Eight-Fold Increased COVID-19 Mortality in Autosomal Dominant Tubulointerstitial Kidney Disease due to Mutations: An Observational Study.

Background: and pathogenic variants cause autosomal dominant tubulointerstitial kidney disease (ADTKD). is expressed in kidney, nasal mucosa and respiratory tract, while is expressed only in kidney. Due to haplo-insufficiency ADTKD- patients produce approximately 50% of normal mucin-1.

Methods: 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.

Results: Surveys were emailed to 637 individuals, with responses from 89 ADTKD- and 132 ADTKD- individuals. 19/83 (23%) ADTKD- survey respondents reported a prior COVID-19 infection vs. 14/125 (11%) ADTKD- respondents (odds ratio (OR) 2.35 (95%CI 1.60-3.11, = 0.0260). Including additional familial cases reported from survey respondents, 10/41 (24%) ADTKD- individuals died of COVID-19 vs. 1/30 (3%) with ADTKD- , with OR 9.21 (95%CI 1.22-69.32), = 0.03. The mean plasma mucin-1 level prior to infection in 14 infected and 27 uninfected ADTKD- individuals was 7.06±4.12 vs. 10.21±4.02 U/mL ( = 0.035). Over three years duration, our longitudinal registry identified 19 COVID-19 deaths in 360 ADTKD- individuals (5%) vs. 3 deaths in 478 ADTKD- individuals (0.6%) ( = 0.0007). Multivariate logistic regression revealed the following odds ratios (95% confidence interval) for COVID-19 deaths: ADTKD- 8.4 (2.9-29.5), kidney transplant 5.5 (1.6-9.1), body mass index (kg/m ) 1.1 (1.0-1.2), age (y) 1.04 (1.0-1.1).

Conclusions: Individuals with ADTKD- are at an eight-fold increased risk of COVID-19 mortality vs. ADTKD- individuals. Haplo-insufficient production of mucin-1 may be responsible.