Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement

Abstract

Background and objectives: dense deposit disease (DDD) is the prototypical membranoproliferative glomerulonephritis (MPGN), in which fluid-phase dysregulation of the alternative pathway (AP) of complement results in the accumulation of complement debris in the glomeruli, often producing an MPGN pattern of injury in the absence of immune complexes. A recently described entity referred to as GN with C3 deposition (GN-C3) bears many similarities to DDD. The purpose of this study was to evaluate AP function in cases of GN-C3.

Design, setting, participants, & measurements: Five recent cases of MPGN with extensive C3 deposition were studied. Renal biopsy in one case exhibited the classic findings of DDD. Three cases showed GN-C3 in the absence of significant Ig deposition; however, the classic hallmark of DDD-dense deposits along the glomerular basement membranes and mesangium-was absent. The remaining case exhibited features of both DDD and GN-C3.

Results: Evidence of AP activation was demonstrable in all cases and included increased levels of soluble membrane attack complex (all cases), positive AP functional assays (four cases), and a positive hemolytic assay (one case). Autoantibodies were found to C3 convertase (two cases) and to factor H (one case). Factor H mutation screening identified the H402 allele (all cases) and a c.C2867T p.T956M missence mutation (one case). Laser microdissection and mass spectrometry of glomeruli of GN-C3 (two cases) showed a proteomic profile very similar to DDD.

Conclusions: These studies implicate AP dysregulation in a spectrum of rare renal diseases that includes GN-C3 and DDD.

Figure 1.

Light microscopy showing an MPGN pattern of injury in cases 1 (A), 2 (B), 3 (D), 4 (E), and case 5 (F). Segmental sclerosis is also seen in case 2 (C), and in case 5, crescents are noted (F).

Figure 2.

Immunofluorescence microscopy showing glomerular capillary wall C3 staining in cases 1 (A), 2 (B), 3 (C), 4 (D), and 5 (E).

Figure 3.

Electron microscopy showing (A) double contours with subendothelial deposits and new basement membranes in case 1; (B) mesangial deposits in case 2; (C) subepithelial, subendothelial, and mesangial deposits in case 3; (D) mesangial, subepithelial, and subendothelial deposits in case 4; and (E and F) osmiophilic wavy sausage-shaped intramembranous deposits and mesangial deposits in cases 4 and 5, respectively (white arrows, electron dense deposits; black arrows, dense deposits along basement membrane).

Figure 4.

Laser microdissection and mass spectrometry. (A) Glomeruli marked before dissection in case 1 (A) and case 2 (B). (B) Representative scaffold readout of proteins of interest for two cases of GN-C3 (cases 1 and 2) by Spectra. Samples are in duplicate (S1 and S2). The proteomic data show C3, FHR-1, vitronectin, FHR-5, apolipoprotein E, clusterin, and C9 in order of abundance with >95% probability. Yellow stars indicate proteins of interest, whereas red stars indicate protein ambiguity when two proteins share conserved regions.

Figure 5.

Proposed evaluation scheme for MPGN based on the presence or absence of immunoglobulins by immunofluorescence. In the absence of immunoglobulins, the genetics and functional activity of the AP should be assessed.