Atypical Haemolytic Uraemic Syndrome

Atypical haemolytic uraemic syndrome is a rare, potentially life-threatening condition where the immune system mistakenly attacks blood vessel cells, forming dangerous clots that can damage kidneys and other vital organs.

Table of contents

• What is atypical haemolytic uraemic syndrome?
• What causes this condition?
• What triggers episodes of aHUS?
• Signs and symptoms
• How is aHUS diagnosed?
• Treatment options
• Outlook and prognosis
• Living with aHUS

What is atypical haemolytic uraemic syndrome?

Atypical haemolytic uraemic syndrome (aHUS) is a rare condition that causes small blood clots to form in tiny blood vessels throughout the body. These clots reduce blood flow to vital organs, particularly the kidneys, and can lead to serious medical problems^[1].

Healthcare providers usually diagnose aHUS when three conditions occur together: microangiopathic haemolytic anaemia (when red blood cells are destroyed faster than the body can replace them), thrombocytopenia (too few platelets in the blood), and acute kidney injury (a type of kidney failure that may be reversible)^[1]. These three conditions can happen in episodes triggered by other health conditions.

The condition is also called complement-mediated thrombotic microangiopathy (CM-TMA), which describes how the disease affects small blood vessels throughout the body^[1][7].

Atypical haemolytic uraemic syndrome is different from typical haemolytic uraemic syndrome. The typical form is caused by certain strains of E. coli bacteria and usually causes severe diarrhea, particularly in children. The atypical form does not cause diarrhea and has different causes^[1][5].

What causes this condition?

Atypical haemolytic uraemic syndrome often results from a combination of genetic and environmental factors. In about half of all cases, the condition is caused by genetic mutations that affect how the body’s immune system works^[1][6].

The mutations affect proteins called complement factors, which are part of the immune system. These proteins normally help identify and destroy harmful germs like bacteria and viruses. Genetic mutations in aHUS most commonly affect complement factors H, I, 3 and B^[1][6].

When complement factor H is not working properly due to a genetic mutation, it fails to protect the body’s cells as it should. This causes immune cells to mistakenly attack and damage cells that line blood vessels. Platelets then form clots around this damage, blocking blood vessels and preventing blood from reaching organs^[1].

These genetic changes can be inherited from a biological parent or they can happen on their own without any family history. Some people develop autoantibodies (proteins that attack the body’s own cells) against complement proteins, which can also cause aHUS^[1][6].

In up to half of people with aHUS, doctors cannot find a specific gene mutation. Researchers believe these cases may be due to genetic mutations that have not yet been identified^[8].

What triggers episodes of aHUS?

Having a genetic mutation alone does not usually cause symptoms of atypical haemolytic uraemic syndrome. More often, symptoms are triggered by other health conditions or events. A genetic mutation creates a predisposition, and then something else acts as a trigger for the disease to manifest^[3][6].

Common triggers include pregnancy, infections (including respiratory infections and other bacterial or viral illnesses), cancer, and certain medications^[1][3]. Medications that can trigger aHUS include some cancer chemotherapy agents, immunosuppressive medications, blood thinners, oral contraceptives (birth control pills), and anti-inflammatory medications^[1].

Other triggers documented in medical literature include various infections such as norovirus, certain strains of bacteria like Campylobacter and Clostridium difficile, influenza, and other viral illnesses^[3].

Signs and symptoms

Symptoms of atypical haemolytic uraemic syndrome can vary from person to person. Some people experience only a few symptoms, while others develop more severe problems. Symptoms often come on suddenly after a trigger^[1][8].

Common symptoms include fatigue, pale skin, nausea or vomiting, decreased urination, blood in the urine, high blood pressure, shortness of breath, and swelling in different parts of the body. Some people also experience confusion and fever^[1].

Many people feel like they have been sick for a while with something they cannot shake. Most people only experience a few symptoms, or symptoms develop slowly over time. Neurological symptoms affecting the brain and nerves, like confusion, are less common^[1].

Laboratory tests may reveal low platelet counts, elevated lactate dehydrogenase (a chemical released from damaged cells), decreased haptoglobin (indicating breakdown of red blood cells), damaged red blood cells, elevated creatinine (indicating kidney problems), and protein in the urine^[7].

In severe cases, aHUS can cause serious complications affecting multiple organs. These may include acute kidney failure, high blood pressure, heart attack, stroke, lung complications, inflammation of the pancreas, liver cell death, brain dysfunction, seizures, or coma^[7].

How is aHUS diagnosed?

Diagnosing atypical haemolytic uraemic syndrome can be challenging, especially if there is no family history of the disease. A specialist doctor, such as a nephrologist (kidney doctor) or haematologist (blood doctor), is most likely to recognize aHUS^[8].

Doctors diagnose aHUS by looking for the three main features: haemolytic anaemia, low platelet count, and kidney problems. To confirm the diagnosis, healthcare providers order several tests^[8].

A complete blood count (CBC) measures platelet and red blood cell levels. An estimated glomerular filtration rate (eGFR) test checks how well the kidneys are working by measuring levels of creatinine (a waste product) in the blood^[8].

Blood tests can show if red blood cells are damaged, reveal low platelet counts or low red blood cell counts, or detect higher than usual levels of creatinine. Urine tests can find unusual levels of protein and blood^[5][12].

Genetic testing can help identify specific genetic mutations causing aHUS. This information is important because the underlying genetic defect can predict both how the disease will progress and how it might respond to treatment^[3][6].

Doctors must also perform tests to rule out other conditions that can look similar to aHUS. One important test checks for ADAMTS13, which helps distinguish aHUS from another condition called thrombotic thrombocytopenic purpura^[8].

Treatment options

Atypical haemolytic uraemic syndrome requires treatment in a hospital, particularly during acute episodes. Treatment approaches have changed dramatically in recent years with the development of new medications^[9][12].

The main treatment for aHUS involves medications called complement inhibitors. Two medications, eculizumab (Soliris) and ravulizumab (Ultomiris), are approved specifically for treating atypical haemolytic uraemic syndrome. These are monoclonal antibodies that work by blocking the part of the immune system causing the disease^[11][12].

These medications bind to a protein called C5a in the complement system, preventing the production of components that cause inflammation and damage to blood vessel cells. The results of treatment with these medications have been very encouraging, and they are now recognized as the treatment of choice for aHUS^[9].

Anyone taking eculizumab or ravulizumab must receive a vaccination to prevent meningitis, which is a possible serious side effect of these medicines. The vaccination should be given at least two weeks before starting treatment^[11][12].

Before these specific treatments were available, plasma exchange or plasma infusion was used as the initial treatment. Plasma exchange might be more effective than infusion because it removes potentially toxic substances from the circulation. However, complement inhibitor medications have now become the preferred first-line treatment^[11].

Supportive care during acute episodes involves replacing lost fluids and minerals to compensate for reduced kidney function. Patients may need red blood cell transfusions to help reverse symptoms of anaemia. Some people may require temporary dialysis if their kidneys are not working well enough^[12].

If kidney damage becomes permanent and progresses to end-stage renal disease, kidney transplantation may be necessary. The recurrence rate in patients who undergo kidney transplantation for aHUS ranges from 0 to 10 percent^[11].

Outlook and prognosis

Before the availability of complement inhibitor medications like eculizumab and ravulizumab, the outlook for people with atypical haemolytic uraemic syndrome was poor. An estimated 33 to 40 percent of patients developed end-stage renal disease or died during the first episode of aHUS. Including subsequent relapses, approximately two-thirds of patients required dialysis, had permanent kidney damage, or died within the first year after diagnosis^[7].

The successful development and use of complement inhibitor medications have revolutionized disease management and dramatically improved outcomes. Many case reports and clinical trials have shown very encouraging results with few serious side effects reported. There have been no reports of treatment resistance with these medications^[9].

The underlying genetic defect can predict the prognosis both in native kidneys and after kidney transplantation. Incomplete penetrance of mutations means that not everyone with a genetic mutation will develop the disease, suggesting that a trigger is required to unmask the complement regulatory deficiency^[3].

Atypical haemolytic uraemic syndrome is typically a lifelong condition. However, with appropriate treatment, symptoms can be managed and complications minimized. Regular medical follow-ups are crucial to monitor kidney function, blood pressure, and overall health^[14][16].

Living with aHUS

Living with atypical haemolytic uraemic syndrome requires ongoing medical care and lifestyle adjustments. It is essential to work closely with healthcare providers and follow their guidance and treatment plan^[14].

Taking prescribed medications as directed is crucial. Patients should attend all scheduled check-ups to monitor kidney function, blood pressure, and overall health. Regular monitoring helps doctors detect any problems early^[14].

Following dietary recommendations from healthcare providers is important. This may include managing salt and fluid intake, especially for people with kidney problems. Engaging in regular, moderate physical activity as recommended can help improve overall health and wellbeing^[14].

Research has shown that many adult patients experience long-term disease symptoms, particularly fatigue, which can significantly impact daily functioning. The emotional toll of aHUS is considerable, with feelings of fear, guilt, and trauma persisting across different disease phases in both patients and family members^[17].

Mental health support is important for people living with aHUS. The chronic nature of the condition and the unpredictable nature of disease recurrence can affect mental wellbeing. Seeking support from a therapist or counselor can help manage emotional stress^[14][17].

Education about the disease is empowering. Learning about aHUS, its symptoms, and potential complications helps patients make informed decisions about their health. Support networks, including friends and family, provide important emotional support. Support groups where patients can connect with others facing similar challenges can also be valuable^[14][16].

Pregnancy can trigger aHUS, and the condition can complicate pregnancy. Women with aHUS should discuss family planning thoroughly with their healthcare team^[16].

Maintaining good hygiene practices and staying up to date with vaccinations is essential to reduce the risk of infections, which can trigger disease episodes^[16].

• Kidneys
• Blood vessels
• Heart
• Brain
• Liver
• Lungs
• Pancreas