Targeting complement in IgA nephropathy

Abstract

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Recent years have witnessed significant improvements in the understanding of the pathogenesis of IgAN and particularly, the pathogenic role of complement activation. The alternative complement pathway is the major complement cascade activator in IgAN, and glomerular C3 deposition has been shown to correlate with disease progression. In addition, several studies have provided insight into the pathogenic role of factor H-related proteins -1 and -5 in IgAN, as independent players in complement dysregulation. The lectin pathway has also been shown to be associated with the severity of IgAN. Glomerular deposition of C4d has been associated with increased histologic disease activity, faster decline in estimated glomerular filtration rate and higher risk of kidney failure. On the other hand, although overlooked in the Oxford classification, numerous studies have shown that the coexistence of thrombotic microangiopathy in IgAN is a significant indicator of a poorer prognosis. All the breakthroughs in the understanding of the contributing role of complement in IgAN have paved the way for the development of new complement-targeted therapies in this disease. Several ongoing trials are evaluating the efficacy of new agents against factor B (iptacopan, Ionis-FB-L_RX), C3 (pegcetacoplan), factor D (vemircopan, pelecopan), C5 (ravulizumab, cemdisiran) and C5a receptor 1 (avacopan). In this study, we provide a comprehensive review of the role of complement in IgAN, including the emerging mechanisms of complement activation and the promising potential of complement inhibitors as a viable treatment option for IgAN.

Keywords: IgA nephropathy; alternative pathway; lectin pathway; thrombotic microangiopathy.

Figure 1:

Graphical illustration of the multi-hit hypothesis. (A) The production of mucosal IgA may be induced by T-cell-dependent or T-cell-independent mechanisms. The secretion of several cytokines such as interleukin-6, interleukin-10, B-cell activation factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) by dendritic cells induce B cells to undergo class switching recombination from IgM to IgA1. IgA-secreting plasma cells migrate to the mucosal lamina propria and release dimeric IgA1 into the lumen. Some misdirected IgA-secreting cells are released to the systemic compartment where they take up residence in systemic sites and secrete poorly O-galactosylated IgA1 to systemic circulation. Several genetic and environmental factors may predispose IgA patients to mount abnormal immune responses to certain common pathogens. This genetic background can also modulate the IgAN phenotype. (B) Specific reactive IgG and IgA antibodies against gd-IgA1 are formed and ultimately result in immune complex formation. This can induce complement activation. (C) Immune complexes get trapped in the mesangium through an increased affinity of gd-IgA1 for extracellular matrix components and trigger inflammatory pathways, which result in glomerular injury and tubulointerstitial scarring.

Figure 2:

The complement system. Diagram of the two main activation pathways in IgAN, which eventually converge in the terminal pathway with the formation of the membrane attack complex. The main regulatory factors at each stage are represented. C4BP: C4-binding protein; CR1: complement receptor type 1; DAF: decay accelerating factor; MCP: membrane cofactor protein.

Figure 3:

Landscape of complement inhibitors currently evaluated by ongoing clinical trials in IgAN and their site of action.