Linsay McCallum, Stefanie Lip, Alex McConnachie, Katriona Brooksbank, Iain 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
{"title":"托拉塞米流动血压反应的 UMOD 基因型对照试验。","authors":"Linsay McCallum, Stefanie Lip, Alex McConnachie, Katriona Brooksbank, Iain 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","doi":"10.1161/HYPERTENSIONAHA.124.23122","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>UMOD (uromodulin) has been linked to hypertension through potential activation of Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>-</sup> cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA <i>UMOD</i> genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2 interaction.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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/m<sup>2</sup>), 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]; <i>P</i><0.0001; AG/GG, -3.22 [95% CI, -5.93 to -0.51]; <i>P</i>=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]; <i>P</i>=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 (<i>P</i>=0.004 for difference in trajectories).</p><p><strong>Conclusions: </strong>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.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354897.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":null,"pages":null},"PeriodicalIF":6.9000,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"<i>UMOD</i> Genotype-Blinded Trial of Ambulatory Blood Pressure Response to Torasemide.\",\"authors\":\"Linsay McCallum, Stefanie Lip, Alex McConnachie, Katriona Brooksbank, Iain 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\",\"doi\":\"10.1161/HYPERTENSIONAHA.124.23122\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>UMOD (uromodulin) has been linked to hypertension through potential activation of Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>-</sup> cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA <i>UMOD</i> genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2 interaction.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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/m<sup>2</sup>), 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]; <i>P</i><0.0001; AG/GG, -3.22 [95% CI, -5.93 to -0.51]; <i>P</i>=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]; <i>P</i>=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 (<i>P</i>=0.004 for difference in trajectories).</p><p><strong>Conclusions: </strong>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.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354897.</p>\",\"PeriodicalId\":13042,\"journal\":{\"name\":\"Hypertension\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.9000,\"publicationDate\":\"2024-07-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Hypertension\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/HYPERTENSIONAHA.124.23122\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PERIPHERAL VASCULAR DISEASE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hypertension","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/HYPERTENSIONAHA.124.23122","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PERIPHERAL VASCULAR DISEASE","Score":null,"Total":0}
UMOD Genotype-Blinded Trial of Ambulatory Blood Pressure Response to Torasemide.
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.
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.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
