Shiga Toxin-Associated Hemolytic Uremic Syndrome

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Pathophysiology

13

Colonic Colonisation and Attaching-and-Effacing Lesion Formation

Ingested STEC colonises the colon. Enterohaemorrhagic strains carry the locus of enterocyte effacement, whose intimin adhesin and type III secretion system produce attaching-and-effacing lesions that bring the organism into intimate contact with the epithelium. This is the site at which toxin is delivered to the host, and the lesion underlies the haemorrhagic colitis of the prodrome.

colon epithelial cell CL:0011108

colon UBERON:0001155

Downstream

Bloody diarrhea Invasion of the colonic mucosa at the attaching-and-effacing lesion produces the haemorrhagic colitis that presents as bloody diarrhoea.

Shiga Toxin Translocation Across the Intestinal Epithelium Colonic colonisation is what places toxin-producing bacteria at the epithelial surface, so that released toxin has access to the barrier it must cross.

Show evidence (1 reference)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Other

"Enterohemorrhagic E. coli (EHEC) are a sub-group of STEC that have the ability to form attaching and effacing lesions (A/E lesions) that facilitate intimate adhesion to the intestinal mucosa."

Defines the attaching-and-effacing lesion and its role in intimate mucosal adhesion.

Shiga Toxin Translocation Across the Intestinal Epithelium

Toxin released in the gut lumen crosses the intestinal epithelium into the systemic circulation. Toxin acting on the epithelium itself also triggers a ribotoxic stress response there, inducing chemokines and apoptosis. The identity of the systemic carrier of the toxin in blood remains unsettled, so the delivery step is the least well established link in this chain.

intestinal epithelial cell CL:0002563

apoptotic process in intestinal epithelium GO:0006915 ↑ INCREASED

Downstream

Shiga Toxin Binding to Globotriaosylceramide on Gb3-Rich Cells Translocation into the circulation is what gives the toxin access to the glomerular endothelium and podocytes that carry its receptor.

Show evidence (1 reference)

PMID:12595468 SUPPORT BACKGROUND In vitro / ex vivo

"Shiga toxins (Stxs) may access the host systemic circulation by absorption across the intestinal epithelium."

States the translocation route this node represents, in the paper that characterised the epithelial response to the toxin.

Shiga Toxin Binding to Globotriaosylceramide on Gb3-Rich Cells

The toxin is an AB5 holotoxin: a pentamer of B subunits binds the neutral glycosphingolipid globotriaosylceramide (Gb3/CD77) on the target cell surface. Gb3 density differs markedly between vascular beds, and endothelial sensitivity to the toxin tracks that density, which is what targets the toxin to the glomerular endothelium and sets the organ tropism of the disease. The podocyte is bound here on the strength of PMID:37863058, whose human biopsy arm and title put the podocyte among the toxin's targets. Do not read it off that paper's mouse alone: Gb3 was engineered into podocytes there, so the model shows what podocyte-restricted receptor does, not that human podocytes carry it.

glomerular endothelial cell CL:0002188 podocyte CL:0000653

receptor-mediated endocytosis of Shiga toxin GO:0006898

renal glomerulus UBERON:0000074

Downstream

Retrograde Trafficking to the Endoplasmic Reticulum Receptor binding is the committed step for internalisation: the bound holotoxin is endocytosed and routed retrogradely to reach the cytosol.

Show evidence (2 references)

PMID:25530917 SUPPORT REVIEW SYNTHESIS Other

"The Stxs consist of two major subunits, an A subunit that joins noncovalently to a pentamer of five identical B subunits."

Establishes the AB5 architecture whose B pentamer performs the receptor binding this node represents.

PMID:23955166 SUPPORT REVIEW SYNTHESIS In vitro / ex vivo

"The presence of Gb3 targets Stx to the glomerular endothelium, where it causes major vascular injury. Endothelial cells from different vascular beds display varying degrees of sensitivity to Stx due, in large part, to the level of Gb3 expression."

Ties receptor density to glomerular tropism and to the differing sensitivity of vascular beds.

Retrograde Trafficking to the Endoplasmic Reticulum

The internalised holotoxin travels from endosome to Golgi to endoplasmic reticulum; the A subunit is then cleaved and reduced, and the A1 fragment enters the cytosol. Curated separately from the enzymatic lesion because transport and catalysis are distinct molecular events: a catalytically dead toxin still traffics, which is what makes the mutant experiment downstream informative.

glomerular endothelial cell CL:0002188

retrograde transport, endosome to Golgi GO:0042147

Downstream

28S rRNA Depurination and Translational Arrest Reaching the cytosol is the precondition for the enzymatic lesion: the A1 fragment can only act on the ribosome once retrograde transport has delivered it there.

Show evidence (1 reference)

PMID:25530917 SUPPORT REVIEW SYNTHESIS Other

"The Stxs traffic in a retrograde manner within the cell, such that the A subunit of the toxin reaches the cytosol only after the toxin moves from the endosome to the Golgi and then to the endoplasmic reticulum."

Gives the retrograde route from endosome through Golgi to endoplasmic reticulum that this node represents.

28S rRNA Depurination and Translational Arrest

In the cytosol the A1 fragment acts as an RNA N-glycosidase, removing a single adenine from the conserved sarcin-ricin loop of 28S rRNA in the 60S subunit and halting translation. This is the toxin's defining enzymatic lesion, and its enzymatic activity is required for the downstream stress signalling.

inhibition of translation by 28S rRNA depurination GO:0017148 ↑ INCREASED

Shiga toxin A1 fragment rRNA N-glycosidase activity GO:0030598 ↑ INCREASED

Downstream

Ribotoxic Stress Response and Target Cell Apoptosis Ribosomal damage is what activates the stress-activated kinases: a catalytically dead toxin mutant activates neither p38 nor JNK, which is what makes this edge causal rather than merely coincident.

Endothelial Activation and Loss of Thromboresistance Toxin reaching the endothelial cytosol also reprograms endothelial gene expression, through NF-kappaB. The link is indirect because the activation phenotype arises at sublethal toxin doses, where it is not accounted for by translational arrest alone.

Show evidence (2 references)

PMID:12595468 SUPPORT BACKGROUND In vitro / ex vivo

"The A subunit inactivates ribosomes by cleaving a specific adenine from the 28S rRNA."

States the single-adenine depurination of 28S rRNA that is the enzymatic lesion of this node.

PMID:23955166 SUPPORT REVIEW SYNTHESIS In vitro / ex vivo

"the Stx A subunit specifically removes an adenine residue within the highly conserved alpha-sarcin/ricin loop on eukaryotic 28S rRNA"

Independently records the site of depurination within the conserved rRNA loop.

Ribotoxic Stress Response and Target Cell Apoptosis

Damage to the ribosome activates the stress-activated protein kinases p38 and JNK, inducing primary response genes, C-X-C chemokines including interleukin-8, and caspase-dependent apoptosis. This is the arm by which toxin kills target cells and recruits inflammation, as distinct from the sublethal gene-reprogramming arm that makes endothelium thrombogenic.

intestinal epithelial cell CL:0002563 glomerular endothelial cell CL:0002188

apoptotic process GO:0006915 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED

Downstream

Glomerular Thrombotic Microangiopathy Apoptotic loss and inflammatory activation of glomerular cells contribute to the microangiopathic lesion. The link is indirect: the cited experiments establish the apoptotic response in epithelial and endothelial cells, not that apoptosis alone produces the glomerular lesion.

Show evidence (1 reference)

PMID:12595468 SUPPORT In vitro / ex vivo

"Stx1 treatment of HCT-8 cells resulted in cell death that was associated with caspase 3 cleavage and internucleosomal DNA fragmentation; this cytotoxicity also required Stx1 enzymatic activity."

Documents caspase-dependent apoptosis downstream of the ribosomal lesion, dependent on toxin enzymatic activity.

Endothelial Activation and Loss of Thromboresistance

At sublethal doses the toxin reprograms endothelial gene expression rather than killing the cell. NF-kappaB activation induces adhesion molecules and chemokines, leukocytes adhere, and the cell loses its normal thromboresistant phenotype and becomes thrombogenic - the event generally taken to trigger the microangiopathy.

glomerular endothelial cell CL:0002188

inflammatory response GO:0006954 ↑ INCREASED

renal glomerulus UBERON:0000074

Downstream

Alternative Complement Pathway Activation on Injured Endothelium Complement activation in response to the toxin acts at the activated endothelial surface, favouring platelet thrombus formation there.

Ultra-Large von Willebrand Factor Secretion and Platelet Capture The same activated endothelium rapidly secretes ultra-large von Willebrand factor multimers onto its surface, to which platelets adhere.

Show evidence (2 references)

PMID:20424866 SUPPORT REVIEW SYNTHESIS In vitro / ex vivo

"Activated endothelial cells in response to Stxs lose the normal thromboresistance phenotype and become thrombogenic, initiating microvascular thrombus formation."

States the loss of thromboresistance and the shift to a thrombogenic phenotype that define this node.

PMID:20424866 SUPPORT REVIEW SYNTHESIS In vitro / ex vivo

"trigger a cascade of signaling events, involving NF-κB activation, that induce expression of genes encoding for adhesion molecules and chemokines, and culminate in the adhesion of leukocytes to endothelial cells"

Gives the NF-kappaB-dependent adhesion-molecule and chemokine programme that constitutes endothelial activation here.

Alternative Complement Pathway Activation on Injured Endothelium

Shiga toxin activates the alternative complement pathway locally on the glomerular endothelial surface. There is no inherited regulator lesion here, which is what distinguishes this disease from atypical HUS; instead the toxin reduces factor H binding at the endothelial surface, so local regulation fails where the toxin has acted. In a mouse model expressing the toxin receptor only in podocytes, toxin challenge reduced podocyte VEGF-A, stripped the glomerular endothelial glycocalyx, lowered inhibitory factor H binding and activated complement locally - and early C5 inhibition rescued the phenotype.

glomerular endothelial cell CL:0002188 podocyte CL:0000653

complement activation, alternative pathway GO:0006957 ↑ INCREASED

renal glomerulus UBERON:0000074

Animal models

Pod-Gb3 transgenic mouse (Gb3 restricted to podocytes) Mouse recapitulates Toxin challenge reproduced the HUS phenotype through the VEGF-A, glycocalyx, factor-H and local complement chain this node asserts, and early C5 inhibition rescued it.

Downstream

Glomerular Thrombotic Microangiopathy Local complement activation on the endothelial surface amplifies injury and platelet thrombus formation, producing the glomerular lesion.

Show evidence (1 reference)

PMID:37863058 SUPPORT Model organism

"This was mediated by a reduction in podocyte vascular endothelial growth factor A (VEGF-A), which led to loss of glomerular endothelial cell (GEnC) glycocalyx, a reduction in GEnC inhibitory complement factor H binding, and local activation of the complement pathway."

Gives the mechanism by which the toxin produces local complement activation, including the loss of factor H binding.

Ultra-Large von Willebrand Factor Secretion and Platelet Capture

Toxin-stimulated glomerular and umbilical-vein endothelial cells secrete ultra-large von Willebrand factor multimeric strings, to which perfused platelets adhere immediately. The toxin additionally delays ADAMTS13 cleavage of those strings, so the platelet-decorated multimers persist. Note that plasma ADAMTS13 activity in this disease is within the normal range - the defect is local and toxin-imposed, not the systemic protease deficiency of thrombotic thrombocytopenic purpura.

glomerular endothelial cell CL:0002188 platelet CL:0000233

platelet activation GO:0030168 ↑ INCREASED

Downstream

Glomerular Thrombotic Microangiopathy Platelet adhesion to persistent VWF strings above the glomerular endothelium initiates the platelet-fibrin thrombi that occlude the capillaries.

Show evidence (2 references)

PMID:16131569 SUPPORT In vitro / ex vivo

"Perfused normal human platelets immediately adhered to the secreted ULVWF multimeric strings."

Direct demonstration of platelet capture on the secreted multimeric strings.

PMID:16131569 SUPPORT In vitro / ex vivo

"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."

Quantifies the toxin-imposed delay in ADAMTS13 cleavage that lets the platelet-decorated strings persist.

Glomerular Thrombotic Microangiopathy

The converging arms produce the defining lesion: fibrin-rich platelet thrombi in the glomerular capillaries, with endothelial swelling, detachment from the basement membrane, subendothelial deposits and luminal narrowing. Pre-glomerular arterioles and medium-sized vessels may also be involved.

glomerular endothelial cell CL:0002188 platelet CL:0000233

blood coagulation GO:0007596 ↑ INCREASED

renal glomerulus UBERON:0000074 kidney UBERON:0002113

Downstream

Oliguria Occlusion of the glomerular capillaries is what collapses filtration to the point of oligoanuria, the renal outcome that decides whether dialysis is needed. The cited model of HUS pathogenesis puts glomerular thrombi upstream of renal shutdown.

Proteinuria Glomerular endothelial injury and the podocyte involvement that accompanies it breach the filtration barrier, which is what admits protein to the urine. Left uncited: the cited sources establish the glomerular lesion and list proteinuria among the renal sequelae, but none of them measures urinary protein against the lesion, so no quote in this entry supports the step itself.

Acute kidney injury Occlusion of the glomerular microvasculature is what produces the acute renal failure of the triad.

Mechanical Erythrocyte Fragmentation Erythrocytes are fragmented as they pass the occluded, fibrin-laden capillaries.

Platelet Consumption in Microvascular Thrombi Platelets are consumed within the thrombi forming in the occluded capillaries.

Show evidence (2 references)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"Histopathological manifestations of Stx-associated HUS include fibrin-rich microvascular thrombi primarily in the renal glomeruli, although pre-glomerular arterioles and medium-sized vessels may also be affected."

Describes the histopathology of the lesion, including its glomerular predominance and arteriolar extension.

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"Endothelial swelling and detachment from the underlying basement membrane and subendothelial deposits accompanied by vascular edema and narrowing of the vessel lumen are also observed."

Gives the endothelial component of the lesion that accompanies the thrombi.

Mechanical Erythrocyte Fragmentation

Erythrocytes are sheared as they traverse the occluded, fibrin-laden microvasculature and appear on the blood film as fragments. The haemolysis is mechanical rather than immune, which is the basis of the negative direct Coombs test used to separate it from immune haemolysis; no reference cached for this entry states that, so it is recorded here as an uncited standard-practice point rather than as a sourced claim.

erythrocyte CL:0000232

Downstream

Microangiopathic hemolytic anemia Mechanical fragmentation of erythrocytes is the basis of the anaemia in this syndrome.

Schistocytosis The fragmented erythrocytes produced by shearing are what appear on the blood film as schistocytes.

Show evidence (1 reference)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"red blood cells become fragmented as they flow through vessels with marked edema, fibrin deposits, and intravascular thrombosis"

States the erythrocyte-shearing half of the classical account, in the occluded vessels this node describes.

Platelet Consumption in Microvascular Thrombi

Platelets captured into the growing thrombi are removed from the circulation, which is the classical account of the thrombocytopenia. Curated separately from erythrocyte shearing because the two are different events on different cells, reported by different laboratory findings, even though one cited sentence covers both.

platelet CL:0000233

Downstream

Thrombocytopenia Platelet consumption within microvascular thrombi produces the thrombocytopenia.

Show evidence (1 reference)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"thrombocytopenia results from platelet consumption in thrombi"

States the platelet-consumption half of the classical account that this node carries.

Extrarenal Microangiopathy in Gb3-Rich Vascular Beds

Gb3 is expressed on cerebral endothelium and in other beds, so the same toxin-driven microangiopathy occurs outside the kidney. Neurological involvement is the commonest cause of death in the acute phase; cardiac involvement is infrequent but carries high mortality, and gastrointestinal, pulmonary and pancreatic involvement is probably under-recognised.

brain UBERON:0000955 pancreas UBERON:0001264 heart UBERON:0000948

Downstream

Encephalopathy Cerebral microvascular involvement is taken to produce the encephalopathy and seizures of severe disease. Left uncited and marked indirect: the cited sources report how often neurological involvement occurs and that it drives acute mortality, which is phenotype frequency rather than mechanism, so no quote in this entry establishes the step itself.

Seizure Seizures are the other common expression of the central nervous system involvement, and are uncited here for the same reason as the encephalopathy edge.

Show evidence (3 references)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"Neurological involvement occurs in 10% to 25% of patients and is the most common cause of mortality during the acute phase of disease."

Quantifies neurological involvement and identifies it as the leading cause of acute mortality.

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"Although infrequent, cardiac complications are associated with a high risk of mortality in HUS patients"

Records cardiac involvement as infrequent but high-risk, supporting the extrarenal scope of this node.

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"Involvement of other organs such as the gastrointestinal tract, lungs, and pancreas is likely under-appreciated."

Supports the pancreatic and other extrarenal sites bound on this node, with the authors' own caveat that they are under-recognised.

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Pathograph

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Phenotypes

12

Blood 3

Microangiopathic hemolytic anemia VERY_FREQUENT HP:0001937

Show evidence (1 reference)

PMID:21784993 SUPPORT Human clinical

"anemia (hematocrit level <30% with smear evidence of intravascular erythrocyte destruction)"

Gives the operational case definition of the microangiopathic anaemia used in a prospective multicentre cohort.

Schistocytosis HP:0001981

Show evidence (1 reference)

PMID:21784993 SUPPORT Human clinical

"smear evidence of intravascular erythrocyte destruction"

The case definition rests on blood-film evidence of erythrocyte destruction, which is the schistocytosis this phenotype records.

Thrombocytopenia VERY_FREQUENT HP:0001873

Show evidence (1 reference)

PMID:21784993 SUPPORT Human clinical

"thrombocytopenia (platelet count <150 × 10³/mm³)"

Gives the platelet threshold used to define the thrombocytopenia of this syndrome in a prospective cohort.

Cardiovascular 1

Hypertension HP:0000822

Show evidence (1 reference)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"25% of survivors experience long-term renal sequelae, including decreased glomerular filtration rate, proteinuria, hypertension, chronic kidney disease, and end-stage renal disease"

Lists hypertension among the long-term renal sequelae of survivors.

Digestive 1

Bloody diarrhea VERY_FREQUENT HP:0025085

Show evidence (1 reference)

PMID:21784993 SUPPORT BACKGROUND Human clinical

"diarrhea that is initially nonbloody but that becomes bloody 1 to 3 days later"

Describes the characteristic evolution of the prodromal diarrhoea in children infected with E. coli O157:H7.

Genitourinary 4

Acute kidney injury VERY_FREQUENT HP:0001919

Sequelae: Chronic kidney disease Hypertension

Show evidence (2 references)

PMID:37303085 SUPPORT BACKGROUND Human clinical

"Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) in children is a severe condition, resulting in approximately 50% of patients requiring RRT."

Quantifies the severity of the renal injury by the proportion of children needing renal replacement therapy.

PMID:37863058 SUPPORT BACKGROUND Human clinical

"Shiga toxin (Stx)-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) is the leading cause of acute kidney injury in children"

States the clinical standing of the renal phenotype. The quote is from the introduction of a mouse study, so it reports the human clinical picture rather than that paper's own experimental result.

Oliguria FREQUENT HP:0100520

Show evidence (2 references)

PMID:21784993 SUPPORT Human clinical

"The overall oligoanuric rate of the 50 participants was 68%"

Gives the observed frequency of oligoanuria in a prospective cohort of children with diarrhoea-associated HUS.

PMID:21784993 SUPPORT BACKGROUND Human clinical

"Patients with oligoanuric HUS usually need dialysis and have longer hospitalizations"

Establishes the prognostic weight of oligoanuria, which is why it is curated separately from acute kidney injury.

Proteinuria HP:0000093

Show evidence (1 reference)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"long-term renal sequelae, including decreased glomerular filtration rate, proteinuria, hypertension, chronic kidney disease, and end-stage renal disease"

Names proteinuria among the renal sequelae documented in survivors.

Chronic kidney disease HP:0012622

Show evidence (2 references)

PMID:39518638 SUPPORT Human clinical

"kidney sequelae were observed at 5-year follow-ups in 31% of children with STEC-HUS"

A national prospective registry quantifies renal sequelae at five years.

PMID:39518638 SUPPORT Human clinical

"The development of CKD5 in childhood as a consequence of HUS has become exceptional."

Qualifies the sequelae figure: chronic kidney disease is common in survivors, but end-stage disease in childhood is now rare.

Metabolism 1

Elevated circulating creatinine concentration HP:0003259

Show evidence (1 reference)

PMID:21784993 SUPPORT Human clinical

"impaired renal function (serum creatinine concentration > upper limit of reference range for age)"

Gives the creatinine criterion by which renal impairment is established in this syndrome.

Nervous System 2

Encephalopathy FREQUENT HP:0001298

Show evidence (2 references)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"Neurological involvement occurs in 10% to 25% of patients and is the most common cause of mortality during the acute phase of disease."

Gives both the frequency of neurological involvement and its contribution to acute mortality.

PMID:32323005 SUPPORT Human clinical

"Twenty-nine patients (33%) developed major neurological symptoms."

An independent nationwide paediatric cohort quantifies major neurological involvement.

Seizure OCCASIONAL HP:0001250

Show evidence (1 reference)

PMID:23955166 SUPPORT INDIRECT REVIEW SYNTHESIS Human clinical

"Neurological involvement occurs in 10% to 25% of patients and is the most common cause of mortality during the acute phase of disease."

Establishes the frequency of neurological involvement, of which seizures are one expression. Indirect because the source does not report a seizure frequency separately.

💊

Medical Actions

6

Supportive Care

Action: Supportive Care NCIT:C15747

Supportive management is the mainstay: there is no approved antitoxin and no specific treatment of proven benefit in the acute phase. It comprises attention to volume status, electrolyte and acid-base management, blood pressure control, transfusion as needed, and renal replacement therapy when the kidney injury demands it.

Mechanism Target:

MODULATES Acute kidney injury — Supportive care moderates the consequences of the renal injury rather than acting on the toxin that causes it.

Show evidence (1 reference)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"Patients currently receive supportive care to manage symptoms, as no specific treatment exists for D+HUS."

States that supportive care is the available management and that no specific therapy exists.

Early Intravenous Volume Expansion

Action: intravenous volume expansion Ontology label: Fluid Therapy NCIT:C116537

Intravenous fluid given in the first four days of diarrhoea, before HUS is established, is associated with a lower rate of oligoanuric renal failure. Children who became oligoanuric had received less intravenous fluid and sodium in that window. This is an observational association from a prospective cohort, not a randomised result, and the authors describe the intervention as underused.

Mechanism Target:

MODULATES Oliguria — Maintaining renal perfusion during the prodrome is associated with preservation of urine output once HUS develops.

Show evidence (1 reference)

PMID:21784993 SUPPORT INDIRECT Human clinical

"The relative risk of oligoanuria when fluids were not given in this interval was 1.6 (95% confidence interval, 1.1-2.4; P = .02)."

Gives the effect estimate for withholding early fluids. Indirect because the design is observational, so the association is not established as causal.

Show evidence (1 reference)

PMID:21784993 SUPPORT Human clinical

"Intravenous volume expansion is an underused intervention that could decrease the frequency of oligoanuric renal failure in patients at risk of HUS."

The authors' own conclusion about the role of early volume expansion in patients at risk.

Renal Replacement Therapy

Action: hemodialysis Ontology label: Hemodialysis NCIT:C15248

Platform: Device

Dialysis supports the patient through oligoanuric acute kidney injury. It is needed by a large share of children in the acute phase - 63% in the Finnish national series quoted below, about half in the French trial cohort - and is usually temporary.

Mechanism Target:

BYPASSES Acute kidney injury — Renal replacement substitutes for excretory function while the glomerular lesion resolves.

Show evidence (1 reference)

PMID:32323005 SUPPORT Human clinical

"Fifty-five patients (63%) needed dialysis."

Quantifies the use of dialysis in a nationwide paediatric STEC-HUS cohort.

Packed Red Blood Cell Transfusion

Action: packed red blood cell transfusion Ontology label: Packed Red Blood Cell Transfusion NCIT:C15409

Transfusion corrects the anaemia of the microangiopathic haemolysis.

Mechanism Target:

RESTORES Microangiopathic hemolytic anemia — Transfusion replaces the erythrocytes lost to mechanical haemolysis.

Eculizumab

Action: Pharmacotherapy NCIT:C15986

Agent: eculizumab NCIT:C48386

Platform: Monoclonal antibody

Terminal complement inhibition is supported mechanistically - toxin-driven complement activation is part of the lesion, and early C5 inhibition rescues a mouse model - but is not standard care. The phase 3 randomised placebo-controlled trial in 100 children found no effect on the acute phase and a lower proportion with renal sequelae at one year. The two results belong together: the acute primary endpoint was negative, and the one-year difference is a follow-up result the trial's own authors frame as needing larger studies. The abstract lists its secondary endpoints as haematologic and extrarenal involvement, so the one-year sequelae figure is not described there as one of them.

Mechanism Target:

INHIBITS Alternative Complement Pathway Activation on Injured Endothelium — Eculizumab blocks C5 cleavage and so the terminal pathway downstream of the complement activation this disease induces at the endothelial surface.

Show evidence (1 reference)

PMID:37863058 SUPPORT Model organism

"Early therapeutic inhibition of the terminal complement pathway with a C5 inhibitor rescued this podocyte-driven, Stx-induced HUS phenotype."

Model-organism evidence that inhibiting the terminal pathway reverses the toxin-driven phenotype.

Show evidence (3 references)

PMID:37303085 REFUTE Human clinical

"The rate of RRT <48 hours did not differ significantly between the two groups (48% in the placebo versus 38% in the eculizumab group; P = 0.31) or in the course of ARF."

The trial's primary endpoint was negative, refuting an acute-phase benefit of eculizumab in this disease.

PMID:37303085 SUPPORT Human clinical

"The proportion of patients experiencing renal sequelae at 1 year was lower in the eculizumab group than in the placebo group (43.48% and 64.44%, respectively, P = 0.04)."

The same trial found fewer renal sequelae at one year. Recorded as a separate SUPPORT item because it bears on a different claim from the negative acute endpoint, and both are needed to state the evidence honestly.

PMID:37303085 SUPPORT Human clinical

"Larger prospective studies would be needed to further explore eculizumab as a potential treatment."

The investigators' own statement of how much weight the one-year result can carry.

Therapeutic Plasma Exchange

Action: plasmapheresis Ontology label: Plasmapheresis NCIT:C15304

Plasma therapy is not established in this disease. A large prospective paediatric study found plasma therapy associated with poor long-term outcome, and its first-line use is described as controversial. Recorded here because it is still used in some settings, not because it is recommended.

Show evidence (1 reference)

PMID:23955166 REFUTE REVIEW SYNTHESIS Human clinical

"a recent prospective study of 619 children with HUS identified an association between plasma therapy and poor long-term outcome"

Reports an association between plasma therapy and poor long-term outcome, which cuts against its use in this disease.

🌍

Environmental Factors

2

Antibiotic administration during STEC colitis

Giving antibiotics during the diarrhoeal prodrome is associated with progression to HUS, which is why antibiotics are not recommended in suspected or confirmed STEC infection. The association is significant in low-risk-of-bias studies but not in the pooled set as a whole, and the proposed mechanism - induction of the bacterial SOS response and phage-mediated toxin release - is not established by these clinical data.

Show evidence (3 references)

PMID:10874060 SUPPORT Human clinical

"antibiotic administration remained a risk factor for the development of the hemolytic uremic syndrome (relative risk, 17.3; 95 percent confidence interval, 2.2 to 137)"

Gives the adjusted effect estimate from the prospective cohort, with the very wide confidence interval that reflects its small size.

PMID:26917812 SUPPORT Human clinical

"after excluding studies at high risk of bias and those that did not employ an acceptable definition of HUS, there was a significant association. Consequently, the use of antibiotics in individuals with STEC infections is not recommended."

The meta-analysis supports the recommendation against antibiotics on the basis of its low-risk-of-bias subset.

PMID:26917812 REFUTE Human clinical

"Overall, use of antibiotics was not associated with an increased risk of developing HUS"

The same meta-analysis found no association across all eligible studies. Recorded as a separate REFUTE item rather than folded into the supporting one, because the pooled and restricted analyses point in opposite directions and both belong in the record.

Mechanism Target:

EXACERBATES Shiga Toxin Translocation Across the Intestinal Epithelium — Antibiotic exposure during colitis is thought to increase the toxin burden reaching the circulation. The link is indirect: the clinical studies measure progression to HUS, not toxin flux across the epithelium.

Show evidence (1 reference)

PMID:10874060 SUPPORT INDIRECT Human clinical

"Antibiotic treatment of children with E. coli O157:H7 infection increases the risk of the hemolytic-uremic syndrome."

A prospective cohort finds antibiotic treatment during infection raises the risk of the syndrome. Indirect evidence for this edge because the outcome measured is HUS, not toxin translocation.

Ingestion of STEC-contaminated food and water

Consumption of food and drinking water contaminated from the ruminant reservoir is the principal route by which infection is acquired, and the exposure that public-health prevention targets.

Show evidence (1 reference)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"The principal route of infection is consumption of contaminated food and drinking water, although infection may also occur via direct contact with animals, person-to-person contact, and environmental exposure."

Establishes the exposure and places it ahead of the other recognised routes.

Mechanism Target:

TRIGGERS Colonic Colonisation and Attaching-and-Effacing Lesion Formation — Ingestion of the contaminated vehicle is the route by which the organism reaches the colon and establishes the colonisation that initiates disease.

Show evidence (1 reference)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"The principal route of infection is consumption of contaminated food and drinking water"

Names ingestion of contaminated food and water as the principal route of the infection that initiates this disease.

🔬

Biochemical Markers

1

Lactate dehydrogenase

Show evidence (1 reference)

PMID:40255570 SUPPORT Human clinical

"Significant improvements were observed in platelet count (63%), lactate dehydrogenase levels (76% within the first week)"

Shows lactate dehydrogenase used as a haemolysis readout followed over treatment in paediatric HUS, including STEC-HUS patients.

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Diagnosis

1

Stool stx1/stx2 nucleic acid amplification testing

Detecting the toxin genes in stool is what identifies the agent, and it is the step that separates this disease from atypical HUS, where management differs. A multiplex real-time PCR for stx1 and stx2 detects both O157 and non-O157 STEC - which matters because the two occur at similar incidence - and outperformed culture-based reference testing. Sorbitol-MacConkey culture, which exploits O157's failure to ferment sorbitol, misses the non-O157 serogroups by construction.

The research report also describes Shiga toxin immunoassay, anti-O157 LPS serology for stool-negative cases, and the point that a negative stool does not exclude STEC-HUS because the toxin may have cleared by the time HUS presents. Those are not recorded as claims here because no reference cached for this entry states them in quotable form; they are a curation gap, not a dismissal.

Show evidence (3 references)

PMID:23843484 SUPPORT Human clinical

"we assessed the performance of a multiplex, real-time PCR assay targeting stx1 and stx2 for the detection of O157 and non-O157 STEC in diarrheal stool samples enriched in Gram-negative broth"

Establishes stool stx1/stx2 PCR as the assay that detects the agent across serogroups.

PMID:23843484 SUPPORT Human clinical

"We show that the assay is 100% sensitive (95% confidence interval [CI], 89.1% to 100%) and 98.5% specific (95% CI, 90.6% to 99.9%)"

Gives the test performance that makes PCR the preferred detection route.

PMID:23843484 SUPPORT Human clinical

"the recommendations of the CDC for laboratories to test all diarrheal stool samples from patients with acute community-acquired diarrhea for non-O157 STEC in addition to the O157 serotype by using a sensitive assay"

Records the recommendation to test for non-O157 STEC as well as O157, which is why an O157-only culture strategy is inadequate.

📈

Progression

3

STEC colitis prodrome

Duration: Several days; HUS emerges about 5-13 days after diarrhoea onset, often as the diarrhoea is resolving.

Diarrhoea that becomes bloody over one to three days, with abdominal tenderness and pain around defecation and frequently no fever at presentation. This is the window in which intervention can alter the renal outcome, and in which antibiotics should be withheld. Most infections stop here: 6.3% of 3464 STEC O157 infections under US surveillance progressed to HUS, rising to 15.3% in children under five.

Show evidence (2 references)

PMID:19827953 SUPPORT Human clinical

"A total of 3464 STEC O157 infections were ascertained; 218 persons (6.3%) developed HUS. The highest proportion of HUS cases (15.3%) occurred among children aged <5 years."

Quantifies how often this phase progresses to HUS, overall and in the highest-risk age group. It is recorded here rather than in prevalence because the denominator is infected persons, not a population.

PMID:21784993 SUPPORT Human clinical

"the brief interval between first presentation with diarrhea and HUS onset could be exploited to maintain or improve renal perfusion, possibly averting renal shutdown"

Identifies the prodrome as a distinct phase with its own therapeutic window ahead of HUS onset.

Acute thrombotic microangiopathy

Duration: Days to a few weeks; dialysis, when needed, usually for days to weeks.

The full triad with acute kidney injury, around half of patients requiring renal replacement therapy, and extrarenal involvement in a minority. Deaths occur in this phase and are mostly neurological.

Show evidence (2 references)

PMID:39518638 SUPPORT Human clinical

"The overall mortality rate was 2% for STEC-HUS and 3.7% for aHUS, with no deaths reported in children on eculizumab and mortality mainly attributed to neurological damage."

Gives the case fatality for this disease and attributes the deaths mainly to neurological damage, which is the claim this phase's notes make.

PMID:37303085 SUPPORT BACKGROUND Human clinical

"characterized by multiorgan thrombotic microangiopathy, mainly affecting children. Renal involvement is severe, with approximately half of patients requiring dialysis."

Characterises the acute phase and the proportion needing dialysis in it.

Recovery and renal sequelae

Duration: Years; sequelae assessed at five-year follow-up and beyond.

Most children recover kidney function - complete renal recovery in 57 patients after a median four years in one national series - but about a third carry kidney sequelae at five years. The course is monophasic, unlike the relapsing course of atypical HUS.

Show evidence (2 references)

PMID:32323005 SUPPORT Human clinical

"Complete renal recovery was observed in 57 patients after a median 4.0 years of follow-up."

Gives the recovery outcome over years of follow-up in a nationwide paediatric cohort.

PMID:37303085 SUPPORT BACKGROUND Human clinical

"at least 30% of survivors experience kidney sequelae"

Quantifies the burden of long-term kidney sequelae among survivors.

📊

Prevalence

2

Children in Finland, 2000-2016

Annual incidence 0.5 per 100,000 per year 1–9 per 1,000,000 per year

Annual incidence of STEC-HUS of 0.5 per 100,000 children in a nationwide study.

Show evidence (1 reference)

PMID:32323005 SUPPORT Human clinical

"the annual incidence of STEC-HUS being 0.5 per 100,000 children"

Gives the nationwide paediatric incidence figure recorded here.

Children in Poland, 2012-2023

Annual incidence 0.39 per 100,000 per year 1–9 per 1,000,000 per year

Mean 3.9 cases per million age-related population per year, rising over the observation period; converted to 0.39 per 100,000.

Show evidence (1 reference)

PMID:39518638 SUPPORT Human clinical

"The incidence of STEC-HUS increased during the observation period, with a mean of 3.9 cases per million age-related population"

Gives the Polish national registry incidence and its upward trend.

🦠

Infectious Agent

2

Shiga toxin-producing Escherichia coli

Shiga toxin-producing (equivalently verotoxigenic) Escherichia coli are Gram-negative Enterobacteriaceae that acquire the stx1 and/or stx2 genes on lambdoid prophages. Enterohaemorrhagic E. coli are the subset that also carry the locus of enterocyte effacement and form attaching-and-effacing lesions on the intestinal mucosa. O157:H7 is the serotype most often responsible worldwide, but the agent is defined by toxin genotype rather than serogroup: the 2011 German outbreak strain was an enteroaggregative O104:H4 that had acquired stx2 by horizontal transfer.

Shiga toxin-producing Escherichia coli NCBITaxon:562

Escherichia coli O157:H7

Show evidence (2 references)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"Stx-producing E. coli O157:H7 has become recognized as the leading cause of HUS worldwide."

Identifies the organism, and O157:H7 as its predominant serotype, as the agent of this disease.

PMID:23955166 SUPPORT REVIEW SYNTHESIS Other

"had acquired the stx2 gene and the ability to produce extended-spectrum beta-lactamase via horizontal gene transfer"

Records that the 2011 outbreak strain gained stx2 by horizontal transfer, which is why the agent is defined by toxin genotype rather than by serogroup. The quoted sentence says only "the outbreak strain"; the review identifies it as O104:H4 two sentences earlier.

Shigella dysenteriae type 1

Shigella dysenteriae serotype 1 carries chromosomally encoded Shiga toxin and is the original source of the toxin's name. It causes the same toxin-mediated syndrome, classically in settings of epidemic bacillary dysentery, and is the reason MONDO scopes this concept to Shiga toxin rather than to E. coli alone. The CURIE is the species, which is broader than the agent - only serotype 1 produces the toxin - so the serotype is carried in preferred_term rather than asserted through the binding.

Shigella dysenteriae serotype 1 NCBITaxon:622

Show evidence (1 reference)

PMID:25530917 SUPPORT REVIEW SYNTHESIS Other

"Stx is found in Shigella dysenteriae 1 and in some serogroups of Escherichia coli"

Establishes S. dysenteriae 1 alongside STEC as a source of the toxin that defines this entity.

↔️

Transmission

2

Foodborne transmission from ruminant-derived food and produce

Cattle and other ruminants carry STEC asymptomatically, so the dominant route is ingestion of contaminated food of bovine origin - undercooked ground beef, unpasteurised milk - or produce and water contaminated from that reservoir. The infectious dose is very low.

Show evidence (1 reference)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"The principal route of infection is consumption of contaminated food and drinking water, although infection may also occur via direct contact with animals, person-to-person contact, and environmental exposure."

Names food and water as the principal vehicle, with animal contact and person-to-person spread as secondary routes.

Direct contact with animals and person-to-person spread

Direct contact with carrier ruminants - farm and petting-zoo exposure - and faecal-oral person-to-person spread in households and childcare settings also transmit STEC, which is why case exclusion from food handling and childcare is part of outbreak control.

Show evidence (1 reference)

PMID:23955166 SUPPORT REVIEW SYNTHESIS Human clinical

"infection may also occur via direct contact with animals, person-to-person contact, and environmental exposure"

Records animal contact and person-to-person spread as transmission routes for the agent.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Shiga Toxin-Associated Hemolytic Uremic Syndrome:

Atypical hemolytic uremic syndrome

Overlapping Features Complement-mediated HUS arising from inherited or acquired defects in alternative-pathway regulation. It lacks the diarrhoeal prodrome, relapses, and is an approved indication for complement inhibition - so the distinction changes management. Genetic testing of complement genes belongs to this work-up.

Show evidence (2 references)

PMID:40255570 SUPPORT Human clinical

"Atypical HUS (aHUS) is a syndrome caused by inherited or acquired defects in regulation of the complement system's alternative pathway"

Defines the aetiology that distinguishes atypical HUS from the toxin-mediated disease.

PMID:40255570 SUPPORT Human clinical

"The various types of HUS are caused by different primary triggers; yet, their clinical features overlap"

States the clinical overlap that makes this a genuine differential rather than an obvious distinction.

Thrombotic thrombocytopenic purpura

Overlapping Features TTP produces the same microangiopathic triad but through severe ADAMTS13 deficiency. In STEC-HUS plasma ADAMTS13 activity lies within a broad normal range - the protease impairment is local and toxin-imposed - so ADAMTS13 activity separates them, and plasma exchange is the treatment for TTP but not for this disease.

Show evidence (1 reference)

PMID:16131569 SUPPORT BACKGROUND Human clinical

"plasma levels of von Willebrand factor (VWF)-cleaving protease (ADAMTS13) activity that are within a broad normal range"

Establishes that plasma ADAMTS13 activity is normal in this disease, which is the laboratory basis for separating it from TTP.

🐁

Animal Models

1

Pod-Gb3 transgenic mouse (Gb3 restricted to podocytes)

A mouse engineered to express the toxin receptor in podocytes alone, then challenged with systemic Shiga toxin. It was built to ask why the glomerulus is the target organ, and it is the experimental basis for the local complement arm of this entry's mechanism and for the C5-inhibition rationale.

Species

Mouse

Genotype

Transgenic expression of the Shiga toxin receptor Gb3 confined to kidney podocytes

Publication

PMID:37863058

Pathograph links

Alternative Complement Pathway Activation on Injured Endothelium recapitulates fidelity: moderate observes: tissue Toxin challenge reproduced the HUS phenotype through the VEGF-A, glycocalyx, factor-H and local complement chain this node asserts, and early C5 inhibition rescued it.

Limitations: Gb3 is confined to podocytes by construction, so the model deliberately removes the glomerular endothelial and extrarenal receptor distribution that shapes human disease. It also cannot speak to the toxin's direct effect on endothelium, which is the arm the human in-vitro work covers.

Divergences from the human mechanism

boundary omission qualifying

Receptor expression outside the podocyte - on glomerular microvascular endothelium, and on the cerebral and other beds that produce extrarenal disease - is outside the model by design. The complement claim holds in the narrower form the model supports.

Readouts

Glomerular endothelial inhibitory complement factor H binding

Direction: DECREASED

Interpretation: Reduced factor H binding at the endothelial surface is the regulatory failure this node turns on, measured here rather than inferred.

Show evidence (1 reference)

PMID:37863058 SUPPORT Model organism

"a reduction in GEnC inhibitory complement factor H binding, and local activation of the complement pathway"

Reports the measured fall in factor H binding alongside local complement activation.

Show evidence (1 reference)

PMID:37863058 SUPPORT Model organism

"Stx-challenged Pod-Gb3 mice developed STEC-HUS."

Establishes that the model reproduces the disease, which is what makes it informative for this node.

Notes

Species differences in Gb3 tissue distribution are the standing caveat on animal models of this disease, and are the reason this model had to put the receptor where it wanted it. Note that the deep-research report's stronger claim - that animals do not reproduce the human renal phenotype - is not adopted here: this model does reproduce it, and PMID:25530917 records that the relative toxicity of Stx2a over Stx1a "is replicated in mice and baboons". The honest statement is that receptor distribution differs and has to be engineered around, not that animal models fail.

Show evidence (1 reference)

PMID:37863058 SUPPORT Model organism

"Transgenic mice were engineered to express the Stx receptor (Gb3) exclusively in their kidney podocytes (Pod-Gb3) and challenged with systemic Stx."

Describes the construction and challenge of the model this record represents.

{ }

Source YAML

click to show

name: Shiga Toxin-Associated Hemolytic Uremic Syndrome
creation_date: "2026-10-28T12:00:00Z"
category: Infectious Disease
parents:
- Thrombotic Microangiopathy
- Post-Infectious Disorder
- Renal Disease
disease_term:
  preferred_term: Shiga toxin-associated hemolytic uremic syndrome
  term:
    id: MONDO:0019536
    label: Shiga toxin-associated hemolytic uremic syndrome
synonyms:
- STEC-HUS
- typical hemolytic uremic syndrome
- diarrhea-associated hemolytic uremic syndrome
- D+ hemolytic uremic syndrome
description: >-
  Shiga toxin-associated hemolytic uremic syndrome (STEC-HUS) is a thrombotic
  microangiopathy defined by the triad of microangiopathic hemolytic anemia,
  thrombocytopenia and acute kidney injury, arising typically about a week after
  an episode of diarrhea - often bloody - caused by Shiga toxin-producing
  Escherichia coli (classically serotype O157:H7, with non-O157 serogroups such
  as O26, O80, O104 and O111 also responsible) or by Shigella dysenteriae
  type 1. It is the leading cause of acute kidney injury in young children. The
  disease is acquired and toxin-mediated rather than inherited: the pathogenic
  determinant is the bacterial Shiga toxin, whose B pentamer binds host
  globotriaosylceramide (Gb3) and whose A subunit depurinates 28S rRNA and halts
  protein synthesis in Gb3-rich cells, chiefly the renal glomerular
  microvascular endothelium and podocytes. Toxin-injured endothelium loses its
  thromboresistance, activates the alternative complement pathway locally, and
  secretes ultra-large von Willebrand factor multimers, producing the
  platelet-fibrin thrombi that occlude glomerular capillaries and shear
  erythrocytes. Treatment is supportive; antibiotics given during the colitis
  prodrome are associated with increased progression to HUS. Most children
  recover kidney function, but a substantial minority carry renal sequelae years
  later. STEC-HUS must be distinguished from complement-mediated atypical HUS
  and from thrombotic thrombocytopenic purpura, which are managed differently.
infectious_agent:
- name: Shiga toxin-producing Escherichia coli
  infectious_agent_term:
    preferred_term: Shiga toxin-producing Escherichia coli
    term:
      id: NCBITaxon:562
      label: Escherichia coli
  description: >-
    Shiga toxin-producing (equivalently verotoxigenic) Escherichia coli are
    Gram-negative Enterobacteriaceae that acquire the stx1 and/or stx2 genes on
    lambdoid prophages. Enterohaemorrhagic E. coli are the subset that also
    carry the locus of enterocyte effacement and form attaching-and-effacing
    lesions on the intestinal mucosa. O157:H7 is the serotype most often
    responsible worldwide, but the agent is defined by toxin genotype rather
    than serogroup: the 2011 German outbreak strain was an enteroaggregative
    O104:H4 that had acquired stx2 by horizontal transfer.
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Stx-producing E. coli O157:H7 has become recognized as the leading cause of HUS worldwide."
    explanation: Identifies the organism, and O157:H7 as its predominant serotype, as the agent of this disease.
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "had acquired the stx2 gene and the ability to produce extended-spectrum beta-lactamase via horizontal gene transfer"
    explanation: >-
      Records that the 2011 outbreak strain gained stx2 by horizontal transfer,
      which is why the agent is defined by toxin genotype rather than by
      serogroup. The quoted sentence says only "the outbreak strain"; the review
      identifies it as O104:H4 two sentences earlier.
  has_subtypes:
  - name: Escherichia coli O157:H7
    classification: serotype
    description: >-
      The sorbitol-non-fermenting serotype historically responsible for most
      STEC-HUS in North America and the United Kingdom, and the serogroup for
      which age-specific progression rates are best quantified.
    subtype_term:
      preferred_term: Escherichia coli O157:H7
      term:
        id: NCBITaxon:83334
        label: Escherichia coli O157:H7
    evidence:
    - reference: PMID:32323005
      reference_title: "Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli in children: incidence, risk factors, and clinical outcome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Eleven different serogroups were detected, O157 being the most common"
      explanation: A nationwide paediatric series establishes O157 as the commonest serogroup among STEC-HUS isolates.
- name: Shigella dysenteriae type 1
  infectious_agent_term:
    preferred_term: Shigella dysenteriae serotype 1
    term:
      id: NCBITaxon:622
      label: Shigella dysenteriae
  description: >-
    Shigella dysenteriae serotype 1 carries chromosomally encoded Shiga toxin
    and is the original source of the toxin's name. It causes the same
    toxin-mediated syndrome, classically in settings of epidemic bacillary
    dysentery, and is the reason MONDO scopes this concept to Shiga toxin
    rather than to E. coli alone. The CURIE is the species, which is broader
    than the agent - only serotype 1 produces the toxin - so the serotype is
    carried in preferred_term rather than asserted through the binding.
  evidence:
  - reference: PMID:25530917
    reference_title: "Shiga Toxin (Stx) Classification, Structure, and Function."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Stx is found in Shigella dysenteriae 1 and in some serogroups of Escherichia coli"
    explanation: Establishes S. dysenteriae 1 alongside STEC as a source of the toxin that defines this entity.
transmission:
- name: Foodborne transmission from ruminant-derived food and produce
  description: >-
    Cattle and other ruminants carry STEC asymptomatically, so the dominant
    route is ingestion of contaminated food of bovine origin - undercooked
    ground beef, unpasteurised milk - or produce and water contaminated from
    that reservoir. The infectious dose is very low.
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The principal route of infection is consumption of contaminated food and drinking water, although infection may also occur via direct contact with animals, person-to-person contact, and environmental exposure."
    explanation: Names food and water as the principal vehicle, with animal contact and person-to-person spread as secondary routes.
- name: Direct contact with animals and person-to-person spread
  description: >-
    Direct contact with carrier ruminants - farm and petting-zoo exposure - and
    faecal-oral person-to-person spread in households and childcare settings
    also transmit STEC, which is why case exclusion from food handling and
    childcare is part of outbreak control.
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "infection may also occur via direct contact with animals, person-to-person contact, and environmental exposure"
    explanation: Records animal contact and person-to-person spread as transmission routes for the agent.
agent_life_cycle:
  description: >-
    STEC has no non-enteric life-cycle phase and no arthropod vector. Ruminants,
    principally cattle, are the natural reservoir and carry the organism in the
    gut without disease; humans are an incidental host in whom the toxin
    produces systemic disease. There is no human-to-ruminant cycle, so humans
    are epidemiologically a dead-end host.
  hosts:
  - preferred_term: Homo sapiens
    role: Incidental host in which Shiga toxin causes thrombotic microangiopathy
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  - preferred_term: Bos taurus
    role: Principal asymptomatic reservoir host carrying STEC in the gut
    term:
      id: NCBITaxon:9913
      label: Bos taurus
  life_cycle_stages:
  - name: Carriage in the ruminant reservoir
    description: >-
      Cattle and other ruminants harbour STEC in the intestine, shedding it into
      the environment and the food chain.
    evidence:
    - reference: PMID:23955166
      reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "infection may also occur via direct contact with animals"
      explanation: >-
        Supports animals as a source of human infection. That the carriage is
        asymptomatic comes from the deep-research report rather than from this
        quote, and is stated in the stage description without its own citation.
  - name: Human colonic colonisation and toxin production
    description: >-
      Ingested STEC colonises the colon, forms attaching-and-effacing lesions
      and releases Shiga toxin into the gut lumen, from which it reaches the
      circulation.
    evidence:
    - reference: PMID:23955166
      reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "STEC release Stx in the gastrointestinal tract, after which the toxin translocates across the intestinal epithelium into the systemic circulation."
      explanation: Describes the enteric production and systemic translocation that make up the human phase.
pathophysiology:
- name: Colonic Colonisation and Attaching-and-Effacing Lesion Formation
  description: >
    Ingested STEC colonises the colon. Enterohaemorrhagic strains carry the locus
    of enterocyte effacement, whose intimin adhesin and type III secretion system
    produce attaching-and-effacing lesions that bring the organism into intimate
    contact with the epithelium. This is the site at which toxin is delivered to
    the host, and the lesion underlies the haemorrhagic colitis of the prodrome.
  biological_scale: TISSUE
  downstream:
  - target: Bloody diarrhea
    causal_link_type: DIRECT
    description: >-
      Invasion of the colonic mucosa at the attaching-and-effacing lesion
      produces the haemorrhagic colitis that presents as bloody diarrhoea.
    evidence:
    - reference: PMID:23955166
      reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "STEC causes a spectrum of diseases, from uncomplicated infection to hemorrhagic colitis and HUS."
      explanation: Places haemorrhagic colitis in the disease spectrum produced by colonic STEC infection.
  - target: Shiga Toxin Translocation Across the Intestinal Epithelium
    causal_link_type: DIRECT
    description: >-
      Colonic colonisation is what places toxin-producing bacteria at the
      epithelial surface, so that released toxin has access to the barrier it
      must cross.
    evidence:
    - reference: PMID:23955166
      reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "STEC release Stx in the gastrointestinal tract, after which the toxin translocates across the intestinal epithelium into the systemic circulation."
      explanation: States the sequence from enteric toxin release to translocation across the epithelium.
  cell_types:
  - preferred_term: colon epithelial cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  locations:
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Enterohemorrhagic E. coli (EHEC) are a sub-group of STEC that have the ability to form attaching and effacing lesions (A/E lesions) that facilitate intimate adhesion to the intestinal mucosa."
    explanation: Defines the attaching-and-effacing lesion and its role in intimate mucosal adhesion.
- name: Shiga Toxin Translocation Across the Intestinal Epithelium
  description: >
    Toxin released in the gut lumen crosses the intestinal epithelium into the
    systemic circulation. Toxin acting on the epithelium itself also triggers a
    ribotoxic stress response there, inducing chemokines and apoptosis. The
    identity of the systemic carrier of the toxin in blood remains unsettled, so
    the delivery step is the least well established link in this chain.
  biological_scale: TISSUE
  downstream:
  - target: Shiga Toxin Binding to Globotriaosylceramide on Gb3-Rich Cells
    causal_link_type: DIRECT
    description: >-
      Translocation into the circulation is what gives the toxin access to the
      glomerular endothelium and podocytes that carry its receptor.
    evidence:
    - reference: PMID:25530917
      reference_title: "Shiga Toxin (Stx) Classification, Structure, and Function."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "The function of the B pentamer is to bind to the cellular receptor, globotriaosylceramide, Gb3, found primarily on endothelial cells."
      explanation: Establishes that circulating toxin acts by binding Gb3 on endothelium, the step this edge leads into.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  biological_processes:
  - preferred_term: apoptotic process in intestinal epithelium
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:12595468
    reference_title: Shiga toxin 1 triggers a ribotoxic stress response leading to p38 and JNK activation and induction of apoptosis in intestinal epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Shiga toxins (Stxs) may access the host systemic circulation by absorption across the intestinal epithelium."
    explanation: States the translocation route this node represents, in the paper that characterised the epithelial response to the toxin.
- name: Shiga Toxin Binding to Globotriaosylceramide on Gb3-Rich Cells
  description: >
    The toxin is an AB5 holotoxin: a pentamer of B subunits binds the neutral
    glycosphingolipid globotriaosylceramide (Gb3/CD77) on the target cell
    surface. Gb3 density differs markedly between vascular beds, and endothelial
    sensitivity to the toxin tracks that density, which is what targets the
    toxin to the glomerular endothelium and sets the organ tropism of the
    disease. The podocyte is bound here on the strength of PMID:37863058, whose
    human biopsy arm and title put the podocyte among the toxin's targets. Do
    not read it off that paper's mouse alone: Gb3 was engineered into podocytes
    there, so the model shows what podocyte-restricted receptor does, not that
    human podocytes carry it.
  biological_scale: MOLECULAR
  downstream:
  - target: Retrograde Trafficking to the Endoplasmic Reticulum
    causal_link_type: DIRECT
    description: >-
      Receptor binding is the committed step for internalisation: the bound
      holotoxin is endocytosed and routed retrogradely to reach the cytosol.
    evidence:
    - reference: PMID:25530917
      reference_title: "Shiga Toxin (Stx) Classification, Structure, and Function."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "The Stxs traffic in a retrograde manner within the cell, such that the A subunit of the toxin reaches the cytosol only after the toxin moves from the endosome to the Golgi and then to the endoplasmic reticulum."
      explanation: States that the bound toxin reaches the cytosol by retrograde trafficking, which is the step this edge leads into.
  cell_types:
  - preferred_term: glomerular endothelial cell
    term:
      id: CL:0002188
      label: glomerular endothelial cell
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: receptor-mediated endocytosis of Shiga toxin
    term:
      id: GO:0006898
      label: receptor-mediated endocytosis
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  evidence:
  - reference: PMID:25530917
    reference_title: "Shiga Toxin (Stx) Classification, Structure, and Function."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The Stxs consist of two major subunits, an A subunit that joins noncovalently to a pentamer of five identical B subunits."
    explanation: Establishes the AB5 architecture whose B pentamer performs the receptor binding this node represents.
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "The presence of Gb3 targets Stx to the glomerular endothelium, where it causes major vascular injury. Endothelial cells from different vascular beds display varying degrees of sensitivity to Stx due, in large part, to the level of Gb3 expression."
    explanation: Ties receptor density to glomerular tropism and to the differing sensitivity of vascular beds.
- name: Retrograde Trafficking to the Endoplasmic Reticulum
  description: >
    The internalised holotoxin travels from endosome to Golgi to endoplasmic
    reticulum; the A subunit is then cleaved and reduced, and the A1 fragment
    enters the cytosol. Curated separately from the enzymatic lesion because
    transport and catalysis are distinct molecular events: a catalytically dead
    toxin still traffics, which is what makes the mutant experiment downstream
    informative.
  biological_scale: MOLECULAR
  downstream:
  - target: 28S rRNA Depurination and Translational Arrest
    causal_link_type: DIRECT
    description: >-
      Reaching the cytosol is the precondition for the enzymatic lesion: the A1
      fragment can only act on the ribosome once retrograde transport has
      delivered it there.
    evidence:
    - reference: PMID:25530917
      reference_title: "Shiga Toxin (Stx) Classification, Structure, and Function."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "the A subunit of the toxin reaches the cytosol only after the toxin moves from the endosome to the Golgi and then to the endoplasmic reticulum"
      explanation: States that cytosolic access depends on completing the retrograde route, which is the dependency this edge asserts.
  biological_processes:
  - preferred_term: retrograde transport, endosome to Golgi
    term:
      id: GO:0042147
      label: retrograde transport, endosome to Golgi
  cell_types:
  - preferred_term: glomerular endothelial cell
    term:
      id: CL:0002188
      label: glomerular endothelial cell
  evidence:
  - reference: PMID:25530917
    reference_title: "Shiga Toxin (Stx) Classification, Structure, and Function."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The Stxs traffic in a retrograde manner within the cell, such that the A subunit of the toxin reaches the cytosol only after the toxin moves from the endosome to the Golgi and then to the endoplasmic reticulum."
    explanation: Gives the retrograde route from endosome through Golgi to endoplasmic reticulum that this node represents.
- name: 28S rRNA Depurination and Translational Arrest
  description: >
    In the cytosol the A1 fragment acts as an RNA N-glycosidase, removing a
    single adenine from the conserved sarcin-ricin loop of 28S rRNA in the 60S
    subunit and halting translation. This is the toxin's defining enzymatic
    lesion, and its enzymatic activity is required for the downstream stress
    signalling.
  biological_scale: MOLECULAR
  downstream:
  - target: Ribotoxic Stress Response and Target Cell Apoptosis
    causal_link_type: DIRECT
    description: >-
      Ribosomal damage is what activates the stress-activated kinases: a
      catalytically dead toxin mutant activates neither p38 nor JNK, which is
      what makes this edge causal rather than merely coincident.
    evidence:
    - reference: PMID:12595468
      reference_title: Shiga toxin 1 triggers a ribotoxic stress response leading to p38 and JNK activation and induction of apoptosis in intestinal epithelial cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Stx1 enzymatic activity was required for kinase activation; a catalytically defective mutant toxin did not activate either."
      explanation: A catalytically defective toxin fails to activate the kinases, establishing the ribosomal lesion as the cause of the stress response.
  - target: Endothelial Activation and Loss of Thromboresistance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Toxin reaching the endothelial cytosol also reprograms endothelial gene
      expression, through NF-kappaB. The link is indirect because the activation
      phenotype arises at sublethal toxin doses, where it is not accounted for by
      translational arrest alone.
    evidence:
    - reference: PMID:23955166
      reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "Among the newer concepts are Stx-mediated gene regulation in the absence of protein synthesis inhibition"
      explanation: Records endothelial gene regulation occurring without protein-synthesis inhibition, which is why this edge is marked indirect.
  biological_processes:
  - preferred_term: inhibition of translation by 28S rRNA depurination
    term:
      id: GO:0017148
      label: negative regulation of translation
    modifier: INCREASED
  molecular_functions:
  - preferred_term: Shiga toxin A1 fragment rRNA N-glycosidase activity
    term:
      id: GO:0030598
      label: rRNA N-glycosylase activity
    modifier: INCREASED
  evidence:
  - reference: PMID:12595468
    reference_title: Shiga toxin 1 triggers a ribotoxic stress response leading to p38 and JNK activation and induction of apoptosis in intestinal epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "The A subunit inactivates ribosomes by cleaving a specific adenine from the 28S rRNA."
    explanation: States the single-adenine depurination of 28S rRNA that is the enzymatic lesion of this node.
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "the Stx A subunit specifically removes an adenine residue within the highly conserved alpha-sarcin/ricin loop on eukaryotic 28S rRNA"
    explanation: Independently records the site of depurination within the conserved rRNA loop.
- name: Ribotoxic Stress Response and Target Cell Apoptosis
  description: >
    Damage to the ribosome activates the stress-activated protein kinases p38 and
    JNK, inducing primary response genes, C-X-C chemokines including
    interleukin-8, and caspase-dependent apoptosis. This is the arm by which
    toxin kills target cells and recruits inflammation, as distinct from the
    sublethal gene-reprogramming arm that makes endothelium thrombogenic.
  biological_scale: CELLULAR
  downstream:
  - target: Glomerular Thrombotic Microangiopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Apoptotic loss and inflammatory activation of glomerular cells contribute
      to the microangiopathic lesion. The link is indirect: the cited experiments
      establish the apoptotic response in epithelial and endothelial cells, not
      that apoptosis alone produces the glomerular lesion.
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  - preferred_term: glomerular endothelial cell
    term:
      id: CL:0002188
      label: glomerular endothelial cell
  evidence:
  - reference: PMID:12595468
    reference_title: Shiga toxin 1 triggers a ribotoxic stress response leading to p38 and JNK activation and induction of apoptosis in intestinal epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Stx1 treatment of HCT-8 cells resulted in cell death that was associated with caspase 3 cleavage and internucleosomal DNA fragmentation; this cytotoxicity also required Stx1 enzymatic activity."
    explanation: Documents caspase-dependent apoptosis downstream of the ribosomal lesion, dependent on toxin enzymatic activity.
- name: Endothelial Activation and Loss of Thromboresistance
  description: >
    At sublethal doses the toxin reprograms endothelial gene expression rather
    than killing the cell. NF-kappaB activation induces adhesion molecules and
    chemokines, leukocytes adhere, and the cell loses its normal thromboresistant
    phenotype and becomes thrombogenic - the event generally taken to trigger the
    microangiopathy.
  biological_scale: CELLULAR
  downstream:
  - target: Alternative Complement Pathway Activation on Injured Endothelium
    causal_link_type: DIRECT
    description: >-
      Complement activation in response to the toxin acts at the activated
      endothelial surface, favouring platelet thrombus formation there.
    evidence:
    - reference: PMID:20424866
      reference_title: "Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "Evidence is emerging that complement activation in response to Stxs favors platelet thrombus formation on endothelial cells"
      explanation: Places toxin-induced complement activation at the endothelial surface, upstream of platelet thrombus formation.
  - target: Ultra-Large von Willebrand Factor Secretion and Platelet Capture
    causal_link_type: DIRECT
    description: >-
      The same activated endothelium rapidly secretes ultra-large von Willebrand
      factor multimers onto its surface, to which platelets adhere.
    evidence:
    - reference: PMID:16131569
      reference_title: Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "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)."
      explanation: Shows toxin-stimulated endothelial cells secreting ultra-large VWF multimers, the step this edge leads into.
  cell_types:
  - preferred_term: glomerular endothelial cell
    term:
      id: CL:0002188
      label: glomerular endothelial cell
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  evidence:
  - reference: PMID:20424866
    reference_title: "Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Activated endothelial cells in response to Stxs lose the normal thromboresistance phenotype and become thrombogenic, initiating microvascular thrombus formation."
    explanation: States the loss of thromboresistance and the shift to a thrombogenic phenotype that define this node.
  - reference: PMID:20424866
    reference_title: "Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "trigger a cascade of signaling events, involving NF-κB activation, that induce expression of genes encoding for adhesion molecules and chemokines, and culminate in the adhesion of leukocytes to endothelial cells"
    explanation: Gives the NF-kappaB-dependent adhesion-molecule and chemokine programme that constitutes endothelial activation here.
- name: Alternative Complement Pathway Activation on Injured Endothelium
  conforms_to: "complement_dysregulation#Unrestrained Alternative Pathway Amplification"
  description: >
    Shiga toxin activates the alternative complement pathway locally on the
    glomerular endothelial surface. There is no inherited regulator lesion here,
    which is what distinguishes this disease from atypical HUS; instead the
    toxin reduces factor H binding at the endothelial surface, so local
    regulation fails where the toxin has acted. In a mouse model expressing the
    toxin receptor only in podocytes, toxin challenge reduced podocyte VEGF-A,
    stripped the glomerular endothelial glycocalyx, lowered inhibitory factor H
    binding and activated complement locally - and early C5 inhibition rescued
    the phenotype.
  biological_scale: CELLULAR
  downstream:
  - target: Glomerular Thrombotic Microangiopathy
    causal_link_type: DIRECT
    description: >-
      Local complement activation on the endothelial surface amplifies injury and
      platelet thrombus formation, producing the glomerular lesion.
    evidence:
    - reference: PMID:37863058
      reference_title: Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Early therapeutic inhibition of the terminal complement pathway with a C5 inhibitor rescued this podocyte-driven, Stx-induced HUS phenotype."
      explanation: >-
        Blocking the terminal pathway rescues the HUS phenotype, which is
        interventional evidence that complement activation causes the lesion
        rather than accompanying it.
  cell_types:
  - preferred_term: glomerular endothelial cell
    term:
      id: CL:0002188
      label: glomerular endothelial cell
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: complement activation, alternative pathway
    term:
      id: GO:0006957
      label: complement activation, alternative pathway
    modifier: INCREASED
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  evidence:
  - reference: PMID:37863058
    reference_title: Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This was mediated by a reduction in podocyte vascular endothelial growth factor A (VEGF-A), which led to loss of glomerular endothelial cell (GEnC) glycocalyx, a reduction in GEnC inhibitory complement factor H binding, and local activation of the complement pathway."
    explanation: Gives the mechanism by which the toxin produces local complement activation, including the loss of factor H binding.
- name: Ultra-Large von Willebrand Factor Secretion and Platelet Capture
  conforms_to: "thrombogenesis#Platelet Adhesion, Activation, and Aggregation"
  description: >
    Toxin-stimulated glomerular and umbilical-vein endothelial cells secrete
    ultra-large von Willebrand factor multimeric strings, to which perfused
    platelets adhere immediately. The toxin additionally delays ADAMTS13 cleavage
    of those strings, so the platelet-decorated multimers persist. Note that
    plasma ADAMTS13 activity in this disease is within the normal range - the
    defect is local and toxin-imposed, not the systemic protease deficiency of
    thrombotic thrombocytopenic purpura.
  biological_scale: CELLULAR
  downstream:
  - target: Glomerular Thrombotic Microangiopathy
    causal_link_type: DIRECT
    description: >-
      Platelet adhesion to persistent VWF strings above the glomerular
      endothelium initiates the platelet-fibrin thrombi that occlude the
      capillaries.
    evidence:
    - reference: PMID:16131569
      reference_title: Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These processes may contribute to the evolution of glomerular occlusion by platelet and fibrin thrombi in diarrhea-associated HUS."
      explanation: The authors draw the link from VWF-platelet string formation to glomerular occlusion by platelet-fibrin thrombi.
  cell_types:
  - preferred_term: glomerular endothelial cell
    term:
      id: CL:0002188
      label: glomerular endothelial cell
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet activation
    term:
      id: GO:0030168
      label: platelet activation
    modifier: INCREASED
  evidence:
  - reference: PMID:16131569
    reference_title: Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Perfused normal human platelets immediately adhered to the secreted ULVWF multimeric strings."
    explanation: Direct demonstration of platelet capture on the secreted multimeric strings.
  - reference: PMID:16131569
    reference_title: Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: Quantifies the toxin-imposed delay in ADAMTS13 cleavage that lets the platelet-decorated strings persist.
- name: Glomerular Thrombotic Microangiopathy
  conforms_to:
  - "thrombogenesis#Pathological Fibrin-Platelet Thrombus Formation"
  - "complement_dysregulation#Complement-Mediated Cell Injury and Endothelial Activation"
  description: >
    The converging arms produce the defining lesion: fibrin-rich platelet thrombi
    in the glomerular capillaries, with endothelial swelling, detachment from the
    basement membrane, subendothelial deposits and luminal narrowing.
    Pre-glomerular arterioles and medium-sized vessels may also be involved.
  biological_scale: TISSUE
  downstream:
  - target: Oliguria
    causal_link_type: DIRECT
    description: >-
      Occlusion of the glomerular capillaries is what collapses filtration to
      the point of oligoanuria, the renal outcome that decides whether dialysis
      is needed. The cited model of HUS pathogenesis puts glomerular thrombi
      upstream of renal shutdown.
    evidence:
    - reference: PMID:21784993
      reference_title: Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Shiga toxins produced by intestinal E coli gain access to the circulation, injure renal microvasculature, and generate thrombi that likely contribute to renal ischemia; this process precedes HUS."
      explanation: >-
        States the mechanism this edge asserts - microvascular injury and thrombi
        producing renal ischaemia - in the paper whose outcome measure is
        oligoanuria.
  - target: Proteinuria
    causal_link_type: DIRECT
    description: >-
      Glomerular endothelial injury and the podocyte involvement that
      accompanies it breach the filtration barrier, which is what admits protein
      to the urine. Left uncited: the cited sources establish the glomerular
      lesion and list proteinuria among the renal sequelae, but none of them
      measures urinary protein against the lesion, so no quote in this entry
      supports the step itself.
  - target: Acute kidney injury
    causal_link_type: DIRECT
    description: >-
      Occlusion of the glomerular microvasculature is what produces the acute
      renal failure of the triad.
    evidence:
    - reference: PMID:20424866
      reference_title: "Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure"
      explanation: Links the microangiopathic process to acute renal failure as a defining feature of the syndrome.
  - target: Mechanical Erythrocyte Fragmentation
    causal_link_type: DIRECT
    description: >-
      Erythrocytes are fragmented as they pass the occluded, fibrin-laden
      capillaries.
    evidence:
    - reference: PMID:23955166
      reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The classical view argues that thrombocytopenia results from platelet consumption in thrombi and that red blood cells become fragmented as they flow through vessels with marked edema, fibrin deposits, and intravascular thrombosis, though newer evidence challenges these long-held beliefs."
      explanation: >-
        States the consumption-and-shearing account of this edge, and is quoted
        in full so that the authors' own caveat about it travels with it.
  - target: Platelet Consumption in Microvascular Thrombi
    causal_link_type: DIRECT
    description: >-
      Platelets are consumed within the thrombi forming in the occluded
      capillaries.
    evidence:
    - reference: PMID:23955166
      reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "thrombocytopenia results from platelet consumption in thrombi"
      explanation: States the platelet-consumption step this edge asserts.
  cell_types:
  - preferred_term: glomerular endothelial cell
    term:
      id: CL:0002188
      label: glomerular endothelial cell
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Histopathological manifestations of Stx-associated HUS include fibrin-rich microvascular thrombi primarily in the renal glomeruli, although pre-glomerular arterioles and medium-sized vessels may also be affected."
    explanation: Describes the histopathology of the lesion, including its glomerular predominance and arteriolar extension.
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Endothelial swelling and detachment from the underlying basement membrane and subendothelial deposits accompanied by vascular edema and narrowing of the vessel lumen are also observed."
    explanation: Gives the endothelial component of the lesion that accompanies the thrombi.
- name: Mechanical Erythrocyte Fragmentation
  description: >
    Erythrocytes are sheared as they traverse the occluded, fibrin-laden
    microvasculature and appear on the blood film as fragments. The haemolysis
    is mechanical rather than immune, which is the basis of the negative direct
    Coombs test used to separate it from immune haemolysis; no reference cached
    for this entry states that, so it is recorded here as an uncited
    standard-practice point rather than as a sourced claim.
  biological_scale: CELLULAR
  downstream:
  - target: Microangiopathic hemolytic anemia
    causal_link_type: DIRECT
    description: Mechanical fragmentation of erythrocytes is the basis of the anaemia in this syndrome.
  - target: Schistocytosis
    causal_link_type: DIRECT
    description: >-
      The fragmented erythrocytes produced by shearing are what appear on the
      blood film as schistocytes.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "red blood cells become fragmented as they flow through vessels with marked edema, fibrin deposits, and intravascular thrombosis"
    explanation: States the erythrocyte-shearing half of the classical account, in the occluded vessels this node describes.
- name: Platelet Consumption in Microvascular Thrombi
  description: >
    Platelets captured into the growing thrombi are removed from the circulation,
    which is the classical account of the thrombocytopenia. Curated separately
    from erythrocyte shearing because the two are different events on different
    cells, reported by different laboratory findings, even though one cited
    sentence covers both.
  biological_scale: CELLULAR
  downstream:
  - target: Thrombocytopenia
    causal_link_type: DIRECT
    description: Platelet consumption within microvascular thrombi produces the thrombocytopenia.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "thrombocytopenia results from platelet consumption in thrombi"
    explanation: States the platelet-consumption half of the classical account that this node carries.
- name: Extrarenal Microangiopathy in Gb3-Rich Vascular Beds
  description: >
    Gb3 is expressed on cerebral endothelium and in other beds, so the same
    toxin-driven microangiopathy occurs outside the kidney. Neurological
    involvement is the commonest cause of death in the acute phase; cardiac
    involvement is infrequent but carries high mortality, and gastrointestinal,
    pulmonary and pancreatic involvement is probably under-recognised.
  biological_scale: ORGANISM
  downstream:
  - target: Encephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cerebral microvascular involvement is taken to produce the encephalopathy
      and seizures of severe disease. Left uncited and marked indirect: the
      cited sources report how often neurological involvement occurs and that
      it drives acute mortality, which is phenotype frequency rather than
      mechanism, so no quote in this entry establishes the step itself.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Seizures are the other common expression of the central nervous system
      involvement, and are uncited here for the same reason as the
      encephalopathy edge.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  - preferred_term: pancreas
    term:
      id: UBERON:0001264
      label: pancreas
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Neurological involvement occurs in 10% to 25% of patients and is the most common cause of mortality during the acute phase of disease."
    explanation: Quantifies neurological involvement and identifies it as the leading cause of acute mortality.
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although infrequent, cardiac complications are associated with a high risk of mortality in HUS patients"
    explanation: Records cardiac involvement as infrequent but high-risk, supporting the extrarenal scope of this node.
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Involvement of other organs such as the gastrointestinal tract, lungs, and pancreas is likely under-appreciated."
    explanation: Supports the pancreatic and other extrarenal sites bound on this node, with the authors' own caveat that they are under-recognised.
diagnosis:
- name: Stool stx1/stx2 nucleic acid amplification testing
  description: >-
    Detecting the toxin genes in stool is what identifies the agent, and it is
    the step that separates this disease from atypical HUS, where management
    differs. A multiplex real-time PCR for stx1 and stx2 detects both O157 and
    non-O157 STEC - which matters because the two occur at similar incidence -
    and outperformed culture-based reference testing. Sorbitol-MacConkey
    culture, which exploits O157's failure to ferment sorbitol, misses the
    non-O157 serogroups by construction.
  evidence:
  - reference: PMID:23843484
    reference_title: "A sensitive multiplex, real-time PCR assay for prospective detection of Shiga toxin-producing Escherichia coli from stool samples reveals similar incidences but variable severities of non-O157 and O157 infections in northern California."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we assessed the performance of a multiplex, real-time PCR assay targeting stx1 and stx2 for the detection of O157 and non-O157 STEC in diarrheal stool samples enriched in Gram-negative broth"
    explanation: Establishes stool stx1/stx2 PCR as the assay that detects the agent across serogroups.
  - reference: PMID:23843484
    reference_title: "A sensitive multiplex, real-time PCR assay for prospective detection of Shiga toxin-producing Escherichia coli from stool samples reveals similar incidences but variable severities of non-O157 and O157 infections in northern California."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that the assay is 100% sensitive (95% confidence interval [CI], 89.1% to 100%) and 98.5% specific (95% CI, 90.6% to 99.9%)"
    explanation: Gives the test performance that makes PCR the preferred detection route.
  - reference: PMID:23843484
    reference_title: "A sensitive multiplex, real-time PCR assay for prospective detection of Shiga toxin-producing Escherichia coli from stool samples reveals similar incidences but variable severities of non-O157 and O157 infections in northern California."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the recommendations of the CDC for laboratories to test all diarrheal stool samples from patients with acute community-acquired diarrhea for non-O157 STEC in addition to the O157 serotype by using a sensitive assay"
    explanation: >-
      Records the recommendation to test for non-O157 STEC as well as O157,
      which is why an O157-only culture strategy is inadequate.
  notes: >-
    The research report also describes Shiga toxin immunoassay, anti-O157 LPS
    serology for stool-negative cases, and the point that a negative stool does
    not exclude STEC-HUS because the toxin may have cleared by the time HUS
    presents. Those are not recorded as claims here because no reference cached
    for this entry states them in quotable form; they are a curation gap, not a
    dismissal.
animal_models:
- name: Pod-Gb3 transgenic mouse (Gb3 restricted to podocytes)
  species: Mouse
  genotype: Transgenic expression of the Shiga toxin receptor Gb3 confined to kidney podocytes
  publication: PMID:37863058
  description: >-
    A mouse engineered to express the toxin receptor in podocytes alone, then
    challenged with systemic Shiga toxin. It was built to ask why the glomerulus
    is the target organ, and it is the experimental basis for the local
    complement arm of this entry's mechanism and for the C5-inhibition
    rationale.
  modeled_mechanisms:
  - target: Alternative Complement Pathway Activation on Injured Endothelium
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Toxin challenge reproduced the HUS phenotype through the VEGF-A,
      glycocalyx, factor-H and local complement chain this node asserts, and
      early C5 inhibition rescued it.
    limitations: >-
      Gb3 is confined to podocytes by construction, so the model deliberately
      removes the glomerular endothelial and extrarenal receptor distribution
      that shapes human disease. It also cannot speak to the toxin's direct
      effect on endothelium, which is the arm the human in-vitro work covers.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Receptor expression outside the podocyte - on glomerular microvascular
        endothelium, and on the cerebral and other beds that produce extrarenal
        disease - is outside the model by design. The complement claim holds in
        the narrower form the model supports.
    readouts:
    - name: Glomerular endothelial inhibitory complement factor H binding
      target: Alternative Complement Pathway Activation on Injured Endothelium
      direction: DECREASED
      interpretation: >-
        Reduced factor H binding at the endothelial surface is the regulatory
        failure this node turns on, measured here rather than inferred.
      evidence:
      - reference: PMID:37863058
        reference_title: Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "a reduction in GEnC inhibitory complement factor H binding, and local activation of the complement pathway"
        explanation: Reports the measured fall in factor H binding alongside local complement activation.
    evidence:
    - reference: PMID:37863058
      reference_title: Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Stx-challenged Pod-Gb3 mice developed STEC-HUS."
      explanation: Establishes that the model reproduces the disease, which is what makes it informative for this node.
  evidence:
  - reference: PMID:37863058
    reference_title: Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transgenic mice were engineered to express the Stx receptor (Gb3) exclusively in their kidney podocytes (Pod-Gb3) and challenged with systemic Stx."
    explanation: Describes the construction and challenge of the model this record represents.
  notes: >-
    Species differences in Gb3 tissue distribution are the standing caveat on
    animal models of this disease, and are the reason this model had to put the
    receptor where it wanted it. Note that the deep-research report's stronger
    claim - that animals do not reproduce the human renal phenotype - is not
    adopted here: this model does reproduce it, and PMID:25530917 records that
    the relative toxicity of Stx2a over Stx1a "is replicated in mice and
    baboons". The honest statement is that receptor distribution differs and has
    to be engineered around, not that animal models fail.
phenotypes:
- category: Clinical
  name: Bloody diarrhea
  description: >-
    The prodromal illness is diarrhoea that typically begins non-bloody and
    becomes bloody over one to three days, reflecting the haemorrhagic colitis
    produced by colonic colonisation. It precedes HUS by about a week and is what
    makes this the "diarrhoea-positive" form of the syndrome.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Bloody diarrhea
    term:
      id: HP:0025085
      label: Bloody diarrhea
  evidence:
  - reference: PMID:21784993
    reference_title: Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "diarrhea that is initially nonbloody but that becomes bloody 1 to 3 days later"
    explanation: Describes the characteristic evolution of the prodromal diarrhoea in children infected with E. coli O157:H7.
- category: Clinical
  name: Microangiopathic hemolytic anemia
  description: >-
    Haemolytic anaemia with schistocytes on the blood film, one of the three
    defining features. Case definitions have used a haematocrit below 30% with
    smear evidence of intravascular erythrocyte destruction. The haemolysis is
    conventionally Coombs-negative; that point is not quoted from any reference
    cached here.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Microangiopathic hemolytic anemia
    term:
      id: HP:0001937
      label: Microangiopathic hemolytic anemia
  evidence:
  - reference: PMID:21784993
    reference_title: Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anemia (hematocrit level <30% with smear evidence of intravascular erythrocyte destruction)"
    explanation: Gives the operational case definition of the microangiopathic anaemia used in a prospective multicentre cohort.
- category: Laboratory
  name: Schistocytosis
  description: >-
    Fragmented erythrocytes on the peripheral blood film are the morphological
    signature of the mechanical haemolysis and are part of how the syndrome is
    defined.
  phenotype_term:
    preferred_term: Schistocytosis
    term:
      id: HP:0001981
      label: Schistocytosis
  evidence:
  - reference: PMID:21784993
    reference_title: Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "smear evidence of intravascular erythrocyte destruction"
    explanation: >-
      The case definition rests on blood-film evidence of erythrocyte
      destruction, which is the schistocytosis this phenotype records.
- category: Clinical
  name: Thrombocytopenia
  description: >-
    Platelet consumption in microvascular thrombi gives a platelet count below
    150 x 10^3/mm3 in case definitions. It is the second element of the triad.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:21784993
    reference_title: Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thrombocytopenia (platelet count <150 × 10³/mm³)"
    explanation: Gives the platelet threshold used to define the thrombocytopenia of this syndrome in a prospective cohort.
- category: Clinical
  name: Acute kidney injury
  description: >-
    The renal element of the triad, and the reason this is the leading cause of
    acute kidney injury in young children. Roughly half of patients require renal
    replacement therapy in the acute phase.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  sequelae:
  - target: Chronic kidney disease
    description: >-
      The minority who do not recover filtration carry chronic kidney disease
      into long-term follow-up; the national registry reports kidney sequelae at
      five years in about a third of children.
    evidence:
    - reference: PMID:39518638
      reference_title: "Changing Epidemiology and Outcomes of Hemolytic Uremic Syndrome in Children: A Prospective National Cohort Study from the Polish Pediatric HUS Registry and the Polish Registry of Renal Replacement Therapy in Children."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "kidney sequelae were observed at 5-year follow-ups in 31% of children with STEC-HUS"
      explanation: Establishes that the acute renal injury leaves chronic kidney sequelae in a substantial minority.
  - target: Hypertension
    description: >-
      Hypertension is one of the recorded long-term renal sequelae of the acute
      injury, and is the reason survivors need blood-pressure surveillance.
    evidence:
    - reference: PMID:23955166
      reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "25% of survivors experience long-term renal sequelae, including decreased glomerular filtration rate, proteinuria, hypertension, chronic kidney disease, and end-stage renal disease"
      explanation: Names hypertension among the renal sequelae that follow the acute kidney injury in survivors.
  evidence:
  - reference: PMID:37303085
    reference_title: "Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) in children is a severe condition, resulting in approximately 50% of patients requiring RRT."
    explanation: Quantifies the severity of the renal injury by the proportion of children needing renal replacement therapy.
  - reference: PMID:37863058
    reference_title: Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Shiga toxin (Stx)-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) is the leading cause of acute kidney injury in children"
    explanation: >-
      States the clinical standing of the renal phenotype. The quote is from the
      introduction of a mouse study, so it reports the human clinical picture
      rather than that paper's own experimental result.
- category: Clinical
  name: Oliguria
  description: >-
    Oligoanuria - urine output at or below 0.5 mL/kg/h for more than a day - is
    the clinically decisive renal outcome: oligoanuric patients usually need
    dialysis, stay in hospital longer, and have more chronic sequelae. It
    occurred in 68% of a prospective multicentre paediatric cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Oliguria
    term:
      id: HP:0100520
      label: Oliguria
  evidence:
  - reference: PMID:21784993
    reference_title: Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall oligoanuric rate of the 50 participants was 68%"
    explanation: Gives the observed frequency of oligoanuria in a prospective cohort of children with diarrhoea-associated HUS.
  - reference: PMID:21784993
    reference_title: Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Patients with oligoanuric HUS usually need dialysis and have longer hospitalizations"
    explanation: Establishes the prognostic weight of oligoanuria, which is why it is curated separately from acute kidney injury.
- category: Laboratory
  name: Elevated circulating creatinine concentration
  description: >-
    A serum creatinine above the age-specific reference range is the laboratory
    criterion for the renal impairment in the case definition.
  phenotype_term:
    preferred_term: Elevated circulating creatinine concentration
    term:
      id: HP:0003259
      label: Elevated circulating creatinine concentration
  reports_on:
  - target: Acute kidney injury
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    description: >-
      The rise in serum creatinine is the measurement by which the acute kidney
      injury is recognised and defined, rather than a separate consequence of
      it - which is why this is a readout link and not a causal edge.
    evidence:
    - reference: PMID:21784993
      reference_title: Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "impaired renal function (serum creatinine concentration > upper limit of reference range for age)"
      explanation: Shows creatinine used as the defining measurement of the renal impairment, which is what makes this a readout.
  evidence:
  - reference: PMID:21784993
    reference_title: Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired renal function (serum creatinine concentration > upper limit of reference range for age)"
    explanation: Gives the creatinine criterion by which renal impairment is established in this syndrome.
- category: Neurological
  name: Encephalopathy
  description: >-
    Neurological involvement - encephalopathy, seizures, altered consciousness,
    stroke - affects 10-25% of patients and is the most common cause of death in
    the acute phase. A nationwide paediatric series found major neurological
    symptoms in a third of patients; the band below reflects that 33% figure,
    which sits above the 10-25% range the review reports.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Neurological involvement occurs in 10% to 25% of patients and is the most common cause of mortality during the acute phase of disease."
    explanation: Gives both the frequency of neurological involvement and its contribution to acute mortality.
  - reference: PMID:32323005
    reference_title: "Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli in children: incidence, risk factors, and clinical outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-nine patients (33%) developed major neurological symptoms."
    explanation: An independent nationwide paediatric cohort quantifies major neurological involvement.
- category: Neurological
  name: Seizure
  description: >-
    Seizures are among the central nervous system manifestations of severe
    disease, alongside encephalopathy, altered consciousness and stroke. They
    sit inside the 10-25% of patients with neurological involvement rather than
    being separately enumerated by the cited sources.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: "Neurological involvement occurs in 10% to 25% of patients and is the most common cause of mortality during the acute phase of disease."
    explanation: >-
      Establishes the frequency of neurological involvement, of which seizures
      are one expression. Indirect because the source does not report a seizure
      frequency separately.
- category: Clinical
  name: Hypertension
  description: >-
    Hypertension occurs acutely and is one of the renal sequelae found on
    long-term follow-up of survivors, alongside proteinuria and reduced
    glomerular filtration rate.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "25% of survivors experience long-term renal sequelae, including decreased glomerular filtration rate, proteinuria, hypertension, chronic kidney disease, and end-stage renal disease"
    explanation: Lists hypertension among the long-term renal sequelae of survivors.
- category: Laboratory
  name: Proteinuria
  description: >-
    Proteinuria accompanies the acute glomerular injury and persists in a
    minority as part of the chronic renal sequelae.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "long-term renal sequelae, including decreased glomerular filtration rate, proteinuria, hypertension, chronic kidney disease, and end-stage renal disease"
    explanation: Names proteinuria among the renal sequelae documented in survivors.
- category: Clinical
  name: Chronic kidney disease
  description: >-
    A substantial minority of survivors carry chronic kidney disease. Kidney
    sequelae were present at five-year follow-up in 31% of children with
    STEC-HUS in the Polish national registry, although progression to stage 5
    disease has become exceptional. No frequency band is set: the 31% figure is
    for "kidney sequelae", which the companion review defines as spanning
    reduced GFR, proteinuria, hypertension, chronic kidney disease and
    end-stage disease, so it is broader than this node and would overstate it.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: PMID:39518638
    reference_title: "Changing Epidemiology and Outcomes of Hemolytic Uremic Syndrome in Children: A Prospective National Cohort Study from the Polish Pediatric HUS Registry and the Polish Registry of Renal Replacement Therapy in Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "kidney sequelae were observed at 5-year follow-ups in 31% of children with STEC-HUS"
    explanation: A national prospective registry quantifies renal sequelae at five years.
  - reference: PMID:39518638
    reference_title: "Changing Epidemiology and Outcomes of Hemolytic Uremic Syndrome in Children: A Prospective National Cohort Study from the Polish Pediatric HUS Registry and the Polish Registry of Renal Replacement Therapy in Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The development of CKD5 in childhood as a consequence of HUS has become exceptional."
    explanation: >-
      Qualifies the sequelae figure: chronic kidney disease is common in
      survivors, but end-stage disease in childhood is now rare.
biochemical:
- name: Lactate dehydrogenase
  biomarker_term:
    preferred_term: lactate dehydrogenase
    term:
      id: HP:0025435
      label: Increased circulating lactate dehydrogenase concentration
  notes: >-
    Lactate dehydrogenase is used to follow the haematological course of
    thrombotic microangiopathy. Read the cited figure carefully: the 76%
    first-week improvement is pooled across atypical HUS, STEC-HUS and
    transplant-associated TMA in a 24-patient retrospective of which only five
    were STEC-HUS, so it is not a STEC-HUS-specific result, and nothing cited
    here quantifies baseline LDH elevation in this disease.
  evidence:
  - reference: PMID:40255570
    reference_title: "Eculizumab is efficacious and safe in pediatric patients with various forms of hemolytic uremic syndrome: a retrospective clinical experience of a tertiary center"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant improvements were observed in platelet count (63%), lactate dehydrogenase levels (76% within the first week)"
    explanation: >-
      Shows lactate dehydrogenase used as a haemolysis readout followed over
      treatment in paediatric HUS, including STEC-HUS patients.
environmental:
- name: Antibiotic administration during STEC colitis
  description: >-
    Giving antibiotics during the diarrhoeal prodrome is associated with
    progression to HUS, which is why antibiotics are not recommended in
    suspected or confirmed STEC infection. The association is significant in
    low-risk-of-bias studies but not in the pooled set as a whole, and the
    proposed mechanism - induction of the bacterial SOS response and
    phage-mediated toxin release - is not established by these clinical data.
  exposure_term:
    preferred_term: antibacterial drug given during STEC colitis
    term:
      id: ECTO:9001757
      label: exposure to antibacterial drug
  influences_mechanisms:
  - target: Shiga Toxin Translocation Across the Intestinal Epithelium
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Antibiotic exposure during colitis is thought to increase the toxin burden
      reaching the circulation. The link is indirect: the clinical studies
      measure progression to HUS, not toxin flux across the epithelium.
    evidence:
    - reference: PMID:10874060
      reference_title: The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Antibiotic treatment of children with E. coli O157:H7 infection increases the risk of the hemolytic-uremic syndrome."
      explanation: >-
        A prospective cohort finds antibiotic treatment during infection raises
        the risk of the syndrome. Indirect evidence for this edge because the
        outcome measured is HUS, not toxin translocation.
  evidence:
  - reference: PMID:10874060
    reference_title: The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "antibiotic administration remained a risk factor for the development of the hemolytic uremic syndrome (relative risk, 17.3; 95 percent confidence interval, 2.2 to 137)"
    explanation: >-
      Gives the adjusted effect estimate from the prospective cohort, with the
      very wide confidence interval that reflects its small size.
  - reference: PMID:26917812
    reference_title: "Shiga Toxin-Producing Escherichia coli Infection, Antibiotics, and Risk of Developing Hemolytic Uremic Syndrome: A Meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "after excluding studies at high risk of bias and those that did not employ an acceptable definition of HUS, there was a significant association. Consequently, the use of antibiotics in individuals with STEC infections is not recommended."
    explanation: >-
      The meta-analysis supports the recommendation against antibiotics on the
      basis of its low-risk-of-bias subset.
  - reference: PMID:26917812
    reference_title: "Shiga Toxin-Producing Escherichia coli Infection, Antibiotics, and Risk of Developing Hemolytic Uremic Syndrome: A Meta-analysis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, use of antibiotics was not associated with an increased risk of developing HUS"
    explanation: >-
      The same meta-analysis found no association across all eligible studies.
      Recorded as a separate REFUTE item rather than folded into the supporting
      one, because the pooled and restricted analyses point in opposite
      directions and both belong in the record.
- name: Ingestion of STEC-contaminated food and water
  description: >-
    Consumption of food and drinking water contaminated from the ruminant
    reservoir is the principal route by which infection is acquired, and the
    exposure that public-health prevention targets.
  exposure_term:
    preferred_term: ingestion of food or water contaminated with Shiga toxin-producing E. coli
    term:
      id: ECTO:3000009
      label: exposure to Escherichia coli
  influences_mechanisms:
  - target: Colonic Colonisation and Attaching-and-Effacing Lesion Formation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Ingestion of the contaminated vehicle is the route by which the organism
      reaches the colon and establishes the colonisation that initiates disease.
    evidence:
    - reference: PMID:23955166
      reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The principal route of infection is consumption of contaminated food and drinking water"
      explanation: Names ingestion of contaminated food and water as the principal route of the infection that initiates this disease.
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The principal route of infection is consumption of contaminated food and drinking water, although infection may also occur via direct contact with animals, person-to-person contact, and environmental exposure."
    explanation: Establishes the exposure and places it ahead of the other recognised routes.
  review_notes: >-
    The binding is the organism-exposure class, not a route-qualified one.
    Searched against the ECTO build itself: `l~coli` returns ECTO:3000009
    exposure to Escherichia coli, which is a leaf under ECTO:3000000 exposure
    to organism, and `descendants ECTO:3000000` confirms it has no "via
    ingestion" child; `l~contaminated food` returns nothing. So ECTO carries the
    organism but not the foodborne route, and the route is carried in
    preferred_term instead, as the Ontology Term Contract permits. The broader
    candidates were rejected on positive grounds: ECTO:7000119 exposure to
    contaminated water and ECTO:9002126 exposure to environmental food
    contaminant both name a chemical-contaminant sense of contamination, and
    ECTO:0070135 exposure to water via ingestion asserts the route without the
    pathogen.
progression:
- phase: STEC colitis prodrome
  duration: Several days; HUS emerges about 5-13 days after diarrhoea onset, often as the diarrhoea is resolving.
  notes: >-
    Diarrhoea that becomes bloody over one to three days, with abdominal
    tenderness and pain around defecation and frequently no fever at
    presentation. This is the window in which intervention can alter the renal
    outcome, and in which antibiotics should be withheld. Most infections stop
    here: 6.3% of 3464 STEC O157 infections under US surveillance progressed to
    HUS, rising to 15.3% in children under five.
  evidence:
  - reference: PMID:19827953
    reference_title: "Hemolytic uremic syndrome and death in persons with Escherichia coli O157:H7 infection, foodborne diseases active surveillance network sites, 2000-2006."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 3464 STEC O157 infections were ascertained; 218 persons (6.3%) developed HUS. The highest proportion of HUS cases (15.3%) occurred among children aged <5 years."
    explanation: >-
      Quantifies how often this phase progresses to HUS, overall and in the
      highest-risk age group. It is recorded here rather than in prevalence
      because the denominator is infected persons, not a population.
  - reference: PMID:21784993
    reference_title: Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the brief interval between first presentation with diarrhea and HUS onset could be exploited to maintain or improve renal perfusion, possibly averting renal shutdown"
    explanation: Identifies the prodrome as a distinct phase with its own therapeutic window ahead of HUS onset.
- phase: Acute thrombotic microangiopathy
  duration: Days to a few weeks; dialysis, when needed, usually for days to weeks.
  notes: >-
    The full triad with acute kidney injury, around half of patients requiring
    renal replacement therapy, and extrarenal involvement in a minority. Deaths
    occur in this phase and are mostly neurological.
  evidence:
  - reference: PMID:39518638
    reference_title: "Changing Epidemiology and Outcomes of Hemolytic Uremic Syndrome in Children: A Prospective National Cohort Study from the Polish Pediatric HUS Registry and the Polish Registry of Renal Replacement Therapy in Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall mortality rate was 2% for STEC-HUS and 3.7% for aHUS, with no deaths reported in children on eculizumab and mortality mainly attributed to neurological damage."
    explanation: >-
      Gives the case fatality for this disease and attributes the deaths mainly
      to neurological damage, which is the claim this phase's notes make.
  - reference: PMID:37303085
    reference_title: "Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "characterized by multiorgan thrombotic microangiopathy, mainly affecting children. Renal involvement is severe, with approximately half of patients requiring dialysis."
    explanation: Characterises the acute phase and the proportion needing dialysis in it.
- phase: Recovery and renal sequelae
  duration: Years; sequelae assessed at five-year follow-up and beyond.
  notes: >-
    Most children recover kidney function - complete renal recovery in 57
    patients after a median four years in one national series - but about a
    third carry kidney sequelae at five years. The course is monophasic, unlike
    the relapsing course of atypical HUS.
  evidence:
  - reference: PMID:32323005
    reference_title: "Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli in children: incidence, risk factors, and clinical outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete renal recovery was observed in 57 patients after a median 4.0 years of follow-up."
    explanation: Gives the recovery outcome over years of follow-up in a nationwide paediatric cohort.
  - reference: PMID:37303085
    reference_title: "Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "at least 30% of survivors experience kidney sequelae"
    explanation: Quantifies the burden of long-term kidney sequelae among survivors.
prevalence:
- population: Children in Finland, 2000-2016
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.5
  rate_denominator: POPULATION_PER_YEAR
  notes: Annual incidence of STEC-HUS of 0.5 per 100,000 children in a nationwide study.
  evidence:
  - reference: PMID:32323005
    reference_title: "Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli in children: incidence, risk factors, and clinical outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the annual incidence of STEC-HUS being 0.5 per 100,000 children"
    explanation: Gives the nationwide paediatric incidence figure recorded here.
- population: Children in Poland, 2012-2023
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.39
  rate_denominator: POPULATION_PER_YEAR
  notes: >-
    Mean 3.9 cases per million age-related population per year, rising over the
    observation period; converted to 0.39 per 100,000.
  evidence:
  - reference: PMID:39518638
    reference_title: "Changing Epidemiology and Outcomes of Hemolytic Uremic Syndrome in Children: A Prospective National Cohort Study from the Polish Pediatric HUS Registry and the Polish Registry of Renal Replacement Therapy in Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of STEC-HUS increased during the observation period, with a mean of 3.9 cases per million age-related population"
    explanation: Gives the Polish national registry incidence and its upward trend.
treatments:
- name: Supportive Care
  description: >-
    Supportive management is the mainstay: there is no approved antitoxin and no
    specific treatment of proven benefit in the acute phase. It comprises
    attention to volume status, electrolyte and acid-base management, blood
    pressure control, transfusion as needed, and renal replacement therapy when
    the kidney injury demands it.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Acute kidney injury
    treatment_effect: MODULATES
    description: >-
      Supportive care moderates the consequences of the renal injury rather than
      acting on the toxin that causes it.
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients currently receive supportive care to manage symptoms, as no specific treatment exists for D+HUS."
    explanation: States that supportive care is the available management and that no specific therapy exists.
- name: Early Intravenous Volume Expansion
  description: >-
    Intravenous fluid given in the first four days of diarrhoea, before HUS is
    established, is associated with a lower rate of oligoanuric renal failure.
    Children who became oligoanuric had received less intravenous fluid and
    sodium in that window. This is an observational association from a
    prospective cohort, not a randomised result, and the authors describe the
    intervention as underused.
  treatment_term:
    preferred_term: intravenous volume expansion
    term:
      id: NCIT:C116537
      label: Fluid Therapy
  target_mechanisms:
  - target: Oliguria
    treatment_effect: MODULATES
    description: >-
      Maintaining renal perfusion during the prodrome is associated with
      preservation of urine output once HUS develops.
    evidence:
    - reference: PMID:21784993
      reference_title: Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The relative risk of oligoanuria when fluids were not given in this interval was 1.6 (95% confidence interval, 1.1-2.4; P = .02)."
      explanation: >-
        Gives the effect estimate for withholding early fluids. Indirect because
        the design is observational, so the association is not established as
        causal.
  evidence:
  - reference: PMID:21784993
    reference_title: Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intravenous volume expansion is an underused intervention that could decrease the frequency of oligoanuric renal failure in patients at risk of HUS."
    explanation: The authors' own conclusion about the role of early volume expansion in patients at risk.
- name: Renal Replacement Therapy
  description: >-
    Dialysis supports the patient through oligoanuric acute kidney injury. It is
    needed by a large share of children in the acute phase - 63% in the Finnish
    national series quoted below, about half in the French trial cohort - and is
    usually temporary.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hemodialysis
    term:
      id: NCIT:C15248
      label: Hemodialysis
  target_mechanisms:
  - target: Acute kidney injury
    treatment_effect: BYPASSES
    description: Renal replacement substitutes for excretory function while the glomerular lesion resolves.
  evidence:
  - reference: PMID:32323005
    reference_title: "Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli in children: incidence, risk factors, and clinical outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifty-five patients (63%) needed dialysis."
    explanation: Quantifies the use of dialysis in a nationwide paediatric STEC-HUS cohort.
- name: Packed Red Blood Cell Transfusion
  description: >-
    Transfusion corrects the anaemia of the microangiopathic haemolysis.
  treatment_term:
    preferred_term: packed red blood cell transfusion
    term:
      id: NCIT:C15409
      label: Packed Red Blood Cell Transfusion
  target_mechanisms:
  - target: Microangiopathic hemolytic anemia
    treatment_effect: RESTORES
    description: Transfusion replaces the erythrocytes lost to mechanical haemolysis.
  notes: >-
    Carried on the strength of the entry-level supportive-care citation; no
    source quoted here states a transfusion threshold. The related practice of
    withholding platelet transfusion unless there is bleeding or a planned
    procedure comes from the deep-research report and is deliberately not
    asserted in the description, because no quoted source in this entry
    supports it.
- name: Eculizumab
  description: >-
    Terminal complement inhibition is supported mechanistically - toxin-driven
    complement activation is part of the lesion, and early C5 inhibition rescues
    a mouse model - but is not standard care. The phase 3 randomised
    placebo-controlled trial in 100 children found no effect on the acute phase
    and a lower proportion with renal sequelae at one year. The two results
    belong together: the acute primary endpoint was negative, and the one-year
    difference is a follow-up result the trial's own authors frame as needing
    larger studies. The abstract lists its secondary endpoints as haematologic
    and extrarenal involvement, so the one-year sequelae figure is not described
    there as one of them.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: eculizumab
      term:
        id: NCIT:C48386
        label: Eculizumab
  target_mechanisms:
  - target: Alternative Complement Pathway Activation on Injured Endothelium
    treatment_effect: INHIBITS
    description: >-
      Eculizumab blocks C5 cleavage and so the terminal pathway downstream of
      the complement activation this disease induces at the endothelial surface.
    evidence:
    - reference: PMID:37863058
      reference_title: Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Early therapeutic inhibition of the terminal complement pathway with a C5 inhibitor rescued this podocyte-driven, Stx-induced HUS phenotype."
      explanation: Model-organism evidence that inhibiting the terminal pathway reverses the toxin-driven phenotype.
  evidence:
  - reference: PMID:37303085
    reference_title: "Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The rate of RRT <48 hours did not differ significantly between the two groups (48% in the placebo versus 38% in the eculizumab group; P = 0.31) or in the course of ARF."
    explanation: >-
      The trial's primary endpoint was negative, refuting an acute-phase benefit
      of eculizumab in this disease.
  - reference: PMID:37303085
    reference_title: "Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proportion of patients experiencing renal sequelae at 1 year was lower in the eculizumab group than in the placebo group (43.48% and 64.44%, respectively, P = 0.04)."
    explanation: >-
      The same trial found fewer renal sequelae at one year. Recorded as a
      separate SUPPORT item because it bears on a different claim from the
      negative acute endpoint, and both are needed to state the evidence
      honestly.
  - reference: PMID:37303085
    reference_title: "Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Larger prospective studies would be needed to further explore eculizumab as a potential treatment."
    explanation: The investigators' own statement of how much weight the one-year result can carry.
- name: Therapeutic Plasma Exchange
  description: >-
    Plasma therapy is not established in this disease. A large prospective
    paediatric study found plasma therapy associated with poor long-term
    outcome, and its first-line use is described as controversial. Recorded here
    because it is still used in some settings, not because it is recommended.
  treatment_term:
    preferred_term: plasmapheresis
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  evidence:
  - reference: PMID:23955166
    reference_title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "a recent prospective study of 619 children with HUS identified an association between plasma therapy and poor long-term outcome"
    explanation: >-
      Reports an association between plasma therapy and poor long-term outcome,
      which cuts against its use in this disease.
differential_diagnoses:
- name: Atypical hemolytic uremic syndrome
  description: >-
    Complement-mediated HUS arising from inherited or acquired defects in
    alternative-pathway regulation. It lacks the diarrhoeal prodrome, relapses,
    and is an approved indication for complement inhibition - so the distinction
    changes management. Genetic testing of complement genes belongs to this
    work-up.
  evidence:
  - reference: PMID:40255570
    reference_title: "Eculizumab is efficacious and safe in pediatric patients with various forms of hemolytic uremic syndrome: a retrospective clinical experience of a tertiary center"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atypical HUS (aHUS) is a syndrome caused by inherited or acquired defects in regulation of the complement system's alternative pathway"
    explanation: Defines the aetiology that distinguishes atypical HUS from the toxin-mediated disease.
  - reference: PMID:40255570
    reference_title: "Eculizumab is efficacious and safe in pediatric patients with various forms of hemolytic uremic syndrome: a retrospective clinical experience of a tertiary center"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The various types of HUS are caused by different primary triggers; yet, their clinical features overlap"
    explanation: States the clinical overlap that makes this a genuine differential rather than an obvious distinction.
- name: Thrombotic thrombocytopenic purpura
  description: >-
    TTP produces the same microangiopathic triad but through severe ADAMTS13
    deficiency. In STEC-HUS plasma ADAMTS13 activity lies within a broad normal
    range - the protease impairment is local and toxin-imposed - so ADAMTS13
    activity separates them, and plasma exchange is the treatment for TTP but
    not for this disease.
  evidence:
  - reference: PMID:16131569
    reference_title: Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "plasma levels of von Willebrand factor (VWF)-cleaving protease (ADAMTS13) activity that are within a broad normal range"
    explanation: >-
      Establishes that plasma ADAMTS13 activity is normal in this disease, which
      is the laboratory basis for separating it from TTP.
notes: >-
  No GeneReviews chapter exists for this disease and none is expected: it is an
  acquired, toxin-mediated infectious disease with no human causal gene, no
  OMIM entry and no Mendelian inheritance pattern, so the GeneReviews phenotype
  baseline does not apply.

  The disease is lumped deliberately across STEC serogroups. O157:H7 is carried
  as an infectious_agent subtype because its progression risk is separately
  quantified, but the non-O157 serogroups (O26, O80, O104, O111, O145) get no
  subtype rows: the cited nationwide series found that neither serogroup nor stx
  type predicted renal outcome or major CNS symptoms, so there is no documented
  axis of difference to carry. Shigella dysenteriae type 1 is a second agent
  rather than a second disease, which is why MONDO scopes this concept to the
  toxin.

  Two mechanistic steps are weaker than the rest of the chain and are marked as
  such rather than smoothed over. The identity of the carrier of Shiga toxin in
  blood is unsettled - the cited review says the major carrier has yet to be
  unequivocally identified - so the systemic-delivery step is the least secure
  link. And the classical account of how thrombocytopenia and erythrocyte
  fragmentation arise is quoted together with the cited authors' own remark that
  newer evidence challenges it.

  The complement regulatory genes (CFH, CD46/MCP, CFI, C3) reported in some
  patients with a severe course are deliberately NOT recorded as a `genetic:`
  entry. No gene-disease relationship can be typed for them from anything cited
  here: the only quotable statement available is about atypical HUS, which is
  the differential diagnosis rather than this disease, and an unsourced typed
  relationship is worse than no record. The same applies to A4GALT, the Gb3
  synthase, which the deep-research report names as a host determinant. The aHUS
  contrast is carried in `differential_diagnoses` instead, where it is actually
  sourced.

  Stx2, and the stx2a subtype in particular, is a documented risk factor for
  progression from infection to HUS (odds ratios of 9.7 and 16.6 in the Finnish
  cohort). That is a property of the infecting organism rather than of the host,
  and the schema has no slot for a bacterial virulence genotype, so it is
  recorded here rather than in the genetic section, which is for host genetics.
references:
- reference: PMID:25530917
  title: "Shiga Toxin (Stx) Classification, Structure, and Function."
- reference: PMID:23955166
  title: New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome
- reference: PMID:20424866
  title: "Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction."
- reference: PMID:37303085
  title: "Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial."

📚

References & Deep Research

References

4

PMID:25530917

Shiga Toxin (Stx) Classification, Structure, and Function.

No top-level findings curated for this source.

PMID:23955166

New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome

No top-level findings curated for this source.

PMID:20424866

Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction.

No top-level findings curated for this source.

PMID:37303085

Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

No GeneReviews chapter exists for this disease and none is expected: it is an acquired, toxin-mediated infectious disease with no human causal gene, no OMIM entry and no Mendelian inheritance pattern, so the GeneReviews phenotype baseline does not apply. The disease is lumped deliberately across STEC serogroups. O157:H7 is carried as an infectious_agent subtype because its progression risk is separately quantified, but the non-O157 serogroups (O26, O80, O104, O111, O145) get no subtype rows: the cited nationwide series found that neither serogroup nor stx type predicted renal outcome or major CNS symptoms, so there is no documented axis of difference to carry. Shigella dysenteriae type 1 is a second agent rather than a second disease, which is why MONDO scopes this concept to the toxin. Two mechanistic steps are weaker than the rest of the chain and are marked as such rather than smoothed over. The identity of the carrier of Shiga toxin in blood is unsettled - the cited review says the major carrier has yet to be unequivocally identified - so the systemic-delivery step is the least secure link. And the classical account of how thrombocytopenia and erythrocyte fragmentation arise is quoted together with the cited authors' own remark that newer evidence challenges it. The complement regulatory genes (CFH, CD46/MCP, CFI, C3) reported in some patients with a severe course are deliberately NOT recorded as a `genetic:` entry. No gene-disease relationship can be typed for them from anything cited here: the only quotable statement available is about atypical HUS, which is the differential diagnosis rather than this disease, and an unsourced typed relationship is worse than no record. The same applies to A4GALT, the Gb3 synthase, which the deep-research report names as a host determinant. The aHUS contrast is carried in `differential_diagnoses` instead, where it is actually sourced. Stx2, and the stx2a subtype in particular, is a documented risk factor for progression from infection to HUS (odds ratios of 9.7 and 16.6 in the Finnish cohort). That is a property of the infecting organism rather than of the host, and the schema has no slot for a bacterial virulence genotype, so it is recorded here rather than in the genetic section, which is for host genetics.

Create: Shiga Toxin-Associated Hemolytic Uremic Syndrome · 2026-10-28T14:54:04Z · View source

Created kb/disorders/Shiga_Toxin-Associated_Hemolytic_Uremic_Syndrome.yaml (MONDO:0019536) de novo. Deep research: falcon was requested but has no EDISON_API_KEY in this environment, so the run was re-issued with --fallback-provider claude_code and the report is recorded as research/Shiga_Toxin-Associated_Hemolytic_Uremic_Syndrome-deep-research-claude_code.md, carrying fell_back/requested_provider/provider_attempts in its frontmatter. Its reference_validation block reported 9/9 resolved, confabulation_rate 0.0; term_validation set needs_review because three CURIEs carried prose captions rather than labels (HP:0030213, UBERON:0001155, UBERON:0000955). All three were checked by hand: HP:0030213 is Emotional dearth and was NOT used; the two UBERON terms are correct for colon and brain and are bound with their canonical labels. The report's suggested NCIT treatment codes were independently verified and four were wrong - eculizumab is NCIT:C48386 not C64762, fluid therapy NCIT:C116537 not C15317, plasmapheresis NCIT:C15304 not C50111, packed RBC transfusion NCIT:C15409 not C15280 - so the verified codes were used. One PMID written from memory (26936670) resolved to an unrelated paper on waterborne healthcare outbreaks; it was deleted from the cache and the correct antibiotic meta-analysis (PMID:26917812) was found by search instead. Pathophysiology is curated as a causal chain from colonic colonisation through toxin translocation, Gb3 binding, retrograde trafficking and 28S rRNA depurination, to the two downstream arms (ribotoxic apoptosis; sublethal endothelial activation), local alternative-pathway complement activation, ULVWF-platelet capture, glomerular TMA, and the haematological and extrarenal consequences, with per-edge evidence. Three nodes conform to complement_dysregulation and thrombogenesis module nodes. Two mechanistic weak points are marked rather than smoothed: the unidentified systemic toxin carrier, and the classical shearing/consumption account, which is quoted together with the cited authors' own caveat against it. The eculizumab record carries the ECULISHU trial as both a REFUTE item (negative acute primary endpoint) and a SUPPORT item (fewer renal sequelae at 1 year), because the report had described the trial as simply showing no benefit. The antibiotic-risk environmental record likewise carries the meta-analysis twice, SUPPORT for the low-risk-of-bias subset and REFUTE for the null pooled estimate. The foodborne exposure was left unbound in the first draft with a review_notes block recording the ECTO queries run; that note turned out to be wrong and both the binding and the note were corrected in the review round described below. Validation: just validate-disorders passed (schema, terms, 95/95 snippets, 99 titles, 0 issues); just validate-terms passed; check-entity-refs, check-causal-targets, check-duplicate-keys, check-block-scalar-comments, check-enum-values, check-delivery-system, check-coarse-phenotypes, check-qualifier-terms, check-logical-rules, check-folded-hyphens, check-folded-yaml, check-snippet-length, check-title-snippets, check-reference-titles, check-retired-support-prose, check-shared-disease-terms, check-snippet-grading and check-granularity all clean; just check-genereviews reports NO_CHAPTER, which is what the notes field claims. A self-review round followed the first validated draft and found real defects, the worst of them mine. (1) The review_notes claiming no ECTO class fitted the foodborne exposure was FALSE: re-run against the ECTO build rather than the cache, `l~coli` returns ECTO:3000009 exposure to Escherichia coli, reachable from ExO:0000002 and bindable. That is the cache-read-backwards error CLAUDE.md names by example, and the note had been written from a cache query while drawing a conclusion about the ontology. ECTO:3000009 is now bound with the route in preferred_term, and the note records what was actually searched and that ECTO has no via-ingestion child for it. ECTO:0900070 was likewise bound to the antibiotic exposure, which had no term at all. (2) A snippet on the TMA->Proteinuria edge quoted 'why the glomerular microvasculature is so susceptible to injury following systemic Stx infection' - the subordinate clause of a sentence whose predicate is 'are unclear'. It presented the paper's statement of what is unknown as a positive finding and was deleted; the edge is now explicitly uncited. (3) prevalence_class on the Finnish record was BAND_1_9_PER_100000 for 0.5/100,000, which belongs in BAND_1_9_PER_1000000 (0.1-0.9 per 100,000); its sibling record had the same rate banded correctly, so the block contradicted itself. (4) The Gb3 node asserted that Gb3 differs between species and that animals do not reproduce the human renal phenotype - uncited, and contradicted by two of this entry's own references (PMID:25530917 reports relative toxicity 'replicated in mice and baboons'; PMID:37863058 is a mouse that does reproduce it). Cut, and the defensible part relocated to the new animal_models record. (5) An animal_models entry for the Pod-Gb3 mouse was added with modeled_mechanisms, a factor-H readout and a BOUNDARY_OMISSION divergence; that mouse was the sole evidence for three claims and had no model record. (6) A diagnosis record for stool stx1/stx2 PCR was added on a newly fetched source (PMID:23843484), since microbiologic confirmation is what separates this disease from aHUS and nothing cached supported the report's other diagnostic claims, which are flagged as a gap rather than asserted. (7) Mortality 'mostly neurological' was uncited while PMID:39518638 carried the exact sentence; now cited. (8) quote_role: BACKGROUND added to 8 items and 5 review quotes describing cell-culture mechanism regraded HUMAN_CLINICAL -> IN_VITRO. (9) Two bundled nodes were split: retrograde trafficking from the depurination lesion, and erythrocyte shearing from platelet consumption, whose two downstream edges came from opposite halves of one node. (10) The genetic: record was deleted - it typed a MODIFIER relationship with no gene_term and its only evidence quoted an aHUS fact, so it asserted a relationship nothing cited supported; the contrast now lives only in differential_diagnoses and notes. (11) Smaller fixes: CL:0011108 colon epithelial cell on the colonic node, UBERON:0000948 heart bound and the available pancreas snippet used, Encephalopathy/Seizure edges marked indirect and explicitly uncited, a Seizure phenotype added, Encephalopathy frequency OCCASIONAL -> FREQUENT with the figure named, the CKD frequency band dropped because the 31% covers all kidney sequelae rather than CKD, the RRT description's 'roughly half' reconciled with the 63% it cited, Coombs-negativity and haptoglobin consumption marked as uncited standard practice, the non-O157 trend claim softened, the LDH note rewritten to say its figure is pooled across three TMA subtypes with only 5 STEC-HUS patients, the Shigella binding annotated as species-level for a serotype-specific agent, and the FoodNet progression risk moved out of prevalence into the prodrome progression phase where its denominator makes sense. Review round 1 (PR #15830, ai4c-reviewer, CHANGES_REQUESTED) raised three blocking items, all confirmed and all fixed in one push. The antibiotic exposure was bound to ECTO:0900070 'exposure to antibacterial drug via ingestion', asserting a route neither cited source states; swapped to the route-neutral ECTO:9001757. Two snippets were truncated at the character before a Greek letter and so stopped short of the words their explanations claimed - the depurination quote named neither the alpha-sarcin/ricin loop nor 28S rRNA, and the O104:H4 quote carried neither 'horizontal' nor 'beta-lactamase'; both were extended and both verify through greek_map normalization, so the truncation had bought nothing. This is the never-truncate-a-snippet rule in CLAUDE.md, broken twice. One PMID:23955166 quote describing ribosome biochemistry was still graded HUMAN_CLINICAL after the earlier regrade pass missed it; it and two neighbours (the A/E lesion definition and the outbreak-strain sequencing sentence) were regraded IN_VITRO and OTHER. Four of the six suggestions were also taken: quote_role BACKGROUND on the ADAMTS13 characterisation, a note on the Gb3 node that the podocyte binding rests on the human biopsy arm rather than the engineered mouse, the eculizumab description no longer calling the one-year sequelae figure a secondary endpoint (the abstract lists only haematologic and extrarenal involvement as secondary), and the empty has_subtypes slot removed. The granularity suggestion was answered on the PR rather than in the file: the entry is excluded from the infectious ladder as a SEQUELA, so the zeroes mean not-assessed, and the PR summary wording was the defect. A connectivity pass also ran: just list-disconnected-phenotypes showed only 4 of 11 phenotypes causally connected, so the colitis, schistocyte, oligoanuria and proteinuria edges were added, chronic kidney disease and hypertension were linked as sequelae of the acute kidney injury, and the creatinine rise was recorded as a reports_on READOUT_OF link rather than a causal edge because it is the measurement that defines the injury. That took connectivity to 11 of 12, with creatinine correctly remaining a readout; every gate above was re-run clean afterwards.

Claude Code ▸

1. Disease Information

claude-haiku-5-5, claude-opus-4-8, claude-opus-5-5 15 citations 2026-10-28T14:15:12.613300

1. Disease Information

STEC-HUS is a thrombotic microangiopathy (TMA) defined by the classic triad of microangiopathic hemolytic anemia (Coombs-negative, with schistocytes), thrombocytopenia, and acute kidney injury, arising typically 5–10 days after an episode of (often bloody) diarrhea caused by STEC. It is the prototypical "typical" / diarrhea-associated (D+) HUS and is the leading cause of acute kidney injury in young children.

Identifiers / synonyms: MONDO:0019536. Synonyms: STEC-HUS; typical HUS; diarrhea-positive (D+) HUS; diarrhea-associated HUS; "classic" HUS; (historically) post-diarrheal HUS. ICD-10 D59.3 (hemolytic-uremic syndrome); MeSH D006463 (Hemolytic-Uremic Syndrome). No OMIM entry (acquired disease).

Information source: derived chiefly from aggregated disease-level resources — surveillance networks (US CDC FoodNet), national pediatric registries (Polish, Italian, French), and clinical cohorts — rather than single-patient EHR data.

2. Etiology

Primary cause (infectious): ingestion of STEC producing Shiga toxin(s). Transmission is fecal-oral via contaminated undercooked ground beef, unpasteurized milk/juice, contaminated produce (leafy greens, sprouts), petting-zoo/farm-animal contact, recreational/drinking water, and person-to-person spread. Cattle are the principal reservoir (asymptomatic carriage). Infectious dose is very low (~10–100 organisms).

Required virulence determinant: the Shiga toxins (Stx1 and/or Stx2). Stx2 — particularly subtypes Stx2a — is strongly associated with progression to HUS, whereas Stx1-only strains more often cause uncomplicated diarrhea. Additional STEC virulence factors: the LEE pathogenicity island encoding intimin (eae) and the type III secretion system that mediates attaching-and-effacing (A/E) lesions on gut epithelium.

Risk factors: - Host-demographic: age < 5 years (highest risk), extremes of age, bloody diarrhea, elevated WBC, fever. - Iatrogenic: antibiotic exposure during STEC colitis (especially bactericidal/fluoroquinolone/β-lactam agents may induce the SOS response and increase phage-mediated Stx release) and antimotility agents — both associated with increased HUS risk. - Microbial: Stx2-producing strains, O157:H7, strains carrying stx2a + eae. - Genetic modifiers (not causal): rare variants in complement regulatory genes (CFH, CD46/MCP, CFI, C3) are reported in a subset with severe/atypical course and may worsen outcome; Gb3 synthase (A4GALT) expression levels on host endothelium modulate susceptibility.

Protective factors: adequate cooking of meat, pasteurization, hand hygiene, safe water; these are environmental/public-health, not molecular. No well-established protective genetic allele. Avoiding antibiotics and antimotility agents during suspected STEC colitis is protective against HUS progression.

Gene–environment interaction: the pathogenic outcome is set by the STEC stx2 genotype (environmental/microbial) interacting with host Gb3 tissue distribution and complement regulatory reserve — the same toxin dose produces disparate outcomes depending on host endothelial Gb3 density and complement-regulation capacity.

3. Phenotypes (with suggested HPO terms)

Prodrome / GI (preceding): - Diarrhea, frequently bloody (hemorrhagic colitis) — HP:0002014 (Diarrhea), HP:0025085 (Bloody diarrhea); abdominal pain HP:0002027; vomiting HP:0002013.

Core triad: - Microangiopathic hemolytic anemia — HP:0001937 (Microangiopathic hemolytic anemia); schistocytes on smear; HP:0001878 (Hemolytic anemia). - Thrombocytopenia — HP:0001873. - Acute kidney injury — HP:0001919; oliguria/anuria HP:0100519; often requiring dialysis.

Renal / laboratory: - Hematuria HP:0000790, proteinuria HP:0000093, elevated creatinine HP:0003259; hypertension HP:0000822; elevated LDH, low haptoglobin, negative direct Coombs.

Extrarenal (severity markers): - CNS involvement (~20–25% of severe cases): seizures HP:0001250, encephalopathy HP:0001298, stroke HP:0001297, altered consciousness HP:0030213 — a major determinant of acute mortality. - Pancreatic: hyperglycemia/pancreatitis HP:0001954, HP:0012090. - Cardiac (rare): HP:0001635; colonic complications: intussusception, necrosis, perforation.

Phenotype characteristics: acute onset, predominantly pediatric (<5 yr); severe but usually self-limited acute phase; monophasic course (vs relapsing aHUS). HUS develops in roughly 5–15% of STEC O157 infections, higher in young children. Quality-of-life impact is driven by the minority with CKD/hypertension/proteinuria sequelae at long-term follow-up.

4. Genetic / Molecular Information

No human causal gene. The operative genetics are bacterial: stx1, stx2 (and subtypes stx2a–stx2g) carried on lambdoid prophages; eae (intimin), ehxA (enterohemolysin), LEE locus.

Host molecular determinants: - A4GALT — encodes Gb3/CD77 synthase; Gb3 is the obligate Stx receptor. Tissue-specific Gb3 expression (high on human renal glomerular endothelium and podocytes, cerebral endothelium) explains organ tropism. - Complement modifier genes (CFH, CD46, CFI, C3, CFB) — rare variants reported in severe STEC-HUS; modifiers of severity, not disease cause.

No ACMG-classified pathogenic germline variants define the disease; it is not inherited, has no Mendelian inheritance pattern, no penetrance/expressivity/anticipation, and no founder effect. Allele-frequency/somatic-vs-germline sections are not applicable. Epigenetic/chromosomal abnormalities: not applicable.

5. Environmental Information

Infectious agent: Escherichia coli (STEC/EHEC) — NCBITaxon:562 (E. coli); O157:H7 lineage. Shiga toxin as the effector (CHEBI/ontology: Shiga toxin is a protein, not a small molecule).
Vehicles/exposures: undercooked beef, unpasteurized dairy, contaminated produce and water, animal/farm contact; large foodborne outbreaks (e.g., the 2011 German O104:H4 sprout outbreak).
Lifestyle/iatrogenic: antibiotic and antimotility use during STEC colitis (risk-increasing).

6. Mechanism / Pathophysiology

Ordered causal chain

Ingestion of STEC → colonization of the colon; intimin-mediated attaching-and-effacing lesions on colonic epithelium → hemorrhagic colitis (bloody diarrhea).
Local Shiga toxin production by phage-borne stx genes → toxin translocates across the gut epithelium into the circulation (transcellular/paracellular; leukocyte- and possibly extracellular-vesicle–associated carriage). Mechanism of systemic delivery partly inferred.
Toxin (AB₅ holotoxin) binds Gb3/CD77 on the surface of Gb3-rich target cells — chiefly human renal glomerular microvascular endothelium and podocytes, and cerebral endothelium. (Receptor = globotriaosylceramide; GO: receptor binding.)
Retrograde intracellular transport: endocytosis → Golgi → endoplasmic reticulum; the A-subunit is cleaved (furin) and reduced, releasing the A1 fragment into the cytosol.
A1 fragment acts as an RNA N-glycosidase → depurinates a single adenine in the 28S rRNA of the 60S ribosomal subunit → halts protein synthesis → cell injury. (This is the canonical demonstrated enzymatic lesion.)
Branch A — ribotoxic stress response: ribosomal damage activates p38 and JNK MAPK signaling → apoptosis and pro-inflammatory cytokine/chemokine induction (IL-8, IL-6, TNF). (Demonstrated in intestinal epithelial and endothelial cells.)
Branch B — endothelial activation (sublethal toxin): at sublethal doses Stx reprograms endothelial gene expression rather than killing → NF-κB activation → upregulated adhesion molecules, chemokines, tissue factor, and P-selectin → loss of thromboresistance → prothrombogenic endothelium.
Complement amplification: Stx2 binds complement factor H, impairing regulation, and induces P-selectin, which activates C3 via the alternative pathway on the endothelial surface → local complement deposition amplifies injury and platelet-thrombus formation. (Mechanistic link established in vitro; drives the eculizumab rationale.)
von Willebrand factor axis: Stx promotes endothelial secretion of ultra-large VWF multimers and impairs their ADAMTS13 cleavage → platelet capture → microvascular platelet-fibrin thrombi.
Microvascular thrombosis + mechanical RBC shearing across occluded/fibrin-laden capillaries → schistocytes, intravascular hemolysis (↑LDH, ↓haptoglobin) and platelet consumption (thrombocytopenia).
Glomerular TMA → endothelial swelling, capillary occlusion, podocyte injury → acute kidney injury (oliguria/anuria). Extrarenal Gb3-rich beds (brain, pancreas) → CNS and pancreatic complications.

Supporting detail

Molecular pathways: NF-κB; p38/JNK MAPK (ribotoxic stress); alternative complement pathway; VWF–ADAMTS13; coagulation (tissue factor).
Cellular processes: inhibition of translation; apoptosis (GO:0006915); inflammation; endothelial activation; platelet aggregation; thrombosis (GO:0007596 — blood coagulation).
Protein dysfunction: Stx A-subunit RNA N-glycosidase activity (enzymatic, not host-protein misfolding).
Cell types (CL): glomerular endothelial cell (CL:1001005 / CL:0002262 endothelial cell of vascular tree), podocyte (CL:0000653), platelet (CL:0000233), colonic epithelial cell (CL:0011108), monocyte/macrophage (CL:0000235).
Immune involvement: innate inflammatory cytokine storm; complement activation; neutrophil-mediated endothelial injury (Stx bound to neutrophils).
Tissue damage mechanisms: ischemia from microvascular occlusion, apoptosis, oxidative/inflammatory injury, fibrin deposition.

7. Anatomical Structures Affected (UBERON)

Primary organ: kidney — UBERON:0002113; specifically the renal glomerulus (UBERON:0000074) and its microvascular endothelium; podocytes. Renal cortex.
GI tract (initiating site): colon — UBERON:0001155 (hemorrhagic colitis).
Secondary/extrarenal: brain UBERON:0000955 (cerebral microvasculature — CNS TMA), pancreas UBERON:0001264, occasionally heart UBERON:0000948.
Body systems: urinary/renal, hematologic/vascular, gastrointestinal, nervous.
Tissue/cell level: vascular endothelium (microvascular), glomerular visceral epithelium (podocytes); subcellular — Stx trafficks through endosome → Golgi (GO:0005794) → ER (GO:0005783) → cytosol/ribosome (GO:0005840).
Localization: bilateral renal involvement.

8. Temporal Development

Onset: acute, predominantly pediatric; HUS emerges ~5–13 days after onset of diarrhea (median ~1 week), often as diarrhea begins to resolve.
Progression: acute phase over days to a few weeks; monophasic/self-limited in most. Oligoanuric AKI may require dialysis for days–weeks.
Course pattern: typically non-relapsing (unlike aHUS). Critical intervention window = early supportive/volume management during the colitis prodrome, before full TMA.
Duration/remission: most children recover kidney function within weeks (treatment-/supportive-care-associated), but a minority progress to chronic kidney disease; long-term renal sequelae (hypertension, proteinuria, reduced GFR) reported in ~25–30% at ≥5-year follow-up.

9. Inheritance and Population Epidemiology

Inheritance: none — acquired infectious disease (no AD/AR/X-linked pattern; penetrance/expressivity/consanguinity/carrier-frequency sections not applicable).
Epidemiology (children):
Pediatric STEC-HUS incidence varies by country/surveillance: e.g. ~0.5 per 100,000 children/year; Polish registry mean ~3.9 per million age-related population (rising over 2012–2023); French data: >4 cases/100,000 in children <3 yr.
~5–15% of STEC O157 infections progress to HUS; FoodNet reported ~6.3% of O157 infections and 15.3% of HUS among children <5 yr.
Mortality / outcome: low in modern cohorts — ~2–4% case fatality (Polish registry 2% for STEC-HUS; Italian network 3.4% STEC-HUS vs 8.3% aHUS; US FoodNet ~3% in <5 yr with HUS). Older surveillance: 3–5% death, 10–30% long-term renal dysfunction.
Demographics: highest in young children (1–2 yr highest for non-O157 O26/O80; O157 across childhood); summer/warm-season peak; geographic variation in serogroups (O157 historically dominant in North America/UK; O80/O26 rising in Europe; O104:H4 in the 2011 German outbreak affected mostly adults).
Sex: roughly equal, slight female predominance reported in some series.

10. Diagnostics

Clinical/laboratory triad: microangiopathic hemolytic anemia (schistocytes, ↑LDH, ↓haptoglobin, negative direct Coombs), thrombocytopenia, and acute kidney injury (↑creatinine). Supportive: hematuria, proteinuria.
Microbiologic confirmation of STEC: stool testing — PCR for stx1/stx2 genes (most sensitive; combined with culture raises detection to ~70%), Shiga toxin immunoassay (EIA), and stool culture on sorbitol-MacConkey agar (O157 is sorbitol-nonfermenting; misses non-O157 and sorbitol-fermenting O157). Send stool/rectal swab early — absence of STEC in stool does not exclude STEC-HUS (toxin may clear by the time HUS presents). Serology (anti-O157 LPS antibodies) aids diagnosis when stool is negative.
Imaging / other: renal ultrasound (nonspecific); neuroimaging (MRI) if CNS involvement.
Essential differential diagnosis: aHUS/complement-mediated HUS (no diarrhea prodrome, relapsing, complement variants) and TTP (severe ADAMTS13 <10% activity). Distinguishing STEC-HUS from aHUS/TTP is critical because management differs (STEC-HUS = supportive; aHUS = eculizumab; TTP = plasma exchange). LOINC-codable: stool Shiga toxin EIA, stx PCR, ADAMTS13 activity, schistocyte count, LDH, haptoglobin, platelet count, creatinine.
Genetic/omics testing: complement gene panel only when aHUS is suspected (negative STEC workup, atypical/relapsing course).
Screening: public-health STEC surveillance and outbreak investigation; no individual genetic screening applicable.

11. Outcome / Prognosis

Survival: acute case fatality ~2–4% (modern pediatric cohorts); death driven mainly by severe CNS involvement or multi-organ failure.
Recovery: majority of children recover kidney function; acute dialysis common but usually temporary.
Long-term morbidity: ~25–30% of survivors have renal sequelae at ≥5 yr (hypertension, proteinuria, reduced GFR, CKD); a small fraction progress to ESKD.
Prognostic factors (poor): early anuria / prolonged dialysis, high peak WBC, CNS involvement, Stx2 (vs Stx1) genotype, young age, need for dialysis >2–3 weeks. These predict chronic kidney outcomes.

12. Treatment (with suggested NCIT terms)

Mainstay = supportive care; there is no approved antitoxin. - Supportive care (NCIT:C15747 Supportive Care): careful IV volume expansion/early isotonic fluids (NCIT:C15317 Fluid Therapy — early hydration during colitis may be renoprotective), electrolyte and acid-base management, blood pressure control, transfusion of packed RBCs for anemia (NCIT:C15280 Blood Transfusion; platelet transfusion generally avoided unless bleeding/procedure). - Renal replacement therapy (NCIT:C15431? — Dialysis, NCIT:C15248): hemodialysis/peritoneal dialysis/CKRT for oligoanuric AKI. - AVOID: antibiotics (NCIT:C254 Antibiotic) in confirmed/suspected STEC — no proven benefit, possible increased HUS risk (especially bactericidal agents); antimotility agents; NSAIDs. - Plasma exchange (NCIT:C50111 Plasmapheresis/Therapeutic Plasma Exchange): not routinely beneficial in children (reserved, controversially, for severe neurologic disease or adults in outbreak settings). - Eculizumab (NCIT:C64762 Eculizumab; complement C5 inhibitor; monoclonal antibody, NCIT:C20401): controversial and not standard. A randomized placebo-controlled trial (100 children) showed no benefit on acute dialysis need, hematologic course, or extrarenal manifestations; systematic review found no definite medium/long-term benefit. Some centers reserve it empirically for severe CNS involvement, acknowledging weak evidence. - Experimental / investigational: Stx-neutralizing agents, Shiga toxin receptor analogs/binders, anti-Stx monoclonal antibodies, and complement-pathway agents — remain investigational (ClinicalTrials.gov). - Pharmacogenomics: not applicable.

13. Prevention

Primary prevention (public health, dominant): thorough cooking of ground beef, pasteurization of milk/juice, produce and water safety, hand hygiene, exclusion of cases from food handling/childcare, careful farm/petting-zoo hygiene. Vector/reservoir control (cattle). NCIT:C15417? Health Education / Hygiene.
Secondary prevention: early recognition of STEC colitis and early IV hydration, and avoidance of antibiotics/antimotility agents to reduce HUS progression; close hematologic/renal monitoring of children with bloody diarrhea.
Tertiary prevention: BP control and nephroprotection (ACE inhibition) and long-term renal surveillance in survivors to limit CKD progression.
Immunization: no licensed human vaccine; STEC/Stx and cattle vaccines are investigational.
Counseling/genetic screening: not applicable (non-genetic).

14. Other Species / Natural Disease

Reservoir: cattle (Bos taurus, NCBITaxon:9913) and other ruminants carry STEC asymptomatically in the gut — the principal zoonotic source. Deer, sheep, goats also carry STEC.
Natural disease / comparative biology: classic HUS-like renal TMA is largely human-specific because Gb3 distribution differs by species — human glomerular endothelium is Gb3-rich, whereas mice express Gb3 mostly extraglomerularly, so animals rarely develop the full human renal phenotype naturally.
Zoonotic potential: high — STEC is a foodborne/zoonotic pathogen; animals are carriers rather than HUS patients.

15. Model Organisms

Mouse models (NCBITaxon:10090): purified Stx injection, STEC gavage, and streptomycin-treated oral infection models; reproduce systemic toxicity, renal injury and neurologic signs but incompletely recapitulate human glomerular TMA due to different Gb3 tissue distribution. Widely used for toxin trafficking, complement, and therapeutic testing.
Rabbit, baboon/non-human primate, piglet (gnotobiotic/neonatal) models reproduce aspects of gut colonization, systemic Stx effects, and CNS/renal injury (piglet neurologic model notable).
In vitro: human glomerular microvascular endothelial cells, podocytes, HUVEC, intestinal epithelial (Caco-2/HCT-8), THP-1 macrophages, and kidney organoids — the most faithful systems for the human Gb3-dependent endothelial/podocyte mechanism.
Limitations: species Gb3 differences; most models require supraphysiologic toxin doses; natural monophasic human course hard to model.
Resources: MGI; ATCC/Cellosaurus (cell lines); published organoid protocols.

Key Citations (verify PMIDs with `just fetch-reference` before KB use)

MDPI Toxins (2020) — "Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review" — mdpi.com/2072-6651/12/2/67 (comprehensive mechanism/clinical review).
"Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction" — PubMed 20424866.
Shiga Toxin Classification, Structure, and Function (ASM, EHEC-0024-2013) — PMC4270005 (A-subunit RNA N-glycosidase, retrograde transport).
Ribotoxic stress response (p38/JNK, apoptosis), Infect Immun 2003 — journals.asm.org/doi/10.1128/iai.71.3.1497-1504.2003.
Stx–VWF–ADAMTS13, Blood 2005 — ashpublications.org/blood/article/106/13/4199.
Shiga toxin targets the podocyte via endothelial complement activation — PMC7617617 (PMID not confirmed — browser block; verify before citing).
New insights into Stx-mediated endothelial dysfunction, Virulence 2013 — tandfonline.com/doi/full/10.4161/viru.26143.
HUS and death in E. coli O157:H7 infection, FoodNet 2000–2006, CID 2009 — PubMed 19827953.
Incidence, risk factors, outcome in children — PMC7385025.
Polish Pediatric HUS Registry prospective cohort (2024) — PMC11546500.
Sporadic pediatric STEC-HUS, France 2012–2021, Emerg Infect Dis 2023 — wwwnc.cdc.gov/eid/article/29/10/23-0382_article.
Eculizumab / supportive-care management review (2025) — Frontiers Pharmacol 2025.1535407.
UK Kidney Association — HUS clinician information — ukkidney.org/rare-renal.

Evidence-type note for KB population: mechanistic claims (steps 3–9) are predominantly IN_VITRO/MODEL_ORGANISM; epidemiology and outcome claims are HUMAN_CLINICAL (registry/surveillance); eculizumab-ineffectiveness is HUMAN_CLINICAL (RCT). A dismech entry for this disease already exists (kb/disorders/Shiga_Toxin-Associated_Hemolytic_Uremic_Syndrome.yaml); reconcile against it and verify every PMID/exact snippet with just fetch-reference and just count-verified-snippets before curating.

Sources: - MDPI Toxins narrative review - Endothelial dysfunction pathophysiology (PubMed 20424866) - Shiga Toxin structure/function PMC4270005 - Ribotoxic stress response, Infect Immun 2003 - Stx/VWF/ADAMTS13, Blood 2005 - Podocyte/complement PMC7617617 - Virulence 2013 endothelial dysfunction - FoodNet HUS/death CID (PubMed 19827953) - Incidence/risk/outcome children PMC7385025 - Polish Pediatric HUS Registry PMC11546500 - France 2012–2021 EID 2023 - Frontiers Pharmacology 2025 management - UK Kidney Association HUS - EHEC diagnosis/management overview

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	9
Resolved	9
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	9
On topic	6
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	51
Resolved	51
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	10
Terms named correctly	6
Terms named as a different term	3
Terms whose name is worth a second look	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0030213 (1 mention) - the report calls it "a major determinant of acute mortality"; HP calls it Emotional dearth
UBERON:0001155 (1 mention) - the report calls it "hemorrhagic colitis"; UBERON calls it colon
UBERON:0000955 (1 mention) - the report calls it "cerebral microvasculature — CNS TMA"; UBERON calls it brain

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

NCBITaxon:10090 (1 mention) - the report calls it "Mouse models"; NCBITaxon calls it Mus musculus, and lists "house mouse" among its other names

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References & Deep Research

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1. Disease Information

2. Etiology

3. Phenotypes (with suggested HPO terms)

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Supporting detail

7. Anatomical Structures Affected (UBERON)

8. Temporal Development

9. Inheritance and Population Epidemiology

10. Diagnostics

11. Outcome / Prognosis

12. Treatment (with suggested NCIT terms)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key Citations (verify PMIDs with just fetch-reference before KB use)

Reference Validation

Term Validation

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Terms whose name is worth a second look

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