN, Italy
  • Devuyst, Olivier, University of Zurich, Zurich, Switzerland
  • Olinger, Eric Gregory, University Hospital Bern, Bern, Switzerland
  • Kidd, Kendrah O., Wake Forest University School of Medicine, Winston-Salem, United States
  • Vyletal, Petr, First Faculty of Medicine, Charles University, Prague, Czechia
  • Zivna, Martina, First Faculty of Medicine, Charles University, Prague, Czechia
  • Schaeffer, Celine, San Raffaele Scientific Institute, MILAN, Italy
  • Scolari, Francesco, University of Brescia, Montichiari (Brescia), Italy
  • Conlon, Peter J., Beaumont Hospital, Dublin, Ireland
  • Reis Almeida, Jorge, Universidade Federal Fluminense, Niteroi, Rio De Janeiro, Brazil
  • Kmoch, Stanislav, First Faculty of Medicine, Charles University, Prague, Czechia
Background

The aim of this work was to identify parameters that may explain the significant intra- and interfamilial variation in the age of onset of ESRD in patients with ADTKD-UMOD. The minor rs4293393 variant residing in the UMOD promoter has an allele frequency of 19% and decreases uromodulin synthesis by approximately 50%. It was postulated that if the minor variant was present in cis with the disease-causing mutation of UMOD (mUMOD), it would result in decreased mUMOD production and improved survival. A Mendelian randomization experiment was therefore attempted.

Methods

The study included 983 individuals with 127 different UMOD mutations, with 722 undergoing genetic testing and 261 being historically affected. An in vitro score was created for 29 prevalent mutations based on transit time through the endoplasmic reticulum. Other parameters included in the evaluation were parental age of ESRD, median age of ESRD for the patient’s family, BMI, history of gout, age of gout.

Results

The rs4293393 minor variant allele frequency was 16.4% when trans to mUMOD and 5.4% when cis to mUMOD, resulting in Hardy Weinberg equilibrium being present (p=0.03) and precluding a Mendelian randomization study. The following factors were found to be significantly associated with age of ESRD: age of gout (p<0.001), parental age of ESRD (p<0.001), body mass index (p=0.033), and median age of ESRD for the family (p=0.007). The in vitro score was also significant (p=0.03).

Conclusion

The minor variant was significantly less commonly linked to the mUMOD. The minor variant may lead to decreased mUMOD production and milder disease that was less frequently identified. An in vitro score was an excellent predictor of age of ESRD according to mutation. Parental age and age of gout were highly predictive of age of ESRD.

Funding

  • NIDDK Support