Skip to main content

Advertisement

SpringerLink
Log in

aHUS caused by complement dysregulation: new therapies on the horizon

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

An Erratum to this article was published on 20 October 2012

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.

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

References

  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 70:423–431

    PubMed  Google Scholar 

  2. Karmali MA, Petric M, Lim C, Fleming PC, Steele BT (1983) Escherichia coli cytotoxin, haemolytic-uraemic syndrome, and haemorrhagic colitis. Lancet 2:1299–1300

    Article  PubMed  CAS  Google Scholar 

  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 24:687–696

    Article  PubMed  Google Scholar 

  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 1:2–3

    Article  PubMed  Google Scholar 

  5. Noris M, Remuzzi G (2009) Atypical hemolytic-uremic syndrome. N Engl J Med 361:1676–1687

    Article  PubMed  CAS  Google Scholar 

  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 148:37–47

    Article  PubMed  CAS  Google Scholar 

  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 12:297–307

    PubMed  CAS  Google Scholar 

  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 12:3385–3395

    Article  PubMed  CAS  Google Scholar 

  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 15:787–795

    Article  PubMed  CAS  Google Scholar 

  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 111:1181–1190

    PubMed  CAS  Google Scholar 

  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 68:478–484

    Article  PubMed  CAS  Google Scholar 

  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:e431

    Article  PubMed  CAS  Google Scholar 

  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 53:836–844

    Article  PubMed  CAS  Google Scholar 

  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 77:339–349

    Article  PubMed  CAS  Google Scholar 

  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 53:321–326

    Article  PubMed  CAS  Google Scholar 

  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 9:1477–1483

    Article  PubMed  CAS  Google Scholar 

  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 43:1769–1775

    Article  PubMed  CAS  Google Scholar 

  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:e84

    Article  PubMed  CAS  Google Scholar 

  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 16:2150–2155

    Article  PubMed  CAS  Google Scholar 

  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 45:95–105

    Article  PubMed  CAS  Google Scholar 

  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 9:1223–1229

    Article  PubMed  Google Scholar 

  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 40:172–185

    Article  CAS  Google Scholar 

  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 45:2764–2771

    Article  PubMed  CAS  Google Scholar 

  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 18:2392–2400

    Article  PubMed  CAS  Google Scholar 

  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 111:1512–1514

    Article  PubMed  CAS  Google Scholar 

  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 114:2439–2447

    Article  PubMed  CAS  Google Scholar 

  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–e9

    Article  PubMed  Google Scholar 

  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 7:2047–2051

    Article  PubMed  CAS  Google Scholar 

  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 17:2017–2025

    Article  PubMed  CAS  Google Scholar 

  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 362:1542–1547

    Article  PubMed  CAS  Google Scholar 

  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 100:12966–12971

    Article  PubMed  CAS  Google Scholar 

  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 104:240–245

    Article  PubMed  CAS  Google Scholar 

  33. Kavanagh D, Goodship TH, Richards A (2006) Atypical haemolytic uraemic syndrome. Br Med Bull 77–78:5–22

    Article  PubMed  Google Scholar 

  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 112:4948–4952

    Article  PubMed  CAS  Google Scholar 

  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 4:1356–1362

    Article  PubMed  CAS  Google Scholar 

  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 22:371–375

    Article  PubMed  Google Scholar 

  37. Skerka C, Jozsi M, Zipfel PF, Dragon-Durey MA, Fremeaux-Bacchi V (2009) Autoantibodies in haemolytic uraemic syndrome (HUS). Thromb Haemost 101:227–232

    PubMed  CAS  Google Scholar 

  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 115:379–387

    Article  PubMed  CAS  Google Scholar 

  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 361:345–357

    Article  PubMed  CAS  Google Scholar 

  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 109:1992–1997

    Article  PubMed  CAS  Google Scholar 

  41. Loirat C, Noris M, Fremeaux-Bacchi V (2008) Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol 23:1957–1972

    Article  PubMed  Google Scholar 

  42. Scheiring J, Rosales A, Zimmerhackl LB (2009) Clinical practice. Today's understanding of the haemolytic uraemic syndrome. Eur J Pediatr 169:7–13

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  44. Kaplan BS, Chesney RW, Drummond KN (1975) Hemolytic uremic syndrome in families. N Engl J Med 292:1090–1093

    Article  PubMed  CAS  Google Scholar 

  45. Kaplan BS (1977) Hemolytic uremic syndrome with recurrent episodes: an important subset. Clin Nephrol 8:495–498

    PubMed  CAS  Google Scholar 

  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 108:1267–1279

    Article  PubMed  CAS  Google Scholar 

  47. Loirat C, Fremeaux-Bacchi V (2008) Hemolytic uremic syndrome recurrence after renal transplantation. Pediatr Transplant 12:619–629

    Article  PubMed  CAS  Google Scholar 

  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 14:703–712

    Article  PubMed  CAS  Google Scholar 

  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 151:210–230

    Article  PubMed  CAS  Google Scholar 

  50. Medzhitov R, Janeway CA Jr (2002) Decoding the patterns of self and nonself by the innate immune system. Science 296:298–300

    Article  PubMed  CAS  Google Scholar 

  51. Ogden CA, Elkon KB (2006) Role of complement and other innate immune mechanisms in the removal of apoptotic cells. Curr Dir Autoimmun 9:120–142

    PubMed  CAS  Google Scholar 

  52. Rooijakkers SH, van Strijp JA (2007) Bacterial complement evasion. Mol Immunol 44:23–32

    Article  PubMed  CAS  Google Scholar 

  53. Zipfel PF, Wurzner R, Skerka C (2007) Complement evasion of pathogens: common strategies are shared by diverse organisms. Mol Immunol 44:3850–3857

    Article  PubMed  CAS  Google Scholar 

  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 146:257–270

    Article  PubMed  CAS  Google Scholar 

  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 73:3268–3272

    Article  PubMed  CAS  Google Scholar 

  56. Whaley K, Ruddy S (1976) Modulation of the alternative complement pathways by beta 1 H globulin. J Exp Med 144:1147–1163

    Article  PubMed  CAS  Google Scholar 

  57. Zipfel PF, Skerka C (1999) FHL-1/reconectin: a human complement and immune regulator with cell-adhesive function. Immunol Today 20:135–140

    Article  PubMed  CAS  Google Scholar 

  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 2:871–872

    Article  PubMed  CAS  Google Scholar 

  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 65:722–727

    Article  PubMed  CAS  Google Scholar 

  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 27:21–30

    Article  PubMed  CAS  Google Scholar 

  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 120:556–573

    Article  PubMed  Google Scholar 

  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 120:934–937

    Article  PubMed  CAS  Google Scholar 

  63. Barz D, Budde U, Hellstern P (2002) Therapeutic plasma exchange and plasma infusion in thrombotic microvascular syndromes. Thromb Res 107(Suppl 1):S23–S27

    Article  PubMed  CAS  Google Scholar 

  64. von Baeyer H (2002) Plasmapheresis in thrombotic microangiopathy-associated syndromes: review of outcome data derived from clinical trials and open studies. Ther Apher 6:320–328

    Article  Google Scholar 

  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 325:398–403

    Article  PubMed  CAS  Google Scholar 

  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 40:896–901

    Article  PubMed  CAS  Google Scholar 

  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 45:415–421

    Article  PubMed  CAS  Google Scholar 

  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):223–225

    PubMed  Google Scholar 

  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 126:11–28

    Article  PubMed  Google Scholar 

  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 19:727–730

    Article  PubMed  CAS  Google Scholar 

  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 8:50–56

    Article  PubMed  CAS  Google Scholar 

  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 22:874–880

    Article  PubMed  Google Scholar 

  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 105:511–516

    Article  PubMed  CAS  Google Scholar 

  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 30:949–956

    Article  PubMed  CAS  Google Scholar 

  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 30:711–718

    Article  PubMed  CAS  Google Scholar 

  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 12:619–624

    Article  PubMed  CAS  Google Scholar 

  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 24:936–941

    PubMed  CAS  Google Scholar 

  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 9:2318–2326

    PubMed  CAS  Google Scholar 

  79. Thompson RA, Winterborn MH (1981) Hypocomplementaemia due to a genetic deficiency of beta 1H globulin. Clin Exp Immunol 46:110–119

    PubMed  CAS  Google Scholar 

  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 69:981–988

    Article  PubMed  CAS  Google Scholar 

  81. Vogt BA, Wyatt RJ, Burke BA, Simonton SC, Kashtan CE (1995) Inherited factor H deficiency and collagen type III glomerulopathy. Pediatr Nephrol 9:11–15

    Article  PubMed  CAS  Google Scholar 

  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 51:671–677

    Article  PubMed  Google Scholar 

  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 138:412–417

    Article  PubMed  CAS  Google Scholar 

  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 23:1363–1366

    Article  PubMed  Google Scholar 

  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 13:526–530

    Article  PubMed  CAS  Google Scholar 

  86. Nathanson S, Fremeaux-Bacchi V, Deschenes G (2001) Successful plasma therapy in hemolytic uremic syndrome with factor H deficiency. Pediatr Nephrol 16:554–556

    Article  PubMed  CAS  Google Scholar 

  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–e30

    Article  PubMed  Google Scholar 

  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 25:97–104

    Article  PubMed  Google Scholar 

  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 19:908–911

    PubMed  Google Scholar 

  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 18:952–955

    Article  PubMed  Google Scholar 

  91. Stratton JD, Warwicker P (2002) Successful treatment of factor H-related haemolytic uraemic syndrome. Nephrol Dial Transplant 17:684–685

    Article  PubMed  Google Scholar 

  92. Nathanson S, Ulinski T, Fremeaux-Bacchi V, Deschenes G (2006) Secondary failure of plasma therapy in factor H deficiency. Pediatr Nephrol 21:1769–1771

    Article  PubMed  Google Scholar 

  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 16:555–563

    Article  PubMed  CAS  Google Scholar 

  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 110:1516–1518

    Article  PubMed  CAS  Google Scholar 

  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 25:136–144

    Article  PubMed  CAS  Google Scholar 

  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 114:4261–4271

    Article  PubMed  CAS  Google Scholar 

  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 66:336–340

    Article  PubMed  CAS  Google Scholar 

  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 10:168–172

    Article  PubMed  CAS  Google Scholar 

  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 23:2088–2090

    Article  PubMed  Google Scholar 

  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 55:708–711

    Article  PubMed  Google Scholar 

  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 1:88–99

    Article  PubMed  CAS  Google Scholar 

  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 44:1835–1844

    Article  PubMed  CAS  Google Scholar 

  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 9:2644–2645

    Article  PubMed  CAS  Google Scholar 

  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 8:216–221

    PubMed  CAS  Google Scholar 

  105. Saland JM, Ruggenenti P, Remuzzi G (2009) Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol 20:940–949

    Article  PubMed  CAS  Google Scholar 

  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 4:201–206

    Article  PubMed  Google Scholar 

  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 359:1671–1672

    Article  PubMed  Google Scholar 

  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 5:1146–1150

    Article  PubMed  Google Scholar 

  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 100:12966–12971

    Article  PubMed  CAS  Google Scholar 

  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:E22

    Article  PubMed  Google Scholar 

  111. Gruppo RA, Rother RP (2009) Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med 360:544–546

    Article  PubMed  CAS  Google Scholar 

  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 4:1312–1316

    Article  PubMed  CAS  Google Scholar 

  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 360:542–544

    Article  PubMed  Google Scholar 

  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 350:552–559

    Article  CAS  Google Scholar 

  115. Parker C (2009) Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet 373:759–767

    Article  PubMed  CAS  Google Scholar 

  116. Wagner E, Frank MM (2010) Therapeutic potential of complement modulation. Nat Rev Drug Discov 9:43–56

    Article  PubMed  CAS  Google Scholar 

  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 25:1256–1264

    Article  PubMed  CAS  Google Scholar 

  118. Parker CJ, Kar S, Kirkpatrick P (2007) Eculizumab. Nat Rev Drug Discov 6:515–516

    Article  PubMed  CAS  Google Scholar 

  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 13:993–1000

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Nephrology, Great Ormond Street Hospital, London, WC1N 3JH, UK

    Aoife M. Waters

  2. University College London, Institute of Child Health, London, UK

    Aoife M. Waters

  3. Division of Nephrology, Hospital for Sick Children, Toronto, ON, Canada

    Christoph Licht

  4. Department of Paediatrics, University of Toronto, Toronto, ON, Canada

    Christoph Licht

Authors
  1. Aoife M. Waters
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christoph Licht
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aoife M. Waters.

Additional information

Answers:

1. b

2. b

3. b

4. c

5. c

6. b

7. c

8. b

9. b

10. c

11. c

An erratum to this article can be found online at http://dx.doi.org/10.1007/s00467-012-2333-3.

Electronic Supplementary Materials

Below is the link to the electronic supplementary material.

Supplementary Materials

(DOC 179 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Waters, A.M., Licht, C. aHUS caused by complement dysregulation: new therapies on the horizon. Pediatr Nephrol 26, 41–57 (2011). https://doi.org/10.1007/s00467-010-1556-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-010-1556-4

Keywords

Search

Navigation