[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies

Nature Reviews Nephrology volume 8, pages 643–657 (2012)Cite this article

Subjects

Abstract

In the past decade, a large body of evidence has accumulated in support of the critical role of dysregulation of the alternative complement pathway in atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathies. These findings have paved the way for innovative therapeutic strategies based on complement blockade, and eculizumab, a monoclonal antibody targeting the human complement component 5, is now widely used to treat aHUS. In this article, we review 28 case reports and preliminary data from 37 patients enrolled in prospective trials of eculizumab treatment for episodes of aHUS involving either native or transplanted kidneys. Eculizumab may be considered as an optimal first-line therapy when the diagnosis of aHUS is unequivocal and this treatment has the potential to rescue renal function when administered early after onset of the disease. However, a number of important issues require further study, including the appropriate duration of treatment according to an individual's genetic background and medical history, the optimal strategy to prevent post-transplantation recurrence of aHUS and a cost–efficacy analysis. Data regarding the efficacy of eculizumab in the control of C3 glomerulopathies are more limited and less clear, but several observations suggest that eculizumab may act on the most inflammatory forms of this disorder.

Key Points

  • Eculizumab has shown greater efficacy than plasma therapy in the prevention and treatment of episodes of atypical haemolytic uraemic syndrome (aHUS)

  • Eculizumab may be considered as a first-line therapy in children with a first episode of aHUS as it avoids the complications associated with apheresis and central venous catheters

  • In adults, eculizumab can be used as a first-line therapy when aHUS diagnosis is undisputable, although plasma therapy should be used as a first-line therapy if uncertainty in diagnosis warrants further investigation

  • Evidence of plasma resistance or dependence should lead to a prompt switch to eculizumab; the sooner eculizumab is initiated, the better the recovery of renal function

  • Renal transplant candidates with a genetically determined risk of post-transplantation aHUS recurrence should be given a prophylactic protocol based on eculizumab if at high risk, and plasma exchange or eculizumab if at moderate risk

  • Eculizumab may be effective in curbing part of the inflammatory process involved in a subset of C3 glomerulopathies

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Eculizumab: molecular structure and mode of action.
Figure 2: Recovery of renal function is better with a shorter interval between onset of aHUS and initiation of eculizumab.
Figure 3: Diagnostic algorithm and therapeutic options for aHUS.
Figure 4: Risk assessment for patients with aHUS who are candidates for renal transplantation.

Similar content being viewed by others

References

  1. Fakhouri, F., Fremeaux-Bacchi, V., Noel, L. H., Cook, H. T. & Pickering, M. C. C3 glomerulopathy: a new classification. Nat. Rev. Nephrol. 8, 494–499 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Roumenina, L. T. et al. Alternative complement pathway assessment in patients with atypical HUS. J. Immunol. Methods 365, 8–26 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. de Cordoba, S. R. & de Jorge, E. G. Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H. Clin. Exp. Immunol. 151, 1–13 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Servais, A. et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 82, 454–464 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Sethi, S. & Fervenza, F. C. Membranoproliferative glomerulonephritis—a new look at an old entity. N. Engl. J. Med. 366, 1119–1131 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Rose, K. L. et al. Factor I is required for the development of membranoproliferative glomerulonephritis in factor H-deficient mice. J. Clin. Invest. 118, 608–618 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Gruppo, R. A. & Rother, R. P. Eculizumab for congenital atypical hemolytic-uremic syndrome. N. Engl. J. Med. 360, 544–546 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Nürnberger, J. et al. Eculizumab for atypical hemolytic-uremic syndrome. N. Engl. J. Med. 360, 542–544 (2009).

    Article  PubMed  Google Scholar 

  10. Hillmen, P. The role of complement inhibition in PNH. Hematology Am. Soc. Hematol. Educ. Program 116–123 (2008).

  11. Hillmen, P. et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 355, 1233–1243 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Kelly, R. J. et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 117, 6786–6792 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Rother, R. P., Rollins, S. A., Mojcik, C. F., Brodsky R. A. & Bell, L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat. Biotechnol. 25, 1256–1264 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Electronic Medicines Compendium. Soliris—Summary of Product Characteristics [online], (2012).

  15. U. S. Food and Drug Administration. Highlights of Prescribing Information: Soliris [online], (2011).

  16. Simister, N. E. Placental transport of immunoglobulin G. Vaccine 21, 3365–3369 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Kelly, R. et al. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Br. J. Haematol. 149, 446–450 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Luzzatto, L., Gianfaldoni, G. & Notaro, R. Management of paroxysmal nocturnal haemoglobinuria: a personal view. Br. J. Haematol. 153, 709–720 (2011).

    Article  PubMed  Google Scholar 

  19. Forneris, F. et al. Structures of C3b in complex with factors B and D give insight into complement convertase formation. Science 330, 1816–1820 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rooijakkers, S. H. et al. Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor. Nat. Immunol. 10, 721–727 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Laursen, N. S. et al. Substrate recognition by complement convertases revealed in the C5-cobra venom factor complex. EMBO J. 30, 606–616 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Overturf, G. D. Indications for the immunological evaluation of patients with meningitis. Clin. Infect. Dis. 36, 189–194 (2003).

    Article  PubMed  Google Scholar 

  23. Ram, S., Lewis, L. A. & Rice, P. A. Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin. Microbiol. Rev. 23, 740–780 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Brodsky, R. A. et al. Long term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal hemoglobinuria (PNH). Presented at the 52nd American Society of Hematology Annual Meeting (2010).

  25. de Jorge, E. G. et al. The development of atypical hemolytic uremic syndrome depends on complement C5. J. Am. Soc. Nephrol. 22, 137–145 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Pickering, M. C. et al. Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. J. Exp. Med. 204, 1249–1256 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Al-Akash, S. I., Almond, P. S., Savell, V. H. Jr, Gharaybeh S. I. & Hogue, C. Eculizumab induces long-term remission in recurrent post-transplant HUS associated with C3 gene mutation. Pediatr. Nephrol. 26, 613–619 (2011).

    Article  PubMed  Google Scholar 

  28. Ardissino, G. et al. Remission of plasma-resistant atypical hemolytic uremic syndrome relapse on kidney graft with eculizumab. Presented at the 2nd International Conference on HUS-MPGN-PNH (2010).

  29. Ariceta, G., Arrizabalaga, B., Aguirre, M., Morteruel, E. & Lopez-Trascasa, M. Eculizumab in the treatment of atypical hemolytic uremic syndrome in infants. Am. J. Kidney Dis. 59, 707–710 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Chatelet, V., Fremeaux-Bacchi, V., Lobbedez, T., Ficheux, M. & de Ligny B. H. Safety and long-term efficacy of eculizumab in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome. Am. J. Transplant. 9, 2644–2645 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Chatelet, V. et al. Eculizumab: safety and efficacy after 17 months of treatment in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome: case report. Transplant. Proc. 42, 4353–4355 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Dorresteijn, E. M., van de Kar, N. C. & Cransberg, K. Eculizumab as rescue therapy for atypical hemolytic uremic syndrome with normal platelet count. Pediatr. Nephrol. 27, 1193–1195 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Durán, C. E., Blasco, M., Maduell, F. & Campistol, J. M. Rescue therapy with eculizumab in a transient recipient with atypical haematologic-uraemic syndrome. Clin. Kidney J. 5, 28–30 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim, J. J., Waller S. C. & Reid, C. J. Eculizumab in atypical haemolytic-uraemic syndrome allows cessation of plasma exchange and dialysis. Clin. Kidney J. 5, 34–36 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lapeyraque, A. L., Frémeaux-Bacchi, V. & Robitaille, P. Efficacy of eculizumab in a patient with factor-H-associated atypical hemolytic uremic syndrome. Pediatr. Nephrol. 26, 621–624 (2011).

    Article  PubMed  Google Scholar 

  36. Larrea, C. F. et al. Efficacy of eculizumab in the treatment of recurrent atypical hemolytic-uremic syndrome after renal transplantation. Transplantation 89, 903–904 (2010).

    Article  PubMed  Google Scholar 

  37. Malina, M. et al. Peripheral gangrene in children with atypical hemolytic uremic syndrome. Presented at the 44th Annual Meeting of the European Society for Pediatric Nephrology (2011).

    Google Scholar 

  38. Nester, C. et al. Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome. Clin. J. Am. Soc. Nephrol. 6, 1488–1494 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ohanian, M., Cable, C. & Halka, K. Eculizumab safely reverses neurologic impairment and eliminates need for dialysis in severe atypical hemolytic uremic syndrome. Clin. Pharmacol. 3, 5–12 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Prescott, H. C., Wu, H. M., Cataland, S. R. & Baiocchi, R. A. Eculizumab therapy in an adult with plasma exchange-refractory atypical hemolytic uremic syndrome. Am. J. Hematol. 85, 976–977 (2010).

    Article  PubMed  Google Scholar 

  41. Tschumi, S., Gugger, M., Bucher, B. S., Riedl, M. & Simonetti, G. D. Eculizumab in atypical hemolytic uremic syndrome: long-term clinical course and histological findings. Pediatr. Nephrol. 26, 2085–2088 (2011).

    Article  PubMed  Google Scholar 

  42. Weitz, M., Amon, O., Bassler, D., Koenigsrainer, A. & Nadalin, S. Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr. Nephrol. 26, 1325–1329 (2011).

    Article  PubMed  Google Scholar 

  43. Zimmerhackl, L. B. et al. Prophylactic eculizumab after renal transplantation in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 362, 1746–1748 (2010).

    Article  PubMed  Google Scholar 

  44. Fremont, O. T., Gordon, C. A. & Hand, M. M. Eculizumab treatment for aHUS in a child with positive family history. Presented at the 42nd Annual Meeting of the American Society of Nephrology (2009).

    Google Scholar 

  45. Garjau, M. et al. Early treatment with eculizumab may be beneficial in atypical haemolytic uraemic syndrome. Clin. Kidney J. 5, 31–33 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Haffner, K., Hofer, J., Zimmerhackl, L. B. & Pohl, M. Effective eculizumab therapy of familiar atypical HUS in a 4 year old patient. Presented at the 2nd International Conference on HUS, MPGN and PNH (2010).

    Google Scholar 

  47. Kose, O., Zimmerhackl, L. B., Jungraithmayr, T., Mache C. & Nurnberger, J. New treatment options for atypical hemolytic uremic syndrome with the complement inhibitor eculizumab. Semin. Thromb. Hemost. 36, 669–672 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Mache, C. J. et al. Complement inhibitor eculizumab in atypical hemolytic uremic syndrome. Clin. J. Am. Soc. Nephrol. 4, 1312–1316 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Davin, J. C. et al. 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 (2010).

    Article  PubMed  Google Scholar 

  50. Heyne, N. Terminal complement blockade by eculizumab effectively reverses recurrent atypical hemolytic uremic syndrome after kidney transplantation. Presented at the 44th Annual Meeting of the American Society of Nephrology (2011).

  51. Legault, D. & Boelkins, M. Successful treatment of aHUS recurrence and arrest of plasma exchange resistant TMA post-renal transplantation with the terminal complement inhibitor eculizumab. Presented at the 51st Annual Meeting of the American Society of Hematology (2009).

  52. Zuber, J. et al. New insights into postrenal transplant hemolytic uremic syndrome. Nat. Rev. Nephrol. 7, 23–35 (2011).

    Article  PubMed  Google Scholar 

  53. European Medicines Agency. Soliris [online], (2012).

  54. Simonetti, G. D. Eculizumab therapy for atypical hemolytic uremic syndrome in pediatric patients: efficacy and safety outcomes from retrospective study. Presented at the 44th Annual Meeting of the European Society for Pediatric Nephrology (2011).

  55. Krid, S. et al. Renal transplantation under prophylactic eculizumab in atypical hemolytic uremic syndrome with CFH/CFHR1 hybrid protein. Am. J. Transplant. 12, 1938–1944 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Koskinen, A. R. et al. Complement activation during liver transplantation-special emphasis on patients with atypical hemolytic uremic syndrome. Am. J. Transplant. 11, 1885–1895 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Lonze, B. E., Singer, A. L. & Montgomery, R. A. Eculizumab and renal transplantation in a patient with CAPS. N. Engl. J. Med. 362, 1744–1745 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  59. Stegall, M. D. et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am. J. Transplant. 11, 2405–2413 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  61. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  62. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  63. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  64. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  65. Legendre, C. et al. Safety and efficacy of eculizumab in aHUS resistant to plasma therapy: interim analysis from a phase II trial. Presented at the 43rd Annual Meeting of the American Society of Nephrology (2010).

  66. Greenbaum, L. A. et al. Continued improvement in renal function with sustained eculizumab in patients with atypical HUS resistant to plasma exchange/infusion. Presented at the 44th Annual Meeting of the American Society of Nephrology (2011).

  67. Greenbaum, L. A. et al. Eculizumab is an effective long-term treatment in patients with atypical hemolytic uremic syndrome resistant to plasma exchange/infusion: results of an extension study. Presented at the 53th Annual Meeting of the American Society of Hematology (2011).

  68. Licht, C. et al. Eculizumab is an effective long-term treatment in patients with atypical haemolytic uremic syndrome previously receiving chronic plasma exchange/infusion: extension study results. Presented at the 53th Annual Meeting of the American Society of Hematology (2011).

  69. Licht, C. et al. Phase II study of eculizumab in patients with atypical HUS receiving chronic plasma exchange/infusion. Presented at the 44th Annual Meeting of the American Society of Nephrology (2011).

  70. Muus, P. et al. Safety and efficacy in aHUS patients on chronic plasma therapy: interim analysis of a phase II trial. Presented at the 43rd Annual Meeting of the American Society of Nephrology (2010).

  71. Loirat, C., Saland, J. & Bitzan, M. Management of hemolytic uremic syndrome. Presse Med. 41, e115–e135 (2012).

    Article  PubMed  Google Scholar 

  72. Zipfel, P. F., Heinen, S. & Skerka, C. Thrombotic microangiopathies: new insights and new challenges. Curr. Opin. Nephrol. Hypertens. 19, 372–378 (2010).

    Article  PubMed  Google Scholar 

  73. Coppo, P. et al. Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience. PLoS ONE 5, e10208 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ferrari, S. et al. Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity. Blood 109, 2815–2822 (2007).

    CAS  PubMed  Google Scholar 

  75. George, J. N. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood 116, 4060–4069 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. Scully, M. et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood 118, 1746–1753 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Noris, M. et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin. J. Am. Soc. Nephrol. 5, 1844–1859 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sellier-Leclerc, A. L. et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol. 18, 2392–2400 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Lapeyraque, A. L. et al. Eculizumab in severe Shiga-toxin-associated HUS. N. Engl. J. Med. 364, 2561–2563 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Hadaya, K. et al. Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation. Am. J. Transplant. 11, 2523–2527 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Shapira, I., Andrade, D., Allen, S. L. & Salmon, J. E. Induction of durable remission in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal complement with eculizumab. Arthritis Rheum. 64, 2719–2723 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Chapin, J., Weksler, B., Magro, C. & Laurence, J. Eculizumab in the treatment of refractory idiopathic thrombotic thrombocytopenic purpura. Br. J. Haematol. 157, 772–774 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Réti, M. et al. Complement activation in thrombotic thrombocytopenic purpura. J. Thromb. Haemost. 10, 791–798 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Trachtman, H., Austin, C., Lewinski, M. & Stahl, R. A. K. Renal and neurological involvement in typical Shiga toxin-associated HUS. http://dx.doi.org/10.1038/nrneph.2012.196.

  85. Fakhouri, F. et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J. Am. Soc. Nephrol. 21, 859–867 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Le Quintrec, M. et al. Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation. Am. J. Transplant. 8, 1694–1701 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Chandran, S., Baxter-Lowe, L., Olson, J. L., Tomlanovich, S. J. & Webber, A. Eculizumab for the treatment of de novo thrombotic microangiopathy post simultaneous pancreas-kidney transplantation—a case report. Transplant. Proc. 43, 2097–2101 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Wilson, C. H. et al. Successful treatment of de novo posttransplant thrombotic microangiopathy with eculizumab. Transplantation 92, e42–e43 (2011).

    Article  PubMed  Google Scholar 

  89. Fakhouri, F. et al. Factor H, membrane cofactor protein, and factor I mutations in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome. Blood 112, 4542–4545 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Fang, C. J., Richards, A., Liszewski, M. K., Kavanagh, D. & Atkinson, J. P. Advances in understanding of pathogenesis of aHUS and HELLP. Br. J. Haematol. 143, 336–348 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Salmon, J. E. et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 8, e1001013 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Boyer, O. et al. Pulse cyclophosphamide therapy and clinical remission in atypical hemolytic uremic syndrome with anti-complement factor H autoantibodies. Am. J. Kidney Dis. 55, 923–927 (2010).

    Article  PubMed  Google Scholar 

  93. Dragon-Durey, M. A. et al. Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J. Am. Soc. Nephrol. 21, 2180–2187 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Kwon, T. et al. Successful pre-transplant management of a patient with anti-factor H autoantibodies-associated haemolytic uraemic syndrome. Nephrol. Dial. Transplant. 23, 2088–2090 (2008).

    Article  PubMed  Google Scholar 

  95. Le Quintrec, M. et al. Anti-factor H autoantibodies in a fifth renal transplant recipient with atypical hemolytic and uremic syndrome. Am. J. Transplant. 9, 1223–1229 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Moore, I. et al. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood 115, 379–387 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ariceta, G. et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr. Nephrol. 24, 687–696 (2009).

    Article  PubMed  Google Scholar 

  98. Taylor, C. M., Machin, S., Wigmore, S. J. & Goodship, T. H. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br. J. Haematol. 148, 37–47 (2010).

    Article  CAS  PubMed  Google Scholar 

  99. Michon, B. et al. Complications of apheresis in children. Transfusion 47, 1837–1842 (2007).

    Article  PubMed  Google Scholar 

  100. Witt, V. et al. World apheresis registry data from 2003 to 2007, the pediatric and adolescent side of the registry. Transfus. Apher. Sci. 39, 255–260 (2008).

    Article  PubMed  Google Scholar 

  101. Som, S. et al. Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 1996 to 2011. Transfusion http://dx.doi.org/10.1111/j.1537-29952012.03646.x.

  102. Roumenina, L. T. et al. A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain-of-function. Blood 119, 4182–4191 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sallee, M. et al. Myocardial infarction is a complication of factor H-associated atypical HUS. Nephrol. Dial. Transplant. 25, 2028–2032 (2010).

    Article  PubMed  Google Scholar 

  104. Loirat, C. et al. Non-atheromatous arterial stenoses in atypical haemolytic uraemic syndrome associated with complement dysregulation. Nephrol. Dial. Transplant. 10, 3421–3425 (2010).

    Article  Google Scholar 

  105. Vergouwen, M. D., Adriani, K. S., Roos, Y. B., Groothoff, J. W. & Majoie, C. B. Proximal cerebral artery stenosis in a patient with hemolytic uremic syndrome. AJNR Am. J. Neuroradiol. 29, e34 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bienaime, F. et al. Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. Kidney Int. 77, 339–349 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Kvarnstrom, A. L., Sarbinowski, R. T., Bengtson, J. P., Jacobsson, L. M. & Bengtsson, A. L. Complement activation and interleukin response in major abdominal surgery. Scand. J. Immunol. 75, 510–516 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Neher, M. D., Weckbach, S., Flierl, M. A., Huber-Lang, M. S. & Stahel, P. F. Molecular mechanisms of inflammation and tissue injury after major trauma—is complement the “bad guy”? J. Biomed. Sci. 18, 90 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Marasca, R. et al. Pregnancy in PNH: another eculizumab baby. Br. J. Haematol. 150, 707–708 (2010).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  111. Zuber, J. et al. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am. J. Transplant. http://dx.doi.org/10.1111/j.1600-6143.2012.04252.x.

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

    Article  CAS  PubMed  Google Scholar 

  113. Hegasy, G. A., Manuelian, T., Hogasen, K., Jansen, J. H. & Zipfel, P. F. The molecular basis for hereditary porcine membranoproliferative glomerulonephritis type II: point mutations in the factor H coding sequence block protein secretion. Am. J. Pathol. 161, 2027–2034 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Pickering, M. C. et al. Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat. Genet. 31, 424–428 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Little, M. A., Dupont, P., Campbell, E., Dorman, A. & Walshe, J. J. Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk. Kidney Int. 69, 504–511 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. Fakhouri, F. et al. Treatment with human complement factor H rapidly reverses renal complement deposition in factor H-deficient mice. Kidney Int. 78, 279–286 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Pickering, M. C. et al. Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice. Proc. Natl Acad. Sci. USA 103, 9649–9654 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bomback, A. S. et al. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin. J. Am. Soc. Nephrol. 7, 748–756 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  120. Radhakrishnan, S. et al. Eculizumab and refractory membranoproliferative glomerulonephritis. N. Engl. J. Med. 366, 1165–1166 (2012).

    Article  CAS  PubMed  Google Scholar 

  121. Vivarelli, M., Pasini, A. & Emma, F. Eculizumab for the treatment of dense-deposit disease. N. Engl. J. Med. 366, 1163–1165 (2012).

    Article  CAS  PubMed  Google Scholar 

  122. McCaughan, J. A., O'Rourke D. M. & Courtney, A. E. Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies. Am. J. Transplant. 12, 1046–1051 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. Herlitz, L. C. et al. Pathology after eculizumab in dense deposit disease and C3 GN. J. Am. Soc. Nephrol. 23, 1229–1237 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bouts, A., Monnens, L., Davin, J. C., Struijk, G. & Spanjaard, L. Insufficient protection by Neisseria meningitidis vaccination alone during eculizumab therapy. Pediatr. Nephrol. 26, 1919–1920 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all members of the French Study Group for aHUS/MPGN who participated in fruitful and constructive discussions regarding these recommendations: M. Buchler (Tours, France), S. Burtey (Marseille, France), D. Chauveau (Toulouse, France), Y. Delmas (Bordeaux, France), G. Deschênes (Paris, France), A. Garnier (Toulouse, France), M. Y. Hourmant (Nantes, France), A. Karras (Paris, France), B. Knebelmann (Paris, France), Y. Lebranchu (Tours, France), B. Legallicier (Rouen, France), C. Legendre (Paris, France), M. Le Quintrec (Suresnes, France), B. Moulin (Strasbourg, France), P. Niaudet (Paris, France), C. Pouteil-Noble (Lyon, France), F. Provost (Lille, France), B. Ranchin (Lyon, France) and E. Rondeau (Paris, France). The authors would also like to thank the following for providing updated data on late outcomes of their patients: S. Al-Akash (Driscoll Children's Hospital, Texas, USA), G. Ardissimo (Osp. Maggiore Policlinico, Milan, Italy), G. Ariceta (Hospital Universitario Cruces, Barakaldo-Bilbao, Spain), J. M. Campistol (Hospital Clinic, ICNU, University of Barcelona, Spain), S. Cataland (Ohio State University, Columbus, USA), J. C. Davin (Emma Children's Hospital, Amsterdam, The Netherlands), E. M. Dorresteijn (Sophia Children's Hospital, Rotterdam, The Netherlands), R. Gruppo (Cincinnati Children's Hospital, USA), K. Halka (The Texas A&M Health Science Center College of Medicine, Temple USA), N. Heyne (University Hospital Tuebingen, Germany), A. L. Lapeyrague (CHU Ste-Justine, Montréal, Canada), M. Lozano (Hospital Clinic, IDIBAPS, University of Barcelona, Spain), C. Nester (University of Iowa Hospitals and Clinics, USA), J. Nürnberger (University Duisburg-Essen, Germany), R. Ramos (Hospital Vall d'Hebron, Barcelona, Spain), C. Reid and J. J. Kim (Evelina Children's Hospital, London, UK), M. Riedl (Medical University Innsbruck, Austria), F. Schaefer (Medical University of Heidelberg, Germany), G. D. Simonetti (Children's Hospital University of Bern, Switzerland), and M. Weitz (University Children's Hospital Tuebingen, Germany).

Author information

Authors and Affiliations

  1. Service de Transplantation Rénale Adulte, Hôpital Necker, 161 rue de Sèvres, Paris, 75015, France

    Julien Zuber

  2. Département de Nephrologie, CHU de Nantes, 1 place Alexis-Ricordeau, Nantes, 44000, France

    Fadi Fakhouri

  3. INSERM UMRS 872, Centre de Recherche des Cordeliers, 15 rue de l'Ecole de Médecine, Paris, 75006, France

    Lubka T. Roumenina

  4. Service de Néphrologie, Hôpital Robert Debré, 48 Boulevard Sérurierm, Paris, 75019, France

    Chantal Loirat

  5. Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, 20–40 rue Leblanc, Paris, 75908, France

    Véronique Frémeaux-Bacchi

Authors
  1. Julien Zuber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fadi Fakhouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lubka T. Roumenina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chantal Loirat
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Véronique Frémeaux-Bacchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of the French Study Group for aHUS/C3G

Contributions

The authors contributed equally to all aspects of the manuscript.

Corresponding author

Correspondence to Véronique Frémeaux-Bacchi.

Ethics declarations

Competing interests

J. Zuber, F. Fakhouri, C. Loirat and V. Frémeaux-Bacchi have received fees from Alexion Pharmaceuticals for invited lectures and participation on advisory boards. L. T. Roumenina declares no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zuber, J., Fakhouri, F., Roumenina, L. et al. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol 8, 643–657 (2012). https://doi.org/10.1038/nrneph.2012.214

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2012.214

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing