Pediatric Nephrology

, Volume 22, Issue 1, pp 2–9

MPGN II – genetically determined by defective complement regulation?

  • Christoph Licht
  • Ursula Schlötzer-Schrehardt
  • Michael Kirschfink
  • Peter F. Zipfel
  • Bernd Hoppe
Editorial Commentary

Abstract

MPGN II is a rare disease which is characterized by complement containing deposits within the GBM. The disease is characterized by functional impairment of the GBM causing progressive loss of renal function eventually resulting in end stage renal disease.

It now becomes evident that in addition to C3NeF, which inhibits the inactivation of the alternative C3 convertase C3bBb, different genetically determined factors are also involved in the pathogenesis of MPGN II. These factors though different from C3NeF also result in defective complement regulation acting either through separate pathways or synergistically with C3NeF. Following the finding of MPGN II in Factor H deficient animals, patients with MPGN II were identified presenting with an activated complement system caused by Factor H deficiency. Factor H gene mutations result in a lack of plasma Factor H or in a functional defect of Factor H protein. Loss of Factor H function can also be caused by inactivating Factor H autoantibodies, C3 mutations preventing interaction between C3 and Factor H, or autoantibodies against C3.

Identification of patients with MPGN II caused by defective complement control may allow treatment by replacement of the missing factor via plasma infusion, thus possibly preventing or at least delaying disease progress.

Keywords

Membranoproliferative glomerulonephritis type II (MPGN II) Alternative pathway of the complement system C3 nephritic factor (C3NeF) Factor H Factor H autoantibodies 

References

  1. 1.
    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 16:1392–1403PubMedCrossRefGoogle Scholar
  2. 2.
    Schaerer K (2002) Membranoproliferative glomerulonephritis. In: Schärer K, Mehls O (eds) Pädiatrische Nephrologie. Springer, Berlin Heidelberg New York, pp 230–232Google Scholar
  3. 3.
    Zipfel PF, Heinen S, Jozsi M, Skerka C (2006) Complement and diseases: defective alternative pathway control results in kidney and eye diseases. Mol Immunol 43:97–106PubMedCrossRefGoogle Scholar
  4. 4.
    Jackson EC, McAdams AJ, Strife CF, Forristal J, Welch TR, West CD (1987) Differences between membranoproliferative glomerulonephritis types I and III in clinical presentation, glomerular morphology, and complement perturbation. Am J Kidney Dis 9:115–120PubMedGoogle Scholar
  5. 5.
    Johnson RJ, Alpers CE, Schena FP (2003) Membranoproliferative glomerulonephritis and cryoglobulinemic glomerulonephritis. In: Johnson RJ, Feehally J (eds) Comprehensive clinical nephrology. Mosby, Edinburgh, pp 25.1–25.10Google Scholar
  6. 6.
    International Study of Kidney Diseases in Children (1981) The primary nephrotic syndrome in children. Identification of patients with minimal change nephritic syndrome from initial response to prednisone. J Pediatr 98:561–564CrossRefGoogle Scholar
  7. 7.
    Ault BH (2000) Factor H and the pathogenesis of renal disease. Pediatr Nephrol 14:1045–1053PubMedCrossRefGoogle Scholar
  8. 8.
    Schwertz R, de Jong R, Gretz N, Kirschfink M, Anders D, Schärer K; Arbeitsgemeinschaft Pädiatrische Nephrologie (1996) Outcome of idiopathic membranoproliferative glomerulonephritis in children. Acta Paediatr 85:308–312PubMedCrossRefGoogle Scholar
  9. 9.
    Hogasen K, Jansen JH, Mollnes TE, Hovdenes J, Harboe M (1995) Hereditary porcine membranoproliferative glomerulonephritis type II is caused by factor H deficiency. J Clin Invest 95:1054–1061PubMedCrossRefGoogle Scholar
  10. 10.
    Jansen JH, Hogasen K, Grondahl AM (1995) Porcine membranoproliferative glomerulonephritis type II: an autosomal recessive deficiency of factor H. Vet Rec 137:240–244PubMedGoogle Scholar
  11. 11.
    Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport MJ, Botto M (2002) Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 31:424–428PubMedGoogle Scholar
  12. 12.
    Daha MR, Fearon DT, Austen KF (1976) C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase. J Immunol 116:1–7PubMedGoogle Scholar
  13. 13.
    West CD (1994) Nephritic factors predispose to chronic glomerulonephritis. Am J Kidney Dis 24:956–963PubMedGoogle Scholar
  14. 14.
    West CD, McAdams AJ (1999) The alternative pathway C3 convertase and glomerular deposits. Pediatr Nephrol 13:448–453PubMedCrossRefGoogle Scholar
  15. 15.
    Thurman JM, Holers VM (2006) The central role of the alternative complement pathway in human disease. J Immunol 176:1305–1310PubMedGoogle Scholar
  16. 16.
    Walport MJ (2001) Complement (first of two parts). N Engl J Med 344:1058–1066PubMedCrossRefGoogle Scholar
  17. 17.
    Walport MJ (2001) Complement (second of two parts). N Engl J Med 344:1140–1144PubMedCrossRefGoogle Scholar
  18. 18.
    Zipfel PF (2001) Complement factor H: physiology and pathophysiology. Semin Thromb Hemost 27:191–199PubMedCrossRefGoogle Scholar
  19. 19.
    Fearon DT (1978) Regulation by membrane sialic acid of beta1H-dependent decay-dissociation of amplification C3 convertase of the alternative complement pathway. Proc Natl Acad Sci USA 75:1971–1975PubMedCrossRefGoogle Scholar
  20. 20.
    Pangburn MK, Pangburn KL, Koistinen V, Meri S, Sharma AK (2000) Molecular mechanisms of target recognition in an innate immune system: interactions among factor H, C3b, and target in the alternative pathway of human complement. J Immunol 164:4742–4751PubMedGoogle Scholar
  21. 21.
    Zipfel PF, Smith RJH, Heinen S (2005) The role of complement in membranoproliferative glomerulonephritis. In: Zipfel PF (ed) Complement and kidney diseases. Birkhäuser, Basel, pp 199–221Google Scholar
  22. 22.
    Caprioli J, Bettinaglio P, Zipfel PF, Amadei B, Daina E, Gamba S, Skerka C, Marziliano N, Remuzzi G, Noris M (2001) The molecular basis of familial hemolytic uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20. J Am Soc Nephrol 12:297–307PubMedGoogle Scholar
  23. 23.
    Licht C, Weyersberg A, Heinen S, Stapenhorst L, Devenge J, Beck B, Waldherr R, Kirschfink M, Zipfel PF, Hoppe B (2005) Successful plasma therapy for atypical hemolytic uremic syndrome (aHUS) caused by factor H deficiency due to a mutation in the complement cofactor protein (CCP) domain 15. Am J Kidney Dis 45:415–421PubMedCrossRefGoogle Scholar
  24. 24.
    Schwertz R, Rother U, Anders D, Gretz N, Schärer K, Kirschfink M (2001) Complement analysis in children with idiopathic membranoproliferative glomerulonephritis: a long-term follow-up. Pediatr Allergy Immunol 12:166–172PubMedCrossRefGoogle Scholar
  25. 25.
    Daha MR, Van Es LA (1981) Stabilization of homologous and heterologous cell-bound amplification convertases, C3bBb, by C3 nephritic factor. Immunology 43:33–38PubMedGoogle Scholar
  26. 26.
    Weiler JM, Daha MR, Austen KF, Fearon DT (1976) Control of the amplification convertase of complement by the plasma protein b1H. Proc Natl Acad Sci USA 73:3268–3272PubMedCrossRefGoogle Scholar
  27. 27.
    Józsi M, Manuelian T, Heinen S, Oppermann M, Zipfel PF (2004) Attachment of the soluble complement regulator factor H to the cell and tissue surfaces: relevance for pathology. Histol Histopathol 19:251–258PubMedGoogle Scholar
  28. 28.
    Ault BH, Schmidt BZ, Fowler NL, Kashtan CE, Ahmed AE, Vogt BA, Colten HR (1997) Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism. J Biol Chem 272:25168–25175PubMedCrossRefGoogle Scholar
  29. 29.
    Cunningham PN, Quigg RJ (2005) Contrasting roles of complement activation and its regulation in membranous nephropathy. J Am Soc Nephrol 16:1214–1222PubMedCrossRefGoogle Scholar
  30. 30.
    Hegasy GA, Manuelian T, Hogasen K, Jansen JH, Zipfel PF (2002) The molecular basis for hereditary porcine membranoproliferative glomerulonephritis type II. Am J Pathol 161:2027–2034PubMedGoogle Scholar
  31. 31.
    Licht C, Heinen S, Józsi M, Löschmann I, Saunders RE, Perkins SJ, Waldherr R, Skerka C, Kirschfink M, Hoppe B, Zipfel PF (2006) Deletion of Lys224 in the regulatory domain 4 of factor H reveals a novel pathomechanism for dense deposit disease. Kidney Int 70:42–50PubMedCrossRefGoogle Scholar
  32. 32.
    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 163:4590–4596PubMedGoogle Scholar
  33. 33.
    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 175:939–950PubMedCrossRefGoogle Scholar
  34. 34.
    Lindshaw MA, Stapleton FB, Cuppage FE, Forristal J, West CD, Schreiber RD, Wilson CB (1987) Hypocomplementemic glomerulonephritis in an infant and mother. Evidence for an abnormal form of C3. Am J Nephrol 7:470–477CrossRefGoogle Scholar
  35. 35.
    Marder HK, Coleman TH, Forristal J, Beischel L, West CD (1983) An inherited defect in the C3 convertase, C3b,Bb, associated with glomerulonephritis. Kidney Int 23:749–758PubMedCrossRefGoogle Scholar
  36. 36.
    Jelezarova E, Lutz HU (2005) IgG naturally occurring antibodies stabilize and promote the generation of the alternative complement pathway C3 convertase. Mol Immunol 42:1393–1403PubMedCrossRefGoogle Scholar
  37. 37.
    Jones G, Juszczak M, Kingdon E, Harber M, Sweny P, Burns A (2004) Treatment of idiopathic membranoproliferative glomerulonephritis with mycophenolate mofetil and steroids. Nephrol Dial Transplant 19:3160–3164PubMedCrossRefGoogle Scholar
  38. 38.
    Levin A (1999) Management of membranoproliferative glomerulonephritis: evidence-based recommendations. Kidney Int 55:S41–S46CrossRefGoogle Scholar
  39. 39.
    Gross O, Beirowski B, Koepke ML, Kuck J, Reiner M, Addicks K, Smyth N, Schulze-Lohoff E, Weber M (2003) Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int 63:438–446PubMedCrossRefGoogle Scholar
  40. 40.
    Gross O, Schulze-Lohoff E, Koepke ML, Beirowski B, Addicks K, Bloch W, Smyth N, Weber M (2004) Antifibrotic, nephroprotective potential of ACE inhibitor vs AT1 antagonist in a murine model of renal fibrosis. Nephrol Dial Transplant 19:1716–1723PubMedCrossRefGoogle Scholar
  41. 41.
    Alexander JJ, Pickering MC, Haas M, Osawe I, Quigg RJ (2005) Complement factor H limits immune complex deposition and prevents inflammation and scarring in glomeruli of mice with chronic serum sickness. J Am Soc Nephrol 16:52–57PubMedCrossRefGoogle Scholar
  42. 42.
    Kurtz KA, Schlueter AJ (2002) Management of membranoproliferative glomerulonephritis type II with plasmapheresis. J Clin Apheresis 17:135–137PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2006

Authors and Affiliations

  • Christoph Licht
    • 1
    • 5
  • Ursula Schlötzer-Schrehardt
    • 2
  • Michael Kirschfink
    • 3
  • Peter F. Zipfel
    • 4
  • Bernd Hoppe
    • 1
  1. 1.Children’s Hospital of the University of CologneCologneGermany
  2. 2.Department of OphthalmologyUniversity of Erlangen-NürnbergErlangenGermany
  3. 3.Institute of ImmunologyUniversity of HeidelbergHeidelbergGermany
  4. 4.Leibniz Institute for Natural Products Research and Infection BiologyJenaGermany
  5. 5.Division of NephrologyThe Hospital for Sick ChildrenTorontoCanada

Personalised recommendations