scholarly journals Shiga Toxin Pathogenesis: Kidney Complications and Renal Failure

2011 ◽  
pp. 105-136 ◽  
Author(s):  
Tom G. Obrig ◽  
Diana Karpman
Keyword(s):  
Renal Failure ◽  
Shiga Toxin

scholarly journals HUS and the case for complement

Blood ◽  
2015 ◽  
Vol 126 (18) ◽  
pp. 2085-2090 ◽  
Author(s):  
Edward M. Conway
Keyword(s):  
Escherichia Coli ◽  
Renal Failure ◽  
Shiga Toxin ◽  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Response To Treatment ◽  
Microangiopathic Hemolytic Anemia ◽  
New Knowledge ◽  
Uremic Syndrome

Abstract Hemolytic-uremic syndrome (HUS) is a thrombotic microangiopathy that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Excess complement activation underlies atypical HUS and is evident in Shiga toxin–induced HUS (STEC-HUS). This Spotlight focuses on new knowledge of the role of Escherichia coli–derived toxins and polyphosphate in modulating complement and coagulation, and how they affect disease progression and response to treatment. Such new insights may impact on current and future choices of therapies for STEC-HUS.

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

2014 ◽  
Vol 83 (1) ◽  
pp. 28-38 ◽  
Author(s):  
Teresa M. DesRochers ◽  
Erica Palma Kimmerling ◽  
Dakshina M. Jandhyala ◽  
Wassim El-Jouni ◽  
Jing Zhou ◽  
...  
Keyword(s):  
Cell Culture ◽  
Renal Failure ◽  
Shiga Toxin ◽  
Three Dimensional ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Three Dimensional Model ◽  
Drug Induced ◽  
Tissue Model

Shiga toxins (Stx) are a family of cytotoxic proteins that can cause hemolytic-uremic syndrome (HUS), a thrombotic microangiopathy, following infections by Shiga toxin-producingEscherichia 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 morein 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 morein 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.

scholarly journals Shiga Toxin 2 Targets the Murine Renal Collecting Duct Epithelium

2009 ◽  
Vol 77 (3) ◽  
pp. 959-969 ◽  
Author(s):  
Mitchell A. Psotka ◽  
Fumiko Obata ◽  
Glynis L. Kolling ◽  
Lisa K. Gross ◽  
Moin A. Saleem ◽  
...  
Keyword(s):  
Renal Failure ◽  
Shiga Toxin ◽  
Cell Damage ◽  
Collecting Duct ◽  
Signs And Symptoms ◽  
Filtration Barrier ◽  
Shiga Toxin 2 ◽  
Collecting Duct Epithelium

ABSTRACT Hemolytic-uremic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli infection is a leading cause of pediatric acute renal failure. Bacterial toxins produced in the gut enter the circulation and cause a systemic toxemia and targeted cell damage. It had been previously shown that injection of Shiga toxin 2 (Stx2) and lipopolysaccharide (LPS) caused signs and symptoms of HUS in mice, but the mechanism leading to renal failure remained uncharacterized. The current study elucidated that murine cells of the glomerular filtration barrier were unresponsive to Stx2 because they lacked the receptor glycosphingolipid globotriaosylceramide (Gb3) in vitro and in vivo. In contrast to the analogous human cells, Stx2 did not alter inflammatory kinase activity, cytokine release, or cell viability of the murine glomerular cells. However, murine renal cortical and medullary tubular cells expressed Gb3 and responded to Stx2 by undergoing apoptosis. Stx2-induced loss of functioning collecting ducts in vivo caused production of increased dilute urine, resulted in dehydration, and contributed to renal failure. Stx2-mediated renal dysfunction was ameliorated by administration of the nonselective caspase inhibitor Q-VD-OPH in vivo. Stx2 therefore targets the murine collecting duct, and this Stx2-induced injury can be blocked by inhibitors of apoptosis in vivo.

scholarly journals Rescue from lethal Shiga toxin 2-induced renal failure with a cell-permeable peptide

2011 ◽  
Vol 26 (11) ◽  
pp. 2031-2039 ◽  
Author(s):  
Deborah J. Stearns-Kurosawa ◽  
Valta Collins ◽  
Scott Freeman ◽  
Diann Debord ◽  
Kiyotaka Nishikawa ◽  
...  
Keyword(s):  
Renal Failure ◽  
Shiga Toxin ◽  
Shiga Toxin 2 ◽  
Cell Permeable Peptide ◽  
A Cell

scholarly journals Paediatric haemolytic uraemic syndrome related to Shiga toxin-producing Escherichia coli, an overview of 10 years of surveillance in France, 2007 to 2016

2019 ◽  
Vol 24 (8) ◽  
Author(s):  
Mathias Bruyand ◽  
Patricia Mariani-Kurkdjian ◽  
Simon Le Hello ◽  
Lisa-A King ◽  
Dieter Van Cauteren ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Renal Failure ◽  
Shiga Toxin ◽  
Haemolytic Uraemic Syndrome ◽  
Raw Milk ◽  
National Reference ◽  
Food Borne ◽  
Raw Milk Cheese ◽  
Over Time ◽  
Microbiological Surveillance

Introduction Haemolytic uraemic syndrome (HUS) related to Shiga toxin-producing Escherichia coli (STEC) is the leading cause of acute renal failure in young children. In France, HUS surveillance in children aged < 15 years was implemented starting from 1996. Aim We present the results of this surveillance between 2007 and 2016. Methods A voluntary nationwide network of 32 paediatric departments notifies cases. Two national reference centres perform microbiological STEC confirmation. Results Over the study period, the paediatric HUS incidence rate (IR) was 1.0 per 100,000 children-years, with a median of 116 cases/year. In 2011, IR peaked at 1.3 per 100,000 children-years, and decreased to 1.0 per 100,000 children-years in 2016. STEC O157 associated HUS peaked at 37 cases in 2011 and decreased to seven cases in 2016. Cases of STEC O26-associated HUS have increased since 2010 and STEC O80 associated HUS has emerged since 2012, with 28 and 18 cases respectively reported in 2016. Four STEC-HUS food-borne outbreaks were detected (three STEC O157 linked to ground beef and raw-milk cheese and one STEC O104 linked to fenugreek sprouts). In addition, two outbreaks related to person-to-person transmission occurred in distinct kindergartens (STEC O111 and O26). Conclusions No major changes in HUS IRs were observed over the study period of 10 years. However, changes in the STEC serogroups over time and the outbreaks detected argue for continuing epidemiological and microbiological surveillance.

A Novel Hybrid CFH/CFHR1–3 Gene in Atypical Hemolytic Uremic Syndrome

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4644-4644
Author(s):  
Mehmet F. Hepgur ◽  
Preeti Chaudhary ◽  
Sarmen Sarkissian ◽  
Richard J. H. Smith ◽  
Howard Liebman ◽  
...  
Keyword(s):  
Renal Failure ◽  
Genetic Testing ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Conflicts Of Interest ◽  
Late Onset ◽  
Past History ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Uremic Syndrome

Abstract Abstract 4644 Background: Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and renal failure in the absence of Shiga toxin exposure. Dysregulation of the alternative pathway by mutations in complement regulatory proteins or antibodies to these proteins have been implicated in the pathogenesis of the disorder. Aims: We report the late onset of aHUS in association with heterozygous deletion of two genes, CFHR1 and CFHR3, and a mutation in CFH, c.497G>T, p.Arg166Leu. The latter mutation has not previously been reported with aHUS. Methods: A 20-year-old female whose past history was unremarkable with the exception of a spontaneous abortion 3 months earlier, presented to an emergency room with abdominal pain and bloody diarrhea three days after eating raw fish. Within 4 days of hospitalization she developed MAHA, thrombocytopenia and renal failure. Studies were negative for Shiga toxin and showed an ADAMTS13 level of 40%. A diagnosis of aHUS was made. Treatment was initiated with daily plasma exchange (PE) which was increased to twice daily for 6 weeks. Response was poor. After discontinuing PE, the patient was treated on an IRB-approved compassionate-use protocol with eculizumab 900 mg weekly for four weeks followed by 1200 mg every two weeks. Results: The patient responded slowly to eculizumab. PK values of eculizumab were sub-therapeutic at week 4. On week 5, she was switched to the maintenance dose of 1200 mg every two weeks, which resulted in a rapid normalization of her platelet count and LDH, with further improvement of her renal function and normalization of her mental status. The patient is doing well on continued eculizumab treatment. Genetic testing revealed a known copy-number variation (CNV), hemizygosity for CFHR1 and CFHR3, and a mutation in short consensus repeat (SCR) 3 of CFH, p.Arg166Leu. Summary/Conclusions: This patient presented with aHUS unresponsive to PE, but responsive to eculizumab treatment. Genetic testing of complement regulatory genes identified a known CNV and a mutation in CFH, p.Arg166Leu. This mutation lies in SCR3 of CFH, a region of the protein important for fluid-phase regulation of the C3 convertase. Although it has been seen in a rare case of dense deposit disease, it has not has not been reported with aHUS. This patient's poor response to PE suggests that additional genetic factors may be present in this patient that affected the course of disorder. Her slow response to eculizumab may have been due to third spacing of the drug secondary to hypoalbuminemia with anasarca as documented sub-therapeutic levels were present on week 4. When the dose was increased to 1200 mg every two weeks, the patient rapidly improved with resolution of the aHUS. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Induction of Neutrophil Extracellular Traps in Shiga Toxin-Associated Hemolytic Uremic Syndrome

2016 ◽  
Vol 8 (4) ◽  
pp. 400-411 ◽  
Author(s):  
Maria Victoria Ramos ◽  
Maria Pilar Mejias ◽  
Florencia Sabbione ◽  
Romina Jimena Fernandez-Brando ◽  
Adriana Patricia Santiago ◽  
...  
Keyword(s):  
Renal Failure ◽  
Inflammatory Response ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Inflammatory Diseases ◽  
Neutrophil Extracellular Traps ◽  
Healthy Children ◽  
Extracellular Traps ◽  
Circulating Free Dna ◽  
Uremic Syndrome

Hemolytic uremic syndrome (HUS), a vascular disease characterized by hemolytic anemia, thrombocytopenia, and acute renal failure, is caused by enterohemorrhagic Shiga toxin (Stx)-producing bacteria, which mainly affect children. Besides Stx, the inflammatory response mediated by neutrophils (PMN) is essential to HUS evolution. PMN can release neutrophil extracellular traps (NET) composed of DNA, histones, and other proteins. Since NET are involved in infectious and inflammatory diseases, the aim of this work was to investigate the contribution of NET to HUS. Plasma from HUS patients contained increased levels of circulating free-DNA and nucleosomes in comparison to plasma from healthy children. Neutrophils from HUS patients exhibited a greater capacity to undergo spontaneous NETosis. NET activated human glomerular endothelial cells, stimulating secretion of the proinflammatory cytokines IL-6 and IL-8. Stx induced PMN activation as judged by its ability to trigger reactive oxygen species production, increase CD11b and CD66b expression, and induce NETosis in PMN from healthy donors. During HUS, NET can contribute to the inflammatory response and thrombosis in the microvasculature and thus to renal failure. Intervention strategies to inhibit inflammatory mechanisms mediated by PMN, such as NETosis, could have a potential therapeutic impact towards amelioration of the severity of HUS.

scholarly journals Risk of haemolytic uraemic syndrome caused by shiga-toxin-producing Escherichia coli infection in adult women in Japan

2015 ◽  
Vol 144 (5) ◽  
pp. 952-961 ◽  
Author(s):  
J. FUJII ◽  
T. MIZOUE ◽  
T. KITA ◽  
H. KISHIMOTO ◽  
K. JOH ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Renal Failure ◽  
Shiga Toxin ◽  
Haemolytic Uraemic Syndrome ◽  
Fatal Case ◽  
Diarrhoeal Disease ◽  
Positive Control ◽  
Renal Tubules ◽  
Adult Women ◽  
Escherichia Coli Infection

SUMMARYShiga-toxin-producing Escherichia coli (STEC) infections usually cause haemolytic uraemic syndrome (HUS) equally in male and female children. This study investigated the localization of globotriaosylceramide (Gb3) in human brain and kidney tissues removed from forensic autopsy cases in Japan. A fatal case was used as a positive control in an outbreak of diarrhoeal disease caused by STEC O157:H7 in a kindergarten in Urawa in 1990. Positive immunodetection of Gb3 was significantly more frequent in female than in male distal and collecting renal tubules. To correlate this finding with a clinical outcome, a retrospective analysis of the predictors of renal failure in the 162 patients of two outbreaks in Japan was performed: one in Tochigi in 2002 and the other in Kagawa Prefecture in 2005. This study concludes renal failure, including HUS, was significantly associated with female sex, and the odds ratio was 4·06 compared to male patients in the two outbreaks. From 2006 to 2009 in Japan, the risk factor of HUS associated with STEC infection was analysed. The number of males and females and the proportion of females who developed HUS were calculated by age and year from 2006 to 2009. In 2006, 2007 and 2009 in adults aged >20 years, adult women were significantly more at risk of developing HUS in Japan.

scholarly journals Treatment of Shiga-Toxin Hus with Severe Neurologic Features with Eculizumab

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Jacob H. Umscheid ◽  
Collin Nevil ◽  
Rhythm Vasudeva ◽  
Mohammed Farhan Ali ◽  
Nisha Agasthya
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Current Literature ◽  
Shiga Toxin ◽  
Complement Activation ◽  
Early Recognition ◽  
Neurological Complications ◽  
Current Data ◽  
Systemic Complications ◽  
Uremic Syndrome

Hemolytic Uremic Syndrome (HUS) is a constellation of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Shiga toxin-producing Escherichia coli- (STEC-) mediated HUS is a common cause of acute renal failure in children and can rarely result in severe neurological complications such as encephalopathy, seizures, cerebrovascular accidents, and coma. Current literature supports use of eculizumab, a monoclonal antibody that blocks complement activation, in atypical HUS (aHUS). However, those with neurologic complications from STEC-HUS have complement activation and deposition of aggregates in microvasculature and may be treated with eculizumab. In this case report, we describe a 3-year-old boy with diarrhea-positive STEC-HUS who developed severe neurologic involvement in addition to acute renal failure requiring renal replacement therapy. He was initiated on eculizumab therapy, with clinical improvement and organ recovery. This case highlights systemic complications of STEC-HUS in a pediatric patient. The current literature is limited but has suggested a role for complement mediation in cases with severe complications. We review the importance of early recognition of complications, use of eculizumab, and current data available.

Haemolytic uraemic syndrome associated with Pseudomonas aeruginosa sepsis

2013 ◽  
Vol 62 (11) ◽  
pp. 1760-1762 ◽  
Author(s):  
Parameswaran Narayanan ◽  
Rashi S. Rustagi ◽  
Prabha Sivaprakasam ◽  
Mahadevan Subramanian ◽  
Sreejith Parameswaran ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Renal Failure ◽  
Influenza Virus ◽  
Shiga Toxin ◽  
Haemolytic Uraemic Syndrome ◽  
Shigella Dysenteriae ◽  
Micro Organisms

Haemolytic uraemic syndrome (HUS) is a recognized complication of infection with Shiga toxin-producing Escherichia coli (STEC) and Shigella dysenteriae type 1. Infections with other micro-organisms, especially Streptococcus pneumoniae, have been cited as causes of HUS. In addition, influenza virus and other viruses may rarely be associated with this syndrome. A 2-year-old girl presented with severe Pseudomonas aeruginosa sepsis with renal failure and ecthyma gangrenosum. Further investigations revealed features of HUS. She was managed with antibiotics and other supportive measures including peritoneal dialysis, and subsequently made a full recovery. A possible role of neuraminidase in the pathogenesis of P. aeruginosa-associated HUS was proposed. This is the first reported case of P. aeruginosa sepsis leading to HUS.

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