Purpose of review This review focuses on latest developments in managing antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), a systemic autoimmune condition characterized by inflammation and necrosis of small blood vessels due to circulating autoantibodies that target neutrophilic granules. Recent findings Our understanding of AAV pathogenesis has evolved in the past decades highlighting the central pathogenic roles of autoantibodies and complement activation. In parallel, the appreciation for glucocorticoid toxicity has led the research on crucial steroid-sparing therapeutic alternatives. Complement inhibitors (like avacopan) that have emerged are associated with better preservation of kidney function in AAV patients with severe kidney impairment. The role of plasma-exchange (PLEX) was revisited in updated guidelines that recommended its potential use in the context of diffuse alveolar hemorrhage associated hypoxia and severe kidney involvement, particularly with a serum creatinine level above 3.4 mg/dl. The ANCA Kidney Risk Score risk prediction and Glucocorticoid Toxicity Index score aid in identifying high-risk patients and individualizing management plans. Summary Kidney involvement in AAV requires prompt diagnosis and initiation of immunosuppression to prevent irreversible nephron loss. Newer therapeutic targets are on the horizon and offer hope for personalized treatment strategies.
Targeting the alternative complement pathway (AP) is an attractive therapeutic strategy because of its role in immunoglobulin A nephropathy (IgAN) pathophysiology. Iptacopan (LNP023), a proximal complement inhibitor that specifically binds to factor B and inhibits the AP, reduced proteinuria and attenuated AP activation in a Phase 2 study of patients with IgAN, thereby supporting the rationale for its evaluation in a Phase 3 study.
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.
