Clinical bottom line
Endothelin receptor antagonists (ERAs), particularly aprocitentan, are emerging as promising adjunct therapies for resistant hypertension in patients with chronic kidney disease (CKD). By targeting endothelin-mediated vasoconstriction and sodium retention, ERAs can provide additional blood pressure reduction beyond standard regimens. Early clinical evidence supports their efficacy and manageable safety profile, but careful volume status monitoring is essential to mitigate fluid retention risks. ERAs may represent a valuable option in personalized treatment strategies for resistant hypertension in CKD, pending further long-term outcome data (Georgianos et al., 2023; Kumbhare et al., 2025; Stambolliu et al., 2026).
What the evidence shows
Resistant hypertension in CKD is multifactorial, with endothelin-1 playing a key role in vasoconstriction, inflammation, and sodium handling (Boesen et al., 2015). ERAs block endothelin receptors (ETA and ETB), reducing these pathophysiological effects.
Kumbhare et al. (2025) review mechanistic insights and clinical trial data on aprocitentan, a dual ERA, demonstrating significant reductions in systolic and diastolic blood pressure in resistant hypertension populations, including those with CKD. The PRECISION trial and related studies showed sustained blood pressure control with acceptable tolerability.
Georgianos et al. (2023) emphasize that ERAs complement existing antihypertensive agents by addressing endothelin-driven pathways not targeted by renin-angiotensin blockers or diuretics.
Stambolliu et al. (2026) discuss the positioning of aprocitentan within CKD management, highlighting its potential to improve outcomes when integrated into multifaceted treatment plans.
Goldman et al. (2026) underscore the importance of volume management strategies to counteract ERA-associated fluid retention, recommending individualized dosing and monitoring.
Caveats and uncertainty
Fluid retention and edema remain notable adverse effects, requiring vigilant clinical assessment.
Long-term renal and cardiovascular outcome data with ERAs in CKD populations are limited.
Optimal patient selection criteria and combination regimens are still being defined.
Potential drug interactions and effects on electrolyte balance warrant consideration.
Cost-effectiveness and accessibility of ERAs in routine nephrology practice need evaluation.
How this may change practice
Nephrologists should consider ERAs as add-on therapy for patients with resistant hypertension unresponsive to standard regimens, particularly when endothelin pathway activation is suspected.
Close monitoring of volume status and renal function is critical during ERA therapy.
Incorporation of ERAs may reduce reliance on escalating diuretic doses, potentially minimizing diuretic-related side effects.
Multidisciplinary collaboration is advised to optimize individualized treatment plans.
Ongoing clinical trials and real-world data will inform guideline updates and reimbursement policies.