J Hum Hypertens. 2026 Jun 2. doi: 10.1038/s41371-026-01163-4. Online ahead of print.
ABSTRACT
Resistant hypertension in chronic kidney disease (CKD) remains a high-risk clinical phenotype associated with poor blood pressure (BP) control, accelerated kidney disease progression, and excess cardiovascular burden. Aprocitentan, a dual endothelin receptor antagonist approved as add-on therapy for hypertension, offers a new option for patients with resistant hypertension, but its incorporation into CKD care remains constrained by persistent concerns regarding fluid retention. This review synthesizes data from the phase 3 PRECISION program and related endothelin literature to examine how BP lowering, albuminuria reduction, and early volume-related adverse effects should be interpreted in patients with resistant hypertension and CKD. Available evidence suggests that aprocitentan provides clinically meaningful and sustained antihypertensive effects while also producing marked reductions in albuminuria in CKD-enriched high-risk phenotypes, with signals supporting at least partial dissociation between antiproteinuric benefit and systemic BP lowering. The major trade-off is a predictable, front-loaded volume signal characterized by early edema, weight gain, and hemodilution, which appears most relevant during the first weeks after treatment initiation and may be manageable with proactive sodium and diuretic strategies. We also discuss the physiological rationale for combining endothelin blockade with SGLT2 inhibitors as a potential strategy to improve the balance between efficacy and tolerability. Overall, aprocitentan should be interpreted within a clinical benefit-risk framework in which resistant hypertension is the primary therapeutic target, while albuminuria reduction and early volume surveillance define its potential role in CKD.
PMID:42230805 | DOI:10.1038/s41371-026-01163-4