TY - JOUR
T1 - Interplay between Chronic Kidney Disease, Hypertension, and Stroke
T2 - Insights from a Multivariable Mendelian Randomization Analysis
AU - Kelly, Dearbhla M.
AU - Georgakis, Marios K.
AU - Franceschini, Nora
AU - Blacker, Deborah
AU - Viswanathan, Anand
AU - Anderson, Christopher D.
N1 - Publisher Copyright:
© American Academy of Neurology.
PY - 2023/11/14
Y1 - 2023/11/14
N2 - Background and ObjectivesChronic 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.MethodsWe 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.ResultsUnivariable 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).DiscussionOur 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.
AB - Background and ObjectivesChronic 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.MethodsWe 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.ResultsUnivariable 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).DiscussionOur 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.
UR - https://www.scopus.com/pages/publications/85176968009
U2 - 10.1212/WNL.0000000000207852
DO - 10.1212/WNL.0000000000207852
M3 - Article
C2 - 37775316
AN - SCOPUS:85176968009
SN - 0028-3878
VL - 101
SP - E1960-E1969
JO - Neurology
JF - Neurology
IS - 20
ER -