C3G and Ig-MPGN-treatment standard

Abstract

Among the broad spectrum of membranoproliferative glomerulonephritis (MPGN), immunofluorescence distinguishes C3 glomerulopathy (C3G), with predominant C3 deposits, and immunoglobulin-associated MPGN (Ig-MPGN), with combined C3 and Ig. However, there are several intersections between C3G and Ig-MPGN. Primary C3G and Ig-MPGN share the same prevalence of low serum C3 levels and of abnormalities of the alternative pathway of complement, and patients who present a bioptic pattern of Ig-MPGN at onset may show a C3G pattern in a subsequent biopsy. There is no specific therapy for primary C3G and Ig-MPGN and prognosis is unfavourable. The only recommended indications are inhibitors of the renin-angiotensin system, lipid-lowering agents and other renoprotective agents. The other drugs used currently, such as corticosteroids and mycophenolate mofetil, are often ineffective. The anti-C5 monoclonal antibody eculizumab has been tested in several patients, with mixed results. One reason for the uncertainty is the extremely variable clinical course, most likely reflecting a heterogeneous pathogenesis. An unsupervised clustering analysis that included histologic, biochemical, genetic and clinical data available at onset in patients with primary C3G and Ig-MPGN identified four clusters characterized by specific pathogenic mechanisms. This approach may facilitate accurate diagnosis and development of targeted therapies. Several trials are ongoing with drugs targeting different molecules of the complement cascade, however it is important to consider which component of the cascade may be the most appropriate for each patient. We review the current standards of treatment and discuss novel developments in the pathophysiology, diagnosis, outcome prediction and management of C3G and Ig-MPGN.

Keywords: C3 glomerulopathy; complement inhibitory drugs; complement system; membranoproliferative glomerulonephritis; unsupervised cluster analysis.

Figure 1:

The complement cascade. The classical pathway is activated by the binding of C1q to antibody–antigen complexes, while the lectin pathway is activated by the binding of mannose-binding lectin (MBL) to mannose residues, which activates mannose-binding lectin serine peptidase (MASP) proteins. Either process results in the formation of the classical/lectin, C3 convertase complex that cleaves C3 to C3b and the anaphylatoxin C3a. The alternative pathway is continuously activated in plasma by low-grade hydrolysis of C3 (C3H2O, tick-over) that together with factor B, forms the initiation C3 pro-convertase. FD cleaves factor B to form the active alternative pathway initiation C3 convertase that cleaves C3 to C3b. Complement activation is then amplified by the covalent binding of C3b produced by all the three pathways to hydroxyl groups on cell surface carbohydrates and proteins of target cells, such as bacterial cells. This C3b binds factor B, to form the amplification loop C3 convertase C3bBb. C3b also binds to the C3 convertases, forming the C5 convertase enzymes of the classical/lectin (C4bC2bC3b) and of the alternative (C3b2Bb) pathways that lead to C5 cleavage and the formation of the anaphylatoxin C5a and of the membrane attack complex, composed of C5b, C6, C7, C8 and many copies of C9. The coloured rectangles denote the categories of complement inhibitors tested in C3G and Ig-MPGN and the red dashed lines mark their targets.

Figure 2:

Flow chart of diagnostic algorithm and currently available treatment algorithm in C3G and Ig-MPGN. Abs, antibodies; RAAS, renin–angiotensin system; IS: immunosuppression; MMF: mycophenolate mofetil; CNV: copy number variation.

Figure 3:

Interventional clinical trials targeting complement in C3G and Ig-MPGN. siRNA, small interfering RNA; HS, healthy subjects; IgAN, IgA nephropathy, MN, membranous nephropathy; LN, lupus nephritis; tx, post-transplant recurrence; PK, pharmacokinetics; PD, pharmacodynamics; NA, not available; e.p.: endpoint; C3HI: C3G histology index of chronicity score. All quoted trials are registered at https://www.clinicaltrials.gov/. Detailed information about participation criteria, contacts and location are provided in the website.