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By: Gerren Hobby MD (@ghobby)
The complement system has been implicated in glomerulonephridities since the 1960s. Since that time, its role in the pathogenesis of glomerular disorders has been expanding. C3 glomerulopathy (C3GN) is a term introduced around a decade ago to describe the clinical phenotype of glomerular disease arising from an overactivation of the alternative complement pathway. In 2013, a consensus report defined C3GN as glomerular disorders characterized histologically by the accumulation of C3 with the absence of immunoglobulin or the dense accumulation of deposits seen with dense deposit disease. This definition keeps with the general movement that shifts glomerular disorder taxonomy away from eponyms towards a classification based on the pathophysiological driver of disease. This trend is notably seen with ANCA vasculitis and anti-GBM disease, but the C3GN definition was special due to the existence of the complement inhibitor, eculizumab – a treatment that could benefit this group specifically. That’s the purpose of this definition – identifying a group of people that could benefit from medications tailored to the particular driver of their kidney disease.
The potential treatments for C3GN have now expanded with the development of iptacopan which targets the alternative complement pathway. The APPEAR-C3G trial is a phase III trial that marks the next step in evaluating iptacopan for C3GN treatment. To understand how this medication works and how it is different from eculizumab requires a good understanding of the alternative complement pathway.
The Complement System
The complement system is composed of more than 30 soluble and membrane-bound proteins which make up the classical, lectin-binding, and alternative pathways. These pathways are complex and a good portion of their Rube Goldberg nature can be explained by the fact that many of these proteins are zymogens which need to be cleaved in order to become active. It’s also important to know that after cleavage, the taxonomy denotes the smaller cleavage fragment “a” and the larger fragment “b” (i.e. C3a and C3b, respectively). The end result of any of these pathways is the formation of the membrane attack complex (MAC), but the initiation and regulation of the specific pathways is distinct and explains why the alternative complement pathway causes C3GN.
Figure 1. Overview of the classical, lectin-binding and alternative complement pathway
The classical pathway is initiated when the C1qrs complex binds the Fc region of IgG or IgM. The bound C1qrs complex cleaves the zymogens C4 and C2 to form the C4bC2b C3 convertase. The lectin-binding pathway is initiated when hexamers of mannose-binding lectins bind bacterial carbohydrate motifs and associated with MBL-associated serine proteases to cleave C4 and C2 to again form the C4bC2b C3 convertase.
In contrast, the initiation of the alternative pathway is distinct in the fact that activation is continuous (figure 2). In a process called “tick over” C3 associates with water to recruit factor D which cleaves factor B, a zymogen, to form it into the active serine esterase Bb (a.k.a. C3 convertase) that cleaves C3 to C3a and C3b. Next, C3b associates with Bb to form C3bBb, a C3 convertase that in turn amplifies the entire process noted above.
Figure 2. The alternative complement pathway
Due to the constitutive nature of the alternative complement pathway activation, regulation is key to keeping the system in check. Some of the regulatory proteins include:
Factor H: a serum protein that promotes the decay of C3 and C5 convertases
Membrane cofactor protein (MCP): a surface protein which is a cofactor for serum factor I, which cleaves and inactivates C3b
Complement receptor 1 (CR1): accelerates decay of C3 and C5 convertases; also a cofactor for serum factor I
Decay accelerating factor (DAF): accelerates decays of C3 and C5 convertases
This tight regulation of the alternative pathway can be dysregulated through several mechanisms. The first and most common way are autoantibodies that stabilize C3 convertase thereby delaying its decay. These autoantibodies are referred to as C3 nephritic factors (C3NeFs). Secondly, loss of regulator activity can happen due to:
Autoantibodies to factor H that prevent it’s action on C3b
Monoclonal immunoglobulins that inhibit factor H
Hereditary deficiency of factor H
Mutations in complement factor H proteins that cause them to compete with factor H to bind to C3b
Any of the above mechanisms can trigger C3GN. When that occurs, patients present with proteinuria with or without hematuria. Around half of patients will have low C3 levels. A decline in kidney function can be seen and on average, 50% will develop ESKD ten years after diagnosis. On kidney biopsy, a variety of findings can be seen on light microscopy including mesangial proliferative, membranoproliferative, endocapillary proliferative, or crescentic glomerulonephritis. Immunofluorescence shows more characteristic findings with bright C3 staining along glomerular, tubular, and Bowman’s capsule membranes. Mesangial C3 staining can be observed too. Electron microscopy can show subendothelial, mesangial, and subepithelial deposits.
Current Treatment of C3GN
Now that we’ve talked about the pathogenesis and presentation of C3GN, let’s move to treatment. The current treatment of C3GN is based on case reports/case series and is initially based on if a monoclonal gammopathy is present or absent. If present, it’s treated accordingly. If a monoclonal gammopathy is absent, treatment depends on the severity of the disease:
Mild disease (hematuria, <1.5g/g proteinuria, normal kidney function): RAAS inhibition
Moderate/severe disease (>1.5g/g proteinuria and/or abnormal kidney function: supportive measure + MMF + steroids. If no response is seen, eculizumab is considered in the absence of an inherited factor H mutation
RPGN: MMF or cyclophosphamide + steroids
As mentioned above, eculizumab is used in the setting of moderate disease refractory to initial therapy. Eculizumab is a humanized monoclonal antibody which binds to C5, preventing its cleavage into C5a and C5b which prevents formation of the membrane attack complex (MAC). Notice that inhibition of the complement pathway at this late step still allows for continuation of the amplification loop and formation of C3a. We’ll talk more about the significance of this in the section below.
Figure 3. Site of action of eculizumab in the alternative complement pathway
The APPEAR-C3G Trial
Could there be a more targeted treatment for C3GN though? Mouse studies of C3GN are informative. Mice with a factor H mutation expectedly develop C3GN. If however, a mutation in factor B is also introduced, C3GN does not develop. Subsequently, iptacopan which is an orally-administered small molecule inhibitor of factor B has been developed. A phase II trial in biopsy-proven C3GN patients showed that iptacopan led to a reduction in proteinuria, preservation of GFR, and reduction in C3 deposits on kidney biopsy.
It is more beneficial to inhibit the alternative complement pathway in earlier, rather than later steps. Inhibition of the alternative pathway at the level of factor B prevents cleavage of C3 into C3a and C3b, preventing propagation of the pathway while preventing the amplification loop thereby blocking the production of the anaphylatoxin C3a. A terminal complement pathway inhibitor like eculizumab, although preventing formation of the MAC, would still allow for significant formation of C3a. This is an important point since the role of C3a and the C3a receptor (C3aR) has been been observed in multiple types of glomerular disease. C3aR is abundant in renal tubular epithelial cells and less so in glomerular epithelial cells. The interaction of C3a and C3aR has a variety of effects, but in general promotes the release of inflammatory factors and is involved in formation of the histologic lesions in IgA nephropathy, minimal change disease, FSGS, lupus nephritis, and diabetic kidney disease.
Figure 4. Site of action of iptacopan in the alternative complement pathway
This brings us to the APPEAR-C3G Trial which is a randomized, double-blind, parallel group, placebo-controlled, and pivotal phase III study in 68 patients with C3GN. The inclusion criteria include
Biopsy-proven C3GN
Low C3
>1g/day proteinuria
eGFR >30
Outcomes
Primary objective: proteinuria reduction at 6 months
Secondary objectives will also be assessed
The results of this trial are expected in August 2023. Although C3GN is rare, there are a host of other kidney diseases as mentioned above affected by the alternative complement pathway. Additionally, it was recently shown that ANCA vasculitis patients with C3 deposition on kidney biopsy have worse outcomes. It’s likely that the nephrology community will find a role of complement in an ever expanding list of disorders. If iptacopan shows promise in this trial, we could be seeing upcoming studies in other glomerular disorders. This could be an exciting space to follow in the future.
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
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