Treatment of IgA nephropathy; focus on reducing proteinuria by endothelin A receptor antagonists

IgA nephropathy (IgAN) is the most frequent primary glomerulonephritis throughout world and a leading cause of chronic renal failure across with end-stage kidney failure. Proteinuria, as a hallmark of IgAN, is a key driver of disease progression and a strong predictor of poor renal outcome. Despite current standard therapies, including RAAS (renin-angiotensin-aldosterone system) blockade with ACEIs (angiotensin-converting enzyme inhibitors) or ARBs (angiotensin II receptor blockers), many patients continue to experience persistent proteinuria and progressive kidney function decline. This condition emphasizes the need for more effective and targeted treatment strategies. The endothelin pathway, particularly endothelin-1 signaling promotes vasoconstriction, inflammation, and fibrosis, contributing to podocyte dysfunction and renal damage. Endothelin A receptor antagonists demonstrate renoprotective properties through various mechanisms in IgAN. By selectively blocking endothelin A receptors, these agents can improve glomerular hemodynamics by reducing intraglomerular pressure, thereby alleviating the damage caused by excessive pressure and promoting an improved renal environment. This blockade leads to decreased proteinuria, as a crucial factor in the progression of the disease. Furthermore, endothelin A receptor antagonists can also mitigate inflammatory pathways that are activated in response to endothelin-1, reducing renal inflammation and subsequent fibrosis. The efficacy of endothelin A receptor antagonists in the treatment of IgAN has been substantiated by numerous clinical trials. In particular, atrasentan, a specific endothelin-A receptor antagonist, has shown significant promise in reducing proteinuria compared to placebo.