Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana.
Department of Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health, Indiana University Center for Aging Research, Indiana University School of Medicine, Regenstrief Institute, Indianapolis, Indiana.
Clin J Am Soc Nephrol. 2024 Aug 1;19(8):1025-1032. doi: 10.2215/CJN.0000000000000484. Epub 2024 Jun 12.
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.
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.
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.
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 -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.
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 -terminal pro-B-type natriuretic peptide.
: CTD in chronic kidney disease ClinicalTrials.gov number: NCT02841280.
氯噻酮可降低液体量和血压，但液体量减少不是降低血压的原因。重要的不是容量损失，而是对容量损失的反应，如降低血压的物质的合成。
在一项慢性肾脏病随机试验中，氯噻酮（CTD）显示出 4 期 CKD 患者收缩压的显著降低。在这项研究中，我们探讨了 CTD 降压作用的机制。
在这个预先指定的分析中，我们在因果中介分析框架中分析了基线 24 小时尿钠和醛固酮水平以及反映体积状态的多种介质从基线到 4 周的变化对降压作用的贡献。这些介质的基线水平作为协变量。未对该分析进行功效计算。
在随机分组的 160 例患者中，有 140 例（87.5%）纳入本分析。与安慰剂相比，CTD 在 4 周内体重减轻 1.5%（95%置信区间[CI]，-2.2 至-0.7），容量减少 1.4%（95%CI，-2.2 至-0.6），血浆肾素增加 40.5%（95%CI，25.4%至 57.4%），血清醛固酮增加 40.2%（95%CI，11.7%至 76%），血浆 B 型利钠肽前体水平降低 19.4%（95%CI，-33.8%至-1.9%）。中介分析显示以下结果：体重变化对收缩压的总效应为-10.8mmHg（95%CI，-16 至-5.7），其中体重变化（间接效应）占-0.9mmHg（95%CI，-4.2 至 2.5），血压变化与体重无关（直接效应）占-10mmHg（-15.7 至-4.2）。因此，中介百分比为 8.1%（95%CI，-22.4 至 38.5）。基线 24 小时尿钠或醛固酮排泄或所检查的上述介质中的任何变化仅占 2mmHg 的血压下降，并且对于任何介质都不具有统计学意义。
CTD 改善了晚期 CKD 患者的血压控制，与基线尿钠、醛固酮、体重减轻或肾素-血管紧张素系统或 B 型利钠肽前体的变化无关。
CTD 在慢性肾脏病临床试验注册处的编号：NCT02841280。
