Membranous glomerulonephritis pathophysiology: Difference between revisions

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==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]].
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]]


==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<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>
* 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]]
* 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 cells|mesangial]] and [[Epithelial cell|epithelial]] cells, damaging the capillary walls and causing them to become "leaky".
* 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"  
'''Phospholipase A2 receptor'''
'''Phospholipase A2 receptor'''
* The [[M-type]] PLA2R is the major antigen in human idiopathic MN. It is expressed in [[glomerular podocytes]].<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 [[M-type]] PLA2R is the major antigen in human idiopathic MN. It is expressed in [[glomerular podocytes]]<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>
* There was no colocalization of PLA2R in secondary MN biopsies.
* There was no colocalization of PLA2R in secondary MN 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
* Detection of the [[Immune complexes|immune complex]] specificity is 100 percent.
* Detection of the [[Immune complexes|immune complex]] specificity is 100 percent


'''Neutral endopeptidase'''
'''Neutral endopeptidase'''
* [[Anti-neutral endopeptidase antibodies]] caused MN in the [[neonates]].  
* [[Anti-neutral endopeptidase antibodies]] caused membranous glomerulonephritis in the [[neonates]].  
* It resolves months after birth.
* It resolves months after birth


* The T helper-2 predominates in MN and minimal change disease.<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 T helper-2 predominates in MN and minimal change disease<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>
{{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}}
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==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
* The two loci are within the genes for the PLA2R on chromosome 2q24.
* 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 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 MN.<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 PLA2R has been identified as a major antigen in idiopathic membranous glomerulonephritis<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>


==Associated Conditions==
==Associated Conditions==
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== Gross Pathology ==
== Gross Pathology ==
* There is no significant gross pathological changes.
* There is no significant gross pathological changes
==Microscopic Pathology==
==Microscopic Pathology==
Microscopic pathologic findings characteristic of MN 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>
Microscopic pathologic findings characteristic of MN 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>
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* 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




Revision as of 17:33, 18 July 2018

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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 like PLA2R, enviromental factors, drug (captopril) side effects, infections like hepatitis B and hepatitis C

Pathophysiology

  • The membranous glomerulonephritis is a result of multiple changes[1][2][3][4][5][6][7][8]
  • 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[3][4][5][6][7][8]
  • There was no colocalization of PLA2R in secondary MN biopsies
  • PLA2R antigen detected within immune deposits by immunofluorescence of the biopsy specimen
  • Detection of the immune complex specificity is 100 percent

Neutral endopeptidase

 
 
 
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 activation MANNAN 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 membranous glomerulonephritis
  • 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[3][4][5][6][7][8]

Associated Conditions

Consitions associated with MN include:[9]

Gross Pathology

  • There is no significant gross pathological changes

Microscopic Pathology

Microscopic pathologic findings characteristic of MN 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. ↑ 3.0 3.1 3.2 3.3 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. ↑ 4.0 4.1 4.2 4.3 Beck LH, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ (July 2009). "M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy". N. Engl. J. Med. 361 (1): 11–21. doi:10.1056/NEJMoa0810457. PMC 2762083. PMID 19571279.
  5. ↑ 5.0 5.1 5.2 5.3 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.
  6. ↑ 6.0 6.1 6.2 6.3 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.
  7. ↑ 7.0 7.1 7.2 7.3 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.
  8. ↑ 8.0 8.1 8.2 8.3 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.
  9. ↑ Wasserstein AG (April 1997). "Membranous glomerulonephritis". J. Am. Soc. Nephrol. 8 (4): 664–74. PMID 10495797.

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