Why the study?
Although chlorthalidone demonstrated robust systolic BP reduction in stage 4 CKD, the mechanisms underlying its antihypertensive effect remained to be explored.
Does chlorthalidone reduce systolic blood pressure in advanced chronic kidney disease primarily through volume reduction?
Does chlorthalidone reduce systolic blood pressure in advanced chronic kidney disease primarily through volume reduction?
Chlorthalidone effectively lowers blood pressure in advanced chronic kidney disease primarily through mechanisms independent of volume reduction, weight loss, or changes in the renin-angiotensin system.
Questions volume-centric mechanism of chlorthalidone BP reduction in stage 4 CKD; leaves open alternative pathways for targeted investigation.
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.
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Agarwal et al. (2024) studied this question.
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