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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 (GWAS) 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 (ischaemic stroke and its subtypes, and intracerebral haemorrhage [ICH). 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 Mendelian randomization revealed associations between genetically determined lower eGFR and risk of all stroke (OR per 1-log decrement in eGFR, 1.77; 95% CI, 1.31-2.40; p<0.001), ischaemic 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 AS; OR, 2.16; 95% CI, 1.48-3.17; p<0.001 for IS; 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.

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