Pediatric Nephrology

, Volume 29, Issue 10, pp 1967–1978 | Cite as

An audit analysis of a guideline for the investigation and initial therapy of diarrhea negative (atypical) hemolytic uremic syndrome

  • Sally JohnsonEmail author
  • Jelena Stojanovic
  • Gema Ariceta
  • Martin Bitzan
  • Nesrin Besbas
  • Michelle Frieling
  • Diana Karpman
  • Daniel Landau
  • Craig Langman
  • Christoph Licht
  • Carmine Pecoraro
  • Magdalena Riedl
  • Ekaterini Siomou
  • Nicole van de Kar
  • Johan Vande Walle
  • Chantal Loirat
  • C. Mark Taylor
Original Article



In 2009, the European Paediatric Study Group for Haemolytic Uraemic Syndrome (HUS) published a clinical practice guideline for the investigation and initial therapy of diarrhea-negative HUS (now more widely referred to as atypical HUS, aHUS). The therapeutic component of the guideline (comprising early, high-volume plasmapheresis) was derived from anecdotal evidence and expert consensus, and the authors committed to auditing outcome.


Questionnaires were distributed to pediatric nephrologists across Europe, North America, and the Middle East, who were asked to complete one questionnaire per patient episode of aHUS between July 1, 2009 and December 31, 2010. Comprehensive, anonymous demographic and clinical data were collected.


Seventy-one children were reported with an episode of aHUS during the audit period. Six cases occurred on a background of influenza A H1N1 infection. Of 71 patients, 59 (83 %) received plasma therapy within the first 33 days, of whom ten received plasma infusion only. Complications of central venous catheters occurred in 16 out of 51 patients with a catheter in-situ (31 %). Median time to enter hematological remission was 11.5 days, and eight of 71 (11 %) patients did not enter hematological remission by day 33. Twelve patients (17 %) remained dialysis dependent at day 33.


This audit provides a snapshot of the early outcome of a group of children with aHUS in the months prior to more widespread use of eculizumab.


Atypical hemolytic-uremic syndrome Alternative complement pathway Plasmapheresis Complement dysregulation Chronic kidney disease Thrombotic microangiopathy 


Declaration of interests

The following authors declare interests. CMT and MB were scientific advisers to Thallion Pharmaceuticals. SJ, NvdK, GA, JVW, C. Licht, and MR have served on Advisory Boards for Alexion Pharmaceuticals. DK, C. Licht, and C. Loirat were the national coordinators of the multi-center Eculizumab trials in aHUS in Sweden, Canada, and France, respectively.

The European Paediatric Study Group for HUS is now known as HUS International and comprises pediatric nephrologists from Europe, North America, and the Middle East.


Anne-Laure Adra1, Klaus Arbeiter2, Yelda Bilginer3, Heiko Billing4, Maria Bitsori5, Bernard Boudailliez6, Francisco de la Cerda – Ojeda7, Gérard Champion8, Amit Dagan9, Bradley Dixon, MD10, Philippe Eckart11, Israel Eisenstein12, Arnaud Garnier13, Clara Gomes14, Karsten Häffner15, Jerome Harambat16, Carol Inward17, Rafael Krmar18, Theresa Kwon19, Anne-Laure Lapeyraque20, Sebastian Loos21, Meeta Malik22, Mignon McCulloch23, David Milford24, Danko Milosevic25, Carla Nester26, François Nobili27, Pedro J Ortega28, Fotios Papachristou29, Antonia Peña - Carrión30, Ludmila Podracká31, Nikoleta Printza29, Bruno Ranchin32, Christopher Reid23, Caroline Rousset-Rouvière33, Rémi Salomon34, Anne-Laure Sellier-Leclerc35, James Springate36, Sophie Taque37, Despoina Tramma38, Sibylle Tschumi39, Ulrike Walden40, Kay Tyerman41, Aoife Waters42, Donald J Weaver Jr43

1Pediatric nephrology department, Hôpital A. de Villeneuve, Montpellier, France

2Medical University Vienna, Pediatric Nephrology, Vienna, Austria

3Hacettepe University Faculty of Medicine Pediatric Nephrology, Ankara, Turkey

4University Hospital Heidelberg, Pediatric Nephrology, Heidelberg, Germany

5Department of Pediatrics, University Hospital of Heraklion, Greece

6Department of Pediatrics, Centre Hospitalier Universitaire Nord, Amiens , France

7Virgen del Rocío Children´s Hospital, Division of Pediatric Nephrology, Seville, Spain

8Department of Pediatrics, Centre Hospitalier Universitaire, Angers, France

9Schneider Children's Hospital, Petach Tikvah (Tel Aviv University), Israel

10Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

11Department of Pediatrics, Centre Hospitalier Universitaire, Caen, France

12Myers Children's Hospital (Rambam Medical Center), Haifa (Technion University), Israel

13Pediatric nephrology department, Centre Hospitalier Universitaire Purpan, Hôpital des enfants, Toulouse, France

14Coimbra Pediatric Hospital, Division of Pediatric Nephrology, Coimbra, Portugal

15University Hospital Freiburg, Department of Pediatrics, Freiburg, Germany

16Department of Pediatrics, Centre Hospitalier Universitaire, Bordeaux, France

17Department of Paediatric Nephrology, Bristol Royal Hospital for Children, Bristol, UK

18Karolinska University Hospital Huddinge, Stockholm, Sweden

19Pediatric nephrology department Hôpital Robert Debré, Paris, France

20Centre Hospitalier Universitaire Sainte Justine, Montreal Quebec

21University Hospital Hamburg, Pediatric Nephrology, Hamburg, Germany

22Children's Renal & Urology Unit, Nottingham University Hospitals, Nottingham, UK

23Paediatric Nephro-urology Unit, Evelina Children’s Hospital, London, UK

24Birmingham Children’s Hospital, Birmingham, UK

25University Hospital Center Zagreb, Croatia

26The University of Iowa, Iowa City, Iowa, USA

27Pediatric Nephrology, Centre Hospitalier Universitaire, Besançon, France

28La Fe Hospital, Division of Pediatric Nephrology, Valencia, Spain

291st Department of Paediatrics, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

30La Paz Universitary Hospital, Division of Pediatric Nephrology, Madrid, Spain

31Children's Hospital of P.J. Safarik's University, 1st Pediatric Department, Košice, Slovakia

32Pediatric nephrology department, Hospices Civils de Lyon, Lyon, France

33Pediatric nephrology department, Hôpital de la Timone, Marseille, France

34Pediatric nephrology department, Hôpital Necker-Enfants Malades, Paris, France

35Pediatric nephrology department, Hôpital Trousseau, Paris, France

36Division of Nephrology, Women & Children's Hospital, Buffalo, New York, USA

37Department of Pediatrics, Centre Hospitalier Universitaire, Rennes, France

38Aristotle University of Thessaloniki, Thessaloniki, Greece

39Paediatric Nephrology, University Children's Hospital Bern, Switzerland

40Childrens Hospital Augsburg, Augsburg, Germany

41Department of Paediatric Nephrology, Leeds General Infirmary, Leeds, UK

42Department of Paediatric Nephrology, Great Ormond Street Hospital, London, UK

43Levine Children's Hospital at Carolinas Medical Center, Charlotte, North Carolina, USA


  1. 1.
    Kavanagh D, Goodship TH (2010) Atypical hemolytic uremic syndrome. Curr Opin Hematol 17:432–438PubMedCrossRefGoogle Scholar
  2. 2.
    Loirat C, Fremeaux-Bacchi V (2011) Atypical hemolytic uremic syndrome. Orphanet J Rare Dis 6:60PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Le Quintrec M, Roumenina L, Noris M, Fremeaux-Bacchi V (2010) Atypical hemolytic uremic syndrome associated with mutations in complement regulator genes. Semin Thromb Hemost 36:641–652PubMedCrossRefGoogle Scholar
  4. 4.
    Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaime F, Dragon-Durey MA, Ngo S, Moulin B, Servais A, Provot F, Rostaing L, Burtey S, Niaudet P, Deschenes G, Lebranchu Y, Zuber J, Loirat C (2013) Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 8:554–562PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji W, Overton JD, Mane SM, Nurnberg G, Altmuller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nurnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP (2013) Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 45:531–536PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, Loirat C, Pecoraro C, Taylor CM, Van der Kar N, Vandewalle J, Zimmerhackl LB, European Paediatric Study Group for HUS (2009) Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 24:687–696PubMedCrossRefGoogle Scholar
  7. 7.
    Dragon-Durey MA, Sethi SK, Bagga A, Blanc C, Blouin J, Ranchin B, Andre JL, Takagi N, Cheong HI, Hari P, Le Quintrec M, Niaudet P, Loirat C, Fridman WH, Fremeaux-Bacchi V (2010) Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J Am Soc Nephrol 21:2180–2187PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    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 N (2007) Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 18:2392–2400PubMedCrossRefGoogle Scholar
  9. 9.
    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 R, Familial HT (2006) Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108:1267–1279PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Witt V, Stegmayr B, Ptak J, Wikstrom B, Berlin G, Axelsson CG, Griskevicius A, Centoni PE, Liumbruno GM, Molfettini P, Audzijoniene J, Mokvist K, Sojka BN, Norda R, Ramlow W, Blaha M, Evergren M, Tomaz J (2008) World apheresis registry data from 2003 to 2007, the pediatric and adolescent side of the registry. Transfus Apher Sci 39:255–260PubMedCrossRefGoogle Scholar
  11. 11.
    Mokrzycki MH, Balogun RA (2011) Therapeutic apheresis: a review of complications and recommendations for prevention and management. J Clin Apher 26:243–248PubMedCrossRefGoogle Scholar
  12. 12.
    Gruppo RA, Rother RP (2009) Eculizumab for congenital atypical hemolytic-uremic syndrome. New Engl J Med 360:544–546PubMedCrossRefGoogle Scholar
  13. 13.
    Lapeyraque AL, Fremeaux-Bacchi V, Robitaille P (2011) Efficacy of eculizumab in a patient with factor-H-associated atypical hemolytic uremic syndrome. Pediatr Nephrol 26:621–624PubMedCrossRefGoogle Scholar
  14. 14.
    Ariceta G, Arrizabalaga B, Aguirre M, Morteruel E, Lopez-Trascasa M (2012) Eculizumab in the treatment of atypical hemolytic uremic syndrome in infants. Am J Kidney Dis 59:707–710PubMedCrossRefGoogle Scholar
  15. 15.
    Dorresteijn EM, van de Kar NC, Cransberg K (2012) Eculizumab as rescue therapy for atypical hemolytic uremic syndrome with normal platelet count. Pediatr Nephrol 27:1193–1195PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Giordano M, Castellano G, Messina G, Divella C, Bellantuono R, Puteo F, Colella V, Depalo T, Gesualdo L (2012) Preservation of renal function in atypical hemolytic uremic syndrome by eculizumab: a case report. Pediatrics 130:e1385–1388PubMedCrossRefGoogle Scholar
  17. 17.
    Povey H, Vundru R, Junglee N, Jibani M (2013) Renal recovery with eculizumab in atypical hemolytic uremic syndrome following prolonged dialysis. Clin Nephrol. doi: 10.5414/CN107958 PubMedGoogle Scholar
  18. 18.
    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 27:2323–2326PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Gulleroglu K, Fidan K, Hancer VS, Bayrakci U, Baskin E, Soylemezoglu O (2013) Neurologic involvement in atypical hemolytic uremic syndrome and successful treatment with eculizumab. Pediatr Nephrol 28:827–830PubMedCrossRefGoogle Scholar
  20. 20.
    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. New Engl J Med 368:2169–2181PubMedCrossRefGoogle Scholar
  21. 21.
    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 (2009) Thrombomodulin mutations in atypical hemolytic-uremic syndrome. New Engl J Med 361:345–357PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Sana G, Dragon-Durey MA, Charbit M, Bouchireb K, Rousset-Rouviere C, Berard E, Salomon R, Fremeaux-Bacchi V, Niaudet P, Boyer O (2014) Long-term remission of atypical HUS with anti-factor H antibodies after cyclophosphamide pulses. Pediatr Nephrol 29:75–83PubMedCrossRefGoogle Scholar
  23. 23.
    Bresin E, Rurali E, Caprioli J, Sanchez-Corral P, Fremeaux-Bacchi V, Rodriguez de Cordoba S, Pinto S, Goodship TH, Alberti M, Ribes D, Valoti E, Remuzzi G, Noris M, European Working Party on Complement Genetics in Renal D (2013) Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol 24:475–486PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Besbas N, Karpman D, Landau D, Loirat C, Proesmans W, Remuzzi G, Rizzoni G, Taylor CM, Van de Kar N, Zimmerhackl LB, European Paediatric Research Group for HUS (2006) A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney Int 70:423–431PubMedGoogle Scholar
  25. 25.
    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 5:1844–1859PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Hofer J, Janecke AR, Zimmerhackl LB, Riedl M, Rosales A, Giner T, Cortina G, Haindl CJ, Petzelberger B, Pawlik M, Jeller V, Vester U, Gadner B, van Husen M, Moritz ML, Wurzner R, Jungraithmayr T, German-Austrian HUSSG (2013) Complement factor H-related protein 1 deficiency and factor H antibodies in pediatric patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 8:407–415PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Watson R, Lindner S, Bordereau P, Hunze EM, Tak F, Ngo S, Zipfel PF, Skerka C, Dragon-Durey MA, Marchbank KJ (2013) Standardisation of the factor H autoantibody assay. Immunobiology 219:9–16PubMedCrossRefGoogle Scholar
  28. 28.
    Coats MT, Murphy T, Paton JC, Gray B, Briles DE (2011) Exposure of Thomsen-Friedenreich antigen in Streptococcus pneumoniae infection is dependent on pneumococcal neuraminidase A. Microb Pathog 50:343–349PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© IPNA 2014

Authors and Affiliations

  • Sally Johnson
    • 1
    • 17
    Email author
  • Jelena Stojanovic
    • 1
  • Gema Ariceta
    • 2
  • Martin Bitzan
    • 3
  • Nesrin Besbas
    • 4
  • Michelle Frieling
    • 5
  • Diana Karpman
    • 6
  • Daniel Landau
    • 7
  • Craig Langman
    • 8
    • 9
  • Christoph Licht
    • 5
  • Carmine Pecoraro
    • 10
  • Magdalena Riedl
    • 11
  • Ekaterini Siomou
    • 12
  • Nicole van de Kar
    • 13
  • Johan Vande Walle
    • 14
  • Chantal Loirat
    • 15
  • C. Mark Taylor
    • 16
  1. 1.Great North Children’s HospitalNewcastle Upon TyneUK
  2. 2.Hospital Vall d’ Hebron BarcelonaBarcelonaSpain
  3. 3.Montreal Children’s Hospital and McGill UniversityMontrealCanada
  4. 4.Hacettepe University Faculty of Medicine, Department of Pediatric NephrologyAnkaraTurkey
  5. 5.The Hospital For Sick ChildrenTorontoCanada
  6. 6.Department of Pediatrics, Clinical SciencesLund UniversityLundSweden
  7. 7.Soroka University Medical CenterBeer ShevaIsrael
  8. 8.Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  9. 9.The Ann and Robert H. Lurie Children’s Hospital of ChicagoChicagoUSA
  10. 10.Santobono Children’s HospitalNaplesItaly
  11. 11.Department of PaediatricsInnsbruck Medical UniversityInnsbruckAustria
  12. 12.University Hospital of IoanninaIoanninaGreece
  13. 13.Radboud University Medical CenterNijmegenThe Netherlands
  14. 14.University Hospital GentGhentBelgium
  15. 15.Assistance Publique-Hôpitaux de ParisHôpital Robert DebréParisFrance
  16. 16.Birmingham Children’s HospitalBirminghamUK
  17. 17.Department of Pediatric Nephrology, Great North Children’s HospitalNewcastle Upon Tyne Hospitals NHS Foundation TrustNewcastle Upon TyneUK

Personalised recommendations