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

TY - JOUR

T1 - UMOD Genotype-Blinded Trial of Ambulatory Blood Pressure Response to Torasemide

AU - McCallum, Linsay

AU - Lip, Stefanie

AU - McConnachie, Alex

AU - Brooksbank, Katriona

AU - MacIntyre, Iain

AU - Doney, Alexander

AU - Llano, Andrea

AU - Aman, Alisha

AU - Caparrotta, Thomas M.

AU - Ingram, Gareth

AU - MacKenzie, Isla S.

AU - Dominiczak, Anna F.

AU - MacDonald, Thomas M.

AU - Webb, David J.

AU - Padmanabhan, Sandosh

N1 - © 2024 The Authors.

PY - 2024/10/1

Y1 - 2024/10/1

N2 - 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.

AB - 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.

KW - blood pressure

KW - genotype

KW - hypertension

KW - torsemide

KW - uromodulin

UR - https://www.scopus.com/pages/publications/85200321033

U2 - 10.1161/HYPERTENSIONAHA.124.23122

DO - 10.1161/HYPERTENSIONAHA.124.23122

M3 - Article

C2 - 39077768

AN - SCOPUS:85200321033

SN - 0194-911X

VL - 81

SP - 2049

EP - 2059

JO - Hypertension

JF - Hypertension

IS - 10

ER -