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__NOTOC__
__NOTOC__
{{Membranous glomerulonephritis}}
{{Membranous glomerulonephritis}}
* {{CMG}}; {{AE}} {{SAH}}
{{CMG}}; {{AE}} {{SAH}} {{Pervaiz Laghari}}


==Overview==
==Overview==
It is thought that MGN is mediated by genetic factors like PLA2R, enviromental factors, drug (captopril) side effects, infections like hepatitis B and hepatitis C.
Membranous glomerulonephritis 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 damage the basement membrane and activates the immune response. The immune complex serves as an activator that triggers a response from the complement system. .PLA2R antigen detected within immune deposits by [[immunofluorescence]] of the [[biopsy]] specimen. Formation of the [[Immune complexes|immune complex]]. Immune complex formation results in release of cytokines which release membrane attack complex C5-C9. Release of C5-C9 lead to injury of podocyte which causes loss of glomerular permeablity. The damage to podocyte reults in proteinuria.


==Pathophysiology==
==Pathophysiology==
* The membranous [[glomerulonephritis]] is a result of multiple changes.<ref name="pmid16159900">{{cite journal |vauthors=Cybulsky AV, Quigg RJ, Salant DJ |title=Experimental membranous nephropathy redux |journal=Am. J. Physiol. Renal Physiol. |volume=289 |issue=4 |pages=F660–71 |date=October 2005 |pmid=16159900 |pmc=1325222 |doi=10.1152/ajprenal.00437.2004 |url=}}</ref><ref name="pmid15800119">{{cite journal |vauthors=Nangaku M, Shankland SJ, Couser WG |title=Cellular response to injury in membranous nephropathy |journal=J. Am. Soc. Nephrol. |volume=16 |issue=5 |pages=1195–204 |date=May 2005 |pmid=15800119 |doi=10.1681/ASN.2004121098 |url=}}</ref><ref name="pmid15800113">{{cite journal |vauthors=Cunningham PN, Quigg RJ |title=Contrasting roles of complement activation and its regulation in membranous nephropathy |journal=J. Am. Soc. Nephrol. |volume=16 |issue=5 |pages=1214–22 |date=May 2005 |pmid=15800113 |doi=10.1681/ASN.2005010096 |url=}}</ref><ref name="pmid19571279">{{cite journal |vauthors=Beck LH, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ |title=M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy |journal=N. Engl. J. Med. |volume=361 |issue=1 |pages=11–21 |date=July 2009 |pmid=19571279 |pmc=2762083 |doi=10.1056/NEJMoa0810457 |url=}}</ref><ref name="pmid23364522">{{cite journal |vauthors=Kanigicherla D, Gummadova J, McKenzie EA, Roberts SA, Harris S, Nikam M, Poulton K, McWilliam L, Short CD, Venning M, Brenchley PE |title=Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy |journal=Kidney Int. |volume=83 |issue=5 |pages=940–8 |date=May 2013 |pmid=23364522 |doi=10.1038/ki.2012.486 |url=}}</ref><ref name="pmid21323563">{{cite journal |vauthors=Debiec H, Ronco P |title=PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy |journal=N. Engl. J. Med. |volume=364 |issue=7 |pages=689–90 |date=February 2011 |pmid=21323563 |doi=10.1056/NEJMc1011678 |url=}}</ref><ref name="pmid22673885">{{cite journal |vauthors=Hoxha E, Kneißler U, Stege G, Zahner G, Thiele I, Panzer U, Harendza S, Helmchen UM, Stahl RA |title=Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy |journal=Kidney Int. |volume=82 |issue=7 |pages=797–804 |date=October 2012 |pmid=22673885 |doi=10.1038/ki.2012.209 |url=}}</ref><ref name="pmid23223223">{{cite journal |vauthors=Svobodova B, Honsova E, Ronco P, Tesar V, Debiec H |title=Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy |journal=Nephrol. Dial. Transplant. |volume=28 |issue=7 |pages=1839–44 |date=July 2013 |pmid=23223223 |doi=10.1093/ndt/gfs439 |url=}}</ref>
*The membranous [[glomerulonephritis]] is a result of multiple changes, which are:<ref name="pmid16159900">{{cite journal |vauthors=Cybulsky AV, Quigg RJ, Salant DJ |title=Experimental membranous nephropathy redux |journal=Am. J. Physiol. Renal Physiol. |volume=289 |issue=4 |pages=F660–71 |date=October 2005 |pmid=16159900 |pmc=1325222 |doi=10.1152/ajprenal.00437.2004 |url=}}</ref><ref name="pmid15800119">{{cite journal |vauthors=Nangaku M, Shankland SJ, Couser WG |title=Cellular response to injury in membranous nephropathy |journal=J. Am. Soc. Nephrol. |volume=16 |issue=5 |pages=1195–204 |date=May 2005 |pmid=15800119 |doi=10.1681/ASN.2004121098 |url=}}</ref><ref name="pmid15800113">{{cite journal |vauthors=Cunningham PN, Quigg RJ |title=Contrasting roles of complement activation and its regulation in membranous nephropathy |journal=J. Am. Soc. Nephrol. |volume=16 |issue=5 |pages=1214–22 |date=May 2005 |pmid=15800113 |doi=10.1681/ASN.2005010096 |url=}}</ref><ref name="pmid23364522">{{cite journal |vauthors=Kanigicherla D, Gummadova J, McKenzie EA, Roberts SA, Harris S, Nikam M, Poulton K, McWilliam L, Short CD, Venning M, Brenchley PE |title=Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy |journal=Kidney Int. |volume=83 |issue=5 |pages=940–8 |date=May 2013 |pmid=23364522 |doi=10.1038/ki.2012.486 |url=}}</ref><ref name="pmid21323563">{{cite journal |vauthors=Debiec H, Ronco P |title=PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy |journal=N. Engl. J. Med. |volume=364 |issue=7 |pages=689–90 |date=February 2011 |pmid=21323563 |doi=10.1056/NEJMc1011678 |url=}}</ref><ref name="pmid22673885">{{cite journal |vauthors=Hoxha E, Kneißler U, Stege G, Zahner G, Thiele I, Panzer U, Harendza S, Helmchen UM, Stahl RA |title=Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy |journal=Kidney Int. |volume=82 |issue=7 |pages=797–804 |date=October 2012 |pmid=22673885 |doi=10.1038/ki.2012.209 |url=}}</ref><ref name="pmid23223223">{{cite journal |vauthors=Svobodova B, Honsova E, Ronco P, Tesar V, Debiec H |title=Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy |journal=Nephrol. Dial. Transplant. |volume=28 |issue=7 |pages=1839–44 |date=July 2013 |pmid=23223223 |doi=10.1093/ndt/gfs439 |url=}}</ref>
* 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]]
** Membranous glomerulonephritis is caused by immune complex formation in the glomerulus.
* 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 cells|mesangial]] and [[Epithelial cell|epithelial]] cells, damaging the capillary walls and causing them to become "leaky".  
** The immune complexes are formed by binding of antibodies to antigens in the [[glomerular basement membrane]].
** The antigens damage the basement membrane and activates the immune response.
** The immune complex serves as an activator that triggers a response from the complement system.  
'''Phospholipase A2 receptor'''
'''Phospholipase A2 receptor'''
* The [[M-type]] PLA2R is the major antigen in human idiopathic MN. It is expressed in [[glomerular podocytes]].
* The [[M-type]] PLA2R is the major antigen in human idiopathic membranous glomerulonephritis. It is expressed in [[glomerular podocytes|glomerular podocytes.]]T
* There was no colocalization of PLA2R in secondary MN biopsies.
* here was no colocalization of PLA2R in secondary [[membranous glomerulonephritis]] [[biopsies]]
* PLA2R antigen detected within immune deposits by immunofluorescence of the biopsy specimen.
* .PLA2R antigen detected within immune deposits by [[immunofluorescence]] of the [[biopsy]] specimen. Formation of the [[Immune complexes|immune complex]].
* Detection of the [[Immune complexes|immune complex]] specificity is 100 percent.
* Immune complex formation results in release of cytokines which release membrane attack complex C5-C9.
'''Thrombospondin type-1'''
* Release of C5-C9 lead to injury of podocyte which causes loss of glomerular permeablity.
* THSD7A has been found in patients with idiopathic MN who are negative for anti-PLA2R antibodies.  
* The damage to podocyte reults in proteinuria.
'''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.
{{Family tree/start}}
{{Family tree/start}}
{{Family tree | | | | A01 | | | | A02 | |A01=HLA susceptibility 1|A02=Environmental factors}}
{{Family tree | | | | A01 | | | | A02 | |A01=HLA susceptibility 1|A02=Environmental factors}}
{{Family tree | | | | |`|-|-|v|-|-|'| | | |}}
{{Family tree | | | | |`|-|-|v|-|-|'| | | |}}
{{Family tree | | | | | | |B01| | | | | |B01=Variant of PLA2R1 on podocyte surface}}
{{Family tree | | | | | | | B01 | | | | | |B01=Variant of PLA2R1 on podocyte surface}}
{{Family tree | | | | | | |!| | | | | |}}
{{Family tree | | | | | | | |!| | | | | |}}
{{Family tree | | | | | | |C01| | | | | |C01=Innate immunity activation and inflammation<br>dendritic cell sense epitope of PLA2R1<br>and present them for adaptive immunity}}
{{Family tree | | | | | | | C01 | | | | | |C01=Innate immunity activation and inflammation<br>dendritic cell sense epitope of PLA2R1<br>and present them for adaptive immunity}}
{{Family tree | | | | | | |!| | | | | |}}
{{Family tree | | | | | | | |!| | | | | |}}
{{Family tree | | | | | | |D01| | | | | |D01=Production of auto-immune antibody IgG4/IgG1 which attach them self to epitope on podocyte surface}}
{{Family tree | | | | | | | D01 | | | | | |D01=Production of auto-immune antibody IgG4/IgG1 which attach them self to epitope on podocyte surface}}
{{Family tree | | | | | | |!| | | | | |}}
{{Family tree | | | | | | | |!| | | | | |}}
{{Family tree | | | | | | |E01| | | | | |E01=In Situ formation and shedding of subepithelial immune complex}}
{{Family tree | | | | | | | E01 | | | | | |E01=In Situ formation and shedding of subepithelial immune complex}}
{{Family tree | | | | | | |!| | | | | |}}
{{Family tree | | | | | | | |!| | | | | |}}
{{Family tree | | | | | | |F01| | | | | |F01=Complement activation[[MANNAN PATHWAY]] and T cell activation}}
{{Family tree | | | | | | | J01 | | | | | |J01=Which lead to<br>cytokine release<br>oxygen derivative release<br>membrane attack complex C5-C9}}
{{Family tree | | | | | | |!| | | | | |}}
{{Family tree | | | | | | | |!| | | | | |}}
{{Family tree | | | | | | |J01| | | | | |J01=Which lead to<br>cytokine release<br>oxygen derivative release<br>membrane attack complex C5-C9}}
{{Family tree | | | | | | | H01 | | | | | |H01=Podocyte injury by apoptosis<br>altered lectin cytoskeleton<br>loss of silt pore integrity<br>loss of glomerular permeability <br>proteinuria}}
{{Family tree | | | | | | |!| | | | | |}}
{{Family tree | | | | | | |H01| | | | | |H01=Podocyte injury by apoptosis<br>altered lectin cytoskeleton<br>loss of silt pore integrity<br>loss of glomerular permeability <br>proteinuria}}
{{familytree/end}}
{{familytree/end}}


==Genetics==
==Genetics==
* Single-nucleotide polymorphisms (SNPs) at two loci that are highly associated with idiopathic MN.
* Single-nucleotide polymorphisms (SNPs) at two loci that are highly associated with idiopathic membranous glomerulonephritis.<ref name="pmid21323563">{{cite journal |vauthors=Debiec H, Ronco P |title=PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy |journal=N. Engl. J. Med. |volume=364 |issue=7 |pages=689–90 |date=February 2011 |pmid=21323563 |doi=10.1056/NEJMc1011678 |url=}}</ref><ref name="pmid22673885">{{cite journal |vauthors=Hoxha E, Kneißler U, Stege G, Zahner G, Thiele I, Panzer U, Harendza S, Helmchen UM, Stahl RA |title=Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy |journal=Kidney Int. |volume=82 |issue=7 |pages=797–804 |date=October 2012 |pmid=22673885 |doi=10.1038/ki.2012.209 |url=}}</ref>
* 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.  
* The two loci are within the genes for the [[PLA2R]] on [[chromosome]] 2q24.
* 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. The PLA2R has been identified as a major antigen in idiopathic MN.
* The human leukocyte antigen (HLA) complex class II alpha chain 1A [[(''HLA-DQA1'')]] on chromosome 6p21.  
* The [[PLA2R]] has been identified as a major [[antigen]] in idiopathic membranous glomerulonephritis.


==Associated Conditions==
==Associated Conditions==
Consitions associated with MN include:
Consitions associated with membranous glomerulonephritis include:<ref name="pmid10495797">{{cite journal |vauthors=Wasserstein AG |title=Membranous glomerulonephritis |journal=J. Am. Soc. Nephrol. |volume=8 |issue=4 |pages=664–74 |date=April 1997 |pmid=10495797 |doi= |url=}}</ref>
*[[Hepatitis B/History & Symptoms|Hepatitis B]]
*[[Hepatitis B/History & Symptoms|Hepatitis B]]
*[[Hepatitis C]]
*[[Hepatitis C]]
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*[[SLE|Systemic Lupus Erythematosis]]
*[[SLE|Systemic Lupus Erythematosis]]
*Malignancy
*Malignancy
**Lung
**[[Lung]]
**Breast  
**[[Breast]]
**Colon
**[[Colon]]
**Stomach
**[[Stomach]]
**Kidney
**[[Kidney]]
**Leukemia
**[[Leukemia]]
**Lymphomas (Hodgkin’s and non-Hodgkin’s)
**[[Lymphomas]] ([[Hodgkin]]’s and [[non-Hodgkin]]’s)


== Gross Pathology ==
== Gross Pathology ==
* There is no significant gross pathological changes.
* On gross pathology examination there is no characteristic findings present
 
==Microscopic Pathology==
==Microscopic Pathology==
Microscopic pathologic findings characteristic of MN include:
Microscopic pathologic findings characteristic of membranous glomerulonephritis include:<ref name="pmid16159900">{{cite journal |vauthors=Cybulsky AV, Quigg RJ, Salant DJ |title=Experimental membranous nephropathy redux |journal=Am. J. Physiol. Renal Physiol. |volume=289 |issue=4 |pages=F660–71 |date=October 2005 |pmid=16159900 |pmc=1325222 |doi=10.1152/ajprenal.00437.2004 |url=}}</ref><ref name="pmid15800119">{{cite journal |vauthors=Nangaku M, Shankland SJ, Couser WG |title=Cellular response to injury in membranous nephropathy |journal=J. Am. Soc. Nephrol. |volume=16 |issue=5 |pages=1195–204 |date=May 2005 |pmid=15800119 |doi=10.1681/ASN.2004121098 |url=}}</ref>
* Early biopsies may be normal
* Early biopsies may be normal.
* Later: uniform diffuse capillary wall thickening without hypercellularity, No mesangial sclerosis and inflammatory cells
* Later: uniform diffuse capillary wall thickening without hypercellularity, no [[mesangial]] [[sclerosis]] and [[inflammatory]] cells.
* Proximal convoluted tubules: hyaline droplets, reflecting protein reabsorption
* Proximal convoluted tubules: [[hyaline]] droplets, reflecting protein reabsorption.
* Membrane thickening and narrow capillary lumina.
* Membrane thickening and narrow capillary lumina.
* Mesangial sclerosis and glomerulosclerosis
* Mesangial [[sclerosis]] and [[glomerulosclerosis]].
'''Immunofluorescence'''
'''Immunofluorescence'''
* Granular diffuse peripheral deposits, usually IgG and C3, also C5b-C9 and occasionally IgM or IgA
* Granular diffuse peripheral deposits, usually [[IgG]] and [[C3]], also [[C5b]]-[[C9]] and occasionally [[IgM]] or [[IgA]].
* C4d immunostaining may be diagnostic.
* [[C4d]] immunostaining may be diagnostic.
'''Stages'''
 
* Stage I: LM - normal for slightly thickened BM,
 
The microscopic,immunofluorscence and electron microscopic features are listed in the following table:<ref name="pmid16159900">{{cite journal |vauthors=Cybulsky AV, Quigg RJ, Salant DJ |title=Experimental membranous nephropathy redux |journal=Am. J. Physiol. Renal Physiol. |volume=289 |issue=4 |pages=F660–71 |date=October 2005 |pmid=16159900 |pmc=1325222 |doi=10.1152/ajprenal.00437.2004 |url=}}</ref><ref name="pmid15800119">{{cite journal |vauthors=Nangaku M, Shankland SJ, Couser WG |title=Cellular response to injury in membranous nephropathy |journal=J. Am. Soc. Nephrol. |volume=16 |issue=5 |pages=1195–204 |date=May 2005 |pmid=15800119 |doi=10.1681/ASN.2004121098 |url=}}</ref>
{| class="wikitable"
{| class="wikitable"
!stage
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Stage
!GBM
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Glomerular Basement Membrane
!IF
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Immunofluorescence
!EM
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Electron Microscopy
|-
|-
|stage 1
| style="background:#DCDCDC;" align="center" + |Stage 1
|normal or slightly thick BM
| style="background:#F5F5F5;" align="center" + |Normal or slightly thickned BM
|fine granular IgG, C3  
| style="background:#F5F5F5;" align="center" + |Fine granular IgG, C3
|subepithelial electron dense deposits, no foot effacement or spikes
| style="background:#F5F5F5;" align="center" + |Scattered small subepithelial electron dense deposits no foot effacement
|-
|-
|stage 2
| style="background:#DCDCDC;" align="center" + |Stage 2  
|moderately thick
| style="background:#F5F5F5;" align="center" + |Moderately thickened BM with spikes and vacuolization
|moderate sized, granular IgG, C3
| style="background:#F5F5F5;" align="center" + |Granular IgG, C3
|diffuse spikes, sub epithelial deposits, diffuse foot process effacement
| style="background:#F5F5F5;" align="center" + |Diffuse spikes due to subepithelial deposits, diffuse foot process effacement
|-
|-
|stage 3
| style="background:#DCDCDC;" align="center" + |Stage 3  
|markedly thick
| style="background:#F5F5F5;" align="center" + |Moderately thickened BM residual spikes and vacuoles
|chain like apperance
| style="background:#F5F5F5;" align="center" + |Chain like appearance IF, coarsely granular IgG, C3
|intamembranous deposits,m spikes, neomembrane formation, diffuse foot prosess effacement
| style="background:#F5F5F5;" align="center" + |Intramembraneous deposits, spikes, neomembrane formation and diffuse foot process effacement
|-
| style="background:#DCDCDC;" align="center" + |Stage 4
| style="background:#F5F5F5;" align="center" + |Markedly thick GBM, few spikes, vacoules and glomerulosclerosis
| style="background:#F5F5F5;" align="center" + |Focal IgG, C3
| style="background:#F5F5F5;" align="center" + |Sclerotic GBM, few deposits and lacunae
|}
|}
* 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. 
* Spikes are demonstrated as irregular projections of the GBM among the subepithelial deposits.
* The podocytes lose their foot processes.


==References==
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[[Category: (name of the system)]]
 
<div align="center">
<gallery heights="175" widths="125">
<gallery heights="175" widths="125">
image:Membranous GN.jpg|Membranous Glomerulonephritis: Electron micrography. An excellent example to show thickened basement membrane and immune complexes.
image:Membranous GN.jpg|Membranous Glomerulonephritis: Electron micrography. An excellent example to show thickened basement membrane and immune complexes.
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==References==
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==References==
==References==
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[[Category:Needs content]]
 
[[Category:Disease]]
[[Category:(name of the system)]]
[[Category:Kidney diseases]]
[[Category:NephrologY]]
[[Category:Nephrology]]
[[Category:Up-to-date]]
[[Category:Inflammations]]

Latest revision as of 09:39, 17 October 2020

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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] Pervaiz Laghari, MD[3]

Overview

Membranous glomerulonephritis 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 damage the basement membrane and activates the immune response. The immune complex serves as an activator that triggers a response from the complement system. .PLA2R antigen detected within immune deposits by immunofluorescence of the biopsy specimen. Formation of the immune complex. Immune complex formation results in release of cytokines which release membrane attack complex C5-C9. Release of C5-C9 lead to injury of podocyte which causes loss of glomerular permeablity. The damage to podocyte reults in proteinuria.

Pathophysiology

  • The membranous glomerulonephritis is a result of multiple changes, which are:[1][2][3][4][5][6][7]
    • Membranous glomerulonephritis 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 damage the basement membrane and activates the immune response.
    • The immune complex serves as an activator that triggers a response from the complement system.

Phospholipase A2 receptor

  • The M-type PLA2R is the major antigen in human idiopathic membranous glomerulonephritis. It is expressed in glomerular podocytes.T
  • here was no colocalization of PLA2R in secondary membranous glomerulonephritis biopsies
  • .PLA2R antigen detected within immune deposits by immunofluorescence of the biopsy specimen. Formation of the immune complex.
  • Immune complex formation results in release of cytokines which release membrane attack complex C5-C9.
  • Release of C5-C9 lead to injury of podocyte which causes loss of glomerular permeablity.
  • The damage to podocyte reults in proteinuria.
 
 
 
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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 membranous glomerulonephritis.[5][6]
  • The two loci are within the genes for the PLA2R on chromosome 2q24.
  • The human leukocyte antigen (HLA) complex class II alpha chain 1A (''HLA-DQA1'') on chromosome 6p21.
  • The PLA2R has been identified as a major antigen in idiopathic membranous glomerulonephritis.

Associated Conditions

Consitions associated with membranous glomerulonephritis include:[8]

Gross Pathology

  • On gross pathology examination there is no characteristic findings present

Microscopic Pathology

Microscopic pathologic findings characteristic of membranous glomerulonephritis include:[1][2]

  • Early biopsies may be normal.
  • Later: uniform diffuse capillary wall thickening without hypercellularity, no mesangial sclerosis and inflammatory cells.
  • Proximal convoluted tubules: hyaline droplets, reflecting protein reabsorption.
  • Membrane thickening and 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.


The microscopic,immunofluorscence and electron microscopic features are listed in the following table:[1][2]

Stage Glomerular Basement Membrane Immunofluorescence Electron Microscopy
Stage 1 Normal or slightly thickned BM Fine granular IgG, C3 Scattered small subepithelial electron dense deposits no foot effacement
Stage 2 Moderately thickened BM with spikes and vacuolization Granular IgG, C3 Diffuse spikes due to subepithelial deposits, diffuse foot process effacement
Stage 3 Moderately thickened BM residual spikes and vacuoles Chain like appearance IF, coarsely granular IgG, C3 Intramembraneous deposits, spikes, neomembrane formation and diffuse foot process effacement
Stage 4 Markedly thick GBM, few spikes, vacoules and glomerulosclerosis Focal IgG, C3 Sclerotic GBM, few deposits and lacunae
  • Membranous Glomerulonephritis: Electron micrography. An excellent example to show thickened basement membrane and immune complexes.

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

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

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

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

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

  • Membranous Glomerulonephritis: Micro PAS med mag

    Membranous Glomerulonephritis: Micro PAS med mag

References

  1. ↑ 1.0 1.1 1.2 Cybulsky AV, Quigg RJ, Salant DJ (October 2005). "Experimental membranous nephropathy redux". Am. J. Physiol. Renal Physiol. 289 (4): F660–71. doi:10.1152/ajprenal.00437.2004. PMC 1325222. PMID 16159900.
  2. ↑ 2.0 2.1 2.2 Nangaku M, Shankland SJ, Couser WG (May 2005). "Cellular response to injury in membranous nephropathy". J. Am. Soc. Nephrol. 16 (5): 1195–204. doi:10.1681/ASN.2004121098. PMID 15800119.
  3. ↑ Cunningham PN, Quigg RJ (May 2005). "Contrasting roles of complement activation and its regulation in membranous nephropathy". J. Am. Soc. Nephrol. 16 (5): 1214–22. doi:10.1681/ASN.2005010096. PMID 15800113.
  4. ↑ Kanigicherla D, Gummadova J, McKenzie EA, Roberts SA, Harris S, Nikam M, Poulton K, McWilliam L, Short CD, Venning M, Brenchley PE (May 2013). "Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy". Kidney Int. 83 (5): 940–8. doi:10.1038/ki.2012.486. PMID 23364522.
  5. ↑ 5.0 5.1 Debiec H, Ronco P (February 2011). "PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy". N. Engl. J. Med. 364 (7): 689–90. doi:10.1056/NEJMc1011678. PMID 21323563.
  6. ↑ 6.0 6.1 Hoxha E, Kneißler U, Stege G, Zahner G, Thiele I, Panzer U, Harendza S, Helmchen UM, Stahl RA (October 2012). "Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy". Kidney Int. 82 (7): 797–804. doi:10.1038/ki.2012.209. PMID 22673885.
  7. ↑ Svobodova B, Honsova E, Ronco P, Tesar V, Debiec H (July 2013). "Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy". Nephrol. Dial. Transplant. 28 (7): 1839–44. doi:10.1093/ndt/gfs439. PMID 23223223.
  8. ↑ Wasserstein AG (April 1997). "Membranous glomerulonephritis". J. Am. Soc. Nephrol. 8 (4): 664–74. PMID 10495797.

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References

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