Abstract Details

Title Chronic Kidney Disease and Risk of Intracerebral Hemorrhage: The Role of Hypertension as a Mediator

Topic Cerebrovascular Disease and Interventional Neurology

Presentation(s) S34 - Stroke Risk Factors and Preventative Strategies (4:06 PM-4:18 PM)

Poster/Presentation
Number 004

Background CKD is a well-established risk factor for ICH. However, the biological pathway underlying this association remains unclear.

Objective To assess for mediators of the association between chronic kidney disease (CKD) and risk of spontaneous intracerebral hemorrhage (ICH).

Design/Methods We conducted a PheWAS using data from the UK Biobank (UKB), a large cohort study that enrolled over 500,000 Britons aged 40-69. We first developed a polygenic risk score that contained 27 independent (r2 <0.1) genetic risk variants known to be associated with CKD at genome-wide significant levels (p<5x10^-8). We subsequently tested for associations between this CKD genetic risk score and the 1,840 disease phenotypes available through the UKB baseline assessment. We used a Bonferroni corrected p<2.7x10^-5 as our threshold for significance. For all phenotypes that reached statistical significance in the PheWAS, we obtained summary results from previously published genome-wide association studies and implemented multivariable Mendelian Randomization (MR) to evaluate the proportion of the total effect of CKD on ICH risk mediated through these phenotypes. The indirect effect of CKD on ICH risk was calculated using the difference in coefficients method.

Results Excluding renal-related diseases, hypertension was the only significant phenotype in the PheWAS (p=3.2x10^-21). Genetically determined CKD was associated with a total increase in ICH risk of 38% in univariable MR (OR 1.38; 95% CI 1.12-1.71; p=0.002). This association was reduced to a 19% increase after adjusting for hypertension in multivariable MR (OR 1.19; 95% CI 1.03-1.39; p=0.021). The proportion of the total effect of CKD on ICH risk mediated through hypertension was estimated to be 55%.

Conclusions Hypertension accounts for approximately 55% of the total effect of CKD on ICH risk in genetic analyses. This aligns with existing knowledge that CKD can worsen hypertension. Further studies are needed to identify other pathways that mediate the remaining effect of CKD on ICH risk.

Authors/Disclosures
Kevin N. Vanent PRESENTER	Mr. Vanent has nothing to disclose.
Cyprien Rivier, MD (Yale University)	Dr. Rivier has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pyxis Partners.
Charles Matouk	No disclosure on file
Michael Levitt	No disclosure on file
Thabele M. Leslie-Mazwi, MD	Dr. Leslie-Mazwi has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for World Care Clinical. Dr. Leslie-Mazwi has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Phillips Health Care. Dr. Leslie-Mazwi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for IQVIA. Dr. Leslie-Mazwi has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zoll.
Thomas Gill	No disclosure on file
Kevin N. Sheth, MD, FAAN (Yale UniversityDivision of Neuro and Critical Care)	Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ceribell. Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zoll. Dr. Sheth has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NControl. Dr. Sheth has received stock or an ownership interest from Astrocyte. Dr. Sheth has received stock or an ownership interest from Alva. The institution of Dr. Sheth has received research support from Biogen. The institution of Dr. Sheth has received research support from Novartis. The institution of Dr. Sheth has received research support from Bard. The institution of Dr. Sheth has received research support from Hyperfine. Dr. Sheth has received intellectual property interests from a discovery or technology relating to health care.
Guido J. Falcone, MD (Yale School of Medicine)	The institution of Dr. Falcone has received research support from NIH. The institution of Dr. Falcone has received research support from AHA.