C3 glomerulonephritis and Dense Deposit Disease

Francesco Emma

Division of Nephrology and DialysisBambino Gesù Children’s Hospital, IRCCS

Rome, Italy

Leslie M., Science 2012

The area of complement….

MPGN Type ISubendothelial depositsWest et al, J Pediatr 1965

MPGN Type II / DDDIntramembranous deposits Galle, Thesis 1962; Habib et al, Kidney Int 1975

MPGN Type IIISubendothelial and subepithelial depositsBurkholder et al, Am J Pathol 1969Anders et al, Virchows Arch A Pathol Anat Histol 1997Strife et al, Clin Nephrol 1984

MPGN – “classic classification”

19 patients with unusual glomerulonephritis and:

- C3NeF positivity (7), CFH (3), CFI (2) or MCP (1) mutations

- overt mesangial and epimembranous C3 deposits

- absence of dense intramembranous deposits

- no Ig deposition

C3GN

• Proteomic profile of microdissected glomeruli:C3, C4, C5, C6, C7, C8, FHR1, FHR5….

• Very similar profile between DDD and C3GN

Sethi et al Kidney Int 2009; Sethi S et al Clin J Am Soc Nephrol 2011

Evidence for a role of complement in DDD/C3GN in humans

DDD C3GNMesangial proliferation 45% 40%MPGN 35% 55%Crescentic / Exudative GN 10% 5%

Servais A, J Med Genet 2007Walker PD et al, Modern Pathol 2007

Fakhouri F et al, Nature Rev Nephrol 2010Sethi S, Kidney Int 2012

Histology in DDD and C3GN

Walker PD et al, Modern Pathol 2007

MPGN Mesangial proliferation

Diffuse endocapillaryproliferation

Crescentic

Glomerular lesions in DDD

Walker PD et al, Modern Pathol 2007 Sethi S et al, Clin J Am Soc Nephrol 2011

DDD C3GN

The diagnosis of DDD requires electron microscopy

Sethi S, Kidney International (2012) 82, 465–473

MPGNMesangial proliferationDiffuse endocapillary

proliferation

Glomerular lesions in C3GN

Sethi S and Fervenza FC, Semin Nephrol 2011

Mesangial proliferative GN and MPGN represent a continuum

New classification based on C3: MPGN1 / DDD / GN-C3

Sethi S and Fervenza FC, Semin Nephrol 2011Sethi S and Fervenza FC, NEJM 2012

*Servais et al, Kidney Int 2012; Dragon-Durey et al. JASN 2004;Vaziri-Sani et al. Kidney Int 2006; Leroy V et al. Ped Nephrol 2011

*

DDD C3GN

New classification based on the MPGN pattern

MPGN1

Servais et al, Kidney Int 2012

MPGN1 can also be secondary to dysregulation of the complement alternative pathway

Zipfel and Skerka, Nat Rev Immunol 2009

A simplified view of the complement system

Sethi S, Fervenza FC NEJM 2012

Complement-mediated MPGN

inflammation

Torreira et al, PNAS 2009

C3bBb

C3 convertase

Sethi S, Fervenza FC NEJM 2012

Rodríguez de Córdoba S et al., Biochem Biophys Acta, 2011

C3 convertase

The C3 convertase can be activated in thefluid-phase or on cell surfaces

Adapted from Rodríguez de Córdoba S et al., Biochem Biophys Acta, 2011

The C3 convertase can be activated in thefluid-phase or on cell surfaces

• Mutation in the C3 gene (923ΔDG) which lacks 2 amino acids• Generates an active C3-convertase that is:

- normally regulated by DAF on the surface of endothelial cells- resistant to decay by factor H in the plasma

Conclusion:fluid phase-restricted dysregulation of the AP

C3 mutations in DDD

C-terminal regionsurface binding(glycosaminoglycans/heparins)

Rodríguez de Córdoba S et al., Biochem Biophys Acta, 2011

The C3 convertase can be activated in thefluid-phase or on cell surfaces

C-terminal regionsurface binding(glycosaminoglycans/heparins)

Rodríguez de Córdoba S et al., Biochem Biophys Acta, 2011

CFH domain mutations in aHUS and DDD

The role of C3 vs. C5 in MPGN

Goicoechea de Jorge, JASN 2011 Rose et al, J Clin Invest, 2008Pickering et al. Nat Genet 2002

Pickering et al. PNAS 2006

Cfh-/- FHD16-20 miceCfh-/- mice

aHUSMPGN

C3 C3

Dependent on C3>>C5 Dependent on C5

Cfi-/- C5-/- or anti-C5Prevented if:

Worsen if: C3 activation

C5-/- or anti-C5Improved if:

Complement dysregulation in kidney diseases

C3 levels in C3G

Servais et al, Kidney Int 2012

Plasma C3 regulation

Adapted from Smith et al. Mol Immunol 2011

Physiopathology of DDD/C3GN

• C3 nephritic factor (C3NeF):- IgG binding to neoepitope on alternative C3 convertase (C3bBb)- Stabilizes C3bBb against intrinsic and extrinsic decay- Present in all MPGN subtypes (DDD: 55% adults and 80% children)- High degree of inter-/intraindividual variability – poor predictive valueSchwertz et al, Acta Paediatr 1986; Schwertz et al, Pediatr Allergy Immunol 2001

• CFH (mini-)antibody:- Binds to CFH SCR3 and inhibits CFH cofactor activity- Phenotype DDDMeri et al, J Exp Med 1992; Jokiranta et al, J Immunol 1999

• CFB autoantibody:- Binds Bb- Similar effect as C3NeF- Enhances C3 conversion- Phenotype DDDStrobel et al, Mol Immunol 2010

DDD / C3GN: autoimmune forms

What epitopes do they bind and how tightly ?

Do they all stabilize the convertase to the same extent ?

Do they act on cell surface ?

Do differences correlate with the phenotype ?

Do they disappear spontaneously ?

C3NeF: still poorly understood…

Gene / Protein Mutation / Variant Function Phenotype Reference

CFH Mutations:- homo- / compound heterozygous- SCRs 1-4 (regulatory domain)- Cys residues (tertiary structure)

- Intact surface binding- Reduced C3b binding- Loss of CFH cofactor and decay accelerating activity

DDDC3GN

Levy, Kidney Int 1986Meri, J Exp Med 1992Vogt, Pediatr Nephrol 1995Ault, J Biol Chem 1997Dragon-Durey, J Am Soc Nephrol 2004Licht, Kidney Int 2006Habbig, Kidney Int 2009

CFH Polymorphisms:- Y402H (SCR 7)

- Impaired C3b / heparin binding- Impaired CFH cofactor activity

DDD Hageman, Proc Nat Acad Sci 2005Abrera-Abeleda, J Med Genet 2006Abrera-Abeleda, J Am Soc Nephrol 2011

CFHR3-1 CNV:- CFHR3-1 hybrid gene

- Not tested- ?Dominant negative effect

C3GN Malik, J Am Soc Nephrol 2012

CFHR5 CNV:- Duplication within CFHR5 exons 2/3

- Not tested- ?Dominant negative effect

C3GN Gale, The Lancet 2010

CFHR5 Polymorphisms - Not tested DDD Abrera-Abeleda, J Med Genet 2006Abrera-Abeleda, J Am Soc Nephrol 2011

C3 Mutations:- Heterozygous deletion

- C3mut resistant to cleavage by C3bBb - C3mut convertase – resistant to CFH inactivation

DDD Martinez-Barricarte, J Clin Invest 2010

C3 Polymorphisms - Not tested DDD Smith, J Am Soc Nephrol 2007Abrera-Abeleda, J Am Soc Nephrol 2011

DDD / C3GN: genetic formsCourtesy of Christoph Licth

No established therapy

Some cases may spontaneously improveSome patients have a relapsing course

Immune-suppressive drugs (PDN, CsA, MMF) may be beneficial in some cases, in particular if evidence of renal inflammation:- anecdotal reports and retrospective cohort studies- generally partial responses

Anti-C5 may be beneficial in some, but not all patients

Treatment of DDD / C3GN

Vivarelli et al, New England J Med 2012

Treatment of DDD with eculizumab

NB: not all patientsrespond so well

NB: expensive!

Presenting symptom in C3G

2 7 9

Kidney International 2012

Atypical APGN

Kidney International 2012

Atypical APGN

Thank you!Thank you!