Advertisement

Pediatric Nephrology

, Volume 33, Issue 8, pp 1277–1281 | Cite as

Eculizumab in STEC-HUS: need for a proper randomized controlled trial

  • Sebastian Loos
  • Jun Oh
  • Markus J. Kemper
Editorial Commentary

Abstract

Hemolytic uremic syndrome caused by Shiga toxin-producing E. coli (STEC-HUS) is often associated with a severe morbidity including neurological involvement and a mortality of 1–5%. Although STEC-HUS is often self-limited, improvement of treatment strategies is needed for cases with complications and, among others, plasma exchange/plasmapheresis and use of antibiotics have been advocated. With the availability of the complement blocker eculizumab, now a standard treatment of atypical HUS, several series have addressed its use in STEC-HUS, with variable response; randomized controlled trials are lacking.

In this issue of Pediatric Nephrology, Pecheron et al. present a cohort of 33 pediatric patients with severe HUS treated with eculizumab. Neurological involvement was observed in 85% of the patients and 94% required dialysis. Most patients (55%) did not benefit from eculizumab and renal dysfunction as well as neurological sequelae did not resolve. In a subgroup of patients, however, rapid neurological improvement was described. In the post-hoc-defined group of patients with favorable outcome, there was a trend towards more sustained complement inhibition, although this finding was not significant compared to patients with an unfavorable outcome.

Because multiple interventions were used and the study did not include any control group, future controlled studies are urgently needed to resolve the debate as to whether eculizumab can be an effective treatment for both prevention and treatment of complications in STEC-HUS.

Keywords

Hemolytic uremic syndrome Shiga toxin Eculizumab Outcome Children 

Notes

Compliance with ethical standards

Conflict of interest

SL, JO, and MK received support for travel, honoraria for lectures by Alexion, and took part in clinical trials sponsored by Alexion.

References

  1. 1.
    Tarr PI, Gordon CA, Chandler WL (2005) Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 365:1073–1086PubMedGoogle Scholar
  2. 2.
    Obrig TG, Karpman D (2012) Shiga toxin pathogenesis: kidney complications and renal failure. Curr Top Microbiol Immunol 357:105–136PubMedPubMedCentralGoogle Scholar
  3. 3.
    Nester CM, Barbour T, Rodriquez de Cordoba S, Dragon-Durey MA, Fremeaux-Bacchi V, Goodship THJ, Kavanagh D, Noris M, Pickering M, Sanchez-Corral P, Skerka C, Zipfel P, Smith RJH (2015) Atypical aHUS: state of the art. Mol Immunol 67:31–42CrossRefPubMedGoogle Scholar
  4. 4.
    Loirat C, Saland J, Bitzan M (2012) Management of hemolytic uremic syndrome. Presse Med 41:e115–e135CrossRefPubMedGoogle Scholar
  5. 5.
    Thurman JM, Marians R, Emlen W, Wood S, Smith C, Akana H, Holers VM, Lesser M, Kline M, Hoffman C, Christen E, Trachtman H (2009) Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol 4:1920–1924CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ferraris JR, Ferraris V, Acquier AB, Sorroche PB, Saez MS, Ginaca A, Mendez CF (2015) Activation of the alternative pathway of complement during the acute phase of typical haemolytic uraemic syndrome. Clin Exp Immunol 181:118–125CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Monnens L, Molenaar J, Lambert PH, Proesmans W, van Munster P (1980) The complement system in hemolytic-uremic syndrome in childhood. Clin Nephrol 13:168–171PubMedGoogle Scholar
  8. 8.
    Ahlenstiel-Grunow T, Hachmeister S, Bange FC, Wehling C, Kirschfink M, Bergmann C, Pape L (2016) Systemic complement activation and complement gene analysis in enterohaemorrhagic Escherichia coli-associated paediatric haemolytic uraemic syndrome. Nephrol Dial Transplant 31:1114–1121CrossRefPubMedGoogle Scholar
  9. 9.
    Morigi M, Galbusera M, Gastoldi S, Locatelli M, Buelli S, Pezzotta A, Pagani C, Noris M, Gobbi M, Stravalaci M, Rottoli D, Tedesco F, Remuzzi G, Zoja C (2011) Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis. J Immunol 187:172–180CrossRefPubMedGoogle Scholar
  10. 10.
    Orth-Holler D, Wurzner R (2014) Role of complement in enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome. Semin Thromb Hemost 40:503–507CrossRefPubMedGoogle Scholar
  11. 11.
    Arvidsson I, Rebetz J, Loos S, Herthelius M, Kristoffersson AC, Englund E, Chromek M, Karpman D (2016) Early terminal complement blockade and C6 deficiency are protective in Enterohemorrhagic Escherichia coli-infected mice. J Immunol 197:1276–1286CrossRefPubMedGoogle Scholar
  12. 12.
    Westra D, Volokhina EB, van der Molen RG, van der Velden TJ, Jeronimus-Klaasen A, Goertz J, Gracchi V, Dorresteijn EM, Bouts AH, Keijzer-Veen MG, van Wijk JA, Bakker JA, Roos A, van den Heuvel LP, van de Kar NC (2017) Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome. Pediatr Nephrol 32:297–309CrossRefPubMedGoogle Scholar
  13. 13.
    Zoja C, Buelli S, Morigi M (2017) Shiga toxin triggers endothelial and podocyte injury: the role of complement activation. Pediatr Nephrol.  https://doi.org/10.1007/s00467-017-3850-x
  14. 14.
    Adamski J (2014) Thrombotic microangiopathy and indications for therapeutic plasma exchange. Hematology Am Soc Hematol Educ Program 2014:444–449PubMedGoogle Scholar
  15. 15.
    Michael M, Elliott EJ, Craig JC, Ridley G, Hodson EM (2009) Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials. Am J Kidney Dis 53:259–272CrossRefPubMedGoogle Scholar
  16. 16.
    Keenswijk W, Raes A, Vande Walle J (2018) Is eculizumab efficacious in Shigatoxin-associated hemolytic uremic syndrome? A narrative review of current evidence. Eur J Pediatr 177:311–318CrossRefPubMedGoogle Scholar
  17. 17.
    Spinale JM, Ruebner RL, Copelovitch L, Kaplan BS (2013) Long-term outcomes of Shiga toxin hemolytic uremic syndrome. Pediatr Nephrol 28:2097–2105CrossRefPubMedGoogle Scholar
  18. 18.
    Lapeyraque AL, Malina M, Fremeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M, Proulx F, Clermont MJ, Le Deist F, Niaudet P, Schaefer F (2011) Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med 364:2561–2563CrossRefPubMedGoogle Scholar
  19. 19.
    Menne J, Nitschke M, Stingele R, Abu-Tair M, Beneke J, Bramstedt J, Bremer JP, Brunkhorst R, Busch V, Dengler R, Deuschl G, Fellermann K, Fickenscher H, Gerigk C, Goettsche A, Greeve J, Hafer C, Hagenmuller F, Haller H, Herget-Rosenthal S, Hertenstein B, Hofmann C, Lang M, Kielstein JT, Klostermeier UC, Knobloch J, Kuehbacher M, Kunzendorf U, Lehnert H, Manns MP, Menne TF, Meyer TN, Michael C, Munte T, Neumann-Grutzeck C, Nuernberger J, Pavenstaedt H, Ramazan L, Renders L, Repenthin J, Ries W, Rohr A, Rump LC, Samuelsson O, Sayk F, Schmidt BM, Schnatter S, Schocklmann H, Schreiber S, von Seydewitz CU, Steinhoff J, Stracke S, Suerbaum S, van de Loo A, Vischedyk M, Weissenborn K, Wellhoner P, Wiesner M, Zeissig S, Buning J, Schiffer M, Kuehbacher T (2012) Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study. BMJ 345:e4565CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wurzner R, Riedl M, Rosales A, Orth-Holler D (2014) Treatment of enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome (eHUS). Semin Thromb Hemost 40:508–516CrossRefPubMedGoogle Scholar
  21. 21.
    Loos S, Ahlenstiel T, Kranz B, Staude H, Pape L, Hartel C, Vester U, Buchtala L, Benz K, Hoppe B, Beringer O, Krause M, Muller D, Pohl M, Lemke J, Hillebrand G, Kreuzer M, Konig J, Wigger M, Konrad M, Haffner D, Oh J, Kemper MJ (2012) An outbreak of Shiga toxin-producing Escherichia coli O104:H4 hemolytic uremic syndrome in Germany: presentation and short-term outcome in children. Clin Infect Dis 55:753–759CrossRefPubMedGoogle Scholar
  22. 22.
    Pape L, Hartmann H, Bange FC, Suerbaum S, Bueltmann E, Ahlenstiel-Grunow T (2015) Eculizumab in typical hemolytic uremic syndrome (HUS) with neurological involvement. Medicine (Baltimore) 94:e1000CrossRefPubMedGoogle Scholar
  23. 23.
    Harambat JDC,C, Godron A, Bordes CD,Y, Llanas B (2013) Eculizumab in shigatoxin associated hemolytic uremic syndrome: a single center matched-cohort study. Pediatr Nephrol 28:1347–1378CrossRefGoogle Scholar
  24. 24.
    Percheron L, Gramada R, Tellier S, Salomon R, Harambat J, Llanas B, Fila M, Allain-Launay E, Lapeyraque AL, Leroy V, Adra AL, Bérard E, Bourdat-Michel G, Chehade H, Eckart P, Merieau E, Piètrement C, Sellier-Leclerc AL, Frémeaux-Bacchi V, Dimeglio C, Garnier A (2018) Eculizumab treatment in severe pediatric STEC-HUS: a multicenter retrospective study. Pediatr Nephrol.  https://doi.org/10.1007/s00467-018-3903-9
  25. 25.
    Loirat C, Fakhouri F, Ariceta G, Besbas N, Bitzan M, Bjerre A, Coppo R, Emma F, Johnson S, Karpman D, Landau D, Langman CB, Lapeyraque AL, Licht C, Nester C, Pecoraro C, Riedl M, van de Kar NC, Van de Walle J, Vivarelli M, Fremeaux-Bacchi V (2016) An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol 31:15–39CrossRefPubMedGoogle Scholar
  26. 26.
    Dundas S, Murphy J, Soutar RL, Jones GA, Hutchinson SJ, Todd WT (1999) Effectiveness of therapeutic plasma exchange in the 1996 Lanarkshire Escherichia coli O157:H7 outbreak. Lancet 354:1327–1330CrossRefPubMedGoogle Scholar

Copyright information

© IPNA 2018

Authors and Affiliations

  1. 1.University Children’s HospitalUniversity Medical Center Hamburg-EppendorfHamburgGermany
  2. 2.Department of PediatricsAK Hamburg Nord, Asklepios Medical SchoolHamburgGermany

Personalised recommendations