Abstract

In April 2012, a group of nephrologists organized a consensus conference in Cambridge (UK) on type II membranoproliferative glomerulonephritis and decided to use a new terminology, “C3 glomerulopathy” (C3 GP). Further knowledge on the complement system and on kidney biopsy contributed toward distinguishing this disease into three subgroups: dense deposit disease (DDD), C3 glomerulonephritis (C3 GN), and the CFHR5 nephropathy. The persistent presence of microhematuria with or without light or heavy proteinuria after an infection episode suggests the potential onset of C3 GP. These nephritides are characterized by abnormal activation of the complement alternative pathway, abnormal deposition of C3 in the glomeruli, and progression of renal damage to end-stage kidney disease. The diagnosis is based on studying the complement system, relative genetics, and kidney biopsies. The treatment gap derives from the absence of a robust understanding of their natural outcome. Therefore, a specific treatment for the different types of C3 GP has not been established. Recommendations have been obtained from case series and observational studies because no randomized clinical trials have been conducted. Current treatment is based on corticosteroids and antiproliferative drugs (cyclophosphamide, mycophenolate mofetil), monoclonal antibodies (rituximab) or complement inhibitors (eculizumab). In some cases, it is suggested to include sessions of plasma exchange.

Highlights

  • Membranoproliferative or mesangiocapillary glomerulonephritis (MPGN) has been traditionally classified based on the light and electron microscopy (EM) findings; here, there are three categories: type I, characterized by the presence of immune deposits in the subendothelial space and mesangium of glomeruli; type II, characterized by C3 deposits within the mesangium and in the basement membranes highly osmiophilic on electron microscopy; and type III, which is a variant of type I [1].In August 2012, a group of experts in renal pathology, nephrology, complementology, and complement therapeutics organized a consensus conference on the C3 glomerulopathy (C3 GP), meeting in Cambridge, UK [2]

  • New information on the complement system has increased our understanding of the MPGN, which has been divided into two groups: (i) MPGN caused by immune complexes (IC-MPGN) that can be caused by polyclonal or monoclonal IgG and (ii) complement-mediated glomerulonephritis (Figure 1)

  • It is necessary to investigate the concomitant presence of low plasma levels of C4, occurrence of C4 nephritic factor (C4NeF) (C4bC2a), and paraproteins because in this case, the patient is affected by MPGN type 1

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Summary

Introduction

Membranoproliferative or mesangiocapillary glomerulonephritis (MPGN) has been traditionally classified based on the light and electron microscopy (EM) findings; here, there are three categories: type I, characterized by the presence of immune deposits in the subendothelial space and mesangium of glomeruli; type II, characterized by C3 deposits within the mesangium and in the basement membranes highly osmiophilic on electron microscopy (dense deposits disease; DDD); and type III, which is a variant of type I [1]. FH is the principal regulator of the alternative pathway both in the fluid phase and on the cellular surface; it inhibits the binding of C3b with FB, enhances C3 convertase dissociation, and. Various autoantibodies enhance the activity of the alternative pathway in different ways. C4NeF binds and stabilizes C3 convertase (C4bC2a) of the classical pathway, causing more production of C3b and C3bBb. Autoantibodies against factor H eliminate the regulatory function of this factor [25], whereas autoantibodies against factor B stabilize the enhancing function of factor B [26,27]. The presence of one of these autoantibodies is responsible for the development of C3 GP caused by an abnormal control of alternative complement pathway activation with reduced C3 degradation and increased C3 fragment deposition in the GBM

Epidemiology
Clinical Manifestations
91 Range 12–88
Immunofluorescence Microscopy
Light Microscopy
Electron Microscopy
Diagnosis
Differential Diagnosis
Recurrence or De Novo C3 GP after Kidney Transplatation
Therapy
10. Conclusions

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