Smoking as a causative factor in chronic kidney disease: a two-sample Mendelian randomization study

Smoking is widely acknowledged for its harmful effects on multiple organs. However, its specific causal relationship with chronic kidney disease (CKD) remains uncertain. This study applied bivariate causal analysis and two-sample Mendelian randomization (MR) methods to examine the association between various smoking behaviors - initiation, cessation, age at initiation, cigarettes smoked per day, and lifetime smoking - and CKD, using genome-wide data. The inverse variance weighted (IVW) method was the primary analytical tool, supported by sensitivity analyses, pleiotropy assessments, and mediation analyses. External validation was conducted using independent datasets. The results revealed positive associations between CKD and smoking initiation (Pivw = 1.8 × 10^-2, OR = 1.192), earlier age at initiation (Pivw = 2.3 × 10^-3, OR = 1.481), cigarettes smoked per day (Pivw = 8.8 × 10^-3, OR = 1.216), and lifetime smoking (Pivw = 2.3 × 10^-7, OR = 2.445). In contrast, smoking cessation demonstrated a protective effect against CKD (Pivw = 4.0 × 10^-12, OR = 0.791). External validation results aligned with the primary findings, and the absence of significant heterogeneity confirmed the robustness of the MR analysis. Additionally, the effect of smoking on CKD was mediated by factors such as body mass index, cardiovascular disease, hypertension, and type 2 diabetes. These findings identify smoking as a contributing factor to CKD and suggest that reducing smoking prevalence could significantly lower the incidence of CKD in the population.