5-2. C3 glomerulonephritis and Dense Deposit Disease. Francesco Emma (eng)

1,545 views

Published on

Published in: Health & Medicine
0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
1,545
On SlideShare
0
From Embeds
0
Number of Embeds
243
Actions
Shares
0
Downloads
41
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide

5-2. C3 glomerulonephritis and Dense Deposit Disease. Francesco Emma (eng)

  1. 1. C3 glomerulonephritis and Dense Deposit Disease Francesco Emma Division of Nephrology and Dialysis Bambino Gesù Children’s Hospital, IRCCS Rome, Italy
  2. 2. The area of complement…. Leslie M., Science 2012
  3. 3. MPGN – “classic classification” MPGN Type I Subendothelial deposits West et al, J Pediatr 1965 MPGN Type II / DDD Intramembranous deposits Galle, Thesis 1962; Habib et al, Kidney Int 1975 MPGN Type III Subendothelial and subepithelial deposits Burkholder et al, Am J Pathol 1969 Anders et al, Virchows Arch A Pathol Anat Histol 1997 Strife et al, Clin Nephrol 1984
  4. 4. C3GN 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
  5. 5. Evidence for a role of complement in DDD/C3GN in humans • 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
  6. 6. Histology in DDD and C3GN DDD Mesangial proliferation MPGN Crescentic / Exudative GN C3GN 45% 35% 10% 40% 55% 5% Servais A, J Med Genet 2007 Walker PD et al, Modern Pathol 2007 Fakhouri F et al, Nature Rev Nephrol 2010 Sethi S, Kidney Int 2012
  7. 7. Glomerular lesions in DDD MPGN Mesangial proliferation Crescentic Diffuse endocapillary proliferation Walker PD et al, Modern Pathol 2007
  8. 8. The diagnosis of DDD requires electron microscopy DDD Walker PD et al, Modern Pathol 2007 C3GN Sethi S et al, Clin J Am Soc Nephrol 2011
  9. 9. Glomerular lesions in C3GN Mesangial proliferation MPGN Diffuse endocapillary proliferation Sethi S, Kidney International (2012) 82, 465–473
  10. 10. Mesangial proliferative GN and MPGN represent a continuum Sethi S and Fervenza FC, Semin Nephrol 2011
  11. 11. New classification based on C3: MPGN1 / DDD / GN-C3
  12. 12. New classification based on the MPGN pattern * MPGN1 DDD C3GN Sethi S and Fervenza FC, Semin Nephrol 2011 Sethi 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
  13. 13. MPGN1 can also be secondary to dysregulation of the complement alternative pathway Servais et al, Kidney Int 2012
  14. 14. A simplified view of the complement system Zipfel and Skerka, Nat Rev Immunol 2009
  15. 15. Complement-mediated MPGN  inflammation Sethi S, Fervenza FC NEJM 2012
  16. 16. C3 convertase C3bBb Sethi S, Fervenza FC NEJM 2012 Torreira et al, PNAS 2009
  17. 17. C3 convertase Rodríguez de Córdoba S et al., Biochem Biophys Acta, 2011
  18. 18. The C3 convertase can be activated in the fluid-phase or on cell surfaces
  19. 19. The C3 convertase can be activated in the fluid-phase or on cell surfaces Adapted from Rodríguez de Córdoba S et al., Biochem Biophys Acta, 2011
  20. 20. C3 mutations in DDD • 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
  21. 21. The C3 convertase can be activated in the fluid-phase or on cell surfaces C-terminal region surface binding (glycosaminoglycans/heparins) Rodríguez de Córdoba S et al., Biochem Biophys Acta, 2011
  22. 22. CFH domain mutations in aHUS and DDD C-terminal region surface binding (glycosaminoglycans/heparins) Rodríguez de Córdoba S et al., Biochem Biophys Acta, 2011
  23. 23. The role of C3 vs. C5 in MPGN Cfh-/- mice Cfh-/- FHD16-20 mice MPGN aHUS C3 Prevented if: Worsen if: Improved if: C3 Cfi-/- C5-/- or anti-C5 C3 activation C5-/- or anti-C5 Dependent on C3>>C5 Dependent on C5 Rose et al, J Clin Invest, 2008 Pickering et al. Nat Genet 2002 Pickering et al. PNAS 2006 Goicoechea de Jorge, JASN 2011
  24. 24. Complement dysregulation in kidney diseases
  25. 25. C3 levels in C3G Servais et al, Kidney Int 2012
  26. 26. Plasma C3 regulation
  27. 27. Physiopathology of DDD/C3GN Adapted from Smith et al. Mol Immunol 2011
  28. 28. DDD / C3GN: autoimmune forms • 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 value Schwertz 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 DDD Meri et al, J Exp Med 1992; Jokiranta et al, J Immunol 1999 • CFB autoantibody: - Binds Bb - Similar effect as C3NeF - Enhances C3 conversion - Phenotype DDD Strobel et al, Mol Immunol 2010
  29. 29. C3NeF: still poorly understood…  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 ?
  30. 30. DDD / C3GN: genetic forms Courtesy of Christoph Licth Gene / Protein Mutation / Variant Function 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 DDD C3GN CFH Polymorphisms: - Y402H (SCR 7) - Impaired C3b / heparin binding - Impaired CFH cofactor activity DDD 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 2006 Abrera-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 2007 Abrera-Abeleda, J Am Soc Nephrol 2011 CFHR3-1 Phenotype Reference Levy, Kidney Int 1986 Meri, J Exp Med 1992 Vogt, Pediatr Nephrol 1995 Ault, J Biol Chem 1997 Dragon-Durey, J Am Soc Nephrol 2004 Licht, Kidney Int 2006 Habbig, Kidney Int 2009 Hageman, Proc Nat Acad Sci 2005 Abrera-Abeleda, J Med Genet 2006 Abrera-Abeleda, J Am Soc Nephrol 2011
  31. 31. Treatment of DDD / C3GN  No established therapy  Some cases may spontaneously improve Some 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
  32. 32. Treatment of DDD with eculizumab NB: not all patients respond so well NB: expensive! Vivarelli et al, New England J Med 2012
  33. 33. Presenting symptom in C3G 2 7 9
  34. 34. Atypical APGN Kidney International 2012
  35. 35. Atypical APGN Kidney International 2012
  36. 36. Thank you! Thank you!

×