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Purpose <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Lucas Maciel de Almeida Corrêa,
  • Luiggi Kevin Virgino Brandão,
  • Yan Roberth Delmiro Silva,
  • Guilherme Diniz Ferreira,
  • Nilson Hitoshi Yoshimoto

摘要

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.