Pediatric Nephrology

, Volume 25, Issue 11, pp 2231–2240 | Cite as

Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction

  • Carla ZojaEmail author
  • Simona Buelli
  • Marina Morigi


Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli O157:H7 has become a global threat to public health, as a primary cause of a worldwide spread of hemorrhagic colitis complicated by diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure that mainly affects early childhood. Endothelial dysfunction has been recognized as the trigger event in the development of microangiopathic processes. Endothelial cells, mainly those located in the renal microvasculature, are primary targets of the toxic effects of Stx1 and 2. Stxs bound to their specific globotriaosylceramide (Gb3Cer) receptor on the cell surface trigger a cascade of signaling events, involving NF-κB activation, that induce expression of genes encoding for adhesion molecules and chemokines, and culminate in the adhesion of leukocytes to endothelial cells, thereby increasing the endothelial susceptibility to leukocyte-mediated injury. Activated endothelial cells in response to Stxs lose the normal thromboresistance phenotype and become thrombogenic, initiating microvascular thrombus formation. Evidence is emerging that complement activation in response to Stxs favors platelet thrombus formation on endothelial cells, which may play a role in amplifying the inflammation–thrombosis circuit in Stx-associated HUS.


Enterohemorrhagic Escherichia coli Hemolytic uremic syndrome Shiga toxin Endothelial injury Chemokines Microvascular thrombosis Complement 



The authors thank Prof. Giuseppe Remuzzi for reviewing the manuscript and Dr. Antonella Piccinelli for helping in figure preparation. Manuela Passera helped to prepare the manuscript.


  1. 1.
    Noris M, Remuzzi G (2005) Hemolytic uremic syndrome. J Am Soc Nephrol 16:1035–1050PubMedCrossRefGoogle Scholar
  2. 2.
    Tarr PI, Gordon CA, Chandler WL (2005) Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 365:1073–1086PubMedGoogle Scholar
  3. 3.
    Siegler R, Oakes R (2005) Hemolytic uremic syndrome; pathogenesis, treatment, and outcome. Curr Opin Pediatr 17:200–204PubMedCrossRefGoogle Scholar
  4. 4.
    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 290:1360–1370PubMedCrossRefGoogle Scholar
  5. 5.
    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 53:259–272PubMedCrossRefGoogle Scholar
  6. 6.
    Bitzan M (2009) Treatment options for HUS secondary to Escherichia coli O157:H7. Kidney Int Suppl 75:S62–S66CrossRefGoogle Scholar
  7. 7.
    Scheiring J, Andreoli SP, Zimmerhackl LB (2008) Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol 23:1749–1760PubMedCrossRefGoogle Scholar
  8. 8.
    Karmali MA (2004) Infection by Shiga toxin-producing Escherichia coli: an overview. Mol Biotechnol 26:117–122PubMedCrossRefGoogle Scholar
  9. 9.
    Karmali MA (2009) Host and pathogen determinants of verocytotoxin-producing Escherichia coli-associated hemolytic uremic syndrome. Kidney Int Suppl 75:S4–S7CrossRefGoogle Scholar
  10. 10.
    Taylor CM (2008) Enterohaemorrhagic Escherichia coli and Shigella dysenteriae type 1-induced haemolytic uraemic syndrome. Pediatr Nephrol 23:1425–1431CrossRefGoogle Scholar
  11. 11.
    Frankel G, Phillips AD (2008) Attaching effacing Escherichia coli and paradigms of Tir-triggered actin polymerization: getting off the pedestal. Cell Microbiol 10:549–556PubMedCrossRefGoogle Scholar
  12. 12.
    Deng W, Puente JL, Gruenheid S, Li Y, Vállance BA, Vázquez A, Barba J, Ibarra JA, O'Donnell P, Metalnikov P, Ashman K, Lee S, Goode D, Pawson T, Finlay BB (2004) Dissecting virulence: systematic and functional analyses of a pathogenicity island. Proc Natl Acad Sci U S A 101:3597–3602PubMedCrossRefGoogle Scholar
  13. 13.
    Tobe T, Beatson SA, Taniguchi H, Abe H, Bailey CM, Fivian A, Younis R, Matthews S, Marches O, Frankel G, Hayashi T, Pallen MJ (2006) An extensive repertoire of type III secretion effectors in Escherichia coli O157 and the role of lambdoid phages in their dissemination. Proc Natl Acad Sci U S A 103:14941–14946PubMedCrossRefGoogle Scholar
  14. 14.
    Tree JJ, Wolfson EB, Wang D, Roe AJ, Gally DL (2009) Controlling injection: regulation of type III secretion in enterohaemorrhagic Escherichia coli. Trends Microbiol 17:361–370PubMedCrossRefGoogle Scholar
  15. 15.
    Donnenberg MS, Whittam TS (2001) Pathogenesis and evolution of virulence in enteropathogenic and enterohemorrhagic Escherichia coli. J Clin Invest 107:539–548PubMedCrossRefGoogle Scholar
  16. 16.
    Campellone KG, Robbins D, Leong JM (2004) EspFU is a translocated EHEC effector that interacts with Tir and N-WASP and promotes Nck-independent actin assembly. Dev Cell 7:217–228PubMedCrossRefGoogle Scholar
  17. 17.
    Garmendia J, Phillips AD, Carlier MF, Chong Y, Schüller S, Marches O, Dahan S, Oswald E, Shaw RK, Knutton S, Frankel G (2004) TccP is an enterohaemorrhagic Escherichia coli O157:H7 type III effector protein that couples Tir to the actin-cytoskeleton. Cell Microbiol 6:1167–1183PubMedCrossRefGoogle Scholar
  18. 18.
    Cheng HC, Skehan BM, Campellone KG, Leong JM, Rosen MK (2008) Structural mechanism of WASP activation by the enterohaemorrhagic E. coli effector EspF(U). Nature 454:1009–1013PubMedCrossRefGoogle Scholar
  19. 19.
    Vingadassalom D, Kazlauskas A, Skehan B, Cheng HC, Magoun L, Robbins D, Rosen MK, Saksela K, Leong JM (2009) Insulin receptor tyrosine kinase substrate links the E. coli O157:H7 actin assembly effectors Tir and EspF(U) during pedestal formation. Proc Natl Acad Sci U S A 106:6754–6759PubMedCrossRefGoogle Scholar
  20. 20.
    Weiss SM, Ladwein M, Schmidt D, Ehinger J, Lommel S, Städing K, Beutling U, Disanza A, Frank R, Jänsch L, Scita G, Gunzer F, Rottner K, Stradal TE (2009) IRSp53 links the enterohemorrhagic E. coli effectors Tir and EspFU for actin pedestal formation. Cell Host Microbe 5:244–258PubMedCrossRefGoogle Scholar
  21. 21.
    Robinson CM, Sinclair JF, Smith MJ, O'Brien AD (2006) Shiga toxin of enterohemorrhagic Escherichia coli type O157:H7 promotes intestinal colonization. Proc Natl Acad Sci U S A 103:9667–9672PubMedCrossRefGoogle Scholar
  22. 22.
    Hughes DT, Sperandio V (2008) Inter-kingdom signalling: communication between bacteria and their hosts. Nat Rev Microbiol 6:111–120PubMedCrossRefGoogle Scholar
  23. 23.
    Mead PS, Griffin PM (1998) Escherichia coli O157:H7. Lancet 352:1207–1212PubMedCrossRefGoogle Scholar
  24. 24.
    Ståhl AL, Svensson M, Mörgelin M, Svanborg C, Tarr PI, Mooney JC, Watkins SL, Johnson R, Karpman D (2006) Lipopolysaccharide from enterohemorrhagic Escherichia coli binds to platelets through TLR4 and CD62 and is detected on circulating platelets in patients with hemolytic uremic syndrome. Blood 108:167–176PubMedCrossRefGoogle Scholar
  25. 25.
    Bitzan M, Moebius E, Ludwig K, Müller-Wiefel DE, Heesemann J, Karch H (1991) High incidence of serum antibodies to Escherichia coli O157 lipopolysaccharide in children with hemolytic-uremic syndrome. J Pediatr 119:380–385PubMedCrossRefGoogle Scholar
  26. 26.
    Louise CB, Obrig TG (1992) Shiga toxin-associated hemolytic uremic syndrome: combined cytotoxic effects of shiga toxin and lipopolysaccharide (endotoxin) on human vascular endothelial cells in vitro. Infect Immun 60:1536–1543PubMedGoogle Scholar
  27. 27.
    Clayton F, Pysher TJ, Lou R, Kohan DE, Denkers ND, Tesh VL, Taylor FB Jr, Siegler RL (2005) Lipopolysaccharide upregulates renal shiga toxin receptors in a primate model of hemolytic uremic syndrome. Am J Nephrol 25:536–540PubMedCrossRefGoogle Scholar
  28. 28.
    Ikeda M, Ito S, Honda M (2004) Hemolytic uremic syndrome induced by lipopolysaccharide and Shiga-like toxin. Pediatr Nephrol 19:485–489PubMedCrossRefGoogle Scholar
  29. 29.
    Keepers TR, Psotka MA, Gross LK, Obrig TG (2006) A murine model of HUS: Shiga toxin with lipopolysaccharide mimics the renal damage and physiologic response of human disease. J Am Soc Nephrol 17:3404–3414PubMedCrossRefGoogle Scholar
  30. 30.
    Zanchi C, Zoja C, Morigi M, Valsecchi F, Liu XY, Rottoli D, Locatelli M, Buelli S, Pezzotta A, Mapelli P, Geelen J, Remuzzi G, Hawiger J (2008) Fractalkine and CX3CR1 mediate leukocyte capture by endothelium in response to Shiga toxin. J Immunol 181:1460–1469PubMedGoogle Scholar
  31. 31.
    Bitzan M, Richardson S, Huang C, Boyd B, Petric M, Karmali MA (1994) Evidence that verotoxins (Shiga-like toxins) from Escherichia coli bind to P blood group antigens of human erythrocytes in vitro. Infect Immun 62:3337–3347PubMedGoogle Scholar
  32. 32.
    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 66:4355–4366PubMedGoogle Scholar
  33. 33.
    Karpman D, Papadopoulou D, Nilsson K, Sjögren AC, Mikaelsson C, Lethagen S (2001) Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome. Blood 97:3100–3108PubMedCrossRefGoogle Scholar
  34. 34.
    Ghosh SA, Polanowska-Grabowska RK, Fujii J, Obrig T, Gear AR (2004) Shiga toxin binds to activated platelets. J Thromb Haemost 2:499–506PubMedCrossRefGoogle Scholar
  35. 35.
    Ståhl AL, Sartz L, Nelsson A, Békássy ZD, Karpman D (2009) Shiga toxin and lipopolysaccharide induce platelet-leukocyte aggregates and tissue factor release, a thrombotic mechanism in hemolytic uremic syndrome. PLoS One 4:e6990PubMedCrossRefGoogle Scholar
  36. 36.
    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
  37. 37.
    Geelen JM, van der Velden TJ, van den Heuvel LP, Monnens LA (2007) Interactions of Shiga-like toxin with human peripheral blood monocytes. Pediatr Nephrol 22:1181–1187PubMedCrossRefGoogle Scholar
  38. 38.
    Te Loo DM, Monnens LA, van Der Velden TJ, Vermeer MA, Preyers F, Demacker PN, van Den Heuvel LP, van Hinsbergh VW (2000) Binding and transfer of verocytotoxin by polymorphonuclear leukocytes in hemolytic uremic syndrome. Blood 95:3396–3402Google Scholar
  39. 39.
    Te Loo DM, van Hinsbergh VW, van den Heuvel LP, Monnens LA (2001) Detection of verocytotoxin bound to circulating polymorphonuclear leukocytes of patients with hemolytic uremic syndrome. J Am Soc Nephrol 12:800–806Google Scholar
  40. 40.
    Geelen JM, van der Velden TJ, Te Loo DM, Boerman OC, van den Heuvel LP, Monnens LA (2007) Lack of specific binding of Shiga-like toxin (verocytotoxin) and non-specific interaction of Shiga-like toxin 2 antibody with human polymorphonuclear leucocytes. Nephrol Dial Transplant 22:749–755PubMedCrossRefGoogle Scholar
  41. 41.
    Fernández GC, Gómez SA, Rubel CJ, Bentancor LV, Barrionuevo P, Alduncín M, Grimoldi I, Exeni R, Isturiz MA, Palermo MS (2005) Impaired neutrophils in children with the typical form of hemolytic uremic syndrome. Pediatr Nephrol 20:1306–1314PubMedCrossRefGoogle Scholar
  42. 42.
    Flagler MJ, Strasser JE, Chalk CL, Weiss AA (2007) Comparative analysis of the abilities of Shiga toxins 1 and 2 to bind to and influence neutrophil apoptosis. Infect Immun 75:760–765PubMedCrossRefGoogle Scholar
  43. 43.
    Brigotti M, Carnicelli D, Ravanelli E, Barbieri S, Ricci F, Bontadini A, Tozzi AE, Scavia G, Caprioli A, Tazzari PL (2008) Interactions between Shiga toxins and human polymorphonuclear leukocytes. J Leukoc Biol 84:1019–1027PubMedCrossRefGoogle Scholar
  44. 44.
    Müthing J, Schweppe CH, Karch H, Friedrich AW (2009) Shiga toxins, glycosphingolipid diversity, and endothelial cell injury. Thromb Haemost 101:252–264PubMedGoogle Scholar
  45. 45.
    O'Brien AD, Tesh VL, Donohue-Rolfe A, Jackson MP, Olsnes S, Sandvig K, Lindberg AA, Keusch GT (1992) Shiga toxin: biochemistry, genetics, mode of action, and role in pathogenesis. Curr Top Microbiol Immunol 180:65–94PubMedGoogle Scholar
  46. 46.
    Lingwood CA (1996) Role of verotoxin receptors in pathogenesis. Trends Microbiol 4:147–153PubMedCrossRefGoogle Scholar
  47. 47.
    O'Loughlin EV, Robins-Browne RM (2001) Effect of Shiga toxin and Shiga-like toxins on eukaryotic cells. Microbes Infect 3:493–507PubMedCrossRefGoogle Scholar
  48. 48.
    Katagiri YU, Mori T, Nakajima H, Katagiri C, Taguchi T, Takeda T, Kiyokawa N, Fujimoto J (1999) Activation of Src family kinase yes induced by Shiga toxin binding to globotriaosyl ceramide (Gb3/CD77) in low density, detergent-insoluble microdomains. J Biol Chem 274:35278–35282PubMedCrossRefGoogle Scholar
  49. 49.
    Nakajima H, Kiyokawa N, Katagiri YU, Taguchi T, Suzuki T, Sekino T, Mimori K, Ebata T, Saito M, Nakao H, Takeda T, Fujimoto J (2001) Kinetic analysis of binding between Shiga toxin and receptor glycolipid Gb3Cer by surface plasmon resonance. J Biol Chem 276:42915–42922PubMedCrossRefGoogle Scholar
  50. 50.
    Louise CB, Obrig TG (1995) Specific interaction of Escherichia coli O157:H7-derived Shiga-like toxin II with human renal endothelial cells. J Infect Dis 172:1397–1401PubMedGoogle Scholar
  51. 51.
    Boyd B, Lingwood C (1989) Verotoxin receptor glycolipid in human renal tissue. Nephron 51:207–210PubMedCrossRefGoogle Scholar
  52. 52.
    Obrig TG, Louise CB, Lingwood CA, Boyd B, Barley-Maloney L, Daniel TO (1993) Endothelial heterogeneity in Shiga Toxin receptors and responses. J Biol Chem 268:15484–15488PubMedGoogle Scholar
  53. 53.
    Hughes AK, Stricklett PK, Kohan DE (2001) Shiga toxin-1 regulation of cytokine production by human glomerular epithelial cells. Nephron 88:14–23PubMedCrossRefGoogle Scholar
  54. 54.
    Van Setten PA, van Hinsbergh VW, Van den Heuvel LP, van der Velden TJ, van de Kar NC, Krebbers RJ, Karmali MA, Monnens LA (1997) Verocytotoxin inhibits mitogenesis and protein synthesis in purified human glomerular mesangial cells without affecting cell viability: evidence for two distinct mechanisms. J Am Soc Nephrol 8:1877–1888PubMedGoogle Scholar
  55. 55.
    Hughes AK, Stricklett PK, Kohan DE (1998) Cytotoxic effect of Shiga toxin-1 on human proximal tubule cells. Kidney Int 54:426–437PubMedCrossRefGoogle Scholar
  56. 56.
    Lingwood CA (1994) Verotoxin-binding in human renal sections. Nephron 66:21–28PubMedCrossRefGoogle Scholar
  57. 57.
    Ergonul Z, Clayton F, Fogo AB, Kohan DE (2003) Shigatoxin-1 binding and receptor expression in human kidneys do not change with age. Pediatr Nephrol 18:246–253PubMedGoogle Scholar
  58. 58.
    Chark D, Nutikka A, Trusevych N, Kuzmina J, Lingwood C (2004) Differential carbohydrate epitope recognition of globotriaosyl ceramide by verotoxins and a monoclonal antibody. Eur J Biochem 271:405–417PubMedCrossRefGoogle Scholar
  59. 59.
    Khan F, Proulx F, Lingwood CA (2009) Detergent-resistant globotriaosyl ceramide may define verotoxin/glomeruli-restricted hemolytic uremic syndrome pathology. Kidney Int 75:1209–1216PubMedCrossRefGoogle Scholar
  60. 60.
    Sandvig K, Garred O, Prydz K, Kozlov JV, Hansen SH, van Deurs B (1992) Retrograde transport of endocytosed Shiga toxin to the endoplasmic reticulum. Nature 358:510–512PubMedCrossRefGoogle Scholar
  61. 61.
    Garred O, van Deurs B, Sandvig K (1995) Furin-induced cleavage and activation of Shiga toxin. J Biol Chem 270:10817–10821PubMedCrossRefGoogle Scholar
  62. 62.
    Endo Y, Tsurugi K, Yutsudo T, Takeda Y, Ogasawara T, Igarashi K (1988) Site of action of a Vero toxin (VT2) from Escherichia coli O157:H7 and of Shiga toxin on eukaryotic ribosomes. RNA N-glycosidase activity of the toxins. Eur J Biochem 171:45–50PubMedCrossRefGoogle Scholar
  63. 63.
    Brigotti M, Alfieri R, Sestili P, Bonelli M, Petronini PG, Guidarelli A, Barbieri L, Stirpe F, Sperti S (2002) Damage to nuclear DNA induced by Shiga toxin 1 and ricin in human endothelial cells. FASEB J 16:365–372PubMedCrossRefGoogle Scholar
  64. 64.
    Brigotti M, Carnicelli D, Ravanelli E, Vara AG, Martinelli C, Alfieri RR, Petronini PG, Sestili P (2007) Molecular damage and induction of proinflammatory cytokines in human endothelial cells exposed to Shiga toxin 1, Shiga toxin 2, and alpha-sarcin. Infect Immun 75:2201–2207PubMedCrossRefGoogle Scholar
  65. 65.
    Fujii J, Wood K, Matsuda F, Carneiro-Filho BA, Schlegel KH, Yutsudo T, Binnington-Boyd B, Lingwood CA, Obata F, Kim KS, Yoshida S, Obrig T (2008) Shiga toxin 2 causes apoptosis in human brain microvascular endothelial cells via C/EBP homologous protein. Infect Immun 76:3679–3689PubMedCrossRefGoogle Scholar
  66. 66.
    Smith WE, Kane AV, Campbell ST, Acheson DW, Cochran BH, Thorpe CM (2003) Shiga toxin 1 triggers a ribotoxic stress response leading to p38 and JNK activation and induction of apoptosis in intestinal epithelial cells. Infect Immun 71:1497–1504PubMedCrossRefGoogle Scholar
  67. 67.
    Kiyokawa N, Taguchi T, Mori T, Uchida H, Sato N, Takeda T, Fujimoto J (1998) Induction of apoptosis in normal human renal tubular epithelial cells by Escherichia coli Shiga toxins 1 and 2. J Infect Dis 178:178–184PubMedGoogle Scholar
  68. 68.
    Lee SY, Lee MS, Cherla RP, Tesh VL (2008) Shiga toxin 1 induces apoptosis through the endoplasmic reticulum stress response in human monocytic cells. Cell Microbiol 10:770–780PubMedCrossRefGoogle Scholar
  69. 69.
    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 98:1828–1835PubMedCrossRefGoogle Scholar
  70. 70.
    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 62:846–856PubMedCrossRefGoogle Scholar
  71. 71.
    Matussek A, Lauber J, Bergau A, Hansen W, Rohde M, Dittmar KE, Gunzer M, Mengel M, Gatzlaff P, Hartmann M, Buer J, Gunzer F (2003) Molecular and functional analysis of Shiga toxin-induced response patterns in human vascular endothelial cells. Blood 102:1323–1332PubMedCrossRefGoogle Scholar
  72. 72.
    Morigi M, Buelli S, Zanchi C, Longaretti L, Macconi D, Benigni A, Moioli D, Remuzzi G, Zoja C (2006) Shigatoxin-induced endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling. Am J Pathol 169:1965–1975PubMedCrossRefGoogle Scholar
  73. 73.
    Bitzan MM, Wang Y, Lin J, Marsden PA (1998) Verotoxin and ricin have novel effects on preproendothelin-1 expression but fail to modify nitric oxide synthase (ecNOS) expression and NO production in vascular endothelium. J Clin Invest 101:372–382PubMedCrossRefGoogle Scholar
  74. 74.
    Thorpe CM, Hurley BP, Lincicome LL, Jacewicz MS, Keusch GT, Acheson DW (1999) Shiga toxins stimulate secretion of interleukin-8 from intestinal epithelial cells. Infect Immun 67:5985–5993PubMedGoogle Scholar
  75. 75.
    Hughes AK, Stricklett PK, Kohan DE (1998) Shiga toxin-1 regulation of cytokine production by human proximal tubule cells. Kidney Int 54:1093–1106PubMedCrossRefGoogle Scholar
  76. 76.
    Ruggenenti P, Noris M, Remuzzi G (2001) Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 60:831–846PubMedCrossRefGoogle Scholar
  77. 77.
    Petruzziello TN, Mawji IA, Khan M, Marsden PA (2009) Verotoxin biology: molecular events in vascular endothelial injury. Kidney Int Suppl 75:S17–S19CrossRefGoogle Scholar
  78. 78.
    Van Setten PA, van Hinsbergh VW, van der Velden TJ, van de Kar NC, Vermeer M, Mahan JD, Assmann KJ, van den Heuvel LP, Monnens LA (1997) Effects of TNF alpha on verocytotoxin cytotoxicity in purified human glomerular microvascular endothelial cells. Kidney Int 51:1245–1256PubMedCrossRefGoogle Scholar
  79. 79.
    Chi JT, Chang HY, Haraldsen G, Jahnsen FL, Troyanskaya OG, Chang DS, Wang Z, Rockson SG, van de Rijn M, Botstein D, Brown PO (2003) Endothelial cell diversity revealed by global expression profiling. Proc Natl Acad Sci U S A 100:10623–10628PubMedCrossRefGoogle Scholar
  80. 80.
    Remuzzi G, Galbusera M, Salvadori M, Rizzoni G, Paris S, Ruggenenti P (1996) Bilateral nephrectomy stopped disease progression in plasma-resistant hemolytic uremic syndrome with neurological signs and coma. Kidney Int 49:282–286PubMedCrossRefGoogle Scholar
  81. 81.
    Milford DV, Staten J, MacGreggor I, Dawes J, Taylor CM, Hill FG (1991) Prognostic markers in diarrhoea-associated haemolytic-uraemic syndrome: initial neutrophil count, human neutrophil elastase and von Willebrand factor antigen. Nephrol Dial Transplant 6:232–237PubMedGoogle Scholar
  82. 82.
    Siegler RL, Pavia AT, Christofferson RD, Milligan MK (1994) A 20-year population-based study of postdiarrheal hemolytic uremic syndrome in Utah. Pediatrics 94:35–40PubMedGoogle Scholar
  83. 83.
    Fitzpatrick MM, Shah V, Trompeter RS, Dillon MJ, Barratt TM (1992) Interleukin-8 and polymorphoneutrophil leucocyte activation in hemolytic uremic syndrome of childhood. Kidney Int 42:951–956PubMedCrossRefGoogle Scholar
  84. 84.
    Forsyth KD, Simpson AC, Fitzpatrick MM, Barratt TM, Levinsky RJ (1989) Neutrophil-mediated endothelial injury in haemolytic uraemic syndrome. Lancet II:411–414CrossRefGoogle Scholar
  85. 85.
    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 11:556–559PubMedCrossRefGoogle Scholar
  86. 86.
    Van Setten PA, van Hinsbergh VW, van den Heuvel LP, Preyers F, Dijkman HB, Assmann KJ, van der Velden TJ, Monnens LA (1998) Monocyte chemoattractant protein-1 and interleukin-8 levels in urine and serum of patents with hemolytic uremic syndrome. Pediatr Res 43:759–767PubMedCrossRefGoogle Scholar
  87. 87.
    Inward CD, Varagunam M, Adu D, Milford DV, Taylor CM (1997) Cytokines in haemolytic uraemic syndrome associated with verocytotoxin-producing Escherichia coli infection. Arch Dis Child 77:145–147PubMedCrossRefGoogle Scholar
  88. 88.
    Sakiri R, Ramegowda B, Tesh VL (1998) Shiga toxin type 1 activates tumor necrosis factor-alpha gene transcription and nuclear translocation of the transcriptional activators nuclear factor-kappaB and activator protein-1. Blood 92:558–566PubMedGoogle Scholar
  89. 89.
    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
  90. 90.
    Van de Kar NCAJ, Monnens LAH, Karmali MA, van Hinsbergh VWM (1992) Tumor necrosis factor and interleukin-1 induce expression of the verocytotoxin receptor globotriaosylceramide on human endothelial cells: implications for the pathogenesis of the hemolytic uremic syndrome. Blood 80:2755–2764PubMedGoogle Scholar
  91. 91.
    Gerard C, Rollins BJ (2001) Chemokines and disease. Nat Immunol 2:108–115PubMedCrossRefGoogle Scholar
  92. 92.
    Roche JK, Keepers TR, Gross LK, Seaner RM, Obrig TG (2007) CXCL1/KC and CXCL2/MIP-2 are critical effectors and potential targets for therapy of Escherichia coli O157:H7-associated renal inflammation. Am J Pathol 170:526–537PubMedCrossRefGoogle Scholar
  93. 93.
    Umehara H, Bloom ET, Okazaki T, Nagano Y, Yoshie O, Imai T (2004) Fractalkine in vascular biology: from basic research to clinical disease. Arterioscler Thromb Vasc Biol 24:34–40PubMedCrossRefGoogle Scholar
  94. 94.
    Ramos MV, Fernández GC, Patey N, Schierloh P, Exeni R, Grimoldi I, Vallejo G, Elías-Costa C, Del Carmen SM, Trachtman H, Combadière C, Proulx F, Palermo MS (2007) Involvement of the fractalkine pathway in the pathogenesis of childhood hemolytic uremic syndrome. Blood 109:2438–2445PubMedCrossRefGoogle Scholar
  95. 95.
    Fong JS, Kaplan BS (1982) Impairment of platelet aggregation in hemolytic uremic syndrome: evidence for platelet "exhaustion". Blood 60:564–570PubMedGoogle Scholar
  96. 96.
    Sassetti B, Vizcargüénaga MI, Zanaro NL, Silva MV, Kordich L, Florentini L, Diaz M, Vitacco M, Sanchez Avalos JC (1999) Hemolytic uremic syndrome in children: platelet aggregation and membrane glycoproteins. J Pediatr Hematol Oncol 21:123–128PubMedCrossRefGoogle Scholar
  97. 97.
    Appiani AC, Edefonti A, Bettinelli A, Cossu MM, Paracchini ML, Rossi E (1982) The relationship between plasma levels of the factor VIII complex and platelet release products (beta-thromboglobulin and platelet factor 4) in children with the hemolytic-uremic syndrome. Clin Nephrol 17:195–199PubMedGoogle Scholar
  98. 98.
    Katayama M, Handa M, Araki Y, Ambo H, Kawai Y, Watanabe K, Ikeda Y (1993) Soluble P-selectin is present in normal circulation and its plasma level is elevated in patients with thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome. Br J Haematol 84:702–710PubMedCrossRefGoogle Scholar
  99. 99.
    Rose PE, Armour JA, Williams CE, Hill FG (1985) Verotoxin and neuraminidase induced platelet aggregating activity in plasma: their possible role in the pathogenesis of the haemolytic uraemic syndrome. J Clin Pathol 38:438–441PubMedCrossRefGoogle Scholar
  100. 100.
    Yoshimura K, Fujii J, Yutsudo T, Kikuchi R, Soejima T, Shirahata S, Yoshida S (1998) No direct effects of Shiga toxin 1 and 2 on the aggregation of human platelets in vitro. Thromb Haemost 80:529–530PubMedGoogle Scholar
  101. 101.
    Thorpe CM, Flaumenhaft R, Hurley B, Jacewicz M, Acheson DW, Keusch GT (1999) Shiga toxins do not directly stimulate alpha-granule secretion or enhance aggregation of human platelets. Acta Haematol 102:51–55PubMedCrossRefGoogle Scholar
  102. 102.
    Nolasco LH, Turner NA, Bernardo A, Tao Z, Cleary TG, Dong JF, Moake JL (2005) Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers. Blood 106:4199–4209PubMedCrossRefGoogle Scholar
  103. 103.
    Guessous F, Marcinkiewicz M, Polanowska-Grabowska R, Kongkhum S, Heatherly D, Obrig T, Gear AR (2005) Shiga toxin 2 and lipopolysaccharide induce human microvascular endothelial cells to release chemokines and factors that stimulate platelet function. Infect Immun 73:8306–8316PubMedCrossRefGoogle Scholar
  104. 104.
    Chu AJ (2006) Role of tissue factor in thrombosis. Coagulation-inflammation-thrombosis circuit. Front Biosci 11:256–271PubMedCrossRefGoogle Scholar
  105. 105.
    Murata K, Higuchi T, Takada K, Oida K, Horie S, Ishii H (2006) Verotoxin-1 stimulation of macrophage-like THP-1 cells up-regulates tissue factor expression through activation of c-Yes tyrosine kinase: possible signal transduction in tissue factor up-regulation. Biochim Biophys Acta 1762:835–843PubMedGoogle Scholar
  106. 106.
    Polley MJ, Nachman R (1978) The human complement system in thrombin-mediated platelet function. J Exp Med 147:1713–1726PubMedCrossRefGoogle Scholar
  107. 107.
    Polley MJ, Nachman RL (1983) Human platelet activation by C3a and C3a des-arg. J Exp Med 158:603–615PubMedCrossRefGoogle Scholar
  108. 108.
    Ståhl AL, Vaziri-Sani F, Heinen S, Kristoffersson AC, Gydell KH, Raafat R, Gutierrez A, Beringer O, Zipfel PF, Karpman D (2008) Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation. Blood 111:5307–5315PubMedCrossRefGoogle Scholar
  109. 109.
    Gralnick HR, Vail M, McKeown LP, Merryman P, Wilson O, Chu I, Kimball J (1995) Activated platelets in paroxysmal nocturnal haemoglobinuria. Br J Haematol 91:697–702PubMedCrossRefGoogle Scholar
  110. 110.
    Noris M, Remuzzi G (2009) Atypical hemolytic-uremic syndrome. N Engl J Med 361:1676–1687PubMedCrossRefGoogle Scholar
  111. 111.
    Tripodo C, Noris M, Macor P, Gastoldi S, Pickering M, Botto M, Wurzner R, Mollnes T, Remuzzi G, Tedesco F (2008) Is local complement activation involved in renal damage in patients with atypical haemolytic uraemic syndrome? Mol Immunol 45:4101–4102CrossRefGoogle Scholar
  112. 112.
    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
  113. 113.
    Robson WL, Leung AK, Fick GH, McKenna AI (1992) Hypocomplementemia and leukocytosis in diarrhea-associated hemolytic uremic syndrome. Nephron 62:296–299PubMedCrossRefGoogle Scholar
  114. 114.
    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 4:1920–1924PubMedCrossRefGoogle Scholar
  115. 115.
    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, Würzner R (2009) Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome. J Immunol 182:6394–6400PubMedCrossRefGoogle Scholar
  116. 116.
    Karmali MA, Petric M, Lim C, Fleming PC, Arbus GS, Lior M (1985) The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli. J Infect Dis 151:775–782PubMedGoogle Scholar
  117. 117.
    Morigi M, Gastoldi S, Galbusera M, Locatelli M, Rottoli D, Pezzotta A, Buelli S, Pagani C, Remuzzi G, Zoja C (2008) Complement (©) activation amplifies platelet deposition in renal microvasculature in response to shigatoxin (Stx). J Am Soc Nephrol 19:423AGoogle Scholar
  118. 118.
    Khanna R, Waechter L, Sargeant J, Clark WF, Garg AX (2008) Environmental prevention of human disease from verocytotoxin-producing Escherichia coli. Nephrol Dial Transplant 23:1819–1822PubMedCrossRefGoogle Scholar
  119. 119.
    Bentancor LV, Bilen M, Brando RJ, Ramos MV, Ferreira LC, Ghiringhelli PD, Palermo MS (2009) A DNA vaccine encoding the enterohemorragic Escherichia coli Shiga-like toxin 2 A2 and B subunits confers protective immunity to Shiga toxin challenge in the murine model. Clin Vaccine Immunol 16:712–718PubMedCrossRefGoogle Scholar
  120. 120.
    Bitzan M, Poole R, Mehran M, Sicard E, Brockus C, Thuning-Roberson C, Rivière M (2009) Safety and pharmacokinetics of chimeric anti-Shiga toxin 1 and anti-Shiga toxin 2 monoclonal antibodies in healthy volunteers. Antimicrob Agents Chemother 53:3081–3087PubMedCrossRefGoogle Scholar
  121. 121.
    López EL, Contrini MM, Glatstein E, Gonzalez Ayala S, Santoro R, Allende D, Ezcurra G, Teplitz E, Koyama T, Matsumoto Y, Sato H, Sakai K, Hoshide S, Komoriya K, Morita T, Harning R, Brookman S (2010) Safety and pharmacokinetics of urtoxazumab, a humanized monoclonal antibody, against Shiga-like toxin 2 in healthy adults and in pediatric patients infected with Shiga-like toxin-producing Escherichia coli. Antimicrob Agents Chemother 54:239–243PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2010

Authors and Affiliations

  1. 1.Mario Negri Institute for Pharmacological ResearchBergamoItaly

Personalised recommendations