Current concepts in C3 glomerulopathy

Abstract

Complement component 3 glomerulopathy (C3G) is a recently defined entity comprising of dense deposit disease and C3 glomerulonephritis. The key histological feature is the presence of isolated C3 deposits without immunoglobulins. Often masqueradng as some of the common glomerulonephritides this is a prototype disorder occurring from dysregulated alternate complement pathway with recently identified genetic defects and autoantibodies. We review the pathophysiology, clinical features, and diagnostic and treatment strategies.

Keywords: Alternate complement pathway; complement component 3 glomerulonephritis; complement component 3 glomerulopathy; complements; dense deposit disease.

Figure 1

Complement activation cascade (C3NeF: Complement component 3 nephritic factor, TCC: Terminal complement cascade)

Figure 2a

Complement factor H with its C terminal which is surface regulatory end and N terminal which is complement component 3 (C3) regulatory end. Defects in C terminal leads to atypical hemolytic uremic syndrome while defects in N terminal leads to C3glomerulonephritis. (Factor I and factor H - Regulators of complement system, C3b - Fragments from breakdown of C3, iC3b - Inactive fragment from breakdown of C3b, factor P-Regulator of complement cascade stabilizes C3 convertase, Bb - Active subunit of CFB, FLUID - Fluid or circulatory phase, SURFACE - Cell surface phase, MAC - Membrane attack complex, C3 Reg - C3 regulatory or N terminal end of factor H, surface reg - Surface regulatory or C terminal end of factor H)

Figure 2b

Animal model with complement factor H deficiency leads to accelerated complement component 3 (C3) convertase activity and formation of inactive C3b, which has a predilection for the glomerular basement membrane. (Factor I and factor H-Regulators of complement system, C3b - Fragments from breakdown of C3, iC3b-Inactive fragment from breakdown of C3b, factor P-Regulator of complement cascade stabilizes C3 convertase, Bb - Active subunit of CFB, FLUID - Fluid or circulatory phase, SURFACE - Cell surface phase, MAC - Membrane attack complex, C3 Reg - C3 regulatory or N terminal end of factor H, surface reg - Surface regulatory or C terminal end of factor H)

Figure 2c

Animal model with complement factor I deficiency with accumulation of C3b, with a predilection for mesangium. (Factor I and factor H - Regulators of complement system, C3b - Fragments from breakdown of C3, iC3b-Inactive fragment from breakdown of C3b, factor P - Regulator of complement cascade stabilizes C3 convertase, Bb-Active subunit of CFB, FLUID-Fluid or circulatory phase, SURFACE-Cell surface phase, MAC - Membrane attack complex, C3 reg-C3 regulatory or N terminal end of factor H, surface reg-Surface regulatory or C terminal end of factor H)

Figure 2d

Uncontrolled complement component 3 convertase activity leads predominantly to dense deposit disease while that of C5 convertase activity causes complement component 3 glomerulonephritis (C3GN). (DDD - Dense deposit disease, C3GN-C3 glomerulonephritis, factor I and factor H - Regulators of complement system, C3b - Fragments from breakdown of C3, iC3b - Inactive fragment from breakdown of C3b, factor P-Regulator of complement cascade stabilizes C3 convertase, Bb-Active subunit of CFB, FLUID - Fluid or circulatory phase, SURFACE-Cell surface phase, MAC - Membrane attack complex, C3 reg-C3 regulatory or N terminal end of factor H, surface reg - Surface regulatory or C terminal end of factor H)

Figure 3

Pathological findings from a 53-year-old man with complement component 3 glomerulonephritis who presented with nephrotic range proteinuria, microscopic hematuria and renal failure. (a) Light microscopy shows accentuated lobularity and global glomerular hypercellularity (H and E) (b) Increased mesangial matrix with tram tracks in peripheral capillary loops (arrowheads) (c) Immunofluorescence showing strong granular capillary loop reactivity for complement component 3. (d) Electron microscopy with an endocapillary inflammatory cell (*), glomerular basement membrane duplication (arrowheads) and subendothelial electron-dense deposits (arrows)

Figure 4

(a) Stepwise serological investigation for complement component 3 glomerulonephritis, (b) Stepwise biopsy diagnosis for complement component 3 glomerulonephritis