Skip to main content
SpringerLink
Log in

Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Membranoproliferative glomerulonephritis (MPGN) is a rare chronic kidney disease associated with complement activation. Recent immunofluorescence-based classification distinguishes between immune complex (IC)-mediated MPGN, with glomerular IgG and C3 deposits, and C3 glomerulopathies (C3G), with predominant C3 deposits. Genetic and autoimmune abnormalities causing hyperactivation of the complement alternative pathway have been found as frequently in patients with immune complex-associated MPGN (IC-MPGN) as in those with C3G. In the last decade, there have been great advances in research into the autoimmune causes of IC-MPGN and C3G. The complement-activating autoantibodies called C3-nephritic factors (C3NeFs), which are present in 40–80% of patients, form a heterogeneous group of autoantibodies that stabilise the C3 convertase or the C5 convertase of the alternative pathway or both. A few patients, mainly with IC-MPGN, carry autoantibodies directed against the two components of the alternative pathway C3 convertase, factors B and C3b. Finally, autoantibodies against factor H, the main regulator of the alternative pathway, have been reported in a small proportion of patients with IC-MPGN or C3G. The identification of distinct pathogenetic patterns leading to kidney injury and of targets in the complement cascade may pave the way for tailored therapies for IC-MPGN and C3G, with specific complement inhibitors in the development pipeline.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Alchi B, Jayne D (2010) Membranoproliferative glomerulonephritis. Pediatr Nephrol 25:1409–1418

    Article  PubMed  Google Scholar 

  2. Noris M, Remuzzi G (2015) Glomerular diseases dependent on complement activation, including atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, and C3 glomerulopathy: Core Curriculum 2015. Am J Kidney Dis 66:359–375

    Article  PubMed  PubMed Central  Google Scholar 

  3. Cook HT, Pickering MC (2015) Histopathology of MPGN and C3 glomerulopathies. Nat Rev Nephrol 11:14–22

    Article  CAS  PubMed  Google Scholar 

  4. Levy M, Gubler MC, Sich M, Beziau A, Habib R (1978) Immunopathology of membranoproliferative glomerulonephritis with subendothelial deposits (type I MPGN). Clin Immunol Immunopathol 10:477–492

    Article  CAS  PubMed  Google Scholar 

  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, Wurzner R, Zipfel PF (2005) Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J Am Soc Nephrol 16:1392–1403

    Article  PubMed  Google Scholar 

  6. Anders D, Agricola B, Sippel M, Thoenes W (1977) Basement membrane changes in membranoproliferative glomerulonephritis. II. Characterization of a third type by silver impregnation of ultra thin sections. Virchows Arch A Pathol Anat Histol 376:1–19

    Article  CAS  PubMed  Google Scholar 

  7. Sethi S, Fervenza FC (2011) Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification. Semin Nephrol 31:341–348

    Article  CAS  PubMed  Google Scholar 

  8. Sethi S, Fervenza FC (2012) Membranoproliferative glomerulonephritis—a new look at an old entity. N Engl J Med 366:1119–1131

    Article  CAS  PubMed  Google Scholar 

  9. Iatropoulos P, Noris M, Mele C, Piras R, Valoti E, Bresin E, Curreri M, Mondo E, Zito A, Gamba S, Bettoni S, Murer L, Fremeaux-Bacchi V, Vivarelli M, Emma F, Daina E, Remuzzi G (2016) Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome. Mol Immunol 71:131–142

    Article  CAS  PubMed  Google Scholar 

  10. Fervenza FC, Sethi S, Glassock RJ (2012) Idiopathic membranoproliferative glomerulonephritis: does it exist? Nephrol Dial Transplant 27:4288–4294

    Article  CAS  PubMed  Google Scholar 

  11. Pickering MC, D'Agati VD, Nester CM, Smith RJ, Haas M, Appel GB, Alpers CE, Bajema IM, Bedrosian C, Braun M, Doyle M, Fakhouri F, Fervenza FC, Fogo AB, Fremeaux-Bacchi V, Gale DP, Goicoechea de Jorge E, Griffin G, Harris CL, Holers VM, Johnson S, Lavin PJ, Medjeral-Thomas N, Paul Morgan B, Nast CC, Noel LH, Peters DK, Rodriguez de Cordoba S, Servais A, Sethi S, Song WC, Tamburini P, Thurman JM, Zavros M, Cook HT (2013) C3 glomerulopathy: consensus report. Kidney Int 84:1079–1089

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hou J, Markowitz GS, Bomback AS, Appel GB, Herlitz LC, Barry Stokes M, D'Agati VD (2014) Toward a working definition of C3 glomerulopathy by immunofluorescence. Kidney Int 85:450–456

    Article  CAS  PubMed  Google Scholar 

  13. Servais A, Noel LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grunfeld JP, Niaudet P, Lesavre P, Fremeaux-Bacchi V (2012) Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 82:454–464

    Article  CAS  Google Scholar 

  14. Noris M, Remuzzi G (2013) Overview of complement activation and regulation. Semin Nephrol 33:479–492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ricklin D, Hajishengallis G, Yang K, Lambris JD (2010) Complement: a key system for immune surveillance and homeostasis. Nat Immunol 11:785–797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lachmann PJ (2009) The amplification loop of the complement pathways. Adv Immunol 104:115–149

    Article  CAS  PubMed  Google Scholar 

  17. Berends ET, Gorham RD Jr, Ruyken M, Soppe JA, Orhan H, Aerts PC, de Haas CJ, Gros P, Rooijakkers SH (2015) Molecular insights into the surface-specific arrangement of complement C5 convertase enzymes. BMC Biol 13:93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM (2009) Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 361:345–357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Podack ER, Kolb WP, Muller-Eberhard HJ (1977) The SC5b-7 complex: formation, isolation, properties. and subunit composition J Immunol 119:2024–2029

    CAS  PubMed  Google Scholar 

  20. Tschopp J, Chonn A, Hertig S, French LE (1993) Clusterin, the human apolipoprotein and complement inhibitor, binds to complement C7, C8 beta, and the b domain of C9. J Immunol 151:2159–2165

    CAS  PubMed  Google Scholar 

  21. Iatropoulos P, Daina E, Curreri M, Piras R, Valoti E, Mele C, Bresin E, Gamba S, Alberti M, Breno M, Perna A, Bettoni S, Sabadini E, Murer L, Vivarelli M, Noris M, Remuzzi G (2018) Cluster analysis identifies distinct pathogenetic patterns in C3 glomerulopathies/immune complex-mediated membranoproliferative GN. J Am Soc Nephrol 29:283–294

    Article  CAS  PubMed  Google Scholar 

  22. Spitzer RE, Vallota EH, Forristal J, Sudora E, Stitzel A, Davis NC, West CD (1969) Serum C'3 lytic system in patients with glomerulonephritis. Science 164:436–437

    Article  CAS  PubMed  Google Scholar 

  23. Daha MR, van Es LA (1979) Further evidence for the antibody nature of C3 nephritic factor (C3NeF). J Immunol 123:755–758

    CAS  PubMed  Google Scholar 

  24. Marinozzi MC, Chauvet S, Le Quintrec M, Mignotet M, Petitprez F, Legendre C, Cailliez M, Deschenes G, Fischbach M, Karras A, Nobili F, Pietrement C, Dragon-Durey MA, Fakhouri F, Roumenina LT, Fremeaux-Bacchi V (2017) C5 nephritic factors drive the biological phenotype of C3 glomerulopathies. Kidney Int 92:1232–1241

    Article  CAS  PubMed  Google Scholar 

  25. Paixao-Cavalcante D, Lopez-Trascasa M, Skattum L, Giclas PC, Goodship TH, de Cordoba SR, Truedsson L, Morgan BP, Harris CL (2012) Sensitive and specific assays for C3 nephritic factors clarify mechanisms underlying complement dysregulation. Kidney Int 82:1084–1092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Blom AM, Corvillo F, Magda M, Stasilojc G, Nozal P, Perez-Valdivia MA, Cabello-Chaves V, Rodriguez de Cordoba S, Lopez-Trascasa M, Okroj M (2016) Testing the activity of complement convertases in serum/plasma for diagnosis of C4NeF-mediated C3 glomerulonephritis. J Clin Immunol 36:517–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang Y, Meyer NC, Fervenza FC, Lau W, Keenan A, Cara-Fuentes G, Shao D, Akber A, Fremeaux-Bacchi V, Sethi S, Nester CM, Smith RJH (2017) C4 nephritic factors in C3 glomerulopathy: a case series. Am J Kidney Dis 70:834–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang Y, Meyer NC, Wang K, Nishimura C, Frees K, Jones M, Katz LM, Sethi S, Smith RJ (2012) Causes of alternative pathway dysregulation in dense deposit disease. Clin J Am Soc Nephrol 7:265–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Strobel S, Zimmering M, Papp K, Prechl J, Jozsi M (2010) Anti-factor B autoantibody in dense deposit disease. Mol Immunol 47:1476–1483

    Article  CAS  PubMed  Google Scholar 

  30. Marinozzi MC, Roumenina LT, Chauvet S, Hertig A, Bertrand D, Olagne J, Frimat M, Ulinski T, Deschenes G, Burtey S, Delahousse M, Moulin B, Legendre C, Fremeaux-Bacchi V, Le Quintrec M (2017) Anti-factor B and anti-C3b autoantibodies in C3 glomerulopathy and Ig-associated membranoproliferative GN. J Am Soc Nephrol 28:1603–1613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chen Q, Muller D, Rudolph B, Hartmann A, Kuwertz-Broking E, Wu K, Kirschfink M, Skerka C, Zipfel PF (2011) Combined C3b and factor B autoantibodies and MPGN type II. N Engl J Med 365:2340–2342

    Article  CAS  PubMed  Google Scholar 

  32. Goodship TH, Pappworth IY, Toth T, Denton M, Houlberg K, McCormick F, Warland D, Moore I, Hunze EM, Staniforth SJ, Hayes C, Cavalcante DP, Kavanagh D, Strain L, Herbert AP, Schmidt CQ, Barlow PN, Harris CL, Marchbank KJ (2012) Factor H autoantibodies in membranoproliferative glomerulonephritis. Mol Immunol 52:200–206

    Article  CAS  PubMed  Google Scholar 

  33. Blanc C, Togarsimalemath SK, Chauvet S, Le Quintrec M, Moulin B, Buchler M, Jokiranta TS, Roumenina LT, Fremeaux-Bacchi V, Dragon-Durey MA (2015) Anti-factor H autoantibodies in C3 glomerulopathies and in atypical hemolytic uremic syndrome: one target two diseases. J Immunol 194:5129–5138

    Article  CAS  PubMed  Google Scholar 

  34. Zipfel PF, Skerka C, Chen Q, Wiech T, Goodship T, Johnson S, Fremeaux-Bacchi V, Nester C, de Cordoba SR, Noris M, Pickering M, Smith R (2015) The role of complement in C3 glomerulopathy. Mol Immunol 67:21–30

    Article  CAS  PubMed  Google Scholar 

  35. Daha MR, Fearon DT, Austen KF (1976) C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase. J Immunol 116:1–7

    CAS  PubMed  Google Scholar 

  36. Davis AE 3rd, Ziegler JB, Gelfand EW, Rosen FS, Alper CA (1977) Heterogeneity of nephritic factor and its identification as an immunoglobulin. Proc Natl Acad Sci U S A 74:3980–3983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Weiler JM, Daha MR, Austen KF, Fearon DT (1976) Control of the amplification convertase of complement by the plasma protein beta1H. Proc Natl Acad Sci U S A 73:3268–3272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ito S, Tamura N, Fujita T (1989) Effect of decay-accelerating factor on the assembly of the classical and alternative pathway C3 convertases in the presence of C4 or C3 nephritic factor. Immunology 68:449–452

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Jelezarova E, Schlumberger M, Sadallah S, Spath PJ, Schifferli JA, Lutz HU (2001) A C3 convertase assay for nephritic factor functional activity. J Immunol Methods 251:45–52

    Article  CAS  PubMed  Google Scholar 

  40. Ohi H, Watanabe S, Fujita T, Seki M, Hatano M (1990) Detection of C3bBb-stabilizing activity (C3 nephritic factor) in the serum from patients with membranoproliferative glomerulonephritis. J Immunol Methods 131:71–76

    Article  CAS  PubMed  Google Scholar 

  41. Fearon DT, Austen KF, Ruddy S (1973) Formation of a hemolytically active cellular intermediate by the interaction between properdin factors B and D and the activated third component of complement. J Exp Med 138:1305–1313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ng YC, Peters DK (1986) C3 nephritic factor (C3NeF): dissociation of cell-bound and fluid phase stabilization of alternative pathway C3 convertase. Clin Exp Immunol 65:450–457

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Fremeaux-Bacchi V, Weiss L, Brun P, Kazatchkine MD (1994) Selective disappearance of C3NeF IgG autoantibody in the plasma of a patient with membranoproliferative glomerulonephritis following renal transplantation. Nephrol Dial Transplant 9:811–814

    CAS  PubMed  Google Scholar 

  44. Scott DM, Amos N, Sissons JG, Lachmann PJ, Peters DK (1978) The immunogloblin nature of nephritic factor (NeF). Clin Exp Immunol 32:12–24

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Tanuma Y, Ohi H, Hatano M (1990) Two types of C3 nephritic factor: properdin-dependent C3NeF and properdin-independent C3NeF. Clin Immunol Immunopathol 56:226–238

    Article  CAS  PubMed  Google Scholar 

  46. Zhang Y, Nester CM, Martin B, Skjoedt MO, Meyer NC, Shao D, Borsa N, Palarasah Y, Smith RJ (2014) Defining the complement biomarker profile of C3 glomerulopathy. Clin J Am Soc Nephrol 9:1876–1882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mollnes TE, Ng YC, Peters DK, Lea T, Tschopp J, Harboe M (1986) Effect of nephritic factor on C3 and on the terminal pathway of complement in vivo and in vitro. Clin Exp Immunol 65:73–79

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ohi H, Watanabe S, Fujita T, Yasugi T (1992) Significance of C3 nephritic factor (C3NeF) in non-hypocomplementaemic serum with membranoproliferative glomerulonephritis (MPGN). Clin Exp Immunol 89:479–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. De Vriese AS, Sethi S, Van Praet J, Nath KA, Fervenza FC (2015) Kidney disease caused by dysregulation of the complement alternative pathway: an etiologic approach. J Am Soc Nephrol 26:2917–2929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Schwertz R, Rother U, Anders D, Gretz N, Scharer K, Kirschfink M (2001) Complement analysis in children with idiopathic membranoproliferative glomerulonephritis: a long-term follow-up. Pediatr Allergy Immunol 12:166–172

    Article  CAS  PubMed  Google Scholar 

  51. Schena FP, Pertosa G, Stanziale P, Vox E, Pecoraro C, Andreucci VE (1982) Biological significance of the C3 nephritic factor in membranoproliferative glomerulonephritis. Clin Nephrol 18:240–246

    CAS  PubMed  Google Scholar 

  52. Seino J, Narita M, Noshiro H, Sato K, Sato H, Saito T, Abe K (1995) Alteration of C3 nephritic factor in a patient with membrano-proliferative glomerulonephritis type II. Nephron 69:114–115

    Article  CAS  PubMed  Google Scholar 

  53. Misra A, Peethambaram A, Garg A (2004) Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Baltimore) 83:18–34

    Article  CAS  Google Scholar 

  54. Walport MJ, Davies KA, Botto M, Naughton MA, Isenberg DA, Biasi D, Powell RJ, Cheung NT, Struthers GR (1994) C3 nephritic factor and SLE: report of four cases and review of the literature. QJM 87:609–615

    CAS  PubMed  Google Scholar 

  55. Sethi S, Fervenza FC, Zhang Y, Zand L, Meyer NC, Borsa N, Nasr SH, Smith RJ (2013) Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement. Kidney Int 83:293–299

    Article  CAS  PubMed  Google Scholar 

  56. Rasmussen JM, Teisner B, Weihe P, Mathiassen B, Petersen T, Isager H (1988) Screening for complement deficiencies in patients surviving from epidemic meningococcal disease. J Clin Lab Immunol 25:161–165

    CAS  PubMed  Google Scholar 

  57. Spitzer RE, Stitzel AE, Tsokos GC (1990) Production of IgG and IgM autoantibody to the alternative pathway C3 convertase in normal individuals and patients with membranoproliferative glomerulonephritis. Clin Immunol Immunopathol 57:10–18

    Article  CAS  PubMed  Google Scholar 

  58. Clardy CW, Forristal J, Strife CF, West CD (1989) A properdin dependent nephritic factor slowly activating C3, C5, and C9 in membranoproliferative glomerulonephritis, types I and III. Clin Immunol Immunopathol 50:333–347

    Article  CAS  PubMed  Google Scholar 

  59. Sethi S, Gamez JD, Vrana JA, Theis JD, Bergen HR 3rd, Zipfel PF, Dogan A, Smith RJ (2009) Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway. Kidney Int 75:952–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sethi S, Fervenza FC, Zhang Y, Zand L, Vrana JA, Nasr SH, Theis JD, Dogan A, Smith RJ (2012) C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up. Kidney Int 82:465–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Leroy V, Fremeaux-Bacchi V, Peuchmaur M, Baudouin V, Deschenes G, Macher MA, Loirat C (2011) Membranoproliferative glomerulonephritis with C3NeF and genetic complement dysregulation. Pediatr Nephrol 26:419–424

    Article  PubMed  Google Scholar 

  62. Abrera-Abeleda MA, Nishimura C, Frees K, Jones M, Maga T, Katz LM, Zhang Y, Smith RJ (2011) Allelic variants of complement genes associated with dense deposit disease. J Am Soc Nephrol 22:1551–1559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Halbwachs L, Leveille M, Lesavre P, Wattel S, Leibowitch J (1980) Nephritic factor of the classical pathway of complement: immunoglobulin G autoantibody directed against the classical pathway C3 convetase enzyme. J Clin Invest 65:1249–1256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Daha MR, van Es LA (1980) Relative resistance of the F-42-stabilized classical pathway C3 convertase to inactivation by C4-binding protein. J Immunol 125:2051–2054

    CAS  PubMed  Google Scholar 

  65. Gigli I, Sorvillo J, Mecarelli-Halbwachs L, Leibowitch J (1981) Mechanism of action of the C4 nephritic factor. Deregulation of the classical pathway of C3 convertase. J Exp Med 154:1–12

    Article  CAS  PubMed  Google Scholar 

  66. Tanuma Y, Ohi H, Watanabe S, Seki M, Hatano M (1989) C3 nephritic factor and C4 nephritic factor in the serum of two patients with hypocomplementaemic membranoproliferative glomerulonephritis. Clin Exp Immunol 76:82–85

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Ohi H, Yasugi T (1994) Occurrence of C3 nephritic factor and C4 nephritic factor in membranoproliferative glomerulonephritis (MPGN). Clin Exp Immunol 95:316–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cook HT (2015) C4d staining in the diagnosis of C3 glomerulopathy. J Am Soc Nephrol 26:2609–2611

    Article  PubMed  PubMed Central  Google Scholar 

  69. Prasto J, Kaplan BS, Russo P, Chan E, Smith RJ, Meyers KE (2014) Streptococcal infection as possible trigger for dense deposit disease (C3 glomerulopathy). Eur J Pediatr 173:767–772

    Article  PubMed  Google Scholar 

  70. Vernon KA, Goicoechea de Jorge E, Hall AE, Fremeaux-Bacchi V, Aitman TJ, Cook HT, Hangartner R, Koziell A, Pickering MC (2012) Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency. Am J Kidney Dis 60:121–125

    Article  PubMed  PubMed Central  Google Scholar 

  71. Meri S, Koistinen V, Miettinen A, Tornroth T, Seppala IJ (1992) Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis. J Exp Med 175:939–950

    Article  CAS  PubMed  Google Scholar 

  72. Zipfel PF, Skerka C (2009) Complement regulators and inhibitory proteins. Nat Rev Immunol 9:729–740

    Article  CAS  PubMed  Google Scholar 

  73. Jokiranta TS, Solomon A, Pangburn MK, Zipfel PF, Meri S (1999) Nephritogenic lambda light chain dimer: a unique human miniautoantibody against complement factor H. J Immunol 163:4590–4596

    CAS  PubMed  Google Scholar 

  74. Lorcy N, Rioux-Leclercq N, Lombard ML, Le Pogamp P, Vigneau C (2011) Three kidneys, two diseases, one antibody? Nephrol Dial Transplant 26:3811–3813

    Article  PubMed  Google Scholar 

  75. Bridoux F, Desport E, Fremeaux-Bacchi V, Chong CF, Gombert JM, Lacombe C, Quellard N, Touchard G (2011) Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association? Clin J Am Soc Nephrol 6:2165–2174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Dragon Durey MA, Sinha A, Togarsimalemath SK, Bagga A (2016) Anti-complement-factor H-associated glomerulopathies. Nat Rev Nephrol 12:563–578

    Article  CAS  Google Scholar 

  77. Nozal P, Strobel S, Ibernon M, Lopez D, Sanchez-Corral P, Rodriguez de Cordoba S, Jozsi M, Lopez-Trascasa M (2012) Anti-factor H antibody affecting factor H cofactor activity in a patient with dense deposit disease. Clin Kidney J 5:133–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Blanc C, Roumenina LT, Ashraf Y, Hyvarinen S, Sethi SK, Ranchin B, Niaudet P, Loirat C, Gulati A, Bagga A, Fridman WH, Sautes-Fridman C, Jokiranta TS, Fremeaux-Bacchi V, Dragon-Durey MA (2012) Overall neutralization of complement factor H by autoantibodies in the acute phase of the autoimmune form of atypical hemolytic uremic syndrome. J Immunol 189:3528–3537

    Article  CAS  PubMed  Google Scholar 

  79. Bhattacharjee A, Reuter S, Trojnar E, Kolodziejczyk R, Seeberger H, Hyvarinen S, Uzonyi B, Szilagyi A, Prohaszka Z, Goldman A, Jozsi M, Jokiranta TS (2015) The major autoantibody epitope on factor H in atypical hemolytic uremic syndrome is structurally different from its homologous site in factor H-related protein 1, supporting a novel model for induction of autoimmunity in this disease. J Biol Chem 290:9500–9510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sethi S, Zand L, Leung N, Smith RJ, Jevremonic D, Herrmann SS, Fervenza FC (2010) Membranoproliferative glomerulonephritis secondary to monoclonal gammopathy. Clin J Am Soc Nephrol 5:770–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Rousset-Rouviere C, Cailliez M, Garaix F, Bruno D, Laurent D, Tsimaratos M (2014) Rituximab fails where eculizumab restores renal function in C3nef-related DDD. Pediatr Nephrol 29:1107–1111

    Article  PubMed  Google Scholar 

  82. Daina E, Noris M, Remuzzi G (2012) Eculizumab in a patient with dense-deposit disease. N Engl J Med 366:1161–1163

    Article  CAS  PubMed  Google Scholar 

  83. Goodship TH, Cook HT, Fakhouri F, Fervenza FC, Fremeaux-Bacchi V, Kavanagh D, Nester CM, Noris M, Pickering MC, Rodriguez de Cordoba S, Roumenina LT, Sethi S, Smith RJ (2017) Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int 91:539–551

    Article  CAS  PubMed  Google Scholar 

  84. Rabasco C, Cavero T, Roman E, Rojas-Rivera J, Olea T, Espinosa M, Cabello V, Fernandez-Juarez G, Gonzalez F, Avila A, Baltar JM, Diaz M, Alegre R, Elias S, Anton M, Frutos MA, Pobes A, Blasco M, Martin F, Bernis C, Macias M, Barroso S, de Lorenzo A, Ariceta G, Lopez-Mendoza M, Rivas B, Lopez-Revuelta K, Campistol JM, Mendizabal S, de Cordoba SR, Praga M (2015) Effectiveness of mycophenolate mofetil in C3 glomerulonephritis. Kidney Int 88:1153–1160

    Article  CAS  PubMed  Google Scholar 

  85. Ricklin D, Mastellos DC, Reis ES, Lambris JD (2017) The renaissance of complement therapeutics. Nat Rev Nephrol 14:26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Vivarelli M, Emma F (2014) Treatment of C3 glomerulopathy with complement blockers. Semin Thromb Hemost 40:472–477

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was partially supported by Fondazione ART per la Ricerca sui Trapianti ART ONLUS (Milano, Italy), The Kidneeds Foundation (Iowa City, Iowa) and by a grant from Ministero della Salute (RF-2016-02361720, Italy). We wish to thank Kerstin Mierke for revising English grammar and style.

Author information

Authors and Affiliations

  1. IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”, Ranica, Bergamo, Italy

    Marina Noris, Roberta Donadelli & Giuseppe Remuzzi

  2. Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy

    Giuseppe Remuzzi

  3. Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy

    Giuseppe Remuzzi

Authors
  1. Marina Noris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberta Donadelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giuseppe Remuzzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marina Noris.

Ethics declarations

Conflict of interest

Marina Noris has received honoraria from Alexion Pharmaceuticals for giving lectures and participating in advisory boards. None of these activities have had any influence on the results or interpretation in this article. GR has consultancy agreements with AbbVie*, Alexion Pharmaceuticals*, Bayer Healthcare*, Reata Pharmaceuticals*, Novartis Pharma*, AstraZeneca*, Otsuka Pharmaceutical Europe* and Concert Pharmaceuticals*.

*No personal remuneration is accepted, and compensations are paid to his institution for research and educational activities. The other authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Noris, M., Donadelli, R. & Remuzzi, G. Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy. Pediatr Nephrol 34, 1311–1323 (2019). https://doi.org/10.1007/s00467-018-3989-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-018-3989-0

Keywords

Search

Navigation