Journal
KIDNEY INTERNATIONAL
Volume 98, Issue 3, Pages 717-731Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2020.04.038
Keywords
diagnostic score; dominant kidney disease; gout; mucin-1; uromodulin
Categories
Funding
- Fonds National de la Recherche Luxembourg [6903109]
- University Research Priority Program Integrative Human Physiology, ZIHP of the University of Zurich
- Early Postdoc Mobility-Stipendium of the Swiss National Science Foundation [P2ZHP3_195181]
- Italian Society of Nephrology (SIN) under the Adotta un progetto di ricerca program, Telethon-Italy [GGP14263]
- Italian Ministry of Health [RF-2010-2319394]
- National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases [R21 DK106584]
- Ministry of Health of the Czech Republic [NV17-29786A]
- Ministry of Education of the Czech Republic [LTAUSA19068]
- Charles University in Prague [UNCE/MED/007, PROGRES-Q26/LF1]
- National Center for Medical Genomics [LM2015091]
- European Community's Seventh Framework Programme [305608]
- European Reference Network for Rare Kidney Diseases [739532]
- Swiss National Science Foundation's National Center of Competence in Research Kidney Control of Homeostasis program
- Swiss National Science Foundation [310030-189044, 31003A_152829, 33IC30_166785/1]
- Gebert-Ruf Foundation for research on ADTKD-UMOD
- Kidney Research UK
- Northern Counties Kidney Research Fund
- Instituto de Salud Carlos III: Redes Tematicas de Investigacion Cooperativa Red de Investigacion Renal [RD16/0009]
- Fondo de Investigacion Sanitarias Fondo Europeo de Desarollo Regional [PI15/01824, PI18/00362]
- Fonds de la Recherche Scientifique-Communaute Francaise de Belgique
- Swiss National Centre of Competence in Research TransCure
- Swiss National Centre of Competence in Research Kidney Control of Homeostasis program
- Slim Initiative for Genomic Medicine in the Americas
- Broad Institute with the Carlos Slim Foundation
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Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. We analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years, respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years, respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for aUMODmutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.
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