RENAL PATHOLOGY LEARNING

Membranoproliferative

Glomerulonephritis

by

Franco Ferrario and Maria Pia Rastaldi

Dr Franco Ferrario
Renal Immunopathology Center
San Carlo Borromeo Hospital
Milan, Italy

 

Membranoproliferative glomerulonephritis (MPGN) is histologically characterized by intense glomerular hypercellularity (mainly due to mesangial proliferation) and diffuse thickening of the glomerular basement membrane with the appearance of ‘double contours’.
Two distinct histological forms have been identified – Type I MPGN and Type II MPGN. Type I MPGN is characterized by the predominant presence of subendothelial deposits, while Type II MPGN presents dense homogenous deposits in the basement membrane. Actually, despite many morphological and clinical similarities, there are enough histological and immunohistological differences to suggest that Type II MPGN is a separate and distinct entity, caused by different pathogenetic and morphogenetic mechanisms.

Some researchers have identified a further entity: Type III MPGN, characterized by the concomitant presence of subendothelial and subepithelial deposits, but many authors at present believe that Type III MPGN is a morphological variant of Type I MPGN, given their clinical, immunological, and immunohistological similarities.

Type I membranoproliferative

 glomerulonephritis

Several different morphological patterns can be observed
The "classic" form is characterized by massive mesangial proliferation, mesangial matrix expansion and diffuse thickening of the glomerular basement membrane.

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Basement membrane thickening is due to mesangial cell and mesangial matrix interposition along the subendothelial side of the lamina densa with consequent neoformation of basement membrane that gives the morphological aspect of ‘double contour’.

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In some cases, not only mesangial proliferation, but also endocapillary leukocyte infiltration can be observed: it is the so-called ‘exudative MPGN’. A differential diagnosis has to be made from acute post-streptococcal GN,  cryoglobulinemic GN, and some cases of lupus nephritis.  

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The mesangial matrix increase can be more severe in peripheral areas of the tuft, giving the glomerular tuft a ‘lobular’ appearance.

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In some cases, mesangial matrix expansion and sclerosis are particularly severe and prevail over mesangial proliferation, giving a true pattern of nodular glomerulosclerosis. Such a morphological picture and the possible morphogenetic mechanism of nodule formation are similar to other nodular forms, such as diabetic glomerulosclerosis, amyloidosis, and  light chain deposition disease.

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Several authors believe that the nodular form is different from the lobular one, because it comes from a different morphogenetic mechanism. Evident aspects of mesangiolysis are in fact commonly observed, likely coming from a more marked mesangial and/or vascular damage.  

The morphological consequence of mesangiolysis is the formation of ‘microaneurisms’ due to detachment of the anchorage point of the basement membrane from the mesangial axis.

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As stated above, morphological alterations in Type I MPGN are heterogeneous. There are cases characterized by proliferative mesangial lesions and glomerular basement membrane thickening limited to some glomeruli (focal) and involving only some areas of the tuft (segmental).

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Extracapillary proliferation can be present, mainly segmental and involving a small percentage of glomeruli. 
Diffuse extracapillary proliferation in a high percentage of glomeruli can be observed in very few cases with a clinical presentation of rapidly progressive renal failure. Differential diagnosis has to be made from other intra-extracapillary diseases, such as rapidly progressive forms of IgA GN, acute post-streptococcal GN, Type II MPGN, and MGN.

In these intra-extracapillary forms there is a clear separation between the intracapillary and the extracapillary proliferation. Furthermore, necrosis (capillaritis) of the glomerular tuft is always absent. 

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By immunohistochemistry, the intense staining of the antibody against cytokeratin suggests that epithelial cells mainly contribute to the crescent formation. 

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Instead monocyte-macrophages (CD68) are almost absent, a feature that differs from necrotizing-extracapillary glomerulonephritis, such as ANCA-associated vasculitis.

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Composition and distribution of immune deposits is variable and reflects the heterogeneity of the morphological lesions. C3 deposits are almost always present, whereas C4 and C1q are present in approximately 50% of cases.  In a third of cases, IgG and IgM are also present. Immune deposits have a granular aspect and a parietal or mesangio-parietal localization in both classic and exudative forms. 

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In lobular and nodular forms, immune deposits are localized along the glomerular basement membrane giving the so-called "peripheral lobular" pattern. Mesangial deposits are usually absent. 

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Electron microscopy observation of the ‘double contour’ shows electrondense subendothelial deposits with interposition of mesangial cells.

Immune deposits are highly variable in terms of dimension and distribution. The picture shows a double contour with small electrondense deposits.

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By contrast, huge subendothelial deposits can be present in the double contour and mesangial cell interposition is evident, with a narrowed capillary lumen. (x 3600)

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In "exudative MPGN", electron microscopy confirms the presence of monocyte-macrophages in the double contour. In close proximity to the electrondense deposits a mesangial cell is activated. These aspects are similar to those found in cryoglobulinemic nephritis. (x 2800).

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QUESTIONS

 

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