scholarly journals Antibody Therapy in the Management of Shiga Toxin-Induced Hemolytic Uremic Syndrome

2004 ◽  
Vol 17 (4) ◽  
pp. 926-941 ◽  
Author(s):  
Saul Tzipori ◽  
Abhineet Sheoran ◽  
Donna Akiyoshi ◽  
Arthur Donohue-Rolfe ◽  
Howard Trachtman
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Clinical Manifestations ◽  
Antibody Therapy ◽  
Major Focus ◽  
Current Management ◽  
Systemic Complications ◽  
Shiga Toxins ◽  
Uremic Syndrome ◽  
Phases Of Development ◽  
A Subunit

SUMMARY Hemolytic uremic syndrome (HUS) is a disease that can lead to acute renal failure and often to other serious sequelae, including death. The majority of cases are attributed to infections with Escherichia coli, serotype O157:H7 strains in particular, which cause bloody diarrhea and liberate one or two toxins known as Shiga toxins 1 and 2. These toxins are thought to directly be responsible for the manifestations of HUS. Currently, supportive nonspecific treatment is the only available option for the management of individuals presenting with HUS. The benefit of antimicrobial therapy remains uncertain because of several reports which claim that such intervention can in fact exacerbate the syndrome. There have been only a few specific therapies directed against neutralizing the activities of these toxins, but none so far has been shown to be effective. This article reviews the literature on the mechanism of action of these toxins and the clinical manifestations and current management and treatment of HUS. The major focus of the article, however, is the development and rationale for using neutralizing human antibodies to combat this toxin-induced disease. Several groups are currently pursuing this approach with either humanized, chimeric, or human antitoxin antibodies produced in transgenic mice. They are at different phases of development, ranging from preclinical evaluation to human clinical trials. The information available from preclinical studies indicates that neutralizing specific antibodies directed against the A subunit of the toxin can be highly protective. Such antibodies, even when administered well after exposure to bacterial infection and onset of diarrhea, can prevent the occurrence of systemic complications.

scholarly journals Infection by verocytotoxin-producing Escherichia coli.

1989 ◽  
Vol 2 (1) ◽  
pp. 15-38 ◽  
Author(s):  
M A Karmali
Keyword(s):  
Escherichia Coli ◽  
Hemolytic Uremic Syndrome ◽  
Mammalian Cells ◽  
Significant Risk ◽  
Public Health Problem ◽  
Hemorrhagic Colitis ◽  
Commercial Development ◽  
High Biological Activity ◽  
Systemic Complications ◽  
Uremic Syndrome

Verocytotoxin (VT)-producing Escherichia coli (VTEC) are a newly recognized group of enteric pathogens which are increasingly being recognized as common causes of diarrhea in some geographic settings. Outbreak studies indicate that most patients with VTEC infection develop mild uncomplicated diarrhea. However, a significant risk of two serious and potentially life-threatening complications, hemorrhagic colitis and the hemolytic uremic syndrome, makes VTEC infection a public health problem of serious concern. The main reservoirs of VTEC appear to be the intestinal tracts of animals, and foods of animal (especially bovine) origin are probably the principal sources for human infection. The term VT refers to a family of subunit exotoxins with high biological activity. Individual VTEC strains elaborate one or both of at least two serologically distinct, bacteriophage-mediated VTs (VT1 and VT2) which are closely related to Shiga toxin and are thus also referred to as Shiga-like toxins. The holotoxins bind to cells, via their B subunits, to a specific receptor which is probably the glycolipid, globotriosyl ceramide (Gb3). Binding is followed by internalization of the A subunit, which, after it is proteolytically nicked and reduced to the A1 fragment, inhibits protein synthesis in mammalian cells by inactivating 60S ribosomal subunits through selective structural modification of 28S ribosomal ribonucleic acid. The mechanism of VTEC diarrhea is still controversial, and the relative roles of locally acting VT and "attaching and effacing adherence" of VTEC to the mucosa have yet to be resolved. There is increasing evidence that hemolytic uremic syndrome and possibly hemorrhagic colitis result from the systemic action of VT on vascular endothelial cells. The role of antitoxic immunity in preventing the systemic complications of VTEC infection is being explored. Antibiotics appear to be contraindicated in the treatment of VTEC infection. The most common VTEC serotype associated with human disease is O157:H7, but over 50 different VT-positive O:H serotypes have now been identified. The best strategies for diagnosing human VTEC infection include testing for the presence of free VT in fecal filtrates and examining fecal cultures for VTEC by means of deoxyribonucleic acid probes that specify genes encoding VT1 and VT2. Both methods are currently confined to specialized laboratories and await commercial development for wider use. In the meantime, most laboratories should continue to screen for the most common human VTEC serotype, O157:H7, using a sorbitol-containing MacConkey medium.

scholarly journals Atypical hemolytic-uremic syndrome in a patient with adenosine deaminase deficiency

2015 ◽  
Vol 2 (4) ◽  
pp. 195-199 ◽  
Author(s):  
Anne Pham-Huy ◽  
Vy Hong-Diep Kim ◽  
Elizabeth Nizalik ◽  
Gabrielle Weiler ◽  
Jennifer Vethamuthu ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Adenosine Deaminase ◽  
Kidney Biopsy ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Shiga Toxins ◽  
Deficient Patient ◽  
Uremic Syndrome ◽  
Platelet Aggregates ◽  
Increased Susceptibility

Inherited defects in the ubiquitous adenosine deaminase (ADA) enzyme disrupt the function of the immune system as well as many other organs and tissues. Some patients may also suffer from kidney damage. Here we report on an ADA-deficient patient who was treated with ADA replacement therapy from infancy and at 6 years of age developed acute kidney failure, thrombocytopenia, and severe anemia. A kidney biopsy demonstrated mesangiolysis and occlusion of kidney loops by erythrocytes and platelet aggregates, which is consistent with hemolytic-uremic syndrome (HUS). There was no evidence of exposure to Shiga toxins, nor were any complement abnormalities detected. The kidney function improved following hemodialysis. Our report demonstrates the increased susceptibility of ADA-deficient patients to develop HUS and expands the nonimmune abnormalities associated with ADA deficiency. This further emphasizes the vigilance required when caring for such patients. Statement of novelty: Here we provide the first detailed clinical and histological characterization of hemolytic-uremic syndrome developing in an ADA-deficient patient.

scholarly journals The Detection of Shiga Toxins in the Kidney of a Patient with Hemolytic Uremic Syndrome

1999 ◽  
Vol 45 (1) ◽  
pp. 133-137 ◽  
Author(s):  
Hiroshi Uchida ◽  
Nobutaka Kiyokawa ◽  
Hiroshi Horie ◽  
Junichiro Fujimoto ◽  
Tae Takeda
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Shiga Toxins ◽  
Uremic Syndrome

The Importance of Nonrenal Involvement in Hemolytic-Uremic Syndrome

PEDIATRICS ◽  
1980 ◽  
Vol 65 (1) ◽  
pp. 115-120
Author(s):  
Kirti Upadhyaya ◽  
Kenneth Barwick ◽  
Mark Fishaut ◽  
Michael Kashgarian ◽  
Norman J. Siegel
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Hemolytic Uremic Syndrome ◽  
Clinical Course ◽  
Important Determinant ◽  
Clinical Manifestations ◽  
Wide Distribution ◽  
Effective Management ◽  
Uremic Syndrome ◽  
The Brain

Fifteen children with the clinical manifestations of hemolytic-uremic syndrome are reported.Prompt recognition of the syndrome and effective therapy for acute renal failure including early dialysis were institured in each case. Analysis of the clinical course and histopathologic features in these patients indicated that early dialysis and effective management of acute renal failure may unmask evidence of nonrenal involvement; microthrombi may be found in a wide distribution of organs, including the brain and myocardium; and extent and severity of nonrenal involvement become an important determinant of ultimate prognosis.

scholarly journals AB5Preassembly Is Not Required for Shiga Toxin Activity

2016 ◽  
Vol 198 (11) ◽  
pp. 1621-1630 ◽  
Author(s):  
Christine A. Pellino ◽  
Sayali S. Karve ◽  
Suman Pradhan ◽  
Alison A. Weiss
Keyword(s):  
Escherichia Coli ◽  
Enzymatic Activity ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Target Cells ◽  
Content Type ◽  
B Subunit ◽  
Uremic Syndrome ◽  
A Subunit ◽  
B Subunits

ABSTRACTShiga toxin (Stx)-producingEscherichia coli(STEC) is a major cause of foodborne illness, including the life-threatening complication hemolytic-uremic syndrome. The German outbreak in 2011 resulted in nearly 4,000 cases of infection, with 54 deaths. Two forms of Stx, Stx1 and Stx2, differ in potency, and subtype Stx2a is most commonly associated with fatal human disease. Stx is considered to be an AB5toxin. The single A (enzymatically active) subunit inhibits protein synthesis by cleaving a catalytic adenine from the eukaryotic rRNA. The B (binding) subunit forms a homopentamer and mediates cellular association and toxin internalization by binding to the glycolipid globotriaosylceramide (Gb3). Both subunits are essential for toxicity. Here we report that unlike other AB5toxin family members, Stx is produced by STEC as unassembled A and B subunits. A preformed AB5complex is not required for cellular toxicity orin vivotoxicity to mice, and toxin assembly likely occurs at the cell membrane. We demonstrate that disruption of A- and B-subunit association by use of A-subunit peptides that lack enzymatic activity can protect mice from lethal doses of toxin. Currently, no treatments have been proven to be effective for hemolytic-uremic syndrome. Our studies demonstrate that agents that interfere with A- and B-subunit assembly may have therapeutic potential. Shiga toxin (Stx) produced by pathogenicEscherichia coliis considered to be an AB5heterohexamer; however, no known mechanisms ensure AB5assembly. Stx released byE. coliis not in the AB5conformation and assembles at the receptor interface. Thus, unassembled Stx can impart toxicity. This finding shows that preventing AB5assembly is a potential treatment for Stx-associated illnesses.IMPORTANCEComplications due to Shiga toxin are frequently fatal, and at present, supportive care is the only treatment option. Furthermore, antibiotic treatment is contraindicated due to the ability of antibiotics to amplify bacterial expression of Shiga toxin. We report, contrary to prevailing assumptions, that Shiga toxin produced by STEC circulates as unassembled A and B subunits at concentrations that are lethal to mice. Similar to the case for anthrax toxin, assembly occurs on receptors expressed on the surfaces of mammalian target cells. Disruption of Shiga toxin assembly by use of A-subunit peptides that lack enzymatic activity protects mice from lethal challenge with Shiga toxin, suggesting a new approach for development of therapeutics.

scholarly journals Hemolytic uremic syndrome–associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers

Blood ◽  
2005 ◽  
Vol 106 (13) ◽  
pp. 4199-4209 ◽  
Author(s):  
Leticia H. Nolasco ◽  
Nancy A. Turner ◽  
Aubrey Bernardo ◽  
Zhenyin Tao ◽  
Thomas G. Cleary ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Hemolytic Uremic Syndrome ◽  
Von Willebrand Factor ◽  
Umbilical Vein ◽  
Enterohemorrhagic Escherichia Coli ◽  
Shiga Toxins ◽  
Uremic Syndrome ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Fibrin Thrombi

Shiga toxin 1 (Stx-1) and Stx-2 produced by enterohemorrhagic Escherichia coli cause the diarrhea-associated hemolytic uremic syndrome (HUS). This type of HUS is characterized by obstruction of the glomeruli and renal microvasculature by platelet-fibrin thrombi, acute renal failure, thrombocytopenia, microvascular hemolytic anemia, and plasma levels of von Willebrand factor (VWF)-cleaving protease (ADAMTS13) activity that are within a broad normal range. We investigated the mechanism of initial platelet accumulation on Stx-stimulated endothelial cells. Stx-1 or Stx-2 (1-10 nM) stimulated the rapid secretion of unusually large (UL) VWF multimeric strings from human umbilical vein endothelial cells (HUVECs) or human glomerular microvascular endothelial cells (GMVECs). Perfused normal human platelets immediately adhered to the secreted ULVWF multimeric strings. Nanomolar concentrations (1-10 nM) of the Shiga toxins were as effective in inducing the formation of ULVWF-platelet strings as millimolar concentrations (0.1-20 mM) of histamine. The rate of ULVWF-platelet string cleavage by plasma or recombinant ADAMTS13 was delayed by 3 to 10 minutes (or longer) in the presence of 10 nM Stx-1 or Stx-2 compared with 20 mM histamine. Stx-induced formation of ULVWF strings, and impairment of ULVWF-platelet string cleavage by ADAMTS13, may promote initial platelet adhesion above glomerular endothelial cells. These processes may contribute to the evolution of glomerular occlusion by platelet and fibrin thrombi in diarrhea-associated HUS.

scholarly journals AB5 Enterotoxin-Mediated Pathogenesis: Perspectives Gleaned from Shiga Toxins

Toxins ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 62
Author(s):  
Erika N. Biernbaum ◽  
Indira T. Kudva
Keyword(s):  
Foodborne Pathogens ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Treatment Strategies ◽  
Antibiotic Use ◽  
Fluid Replacement ◽  
Shiga Toxins ◽  
Increased Risk ◽  
Uremic Syndrome ◽  
Primary Focus

Foodborne diseases affect an estimated 600 million people worldwide annually, with the majority of these illnesses caused by Norovirus, Vibrio, Listeria, Campylobacter, Salmonella, and Escherichia coli. To elicit infections in humans, bacterial pathogens express a combination of virulence factors and toxins. AB5 toxins are an example of such toxins that can cause various clinical manifestations, including dehydration, diarrhea, kidney damage, hemorrhagic colitis, and hemolytic uremic syndrome (HUS). Treatment of most bacterial foodborne illnesses consists of fluid replacement and antibiotics. However, antibiotics are not recommended for infections caused by Shiga toxin-producing E. coli (STEC) because of the increased risk of HUS development, although there are conflicting views and results in this regard. Lack of effective treatment strategies for STEC infections pose a public health threat during outbreaks; therefore, the debate on antibiotic use for STEC infections could be further explored, along with investigations into antibiotic alternatives. The overall goal of this review is to provide a succinct summary on the mechanisms of action and the pathogenesis of AB5 and related toxins, as expressed by bacterial foodborne pathogens, with a primary focus on Shiga toxins (Stx). The role of Stx in human STEC disease, detection methodologies, and available treatment options are also briefly discussed.

scholarly journals Clinical characteristics and genetic backgrounds of Japanese patients with atypical hemolytic uremic syndrome

2018 ◽  
Vol 22 (5) ◽  
pp. 1088-1099 ◽  
Author(s):  
Madoka Fujisawa ◽  
Hideki Kato ◽  
Yoko Yoshida ◽  
Tomoko Usui ◽  
Munenori Takata ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Hemolytic Uremic Syndrome ◽  
Clinical Characteristics ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Clinical Manifestations ◽  
Total Mortality ◽  
Plasma Therapy ◽  
Laboratory Findings ◽  
Frequent Relapses ◽  
Uremic Syndrome

Abstract Background Atypical hemolytic uremic syndrome (aHUS) is caused by complement overactivation, and its presentation and prognosis differ according to the underlying molecular defects. The aim of this study was to characterize the genetic backgrounds of aHUS patients in Japan and to elucidate the associations between their genetic backgrounds, clinical findings, and outcomes. Methods We conducted a nationwide epidemiological survey of clinically diagnosed aHUS patients and examined 118 patients enrolled from 1998 to 2016 in Japan. We screened variants of seven genes related to complement and coagulation, as well as positivity for anti-CFH antibodies, and assessed clinical manifestations, laboratory findings, and clinical course. Results The most frequent genetic abnormalities were in C3 (31%) and the frequency of CFH variants was relatively low (10%) compared to Western countries. The predominant variant in this cohort was C3 p.I1157T (23%), which was related to favorable outcomes despite frequent relapses. A total of 72% of patients received plasma therapy, while 42% were treated with eculizumab. The prognosis of Japanese aHUS patients was relatively favorable, with a total mortality rate of 5.4% and a renal mortality rate of 15%. Conclusions The common occurrence of genotype C3, especially the p.I1157T variant was the characteristic of the genetic backgrounds of Japanese aHUS patients that differed from those of Caucasian patients. In addition, the favorable prognosis of patients with the unique C3 p.I1157T variant indicates that understanding the clinical characteristics of individual gene alterations is important for predicting prognosis and determining therapeutic strategies in aHUS.

scholarly journals Phenotypic manifestation of homozygous partial deletion of the chromosome 1 segment spanning CFHR3 region

2020 ◽  
Vol 22 (3) ◽  
pp. 569-576
Author(s):  
I. A. Tuzankina ◽  
M. A. Bolkov ◽  
N. S. Zhuravleva ◽  
Yu. O. Vaseneva ◽  
Kh. Shinvari ◽  
...  
Keyword(s):  
Renal Failure ◽  
Hemolytic Uremic Syndrome ◽  
Clinical Case ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Clinical Manifestations ◽  
Factor H ◽  
Complement Factor H ◽  
Chromosome 1 ◽  
Complement Factor ◽  
Uremic Syndrome

This article presents two clinical cases of patients with a homozygous deletion of segment of chromosome 1, which covers regions of genes associated with complement factor H, in particular CFHR3. Patients underwent in-depth clinical studies, heredity assessment, laboratory, instrumental and genetic diagnostics. The first clinical case describes a clinical case with deleted chromosome 1 segment in a 9-year-old girl who was diagnosed with atypical hemolytic-uremic syndrome. This is a complement-dependent disease that affects both adults and children. It is known that a defect in any proteins included in the alternative complement activation pathway can lead to atypical hemolytic-uremic syndrome. However, this syndrome is most often caused by defects in chromosome 1 region, including gene sequences associated with complement factor H – CFHR1 and CFHR3. Modern treatment of atypical hemolytic uremic syndrome involves targeted pathogenetic treatment, therefore, the genetic diagnosis seems to be a necessary step for differential diagnosis and confirmation. The patient had fairly typical clinical symptoms, including signs of thrombotic microangiopathy, thrombocytopenia, hemolytic anemia and increasing renal failure. It is also known that her mother had congenital hydronephrosis, and the pregnancy proceeded against a background of ureaplasma, mycoplasma, cytomegalovirus infection, chronic pyelonephritis, and preeclampsia.The second clinical case of a deleted chromosome 1 region, involving the CFHR3 gene, is a description of the disease in a boy of 8 years old, while the disease manifested with alopecia at the age of 4. Intermittent alopecia was the main symptom, while there were no signs of renal failure, thrombocytopenic purpura, and other symptoms characteristic of atypical hemolytic-uremic syndrome. The boy also revealed some congenital defects of the urinary system: bladder diverticulum, unilateral ureterohydronephrosis, and bilateral dilatation of the pyelocaliceal system. The detected genetic defect is usually associated with atypical hemolytic uremic syndrome. However, the phenotype, i.e., clinical manifestations, determined a completely different diagnosis – primary immunodeficiency, a group of complement defects, and a deficiency of complement factor H-related protein. After analyzing the given clinical cases, we can conclude that clinical manifestations may vary significantly in carriers of same gene mutations. This suggests that there are additional factors (genetic or environmental) that can influence the formation of various phenotypic manifestations of this pathology.

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