C3 glomerulopathy and post-infectious glomerulonephritis

C3 glomerulopathy (C3G) is a disease caused by abnormal activation of alternative complement pathway, usually by genetic defect of proteins controlling the pathway or antibodies to them. Post-infectious GN (PIGN) is a disease caused by overactivation of alternative complement pathway by bacterial-immunoglobulin immune complex depositing in glomeruli. Before C3 glomerulopathy has been recognized, patients with the disease were diagnosed with atypical PIGN because of similar clinico-pathologic findings.
Al-Ghaithi et al. studied 33 children with PIGN and found almost one fourth of them could be reclassified as C3G. These patients had slow progressive clinical course and lacked classic subepithelial deposits or humps by electron microscopy (EM). Although some PIGN cases showed no IgG staining by immunofluorescence, the humps were identified by EM.

Toward a working definition of C3 glomerulopathy

Hou et al. proposed histological criteria for diagnosis of C3 glomerulopathy (C3G) by mean of immunofluorescence. Using dense deposit disease (membranoproliferative glomerulonephritis type II or DDD) as the gold standard, they defined C3G as dominant C3 staining with intensity at least 2x of immunoglobulins (IgG, IgA, IgM). For example, C3G is diagnosed if C3 2+ and IgG trace but not if IgG 1+. The intensity scale is 0, trace, 1+, 2+, 3+.
The original definition of C3G is C3 positive without Igs was proved to be insensitive. When it was applied in DDD, only 50% of 44 cases were characterized as C3G. DDD was used as the gold standard for C3G because the electron microscopic finding is pathognomonic. Its pathogenesis was a definite alternative complement pathway impairment.

C3 glomerulopathy

Pathogenesis of the C3 glomerulopathies and reclassification of MPGN
There have been a number of major development in the understanding of glomerular diseases recently. Membranoproliferative glomerulonephritis (MPGN) with only C3 staining was recognized as a new entity called C3 glomerulonephritis (C3GN). C3GN and dense deposit disease (DDD) are grouped under the term C3 glomerulopathy based on the presence of C3 deposits and the underlying abnormality of alternative complement system.

New Concept of MPGN

The diagnosis of membranoproliferative glomerulonephritis (MPGN) or mesangiocapillary GN is based on renal biopsy. The light microscope (LM) shows lobular pattern of glomeruli with endocapillary proliferation and double contour of their capillary walls. Immunofluorescence (IF) typically shows positivity with IgG and C3 except for type II or dense deposit disease in which only C3 is positive.