Atrasentan in Patients with IgA Nephropathy
In the phase 3 ALIGN trial, the selective endothelin type A receptor antagonist atrasentan produced a clinically meaningful, statistically significant reduction in proteinuria versus placebo in patients with IgA nephropathy at high risk of progression.
Background
Patients with IgA nephropathy and severe proteinuria carry a high lifetime risk of kidney failure, and many continue to lose kidney function despite maximally tolerated renin-angiotensin system inhibition. Endothelin type A receptor activation is a driver of proteinuria, kidney inflammation, and fibrosis. Atrasentan is a selective endothelin type A receptor antagonist developed to reduce proteinuria and preserve kidney function in this population.
Study design
ALIGN was a phase 3, multinational, double-blind, randomized, placebo-controlled trial in adults with biopsy-proven IgA nephropathy, total urinary protein excretion of at least 1 g per day, and an estimated glomerular filtration rate of at least 30 ml/min/1.73 m2. Patients were assigned to atrasentan 0.75 mg daily or placebo for 132 weeks while continuing a maximally tolerated dose of a renin-angiotensin system inhibitor. The prespecified interim primary outcome was the change in 24-hour urinary protein-to-creatinine ratio from baseline to week 36.
Key findings
Among the first 270 patients in the main stratum who completed the week 36 visit, the geometric mean percentage change in urinary protein-to-creatinine ratio from baseline was -38.1% with atrasentan versus -3.1% with placebo, a geometric mean between-group difference of -36.1 percentage points (95% CI, -44.6 to -26.4; P<0.001). Adverse event rates were similar between groups. Fluid retention was reported in 11.2% of atrasentan patients versus 8.2% of placebo patients but did not lead to discontinuation, and no cases of cardiac failure or severe edema occurred.
Clinical implications
These interim results support atrasentan as a targeted option to lower proteinuria on top of standard renin-angiotensin system blockade in high-risk IgA nephropathy. Because the analysis was based on proteinuria at week 36, longer-term data on estimated glomerular filtration rate are needed to confirm that this proteinuria reduction translates into preserved kidney function.
Category
Research
Source
The Lancet
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