Reclassification of membranoproliferative glomerulonephritis: Identification of a new GN: C3GN

Table 1 Classification of glomerulonephritis

Pathogenetic type	Specific disease entity	Pattern of injury: Focal or diffuse	Score or class
Immune-complex GN	IgA nephropathy, IgA vasculitis, lupus nephritis,	Mesangial, endocapillary, exudative, membranoproliferative, necrotizing, crescentic, sclerosing or multiple	Oxford/MEST scores for IgA nephropathy
	infection-related GN, fibrillary GN with polyclonal Ig deposits		ISN/RPS class for lupus nephritis
Pauci-immune GN	MPO-ANCA GN,	Necrotizing, crescentic, sclerosing, or multiple	Focal, crescentic, mixed, or sclerosing class (Berden/EUVAS class)
	proteinase 3-ANCA GN,
	ANCA-negative GN
Anti-GBM GN	Anti-GBM GN	Necrotizing, crescentic, sclerosing, or mixed
Monoclonal Ig GN	Monoclonal Ig deposition disease, proliferative GN with monoclonal Ig deposits,	Mesangial, endocapillary, exudative, membranoproliferative, necrotizing, crescentic, sclerosing or multiple
	immunotactoid glomerulopathy, fibrillary GN with monoclonal Ig deposits
C3 glomerulopathy	C3 GN, dense deposit disease	Mesangial, endocapillary, exudative, membranoproliferative, necrotizing, crescentic, sclerosing or multiple

GN: Glomerulonephritis; MEST: Mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy; ISN/RPS: International Society of Nephrology/Renal Pathology Society; MPO: Myeloperoxidase antibodies; ANCA: Antineutrophil cytoplasmic antibodies; EUVAS: European vasculitis study group; GBM: Glomerular basement membrane.

Table 2 Complement testing in patients with C3 glomerulopathy

Test	Interpretation	Limitations
C3 and C4 levels	C3 frequently depressed and support diagnosis; Normal C4 suggests an alternative pathway process	Non-specific
Soluble C5b-9	May be indicator of active disease; May identify patients who will benefit from C5 blockade	Test not widely available
C3 nephritic factor	Associated with C3 glomerulopathy; May identify patients who will benefit from B cell targeted therapies	Levels do not correlate with disease activity; also seen in MPGN type I
Factor H protein levels	May identify underlying mechanism of alternative pathway activity; May identify patients who will benefit from plasma infusion/exchange
Autoantibodies to factor H and factor B	May identify underlying mechanism of alternative pathway activity; May identify patients who will benefit from B cell targeted therapies	Test not widely available
Genetic mutation screening Factor H CFHR1, 2, and 5 Factor I C3 Factor B	May identify underlying mechanism of alternative pathway activity	Not widely available; Clinical implications unknown

MPGN: Membranoproliferative glomerulonephritis; CFHR: Complement factor H related proteins.

Table 3 Possible treatment of C3 glomerulopathies

Nonspecific treatment

Replace deficient gene products

Plasma infusion

Liver Transplantation

Eliminate autoantibodies and/or mutant proteins

Plasma exchange

Immunosuppression

Treatment of plasma cell dyscrasia

Inhibition of complement activation

Eculizumab (anti C5)

Inhibition of the C3 Convertase

Renal transplantation

New trials ongoing