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

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

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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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/m 2), 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.

Original language	English
Journal	Hypertension
DOIs	https://doi.org/10.1161/HYPERTENSIONAHA.124.23122
Publication status	Published - 30 Jul 2024

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10.1161/HYPERTENSIONAHA.124.23122

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McCallum, L., Lip, S., McConnachie, A., Brooksbank, K., MacIntyre, I., Doney, A., Llano, A., Aman, A., Caparrotta, T. M., Ingram, G., Mackenzie, I. S., Dominiczak, A. F., MacDonald, T. M., Webb, D. J., & Padmanabhan, S. (2024). UMOD Genotype-Blinded Trial of Ambulatory Blood Pressure Response to Torasemide. Hypertension. https://doi.org/10.1161/HYPERTENSIONAHA.124.23122

@article{cb5f433c3097434b808d13c0fb1f65b8,

title = "UMOD Genotype-Blinded Trial of Ambulatory Blood Pressure Response to Torasemide.",

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/m 2), 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.",

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

year = "2024",

month = jul,

day = "30",

doi = "10.1161/HYPERTENSIONAHA.124.23122",

language = "English",

journal = "Hypertension",

issn = "0194-911X",

publisher = "Lippincott Williams & Wilkins",

}

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

PY - 2024/7/30

Y1 - 2024/7/30

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/m 2), 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.

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/m 2), 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.

U2 - 10.1161/HYPERTENSIONAHA.124.23122

DO - 10.1161/HYPERTENSIONAHA.124.23122

M3 - Article

C2 - 39077768

SN - 0194-911X

JO - Hypertension

JF - Hypertension

ER -

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

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