Pathophysiology of Typical Hemolytic Uremic Syndrome

Diana Karpman; Lisa Sartz; Sally Johnson

doi:10.1055/s-0030-1262879

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2010; 36(6): 575-585
DOI: 10.1055/s-0030-1262879

Pathophysiology of Typical Hemolytic Uremic Syndrome

Diana Karpman¹ , Lisa Sartz¹ , Sally Johnson²

¹Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden
²Department of Paediatric Nephrology, Birmingham Children's Hospital, Steelhouse Lane, Birmingham, United Kingdom

Abstract

ABSTRACT

The typical form of hemolytic uremic syndrome (HUS) is associated with enterohemorrhagic Escherichia coli (EHEC) infection. The disease process is initiated and perpetuated by interactions between the pathogen or its virulence factors and host cells, as well as the host response. During EHEC-associated HUS, alterations occurring at the intestinal mucosal barrier and in the circulation, as well as on endothelial cells and other target-organ cells, lead to cell activation and/or cytotoxicity, and trigger a prothrombotic state. This review summarizes current knowledge regarding the interactions of the pathogen and its virulence factors with cells in the intestine, bloodstream, kidney, and brain. Mechanisms of bacterial colonization, toxin circulation, and induction of target organ damage are discussed.

KEYWORDS

Hemolytic uremic syndrome - Shiga toxin - enterohemorrhagic Escherichia coli - thrombotic microangiopathy - kidney

Full Text

References

REFERENCES

1 Lynn R M, O'Brien S J, Taylor C M et al. Childhood hemolytic uremic syndrome, United Kingdom and Ireland. Emerg Infect Dis. 2005; 11(4) 590-596
2 Loirat C, Marczak E. Haemolytic uraemic syndrome. In: Cochat P European Society for Paediatric Nephrology Handbook. Lyon, France; Medcom 2002: 337-342
3 López E L, Contrini M M, Devoto S et al. Incomplete hemolytic-uremic syndrome in Argentinean children with bloody diarrhea. J Pediatr. 1995; 127(3) 364-367
4 Borczyk A A, Karmali M A, Lior H, Duncan L MC. Bovine reservoir for verotoxin-producing Escherichia coli O157:H7. Lancet. 1987; 1(8524) 98
5 Karmali M A. Host and pathogen determinants of verocytotoxin-producing Escherichia coli-associated hemolytic uremic syndrome. Kidney Int Suppl. 2009; 112(112) S4-S7
6 Goode B, O'Reilly C, Dunn J et al. Outbreak of Escherichia coli O157: H7 infections after Petting Zoo visits, North Carolina State Fair, October-November 2004. Arch Pediatr Adolesc Med. 2009; 163(1) 42-48
7 Milford D V, Taylor C M, Guttridge B, Hall S M, Rowe B, Kleanthous H. Haemolytic uraemic syndromes in the British Isles 1985-8: association with verocytotoxin producing Escherichia coli. Part 1: Clinical and epidemiological aspects. Arch Dis Child. 1990; 65(7) 716-721
8 Johnson S, Taylor C M. What's new in haemolytic uraemic syndrome?. Eur J Pediatr. 2008; 167(9) 965-971
9 Ruggenenti P, Noris M, Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int. 2001; 60(3) 831-846
10 Gagnadoux M F, Habib R, Gubler M C, Bacri J L, Broyer M. Long-term (15-25 years) outcome of childhood hemolytic-uremic syndrome. Clin Nephrol. 1996; 46(1) 39-41
11 Dean P, Kenny B. The effector repertoire of enteropathogenic E. coli: ganging up on the host cell. Curr Opin Microbiol. 2009; 12(1) 101-109
12 Delahay R M, Frankel G, Knutton S. Intimate interactions of enteropathogenic Escherichia coli at the host cell surface. Curr Opin Infect Dis. 2001; 14(5) 559-565
13 Fürst S, Scheef J, Bielaszewska M, Rüssmann H, Schmidt H, Karch H. Identification and characterisation of Escherichia coli strains of O157 and non-O157 serogroups containing three distinct Shiga toxin genes. J Med Microbiol. 2000; 49(4) 383-386
14 Boerlin P, McEwen S A, Boerlin-Petzold F, Wilson J B, Johnson R P, Gyles C L. Associations between virulence factors of Shiga toxin-producing Escherichia coli and disease in humans. J Clin Microbiol. 1999; 37(3) 497-503
15 Shimizu T, Ohta Y, Noda M. Shiga toxin 2 is specifically released from bacterial cells by two different mechanisms. Infect Immun. 2009; 77(7) 2813-2823
16 Zhang X, McDaniel A D, Wolf L E, Keusch G T, Waldor M K, Acheson D W. Quinolone antibiotics induce Shiga toxin-encoding bacteriophages, toxin production, and death in mice. J Infect Dis. 2000; 181(2) 664-670
17 Zoja C, Corna D, Farina C et al. Verotoxin glycolipid receptors determine the localization of microangiopathic process in rabbits given verotoxin-1. J Lab Clin Med. 1992; 120(2) 229-238
18 Obrig T G, Moran T P, Brown J E. The mode of action of Shiga toxin on peptide elongation of eukaryotic protein synthesis. Biochem J. 1987; 244(2) 287-294
19 Zoja C, Angioletti S, Donadelli R et al. Shiga toxin-2 triggers endothelial leukocyte adhesion and transmigration via NF-kappaB dependent up-regulation of IL-8 and MCP-1. Kidney Int. 2002; 62(3) 846-856
20 Matussek A, Lauber J, Bergau A et al. Molecular and functional analysis of Shiga toxin-induced response patterns in human vascular endothelial cells. Blood. 2003; 102(4) 1323-1332
21 Petruzziello T N, Mawji I A, Khan M, Marsden P A. Verotoxin biology: molecular events in vascular endothelial injury. Kidney Int Suppl. 2009; 75 S17-S19
22 Zoja C, Angioletti S, Donadelli R et al. Shiga toxin-2 triggers endothelial leukocyte adhesion and transmigration via NF-kappaB dependent up-regulation of IL-8 and MCP-1. Kidney Int. 2002; 62(3) 846-856
23 Obrig T G, Louise C B, Lingwood C A, Boyd B, Barley-Maloney L, Daniel T O. Endothelial heterogeneity in Shiga toxin receptors and responses. J Biol Chem. 1993; 268(21) 15484-15488
24 Friedrich A W, Zhang W, Bielaszewska M et al. Prevalence, virulence profiles, and clinical significance of Shiga toxin-negative variants of enterohemorrhagic Escherichia coli O157 infection in humans. Clin Infect Dis. 2007; 45(1) 39-45
25 Bielaszewska M, Karch H. Consequences of enterohaemorrhagic Escherichia coli infection for the vascular endothelium. Thromb Haemost. 2005; 94(2) 312-318
26 Friedrich A W, Lu S, Bielaszewska M et al. Cytolethal distending toxin in Escherichia coli O157:H7: spectrum of conservation, structure, and endothelial toxicity. J Clin Microbiol. 2006; 44(5) 1844-1846
27 Bielaszewska M, Sinha B, Kuczius T, Karch H. Cytolethal distending toxin from Shiga toxin-producing Escherichia coli O157 causes irreversible G2/M arrest, inhibition of proliferation, and death of human endothelial cells. Infect Immun. 2005; 73(1) 552-562
28 Aldick T, Bielaszewska M, Zhang W et al. Hemolysin from Shiga toxin-negative Escherichia coli O26 strains injures microvascular endothelium. Microbes Infect. 2007; 9(3) 282-290
29 Paton A W, Srimanote P, Talbot U M, Wang H, Paton J C. A new family of potent AB(5) cytotoxins produced by Shiga toxigenic Escherichia coli . J Exp Med. 2004; 200(1) 35-46
30 Paton A W, Beddoe T, Thorpe C M et al. AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP. Nature. 2006; 443(7111) 548-552
31 Hu C C, Dougan S K, Winter S V, Paton A W, Paton J C, Ploegh H L. Subtilase cytotoxin cleaves newly synthesized BiP and blocks antibody secretion in B lymphocytes. J Exp Med. 2009; 206(11) 2429-2440
32 McKee M L, O'Brien A D. Investigation of enterohemorrhagic Escherichia coli O157:H7 adherence characteristics and invasion potential reveals a new attachment pattern shared by intestinal E. coli. Infect Immun. 1995; 63(5) 2070-2074
33 Kaper J B, Nataro J P, Mobley H L. Pathogenic Escherichia coli . Nat Rev Microbiol. 2004; 2(2) 123-140
34 Malyukova I, Murray K F, Zhu C et al. Macropinocytosis in Shiga toxin 1 uptake by human intestinal epithelial cells and transcellular transcytosis. Am J Physiol Gastrointest Liver Physiol. 2009; 296(1) G78-G92
35 Phillips A D, Navabpour S, Hicks S, Dougan G, Wallis T, Frankel G. Enterohaemorrhagic Escherichia coli O157:H7 target Peyer's patches in humans and cause attaching/effacing lesions in both human and bovine intestine. Gut. 2000; 47(3) 377-381
36 Chong Y, Fitzhenry R, Heuschkel R, Torrente F, Frankel G, Phillips A D. Human intestinal tissue tropism in Escherichia coli O157: H7—initial colonization of terminal ileum and Peyer's patches and minimal colonic adhesion ex vivo. Microbiology. 2007; 153(Pt 3) 794-802
37 Nataro J P, Kaper J B. Diarrheagenic Escherichia coli . Clin Microbiol Rev. 1998; 11(1) 142-201
38 Pacheco A R, Sperandio V. Inter-kingdom signaling: chemical language between bacteria and host. Curr Opin Microbiol. 2009; 12(2) 192-198
39 Hughes D T, Clarke M B, Yamamoto K, Rasko D A, Sperandio V. The QseC adrenergic signaling cascade in enterohemorrhagic E. coli (EHEC). PLoS Pathog. 2009; 5(8) e1000553
40 Dytoc M T, Ismaili A, Philpott D J, Soni R, Brunton J L, Sherman P M. Distinct binding properties of eaeA-negative verocytotoxin-producing Escherichia coli of serotype O113:H21. Infect Immun. 1994; 62(8) 3494-3505
41 Vidal M, Prado V, Whitlock G C, Solari A, Torres A G, Vidal R M. Subtractive hybridization and identification of putative adhesins in a Shiga toxin-producing eae-negative Escherichia coli . Microbiology. 2008; 154(Pt 12) 3639-3648
42 Bardiau M, Labrozzo S, Mainil J G. Putative adhesins of enteropathogenic and enterohemorrhagic Escherichia coli of serogroup O26 isolated from humans and cattle. J Clin Microbiol. 2009; 47(7) 2090-2096
43 Mundy R, Jenkins C, Yu J, Smith H, Frankel G. Distribution of espI among clinical enterohaemorrhagic and enteropathogenic Escherichia coli isolates. J Med Microbiol. 2004; 53(Pt 11) 1145-1149
44 Xicohtencatl-Cortes J, Monteiro-Neto V, Saldaña Z, Ledesma M A, Puente J L, Girón J A. The type 4 pili of enterohemorrhagic Escherichia coli O157:H7 are multipurpose structures with pathogenic attributes. J Bacteriol. 2009; 191(1) 411-421
45 Fontaine A, Arondel J, Sansonetti P J. Role of Shiga toxin in the pathogenesis of bacillary dysentery, studied by using a Tox- mutant of Shigella dysenteriae 1. Infect Immun. 1988; 56(12) 3099-3109
46 Schüller S, Heuschkel R, Torrente F, Kaper J B, Phillips A D. Shiga toxin binding in normal and inflamed human intestinal mucosa. Microbes Infect. 2007; 9(1) 35-39
47 Smith W E, Kane A V, Campbell S T, Acheson D W, Cochran B H, Thorpe C M. Shiga toxin 1 triggers a ribotoxic stress response leading to p38 and JNK activation and induction of apoptosis in intestinal epithelial cells. Infect Immun. 2003; 71(3) 1497-1504
48 Schüller S, Frankel G, Phillips A D. Interaction of Shiga toxin from Escherichia coli with human intestinal epithelial cell lines and explants: Stx2 induces epithelial damage in organ culture. Cell Microbiol. 2004; 6(3) 289-301
49 Kashiwamura M, Kurohane K, Tanikawa T, Deguchi A, Miyamoto D, Imai Y. Shiga toxin kills epithelial cells isolated from distal but not proximal part of mouse colon. Biol Pharm Bull. 2009; 32(9) 1614-1617
50 Hurley B P, Jacewicz M, Thorpe C M et al. Shiga toxins 1 and 2 translocate differently across polarized intestinal epithelial cells. Infect Immun. 1999; 67(12) 6670-6677
51 Hurley B P, Thorpe C M, Acheson D W. Shiga toxin translocation across intestinal epithelial cells is enhanced by neutrophil transmigration. Infect Immun. 2001; 69(10) 6148-6155
52 de Sablet T, Chassard C, Bernalier-Donadille A, Vareille M, Gobert A P, Martin C. Human microbiota-secreted factors inhibit shiga toxin synthesis by enterohemorrhagic Escherichia coli O157:H7. Infect Immun. 2009; 77(2) 783-790
53 Bielaszewska M, Friedrich A W, Aldick T, Schürk-Bulgrin R, Karch H. Shiga toxin activatable by intestinal mucus in Escherichia coli isolated from humans: predictor for a severe clinical outcome. Clin Infect Dis. 2006; 43(9) 1160-1167
54 Cherla R P, Lee S Y, Tesh V L. Shiga toxins and apoptosis. FEMS Microbiol Lett. 2003; 228(2) 159-166
55 Byres E, Paton A W, Paton J C et al. Incorporation of a non-human glycan mediates human susceptibility to a bacterial toxin. Nature. 2008; 456(7222) 648-652
56 Löfling J C, Paton A W, Varki N M, Paton J C, Varki A. A dietary non-human sialic acid may facilitate hemolytic-uremic syndrome. Kidney Int. 2009; 76(2) 140-144
57 Thorpe C M, Hurley B P, Lincicome L L, Jacewicz M S, Keusch G T, Acheson D W. Shiga toxins stimulate secretion of interleukin-8 from intestinal epithelial cells. Infect Immun. 1999; 67(11) 5985-5993
58 Thorpe C M, Smith W E, Hurley B P, Acheson D W. Shiga toxins induce, superinduce, and stabilize a variety of C-X-C chemokine mRNAs in intestinal epithelial cells, resulting in increased chemokine expression. Infect Immun. 2001; 69(10) 6140-6147
59 Bellmeyer A, Cotton C, Kanteti R, Koutsouris A, Viswanathan V K, Hecht G. Enterohemorrhagic Escherichia coli suppresses inflammatory response to cytokines and its own toxin. Am J Physiol Gastrointest Liver Physiol. 2009; 297(3) G576-G581
60 van de Kar N C, Monnens L A, Karmali M A, van Hinsbergh V W. 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. 1992; 80(11) 2755-2764
61 Karpman D, Connell H, Svensson M, Scheutz F, Alm P, Svanborg C. The role of lipopolysaccharide and Shiga-like toxin in a mouse model of Escherichia coli O157:H7 infection. J Infect Dis. 1997; 175(3) 611-620
62 Calderon Toledo C, Rogers T J, Svensson M et al. Shiga toxin-mediated disease in MyD88-deficient mice infected with Escherichia coli O157:H7. Am J Pathol. 2008; 173(5) 1428-1439
63 Iimura M, Gallo R L, Hase K, Miyamoto Y, Eckmann L, Kagnoff M F. Cathelicidin mediates innate intestinal defense against colonization with epithelial adherent bacterial pathogens. J Immunol. 2005; 174(8) 4901-4907
64 Ståhl A L, Sartz L, Nelsson A, Békássy Z D, Karpman D. Shiga toxin and lipopolysaccharide induce platelet-leukocyte aggregates and tissue factor release, a thrombotic mechanism in hemolytic uremic syndrome. PLoS One. 2009; 4(9) e6990
65 Ståhl A L, Svensson M, Mörgelin M et al. 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. 2006; 108(1) 167-176
66 Tazzari P L, Ricci F, Carnicelli D et al. Flow cytometry detection of Shiga toxins in the blood from children with hemolytic uremic syndrome. Cytometry B Clin Cytom. 2004; 61(1) 40-44
67 Cooling L L, Walker K E, Gille T, Koerner T A. Shiga toxin binds human platelets via globotriaosylceramide (Pk antigen) and a novel platelet glycosphingolipid. Infect Immun. 1998; 66(9) 4355-4366
68 te Loo D M, Monnens L A, van Der Velden T J et al. Binding and transfer of verocytotoxin by polymorphonuclear leukocytes in hemolytic uremic syndrome. Blood. 2000; 95(11) 3396-3402
69 van Setten P A, Monnens L A, Verstraten R G, van den Heuvel L P, van Hinsbergh V W. Effects of verocytotoxin-1 on nonadherent human monocytes: binding characteristics, protein synthesis, and induction of cytokine release. Blood. 1996; 88(1) 174-183
70 Obrig T G, Moran T P, Colinas R J. Ribonuclease activity associated with the 60S ribosome-inactivating proteins ricin A, phytolaccin and Shiga toxin. Biochem Biophys Res Commun. 1985; 130(2) 879-884
71 Liu J, Akahoshi T, Sasahana T et al. Inhibition of neutrophil apoptosis by verotoxin 2 derived from Escherichia coli O157:H7. Infect Immun. 1999; 67(11) 6203-6205
72 Cohen A, Madrid-Marina V, Estrov Z, Freedman M H, Lingwood C A, Dosch H M. Expression of glycolipid receptors to Shiga-like toxin on human B lymphocytes: a mechanism for the failure of long-lived antibody response to dysenteric disease. Int Immunol. 1990; 2(1) 1-8
73 Brigotti M, Carnicelli D, Ravanelli E et al. Interactions between Shiga toxins and human polymorphonuclear leukocytes. J Leukoc Biol. 2008; 84(4) 1019-1027
74 Lee S Y, Cherla R P, Tesh V L. Simultaneous induction of apoptotic and survival signaling pathways in macrophage-like THP-1 cells by Shiga toxin 1. Infect Immun. 2007; 75(3) 1291-1302
75 Walters M D, Matthei I U, Kay R, Dillon M J, Barratt T M. The polymorphonuclear leucocyte count in childhood haemolytic uraemic syndrome. Pediatr Nephrol. 1989; 3(2) 130-134
76 Fitzpatrick M M, Shah V, Filler G, Dillon M J, Barratt T M. Neutrophil activation in the haemolytic uraemic syndrome: free and complexed elastase in plasma. Pediatr Nephrol. 1992; 6(1) 50-53
77 Fernandez G C, Gomez S A, Ramos M V et al. The functional state of neutrophils correlates with the severity of renal dysfunction in children with hemolytic uremic syndrome. Pediatr Res. 2007; 61(1) 123-128
78 Fernandez G C, Lopez M F, Gomez S A et al. Relevance of neutrophils in the murine model of haemolytic uraemic syndrome: mechanisms involved in Shiga toxin type 2-induced neutrophilia. Clin Exp Immunol. 2006; 146(1) 76-84
79 Szabady R L, Lokuta M A, Walters K B, Huttenlocher A, Welch R A. Modulation of neutrophil function by a secreted mucinase of Escherichia coli O157:H7. PLoS Pathog. 2009; 5(2) e1000320
80 Inward C D, Howie A J, Fitzpatrick M M, Rafaat F, Milford D V, Taylor C M. British Association for Paediatric Nephrology . Renal histopathology in fatal cases of diarrhoea-associated haemolytic uraemic syndrome. Pediatr Nephrol. 1997; 11(5) 556-559
81 Exeni R A, Fernandez G C, Palermo M S. Role of polymorphonuclear leukocytes in the pathophysiology of typical hemolytic uremic syndrome. Scient World J. 2007; 7 1155-1164
82 Geelen J M, van der Velden T J, van den Heuvel L P, Monnens L A. Interactions of Shiga-like toxin with human peripheral blood monocytes. Pediatr Nephrol. 2007; 22(8) 1181-1187
83 Sakiri R, Ramegowda B, Tesh V L. 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. 1998; 92(2) 558-566
84 Guessous F, Marcinkiewicz M, Polanowska-Grabowska R, Keepers T R, Obrig T, Gear A R. Shiga toxin 2 and lipopolysaccharide cause monocytic THP-1 cells to release factors which activate platelet function. Thromb Haemost. 2005; 94(5) 1019-1027
85 Murata K, Higuchi T, Takada K, Oida K, Horie S, Ishii H. 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. 2006; 1762(9) 835-843
86 Karpman D, Manea M, Vaziri-Sani F, Ståhl A L, Kristoffersson A C. Platelet activation in hemolytic uremic syndrome. Semin Thromb Hemost. 2006; 32(2) 128-145
87 Karpman D, Papadopoulou D, Nilsson K, Sjögren A C, Mikaelsson C, Lethagen S. Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome. Blood. 2001; 97(10) 3100-3108
88 Ghosh S A, Polanowska-Grabowska R K, Fujii J, Obrig T, Gear A R. Shiga toxin binds to activated platelets. J Thromb Haemost. 2004; 2(3) 499-506
89 Keepers T R, Psotka M A, Gross L K, Obrig T G. A murine model of HUS: Shiga toxin with lipopolysaccharide mimics the renal damage and physiologic response of human disease. J Am Soc Nephrol. 2006; 17(12) 3404-3414
90 Kamitsuji H, Nonami K, Murakami T, Ishikawa N, Nakayama A, Umeki Y. Elevated tissue factor circulating levels in children with hemolytic uremic syndrome caused by verotoxin-producing E. coli . Clin Nephrol. 2000; 53(5) 319-324
91 Ishii H, Takada K, Higuchi T, Sugiyama J. Verotoxin-1 induces tissue factor expression in human umbilical vein endothelial cells through activation of NF-kappaB/Rel and AP-1. Thromb Haemost. 2000; 84(4) 712-721
92 Nestoridi E, Tsukurov O, Kushak R I, Ingelfinger J R, Grabowski E F. Shiga toxin enhances functional tissue factor on human glomerular endothelial cells: implications for the pathophysiology of hemolytic uremic syndrome. J Thromb Haemost. 2005; 3(4) 752-762
93 Nestoridi E, Kushak R I, Tsukurov O, Grabowski E F, Ingelfinger J R. Role of the renin angiotensin system in TNF-alpha and Shiga-toxin-induced tissue factor expression. Pediatr Nephrol. 2008; 23(2) 221-231
94 Sugatani J, Igarashi T, Munakata M et al. Activation of coagulation in C57BL/6 mice given verotoxin 2 (VT2) and the effect of co-administration of LPS with VT2. Thromb Res. 2000; 100(1) 61-72
95 Raife T, Friedman K D, Fenwick B. Lepirudin prevents lethal effects of Shiga toxin in a canine model. Thromb Haemost. 2004; 92(2) 387-393
96 Taylor Jr F B, Tesh V L, DeBault L et al. Characterization of the baboon responses to Shiga-like toxin: descriptive study of a new primate model of toxic responses to Stx-1. Am J Pathol. 1999; 154(4) 1285-1299
97 Túri S, Németh I, Vargha I, Matkovics B. Oxidative damage of red blood cells in haemolytic uraemic syndrome. Pediatr Nephrol. 1994; 8(1) 26-29
98 Bitzan M, Bickford B B, Foster G H. Verotoxin (shiga toxin) sensitizes renal epithelial cells to increased heme toxicity: possible implications for the hemolytic uremic syndrome. J Am Soc Nephrol. 2004; 15(9) 2334-2343
99 Gallo E G, Gianantonio C A. Extrarenal involvement in diarrhoea-associated haemolytic-uraemic syndrome. Pediatr Nephrol. 1995; 9(1) 117-119
100 Hughes A K, Ergonul Z, Stricklett P K, Kohan D E, Ergonal Z. Molecular basis for high renal cell sensitivity to the cytotoxic effects of shigatoxin-1: upregulation of globotriaosylceramide expression. J Am Soc Nephrol. 2002; 13(9) 2239-2245
101 Okuda T, Tokuda N, Numata S et al. Targeted disruption of Gb3/CD77 synthase gene resulted in the complete deletion of globo-series glycosphingolipids and loss of sensitivity to verotoxins. J Biol Chem. 2006; 281(15) 10230-10235
102 Ergonul Z, Clayton F, Fogo A B, Kohan D E. Shigatoxin-1 binding and receptor expression in human kidneys do not change with age. Pediatr Nephrol. 2003; 18(3) 246-253
103 Karpman D, Håkansson A, Perez M T et al. Apoptosis of renal cortical cells in the hemolytic-uremic syndrome: in vivo and in vitro studies. Infect Immun. 1998; 66(2) 636-644
104 Kaneko K, Kiyokawa N, Ohtomo Y et al. Apoptosis of renal tubular cells in Shiga-toxin-mediated hemolytic uremic syndrome. Nephron. 2001; 87(2) 182-185
105 van Setten P A, van Hinsbergh V W, van der Velden T J et al. Effects of TNF alpha on verocytotoxin cytotoxicity in purified human glomerular microvascular endothelial cells. Kidney Int. 1997; 51(4) 1245-1256
106 Pijpers A H, van Setten P A, van den Heuvel L P et al. Verocytotoxin-induced apoptosis of human microvascular endothelial cells. J Am Soc Nephrol. 2001; 12(4) 767-778
107 Williams J M, Boyd B, Nutikka A et al. A comparison of the effects of verocytotoxin-1 on primary human renal cell cultures. Toxicol Lett. 1999; 105(1) 47-57
108 Hughes A K, Stricklett P K, Schmid D, Kohan D E. Cytotoxic effect of Shiga toxin-1 on human glomerular epithelial cells. Kidney Int. 2000; 57(6) 2350-2359
109 Hughes A K, Stricklett P K, Kohan D E. Shiga toxin-1 regulation of cytokine production by human glomerular epithelial cells. Nephron. 2001; 88(1) 14-23
110 Lee J E, Kim J S, Choi I H, Tagawa M, Kohsaka T, Jin D K. Cytokine expression in the renal tubular epithelial cells stimulated by Shiga toxin 2 of Escherichia coli O157:H7. Ren Fail. 2002; 24(5) 567-575
111 Zanchi C, Zoja C, Morigi M et al. Fractalkine and CX3CR1 mediate leukocyte capture by endothelium in response to Shiga toxin. J Immunol. 2008; 181(2) 1460-1469
112 Ramos M V, Fernández G C, Patey N et al. Involvement of the fractalkine pathway in the pathogenesis of childhood hemolytic uremic syndrome. Blood. 2007; 109(6) 2438-2445
113 Trachtman H, Christen E, Cnaan A Investigators of the HUS-SYNSORB Pk Multicenter Clinical Trial et al. Urinary neutrophil gelatinase-associated lipocalcin in D+ HUS: a novel marker of renal injury. Pediatr Nephrol. 2006; 21(7) 989-994
114 Ake J A, Jelacic S, Ciol M A et al. Relative nephroprotection during Escherichia coli O157:H7 infections: association with intravenous volume expansion. Pediatrics. 2005; 115(6) e673-e680
115 Wadolkowski E A, Sung L M, Burris J A, Samuel J E, O'Brien A D. Acute renal tubular necrosis and death of mice orally infected with Escherichia coli strains that produce Shiga-like toxin type II. Infect Immun. 1990; 58(12) 3959-3965
116 Zotta E, Lago N, Ochoa F, Repetto H A, Ibarra C. Development of an experimental hemolytic uremic syndrome in rats. Pediatr Nephrol. 2008; 23(4) 559-567
117 Silberstein C, Pistone Creydt V, Gerhardt E, Núñez P, Ibarra C. Inhibition of water absorption in human proximal tubular epithelial cells in response to Shiga toxin-2. Pediatr Nephrol. 2008; 23(11) 1981-1990
118 Sugatani J, Komiyama N, Mochizuki T et al. Urinary concentrating defect in rats given Shiga toxin: elevation in urinary AQP2 level associated with polyuria. Life Sci. 2002; 71(2) 171-189
119 Psotka M A, Obata F, Kolling G L et al. Shiga toxin 2 targets the murine renal collecting duct epithelium. Infect Immun. 2009; 77(3) 959-969
120 Nestoridi E, Kushak R I, Duguerre D, Grabowski E F, Ingelfinger J R. Up-regulation of tissue factor activity on human proximal tubular epithelial cells in response to Shiga toxin. Kidney Int. 2005; 67(6) 2254-2266
121 Morigi M, Buelli S, Zanchi C et al. Shigatoxin-induced endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling. Am J Pathol. 2006; 169(6) 1965-1975
122 Bitzan M M, Wang Y, Lin J, Marsden P A. 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. 1998; 101(2) 372-382
123 Shigematsu H, Dikman S H, Churg J, Grishman E, Duffy J L. Mesangial involvement in hemolytic-uremic syndrome. A light and electron microscopic study. Am J Pathol. 1976; 85(2) 349-362
124 Warnier M, Römer W, Geelen J et al. Trafficking of Shiga toxin/Shiga-like toxin-1 in human glomerular microvascular endothelial cells and human mesangial cells. Kidney Int. 2006; 70(12) 2085-2091
125 Simon M, Cleary T G, Hernandez J D, Abboud H E. Shiga toxin 1 elicits diverse biologic responses in mesangial cells. Kidney Int. 1998; 54(4) 1117-1127
126 Te Loo D M, Monnens L, van der Velden T, Karmali M, van den Heuvel L, van Hinsbergh V. Shiga toxin-1 affects nitric oxide production by human glomerular endothelial and mesangial cells. Pediatr Nephrol. 2006; 21(12) 1815-1823
127 Van Setten P A, van Hinsbergh V W, Van den Heuvel L P et al. 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. 1997; 8(12) 1877-1888
128 Obata F, Tohyama K, Bonev A D et al. Shiga toxin 2 affects the central nervous system through receptor globotriaosylceramide localized to neurons. J Infect Dis. 2008; 198(9) 1398-1406
129 Fujii J, Wood K, Matsuda F et al. Shiga toxin 2 causes apoptosis in human brain microvascular endothelial cells via C/EBP homologous protein. Infect Immun. 2008; 76(8) 3679-3689
130 Ergonul Z, Hughes A K, Kohan D E. Induction of apoptosis of human brain microvascular endothelial cells by Shiga toxin 1. J Infect Dis. 2003; 187(1) 154-158
131 Stricklett P K, Hughes A K, Ergonul Z, Kohan D E. Molecular basis for up-regulation by inflammatory cytokines of Shiga toxin 1 cytotoxicity and globotriaosylceramide expression. J Infect Dis. 2002; 186(7) 976-982
132 Goldstein J, Loidl C F, Creydt V P, Boccoli J, Ibarra C. Intracerebroventricular administration of Shiga toxin type 2 induces striatal neuronal death and glial alterations: an ultrastructural study. Brain Res. 2007; 1161 106-115
133 Boccoli J, Loidl C F, Lopez-Costa J J, Creydt V P, Ibarra C, Goldstein J. Intracerebroventricular administration of Shiga toxin type 2 altered the expression levels of neuronal nitric oxide synthase and glial fibrillary acidic protein in rat brains. Brain Res. 2008; 1230 320-333
134 Eisenhauer P B, Jacewicz M S, Conn K J et al. Escherichia coli Shiga toxin 1 and TNF-alpha induce cytokine release by human cerebral microvascular endothelial cells. Microb Pathog. 2004; 36(4) 189-196
135 Manuelian T, Hellwage J, Meri S et al. Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J Clin Invest. 2003; 111(8) 1181-1190
136 Ståhl A L, Vaziri-Sani F, Heinen S et al. Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation. Blood. 2008; 111(11) 5307-5315
137 Thurman J M, Marians R, Emlen W et al. Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2009; 4(12) 1920-1924
138 Orth D, Khan A B, Naim A et al. Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome. J Immunol. 2009; 182(10) 6394-6400
139 Hughes D T, Sperandio V. Inter-kingdom signalling: communication between bacteria and their hosts. Nat Rev Microbiol. 2008; 6(2) 111-120
140 Chandler W L, Jelacic S, Boster D R et al. Prothrombotic coagulation abnormalities preceding the hemolytic-uremic syndrome. N Engl J Med. 2002; 346(1) 23-32
141 Manea M, Kristoffersson A, Schneppenheim R et al. Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura. Br J Haematol. 2007; 138(5) 651-662

Diana KarpmanM.D. Ph.D.

Department of Pediatrics, Clinical Sciences Lund

Lund University, Lund, Sweden

Email: diana.karpman@med.lu.se