C3 glomerulopathy: Difference between revisions

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__NOTOC__
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{{SI}}                                                                 
{{SI}}                                                                 
{{CMG}} {{AE}} Your Name
{{CMG}};{{AE}} {{Vbe}} {{ADG}}
 
{{SK}} Synonym 1; Synonym 2; Synonym 3
'''''For more information of Complement mediated glomerular disorders, [[Complement mediated glomerular disorders|Click here]]'''''
   
   
{{SK}} Glomerulonephritis; C3 glomerulonephritis; dense deposit disease
==Overview==
==Overview==
C3 glomerulopathy is a disorder of complement system, and can be due to inherited or acquired complement dysregulation. The inherited forms of complement dysregulation are due to numerous identified (and potentially yet to be identified) mutations of genes involved in complement pathway (see causes). Other disorders of complement pathway include the atypical hemolytic uremic syndrome.  
[[C3 (complement)|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 Livelihood|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==
==Historical Perspective==
*[Disease name] was first discovered by [scientist name], a [nationality + occupation], in [year] during/following [event].
*In 1915, William C. Gunn was first to report an association of low [[Circulating immune complexes|circulating]] [[complement]] levels in [[patients]] with acute [[infection]] and [[Nephritic syndrome|nephritic]] presentation.  
*In [year], [gene] mutations were first identified in the pathogenesis of [disease name].
*Based on the William's observations, role of [[complement]] system in [[inflammatory]] [[glomerulonephritis]] was well described.<ref name="pmid13568372">{{cite journal |vauthors=SELIGMANN M, HANAU C |title=[Immuno-electrophoretic study of the blood of disseminated lupus erythematosus patients] |language=French |journal=Rev Hematol |volume=13 |issue=2 |pages=239–48 |date=1958 |pmid=13568372 |doi= |url=}}</ref><ref name="pmid14201535">{{cite journal |vauthors=WEST CD, NORTHWAY JD, DAVIS NC |title=SERUM LEVELS OF BETA-1C GLOBULIN, A COMPLEMENT COMPONENT, IN THE NEPHRITIDES, LIPOID NEPHROSIS, AND OTHER CONDITIONS |journal=J. Clin. Invest. |volume=43 |issue= |pages=1507–17 |date=August 1964 |pmid=14201535 |pmc=441951 |doi=10.1172/JCI105027 |url=}}</ref>
*In [year], the first [discovery] was developed by [scientist] to treat/diagnose [disease name].
* In 1962, Jean Berger and Pierre Galle, Nephro-pathologists, was the first to identify [[dense]] [[Intramembranous ossification|intramembranous]] deposits on transmission [[EMERAS|EM]] <ref name="pmid13867660">{{cite journal| author=BERGER J, GALLE P| title=[Unusual change of the basal membranes of the kidney]. | journal=J Urol Nephrol (Paris) | year= 1962 | volume= 68 | issue=  | pages= 116-22 | pmid=13867660 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13867660  }} </ref>.
*Mathew TH, Kinaid Smith P coined the term dense deposit disease (DDD).<ref name="pmid20606628">{{cite journal |vauthors=Fakhouri F, Frémeaux-Bacchi V, Noël LH, Cook HT, Pickering MC |title=C3 glomerulopathy: a new classification |journal=Nat Rev Nephrol |volume=6 |issue=8 |pages=494–9 |date=August 2010 |pmid=20606628 |doi=10.1038/nrneph.2010.85 |url=}}</ref>
 
==Classification==
==Classification==
*[Disease name] may be classified according to [classification method] into [number] subtypes/groups:
*Initially, [[C3 (complement)|C3]] [[glomerulopathy]] was categorized as a variant of [[MPGN]], namely MPGN type 2. <ref name="pmid15800116">{{cite journal |vauthors=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 |title=Membranoproliferative glomerulonephritis type II (dense deposit disease): an update |journal=J. Am. Soc. Nephrol. |volume=16 |issue=5 |pages=1392–403 |date=May 2005 |pmid=15800116 |doi=10.1681/ASN.2005010078 |url=}}</ref><ref name="pmid17018561">{{cite journal| author=Servais A, Frémeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B et al.| title=Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. | journal=J Med Genet | year= 2007 | volume= 44 | issue= 3 | pages= 193-9 | pmid=17018561 | doi=10.1136/jmg.2006.045328 | pmc=2598029 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17018561  }} </ref>
:*[group1]
*However in 2007, Servais A. et al described C3GN as an separate entity.
:*[group2]
*C3 Glomerulopathy may be classified into 2 main subtypes based on the appearance of complement deposition in the glomerular basement membrane on EM:
:*[group3]
**'''Dense deposit disease (DDD)'''
*Other variants of [disease name] include [disease subtype 1], [disease subtype 2], and [disease subtype 3].
***Dense deposition of compliment in linear pattern.
**'''[[C3 (complement)|C3]] [[Glomerulonephritis]] (C3GN)'''
***Isolated deposition of C3.
==Pathophysiology==
==Pathophysiology==
*The pathogenesis of [disease name] is characterized by [feature1], [feature2], and [feature3].
*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>
*The [gene name] gene/Mutation in [gene name] has been associated with the development of [disease name], involving the [molecular pathway] pathway.
*Activation of alternative pathway results in  excessive deposition of complement along the glomerular basement membrane.
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
*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>
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
**Leukocytic chemotaxis
**Cytolytic effects of C5b-9
 
==== 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]])
 
==== 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>
** C3 convertase autoantibody C3 nephritic factor
** Loss of factor H
 
==Causes==
==Causes==
* [Disease name] may be caused by either [cause1], [cause2], or [cause3].
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>
* [Disease name] is caused by a mutation in the [gene1], [gene2], or [gene3] gene[s].
* C3 [[mutations]]
* There are no established causes for [disease name].
* [[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]] .
==Differentiating [disease name] from other Diseases==
** Primary role of factor H is to inhibit C3 convertase and thus not activating alternative complement pathway.
*[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as:
** Two types of mutations are of important significance
:*[Differential dx1]
*** Type 1 [[mutations]] are associated with decreased levels of CFH.
:*[Differential dx2]
*** Type 2 mutations decrease or diminish the functional activity of CHF.
:*[Differential dx3]
** [[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>
 
* Mutation of membrane cofactor protein ( MCP)
** MCP is a<nowiki/> [[transmembrane protein]], expressed by all [[Nucleated|nucleate]]<nowiki/>d [[cells]] and located at the [[cell]] surfaces.  
** Together with [[Complement]] Factor I (CFI), MCP is required <nowiki/>for the inactivation of C3b,
 
* 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>
 
==Differentiating C3 Glomerulopathy from other Diseases==
{| style="border: 0px; font-size: 90%; margin: 3px; width: 1000px" align="center"
|
|
|+
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Medical condition}}
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF| Differentiating features }}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[C3 glomerulopathy]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* Persistent glomerulonephritis over prolonged period
* Decreased C3 levels persist
* Immunofluorescence microscopy shows intense C3 staining without immunoglobulin staining.
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[Lupus nephritis]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* Anti C1q autoantibodies
* Immune complex glomerulonephritis
* Glomerular deposits of IgG, IgM, IgA, C3 and C1q
*
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[Poststreptococcal glomerulonephritis]]
| style="padding: 5px 5px; background: #F5F5F5;" |
 
*Glomeruonephritis in most cases resolves after infection subsides
*Decreased levels of C3 is transient
* Immunoflouroescence microscopy shows immunoglobulin deposition in poststreptococcal infection
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[Staphylococcal associated glomerulonephritis]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* Glomerulonephritis resolves after infection subsides
*Decreased C3 is transient
* Immunofluorescence microscopy shows immunoglobulin deposition in staphylococcal associated glomerulonephritis.
|}
 
==Epidemiology and Demographics==
==Epidemiology and Demographics==
* The prevalence of [disease name] is approximately [number or range] per 100,000 individuals worldwide.
* 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>
* In [year], the incidence of [disease name] was estimated to be [number or range] cases per 100,000 individuals in [location].
 
*[[Patients]] of all [[age]] groups may develop [[C3 glomerulopathy MRI|C3 glomerulopathy]] but it commonly affects young adults and children (Dense deposit disease)
===Age===
 
*Patients of all age groups may develop [disease name].
* C3 [[glomerulopathy]] affects [[men]] and [[Women's College Hospital|women]] equally.
 
*[Disease name] is more commonly observed among patients aged [age range] years old.
*There is no racial predilection for [[C3 glomerulopathy MRI|C3 glomerulopathy]].
*[Disease name] is more commonly observed among [elderly patients/young patients/children].
 
===Gender===
*[Disease name] affects men and women equally.
*[Gender 1] are more commonly affected with [disease name] than [gender 2].
* The [gender 1] to [Gender 2] ratio is approximately [number > 1] to 1.
===Race===
*There is no racial predilection for [disease name].
*[Disease name] usually affects individuals of the [race 1] race.
*[Race 2] individuals are less likely to develop [disease name].
==Risk Factors==
==Risk Factors==
*Common risk factors in the development of [disease name] are [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].
Common risk factors in the development of [[C3 glomerulopathy MRI|C3 glomerulopathy]] include:
* [[Family]] [[History and Physical examination|history]] of C3 glomerulopathy
* H/O  [[autoimmune disorders]]
 
==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==
== Natural History, Complications and Prognosis==
*The majority of patients with [disease name] remain asymptomatic for [duration/years].
 
*Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
*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>
*If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
*[[Prognosis]] of [[C3 glomerulopathy MRI|C3 glomerulopathy]] is generally poor without proper treatment.
*Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
*10 ­year [[mortality]] of [[patients]] with C3 glomerulopathy is approximately 36%.
*Prognosis is generally [excellent/good/poor], and the [1/5/10­year mortality/survival rate] of patients with [disease name] is approximately [#%].
 
== Diagnosis ==
== Diagnosis ==
===Diagnostic Criteria===
====Diagnostic test of choice====
*The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met:
Kidney biopsy is the gold standard test for the diagnosis of [[C3 glomerulopathy MRI|C3 glomerulopathy]].
:*[criterion 1]
 
:*[criterion 2]
==== Symptoms ====
:*[criterion 3]
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>
:*[criterion 4]
*Foamy [[urine]] due [[proteinuria]]
*[[Hematuria]]
=== Symptoms ===
*Signs of [[renal]] [[Aortic insufficiency|insufficiency]] like general [[fatigue]] or [[malaise]]
*[Disease name] is usually asymptomatic.
*[[Hypertension]]  
*Symptoms of [disease name] may include the following:
*Hypocomplementimia
:*[symptom 1]
*Acquired [[lipodystrophy]]
:*[symptom 2]
*[[Macular]] ([[Drusen]]) deposits in the [[retina]] of the [[eye]]
:*[symptom 3]
 
:*[symptom 4]
{| class="wikitable"
:*[symptom 5]
|+
:*[symptom 6]
!Characterstics
!DDD
=== Physical Examination ===
!C3GN
*Patients with [disease name] usually appear [general appearance].
|-
*Physical examination may be remarkable for:
|Mean age
:*[finding 1]
|14
:*[finding 2]
|24
:*[finding 3]
|-
:*[finding 4]
|ESRD
:*[finding 5]
|50% in 10 years
:*[finding 6]
|10% in 2.5 years
|-
=== Laboratory Findings ===
|Associated conditions
*There are no specific laboratory findings associated with [disease name].
|
* Acquired [[lipodystrophy]]
* Type 1 DM
* Macular degeneration
| -
|-
|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<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.
 
==== 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:
 
*High [[blood pressure]]
*[[Pallor]] skin
*[[Edema]] of extremities
*Periorbital [[Edema]]
*[[Lipodystrophy]]
 
====Imaging Findings====
 
* There are no specific [[imaging]] findings associated with [[C3 glomerulopathy MRI|C3 glomerulopathy]].
 
*


*A  [positive/negative] [test name] is diagnostic of [disease name].
*An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
*Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].
===Imaging Findings===
*There are no [imaging study] findings associated with [disease name].
*[Imaging study 1] is the imaging modality of choice for [disease name].
*On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
*[Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].
=== Other Diagnostic Studies ===
*[Disease name] may also be diagnosed using [diagnostic study name].
*Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].
== Treatment ==
== Treatment ==
=== Medical Therapy ===
 
*There is no treatment for [disease name]; the mainstay of therapy is supportive care.
===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>
*The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
* Pharmacotherpay can be catagorized into:
*[Medical therapy 1] acts by [mechanism of action 1].
** Supportive therapy
*Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].
** Specific therapy based on disease severity  
 
==== Supportive Therapy ====
Supportive therapy include antihypertensive medications and lipid lowering
* Indicated in C3 glomerulopathy patients associated with [[Hypertension|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'''
*** 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>
 
=== Surgery ===
=== Surgery ===
*Surgery is the mainstay of therapy for [disease name].
* Surgical intervention is not recommended for the management of C3 glomerulopathy
*[Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
 
*[Surgical procedure] can only be performed for patients with [disease stage] [disease name].
=== Prevention ===
=== Prevention ===
*There are no primary preventive measures available for [disease name].
*There are no [[primary]] [[preventive]] measures available for [[C3 glomerulopathy MRI|C3 glomerulopathy]].
*Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].


*Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
   
   
[[Category:Pick One of 28 Approved]]
[[Category:Nephrology]]

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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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