Endothelin receptor antagonism for resistant hypertension in chronic kidney disease: where does aprocitentan fit?

Abstract

Resistant hypertension, defined as blood pressure (BP) above target despite maximally tolerated doses of at least three antihypertensive agents, including a diuretic, after excluding pseudo-resistance, is common in chronic kidney disease (CKD), and is associated with persistently low rates of BP control [ 1 , 2 ]. Uncon-trolled hypertension contributes to the elevated cardiovascular morbidity and mortality seen in this population, hence merits aggressive and sustained management [ 2 ]. Hypertension in CKD is multifactorial, reflecting volume expansion, neurohormonal activation, vascular stiffness, and endothelial dysfunction, hence therapeutic strategies beyond conventional renin–angiotensin system (RAS) blockade and diuretics remain attractive. Among these, the endothelin (ET) pathway is particularly relevant, given its role in vasoconstriction, sodium handling, inflammation, fibrosis, and proteinuria. Indeed, ET-pathway modulators have already shown efficacy in glomeru-lonephritis [ 3 ]. Aprocitentan, a dual ETA/ETB receptor antagonist, demonstrated efficacy for resistant hypertension in the phase 3 PRECI-SION trial [ 4 ]. A post hoc analysis of this 48-week trial assessed