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Observational Study
. 2024 Dec 18;25(1):449.
doi: 10.1186/s12882-024-03896-1.

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

Kendrah O Kidd  1   2 , Adrienne H Williams  3 , Abbigail Taylor  1 , Lauren Martin  1 , Victoria Robins  1 , John A Sayer  4   5   6 , Eric Olinger  7 , Holly R Mabillard  4 , Gregory Papagregoriou  8 , Constantinos Deltas  8 , Christoforos Stavrou  9 , Peter J Conlon  10   11 , Richard Edmund Hogan  10   11 , Elhussein A E Elhassan  10   11 , Drahomíra Springer  12 , Tomáš Zima  12 , Claudia Izzi  13 , Alena Vrbacká  2 , Lenka Piherová  2 , Michal Pohludka  14 , Martin Radina  2 , Petr Vylet'al  2 , Katerina Hodanova  2 , Martina Zivna  1   2 , Stanislav Kmoch  1   2   15 , Anthony J Bleyer Sr  16   17
Affiliations
Observational Study

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

Kendrah O Kidd et al. BMC Nephrol. .

Abstract

Background: MUC1 and UMOD pathogenic variants cause autosomal dominant tubulointerstitial kidney disease (ADTKD). MUC1 is expressed in kidney, nasal mucosa and respiratory tract, while UMOD is expressed only in kidney. Due to haplo-insufficiency ADTKD-MUC1 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-MUC1 and 132 ADTKD-UMOD individuals. 19/83 (23%) ADTKD-MUC1 survey respondents reported a prior COVID-19 infection vs. 14/125 (11%) ADTKD-UMOD respondents (odds ratio (OR) 2.35 (95%CI 1.60-3.11, P = 0.0260). Including additional familial cases reported from survey respondents, 10/41 (24%) ADTKD-MUC1 individuals died of COVID-19 vs. 1/30 (3%) with ADTKD-UMOD, with OR 9.21 (95%CI 1.22-69.32), P = 0.03. The mean plasma mucin-1 level prior to infection in 14 infected and 27 uninfected ADTKD-MUC1 individuals was 7.06 ± 4.12 vs. 10.21 ± 4.02 U/mL (P = 0.035). Over three years duration, our longitudinal registry identified 19 COVID-19 deaths in 360 ADTKD-MUC1 individuals (5%) vs. 3 deaths in 478 ADTKD-UMOD individuals (0.6%) (P = 0.0007). Multivariate logistic regression revealed the following odds ratios (95% confidence interval) for COVID-19 deaths: ADTKD-MUC1 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).

Conclusions: Individuals with ADTKD-MUC1 are at an eight-fold increased risk of COVID-19 mortality vs. ADTKD-UMOD individuals. Haplo-insufficient production of mucin-1 may be responsible.

Keywords: Autosomal Dominant Tubulointerstitial kidney disease; CA15-3; COVID-19; MUC1; Mucin-1; UMOD.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was approved by the Wake Forest University Health Sciences Institutional Review Board, Winston-Salem, NC, United States, in accordance with the Declaration of Helsinki. All individuals presented in the study provided voluntary, autonomous consent to participate. Consent for publication: Not applicable. Competing interests: AJB has also received funding from the Black Brogan Foundation, The Slim Health Foundation, Soli Deo Gloria. He has received compensation as follows: advisory board, Horizon Pharma; speaker, Natera; author, UpToDate; advisor, First Faculty of Medicine, Charles University; royalty; patent for UMOD genetic diagnosis. PJC has received funding from Astra Zeneca, Bohringher, Hansa, and medical advisory board fees. KOK, AHW, AT, AK, LM, VR, APR-C, JAS, EO, HRM, GP, CD, CS, REH, EE, DS, CI, AV, LP, TZ, MP, MR, PV, KH, MZ, and SK have nothing to disclose.

Figures

Fig. 1
Fig. 1
Study timeline and COVID-19 related deaths in ADTKD patients
Fig. 2
Fig. 2
Flow diagram for the study. A Initial ADTKD Registry COVID-19 Survey. aSurvey respondents and non-respondents described in Supplementary Table S1.bSurvey respondent results are described in Table 1 and Supplemetary Table S2. B Cohort study reviewing the ADTKD registry for COVID-19 related deaths. cThis includes the 11 COVID-19 deaths reported in the 2021 survey and used for analysis described in Table 2, Table 3, and Supplementary Table S3
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