Hemolytic Uremic Syndrome in Children

Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by Shiga-like toxin-producing bacteria. Laboratory analysis confirms microangiopathic hemolytic anemia (hemoglobin < 8 g/dL, schistocytes, and negative direct Coombs), thrombocytopenia (platelet count < 140,000/mm³), and acute kidney injury (elevated creatinine and blood urea nitrogen (BUN)). The management of HUS is primarily through supportive care.

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Overview

Definition

Hemolytic uremic syndrome (HUS) is a disease of the capillaries (microangiopathy) that causes the formation of blood clots, anemia caused by the destruction of RBC in these clotted capillaries (hemolytic anemia), acute kidney injury, and low platelets (thrombocytopenia).

Epidemiology

  • Majority of cases seen in children < 5 years of age
  • 2–3 cases per 100,000 children in the United States
  • Major cause of acute kidney injury in children (> 6 months to 5 years of age)
  • 90% of cases are associated with diarrhea caused by enterohemorrhagic Escherichia coli (EHEC) 
  • Most commonly seen in the summer and in rural populations

Etiology

Etiology is classified as acquired (infectious versus noninfectious) or hereditary.

  • Acquired HUS
    • Infectious
      • Shiga-like toxin-producing E. coli O157: H7 (EHEC): most common
      • Shigella species
      • Streptococcus pneumoniae
      • HIV
    • Autoantibodies to complement factors
    • Drug toxicity
      • Drugs associated with malignancy or organ transplant recipients (cyclosporine and tacrolimus)
      • Drugs of abuse (cocaine)
    • Other:
      • Systemic lupus erythematosus
      • Antiphospholipid syndrome
  • Hereditary HUS
    • Complement gene mutations (C3 and CD46)
    • Inborn errors of metabolism (cobalamin C metabolism)

Pathophysiology

The pathophysiology for HUS secondary to Shiga-like toxin has been well described. 

  1. Bacterial toxins are absorbed by the gut and enter the systemic circulation.
  2. Bind to endothelial cells causing direct endothelial injury via:
    • Nitric oxide (NO) production
    • Secretion of interleukin-1 (IL-1) and tumor necrosis factor (TNF)
    • Macrophage activation
  3. Cause platelet aggregation and localized thrombosis in capillaries and arterioles:
    • Glomeruli vessels are especially affected → decreased glomerular filtration rate (GFR)
    • Decreased renal blood flow → increased renin
  4. Erythrocytes are mechanically injured when going through the thrombotic microvasculature: causes microangiopathic hemolytic anemia

Other forms of HUS:

  • Varied pathological mechanisms
  • All have endothelial damage in common.
  • Lead to thrombus production and hemolytic anemia

Clinical Presentation

History

  • Prodromal illness with abdominal pain, vomiting, and bloody diarrhea
  • Other historical clues may include:
    • Concurrent known HUS outbreak/family member with concurrent HUS
    • Family member with history of HUS (may be suggestive of a genetic cause)
    • Previous episode of HUS (may be suggestive of a complement-mediated cause)

Physical examination

Symptoms usually occur 57 days after diarrhea and may include:

  • Acute-onset lethargy or irritability
  • Pallor
  • Nephritic syndrome:
    • Oliguria, volume overload, or dehydration
  • Progression to neurologic symptoms:
    • Altered mental status
    • Seizures

Diagnosis

Diagnosis is clinical, based on the classic triad of:

  1. Microangiopathic hemolytic anemia
    • Normocytic anemia with hemoglobin level < 8 g/dL
    • Negative direct Coombs test
    • Peripheral blood smear → schistocytes and helmet cells
  2. Thrombocytopenia:
    • Platelet count < 140,000/mm³ (usually around 40,000/mm³)
  3. Acute kidney injury:
    • Elevated serum creatinine and blood urea nitrogen (BUN)
    • May manifest as hematuria, proteinuria, or oliguria
Blood slide of a patient with Hemolytic uremic syndrome

Blood slide of a patient with HUS. Note the schistocytes, fragments of erythrocytes left after mechanical injury of the cells in the microvasculature.

Image by Lecturio.

Management

Management of HUS is primarily through supportive care.

  • Anemia: RBC transfusions when indicated (hemoglobin < 6 or 7 g/dL)
  • Thrombocytopenia: platelet transfusions only for significant clinical bleeding
  • Acute kidney injury:
    • IV fluids
    • Electrolyte management
    • Discontinuation of any nephrotoxic drugs
    • Dialysis if severe
  • Hypertension: calcium channel blockers
  • Nutrition: caloric intake according to needs

Note that antibiotic treatment during bloody diarrheal illnesses caused by Shiga toxin-producing bacteria is associated with an increased risk of developing HUS.

Prognosis

  • Early diagnosis and treatment have a favorable outcome: mortality: < 5%
  • Most recover renal function completely; however:
    • 30% are left with some degree of renal insufficiency.
    • 5% are left dependent on dialysis.
  • When HUS is not associated with diarrhea, the prognosis is more severe:
    • Pneumococci-related HUS:
      • 20% mortality
      • 80% of patients require dialysis

Differential Diagnosis

  • Disseminated intravascular coagulation (DIC): associated with children with serious illnesses, such as septic shock. Unlike HUS, DIC presents with abnormal coagulation studies, including prolonged prothrombin time (PT) and partial thromboplastin time (PTT), decreased fibrinogen, and increased D-dimer.
  • Thrombotic thrombocytopenic purpura (TTP): occurs due to inhibition or deficiency of ADAMTS13, which causes decreased degradation of von Willebrand factor (VWF) multimers, and increased platelet aggregation and thrombosis. Laboratory analysis shows schistocytes, increased lactate dehydrogenase (LDH), and normal coagulation parameters. Symptoms include a classic pentad of neurologic and renal symptoms, fever, thrombocytopenia, and microangiopathic hemolytic anemia. 
  • Systemic vasculitis: Patients with systemic vasculitis would not have a prodrome of diarrhea associated with illness. They would also likely have systemic symptoms, such as arthralgias and/or rash.

References

  1. Devarajan, P. (2020). Multisystem disease associated with hematuria. In R. M. Kliegman MD et al. (Eds.), Nelson textbook of pediatrics (pp. 272-2736.e3). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323529501005381
  2. Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol. 2005 Apr;16(4):1035-50. doi: 10.1681/ASN.2004100861. Epub 2005 Feb 23. PMID: 15728781.
  3. Ito K, Komatsu Y. [Drug induced hemolytic uremic syndrome]. Nihon Rinsho. 1993 Jan;51(1):204-9. Japanese. PMID: 7679450.

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