Cannabis Use and CKD: Epidemiological Associations and Mendelian Randomization.

Rationale & Objective: The association between cannabis use and chronic kidney disease (CKD) is controversial. We aimed to assess association of CKD with cannabis use in a large cohort study and then assess causality using Mendelian randomization with a genome-wide association study (GWAS).

Study Design: Retrospective cohort study and genome-wide association study.

Setting & Participants: The retrospective study was conducted on the All of Us cohort (N=223,354). Genetic instruments for cannabis use disorder were identified from 3 GWAS: the Psychiatric Genomics Consortium Substance Use Disorders, iPSYCH, and deCODE (N=384,032). Association between genetic instruments and CKD was investigated in the CKDGen GWAS (N > 1.2 million).

Exposure: Cannabis consumption.

Outcomes: CKD outcomes included: cystatin-C and creatinine-based kidney function, proteinuria, and blood urea nitrogen.

Analytical Approach: We conducted association analyses to test for frequency of cannabis use and CKD. To evaluate causality, we performed a 2-sample Mendelian randomization.

Results: In the retrospective study, compared to former users, less than monthly (OR, 1.01; 95% CI, 0.87-1.18;  = 0.87) and monthly cannabis users (OR, 1.15; 95% CI, 0.86-1.52;  = 0.33) did not have higher CKD odds. Conversely, weekly (OR, 1.28; 95% CI, 1.01-1.60;  = 0.04) and daily use (OR, 1.25; 95% CI, 1.04-1.50;  = 0.02) was significantly associated with CKD, adjusted for multiple confounders. In Mendelian randomization, genetic liability to cannabis use disorder was not associated with increased odds for CKD (OR, 1.00; 95% CI, 0.99-1.01;  = 0.96). These results were robust across different Mendelian randomization techniques and multiple kidney traits.

Limitations: Likely underreporting of cannabis use. In Mendelian randomization, genetic instruments were identified in the GWAS that included individuals primarily of European ancestry.

Conclusions: Despite the epidemiological association between cannabis use and CKD, there was no evidence of a causal effect, indicating confounding in observational studies.