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

KEY POINTS: Endothelin receptor antagonists should be applied for patients with CKD whose proteinuria and high risk of kidney function decline remains insufficiently controlled. We recommend that endothelin A receptor-selective endothelin receptor antagonists should be preferable for patients with CKD with consideration for combination therapy with sodium-glucose cotransporter-2 inhibitors. BACKGROUND: Endothelin receptor antagonists (ERAs) are considered a potential effective treatment to reduce proteinuria and protect kidney function for patients with 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 6412 patients were included. Compared with the control group, ERAs decreased the risk of ESKD (RR=0.76, 95% CI [0.61 to 0.96]), reduced the urine protein-to-creatinine ratio (SMD=-0.56, 95% CI [-0.78 to -0.35]) and urine albumin-to-creatinine ratio (SMD=-0.64, 95% CI [-0.75 to -0.53]), achieved more frequent complete proteinuria remission (RR=2.61, 95% CI [1.84 to 3.71]) and partial proteinuria remission (RR=1.51, 95% CI [1.32 to 1.73]), slowed the decline of eGFR in the subgroup with a follow-up duration of at least 1 year (SMD=0.18, 95% CI [0.04 to 0.32]), improved the chronic eGFR slope (SMD=0.15, 95% CI [0.01 to 0.30]), and decreased systolic BP (SMD=-0.53, 95% CI [-0.76 to -0.30]) and diastolic BP (SMD=-0.78, 95% CI [-1.18 to -0.38]). Although the risk was increased in B-type natriuretic peptide (SMD=0.08, 95% CI [0.01 to 0.16]) and body weight (SMD=0.15, 95% CI [0.01 to 0.29]), ERAs did not increase the incidence of edema, fluid retention, or heart failure. The risk of hypotension was higher with ERAs compared with the control group (RR=1.92, 95% CI [1.36 to 2.70]). CONCLUSION: These findings suggest that ERAs may reduce proteinuria, prevent kidney disease progression, and lower BP in individuals with CKD.