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 a UMOD mutation. 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.

Center for Human Genetics Institute of Pathology and Genetics Gosselies Belgium

Department of Internal Medicine Cantonal Hospital Frauenfeld Frauenfeld Switzerland

Department of Medical Genetics Cambridge Biomedical Campus Cambridge UK

Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston Massachusetts USA; Broad Institute of MIT and Harvard Massachusetts Institute of Technology Cambridge Massachusetts USA

Department of Nephrology and Hypertension Inselspital Bern University Hospital Bern Switzerland

Department of Nephrology University College of London London UK

Division of Genetics and Cell Biology San Raffaele Scientific Institute Milan Italy

Division of Nephrology Cliniques Universitaires Saint Luc Brussels Belgium

Division of Nephrology Cliniques Universitaires Saint Luc Brussels Belgium; Institut de Recherche Expérimentale et Clinique Université catholique de Louvain Brussels Belgium

Division of Nephrology Department of Internal Medicine Cantonal Hospital Graubuenden Chur Switzerland

Division of Nephrology Department of Internal Medicine Hospital Davos Davos Switzerland

Inherited Renal Disorders Nephrology Department Fundació Puigvert Spanish Renal Research Network Instituto de Investigaciones Biomédicas Sant Pau Universitat Autònoma de Barcelona Barcelona Spain

Institute of Physiology University of Zurich Zurich Switzerland

Institute of Physiology University of Zurich Zurich Switzerland; Department of Internal Medicine Cantonal Hospital Graubuenden Chur Switzerland

Institute of Physiology University of Zurich Zurich Switzerland; Department of Internal Medicine Hospital Uster Uster Switzerland

Institute of Physiology University of Zurich Zurich Switzerland; Department of Nephrology and Hypertension Inselspital Bern University Hospital Bern Switzerland; Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK

Institute of Physiology University of Zurich Zurich Switzerland; Division of Nephrology Cliniques Universitaires Saint Luc Brussels Belgium

Molecular Medicine Research Center Department of Biological Sciences University of Cyprus Nicosia Cyprus

Renal Services Newcastle upon Tyne Hospitals National Health Service Trust Newcastle upon Tyne UK; Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK

Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague Czech Republic

Section on Nephrology Wake Forest School of Medicine Winston Salem North Carolina USA; Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague Czech Republic

Service of Nephrology Lausanne University Hospital Lausanne Switzerland

Citace poskytuje Crossref.org

Eight-fold increased COVID-19 mortality in autosomal dominant tubulointerstitial kidney disease due to MUC1 mutations: an observational study

Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors

Description of a New Simple and Cost-Effective Molecular Testing That Could Simplify MUC1 Variant Detection

Maternal health and pregnancy outcomes in autosomal dominant tubulointerstitial kidney disease

Autosomal dominant tubulointerstitial kidney disease: A review

An intermediate-effect size variant in UMOD confers risk for chronic kidney disease

Autosomal dominant tubulointerstitial kidney disease: more than just HNF1β

Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin

Mitochondriopathy Manifesting as Inherited Tubulointerstitial Nephropathy Without Symptomatic Other Organ Involvement

Plasma Mucin-1 (CA15-3) Levels in Autosomal Dominant Tubulointerstitial Kidney Disease due to MUC1 Mutations