Shiga Toxin Pathogenesis: Kidney Complications and Renal Failure

Obrig, Tom G.; Karpman, Diana

doi:10.1007/82_2011_172

Cited by 51 publications

(51 citation statements)

References 241 publications

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“…With regard to the intracellular response, apoptosis in microvascular endothelial cells from human renal glomeruli caused by Stx has been documented [48] and induction of apoptosis by SubAB has also been reported for a variety of cell types, including Vero and HeLa cells [30,36]. To analyze these mechanisms, we studied necrosis and apoptosis of HGEC exposed to Stx2 and SubAB.…”

Section: Discussionmentioning

confidence: 99%

“…Also relevant may be the potential role of erythrocytes in the development of the microvascular lesion of HUS. It is assumed that the presence of fragmented erythrocytes during HUS is consequence of mechanical fragmentation of these cells while passing through partially occluded capillaries [48]. One study also reported that erythrocyte membranes were affected by oxidative damage during HUS [50], leading to eryptosis [51].…”

Section: Discussionmentioning

confidence: 99%

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Action of Shiga Toxin Type-2 and Subtilase Cytotoxin on Human Microvascular Endothelial Cells

et al. 2013

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The hemolytic uremic syndrome (HUS) associated with diarrhea is a complication of Shiga toxin (Stx)-producing Escherichia coli (STEC) infection. In Argentina, HUS is endemic and responsible for acute and chronic renal failure in children younger than 5 years old. The human kidney is the most affected organ due to the presence of very Stx-sensitive cells, such as microvascular endothelial cells. Recently, Subtilase cytotoxin (SubAB) was proposed as a new toxin that may contribute to HUS pathogenesis, although its action on human glomerular endothelial cells (HGEC) has not been described yet. In this study, we compared the effects of SubAB with those caused by Stx2 on primary cultures of HGEC isolated from fragments of human pediatric renal cortex. HGEC were characterized as endothelial since they expressed von Willebrand factor (VWF) and platelet/endothelial cell adhesion molecule 1 (PECAM-1). HGEC also expressed the globotriaosylceramide (Gb3) receptor for Stx2. Both, Stx2 and SubAB induced swelling and detachment of HGEC and the consequent decrease in cell viability in a time-dependent manner. Preincubation of HGEC with C-9 −a competitive inhibitor of Gb3 synthesis-protected HGEC from Stx2 but not from SubAB cytotoxic effects. Stx2 increased apoptosis in a time-dependent manner while SubAB increased apoptosis at 4 and 6 h but decreased at 24 h. The apoptosis induced by SubAB relative to Stx2 was higher at 4 and 6 h, but lower at 24 h. Furthermore, necrosis caused by Stx2 was significantly higher than that induced by SubAB at all the time points evaluated. Our data provide evidence for the first time how SubAB could cooperate with the development of endothelial damage characteristic of HUS pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Action of Shiga Toxin Type-2 and Subtilase Cytotoxin on Human Microvascular Endothelial Cells

et al. 2013

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“…Infections by Stx-producing organisms can result in the onset of a disease termed the hemolytic-uremic syndrome (HUS) that is characterized by renal failure, hemolytic anemia, and thrombocytopenia. Shiga toxins are considered the key STEC virulence factor required for the onset of HUS with Stx2 being the toxin most often associated with severe disease (2)(3)(4). In the United States, HUS is the most common cause of acute renal failure in children under 5 years of age (5)(6)(7).…”

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confidence: 99%

“…While renal failure is a key feature of HUS and renal samples from patients with HUS show extensive damage (2), the temporal pattern of Stx-mediated renal damage has not been determined, and it remains unclear which renal cells are the primary targets during disease. This is largely due to an inability to monitor renal damage on a molecular and cellular level during the course of disease in human patients and to access patients during the early stages of disease progression.…”

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confidence: 99%

Effects of Shiga Toxin Type 2 on a Bioengineered Three-Dimensional Model of Human Renal Tissue

et al. 2015

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dShiga toxins (Stx) are a family of cytotoxic proteins that can cause hemolytic-uremic syndrome (HUS), a thrombotic microangiopathy, following infections by Shiga toxin-producing Escherichia coli (STEC). Renal failure is a key feature of HUS and a major cause of childhood renal failure worldwide. There are currently no specific therapies for STEC-associated HUS, and the mechanism of Stx-induced renal injury is not well understood primarily due to a lack of fully representative animal models and an inability to monitor disease progression on a molecular or cellular level in humans at early stages. Three-dimensional (3D) tissue models have been shown to be more in vivo-like in their phenotype and physiology than 2D cultures for numerous disease models, including cancer and polycystic kidney disease. It is unknown whether exposure of a 3D renal tissue model to Stx will yield a more in vivo-like response than 2D cell culture. In this study, we characterized Stx2-mediated cytotoxicity in a bioengineered 3D human renal tissue model previously shown to be a predictor of drug-induced nephrotoxicity and compared its response to Stx2 exposure in 2D cell culture. Our results demonstrate that although many mechanistic aspects of cytotoxicity were similar between 3D and 2D, treatment of the 3D tissues with Stx resulted in an elevated secretion of the kidney injury marker 1 (Kim-1) and the cytokine interleukin-8 compared to the 2D cell cultures. This study represents the first application of 3D tissues for the study of Stx-mediated kidney injury.

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“…After oral ingestion and intestinal infection, STEC elaborate Stx1 and/or Stx2, and these toxins then induce systemic proinflammatory and prothrombotic pathways [4]. Approximately 15% of cases are thought to progress from STEC gastroenteritis to HUS.…”

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confidence: 99%

Intermediate Follow-up of Pediatric Patients With Hemolytic Uremic Syndrome During the 2011 Outbreak Caused by E. coli O104:H4

Loos

Aulbert

Höppe

et al. 2017

Clinical Infectious Diseases

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Background. In 2011 Escherichia coli O104:H4 caused an outbreak with >800 cases of hemolytic uremic syndrome (HUS) in Germany, including 90 children. Data on the intermediate outcome in children after HUS due to E. coli O104:H4 have been lacking.Methods. Follow-up data were gathered retrospectively from the medical records of patients who had been included in the German Pediatric HUS Registry during the 2011 outbreak.Results. Seventy-two of the 89 (81%) patients were included after a median follow-up of 3.0 (0.9-4.7) years. Hypertension and proteinuria were present in 19% and 28% of these patients, respectively. Of 4 patients with chronic kidney disease (CKD) > stage 2 at short-term follow-up, 1 had a normalized estimated glomerular filtration rate, and 3 (4%) had persistent CKD > stage 2. In 1 of these patients, CKD improved from stage 4 to 3; 1 who had CKD stage 5 at presentation received kidney transplantation; and 1 patient required further hemodialysis during follow-up. One patient (1.4%) still had major neurological symptoms at the latest follow-up. Dialysis during the acute phase (P = .01), dialysis duration (P = .01), and the duration of oligo-/anuria (P = .005) were associated with the development of renal sequelae. Patients treated with eculizumab (n = 11) and/or plasmapheresis (n = 13) during the acute phase of HUS had comparable outcomes.Conclusions. The overall outcome of pediatric patients after HUS due to E. coli O104:H4 was equivalent to previous reports on HUS due to other types of Shiga toxin-producing E. coli (STEC). Regular follow-up visits in patients are recommended after STEC-HUS.

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Shiga Toxin Pathogenesis: Kidney Complications and Renal Failure

Cited by 51 publications

References 241 publications

Action of Shiga Toxin Type-2 and Subtilase Cytotoxin on Human Microvascular Endothelial Cells

Action of Shiga Toxin Type-2 and Subtilase Cytotoxin on Human Microvascular Endothelial Cells

Effects of Shiga Toxin Type 2 on a Bioengineered Three-Dimensional Model of Human Renal Tissue

Intermediate Follow-up of Pediatric Patients With Hemolytic Uremic Syndrome During the 2011 Outbreak Caused by E. coli O104:H4

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