c3 glomerulopathy - nyu langone health...c3 or complement factor i. idiopathic c3 glomerulonephritis...

C3 GlomerulopathyJun-Ki Park03.08.11

• For the last 30 years classification MPGN is based on glomerular findings by light microscopy with further specification on EM and staining for Ig and complement components .

• MPGN refers to a glomerular lesion characterized by thickening of the glomerular capillary wall and increase in mesangial components (both matrix size and cellularity)

• MPGN I: subendothelial deposits of IgG and C3 or isolated C3 (‘MPGN w/ isolated C3’ )

• MPGN II (DDD): electron dense deposits within the lamina densa of GBM. Glomerular staining of C3 with little/no staining of Ig.

• MPGN III: with subendothelial, mesangial, subepithelial IgG and C3 deposits; very rare

• In 1978 Levy et al. described some cases of MPGN I, which had negative glomerular staining for Ig’s, which were referred to as “MPGN I with isolated subendothelial deposition of C3”

• Often a/w complement abnormalities and appeared pathologically distinct form idiopathic and secondary forms of MPGN I.

Levy et al. Clin Immunol Immunopathol 1978

Isolated C3 deposition

‘DDD is not a MPGN’

Walker et al. Modern Pathology 2007

Servais et al. J Med Genet 2007

Primary MPGN with isolated C3 deposits shares genetic risk factors with HUS

Servais et al. J Med Genet 2007

Complement Pathway

C1-est inhib

C4bp

CFH, CFI

CD 52

CR1CFIDAFMCP(CD46)

Archaeo-Complement System

Primitive Feetback

The Alternative Pathway (AP) C3 feedback and breakdown cycles

Animal Models of MPGN

Licht et al. Thromb. Haemost. 2009

Acquired Causes of AP Dysregulation

• Ab’s that either block the action of natural regulators of the alternative pathway (e.g. Anti-CFH or Anti-CFI Ab’s) or directly stimulate activation of the alternative pathway (e.g. C3NeF)

• C3NeF is an IgG auto-Ab that directly stabilizes the C3 activating complex (C3-Convertase) of the alternative pathway. C3NeF causes activation of plasma C3 despite normal levels of CFH

Genetic Causes of AP Dysregulation

• Loss of function mutations of AP regulator genes

• Gain of function mutations in genes that encode proteins that activate the alternative pathway

• Polymorphic protein variants present: e.g. CFB8 and CFH9 have been associated with reduced activation of the alternative pathway and reduced susceptibility to complement mediated diseases

• Functional differences exist that may influence disease penetrance or disease severity

Forms of C3 Glomerulopathy

• Dense deposit disease

• Idiopathic C3 glomerulonephritis

• MPGN type I with isolated subendothelial deposition of C3

• Familial MPGN type III

• CFHR5 nephropathy (familial C3 glomerulonephritis a/w heterozygos mutation in CFHR5)

Fakouri et al. Nat. Rev. Nephrol 2010

Dense Deposit Disease

• Glomerular deposits of C3, with no or only scanty Ig’s

• Dense osmophilic deposits in the mesangium, GBM and TBM

• Presence of auto-Ab’s against CFH, C3NeF and genetic deficiency of complement factor H

• High recurrence rate of DDD in renal transplant recipients suggests a systemic etiology for the disease

• iC3b plays key role in the pathogenesis of DDD. DDD has not been reported in humans deficient in either C3 or complement factor I.

Idiopathic C3 Glomerulonephritis • Isolated C3 deposits on immunohistochemistry

• Typically subendothelial and mesangial electron-dense deposits.

• 75%: C3GN with MPGN25%: C3GN without MPGN

• Both C3NeF and mutations in regulatory proteins of alternative pathway have been detected.

Familial MPGN3

• Linkage of MPGN3 to chromosome 1 has been demonstrated in familial MPGN3

• The region of chromosome 1 linked to the disease included the gene that encodes the alternative pathway regulator CFH

• Renal biopsies showed glomerular deposition of C3 in the absence of immunoglobulin

• Renal biopsy findings together with genetic studies suggest dysregulation of the complement system

CFHR 5 nephropathy

• Two Cypriot families with inherited renal disease described in 2009, characterized by variable glomerular inflammation and subendothelial deposits of C3, with absent Ig’s in the GBM.

• Found to have mutation in complement factor H related protein 5, encoded by CFHR5.

Goicoechea de Jorge et al. Mol Immunol. 2009

Investigations for C3 glomerulopathy

Treatment Perspectives• Plasma infusions of purified or recombinantly

expressed pure missing or defective protein.

• Pt with an antibody (e.g. CNeF) would benefit from plasma exchange/pheresis or the use of immunosuppressants ( Rituximab)

• Ab’s directed against certain components of complement cascade by preventing activation of cascade from progressing (e.g. eculizumab, anti- C5 IgG Ab)

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