Efficacy and Safety of Endothelin Receptor Antagonists in CKD: Meta-Analysis of Randomized Controlled Trials

Background: Endothelin receptor antagonists (ERAs) are considered as a potential effective treatment to reduce proteinuria and protect renal function for patients with chronic kidney disease (CKD), however limited by causing fluid retention. We conducted this meta-analysis to quantify the efficacy and safety of ERAs in CKD. Methods: We searched Cochrane Library, Ovid Medline and Ovid Embase for randomized controlled trails to 11 January 2025. Continuous and dichotomous data were reported as standardized mean difference (SMD) with 95% confidence intervals (CIs) and risk ratio (RR) with 95% CIs respectively. Results: Fourteen trials enrolling 6412 patients were included. Compared to control groups, ERAs reduced the UPCR [SMD=-0.564, 95%CI (-0.777, -0.351)] and UACR [SMD=-0.639, 95%CI (-0.745, -0.534)], achieved more frequent complete proteinuria remission [RR=2.612, 95%CI (1.840, 3.710)] and partial proteinuria remission [RR=1.509, 95%CI (1.316, 1.731)], slowed the decline of eGFR in the subgroup with a follow-up duration of ≥1 year [SMD=0.182, 95%CI (0.044, 0.320)], improved the chronic eGFR slope [SMD=0.154, 95%CI (0.013, 0.295)], reduced the risk of ESRD [RR=0.764, 95%CI (0.606, 0.964)] and decreased systolic blood pressure [SMD=-0.531, 95%CI (-0.763, -0.299)] and diastolic blood pressure [SMD=-0.779, 95%CI (-1.177, -0.381)]. ERAs did not significantly increase the incidence of edema, fluid retention and heart failure, except hypotension [RR=1.917, 95%CI (1.361, 2.702)]. Conclusion: ERAs reduced proteinuria, slow the decline of eGFR with long-term use, prevent ESRD and lower blood pressure in CKD, without significant increasing risk of fluid retention, especially combined with SGLT2i. However, risk of hypotension might increase for patients with low baseline blood pressure.