C3 glomerulopathy: Difference between revisions

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__NOTOC__
__NOTOC__
{{SI}}                                                                 
{{SI}}                                                                 
{{CMG}}, {{APM}};{{AE}} {{Vbe}}, {{OO}}
{{CMG}};{{AE}} {{Vbe}} {{ADG}}


'''''For more information of Complement mediated glomerular disorders, [[Complement mediated glomerular disorders|Click here]]'''''
'''''For more information of Complement mediated glomerular disorders, [[Complement mediated glomerular disorders|Click here]]'''''
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*However in 2007, Servais A. et al described C3GN as an separate entity.
*However in 2007, Servais A. et al described C3GN as an separate entity.
*C3 Glomerulopathy may be classified into 2 main subtypes based on the appearance of complement deposition in the glomerular basement membrane on EM:
*C3 Glomerulopathy may be classified into 2 main subtypes based on the appearance of complement deposition in the glomerular basement membrane on EM:
**Dense deposit disease (DDD)
**'''Dense deposit disease (DDD)'''
***Dense deposition of compliment in linear pattern  
***Dense deposition of compliment in linear pattern.
**[[C3 (complement)|C3]] [[Glomerulonephritis]] (C3GN)
**'''[[C3 (complement)|C3]] [[Glomerulonephritis]] (C3GN)'''
***Isolated deposition of C3
***Isolated deposition of C3.
==Pathophysiology==
==Pathophysiology==
*[[C3 glomerulopathy MRI|C3 glomerulopathy]] results from the appropriate or inappropriate [[Activation-Induced (Cytidine) Deaminase|activation]] of the [[Alternative Livelihood|alternative]] [[Pathways Health and Research Centre|pathway]] of the [[complement]] system.
*Excessive activation of the [[Alternative Livelihood|alternative]] complement [[Pathways Health and Research Centre|pathway]] is the inciting event in the pathogenesis of C3 glomerulopathy.<ref name="pmid8695987">{{cite journal |vauthors=Schwertz R, de Jong R, Gretz N, Kirschfink M, Anders D, Schärer K |title=Outcome of idiopathic membranoproliferative glomerulonephritis in children. Arbeitsgemeinschaft Pädiatrische Nephrologie |journal=Acta Paediatr. |volume=85 |issue=3 |pages=308–12 |date=March 1996 |pmid=8695987 |doi= |url=}}</ref>
*Activation of alternative pathway results in  excessive deposition of complement along the glomerular basement membrane.
*Pattern of  compliment deposition is regulated by:<ref name="pmid254845263">{{cite journal |vauthors=Thomas S, Ranganathan D, Francis L, Madhan K, John GT |title=Current concepts in C3 glomerulopathy |journal=Indian J Nephrol |volume=24 |issue=6 |pages=339–48 |date=November 2014 |pmid=25484526 |pmc=4244712 |doi=10.4103/0971-4065.134089 |url=}}</ref>
**Leukocytic chemotaxis
**Cytolytic effects of C5b-9


*The appropriate [[Activation-Induced (Cytidine) Deaminase|activation]] of [[complement system]] is under general circumstances triggered by [[infection]]. The inappropriate [[Activation-Induced (Cytidine) Deaminase|activation]] can be due to [[inherited]] or acquired [[disorders]] of [[complement]] pathway. Either a gain of function of complement “activators”, or a loss of function of [[complement]] “inhibitors” can lead to an activation of complement alternative pathway.
==== Physiology ====
* Spontaneous cleavage of [[C3 (complement)|C3]] to C3b results in activation of [[C3 convertase|C3 convertase.]]<ref name="pmid24161035">{{cite journal |vauthors=Noris M, Remuzzi G |title=Overview of complement activation and regulation |journal=Semin. Nephrol. |volume=33 |issue=6 |pages=479–92 |date=November 2013 |pmid=24161035 |pmc=3820029 |doi=10.1016/j.semnephrol.2013.08.001 |url=}}</ref>
* [[C3 convertase]] along with factor B and [[properdin]] catalyses the cascade of producing [[C5-convertase|C5 convertase]].
* [[C5]] convertse cleaves 5 to C5a initiating C5b-9 ( MAC complex)
* Physiologically activation of [[C5-convertase|C5 convertase]] is directly related to [[C3 convertase]].
* Factors that can influence and control [[C3 convertase]] activity include
** Serum protein
** Factor H (inhibits the [[C3 convertase]])


*Possible [[physiological]] and [[pathological]] [[Activation-Induced (Cytidine) Deaminase|activation]] mechanisms of the [[complement]] pathways which can contribute or lead to [[complement]] mediated [[glomerulopathy]]:
==== Pathogenesis ====
 
* Any mechanism by which C3 activity is increased leads to activation of alternate pathway activation resulting in complement deposition.<ref name="pmid254845262">{{cite journal |vauthors=Thomas S, Ranganathan D, Francis L, Madhan K, John GT |title=Current concepts in C3 glomerulopathy |journal=Indian J Nephrol |volume=24 |issue=6 |pages=339–48 |date=November 2014 |pmid=25484526 |pmc=4244712 |doi=10.4103/0971-4065.134089 |url=}}</ref><ref name="pmid23026947">{{cite journal |vauthors=Bomback AS, Appel GB |title=Pathogenesis of the C3 glomerulopathies and reclassification of MPGN |journal=Nat Rev Nephrol |volume=8 |issue=11 |pages=634–42 |date=November 2012 |pmid=23026947 |doi=10.1038/nrneph.2012.213 |url=}}</ref>
{| class="wikitable"
** C3 convertase autoantibody C3 nephritic factor
! colspan="2" |Activation of Classic Complement Pathway
** Loss of factor H
!Activation of the Mannose-Binding-Lectin Pathway
! colspan="4" |Activation of Alternative Complement Pathway
|-
| colspan="2" |Acquired
|Acquired
| colspan="3" |Acquired
|Inherited
|-
|Infection
|[[Apoptosis]] and [[necrosis]]
|Infection
|Infection
|[[Autoimmune]] disorder
|[[Paraneoplastic]]
|Genetic mutations
|}


==Causes==
==Causes==
* Several [[genetic]] or acquired [[causes]] have been described to date:
Common causes of C3 glomerulopathy include:<ref name="pmid23728171">{{cite journal |vauthors=Holers VM |title=Human C3 glomerulopathy provides unique insights into complement factor H-related protein function |journal=J. Clin. Invest. |volume=123 |issue=6 |pages=2357–60 |date=June 2013 |pmid=23728171 |pmc=3668810 |doi=10.1172/JCI69684 |url=}}</ref>
** C3 [[mutations]]
* C3 [[mutations]]
** [[Complement]] Factor H (CFH):
* [[Mutation]] of Factor H (CHF)<ref name="pmid15163532">{{cite journal |vauthors=Rodríguez de Córdoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sánchez-Corral P |title=The human complement factor H: functional roles, genetic variations and disease associations |journal=Mol. Immunol. |volume=41 |issue=4 |pages=355–67 |date=June 2004 |pmid=15163532 |doi=10.1016/j.molimm.2004.02.005 |url=}}</ref>
 
** CFH is a small glycoprotein which is produced in the [[liver]], and circulates freely in the [[blood plasma]] .  
* Like the majority of [[complement]] factors, CFH is a small glycoprotein which is produced in the [[liver]], and circulates freely in the [[blood plasma]] .  
** Primary role of factor H is to inhibit C3 convertase and thus not activating alternative complement pathway.
* Several [[mutations]] in the CFH gene have been identified. While in type 1 [[mutations]] in this [[gene]] lead to a decrease in the level of functional CFH, the majority of mutations (type 2) do not affect the level of CFH, but rather decrease or diminish the function activity of this [[glycoprotein]].
** Two types of mutations are of important significance
* [[Autoantibodies]] against CFH have been identified . <ref name="pmid29948306">{{cite journal |vauthors=Noris M, Donadelli R, Remuzzi G |title=Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy |journal=Pediatr. Nephrol. |volume= |issue= |pages= |date=June 2018 |pmid=29948306 |doi=10.1007/s00467-018-3989-0 |url=}}</ref>
*** Type 1 [[mutations]] are associated with decreased levels of CFH.
** [[Complement]] Factor I (CFI):
*** Type 2 mutations decrease or diminish the functional activity of CHF.
** Membrane Cofactor [[Protein]] (MCP):
** [[Autoantibodies]] against CFH. <ref name="pmid29948306">{{cite journal |vauthors=Noris M, Donadelli R, Remuzzi G |title=Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy |journal=Pediatr. Nephrol. |volume= |issue= |pages= |date=June 2018 |pmid=29948306 |doi=10.1007/s00467-018-3989-0 |url=}}</ref>


* MCP is a [[transmembrane protein]], expressed by all [[Nucleated|nucleate]]<nowiki/>d [[cells]] and located at the [[cell]] surfaces.  
* Mutation of membrane cofactor protein ( MCP)
* Together with [[Complement]] Factor I (CFI), MCP is required for the inactivation of C3b, which otherwise may initiate the formation of [[membrane attack complex]].
** MCP is a<nowiki/> [[transmembrane protein]], expressed by all [[Nucleated|nucleate]]<nowiki/>d [[cells]] and located at the [[cell]] surfaces.  
* [[Mutations]] in the MCP gene can, similar to [[mutations]] in CFH lead to both, either a decrease in synthesis and expression of this [[protein]], or a decreased activity.
** Together with [[Complement]] Factor I (CFI), MCP is required <nowiki/>for the inactivation of C3b,  


* C3 [[Nephritic syndrome|nephritic]] factor (C3bBb antibody)
* Auto antibody against C3 called as [[Nephritic syndrome|nephritic]] factor (C3bBb antibody).<ref name="pmid28729035">{{cite journal |vauthors=Togarsimalemath SK, Sethi SK, Duggal R, Le Quintrec M, Jha P, Daniel R, Gonnet F, Bansal S, Roumenina LT, Fremeaux-Bacchi V, Kher V, Dragon-Durey MA |title=A novel CFHR1-CFHR5 hybrid leads to a familial dominant C3 glomerulopathy |journal=Kidney Int. |volume=92 |issue=4 |pages=876–887 |date=October 2017 |pmid=28729035 |doi=10.1016/j.kint.2017.04.025 |url=}}</ref>
** Factor H [[antibody]]
** Factor I [[antibody]]
** Factor H [[mutations]]
** Factor I [[mutations]]
** Factor B [[mutations]]
** CR1 mutations
** CFHRs [[mutations]]<ref name="pmid28729035">{{cite journal |vauthors=Togarsimalemath SK, Sethi SK, Duggal R, Le Quintrec M, Jha P, Daniel R, Gonnet F, Bansal S, Roumenina LT, Fremeaux-Bacchi V, Kher V, Dragon-Durey MA |title=A novel CFHR1-CFHR5 hybrid leads to a familial dominant C3 glomerulopathy |journal=Kidney Int. |volume=92 |issue=4 |pages=876–887 |date=October 2017 |pmid=28729035 |doi=10.1016/j.kint.2017.04.025 |url=}}</ref>
** Dense Deposit [[Disease]]


==Differentiating C3 Glomerulopathy from other Diseases==
==Differentiating C3 Glomerulopathy from other Diseases==
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* The [[prevalence]] of [[C3 glomerulopathy MRI|C3 glomerulopathy]] is approximately 3 per 100,000 individuals worldwide.<ref name="pmid17675665">{{cite journal| author=Smith RJ, Alexander J, Barlow PN, Botto M, Cassavant TL, Cook HT et al.| title=New approaches to the treatment of dense deposit disease. | journal=J Am Soc Nephrol | year= 2007 | volume= 18 | issue= 9 | pages= 2447-56 | pmid=17675665 | doi=10.1681/ASN.2007030356 | pmc=4853920 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17675665  }} </ref>
* The [[prevalence]] of [[C3 glomerulopathy MRI|C3 glomerulopathy]] is approximately 3 per 100,000 individuals worldwide.<ref name="pmid17675665">{{cite journal| author=Smith RJ, Alexander J, Barlow PN, Botto M, Cassavant TL, Cook HT et al.| title=New approaches to the treatment of dense deposit disease. | journal=J Am Soc Nephrol | year= 2007 | volume= 18 | issue= 9 | pages= 2447-56 | pmid=17675665 | doi=10.1681/ASN.2007030356 | pmc=4853920 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17675665  }} </ref>


===Age===
*[[Patients]] of all [[age]] groups may develop [[C3 glomerulopathy MRI|C3 glomerulopathy]] but it commonly affects young adults and children (Dense deposit disease)
*[[Patients]] of all [[age]] groups may develop [[C3 glomerulopathy MRI|C3 glomerulopathy]] but it commonly affects young adults and children (Dense deposit disease)


===Gender===
* C3 [[glomerulopathy]] affects [[men]] and [[Women's College Hospital|women]] equally.
* C3 [[glomerulopathy]] affects [[men]] and [[Women's College Hospital|women]] equally.


===Race===
*There is no racial predilection for [[C3 glomerulopathy MRI|C3 glomerulopathy]].
*There is no racial predilection for [[C3 glomerulopathy MRI|C3 glomerulopathy]].


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==Screening==
==Screening==
*There is no evidence for screening of C3 glomerulopathy.
*There is insufficient evidence to recommend routine screening for C3 glomerulopathy. However, screening is indicated for family members of affected individuals using genetic testing.


== Natural History, Complications and Prognosis==
== Natural History, Complications and Prognosis==
    
    
*Common [[Complications During and Following Cardiac Catheterization and Percutaneous Coronary Intervention|complications]] of C3 [[glomerulopathy]] include [[renal failure]], [[atherosclerosis]], and [[vision loss]]
*Common [[Complications During and Following Cardiac Catheterization and Percutaneous Coronary Intervention|complications]] of C3 [[glomerulopathy]] include [[renal failure]], [[atherosclerosis]], and [[vision loss]].<ref name="pmid22456601">{{cite journal |vauthors=Servais A, Noël LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grünfeld JP, Niaudet P, Lesavre P, Frémeaux-Bacchi V |title=Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies |journal=Kidney Int. |volume=82 |issue=4 |pages=454–64 |date=August 2012 |pmid=22456601 |doi=10.1038/ki.2012.63 |url=}}</ref>
*[[Prognosis]] of [[C3 glomerulopathy MRI|C3 glomerulopathy]] is generally poor, and 10 ­year [[mortality]] of [[patients]] is approximately 36%.
*[[Prognosis]] of [[C3 glomerulopathy MRI|C3 glomerulopathy]] is generally poor without proper treatment.
*10 ­year [[mortality]] of [[patients]] with C3 glomerulopathy is approximately 36%.


== Diagnosis ==
== Diagnosis ==
===Diagnostic test of choice===
====Diagnostic test of choice====
Gold standard [[test]] of choice for [[C3 glomerulopathy MRI|C3 glomerulopathy]]  is [[kidney]] [[biopsy]].
Kidney biopsy is the gold standard test for the diagnosis of [[C3 glomerulopathy MRI|C3 glomerulopathy]].


=== Symptoms ===
==== Symptoms ====
Common symptoms of [[C3 glomerulopathy MRI|C3 glomerulopathy]] may include:<ref name="pmid20301598">{{cite journal |vauthors=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, Martín B, Smith RJH |title= |journal= |volume= |issue= |pages= |date= |pmid=20301598 |doi= |url=}}</ref><ref name="pmid27878657">{{cite journal |vauthors=Ito N, Ohashi R, Nagata M |title=C3 glomerulopathy and current dilemmas |journal=Clin. Exp. Nephrol. |volume=21 |issue=4 |pages=541–551 |date=August 2017 |pmid=27878657 |pmc=5721121 |doi=10.1007/s10157-016-1358-5 |url=}}</ref>
*Foamy [[urine]] due [[proteinuria]]
*[[Hematuria]]
*Signs of [[renal]] [[Aortic insufficiency|insufficiency]] like general [[fatigue]] or [[malaise]]
*[[Hypertension]]
*Hypocomplementimia
*Acquired [[lipodystrophy]]
*[[Macular]] ([[Drusen]]) deposits in the [[retina]] of the [[eye]]


*[[Symptoms]] of [[C3 glomerulopathy MRI|C3 glomerulopathy]]  may include the following:
{| class="wikitable"
**Foamy [[urine]] due [[proteinuria]] ( excessive [[protein]] in [[urine]])or [[hematuria]] (blood in the urine)<ref name="pmid20301598">{{cite journal |vauthors=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, Martín B, Smith RJH |title= |journal= |volume= |issue= |pages= |date= |pmid=20301598 |doi= |url=}}</ref>
|+
**Signs of [[renal]] [[Aortic insufficiency|insufficiency]] like general [[fatigue]] or [[malaise]]
!Characterstics
**[[Hypertension]] (especially in children is a red flag )<ref name="pmid27878657">{{cite journal |vauthors=Ito N, Ohashi R, Nagata M |title=C3 glomerulopathy and current dilemmas |journal=Clin. Exp. Nephrol. |volume=21 |issue=4 |pages=541–551 |date=August 2017 |pmid=27878657 |pmc=5721121 |doi=10.1007/s10157-016-1358-5 |url=}}</ref>
!DDD
**Low [[serum]] [[C3 convertase|C3]] level
!C3GN
**Acquired [[lipodystrophy]] (loss of subcutaneous [[fat]] in the upper half of the body) in DDD
|-
**[[Macular]] ([[Drusen]]) deposits in the [[retina]] of the [[eye]] (also seen in DDD)
|Mean age
=== Laboratory Findings ===
|14
*The following [[blood]] [[tests]] need to be done in the evaluation of [[C3 glomerulopathy MRI|C3 glomerulopathy]] .
|24
 
|-
*[[CBC]]
|ESRD
*[[Blood glucose]] levels and [[Hemoglobin]] A1C
|50% in 10 years
* [[BUN]] and [[Creatinine]] levels
|10% in 2.5 years
* [[Blood]] levels of [[Complement]] C3, [[C3 Nef]], Serum factor H, CFHR ( Complement factor H-related protein)
|-
* 24-hr [[urine]] [[protein]] analysis
|Associated conditions
=== Physical Examination ===
|
 
* Acquired [[lipodystrophy]]
====Appearance of the Patient====
* Type 1 DM
*[[Patients]] with [[C3 (complement)|C3]] [[glomerulopathy]] usually appear cachectic.
* Macular degeneration
 
| -
====Vital Signs====
|-
* New onset [[hypertension]]
|C3 convertase dysregulation
|↑↑
|↑
|-
|C5 convertase dysregulation
|↑
|↑↑
|-
|C3NF
| +++
| +
|-
|MAC
|↑
|↑↑↑
|}


====Skin====
==== Laboratory Findings ====
* [[Pallor]]
*C3 [[glomerulopathy]] is diagnosed using [[immunofluorescence]] [[microscopy]] and electron [[microscopy]].
*There are no specific findings for C3 glomerulopathy on light microscopic.
*Findings on electron [[microscopy]] include<ref name="pmid25484526">{{cite journal |vauthors=Thomas S, Ranganathan D, Francis L, Madhan K, John GT |title=Current concepts in C3 glomerulopathy |journal=Indian J Nephrol |volume=24 |issue=6 |pages=339–48 |date=November 2014 |pmid=25484526 |pmc=4244712 |doi=10.4103/0971-4065.134089 |url=}}</ref><ref name="pmid1095806">{{cite journal |vauthors=Habib R, Gubler MC, Loirat C, Mäiz HB, Levy M |title=Dense deposit disease: a variant of membranoproliferative glomerulonephritis |journal=Kidney Int. |volume=7 |issue=4 |pages=204–15 |date=April 1975 |pmid=1095806 |doi= |url=}}</ref>
**Sub-epithelial lumps
**Abnormal electron-dense material within the GBM
***Dense and linear in DDD
***Isolated in C3GN
* Findings on immunofluorescence [[microscopy]] include:
** C3 deposits along the [[Bowman's]] capsule of glomerular and tubular basement membranes.


====HEENT====
==== Other Diagnostic tests ====
* HEENT [[examination]] of [[patients]] with [[C3 glomerulopathy MRI|C3 glomerulopathy]] is usually normal.
Other diagnostic tests that can help in diagnosing C3 glomerulopathy include:
*Measurement of complement C3, [[C3 Nef]], serum factor H, CFHR ( Complement factor H-related protein)
*Serum protein electrophoresis, immunofixation and serum free light chains
*sMAC level activity
==== Physical Examination ====
Common physical examination findings of patients with C3 glomerulopathy include:


====Neck====
*High [[blood pressure]]
* Neck [[examination]] of [[patients]] with [[C3 glomerulopathy MRI|C3 glomerulopathy]] is usually normal.
*[[Pallor]] skin
*[[Edema]] of extremities
*Periorbital [[Edema]]
*[[Lipodystrophy]]


====Lungs====
====Imaging Findings====
* Rales may be heard


====Heart====
* There are no specific [[imaging]] findings associated with [[C3 glomerulopathy MRI|C3 glomerulopathy]].
* [[Cardiovascular]] [[examination]] of [[patients]] with [[C3 glomerulopathy MRI|C3 glomerulopathy]] is usually normal.


====Abdomen====
*  
* [[Edema]]


===Imaging Findings===
== Treatment ==


* There are no  [[imaging]] findings specific to [[C3 glomerulopathy MRI|C3 glomerulopathy]].
===Medical Therapy===
* The mainstay of treatment for C3 glomerulopathy is pharmacotherapy.<ref name="pmid22673887">{{cite journal |vauthors=Sethi S, Fervenza FC, Zhang Y, Zand L, Vrana JA, Nasr SH, Theis JD, Dogan A, Smith RJ |title=C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up |journal=Kidney Int. |volume=82 |issue=4 |pages=465–73 |date=August 2012 |pmid=22673887 |pmc=4438675 |doi=10.1038/ki.2012.212 |url=}}</ref><ref name="pmid170185612">{{cite journal |vauthors=Servais A, Frémeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B, Grünfeld JP, Lesavre P, Noël LH, Fakhouri F |title=Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome |journal=J. Med. Genet. |volume=44 |issue=3 |pages=193–9 |date=March 2007 |pmid=17018561 |pmc=2598029 |doi=10.1136/jmg.2006.045328 |url=}}</ref>
* Pharmacotherpay can be catagorized into:
** Supportive therapy
** Specific therapy based on disease severity 


=== Other Diagnostic Studies ===
==== Supportive Therapy ====
*C3 [[glomerulopathy]] may also be diagnosed using light [[microscopy]], [[immunofluorescence]] [[microscopy]] and electron [[microscopy]].
Supportive therapy include antihypertensive medications and lipid lowering
*Findings on electron [[microscopy]] include mesangial proliferative glomerulonephritis, membranoproliferative [[glomerulonephritis]] and crescentic [[glomerulonephritis]].<ref name="pmid25484526">{{cite journal |vauthors=Thomas S, Ranganathan D, Francis L, Madhan K, John GT |title=Current concepts in C3 glomerulopathy |journal=Indian J Nephrol |volume=24 |issue=6 |pages=339–48 |date=November 2014 |pmid=25484526 |pmc=4244712 |doi=10.4103/0971-4065.134089 |url=}}</ref>
* Indicated in C3 glomerulopathy patients associated with [[Hypertension|HTN]] and [[proteinuria]].
* [[Immunofluorescence]] [[microscopy]]: C3 deposits along the [[Bowman's]] capsule, glomerular and tubular basement membranes.
* Preferred regimen (1): ACE-inhibitors
* [[Electron]] [[microscopy]] findings in [[Dense]] [[Deposition (chemistry)|Deposit]] [[Disease]]: [[Electron]] [[dense]] [[Material conditional|material]] in the [[glomerular basement membrane]], lamina densa widening. [[Electron]] dense material is absent in C3 [[glomerulopathy]]. [[Subepithelial connective tissue graft|Subepithelial]] "humps" are found in both [[C3GN]] and [[Dense deposit disease]]. <ref name="pmid1095806">{{cite journal |vauthors=Habib R, Gubler MC, Loirat C, Mäiz HB, Levy M |title=Dense deposit disease: a variant of membranoproliferative glomerulonephritis |journal=Kidney Int. |volume=7 |issue=4 |pages=204–15 |date=April 1975 |pmid=1095806 |doi= |url=}}</ref>
* Preferred regimen (2): Angiotensin-11 receptor blockers


==Medical Therapy==
==== Specific therapy based on disease severity  ====
* [[Patients]] with C3 [[glomerulopathy]] presents with rare form of [[glomerulonephritis]] called dense deposit disease which might end up in [[membranoproliferative glomerulonephritis]] (MPGN) pattern of injury on renal [[biopsy]].<ref name="pmid22673887">{{cite journal |vauthors=Sethi S, Fervenza FC, Zhang Y, Zand L, Vrana JA, Nasr SH, Theis JD, Dogan A, Smith RJ |title=C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up |journal=Kidney Int. |volume=82 |issue=4 |pages=465–73 |date=August 2012 |pmid=22673887 |pmc=4438675 |doi=10.1038/ki.2012.212 |url=}}</ref><ref name="pmid170185612">{{cite journal |vauthors=Servais A, Frémeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B, Grünfeld JP, Lesavre P, Noël LH, Fakhouri F |title=Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome |journal=J. Med. Genet. |volume=44 |issue=3 |pages=193–9 |date=March 2007 |pmid=17018561 |pmc=2598029 |doi=10.1136/jmg.2006.045328 |url=}}</ref>
* '''Mild disease'''
** Supportive therapy
** Regular follow up
* '''Moderate disease'''
** '''Disease due to auto-antibody'''
*** Preferred regimen (1): Plasma exchange
*** Alternative regimen (1): [[Rituximab]]
*** Alternative regimen (2): [[Eculizumab]] 900 mg IV/week for 4-5 weeks followed by 1200 mg every 2 weeks for approximately one year.
** '''Disease due to factor H deficiency'''
*** Preferred regimen (1): [[Fresh frozen plasma]] 10-15 mL/ kg body weight infused regularly x 14 days
** '''Disease due to C3 mutation'''
*** Preferred regimen (1): Plasma exchange<ref name="pmid4022205">{{cite journal |vauthors=McGinley E, Watkins R, McLay A, Boulton-Jones JM |title=Plasma exchange in the treatment of mesangiocapillary glomerulonephritis |journal=Nephron |volume=40 |issue=4 |pages=385–90 |date=1985 |pmid=4022205 |doi=10.1159/000183504 |url=}}</ref><ref name="pmid12378549">{{cite journal |vauthors=Kurtz KA, Schlueter AJ |title=Management of membranoproliferative glomerulonephritis type II with plasmapheresis |journal=J Clin Apher |volume=17 |issue=3 |pages=135–7 |date=2002 |pmid=12378549 |doi=10.1002/jca.10026 |url=}}</ref><ref name="pmid21269585">{{cite journal |vauthors=Krmar RT, Holtbäck U, Linné T, Berg UB, Celsi G, Söderberg MP, Wernerson A, Szakos A, Larsson S, Skattum L, Bárány P |title=Acute renal failure in dense deposit disease: complete recovery after combination therapy with immunosuppressant and plasma exchange |journal=Clin. Nephrol. |volume=75 Suppl 1 |issue= |pages=4–10 |date=February 2011 |pmid=21269585 |doi= |url=}}</ref>
* Severe disease with rapidly progressive worsening [[renal]] function:
** Preferred regimen (1): [[Cyclophosphamide]]
** Preferred regimen (2): [[Mycophenolate sodium|Mycophenolate mofetil]]<ref name="pmid26221755">{{cite journal |vauthors=Rabasco C, Cavero T, Román E, Rojas-Rivera J, Olea T, Espinosa M, Cabello V, Fernández-Juarez G, González F, Ávila A, Baltar JM, Díaz M, Alegre R, Elías S, Antón M, Frutos MA, Pobes A, Blasco M, Martín F, Bernis C, Macías M, Barroso S, de Lorenzo A, Ariceta G, López-Mendoza M, Rivas B, López-Revuelta K, Campistol JM, Mendizábal S, de Córdoba SR, Praga M |title=Effectiveness of mycophenolate mofetil in C3 glomerulonephritis |journal=Kidney Int. |volume=88 |issue=5 |pages=1153–60 |date=November 2015 |pmid=26221755 |doi=10.1038/ki.2015.227 |url=}}</ref>


* [[Patients]] with [[C3GN]] and [[Dense Deposit Disease]] who have [[hypertension]] or [[proteinuria]] receive an [[ACE-Inhibitor]] or Angiotensin-11 receptor blocker
=== Surgery ===
* Disease due to [[genetic]] [[deficiency]]: The missing [[mutant]] [[protein]] should be replaced by the periodic infusion of [[fresh frozen plasma]]
* Surgical intervention is not recommended for the management of C3 glomerulopathy
* Disease secondary to [[autoantibody]]: [[Immunosuppression]] with
** Preferred regimen (1): [[Eculizumab]]
** Preferred regimen (2): [[rituximab]]
** Preferred regimen (3): [[plasma exchange]]
*[[Genetic]] activating [[mutation]] in C3: Plasma exchange<ref name="pmid21269585">{{cite journal |vauthors=Krmar RT, Holtbäck U, Linné T, Berg UB, Celsi G, Söderberg MP, Wernerson A, Szakos A, Larsson S, Skattum L, Bárány P |title=Acute renal failure in dense deposit disease: complete recovery after combination therapy with immunosuppressant and plasma exchange |journal=Clin. Nephrol. |volume=75 Suppl 1 |issue= |pages=4–10 |date=February 2011 |pmid=21269585 |doi= |url=}}</ref><ref name="pmid4022205">{{cite journal |vauthors=McGinley E, Watkins R, McLay A, Boulton-Jones JM |title=Plasma exchange in the treatment of mesangiocapillary glomerulonephritis |journal=Nephron |volume=40 |issue=4 |pages=385–90 |date=1985 |pmid=4022205 |doi=10.1159/000183504 |url=}}</ref><ref name="pmid12378549">{{cite journal |vauthors=Kurtz KA, Schlueter AJ |title=Management of membranoproliferative glomerulonephritis type II with plasmapheresis |journal=J Clin Apher |volume=17 |issue=3 |pages=135–7 |date=2002 |pmid=12378549 |doi=10.1002/jca.10026 |url=}}</ref>
* [[Patients]] with progressively worsening [[renal]] function:
** Preferred regimen (1): [[cyclophosphamide]]
** Preferred regimen (2): [[mycophenolate mofetil]]<ref name="pmid26221755">{{cite journal |vauthors=Rabasco C, Cavero T, Román E, Rojas-Rivera J, Olea T, Espinosa M, Cabello V, Fernández-Juarez G, González F, Ávila A, Baltar JM, Díaz M, Alegre R, Elías S, Antón M, Frutos MA, Pobes A, Blasco M, Martín F, Bernis C, Macías M, Barroso S, de Lorenzo A, Ariceta G, López-Mendoza M, Rivas B, López-Revuelta K, Campistol JM, Mendizábal S, de Córdoba SR, Praga M |title=Effectiveness of mycophenolate mofetil in C3 glomerulonephritis |journal=Kidney Int. |volume=88 |issue=5 |pages=1153–60 |date=November 2015 |pmid=26221755 |doi=10.1038/ki.2015.227 |url=}}</ref>
*Patients with DDD or [[C3GN]] may be treated with lipid-lowering [[medications]] to prevent [[cardiovascular]] events.


=== Prevention ===
=== Prevention ===

Latest revision as of 00:39, 3 August 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2] Aditya Ganti M.B.B.S. [3]

For more information of Complement mediated glomerular disorders, Click here

Synonyms and keywords: Glomerulonephritis; C3 glomerulonephritis; dense deposit disease

Overview

C3 glomerulopathy is a complement system dysregulatory disorder resulting in abnormal activation of the alternative pathway. C3 glomerulopathy includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Both, C3GN and dense deposit disease are characterized by marked by C3 deposition along the capillary loop, the basement membrane, and the mesangium. Identification of C3 deposits without any concomitant immunoglobulin deposition is characteristic for diagnosing C3 glomerulopathy. The activation of the alternative pathway of the complement system can be either due to inherited, or acquired defects of the complement system. Gene mutations are the most common inherited causes while autoimmune disorders are responsible for acquired glomerulopathy.

Historical Perspective

Classification

  • Initially, C3 glomerulopathy was categorized as a variant of MPGN, namely MPGN type 2. [5][6]
  • However in 2007, Servais A. et al described C3GN as an separate entity.
  • C3 Glomerulopathy may be classified into 2 main subtypes based on the appearance of complement deposition in the glomerular basement membrane on EM:
    • Dense deposit disease (DDD)
      • Dense deposition of compliment in linear pattern.
    • C3 Glomerulonephritis (C3GN)
      • Isolated deposition of C3.

Pathophysiology

  • Excessive activation of the alternative complement pathway is the inciting event in the pathogenesis of C3 glomerulopathy.[7]
  • Activation of alternative pathway results in excessive deposition of complement along the glomerular basement membrane.
  • Pattern of compliment deposition is regulated by:[8]
    • Leukocytic chemotaxis
    • Cytolytic effects of C5b-9

Physiology

Pathogenesis

  • Any mechanism by which C3 activity is increased leads to activation of alternate pathway activation resulting in complement deposition.[10][11]
    • C3 convertase autoantibody C3 nephritic factor
    • Loss of factor H

Causes

Common causes of C3 glomerulopathy include:[12]

  • C3 mutations
  • Mutation of Factor H (CHF)[13]
    • CFH is a small glycoprotein which is produced in the liver, and circulates freely in the blood plasma .
    • Primary role of factor H is to inhibit C3 convertase and thus not activating alternative complement pathway.
    • Two types of mutations are of important significance
      • Type 1 mutations are associated with decreased levels of CFH.
      • Type 2 mutations decrease or diminish the functional activity of CHF.
    • Autoantibodies against CFH. [14]
  • Auto antibody against C3 called as nephritic factor (C3bBb antibody).[15]

Differentiating C3 Glomerulopathy from other Diseases
Medical condition Differentiating features
C3 glomerulopathy
  • Persistent glomerulonephritis over prolonged period
  • Decreased C3 levels persist
  • Immunofluorescence microscopy shows intense C3 staining without immunoglobulin staining.
Lupus nephritis
  • Anti C1q autoantibodies
  • Immune complex glomerulonephritis
  • Glomerular deposits of IgG, IgM, IgA, C3 and C1q
Poststreptococcal glomerulonephritis
  • Glomeruonephritis in most cases resolves after infection subsides
  • Decreased levels of C3 is transient
  • Immunoflouroescence microscopy shows immunoglobulin deposition in poststreptococcal infection
Staphylococcal associated glomerulonephritis
  • Glomerulonephritis resolves after infection subsides
  • Decreased C3 is transient
  • Immunofluorescence microscopy shows immunoglobulin deposition in staphylococcal associated glomerulonephritis.

Epidemiology and Demographics

Risk Factors

Common risk factors in the development of C3 glomerulopathy include:

Screening

  • There is insufficient evidence to recommend routine screening for C3 glomerulopathy. However, screening is indicated for family members of affected individuals using genetic testing.

Natural History, Complications and Prognosis

Diagnosis

Diagnostic test of choice

Kidney biopsy is the gold standard test for the diagnosis of C3 glomerulopathy.

Symptoms

Common symptoms of C3 glomerulopathy may include:[18][19]

Characterstics DDD C3GN
Mean age 14 24
ESRD 50% in 10 years 10% in 2.5 years
Associated conditions -
C3 convertase dysregulation ↑↑ ↑
C5 convertase dysregulation ↑ ↑↑
C3NF +++ +
MAC ↑ ↑↑↑

Laboratory Findings

  • C3 glomerulopathy is diagnosed using immunofluorescence microscopy and electron microscopy.
  • There are no specific findings for C3 glomerulopathy on light microscopic.
  • Findings on electron microscopy include[20][21]
    • Sub-epithelial lumps
    • Abnormal electron-dense material within the GBM
      • Dense and linear in DDD
      • Isolated in C3GN
  • Findings on immunofluorescence microscopy include:
    • C3 deposits along the Bowman's capsule of glomerular and tubular basement membranes.

Other Diagnostic tests

Other diagnostic tests that can help in diagnosing C3 glomerulopathy include:

  • Measurement of complement C3, C3 Nef, serum factor H, CFHR ( Complement factor H-related protein)
  • Serum protein electrophoresis, immunofixation and serum free light chains
  • sMAC level activity

Physical Examination

Common physical examination findings of patients with C3 glomerulopathy include:

Imaging Findings

Treatment

Medical Therapy

  • The mainstay of treatment for C3 glomerulopathy is pharmacotherapy.[22][23]
  • Pharmacotherpay can be catagorized into:
    • Supportive therapy
    • Specific therapy based on disease severity

Supportive Therapy

Supportive therapy include antihypertensive medications and lipid lowering

  • Indicated in C3 glomerulopathy patients associated with HTN and proteinuria.
  • Preferred regimen (1): ACE-inhibitors
  • Preferred regimen (2): Angiotensin-11 receptor blockers

Specific therapy based on disease severity

  • Mild disease
    • Supportive therapy
    • Regular follow up
  • Moderate disease
    • Disease due to auto-antibody
      • Preferred regimen (1): Plasma exchange
      • Alternative regimen (1): Rituximab
      • Alternative regimen (2): Eculizumab 900 mg IV/week for 4-5 weeks followed by 1200 mg every 2 weeks for approximately one year.
    • Disease due to factor H deficiency
      • Preferred regimen (1): Fresh frozen plasma 10-15 mL/ kg body weight infused regularly x 14 days
    • Disease due to C3 mutation
  • Severe disease with rapidly progressive worsening renal function:

Surgery

  • Surgical intervention is not recommended for the management of C3 glomerulopathy

Prevention

References

  1. ↑ SELIGMANN M, HANAU C (1958). "[Immuno-electrophoretic study of the blood of disseminated lupus erythematosus patients]". Rev Hematol (in French). 13 (2): 239–48. PMID 13568372.
  2. ↑ WEST CD, NORTHWAY JD, DAVIS NC (August 1964). "SERUM LEVELS OF BETA-1C GLOBULIN, A COMPLEMENT COMPONENT, IN THE NEPHRITIDES, LIPOID NEPHROSIS, AND OTHER CONDITIONS". J. Clin. Invest. 43: 1507–17. doi:10.1172/JCI105027. PMC 441951. PMID 14201535.
  3. ↑ BERGER J, GALLE P (1962). "[Unusual change of the basal membranes of the kidney]". J Urol Nephrol (Paris). 68: 116–22. PMID 13867660.
  4. ↑ Fakhouri F, Frémeaux-Bacchi V, Noël LH, Cook HT, Pickering MC (August 2010). "C3 glomerulopathy: a new classification". Nat Rev Nephrol. 6 (8): 494–9. doi:10.1038/nrneph.2010.85. PMID 20606628.
  5. ↑ Appel GB, Cook HT, Hageman G, Jennette JC, Kashgarian M, Kirschfink M, Lambris JD, Lanning L, Lutz HU, Meri S, Rose NR, Salant DJ, Sethi S, Smith RJ, Smoyer W, Tully HF, Tully SP, Walker P, Welsh M, Würzner R, Zipfel PF (May 2005). "Membranoproliferative glomerulonephritis type II (dense deposit disease): an update". J. Am. Soc. Nephrol. 16 (5): 1392–403. doi:10.1681/ASN.2005010078. PMID 15800116.
  6. ↑ Servais A, Frémeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B; et al. (2007). "Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome". J Med Genet. 44 (3): 193–9. doi:10.1136/jmg.2006.045328. PMC 2598029. PMID 17018561.
  7. ↑ Schwertz R, de Jong R, Gretz N, Kirschfink M, Anders D, Schärer K (March 1996). "Outcome of idiopathic membranoproliferative glomerulonephritis in children. Arbeitsgemeinschaft Pädiatrische Nephrologie". Acta Paediatr. 85 (3): 308–12. PMID 8695987.
  8. ↑ Thomas S, Ranganathan D, Francis L, Madhan K, John GT (November 2014). "Current concepts in C3 glomerulopathy". Indian J Nephrol. 24 (6): 339–48. doi:10.4103/0971-4065.134089. PMC 4244712. PMID 25484526.
  9. ↑ Noris M, Remuzzi G (November 2013). "Overview of complement activation and regulation". Semin. Nephrol. 33 (6): 479–92. doi:10.1016/j.semnephrol.2013.08.001. PMC 3820029. PMID 24161035.
  10. ↑ Thomas S, Ranganathan D, Francis L, Madhan K, John GT (November 2014). "Current concepts in C3 glomerulopathy". Indian J Nephrol. 24 (6): 339–48. doi:10.4103/0971-4065.134089. PMC 4244712. PMID 25484526.
  11. ↑ Bomback AS, Appel GB (November 2012). "Pathogenesis of the C3 glomerulopathies and reclassification of MPGN". Nat Rev Nephrol. 8 (11): 634–42. doi:10.1038/nrneph.2012.213. PMID 23026947.
  12. ↑ Holers VM (June 2013). "Human C3 glomerulopathy provides unique insights into complement factor H-related protein function". J. Clin. Invest. 123 (6): 2357–60. doi:10.1172/JCI69684. PMC 3668810. PMID 23728171.
  13. ↑ Rodríguez de Córdoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sánchez-Corral P (June 2004). "The human complement factor H: functional roles, genetic variations and disease associations". Mol. Immunol. 41 (4): 355–67. doi:10.1016/j.molimm.2004.02.005. PMID 15163532.
  14. ↑ Noris M, Donadelli R, Remuzzi G (June 2018). "Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy". Pediatr. Nephrol. doi:10.1007/s00467-018-3989-0. PMID 29948306.
  15. ↑ Togarsimalemath SK, Sethi SK, Duggal R, Le Quintrec M, Jha P, Daniel R, Gonnet F, Bansal S, Roumenina LT, Fremeaux-Bacchi V, Kher V, Dragon-Durey MA (October 2017). "A novel CFHR1-CFHR5 hybrid leads to a familial dominant C3 glomerulopathy". Kidney Int. 92 (4): 876–887. doi:10.1016/j.kint.2017.04.025. PMID 28729035.
  16. ↑ Smith RJ, Alexander J, Barlow PN, Botto M, Cassavant TL, Cook HT; et al. (2007). "New approaches to the treatment of dense deposit disease". J Am Soc Nephrol. 18 (9): 2447–56. doi:10.1681/ASN.2007030356. PMC 4853920. PMID 17675665.
  17. ↑ Servais A, Noël LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grünfeld JP, Niaudet P, Lesavre P, Frémeaux-Bacchi V (August 2012). "Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies". Kidney Int. 82 (4): 454–64. doi:10.1038/ki.2012.63. PMID 22456601.
  18. ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean L, Stephens K, Amemiya A, Martín B, Smith R. PMID 20301598. Vancouver style error: initials (help); Missing or empty |title= (help)
  19. ↑ Ito N, Ohashi R, Nagata M (August 2017). "C3 glomerulopathy and current dilemmas". Clin. Exp. Nephrol. 21 (4): 541–551. doi:10.1007/s10157-016-1358-5. PMC 5721121. PMID 27878657.
  20. ↑ Thomas S, Ranganathan D, Francis L, Madhan K, John GT (November 2014). "Current concepts in C3 glomerulopathy". Indian J Nephrol. 24 (6): 339–48. doi:10.4103/0971-4065.134089. PMC 4244712. PMID 25484526.
  21. ↑ Habib R, Gubler MC, Loirat C, Mäiz HB, Levy M (April 1975). "Dense deposit disease: a variant of membranoproliferative glomerulonephritis". Kidney Int. 7 (4): 204–15. PMID 1095806.
  22. ↑ Sethi S, Fervenza FC, Zhang Y, Zand L, Vrana JA, Nasr SH, Theis JD, Dogan A, Smith RJ (August 2012). "C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up". Kidney Int. 82 (4): 465–73. doi:10.1038/ki.2012.212. PMC 4438675. PMID 22673887.
  23. ↑ Servais A, Frémeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B, Grünfeld JP, Lesavre P, Noël LH, Fakhouri F (March 2007). "Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome". J. Med. Genet. 44 (3): 193–9. doi:10.1136/jmg.2006.045328. PMC 2598029. PMID 17018561.
  24. ↑ McGinley E, Watkins R, McLay A, Boulton-Jones JM (1985). "Plasma exchange in the treatment of mesangiocapillary glomerulonephritis". Nephron. 40 (4): 385–90. doi:10.1159/000183504. PMID 4022205.
  25. ↑ Kurtz KA, Schlueter AJ (2002). "Management of membranoproliferative glomerulonephritis type II with plasmapheresis". J Clin Apher. 17 (3): 135–7. doi:10.1002/jca.10026. PMID 12378549.
  26. ↑ Krmar RT, Holtbäck U, Linné T, Berg UB, Celsi G, Söderberg MP, Wernerson A, Szakos A, Larsson S, Skattum L, Bárány P (February 2011). "Acute renal failure in dense deposit disease: complete recovery after combination therapy with immunosuppressant and plasma exchange". Clin. Nephrol. 75 Suppl 1: 4–10. PMID 21269585.
  27. ↑ Rabasco C, Cavero T, Román E, Rojas-Rivera J, Olea T, Espinosa M, Cabello V, Fernández-Juarez G, González F, Ávila A, Baltar JM, Díaz M, Alegre R, Elías S, Antón M, Frutos MA, Pobes A, Blasco M, Martín F, Bernis C, Macías M, Barroso S, de Lorenzo A, Ariceta G, López-Mendoza M, Rivas B, López-Revuelta K, Campistol JM, Mendizábal S, de Córdoba SR, Praga M (November 2015). "Effectiveness of mycophenolate mofetil in C3 glomerulonephritis". Kidney Int. 88 (5): 1153–60. doi:10.1038/ki.2015.227. PMID 26221755.
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