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

Kendrah O Kidd; Adrienne H Williams; Abbigail Taylor; Lauren Martin; Victoria Robins; John A Sayer; Eric Olinger; Holly R Mabillard; Gregory Papagregoriou; Constantinos Deltas; Christoforos Stavrou; Peter J Conlon; Richard Edmund Hogan; Elhussein A E Elhassan; Drahomíra Springer; Tomáš Zima; Claudia Izzi; Alena Vrbacká; Lenka Piherová; Michal Pohludka; Martin Radina; Petr Vylet'al; Katerina Hodanova; Martina Zivna; Stanislav Kmoch; Anthony J Bleyer Sr

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

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

Authors

Kendrah O Kidd^{1

2}, Adrienne H Williams³, Abbigail Taylor¹, Lauren Martin¹, Victoria Robins¹, John A Sayer^{4

5

6}, Eric Olinger⁷, Holly R Mabillard⁴, Gregory Papagregoriou⁸, Constantinos Deltas⁸, Christoforos Stavrou⁹, Peter J Conlon^{10

11}, Richard Edmund Hogan^{10

11}, Elhussein A E Elhassan^{10

11}, Drahomíra Springer¹², Tomáš Zima¹², Claudia Izzi¹³, Alena Vrbacká², Lenka Piherová², Michal Pohludka¹⁴, Martin Radina², Petr Vylet'al², Katerina Hodanova², Martina Zivna^{1

2}, Stanislav Kmoch^{1

2

15}, Anthony J Bleyer Sr^{16

17}

Affiliations

¹ Wake Forest School of Medicine, Section on Nephrology, Winston-Salem, NC, 27157, USA.
² Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czech Republic.
³ DNA Data Solutions, LLC, St. Petersburg, FL, USA.
⁴ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
⁵ Renal Services, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁶ Newcastle Biomedical Research Centre, NIHR, Newcastle upon Tyne, UK.
⁷ Center for Human Genetics, Cliniques universitaires Saint-Luc, Brussels, Belgium.
⁸ Department of Biological Sciences, Molecular Medicine Research Center, University of Cyprus, Nicosia, Cyprus.
⁹ Department of Nephrology, Evangelismos Hospital, Paphos, Cyprus.
¹⁰ Department of Nephrology and Transplantation Beaumont Hospital, Dublin, Ireland.
¹¹ Royal College of Surgeons in Ireland, Dublin, Ireland.
¹² Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and the First Faculty of Medicine of Charles University, Prague, Czech Republic.
¹³ Clinical Genetics Unit, University of Brescia and Spedali Civili, Brescia, Italy.
¹⁴ Genespector, Prague, Czech Republic.
¹⁵ Medirex Group Academy, Trnava, Slovakia.
¹⁶ Wake Forest School of Medicine, Section on Nephrology, Winston-Salem, NC, 27157, USA. ableyer@wakehealth.edu.
¹⁷ Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czech Republic. ableyer@wakehealth.edu.

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.

Publication types

Observational Study

MeSH terms

Adult
Aged
COVID-19* / genetics
COVID-19* / mortality
Female
Humans
Male
Middle Aged
Mucin-1* / blood
Mutation*
Nephritis, Interstitial / genetics
Registries
SARS-CoV-2 / genetics
Uromodulin

Substances

Mucin-1
MUC1 protein, human
UMOD protein, human
Uromodulin

Abstract

Publication types

MeSH terms

Substances

Grants and funding