Pediatric Nephrology

, Volume 26, Issue 4, pp 613–619 | Cite as

Eculizumab induces long-term remission in recurrent post-transplant HUS associated with C3 gene mutation

  • Samhar I. Al-Akash
  • P. Stephen Almond
  • Van H. SavellJr
  • Salam I. Gharaybeh
  • Cris Hogue
Brief Report

Abstract

A 15-year-old male patient developed atypical hemolytic uremic syndrome (aHUS) at 16 months of age leading to end-stage renal disease. The family history was suggestive of autosomal dominant aHUS, and he was more recently found to have a C3 heterozygous gene mutation (1835C>T mutation in exon 14, which determines the amino-acidic substitution R570W) with no other complement abnormalities. He had two renal transplants, the first at 2.5 years, and the second at 8 years of age, but allograft dysfunction developed in both transplants leading to graft failure due to recurrent HUS at 5 years and 18 months post-transplantation respectively. At 15 years of age he received a third transplant from a deceased donor with pre-emptive plasmapheresis. He had immediate graft function and nadir serum creatinine was 1.3–1.4 mg/dl. Severe allograft dysfunction and hypertension developed 2 months after transplantation following influenza infection. Renal allograft biopsy showed thrombotic microangiopathy. He received plasmapheresis followed by eculizumab therapy. Allograft function returned to baseline 3 weeks after starting therapy, and post-treatment allograft biopsies showed improvement in thrombotic microangiopathy. He continues to receive eculizumab every 2 weeks with stable graft function 13 months after transplantation.

Keywords

Atypical hemolytic uremic syndrome Renal transplantation Eculizumab Pediatric Plasma exchange Complement 

References

  1. 1.
    Zimmerhackl LB, Scheiring J, Prufer J, Taylor CM, Loirat C (2007) Renal transplantation in HUS patients with disorders of complement regulation. Pediatr Nephrol 22:10–16CrossRefPubMedGoogle Scholar
  2. 2.
    Kaplan BS, Leonard M (2000) Autosomal dominant hemolytic uremic syndrome: variable phenotypes and transplant results. Pediatr Nephrol 14:464–468CrossRefPubMedGoogle Scholar
  3. 3.
    Loirat C, Niaudet P (2003) The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children. Pediatr Nephrol 18:1095–1101CrossRefPubMedGoogle Scholar
  4. 4.
    Zimmerhackl LB, Besbas N, Jungraithmayr T, van de Kar N, Karch H, Karpman D, Landau D, Loirat C, Proesmans W, Prüfer F, Rizzoni G, Taylor MC, European Study Group for Hemolytic Uraemic Syndromes and Related Disorders (2006) Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome. Semin Thromb Hemost 32:113–120CrossRefPubMedGoogle Scholar
  5. 5.
    Kavanagh D, Goodship T (2010) Genetics and complement in atypical HUS. Pediatr Nephrol 25:2431–2442CrossRefPubMedGoogle Scholar
  6. 6.
    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, International Registry of Recurrent and Familial HUS/TTP (2006) Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108:1267–1279CrossRefPubMedGoogle Scholar
  7. 7.
    Loirat C, Noris M, Fremeaux-Bacchi V (2008) Hemolytic uremic syndrome recurrence after renal transplantation. Pediatr Transplant 12:619–629CrossRefPubMedGoogle Scholar
  8. 8.
    Olie KH, Florquin S, Groothoff JW, Verlaak R, Strain L, Goodship TH, Weening JJ, Davin JC (2004) Atypical relapse of hemolytic uremic syndrome after renal transplantation. Pediatr Nephrol 19:1173–1176CrossRefPubMedGoogle Scholar
  9. 9.
    Florman S, Benchimol C, Lieberman K, Burrows L, Bromberg JS (2002) Fulminant recurrence of atypical hemolytic uremic syndrome during a calcineurin inhibitor-free immunosuppression regimen. Pediatr Transplant 6:352–355CrossRefPubMedGoogle Scholar
  10. 10.
    Stühlinger W, Kourilsky O, Kanfer A, Sraer JD (1974) Letter: Haemolytic-uraemic syndrome: evidence for intravascular C3 activation. Lancet 2:788–789CrossRefPubMedGoogle Scholar
  11. 11.
    Barré P, Kaplan BS, de Chadarévian JP, Drummond KN (1977) Hemolytic uremic syndrome with hypocomplementemia, serum C3NeF, and glomerular deposits of C3. Arch Pathol Lab Med 101:357–361PubMedGoogle Scholar
  12. 12.
    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 53:836–844CrossRefPubMedGoogle Scholar
  13. 13.
    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
  14. 14.
    Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F, Gamba S, Remuzzi G, International Registry of Recurrent and Familial HUS/TTP (2003) Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 362:1542–1547CrossRefPubMedGoogle Scholar
  15. 15.
    Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, López-Trascasa M, Sánchez-Corral P, Morgan BP, Rodríguez de Córdoba S (2007) Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci USA 104:240–245CrossRefPubMedGoogle Scholar
  16. 16.
    Frémeaux-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 112:4948–4952CrossRefPubMedGoogle Scholar
  17. 17.
    Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, Daina E, Fenili C, Castelletti F, Sorosina A, Piras R, Donadelli R, Maranta R, van der Meer I, Conway EM, Zipfel PF, Goodship TH, Remuzzi G (2010) Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 5:1844–1859CrossRefPubMedGoogle Scholar
  18. 18.
    Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM (2010) Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 361:345–357CrossRefGoogle Scholar
  19. 19.
    Heinen S, Hartmann A, Lauer N, Wiehl U, Dahse HM, Schirmer S, Gropp K, Enghardt T, Wallich R, Hälbich S, Mihlan M, Schlötzer-Schrehardt U, Zipfel PF, Skerka C (2009) Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood 114:2439–2447CrossRefPubMedGoogle Scholar
  20. 20.
    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 hemolytic uremic syndrome. Blood 115:379–387CrossRefPubMedGoogle Scholar
  21. 21.
    Davin JC, Strain L, Goodship TH (2008) Plasma therapy in atypical haemolytic uremic syndrome: lessons from a family with a factor H mutation. Pediatr Nephrol 23:1517–1521CrossRefPubMedGoogle Scholar
  22. 22.
    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 5:1146–1150CrossRefPubMedGoogle Scholar
  23. 23.
    Saland JM, Emre SH, Shneider BL, Benchimol C, Ames S, Bromberg JS, Remuzzi G, Strain L, Goodship TH (2006) Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation. Am J Transplant 6:1948–1952CrossRefPubMedGoogle Scholar
  24. 24.
    Jalanko H, Peltonen S, Koskinen A, Puntila J, Isoniemi H, Holmberg C, Pinomäki A, Armstrong E, Koivusalo A, Tukiainen E, Mäkisalo 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
  25. 25.
    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 4:201–206CrossRefPubMedGoogle Scholar
  26. 26.
    Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G, Muus P, Röth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L (2006) The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 355:1233–1243CrossRefPubMedGoogle Scholar
  27. 27.
    Noris M, Remuzzi G (2009) Atypical hemolytic–uremic syndrome. N Engl J Med 361:1676–1687CrossRefPubMedGoogle Scholar
  28. 28.
    Ducloux D, Rebibou JM, Semhoun-Ducloux S, Jamali M, Fournier V, Bresson-Vautrin C, Chalopin JM (1998) Recurrence of hemolytic-uremic syndrome in renal transplant recipients: a meta-analysis. Transplantation 65:1405–1407CrossRefPubMedGoogle Scholar
  29. 29.
    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, French Society of Pediatric Nephrology (2007) Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 18:2392–2400CrossRefPubMedGoogle Scholar
  30. 30.
    Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship TH, Remuzzi G, International Registry of Recurrent and Familial HUS/TTP (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 1:88–99CrossRefPubMedGoogle Scholar
  31. 31.
    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 45:415–421CrossRefPubMedGoogle Scholar
  32. 32.
    Nathanson S, Frémeaux-Bacchi V, Deschênes G (2001) Successful plasma therapy in hemolytic uremic syndrome with factor H deficiency. Pediatr Nephrol 16:554–556CrossRefPubMedGoogle Scholar
  33. 33.
    Nathanson S, Ulinski T, Frémeaux-Bacchi V, Deschênes G (2006) Secondary failure of plasma therapy in factor H deficiency. Pediatr Nephrol 21:1769–1771CrossRefPubMedGoogle Scholar
  34. 34.
    Olie KH, Goodship TH, Verlaak R, Florquin S, Groothoff JW, Strain L, Weening JJ, Davin JC (2005) Posttransplantation cytomegalovirus-induced recurrence of atypical hemolytic uremic syndrome associated with a factor H mutation: successful treatment with intensive plasma exchanges and ganciclovir. Am J Kidney Dis 45:e12–e15CrossRefPubMedGoogle Scholar
  35. 35.
    Nuernberger J, Witzke O, Rother RP, Philipp T, Vester U, Baba H, Zimmerhackl LB, Kribben A (2008) Successful treatment of atypical hemolytic uremic syndrome with the complement inhibitor eculizumab. Blood 112: abstract 2294Google Scholar
  36. 36.
    Nürnberger J, Philipp T, 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 360:542–544CrossRefPubMedGoogle Scholar
  37. 37.
    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 55:708–711CrossRefPubMedGoogle Scholar
  38. 38.
    Chatelet V, Frémeaux-Bacchi V, Lobbedez T, Ficheux M, Hurault de Ligny B (2009) Safety and long-term efficacy of eculizumab in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome. Am J Transplant 9:2644–2645CrossRefPubMedGoogle Scholar
  39. 39.
    Gruppo RA, Rother RP (2009) Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med 360:544–546CrossRefPubMedGoogle Scholar
  40. 40.
    Legault DJ, Boelkins MR (2009) Successful treatment of aHUS recurrence and arrest of plasma exchange resistant TMA post-renal transplantation with the terminal complement inhibitor eculizumab. 51st ASH Annual Meeting 2009, abstract 2421Google Scholar
  41. 41.
    Mache CJ, Acham-Roschitz B, Frémeaux-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 4:1312–1316CrossRefPubMedGoogle Scholar
  42. 42.
    Trachtman H, Sethna C, Epstein R, D’Souza M, Rubin LG, Ginocchio CC (2010) Atypical hemolytic uremic syndrome associated with H1N1 influenza A virus infection. Pediatr Nephrol doi:10.1007/s00467-010-1636-5 Google Scholar
  43. 43.
    Fortin MC, Raymond MA, Madore F, Fugère JA, Pâquet M, St-Louis G, Hébert MJ (2004) Increased risk of thrombotic microangiopathy in patients receiving cyclosporine-sirolimus combination. Am J Transplant 4:946–952CrossRefPubMedGoogle Scholar
  44. 44.
    Zimmerhackl LB, Hofer J, Cortina G, Mark W, Würzner R, Jungraithmayr TC, Khursigara G, Kliche KO, Radauer W (2010) Prophylactic eculizumab after renal transplantation in atypical hemolytic–uremic syndrome. N Engl J Med 362:1746–1748CrossRefPubMedGoogle Scholar

Copyright information

© IPNA 2010

Authors and Affiliations

  • Samhar I. Al-Akash
    • 1
  • P. Stephen Almond
    • 2
  • Van H. SavellJr
    • 3
  • Salam I. Gharaybeh
    • 1
  • Cris Hogue
    • 4
  1. 1.Division of Pediatric NephrologyDriscoll Children’s HospitalCorpus ChristiUSA
  2. 2.Department of Surgery and TransplantationDriscoll Children’s HospitalCorpus ChristiUSA
  3. 3.Department of Pathology and Laboratory MedicineDriscoll Children’s HospitalCorpus ChristiUSA
  4. 4.Pharmacy DepartmentDriscoll Children’s HospitalCorpus ChristiUSA

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