There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.Copyright © 2020. Published by Elsevier Inc.
About The Expert
Martina Živná
Kendrah Kidd
Mohamad Zaidan
Petr Vyleťal
Veronika Barešová
Kateřina Hodaňová
Jana Sovová
Hana Hartmannová
Miroslav Votruba
Helena Trešlová
Ivana Jedličková
Jakub Sikora
Helena Hůlková
Victoria Robins
Aleš Hnízda
Jan Živný
Gregory Papagregoriou
Laurent Mesnard
Bodo B Beck
Andrea Wenzel
Kálmán Tory
Karsten Häeffner
Matthias T F Wolf
Michael E Bleyer
John A Sayer
Albert C M Ong
Lídia Balogh
Anna Jakubowska
Agnieszka Łaszkiewicz
Rhian Clissold
Charles Shaw-Smith
Raj Munshi
Robert M Haws
Claudia Izzi
Irene Capelli
Marisa Santostefano
Claudio Graziano
Francesco Scolari
Amy Sussman
Howard Trachtman
Stephane Decramer
Marie Matignon
Philippe Grimbert
Lawrence R Shoemaker
Christoforos Stavrou
Mayssa Abdelwahed
Neila Belghith
Matthew Sinclair
Kathleen Claes
Tal Kopel
Sharon Moe
Constantinos Deltas
Bertrand Knebelmann
Luca Rampoldi
Stanislav Kmoch
Anthony J Bleyer
References
PubMed