Efficacy and safety of endothelin receptor antagonists in CKD: a meta‑analysis

While a number of drugs have demonstrated benefit in reducing proteinuria and preserving kidney function in people with chronic kidney disease (CKD), new therapies are still needed for individuals with poor clinical outcomes. In recent years, endothelin receptor antagonists (ERAs) have attracted interest as emerging treatments for kidney diseases, with sparsentan, a dual endothelial angiotensin II receptor antagonist, being approved for the treatment of IgA nephropathy. However, concerns remain that they may cause fluid retention, which, in severe cases, can lead to oedema and congestive heart failure. 

Shi and colleagues conducted a meta-analysis of trials to quantify the efficacy and safety of different types of ERAs (including when used in combination with SGLT2 inhibitors) in people with various forms of CKD. The Cochrane Library, Ovid Medline and Ovid Embase were searched for eligible randomised controlled trials up to January 2025. Standardised mean difference (SMD) with 95% confidence intervals (CIs) was used to report continuous variables of interest, while dichotomous data were reported as risk ratio (RR) with 95% CIs.

Fourteen trials were included, with a total of 6412 participants (70% male) enrolled. Compared with the control group, ERAs demonstrated several benefits. They reduced the risk of progression to end-stage kidney disease (RR , 0.76 [95% CI, 0.61 to 0.96) and lowered both urine protein-to-creatinine ratio (SMD, −0.56 [−0.78 to −0.35]) and urine albumin-to-creatinine ratio (SMD, −0.64 [−0.75 to −0.53). ERAs also achieved more frequent complete proteinuria remission (RR,  2.61 [1.84 to 3.71]) and partial remission (RR, 1.51 [1.32 to 1.73]).

ERAs slowed the decline in estimated glomerular filtration rate (eGFR) in the sub-group with at least 1 year of follow-up (SMD,  0.18 [0.04 to 0.32]) and improved the chronic eGFR slope (SMD, 0.15 [0.01 to 0.30]). They also reduced systolic blood pressure (SMD , −0.53 [−0.76 to −0.30]) and diastolic blood pressure (SMD, −0.78 [−1.18 to −0.38]).

Although slight increases were observed in B‑type natriuretic peptide (SMD, 0.08 [0.01 to 0.16]) and body weight (SMD, 0.15 [0.01 to 0.29]), ERAs did not raise the incidence of oedema, fluid retention or heart failure. Lower rates of fluid retention were reported when used in combination with SGLT2 inhibitors. However, ERAs were associated with an increased risk of hypotension compared with the control group (RR, 1.92 [1.36–2.70]).

The findings indicate that ERAs offer therapeutic potential for individuals with CKD whose proteinuria and high risk of kidney function decline remains insufficiently controlled. Sub-group analysis revealed that endothelin A receptor-selective ERAs are preferable to non-selective ERAs for people with CKD and should be considered in combination with SGLT2 inhibitors.

The full article can be read here.