Shiga toxin-induced tubular injury in hemolytic uremic syndrome
Authors: Bernard S. Kaplan
Journal: Kidney International (1998)

To conform with a proposed new terminology for the shiga-like toxin (Stx) family [1.Calderwood S.B. Acheson D.W.K. Keusch G.T. Barrett T.J. Griffen P.M. Strockbine N.A. Swaminathan B. Kaper J.B. Levine M.M. Kaplan B.S. Karch H. O'brien A.D. Obrig T.G. Takeda Y. Tarr P.L. Wachsmuth I.K. Proposed new nomenclature for SLT (VT) family.Am Soc Microbiol News. 1996; 62: 118-119Google Scholar], we use the term Shiga toxin-associated hemolytic uremic syndrome (Stx HUS) for cases caused by Stx-producing bacteria [2.Kaplan BS, Meyers KW, Schulman SL: Pathogenesis and treatment of hemolytic uremic syndrome. J Am Society Nephrol (in press).Google Scholar]; however, diarrhea-associated HUS (D+ HUS) and Stx HUS are still used interchangeably. Stx HUS is a well-defined clinico-pathologic entity in which acute renal injury is usually the major component. Stx HUS is a complication of Stx-producing E. coli, usually but not always, serotype 0157:H7 and Shigella dysenteriae type 1. Patients with Stx HUS may have normal urine output. More often they may be anuric or oliguric and some may have non-oliguric renal failure [3.Schulman S.L. Kaplan B.S. Management of patients with HUS demonstrating severe azotemia but not anuria.Pediatr Nephrol. 1996; 10: 671-674Crossref PubMed Scopus (21) Google Scholar]. There is abundant clinical, pathophysiologic and histopathologic evidence for glomerular endothelial cell injury in Stx HUS. Renal tubular injury has been considered to be secondary to glomerular and arteriolar injury in Stx HUS. However, evidence for direct renal tubular cell damage in Stx HUS is increasing [4.Takeda T. Dohi S. Igarashi T. Yoshiya K. Kobayashi N. Impairment by verotoxin of tubular function contributes to the renal damage seen in haemolytic uraemic syndrome.J Infect. 1993; 27: 339-341Abstract Full Text PDF PubMed Scopus (37) Google Scholar, 5.Shibolet O. Shina A. Rosen S. Cleary T.G. Brezis M. Ashkenazi S. Shiga toxin induces medullary tubular injury in isolated perfused rat kidneys.FEMS Immunol Med Microbiol. 1997; 18: 55-60Crossref Google Scholar, 6.Karpman D. Håkansson A. Perez M-TR Isaksson C. Carlemalm E. Caprioli A. Svanborg C. Apoptosis of renal cortical cells in the hemolytic-uremic syndrome: In vivo and in vitro studies.Infect Immun. 1998; 66: 636-644Crossref PubMed Google Scholar, 7.Taguchi T, Uchida H, Nobutaka K, Mori T, Horie H, Takeda T, Fujimoto J: Verotoxins induce apoptosis in human renal tubular epithelial cells Kidney Int (in press).Google Scholar]. In HUS caused by Shigella dysenteriae type I, there are glomerular injury and fibrin thrombi. However, in 1978 Raghupathy et al noted that there were also histopathologic changes of acute tubular necrosis manifested by tubular epithelial shedding, casts, interstitial edema, interstitial inflammation at the cortico-medullary junction and mononuclear cells in the vasa rectae [8.Raghupathy P. Date A. Shastry J.C.M. Sudarsanam A. Jadhav M. Haemolytic-uraemic syndrome complicating shigella dysentery in south Indian children.Brit Med J. 1978; 1: 1518-1521Crossref PubMed Scopus (64) Google Scholar]. It is of historical interest that the title of what may have been the first reported case of HUS, in 1954, was Acute Tubular Necrosis with Anaemia [9.Wagner J. Acute tubular necrosis with anaemia.Great Ormond Str J. 1954; 7: 66-72Google Scholar]. The four-year-old patient presented with vomiting and watery diarrhea with blood and mucus complicated by acute hemolytic anemia, thrombocytopenia, acute renal failure and seizures [9.Wagner J. Acute tubular necrosis with anaemia.Great Ormond Str J. 1954; 7: 66-72Google Scholar]. Evidence for primary renal tubular cell damage in Stx HUS has been derived mainly from in vitro and in vivo studies in animals [4.Takeda T. Dohi S. Igarashi T. Yoshiya K. Kobayashi N. Impairment by verotoxin of tubular function contributes to the renal damage seen in haemolytic uraemic syndrome.J Infect. 1993; 27: 339-341Abstract Full Text PDF PubMed Scopus (37) Google Scholar, 5.Shibolet O. Shina A. Rosen S. Cleary T.G. Brezis M. Ashkenazi S. Shiga toxin induces medullary tubular injury in isolated perfused rat kidneys.FEMS Immunol Med Microbiol. 1997; 18: 55-60Crossref Google Scholar, 6.Karpman D. Håkansson A. Perez M-TR Isaksson C. Carlemalm E. Caprioli A. Svanborg C. Apoptosis of renal cortical cells in the hemolytic-uremic syndrome: In vivo and in vitro studies.Infect Immun. 1998; 66: 636-644Crossref PubMed Google Scholar, 7.Taguchi T, Uchida H, Nobutaka K, Mori T, Horie H, Takeda T, Fujimoto J: Verotoxins induce apoptosis in human renal tubular epithelial cells Kidney Int (in press).Google Scholar]. Takeda et al showed that human adenocarcinoma cells of renal tubular origin were highly sensitive to Stx1 and Stx2 [4.Takeda T. Dohi S. Igarashi T. Yoshiya K. Kobayashi N. Impairment by verotoxin of tubular function contributes to the renal damage seen in haemolytic uraemic syndrome.J Infect. 1993; 27: 339-341Abstract Full Text PDF PubMed Scopus (37) Google Scholar]. They also found significantly increased urine concentrations of N-acetyl glucosaminidase and β2 microglobulin in patients with Stx HUS [4.Takeda T. Dohi S. Igarashi T. Yoshiya K. Kobayashi N. Impairment by verotoxin of tubular function contributes to the renal damage seen in haemolytic uraemic syndrome.J Infect. 1993; 27: 339-341Abstract Full Text PDF PubMed Scopus (37) Google Scholar]. This pointed to renal tubular injury but did not provide convincing evidence for a direct effect of Stx on the tubules. Induction of medullary renal tubular injury by Stx in an isolated perfused rat kidney model was more compelling evidence for a direct effect of Stx on the renal tubule [5.Shibolet O. Shina A. Rosen S. Cleary T.G. Brezis M. Ashkenazi S. Shiga toxin induces medullary tubular injury in isolated perfused rat kidneys.FEMS Immunol Med Microbiol. 1997; 18: 55-60Crossref Google Scholar]. Hughes et al have studied the effects of Stx1 on human proximal tubule cells in vitro and have provided additional compelling evidence to support the hypothesis that Stx directly injures these cells [10.Hughes A.K. Stricklett P.K. Kohan D.E. Cytotoxic effect of Shiga toxin-1 on human proximal tubule cells.Kidney Int. 1998; 54: 426-437Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar]. Their findings complement those of others [4.Takeda T. Dohi S. Igarashi T. Yoshiya K. Kobayashi N. Impairment by verotoxin of tubular function contributes to the renal damage seen in haemolytic uraemic syndrome.J Infect. 1993; 27: 339-341Abstract Full Text PDF PubMed Scopus (37) Google Scholar, 5.Shibolet O. Shina A. Rosen S. Cleary T.G. Brezis M. Ashkenazi S. Shiga toxin induces medullary tubular injury in isolated perfused rat kidneys.FEMS Immunol Med Microbiol. 1997; 18: 55-60Crossref Google Scholar, 6.Karpman D. Håkansson A. Perez M-TR Isaksson C. Carlemalm E. Caprioli A. Svanborg C. Apoptosis of renal cortical cells in the hemolytic-uremic syndrome: In vivo and in vitro studies.Infect Immun. 1998; 66: 636-644Crossref PubMed Google Scholar, 7.Taguchi T, Uchida H, Nobutaka K, Mori T, Horie H, Takeda T, Fujimoto J: Verotoxins induce apoptosis in human renal tubular epithelial cells Kidney Int (in press).Google Scholar]. Human renal tubular cells undergo apoptosis in vivo following D+ HUS and in an in vivo mouse model of E. coli-associated HUS [6.Karpman D. Håkansson A. Perez M-TR Isaksson C. Carlemalm E. Caprioli A. Svanborg C. Apoptosis of renal cortical cells in the hemolytic-uremic syndrome: In vivo and in vitro studies.Infect Immun. 1998; 66: 636-644Crossref PubMed Google Scholar]. Apoptosis was also shown in human adenocarcinoma-derived renal tubular epithelial cells [7.Taguchi T, Uchida H, Nobutaka K, Mori T, Horie H, Takeda T, Fujimoto J: Verotoxins induce apoptosis in human renal tubular epithelial cells Kidney Int (in press).Google Scholar]. In these models the effect of Stx is enhanced by tumor necrosis factor-α (TNF-α) [6.Karpman D. Håkansson A. Perez M-TR Isaksson C. Carlemalm E. Caprioli A. Svanborg C. Apoptosis of renal cortical cells in the hemolytic-uremic syndrome: In vivo and in vitro studies.Infect Immun. 1998; 66: 636-644Crossref PubMed Google Scholar7.Taguchi T, Uchida H, Nobutaka K, Mori T, Horie H, Takeda T, Fujimoto J: Verotoxins induce apoptosis in human renal tubular epithelial cells Kidney Int (in press).Google Scholar]. Hughes et al have found that Stx1 binds to receptors and injures the proximal renal tubular cells [10.Hughes A.K. Stricklett P.K. Kohan D.E. Cytotoxic effect of Shiga toxin-1 on human proximal tubule cells.Kidney Int. 1998; 54: 426-437Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar]. Incubation with interleukin-1 (IL-1) enhanced the cytotoxic effect of Stx1 and lipopolysaccharide increased cell sensitivity to Stx without altering Stx binding. Neither IL-6 nor TNF-α had any effects. A similar cascade of effects has been found in human renal endothelial cells. Learning how Stx is able to pass through the glomerular capillary wall in order to reach the tubular epithelial cells will add considerably to understanding the biology of Stx-induced renal injury. These findings suggest that the oligo-anuria that occurs in many of these patients, and the non-oliguric renal failure that occur in some [3.Schulman S.L. Kaplan B.S. Management of patients with HUS demonstrating severe azotemia but not anuria.Pediatr Nephrol. 1996; 10: 671-674Crossref PubMed Scopus (21) Google Scholar] may not be the result of glomerular and vascular injury alone. These observations may help to differentiate Stx HUS more precisely from other types of HUS such as malignancy-associated HUS, inherited HUS, and atypical D- HUS, and from thrombotic thrombocytopenic purpura. Taken together, these studies add considerably to our understanding of the pathogenesis of acute renal injury in Stx HUS. These findings do not, as yet, change the treatment or prognosis of this entity.