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__NOTOC__
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{{Membranous glomerulonephritis}}
{{Membranous glomerulonephritis}}
{{CMG}}; {{AE}}  
{{CMG}}; {{AE}} {{SAH}} {{Pervaiz Laghari}}
 
==Overview==
==Overview==
It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
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==
Phospholipase A2 receptor — The M-type PLA2R, a transmembrane receptor that is highly expressed in glomerular podocytes, has been identified as a major antigen in human idiopathic MN [22]. In this study, circulating autoantibodies to PLA2R were identified in 26 of 37 (70 percent) patients with idiopathic MN and could be associated with disease activity in patients for whom serial serum samples were available [22]. By contrast, there was no evidence of PLA2R antibodies in serum from eight patients with secondary MN due to lupus or hepatitis B; from 15 patients with proteinuric conditions other than MN (such as diabetic nephropathy or focal segmental glomerulosclerosis); or from 30 healthy control individuals. The circulating anti-PLA2R antibodies were predominantly IgG4, the IgG subclass that is most abundant in the glomerular immune deposits in idiopathic (but not secondary) MN. PLA2R colocalized with IgG4 in immune deposits of kidney tissue obtained by kidney biopsy from patients with MN, and anti-PLA2R antibodies could be eluted from this tissue. This was in contrast to the findings in secondary MN biopsies, in which there was no colocalization of IgG4 and PLA2R and from which no anti-PLA2R antibodies could be eluted.
*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>
** 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|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 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.
{{Family tree/start}}
{{Family tree | | | | A01 | | | | A02 | |A01=HLA susceptibility 1|A02=Environmental factors}}
{{Family tree | | | | |`|-|-|v|-|-|'| | | |}}
{{Family tree | | | | | | | B01 | | | | | |B01=Variant of PLA2R1 on podocyte surface}}
{{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 | | | | | | | |!| | | | | |}}
{{Family tree | | | | | | | D01 | | | | | |D01=Production of auto-immune antibody IgG4/IgG1 which attach them self to epitope on podocyte surface}}
{{Family tree | | | | | | | |!| | | | | |}}
{{Family tree | | | | | | | E01 | | | | | |E01=In Situ formation and shedding of subepithelial immune complex}}
{{Family tree | | | | | | | |!| | | | | |}}
{{Family tree | | | | | | | J01 | | | | | |J01=Which lead to<br>cytokine release<br>oxygen derivative release<br>membrane attack complex C5-C9}}
{{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}}


The majority of anti-PLA2R autoantibodies appear to target a specific region of the PLA2R protein [23-25]. Two independent studies identified three domains near the N-terminus of PLA2R as the dominant epitope for anti-PLA2R [23,24], and one study further identified a small, nine-amino acid sequence that could largely inhibit the antibody-antigen interaction [23].
==Genetics==
* 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.
* 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.


Anti-PLA2R antibodies have been identified in 57, 74, 75, 78, 80, and 82 percent of patients with primary MN in six additional cohorts from Europe and China [26-31]. In one study, anti-PLA2R strongly correlated with clinical status [28]; in another study, lower anti-PLA2R titers were associated with a higher rate of spontaneous remission [29], and, in two other studies, a decline in anti-PLA2R predicted the clinical response to immunosuppressive therapy [31,32]. A fifth study found that higher anti-PLA2R titers within two years of diagnosis predicted substantially greater progression of kidney function decline over the subsequent five years of follow-up [30]. However, this may have reflected increased disease activity at the time the serum was collected; lower titers may have identified individuals already undergoing immunological and clinical remission. (See "Treatment of idiopathic membranous nephropathy", section on 'Resistant disease'.)
==Associated Conditions==
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 C]]
*Congenital [[Syphilis]]
*[[SLE|Systemic Lupus Erythematosis]]
*Malignancy
**[[Lung]]
**[[Breast]]
**[[Colon]]
**[[Stomach]]
**[[Kidney]]
**[[Leukemia]]
**[[Lymphomas]] ([[Hodgkin]]’s and [[non-Hodgkin]]’s)


Staining the kidney biopsy specimen for PLA2R, either by immunofluorescence or immunohistochemistry, provides another assay by which to identify PLA2R-associated primary MN [26,33,34]. As an example, in the study mentioned above that reported a relatively low sensitivity of circulating anti-PLA2R (57 percent), an additional 24 percent of patients who did not have circulating antibodies had the PLA2R antigen detected within immune deposits by immunofluorescence of the biopsy specimen [26]. This may occur as patients enter serological remission with still unresolved proteinuria and persistent immune deposits in glomeruli. Theoretically, it could also occur in the early stages of disease as anti-PLA2R antibodies are "soaked up" in the immune deposits and have not yet reached sufficiently high levels to be detected in the serum by existing immunoassays (figure 1) [35-37]. In general, tissue staining for PLA2R may be more sensitive (69 to 84 percent in various studies) than circulating anti-PLA2R in patients with primary MN [26,33,34,38,39]. Specificity is close to 100 percent; however, PLA2R has been detected in the immune deposits of some patients with secondary MN associated with hepatitis B virus infection, neoplasms, nonsteroidal antiinflammatory drug (NSAID) use, or sarcoidosis, but not systemic lupus nephritis [33,34,38,39]. It is possible that this represents a coincidental association, and we regard such cases as having PLA2R-associated MN.
== Gross Pathology ==
* On gross pathology examination there is no characteristic findings present


The detection of circulating anti-PLA2R and/or PLA2R kidney immune deposits in the majority of adult patients with idiopathic MN represents a large step forward in our understanding of the disease as investigators will now be able to test whether the pathogenetic mechanisms learned from experimental models are also involved in human disease. The sensitivity and specificity of anti-PLA2R autoantibodies in individuals with immunologically active idiopathic MN have also enabled the development of a serologic immunoassay for the noninvasive diagnosis of primary MN and monitoring of disease activity. It should be noted that, while the association of these anti-PLA2R autoantibodies with disease suggests a causal role, this has not yet been confirmed experimentally.
==Microscopic Pathology==
 
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>
Thrombospondin type-1 domain-containing 7A — THSD7A is, like PLA2R, a transmembrane protein expressed on podocytes [40,41]. THSD7A may be the responsible antigen in approximately 10 percent of patients with idiopathic MN who are negative for anti-PLA2R antibodies. The association of THSD7A with MN was examined in a study of 154 patients with anti-PLA2R-negative idiopathic MN, 74 patients with anti-PLA2R-positive idiopathic MN, 76 patients with other glomerular disease, and 44 healthy controls [40]. Autoantibodies specific for THSD7A were identified in sera from 15 of 154 patients with anti-PLA2R-negative idiopathic MN but not in the sera from other individuals. In addition, the IgG that was eluted from the kidney biopsies of 1 of these 15 patients was specific for THSD7A, providing further support that THSD7A was the target antigen in these patients. THSD7A-associated MN has been found at a low frequency in North American and European cohorts, but it may be more prevalent in Japanese patients with primary MN [42].
* Early biopsies may be normal.
 
* Later: uniform diffuse capillary wall thickening without hypercellularity, no [[mesangial]] [[sclerosis]] and [[inflammatory]] cells.
THSD7A may also be involved in the pathogenesis of some cases of malignancy-associated MN [43]. (See 'Malignancy' below.)
* Proximal convoluted tubules: [[hyaline]] droplets, reflecting protein reabsorption.
 
* Membrane thickening and narrow capillary lumina.
Neutral endopeptidase — Neutral endopeptidase (NEP), which is expressed on podocytes, is the probable target in a rare antenatal form of MN [44,45]. The transplacental passage of anti-NEP antibodies (from mothers genetically deficient in NEP who were alloimmunized during a prior pregnancy) caused MN with subepithelial immune deposits (anti-NEP and NEP) in the fetus/neonate. Nephrotic syndrome resolved several months after birth, with disappearance of the deposits, upon clearance of the maternal antibodies. Although noncomplement-fixing IgG4 was the predominant IgG subclass of anti-NEP in alloimmunized NEP-deficient mothers, the development of proteinuria in their babies correlated with the additional presence of complement-fixing IgG1 anti-NEP [45]. This finding, together with reports showing that C5b-9 is shed into the urine of patients with recent-onset MN [46,47], provides additional evidence that the observations in Heymann nephritis are relevant to the human disease. It has yet to be determined, however, whether the IgG4 anti-PLA2R antibodies that predominate in idiopathic MN or accompanying IgG1 antibodies are responsible for complement activation.
* Mesangial [[sclerosis]] and [[glomerulosclerosis]].
 
'''Immunofluorescence'''
Intracellular antigens — In addition to the PLA2R, THSD7A, and NEP, antibodies directed against other antigens expressed by podocytes may contribute to the pathogenesis of MN [48-50]. In one study, for example, serum IgG4 reactivity against aldose reductase, superoxide dismutase 2, and alpha-enolase, as well as the PLA2R and neutral endopeptidase, was measured in 186 patients with MN, 36 patients with focal glomerulosclerosis, and 60 patients with immunoglobulin A (IgA) nephropathy [48]. Elevated titers of IgG4 against the PLA2R, alpha-enolase, aldose reductase, and superoxide dismutase 2 were found in 60, 43, 34, and 28 percent of patients with MN, respectively, but not in patients with other glomerular diseases. Approximately one-half of the patients who were negative for antibodies against the PLA2R had an elevated titer for one of the other three antibodies. Although these antigens are predominantly intracellular, it has been proposed that podocyte injury causes the intracellular enzymes to translocate to the cell surface where they are accessible to the circulating antibodies, causing amplification of the immune injury and possibly aggravating the course of the disease.
* Granular diffuse peripheral deposits, usually [[IgG]] and [[C3]], also [[C5b]]-[[C9]] and occasionally [[IgM]] or [[IgA]].
 
* [[C4d]] immunostaining may be diagnostic.
Cationic bovine serum albumin — Antibodies to a cationic form of bovine serum albumin (BSA) are present in a small number of children with MN [51]. The BSA antigen, which was found within the immune deposits of biopsy specimens from these patients, is thought to be absorbed from the relatively underdeveloped pediatric intestinal tract in a partially digested or undigested form and then serve as a planted antigen within the glomerular capillary wall. Antibodies reactive with bovine, but not human, serum albumin were eluted from the kidney biopsy specimen in one case.


Other antigens — Other antigens have been identified within the glomerular immune deposits in patients with secondary MN [52]. These antigens include double-stranded DNA in systemic lupus erythematosus (SLE), thyroglobulin in thyroiditis, hepatitis B antigen, treponemal antigen and Helicobacter pylori in the relevant infections, and carcinoembryonic antigen and prostate specific antigen in malignancy. The pathogenicity of these antigens is unproven.


Role of T cells — T helper cells activate different immune effector mechanisms and appear to play a role in the pathogenesis of glomerulonephritis and may also participate in the genesis of proteinuria in MN. The T helper subset Th1 tends to predominate in proliferative and crescentic forms of glomerulonephritis, whereas Th2 predominates in MN and minimal change disease [53,54]. (See "The adaptive cellular immune response", section on 'Cytokine secretion profiles of activated T cells' and "Mechanisms of immune injury of the glomerulus", section on 'T cells'.)
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"
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Stage
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Glomerular Basement Membrane
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Immunofluorescence
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Electron Microscopy
|-
| style="background:#DCDCDC;" align="center" + |Stage 1
| style="background:#F5F5F5;" align="center" + |Normal or slightly thickned BM
| style="background:#F5F5F5;" align="center" + |Fine granular IgG, C3
| style="background:#F5F5F5;" align="center" + |Scattered small subepithelial electron dense deposits no foot effacement
|-
| style="background:#DCDCDC;" align="center" + |Stage 2
| style="background:#F5F5F5;" align="center" + |Moderately thickened BM with spikes and vacuolization
| style="background:#F5F5F5;" align="center" + |Granular IgG, C3
| style="background:#F5F5F5;" align="center" + |Diffuse spikes due to subepithelial deposits, diffuse foot process effacement
|-
| style="background:#DCDCDC;" align="center" + |Stage 3
| style="background:#F5F5F5;" align="center" + |Moderately thickened BM residual spikes and vacuoles
| style="background:#F5F5F5;" align="center" + |Chain like appearance IF, coarsely granular IgG, C3
| 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
|}


In support of a pathogenetic role for Th2 in MN is the observation in a model of lupus nephritis that deletion of the ''WSX-1'' gene (encoding a cytokine receptor integral for mounting a Th1 response) causes a shift toward a Th2 response and converts the diffuse proliferative pattern that is typically seen to a membranous pattern [55]. The site of the target antigen and subepithelial location of the immune deposits also favor antibody- and complement-mediated injury to the podocyte, rather than a direct cellular inflammatory lesion (which is typically associated with subendothelial immune deposits and glomerular endothelial injury) [56,57].
<div align="center">
 
==Genetics==
==Associated Conditions==
 
==Gross Pathology==
==Microscopic Pathology==
==References==
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<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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[[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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