A complicated case of atypical hemolytic uremic syndrome with frequent relapses under eculizumab

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• 作者：Gesa Schalk ; Michael Kirschfink ; Cyrill Wehling ; Sara Gastoldi…
• 关键词：Complement ; associated renal disease ; Drug level ; Eculizumab ; Genetic disease ; Long ; term treatment ; Terminal complement complex
• 刊名：Pediatric Nephrology
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：30
• 期：6
• 页码：1039-1042
• 全文大小：268 KB
• 参考文献：1.Zuber J, Fakhouri F, Roumenina LT, Loirat C, Fremeaux-Bacchi V, French Study Group for a HCG (2012) Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol 8:643鈥?57View Article PubMed
  2.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鈥?279View Article PubMed Central PubMed
  3.Noris M, Mescia F, Remuzzi G (2012) STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 8:622鈥?33View Article PubMed
  4.Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T, Fouque D, Furman RR, Gaber O, Herthelius M, Hourmant M, Karpman D, Lebranchu Y, Mariat C, Menne J, Moulin B, Nurnberger J, Ogawa M, Remuzzi G, Richard T, Sberro-Soussan R, Severino B, Sheerin NS, Trivelli A, Zimmerhackl LB, Goodship T, Loirat C (2013) Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 368:2169鈥?181View Article PubMed
  5.Kavanagh D, Goodship T (2010) Genetics and complement in atypical HUS. Pediatr Nephrol 25:2431鈥?442View Article PubMed Central PubMed
  6.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鈥?87View Article PubMed Central PubMed
  7.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鈥?12View Article PubMed
  8.Noris M, Galbusera M, Gastoldi S, Macor P, Banterla F, Bresin E, Tripodo C, Bettoni S, Donadelli R, Valoti E, Tedesco F, Amore A, Coppo R, Ruggenenti P, Gotti E, Remuzzi G (2014) Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood 124:1715鈥?726View Article PubMed Central PubMed
  9.Gilbert RD, Fowler DJ, Angus E, Hardy SA, Stanley L, Goodship TH (2013) Eculizumab therapy for atypical haemolytic uraemic syndrome due to a gain-of-function mutation of complement factor B. Pediatr Nephrol 28:1315鈥?318View Article PubMed
  10.Vilalta R, Lara E, Madrid A, Chocron S, Munoz M, Casquero A, Nieto J (2012) Long-term eculizumab improves clinical outcomes in atypical hemolytic uremic syndrome. Pediatr Nephrol 27:2323鈥?326View Article PubMed Central PubMed
  11.Volokhina EB, Westra D, van der Velden TJ, van de Kar NC, Mollnes TE, van den Heuvel LP (2014) Complement activation patterns in atypical hemolytic uremic syndrome during acute phase and in remission. Clin Exp Immunol. doi:10.鈥?111/鈥媍ei.鈥?2426
  12.Rinder CS, Rinder HM, Smith BR, Fitch JC, Smith MJ, Tracey JB, Matis LA, Squinto SP, Rollins SA (1995) Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation. J Clin Invest 96:1564鈥?572View Article PubMed Central PubMed
  13.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鈥?49View Article PubMed
  14.Wehling C, Kirschfink M (2014) Tailored eculizumab regimen for patients with atypical hemolytic uremic syndrome: requirement for comprehensive complement analysis. J Thromb Haemost 12:1437鈥?439View Article PubMed
  
• 作者单位：Gesa Schalk (1)
  Michael Kirschfink (2)
  Cyrill Wehling (2)
  Sara Gastoldi (3)
  Carsten Bergmann (4) (5)
  Bernd Hoppe (6)
  Lutz T. Weber (1)
  
  1. Pediatric Nephrology, Children鈥檚 Hospital, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany
  2. Institute of Immunology, University of Heidelberg, Heidelberg, Germany
  3. IRCCS鈥擬ario Negri Institute for Pharmacological Research, Bergamo, Italy
  4. Center for Human Genetics, Bioscientia, Ingelheim, Germany
  5. Renal Division, Department of Medicine, University Freiburg Medical Center, Freiburg im Breisgau, Germany
  6. Pediatric Nephrology, Children鈥檚 Hospital, University of Bonn, Bonn, Germany
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Pediatrics
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-198X

文摘

Background Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy characterized by uncontrolled activation of the alternative complement pathway with consecutive generation of the terminal complement complex. Mortality is increased, particularly in the first year of the disease. Therapeutic options include plasma therapy and terminal complement blockade using the anti-C5 monoclonal antibody eculizumab. Eculizumab prevents activation of the terminal sequence of the complement cascade and formation of the potentially lytic terminal complement complex (C5b-9). Case-diagnosis/treatment We report a 3-year-old boy with aHUS due to a novel heterozygous truncating complement Factor H mutation in combination with other changes known to be associated with an increased risk for aHUS. Despite eculizumab treatment and maximal suppression of the classical and alternative complement pathways, C3d and sC5b-9 remained consistently elevated and the patient showed repeated relapses. Conclusions Not every patient with aHUS and uncontrolled complement activation shows optimal therapeutic response to eculizumab with the recommended or even increased dosing regimen. Reliable outcome measures to determine the efficacy of treatment have to be defined.