Improving the Cardiorenal Usability of Endothelin Receptor Antagonism in Albuminuric Chronic Kidney Disease: A Testable Role for SGLT2 Inhibitor-based Mitigation of Fluid Retention.

PURPOSE: Albuminuric chronic kidney disease (CKD) remains a high cardiorenal-risk state despite renin-angiotensin system blockade and sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy. Endothelin receptor antagonists (ERAs) reduce albuminuria, but clinical use is limited by fluid retention, edema, hemodilution, and concern for heart-failure decompensation. This review examines the testable hypothesis that SGLT2i background therapy may mitigate ERA-associated fluid retention and improve ERA usability in albuminuric CKD without compromising antiproteinuric efficacy.

METHODS

We conducted a narrative review prioritizing human studies and practice-relevant data on selective endothelin A receptor antagonism in albuminuric CKD, emphasizing quantitative efficacy signals, fluid retention, heart-failure risk, SGLT2i combination therapy, molecular mechanisms, and therapeutic sequencing and monitoring.

RESULTS

Available evidence supports a biologically coherent but not yet clinically established strategy. SONAR showed that atrasentan reduced kidney events in a responder-enriched population but retained a numerically higher heart-failure hospitalization signal. ZENITH-CKD showed that zibotentan added to dapagliflozin reduced urinary albumin-to-creatinine ratio at 12 weeks, with dose-sensitive fluid-retention events that were more favorable with lower-dose zibotentan. However, evidence remains short-term, agent-specific, and centered mainly on zibotentan plus dapagliflozin. Mechanistically, ERA-associated fluid retention probably reflects interacting tubular, neurohormonal, vascular-permeability, and hemodilution pathways, whereas SGLT2i mitigation may involve natriuresis, plasma-volume contraction, hemoconcentration, tubuloglomerular effects, and non-diuretic cardiovascular mechanisms.

CONCLUSION

Combined ERA/SGLT2i therapy should be viewed as a mechanistically plausible and clinically testable positioning strategy, not an established treatment paradigm. Broader adoption requires confirmation of durable kidney benefit, cardiovascular safety, real-world feasibility, and reproducible tolerability across eGFR strata and congestion-prone CKD phenotypes.