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

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.

CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:: CTD in chronic kidney disease ClinicalTrials.gov number: NCT02841280.