OVERVIEW

What is atypical hemolytic uremic syndrome?

Hemolytic uremic syndrome refers to a group of clinical syndromes characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Among them, cases caused by Shiga toxin-producing Escherichia coli are called typical hemolytic uremic syndrome, while those caused by other etiologies are called atypical hemolytic uremic syndrome (aHUS), also known as familial hemolytic uremic syndrome or familial HUS.

aHUS has an acute onset and severe condition, which can even be life-threatening. Specific treatments and supportive therapies such as plasma exchange can improve patient survival rates. If the disease progresses to end-stage renal disease, it can significantly impact quality of life.

Is atypical hemolytic uremic syndrome (aHUS) common?

aHUS is a relatively rare disease and has been included in China's "First List of Rare Diseases." aHUS predominantly affects infants, young children, and school-aged children, with an estimated prevalence of 7 per million among European children.

SYMPTOMS

Which populations are commonly affected by atypical hemolytic uremic syndrome?

• Family members with a history of atypical hemolytic uremic syndrome;
• Family members diagnosed with hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, or systemic thrombotic microangiopathy;
• Personal history of unexplained renal failure.

What symptoms does atypical hemolytic uremic syndrome cause?

The typical clinical manifestations include the "triad" of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. About 20% of patients may exhibit extrarenal symptoms, such as neurological, cardiac, or gastrointestinal symptoms.

• Microangiopathic hemolytic anemia: Destruction of red blood cells due to microthrombi, leading to anemia symptoms like dizziness, pallor, and fatigue. Hemoglobin levels are often below 80 g/L.
• Thrombocytopenia: Approximately 90% of patients have thrombocytopenia, typically below 50 × 10⁹/L, but skin purpura (bruising or petechiae) or active bleeding (e.g., intracranial hemorrhage) is rare.
• Acute renal failure: Acute kidney injury usually occurs simultaneously with anemia, presenting as oliguria or anuria, edema, anorexia, nausea, vomiting, and difficulty breathing. Renal impairment often leads to elevated blood pressure. Some patients may require dialysis.

How does atypical hemolytic uremic syndrome differ from typical hemolytic uremic syndrome?

Both may exhibit the classic "triad," but:

• Typical hemolytic uremic syndrome: Caused by Shiga toxin-producing Escherichia coli, primarily affecting children under 5 years old, with half of cases occurring in summer (June–September). About 90% of patients experience gastrointestinal symptoms like abdominal pain, diarrhea, or vomiting 5–10 days before onset.
• Atypical hemolytic uremic syndrome (aHUS): Not associated with E. coli infection, usually lacks a history of diarrhea before onset. About 20%–30% of patients have a family history of aHUS, and approximately 60% develop symptoms in adulthood. In 70%–80% of cases, triggers such as infection, pregnancy, trauma, or surgery precede the onset.

What severe complications can atypical hemolytic uremic syndrome (aHUS) cause?

Patients with aHUS have a very poor prognosis.

In children, the first episode of aHUS can lead to multi-organ damage, with progressive worsening of the condition. Without timely treatment, about 25% of affected children may die, and approximately 50% progress to end-stage renal disease (ESRD), requiring long-term dialysis.

CAUSES

What causes atypical hemolytic uremic syndrome (aHUS)?

The pathogenesis of aHUS involves individuals with inherited or acquired complement protein gene mutations, or those susceptible to complement protein antibodies. Triggering events (such as infections, pregnancy, trauma, or surgery) induce uncontrolled continuous activation of the alternative complement pathway, leading to the formation of membrane attack complexes. This results in renal endothelial damage, coagulation cascade activation, and arteriolar microthrombosis, subsequently causing manifestations such as microangiopathic anemia, thrombocytopenia, and acute renal failure.

Is atypical hemolytic uremic syndrome (aHUS) a genetic disease? How is it inherited?

Yes, it is a genetic disease.

50%–60% of aHUS cases are caused by identified mutations in genes encoding complement proteins, including CFH (20%–30%), CD46 (5%–15%), complement factor 1 (4%–10%), complement factor 3 (2%–10%), among others. New gene mutations continue to be identified.

However, inheriting a mutated gene does not necessarily mean aHUS will manifest. Studies show that less than half of family members carrying the same mutation as aHUS patients develop clinical symptoms.

DIAGNOSIS

What tests are needed for atypical hemolytic uremic syndrome (aHUS)?

The classic triad (microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure) without a history of diarrhea is the primary clinical basis for diagnosing aHUS. Most patients have reduced complement C3, but normal plasma levels of C3, C4, CFB, CFH, and CFI do not rule out aHUS. Detection of complement protein-related gene mutations and complement factor antibodies can help further confirm the diagnosis.

Required tests include:

• Tests related to microangiopathic hemolytic anemia.
• Tests related to acute kidney injury. The kidneys are the primary affected organs in aHUS, with the basic pathological changes being thrombotic microangiopathy, which can involve the glomeruli, renal arterioles, and renal interstitium.
• Complement factor and autoantibody evaluation.
• Complement gene screening.

Which diseases is atypical hemolytic uremic syndrome (aHUS) easily confused with? How to differentiate them?

aHUS primarily needs to be differentiated from other thrombotic microangiopathies.

• Typical hemolytic uremic syndrome: Caused by Shiga toxin-producing Escherichia coli infection, mainly seen in children under 5 years old but rarely in infants under 6 months. About half of cases occur in summer (June to September). Approximately 90% of patients experience gastrointestinal symptoms such as abdominal pain, diarrhea, and vomiting 5–10 days before HUS onset.
• Thrombotic thrombocytopenic purpura: Caused by congenital or acquired severe deficiency of von Willebrand factor-cleaving protease (ADAMTS13). Clinically, it can also present with thrombotic microangiopathic hemolysis and thrombocytopenia. It is often accompanied by central nervous system symptoms such as seizures, impaired consciousness, and cerebrovascular disease. Kidney involvement is relatively mild, and severe renal failure requiring dialysis is rare. Laboratory tests show abnormally low ADAMTS13 activity.

TREATMENT

Which department should atypical hemolytic uremic syndrome patients consult?

Nephrology, Hematology, Pediatrics.

Can atypical hemolytic uremic syndrome be completely cured?

No.

The clinical condition is prone to recurrence and may involve the nervous, cardiovascular, and digestive systems, eventually progressing to end-stage renal disease (ESRD), requiring long-term regular dialysis or kidney transplantation.

How is atypical hemolytic uremic syndrome treated?

Treatment for atypical hemolytic uremic syndrome includes two main components: targeted therapy and comprehensive therapy. Targeted therapy further involves blocking the complement activation pathway and plasma exchange.

How is the complement activation pathway blocked in atypical hemolytic uremic syndrome (aHUS)?

Eculizumab is a commonly used drug.

Eculizumab binds to complement protein C5, preventing its cleavage and thereby inhibiting the generation of terminal complement components C5a and membrane attack complex C5b-9. This reduces endothelial damage, thrombosis, and subsequent kidney injury.

In various aHUS case series, eculizumab has shown an efficacy rate of up to 90% and is effective for both genetic defects in complement proteins and autoantibody-induced aHUS. It is currently the first-line treatment for aHUS.

For suspected aHUS patients, eculizumab should be administered as soon as possible within 48 hours of hospitalization if conditions permit.

The main adverse effect of eculizumab is life-threatening Neisseria meningitidis infection, with an annual incidence of about 5%. Other infections, such as Streptococcus pneumoniae and Haemophilus influenzae type B, may also occur. Therefore, patients on long-term treatment should receive appropriate vaccinations (see pneumococcal vaccine and Haemophilus influenzae type B vaccine).

What is plasma exchange therapy for atypical hemolytic uremic syndrome (aHUS)?

Plasma exchange helps remove defective mutant complement proteins and autoantibodies while replenishing functional complement proteins. It also prevents volume overload and hypertension risks in patients with acute kidney injury.

Due to the rapid progression of aHUS, often leading to irreversible kidney damage, and the practical challenges of using eculizumab in clinical settings, empirical plasma exchange therapy should be initiated as early as possible for all suspected aHUS patients.

Approximately half of aHUS patients respond to plasma exchange, showing improved kidney function and hematologic remission.

Possible complications of plasma exchange include hypotension, catheter-related infections, and systemic allergic reactions to plasma.

What is comprehensive therapy for atypical hemolytic uremic syndrome (aHUS)?

Comprehensive therapy mainly involves symptomatic treatment, such as:

• For severe anemia, red blood cell transfusions to improve anemia and hypoxia.
• For patients with significant bleeding tendencies or those requiring invasive procedures, platelet transfusions to prevent bleeding.
• Providing adequate nutritional support to maintain fluid and electrolyte balance.
• Discontinuing nephrotoxic drugs or medications associated with aHUS onset.
• Initiating dialysis or kidney transplantation when appropriate. All HUS patients should undergo complement genotyping before transplantation to identify genetic mutations. High-risk recurrence patients should receive plasma exchange or prophylactic eculizumab therapy alongside kidney transplantation. Notably, for living related donors, genetic testing must confirm the absence of the same mutation.

Is the mortality risk high for atypical hemolytic uremic syndrome?

About 30% of patients progress to ESRD during their first episode, with a mortality rate of approximately 2%–10%.

DIET & LIFESTYLE

What dietary precautions should patients with atypical hemolytic uremic syndrome take?

The general dietary principles for uremic patients include:

• Maintaining adequate calorie intake;
• Ensuring sufficient protein intake;
• Strictly controlling the intake of water, salt, and potassium ions;
• Renal dialysis patients should also limit phosphorus intake.

What lifestyle precautions should patients with atypical hemolytic uremic syndrome take?

Patients should take protective measures to avoid infections and trauma, and minimize triggering events such as surgery and pregnancy.

How should patients with atypical hemolytic uremic syndrome be cared for?

• Maintain a balanced diet and proper nutrition;
• Strengthen daily care to prevent infections and trauma;
• Monitor urine color, volume, and changes in skin/mucous membrane color, seeking medical attention promptly if abnormalities occur;
• Schedule regular check-ups to monitor blood pressure, hemoglobin, electrolytes, and kidney function indicators.

Can patients with atypical hemolytic uremic syndrome (aHUS) grow up normally, get married, and have children?

20%–30% of patients have a family history of aHUS, and about 60% develop the condition in adulthood.

Male patients can marry and have children, but genetic testing and counseling should be conducted before conception. Female patients should avoid pregnancy and childbirth to prevent triggering aHUS.

Can patients with atypical hemolytic uremic syndrome care for themselves?

As the disease progresses, patients often experience fatigue, hypertension, nerve damage, gastrointestinal discomfort, clotting at venous access sites, and kidney complications, leading to a significantly reduced quality of life. They require joint care from family and society.

PREVENTION

Can atypical hemolytic uremic syndrome be prevented? How to prevent it?

• Atypical hemolytic uremic syndrome (aHUS) is associated with genetic factors, and about half of patients with genetic risk factors will develop the disease. Therefore, if there is a family history of aHUS, triggering factors such as infections, trauma, surgery, and pregnancy should be avoided as much as possible.
• If there is a clear family history of aHUS but the individual has not developed the disease, genetic counseling can be sought before planning pregnancy to avoid developing the condition or passing it on to offspring.
• If there is a clear family history of aHUS but genetic counseling has not been conducted, prenatal diagnosis through genetic testing can still be performed during pregnancy to prevent the birth of affected offspring.

How to reduce the risk of recurrence in atypical hemolytic uremic syndrome (aHUS)?

Preventive treatments to reduce the risk of aHUS recurrence include eculizumab and plasma exchange therapy. Patients with a low risk of recurrence do not require preventive treatment.