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Clinical Trial Summary

The hypothesis is based on UMOD rs13333226 genotype, there are two strata of hypertensive patients. The High-UMOD group (AA genotype) has increased UMOD excretion, greater salt sensitivity, HTN, normal eGFR and greater BP response to loop diuretics like furosemide. The Low-UMOD group (G allele) has decreased UMOD excretion, salt resistance, increased eGFR, increased proximal tubular reabsorption of Na (possibly related to increased GFR), a poor BP response to loop diuretics, and possibly diminished function of NKCC2. The High-UMOD strata will have decreased delivery of Na+ to the distal tubule and collecting duct because NKCC2 function is normal and the study hypothesis is that the participants will be more responsive to loop diuretics. In contrast, the Low-UMOD group (G allele) will not show a similar response to loop diuretics. This may be related either to lower Na delivery to the TAL, because of increased proximal tubular reabsorption of Na+, or a suppressed function of NKCC2. The population distribution of the High-UMOD group (AA) is 67%. Our overall objective is to test the hypothesis that hypertensive subjects with uncontrolled HTN open possessing the AA genotype of rs13333226 will be better responders to loop diuretics compared to those possessing the G allele.

Clinical Trial Description

There are over 1 billion people with HTN worldwide, and the World Health Organisation suggests this will rise to 1.5 billion by 2020.(1) Up to 30% of hypertensive patients have resistant HTN (uncontrolled BP on > 3 drugs of which one must be a diuretic) and ~50% have uncontrolled HTN, with a 7-fold higher cardiovascular risk.

In clinical practice, criteria such as ancestry and serum renin levels provide only a rough indication of the underlying disease pathway and, while pharmacotherapy is the mainstay of HTN management, the selection of antihypertensive therapy is essentially by trial-and-error. Five drug classes are the main first-line agents for HTN, but response rates to any given drug are only ~50%. There are no new anti-hypertensive drugs in clinical trials and there is a need to either develop newer agents or target existing drugs to specific strata of hypertensive patients in whom they would be beneficial. The recent failure of the Renal Sympathetic Denervation trial, which used a novel device strategy for resistant HTN, highlights the limited options available in the management of uncontrolled or resistant HTN.

HTN as a phenotype demonstrates stratification in the population, based on the specific pathophysiological and molecular pathways that are operative and this is reflected in the current NICE guidelines. However, there has been little progress in stratification by leveraging genomic and molecular information, although there is evidence that this may be useful. Monogenic forms of HTN show that identification of the many causative mutations, primarily affecting the kidney and sodium balance, can inform therapy - for example, glucocorticoids in glucocorticoid remediable aldosteronism and amiloride in Liddle syndrome. Despite the successful adoption of the BHS/NICE treatment algorithm for the treatment of HTN, there remains substantial clinical uncertainty about the preferred clinical management of people with uncontrolled or treatment resistant HTN. Moreover, the choice of diuretic, suggested in HTN guidelines, is not based on clinical trials for third line antihypertensive agents. There is general consensus that resistant HTN is due to excessive sodium retention and thus "further diuretic therapy" may be an effective treatment. The choice that one type of diuretic will be superior to another has however not been studied and is usually prescribed in a trial and error manner with diuretics that primarily target the distal nephron (thiazide-like diuretic or spironolactone). ;

Study Design

Related Conditions & MeSH terms

NCT number NCT03354897
Study type Interventional
Source NHS Greater Glasgow and Clyde
Contact Katriona JM Brooksbank, PhD
Phone 0141 330 2627
Status Recruiting
Phase Phase 4
Start date April 5, 2017
Completion date April 5, 2019

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