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

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.

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.

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.

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]).

These findings suggest that ERAs may reduce proteinuria, prevent kidney disease progression, and lower BP in individuals with CKD.