scholarly journals The Path physiology of Renal Failure in a Shiga Toxin plus Lipopolysaccharide Induced Murine Model of Hemolytic Uremic Syndrome

2008 ◽  
Author(s):  
Mitchell Adam Psotka
Keyword(s):  
Renal Failure ◽  
Hemolytic Uremic Syndrome ◽  
Murine Model ◽  
Shiga Toxin ◽  
Uremic Syndrome

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.

Shiga Toxin-2 Induces Neutrophilia and Neutrophil Activation in a Murine Model of Hemolytic Uremic Syndrome

2000 ◽  
Vol 95 (3) ◽  
pp. 227-234 ◽  
Author(s):  
Gabriela C. Fernández ◽  
Carolina Rubel ◽  
Graciela Dran ◽  
Sonia Gómez ◽  
Martı́n A. Isturiz ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Murine Model ◽  
Shiga Toxin ◽  
Neutrophil Activation ◽  
Shiga Toxin 2 ◽  
Uremic Syndrome

scholarly journals Eculizumab Use in a Temporarily Dialysis-Dependent Patient With Shiga Toxin–Producing Escherichia Coli Hemolytic Uremic Syndrome With Neurological Complications

2021 ◽  
Vol 27 (1) ◽  
pp. 90-95
Author(s):  
Bo Weber ◽  
Dominic Chan ◽  
Sandy Hammer
Keyword(s):  
Escherichia Coli ◽  
Renal Failure ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Dose Adjustment ◽  
Inpatient Rehabilitation ◽  
Cellular Damage ◽  
Neurological Involvement ◽  
Organ Systems ◽  
Uremic Syndrome

Shiga toxin–producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) is the most common cause of acute renal failure in children, and it is associated with thrombocytopenia and hemolytic anemia. Although this disease primarily affects the kidney, it can also contribute to cellular damage in other organ systems, such as the CNS. Eculizumab is a monoclonal antibody that binds to complement proteins to prevent complement-mediated intravascular hemolysis in atypical HUS. In STEC-HUS, complement activation also occurs by Shiga toxin, and previous cases of eculizumab use in the setting of neurological involvement have been shown to be successful. We report the successful use of eculizumab in the setting of typical STEC-HUS–induced neurological symptoms including seizure, altered mental status, and left arm weakness. The patient also experienced concomitant renal failure requiring dose adjustment for hemodialysis. Following 2 doses of eculizumab, our patient was discharged to an inpatient rehabilitation facility with resolution of her renal injury, seizures, and altered mentation without adverse effects from eculizumab throughout the admission. Based on our case study, it appears that eculizumab may be given during or between hemodialysis without dose adjustment.

scholarly journals Deterioration in Clinical Status Is Not Enough to Suspend Eculizumab: A Genetic Complement-Mediated Atypical Hemolytic Uremic Syndrome Case Report

2019 ◽  
Vol 2019 ◽  
pp. 1-5 ◽  
Author(s):  
Luca Calvaruso ◽  
Alessandro Naticchia ◽  
Pietro Manuel Ferraro ◽  
Gisella Vischini ◽  
Stefano Costanzi
Keyword(s):  
Renal Failure ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Hematological Parameters ◽  
Clinical Status ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Graft Function ◽  
Severe Renal Failure ◽  
Gene Coding ◽  
Uremic Syndrome

Background. Atypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Mutations in CFI gene coding for complement regulation factors and in THBD gene coding for endothelial cell receptor thrombomodulin could predispose to the disease and hypertension can trigger the onset. Case Presentation. A 51-year-old female patient who had received kidney transplant eighteen years ago presented with hypertensive peak and hemolysis pattern. Normal ADAMTS13 levels as well as negative culture and serology for Shiga-toxin excluded, respectively, thrombotic thrombocytopenic purpura (TTP) and typical HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS). In suspicion of aHUS, we administered eculizumab and hemodialysis sessions were started as the patient showed severe renal failure. After an initial response, the patient developed cerebral hemorrhage. After last eculizumab administration, according to hematological parameters, an unsatisfactory response was observed: given the worsening clinical scenario, we withdrew eculizumab. Pathogenic mutations in CFI and THBD genes were found. After eculizumab reinitiation, looking at hemolysis indexes, we observed a suboptimal response as well as an otherwise adequate renal one: renal graft function was recovered despite persistence of hemolysis signs, after 6 months on regular dialysis. Conclusion. For the first time, we report an aHUS case in which a peculiar combination of mutations in CFI and THBD is found. We describe the importance of continuing eculizumab despite deterioration of patient’s clinical conditions.

Tissue-resident macrophages mediate neutrophil recruitment and kidney injury in shiga toxin-induced hemolytic uremic syndrome.

2021 ◽  
Author(s):  
Julia K. Lill ◽  
Stephanie Thiebes ◽  
Judith-Mira Pohl ◽  
Jenny Bottek ◽  
Nirojah Subramaniam ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Kidney Injury ◽  
Neutrophil Recruitment ◽  
Uremic Syndrome

scholarly journals Hemoconcentration and predictors in Shiga toxin-producing E. coli-hemolytic uremic syndrome (STEC-HUS)

2021 ◽  
Author(s):  
Sebastian Loos ◽  
Jun Oh ◽  
Laura van de Loo ◽  
Markus J. Kemper ◽  
Martin Blohm ◽  
...  
Keyword(s):  
Risk Factor ◽  
Serum Creatinine ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Neurological Symptoms ◽  
Fluid Loss ◽  
Good Prediction ◽  
E Coli ◽  
Complicated Course ◽  
Uremic Syndrome

Abstract Background Hemoconcentration has been identified as a risk factor for a complicated course in Shiga toxin-producing E. coli-hemolytic uremic syndrome (STEC-HUS). This single-center study assesses hemoconcentration and predictors at presentation in STEC-HUS treated from 2009–2017. Methods Data of 107 pediatric patients with STEC-HUS were analyzed retrospectively. Patients with mild HUS (mHUS, definition: max. serum creatinine < 1.5 mg/dL and no major neurological symptoms) were compared to patients with severe HUS (sHUS, definition: max. serum creatinine ≥ 1.5 mg/dL ± major neurological symptoms). Additionally, predictors of complicated HUS (dialysis ± major neurological symptoms) were analyzed. Results Sixteen of one hundred seven (15%) patients had mHUS. Admission of patients with sHUS occurred median 2 days earlier after the onset of symptoms than in patients with mHUS. On admission, patients with subsequent sHUS had significantly higher median hemoglobin (9.5 g/dL (3.6–15.7) vs. 8.5 g/dL (4.2–11.5), p = 0.016) than patients with mHUS. The product of hemoglobin (g/dL) and LDH (U/L) (cutoff value 13,302, sensitivity 78.0%, specificity of 87.5%) was a predictor of severe vs. mild HUS. Creatinine (AUC 0.86, 95% CI 0.79–0.93) and the previously published score hemoglobin (g/dL) + 2 × creatinine (mg/dL) showed a good prediction for development of complicated HUS (AUC 0.87, 95% CI 0.80–0.93). Conclusions At presentation, patients with subsequent severe STEC-HUS had a higher degree of hemoconcentration. This underlines that fluid loss or reduced fluid intake/administration may be a risk factor for severe HUS. The good predictive value of the score hemoglobin (g/dL) + 2 × creatinine (mg/dL) for complicated HUS could be validated in our cohort. Graphical abstract

scholarly journals Whole-genome characterization of hemolytic uremic syndrome-causing Shiga toxin-producing Escherichia coli in Sweden

Virulence ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 1296-1305
Author(s):  
Ying Hua ◽  
Milan Chromek ◽  
Anne Frykman ◽  
Cecilia Jernberg ◽  
Valya Georgieva ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Whole Genome ◽  
Genome Characterization ◽  
Uremic Syndrome

scholarly journals Neonatal Atypical Hemolytic Uremic Syndrome in the Eculizumab Era

2021 ◽  
Vol 11 (02) ◽  
pp. e95-e98
Author(s):  
Sara Madureira Gomes ◽  
Rita Pissarra Teixeira ◽  
Gustavo Rocha ◽  
Paulo Soares ◽  
Hercilia Guimaraes ◽  
...  
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Hemolytic Uremic Syndrome ◽  
Perinatal Asphyxia ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Congenital Infection ◽  
High Morbidity ◽  
Severe Renal Failure ◽  
Emergency Cesarean ◽  
Uremic Syndrome

AbstractThe atypical hemolytic uremic syndrome (aHUS) in the newborn is a rare disease, with high morbidity. Eculizumab, considered a first-line drug in older children, is not approved in neonates and in children weighing less than 5 kg. We present a 5-day-old female newborn, born at 36 weeks' twin gestation, by emergency cesarean section due to cord prolapse, with birth weight of 2,035 g and Apgar score of 7/7/7, who develops microangiopathic hemolytic anemia, thrombocytopenia, and progressive acute renal failure. In day 5, after diagnosis of aHUS, a daily infusion of fresh frozen plasma begins, with improvement of thrombocytopenia and very slight improvement in renal function. The etiologic study (congenital infection, Shiga toxin, ADAMTS13 activity, directed metabolic study) was normal. C3c was slightly decreased. On day 16 for maintenance of anemia and severe renal failure, she started 300 mg/dose eculizumab. Anemia resolves in 10 weeks and creatinine has normal values after 13 weeks of treatment. The genetic study was normal. In this case, eculizumab is effective in controlling microangiopathy and in the recovery of renal function. Diagnosis of neonatal aHUS can be challenging because of phenotypic heterogeneity and potential overlap with other manifestations that may confound it, such as perinatal asphyxia or sepsis/disseminated intravascular coagulation.

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