Genetic and Clinical Predictors of Age of ESKD in Individuals With Autosomal Dominant Tubulointerstitial Kidney Disease Due to UMOD Mutations.
- Kidd K Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- Vylet'al P Research Unit of Rare Diseases, Department of Pediatric and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
- Schaeffer C Molecular Genetics of Renal Disorders, Division of Genetics and Cell Biology, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.
- Olinger E University of Zurich, Institute of Mechanisms of Inherited Kidney Disorders, Zurich, Switzerland.
- Živná M Research Unit of Rare Diseases, Department of Pediatric and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
- Hodaňová K Research Unit of Rare Diseases, Department of Pediatric and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
- Robins V Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- Johnson E Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- Taylor A Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- Martin L Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- Izzi C Division of Nephrology and Dialysis, University of Brescia and Montichiari Hospital, Brescia, Italy.
- Jorge SC Department of Nephrology and Renal Transplant of Centro Hospitalar Universitário Lisboa Norte, EPE, Lisbon, Portugal.
- Calado J ToxOmics, Centre for Toxicogenomics and Human Health, NOVA Medical School, New University of Lisbon, Lisbon, Portugal.
- Torres RJ Foundation for Biomedical Research of La Paz University Hospital (FIBHULP), IdiPaz, Madrid, Spain.
- Lhotta K Department of Internal Medicine, Academic Teaching Hospital Feldkirch, Feldkirch, Austria.
- Steubl D Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
- Gale DP Department of Renal Medicine, University College London, London, UK.
- Gast C Wessex Kidney Centre, Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Portsmouth, UK.
- Gombos E Department of Nephrology and Gastroenterology, Heim Pál Hospital for Children, Budapest, Hungary.
- Ainsworth HC Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- Chen YM Division of Nephrology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
- Almeida JR Multi-User Laboratory to Support Research in Nephrology and Medical Sciences (LAMAP), Federal Fluminense University, Niterói, Rio de Janeiro, Brazil.
- de Souza CF Multi-User Laboratory to Support Research in Nephrology and Medical Sciences (LAMAP), Federal Fluminense University, Niterói, Rio de Janeiro, Brazil.
- Silveira C GenoMed SA, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
- Raposeiro R GenoMed SA, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
- Weller N Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- Conlon PJ Nephrology Department, Beaumont Hospital, Dublin, Ireland.
- Murray SL Nephrology Department, Beaumont Hospital, Dublin, Ireland.
- Benson KA Nephrology Department, Beaumont Hospital, Dublin, Ireland.
- Cavalleri GL Nephrology Department, Beaumont Hospital, Dublin, Ireland.
- Votruba M Research Unit of Rare Diseases, Department of Pediatric and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
- Vrbacká A Research Unit of Rare Diseases, Department of Pediatric and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
- Amoroso A Medical Genetics, Department of Medical Sciences, University of Turin, Turin, Italy.
- Gianchino D Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
- Caridi G Department of Nephrology and Transplantation, Istituto G. Gaslini Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Genoa, Italy.
- Ghiggeri GM Department of Nephrology and Transplantation, Istituto G. Gaslini Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Genoa, Italy.
- Divers J Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- Scolari F Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and Montichiari Hospital, Brescia, Italy.
- Devuyst O University of Zurich, Institute of Mechanisms of Inherited Kidney Disorders, Zurich, Switzerland.
- Rampoldi L Molecular Genetics of Renal Disorders, Division of Genetics and Cell Biology, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.
- Kmoch S Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- Bleyer AJ Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- 2020-09-21
Published in:
- Kidney international reports. - 2020
English
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.
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1016/j.ekir.2020.06.029
- PMID 32954071
- Persistent URL
- https://sonar.ch/global/documents/200371
Statistics
Document views: 11
File downloads:
- fulltext.pdf: 0