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

<p dir="ltr"><b>Background: </b><i>MUC1</i> and <i>UMOD</i> pathogenic variants cause autosomal dominant tubulointerstitial kidney disease (ADTKD). <i>MUC1</i> is expressed in kidney, nasal mucosa and respiratory tract, while <i>UMOD</i> is expressed only in kidney. Due to haplo-insufficiency ADTKD-<i>MUC1</i> patients produce approximately 50% of normal mucin-1.</p><p dir="ltr"><b>Methods: </b>To determine whether decreased mucin-1 production was associated with an increased COVID-19 risk, we sent a survey to members of an ADTKD registry in September 2021, after the initial, severe wave of COVID-19. We linked results to previously obtained ADTKD genotype and plasma CA15-3 (mucin-1) levels and created a longitudinal registry of COVID-19 related deaths.</p><p dir="ltr"><b>Results: </b>Surveys were emailed to 637 individuals, with responses from 89 ADTKD-<i>MUC1</i> and 132 ADTKD-<i>UMOD</i> individuals. 19/83 (23%) ADTKD-<i>MUC1</i> survey respondents reported a prior COVID-19 infection vs. 14/125 (11%) ADTKD-<i>UMOD</i> respondents (odds ratio (OR) 2.35 (95%CI 1.60–3.11, <i>P</i> = 0.0260). Including additional familial cases reported from survey respondents, 10/41 (24%) ADTKD-<i>MUC1</i> individuals died of COVID-19 vs. 1/30 (3%) with ADTKD-<i>UMOD</i>, with OR 9.21 (95%CI 1.22–69.32), <i>P</i> = 0.03. The mean plasma mucin-1 level prior to infection in 14 infected and 27 uninfected ADTKD-<i>MUC1</i> individuals was 7.06 ± 4.12 vs. 10.21 ± 4.02 U/mL (<i>P</i> = 0.035). Over three years duration, our longitudinal registry identified 19 COVID-19 deaths in 360 ADTKD-<i>MUC1</i> individuals (5%) vs. 3 deaths in 478 ADTKD-<i>UMOD</i> individuals (0.6%) (<i>P</i> = 0.0007). Multivariate logistic regression revealed the following odds ratios (95% confidence interval) for COVID-19 deaths: ADTKD-<i>MUC1</i> 8.4 (2.9–29.5), kidney transplant 5.5 (1.6–9.1), body mass index (kg/m²) 1.1 (1.0-1.2), age (y) 1.04 (1.0-1.1).</p><p dir="ltr"><b>Conclusions: </b>Individuals with ADTKD-<i>MUC1</i> are at an eight-fold increased risk of COVID-19 mortality vs. ADTKD-<i>UMOD</i> individuals. Haplo-insufficient production of mucin-1 may be responsible.</p>