Mendelian randomization analyses identified a significant association between genetically determined chronic kidney disease and intracerebral hemorrhage risk, supporting a causal association between the 2 conditions.
Guido Falcone, MD, ScD, MPH
According to a data from a 3-stage study that combined epidemiologic and genetic analyses, chronic kidney disease (CKD) was independently associated with a higher risk of intracerebral hemorrhage (ICH), regardless of race or ethnicity. In addition, CKD was associated with poor functional outcome following ICH.
The first of the studies, titled ERICH (NCT01202864), included 2914 participants with ICH and 2954 controls, with a similar mix of races and ethnicities across the cohort. CKD, present in 4.3% of ICH cases vs 1.3% of controls, was associated with an increased odds of ICH in unadjusted (odds ratio [OR], 3.35; 95% CI, 2.33-4.82; P <.001) and adjusted (OR, 1.95; 95% CI, 1.35-2.89; P <.001) analyses. In patients with CKD, the risk of ICH was not modified by race and ethnicity or hemorrhage location.
Senior author Guido Falcone, MD, ScD, MPH, assistant professor of neurology, Yale School of Medicine, and colleagues concluded, "Future research is needed to elucidate the biologic mechanisms responsible for the associations of CKD with the risk and severity of ICH and to study the genetic associations reported here in Asian, Black, and Hispanic or Latino populations."
ERICH was conducted from August 2010 to August 2017 and observed participants for 1 year. The second analysis aimed to replicate the data using participants enrolled in the UK Biobank (UKB), an ongoing population study in the UK. Among 502,536 participants enrolled in UKB, 1341 individuals with ICH and 501,195 controls were identified. Here, findings confirmed what was observed in ERICH, as CKD was associated with higher odds of ICH in unadjusted (OR, 3.60; 95% CI, 2.89-4.48; P <.001) and adjusted analyses (OR, 1.28; 95% CI, 1.01-1.62; P = .04).
Similar to findings from ERICH, end-stage kidney disease was associated with an even higher odds of ICH in unadjusted (OR, 7.00; 95% CI, 2.88-16.97; P <.001) and adjusted analyses (OR, 3.21; 95% CI, 1.31-7.87; P = .01) analyses. Sensitivity analyses matching ICH cases and controls by their propensity score produced similar results for CKD in unadjusted analyses (OR, 1.31; 95% CI, 1.02-1.68; P = .04) and adjusted analyses (OR, 1.29; 95% CI, 1.01-1.66; P = .04). Random-effects models that pooled the estimates from the ERICH study and the UKB yielded consistent findings.
In Mendelian randomization analyses that featured mostly participants of European ancestry (83.9%), genetically determined CKD was associated with higher odds of ICH when using both the inverse variance-weighted method (OR, 1.56; 95% CI, 1.13-2.16; P = .007) and the more conservative weighted-median approach (OR, 1.72; 95% CI, 1.06-2.82; P = .03). Investigators found no signs of horizontal pleiotropy, as demonstrated by null results on Mendelian randomization-Egger (intercept OR, 1.00; 95% CI, 0.96-1.03; P = .81) and Mendelian randomization-PRESSO global tests (residual sum of squares, 23.22; P = .73).
Falcone et al also noted, "Although our study provides important evidence to support a causal association between CKD and ICH, the pathways mediating this association remain to be identified. One possible pathway is the exacerbation of existing hypertension. The kidneys play a central role in regulating blood pressure and fluid balance via neurohormonal pathways and pressure natriuresis."
In a separate analysis of CKD and functional outcome after ICH in ERICH, 48.8% (n = 1230) had a poor functional outcome, as indicated by modified Rankin Scale (mRS) scores of 4-6. There was an increased risk of poor outcome for those with CKD (58.8% vs 47.9%; unadjusted P = .003), which was confirmed in multivariable regression analyses (OR, 2.05; 95% CI, 1.13-3.07; P <.001). Hemorrhage location modified the association between CKD and poor outcome, as CKD was associated with higher odds of poor outcome in lobar ICH (OR, 4.03; 95% CI, 1.69-10.12; P = .002) compared with nonlobar ICH (OR, 1.74; 95% CI, 1.10-2.76; P = .02). Notably, similar findings were observed on sensitivity analyses when mRS was dichotomized as 0 to 2 vs 3 to 6.