UMOD Genotype-Blinded Trial of Ambulatory Blood Pressure Response to Torasemide
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, and Sandosh Padmanabhan
Link to Paper
![Professor Dame Anna Dominiczak and Professor Sandosh Pandmanbhan](/media/Media_1061123_smxx.jpg)
Summary
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.
First published: 8 October 2024