Hemolytic-Uremic Syndrome (HUS)

Definition, Etiology, PathogenesisTop

Hemolytic-uremic syndrome (HUS) is a severe, rare disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The dominant clinical feature is kidney dysfunction. In >90% of cases HUS is caused by verotoxin-producing bacteria: Shiga toxin–producing Escherichia coli (STEC) strains (serotype O157:H7 or O104:H4) or Shigella spp (more frequent in children). Other causes responsible for the development of HUS include bacterial and viral infections, autoimmune diseases, malignant hypertension, solid organ and hematopoietic stem cell transplants, malignancies, and certain drugs. Epidemics of HUS are well described and associated with food or water contamination with pathognomonic bacteria.

Approximately 5% to 10% of the cases are due to atypical HUS, which is caused by uncontrolled activation of the alternative complement pathway. Genetic abnormalities or autoantibodies leading to increased activation of the alternative complement pathway are essential to the pathogenesis.

Clinical Features and Natural HistoryTop

STEC-related HUS may be preceded by bloody diarrhea, nausea, and vomiting. Dominant clinical features include hemolytic anemia, thrombocytopenia, and renal failure, which are frequently associated with hypertension and fever. Neurologic symptoms are less common. The course of atypical HUS is markedly more severe than that of the typical syndrome.

DiagnosisTop

Diagnostic Tests

1. Complete blood count (CBC): Normocytic or macrocytic anemia, erythroblasts and schistocytes present in peripheral blood smears, reticulocyte count increase, thrombocytopenia.

2. Blood biochemical tests: Elevated serum unconjugated bilirubin and lactate dehydrogenase levels, low haptoglobin levels, features of impaired renal function.

3. Urinalysis: Proteinuria, microscopic hematuria.

4. Coagulation parameters: Normal coagulation parameters; occasionally D-dimer concentration may be elevated.

5. Serologic studies: Normal or slightly decreased ADAMTS-13 (von Willebrand factor–cleaving protease) levels, negative direct antiglobulin test and markers of autoimmune diseases such as lupus (antinuclear antibodies [ANAs]), scleroderma, and catastrophic antiphospholipid syndrome.

6. Documentation of Shiga toxin–producing infections: Classically E coli serotype H7:O157 (rarely identified but pathognomonic if found).

7. Atypical HUS is usually a diagnosis of exclusion and subsequently requires genetic testing, complement protein quantification, and complement functional testing.

Diagnostic Criteria

Diagnosis is based on clinical features.

Differential Diagnosis

Disseminated intravascular coagulation, Evans syndrome, catastrophic antiphospholipid syndrome, bacterial sepsis, thrombotic thrombocytopenic purpura (TTP) (Table 1).

TreatmentTop

In most patients supportive care, early renal replacement therapy, and packed red blood cell transfusions are necessary. Plasmapheresis is administered in many patients in whom differentiating TTP and HUS is difficult. Atypical HUS with documented complement mutations may respond to complement-directed therapies (eculizumab or ravulizumab). In epidemic cases public health intervention is required to identify and mitigate the source of the contamination.

PrognosisTop

Mortality rates are up to 25%. Chronic kidney disease develops in ~25% of surviving patients.

TablesTop