NORD gratefully acknowledges Kenneth Lieberman, MD, Chief, Pediatric Nephrology, Hackensack University Medical Center, for assistance in the preparation of this report.
Atypical hemolytic uremic syndrome (aHUS) is an extremely rare disease characterized by low levels of circulating red blood cells due to their destruction (hemolytic anemia), low platelet count (thrombocytopenia) due to their consumption and inability of the kidneys to process waste products from the blood and excrete them into the urine (acute kidney failure), a condition known as uremia. It is a distinctly different illness from the more common disorder known as typical hemolytic uremic syndrome, which is caused by E.coli-producing Shiga toxins (Stx HUS) and is generally foodborne. Most cases of aHUS are genetic, although some may be acquired due to autoantibodies or occur for unknown reasons (idiopathic). aHUS may become chronic, and affected individuals may experience repeated episodes of the disorder. Unlike individuals with typical HUS, who usually recover from the life-threatening initial episode and usually respond well to supportive treatment, individuals with aHUS are much more likely to develop chronic serious complications such as severe high blood pressure (hypertension) and kidney (renal) failure. The signs and symptoms of aHUS result from the formation of tiny blood clots (microthrombi) in various small blood vessels of the body. These clots reduce or prevent proper blood flow to various organs of the body, especially the kidneys. aHUS is a complex disorder and multiple factors, including certain genetic, environmental and immunologic factors, all play a role in its development.
The nomenclature and terminology surrounding this disorder can be confusing. aHUS is considered a form of thrombotic microangiopathy (TMA). TMA is broken down into two main forms – thrombotic thrombocytopenia purpura and hemolytic uremic syndrome. Generally, hemolytic uremic syndrome is also broken down into two main forms – aHUS and Stx HUS. More than 90% of individuals with hemolytic uremic syndrome have Stx HUS. aHUS is extremely rare and for many years was used to describe any form that was not Stx HUS. aHUS is now used specifically for instances of the disorder associated with excess activation or dysregulation of the alternate pathway of complement, which is part of the innate immune system. This excludes instances of secondary HUS, in which hemolytic uremic syndrome occurs as a secondary finding of a different disorder or condition. Causes of secondary HUS include malignancy, HIV infection, solid organ transplants, hematopoietic stem cell transplants, autoimmune disorders and the use of certain drugs or medications.
The onset of atypical hemolytic uremic syndrome ranges from before birth (prenatally) to adulthood. In young children, the disorder often develops suddenly and usually follows an infection, particularly an upper respiratory infection or gastroenteritis. When it follows an episode of gastroenteritis it can more easily be confused with Stx HUS which almost always is preceded by diarrhea. The disease has different causes and can be unpredictable in how it will progress in one individual as opposed to another.
Many affected individuals present with vague feelings of illness, fatigue, irritability, and lethargy that can potentially lead to hospitalization. The early phases may be difficult to diagnose, and the condition tends to be progressive. Because complications and relapse are common, it is critical that aHUS be recognized at this stage.
The three main findings of aHUS are hemolytic anemia, thrombocytopenia, and acute kidney failure. Although most affected individuals develop these three conditions, some individuals will not. Hemolytic anemia is a condition in which there is a premature destruction (hemolysis) of red blood cells. Thrombocytopenia is a condition in which there are low levels of platelets, a blood cell that is involved in clotting.
Kidney disease can be mild or severe. Kidney damage tends to worsen with each subsequent episode. Blood and protein in the urine (hematuria and proteinuria), frequent indicators of kidney disease, are common, especially during acute episodes. Kidney disease is progressive and can potentially progress to cause end stage renal failure, necessitating chronic dialysis or a kidney transplant.
High blood pressure (hypertension) is common and can result from kidney disease or because of lack of blood flow (ischemia) due to the formation small blood clots (microthrombi). Hypertension can be severe and may be associated with headaches and seizures.
Because small blood clots can potentially form in blood vessels serving other organs of the body, organ damage and failure can occur elsewhere besides the kidneys (which is the organ that is most commonly affected). The brain, gastrointestinal tract, liver, lungs, and heart can also be affected. Specific symptoms can vary based upon the specific organ system involved. Cardiovascular complications can include disease of the heart muscle (cardiomyopathy) or heart attack (myocardial infarction). Neurological complications can include headaches, double vision (diplopia), irritability, drowsiness, facial paralysis, seizures, transient ischemic attacks, stroke, and coma. Gastrointestinal bleeding may also occur. The lungs can be affected and bleeding or fluid accumulation in the lungs (pulmonary edema) can occur.
Most cases of aHUS are associated with mutations amongst the multiple genes that produce (encode) proteins involved in the alternate pathway of complement, which is part of the complement system of the innate immune system. The complement system is a complex group of proteins that work together to fight infection in the body. Complement proteins respond to bacteria, viruses or other foreign substances in the body and ultimately produce a large multi-protein complex that directly attacks these foreign invaders. Other complement proteins regulate the formation of this attack complex in order to protect the body’s own cells from being damaged. Most individuals with aHUS have a mutation in one or more of the genes that encode these regulatory proteins.
A mutation in one of these genes is not enough to cause aHUS on its own. These genes most likely convey a genetic predisposition to developing aHUS rather than causing the disorder outright. A genetic predisposition means that a person carries a gene (or genes) for a disorder, but it may not be expressed unless it is triggered or “activated” under certain circumstances such as because of particular environmental factors or because of an another illness.
In most individuals, there is a triggering occurrence or event such as an acute infection. Other triggers have included chicken pox (varicella) or H1N1 influenza. In women, pregnancy is a common trigger. In addition to an environmental trigger, affected individuals may require a mutation in a second complement gene or a second genetic variant such as single nucleotide polymorphisms (SNP) for the development the disorder. SNPs are the most common genetic variation in humans and occur frequently in a person’s DNA. Most SNPs have no effect on a person’s health.
At least six different genes have been identified to be associated with aHUS. About 30% of the time, aHUS is associated with malfunctions in the gene (CFH) responsible for the production of a blood protein known as factor H. This is the most common gene mutation associated with aHUS. Factor H is one of the regulatory proteins of the complement system that protect blood vessels from injury. When factor H is deficient or inactive, there is the potential for damage to the small vessels in the kidneys with secondary injury to red blood cells and platelets.
Other cases are associated with loss-of-function mutations in genes encoding other complement regulatory proteins, membrane cofactor protein (MCP) and factor I, or with gain-of-function mutations in genes encoding the key complement proteins complement factor B and C3. Finally, mutations in the gene encoding thrombomodulin (THBD), an endothelial anticoagulant glycoprotein with complement regulatory properties, have been found in 3-5% of individuals with aHUS.
A seventh gene known as DGKE has been identified as being associated with aHUS. Some researchers believe DGKE-associated aHUS is a similar, but distinct disorder. The protein produced by the DGKE gene is not associated with the alternate pathway of complement and instead appears to be involved in the coagulation process.
The specific genetic mutation present may be more likely to be associated with specific symptoms or severity of the disorder. This is known as genotype-phenotype correlation. The response to treatment can also be influenced by the specific underlying genetic mutation. For example, MCP mutations have a lower risk of permanent kidney failure and a low risk of disease recurrence following a kidney transplant. Individuals with mutations in the CFH or THBD genes are more likely to present during childhood.
Some individuals develop aHUS because of autoantibodies that target proteins encoded by complement genes. Antibodies are specialized proteins that react against foreign materials in the body, bringing about their destruction. When antibodies react against healthy tissue, they are known as autoantibodies. Anti-factor H autoantibodies have been reported in 6-10% of cases, mainly children. Less often, autoantibodies that target other complement proteins have been identified. The reason why these autoantibodies develop is unknown.
In approximately 30%-50% of individuals with aHUS, no mutation in a complement gene and no autoantibodies can be detected. These individuals may be referred to as having idiopathic aHUS. However, many researchers believe these individuals most likely have yet unidentified mutations in complement genes.
The genetic mutations in complement genes that predispose individuals to aHUS usually occur sporadically, meaning that there is no previous family history of the disorder. The disorder has run in families only about 20% of the time. In such instances, these mutations are transmitted (inherited) as an autosomal dominant trait or, less often, as an autosomal recessive trait. The dominant form affects adults more often than children.
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
In childhood, aHUS affects males and females in equal numbers. In adulthood, females are affected more often than males, most likely because pregnancy is a triggering event. The exact overall incidence and prevalence is unknown. One study placed the incidence in the United States at 2 individuals per 1 million in the general population. In Europe, the disorder is estimated to affect approximately .11 per 1 million individuals between the ages of 0-18. aHUS accounts for approximately 5-10% of all cases of hemolytic uremic syndrome.
Diagnosing aHUS is complicated by the fact that it is more difficult to establish without a family history of the disorder. The diagnostic criteria associated with aHUS are hemolytic anemia (anemia in the presence of broken red blood cells), low platelet count (thrombocytopenia) and kidney dysfunction. aHUS is considered genetic when two or more members of the same family are affected by the disease at least six months apart and exposure to a common triggering infectious agent has been excluded, or when a disease-causing mutation(s) is identified in one of the genes known to be associated with aHUS, irrespective of familial history.
Individuals with aHUS do not present with the aggressive and bloody diarrhea that characterize the onset of Stx HUS, although 30-50% of children with aHUS may have diarrhea. The absence of bloody diarrhea, negative stool cultures for Shiga toxin producing-E. coli (most frequently E. coli 0157:H7) associated with HUS, a progressive course, and prior manifestations of nephrotic syndrome, such as swelling from the accumulation of fluid (edema), presence of blood in the urine (hematuria), excessive protein in the urine (proteinuria), and reduced albumin in the serum (hypoalbuminemia), with marked elevation in blood pressure are features that alert pediatricians and kidney specialists (nephrologists) to the possible diagnosis of aHUS.
Treatment by a medical team familiar with the unique challenges of aHUS is recommended and can include pediatricians or general internists, kidney specialists (nephrologists), intensive care physicians, nurses, nutritionists and social workers.
Initially, affected individuals may receive supportive care including maintaining proper nutrition and electrolyte and fluid balance through intravenous feeding (parenteral) when and if necessary. Blood transfusions are administered when the hemoglobin level is below 7 g/dl. Platelet transfusions are avoided if at all possible. Drugs that expand the blood vessels (vasodilators) are used to control blood pressure (hypertension). In some instances, individuals are diagnosed with aHUS when they already have kidney damage and may initially require supportive measures such as peritoneal dialysis or hemodialysis.
In 2011, the U.S Food and Drug Administration (FDA) approved the use of the humanized anti-C5 monoclonal antibody eculizumab as a treatment for acute hemolytic uremic syndrome. This drug is used to block excessive complement activation in individuals with aHUS. Eculizumab has led to improvement with the blood abnormalities (reduced hemolysis and stabilized platelet counts) and reversed acute kidney injury. Eculizumab is now recommended as first-line therapy in both children and adults with a confirmed or strongly suspected diagnosis of aHUS.
For years, plasma therapy was the standard treatment for individuals with aHUS. Both infusions of fresh frozen plasma (plasma infusion) as well as plasma exchange (plasmapheresis) were utilized. Fresh frozen plasma is a blood derivative that is obtained from donors. Plasma exchange is a method for removing potentially harmful substances (e.g. toxins, metabolic substances, and plasma parts) from the blood. Blood is removed from the affected individual and blood cells are separated from the plasma. The plasma is then replaced with other human plasma and the blood is transfused into the affected individuals. Plasma exchange can also remove mutant factors and autoantibodies.
Plasma therapy has led to a remission in a subset of individuals. However, many of these individuals experience relapses if they don’t receive long term maintenance therapy. Other individuals, while seeing an improvement in the blood complications (e.g. hemolysis and thrombocytopenia), still experience progressive kidney damage, ultimately progressing to end stage renal disease. Plasma therapy has not been studied as a treatment for aHUS in a controlled fashion.
Individuals who fail to recover kidney function after treatment may require a kidney (renal) transplant. Renal transplantation had been a controversial option for aHUS because an estimated 50% of affected individuals who underwent this procedure had a recurrence of the disease in the newly grafted organ. Molecular genetic tests could help to define graft prognosis; thus, all patients should undergo such testing prior to transplantation. Molecular genetic testing should be particularly recommended before live related donation to avoid the risk of triggering disease in the donors. Eculizumab has been shown to be effective in preventing and treating post-transplant aHUS recurrences.
Plasmapheresis in conjunction with drugs that suppress the immune system (immunosuppressive therapy) can be used to treat individuals with aHUS due to autoantibodies to factor H.
The optimal treatment strategy for individuals with aHUS due to mutations in the DGKE gene has not been established. The effectiveness of eculizumab for these individuals has not been established presumably because the underlying defect does not involve complement proteins. Several affected individuals received a kidney transplant with no reported recurrence of the disorder.
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Accessed September 28, 2016
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