C3 glomerulopathies: dense deposit disease and C3 glomerulonephritis

Abstract

Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are types of membranoproliferative glomerulonephritis classified as C3 glomerulopathies. These conditions are characterized by an increased number of intraglomerular cells and diffuse thickening of the glomerular capillary walls, along with the deposition of C3 and minimal or absent immunoglobulin deposits. The underlying cause of both DDD and C3Gn is an abnormal activation of the alternative complement pathway, which can result from acquired or genetic alteration. In acquired forms of DDD and C3GN, the dysregulation of the alternative pathway is commonly induced by the presence of C3 nephritic factors (C3NeFs), which are autoantibodies that stabilize C3 convertase. Both DDD and C3GN can affect individuals of any age, but DDD is primarily diagnosed in children, whereas C3GN tends to be diagnosed at a significantly higher age. The presenting features of these diseases are variable and may include proteinuria, hematuria, hypertension, or kidney failure. A common finding in these diseases is low serum C3 levels with normal serum C4 levels. Chronic deterioration of renal function is commonly observed in DDD and C3GN, often leading to end-stage renal disease (ESRD), especially in DDD. Kidney transplantation outcomes in patients with these conditions are characterized by histological recurrence, which may contribute to higher rates of allograft failure.

Keywords: C3 glomerulonephritis; C3 glomerulopathies; alternative complement pathway; dense deposit disease; membra-noproliferative glomerulonephritis.

Figure 1

(A, B) C3 DDD with mesangial and capillary staining for C3 in immunofluorescence microscopy. (C, D) DDD with ribbon-like deposits along the basement membrane lamina densa at electron microscopy. (E) The glomerulus shows mesangial hypercellularity and increase in mesangial which gives lobulated appearance and capillary wall thickening. Light microscopy, AFOG's trichrome.

Figure 2

Schematic diagram of the alternative pathway of the complement system. The alternative pathway is constitutively active and is upregulated by binding of C3b to an activating surface. When C3b binds to an activating surface, it triggers a cascade of events, leading the formation of C3 convertase (C3bBb). C3 convertase cleaves C3 in C3a, an anaphylatoxin, and C3b, an opsonin. C3b may form C5 convertase (C3bBbC3b) with generation of C5a, an anaphylatoxin, and C5b, that forms the C5b-9, MAC. This pathway is regulated by regulator factors (in green) to prevent the excessive activation. On the other hand, the promoters or positive regulators factors (in red) play a role in prolonging the activation of the pathway, ensuring a balanced and effective immune response. FB, factor B; FD, factor D; P, properdin; FH, factor H; FI, factor I; DAF, decay-accelerating factor; MCP, membrane cofactor protein; CR1, complement receptor 1; MAC, membrane attack complex.