What is Hemolytic Uremic Syndrome?
Hemolytic uremic syndrome (HUS) is a disease that has three main features: low platelet count, an abnormal breakdown of red blood cells, and acute damage to the kidneys. It can often be caused by toxic bacteria (typical HUS), or, less commonly, by infections or genetic abnormalities that affect part of the immune system, known as the alternative complement pathway (atypical HUS). Other causes may also involve cancer, autoimmune disorders, genetic mutations, and certain medications. It’s common for people with HUS to experience symptoms in other parts of the body, especially neurological ones. Quickly spotting the different causes and signs of HUS is crucial for fast diagnosis and treatment, which can improve the outcome for patients.
The term ‘thrombotic microangiopathy’ refers to a group of illnesses that involve damage to the blood vessel walls, causing blood clots in the small blood vessels. This makes it difficult for blood cells to flow through, which breaks them apart and damages parts of the body. Thrombotic microangiopathy is characterized by a low platelet count, abnormal breakdown of red blood cells, and damage to organs due to poor blood flow. It’s crucial to differentiate HUS from other diseases that fall under this umbrella, as the treatment can be quite different.
In the past, doctors often categorized HUS based on whether or not the individual had bloody diarrhea, which was used to diagnose typical HUS associated with toxic bacteria. However, atypical HUS could also present with bloody diarrhea in some cases, so it’s now preferred to classify it based on the cause.
Typical HUS, which accounts for up to 95% of HUS cases, is most commonly caused by a type of bacteria called Shiga toxin–producing Escherichia coli. These bacteria can be ingested through contaminated food or drink, or from other people. The chance of developing HUS from these bacteria is between 5% to 15%, with children under 5 being especially vulnerable. Symptoms often start with bloody diarrhea 2 or 3 days after exposure and can then develop into HUS after 3 to 10 days. Other commonly reported symptoms are vomiting, fever, and abdominal pain.
Atypical HUS (aHUS) makes up 5% to 10% of HUS cases and is usually linked to genetic mutations that affect the alternative complement pathway, an integral part of our immune system. When in imbalance due to inflammatory conditions like infections, it can bring about damage to blood vessels, triggering coagulation and causing a thrombotic microangiopathy presentation. The first signs of aHUS are often non-specific, such as fatigue, paleness, or sleepiness, but these can advance to obvious kidney problems including reduced urine output, buildup of waste products in the blood, and fluid retention. The likelihood of aHUS progressing to severe kidney disease is high and unlike typical HUS, patients with aHUS often don’t recover kidney function without treatment. If left untreated, approximately half of aHUS cases will need dialysis, with a mortality rate of 25%.
Additionally, just like typical HUS, aHUS can cause problems in other parts of the body, especially the heart and nervous system. Conditions such as heart failure, high blood pressure in the lungs, seizures, coma, and blindness often contribute to the severity of aHUS. It’s also noted that compared to typical HUS, aHUS often recurs – meaning that patients have to be closely monitored after treatment has ended.
The final group of HUS involves patients with HUS due to underlying conditions or infections that behave like aHUS by abnormally activating the immune system. A notable part of this category includes HUS caused by a type of bacteria called Streptococcus pneumoniae, which accounts for 5% to 15% of all HUS cases in children. In addition to these, secondary aHUS can also be caused by inherited disorders related to vitamin B12 metabolism, certain genetic mutations, HIV, the flu virus, autoimmune diseases, certain medications, and severe high blood pressure.
Recent studies have found that COVID-19 can potentially trigger aHUS in both adults and children, and it’s been noted that pregnancy can activate aHUS, leading to increased complications in pregnant women who already have aHUS as opposed to those who do not.
What Causes Hemolytic Uremic Syndrome?
One major cause of a type of kidney disease known as Hemolytic Uremic Syndrome (HUS) is a toxin produced by bacteria, which can come in two main types – Stx1 and Stx2. Among these, Stx2 can often lead to more severe disease and may require more intensive treatment methods, like kidney replacement therapy. Traditionally, HUS was thought to be most commonly caused by a specific strain of Escherichia coli bacteria (E. coli 0157:H7), but in recent years, other types have become more prevalent, particularly E. coli 026:H11. Currently, this is the most common cause of HUS in North America and Europe.
Some other bacteria like Shigella dysenteriae produce a similar toxin and can also cause HUS, but typically lead to more severe disease with a high mortality rate (around 36%). In rare cases, a type of bacteria called Salmonella has been associated with HUS as well.
aHUS, another type of Hemolytic Uremic Syndrome, arises due to abnormal activation of a defense mechanism in our body known as the complement system. This system, which is part of our immune response, has three pathways of activation: classical, alternative, and lectin-binding. All three pathways have a common point where they work together to form C3 convertase. This then leads to the creation of something called the membrane-attack complex (MAC), which destroys harmful cells.
In aHUS, however, there is a problem: the complement pathway doesn’t switch off as it usually would. This can often be due to changes or alterations in the genes that help kick-start the alternative complement pathway, or control its activity. For example, the most common identifiable genetic change in people with aHUS is a variant of a gene called “CFH”. Even if someone has these genetic changes, it typically takes a second trigger, often an infection, for aHUS to develop.
Risk Factors and Frequency for Hemolytic Uremic Syndrome
HUS and aHUS are illnesses often seen in children under 10 years old, especially those under 5. In general, STEC causes 43 acute illnesses for every 100,000 person-years globally, as well as 3890 cases of HUS. STEC-HUS is a common reason for kidney replacement therapy in children. From a large study, we learned that 15% of children under 18 coming to the emergency room with severe diarrhea ended up developing STEC-HUS.
The rate of STEC-HUS is thought to be about 0.57 instances per 100,000 kids, but for the most susceptible group – kids aged between 6 months and 2 years – the rate can be as high as 3 per 100,000 children. We see more cases between April and September, which coincides with certain environmental factors and farming practices, like cattle raising. This is the time of year when cattle are more likely to carry STEC.
Compared to HUS, aHUS is rarer but comes with serious health risks and high rates of illness and death. Like HUS, aHUS primarily affects young children, particularly those under 5 years old. The estimated rate is between 2 and 9 cases per million people 20 years old or younger. aHUS cases related to S Pneumonia typically happen in winter during the cold season.
Signs and Symptoms of Hemolytic Uremic Syndrome
Hemolytic Uremic Syndrome (HUS) often affects children under 5 years old. It starts with painful diarrhea and stomach cramps 1 to 10 days after exposure to a bacteria called STEC. Fever and vomiting might also occur. Later, usually 5 to 13 days after diarrhea begins, signs of HUS appear. These include kidney-related symptoms (such as low or no urine output and symptoms linked to fluid overload), and other symptoms related to a shortage of red blood cells (like fainting, weakness, and pallor or paleness of skin). You might also notice tiny, rounded, purple-red spots due to bleeding under the skin, or easy bleeding because of a drop in blood platelets.
Adults can also get HUS, although it’s less common. When it happens in adults, especially during food-related outbreaks, the disease varies more and usually has a worse outcome. Most deaths due to HUS occur in older adults, aged 60 and over. Neurological symptoms, including confusion, seizures, and coma, are often more common in adults than in children. Older patients may have mental health symptoms too.
Atypical HUS, or aHUS, often begins with non-specific symptoms like fatigue, pale skin, or sleepiness. It can worsen to show signs of acute kidney damage, such as low urine output, an excess of waste products in the blood, and fluid overload. If the trigger is a bacteria called S Pneumoniae, patients may also have pneumonia, pus in the body tissues, or meningitis. Diarrhea, including bloody diarrhea, can be prominent in atypical HUS.
Whether it’s typical or atypical HUS, it’s common to see symptoms affecting parts of the body other than the kidneys. These non-kidney symptoms, especially those related to the nerves and the heart, often cause heavily impact the health and cause high rates of death from HUS.
Testing for Hemolytic Uremic Syndrome
If a doctor suspects a patient has Hemolytic Uremic Syndrome (HUS), a condition that affects kidney function, they’ll need to gather a lot of information. This can include the patient’s symptoms, travel history, daily diet, and results from certain lab tests.
A variety of blood tests including a complete blood count (a test to check your body’s overall health) and a detailed blood test panel (a deeper analysis of the patient’s blood) will be ordered. The doctor will be looking for signs of hemolytic anemia (a condition where red blood cells get destroyed faster than the body can replace them), such as high carboxylic acid (LDH) and bilirubin (a waste product from the breakdown of red blood cells), low haptoglobin (a protein that binds free hemoglobin released from red blood cells) and high plasma hemoglobin levels. In these cases, there’re broken red blood cells (schistocytes) can be seen under a microscope.
Another test called Coombs, which identifies antibodies that destroy red blood cells, should turn out negative. The only exception would be if the HUS was triggered by a Streptococcus pneumoniae infection.
In some patients, especially those who may also have pancreatic damage, the level of enzymes like amylase and lipase also go up. This might show up as high blood sugar levels. If diarrhea is present, doctors may ask for a stool sample to check for a harmful toxin (Shiga toxin).
Additional tests may be used to check for low complement levels (part of the immune system) in the blood suggestive of aHUS, another variant of HUS that occurs when the complement system gets activated uncontrollably, and to rule out other conditions like Thrombotic Thrombocytopenic Purpura (TTP – a rare blood disorder) and Disseminated Intravascular Coagulation (DIC – a serious illness in which blood clotting becomes abnormal).
Results from all these tests can help the doctor decide what treatment to use. However, if the doctor thinks the patient has HUS based on their symptoms and examination, they might start treatment before all the test results come back. Starting treatment earlier can lead to better outcomes for the patient.
Treatment Options for Hemolytic Uremic Syndrome
Typical Hemolytic Uremic Syndrome (HUS) caused by Shiga toxin-producing E. coli (STEC) is usually treated with supportive care. Patients often need fluid because they are dehydrated, and a lack of fluids can result in the need for kidney dialysis, which half of all patients might require. Blood transfusions are also generally given as needed, but platelet transfusions (platelets help your blood to clot) should be used sparingly to avoid blood clot problems.
In this type of HUS, doctors generally avoid using drugs that affect gut movements and antibiotics, as these can lead to worse outcomes, potentially due to increased exposure to Shiga toxin, a dangerous substance produced by some bacteria. However, if other bacteria, such as S. dysenteriae or S. pneumonia, are present, early antibiotics can actually improve outcomes.
In the case of atypical HUS (aHUS), it’s crucial to start treatment early to prevent kidney failure and risk of death. The main treatments are a medicine called eculizumab and plasma exchange (a procedure where the plasma in your blood, which contains antibodies and proteins, is replaced). Eculizumab is a synthetic monoclonal antibody (a type of protein that can bind to specific substances) that works by targeting a part of our immune system called complement activation, preventing its activation. Studies show that the earlier this drug is used, the more effective it tends to be. The use of eculizumab has reduced the rate of progression to kidney failure or death significantly.
Ravulizumab, another drug similar to eculizumab but with a longer duration of action, was approved in the USA in 2019 and the EU in 2020. Plasma exchange used to be the standard of care for HUS before eculizumab and is still used if eculizumab isn’t available or if more treatment is needed.
One contentious issue is treating patients who have developed kidney failure due to aHUS. Patients with aHUS often experience kidney failure and require a kidney transplant. However, there is a high rate of aHUS recurrence in the transplanted kidney. Studies suggest that using eculizumab as a preventative measure in patients with a high risk of aHUS recurrence can increase graft survival (the success of the transplant) and may also be cost-effective. However, the drug can have side effects like infection, which is why all patients should be vaccinated and monitored properly.
The treatment of secondary HUS largely depends on treating the underlying condition that caused it. Some small studies have shown that eculizumab can be effective in treating secondary HUS related to pregnancy. However, many of these patients are found to have a genetic component that increases their risk of aHUS. Another small study showed that patients with secondary HUS whose kidney condition worsened despite treating the underlying disease saw improvements in kidney and other symptoms after being administered eculizumab.
What else can Hemolytic Uremic Syndrome be?
At first, Hemolytic Uremic Syndrome (HUS) may seem similar to other blood disorders, including Thrombotic Thrombocytopenic Purpura (TTP), Disseminated Intravascular Coagulation (DIC), HELLP Syndrome, and Systemic Vasculitis. However, doctors can usually rule out these other conditions through certain signs, symptoms, and lab tests.
Thrombotic Thrombocytopenic Purpura exists when one has low platelet count, anemia, kidney issues, fever, and nervous system problems. It is usually due to a flaw in a specific enzyme and most often appears in adults.
Disseminated Intravascular Coagulation is a condition where the blood starts clotting throughout the body. It is indicated by abnormal coagulation tests, such as prolonged prothrombin time and activated partial thromboplastin time, increased D dimer, and increased fibrin degradation products, which are usually normal in HUS. Patients with DIC are often seriously ill and may suffer from septic shock, trauma, or cancer.
HELLP Syndrome is a condition that appears in the third trimester of pregnancy or immediately following childbirth. It is characterized by the breakdown of red blood cells, elevated liver enzymes, and a low platelet count. This condition often happens in tandem with preeclampsia.
Systemic Vasculitis patients usually show up with inflammatory indicators like fever, rash, and joint pain, and do not have prodromal diarrhea. These patients generally have a significantly elevated erythrocyte sedimentation rate.
What to expect with Hemolytic Uremic Syndrome
The general prognosis for Hemolytic Uremic Syndrome (HUS), a type of kidney disease, is generally positive, with only about 5% of cases leading to death. However, about 25% of patients develop long-term kidney problems. This means that their kidneys don’t filter blood as efficiently as they should or they have high blood pressure or abnormal amounts of protein in their urine. These complications could lead to further kidney problems as they age.
The duration of time spent on dialysis, a treatment which helps your body remove waste and extra fluid when your kidneys aren’t working properly, can be a good indicator of future kidney troubles. If someone is dependent on dialysis for 2 to 3 weeks, this could point to long-term complications.
One major exception to this generally positive outlook, is in adults older than 60, who account for most deaths from typical HUS.
The prognosis for atypical HUS, a more severe form of the disease, used to be worse than typical HUS, but the introduction of a treatment called eculizumab has led to remarkable improvements. The risk of the disease resulting in end-stage renal disease (ESRD, when the kidneys permanently fail to work) or death has dramatically dropped from 30%-50% to 9% in children and from 60%-6% to 15% in adults.
