Clinical and Experimental Nephrology

, Volume 20, Issue 2, pp 265–272 | Cite as

Efficacy and safety of eculizumab in childhood atypical hemolytic uremic syndrome in Japan

  • Naoko Ito
  • Hiroshi Hataya
  • Ken Saida
  • Yoshiro Amano
  • Yoshihiko Hidaka
  • Yaeko Motoyoshi
  • Toshiyuki Ohta
  • Yasuhiro Yoshida
  • Chikako Terano
  • Tadashi Iwasa
  • Wataru Kubota
  • Hidetoshi Takada
  • Toshiro Hara
  • Yoshihiro Fujimura
  • Shuichi Ito
Original Article

Abstract

Background

Atypical hemolytic uremic syndrome (aHUS) is a severe life-threatening disease with frequent progression to end-stage renal disease (ESRD). Eculizumab, a humanized anti-C5 monoclonal antibody targeting the activated complement pathway, has recently been introduced as a novel therapy against aHUS. We, therefore, investigated the efficacy and safety of eculizumab in Japanese pediatric patients.

Methods

We retrospectively analyzed clinical course and laboratory data of the first ten children with aHUS treated with eculizumab nationwide.

Results

Seven patients were resistant to plasma therapy and three were dependent on it. Causative gene mutations were found in five patients. Two patients had anti-complement factor H autoantibody. Three patients had a family history of thrombotic microangiopathy (TMA). After initiation of eculizumab, all patients immediately achieved hematological remission and could successfully discontinue plasma therapy. The median periods to normalization of platelet count, lactate dehydrogenase levels and disappearance of schistocytes were 5.5, 17 and 12 days, respectively. Nine patients recovered their renal function and the median period to terminate renal replacement therapy (RRT) was 3 days. However, two patients progressed to ESRD and required chronic RRT at the last observation. No patients had a relapse of TMA under regular eculizumab therapy. No serious adverse events occurred during the follow-up period.

Conclusions

Eculizumab is efficacious and well-tolerated therapy for children with aHUS. Although pathogenic mutations could not be detected in five patients, all patients showed immediate normalization of hematological abnormalities, strongly suggesting complement-related aHUS. This prompt hematological amelioration can become an indicator for therapeutic efficacy of eculizumab. However, appropriate indications and optimal duration of the treatment remain unclear.

Keywords

Eculizumab Atypical hemolytic uremic syndrome Plasma therapy Alternative complement pathway Children 

References

  1. 1.
    Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87.CrossRefPubMedGoogle Scholar
  2. 2.
    Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, Macher MA, Niaudet P, Guest G, et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007;18:2392–400.CrossRefPubMedGoogle Scholar
  4. 4.
    Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol. 2010;5:1844–59.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kavanagh D, Goodship T. Genetics and complement in atypical HUS. Pediatr Nephrol. 2010;25:2431–42.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaime F, Dragon-Durey MA, Ngo S, et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol. 2013;8:554–62.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Waters AM, Licht C. aHUS caused by complement dysregulation: new therapies on the horizon. Pediatr Nephrol. 2011;26:41–57.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Verhave JC, Wetzels JF, van de Kar NC. Novel aspects of atypical haemolytic uraemic syndrome and the role of eculizumab. Nephrol Dial Transplant. 2014;29:iv131–41.CrossRefPubMedGoogle Scholar
  9. 9.
    Zuber J, Fakhouri F, Roumenina LT, Loirat C, Fremeaux-Bacchi V. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol. 2012;8:643–57.CrossRefPubMedGoogle Scholar
  10. 10.
    Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–81.CrossRefPubMedGoogle Scholar
  11. 11.
    Fakhouri F, Delmas Y, Provot F, Barbet C, Karras A, Makdassi R, et al. Insights from the use in clinical practice of eculizumab in adult patients with atypical hemolytic uremic syndrome affecting the native kidneys: an analysis of 19 cases. Am J Kidney Dis. 2014;63:40–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Wong EK, Goodship TH, Kavanagh D. Complement therapy in atypical haemolytic uraemic syndrome (aHUS). Mol Immunol. 2013;56:199–212.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Gruppo RA, Rother RP. Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med. 2009;360:544–6.CrossRefPubMedGoogle Scholar
  14. 14.
    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. 2012;59:707–10.CrossRefPubMedGoogle Scholar
  15. 15.
    Besbas N, Gulhan B, Karpman D, Topaloglu R, Duzova A, Korkmaz E, et al. Neonatal onset atypical hemolytic uremic syndrome successfully treated with eculizumab. Pediatr Nephrol. 2013;28:155–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Christmann M, Hansen M, Bergmann C, Schwabe D, Brand J, Schneider W. Eculizumab as first-line therapy for atypical hemolytic uremic syndrome. Pediatrics. 2014;133:e1759–63.CrossRefPubMedGoogle Scholar
  17. 17.
    Sawai T, Nangaku M, Ashida A, Fujimaru R, Hataya H, Hidaka Y, et al. Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee of the Japanese Society of Nephrology and the Japan Pediatric Society. Clin Exp Nephrol. 2014;18:4–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Uemura O, Nagai T, Ishikura K, Ito S, Hataya H, Gotoh Y, et al. Creatinine-based equation to estimate the glomerular filtration rate in Japanese children and adolescents with chronic kidney disease. Clin Exp Nephrol. 2014;18:626–33.CrossRefPubMedGoogle Scholar
  19. 19.
    Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am. 1987;34:571–90.PubMedGoogle Scholar
  20. 20.
    Fan X, Yoshida Y, Honda S, Matsumoto M, Sawada Y, Hattori M, et al. Analysis of genetic and predisposing factors in Japanese patients with atypical hemolytic uremic syndrome. Mol Immunol. 2013;54:238–46.CrossRefPubMedGoogle Scholar
  21. 21.
    Administration USFaD. Prescribing information for Soliris. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125166s172lbl.pdf.
  22. 22.
    Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. 2009;24:687–96.CrossRefPubMedGoogle Scholar
  23. 23.
    Johnson S, Stojanovic J, Ariceta G, Bitzan M, Besbas N, Frieling M, et al. An audit analysis of a guideline for the investigation and initial therapy of diarrhea negative (atypical) hemolytic uremic syndrome. Pediatr Nephrol. 2014;29:1967–78.CrossRefPubMedGoogle Scholar
  24. 24.
    Kim J, Waller S, Reid C. Eculizumab in atypical haemolytic-uraemic syndrome allows cessation of plasma exchange and dialysis. Clin Kidney J. 2012;5:34–6.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Povey H, Vundru R, Junglee N, Jibani M. Renal recovery with eculizumab in atypical hemolytic uremic syndrome following prolonged dialysis. Clin Nephrol. 2014;82:326–31.CrossRefPubMedGoogle Scholar
  26. 26.
    Hillmen P, Muus P, Roth A, Elebute MO, Risitano AM, Schrezenmeier H, et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013;162:62–73.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lewis LA, Ram S. Meningococcal disease and the complement system. Virulence. 2014;5:98–126.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Takahashi H, Kuroki T, Watanabe Y, Tanaka H, Inouye H, Yamai S, et al. Characterization of Neisseria meningitidis isolates collected from 1974 to 2003 in Japan by multilocus sequence typing. J Med Microbiol. 2004;53:657–62.CrossRefPubMedGoogle Scholar
  29. 29.
    Tanimoto T, Kusumi E, Hosoda K, Kouno K, Hamaki T, Kami M. Concerns about unapproved meningococcal vaccination for eculizumab therapy in Japan. Orphanet J Rare Dis. 2014;9:48.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Bouts A, Monnens L, Davin JC, Struijk G, Spanjaard L. Insufficient protection by Neisseria meningitidis vaccination alone during eculizumab therapy. Pediatr Nephrol. 2011;26:1919–20.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ardissino G, Testa S, Possenti I, Tel F, Paglialonga F, Salardi S, et al. Discontinuation of eculizumab maintenance treatment for atypical hemolytic uremic syndrome: a report of 10 cases. Am J Kidney Dis. 2014;64:633–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013;45:531–6.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Nishimura J, Yamamoto M, Hayashi S, Ohyashiki K, Ando K, Brodsky AL, et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med. 2014;370:632–9.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2015

Authors and Affiliations

  • Naoko Ito
    • 1
  • Hiroshi Hataya
    • 2
  • Ken Saida
    • 3
  • Yoshiro Amano
    • 4
  • Yoshihiko Hidaka
    • 5
  • Yaeko Motoyoshi
    • 6
  • Toshiyuki Ohta
    • 7
  • Yasuhiro Yoshida
    • 2
  • Chikako Terano
    • 2
  • Tadashi Iwasa
    • 8
  • Wataru Kubota
    • 2
  • Hidetoshi Takada
    • 1
  • Toshiro Hara
    • 1
  • Yoshihiro Fujimura
    • 9
  • Shuichi Ito
    • 3
    • 10
  1. 1.Department of Pediatrics, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  2. 2.Department of Pediatric NephrologyTokyo Metropolitan Children’s Medical CenterTokyoJapan
  3. 3.Division of Nephrology and RheumatologyNational Center for Child Health and DevelopmentTokyoJapan
  4. 4.Department of PediatricsNagano Red Cross HospitalNaganoJapan
  5. 5.Department of PediatricsShinshu University School of MedicineNaganoJapan
  6. 6.Department of Pediatrics and Developmental BiologyTokyo Medical and Dental University Graduate School of MedicineTokyoJapan
  7. 7.Department of Pediatric NephrologyHiroshima Prefectural HospitalHiroshimaJapan
  8. 8.Department of PediatricsMie University Graduate School of MedicineMieJapan
  9. 9.Department of Blood Transfusion MedicineNara Medical UniversityNaraJapan
  10. 10.Department of Pediatrics, Graduate School of MedicineYokohama City UniversityKanagawaJapan

Personalised recommendations