Endothelin Receptor Antagonists in Resistant Hypertension and Proteinuric Kidney Disease: Receptor Strategy and Volume Management

Figures

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  FIGURE 1. Stepwise algorithm for endothelin receptor antagonist use at the hypertension‐CKD interface. The algorithm summarizes the implementation pathway developed in Section 8 for patients with resistant or difficult‐to‐control hypertension, CKD, albuminuria or proteinuria, and vulnerability to volume expansion. Step 1 confirms the indication, including standardized office and out‐of‐office blood‐pressure measurement. Step 2 optimizes background therapy, including sodium and lifestyle intervention, adherence review, thiazide‐like or loop‐diuretic selection, MRA use when tolerated, potassium‐binder support when needed to preserve an MRA, SGLT2‐inhibitor use when indicated, and secondary‐cause evaluation. Step 3 stratifies baseline volume risk by heart‐failure history, eGFR, baseline edema, albuminuria or proteinuria, sodium intake, anemia, liver disease, pregnancy potential, and monitoring feasibility. Step 4 applies product‐specific eligibility, dose, contraindications, boxed warnings, REMS requirements, and pregnancy precautions. Step 5 sets early surveillance for weight, edema, dyspnea, blood pressure, kidney function, electrolytes, hemoglobin, liver tests, pregnancy status, and…

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  FIGURE 2. Conceptual map of clinical contexts for endothelin‐directed therapies. The figure orients the reader to current and emerging endothelin‐directed strategies across PAH, resistant or difficult‐to‐control systemic hypertension, and IgAN or proteinuric CKD. It depicts disease settings and therapeutic strategies; it is not a quantitative scale of receptor affinity, receptor occupancy, comparative efficacy, evidentiary strength, or regulatory equivalence. PAH provides historical and pharmacologic context. Aprocitentan appears in the systemic‐hypertension panel as the only ERA approved for hypertension, with evidence from resistant‐hypertension patients. Sparsentan and atrasentan appear as kidney‐disease therapies according to their indications, and zibotentan plus dapagliflozin appears as an investigational proteinuric‐CKD strategy. Fluid retention is shown as the constraint shared across all settings that defines the therapeutic window. All figure elements were generated de novo for this manuscript and were not adapted from third‐party copyrighted images, templates, or commercial icon libraries.