Jan A. Bruijn
Membranous glomerulopathy is a major cause of the nephrotic syndrome in adults (1,2). Only in the past decades has it been surpassed by focal and segmental glomerulosclerosis as the main cause of the nephrotic syndrome (3-5). Membranous glomerulopathy develops mostly idiopathically, but can also be seen in relation with and possibly secondary to, among others, hepatitis B, Sjogren's syndrome, transplantation, lupus erythematosus, diabetes mellitus, sarcoidosis, syphilis, exposure to certain drugs and heavy metals (penicillamine, bucillamine, gold, mercuric chloride), and malignancies (10%), including carcinomas, carcinoids, sarcomas, lymphoma's, and leukemias (2,6-10). The possibility of a malignancy must be considered especially in older patients with membranous glomerulopathy. In these patients it is also imperative to perform urinary immunoelectropho-resis routinely to rule out myeloma and renal primary amyloidosis (AL) (2). Finally, idiopathic membranous glomerulopathy, of which an autoimmune origin has not been established, must be distinguished from membranous lupus glomerulonephritis (11), as discussed in Chapter 8. Synonyms for membranous glomerulopathy are membranous nephritis, (epi) membranous nephropathy, extramembranous glomerulopathy, and perimembranous nephropathy (7,12).
Membranous glomerulopathy occurs mostly in adults with a peak incidence in the fourth and fifth decades; at all ages men are more often affected than women. Patients present most often with a nephrotic syndrome, sometimes with asymptomatic proteinuria or hematuria. The prognosis seems to be related to the level of proteinuria at presentation. In general the prognosis is excellent in children, whereas in adults 10-year patient survival is around 75%. In secondary forms the underlying disease determines the prognosis. Still, a reported fraction of around 30% of patients with membranous glo-merulopathy develop chronic renal failure with depression of the glomerular filtration rate (GFR) (13). The therapeutic approach to patients with membranous glomerulopathy is still controversial (14-19).
Morphologic changes in membranous glomerulopathy are usually present in all glomeruli found in a biopsy, with little variation in the severity of the lesions between glomeruli. Morphologic lesions, however, can differ between patients, or between biopsies taken from one patient at different time points. This is caused by the evolutionary pathologic changes occurring in the glomerular capillary walls in the course of time. These morphologic changes can be very subtle and sometimes hardly or not at all visible. This illustrates the need of performing immunofluorescence and electron microscopic studies.
In typical cases the glomerular capillary wall is diffusely thickened in different stains, as a result of the presence of nonargyrophilic, subepitheli-ally localized immune deposits. In the methenamine-silver staining in early stages a somewhat rough aspect of the glomerular capillary walls is seen, which is not specific for membranous glomerulopathy. Irregular thickenings at the outer side of the glomerular basement membrane grow around the immune deposits and appear in the silver staining as "spikes" (Fig. 2.1). These are at first small and segmental, but they grow in the course of the disease, while they may broaden toward their end (club-shaped), embracing the deposits. Three-dimensionally they are in fact "craters," as can be well observed at places where the capillary wall is cut tangentially. As mentioned before, spike formation results from the presence of subepithelial deposits, which trigger the epithelial cells to increase their production of extracellular matrix, especially laminin (20).
In membranous glomerulopathy, due to the glomerular protein leak, the tubules often show epithelial protein resorption droplets and there may be
protein cylinders. Foam cells may be present in the interstitium or between tubular epithelial cells and are related to the hyperlipidemia and reabsorption of filtered lipoproteins, as can be seen also in nephrotic syndrome due to other causes. With progression of the glomerular lesions, nephron loss and interstitial fibrosis may occur. In late stages the glomeruli show nonspecific global sclerosis. Interstitial vessels show mostly no abnormalities in membranous glomerulopathy. The extent of interstitial damage correlates strongly with prognosis (21).
Immunofluorescence investigations in membranous glomerulopathy generally reveal granular deposits of immune reactants, which follow the contours of the glomerular basement membrane. Immuno-electron microscopical studies have shown that these immune reactants are present in the electron dense deposits described above. The deposits can sometimes be very finely granular, which may lead to the immunofluorescence pattern being falsely interpreted as linear. Deposits in the mesangium are absent in most cases. The most often occurring component in the immune deposits is immunoglobulin G (IgG) (Fig. 2.2). In addition, C3 is often found, while IgM and IgA have been found in about half of the published cases. When in addition to IgG, IgM, and C3 also IgA and C1q are found ("full
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