UMOD Genotype-Blinded Trial of Ambulatory Blood Pressure Response to Torasemide.

IF 6.9 1区医学 Q1 PERIPHERAL VASCULAR DISEASE Hypertension Pub Date : 2024-10-01 Epub Date: 2024-07-30 DOI:10.1161/HYPERTENSIONAHA.124.23122

Linsay McCallum, Stefanie Lip, Alex McConnachie, Katriona Brooksbank, Iain M MacIntyre, Alexander Doney, Andrea Llano, Alisha Aman, Thomas M Caparrotta, Gareth Ingram, Isla S Mackenzie, Anna F Dominiczak, Thomas M MacDonald, David J Webb, Sandosh Padmanabhan

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Abstract

Background: UMOD (uromodulin) has been linked to hypertension through potential activation of Na⁺-K⁺-2Cl^- cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA UMOD genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2 interaction.

Methods: This prospective, multicenter, genotype-blinded trial evaluated torasemide (torsemide) efficacy on systolic blood pressure (SBP) reduction over 16 weeks in nondiabetic, hypertensive participants uncontrolled on ≥1 nondiuretic antihypertensive for >3 months. The primary end point was the change in 24-hour ambulatory SBP (ABPM SBP) and SBP response trajectories between baseline and 16 weeks by genotype (AA versus AG/GG) due to nonrandomized groups at baseline (ClinicalTrials.gov: NCT03354897).

Results: Of 251 enrolled participants, 222 received torasemide and 174 demonstrated satisfactory treatment adherence and had genotype data. The study participants were middle-aged (59±11 years), predominantly male (62%), obese (body mass index, 32±7 kg/m²), with normal eGFR (92±17 mL/min/1.73 m²) and an average baseline ABPM of 138/81 mm Hg. Significant reductions in mean ABPM SBP were observed in both groups after 16 weeks (AA, -6.57 mm Hg [95% CI, -8.44 to -4.69]; P<0.0001; AG/GG, -3.22 [95% CI, -5.93 to -0.51]; P=0.021). The change in mean ABPM SBP (baseline to 16 weeks) showed a difference of -3.35 mm Hg ([95% CI, -6.64 to -0.05]; P=0.048) AA versus AG/GG genotypes. The AG/GG group displayed a rebound in SBP from 8 weeks, differing from the consistent decrease in the AA group (P=0.004 for difference in trajectories).

Conclusions: Our results confirm a plausible interaction between UMOD and NKCC2 and suggest a potential role for genotype-guided use of loop diuretics in hypertension management.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354897.

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托拉塞米流动血压反应的 UMOD 基因型对照试验。

背景：UMOD（uromodulin）通过可能激活襻利尿剂的靶标--Na+-K+-2Cl-共转运体（NKCC2）而与高血压有关。我们推测，携带 rs13333226-AA UMOD 基因型的高血压患者对襻利尿剂的血压反应会更大，这可能是由 UMOD/NKCC2 的相互作用介导的：这项前瞻性、多中心、基因型盲法试验评估了托拉塞米（torasemide）在 16 周内降低收缩压（SBP）的疗效，研究对象为服用≥1 种非利尿型降压药超过 3 个月仍未得到控制的非糖尿病高血压患者。主要终点是 24 小时动态 SBP（ABPM SBP）和 SBP 反应轨迹在基线和 16 周之间的变化，按基因型（AA 与 AG/GG）划分，因为基线时未随机分组（ClinicalTrials.gov：NCT03354897）：在 251 名入组参与者中，222 人接受了托拉塞米治疗，174 人的治疗依从性令人满意，并提供了基因型数据。研究参与者均为中年人（59±11 岁），以男性为主（62%），肥胖（体重指数为 32±7 kg/m2），eGFR 正常（92±17 mL/min/1.73 m²），平均 ABPM 基线为 138/81 mm Hg。16 周后，两组患者的平均 ABPM SBP 均显著下降（AA，-6.57 mm Hg [95% CI，-8.44 至-4.69]；PP=0.021）。平均 ABPM SBP 的变化（基线至 16 周）显示，AA 与 AG/GG 基因型的差异为 -3.35 mm Hg（[95% CI, -6.64 to -0.05]；P=0.048）。AG/GG组的SBP从8周开始出现反弹，与AA组的持续下降不同（轨迹差异P=0.004）：我们的研究结果证实了 UMOD 和 NKCC2 之间似有似无的相互作用，并提示了在高血压管理中基因型指导使用襻利尿剂的潜在作用：URL: https://www.clinicaltrials.gov; 唯一标识符：NCT03354897。

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来源期刊

Hypertension 医学-外周血管病

CiteScore

15.90

自引率

4.80%

发文量

1006

审稿时长

1 months

期刊介绍： Hypertension presents top-tier articles on high blood pressure in each monthly release. These articles delve into basic science, clinical treatment, and prevention of hypertension and associated cardiovascular, metabolic, and renal conditions. Renowned for their lasting significance, these papers contribute to advancing our understanding and management of hypertension-related issues.