Table 1.
The rationale for the use of therapeutic complement inhibition in various glomerular diseases is summarized
| Type of glomerular diseases | Rationale for therapeutic complement blockade | Registered or completed trials with complement inhibitors. Retrospective series and case reports |
|---|---|---|
| Nephropathies with exclusive or predominant C3 deposits | ||
| Acute postinfectious glomerulonephritis | Low C3 plasma levels and dominant C3 staining in kidney biopsy (with the absence of C1q and C4 deposits) are cardinal features of acute postinfectious glomerulonephritis. Acquired (C3 nephritic factor, anti-factor B antibodies) and more rarely constitutional dysregulation of the CAP has been reported in patients with acute postinfectious glomerulonephritis.46,72,73 Clinical and pathologic features of acute postinfectious glomerulonephritis may overlap with those of C3 glomerulopathy. |
No trials registered C5 inhibition used in case reports74,75 |
| C3 glomerulopathy | Predominant or exclusive C3 deposits are pathologic hallmarks of C3 glomerulopathy. Acquired (autoantibodies) or constitutional (genetic variants) dysregulation of the CAP has been reported in patients with C3 glomerulopathy.76 Animal models have linked C3 glomerulopathy to alternative C3 convertase dysregulation.77 |
Clinical trials registered for: anti-C5 (eculizumab), anti-C3 (AMY-101, ARO-C3, pegcetacopan), anti-C5a receptor (avacopan), anti-factor D (danicopan, BCX9930), anti-factor B (iptacopan), MAPS2 inhibitor (narsolimab) Use of eculizumab reported in retrospective series42 and a small prospective open-label trial.78 |
| Nephropathies with Igs, immune complexes, and complement deposits | ||
| Immunoglobulin A nephropathy | Co-dominant IgA and C3 glomerular deposits (90%), along with properdin, C4d, MBL, and C5b-9 deposits are characteristic pathologic features of IgA nephropathy. Markers of glomerular activation of the lectin pathway (MBL, L-ficolin, MASP2, MASP1/3, and C4d) have been associated with a worse outcome of IgA nephropathy.79,80 Variations in complement genes have been associated with better (CFHR3,1 deletion)81 or worse outcome (CFH, CFHR5)82, 83, 84 of IgA nephropathy. Plasma levels of FHR-1 and FHR-1/FH ratio are associated with a progressive course of IgA nephropathy.85 C3a receptor/C5a receptor deficiency in mice alleviates IgA nephropathy in mice.86 |
Clinical trials registered: anti-C5 (eculizumab, ravulizumab, cemdisiran), anti-C5a receptor (avacopan), anti-C3 (ARO-C3, pegcetacopan), anti-factor B (iptacopan, IONIS-FB-LRx), anti-factor D (vemircopan, BCX9930, ALXN2050), MAPS-2 inhibitor (narsoplimab). Salvage treatment with eculizumab in case reports.87 |
| Immunoglobulin-mediated membranoproliferative glomerulonephritis | Co-deposition in glomeruli of Igs and complement components characterize the disease. Features of CAP (and to much lesser extent of the CP) activation reported in up to 39%–59% of patients.88 Acquired CAP dysregulation detected in 45%–86% of patients89 | Clinical trials registered: anti-C3 (pegcetacopan), anti-factor D (danicopan) |
| Lupus nephritis | Glomerular co-localization of IgG, IgA, and IgM with C1q, C4 and C3, and C5b-9 (“full house” pattern) is characteristic of proliferative lupus nephritis. Decreased systemic levels of C3 and C4 reflect disease activity. The role of complement in lupus is dual: 1. Altered clearance of immune complexes by complement. Deficiency of C1q, C2, and C4 is associated with a high risk of systemic lupus erythematous. 2. Complement activation by immune complexes deposition contributes to glomerular inflammation through C3a and C5-dependent inflammatory cell recruitment and C5b-9-induced tissular damage. Earlier onset of lupus nephritis has been observed in patients with variants in CFH or CD46 (MCP) genes89 Animal models have underlined the role of CAP in the pathogenesis of lupus nephritis90,91 |
Clinical trials registered: anti-C5 (ravulizumab), anti-C3 (pegcetacopan), anti-factor D (vemircopan, ALXN2050), MAPS-2 inhibitor (narsoplimab). |
| Membranous nephropathy | C3 fragments and C5b-9 colocalize with IgG in subepithelial glomerular deposits (even though IgG4, the predominant IgG subclass in membranous nephropathy, do not activate complement). In experimental models of membranous nephropathy, C3 depletion prevents the development of proteinuria92 and C5b-9 is a key mediator of podocyte injury.93 CP,94 lectin95 and alternative96,97 pathways are likely to play a role in podocyte injury in the setting of membranous nephropathy. |
Registered trials: anti-C3 (pegcetacopan), anti-factor B (iptacopan), anti-factor D (BCX9930), MAPS2 inhibitor (narsoplimab). |
| Cryoglobulinemic glomerulopathy | Glomerular Igs and C3 deposits are characteristic of the cryoglobulinemic glomerulopathy. Severely decreased serum levels of C4 and low levels of C3 correlate with disease activity. In animal models, C5, C1q, C3, and factor B deficiency protect against or attenuate the severity of cryoglobulinemic glomerulopathy (reviewed in Trendelenburg et al.98). |
Eculizumab use reported in a single case.99 |
| Antiglomerular basement membrane antibody disease | Co-deposition of C1q and C3 and linear IgG along the glomerular basement membrane are characteristic of the disease. Presence of MBL, C4d, factor B, properdin, and C5b-9 deposits along the glomerular basement membrane suggest lectin and alternative pathway involvement.21 Murine models demonstrated that C3 and C4 deficiency prevented full manifestation of renal disease.100 |
No trials registered. Salvage treatment with eculizumab in case reports.101,102 |
| Nephropathies with nonspecific complement-induced inflammation | ||
| ANCA-renal vasculitis | Despite the absence of significant complement deposits in the kidney, high levels of circulating C3a, C5a, sC5b-9, and Bb have been reported in patients with active ANCA vasculitis.103 Low C3 levels are associated with worse prognosis.104 ANCA can induce NETosis by neutrophils that activate CAP. C5a activates neutrophils through C5a receptor (positive feedback loop)105 Murine models of antimyeloperoxidase antibody-associated vasculitis confirm the crucial role of C5a, C3 and factor B in the pathogenesis of the disease.106 |
Published clinical phase II and III trials: anti-C5a receptor (avacopan)40,107 Ongoing trials: anti-C5a receptor (vilobelimab) |
| Complement-mediated TMA | ||
| Atypical hemolytic uremic syndrome | Alternative pathway dysregulation (inherited or acquired) reported in up to 60% of pateints.2,44 Animal models confirm the central role of alternative C3 convertase dysregulation in the disease.108 |
Ongoing clinical trials: anti-C5 (eculizumab, ravulizumab, crovalimab), anti-C5a receptor (avacopan), anti-factor B (iptacopan), MAPS-2 inhibitor (narsolimab) Efficacy of eculizumab reported in prospective noncontrolled trials1,6,109 and in retrospective series.13 Data on ravulizumab use have been recently reported.110 |
ANCA, anti-neutrophil cytoplasmic autoantibody; CAP, complement alternative pathway; CP, complement classical pathway; FH, factor H; FHR-1, factor H-related protein 1; MBL, mannose-binding lectin; TMA, thrombotic microangiopathy.
A list of published, ongoing trials, retrospective series, and case reports regarding the use of complement inhibitors in glomerular diseases is provided.