The Complement System in Membranous Nephropathy: Pathogenesis and Targeted Therapies

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults, marked by the thickening of the glomerular basement membrane due to the deposition of immune complexes. The complement system, a key part of the innate immune response, plays a crucial role in the pathogenesis of MN. Activation of the complement cascade results in glomerular damage, inflammation, and proteinuria. Recent studies have expanded our understanding of the complement system’s involvement in MN and the development of therapies targeting complement to treat the disease.1 In phospholipase A2 receptor 1 (PLA2R) and thrombospondin Type-1 domain-containing 7A (THSD7A)-associated primary MN, IgG4 is the dominant antibody subclass. Although IgG4 is generally considered unable to activate complement via C1q binding, evidence of classical pathway activation exists in MN. Our previous research detected glomerular C1q deposition in 23% of MN patients, with immunofluorescence revealing C1q on capillary walls.2 Seifert et al. further demonstrated that at least one of the C1q-binding IgG subclasses (IgG1-3) was present in 100% of MN biopsies examined.3 These findings, along with strong correlations between IgG1-3 deposition and classical C3 convertase activity, suggest a key role for C1q-binding autoantibodies in classical pathway activation in PLA2R and THSD7A-associated MN. Moreover, Huang et al. found that in kidney pathological stage I of primary MN, glomerular deposits were predominantly IgG1 in most cases; in later stages, IgG4 deposits became dominant. The intensity of IgG4 and C1q staining showed an inverse relationship, suggesting that the classical pathway may be involved in the early stage of primary MN.4 The lectin pathway, typically involved in recognizing carbohydrate patterns on pathogens, has also been implicated in MN. Although primarily linked to infections and acute inflammation, mannose-binding lectin and other lectin pathway components have been identified in the glomeruli of MN patients. This indicates a potential role for the lectin pathway in MN pathogenesis. Our studies have shown elevated levels of alternative pathway components, such as Bb, in MN, suggesting their involvement in disease progression. The deposition of factor B in MN biopsies further supports alternative pathway activation. Moreover, MN development in a patient with C4 deficiency, in which the classical and lectin pathways were nonfunctional, highlights the alternative pathway’s independent contribution. Continuous low-grade activation of this pathway can sustain inflammatory damage, contributing to MN’s chronic nature. In addition, the relative contribution of each complement pathway likely varies between patients. One pathway may become more active if another is defective or inhibited. Given the central role of complement activation in MN pathogenesis, therapeutic strategies have been developed to target specific components of the complement system. These therapies aim to reduce complement-mediated podocyte injury, inflammation, and proteinuria, ultimately preserving kidney function.5 Factor B inhibitors (e.g., LNP023) and factor D inhibitors (e.g., BCX9930) block the formation of C3 convertase by inhibiting alternative pathway activation. Although preclinical studies showed a reduction in complement deposition and proteinuria, a phase II trial (NCT04154787) of LNP023 was terminated early after interim analysis, which predicted no superiority of LNP023 versus rituximab in the reduction of urine protein-creatinine ratio at 24 weeks.6 C3 inhibitors, such as pegcetacoplan and APL2, provide broad inhibition by blocking all three complement pathways. While this approach could be highly effective, it may carry a higher risk of adverse events. A phase II trial (NCT03453619) of APL2 is currently being conducted to assess its efficacy in MN. Lectin pathway inhibitors, targeting components such as mannose-binding lectin-associated serine protease (MASP-2), narsoplimab, hold promise for preventing complement activation in MN. An interim analysis from a phase II trial (NCT02682407) demonstrated significant reductions in proteinuria and stabilization of kidney function. A subsequent phase III trial (NCT03608033) is evaluating its long-term efficacy and safety. More research is needed to determine the exact role of the lectin pathway in MN. Traditional Chinese medicines (TCMs) and their active components can regulate the complement system through a multicomponent and multitarget mechanism, demonstrating unique advantages in the treatment of MN. It can simultaneously intervene in multiple links, including complement activation, clearance of immune complexes, and podocyte protection. Furthermore, compared with traditional complement inhibitors, TCM often exhibits tissue-specific inhibitory effects. For example, Mo Shen Fang could reduce the levels of complement C1q and PLA2R in patients with MN, thereby decreasing proteinuria and improving clinical outcomes.7 Mahuang Fuzi and Shenzhuo Decoction,8 Sanqi Qushi Formula,9 and Jianpi Qushi Heluo Formula have shown therapeutic effects in Passive Heymann Nephritis rats, such as reduced renal injury and glomerular IgG deposition. Tripterygium glycosides reduce autoantibody production (e.g., anti-PLA2R), thereby decreasing C1q activation. Astragaloside (from Astragalus membranaceus) downregulates C1q receptor expression in podocytes, blocking C1q binding and subsequent complement activation.10 The complement system plays a pivotal role in the pathogenesis of MN through activation of the classical, alternative, and lectin pathways, leading to podocyte damage, proteinuria, and progressive glomerular injury. As our understanding of these mechanisms deepens, therapies targeting specific complement components are emerging as promising treatments. Inhibitors targeting C5, factor B, and C3 offer new approaches for reducing complement-mediated damage and improving patient outcomes. However, further clinical trials are required to confirm their long-term efficacy and safety. Future research should focus on identifying biomarkers to guide the use of these therapies and to better stratify MN patients.