A Narrative Review on C3 Glomerulopathy: A Rare Renal Disease

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.

Keywords: C3 glomerulonephritis; C3 glomerulopathy; CFHR5 nephropathy; Dense deposits disease.

Figure 1

Classification of the membranoproliferative glomerulonephritis (MPGN). Abbreviations: IC-MPGN (immune complex MPGN); Ig (immunoglobulin); C3 GP (C3 glomerulopathy); DDD (dense deposits disease); C3 GN (C3 glomerulonephrits); CFHR5 GP (complement factor H-related protein 5 glomerulopathy).

Figure 2

Complement system pathways.

Figure 3

Schematic dysregulation of the C3 activation in C3 GP.

Figure 4

(a) Ribbon like pattern of C3 deposition along glomerular basement membrane in a patient with DDD (×400). (b) Linear C3 deposition along tubular basement membrane in DDD (×400). (c) Granular mesangial C3 deposits in a patient with a mesangial proliferative C3 GN (×400). (d) Coarsely granular mesangial and glomerular capillary wall C3 deposits in a patient with membranoproliferative pattern of C3 GN (×400). (e) Glomerulus with segmental mesangial proliferation in a patient with C3 GN (PAS). (f) Glomerulus with global membranoproliferative pattern of injury in a patient with C3 GN. Several aspects of glomerular basement membrane double contours (black arrows) are present (Jones silver stain). (g) Glomerulus with thickened strongly PAS positive glomerular basement membranes with several double contours (black arrows) (PAS) in a patient with DDD. (h) Silver negative glomerular basement membrane in a patient with DDD (white arrows). Glomerular basement membranes appear eosinophilic and refractile (Jones silver stain). (i) Highly osmiophilic electron dense deposits permeating lamina densa in a patient with DDD (TEM, ×8900). (j) Mesangial electron dense deposits (black arrows) in a patient with mesangial proliferative C3 GN (TEM, ×11000). (k) Subendothelial electron dense deposits (black arrows) with newly formed lamina densa (i.e., double contours) and cellular interposition (white arrow) in a patient with membranoproliferative patter of C3 GN (US: urinary space, CL: capillary lumen) (TEM, ×8900).

Figure 5

Clinical and Laboratory Work-up for diagnosis of C3 glomerulopathy.