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Lookup NU author(s): Professor John SayerORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2020 International Society of NephrologyAutosomal 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.
Author(s): Olinger E, Hofmann P, Kidd K, Dufour I, Belge H, Schaeffer C, Kipp A, Bonny O, Deltas C, Demoulin N, Fehr T, Fuster DG, Gale DP, Goffin E, Hodanova K, Huynh-Do U, Kistler A, Morelle J, Papagregoriou G, Pirson Y, Sandford R, Sayer JA, Torra R, Venzin C, Venzin R, Vogt B, Zivna M, Greka A, Dahan K, Rampoldi L, Kmoch S, Bleyer AJ, Devuyst O
Publication type: Article
Publication status: Published
Journal: Kidney International
Year: 2020
Volume: 98
Issue: 3
Pages: 717-731
Print publication date: 01/09/2020
Online publication date: 21/05/2020
Acceptance date: 02/04/2020
Date deposited: 21/08/2020
ISSN (print): 0085-2538
ISSN (electronic): 1523-1755
Publisher: Elsevier B.V.
URL: https://doi.org/10.1016/j.kint.2020.04.038
DOI: 10.1016/j.kint.2020.04.038
PubMed id: 32450155
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