Abstract
BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) increases the risk of stroke, but the extent through which this association is mediated by hypertension is unknown. We leveraged large-scale genetic data to explore causal relationships between CKD, hypertension, and cerebrovascular disease phenotypes. METHODS: We used data from genome-wide association studies of European ancestry to identify genetic proxies for kidney function (CKD diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]), systolic blood pressure (SBP), and cerebrovascular disease (ischemic stroke and its subtypes and intracerebral hemorrhage). We then conducted univariable, multivariable, and mediation Mendelian randomization (MR) analyses to investigate the effect of kidney function on stroke risk and the proportion of this effect mediated through hypertension. RESULTS: Univariable MR revealed associations between genetically determined lower eGFR and risk of all stroke (odds ratio [OR] per 1-log decrement in eGFR, 1.77; 95% CI 1.31-2.40; p < 0.001), ischemic stroke (OR 1.81; 95% CI 1.31-2.51; p < 0.001), and most strongly with large artery stroke (LAS) (OR 3.00; 95% CI 1.33-6.75; p = 0.008). These associations remained significant in the multivariable MR analysis, controlling for SBP (OR 1.98; 95% CI 1.39-2.82; p < 0.001 for all stroke; OR 2.16; 95% CI 1.48-3.17; p < 0.001 for ischemic stroke; OR 4.35; 95% CI 1.84-10.27; p = 0.001 for LAS), with only a small proportion of the total effects mediated by SBP (6.5% [0.7%-16.8%], 6.6% [0.8%-18.3%], and 7.2% [0.5%-24.8%], respectively). Total, direct and indirect effect estimates were similar across a number of sensitivity analyses (weighted median, MR-Egger regression). DISCUSSION: Our results demonstrate an independent causal effect of impaired kidney function, as assessed by decreased eGFR, on stroke risk, particularly LAS, even when controlled for SBP. Targeted prevention of kidney disease could lower atherosclerotic stroke risk independent of hypertension.