Mechanisms of antihypertensive effect of chlorthalidone in advanced chronic kidney disease—a causal mediation analysis

Abstract

Background: Chlorthalidone in chronic kidney disease (CLICK) randomized trial demonstrated a robust reduction in systolic blood pressure (BP) in stage 4 chronic kidney disease (CKD). Here we explore the mechanisms underlying the antihypertensive effect of chlorthalidone. Methods: In this prespecified analysis, we analyzed the contributions of baseline levels of 24-hour urinary sodium and aldosterone and the changes from baseline to 4 weeks in the multiple mediators reflecting volume status in a causal mediation analysis framework. Baseline levels of these mediators served as covariates. No power calculationfor this analysis was performed. Results: Of the 160 patients randomized, 140 (87.5%) were included in this analysis. Compared to placebo, chlorthalidone within 4 weeks reduced weight -1.5 % (95% CI -2.2 to -0.7) and volume -1.4 % (95% CI -2.2 to -0.6), stimulated plasma renin 40.5% (95% CI 25.4 to 57.4%) and serum aldosterone 40.2% (95% CI 11.7% to 76%), and reduced plasma NT-pro BNP levels -19.4% (95% CI -33.8% to -1.9%). Mediation analysis revealed the following results: for weight change, the total effect on systolic BP was -10.8 mmHg (95% CI -16 to -5.7), of which weight change (indirect effect) accounted for -0.9 mmHg (95% CI -4.2 to 2.5) and BP change independent of weight (direct effect) accounted for -10 mmHg (-15.7 to – 4.2). Thus, the percent mediation was 8.1% (95% CI -22.4 to 38.5). Baseline excretion of 24-hour sodium or aldosterone or any of the changes in the above mediators examined accounted for <2 mmHg BP drop and were not significant for any of the mediators. Conclusion: Chlorthalidone improved BP control among patients with advanced CKD independently of baseline urinary sodium, aldosterone, weight loss, or changes in the renin-angiotensin system or NT-pro BNP. (Funded by the National Heart Lung and Blood Institute; CLICK ClinicalTrials.gov number, NCT02841280)