Key result
Combined ERA and SGLT2i therapy may mitigate fluid retention in albuminuric CKD but requires confirmation.
Why the study?
Albuminuric CKD remains high risk despite standard therapies, and while ERAs reduce albuminuria, clinical use is limited by fluid retention and heart-failure concerns that background SGLT2i therapy might mitigate.
Does SGLT2 inhibitor background therapy mitigate ERA-associated fluid retention and improve ERA usability in patients with albuminuric chronic kidney disease?
Does SGLT2 inhibitor background therapy mitigate ERA-associated fluid retention and improve ERA usability in patients with albuminuric chronic kidney disease?
Combined ERA and SGLT2 inhibitor therapy is a mechanistically plausible strategy to mitigate ERA-associated fluid retention in albuminuric CKD, but requires further confirmation of long-term safety and efficacy.
Hypothesis-generating for SGLT2 inhibitor–endothelin antagonist combinations to limit fluid retention in CKD; leaves open confirmation in randomized trials.
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.
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Corrêa et al. (2026) conducted a review in Albuminuric chronic kidney disease. Endothelin receptor antagonists (ERAs) combined with SGLT2 inhibitors was evaluated. Combined endothelin receptor antagonist and SGLT2 inhibitor therapy represents a mechanistically plausible strategy to mitigate fluid retention in albuminuric chronic kidney disease, but requires further confirmation.
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