Skip to main content
SpringerLink
Log in

Pathogenic role of inflammatory response during Shiga toxin-associated hemolytic uremic syndrome (HUS)

  • Educational Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Hemolytic uremic syndrome (HUS) is defined as a triad of noninmune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The most frequent presentation is secondary to Shiga toxin (Stx)-producing Escherichia coli (STEC) infections, which is termed postdiarrheal, epidemiologic or Stx-HUS, considering that Stx is the necessary etiological factor. After ingestion, STEC colonize the intestine and produce Stx, which translocates across the intestinal epithelium. Once Stx enters the bloodstream, it interacts with renal endothelial and epithelial cells, and leukocytes. This review summarizes the current evidence about the involvement of inflammatory components as central pathogenic factors that could determine outcome of STEC infections. Intestinal inflammation may favor epithelial leakage and subsequent passage of Stx to the systemic circulation. Vascular damage triggered by Stx promotes not only release of thrombin and increased fibrin concentration but also production of cytokines and chemokines by endothelial cells. Recent evidence from animal models and patients strongly indicate that several immune cells types may participate in HUS physiopathology: neutrophils, through release of proteases and reactive oxygen species (ROS); monocytes/macrophages through secretion of cytokines and chemokines. In addition, high levels of Bb factor and soluble C5b-9 (sC5b-9) in plasma as well as complement factors adhered to platelet-leukocyte complexes, microparticles and microvesicles, suggest activation of the alternative pathway of complement. Thus, acute immune response secondary to STEC infection, the Stx stimulatory effect on different immune cells, and inflammatory stimulus secondary to endothelial damage all together converge to define a strong inflammatory status that worsens Stx toxicity and disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Jacewicz M, Clausen H, Nudelman E, Donohue-Rolfe A, Keusch GT (1986) Pathogenesis of shigella diarrhea. XI. Isolation of a shigella toxin-binding glycolipid from rabbit jejunum and HeLa cells and its identification as globotriaosylceramide. J Exp Med 163:1391–1404

    CAS  PubMed  Google Scholar 

  2. Samuel JE, Perera LP, Ward S, O’Brien AD, Ginsburg V, Krivan HC (1990) Comparison of the glycolipid receptor specificities of Shiga-like toxin type II and Shiga-like toxin type II variants. Infect Immun 58:611–618

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Muthing J, Schweppe CH, Karch H, Friedrich AW (2009) Shiga toxins, glycosphingolipid diversity, and endothelial cell injury. Thromb Haemost 101:252–264

    PubMed  Google Scholar 

  4. Khan F, Proulx F, Lingwood CA (2009) Detergent-resistant globotriaosyl ceramide may define verotoxin/glomeruli-restricted hemolytic uremic syndrome pathology. Kidney Int 75:1209–1216

    PubMed  Google Scholar 

  5. Tesh VL (2010) Induction of apoptosis by Shiga toxins. Future Microbiol 5:431–453

    CAS  PubMed  Google Scholar 

  6. Trachtman H, Austin C, Lewinski M, Stahl RA (2012) Renal and neurological involvement in typical Shiga toxin-associated HUS. Nat Rev Nephrol 8:658–669

    CAS  PubMed  Google Scholar 

  7. 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 67:5985–5993

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Foster GH, Armstrong CS, Sakiri R, Tesh VL (2000) Shiga toxin-induced tumor necrosis factor alpha expression: requirement for toxin enzymatic activity and monocyte protein kinase C and protein tyrosine kinases. Infect Immun 68:5183–5189

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 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 122:759–776

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 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 106:4199–4209

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 101:372–382

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Morigi M, Zoja C, Figliuzzi M, Foppolo M, Micheletti G, Bontempelli M, Saronni M, Remuzzi G, Remuzzi A (1995) Fluid shear stress modulates surface expression of adhesion molecules by endothelial cells. Blood 85:1696–1703

    CAS  PubMed  Google Scholar 

  13. 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 98:1828–1835

    CAS  PubMed  Google Scholar 

  14. 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 268:15484–15488

    CAS  PubMed  Google Scholar 

  15. Kaye SA, Louise CB, Boyd B, Lingwood CA, Obrig TG (1993) Shiga toxin-associated hemolytic uremic syndrome:interleukin-1 beta enhancement of Shiga toxin cytotoxicity toward human vascular endothelial cells in vitro. Infect Immun 61:3886–3891

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 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 62:846–856

    CAS  PubMed  Google Scholar 

  17. Obrig TG (2010) Escherichia coli Shiga toxin mechanisms of action in renal disease. Toxins (Basel) 2:2769–2794

    CAS  Google Scholar 

  18. Williams JM, Boyd B, Nutikka A, Lingwood CA, Barnett Foster DE, Milford DV, Taylor CM (1999) A comparison of the effects of verocytotoxin-1 on primary human renal cell cultures. Toxicol Lett 105:47–57

    CAS  PubMed  Google Scholar 

  19. Obrig TG, Karpman D (2012) Shiga toxin pathogenesis: kidney complications and renal failure. Curr Top Microbiol Immunol 357:105–136

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 169:1965–1975

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ohara S, Kawasaki Y, Abe Y, Watanabe M, Ono A, Suyama K, Hashimoto K, Honda T, Suzuki J, Hosoya M (2012) Role of vascular endothelial growth factor and angiopoietin 1 in renal injury in hemolytic uremic syndrome. Am J Nephrol 36:516–523

    CAS  PubMed  Google Scholar 

  22. Kita E, Yunou Y, Kurioka T, Harada H, Yoshikawa S, Mikasa K, Higashi N (2000) Pathogenic mechanism of mouse brain damage caused by oral infection with Shiga toxin-producing Escherichia coli O157:H7. Infect Immun 68:1207–1214

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ramos MV, Mejias MP, Sabbione F, Fernandez-Brando RJ, Santiago AP, Amaral MM, Exeni R, Trevani AS, Palermo MS (2016) Induction of neutrophil extracellular traps in Shiga toxin-associated hemolytic uremic syndrome. J Innate Immun 8:400–411

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 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 191:4748–4758

    CAS  PubMed  Google Scholar 

  25. Kniep B, Monner DA, Schwulera U, Muhlradt PF (1985) Glycosphingolipids of the globo-series are associated with the monocytic lineage of human myeloid cells. Eur J Biochem 149:187–191

    CAS  PubMed  Google Scholar 

  26. 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 88:174–183

    PubMed  Google Scholar 

  27. Tesh VL, Ramegowda B, Samuel JE (1994) Purified Shiga-like toxins induce expression of proinflammatory cytokines from murine peritoneal macrophages. Infect Immun 62:5085–5094

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Lee SY, Cherla RP, Tesh VL (2007) Simultaneous induction of apoptotic and survival signaling pathways in macrophage-like THP-1 cells by Shiga toxin 1. Infect Immun 75:1291–1302

    CAS  PubMed  Google Scholar 

  29. Brando RJ, Miliwebsky E, Bentancor L, Deza N, Baschkier A, Ramos MV, Fernandez GC, Meiss R, Rivas M, Palermo MS (2008) Renal damage and death in weaned mice after oral infection with Shiga toxin 2-producing Escherichia coli strains. Clin Exp Immunol 153:297–306

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Cabrera G, Fernandez-Brando RJ, Abrey-Recalde MJ, Baschkier A, Pinto A, Goldstein J, Zotta E, Meiss R, Rivas M, Palermo MS (2014) Retinoid levels influence enterohemorrhagic Escherichia coli infection and Shiga toxin 2 susceptibility in mice. Infect Immun 82:3948–3957

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Palermo M, Alves-Rosa F, Rubel C, Fernandez GC, Fernandez-Alonso G, Alberto F, Rivas M, Isturiz M (2000) Pretreatment of mice with lipopolysaccharide (LPS) or IL-1beta exerts dose-dependent opposite effects on Shiga toxin-2 lethality. Clin Exp Immunol 119:77–83

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Stearns-Kurosawa DJ, SY O, Cherla RP, Lee MS, Tesh VL, Papin J, Henderson J, Kurosawa S (2013) Distinct renal pathology and a chemotactic phenotype after enterohemorrhagic Escherichia coli Shiga toxins in non-human primate models of hemolytic uremic syndrome. Am J Pathol 182:1227–1238

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Mohawk KL, O’Brien AD (2011) Mouse models of Escherichia coli O157:H7 infection and Shiga toxin injection. J Biomed Biotechnol 2011:258185

    PubMed  PubMed Central  Google Scholar 

  34. Obata F, Tohyama K, Bonev AD, Kolling GL, Keepers TR, Gross LK, Nelson MT, Sato S, Obrig TG (2008) Shiga toxin 2 affects the central nervous system through receptor globotriaosylceramide localized to neurons. J Infect Dis 198:1398–1406

    CAS  PubMed  Google Scholar 

  35. Takahashi K, Funata N, Ikuta F, Sato S (2008) Neuronal apoptosis and inflammatory responses in the central nervous system of a rabbit treated with Shiga toxin-2. J Neuroinflammation 5:11

    PubMed  PubMed Central  Google Scholar 

  36. Tironi-Farinati C, Geoghegan PA, Cangelosi A, Pinto A, Loidl CF, Goldstein J (2013) A translational murine model of sub-lethal intoxication with Shiga toxin 2 reveals novel ultrastructural findings in the brain striatum. PLoS One 8:e55812

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Fernandez GC, Lopez MF, Gomez SA, Ramos MV, Bentancor LV, Fernandez-Brando RJ, Landoni VI, Dran GI, Meiss R, Isturiz MA, Palermo MS (2006) Relevance of neutrophils in the murine model of haemolytic uraemic syndrome: mechanisms involved in Shiga toxin type 2-induced neutrophilia. Clin Exp Immunol 146:76–84

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Ibarra C, Amaral MM, Palermo MS (2013) Advances in pathogenesis and therapy of hemolytic uremic syndrome caused by Shiga toxin-2. IUBMB Life 65:827–835

    CAS  PubMed  Google Scholar 

  39. Miyamoto Y, Iimura M, Kaper JB, Torres AG, Kagnoff MF (2006) Role of Shiga toxin versus H7 flagellin in enterohaemorrhagic Escherichia coli signalling of human colon epithelium in vivo. Cell Microbiol 8:869–879

    CAS  PubMed  Google Scholar 

  40. Calderon Toledo C, Rogers TJ, Svensson M, Tati R, Fischer H, Svanborg C, Karpman D (2008) Shiga toxin-mediated disease in MyD88-deficient mice infected with Escherichia coli O157:H7. Am J Pathol 173:1428–1439

    PubMed  Google Scholar 

  41. Gibson DL, Ma C, Bergstrom KS, Huang JT, Man C, Vallance BA (2008) MyD88 signalling plays a critical role in host defence by controlling pathogen burden and promoting epithelial cell homeostasis during Citrobacter rodentium-induced colitis. Cell Microbiol 10:618–631

    CAS  PubMed  Google Scholar 

  42. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118:229–241

    CAS  PubMed  Google Scholar 

  43. Kramer S, Sellge G, Lorentz A, Krueger D, Schemann M, Feilhauer K, Gunzer F, Bischoff SC (2008) Selective activation of human intestinal mast cells by Escherichia coli hemolysin. J Immunol 181:1438–1445

    PubMed  Google Scholar 

  44. Bell CJ, Elliott EJ, Wallace JL, Redmond DM, Payne J, Li Z, O’Loughlin EV (2000) Do eicosanoids cause colonic dysfunction in experimental E. coli O157:H7 (EHEC) infection? Gut 46:806–812

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Cabrera G, Fernandez-Brando RJ, Mejias MP, Ramos MV, Abrey-Recalde MJ, Vanzulli S, Vermeulen M, Palermo MS (2015) Leukotriene C4 increases the susceptibility of adult mice to Shiga toxin-producing Escherichia coli infection. Int J Med Microbiol 305:910–917

    CAS  PubMed  Google Scholar 

  46. Fernandez GC, Rubel C, Dran G, Gomez S, Isturiz MA, Palermo MS (2000) Shiga toxin-2 induces neutrophilia and neutrophil activation in a murine model of hemolytic uremic syndrome. Clin Immunol 95:227–234

    CAS  PubMed  Google Scholar 

  47. Gomez SA, Fernandez GC, Camerano G, Dran G, Rosa FA, Barrionuevo P, Isturiz MA, Palermo MS (2005) Endogenous glucocorticoids modulate neutrophil function in a murine model of haemolytic uraemic syndrome. Clin Exp Immunol 139:65–73

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Gomez SA, Fernandez GC, Vanzulli S, Dran G, Rubel C, Berki T, Isturiz MA, Palermo MS (2003) Endogenous glucocorticoids attenuate Shiga toxin-2-induced toxicity in a mouse model of haemolytic uraemic syndrome. Clin Exp Immunol 131:217–224

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Gomez SA, Abrey-Recalde MJ, Panek CA, Ferrarotti NF, Repetto MG, Mejias MP, Fernandez GC, Vanzulli S, Isturiz MA, Palermo MS (2013) The oxidative stress induced in vivo by Shiga toxin-2 contributes to the pathogenicity of haemolytic uraemic syndrome. Clin Exp Immunol 173:463–472

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Salvemini D, de Nucci G, Sneddon JM, Vane JR (1989) Superoxide anions enhance platelet adhesion and aggregation. Br J Pharmacol 97:1145–1150

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Nath KA, Norby SM (2000) Reactive oxygen species and acute renal failure. Am J Med 109:665–678

    CAS  PubMed  Google Scholar 

  52. Palermo MS, Alves Rosa MF, Van Rooijen N, Isturiz MA (1999) Depletion of liver and splenic macrophages reduces the lethality of Shiga toxin-2 in a mouse model. Clin Exp Immunol 116:462–467

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ramos MV, Auvynet C, Poupel L, Rodero M, Mejias MP, Panek CA, Vanzulli S, Combadiere C, Palermo M (2012) Chemokine receptor CCR1 disruption limits renal damage in a murine model of hemolytic uremic syndrome. Am J Pathol 180:1040–1048

    CAS  PubMed  Google Scholar 

  54. Keepers TR, Gross LK, Obrig TG (2007) Monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, and RANTES recruit macrophages to the kidney in a mouse model of hemolytic-uremic syndrome. Infect Immun 75:1229–1236

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 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 170:526–537

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Obata F, Obrig T (2014) Role of Shiga/Vero toxins in pathogenesis. Microbiol Spectr. https://doi.org/10.1128/microbiolspec.EHEC-0005-2013

  57. Lucero MS, Mirarchi F, Goldstein J, Silberstein C (2012) Intraperitoneal administration of Shiga toxin 2 induced neuronal alterations and reduced the expression levels of aquaporin 1 and aquaporin 4 in rat brain. Microb Pathog 53:87–94

    CAS  PubMed  Google Scholar 

  58. Amran MY, Fujii J, Suzuki SO, Kolling GL, Villanueva SY, Kainuma M, Kobayashi H, Kameyama H, Yoshida S (2013) Investigation of encephalopathy caused by Shiga toxin 2c-producing Escherichia coli infection in mice. PLoS One 8:e58959

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Isogai E, Isogai H, Kimura K, Hayashi S, Kubota T, Fujii N, Takeshi K (1998) Role of tumor necrosis factor alpha in gnotobiotic mice infected with an Escherichia coli O157:H7 strain. Infect Immun 66:197–202

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Pradhan S, Pellino C, MacMaster K, Coyle D, Weiss AA (2016) Shiga toxin mediated neurologic changes in Murine model of disease. Front Cell Infect Microbiol 6:114

    PubMed  PubMed Central  Google Scholar 

  61. Porubsky S, Federico G, Muthing J, Jennemann R, Gretz N, Buttner S, Obermuller N, Jung O, Hauser IA, Grone E, Geiger H, Grone HJ, Betz C (2014) Direct acute tubular damage contributes to Shigatoxin-mediated kidney failure. J Pathol 234:120–133

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Buteau C, Proulx F, Chaibou M, Raymond D, Clermont MJ, Mariscalco MM, Lebel MH, Seidman E (2000) Leukocytosis in children with Escherichia coli O157:H7 enteritis developing the hemolytic-uremic syndrome. Pediatr Infect Dis J 19:642–647

    CAS  PubMed  Google Scholar 

  63. Fernandez GC, Gomez SA, Ramos MV, Bentancor LV, Fernandez-Brando RJ, Landoni VI, Lopez L, Ramirez F, Diaz M, Alduncin M, Grimoldi I, Exeni R, Isturiz MA, Palermo MS (2007) The functional state of neutrophils correlates with the severity of renal dysfunction in children with hemolytic uremic syndrome. Pediatr Res 61:123–128

    PubMed  Google Scholar 

  64. 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 11:556–559

    CAS  PubMed  Google Scholar 

  65. 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 43:759–767

    PubMed  Google Scholar 

  66. Brigotti M, Tazzari PL, Ravanelli E, Carnicelli D, Barbieri S, Rocchi L, Arfilli V, Scavia G, Ricci F, Bontadini A, Alfieri RR, Petronini PG, Pecoraro C, Tozzi AE, Caprioli A (2010) Endothelial damage induced by Shiga toxins delivered by neutrophils during transmigration. J Leukoc Biol 88:201–210

    CAS  PubMed  Google Scholar 

  67. Valles PG, Melechuck S, Gonzalez A, Manucha W, Bocanegra V, Valles R (2012) Toll-like receptor 4 expression on circulating leucocytes in hemolytic uremic syndrome. Pediatr Nephrol 27:407–415

    PubMed  Google Scholar 

  68. Fernandez GC, Gomez SA, Rubel CJ, Bentancor LV, Barrionuevo P, Alduncin M, Grimoldi I, Exeni R, Isturiz MA, Palermo MS (2005) Impaired neutrophils in children with the typical form of hemolytic uremic syndrome. Pediatr Nephrol 20:1306–1314

    PubMed  Google Scholar 

  69. Fernandez GC, Rubel C, Barrionuevo P, Lopez L, Ramirez F, Diaz M, Isturiz MA, Palermo MS (2002) Phenotype markers and function of neutrophils in children with hemolytic uremic syndrome. Pediatr Nephrol 17:337–344

    PubMed  Google Scholar 

  70. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535

    CAS  PubMed  Google Scholar 

  71. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, Jr., Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD (2010) Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 107:15880-15885

    CAS  Google Scholar 

  72. Kessenbrock K, Krumbholz M, Schonermarck U, Back W, Gross WL, Werb Z, Grone HJ, Brinkmann V, Jenne DE (2009) Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 15:623–625

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Fuchs TA, Kremer Hovinga JA, Schatzberg D, Wagner DD, Lammle B (2012) Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies. Blood 120:1157–1164

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Leffler J, Prohaszka Z, Mikes B, Sinkovits G, Ciacma K, Farkas P, Reti M, Kelen K, Reusz GS, Szabo AJ, Martin M, Blom AM (2017) Decreased neutrophil extracellular trap degradation in Shiga toxin-associated haemolytic uraemic syndrome. J Innate Immun 9:12–21

    CAS  PubMed  Google Scholar 

  75. von Bruhl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, Khandoga A, Tirniceriu A, Coletti R, Kollnberger M, Byrne RA, Laitinen I, Walch A, Brill A, Pfeiler S, Manukyan D, Braun S, Lange P, Riegger J, Ware J, Eckart A, Haidari S, Rudelius M, Schulz C, Echtler K, Brinkmann V, Schwaiger M, Preissner KT, Wagner DD, Mackman N, Engelmann B, Massberg S (2012) Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 209:819–835

    Google Scholar 

  76. Wang H, Wang C, Zhao MH, Chen M (2015) Neutrophil extracellular traps can activate alternative complement pathways. Clin Exp Immunol 181:518–527

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Leffler J, Martin M, Gullstrand B, Tyden H, Lood C, Truedsson L, Bengtsson AA, Blom AM (2012) Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J Immunol 188:3522–3531

    CAS  PubMed  Google Scholar 

  78. 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 187:172–180

    CAS  PubMed  Google Scholar 

  79. Stahl AL, Sartz L, Karpman D (2011) Complement activation on platelet-leukocyte complexes and microparticles in enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome. Blood 117:5503–5513

    PubMed  Google Scholar 

  80. Locatelli M, Buelli S, Pezzotta A, Corna D, Perico L, Tomasoni S, Rottoli D, Rizzo P, Conti D, Thurman JM, Remuzzi G, Zoja C, Morigi M (2014) Shiga toxin promotes podocyte injury in experimental hemolytic uremic syndrome via activation of the alternative pathway of complement. J Am Soc Nephrol 25:1786–1798

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Freedman JE (2008) Oxidative stress and platelets. Arterioscler Thromb Vasc Biol 28:s11–s16

    CAS  PubMed  Google Scholar 

  82. Perricone C, De Carolis C, Perricone R (2009) Glutathione: a key player in autoimmunity. Autoimmun Rev 8:697–701

    CAS  PubMed  Google Scholar 

  83. Ferraris V, Acquier A, Ferraris JR, Vallejo G, Paz C, Mendez CF (2011) Oxidative stress status during the acute phase of haemolytic uraemic syndrome. Nephrol Dial Transplant 26:858–864

    CAS  PubMed  Google Scholar 

  84. Aiassa V, Baronetti JL, Paez PL, Barnes AI, Albrecht C, Pellarin G, Eraso AJ, Albesa I (2011) Increased advanced oxidation of protein products and enhanced total antioxidant capacity in plasma by action of toxins of Escherichia coli STEC. Toxicol in Vitro 25:426–431

    CAS  PubMed  Google Scholar 

  85. Li Volti S, Di Giacomo C, Garozzo R, Campisi A, Mollica F, Vanella A (1993) Impaired antioxidant defense mechanisms in two children with hemolytic-uremic syndrome. Ren Fail 15:523–528

    CAS  PubMed  Google Scholar 

  86. Facorro G, Aguirre F, Florentin L, Diaz M, De Paoli T, Ihlo JE, Hager AA, Sanchez Avalos JC, Farach HA, Poole CP Jr (1997) Oxidative stress and membrane fluidity in erythrocytes from patients with hemolytic uremic syndrome. Acta Physiol Pharmacol Ther Latinoam 47:137–146

    CAS  PubMed  Google Scholar 

  87. Dubey NK, Yadav P, Dutta AK, Kumar V, Ray GN, Batra S (2000) Free oxygen radicals in acute renal failure. Indian Pediatr 37:153–158

    CAS  PubMed  Google Scholar 

  88. Powell HR, McCredie DA, Taylor CM, Burke JR, Walker RG (1984) Vitamin E treatment of haemolytic uraemic syndrome. Arch Dis Child 59:401–404

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Fernandez GC, Ramos MV, Gomez SA, Dran GI, Exeni R, Alduncin M, Grimoldi I, Vallejo G, Elias-Costa C, Isturiz MA, Palermo MS (2005) Differential expression of function-related antigens on blood monocytes in children with hemolytic uremic syndrome. J Leukoc Biol 78:853–861

    CAS  PubMed  Google Scholar 

  90. Fernandez GC, Ramos MV, Landoni VI, Bentancor LV, Fernandez-Brando RJ, Exeni R, Laso Mdel C, Exeni A, Grimoldi I, Isturiz MA, Palermo MS (2012) Cytokine production is altered in monocytes from children with hemolytic uremic syndrome. J Clin Immunol 32:622–631

    CAS  PubMed  Google Scholar 

  91. Ramos MV, Ruggieri M, Panek AC, Mejias MP, Fernandez-Brando RJ, Abrey-Recalde MJ, Exeni A, Barilari C, Exeni R, Palermo MS (2015) Association of haemolytic uraemic syndrome with dysregulation of chemokine receptor expression in circulating monocytes. Clin Sci (Lond) 129:235–244

    CAS  Google Scholar 

  92. Ramos MV, Fernandez GC, Patey N, Schierloh P, Exeni R, Grimoldi I, Vallejo G, Elias-Costa C, Del Carmen Sasiain M, Trachtman H, Combadiere C, Proulx F, Palermo MS (2007) Involvement of the fractalkine pathway in the pathogenesis of childhood hemolytic uremic syndrome. Blood 109:2438–2445

    CAS  PubMed  Google Scholar 

  93. Proulx F, Toledano B, Phan V, Clermont MJ, Mariscalco MM, Seidman EG (2002) Circulating granulocyte colony-stimulating factor, C-X-C, and C-C chemokines in children with Escherichia coli O157:H7 associated hemolytic uremic syndrome. Pediatr Res 52:928–934

    CAS  PubMed  Google Scholar 

  94. Proulx F, Litalien C, Turgeon JP, Mariscalco MM, Seidman E (2000) Circulating levels of transforming growth factor-beta1 and lymphokines among children with hemolytic uremic syndrome. Am J Kidney Dis 35:29–34

    CAS  PubMed  Google Scholar 

  95. Shimizu M, Kuroda M, Inoue N, Konishi M, Igarashi N, Taneichi H, Kanegane H, Ito M, Saito S, Yachie A (2014) Extensive serum biomarker analysis in patients with enterohemorrhagic Escherichia coli O111-induced hemolytic-uremic syndrome. Cytokine 66:1–6

    CAS  PubMed  Google Scholar 

  96. Shiraishi M, Ichiyama T, Matsushige T, Iwaki T, Iyoda K, Fukuda K, Makata H, Matsubara T, Furukawa S (2008) Soluble tumor necrosis factor. Receptor 1 and tissue inhibitor of metalloproteinase-1 in hemolytic uremic syndrome with encephalopathy. J Neuroimmunol 196:147–152

    CAS  PubMed  Google Scholar 

  97. Murata A, Shimazu T, Yamamoto T, Taenaka N, Nagayama K, Honda T, Sugimoto H, Monden M, Matsuura N, Okada S (1998) Profiles of circulating inflammatory- and anti-inflammatory cytokines in patients with hemolytic uremic syndrome due to E. coli O157 infection. Cytokine 10:544–548

    CAS  PubMed  Google Scholar 

  98. Page AV, Tarr PI, Watkins SL, Rajwans N, Petruzziello-Pellegrini TN, Marsden PA, Kain KC, Liles WC (2013) Dysregulation of angiopoietin 1 and 2 in Escherichia coli O157:H7 infection and the hemolytic-uremic syndrome. J Infect Dis 208:929–933

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Siegler RL, Edwin SS, Christofferson RD, Mitchell MD (1991) Endothelin in the urine of children with the hemolytic uremic syndrome. Pediatrics 88:1063–1066

    CAS  PubMed  Google Scholar 

  100. Yamamoto T, Nagayama K, Satomura K, Honda T, Okada S (2000) Increased serum IL-10 and endothelin levels in hemolytic uremic syndrome caused by Escherichia coli O157. Nephron 84:326–332

    CAS  PubMed  Google Scholar 

  101. Decaluwe H, Harrison LM, Mariscalco MM, Gendrel D, Bohuon C, Tesh VL, Proulx F (2006) Procalcitonin in children with Escherichia coli O157:H7 associated hemolytic uremic syndrome. Pediatr Res 59:579–583

    CAS  PubMed  Google Scholar 

  102. Robson WL, Leung AK, Fick GH, McKenna AI (1992) Hypocomplementemia and leukocytosis in diarrhea-associated hemolytic uremic syndrome. Nephron 62:296–299

    CAS  PubMed  Google Scholar 

  103. 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 4:1920–1924

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Ferraris JR, Ferraris V, Acquier AB, Sorroche PB, Saez MS, Ginaca A, Mendez CF (2015) Activation of the alternative pathway of complement during the acute phase of typical haemolytic uraemic syndrome. Clin Exp Immunol 181:118–125

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Arvidsson I, Stahl AL, Hedstrom MM, Kristoffersson AC, Rylander C, Westman JS, Storry JR, Olsson ML, Karpman D (2015) Shiga toxin-induced complement-mediated hemolysis and release of complement-coated red blood cell-derived microvesicles in hemolytic uremic syndrome. J Immunol 194:2309–2318

    CAS  PubMed  Google Scholar 

  106. Ahlenstiel-Grunow T, Hachmeister S, Bange FC, Wehling C, Kirschfink M, Bergmann C, Pape L (2016) Systemic complement activation and complement gene analysis in enterohaemorrhagic Escherichia coli-associated paediatric haemolytic uraemic syndrome. Nephrol Dial Transplant 31:1114–1121

    CAS  PubMed  Google Scholar 

  107. Orth-Holler D, Wurzner R (2014) Role of complement in enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome. Semin Thromb Hemost 40:503–507

    PubMed  Google Scholar 

  108. Rosales A, Hofer J, Zimmerhackl LB, Jungraithmayr TC, Riedl M, Giner T, Strasak A, Orth-Holler D, Wurzner R, Karch H (2012) Need for long-term follow-up in enterohemorrhagic Escherichia coli-associated hemolytic uremic syndrome due to late-emerging sequelae. Clin Infect Dis 54:1413–1421

    PubMed  Google Scholar 

  109. Exeni RA (2006) Hemolytic uremic syndrome. Clinical manifestations. Treatment. Medicina (B Aires) 66(Suppl 3):6–10

    Google Scholar 

  110. Magnus T, Rother J, Simova O, Meier-Cillien M, Repenthin J, Moller F, Gbadamosi J, Panzer U, Wengenroth M, Hagel C, Kluge S, Stahl RK, Wegscheider K, Urban P, Eckert B, Glatzel M, Fiehler J, Gerloff C (2012) The neurological syndrome in adults during the 2011 northern German E. coli serotype O104:H4 outbreak. Brain 135:1850–1859

    PubMed  Google Scholar 

  111. Menne J, Nitschke M, Stingele R, Abu-Tair M, Beneke J, Bramstedt J, Bremer JP, Brunkhorst R, Busch V, Dengler R, Deuschl G, Fellermann K, Fickenscher H, Gerigk C, Goettsche A, Greeve J, Hafer C, Hagenmuller F, Haller H, Herget-Rosenthal S, Hertenstein B, Hofmann C, Lang M, Kielstein JT, Klostermeier UC, Knobloch J, Kuehbacher M, Kunzendorf U, Lehnert H, Manns MP, Menne TF, Meyer TN, Michael C, Munte T, Neumann-Grutzeck C, Nuernberger J, Pavenstaedt H, Ramazan L, Renders L, Repenthin J, Ries W, Rohr A, Rump LC, Samuelsson O, Sayk F, Schmidt BM, Schnatter S, Schocklmann H, Schreiber S, von Seydewitz CU, Steinhoff J, Stracke S, Suerbaum S, van de Loo A, Vischedyk M, Weissenborn K, Wellhoner P, Wiesner M, Zeissig S, Buning J, Schiffer M, Kuehbacher T (2012) Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study. BMJ 345:e4565

    PubMed  PubMed Central  Google Scholar 

  112. 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 (2014) Outbreak of Escherichia coli O104:H4 haemolytic uraemic syndrome in France: outcome with eculizumab. Nephrol Dial Transplant 29:565–572

    CAS  PubMed  Google Scholar 

  113. Saini A, Emke AR, Silva MC, Perlman SJ (2015) Response to Eculizumab in Escherichia coli O157:H7-induced hemolytic uremic syndrome with severe neurological manifestations. Clin Pediatr (Phila) 54:387–389

    Google Scholar 

  114. Pape L, Hartmann H, Bange FC, Suerbaum S, Bueltmann E, Ahlenstiel-Grunow T (2015) Eculizumab in typical hemolytic uremic syndrome (HUS) with neurological involvement. Medicine (Baltimore) 94:e1000

    CAS  PubMed  Google Scholar 

  115. 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 364:2561–2563

    CAS  PubMed  Google Scholar 

  116. Takanashi J, Taneichi H, Misaki T, Yahata Y, Okumura A, Ishida Y, Miyawaki T, Okabe N, Sata T, Mizuguchi M (2014) Clinical and radiologic features of encephalopathy during 2011 E. coli O111 outbreak in Japan. Neurology 82:564–572

    PubMed  Google Scholar 

  117. Valles PG, Pesle S, Piovano L, Davila E, Peralta M, Principi I, Lo Giudice P (2005) Postdiarrheal Shiga toxin-mediated hemolytic uremic syndrome similar to septic shock. Medicina (B Aires) 65:395–401

    Google Scholar 

  118. Igarashi T, Ito S, Sako M, Saitoh A, Hataya H, Mizuguchi M, Morishima T, Ohnishi K, Kawamura N, Kitayama H, Ashida A, Kaname S, Taneichi H, Tang J, Ohnishi M (2014) Guidelines for the management and investigation of hemolytic uremic syndrome. Clin Exp Nephrol 18:525–557

    PubMed  Google Scholar 

  119. Hagel C, Krasemann S, Loffler J, Puschel K, Magnus T, Glatzel M (2015) Upregulation of Shiga toxin receptor CD77/Gb3 and interleukin-1beta expression in the brain of EHEC patients with hemolytic uremic syndrome and neurologic symptoms. Brain Pathol 25:146–156

    CAS  PubMed  Google Scholar 

  120. Kuroda M, Shimizu M, Inoue N, Ikeno I, Nakagawa H, Yokoi A, Niida Y, Konishi M, Kaneda H, Igarashi N, Yamahana J, Taneichi H, Kanegane H, Ito M, Saito S, Furuichi K, Wada T, Nakagawa M, Yokoyama H, Yachie A (2015) Serum tau protein as a marker of disease activity in enterohemorrhagic Escherichia coli O111-induced hemolytic uremic syndrome. Neurochem Int 85–86:24–30

    CAS  PubMed  Google Scholar 

  121. Exeni RA, Fernandez GC, Palermo MS (2007) Role of polymorphonuclear leukocytes in the pathophysiology of typical hemolytic uremic syndrome. Sci World J 7:1155–1164

    CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from Agencia Nacional de Promoción Científica y Tecnológica, Argentina (PIDC 2014/0020).

Author information

Authors and Affiliations

  1. Departamento de Nefrología, Hospital Municipal del Niño, San Justo, Provincia de Buenos Aires, Argentina

    Ramon Alfonso Exeni & Adriana Patricia Santiago

  2. Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental Medicine (IMEX-CONICET), Academia Nacional de Medicina, Buenos Aires, Argentina

    Romina Jimena Fernandez-Brando, Gabriela Alejandra Fiorentino, Maria Victoria Ramos & Marina Sandra Palermo

  3. Laboratorio, Hospital Municipal del Niño, San Justo, Provincia de Buenos Aires, Argentina

    Gabriela Alejandra Fiorentino

  4. Servicio de Nefrología, Hospital Austral, Pilar, Provincia de Buenos Aires, Argentina

    Andrea Mariana Exeni

Authors
  1. Ramon Alfonso Exeni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Romina Jimena Fernandez-Brando
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adriana Patricia Santiago
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gabriela Alejandra Fiorentino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrea Mariana Exeni
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Victoria Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marina Sandra Palermo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marina Sandra Palermo.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Answers to questions:

1. a; 2. c; 3. d; 4. a; 5. b

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Exeni, R.A., Fernandez-Brando, R.J., Santiago, A.P. et al. Pathogenic role of inflammatory response during Shiga toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol 33, 2057–2071 (2018). https://doi.org/10.1007/s00467-017-3876-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-017-3876-0

Keywords

Search

Navigation