Atypical hemolytic uremic syndrome (aHUS) is an extremely rare disease characterized by hemolytic anemia, low platelet count (thrombocytopenia) and acute renal failure. It is a distinctly different illness from hemolytic uremic syndrome caused by particular strains of the bacterium E.coli producing Shiga toxins, most frequently the 0157:H7 strain (Stx HUS). While Stx HUS typically is preceded by a gastroenteritis and is associated with infection by Shiga toxin producing-E.coli, there is substantial evidence that aHUS is a genetic disorder.
Atypical hemolytic uremic syndrome may become a chronic condition, and patients with aHUS may experience repeated attacks of the disorder. When children with Stx HUS recover from the life-threatening initial episode, they are likely to respond well to supportive treatment and to make a good recovery. Children with aHUS are much more likely to develop chronic serious complications such as kidney failure and severe high blood pressure.
Atypical hemolytic uremic syndrome presents with vague feelings of illness, fatigue, irritability, and lethargy that often 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.
Patients 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 diagnosis of aHUS.
Evidence is emerging that 50%-60% of the aHUS is associated with genetically determined alterations of the complement system. About 30% of aHUS cases are associated with malfunctions in the gene responsible for the production of a blood protein known as Factor H. 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. Anti-factor H autoantibodies have been reported in 6-10% of cases, mainly children. Other cases are associated with loss-of-function mutations in genes encoding other complement regulatory proteins, membrane cofactor protein 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, an endothelial anticoagulant glycoprotein with complement regulatory properties, have been found in 3-5% of aHUS patients.
In some families, atypical hemolytic uremic syndrome (aHUS) is transmitted (inherited) as an autosomal dominant trait while in other families it appears to be transmitted as an autosomal recessive trait. The mainly responsible gene has been mapped to chromosome 1q32.
An episode of aHUS may occur without the stimulation of a precipitating event such as a bacterial or viral infection.
The recessive form of aHUS most often affects infants and children who may or may not experience relapses. The dominant form affects adults more often than children. Patients rarely recover completely. Unfortunately, many patients have recurrences after kidney transplants.
Because of the high likelihood of recurrences after renal transplants, and the possibility that this likelihood may be increased when kidneys are obtained from a family member, it is not advisable to use kidneys from family members.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q32″ refers to band 32 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are the result of mutations of genes for any particular trait that are on the chromosomes received from the father and 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 affected parent to 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 receives 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 defective 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
There are at least 300 cases of aHUS in the United States and about 500 cases have been reported in Italy. AHUS may represent fewer than 5 percent of all cases of HUS.
The diagnosis of aHUS is difficult and complicated by the fact that the diagnosis is difficult to make 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 severe kidney lesions. 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.
Proper nutrition and electrolyte and fluid balance are maintained by intravenous feeding (parenteral) when and if necessary. Blood transfusions are administered when the haemoglobin 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). Plasma manipulation (plasma infusion or exchange) may be indicated. Bilateral nephrectomy has been performed in a small number of rare individuals with extensive microvascular thrombosis at renal biopsy, refractory hypertension, and signs of hypertensive encephalopathy, in whom conventional therapies including plasma manipulation are not adequate to control the disease.
Recently the humanized anti-C5 monoclonal antibody Eculizumab has been used to block excessive complement activation in patients with aHUS. More than 20 aHUS patients treated with Eculizumab have been reported in the literature thus far. Some patients were treated for aHUS on the native kidneys, others received Eculizumab to treat or to prevent post-transplant aHUS recurrences. The efficacy of Eculizumab in aHUS has been clearly shown in two open label controlled trials (ClinicalTrials.gov) of adult and adolescent patients age 12 years and older with plasma therapy-sensitive or plasma-therapy resistant aHUS.
Patients who do not recover kidney function are treated with peritoneal or haemodialysis.
Renal transplantation is not necessarily an option for aHUS in contrast to typical HUS. An estimated 50% of individuals with aHUS who underwent renal transplantation had a recurrence of the disease in the 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 or treating post-transplant aHUS recurrences.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
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