Membranous glomerulonephritis pathophysiology

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• Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Ahsan Hussain, M.D.[2]

Overview

It is thought that MGN is mediated by genetic factors and environmental factors.

Pathophysiology

• MGN is caused by immune complex formation in the glomerulus. The immune complexes are formed by binding of antibodies to antigens in the glomerular basement membrane. The antigens may be part of the basement membrane, or deposited from elsewhere by the systemic circulation.
• The immune complex serves as an activator that triggers a response from the complement system and form a membrane attack complex which stimulates release of proteases and oxidants by the mesangial and epithelial cells, damaging the capillary walls and causing them to become "leaky".

Phospholipase A2 receptor

• The M-type PLA2R is the major antigen in human idiopathic MN. It is expressed in glomerular podocytes.
• There was no colocalization of PLA2R in secondary MN biopsies.
• PLA2R antigen detected within immune deposits by immunofluorescence of the biopsy specimen. [26]
• Detection of the immune complex specificity is 100 percent.

Thrombospondin type-1

• THSD7A has been found in patients with idiopathic MN who are negative for anti-PLA2R antibodies.

Neutral endopeptidase

• Anti-neutral endopeptidase antibodies caused MN in the neonates.
• It resolves months after birth.

• The T helper-2 predominates in MN and minimal change disease.

HLA susceptibility 1

Environmental factors

Variant of PLA2R1 on podocyte surface

Innate immunity activation and inflammation dendritic cell sense epitope of PLA2R1 and present them for adaptive immunity

Production of auto-immune antibody IgG4/IgG1 which attach them self to epitope on podocyte surface

In Situ formation and shedding of subepithelial immune complex

Complement activationMANNAN PATHWAY and T cell activation

Which lead to cytokine release oxygen derivative release membrane attack complex C5-C9

Podocyte injury by apoptosis altered lectin cytoskeleton loss of silt pore integrity loss of glomerular permeability proteinuria

Genetics

• Single-nucleotide polymorphisms (SNPs) at two loci that are highly associated with idiopathic MN. [58]
• The two loci are within the genes for the PLA2R on chromosome 2q24, and the human leukocyte antigen (HLA) complex class II alpha chain 1A (HLA-DQA1) on chromosome 6p21.
• PLA2R variants have also been found in other cohorts with idiopathic MN, although no single variant was consistently found that could explain the association with disease [59]. The PLA2R has been identified as a major antigen in idiopathic MN.

Associated Conditions

Hepatitis B

The most frequent glomerulopathy in patients infected with hepatitis B virus is MGN followed by membranoproliferative GN. The antigens Core (HBcAg) and e (HBeAg) seem the most important in the pathogenesis of hepatitis B-associated MGN. In these cases the antigens, or their antibodies, are identified in the glomerular immune deposits. It is not clear what is first deposited: the Ag., the Ac. or the Ag-Ac complex previously formed (circulating). Prevalence of MGN in the infection is not known, but in children with MGN the carrier stage is detected in around 20% of cases, with higher rates in endemic countries. In adults the percentage of patients with MGN carrying hepatitis B virus is lower than in children. In GNM cases associated with this infection there are more frequently mesangial hypercellularity, endocapillary proliferation, subendothelial immune deposits, and tubuloreticular endothelial structures (electron microscopy). It is frequent that appears with hypocomplementemia. The prognosis of MGN in hepatitis B patients seem more favorable, with most frequency of remission and less probability of evolution to terminal renal damage.

Hepatitis C

In this infection disease also secondary MGN can appear, although membranoproliferative GN is more frequent. In many studies have not been identified antigens of the virus, or Acs against these, in the glomerular deposits. Clinic expression can be similar to idiopathic MGN or it may appear with asymptomatic proteinuria.

Congenital Syphilis

MGN is a rare complication in congenital syphilis, but it is a well-recognized cause of NS in children with this infection. Other glomerular disease in congenital syphilis include nephritic syndrome and crescentic GN with rapidly progressive disease. We have seen cases with these types of glomerular disease and there is a dramatic improvement with the antibiotic treatment. Several studies have demonstrated the presence of antigens of Treponema pallidum in the immune glomerular deposits.

Systemic Lupus Erythematosis

the histopathologic presentation is very variable and there is combination of morphologic changes: MGN with subendothelial deposits, endocapillary and/or mesangial proliferation, crescents, combination with characteristics of membranoproliferative GN, and other patterns. In the most recent lupus nephritis classification, pure MGN (class V) is only diagnosed if there are no other active lesions; if there is combination with active lesions it is diagnosed as combination of class V and class III or IV only if there are lesions with membranous characteristics in more than 50% of the tuft in more than 50% of glomeruli. Occasional subepithelial deposits and “spikes” formation are very frequent in class III and IV lupus nephritis. In most of these cases we find C1q glomerular deposits.

Malignancy

The neoplasms more frequently associated with MGN are lung, breast, colon, stomach and kidney carcinomas, leukemia and lymphomas (Hodgkin’s and non-Hodgkin’s), but there is information of MGN in many other cancer types. Incidence of cancer in patients with MGN is approximately 1%. The histologic and immunopathologic findings and the clinical presentation are similar to those of idiopathic forms of MGN. The association between MGN and neoplasms is supported by the clinical course, the immune response of the host to the tumor and the glomerular pathology, nevertheless, in very few cases is documented an antigen of the tumor, or its antibody, in glomerular deposits. It is possible that the immune response against the neoplasm, in a propitious genetic context, allow the development of MGN. The prognosis of the glomerulopathy depend on that of the neoplasm. If there are treatment and response of this last one, the MGN tends to disappear.

Microscopic Pathology

• Early biopsies may be normal
• Later: uniform diffuse capillary wall thickening without hypercellularity, without mesangial sclerosis and without inflammatory cells
• Proximal convoluted tubules contain hyaline droplets, reflecting protein reabsorption
• With progression, get membrane thickening, narrow capillary lumina, mesangial sclerosis and glomerulosclerosis

Immunofluorescence

• Granular diffuse peripheral deposits, usually IgG and C3, also C5b-C9 and occasionally IgM or IgA
• C4d immunostaining may be diagnostic (Histol Histopathol 2011;26:1391) 

Stages

• Stage I: LM - normal for slightly thickened BM, slight GMB vacuolization; IF - fine granular IgG, C3; EM - scattered small subepithelial electron dense deposits, no foot process effacement or spikes
• Stage II: LM - moderately thickened BM with spikes and vacuolization; IF - moderate sized, granular IgG, C3; EM - diffuse spikes due to subepithelial deposits, diffuse foot process effacement
• Stage III: LM - markedly thickened GBM, residual spikes and vacuoles, chain like appearance; IF - coarsely granular IgG, C3; EM - intramembranous deposits, spikes, neomembrane formation and diffuse foot process effacement
• Stage IV: LM - markedly thickened GBM, few spikes, vacuoles and glomerulosclerosis; IF - focal IgG, C3; EM - sclerotic GBM, few deposits and lacunae

Electron microscopy

• There are electron-dense deposits in the epithelial aspect (external) of the GBM, between this one and the epithelial cell: subepithelials or epimembranous. Subepithelial deposits that nestle against the glomerular basement membrane seems to be the cause of the thickening. These deposits are usually diffuse and homogenously distributed, but they can be, in some cases, irregularly distributed.
• Spikes are demonstrated as irregular projections of the GBM among the subepithelial deposits; with progression of the disease these projections become longer and surround the deposits incorporating them in a thickened GBM.
• The podocytes lose their foot processes.
• As the disease progresses, the deposits will eventually be cleared, leaving cavities in the basement membrane.

References

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  Membranous Glomerulonephritis: Electron micrography. An excellent example to show thickened basement membrane and immune complexes.

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  Membranous Glomerulonephritis: Micro trichrome high mag excellent to show thickened capillary basement membranes

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  Membranous Glomerulonephritis: Micro PAS high mag excellent example of this lesion

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  Membranous Glomerulonephritis: Micro PAS med mag