Seminars in Immunopathology

, Volume 36, Issue 4, pp 399–420 | Cite as

Hemolytic uremic syndrome

  • Caterina Mele
  • Giuseppe Remuzzi
  • Marina Noris


Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy defined by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute renal failure. The most frequent form is associated with infections by Shiga-like toxin-producing bacteria (STEC-HUS). Rarer cases are triggered by neuraminidase-producing Streptococcus pneumoniae (pneumococcal-HUS). The designation of aHUS is used to refer to those cases in which an infection by Shiga-like toxin-producing bacteria or S. pneumoniae can be excluded. Studies performed in the last two decades have documented that hyperactivation of the complement system is the pathogenetic effector mechanism leading to the endothelial damage and the microvascular thrombosis in aHUS. Recent data suggested the involvement of the complement system in the pathogenesis of STEC-HUS and pneumococcal-HUS as well. Clinical signs and symptoms may overlap among the different forms of HUS; however, pneumococcal-HUS and aHUS have a worse prognosis compared with STEC-HUS. Early diagnosis and identification of underlying pathogenetic mechanism allows instating specific support measures and therapies. In clinical trials in patients with aHUS, complement inhibition by eculizumab administration leads to a rapid and sustained normalization of hematological parameters with improvement in long-term renal function. This review summarizes current concepts about the epidemiological findings, the pathological and clinical aspects of STEC-HUS, pneumococcal-HUS, and aHUS, and their diagnosis and management.


STEC-HUS Pneumococcal-HUS aHUS Complement system activation Eculizumab 



This work has been partially supported by grants from Fondazione ART per la Ricerca sui Trapianti ONLUS (Milano Italy) and the European Community (FP7 Grant 2012-305608 EURenOmics). The authors wish to thank Dr. Claudio Tripodo (University of Palermo, Italy) for kindly providing the images of C3 and C9 staining in kidney biopsies from HUS patients.


  1. 1.
    Gianantonio CA, Vitacco M, Mendilaharzu F, Gallo GE, Sojo ET (1973) The hemolytic-uremic syndrome. Nephron 11:174–192PubMedGoogle Scholar
  2. 2.
    Gasser C, Gautier E, Steck A, Siebenmann RE, Oechslin R (1955) Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia. Schweiz Med Wochenschr 85:905–909PubMedGoogle Scholar
  3. 3.
    Noris M, Remuzzi G (2009) Atypical hemolytic-uremic syndrome. N Engl J Med 361:1676–1687PubMedGoogle Scholar
  4. 4.
    Ruggenenti P, Noris M, Remuzzi G (2001) Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 60:831–846PubMedGoogle Scholar
  5. 5.
    Besbas N, Karpman D, Landau D, Loirat C, Proesmans W, Remuzzi G, Rizzoni G, Taylor CM, Van de Kar N, Zimmerhackl LB (2006) A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney Int 70:423–431PubMedGoogle Scholar
  6. 6.
    Frank C, Werber D, Cramer JP, Askar M, Faber M, an der Heiden M, Bernard H, Fruth A, Prager R, Spode A, Wadl M, Zoufaly A, Jordan S, Kemper MJ, Follin P, Muller L, King LA, Rosner B, Buchholz U, Stark K, Krause G (2011) Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med 365:1771–1780PubMedGoogle Scholar
  7. 7.
    Tarr PI, Gordon CA, Chandler WL (2005) Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 365:1073–1086PubMedGoogle Scholar
  8. 8.
    Copelovitch L, Kaplan BS (2010) Streptococcus pneumoniae-associated hemolytic uremic syndrome: classification and the emergence of serotype 19A. Pediatrics 125:e174–e182PubMedGoogle Scholar
  9. 9.
    Shimizu M, Yokoyama T, Sakashita N, Sato A, Ueno K, Akita C, Ohta K, Kitano E, Hatanaka M, Kitamura H, Saikawa Y, Yachie A (2012) Thomsen-Friedenreich antigen exposure as a cause of Streptococcus pyogenes-associated hemolytic-uremic syndrome. Clin Nephrol 78:328–331PubMedGoogle Scholar
  10. 10.
    Kaplan BS, Chesney RW, Drummond KN (1975) Hemolytic uremic syndrome in families. N Engl J Med 292:1090–1093PubMedGoogle Scholar
  11. 11.
    Sharma AP, Greenberg CR, Prasad AN, Prasad C (2007) Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder. Pediatr Nephrol 22:2097–2103PubMedGoogle Scholar
  12. 12.
    Fakhouri F, Roumenina L, Provot F, Sallee M, Caillard S, Couzi L, Essig M, Ribes D, Dragon-Durey MA, Bridoux F, Rondeau E, Fremeaux-Bacchi V (2010) Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol 21:859–867PubMedCentralPubMedGoogle Scholar
  13. 13.
    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 5:1844–1859PubMedCentralPubMedGoogle Scholar
  14. 14.
    Noris M, Mescia F, Remuzzi G (2012) STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 8:622–633PubMedGoogle Scholar
  15. 15.
    Crump JA, Sulka AC, Langer AJ, Schaben C, Crielly AS, Gage R, Baysinger M, Moll M, Withers G, Toney DM, Hunter SB, Hoekstra RM, Wong SK, Griffin PM, Van Gilder TJ (2002) An outbreak of Escherichia coli O157:H7 infections among visitors to a dairy farm. N Engl J Med 347:555–560PubMedGoogle Scholar
  16. 16.
    Haack JP, Jelacic S, Besser TE, Weinberger E, Kirk DJ, McKee GL, Harrison SM, Musgrave KJ, Miller G, Price TH, Tarr PI (2003) Escherichia coli O157 exposure in Wyoming and Seattle: serologic evidence of rural risk. Emerg Infect Dis 9:1226–1231PubMedGoogle Scholar
  17. 17.
    Boyce TG, Swerdlow DL, Griffin PM (1995) Escherichia coli O157:H7 and the hemolytic-uremic syndrome. N Engl J Med 333:364–368PubMedGoogle Scholar
  18. 18.
    Palermo MS, Exeni RA, Fernandez GC (2009) Hemolytic uremic syndrome: pathogenesis and update of interventions. Expert Rev Anti Infect Ther 7:697–707PubMedGoogle Scholar
  19. 19.
    Navarro A, Eslava C, Hernandez U, Navarro-Henze JL, Aviles M, Garcia-de la Torre G, Cravioto A (2003) Antibody responses to Escherichia coli O157 and other lipopolysaccharides in healthy children and adults. Clin Diagn Lab Immunol 10:797–801PubMedCentralPubMedGoogle Scholar
  20. 20.
    Mead PS, Griffin PM (1998) Escherichia coli O157:H7. Lancet 352:1207–1212PubMedGoogle Scholar
  21. 21.
    Rivas M, Miliwebsky E, Chinen I, Roldan CD, Balbi L, Garcia B, Fiorilli G, Sosa-Estani S, Kincaid J, Rangel J, Griffin PM (2006) Characterization and epidemiologic subtyping of Shiga toxin-producing Escherichia coli strains isolated from hemolytic uremic syndrome and diarrhea cases in Argentina. Foodborne Pathog Dis 3:88–96PubMedGoogle Scholar
  22. 22.
    Manning SD, Motiwala AS, Springman AC, Qi W, Lacher DW, Ouellette LM, Mladonicky JM, Somsel P, Rudrik JT, Dietrich SE, Zhang W, Swaminathan B, Alland D, Whittam TS (2008) Variation in virulence among clades of Escherichia coli O157:H7 associated with disease outbreaks. Proc Natl Acad Sci U S A 105:4868–4873PubMedCentralPubMedGoogle Scholar
  23. 23.
    Isaacson M, Canter PH, Effler P, Arntzen L, Bomans P, Heenan R (1993) Haemorrhagic colitis epidemic in Africa. Lancet 341:961PubMedGoogle Scholar
  24. 24.
    Buchholz U, Bernard H, Werber D, Bohmer MM, Remschmidt C, Wilking H, Delere Y, an der Heiden M, Adlhoch C, Dreesman J, Ehlers J, Ethelberg S, Faber M, Frank C, Fricke G, Greiner M, Hohle M, Ivarsson S, Jark U, Kirchner M, Koch J, Krause G, Luber P, Rosner B, Stark K, Kuhne M (2011) German outbreak of Escherichia coli O104:H4 associated with sprouts. N Engl J Med 365:1763–1770PubMedGoogle Scholar
  25. 25.
    Keene WE, McAnulty JM, Hoesly FC, Williams LP Jr, Hedberg K, Oxman GL, Barrett TJ, Pfaller MA, Fleming DW (1994) A swimming-associated outbreak of hemorrhagic colitis caused by Escherichia coli O157:H7 and Shigella sonnei. N Engl J Med 331:579–584PubMedGoogle Scholar
  26. 26.
    Brandt J, Wong C, Mihm S, Roberts J, Smith J, Brewer E, Thiagarajan R, Warady B (2002) Invasive pneumococcal disease and hemolytic uremic syndrome. Pediatrics 110:371–376PubMedGoogle Scholar
  27. 27.
    Szilagyi A, Kiss N, Bereczki C, Talosi G, Racz K, Turi S, Gyorke Z, Simon E, Horvath E, Kelen K, Reusz GS, Szabo AJ, Tulassay T, Prohaszka Z (2013) The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome. Nephrol Dial Transplant 28:2237–2245PubMedGoogle Scholar
  28. 28.
    Mizusawa Y, Pitcher LA, Burke JR, Falk MC, Mizushima W (1996) Survey of haemolytic-uraemic syndrome in Queensland 1979–1995. Med J Aust 165:188–191PubMedGoogle Scholar
  29. 29.
    Constantinescu AR, Bitzan M, Weiss LS, Christen E, Kaplan BS, Cnaan A, Trachtman H (2004) Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis 43:976–982PubMedGoogle Scholar
  30. 30.
    Ohanian M, Cable C, Halka K (2011) Eculizumab safely reverses neurologic impairment and eliminates need for dialysis in severe atypical hemolytic uremic syndrome. Clin Pharmacol 3:5–12PubMedCentralPubMedGoogle Scholar
  31. 31.
    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 (2007) Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 18:2392–2400PubMedGoogle Scholar
  32. 32.
    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 (2006) Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108:1267–1279PubMedCentralPubMedGoogle Scholar
  33. 33.
    Milford DV, Taylor CM, Guttridge B, Hall SM, Rowe B, Kleanthous H (1990) Haemolytic uraemic syndromes in the British Isles 1985–8: association with verocytotoxin producing Escherichia coli. Part 1: Clinical and epidemiological aspects. Arch Dis Child 65:716–721PubMedCentralPubMedGoogle Scholar
  34. 34.
    Sullivan M, Erlic Z, Hoffmann MM, Arbeiter K, Patzer L, Budde K, Hoppe B, Zeier M, Lhotta K, Rybicki LA, Bock A, Berisha G, Neumann HP (2010) Epidemiological approach to identifying genetic predispositions for atypical hemolytic uremic syndrome. Ann Hum Genet 74:17–26PubMedGoogle Scholar
  35. 35.
    Loirat C, Fremeaux-Bacchi V (2011) Atypical hemolytic uremic syndrome. Orphanet J Rare Dis 6:60PubMedCentralPubMedGoogle Scholar
  36. 36.
    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 28:1315–1318PubMedGoogle Scholar
  37. 37.
    Kaplan BS, Proesmans W (1987) The hemolytic uremic syndrome of childhood and its variants. Semin Hematol 24:148–160PubMedGoogle Scholar
  38. 38.
    Habib R (1992) Pathology of the hemolytic uremic syndrome. In: TR Kaplan B, Moake J (eds) Hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Marcel Dekker, New York, p 315Google Scholar
  39. 39.
    Inward CD, Howie AJ, Fitzpatrick MM, Rafaat F, Milford DV, Taylor CM (1997) Renal histopathology in fatal cases of diarrhoea-associated haemolytic uraemic syndrome. British Association for Paediatric Nephrology. Pediatr Nephrol 11:556–559PubMedGoogle Scholar
  40. 40.
    Alberti M, Valoti E, Piras R, Bresin E, Galbusera M, Tripodo C, Thaiss F, Remuzzi G, Noris M (2013) Two patients with history of STEC-HUS, posttransplant recurrence and complement gene mutations. Am J Transplant 13:2201–2206PubMedGoogle Scholar
  41. 41.
    Landau D, Shalev H, Levy-Finer G, Polonsky A, Segev Y, Katchko L (2001) Familial hemolytic uremic syndrome associated with complement factor H deficiency. J Pediatr 138:412–417PubMedGoogle Scholar
  42. 42.
    Moghal NE, Ferreira MA, Howie AJ, Milford DV, Raafat E, Taylor CM (1998) The late histologic findings in diarrhea-associated hemolytic uremic syndrome. J Pediatr 133:220–223PubMedGoogle Scholar
  43. 43.
    Garg AX, Suri RS, Barrowman N, Rehman F, Matsell D, Rosas-Arellano MP, Salvadori M, Haynes RB, Clark WF (2003) Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. JAMA 290:1360–1370PubMedGoogle Scholar
  44. 44.
    Grodinsky S, Telmesani A, Robson WL, Fick G, Scott RB (1990) Gastrointestinal manifestations of hemolytic uremic syndrome: recognition of pancreatitis. J Pediatr Gastroenterol Nutr 11:518–524PubMedGoogle Scholar
  45. 45.
    Abu-Arafeh I, Gray E, Youngson G, Auchterlonie I, Russell G (1995) Myocarditis and haemolytic uraemic syndrome. Arch Dis Child 72:46–47PubMedCentralPubMedGoogle Scholar
  46. 46.
    Ruggenenti P, Remuzzi G (2011) A German outbreak of haemolytic uraemic syndrome. Lancet 378:1057–1058PubMedGoogle Scholar
  47. 47.
    Blaser MJ (2011) Deconstructing a lethal foodborne epidemic. N Engl J Med 365:1835–1836PubMedGoogle Scholar
  48. 48.
    Mellmann A, Harmsen D, Cummings CA, Zentz EB, Leopold SR, Rico A, Prior K, Szczepanowski R, Ji Y, Zhang W, McLaughlin SF, Henkhaus JK, Leopold B, Bielaszewska M, Prager R, Brzoska PM, Moore RL, Guenther S, Rothberg JM, Karch H (2011) Prospective genomic characterization of the German enterohemorrhagic Escherichia coli O104:H4 outbreak by rapid next generation sequencing technology. PLoS One 6:e22751PubMedCentralPubMedGoogle Scholar
  49. 49.
    Qin J, Cui Y, Zhao X, Rohde H, Liang T, Wolters M, Li D, Belmar Campos C, Christner M, Song Y, Yang R (2011) Identification of the Shiga toxin-producing Escherichia coli O104:H4 strain responsible for a food poisoning outbreak in Germany by PCR. J Clin Microbiol 49:3439–3440PubMedCentralPubMedGoogle Scholar
  50. 50.
    Tarr PI, Neill MA, Clausen CR, Watkins SL, Christie DL, Hickman RO (1990) Escherichia coli O157:H7 and the hemolytic uremic syndrome: importance of early cultures in establishing the etiology. J Infect Dis 162:553–556PubMedGoogle Scholar
  51. 51.
    Gerritzen A, Wittke JW, von Ahsen N, Wolff D (2012) Direct faecal PCR for diagnosis of Shiga-toxin-producing Escherichia coli. Lancet Infect Dis 12:102PubMedGoogle Scholar
  52. 52.
    Donnenberg MS, Tacket CO, James SP, Losonsky G, Nataro JP, Wasserman SS, Kaper JB, Levine MM (1993) Role of the eaeA gene in experimental enteropathogenic Escherichia coli infection. J Clin Invest 92:1412–1417PubMedCentralPubMedGoogle Scholar
  53. 53.
    Brigotti M, Carnicelli D, Arfilli V, Tamassia N, Borsetti F, Fabbri E, Tazzari PL, Ricci F, Pagliaro P, Spisni E, Cassatella MA (2013) Identification of TLR4 as the receptor that recognizes Shiga toxins in human neutrophils. J Immunol 191:4748–4758PubMedGoogle Scholar
  54. 54.
    Cooling LL, Walker KE, Gille T, Koerner TA (1998) Shiga toxin binds human platelets via globotriaosylceramide (Pk antigen) and a novel platelet glycosphingolipid. Infect Immun 66:4355–4366PubMedCentralPubMedGoogle Scholar
  55. 55.
    van Setten PA, Monnens LA, Verstraten RG, van den Heuvel LP, van Hinsbergh VW (1996) Effects of verocytotoxin-1 on nonadherent human monocytes: binding characteristics, protein synthesis, and induction of cytokine release. Blood 88:174–183PubMedGoogle Scholar
  56. 56.
    Hurley BP, Thorpe CM, Acheson DW (2001) Shiga toxin translocation across intestinal epithelial cells is enhanced by neutrophil transmigration. Infect Immun 69:6148–6155PubMedCentralPubMedGoogle Scholar
  57. 57.
    O'Brien AD, Lively TA, Chang TW, Gorbach SL (1983) Purification of Shigella dysenteriae 1 (Shiga)-like toxin from Escherichia coli O157:H7 strain associated with haemorrhagic colitis. Lancet 2:573PubMedGoogle Scholar
  58. 58.
    Cimolai N, Carter JE, Morrison BJ, Anderson JD (1990) Risk factors for the progression of Escherichia coli O157:H7 enteritis to hemolytic-uremic syndrome. J Pediatr 116:589–592PubMedGoogle Scholar
  59. 59.
    Scotland SM, Willshaw GA, Smith HR, Rowe B (1987) Properties of strains of Escherichia coli belonging to serogroup O157 with special reference to production of Vero cytotoxins VT1 and VT2. Epidemiol Infect 99:613–624PubMedCentralPubMedGoogle Scholar
  60. 60.
    Jenkins C, Willshaw GA, Evans J, Cheasty T, Chart H, Shaw DJ, Dougan G, Frankel G, Smith HR (2003) Subtyping of virulence genes in verocytotoxin-producing Escherichia coli (VTEC) other than serogroup O157 associated with disease in the United Kingdom. J Med Microbiol 52:941–947PubMedGoogle Scholar
  61. 61.
    O'Loughlin EV, Robins-Browne RM (2001) Effect of Shiga toxin and Shiga-like toxins on eukaryotic cells. Microbes Infect 3:493–507PubMedGoogle Scholar
  62. 62.
    Chaisri U, Nagata M, Kurazono H, Horie H, Tongtawe P, Hayashi H, Watanabe T, Tapchaisri P, Chongsa-nguan M, Chaicumpa W (2001) Localization of Shiga toxins of enterohaemorrhagic Escherichia coli in kidneys of paediatric and geriatric patients with fatal haemolytic uraemic syndrome. Microb Pathog 31:59–67PubMedGoogle Scholar
  63. 63.
    Auray-Blais C, Cyr D, Ntwari A, West ML, Cox-Brinkman J, Bichet DG, Germain DP, Laframboise R, Melancon SB, Stockley T, Clarke JT, Drouin R (2008) Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease. Mol Genet Metab 93:331–340PubMedGoogle Scholar
  64. 64.
    Zoja C, Angioletti S, Donadelli R, Zanchi C, Tomasoni S, Binda E, Imberti B, te Loo M, Monnens L, Remuzzi G, Morigi M (2002) Shiga toxin-2 triggers endothelial leukocyte adhesion and transmigration via NF-kappaB dependent up-regulation of IL-8 and MCP-1. Kidney Int 62:846–856PubMedGoogle Scholar
  65. 65.
    Petruzziello-Pellegrini TN, Yuen DA, Page AV, Patel S, Soltyk AM, Matouk CC, Wong DK, Turgeon PJ, Fish JE, Ho JJ, Steer BM, Khajoee V, Tigdi J, Lee WL, Motto DG, Advani A, Gilbert RE, Karumanchi SA, Robinson LA, Tarr PI, Liles WC, Brunton JL, Marsden PA (2012) The CXCR4/CXCR7/SDF-1 pathway contributes to the pathogenesis of Shiga toxin-associated hemolytic uremic syndrome in humans and mice. J Clin Invest 122:759–776PubMedCentralPubMedGoogle Scholar
  66. 66.
    Morigi M, Micheletti G, Figliuzzi M, Imberti B, Karmali MA, Remuzzi A, Remuzzi G, Zoja C (1995) Verotoxin-1 promotes leukocyte adhesion to cultured endothelial cells under physiologic flow conditions. Blood 86:4553–4558PubMedGoogle Scholar
  67. 67.
    Morigi M, Galbusera M, Binda E, Imberti B, Gastoldi S, Remuzzi A, Zoja C, Remuzzi G (2001) Verotoxin-1-induced up-regulation of adhesive molecules renders microvascular endothelial cells thrombogenic at high shear stress. Blood 98:1828–1835PubMedGoogle Scholar
  68. 68.
    Karpman D, Papadopoulou D, Nilsson K, Sjogren AC, Mikaelsson C, Lethagen S (2001) Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome. Blood 97:3100–3108PubMedGoogle Scholar
  69. 69.
    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 187:172–180PubMedGoogle Scholar
  70. 70.
    Lo NC, Turner NA, Cruz MA, Moake J (2013) Interaction of Shiga toxin with the A-domains and multimers of von Willebrand factor. J Biol Chem 288:33118–33123PubMedCentralPubMedGoogle Scholar
  71. 71.
    Hughes AK, Stricklett PK, Kohan DE (1998) Cytotoxic effect of Shiga toxin-1 on human proximal tubule cells. Kidney Int 54:426–437PubMedGoogle Scholar
  72. 72.
    Ricklin D, Hajishengallis G, Yang K, Lambris JD (2010) Complement: a key system for immune surveillance and homeostasis. Nat Immunol 11:785–797PubMedCentralPubMedGoogle Scholar
  73. 73.
    Cameron JS, Vick R (1973) Letter: Plasma-C3 in haemolytic-uraemic syndrome and thrombotic thrombocytopenic purpura. Lancet 2:975PubMedGoogle Scholar
  74. 74.
    Robson WL, Leung AK, Fick GH, McKenna AI (1992) Hypocomplementemia and leukocytosis in diarrhea-associated hemolytic uremic syndrome. Nephron 62:296–299PubMedGoogle Scholar
  75. 75.
    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 364:2561–2563PubMedGoogle Scholar
  76. 76.
    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
  77. 77.
    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 4:1920–1924PubMedCentralPubMedGoogle Scholar
  78. 78.
    Stahl AL, Sartz L, Karpman D (2011) Complement activation on platelet-leukocyte complexes and microparticles in enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome. Blood 117:5503–5513PubMedGoogle Scholar
  79. 79.
    Del Conde I, Cruz MA, Zhang H, Lopez JA, Afshar-Kharghan V (2005) Platelet activation leads to activation and propagation of the complement system. J Exp Med 201:871–879PubMedCentralPubMedGoogle Scholar
  80. 80.
    Orth D, Khan AB, Naim A, Grif K, Brockmeyer J, Karch H, Joannidis M, Clark SJ, Day AJ, Fidanzi S, Stoiber H, Dierich MP, Zimmerhackl LB, Wurzner R (2009) Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome. J Immunol 182:6394–6400PubMedGoogle Scholar
  81. 81.
    Fischer K, Poschmann A, Oster H (1971) Severe pneumonia with hemolysis caused by neuraminidase. Detection of cryptantigens by indirect immunofluorescent technic. Monatsschr Kinderheilkd 119:2–8PubMedGoogle Scholar
  82. 82.
    Cochran JB, Panzarino VM, Maes LY, Tecklenburg FW (2004) Pneumococcus-induced T-antigen activation in hemolytic uremic syndrome and anemia. Pediatr Nephrol 19:317–321PubMedGoogle Scholar
  83. 83.
    McGraw ME, Lendon M, Stevens RF, Postlethwaite RJ, Taylor CM (1989) Haemolytic uraemic syndrome and the Thomsen Friedenreich antigen. Pediatr Nephrol 3:135–139PubMedGoogle Scholar
  84. 84.
    Eder AF, Manno CS (2001) Does red-cell T activation matter? Br J Haematol 114:25–30PubMedGoogle Scholar
  85. 85.
    Sallee M, Daniel L, Piercecchi MD, Jaubert D, Fremeaux-Bacchi V, Berland Y, Burtey S (2010) Myocardial infarction is a complication of factor H-associated atypical HUS. Nephrol Dial Transplant 25:2028–2032PubMedGoogle Scholar
  86. 86.
    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 21:2180–2187PubMedCentralPubMedGoogle Scholar
  87. 87.
    Loirat C, Noris M, Fremeaux-Bacchi V (2008) Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol 23:1957–1972PubMedGoogle Scholar
  88. 88.
    Loirat C, Macher MA, Elmaleh-Berges M, Kwon T, Deschenes G, Goodship TH, Majoie C, Davin JC, Blanc R, Savatovsky J, Moret J, Fremeaux-Bacchi V (2010) Non-atheromatous arterial stenoses in atypical haemolytic uraemic syndrome associated with complement dysregulation. Nephrol Dial Transplant 25:3421–3425PubMedGoogle Scholar
  89. 89.
    Bekassy ZD, Kristoffersson AC, Cronqvist M, Roumenina LT, Rybkine T, Vergoz L, Hue C, Fremeaux-Bacchi V, Karpman D (2013) Eculizumab in an anephric patient with atypical haemolytic uraemic syndrome and advanced vascular lesions. Nephrol Dial Transplant 28:2899–2907PubMedGoogle Scholar
  90. 90.
    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 368:2169–2181PubMedGoogle Scholar
  91. 91.
    Rathbone J, Kaltenthaler E, Richards A, Tappenden P, Bessey A, Cantrell A (2013) A systematic review of eculizumab for atypical haemolytic uraemic syndrome (aHUS). BMJ Open 3:e003573PubMedCentralPubMedGoogle Scholar
  92. 92.
    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 8:554–562PubMedCentralPubMedGoogle Scholar
  93. 93.
    Schmidt CQ, Herbert AP, Kavanagh D, Gandy C, Fenton CJ, Blaum BS, Lyon M, Uhrin D, Barlow PN (2008) A new map of glycosaminoglycan and C3b binding sites on factor H. J Immunol 181:2610–2619PubMedGoogle Scholar
  94. 94.
    Ferreira VP, Pangburn MK, Cortes C (2010) Complement control protein factor H: the good, the bad, and the inadequate. Mol Immunol 47:2187–2197PubMedCentralPubMedGoogle Scholar
  95. 95.
    Clark SJ, Ridge LA, Herbert AP, Hakobyan S, Mulloy B, Lennon R, Wurzner R, Morgan BP, Uhrin D, Bishop PN, Day AJ (2013) Tissue-specific host recognition by complement factor H is mediated by differential activities of its glycosaminoglycan-binding regions. J Immunol 190:2049–2057PubMedCentralPubMedGoogle Scholar
  96. 96.
    Thompson RA, Winterborn MH (1981) Hypocomplementaemia due to a genetic deficiency of beta 1H globulin. Clin Exp Immunol 46:110–119PubMedCentralPubMedGoogle Scholar
  97. 97.
    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 53:836–844PubMedGoogle Scholar
  98. 98.
    Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ (2010) Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat 31:E1445–E1460PubMedGoogle Scholar
  99. 99.
    Venables JP, Strain L, Routledge D, Bourn D, Powell HM, Warwicker P, Diaz-Torres ML, Sampson A, Mead P, Webb M, Pirson Y, Jackson MS, Hughes A, Wood KM, Goodship JA, Goodship TH (2006) Atypical haemolytic uraemic syndrome associated with a hybrid complement gene. PLoS Med 3:e431PubMedCentralPubMedGoogle Scholar
  100. 100.
    Francis NJ, McNicholas B, Awan A, Waldron M, Reddan D, Sadlier D, Kavanagh D, Strain L, Marchbank KJ, Harris CL, Goodship TH (2012) A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome. Blood 119:591–601PubMedGoogle Scholar
  101. 101.
    Eyler SJ, Meyer NC, Zhang Y, Xiao X, Nester CM, Smith RJ (2013) A novel hybrid CFHR1/CFH gene causes atypical hemolytic uremic syndrome. Pediatr Nephrol 28:2221–2225PubMedGoogle Scholar
  102. 102.
    Dragon-Durey MA, Loirat C, Cloarec S, Macher MA, Blouin J, Nivet H, Weiss L, Fridman WH, Fremeaux-Bacchi V (2005) Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 16:555–563PubMedGoogle Scholar
  103. 103.
    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 115:379–387PubMedCentralPubMedGoogle Scholar
  104. 104.
    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 (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 8:407–415PubMedCentralPubMedGoogle Scholar
  105. 105.
    Sinha A, Gulati A, Saini S, Blanc C, Gupta A, Gurjar BS, Saini H, Kotresh ST, Ali U, Bhatia D, Ohri A, Kumar M, Agarwal I, Gulati S, Anand K, Vijayakumar M, Sinha R, Sethi S, Salmona M, George A, Bal V, Singh G, Dinda AK, Hari P, Rath S, Dragon-Durey MA, Bagga A (2013) Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children. Kidney Int. doi: 10.1038/ki.2013.373 PubMedGoogle Scholar
  106. 106.
    Jozsi M, Licht C, Strobel S, Zipfel SL, Richter H, Heinen S, Zipfel PF, Skerka C (2008) Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood 111:1512–1514PubMedGoogle Scholar
  107. 107.
    Zipfel PF, Edey M, Heinen S, Jozsi M, Richter H, Misselwitz J, Hoppe B, Routledge D, Strain L, Hughes AE, Goodship JA, Licht C, Goodship TH, Skerka C (2007) Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome. PLoS Genet 3:e41PubMedCentralPubMedGoogle Scholar
  108. 108.
    Abarrategui-Garrido C, Martinez-Barricarte R, Lopez-Trascasa M, de Cordoba SR, Sanchez-Corral P (2009) Characterization of complement factor H-related (CFHR) proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical hemolytic uremic syndrome. Blood 114:4261–4271PubMedGoogle Scholar
  109. 109.
    Jozsi M, Strobel S, Dahse HM, Liu WS, Hoyer PF, Oppermann M, Skerka C, Zipfel PF (2007) Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome. Blood 110:1516–1518PubMedGoogle Scholar
  110. 110.
    Blanc C, Roumenina LT, Ashraf Y, Hyvarinen S, Sethi SK, Ranchin B, Niaudet P, Loirat C, Gulati A, Bagga A, Fridman WH, Sautes-Fridman C, Jokiranta TS, Fremeaux-Bacchi V, Dragon-Durey MA (2012) Overall neutralization of complement factor H by autoantibodies in the acute phase of the autoimmune form of atypical hemolytic uremic syndrome. J Immunol 189:3528–3537PubMedGoogle Scholar
  111. 111.
    Richards A, Kathryn Liszewski M, Kavanagh D, Fang CJ, Moulton E, Fremeaux-Bacchi V, Remuzzi G, Noris M, Goodship TH, Atkinson JP (2007) Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Mol Immunol 44:111–122PubMedGoogle Scholar
  112. 112.
    Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F, Gamba S, Remuzzi G (2003) Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 362:1542–1547PubMedGoogle Scholar
  113. 113.
    Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, Decorte R, Muslumanoglu MH, Kavukcu S, Filler G, Pirson Y, Wen LS, Atkinson JP, Goodship TH (2003) Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci U S A 100:12966–12971PubMedCentralPubMedGoogle Scholar
  114. 114.
    Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, Vigneau C, Kuypers D, Boudailliez B, Loirat C, Rondeau E, Fridman WH (2004) Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet 41:e84PubMedCentralPubMedGoogle Scholar
  115. 115.
    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 77:339–349PubMedGoogle Scholar
  116. 116.
    Kavanagh D, Richards A, Noris M, Hauhart R, Liszewski MK, Karpman D, Goodship JA, Fremeaux-Bacchi V, Remuzzi G, Goodship TH, Atkinson JP (2008) Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome. Mol Immunol 45:95–105PubMedGoogle Scholar
  117. 117.
    Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, Lopez-Trascasa M, Sanchez-Corral P, Morgan BP, Rodriguez de Cordoba S (2007) Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci U S A 104:240–245PubMedGoogle Scholar
  118. 118.
    Fremeaux-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 112:4948–4952PubMedCentralPubMedGoogle Scholar
  119. 119.
    Lhotta K, Janecke AR, Scheiring J, Petzlberger B, Giner T, Fally V, Wurzner R, Zimmerhackl LB, Mayer G, Fremeaux-Bacchi V (2009) A large family with a gain-of-function mutation of complement C3 predisposing to atypical hemolytic uremic syndrome, microhematuria, hypertension and chronic renal failure. Clin J Am Soc Nephrol 4:1356–1362PubMedCentralPubMedGoogle Scholar
  120. 120.
    Roumenina LT, Jablonski M, Hue C, Blouin J, Dimitrov JD, Dragon-Durey MA, Cayla M, Fridman WH, Macher MA, Ribes D, Moulonguet L, Rostaing L, Satchell SC, Mathieson PW, Sautes-Fridman C, Loirat C, Regnier CH, Halbwachs-Mecarelli L, Fremeaux-Bacchi V (2009) Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome. Blood 114:2837–2845PubMedGoogle Scholar
  121. 121.
    Roumenina LT, Frimat M, Miller EC, Provot F, Dragon-Durey MA, Bordereau P, Bigot S, Hue C, Satchell SC, Mathieson PW, Mousson C, Noel C, Sautes-Fridman C, Halbwachs-Mecarelli L, Atkinson JP, Lionet A, Fremeaux-Bacchi V (2012) A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function. Blood 119:4182–4191PubMedCentralPubMedGoogle Scholar
  122. 122.
    Tawadrous H, Maga T, Sharma J, Kupferman J, Smith RJ, Schoeneman M (2010) A novel mutation in the complement factor B gene (CFB) and atypical hemolytic uremic syndrome. Pediatr Nephrol 25:947–951PubMedGoogle Scholar
  123. 123.
    Weiler H, Isermann BH (2003) Thrombomodulin. J Thromb Haemost 1:1515–1524PubMedGoogle Scholar
  124. 124.
    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. N Engl J Med 361:345–357PubMedCentralPubMedGoogle Scholar
  125. 125.
    Fan X, Yoshida Y, Honda S, Matsumoto M, Sawada Y, Hattori M, Hisanaga S, Hiwa R, Nakamura F, Tomomori M, Miyagawa S, Fujimaru R, Yamada H, Sawai T, Ikeda Y, Iwata N, Uemura O, Matsukuma E, Aizawa Y, Harada H, Wada H, Ishikawa E, Ashida A, Nangaku M, Miyata T, Fujimura Y (2013) Analysis of genetic and predisposing factors in Japanese patients with atypical hemolytic uremic syndrome. Mol Immunol 54:238–246PubMedGoogle Scholar
  126. 126.
    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 (2013) Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol 24:475–486PubMedCentralPubMedGoogle Scholar
  127. 127.
    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 45:531–536PubMedCentralPubMedGoogle Scholar
  128. 128.
    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 14:703–712PubMedGoogle Scholar
  129. 129.
    Esparza-Gordillo J, Jorge EG, Garrido CA, Carreras L, Lopez-Trascasa M, Sanchez-Corral P, de Cordoba SR (2006) Insights into hemolytic uremic syndrome: segregation of three independent predisposition factors in a large, multiple affected pedigree. Mol Immunol 43:1769–1775PubMedGoogle Scholar
  130. 130.
    Fremeaux-Bacchi V, Kemp EJ, Goodship JA, Dragon-Durey MA, Strain L, Loirat C, Deng HW, Goodship TH (2005) The development of atypical haemolytic-uraemic syndrome is influenced by susceptibility factors in factor H and membrane cofactor protein: evidence from two independent cohorts. J Med Genet 42:852–856PubMedCentralPubMedGoogle Scholar
  131. 131.
    Caprioli J, Castelletti F, Bucchioni S, Bettinaglio P, Bresin E, Pianetti G, Gamba S, Brioschi S, Daina E, Remuzzi G, Noris M (2003) Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease. Hum Mol Genet 12:3385–3395PubMedGoogle Scholar
  132. 132.
    Kwon T, Belot A, Ranchin B, Baudouin V, Fremeaux-Bacchi V, Dragon-Durey MA, Cochat P, Loirat C (2009) Varicella as a trigger of atypical haemolytic uraemic syndrome associated with complement dysfunction: two cases. Nephrol Dial Transplant 24:2752–2754PubMedGoogle Scholar
  133. 133.
    Allen U, Licht C (2011) Pandemic H1N1 influenza A infection and (atypical) HUS—more than just another trigger? Pediatr Nephrol 26:3–5PubMedGoogle Scholar
  134. 134.
    Fang CJ, Fremeaux-Bacchi V, Liszewski MK, Pianetti G, Noris M, Goodship TH, Atkinson JP (2008) Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 111:624–632PubMedCentralPubMedGoogle Scholar
  135. 135.
    Bitzan M, Schaefer F, Reymond D (2010) Treatment of typical (enteropathic) hemolytic uremic syndrome. Semin Thromb Hemost 36:594–610PubMedGoogle Scholar
  136. 136.
    Copelovitch L, Kaplan BS (2008) Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr Nephrol 23:1951–1956PubMedGoogle Scholar
  137. 137.
    Remuzzi G (1987) HUS and TTP: variable expression of a single entity. Kidney Int 32:292–308PubMedGoogle Scholar
  138. 138.
    Sadler JE (2008) Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 112:11–18PubMedCentralPubMedGoogle Scholar
  139. 139.
    Kavanagh D, Richards A, Fremeaux-Bacchi V, Noris M, Goodship T, Remuzzi G, Atkinson JP (2007) Screening for complement system abnormalities in patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 2:591–596PubMedGoogle Scholar
  140. 140.
    Ake JA, Jelacic S, Ciol MA, Watkins SL, Murray KF, Christie DL, Klein EJ, Tarr PI (2005) Relative nephroprotection during Escherichia coli O157:H7 infections: association with intravenous volume expansion. Pediatrics 115:e673–e680PubMedGoogle Scholar
  141. 141.
    Hickey CA, Beattie TJ, Cowieson J, Miyashita Y, Strife CF, Frem JC, Peterson JM, Butani L, Jones DP, Havens PL, Patel HP, Wong CS, Andreoli SP, Rothbaum RJ, Beck AM, Tarr PI (2011) Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome. Arch Pediatr Adolesc Med 165:884–889PubMedCentralPubMedGoogle Scholar
  142. 142.
    Tarr PI, Neill MA (2001) Escherichia coli O157:H7. Gastroenterol Clin North Am 30:735–751PubMedGoogle Scholar
  143. 143.
    Cavari Y, Pitfield AF, Kissoon N (2013) Intravenous maintenance fluids revisited. Pediatr Emerg Care 29:1225–1228PubMedGoogle Scholar
  144. 144.
    Chowdhury AH, Cox EF, Francis ST, Lobo DN (2012) A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte(R) 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 256:18–24PubMedGoogle Scholar
  145. 145.
    Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M (2012) Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 308:1566–1572PubMedGoogle Scholar
  146. 146.
    Bitzan M (2009) Treatment options for HUS secondary to Escherichia coli O157:H7. Kidney Int Suppl: S62-6Google Scholar
  147. 147.
    Van Dyck M, Proesmans W (2004) Renoprotection by ACE inhibitors after severe hemolytic uremic syndrome. Pediatr Nephrol 19:688–690PubMedGoogle Scholar
  148. 148.
    Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI (2000) The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 342:1930–1936PubMedCentralPubMedGoogle Scholar
  149. 149.
    Safdar N, Said A, Gangnon RE, Maki DG (2002) Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: a meta-analysis. JAMA 288:996–1001PubMedGoogle Scholar
  150. 150.
    Nitschke M, Sayk F, Hartel C, Roseland RT, Hauswaldt S, Steinhoff J, Fellermann K, Derad I, Wellhoner P, Buning J, Tiemer B, Katalinic A, Rupp J, Lehnert H, Solbach W, Knobloch JK (2012) Association between azithromycin therapy and duration of bacterial shedding among patients with Shiga toxin-producing enteroaggregative Escherichia coli O104:H4. JAMA 307:1046–1052PubMedGoogle Scholar
  151. 151.
    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 354:1327–1330PubMedGoogle Scholar
  152. 152.
    Carter AO, Borczyk AA, Carlson JA, Harvey B, Hockin JC, Karmali MA, Krishnan C, Korn DA, Lior H (1987) A severe outbreak of Escherichia coli O157:H7–associated hemorrhagic colitis in a nursing home. N Engl J Med 317:1496–1500PubMedGoogle Scholar
  153. 153.
    Kielstein JT, Beutel G, Fleig S, Steinhoff J, Meyer TN, Hafer C, Kuhlmann U, Bramstedt J, Panzer U, Vischedyk M, Busch V, Ries W, Mitzner S, Mees S, Stracke S, Nurnberger J, Gerke P, Wiesner M, Sucke B, Abu-Tair M, Kribben A, Klause N, Schindler R, Merkel F, Schnatter S, Dorresteijn EM, Samuelsson O, Brunkhorst R (2012) Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing E. coli O104:H4 induced haemolytic-uraemic syndrome: an analysis of the German STEC-HUS registry. Nephrol Dial Transplant 27:3807–3815PubMedGoogle Scholar
  154. 154.
    Ruggenenti P, Remuzzi G (2012) Thrombotic microangiopathy: E. coli O104:H4 German outbreak: a missed opportunity. Nat Rev Nephrol 8:558–560PubMedGoogle Scholar
  155. 155.
    Delmas Y, Vendrely B, Clouzeau B, Bachir H, Bui HN, Lacraz A, Helou S, Bordes C, Reffet A, Llanas B, Skopinski S, Rolland P, Gruson D, Combe C. 2013. Outbreak of Escherichia coli O104:H4 haemolytic uraemic syndrome in France: outcome with eculizumab. Nephrol Dial Transplant 0: 1–9 doi:  10.1093/ndt/gft470
  156. 156.
    Ferraris JR, Ramirez JA, Ruiz S, Caletti MG, Vallejo G, Piantanida JJ, Araujo JL, Sojo ET (2002) Shiga toxin-associated hemolytic uremic syndrome: absence of recurrence after renal transplantation. Pediatr Nephrol 17:809–814PubMedGoogle Scholar
  157. 157.
    Artz MA, Steenbergen EJ, Hoitsma AJ, Monnens LA, Wetzels JF (2003) Renal transplantation in patients with hemolytic uremic syndrome: high rate of recurrence and increased incidence of acute rejections. Transplantation 76:821–826PubMedGoogle Scholar
  158. 158.
    Loirat C, Niaudet P (2003) The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children. Pediatr Nephrol 18:1095–1101PubMedGoogle Scholar
  159. 159.
    Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, Loirat C, Pecoraro C, Taylor CM, Van de Kar N, Vandewalle J, Zimmerhackl LB (2009) Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 24:687–696PubMedGoogle Scholar
  160. 160.
    Taylor CM, Machin S, Wigmore SJ, Goodship TH (2010) Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 148:37–47PubMedGoogle Scholar
  161. 161.
    Nathanson S, Fremeaux-Bacchi V, Deschenes G (2001) Successful plasma therapy in hemolytic uremic syndrome with factor H deficiency. Pediatr Nephrol 16:554–556PubMedGoogle Scholar
  162. 162.
    de Jorge EG, Macor P, Paixao-Cavalcante D, Rose KL, Tedesco F, Cook HT, Botto M, Pickering MC (2011) The development of atypical hemolytic uremic syndrome depends on complement C5. J Am Soc Nephrol 22:137–145PubMedCentralPubMedGoogle Scholar
  163. 163.
    Salant DJ (2011) Targeting complement C5 in atypical hemolytic uremic syndrome. J Am Soc Nephrol 22:7–9PubMedGoogle Scholar
  164. 164.
    Wong EK, Goodship TH, Kavanagh D (2013) Complement therapy in atypical haemolytic uraemic syndrome (aHUS). Mol Immunol 56:199–212PubMedCentralPubMedGoogle Scholar
  165. 165.
    Campistol JM, Arias M, Ariceta G, Blasco M, Espinosa M, Grinyo JM, Praga M, Torra R, Vilalta R, Rodriguez de Cordoba S (2013) An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document. Nefrologia 33:27–45PubMedGoogle Scholar
  166. 166.
    Noris M, Remuzzi G (2013) Managing and preventing atypical hemolytic uremic syndrome recurrence after kidney transplantation. Curr Opin Nephrol Hypertens 22:704–712PubMedGoogle Scholar
  167. 167.
    Hirt-Minkowski P, Schaub S, Mayr M, Schifferli JA, Dickenmann M, Fremeaux-Bacchi V, Steiger J (2009) Haemolytic uraemic syndrome caused by factor H mutation: is single kidney transplantation under intensive plasmatherapy an option? Nephrol Dial Transplant 24:3548–3551PubMedGoogle Scholar
  168. 168.
    Remuzzi G, Ruggenenti P, Codazzi D, Noris M, Caprioli J, Locatelli G, Gridelli B (2002) Combined kidney and liver transplantation for familial haemolytic uraemic syndrome. Lancet 359:1671–1672PubMedGoogle Scholar
  169. 169.
    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 5:1146–1150PubMedGoogle Scholar
  170. 170.
    Koskinen AR, Tukiainen E, Arola J, Nordin A, Hockerstedt HK, Nilsson B, Isoniemi H, Jokiranta TS (2011) Complement activation during liver transplantation—special emphasis on patients with atypical hemolytic uremic syndrome. Am J Transplant 11:1885–1895PubMedGoogle Scholar
  171. 171.
    Saland JM, Ruggenenti P, Remuzzi G (2009) Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol 20:940–949PubMedGoogle Scholar
  172. 172.
    Haller W, Milford DV, Goodship TH, Sharif K, Mirza DF, McKiernan PJ (2010) Successful isolated liver transplantation in a child with atypical hemolytic uremic syndrome and a mutation in complement factor H. Am J Transplant 10:2142–2147PubMedGoogle Scholar
  173. 173.
    Jalanko H, Peltonen S, Koskinen A, Puntila J, Isoniemi H, Holmberg C, Pinomaki A, Armstrong E, Koivusalo A, Tukiainen E, Makisalo 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
  174. 174.
    Forbes TA, Bradbury MG, Goodship TH, McKiernan PJ, Milford DV (2013) Changing strategies for organ transplantation in atypical haemolytic uraemic syndrome: a tertiary case series. Pediatr Transplant 17:E93–E99PubMedGoogle Scholar
  175. 175.
    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 4:201–206PubMedCentralPubMedGoogle Scholar
  176. 176.
    Tran H, Chaudhuri A, Concepcion W, Grimm PC (2013) Use of eculizumab and plasma exchange in successful combined liver-kidney transplantation in a case of atypical HUS associated with complement factor H mutation. Pediatr Nephrol. doi: 10.1007/s00467-013-2630-5 Google Scholar
  177. 177.
    Zimmerhackl LB, Hofer J, Cortina G, Mark W, Wurzner R, Jungraithmayr TC, Khursigara G, Kliche KO, Radauer W (2010) Prophylactic eculizumab after renal transplantation in atypical hemolytic-uremic syndrome. N Engl J Med 362:1746–1748PubMedGoogle Scholar
  178. 178.
    Zuber J, Le Quintrec M, Krid S, Bertoye C, Gueutin V, Lahoche A, Heyne N, Ardissino G, Chatelet V, Noel LH, Hourmant M, Niaudet P, Fremeaux-Bacchi V, Rondeau E, Legendre C, Loirat C (2012) Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant 12:3337–3354PubMedGoogle Scholar
  179. 179.
    Nester C, Stewart Z, Myers D, Jetton J, Nair R, Reed A, Thomas C, Smith R, Brophy P (2011) Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 6:1488–1494PubMedCentralPubMedGoogle Scholar
  180. 180.
    Krid S, Roumenina LT, Beury D, Charbit M, Boyer O, Fremeaux-Bacchi V, Niaudet P (2012) Renal transplantation under prophylactic eculizumab in atypical hemolytic uremic syndrome with CFH/CFHR1 hybrid protein. Am J Transplant 12:1938–1944PubMedGoogle Scholar
  181. 181.
    Le Quintrec M, Zuber J, Moulin B, Kamar N, Jablonski M, Lionet A, Chatelet V, Mousson C, Mourad G, Bridoux F, Cassuto E, Loirat C, Rondeau E, Delahousse M, Fremeaux-Bacchi V (2013) Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am J Transplant 13:663–675PubMedGoogle Scholar
  182. 182.
    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 55:708–711PubMedGoogle Scholar
  183. 183.
    Nurnberger 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 360:542–544PubMedGoogle Scholar
  184. 184.
    Al-Akash SI, Almond PS, Savell VH Jr, Gharaybeh SI, Hogue C (2011) Eculizumab induces long-term remission in recurrent post-transplant HUS associated with C3 gene mutation. Pediatr Nephrol 26:613–619PubMedGoogle Scholar
  185. 185.
    Alachkar N, Bagnasco SM, Montgomery RA (2012) Eculizumab for the treatment of two recurrences of atypical hemolytic uremic syndrome in a kidney allograft. Transpl Int 25:e93–e95PubMedGoogle Scholar
  186. 186.
    Barrow M (2013) Health chiefs refuse to pay for lifesaving kidney treatment. In The Times 16 JanuaryGoogle Scholar
  187. 187.
    Laurance J (2013) At what cost? Live saving drug withheld. In The Independent 26 May 2013Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Caterina Mele
    • 1
  • Giuseppe Remuzzi
    • 1
    • 2
  • Marina Noris
    • 1
  1. 1.IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”RanicaItaly
  2. 2.Unit of Nephrology and DialysisAzienda Ospedaliera Papa Giovanni XXIIIBergamoItaly

Personalised recommendations