Causal Effect of Low‐Density Lipoprotein Cholesterol on Chronic Kidney Disease: A Mendelian Randomization Study

Background While dyslipidemia is associated with chronic kidney disease (CKD), conventional observational studies cannot establish causality, and previous Mendelian randomization (MR) findings on low‐density lipoprotein cholesterol (LDL‐C) and CKD remain inconsistent. Objective To further investigate the causal relationship between LDL‐C and CKD using MR and evaluate its independence. Methods We employed a two‐sample and multivariable MR (MVMR) framework. Initially, two‐sample and reverse MR analyses were performed for four lipid traits on CKD using genetic data from the IEU Open GWAS and the UK Biobank separately, with a Bonferroni‐corrected significance threshold of p < 0.0125. Subsequently, MVMR was conducted to assess the independent effect of LDL‐C after adjusting for other lipid traits ( p < 0.05). Finally, an MVMR model incorporating LDL‐C, smoking, alcohol consumption, and body mass index (BMI) was fitted to test the independence from these lifestyle confounders, followed by a sensitivity analysis with linkage disequilibrium–based confounder filtering to verify robustness. Results Two‐sample MR showed a significant causal effect of LDL‐C on increased CKD risk (IEU source: OR = 1.13, 95% CI: 1.03–1.23, p < 0.01; consistent results from UK Biobank), with no evidence of reverse causation. MVMR confirmed the independence of this association: LDL‐C remained significantly associated with CKD after adjusting for other lipid traits (OR = 1.21, 95% CI: 1.08–1.35, p = 0.0007) and after further adjustment for BMI, smoking, and alcohol (OR = 1.14, 95% CI: 1.04–1.25, p = 0.068). The effect direction remained consistent in the stringent sensitivity analysis. Conclusion LDL‐C may be an independent risk factor for CKD, the independence of which warrants further validation.