Acknowledgement of Atypical Hemolytic Uremic Syndrome has not been added yet.

Atypical HUS is extremely rare and the exact prevalence is unknown. About one-tenth of hemolytic uremic syndromes are aHUS. One study found that there are about two new cases per 1 million individuals in the US per year. aHUS is more common in childhood during which time it affects males and females in equal numbers. However, it also occurs in adulthood but adult females are more commonly affected than males. This could potentially be due to pregnancy as a triggering factor. 

 

In addition, aHUS has incomplete penetrance. That means many individuals who carry a disease-causing mutation in one of the associated genes, may not necessarily develop aHUS, but they can still pass the gene to their children. 

 

Name	Abbreviation
Atypical Hemolytic Uremic Syndrome	aHUS

Most cases of aHUS are linked to a change in genes involved in the regulation of the complement system. The complement system is a component of the immune system and consists of a group of proteins that together form a large protein complex involved in triggering inflammation, destroying foreign particles, and removing debris from tissues. The specific component of the complement pathway involved in aHUS is known as the alternative pathway. The alternative pathway tags foreign particles to make it easier for immune cells to identify and destroy them. Other complement proteins have a regulatory role to avoid damage to healthy tissue by the complement system.

 

Most commonly, mutations in a gene called Complement Factor H (CFH) are associated with aHUS. Factor H, the protein encoded by CFH, is a protein that regulates the complement system. If factor H does not function properly, the uncontrolled activity of the complement system can damage small vessels. Other genes that could be involved include Membrane Cofactor Protein (MCP), Complement Factor I (CFI), Complement Factor B (CFB), and Complement Component 3 (C3), all of which are regulatory complement proteins. Thrombomodulin is encoded by the gene THBD and is a protein in the walls of blood vessels which both regulate the complement system and also reduces blood clotting. Mutations in THBD can also predispose individuals to aHUS. Lastly, mutations in Diacylglycerol Kinase Epsilon (DGKE) are also associated with aHUS. DKGE is a gene that encodes a protein that is not a part of the complement system, but rather involved in blood clot formation. 

 

Most cases of aHUS are caused by sporadic mutations. This means that the mutation is not inherited from a family member and does not run in families. However, cases of aHUS running in families have also been reported. In such cases, these mutations are more often autosomal dominant, and less commonly, autosomal recessive. Each individual inherits two copies of each gene, one from each parent. A dominant mode of inheritance occurs when one defective gene is enough to cause the disease. A recessive mode of inheritance occurs when both copies must be defective for the disease to develop. Some individuals affected with aHUS do not carry a mutation in any of the associated genes. Having a mutation predisposes the individual but doesn’t necessarily cause aHUS. 

 

Environmental triggers such as pregnancy, infections, autoimmune conditions, organ and stem cell transplants, and certain medications in genetically predisposed individuals can trigger aHUS. This is known as idiopathic aHUS. It is likely that these individuals have mutations in a gene that has not yet been associated with aHUS.

 

The uncontrolled activation of the complement system and prolonged inflammation leads to the thickening of small blood vessels in the kidneys. Cells that make up the blood vessel walls become swollen and detached and the blood vessels become occluded by protein aggregates and cell debris. As blood vessels are damaged, the coagulation pathway is activated to heal the blood vessels which further occludes them and leads to the formation of blood clots. The kidney can no longer function properly as its blood vessels are obstructed. As red blood cells try to pass through these occluded, small blood vessels, they become damaged and fragmented.

 

Atypical HUS often presents with three primary symptoms: hemolytic anemia, thrombocytopenia, and kidney disease. Hemolytic anemia describes a condition where red blood cell levels are low, not because they are not produced in adequate amounts, but because they are being destroyed more rapidly than normal. Thrombocytopenia occurs when blood platelet levels are low. Platelets are cellular fragments in the blood that stop bleeding and initiate tissue recovery by forming blood clots and the coagulation process. 

 

Due to anemia, affected individuals may have a pale complexion, experience fatigue, and shortness of breath. Thrombocytopenia can lead to easy bruising or excessive or unusual bleeding. Kidney damage is often progressive and symptoms become more evident as aHUS progresses. This occurs in aHUS because platelets are consumed rapidly to form blood clots in the kidney. Symptoms associated with kidney damage include high blood pressure, decreased urination, or the presence of blood in the urine. Some individuals experience symptoms related to organs other than kidneys. These symptoms include confusion, seizures, and other neurologic deficits. Although HUS and aHUS have many similar symptoms, HUS presents with diarrhea while aHUS usually does not. Atypical HUS can develop any time from before birth to adulthood.

 

Diagnosis of aHUS is also dependent on the presence of physical symptoms, in particular, hemolytic anemia, thrombocytopenia, and kidney damage. However, not everyone presents with all three symptoms. Diagnosis of aHUS typically starts with an initial suspicion of Thrombotic Microangiopathy (TMA). TMA refers to the damage incurred to kidney blood vessels as a result of aHUS.The diagnostic process involves excluding other causes of TMA and confirming that HUS is present. Next, typical HUS needs to be excluded. This involves a series of diagnostic tests and evaluations that identify complement dysregulation as well as genetic testing to identify mutations in genes associated with aHUS. Atypical HUS is considered genetic either if this has been confirmed by genetic testing or if two or more family members have been affected and exposure to a common trigger has been excluded.

Tests that are used to diagnose aHUS include blood tests, urine tests, and stool samples. Blood tests can test for hemolytic anemia and thrombocytopenia by identifying damaged or low levels of red blood cells and platelets. A blood test can also measure the amounts of creatinine. Creatinine is a substance that is cleared from the blood very effectively in the absence of kidney damage. An increase in blood creatinine levels can be an indication of kidney damage. A urine test may be performed to test for the presence of proteins or blood in the urine. Proteins and blood are absent in healthy individuals but in case of kidney damage, some might leak into urine. Stool samples could be helpful in distinguishing typical and atypical HUS as individuals affected by aHUS do not express severe and bloody diarrhea. The presence of blood in the stool or the detection of E. coli in the stool can indicate typical HUS as opposed to aHUS.

 

In addition, the activity of the complement system is also tested to diagnose aHUS. In aHUS, the activity of the alternative complement pathway is reduced because complement proteins are consumed. Tests that measure complement system activity are important for the management of aHUS because depending on the specific proteins involved, individuals are more prone to kidney failure or more responsive to certain treatments. Finally, genetic testing may be performed to identify the specific gene involved. This, similar to the complement activity, has therapeutic implications as well. However, the absence of genetic mutations does not exclude aHUS as some individuals are affected by idiopathic aHUS.

 

Treatment of aHUS depends on the stage of the disease as well as the genetic profile of the affected individual. Initially, maintaining a balanced diet and controlling fluid and electrolyte levels are recommended. If red blood cell levels are too low, blood transfusions could be helpful. If high blood pressure is present, medications that dilate blood vessels may be helpful in controlling blood pressure. 

 

Plasma-based therapy used to be the standard treatment for aHUS. This could be done in the form of administering fresh frozen plasma from donors or plasma exchange (plasmapheresis). Plasmapheresis involves removing the affected individual’s blood, separating the plasma from blood cells, and replacing the plasma with donor plasma. This can also remove the defective complement proteins from the blood.  Plasma-based treatment may be successful or may lead to remissions. The success of this form of treatment depends on the genetic profile of the individual. For example, individuals with mutations in MCP experience the highest success rate in response to plasma-based treatments. This is while individuals with a CFI mutation tend to be least responsive. 

Some medications that inhibit the complement system have been approved for the treatment of aHUS. Eculizumab is currently the first-line treatment for aHUS in both children and adults. It is a humanized monoclonal antibody which means that it resembles proteins produced by the immune system and tightly binds to specific complement proteins and inhibits their excessive function. However, the success of this drug for individuals with a DGKE mutation is not well-known because DGKE is not involved in the complement pathway. 

 

Finally, individuals with severe kidney damage may benefit from a kidney transplant. However, some individuals who undergo a kidney transplant experience a recurrence which also increases the risk of transplant failure. The success of this procedure depends on the genetic profile of the individual. The use of eculizumab to prevent recurrence before the transplant and after can significantly increase the chance of success. Individuals with MCP mutations typically do not relapse after the procedure and may not need eculizumab while individuals with CFH mutations are more likely to experience recurrence and may require lifelong eculizumab.

 

Prognosis of aHUS is highly variable and depends on the specific mutations present in the affected individuals. Kidney failure is a life-threatening complication of aHUS. However, depending on the genetic profile of the individual, their responsiveness to treatment may vary which ultimately determines the prognosis.

Tips or Suggestions of Atypical Hemolytic Uremic Syndrome has not been added yet.

Mayoclinic. Hemolytic uremic syndrome (HUS). 2019. https://www.mayoclinic.org/diseases-conditions/hemolytic-uremic-syndrome/symptoms-causes/syc-20352399

 

Genetic and Rare Disease Information Center. Atypical hemolytic uremic syndrome. 2020. https://rarediseases.info.nih.gov/diseases/8702/atypical-hemolytic-uremic-syndrome

 

Franchini M, Ma. Atypical hemolytic uremic syndrome: from diagnosis to treatment. Clinical Chemistry and Laboratory Medicine (CCLM). 2015; 53(11): 1679-1688. doi:10.1515/cclm-2015-0024

 

Zhang K, Lu Y, Harley KT, Tran MH. Atypical Hemolytic Uremic Syndrome: A Brief Review. Hematol Rep. 2017;9(2):7053. Published 2017 Jun 1. doi:10.4081/hr.2017.7053

 

Afshar-Kharghan V. Atypical hemolytic uremic syndrome. Hematology Am Soc Hematol Educ Program. 2016;2016(1):217–225. doi:10.1182/asheducation-2016.1.217

 

Genetic Home Reference. Atypical hemolytic-uremic syndrome. https://ghr.nlm.nih.gov/condition/atypical-hemolytic-uremic-syndrome#diagnosis