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Pediatric Nephrology

, Volume 26, Issue 1, pp 41–57 | Cite as

aHUS caused by complement dysregulation: new therapies on the horizon

  • Aoife M. Waters
  • Christoph Licht
Educational Review

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a heterogeneous disease that is caused by defective complement regulation in over 50% of cases. Mutations have been identified in genes encoding both complement regulators [complement factor H (CFH), complement factor I (CFI), complement factor H-related proteins (CFHR), and membrane cofactor protein (MCP)], as well as complement activators [complement factor B (CFB) and C3]. More recently, mutations have also been identified in thrombomodulin (THBD), an anticoagulant glycoprotein that plays a role in the inactivation of C3a and C5a. Inhibitory autoantibodies to CFH account for an additional 5–10% of cases and can occur in isolation or in association with mutations in CFH, CFI, CFHR 1, 3, 4, and MCP. Plasma therapies are considered the mainstay of therapy in aHUS secondary to defective complement regulation and may be administered as plasma infusions or plasma exchange. However, in certain cases, despite initiation of plasma therapy, renal function continues to deteriorate with progression to end-stage renal disease and renal transplantation. Recently, eculizumab, a humanized monoclonal antibody against C5, has been described as an effective therapeutic strategy in the management of refractory aHUS that has failed to respond to plasma therapy. Clinical trials are now underway to further evaluate the efficacy of eculizumab in the management of both plasma-sensitive and plasma-resistant aHUS.

Keywords

Atypical hemolytic uremic syndrome Defective complement regulation Plasma therapy Eculizumab 

Notes

Supplementary material

467_2010_1556_MOESM1_ESM.doc (180 kb)
Supplementary Materials (DOC 179 kb)

References

  1. 1.
    Karpman D, Landau D, Loirat C, Proesmans W, Remuzzi G, Rizzoni G, Taylor CM, Van de Kar N, Zimmerhackl LB (2006) A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney Int 70:423–431PubMedGoogle Scholar
  2. 2.
    Karmali MA, Petric M, Lim C, Fleming PC, Steele BT (1983) Escherichia coli cytotoxin, haemolytic-uraemic syndrome, and haemorrhagic colitis. Lancet 2:1299–1300PubMedCrossRefGoogle Scholar
  3. 3.
    Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, Loirat C, Pecoraro C, Taylor CM, Van de Kar N, Vandewalle J, Zimmerhackl LB (2009) Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 24:687–696PubMedCrossRefGoogle Scholar
  4. 4.
    Noris M, Remuzzi G (2005) Genetic abnormalities of complement regulators in hemolytic uremic syndrome: how do they affect patient management? Nat Clin Pract Nephrol 1:2–3PubMedCrossRefGoogle Scholar
  5. 5.
    Noris M, Remuzzi G (2009) Atypical hemolytic-uremic syndrome. N Engl J Med 361:1676–1687PubMedCrossRefGoogle Scholar
  6. 6.
    Taylor CM, Machin S, Wigmore SJ, Goodship TH (2010) Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 148:37–47PubMedCrossRefGoogle Scholar
  7. 7.
    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
  8. 8.
    Caprioli J, Castelletti F, Bucchioni S, Bettinaglio P, Bresin E, Pianetti G, Gamba S, Brioschi S, Daina E, Remuzzi G, Noris M (2003) Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease. Hum Mol Genet 12:3385–3395PubMedCrossRefGoogle Scholar
  9. 9.
    Dragon-Durey MA, Fremeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, Coppo P, Herman Fridman W, Weiss L (2004) Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol 15:787–795PubMedCrossRefGoogle Scholar
  10. 10.
    Manuelian T, Hellwage J, Meri S, Caprioli J, Noris M, Heinen S, Jozsi M, Neumann HP, Remuzzi G, Zipfel PF (2003) Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J Clin Invest 111:1181–1190PubMedGoogle Scholar
  11. 11.
    Perez-Caballero D, Gonzalez-Rubio C, Gallardo ME, Vera M, Lopez-Trascasa M, Rodriguez de Cordoba S, Sanchez-Corral P (2001) Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. Am J Hum Genet 68:478–484PubMedCrossRefGoogle Scholar
  12. 12.
    Venables JP, Strain L, Routledge D, Bourn D, Powell HM, Warwicker P, Diaz-Torres ML, Sampson A, Mead P, Webb M, Pirson Y, Jackson MS, Hughes A, Wood KM, Goodship JA, Goodship TH (2006) Atypical haemolytic uraemic syndrome associated with a hybrid complement gene. PLoS Med 3:e431PubMedCrossRefGoogle Scholar
  13. 13.
    Warwicker P, Goodship TH, Donne RL, Pirson Y, Nicholls A, Ward RM, Turnpenny P, Goodship JA (1998) Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 53:836–844PubMedCrossRefGoogle Scholar
  14. 14.
    Bienaime F, Dragon-Durey MA, Regnier CH, Nilsson SC, Kwan WH, Blouin J, Jablonski M, Renault N, Rameix-Welti MA, Loirat C, Sautes-Fridman C, Villoutreix BO, Blom AM, Fremeaux-Bacchi V (2010) Mutations in components of complement influence the outcome of factor I-associated atypical hemolytic uremic syndrome. Kidney Int 77:339–349PubMedCrossRefGoogle Scholar
  15. 15.
    Chan MR, Thomas CP, Torrealba JR, Djamali A, Fernandez LA, Nishimura CJ, Smith RJ, Samaniego MD (2009) Recurrent atypical hemolytic uremic syndrome associated with factor I mutation in a living-related renal transplant recipient. Am J Kidney Dis 53:321–326PubMedCrossRefGoogle Scholar
  16. 16.
    Cruzado JM, de Cordoba SR, Melilli E, Bestard O, Rama I, Sanchez-Corral P, Lopez-Trascasa M, Navarro I, Torras J, Goma M, Grinyo JM (2009) Successful renal transplantation in a patient with atypical hemolytic uremic syndrome carrying mutations in both factor I and MCP. Am J Transplant 9:1477–1483PubMedCrossRefGoogle Scholar
  17. 17.
    Esparza-Gordillo J, Jorge EG, Garrido CA, Carreras L, Lopez-Trascasa M, Sanchez-Corral P, de Cordoba SR (2006) Insights into hemolytic uremic syndrome: segregation of three independent predisposition factors in a large, multiple affected pedigree. Mol Immunol 43:1769–1775PubMedCrossRefGoogle Scholar
  18. 18.
    Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, Vigneau C, Kuypers D, Boudailliez B, Loirat C, Rondeau E, Fridman WH (2004) Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet 41:e84PubMedCrossRefGoogle Scholar
  19. 19.
    Kavanagh D, Kemp EJ, Mayland E, Winney RJ, Duffield JS, Warwick G, Richards A, Ward R, Goodship JA, Goodship TH (2005) Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J Am Soc Nephrol 16:2150–2155PubMedCrossRefGoogle Scholar
  20. 20.
    Kavanagh D, Richards A, Noris M, Hauhart R, Liszewski MK, Karpman D, Goodship JA, Fremeaux-Bacchi V, Remuzzi G, Goodship TH, Atkinson JP (2008) Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome. Mol Immunol 45:95–105PubMedCrossRefGoogle Scholar
  21. 21.
    Le Quintrec M, Zuber J, Noel LH, Thervet E, Fremeaux-Bacchi V, Niaudet P, Fridman WH, Legendre C, Dragon-Durey MA (2009) Anti-factor H autoantibodies in a fifth renal transplant recipient with atypical hemolytic and uremic syndrome. Am J Transplant 9:1223–1229PubMedCrossRefGoogle Scholar
  22. 22.
    Nilsson SC, Kalchishkova N, Trouw LA, Fremeaux-Bacchi V, Villoutreix BO, Blom AM (2009) Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I. Eur J Immunol 40:172–185CrossRefGoogle Scholar
  23. 23.
    Ponce-Castro IM, Gonzalez-Rubio C, Delgado-Cervino EM, Abarrategui-Garrido C, Fontan G, Sanchez-Corral P, Lopez-Trascasa M (2008) Molecular characterization of complement factor I deficiency in two Spanish families. Mol Immunol 45:2764–2771PubMedCrossRefGoogle Scholar
  24. 24.
    Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, Macher MA, Niaudet P, Guest G, Boudailliez B, Bouissou F, Deschenes G, Gie S, Tsimaratos M, Fischbach M, Morin D, Nivet H, Alberti C, Loirat C (2007) Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 18:2392–2400PubMedCrossRefGoogle Scholar
  25. 25.
    Jozsi M, Licht C, Strobel S, Zipfel SL, Richter H, Heinen S, Zipfel PF, Skerka C (2008) Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood 111:1512–1514PubMedCrossRefGoogle Scholar
  26. 26.
    Heinen S, Hartmann A, Lauer N, Wiehl U, Dahse HM, Schirmer S, Gropp K, Enghardt T, Wallich R, Halbich S, Mihlan M, Schlotzer-Schrehardt U, Zipfel PF, Skerka C (2009) Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood 114:2439–2447PubMedCrossRefGoogle Scholar
  27. 27.
    Couzi L, Contin-Bordes C, Marliot F, Sarrat A, Grimal P, Moreau JF, Merville P, Fremeaux-Bacchi V (2008) Inherited deficiency of membrane cofactor protein expression and varying manifestations of recurrent atypical hemolytic uremic syndrome in a sibling pair. Am J Kidney Dis 52:e5–e9PubMedCrossRefGoogle Scholar
  28. 28.
    Fremeaux-Bacchi V, Arzouk N, Ferlicot S, Charpentier B, Snanoudj R, Durrbach A (2007) Recurrence of HUS due to CD46/MCP mutation after renal transplantation: a role for endothelial microchimerism. Am J Transplant 7:2047–2051PubMedCrossRefGoogle Scholar
  29. 29.
    Fremeaux-Bacchi V, Moulton EA, Kavanagh D, Dragon-Durey MA, Blouin J, Caudy A, Arzouk N, Cleper R, Francois M, Guest G, Pourrat J, Seligman R, Fridman WH, Loirat C, Atkinson JP (2006) Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. J Am Soc Nephrol 17:2017–2025PubMedCrossRefGoogle Scholar
  30. 30.
    Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F, Gamba S, Remuzzi G (2003) Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 362:1542–1547PubMedCrossRefGoogle Scholar
  31. 31.
    Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, Decorte R, Muslumanoglu MH, Kavukcu S, Filler G, Pirson Y, Wen LS, Atkinson JP, Goodship TH (2003) Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci USA 100:12966–12971PubMedCrossRefGoogle Scholar
  32. 32.
    Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, Lopez-Trascasa M, Sanchez-Corral P, Morgan BP, Rodriguez de Cordoba S (2007) Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci USA 104:240–245PubMedCrossRefGoogle Scholar
  33. 33.
    Kavanagh D, Goodship TH, Richards A (2006) Atypical haemolytic uraemic syndrome. Br Med Bull 77–78:5–22PubMedCrossRefGoogle Scholar
  34. 34.
    Fremeaux-Bacchi V, Miller EC, Liszewski MK, Strain L, Blouin J, Brown AL, Moghal N, Kaplan BS, Weiss RA, Lhotta K, Kapur G, Mattoo T, Nivet H, Wong W, Gie S, Hurault de Ligny B, Fischbach M, Gupta R, Hauhart R, Meunier V, Loirat C, Dragon-Durey MA, Fridman WH, Janssen BJ, Goodship TH, Atkinson JP (2008) Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 112:4948–4952PubMedCrossRefGoogle Scholar
  35. 35.
    Lhotta K, Janecke AR, Scheiring J, Petzlberger B, Giner T, Fally V, Wurzner R, Zimmerhackl LB, Mayer G, Fremeaux-Bacchi V (2009) A large family with a gain-of-function mutation of complement C3 predisposing to atypical hemolytic uremic syndrome, microhematuria, hypertension and chronic renal failure. Clin J Am Soc Nephrol 4:1356–1362PubMedCrossRefGoogle Scholar
  36. 36.
    Geelen J, van den Dries K, Roos A, van de Kar N, de Kat AC, Klasen I, Monnens L, van den Heuvel L (2007) A missense mutation in factor I (IF) predisposes to atypical haemolytic uraemic syndrome. Pediatr Nephrol 22:371–375PubMedCrossRefGoogle Scholar
  37. 37.
    Skerka C, Jozsi M, Zipfel PF, Dragon-Durey MA, Fremeaux-Bacchi V (2009) Autoantibodies in haemolytic uraemic syndrome (HUS). Thromb Haemost 101:227–232PubMedGoogle Scholar
  38. 38.
    Moore I, Strain L, Pappworth I, Kavanagh D, Barlow PN, Herbert AP, Schmidt CQ, Staniforth SJ, Holmes LV, Ward R, Morgan L, Goodship TH, Marchbank KJ (2010) Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4 and with mutations in CFH, CFI, CD46, and C3 in patients with atypical haemolytic uraemic syndrome. Blood 115:379–387PubMedCrossRefGoogle Scholar
  39. 39.
    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 361:345–357PubMedCrossRefGoogle Scholar
  40. 40.
    Nishimura T, Myles T, Piliponsky AM, Kao PN, Berry GJ, Leung LL (2007) Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo. Blood 109:1992–1997PubMedCrossRefGoogle Scholar
  41. 41.
    Loirat C, Noris M, Fremeaux-Bacchi V (2008) Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol 23:1957–1972PubMedCrossRefGoogle Scholar
  42. 42.
    Scheiring J, Rosales A, Zimmerhackl LB (2009) Clinical practice. Today's understanding of the haemolytic uraemic syndrome. Eur J Pediatr 169:7–13Google Scholar
  43. 43.
    Zipfel PF, Skerka C (2009) Complement regulators and inhibitory proteins. Nat Rev Immunol 9:729–740PubMedGoogle Scholar
  44. 44.
    Kaplan BS, Chesney RW, Drummond KN (1975) Hemolytic uremic syndrome in families. N Engl J Med 292:1090–1093PubMedCrossRefGoogle Scholar
  45. 45.
    Kaplan BS (1977) Hemolytic uremic syndrome with recurrent episodes: an important subset. Clin Nephrol 8:495–498PubMedGoogle Scholar
  46. 46.
    Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G (2006) Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108:1267–1279PubMedCrossRefGoogle Scholar
  47. 47.
    Loirat C, Fremeaux-Bacchi V (2008) Hemolytic uremic syndrome recurrence after renal transplantation. Pediatr Transplant 12:619–629PubMedCrossRefGoogle Scholar
  48. 48.
    Esparza-Gordillo J, Goicoechea de Jorge E, Buil A, Carreras Berges L, Lopez-Trascasa M, Sanchez-Corral P, Rodriguez de Cordoba S (2005) Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum Mol Genet 14:703–712PubMedCrossRefGoogle Scholar
  49. 49.
    Pickering MC, Cook HT (2008) Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals. Clin Exp Immunol 151:210–230PubMedCrossRefGoogle Scholar
  50. 50.
    Medzhitov R, Janeway CA Jr (2002) Decoding the patterns of self and nonself by the innate immune system. Science 296:298–300PubMedCrossRefGoogle Scholar
  51. 51.
    Ogden CA, Elkon KB (2006) Role of complement and other innate immune mechanisms in the removal of apoptotic cells. Curr Dir Autoimmun 9:120–142PubMedGoogle Scholar
  52. 52.
    Rooijakkers SH, van Strijp JA (2007) Bacterial complement evasion. Mol Immunol 44:23–32PubMedCrossRefGoogle Scholar
  53. 53.
    Zipfel PF, Wurzner R, Skerka C (2007) Complement evasion of pathogens: common strategies are shared by diverse organisms. Mol Immunol 44:3850–3857PubMedCrossRefGoogle Scholar
  54. 54.
    Pangburn MK, Schreiber RD, Muller-Eberhard HJ (1977) Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein beta1H for cleavage of C3b and C4b in solution. J Exp Med 146:257–270PubMedCrossRefGoogle Scholar
  55. 55.
    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 USA 73:3268–3272PubMedCrossRefGoogle Scholar
  56. 56.
    Whaley K, Ruddy S (1976) Modulation of the alternative complement pathways by beta 1 H globulin. J Exp Med 144:1147–1163PubMedCrossRefGoogle Scholar
  57. 57.
    Zipfel PF, Skerka C (1999) FHL-1/reconectin: a human complement and immune regulator with cell-adhesive function. Immunol Today 20:135–140PubMedCrossRefGoogle Scholar
  58. 58.
    Remuzzi G, Misiani R, Marchesi D, Livio M, Mecca G, de Gaetano G, Donati MB (1978) Haemolytic-uraemic syndrome: deficiency of plasma factor(s) regulating prostacyclin activity? Lancet 2:871–872PubMedCrossRefGoogle Scholar
  59. 59.
    Kleanthous H, Smith HR, Scotland SM, Gross RJ, Rowe B, Taylor CM, Milford DV (1990) Haemolytic uraemic syndromes in the British Isles, 1985-8: association with verocytotoxin producing Escherichia coli. Part 2: Microbiological aspects. Arch Dis Child 65:722–727PubMedCrossRefGoogle Scholar
  60. 60.
    Saunders RE, Goodship TH, Zipfel PF, Perkins SJ (2006) An interactive Web database of factor H-associated hemolytic uremic syndrome mutations: insights into the structural consequences of disease-associated mutations. Hum Mutat 27:21–30PubMedCrossRefGoogle Scholar
  61. 61.
    Allford SL, Hunt BJ, Rose P, Machin SJ (2003) Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol 120:556–573PubMedCrossRefGoogle Scholar
  62. 62.
    Geraghty MT, Perlman EJ, Martin LS, Hayflick SJ, Casella JF, Rosenblatt DS, Valle D (1992) Cobalamin C defect associated with hemolytic-uremic syndrome. J Pediatr 120:934–937PubMedCrossRefGoogle Scholar
  63. 63.
    Barz D, Budde U, Hellstern P (2002) Therapeutic plasma exchange and plasma infusion in thrombotic microvascular syndromes. Thromb Res 107(Suppl 1):S23–S27PubMedCrossRefGoogle Scholar
  64. 64.
    von Baeyer H (2002) Plasmapheresis in thrombotic microangiopathy-associated syndromes: review of outcome data derived from clinical trials and open studies. Ther Apher 6:320–328CrossRefGoogle Scholar
  65. 65.
    Bell WR, Braine HG, Ness PM, Kickler TS (1991) Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med 325:398–403PubMedCrossRefGoogle Scholar
  66. 66.
    Rizvi MA, Vesely SK, George JN, Chandler L, Duvall D, Smith JW, Gilcher RO (2000) Complications of plasma exchange in 71 consecutive patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome. Transfusion 40:896–901PubMedCrossRefGoogle Scholar
  67. 67.
    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 caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15. Am J Kidney Dis 45:415–421PubMedCrossRefGoogle Scholar
  68. 68.
    Zurowska A, Zaluska-Lesniewska I, Hladny-Czerska W (2006) Successful prophylactic plasma infusions in recurrent atypical hemolytic-uremic syndrome. Przegl Lek 63(Suppl 3):223–225PubMedGoogle Scholar
  69. 69.
    O'Shaughnessy DF, Atterbury C, Bolton Maggs P, Murphy M, Thomas D, Yates S, Williamson LM (2004) Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 126:11–28PubMedCrossRefGoogle Scholar
  70. 70.
    Bircan Z, Toprak D, Kilicaslan I, Solakoglu S, Uysal V, Ponard D, Turker G (2004) Factor H deficiency and fibrillary glomerulopathy. Nephrol Dial Transplant 19:727–730PubMedCrossRefGoogle Scholar
  71. 71.
    Brai M, Misiano G, Maringhini S, Cutaja I, Hauptmann G (1988) Combined homozygous factor H and heterozygous C2 deficiency in an Italian family. J Clin Immunol 8:50–56PubMedCrossRefGoogle Scholar
  72. 72.
    Cho HY, Lee BS, Moon KC, Ha IS, Cheong HI, Choi Y (2007) Complete factor H deficiency-associated atypical hemolytic uremic syndrome in a neonate. Pediatr Nephrol 22:874–880PubMedCrossRefGoogle Scholar
  73. 73.
    Fijen CA, Kuijper EJ, Te Bulte M, van de Heuvel MM, Holdrinet AC, Sim RB, Daha MR, Dankert J (1996) Heterozygous and homozygous factor H deficiency states in a Dutch family. Clin Exp Immunol 105:511–516PubMedCrossRefGoogle Scholar
  74. 74.
    Levy M, Halbwachs-Mecarelli L, Gubler MC, Kohout G, Bensenouci A, Niaudet P, Hauptmann G, Lesavre P (1986) H deficiency in two brothers with atypical dense intramembranous deposit disease. Kidney Int 30:949–956PubMedCrossRefGoogle Scholar
  75. 75.
    Nielsen HE, Christensen KC, Koch C, Thomsen BS, Heegaard NH, Tranum-Jensen J (1989) Hereditary, complete deficiency of complement factor H associated with recurrent meningococcal disease. Scand J Immunol 30:711–718PubMedCrossRefGoogle Scholar
  76. 76.
    Ohali M, Shalev H, Schlesinger M, Katz Y, Kachko L, Carmi R, Sofer S, Landau D (1998) Hypocomplementemic autosomal recessive hemolytic uremic syndrome with decreased factor H. Pediatr Nephrol 12:619–624PubMedCrossRefGoogle Scholar
  77. 77.
    Pichette V, Querin S, Schurch W, Brun G, Lehner-Netsch G, Delage JM (1994) Familial hemolytic-uremic syndrome and homozygous factor H deficiency. Am J Kidney Dis 24:936–941PubMedGoogle Scholar
  78. 78.
    Rougier N, Kazatchkine MD, Rougier JP, Fremeaux-Bacchi V, Blouin J, Deschenes G, Soto B, Baudouin V, Pautard B, Proesmans W, Weiss E, Weiss L (1998) Human complement factor H deficiency associated with hemolytic uremic syndrome. J Am Soc Nephrol 9:2318–2326PubMedGoogle Scholar
  79. 79.
    Thompson RA, Winterborn MH (1981) Hypocomplementaemia due to a genetic deficiency of beta 1H globulin. Clin Exp Immunol 46:110–119PubMedGoogle Scholar
  80. 80.
    Vaziri-Sani F, Holmberg L, Sjoholm AG, Kristoffersson AC, Manea M, Fremeaux-Bacchi V, Fehrman-Ekholm I, Raafat R, Karpman D (2006) Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome. Kidney Int 69:981–988PubMedCrossRefGoogle Scholar
  81. 81.
    Vogt BA, Wyatt RJ, Burke BA, Simonton SC, Kashtan CE (1995) Inherited factor H deficiency and collagen type III glomerulopathy. Pediatr Nephrol 9:11–15PubMedCrossRefGoogle Scholar
  82. 82.
    Boyer O, Noel LH, Balzamo E, Guest G, Biebuyck N, Charbit M, Salomon R, Fremeaux-Bacchi V, Niaudet P (2008) Complement factor H deficiency and posttransplantation glomerulonephritis with isolated C3 deposits. Am J Kidney Dis 51:671–677PubMedCrossRefGoogle Scholar
  83. 83.
    Landau D, Shalev H, Levy-Finer G, Polonsky A, Segev Y, Katchko L (2001) Familial hemolytic uremic syndrome associated with complement factor H deficiency. J Pediatr 138:412–417PubMedCrossRefGoogle Scholar
  84. 84.
    Lapeyraque AL, Wagner E, Phan V, Clermont MJ, Merouani A, Fremeaux-Bacchi V, Goodship TH, Robitaille P (2008) Efficacy of plasma therapy in atypical hemolytic uremic syndrome with complement factor H mutations. Pediatr Nephrol 23:1363–1366PubMedCrossRefGoogle Scholar
  85. 85.
    Sethi SK, Marie-Agnes DD, Thaker N, Hari P, Bagga A (2009) Hemolytic uremic syndrome due to homozygous factor H deficiency. Clin Exp Nephrol 13:526–530PubMedCrossRefGoogle Scholar
  86. 86.
    Nathanson S, Fremeaux-Bacchi V, Deschenes G (2001) Successful plasma therapy in hemolytic uremic syndrome with factor H deficiency. Pediatr Nephrol 16:554–556PubMedCrossRefGoogle Scholar
  87. 87.
    Davin JC, Olie KH, Verlaak R, Horuz F, Florquin S, Weening JJ, Groothoff JW, Strain L, Goodship TH (2006) Complement factor H-associated atypical hemolytic uremic syndrome in monozygotic twins: concordant presentation, discordant response to treatment. Am J Kidney Dis 47:e27–e30PubMedCrossRefGoogle Scholar
  88. 88.
    De S, Waters AM, Segal AO, Trautmann A, Harvey EA, Licht C (2010) Severe atypical HUS caused by CFH S1191L-case presentation and review of treatment options. Pediatr Nephrol 25:97–104PubMedCrossRefGoogle Scholar
  89. 89.
    Filler G, Radhakrishnan S, Strain L, Hill A, Knoll G, Goodship TH (2004) Challenges in the management of infantile factor H-associated hemolytic uremic syndrome. Pediatr Nephrol 19:908–911PubMedGoogle Scholar
  90. 90.
    Gerber A, Kirchhoff-Moradpour AH, Obieglo S, Brandis M, Kirschfink M, Zipfel PF, Goodship JA, Zimmerhackl LB (2003) Successful (?) therapy of hemolytic-uremic syndrome with factor H abnormality. Pediatr Nephrol 18:952–955PubMedCrossRefGoogle Scholar
  91. 91.
    Stratton JD, Warwicker P (2002) Successful treatment of factor H-related haemolytic uraemic syndrome. Nephrol Dial Transplant 17:684–685PubMedCrossRefGoogle Scholar
  92. 92.
    Nathanson S, Ulinski T, Fremeaux-Bacchi V, Deschenes G (2006) Secondary failure of plasma therapy in factor H deficiency. Pediatr Nephrol 21:1769–1771PubMedCrossRefGoogle Scholar
  93. 93.
    Dragon-Durey MA, Loirat C, Cloarec S, Macher MA, Blouin J, Nivet H, Weiss L, Fridman WH, Fremeaux-Bacchi V (2005) Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 16:555–563PubMedCrossRefGoogle Scholar
  94. 94.
    Jozsi M, Strobel S, Dahse HM, Liu WS, Hoyer PF, Oppermann M, Skerka C, Zipfel PF (2007) Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome. Blood 110:1516–1518PubMedCrossRefGoogle Scholar
  95. 95.
    Strobel S, Hoyer PF, Mache CJ, Sulyok E, Liu WS, Richter H, Oppermann M, Zipfel PF, Jozsi M (2010) Functional analyses indicate a pathogenic role of factor H autoantibodies in atypical haemolytic uraemic syndrome. Nephrol Dial Transplant 25:136–144PubMedCrossRefGoogle Scholar
  96. 96.
    Abarrategui-Garrido C, Martinez-Barricarte R, Lopez-Trascasa M, de Cordoba SR, Sanchez-Corral P (2009) Characterization of complement factor H-related (CFHR) proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical hemolytic uremic syndrome. Blood 114:4261–4271PubMedCrossRefGoogle Scholar
  97. 97.
    Lee BH, Kwak SH, Shin JI, Lee SH, Choi HJ, Kang HG, Ha IS, Lee JS, Dragon-Durey MA, Choi Y, Cheong HI (2009) Atypical hemolytic uremic syndrome associated with complement factor H autoantibodies and CFHR1/CFHR3 deficiency. Pediatr Res 66:336–340PubMedCrossRefGoogle Scholar
  98. 98.
    Waters AM, Pappworth I, Marchbank K, Bockenhauer D, Tullus K, Pickering MC, Strain L, Sebire N, Shroff R, Marks SD, Goodship TH, Rees L (2010) Successful renal transplantation in factor H autoantibody associated HUS with CFHR1 and 3 deficiency and CFH variant G2850T. Am J Transplant 10:168–172PubMedCrossRefGoogle Scholar
  99. 99.
    Kwon T, Dragon-Durey MA, Macher MA, Baudouin V, Maisin A, Peuchmaur M, Fremeaux-Bacchi V, Loirat C (2008) Successful pre-transplant management of a patient with anti-factor H autoantibodies-associated haemolytic uraemic syndrome. Nephrol Dial Transplant 23:2088–2090PubMedCrossRefGoogle Scholar
  100. 100.
    Davin JC, Gracchi V, Bouts A, Groothoff J, Strain L, Goodship T (2010) Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a CFH Mutation. Am J Kidney Dis 55:708–711PubMedCrossRefGoogle Scholar
  101. 101.
    Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship TH, Remuzzi G (2006) Outcome of renal transplantation in patients with non-Shiga toxin-associated hemolytic uremic syndrome: prognostic significance of genetic background. Clin J Am Soc Nephrol 1:88–99PubMedCrossRefGoogle Scholar
  102. 102.
    Nilsson SC, Karpman D, Vaziri-Sani F, Kristoffersson AC, Salomon R, Provot F, Fremeaux-Bacchi V, Trouw LA, Blom AM (2007) A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation. Mol Immunol 44:1835–1844PubMedCrossRefGoogle Scholar
  103. 103.
    Chatelet V, Fremeaux-Bacchi V, Lobbedez T, Ficheux M, de Ligny BH (2009) Safety and long-term efficacy of eculizumab in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome. Am J Transplant 9:2644–2645PubMedCrossRefGoogle Scholar
  104. 104.
    Jalanko H, Peltonen S, Koskinen A, Puntila J, Isoniemi H, Holmberg C, Pinomaki A, Armstrong E, Koivusalo A, Tukiainen E, Makisalo H, Saland J, Remuzzi G, de Cordoba S, Lassila R, Meri S, Jokiranta TS (2008) Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H. Am J Transplant 8:216–221PubMedGoogle Scholar
  105. 105.
    Saland JM, Ruggenenti P, Remuzzi G (2009) Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol 20:940–949PubMedCrossRefGoogle Scholar
  106. 106.
    Saland JM, Shneider BL, Bromberg JS, Shi PA, Ward SC, Magid MS, Benchimol C, Seikaly MG, Emre SH, Bresin E, Remuzzi G (2009) Successful split liver-kidney transplant for factor H associated hemolytic uremic syndrome. Clin J Am Soc Nephrol 4:201–206PubMedCrossRefGoogle Scholar
  107. 107.
    Remuzzi G, Ruggenenti P, Codazzi D, Noris M, Caprioli J, Locatelli G, Gridelli B (2002) Combined kidney and liver transplantation for familial haemolytic uraemic syndrome. Lancet 359:1671–1672PubMedCrossRefGoogle Scholar
  108. 108.
    Remuzzi G, Ruggenenti P, Colledan M, Gridelli B, Bertani A, Bettinaglio P, Bucchioni S, Sonzogni A, Bonanomi E, Sonzogni V, Platt JL, Perico N, Noris M (2005) Hemolytic uremic syndrome: a fatal outcome after kidney and liver transplantation performed to correct factor H gene mutation. Am J Transplant 5:1146–1150PubMedCrossRefGoogle Scholar
  109. 109.
    Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, Decorte R, Muslumanoglu MH, Kavukcu S, Filler G, Pirson Y, Wen LS, Atkinson JP, Goodship TH (2003) Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci USA 100:12966–12971PubMedCrossRefGoogle Scholar
  110. 110.
    Donne RL, Abbs I, Barany P, Elinder CG, Little M, Conlon P, Goodship TH (2002) Recurrence of hemolytic uremic syndrome after live-related renal transplantation associated with subsequent de novo disease in the donor. Am J Kidney Dis 40:E22PubMedCrossRefGoogle Scholar
  111. 111.
    Gruppo RA, Rother RP (2009) Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med 360:544–546PubMedCrossRefGoogle Scholar
  112. 112.
    Mache CJ, Acham-Roschitz B, Fremeaux-Bacchi V, Kirschfink M, Zipfel PF, Roedl S, Vester U, Ring E (2009) Complement inhibitor eculizumab in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 4:1312–1316PubMedCrossRefGoogle Scholar
  113. 113.
    Nurnberger J, Witzke O, Opazo Saez A, Vester U, Baba HA, Kribben A, Zimmerhackl LB, Janecke AR, Nagel M, Kirschfink M (2009) Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med 360:542–544PubMedCrossRefGoogle Scholar
  114. 114.
    Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP (2004) Effect of eculizumab on hemolysis and transfusion requirements in paroxysmal nocturnal hemoglobinuria. N Eng J Med 350:552–559CrossRefGoogle Scholar
  115. 115.
    Parker C (2009) Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet 373:759–767PubMedCrossRefGoogle Scholar
  116. 116.
    Wagner E, Frank MM (2010) Therapeutic potential of complement modulation. Nat Rev Drug Discov 9:43–56PubMedCrossRefGoogle Scholar
  117. 117.
    Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L (2007) Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol 25:1256–1264PubMedCrossRefGoogle Scholar
  118. 118.
    Parker CJ, Kar S, Kirkpatrick P (2007) Eculizumab. Nat Rev Drug Discov 6:515–516PubMedCrossRefGoogle Scholar
  119. 119.
    Dmytrijuk A, Robie-Suh K, Cohen MH, Rieves D, Weiss K, Pazdur R (2008) FDA report: eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Oncologist 13:993–1000PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2010

Authors and Affiliations

  1. 1.Department of NephrologyGreat Ormond Street HospitalLondonUK
  2. 2.University College London, Institute of Child HealthLondonUK
  3. 3.Division of NephrologyHospital for Sick ChildrenTorontoCanada
  4. 4.Department of PaediatricsUniversity of TorontoTorontoCanada

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