State-of-Art Therapeutics in IgA Nephropathy.

Abstract

Immunoglobulin-A nephropathy (IgAN) is the most common primary glomerulonephritis in the world, with up to 40% of patients progressing to end-stage kidney disease (ESKD) within 30 years of diagnosis. IgAN is characterized by elevated serum levels of galactose-deficient IgA1 (Gd-IgA1), which leads to immune complex formation and deposition in the glomerular mesangium, causing kidney injury. A diverse disease course and the long-term follow-up required for clinically relevant endpoints (e.g., ESKD) have been barriers to the development of novel therapies in IgAN. Disease management has focused on supportive care with inhibitors of the renin-angiotensin system and, more recently, sodium-glucose transporter inhibitors to control proteinuria. The recent acceptance of proteinuria as a surrogate endpoint by regulatory bodies and a better understanding of disease pathology have helped to initiate the development of several novel treatments. Subsequently, a targeted-release formulation of budesonide and a dual endothelin/angiotensin inhibitor (sparsentan) have received accelerated approval for patients with IgAN. However, additional therapies are needed to target the different pathogenic mechanisms and individualize patient care. Several compounds currently under investigation target various effectors of pathology. There are promising clinical results from emerging compounds that target the generation of Gd-IgA1 by B cells, including inhibitors of A PRoliferation-Inducing Ligand (APRIL) and dual inhibitors of APRIL and B-cell activating factor (BAFF). Other investigational therapies target the complement cascade by inhibiting proteins of the lectin or alternative pathways. As the therapeutic landscape evolves, it will be important to revise treatment guidelines and develop updated standards of care.