Slide 16 shows the frequency of causes for nephrotic range proteinuria relative to age in my renal biopsy population. From age 16 to 65, membranous glomerulopathy is rather frequent, but its highest frequency is in the 40-60 year old age group.
Slide 17 shows an H&E stained section of an early stage. If you don't have a good internal reference as to the thickness of capillary loops, it is hard to look at a membranous glomerulopathy biopsy and be sure there is something wrong by light microscopy, especially during early stages to the disease. Slide 17a shows a late stage membranous glomerulopathy with markedly thickened capillary walls.
Looking at higher magnification in the split-screen projection in Slide 18, the very thick capillary wall of an overt case of membranous glomerulopathy can be recognized. On a trichrome stained section (middle panel), if you have a good stain and if the stage of the disease is just right and there are big deposits, you can see the subepithelial immune complex deposits as fuchsinophilic (red) granular deposits. The blue basement membrane is beneath the deposits and there are projections of blue between them. On a silver stained section, and sometimes on a well- stained PAS stained section, as shown in the panel on the right, you can see the so-called spikes of basement membrane that project between the deposits in certain stages of membranous glomerulopathy, in particular stage II.
Slide 19 is a diagram of the ultrastructural features of membranous glomerulopathy (stage II) compared to a normal glomerulus. The characteristic lesion of membranous glomerulopathy is deposition of immune complexes in the subepithelial zone. In later stages of the disease, the deposits are transformed into intramembranous deposits. Slide 19 diagrams a stage II lesion with regularly distributed deposits with projections of basement membrane between them. There also is effacement of foot processes in microvillous transformation. The electron micrograph (Slide 20) of a stage II membranous lesion demonstrates: capillary lumen, endothelial cytoplasm, original basement membrane, subepithelial deposits (with actin condensation in the overlying epithelium), and projections of basement membrane material between the deposits.
Slide 21 diagrams the different stages of membranous glomerulopathy. In stage I there are no basement membrane projections adjacent to deposits. In stage II there are GBM projections between deposits. In stage III, the deposits become incorporated in the basement membrane. In stage IV, the deposits start to fade away leaving lucent gaps and a thickened basement membrane. The stage V lesion, paradoxically, has a normal subepithelial zone of the basement membrane, which has been repaired, and the disturbance has been pushed to the subendothelial zone.
Slide 22 demonstrates the typical immunofluorescence microscopy pattern of membranous glomerulopathy, in a panel adjacent to a low magnification electron micrograph. The grains seen by immunofluorescence microscopy correspond to the electron dense deposits. Typically, the granular staining of membranous glomerulopathy is diffuse and global(Slide 22a). Diffuse means all of the glomeruli are involved, as opposed to focal, which means that some glomeruli are involved and some are not. Global means that all the glomerular segments and capillaries are involved in a given glomerulus, as opposed to segmental, which means that only some of them are. Typically, membranous glomerulopathy has diffuse global granular staining of capillary walls. Rare specimens will have segmental staining. The composition of immune deposits is almost always IgG-dominant. Usually there is some IgM and IgA. C3 staining is usually very low intensity in idiopathic(primary) membranous glomerulopathy, which is very different from a post-infectious glomerulonephritis in which there is usually intense C3 staining along with very low intensity or absent IgG staining.
The pathogenesis of membranous glomerulopathy is still not fully known. Current theory holds that a likely pathogenesis for idiopathic or primary membranous glomerulopathy involves an autoimmune disease in which circulating autoantibodies with specificity for determinants on visceral epithelial cells develop. The autoantibodies cross the glomerular basement membrane and form immune complexes in-situ in the subepithelial zone. If this is the mechanism for forming the subepithelial deposits, there could never be mesangial or subendothelial deposits because the antigen is on the epithelial cell and ultrafiltration is moving away from the lumen. However, if the membranous glomerulopathy is caused by (secondary to) immune complexes that are composed of antigens from the circulation (such as a hepatitis B antigen) and antibodies from the circulation, some of the antibodies would bind to antigen that had crossed into the subepithelial zone while other antibodies would form complexes in subendothelial or mesangial locations (Slide 23). This is the theoretical basis for secondary membranous glomerulopathy, such as that caused by a neoplasm, an infection or a systemic autoimmune disease. The presence of mesangial or subendothelial dense deposits, therefore, raises the possibility of some type of secondary membranous glomerulopathy.
