Endothelin Receptor Antagonists in CKD-Associated Resistant Hypertension: Trial Lessons, Safety Boundaries, and Conditions for Future Clinical Testing

Resistant hypertension in chronic kidney disease (CKD) remains a common and difficult-to-treat phenotype after confirmation of true resistance, exclusion of pseudoresistance, and optimization of standard multidrug therapy. Endothelin receptor antagonists (ERAs) have re-entered this space largely through aprocitentan, a dual ETA/ETB receptor antagonist that provides modest but significant blood-pressure lowering in resistant hypertension. However, the clinical interpretation of this class remains constrained by edema/fluid retention, absence of direct comparison with spironolactone, and lack of established hard renal or cardiovascular outcome benefit in CKD-associated resistant hypertension. This Current Opinion reframes the ERA evidence as a set of trial-design lessons rather than as broad class rehabilitation. ASCEND showed that albuminuria reduction is insufficient when exposure and congestion risk are poorly controlled. SONAR demonstrated the value of response and tolerability enrichment. PRECISION clarified the incremental blood-pressure effect of aprocitentan on standardized background therapy, while confirming clinically relevant edema risk. ZENITH-CKD suggests that low-dose ERA strategies combined with SGLT2 inhibition may improve tolerability and testability. The practical implication is a narrow and monitored phenotype: rigorously confirmed resistant hypertension, CKD with residual cardiorenal risk, absence of unstable heart failure or marked natriuretic-peptide elevation, and capacity for close surveillance of weight, edema, renal function, hemoglobin, and albuminuria. At present, aprocitentan should be viewed as a selective add-on option rather than a routine fourth-line default, while future trials should test ERA strategies against contemporary guideline-based comparators and prespecified congestion-risk algorithms.