New classification of membranoproliferative glomerulonephritis: a good start but a long way to go

As with other primary glomerulonephritis, pathologic diagnosis of membranoproliferative glomerulonephritis (MPGN) is based on characteristic histologic findings such as mesangial and endocapillary proliferation accompanied by thickening of the glomerular basement membrane (GBM) frequently demonstrating “double contour” due to the interposition of mesangium and infiltration of mononuclear cells into the subendothelial region, deposition of immune complex and/or complement, and the formation of new GBM material. MPGN has traditionally been classified according to the locations of electron dense deposits, where MPGN I is characterized by mesangial and subendothelial deposits, and MPGN III by the presence of subepithelial deposits in addition to mesangial and subendothelial deposits. Burkholder subtype of MPGN III has prominent subepithelial deposits which correspond to spikes of GBM in light microscopy [1] whereas the Strife and Andes subtype of MPGN III is characterized by subendothelial deposits extending into subepithelial regions across the GBM causing disruption and lamination of lamina densa of GBM [2]. MPGN II, which is diagnosed by very unique electron dense transformations of GBM due to extensive deposition of complement 3 (C3) and other alternative complement pathway (AP) proteins, was considered a separate entity from MPGN mainly because typical microscopic features of MPGN were observed only in a minority of cases and consequently the term was appropriately replaced by “dense deposit disease (DDD)” [3]. Intense staining of the glomerular capillary walls for C3 is the rule in MPGN, and the activation of complement pathways —irrespective of classical or alternative—plays a major role in pathogenesis of MPGN via deposition of complement proteins followed by activation of mesangial and endothelial cells and chemoattraction of leukocytes with resultant damages to capillary walls from released protease and cytokines [4]. One issue related to this important role of complement pathways in MPGN is the question “what causes complement activation in patients with MPGN?” The simultaneous presence of both immunoglobulin (Ig) and complement in immunofluorescence microscopy (IF) suggests that antigen–antibody immune complex (IC) mediates the activation of classical complement pathways (CP). The presence of early complement components