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Observational Study
. 2022 Sep 1;79(9):911-918.
doi: 10.1001/jamaneurol.2022.2299.

Association of Chronic Kidney Disease With Risk of Intracerebral Hemorrhage

Kevin N Vanent  1 , Audrey C Leasure  1 , Julian N Acosta  1 , Lindsey R Kuohn  1 , Daniel Woo  2 , Santosh B Murthy  3 , Hooman Kamel  3   4 , Steven R Messé  5 , Michael T Mullen  5 , Jordana B Cohen  6   7 , Debbie L Cohen  6 , Raymond R Townsend  6 , Nils H Petersen  1 , Lauren H Sansing  1 , Thomas M Gill  8 , Kevin N Sheth  1 , Guido J Falcone  1
Affiliations
Observational Study

Association of Chronic Kidney Disease With Risk of Intracerebral Hemorrhage

Kevin N Vanent et al. JAMA Neurol. .

Abstract

Importance: The evidence linking chronic kidney disease (CKD) to spontaneous intracerebral hemorrhage (ICH) is inconclusive owing to possible confounding by comorbidities that frequently coexist in patients with these 2 diseases.

Objective: To determine whether there is an association between CKD and ICH risk.

Design, setting, and participants: A 3-stage study that combined observational and genetic analyses was conducted. First, the association between CKD and ICH risk was tested in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, a multicenter case-control study in the US. All participants with available data on CKD from ERICH were included. Second, this analysis was replicated in the UK Biobank (UKB), an ongoing population study in the UK. All participants in the UKB were included in this study. Third, mendelian randomization analyses were implemented in the UKB using 27 CKD-related genetic variants to test for genetic associations. ERICH was conducted from August 1, 2010, to August 1, 2017, and observed participants for 1 year. The UKB enrolled participants between 2006 and 2010 and will continue to observe them for 30 years. Data analysis was performed from November 11, 2019, to May 10, 2022.

Exposures: CKD stages 1 to 5.

Main outcomes and measures: The outcome of interest was ICH, ascertained in ERICH via expert review of neuroimages and in the UKB via a combination of self-reported data and International Statistical Classification of Diseases, Tenth Revision, codes.

Results: In the ERICH study, a total of 2914 participants with ICH and 2954 controls who had available data on CKD were evaluated (mean [SD] age, 61.6 [14.0] years; 2433 female participants [41.5%]; 3435 male participants [58.5%]); CKD was found to be independently associated with higher risk of ICH (odds ratio [OR], 1.95; 95% CI, 1.35-2.89; P < .001). This association was not modified by race and ethnicity. Replication in the UKB with 1341 participants with ICH and 501 195 controls (mean [SD] age, 56.5 [8.1] years; 273 402 female participants [54.4%]; 229 134 male participants [45.6%]) confirmed this association (OR, 1.28; 95% CI, 1.01-1.62; P = .04). Mendelian randomization analyses indicated that genetically determined CKD was associated with ICH risk (OR, 1.56; 95% CI, 1.13-2.16; P = .007).

Conclusions and relevance: In this 3-stage study that combined observational and genetic analyses among study participants enrolled in 2 large observational studies with different characteristics and study designs, CKD was consistently associated with higher risk of ICH. Mendelian randomization analyses suggest that this association was causal. Further studies are needed to identify the specific biological pathways that mediate this association.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Acosta reported being an employee of Rad AI outside the submitted work. Dr Woo reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Murthy reported receiving grants from the National Institutes of Health outside the submitted work. Dr Kamel reported serving as a principal investigator for the National Institutes of Health–funded ARCADIA trial, which receives in-kind study drug from the Bristol Myers Squibb–Pfizer Alliance for apixaban (Eliquis) and ancillary study support from Roche Diagnostics; being Deputy Editor for JAMA Neurology; serving on the clinical trial steering/executive committees for Medtronic, Janssen, and Javelin Medical; and serving on end point adjudication committees for Novo Nordisk and Boehringer Ingelheim. Dr Mullen reported receiving grants from the American Heart Association as site principal investigator for the REDUCE trial. Dr J. Cohen reported receiving grants from the National Institutes of Health and from the American Heart Association Bugher Award outside the submitted work. Dr Sheth reported receiving grants from the National Institutes of Health, the American Heart Association, Hyperfine, and Biogen; serving as data safety monitoring board chair of Zoll Medical; receiving equity from Alva; and receiving personal fees from Cerovasc outside the submitted work. Dr Falcone reported receiving grants from the National Institutes of Health and the American Heart Association during the conduct of the study. No other disclosures were reported.

Figures

Figure.
Figure.. Mendelian Randomization (MR) Results for Genetically Determined Chronic Kidney Disease and Risk of Intracerebral Hemorrhage
A, Association of single-nucleotide variations (SNVs) with chronic kidney disease and intracerebral hemorrhage. The blue summary line corresponds to the inverse variance–weighted slope. B, Forest plot of different MR methods. MR pleiotropy residual sum and outlier (PRESSO) corresponds to the outlier corrected estimate. IVW indicates inverse variance weighted; OR, odds ratio; WM, weighted median.
See this image and copyright information in PMC

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