Hemolytic Uremic Syndrome

• Shiga Toxin-Mediated Endothelial Injury (Typical HUS): Shiga toxins (Stx1 and Stx2, primarily from STEC O157:H7) are AB5 toxins that damage the host through a multi-step process. The B subunit binds to globotriaosylceramide (Gb3), a glycosphingolipid receptor highly expressed on renal endothelial cells, glomerular podocytes, and colonic epithelium. Following internalization, the catalytic A subunit depurinates a specific adenine (A4324) in the 28S rRNA of the 60S ribosomal subunit, irreversibly inhibiting protein synthesis. This triggers activation of the unfolded protein response (UPR) and stress-activated mitogen-activated protein kinase (MAPK) pathways, leading to endothelial cell apoptosis, release of tissue factor (TF), and expression of adhesion molecules (ICAM-1, E-selectin). The result is profound endothelial dysfunction with microthrombi formation predominantly affecting the renal microvasculature, particularly affecting glomerular capillaries and arterioles. Neutrophil infiltration amplifies injury through release of proteases and reactive oxygen species (ROS).

• Complement-Mediated Endothelial Injury (Atypical HUS): Atypical HUS (aHUS) results from dysregulation of the alternative complement pathway, typically via loss-of-function mutations in complement regulators or gain-of-function mutations in complement pathway components. Key genetic abnormalities include mutations in genes encoding complement factor H (CFH), membrane cofactor protein (MCP/CD46), complement factor I (CFI), C3, and thrombin-mediated complement activation (THBD). These mutations prevent adequate control of C3 convertase (C3bBb), permitting uncontrolled generation of C3a and C5a anaphylatoxins and C5b-9 membrane attack complex (MAC). Persistent alternative pathway activation leads to continuous endothelial inflammation, with the glomerular endothelium serving as a site of particular vulnerability due to constant complement activation. Phosphatidylserine (PS) exposure on endothelial cells activates tissue factor pathway and promotes microthrombi formation. Unlike typical HUS, aHUS involves direct complement-mediated injury without an infectious trigger and demonstrates a more indolent course with chronic progression to end-stage renal disease (ESRD).

• Thrombotic Microangiopathy as the Final Common Pathway: Regardless of initial trigger, both typical and atypical HUS converge on microvascular thrombosis via multiple mechanisms: (1) endothelial cell activation and dysfunction with increased expression of von Willebrand factor (vWF) multimers and tissue factor; (2) platelet activation mediated by vWF multimers, complement components (particularly C5a), and tissue factor-bearing microparticles; (3) coagulation cascade amplification through tissue factor expression and contact pathway activation; and (4) microthrombi deposition within the renal microvasculature. Platelet consumption and mechanical fragmentation of red blood cells passing through microthrombi generate MAHA. Intrarenal vasoconstriction secondary to endothelin release and loss of nitric oxide bioavailability further compromises renal perfusion, culminating in acute tubular necrosis (ATN) and acute cortical necrosis in severe cases.

• Gastrointestinal Pathology in Typical HUS: In STEC-associated HUS, intestinal infection directly damages the colonic epithelium (explaining the hemorrhagic colitis prodrome), with epithelial destruction facilitating bacterial translocation and lipopolysaccharide (LPS) entry. LPS amplifies systemic inflammation through toll-like receptor (TLR) signaling, exacerbating endothelial injury through NF-κB pathway activation and cytokine release (IL-6, TNF-α, IL-8). The disrupted intestinal barrier permits bacterial translocation, which can perpetuate endotoxemia and multi-organ involvement.

• Systemic Inflammation and Multi-organ Effects: Both HUS subtypes provoke a profound inflammatory response with release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8) from endothelial cells, macrophages, and neutrophils. This cytokine storm contributes to the systemic manifestations beyond the kidney, including neurological involvement (seizures, stroke from microthrombi in cerebral vessels), cardiac complications (myocarditis, arrhythmias), pulmonary edema, and gastrointestinal bleeding. The degree of inflammation correlates with disease severity and long-term sequelae.

• Shiga Toxin-Producing E. coli (STEC) O157:H7—Most Common Typical HUS Cause: STEC O157:H7 is responsible for 90% of typical HUS cases in developed nations. Infection typically follows consumption of undercooked ground beef, contaminated produce (spinach, lettuce, sprouts), unpasteurized dairy, or exposure in childcare settings. The O157:H7 serotype elaborates primarily Stx2, which demonstrates higher nephrotoxicity than Stx1. Infection risk is amplified in children under 5 years (peak incidence 6-24 months), though older children and adults can be affected. Hemolytic uremic syndrome develops in approximately 5-10% of symptomatic STEC O157:H7 infections, typically 5-10 days after symptom onset. Seasonal clustering (late summer/early fall in temperate climates) reflects agricultural practices and food handling seasonal variations.

• Other Shiga Toxin-Producing Enterobacteriaceae (Typical HUS): Non-O157 STEC serotypes (particularly O111, O26, O103, O145) account for 10-20% of STEC-HUS cases and may cause more severe disease with higher mortality. These strains are often sorbitol-fermentable (unlike O157:H7) and may be missed on standard screening. Shigella dysenteriae type 1 causes a clinically identical syndrome historically in developing nations but remains rare in resource-rich countries. Streptococcus pneumoniae neuraminidase production can unmask Thomsen-Friedenreich antigen on red blood cells and platelets, triggering pneumococcal HUS through antibody-mediated platelet and RBC destruction—this variant presents without diarrheal prodrome.

• Complement-Mediated Atypical HUS (aHUS)—Primary Genetic/Acquired Forms: Approximately 10-15% of HUS cases are non-Shiga toxin mediated. Genetic mutations in complement regulatory proteins account for 40-60% of aHUS cases: CFH mutations (most common, ~30% of aHUS), MCP/CD46 mutations (~10%), CFI mutations (~5%), C3 mutations (~5%), FB mutations (<5%), and THBD mutations (~1%). Autosomal recessive inheritance is typical for CFH and CFI mutations, while autosomal dominant inheritance predominates for MCP mutations (de novo mutations are frequent). Disease penetrance is incomplete (approximately 50%), suggesting that genetic predisposition requires additional triggers (infection, pregnancy, medication). Acquired aHUS can result from anti-CFH autoantibodies (particularly in patients with CFHR1 deletions), which represent approximately 5-10% of aHUS cases and demonstrate aggressive disease with poor prognosis if untreated.

• Atypical HUS Secondary to Infection (Post-Infectious aHUS): Infections beyond STEC can trigger complement-mediated HUS in genetically susceptible individuals. Streptococcus pneumoniae (as above), HIV, human parvovirus B19, influenza, and CMV have been implicated. These cases likely represent complement activation triggered by infection in individuals with borderline complement dysregulation.

• Drug-Associated aHUS: Quinine (particularly in tonic water and some herbal preparations) causes HUS through immune complex formation and complement activation; it remains an important preventable cause. Calcineurin inhibitors (tacrolimus, cyclosporine) used in transplantation promote aHUS through vascular endothelial growth factor (VEGF) pathway inhibition and direct complement activation. Gemcitabine chemotherapy causes HUS through endothelial injury mechanisms. Ticlopidine and clopidogrel rarely cause thrombotic thrombocytopenic purpura (TTP) rather than HUS, but the distinction can be clinically challenging. Eculizumab (complement C5 inhibitor) conversely treats aHUS by preventing MAC formation.

• Pregnancy-Associated Atypical HUS: Pregnancy represents a state of enhanced complement activation (particularly in women with pre-existing mutations), with HUS manifestation typically occurring in the third trimester or postpartum period. Approximately 5-10% of postpartum HUS cases involve complement dysfunction. The pathophysiology remains incompletely understood but involves enhanced endothelial permeability, reduced complement regulatory protein expression, and potential placental injury amplifying thrombotic mechanisms.

• Secondary Forms: Malignancy (particularly adenocarcinomas), systemic sclerosis (scleroderma renal crisis), systemic lupus erythematosus, thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulation (DIC) can mimic HUS through TMA mechanisms. Distinguishing HUS from these conditions is clinically critical, as treatment differs substantially.

• Prodromal Phase and Initial Diarrhea (Typical HUS): In typical STEC-HUS, disease begins with a diarrheal prodrome 1-8 days (median 3 days) before HUS manifestation. Watery diarrhea initially progresses to hemorrhagic colitis with grossly bloody stools (present in >75% of typical HUS), abdominal pain (often severe, crampy), and fever (usually modest, <39°C). Vomiting and anorexia accompany the gastrointestinal symptoms. This prodrome typically lasts 5-10 days, with diarrhea resolution preceding HUS manifestation by 1-2 weeks (a critical teaching point—HUS develops as diarrhea improves, making diagnosis initially challenging). In atypical HUS, diarrheal prodrome is absent, representing a key clinical distinction; aHUS more frequently presents in the setting of non-gastrointestinal infections, pregnancy, or medication exposure.

• Acute Kidney Injury—Central Manifestation: Oliguria or anuria develops in the majority of HUS patients, representing the most clinically significant component. Serum creatinine elevation occurs abruptly, with creatinine doubling within 24-48 hours in severe cases. Urine output characteristically falls to <0.5 mL/kg/hour (oliguria) or even <0.3 mL/kg/hour (severe oliguria). Hyperkalemia results from both oliguria-related potassium retention and hemolysis-related cellular potassium release; life-threatening dysrhythmias (peaked T waves, loss of P waves, ventricular fibrillation) can develop acutely. Metabolic acidosis with elevated anion gap accompanies AKI from both organic acid accumulation and bicarbonate loss in diarrheal fluid. Hypertension develops in 40-60% of HUS patients secondary to salt and water retention; blood pressure elevation may be severe enough to precipitate hypertensive encephalopathy with seizures, altered mental status, and headache. Pulmonary edema from fluid overload and cardiac dysfunction can be rapidly progressive. Elevated blood urea nitrogen (BUN) and creatinine reflect reduced glomerular filtration; BUN/Cr ratios exceeding 20:1 suggest prerenal component, while ratios <10:1 indicate intrinsic renal injury.

• Microangiopathic Hemolytic Anemia (MAHA)—Key Laboratory Finding: Anemia develops acutely, with hemoglobin declining 1-3 g/dL over 24-48 hours. The mechanism is mechanical fragmentation of red blood cells (schistocytes) as they traverse microthrombi-occluded glomerular capillaries and arterioles—hence the characteristic fragmented RBCs on blood smear (schistocytes, helmet cells, polychromasia reflecting reticulocytosis). Reticulocyte count is markedly elevated (>10% typical), and indirect hyperbilirubinemia develops from hemoglobin catabolism. Haptoglobin is depleted (virtually absent, typically <10 mg/dL; normal >36 mg/dL) due to consumption by free hemoglobin. Lactate dehydrogenase (LDH) is profoundly elevated (often >1000 U/L), reflecting both hemolysis and tissue ischemia. Direct antiglobulin test (Coombs) is negative, distinguishing immune hemolysis; this negative test in the setting of severe MAHA is virtually pathognomonic for TMA. Hemoglobin-containing urine produces dark cola-colored or tea-colored urine if sufficient free hemoglobin is present; however, dipstick testing for hemoglobin is positive despite absence of RBCs on urinalysis (hemoglobin precipitate rather than intact RBCs creates this dissociation).

• Thrombocytopenia—Critical Diagnostic Feature: Platelet counts typically range from 10,000 to 50,000/μL at disease nadir, with counts <10,000/μL indicating severe disease. The thrombocytopenia represents platelet consumption by microthrombi rather than immune-mediated destruction; platelet-associated IgG levels are typically normal. Distinguishing HUS-associated thrombocytopenia from immune thrombocytopenic purpura (ITP) is essential, as ITP treatment (corticosteroids, IVIG) can exacerbate HUS. Bleeding manifestations are typically absent despite severe thrombocytopenia (in contradistinction to ITP), suggesting adequate qualitative platelet function; when bleeding occurs, it suggests progression to disseminated intravascular coagulation (DIC) with consumption coagulopathy.

• Neurological Manifestations—Severe Disease Indicator: Neurological involvement affects 10-50% of HUS patients and correlates strongly with disease severity and mortality. Seizures represent the most common neurological manifestation, typically generalized tonic-clonic, occurring in the context of hyperkalemia, hypertension, or cerebral edema. Stroke from microvascular thrombosis can cause focal neurological deficits, with imaging revealing cortical or subcortical ischemia. Posterior reversible encephalopathy syndrome (PRES) presents with seizures, headache, visual disturbances, and altered mental status, particularly in patients with severe hypertension; MRI demonstrates characteristic reversible white matter edema in the parietal and occipital regions. Hypertensive encephalopathy from uncontrolled blood pressure elevation produces confusion, headache, and visual disturbances. **

Initial studies (establish the TMA)

• CBC with peripheral smear: normocytic anemia with schistocytes, helmet cells, and polychromasia; platelets typically in the tens of thousands. Schistocytes are the pivotal finding — a smear should be requested explicitly, not assumed.
• Hemolysis panel: LDH markedly elevated, haptoglobin unmeasurably low, indirect bilirubin elevated, reticulocytosis. Direct antiglobulin (Coombs) test negative — mechanical, not immune, hemolysis. The exception is pneumococcal HUS, where neuraminidase-exposed T antigen makes the DAT positive.
• Coagulation studies: PT, aPTT, and fibrinogen are normal or near-normal. This is the single most useful discriminator from DIC, where they are deranged.
• Renal panel and urinalysis: rising creatinine, hyperkalemia, metabolic acidosis; urine shows hematuria and proteinuria with granular casts.

Establishing etiology

• Stool testing: CDC and the IDSA 2017 infectious diarrhea guideline advise simultaneous stool culture and a Shiga toxin immunoassay or PCR, because non-O157 STEC ferments sorbitol and is missed by sorbitol-MacConkey agar alone. Stool may already be negative by the time HUS appears.
• ADAMTS13 activity, drawn before any plasma is given: activity below roughly 10% defines TTP, not HUS. The PLASMIC score stratifies pretest probability of severe ADAMTS13 deficiency while the assay is pending.
• Complement work-up when there is no diarrheal prodrome and no Shiga toxin: C3/C4, factor H and I levels, anti-factor H antibodies, and germline complement gene sequencing. Normal C3 does not exclude aHUS; per KDIGO consensus work on complement-mediated TMA, aHUS remains a diagnosis of exclusion made clinically, with genetics returning later.
• Renal biopsy is rarely required and is usually deferred given thrombocytopenia.

Immediate stabilization

• Volume expansion with isotonic crystalloid: early, generous IV isotonic fluid during the STEC prodrome (before oliguria) is associated with less oliguric AKI and less dialysis. Once anuric, switch to strict fluid restriction to avoid pulmonary edema.
• Treat the life threats first: hyperkalemia (calcium gluconate for membrane stabilization, insulin/dextrose, then definitive removal), hypertensive emergency, and seizures. Hyperkalemia with ECG changes is the immediate killer.
• Packed RBC transfusion for symptomatic anemia. Platelet transfusion is avoided unless there is active bleeding or an invasive procedure is planned — transfused platelets feed ongoing microthrombosis.

Typical (STEC) HUS

• Supportive care is the treatment. There is no disease-specific therapy; most children recover renal function with meticulous fluid, electrolyte, and blood pressure management.
• Renal replacement therapy for refractory hyperkalemia, acidosis, volume overload, or uremia; roughly half of hospitalized children require dialysis.
• Contraindicated: the IDSA 2017 infectious diarrhea guideline recommends against antibiotics in suspected STEC O157:H7 — bacteriolysis and SOS-response induction increase Shiga toxin release and HUS risk. Antimotility agents (loperamide) and opioids are likewise contraindicated, as is empiric plasma exchange, which has no proven benefit in STEC-HUS.

Atypical (complement-mediated) HUS

• Terminal complement inhibitors are first-line: eculizumab (anti-C5 monoclonal antibody), or long-acting ravulizumab, both FDA-approved for aHUS. Blocking C5 prevents C5a generation and MAC assembly, halting endothelial injury; renal recovery is best when started early.
• Meningococcal vaccination is mandatory before dosing (REMS requirement), with antibiotic prophylaxis if therapy cannot be delayed — C5 blockade removes MAC-dependent killing of Neisseria.
• Therapeutic plasma exchange is the ASFA-supported bridge when complement inhibition is unavailable or the diagnosis is still ambiguous with TTP; it also removes anti-factor H antibodies.
• Immunosuppression (corticosteroids ± rituximab) is added for anti-factor H antibody-mediated disease.
• Kidney transplantation for ESRD, with complement blockade to prevent recurrence; MCP/CD46 mutations, being membrane-bound, recur far less often.

Renal

• End-stage renal disease: cortical necrosis from sustained glomerular microthrombosis; signaled by failure to regain urine output over weeks. Roughly a quarter to a third of STEC-HUS survivors carry chronic sequelae — hypertension, proteinuria, or reduced GFR — mandating lifelong follow-up. aHUS progresses to ESRD far more often.
• Hyperkalemia and volume overload: emergencies. Peaked T waves, widened QRS, or loss of P waves demand immediate calcium and dialysis access.

Neurologic (the leading cause of acute death)

• Seizures, stroke, PRES, cerebral edema: cerebral microthrombi plus hypertension. Any new altered mental status or focal deficit is an emergency requiring imaging and blood pressure control.

Gastrointestinal

• Colonic necrosis, perforation, intussusception, rectal prolapse: transmural ischemia from Shiga toxin-mediated microvascular thrombosis. Peritonitis, free air, or a sudden hemoglobin drop signals perforation — a surgical emergency.
• Pancreatitis with transient or permanent insulin-dependent diabetes: islet microinfarction; suspect with hyperglycemia and elevated lipase.

Cardiac and hematologic

• Myocarditis, cardiomyopathy, arrhythmia: microthrombi plus uremia and electrolyte derangement; rising troponin or new heart failure is the tell.
• Transfusion-associated iron and volume load; profound anemia requiring repeated transfusion.

Treatment-related

• Meningococcal sepsis on eculizumab/ravulizumab: terminal complement blockade abolishes MAC-mediated killing of encapsulated Neisseria. Fever in any patient on a C5 inhibitor is a medical emergency — cultures and empiric ceftriaxone immediately, do not wait.
• Plasma exchange complications: central line infection, thrombosis, pneumothorax, citrate-induced hypocalcemia (perioral tingling, QT prolongation), and transfusion reactions.
• Antibiotic-precipitated HUS: treating STEC colitis with antibiotics increases toxin release and HUS incidence — an iatrogenic complication, not a cure.
• Platelet transfusion: may propagate microthrombosis and worsen organ ischemia.

• The stem: a toddler with bloody diarrhea after a picnic, undercooked ground beef, a petting zoo, or a daycare outbreak, whose diarrhea is improving when pallor, oliguria, and bruising appear 5–10 days later. HUS follows the colitis; it does not accompany it.
• The triad is MAHA + thrombocytopenia + AKI. The single most valuable test on the answer list is the peripheral blood smear showing schistocytes and helmet cells, with a negative Coombs test.
• Normal PT, aPTT, and fibrinogen separate HUS from DIC. If coags are deranged and fibrinogen is low, the answer is DIC, not HUS.
• The single best next step in suspected STEC-HUS is supportive care with isotonic IV fluids — and explicitly withholding antibiotics and antimotility agents (IDSA 2017). Choosing azithromycin or loperamide is the classic trap; both increase HUS risk or severity.
• Do not transfuse platelets for the low count alone. Thrombocytopenia here is consumptive, and platelets fuel microthrombi.
• HUS vs. TTP: HUS is kidney-dominant in a child after Shiga toxin exposure with normal ADAMTS13; TTP is neurologic-dominant in an adult with ADAMTS13 activity below ~10% from an autoantibody, and is treated with plasma exchange plus caplacizumab and rituximab. Send ADAMTS13 before giving plasma.
• No diarrhea = think atypical HUS. Alternative complement pathway dysregulation, most often factor H mutation; treat with a C5 inhibitor (eculizumab) and vaccinate against meningococcus first. Fever on eculizumab means meningococcal sepsis until proven otherwise.
• The association examiners love: Streptococcus pneumoniae HUS via neuraminidase unmasking the Thomsen-Friedenreich (T) antigen — the one HUS variant with a positive direct Coombs test, and a reason to avoid plasma-containing products.
• Sorbitol-MacConkey agar detects O157:H7, which does not ferment sorbitol; non-O157 STEC is caught only by Shiga toxin immunoassay or PCR.