RARE DISEASE
Shiga toxin-associated hemolytic uremic syndrome
Shiga toxin-associated hemolytic uremic syndrome
Shiga toxin-associated hemolytic uremic syndrome
Synonyms: D+ HUS, EHEC-HUS, Hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli, Hemolytic uremic syndrome with diarrhea, STEC-HUS, Shiga-like toxin-associated HUS, Stx-HUS, Typical HUS, Typical hemolytic uremic syndrome
Synonyms: D+ HUS, EHEC-HUS, Hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli, Hemolytic uremic syndrome with diarrhea, STEC-HUS, Shiga-like toxin-associated HUS, Stx-HUS, Typical HUS, Typical hemolytic uremic syndrome
Synonyms: D+ HUS, EHEC-HUS, Hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli, Hemolytic uremic syndrome with diarrhea, STEC-HUS, Shiga-like toxin-associated HUS, Stx-HUS, Typical HUS, Typical hemolytic uremic syndrome
Drug discovery
6
drugs
With orphan designations
Overview
Shiga toxin-associated hemolytic uremic syndrome (STEC-HUS) is a thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, typically triggered by Shiga toxin-producing E. coli (STEC) infections. It often follows bloody diarrhea and can progress to renal failure, neurologic complications, or death. Diagnosis relies on clinical triad confirmation and STEC detection via stool PCR or serology [1][2][6][9].
Burden
Acute kidney failure occurs in 50–70% of patients; mortality ranges 2–5% in children but rises to 20% in adults with comorbidities [6][17][18].
Chronic kidney disease develops in 10–25% of survivors, necessitating lifelong monitoring [13][16].
Annual global economic burden exceeds $400 million, driven by dialysis costs and long-term renal sequelae [6][13].
Therapies
Supportive care: Isotonic fluid resuscitation, dialysis (peritoneal preferred in children), and transfusions (avoid platelets unless bleeding) [3][5][16].
Targeted therapies: Eculizumab use remains controversial; limited evidence supports plasma exchange [3][18].
Investigational: Monoclonal antibodies (e.g., Shigamabs®) and Gb3 analogs show preclinical promise [8][16].
Categories: rare hematological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
615 drug discovery papers about Shiga toxin-associated hemolytic uremic syndrome, with 4 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
615 drug discovery papers about Shiga toxin-associated hemolytic uremic syndrome, with 4 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-12 | Protective effects of bismuth hydroxide against hemolytic uremic syndrome caused by Shiga toxin producing Escherichia coli.
Shiga toxin-producing Escherichia coli (STEC) is a major cause of foodborne disease and hemolytic uremic syndrome (HUS), a severe condition for which no specific therapies are currently available. The major virulence factor of STEC is Shiga toxin 2 (Stx2), which is encoded by the Stx2-converting bacteriophage 933 W used in this study, and phage induction plays a central role in toxin release and disease progression.In this study, we evaluated the protective in vivo effects of bismuth hydroxide gel (BHOG), a low-cost gastrointestinal compound with previously described antimicrobial and anti-toxin activities, in a murine model of STEC infection driven by the Stx2-converting bacteriophage 933 W. Mice treated with BHOG showed significantly higher survival rates compared than untreated controls (P = 0.0115), together with preservation of renal function, evidenced by significantly lower blood urea nitrogen and plasma urea levels (P < 0.05). Histological analysis demonstrated significantly reduced intestinal and renal tissues damage in treated animals compared with untreated controls. Overall, our findings provide in vivo evidence supporting a protective effect of BHOG against Shiga toxin-mediated disease. This study suggests that bismuth-based compounds may represent a potential adjunct to, or an alternative strategy for, the management of STEC-associated disease.
2026-08-08 | Pediatric Hemolytic Uremic Syndrome in North-Eastern Germany During the STEC O45:H2 Outbreak in 2025: Clinical Features and Short-Term Outcomes.
Shiga toxin-producing Escherichia coli (STEC)-associated hemolytic uremic syndrome (HUS) is a leading cause of pediatric acute kidney injury. Between August and October 2025, Germany experienced an outbreak of the rare STEC serotype O45:H2, comprising 53 laboratory-confirmed pediatric HUS cases. Because O45:H2-associated HUS had previously been reported only sporadically, this study characterized its clinical course and compared it with HUS caused by non-O45:H2 STEC serotypes. We retrospectively included all pediatric STEC-HUS cases treated in Northeastern Germany during the outbreak period. Microbiological confirmation was performed through cultivation and molecular typing at the National Reference and Consulting Laboratories. Patients were classified as O45:H2 or non-O45:H2 based on serotyping and the Robert Koch Institute (RKI) O45:H2 outbreak case definition. Clinical and laboratory parameters, dialysis requirements, transfusion needs, and short-term outcomes were compared. Thirty-seven children with STEC-associated HUS were included: 18 with O45:H2 and 19 with other serotypes. Patients with O45:H2 were significantly younger (median 2.0 vs 4.0 years, P = .01), while renal impairment at onset was comparable (minimal estimated glomerular filtration rate 8.0 vs 12 mL/min/1.73 m2). Dialysis was required in 65% of patients in both groups, with a trend toward longer duration in O45:H2 cases (median 10 vs 6 days). Hematologic parameters, markers of hemolysis, transfusion needs, neurological symptoms, and intensive care treatment were similar. One child died from myocardial failure. At 3-month follow-up, kidney function had recovered well in both groups. O45:H2-associated HUS was comparable in severity to non-O45:H2 STEC-HUS, while the younger age of affected children may indicate distinct host susceptibility or exposure patterns.
2026-08-06 | Shiga toxins and hemolytic uremic syndrome: pathogenesis, diagnosis, and therapy
Hemolytic Uremic Syndrome (HUS) is a severe thrombotic microangiopathy characterized by non-immune hemolytic anemia, thrombocytopenia, and acute renal failure. The most common form is caused by infections with Shiga toxin-producing Escherichia coli (STEC), which release potent Shiga toxins (Stx). This research addresses three objectives: elucidating mechanisms by which Stx subtypes contribute to HUS pathogenesis, developing a diagnostic platform for Stx detection, and evaluating novel therapeutic strategies. Patients infected with STEC co-producing Stx1 and Stx2 exhibit milder clinical manifestations than those infected with Stx2-producing strains. To investigate this, human blood was exposed to toxins, and extracellular vesicles (EV) were isolated and characterized. Co-exposure to both toxins produced a less toxic EV population, showing reduced number, size, and toxic cargo compared to EV generated by Stx2 alone, which are most strongly associated with HUS. Prompt STEC diagnosis is crucial for preventing HUS. A gold plasmonic biosensor was developed, coupling surface-enhanced Raman spectroscopy (SERS) with principal component analysis (PCA) for rapid Stx detection. The system recognizes Stx1a, Stx2a, and Stx2a-cleaved, enabling real-time analysis. Currently, no specific HUS therapy exists. NAB815, a polymyxin B derivative, emerged as a promising candidate. Previous studies showed sub-bactericidal NAB815 doses reduce Stx2a-containing EV formation in human blood. In vivo evaluation using CD1 mice demonstrated effective protection against kidney damage when NAB815 was co-administered with either free Stx2a or blood-derived Stx2a containing EV. Since antibiotics can trigger bacterial SOS response and increase Stx production, NAB815's safety was evaluated in both engineered and wildtype STEC strains. Results confirmed NAB815 as a safe strategy for HUS prevention and management. These findings provide new insights into HUS pathogenesis while offering innovative approaches for early diagnosis and targeted intervention in STEC infections.
2026-08-05 | Favorable Outcome With Eculizumab in Hemolytic Uremic Syndrome Presenting With Severe Neurological Complications: A Case Report.
Thrombotic microangiopathies (TMAs) are a group of rare, life-threatening disorders characterized by a classic triad of MAHA, severe thrombocytopenia, and ischemic tissue injury. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are the main types of TMAs. Based on the cause, HUS can be classified as typical or atypical. We present the case of a 4-year-old child referred to King Fahad Medical City in Riyadh, Saudi Arabia, with complaints of bloody diarrhea, vomiting, and fever. The condition progressed to altered consciousness, seizures, and quadriparesis. Upon admission, the patient received plasma infusion and underwent peritoneal dialysis. Eculizumab therapy was initiated 1 week after the presentation. Hematological and renal parameters improved rapidly, but neurological recovery was gradual, with significant progress observed over 6 years of follow-up. This case highlights that severe neurological manifestations can be an initial feature of HUS, not just TTP. Eculizumab was effective and life-saving in pediatric patients with TMA and severe neurological involvement, though CNS recovery may take years.
2026-07-25 | Typical or atypical hemolytic uremic syndrome? That is the question.
An 11-month-old boy with a clinical diagnosis of hemolytic uremic syndrome (HUS) associated with Shiga toxin-producing Escherichia coli infection (STEC-HUS) and a documented presence of both Shiga toxin (Stx) 1 and 2 in his stool showed an unexpected drop in platelet count during recovery (day 13 after diagnosis, day 10 after platelet nadir). Although clinically mild (from 305,000/mm3 to 216,000/mm3), this decline diverged from the expected platelet course observed in a cohort of 148 confirmed STEC-HUS patients treated at our center during the last decade and described in detail elsewhere, raising suspicion of an overlapping condition. Differential diagnoses were therefore investigated. ADAMTS13 activity and homocysteine levels were within normal range, and blood tests revealed a C3 level of 0.62 g/L. Given the unusual course of platelet count, which further dropped to 157,000/mm3, alongside the decreased C3 level, atypical HUS (aHUS) was suspected and treated accordingly with intravenous eculizumab. Platelet count peaked at 417,000/mm3 within 7 days, kidney function normalized, and the patient was discharged 23 days after admission. Genetic analysis revealed two heterozygous rare variants of uncertain significance: p.(Gly759Arg) and p.(Gly110Arg) in the complement factor H (CFH) and factor I (CFI) genes, respectively. Given the diagnostic uncertainty, C5 inhibition (C5i) was discontinued, but HUS relapsed 3.5 months later following a febrile upper respiratory tract infection. This case highlights the diagnostic challenge of discriminating aHUS when STEC infection coexists. As variants in complement regulatory genes (including pathogenic, likely pathogenic, or variants of unknown significance) are not uncommon in the general population, careful monitoring of platelet count using disease-specific reference trajectories may represent a clinically useful tool to detect early deviation from classical STEC-HUS evolution and prompt timely C5i, preventing severe consequences.
2026-08-12 | Protective effects of bismuth hydroxide against hemolytic uremic syndrome caused by Shiga toxin producing Escherichia coli.
Shiga toxin-producing Escherichia coli (STEC) is a major cause of foodborne disease and hemolytic uremic syndrome (HUS), a severe condition for which no specific therapies are currently available. The major virulence factor of STEC is Shiga toxin 2 (Stx2), which is encoded by the Stx2-converting bacteriophage 933 W used in this study, and phage induction plays a central role in toxin release and disease progression.In this study, we evaluated the protective in vivo effects of bismuth hydroxide gel (BHOG), a low-cost gastrointestinal compound with previously described antimicrobial and anti-toxin activities, in a murine model of STEC infection driven by the Stx2-converting bacteriophage 933 W. Mice treated with BHOG showed significantly higher survival rates compared than untreated controls (P = 0.0115), together with preservation of renal function, evidenced by significantly lower blood urea nitrogen and plasma urea levels (P < 0.05). Histological analysis demonstrated significantly reduced intestinal and renal tissues damage in treated animals compared with untreated controls. Overall, our findings provide in vivo evidence supporting a protective effect of BHOG against Shiga toxin-mediated disease. This study suggests that bismuth-based compounds may represent a potential adjunct to, or an alternative strategy for, the management of STEC-associated disease.
2026-08-08 | Pediatric Hemolytic Uremic Syndrome in North-Eastern Germany During the STEC O45:H2 Outbreak in 2025: Clinical Features and Short-Term Outcomes.
Shiga toxin-producing Escherichia coli (STEC)-associated hemolytic uremic syndrome (HUS) is a leading cause of pediatric acute kidney injury. Between August and October 2025, Germany experienced an outbreak of the rare STEC serotype O45:H2, comprising 53 laboratory-confirmed pediatric HUS cases. Because O45:H2-associated HUS had previously been reported only sporadically, this study characterized its clinical course and compared it with HUS caused by non-O45:H2 STEC serotypes. We retrospectively included all pediatric STEC-HUS cases treated in Northeastern Germany during the outbreak period. Microbiological confirmation was performed through cultivation and molecular typing at the National Reference and Consulting Laboratories. Patients were classified as O45:H2 or non-O45:H2 based on serotyping and the Robert Koch Institute (RKI) O45:H2 outbreak case definition. Clinical and laboratory parameters, dialysis requirements, transfusion needs, and short-term outcomes were compared. Thirty-seven children with STEC-associated HUS were included: 18 with O45:H2 and 19 with other serotypes. Patients with O45:H2 were significantly younger (median 2.0 vs 4.0 years, P = .01), while renal impairment at onset was comparable (minimal estimated glomerular filtration rate 8.0 vs 12 mL/min/1.73 m2). Dialysis was required in 65% of patients in both groups, with a trend toward longer duration in O45:H2 cases (median 10 vs 6 days). Hematologic parameters, markers of hemolysis, transfusion needs, neurological symptoms, and intensive care treatment were similar. One child died from myocardial failure. At 3-month follow-up, kidney function had recovered well in both groups. O45:H2-associated HUS was comparable in severity to non-O45:H2 STEC-HUS, while the younger age of affected children may indicate distinct host susceptibility or exposure patterns.
2026-08-06 | Shiga toxins and hemolytic uremic syndrome: pathogenesis, diagnosis, and therapy
Hemolytic Uremic Syndrome (HUS) is a severe thrombotic microangiopathy characterized by non-immune hemolytic anemia, thrombocytopenia, and acute renal failure. The most common form is caused by infections with Shiga toxin-producing Escherichia coli (STEC), which release potent Shiga toxins (Stx). This research addresses three objectives: elucidating mechanisms by which Stx subtypes contribute to HUS pathogenesis, developing a diagnostic platform for Stx detection, and evaluating novel therapeutic strategies. Patients infected with STEC co-producing Stx1 and Stx2 exhibit milder clinical manifestations than those infected with Stx2-producing strains. To investigate this, human blood was exposed to toxins, and extracellular vesicles (EV) were isolated and characterized. Co-exposure to both toxins produced a less toxic EV population, showing reduced number, size, and toxic cargo compared to EV generated by Stx2 alone, which are most strongly associated with HUS. Prompt STEC diagnosis is crucial for preventing HUS. A gold plasmonic biosensor was developed, coupling surface-enhanced Raman spectroscopy (SERS) with principal component analysis (PCA) for rapid Stx detection. The system recognizes Stx1a, Stx2a, and Stx2a-cleaved, enabling real-time analysis. Currently, no specific HUS therapy exists. NAB815, a polymyxin B derivative, emerged as a promising candidate. Previous studies showed sub-bactericidal NAB815 doses reduce Stx2a-containing EV formation in human blood. In vivo evaluation using CD1 mice demonstrated effective protection against kidney damage when NAB815 was co-administered with either free Stx2a or blood-derived Stx2a containing EV. Since antibiotics can trigger bacterial SOS response and increase Stx production, NAB815's safety was evaluated in both engineered and wildtype STEC strains. Results confirmed NAB815 as a safe strategy for HUS prevention and management. These findings provide new insights into HUS pathogenesis while offering innovative approaches for early diagnosis and targeted intervention in STEC infections.
2026-08-05 | Favorable Outcome With Eculizumab in Hemolytic Uremic Syndrome Presenting With Severe Neurological Complications: A Case Report.
Thrombotic microangiopathies (TMAs) are a group of rare, life-threatening disorders characterized by a classic triad of MAHA, severe thrombocytopenia, and ischemic tissue injury. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are the main types of TMAs. Based on the cause, HUS can be classified as typical or atypical. We present the case of a 4-year-old child referred to King Fahad Medical City in Riyadh, Saudi Arabia, with complaints of bloody diarrhea, vomiting, and fever. The condition progressed to altered consciousness, seizures, and quadriparesis. Upon admission, the patient received plasma infusion and underwent peritoneal dialysis. Eculizumab therapy was initiated 1 week after the presentation. Hematological and renal parameters improved rapidly, but neurological recovery was gradual, with significant progress observed over 6 years of follow-up. This case highlights that severe neurological manifestations can be an initial feature of HUS, not just TTP. Eculizumab was effective and life-saving in pediatric patients with TMA and severe neurological involvement, though CNS recovery may take years.
2026-07-25 | Typical or atypical hemolytic uremic syndrome? That is the question.
An 11-month-old boy with a clinical diagnosis of hemolytic uremic syndrome (HUS) associated with Shiga toxin-producing Escherichia coli infection (STEC-HUS) and a documented presence of both Shiga toxin (Stx) 1 and 2 in his stool showed an unexpected drop in platelet count during recovery (day 13 after diagnosis, day 10 after platelet nadir). Although clinically mild (from 305,000/mm3 to 216,000/mm3), this decline diverged from the expected platelet course observed in a cohort of 148 confirmed STEC-HUS patients treated at our center during the last decade and described in detail elsewhere, raising suspicion of an overlapping condition. Differential diagnoses were therefore investigated. ADAMTS13 activity and homocysteine levels were within normal range, and blood tests revealed a C3 level of 0.62 g/L. Given the unusual course of platelet count, which further dropped to 157,000/mm3, alongside the decreased C3 level, atypical HUS (aHUS) was suspected and treated accordingly with intravenous eculizumab. Platelet count peaked at 417,000/mm3 within 7 days, kidney function normalized, and the patient was discharged 23 days after admission. Genetic analysis revealed two heterozygous rare variants of uncertain significance: p.(Gly759Arg) and p.(Gly110Arg) in the complement factor H (CFH) and factor I (CFI) genes, respectively. Given the diagnostic uncertainty, C5 inhibition (C5i) was discontinued, but HUS relapsed 3.5 months later following a febrile upper respiratory tract infection. This case highlights the diagnostic challenge of discriminating aHUS when STEC infection coexists. As variants in complement regulatory genes (including pathogenic, likely pathogenic, or variants of unknown significance) are not uncommon in the general population, careful monitoring of platelet count using disease-specific reference trajectories may represent a clinically useful tool to detect early deviation from classical STEC-HUS evolution and prompt timely C5i, preventing severe consequences.
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Drug Discovery Landscape
6 orphan drug designations for Shiga toxin-associated hemolytic uremic syndrome.
6 orphan drug designations for Shiga toxin-associated hemolytic uremic syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Phage-derived, non-replicative delivery vector carrying a DNA payload encoding an RNA-guided nuclease that targets stx genes of Shiga toxin-producing Escherichia coli (STEC) | gene therapies | FDA | 2022-03-17 | — | Eligo Bioscience SA |
neutralizing equine anti-Stx hyperimmune immunoglobulin F(ab')2 fragment | antibodies | FDA | 2019-08-19 | — | Inmunova SA |
eculizumab | antibodies | FDA | 2011-10-18 | — | Alexion Pharmaceuticals, Inc. |
chimeric monoclonal antibodies, c-alphaStx2 | antibodies | FDA | 2005-10-04 | — | Taro Pharmaceuticals Inc. |
humanized monoclonal antibody against Shiga-like toxin II | antibodies | FDA | 2001-09-12 | — | Teijin America, Inc. |
Synsorb Pk | other | FDA | 1995-07-17 | — | Synsorb Biotech Inc. |
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