Historically, IgA nephropathy (IgAN) was managed using supportive care, with a suggested 6 months of immunosuppressive therapy considered for patients at high risk of progressive kidney function decline (proteinuria, >0.75-1 g/d) despite ≥90 days of optimized supportive care. The evolving treatment landscape includes agents that target immunologic aspects of IgAN or better preserve kidney function, or both. Recent approvals include Nefecon, sparsentan, iptacopan, atrasentan, and sibeprenlimab. Nefecon, a targeted-release formulation of budesonide, is the only US Food and Drug Administration and European Medicines Agency fully approved agent that is designed to target the primary source of IgAN: galactose-deficient IgA1 production in the gut mucosa. Phase 3 data showed that Nefecon slowed estimated glomerular filtration rate decline and decreased proteinuria versus placebo, with an acceptable safety profile. Sparsentan, a fully US Food and Drug Administration- and European Medicines Agency-approved dual endothelin A/angiotensin II receptor antagonist, affects the generic responses to IgAN-induced nephron loss, potentially including glomerular inflammation and fibrosis. Sparsentan demonstrated a significant reduction in proteinuria and estimated glomerular filtration rate decline compared with irbesartan. Iptacopan inhibits complement factor B and has received accelerated US Food and Drug Administration approval. Interim phase 3 study data have shown that iptacopan significantly reduces proteinuria when compared with placebo. The endothelin A receptor antagonist atrasentan and A proliferation binding ligand inhibitor sibeprenlimab have also received accelerated US Food and Drug Administration approval, based on interim phase 3 results showing significant proteinuria reduction versus placebo in patients with IgAN. This expanded clinical armamentarium offers clinicians and patients greater choice and improved disease control in IgAN management.
Increased understanding of the pathogenesis of IgA nephropathy (IgAN) has led to the development of new investigational agents tailored to this disease. The identification of surrogate markers of early treatment benefit has facilitated regulatory approval of these novel therapies. The surge in available data from several completed trials has prompted the recent revision of the Kidney Disease: Improving Global Outcomes guidelines for IgAN. Two agents have been fully approved for use in patients with IgAN in some regions: Nefecon, an oral targeted-release formulation of budesonide, and sparsentan, a dual endothelin A and angiotensin II receptor antagonist. Iptacopan and atrasentan are conditionally approved on the basis of proteinuria data; full approval will be evaluated once data on kidney function are available. With the potential future expansion of the IgAN treatment armamentarium, a dual approach to IgAN management is highly likely, addressing the overproduction of galactose-deficient IgA1 and downstream consequences of deposition of nephritogenic immune complexes, as well as considering supportive strategies targeting common non-disease-specific ongoing nephron loss. Combination therapies with different classes of drugs will likely become the new standard of care for chronic kidney disease as they target distinct pathogenic mechanisms or "hits" (namely, hemodynamic, immune, galactose-deficient IgA1-generating, inflammatory, and fibrotic processes involved in IgAN and chronic kidney disease progression). To improve personalized care for patients with IgAN, further research is needed to identify and validate noninvasive biomarkers for diagnosis, prognosis, treatment selection, and monitoring response.
IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. Its incidence and prevalence vary widely, with estimates of annual incidence ranging from 0.06 to 10.5 per 100,000 per year in adults and children. IgAN represents an important cause of progressive kidney disease, leading to kidney failure in a large proportion of patients, and is associated with a wide spectrum of clinical symptoms, which negatively impact quality of life. Although the consequences of IgAN manifest in the kidney, multiple lines of evidence support a major role for the gut in the pathogenesis of IgAN, including genome-wide association studies that identify risk loci for IgAN that encode genes related to mucosal immunity, maintenance of the intestinal epithelial barrier, and inflammatory bowel disease. Further insights into the underlying disease pathogenesis have led to the development of a multihit model comprising 4 sequential "hits": (i) increased levels of galactose-deficient IgA1 in the systemic circulation, (ii) followed by binding of specific autoantibodies directed against galactose-deficient IgA1, which (iii) form pathogenic IgA-containing immune complexes that (iv) deposit within the glomerular mesangium of the kidney, triggering inflammation, damage, and progressive decline in kidney function. The purpose of this article is to provide an overview of IgAN, examining its epidemiology and clinical features, and the mechanisms underlying its pathophysiology.
IgA nephropathy (IgAN) requires effective long-term management to avoid kidney failure. Proteinuria and reductions in estimated glomerular filtration rate are important clinical markers of progression, and they are established surrogate efficacy outcomes in clinical trials of new and emerging IgAN therapies. Despite optimized supportive care (including lifestyle modification and renin-angiotensin system inhibition) as a mainstay of IgAN management, many patients will still develop kidney failure, and the concept of "disease modification" refers to interventions that prevent irreversible kidney damage. Disease-modifying therapies may include IgAN-specific and anti-inflammatory strategies, whereas supportive care encompasses interventions that address generic mechanisms of nephron loss and interstitial injury that lead to chronic kidney disease. Targeted therapies, such as Nefecon (targeted-release formulation budesonide) and iptacopan, which address the immune-mediated pathogenic triggers of nephron loss, are important additions. Lifestyle modification, renin-angiotensin system inhibition, sodium-glucose cotransporter-2 inhibitors, and newer agents, such as sparsentan and atrasentan, are also available to manage the generic responses to IgAN-induced nephron loss common to many forms of proteinuric chronic kidney disease. As our understanding of the pathogenic mechanisms underlying disease progression in IgAN has expanded, so has the recognition that IgAN-specific, targeted immunomodulatory therapies are needed, and that these can be used in combination with other agents addressing the more generic causes of nephron loss. These approaches together can help to modify the course of the disease in patients and avoid progression to kidney failure.
