Association between a history of hypothyroidism and incident chronic kidney disease and potential mediators: A cohort study with Mendelian randomization analysis

ObjectiveTo investigate the association between hypothyroidism and incident chronic kidney disease and identify potential mediators.MethodsThis study included a retrospective cohort and Mendelian randomization analysis. Data were obtained from the UK Biobank and FinnGen via the Integrative Epidemiology Unit Open Genome-Wide Association Studies Project. After exclusions, 439,381 participants were included. The risk of incident chronic kidney disease was the primary outcome. Associations were assessed using Fine and Gray models as well as stratified and sensitivity analyses, and the cumulative risk was presented using Kaplan-Meier curves. For Mendelian randomization analyses, causal effects were estimated using the inverse-variance weighted method. Mendelian randomization-Egger regression, Mendelian randomization-pleiotropy residual sum and outlier test, weighted median method, and weighted mode method were used to assess the robustness of the causal estimates. Mediation analysis was conducted to explore the effects of body mass index, inflammatory factors, and senescence-associated secretory phenotype proteins.ResultsHypothyroidism was associated with a higher risk of incident chronic kidney disease (hazard ratio: 1.35, 95% confidence interval: 1.19-1.53). Mendelian randomization analysis supported a causal effect (odds ratio: 8.23, 95% confidence interval: 3.22-21.00). Absolute risk differences increased over time (5 years, 1.10; 8 years, 1.80; 10 years, 2.40; and 12 years, 3.13). Body mass index and obesity partially mediated this effect. Senescence-associated secretory phenotype proteins were also identified as important mediators, including transforming growth factor-alpha, transforming growth factor-beta, transforming growth factor-beta receptors 2 and 3, growth differentiation factor 15, C-X-C motif chemokine-10, matrix metalloproteinase 1, and matrix metalloproteinase 9.ConclusionsHypothyroidism was associated with incident chronic kidney disease. Obesity and senescence-associated secretory phenotype proteins may mediate this relationship.