Atypical Hemolytic Uremic Syndrome (Atypical-HUS, AHUS, Familial Hemolytic Uremic Disease, Familial-HUS)

Atypical Hemolytic Uremic Syndrome

What Is Atypical-HUS?

What is the Atypical Hemolytic Uremic Syndrome?

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

AHUS is characterized by acute onset and severe disease, which can even be life-threatening. The survival rate of patients can be improved by specific treatment as well as supportive treatment such as plasma exchange. If the disease develops to end-stage renal disease, the quality of life will be seriously affected.

Is atypical hemolytic uremic syndrome common?

AHUS is a relatively rare disease, with an estimated prevalence of 7/1 million children in Europe, particularly in infants and school-age children.


What Is The Cause Of Atypical-HUS?

What causes atypical hemolytic uremic syndrome?

The pathogenesis of aHUS is that individuals with genetic or acquired complement protein gene mutations, or susceptible individuals with complement protein antibodies, under the induction of trigger events (such as infection, pregnancy, trauma, surgery), cause sustained activation of the alternative complement pathway that is not inhibited, leading to the formation of membrane attack complexes, which cause renal endothelial damage, activation of the clotting cascade, and arteriole microthrombosis, which in turn cause various manifestations of microangiopathic anemia, thrombocytopenia, and acute renal failure.

Is atypical hemolytic uremic syndrome a genetic disease?

Atypical hemolytic uremic syndrome is an inherited disease.

Fifty to 60% of cases of aHUS are caused by identified gene mutations encoding complement protein, with the common ones including CFH (20%–30%), CD46 (5%–15%), complement factor 1 (4%–10%) and complement factor 3 (2%–10%), and new gene mutations are still being identified.

However, it is not the mutated gene that is necessarily responsible for the atypical hemolytic-uremic syndrome. It has been reported that less than half of the family members who carry the same mutated gene as those with aHUS have disease manifestations.


What Is The Symptoms Of Atypical-HUS?

Who are the common people with atypical hemolytic uremic syndrome?

  • Some family members have atypical hemolytic uremic syndrome.
  • Some members of the family have been diagnosed with hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, or systemic thrombotic microangiopathies.
  • I have a history of unexplained renal failure.

What are the symptoms of atypical hemolytic uremic syndrome?

Typical clinical manifestations include microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure triad. Extra-renal manifestations such as neurological, cardiac and gastrointestinal symptoms can occur in 20% of patients.

  • Microangiopathy hemolytic anemia: refers to the red blood cell destruction caused by microthrombosis, which can lead to anemia symptoms, such as dizziness, pallor, and fatigue. Hemoglobin level after blood test is often lower than 80 g/L.
  • Thrombocytopenia: Thrombocytopenia occurs in about 90% of patients, usually less than 50 × 109/L, but cutaneous purpura (skin ecchymosis) and active bleeding (such as intracranial hemorrhage) are rare.
  • Acute renal failure: Acute renal impairment occurs almost simultaneously with anemia, manifested as oliguria or anuria, edema, anorexia, nausea, vomiting, dyspnea, and renal impairment often leads to increased blood pressure. Some patients require dialysis treatment.

What is the difference between atypical hemolytic uremic syndrome and typical hemolytic-uremic syndrome?

Both may have the classic triad described above, but:

  • Typical hemolytic uremia: it is caused by Shiga toxin-producing Escherichia coli, mainly affecting children under 5 years of age, half of which occurs in summer (June–September). About 90% of patients have gastrointestinal symptoms such as abdominal pain, diarrhea, and vomiting 5–10 days before the onset.
  • Atypical hemolytic uremia (aHUS): It is unrelated to Escherichia coli infection. There is usually no history of diarrhea before the onset of aHUS. 20%–30% of patients have a family history of AHUS, about 60% of patients have an adult onset, and 70%–80% of patients have precipitating factors such as infection, pregnancy, trauma, and surgery before the onset.

What are the serious consequences of atypical hemolytic uremic syndrome?

Patients with aHUS have a very poor prognosis. The first occurrence of aHUS in children can lead to multiple organ damage and progressive aggravation of the disease. If it is not treated in time, 25% of children may die, and about 50% of children develop end-stage renal disease (ESRD), requiring long-term maintenance of dialysis treatment.


How To Check Atypical-HUS?

What check does atypical hemolytic uremic syndrome need to do?

The classic triad (microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure) without a history of diarrhea is the primary clinical basis for the diagnosis of aHUS. Complement C3 is decreased in most patients, but aHUS cannot be ruled out due to normal plasma levels of C3, C4, CFB, CFH and CFI. The detection of complement protein-related gene mutation and complement factor antibody can help to further clarify the diagnosis.

Relevant inspections to be performed include:

  • Examination of microangiopathic hemolytic anemia.
  • Related examinations of acute kidney injury. The kidney is the main affected organ of aHUS, and the basic pathological change of the kidney is thrombotic microangiopathy, which can affect the glomerulus, renal arterioles and renal interstitium.
  • Evaluation of complement factor and autoantibody.
  • Complement gene screening.

Which diseases are easily confused with atypical hemolytic uremic syndrome?

aHUS mainly needs to be differentiated from other thrombotic microangiopathies.

  • Typical hemolytic uremic syndrome: It is caused by Shiga toxin-producing Escherichia coli infection. It is mainly found in children under 5 years of age, but is rare in infants under 6 months of age. Half of the cases occur in summer (from June to September). About 90% of patients had gastrointestinal symptoms such as abdominal pain, diarrhea, and vomiting 5–10 days before the occurrence of HUS.
  • Thrombotic thrombocytopenic purpura: It is caused by severe deficiency of congenital or acquired von Willebrand factor lyase (ADAMTS13). Clinical manifestations include thrombotic microangiopathic hemolytic and thrombocytopenia. It is often accompanied by symptoms of central nervous system, such as epilepsy, disorder of consciousness, and cerebrovascular disease. Renal involvement is relatively mild and patients requiring dialysis for severe renal failure are rare. Laboratory tests showed abnormally low activity of ADAMTS13.

How To Prevent Atypical-HUS?

Can atypical hemolytic uremic syndrome be prevented?

  • The pathogenesis of aHUS is related to heredity, and about half of the patients with genetic risk factors will suffer from AHUS. Therefore, if there is a family history of aHUS, triggers such as infection, trauma, surgery, and pregnancy should be avoided.
  • If there is a clear family history of aHUS but the disease does not occur to me, genetic counseling can be conducted before preparing for childbirth to avoid my disease or passing it on to my offspring.
  • If there is a clear history of aHUS in the family, but no genetic counseling, prenatal diagnosis can be made after pregnancy through genetic testing and so on, to avoid the birth of diseased offspring.

How does atypical hemolytic uremic syndrome reduce the risk of recurrence?

Prophylactic treatment, including eculizumab and plasmapheresis, to reduce the risk of recurrent aHUS. Patients with a low risk of recurrence do not need preventive treatment.


How To Treat Atypical-HUS?

Atypical hemolytic uremic syndrome should see a doctor to what department?

Nephrology, hematology, pediatrics.

Can atypical hemolytic uremic syndrome be cured completely?

Atypical hemolytic uremic syndrome cannot be completely cured. The clinical condition is prone to relapse, and nervous, cardiac, digestive tract and other systems may be involved, finally progressing to end-stage renal disease (ESRD), requiring long-term regular dialysis treatment or kidney transplantation.

How to treat atypical hemolytic uremic syndrome?

The treatment of atypical hemolytic uremic syndrome includes two parts: specific treatment and comprehensive treatment. Specific treatments include blocking the complement activation pathway and plasma exchange.

How to block complement activation pathway in atypical hemolytic uremic syndrome?

Eculizumab is a commonly used drug.

Eculizumab blocks the cleavage of complement protein C5 by binding to it, thereby blocking the production of terminal complement component C5a and membrane attack complex C5b-9, which in turn reduces endothelial damage, thrombosis, and subsequent kidney injury.

In different case series of aHUS, eculizumab has an effective rate of up to 90% and is effective for both aHU S caused by genetic defects in complement protein and by autoantibodies to complement factors, thus making it the first choice for the treatment of aHUS.

Patients suspected of aHUS should be treated with eculizumab as soon as possible within 48 hours of admission, provided the conditions are met.

The major adverse effect of eculizumab is life-threatening Neisseria meningitidis infection, with an annual incidence of approximately 5%. In addition, other infections may arise, most commonly including Streptococcus pneumoniae infection and Haemophilus influenzae type b infection. Therefore, patients taking this drug for a long period of time should receive the corresponding vaccine, as shown in pneumonia vaccine, Haemophilus influenzae type b vaccine.

What is plasma exchange treatment of atypical hemolytic uremic syndrome?

Plasma exchange helps remove defective mutant complement proteins and autoantibodies, and supplements functional complement proteins. It also helps patients with acute kidney injury avoid the risks of volume overload and hypertension.

Because of the rapid development of aHUS, which often leads to irreversible renal impairment, and the practical difficulties in the current clinical application of eculizumab, empirical plasma exchange therapy should be started as early as possible for all patients suspected of aHUS.

Approximately half of patients with aHUS respond to plasmapheresis therapy with improved renal function and hematological remission.

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

What is the comprehensive treatment of atypical hemolytic uremic syndrome?

Comprehensive treatment is mainly symptomatic treatment, such as:

  • For patients with severe anemia, red blood cells are infused to improve the state of anemia and hypoxia.
  • Platelet transfusions are used to prevent bleeding in patients with a significant bleeding tendency, or in patients who clinically need invasive procedures.
  • Provide patients with adequate nutritional support to maintain capacity and electrolyte balance.
  • Discontinuation of nephrotoxic drugs or drugs associated with the onset of aHUS.
  • Timely dialysis treatment and kidney transplantation. Complement genotyping should be performed in all patients with HUS prior to transplantation to determine the presence of genetic mutations. Plasma exchange therapy or prophylactic eculizumab treatment should be performed simultaneously with renal transplantation in patients at high risk for relapse. Of particular note, in vivo kidney donation requires genetic testing to confirm that the donor does not have the same gene mutation.

Is the risk of death high in atypical hemolytic uremic syndrome?

About 30% of patients enter end-stage renal disease at the first onset, and the mortality rate is about 2%–10%.


What Should Patients With Atypical Hemolytic Uremic Syndrome Pay Attention To In Life?

What are the precautions for the diet of patients with atypical hemolytic uremic syndrome?

The general principles of diet in uremia patients include:

  • Maintain adequate caloric intake.
  • Ensure adequate intake of protein.
  • Strictly control the intake of water, salt and potassium ions.
  • Phosphate intake should be limited for renal dialysis patients.

What are the precautions for patients with atypical hemolytic uremic syndrome?

Should do a good job in protection, avoid infection, trauma, try to avoid surgery, pregnancy and other triggering events.

How to care for patients with atypical hemolytic uremic syndrome?

  • Reasonable diet and nutrition.
  • Strengthen life care to avoid infection and trauma.
  • Pay attention to the changes in urine color and urine volume, and skin and mucosa color, and timely visit doctor if there is any abnormality.
  • Regular review, monitoring of blood pressure, hemoglobin, electrolytes and renal function and other indicators of change.

Can patients with aHUS grow up, marry and have children normally?

AHUS family history exists in 20%–30% of patients, and onset of disease occurs in about 60% of patients after adulthood.

Male patients can get married and have children, but genetic testing and genetic counseling should be conducted before giving birth. Pregnancy and childbirth should be avoided in female patients to avoid inducing aHUS.

Can patients with atypical hemolytic uremic syndrome take care of themselves?

With the disease progression, patients often suffer from fatigue, hypertension, nerve damage, gastrointestinal discomfort, coagulation at the venous access site and kidney complications, with a very poor quality of life and need common care from family and society.

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