Causal Associations of Insomnia With Chronic Kidney Diseases and Underlying Blood Proteins: An Observational and Mendelian Randomization Study.

Objective: To investigate the causal association between insomnia and chronic kidney disease (CKD) and to explore the underlying protein pathways.

Methods: In primary analyses, multivariate regression and 1-sample mendelian randomization (1SMR) analyses were performed to estimate the associations between insomnia and CKD in the UK Biobank cohort. The study was conducted from March 13, 2006, to November 12, 2021. Thereafter, a 2-sample MR (2SMR) analysis was used to validate the findings from primary analyses. Finally, proteome-wide MR analysis was conducted to pinpoint CKD-associated blood proteins, supplemented by the colocalization analysis. In addition, the potential mediation effects of blood proteins on the pathway of insomnia giving rise to CKD were explored through a 2-step MR design.

Results: Across the multivariate regression, 1SMR, and their sensitivity analyses, we found consistent evidence suggesting that more frequent insomnia was associated with a higher risk of CKD (multivariate regression: hazard ratio, 1.21 [95% CI, 1.17 to 1.25; P<.001]; 1SMR: odds ratio, 1.35 [95% CI, 1.02 to 1.79; P=.04]). Consistent evidence was obtained by using 2SMR (odds ratio,1.06; 95% CI, 1.02 to 1.11; P=.009). Genetically predicted 124 circulating proteins were associated with CKD in proteome-wide MR analysis. ENPP5 is a promising novel target that mediates the association between insomnia and CKD.

Conclusion: More frequent insomnia is causally associated with increased risk of CKD, and ENPP5 as a potential blood protein mediates the association between insomnia and CKD. These findings indicate that addressing insomnia could serve as a viable and valid intervention to mitigate CKD risk.