Membranoproliferative glomerulonephritis pathophysiology: Difference between revisions
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{{Membranoproliferative glomerulonephritis}} | {{Membranoproliferative glomerulonephritis}} | ||
{{CMG}}{{APM}} {{AE}} {{OO}} | {{CMG}}{{APM}} {{AE}} {{OO}},{{N.F}} | ||
==Overview:== | ==Overview:== | ||
MPGN membrano proliferative glomerulonephritis, also known as mesangiocapillary glomerulonephritis, | MPGN membrano proliferative glomerulonephritis, also known as mesangiocapillary glomerulonephritis, is a [[glomerular]] injury on light [[microscopy]] that is characterized by [[mesangial hypercellularity]], endocapillary [[proliferation]], and double-contour formation along the glomerular [[capillary]] walls. "MPGN" includes two characteristic histologic changes:Thickened [[glomerular basement membrane]] (GBM) due to deposition of [[immune complexes]] and/or complement factors, intrusion of the [[Mesangial cell|mesangial cells]] and other cellular elements between the [[glomerular basement membrane]] and the [[endothelial cells]], and new basement membrane formation. [[Mesangial cell|Mesangial]] and endocapillary cellularity is increased resulting in [[lobular]] appearance of the glomerular tuft. Proliferation of mesangial cells and circulating [[monocytes]] results in increased cellularity.Two mechanisms are involved in the pathogenesis of MPGN,Immune complex deposition leading to activation of [[Complement (biology)|complement]] (immune complex-mediated) and dysregulation and persistent activation of the [[alternative complement pathway]]. | ||
==Pathophysiology== | ==Pathophysiology== | ||
* '''Type I MPGN''':<ref name="pmid21839367">{{cite journal |vauthors=Sethi S, Fervenza FC |title=Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification |journal=Semin. Nephrol. |volume=31 |issue=4 |pages=341–8 |date=July 2011 |pmid=21839367 |doi=10.1016/j.semnephrol.2011.06.005 |url=}}</ref><ref name="Glassock2010">{{cite journal|last1=Glassock|first1=Richard J.|title=The Pathogenesis of Idiopathic Membranous Nephropathy: A 50-Year Odyssey|journal=American Journal of Kidney Diseases|volume=56|issue=1|year=2010|pages=157–167|issn=02726386|doi=10.1053/j.ajkd.2010.01.008}}</ref> | * '''Type I MPGN''':<ref name="pmid21839367">{{cite journal |vauthors=Sethi S, Fervenza FC |title=Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification |journal=Semin. Nephrol. |volume=31 |issue=4 |pages=341–8 |date=July 2011 |pmid=21839367 |doi=10.1016/j.semnephrol.2011.06.005 |url=}}</ref><ref name="Glassock2010">{{cite journal|last1=Glassock|first1=Richard J.|title=The Pathogenesis of Idiopathic Membranous Nephropathy: A 50-Year Odyssey|journal=American Journal of Kidney Diseases|volume=56|issue=1|year=2010|pages=157–167|issn=02726386|doi=10.1053/j.ajkd.2010.01.008}}</ref> | ||
* It results from presesnce of a persistent [[antigen]] in blood. | ** It results from presesnce of a persistent [[antigen]] in blood. | ||
* This leads to generation of nephritogenic [[immune complexes]] that localize to the subendothelial spaces. | ** This leads to generation of nephritogenic [[immune complexes]] that localize to the subendothelial spaces. | ||
* [[Innate immunity]] to both the generation of [[antibodies]] that are deposited as immune complexes and to the local [[inflammatory responses]] directed at the [[glomerular]] immune deposits plays a role. | ** [[Innate immunity]] to both the generation of [[antibodies]] that are deposited as immune complexes and to the local [[inflammatory responses]] directed at the [[glomerular]] immune deposits plays a role. | ||
* The [[Immune complex|immune complexes]] activate the [[complement system]] via the classical pathway. | ** The [[Immune complex|immune complexes]] activate the [[complement system]] via the classical pathway. | ||
* This results in the generation of [[chemotactic]] factors (C3a, C5a) that mediate the accumulation of [[platelets]] and [[leukocytes]]. | ** This results in the generation of [[chemotactic]] factors (C3a, C5a) that mediate the accumulation of [[platelets]] and [[leukocytes]]. | ||
* Activation of [[complements]] (C5b-9) directly induce cell injury. | ** Activation of [[complements]] (C5b-9) directly induce cell injury. | ||
* [[Leukocytes]] release oxidants and [[proteases]] that result in [[capillary]] wall damage and cause [[proteinuria]]. | ** [[Leukocytes]] release oxidants and [[proteases]] that result in [[capillary]] wall damage and cause [[proteinuria]]. | ||
* [[Cytokines]] and [[Growth factor|growth factors]] released by [[glomerular]] cells lead to [[Mesangial cell|mesangial]] [[proliferation]] and expansion. | ** [[Cytokines]] and [[Growth factor|growth factors]] released by [[glomerular]] cells lead to [[Mesangial cell|mesangial]] [[proliferation]] and expansion. | ||
* '''Type II MPGN''': | * '''Type II MPGN''': | ||
* It results from the uncontrolled systemic activation of the alternative pathway of the [[Complement cascade|complement cascade.]] | ** It results from the uncontrolled systemic activation of the alternative pathway of the [[Complement cascade|complement cascade.]] | ||
* In most patients, loss of [[complement]] regulation is caused by the C3 nephritic factor , an [[immunoglobulin]] (Ig)G [[autoantibody]] that binds and prevents the inactivation of [[C3 convertase|C3 convertase (C3bBb) of the alternative pathway.]] | ** In most patients, loss of [[complement]] regulation is caused by the C3 nephritic factor , an [[immunoglobulin]] (Ig)G [[autoantibody]] that binds and prevents the inactivation of [[C3 convertase|C3 convertase (C3bBb) of the alternative pathway.]] | ||
* This results in the breakdown of C3. | ** This results in the breakdown of C3. | ||
* Another cause of type II MPGN is due to [[Mutation|mutations]] in the [[Regulatory protein|complement regulatory protein]], factor H, or to [[autoantibodies]] that impede factor H function, highlighting the role of deregulated alternative complement pathway activity in type II MPGN. | ** Another cause of type II MPGN is due to [[Mutation|mutations]] in the [[Regulatory protein|complement regulatory protein]], factor H, or to [[autoantibodies]] that impede factor H function, highlighting the role of deregulated alternative complement pathway activity in type II MPGN. | ||
* '''Type III MPGN''': | * '''Type III MPGN''': | ||
* It is thought to be due to a slow-acting nephritic factor that stabilizes a [[properdin]] dependent [[C5-convertase]], (Cb3)2BbP. | ** It is thought to be due to a slow-acting nephritic factor that stabilizes a [[properdin]] dependent [[C5-convertase]], (Cb3)2BbP. | ||
* (Cb3)2BbP activates the terminal pathway of the [[complement system]]. | ** (Cb3)2BbP activates the terminal pathway of the [[complement system]]. | ||
* This nephritic factor has not been reported in healthy subjects.unnlike C3NeF. | ** This nephritic factor has not been reported in healthy subjects.unnlike C3NeF. | ||
* In addition, the deposits present in [[Biopsy|renal biopsies]] of patients with type III MPGN are closely associated with the circulating nephritic factor-stabilized convertase and with [[hypocomplementemia]] suggesting that NeFt is fundamental to the pathogenesis of type III MPGN. | ** In addition, the deposits present in [[Biopsy|renal biopsies]] of patients with type III MPGN are closely associated with the circulating nephritic factor-stabilized convertase and with [[hypocomplementemia]] suggesting that NeFt is fundamental to the pathogenesis of type III MPGN. | ||
* '''Cryoglobulinemic MPGN''' : | * '''Cryoglobulinemic MPGN''' : | ||
* A large percentage of patients with chronic HCV infection develop [[Cryoglobulins|type II cryoglobulins]]. | ** A large percentage of patients with chronic HCV infection develop [[Cryoglobulins|type II cryoglobulins]]. | ||
* However, only a minority of such patients with detectible [[cryoglobulinemia]] have clinical manifestations of cryoglobulinemic MPGN. | ** However, only a minority of such patients with detectible [[cryoglobulinemia]] have clinical manifestations of cryoglobulinemic MPGN. | ||
* It is unclear why some [[cryoglobulins]] are more pathogenic than others, or why [[cryoglobulins]] deposit in the kidneys. | ** It is unclear why some [[cryoglobulins]] are more pathogenic than others, or why [[cryoglobulins]] deposit in the kidneys. | ||
* Recognition of the components of cryoprecipitates, which contain HCV core protein, by circulating [[leukocytes]] and intrinsic glomerular cells leads to the production of [[inflammatory mediators]] that characterize the [[glomerular]] injury of [[Cryoglobulinemia|cryoglobulinemic]] MPGN. | ** Recognition of the components of cryoprecipitates, which contain HCV core protein, by circulating [[leukocytes]] and intrinsic glomerular cells leads to the production of [[inflammatory mediators]] that characterize the [[glomerular]] injury of [[Cryoglobulinemia|cryoglobulinemic]] MPGN. | ||
==Histologic Findings== | ==Histologic Findings== | ||
Latest revision as of 18:07, 29 July 2018
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2] Associate Editor(s)-in-Chief: Olufunmilola Olubukola M.D.[3],Nazia Fuad M.D.
Overview:
MPGN membrano proliferative glomerulonephritis, also known as mesangiocapillary glomerulonephritis, is a glomerular injury on light microscopy that is characterized by mesangial hypercellularity, endocapillary proliferation, and double-contour formation along the glomerular capillary walls. "MPGN" includes two characteristic histologic changes:Thickened glomerular basement membrane (GBM) due to deposition of immune complexes and/or complement factors, intrusion of the mesangial cells and other cellular elements between the glomerular basement membrane and the endothelial cells, and new basement membrane formation. Mesangial and endocapillary cellularity is increased resulting in lobular appearance of the glomerular tuft. Proliferation of mesangial cells and circulating monocytes results in increased cellularity.Two mechanisms are involved in the pathogenesis of MPGN,Immune complex deposition leading to activation of complement (immune complex-mediated) and dysregulation and persistent activation of the alternative complement pathway.
Pathophysiology
- Type I MPGN:[1][2]
- It results from presesnce of a persistent antigen in blood.
- This leads to generation of nephritogenic immune complexes that localize to the subendothelial spaces.
- Innate immunity to both the generation of antibodies that are deposited as immune complexes and to the local inflammatory responses directed at the glomerular immune deposits plays a role.
- The immune complexes activate the complement system via the classical pathway.
- This results in the generation of chemotactic factors (C3a, C5a) that mediate the accumulation of platelets and leukocytes.
- Activation of complements (C5b-9) directly induce cell injury.
- Leukocytes release oxidants and proteases that result in capillary wall damage and cause proteinuria.
- Cytokines and growth factors released by glomerular cells lead to mesangial proliferation and expansion.
- Type II MPGN:
- It results from the uncontrolled systemic activation of the alternative pathway of the complement cascade.
- In most patients, loss of complement regulation is caused by the C3 nephritic factor , an immunoglobulin (Ig)G autoantibody that binds and prevents the inactivation of C3 convertase (C3bBb) of the alternative pathway.
- This results in the breakdown of C3.
- Another cause of type II MPGN is due to mutations in the complement regulatory protein, factor H, or to autoantibodies that impede factor H function, highlighting the role of deregulated alternative complement pathway activity in type II MPGN.
- Type III MPGN:
- It is thought to be due to a slow-acting nephritic factor that stabilizes a properdin dependent C5-convertase, (Cb3)2BbP.
- (Cb3)2BbP activates the terminal pathway of the complement system.
- This nephritic factor has not been reported in healthy subjects.unnlike C3NeF.
- In addition, the deposits present in renal biopsies of patients with type III MPGN are closely associated with the circulating nephritic factor-stabilized convertase and with hypocomplementemia suggesting that NeFt is fundamental to the pathogenesis of type III MPGN.
- Cryoglobulinemic MPGN :
- A large percentage of patients with chronic HCV infection develop type II cryoglobulins.
- However, only a minority of such patients with detectible cryoglobulinemia have clinical manifestations of cryoglobulinemic MPGN.
- It is unclear why some cryoglobulins are more pathogenic than others, or why cryoglobulins deposit in the kidneys.
- Recognition of the components of cryoprecipitates, which contain HCV core protein, by circulating leukocytes and intrinsic glomerular cells leads to the production of inflammatory mediators that characterize the glomerular injury of cryoglobulinemic MPGN.
Histologic Findings
Light microscopy:
- Glomeruli generally are enlarged and hypercellular
- There is increase in mesangial cellularity and matrix.
- Mesangial increase, when generalized throughout the glomeruli, causes an exaggeration of their lobular form.
- This give rise to the alternative name of lobular nephritis.
- Infiltrating neutrophils and monocytes contribute to glomerular hypercellularity.
- The capillary basement membranes are thickened by interposition of mesangial cells and matrix into the capillary wall.
- This gives rise to the double-contoured appearance of the capillary wall, best appreciated with the methenamine silver stain or the periodic acid-Schiff reagent.
- Crescents may be visible in 10% of patient biopsy specimens.
- Interstitial changes, including inflammation, interstitial fibrosis, and tubular atrophy, are observed in patients with progressive decline in GFR.
References
- ↑ Sethi S, Fervenza FC (July 2011). "Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification". Semin. Nephrol. 31 (4): 341–8. doi:10.1016/j.semnephrol.2011.06.005. PMID 21839367.
- ↑ Glassock, Richard J. (2010). "The Pathogenesis of Idiopathic Membranous Nephropathy: A 50-Year Odyssey". American Journal of Kidney Diseases. 56 (1): 157–167. doi:10.1053/j.ajkd.2010.01.008. ISSN 0272-6386.