Interplay Between Chronic Kidney Disease, Hypertension, and Stroke: Insights From a Multivariable Mendelian Randomization Analysis

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.

Figure 1. Direct Acyclic Graph to Illustrate Total, Direct, and Indirect Effects of CKD on Stroke Risk

Directed acyclic graphs demonstrating the hypothesized direction for the total effect of CKD on increased odds of stroke (A) and the hypothesized direction for the effect of CKD on increased hypertension (B), which may partially mediate the effect of CKD on stroke risk. CKD = chronic kidney disease.

Figure 2. Univariable and Multivariable Mendelian Randomization Associations Between Genetically Determined Kidney Disease Traits and Cerebrovascular Disease Phenotypes, Controlling for Systolic Blood Pressure

Shown are the results derived from inverse-variance weighted Mendelian randomization analysis. AS = all stroke; CES = cardioembolic stroke; eGFR = estimated glomerular filtration rate; ICH = intracerebral hemorrhage; IS = ischemic stroke; LAS = large artery stroke; OR = odds ratio; SVS = small vessel stroke; UACR = urine albumin-to-creatinine ratio.

Figure 3. Mediation Mendelian Randomization Association Between Genetically Determined Estimated Glomerular Filtration Rate and Large Artery Stroke, Controlling for Systolic Blood Pressure

Directed acyclic graph demonstrating the total, direct, and indirect effects of estimated glomerular filtration rate on large artery stroke risk as well as the proportion of the total effect mediated by systolic blood pressure. Shown are the results derived from inverse-variance weighted Mendelian randomization analysis. eGFR = estimated glomerular filtration rate; SBP = systolic blood pressure.