Meta-Analysis of Randomized Controlled Trials Assessing the Efficacy and Safety of Endothelin Receptor Antagonists in Chronic Kidney Disease

Background: Endothelin receptor antagonists (ERAs) are considered a potential effective treatment to reduce proteinuria and protect kidney function for patients with chronic kidney disease (CKD); however, they may cause 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 trials up to January 2025. Continuous and dichotomous data were reported as standardized mean differences (SMDs) with 95% confidence intervals (CIs) and risk ratios (RRs) with 95% Cis, respectively. Results: Fourteen trials enrolling 6,412 patients were included. Compared to the control group, ERAs decreased the risk of end-stage kidney disease (ESKD) [RR=0.76, 95%CI (0.61, 0.96)], reduced the urine protein-to-creatinine ratio (UPCR) [SMD=-0.56, 95%CI (-0.78, -0.35)] and urine albumin-to-creatinine ratio (UACR) [SMD=-0.64, 95%CI (-0.75, -0.53)], achieved more frequent complete proteinuria remission [RR=2.61, 95%CI (1.84, 3.71)] and partial proteinuria remission [RR=1.51, 95%CI (1.32, 1.73)], slowed the decline of estimated glomerular filtration rate (eGFR) in the subgroup with a follow-up duration of at least one year [SMD=0.18, 95%CI (0.04, 0.32)], improved the chronic eGFR slope [SMD=0.15, 95%CI (0.01, 0.30)], and decreased systolic blood pressure [SMD=-0.53, 95%CI (-0.76, -0.30)] and diastolic blood pressure [SMD=-0.78, 95%CI (-1.18, -0.38)]. Although the risk was increased in B-type natriuretic peptide (BNP) [SMD=0.08, 95%CI (0.01, 0.16)] and body weight [SMD=0.15, 95%CI (0.01, 0.29)], ERAs did not increase the incidence of edema, fluid retention, or heart failure. The risk of hypotension was higher with ERAs compared to the control group [RR=1.92, 95%CI (1.36, 2.70)]. Conclusion: These findings suggest that ERAs may reduce proteinuria, prevent kidney disease progression, and lower blood pressure in individuals with CKD.