TY - JOUR
T1 - An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes
AU - Živná, Martina
AU - Kidd, Kendrah
AU - Zaidan, Mohamad
AU - Vyleťal, Petr
AU - Barešová, Veronika
AU - Hodaňová, Kateřina
AU - Sovová, Jana
AU - Hartmannová, Hana
AU - Votruba, Miroslav
AU - Trešlová, Helena
AU - Jedličková, Ivana
AU - Sikora, Jakub
AU - Hůlková, Helena
AU - Robins, Victoria
AU - Hnízda, Aleš
AU - Živný, Jan
AU - Papagregoriou, Gregory
AU - Mesnard, Laurent
AU - Beck, Bodo B.
AU - Wenzel, Andrea
AU - Tory, Kálmán
AU - Häeffner, Karsten
AU - Wolf, Matthias T.F.
AU - Bleyer, Michael E.
AU - Sayer, John A.
AU - Ong, Albert C.M.
AU - Balogh, Lídia
AU - Jakubowska, Anna
AU - Łaszkiewicz, Agnieszka
AU - Clissold, Rhian
AU - Shaw-Smith, Charles
AU - Munshi, Raj
AU - Haws, Robert M.
AU - Izzi, Claudia
AU - Capelli, Irene
AU - Santostefano, Marisa
AU - Graziano, Claudio
AU - Scolari, Francesco
AU - Sussman, Amy
AU - Trachtman, Howard
AU - Decramer, Stephane
AU - Matignon, Marie
AU - Grimbert, Philippe
AU - Shoemaker, Lawrence R.
AU - Stavrou, Christoforos
AU - Abdelwahed, Mayssa
AU - Belghith, Neila
AU - Sinclair, Matthew
AU - Claes, Kathleen
AU - Kopel, Tal
AU - Moe, Sharon
AU - Deltas, Constantinos
AU - Knebelmann, Bertrand
AU - Rampoldi, Luca
AU - Kmoch, Stanislav
AU - Bleyer, Anthony J.
N1 - Funding Information:
The authors thank all participating patients and families, and the referring physicians. We also thank Dr. Heike G?bel (Institute of Pathology, University Hospital of Cologne, Cologne, Germany) and Dr. Helmut Hopfer (Institute of Pathology, University Hospital Basel, Basel, Switzerland) for providing renal sections. This study was supported by a grant from the Ministry of Health of the Czech Republic (NV17-29786A) and by institutional programs of Charles University in Prague, Czech Republic (UNCE/MED/007 and PROGRES-Q26/LF1). Sequencing and genotyping were kindly provided by the National Center for Medical Genomics (LM2018132). AJB was funded by the Slim Health Foundation, the Black-Brogan Foundation, and the National Institutes of Health (NIH) (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK] R21 DK106584). KT was supported by an MTA-SE Lendulet research grant (LP2015-11/2015). JAS was supported by Kidney Research UK and the Northern Counties Kidney Research Fund. BBB and AW were supported by intramural grants from the Koeln Fortune Program/Faculty of Medicine (KF Nr 245/2011, KF Nr 172/2013, and KF 472/18), University of Cologne, Germany. LR was supported by the Italian Society of Nephrology under the ?Adotta un progetto di ricerca? program, Telethon-Italy (GGP14263), and a grant from the Italian Ministry of Health (RF-2010-2319394), Soli Deo Gloria. MTFW received grants from the NIH/NIDDK, Children's Health Dallas, and the Department of Defense, during this study.
Publisher Copyright:
© 2020 International Society of Nephrology
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
KW - autosomal dominant tubulointerstitial kidney disease
KW - characterization
KW - mutation
KW - prosegment
KW - renin
KW - signal peptide
UR - http://www.scopus.com/inward/record.url?scp=85097369366&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097369366&partnerID=8YFLogxK
U2 - 10.1016/j.kint.2020.06.041
DO - 10.1016/j.kint.2020.06.041
M3 - Article
C2 - 32750457
AN - SCOPUS:85097369366
VL - 98
SP - 1589
EP - 1604
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 6
ER -