Home Nephro News Clinical and Genetic Spectra of Autosomal Dominant Tubulointerstitial Kidney Disease due to Mutations in UMOD and MUC1

Clinical and Genetic Spectra of Autosomal Dominant Tubulointerstitial Kidney Disease due to Mutations in UMOD and MUC1

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This international cohort study represents the largest dataset of ADTKD-UMOD and ADTKD-MUC1 patients reported to date, providing new insights into the phenotype and disease progression of the main subtypes of ADTKD. Because of the autosomal dominant inheritance and regional familial clustering, considerable differences in the prevalence of ADTKD-subgroups are mentioned in national cohorts 2x2Eckardt, K.U., Alper, S.L., Antignac, C. et al. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management–A KDIGO consensus report. Kidney Int. 2015;
88: 676–683
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Based on the large sample size, we observed distinct features in the clinical presentation of ADTKD-UMOD and ADTKD-MUC1, with relevance for clinical practice and patient counselling. Kidney disease appears more severe in ADTKD-MUC1, with a higher prevalence of ESKD (58% vs. 44% in ADTKD-UMOD, p=0.04), an earlier onset of ESKD (36 years vs. 46 years in ADTKD-UMOD, p<0.001) and a shorter median renal survival (46 years vs. 54 years in ADTKD-UMOD, p=0.013). Previous studies reported an older age at ESKD (Mean: 44.9 years) in ADTKD-MUC1 patients 8x8Bleyer, A.J., Kmoch, S., Antignac, C. et al. Variable Clinical Presentation of an MUC1 Mutation Causing Medullary Cystic Kidney Disease Type 1. Clin J Am Soc Nephrol. 2014;
9: 527–535
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Gout has been classically described in patients with UMOD mutations. Indeed, our data suggest that gout is strikingly more prevalent and of significantly earlier onset in ADTKD-UMOD compared to ADTKD-MUC1. Defective urinary concentration resulting in polydipsia and polyuria has been described in ADTKD-UMOD patients, most likely because of impaired activity of TAL-based Na+-K+-2Cl-cotransporter NKCC2 16x16Ayasreh, N., Bullich, G., Miquel, R. et al. Autosomal Dominant Tubulointerstitial Kidney Disease: Clinical Presentation of Patients With ADTKD-UMOD and ADTKD-MUC1. Am J Kidney Dis. 2018;
72: 411–418
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We investigated two cardinal biological features described in ADTKD-UMOD with likely pathophysiological relevance: aberration in uromodulin export mechanisms and induction of ER stress. Based on the observation that mucin-1 is expressed in the distal kidney tubule including the TAL where it colocalizes with uromodulin 6x6Knaup, K.X., Hackenbeck, T., Popp, B. et al. Biallelic Expression of Mucin-1 in Autosomal Dominant Tubulointerstitial Kidney Disease: Implications for Nongenetic Disease Recognition. J Am Soc Nephrol. 2018;
29: 2298–2309
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Previous reports described intracellular accumulation of uromodulin in kidney biopsies from ADTKD-UMOD patients 1x1Devuyst, O., Olinger, E., Weber, S. et al. Autosomal dominant tubulointerstitial kidney disease. Nat Rev Dis Primers. 2019;
5: 60
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A recent study based on exome sequencing reported mutations in UMOD accounting for ∼3% of all patients with a genetic finding in this cohort 13x13Groopman, E.E., Marasa, M., Cameron-Christie, S. et al. Diagnostic Utility of Exome Sequencing for Kidney Disease. N Engl J Med. 2019;
380: 142–151
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The limits of this study include the retrospective “real-life” cohort design of consecutively recruited patients, with inherent difficulties such as limited access to full clinical information, missing DNA samples for further genetic testing and lack of strict inclusion/exclusion criteria. We included all genetically resolved cases of a given family, potentially introducing the risk for selection bias. However, we estimate that this represents a neglectable risk as only 1-2 patients were in general included per family and considerable intrafamilial clinical variability exists in ADTKD 8x8Bleyer, A.J., Kmoch, S., Antignac, C. et al. Variable Clinical Presentation of an MUC1 Mutation Causing Medullary Cystic Kidney Disease Type 1. Clin J Am Soc Nephrol. 2014;
9: 527–535
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It should be pointed that systematic screening for UMOD mutations in all 10 coding exons has only been performed in a subset of ADTKD patients. Based on previous screens and WES, we estimate that very few UMOD mutations outside exons 3 and 4 might have been missed in ADTKD-UMOD 13x13Groopman, E.E., Marasa, M., Cameron-Christie, S. et al. Diagnostic Utility of Exome Sequencing for Kidney Disease. N Engl J Med. 2019;
380: 142–151
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In conclusion, this large international retrospective cohort study provides a detailed phenotype analysis of ADTKD-UMOD and ADTKD-MUC1 patients. The clinical hallmarks of the two most common ADTKD subtypes are hyperuricemia and early gout in ADTKD-UMOD and a heterogeneous, but generally more severe kidney disease in ADTKD-MUC1. The clinical UMOD-score is a sensitive and, coupled to urinary uromodulin levels, potentially specific tool to select patients for genetic UMOD testing. These results should help clinicians to improve diagnostic rates, clinical management and patient counselling in ADTKD.

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