LAUSR

Aims/hypothesis Reasons for the sexual disparity in chronic kidney disease (CKD) are unclear. To provide insight we contextualised these differences within evolutionary biology, and explored sex-specific effects of insulin resistance because it may have sex-specific effects on the reproductive axis. Impaired kidney function may also cause insulin resistance. We assessed these possibilities using bi-directional, sex-specific, two-sample Mendelian randomisation (MR). Methods Given that fasting insulin, fasting glucose and HbA 1c are related, we used MR-Bayesian model averaging (MR-BMA) to identify the best-fitting model and most influential exposure. Genetic associations with glycaemic traits were obtained from genome-wide association studies (GWAS) in Europeans without diabetes ( n  = 108,557 for fasting insulin, as a proxy for insulin resistance, and for fasting glucose, n  = 123,665 for HbA 1c in the Meta-Analyses of Glucose and Insulin-related traits Consortium [MAGIC]), and applied to GWAS of 480,698 Europeans for overall associations with CKD (cases n  = 41,395) and eGFR. We also used sex-specific individual information in white British (179,917 men, 6016 CKD cases; 212,079 women, 5958 CKD cases) from the UK Biobank. Univariable or multivariable MR was used to assess the role of glycaemic trait(s) selected by MR-BMA in CKD and kidney function. Genetic variants predicting eGFR were used to assess the role of kidney function in the most influential exposure(s). Results Fasting insulin was selected as the most likely exposure by both overall and sex-specific MR-BMA. It increased CKD in men (OR 7.23 per pmol/l higher fasting insulin [95% CI 2.46, 21.2]) but not in women (OR 1.05 [95% CI 0.21, 5.21]), and reduced eGFR in men (−0.04 [95% CI −0.07, −0.01]) but not in women (0.01 [95% CI −0.02, 0.03]). Genetically predicted eGFR was unrelated to fasting insulin. Conclusions/interpretation Genetically predicted fasting insulin was sex-specifically associated with CKD and unhealthier kidney function but was not affected by kidney function. Graphical abstract