Hemolytic uremic syndrome

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy in which microthrombi, consisting primarily of platelets, form and occlude the arterioles and capillaries. These occlusions result in the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). HUS predominantly affects children and is caused by bacterial toxins, most commonly the Shiga-like toxin of enterohemorrhagic Escherichia coli (E. coli) O157:H7. If there is a strong suspicion of HUS based on clinical presentation and initial laboratory tests, treatment should begin immediately, as the condition may result in renal failure. Patients receive symptomatic treatment for renal symptoms, anemia, and complications affecting other organs, such as the brain and GI tract.

Thrombotic thrombocytopenic purpura (TTP), the other main type of thrombotic angiopathy, is discussed in the respective article.

Mainly children < 5 years of age ^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Bacterial exotoxins ^[2]
  • Shiga-like toxin (verotoxin)
    • From enterohemorrhagic E. coli (EHEC) strain O157:H7
    • Usually transmitted via contaminated foods (e.g., undercooked beef or raw leafy vegetables)
  • Shiga toxin produced by Shigella dysenteriae
• Streptococcus pneumoniae infection
• Atypical hemolytic uremic syndrome: Complement dysregulation (hereditary or acquired) accounts for approx. 5% of HUS cases with noninfectious etiologies, referred to as atypical HUS (aHUS). ^[3]

Approx. 15% of children infected with E. coli O157:H7 will go on to develop HUS.

HUS is a thrombotic microangiopathy, a condition characterized by the formation of microthrombi occluding the microvasculature. The other main thrombotic microangiopathy is thrombotic thrombocytopenic purpura (TTP). The two conditions have some pathophysiology and clinical findings in common, but different etiologies. HUS is caused by bacterial toxins. ^[4]

1. Infection with enterohemorrhagic E. coli (EHEC) or another causative organism
2. Mucosal inflammation facilitates bacterial toxins; entering systemic circulation.
3. Toxins cause endothelial cell damage (especially in the glomerulus ).
4. Damaged endothelial cells secrete cytokines that promote vasoconstriction and platelet microthrombus formation at the site of damage (intravascular coagulopathy) → thrombocytopenia (consumption of platelets)
5. RBCs are mechanically destroyed as they pass through the platelet microthrombi occluding small blood vessels (i.e., arterioles, capillaries) → hemolysis (schistocytes), and end-organ ischemia and damage, especially in the kidneys → decreased glomerular filtration rate (GFR)

E. coli O157:H7 infection → Shiga-like toxin in systemic circulation → toxin-mediated endothelial injury → microthrombus formation → blockage of small vessels → RBC fragmentation (hemolysis) and end-organ damage

A diarrheal illness (usually bloody) for the past 5–10 days precedes the onset of HUS symptoms in many children. The triad of clinical findings occurring in HUS consists of:

• Thrombocytopenia
  • Petechiae, purpura
  • Mucosal bleeding
  • Prolonged bleeding after minor cuts
• Microangiopathic hemolytic anemia
  • Fatigue, dyspnea, and pallor
  • Jaundice
• Impaired renal function
  • Hematuria, proteinuria
  • Oliguria, anuria

The typical HUS patient is a preschooler who has had a diarrheal illness for the past 5–10 days and presents with petechiae, jaundice, and oliguria.

• Hematology
  • Hemolytic markers
    • ↓ Hemoglobin
    • ↓ Haptoglobin
    • ↑ Indirect bilirubin
    • ↑ Reticulocytes
    • ↑ LDH
    • ↑ Schistocytes on blood smear (up to 10% of RBCs)
  • Coagulation profile
    • ↓ Platelets
    • Normal/slightly elevated prothrombin time (PT) and activated partial thromboplastin time (aPTT) in contrast to DIC; (see “Differential diagnoses” below)
    • Normal/slightly elevated fibrin degradation products and D-dimer levels
  • ↑ WBC count
  • Negative Coombs test
• Serum chemistry: ↑ BUN and ↑ creatinine (impaired renal function)
• Urinalysis: hematuria, proteinuria

Other platelet disorders

• Von Willebrand disease
• Acquired disorders of platelet function (e.g., drugs such as aspirin, NSAIDs; uremia, paraproteins)
• See also “Thrombocytopenia” and “Heparin-induced thrombocytopenia.”

The differential diagnoses listed here are not exhaustive.

• Supportive care ^[2]
  • Avoid antibiotics and antimotility agents; (may increase the likelihood of HUS in suspected infection with EHEC).
  • Monitor and correct:
    • Fluid status abnormalities (for more information, see “Clinical assessment of volume status”)
    • Electrolyte disturbances (for more information, see “Electrolyte metabolism”)
    • Acid-base disorders
    • Blood pressure (due to hypertension or septic shock)
    • RBC transfusions
  • Antiepileptic drugs (e.g., diazepam, phenytoin) in patients with seizures
• Dialysis (as indicated for AKI): Up to 50% of HUS patients require dialysis.
• Plasma exchange therapy: only in refractory cases
• Eculizumab
  • Effective for the treatment of aHUS ^[5]
  • May be beneficial in HUS with neurological symptoms ^[6]

Post-diarrheal HUS is a nationally notifiable condition. ^[7]

Platelet transfusions should be administered with caution unless patients are bleeding or require an invasive procedure. Some studies suggest that they can exacerbate microangiopathy.

HUS can result in microthrombus formation and complications in various organs:

• CNS
  • Seizures
  • Paresis
  • Stroke
  • Coma
• GI tract
  • Hemorrhagic colitis
  • Bowel necrosis, perforation, stricture
  • Peritonitis
  • Intussusception
• Heart: ischemia and fluid overload
• Pancreas: transient or permanent diabetes mellitus
• Liver: hepatomegaly, transaminase elevations
• Kidney
  • Hypertension
  • Chronic kidney disease (CKD)
  • End-stage renal disease (ESRD)

We list the most important complications. The selection is not exhaustive.

The prognosis depends primarily on prompt initiation of treatment. Timely treatment can prevent acute complications (AKI, coma, and death) as well as progression to chronic renal failure.

• With treatment, the mortality rate of HUS is low: < 10%. ^[1]
• Long-term renal sequelae occur in 35–55% of children with HUS. ^[8][9]
• Atypical HUS has a less favorable prognosis and a higher risk of progressing to end-stage renal disease. ^[10]