Aprocitentan in resistant hypertension with chronic kidney disease: balancing albuminuria reduction against early volume risk

Journal of Human Hypertension REVIEW ARTICLE www.nature.com/jhh OPEN Aprocitentan in resistant hypertension with chronic kidney disease: balancing albuminuria reduction against early volume risk Lucas Maciel de Almeida Corrêa 1✉ , Yan Roberth Delmiro Silva 2 , Juliana Zanella3 and Gabriel Costa de Santana4 1234567890();,: © The Author(s) 2026 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. Journal of Human Hypertension; https://doi.org/10.1038/s41371-026-01163-4 RESISTANT HYPERTENSION IN CKD: THE RE-EMERGENCE OF ENDOTHELIN BLOCKADE Resistant hypertension (RHT), defined as blood pressure that remains above goal despite treatment with 3 antihypertensive drugs of different classes at maximally tolerated doses, ideally including a diuretic, or as blood pressure controlled only with ≥4 agents after exclusion of pseudoresistance, remains a high-risk phenotype associated with accelerated cardiovascular and kidney complications, and is particularly prevalent in patients with chronic kidney disease (CKD), where sodium retention, sympathetic activation, and neurohormonal dysregulation converge to blunt the response to conventional multidrug therapy [1–3]. Against this backdrop, endothelin-1 (ET-1) has re-emerged as a clinically actionable node: ET-1 is a potent vasoconstrictor and pro-fibrotic mediator that amplifies vascular tone, inflammation, and glomerular injury, and its activity is upregulated in CKD and has been implicated in treatment-resistant hypertension [4, 5]. Aprocitentan is an oral, dual endothelin receptor antagonist (ETA/ETB) developed as add-on therapy for difficult-to-control and resistant hypertension, with a pharmacologic profile designed to provide sustained blood pressure (BP) lowering while minimizing off-target liabilities [4, 6, 7]. In March 2024, aprocitentan received its first approval in the United States for the treatment of hypertension, in combination with other antihypertensive drugs, in adults not adequately controlled on other drugs [8]. This regulatory milestone was largely informed by the phase 3 PRECISION program, which evaluated aprocitentan in patients with resistant hypertension [9]. More importantly, aprocitentan should be viewed as the latest attempt to solve a longstanding endothelin paradox: substantial antiproteinuric and antihypertensive potential on one side, and fluid-retention liability on the other. Prior ERA programs showed that the key question is not whether the class can reduce albuminuria, but whether efficacy can be separated from edema and heart-failure risk through dose selection, patient selection, and early surveillance [10, 11]. Although prior experience with other endothelin receptor antagonists helps contextualize both antiproteinuric potential and fluid-retention liability, this review focuses on aprocitentan because its dual ETA/ETB profile and resistant-hypertension indication create a distinct clinical positioning that should not be considered interchangeable with earlier class programs [4, 9–12]. STRATEGY AND SELECTION OF EVIDENCE This narrative review was informed by a focused literature search performed in PubMed/MEDLINE, Scopus, Embase, and Web of 1 Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, Brazil. 2Universidade Federal de Alagoas (UFAL), Arapiraca, Brazil. 3Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil. 4Universidade Salvador (UNIFACS), Salvador, Brazil. ✉email: Received: 10 March 2026 Revised: 30 April 2026 Accepted: 22 May 2026 L.M. de Almeida Corrêa et al. 2 Science using the terms “aprocitentan”, “chronic kidney disease”, and “resistant hypertension”. Priority was given to randomized clinical trials, mechanistic studies, clinically relevant reviews, and key translational reports directly informing the efficacy and safety profile of aprocitentan in resistant hypertension and CKD. Reference lists of selected articles were also screened to identify additional relevant publications. This review was designed as a focused clinical synthesis centered on aprocitentan in resistant hypertension with CKD, rather than a comprehensive class-wide review of endothelin receptor antagonists. THE KIDNEY SIGNAL WITHIN A RESISTANT HYPERTENSION FRAMEWORK: ALBUMINURIA REDUCTION BEYOND BP LOWERING Beyond BP reduction, an important rationale for targeting the endothelin axis in resistant hypertension with CKD is the possibility of kidney protection beyond BP lowering. ET-1 signaling promotes podocyte dysfunction, mesangial activation, and intrarenal inflammation, pathways that are tightly linked to albuminuria and progressive nephron loss [5]. Accordingly, a clinically meaningful and reproducible reduction in urine albumin-to-creatinine ratio (UACR) could represent a biologically plausible and trial-supported surrogate of kidney benefit in albuminuric CKD, particularly when the magnitude of reduction exceeds what would be expected from BP lowering alone, potentially signaling attenuation of intrarenal endothelin-driven injury [13]. This kidney-centric signal has been most clearly demonstrated in the CKD-enriched subgroup analyses from the phase 3 PRECISION program. In participants categorized as KDIGO ≥high risk (a group enriched for CKD stages 3–4 and/or significant albuminuria), aproc (...truncated)