Mechanisms of Antihypertensive Effect of Chlorthalidone in Advanced Chronic Kidney Disease: A Causal Mediation Analysis

Abstract

Key Points: *Chlorthalidone reduces the amount of fluid and the BP, but fluid volume reduction is not the cause of lowering of BP. *It is not volume loss but the response to volume loss such as the synthesis of substances that lower BP is important. Background: Chlorthalidone (CTD) in a chronic kidney disease randomized trial demonstrated a robust reduction in systolic BP in stage 4 CKD. In this study, we explore the mechanisms underlying the antihypertensive effect of CTD. 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 calculation for this analysis was performed. Results: Of the 160 patients randomized, 140 (87.5%) were included in this analysis. Compared with placebo, CTD within 4 weeks reduced weight −1.5% (95% confidence interval [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 N-terminal pro-B-type natriuretic peptide 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 mm Hg (95% CI, −16 to −5.7), of which weight change (indirect effect) accounted for −0.9 mm Hg (95% CI, −4.2 to 2.5) and BP change independent of weight (direct effect) accounted for −10 mm Hg (−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 mm Hg BP drop and were not significant for any of the mediators. Conclusions: CTD improved BP control among patients with advanced CKD independent of baseline urinary sodium, aldosterone, weight loss, or changes in the renin-angiotensin system or N-terminal pro-B-type natriuretic peptide.