Transformation of approaches to immunosuppressive therapy of IgA nephropathy: from systemic non‑specific to targeted drugs (Part 1)

Abstract

IgA nephropathy (IgAN) is the most common primary chronic glomerulonephritis worldwide and a major cause of kidney failure requiring kidney replacement therapy. Current evidence indicates that its prognosis is considerably worse than previously assumed, while the proteinuria threshold associated with unfavorable outcome has decreased from 1.0 to 0.5 g/day. Until recently, high-dose systemic glucocorticosteroids, which can cause a wide range of complications, were virtually the only effective treatment. Improved understanding of the mechanisms underlying the development and progression of IgAN has led to new therapeutic approaches. Nefecone, iptacopan, and sibeprenlimab have been approved for clinical use, although the strength of the supporting evidence and their regulatory status may vary. These agents have different mechanisms of action and target distinct components of the pathogenic cascade, including the production of galactose-deficient IgA1 (GdIgA1) and activation of the complement system. GdIgA1acts as an autoantigen promoting the formation of nephritogenic immune complexes and subsequent glomerular inflammation. Nefecone, a targeted-release formulation of budesonide, is thought to modulate B-cell activity and reduce GdIgA1 production in the distal small intestine, where gut-associated lymphoid tissue is concentrated. Sibeprenlimab is a humanized monoclonal antibody that inhibits APRIL (proliferation-inducing ligand), thereby preventing its interaction with receptors on the surface of B cells and, particularly, plasma cells. Iptacopane is a selective proximal inhibitor of factor B, a key protein involved in activation of the alternative complement pathway. Randomized controlled trials, as well as real-world studies of some agents, have demonstrated their efficacy and safety. Fifteen months after completion of Nephecone treatment, proteinuria remained approximately 40% lower than in patients who had received placebo. By this time, the reduction in estimated glomerular filtration rate (eGFR) was 2.47 mL/min/1.73 m 2 in the Nephecone group compared with 7.52 mL/min/1.73 m 2 in the control group, p<0.0001. This literature review examined the evolution of therapeutic approaches to IgAN, from the period of the predominance of systemic glucocorticosteroid therapy to the emergence of targeted treatments. Part 1 discusses controversies surrounding corticosteroid therapy and reviews clinical studies evaluating Nefekon. Part 2 will examine promising classes of targeted therapies.