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RCT: Atrasentan Reduces Proteinuria in Patients with IgA Nephropathy

3 Nov, 2024 | 18:29h | UTC

Background: IgA nephropathy is the most common primary glomerular disease worldwide, leading to a substantial risk of kidney failure. Despite treatment with renin–angiotensin system (RAS) inhibitors, many patients experience persistent proteinuria and progressive kidney function decline. Endothelin-1, acting via the endothelin type A receptor, contributes to the disease’s pathophysiology. Atrasentan, a selective endothelin type A receptor antagonist, has shown potential in reducing proteinuria in prior studies.

Objective: To evaluate the efficacy and safety of atrasentan in reducing proteinuria among patients with IgA nephropathy.

Methods: In this phase 3, multinational, double-blind, randomized controlled trial, adults with biopsy-proven IgA nephropathy, urinary protein excretion of at least 1 g/day, and an estimated glomerular filtration rate (eGFR) of at least 30 ml/min/1.73 m² were enrolled. Patients on maximum tolerated doses of ACE inhibitors or ARBs were randomized 1:1 to receive atrasentan (0.75 mg/day) or placebo for 132 weeks. The primary outcome was the change in the 24-hour urinary protein-to-creatinine ratio from baseline to week 36, assessed in a prespecified interim analysis of the first 270 patients.

Results: Among these patients (135 per group), the geometric mean percentage reduction in the urinary protein-to-creatinine ratio at week 36 was significantly greater with atrasentan (−38.1%) compared to placebo (−3.1%), yielding a between-group difference of −36.1 percentage points (95% CI, −44.6 to −26.4; P<0.001). Adverse events were similar between groups. Fluid retention was reported in 11.2% of the atrasentan group and 8.2% of the placebo group but did not lead to discontinuation. No cases of cardiac failure or severe edema occurred.

Conclusions: Atrasentan significantly reduced proteinuria compared to placebo in patients with IgA nephropathy without significant safety concerns.

Implications for Practice: Atrasentan may serve as an effective additional therapy for patients with IgA nephropathy who remain at high risk of progression despite standard care, potentially influencing clinical decision-making toward more aggressive proteinuria reduction strategies.

Study Strengths and Limitations: Strengths include the randomized controlled design and a representative high-risk population. Limitations involve the interim analysis nature of the data and underrepresentation of Black patients, which may limit generalizability.

Future Research: Long-term effects on eGFR decline and the potential benefits of combining atrasentan with other therapies, such as SGLT2 inhibitors, warrant further investigation.

Reference: Heerspink HJL, Jardine M, Kohan DE, Lafayette RA, Levin A, Liew A, Zhang H, et al. Atrasentan in Patients with IgA Nephropathy. New England Journal of Medicine. Published October 25, 2024. DOI: http://doi.org/10.1056/NEJMoa2409415

 


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