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Atypical Hemolytic Uremic Syndrome

NORD is very grateful to Giuseppe Remuzzi, MD, Mario Negri Institute for Pharmacological Research, Italy, for assistance in the preparation of this report.

Synonyms of Atypical Hemolytic Uremic Syndrome

  • aHUS
  • familial hemolytic-uremic syndrome
  • hereditary hemolytic-uremic syndrome

Disorder Subdivisions

  • No subdivisions found.

General Discussion

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.

Symptoms

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.

Causes

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.

Affected Populations

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.

Related Disorders

Shiga toxin-associated hemolytic-uremic syndrome (Stx HUS) is an uncommon disorder that primarily affects young children between the ages of one and 10 years, with a peak incidence around three years of age. The onset of Stx HUS is preceded by a gastroenteritis characterized by vomiting, abdominal pain, fever, and diarrhea that becomes bloody. Symptoms of Stx HUS usually become apparent three to 10 days after the development of gastroenteritis, and include sudden paleness (pallor), irritability, weakness, lack of energy (lethargy), and/or excretion of diminished amounts of urine (oliguria). The disease typically progresses to include inability of the kidneys to process waste products from the blood and excrete them into the urine (acute renal failure), a decrease in circulating red blood cells (microangiopathic hemolytic anemia), a decrease in circulating blood platelets, which assist in blood-clotting functions (thrombocytopenia); and the abnormal accumulation of platelets within certain blood vessels (microthrombi), reducing the blood flow to several organs (kidneys, pancreas, brain). This potentially leads to multiple organ dysfunction or failure. In some cases, neurological problems may be present at the onset of Stx HUS or may occur at any time during the illness. Neurological symptoms are uncommon and may include dizziness, seizures (partial or generalized), disorientation or confusion, and/or loss of consciousness (coma). The cause of Stx HUS most frequently is infection by a particular strain (0157:H7) of Escherichia coli (E. coli) bacterium. Occasionally, adults may be affected by StxHUS. Disease presentation and outcome, were particularly unusual during the German outbreak of May 2010 that was caused by the O104:H4 E.coli strain. Almost 90% of affected patients were adults and, compared to previous StxHUS epidemics, there was a higher prevalence of affected young and middle-aged women and extremely high incidence of dialysis-dependent kidney failure (20% vs 6%) and death (6% vs 1%), respectively. (For more information on this disorder, choose Hemolytic Uremic Syndrome as your search term in the Rare Disease Database.)

Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder characterized by the development of blood clots in small blood vessels (thrombotic microangiopathy). There is considerable overlap between the physical findings of this disorder and those associated with HUS. Recent studies show that these are completely different conditions. HUS occurs more commonly in children. TTP occurs most often in females in the third or fourth decade of life. Findings may include low levels of platelets in the blood (thrombocytopenia), a diminished number of circulating red blood cells (microangiopathic hemolytic anemia), and/or neurological abnormalities.

Thrombocytopenia is associated with a variety of symptoms, including the development of purple bruises on the skin, hematuria, and/or small red or purple spots on the skin and/or mucous membranes (petechiae). Neurological abnormalities may include disorientation, headaches, visual abnormalities, seizures, paralysis (paresis), and/or, in severe cases, coma. In addition, affected individuals may also experience fever, fatigue, weakness, abdominal pain, and/or diarrhea. In some cases, individuals with TTP may have acute renal failure that may result in diminished excretion of urine, blood in the urine (hematuria), high blood pressure (hypertension); an abnormal accumulation of fluid between layers of tissue under the skin (oedema); and/or unusually low water content in the body (dehydration). In some cases, acute renal failure may lead to life-threatening complications. The causes of TTP are either an inherited deficiency of an enzyme (metalloproteinase) or acquired antibodies to this enzyme. (For more information on this disorder, choose Thrombotic Thrombocytopenic Purpura as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
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.

Treatment
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.

Investigational Therapies

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.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Atypical Hemolytic Uremic Syndrome Resources

NORD offers an online community for this rare disease. RareConnect was created by EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders) to provide a safe space where individuals and families affected by rare diseases can connect with each other, share vital experiences, and find helpful information and resources. You can view these international, rare disease communities at www.rareconnect.org.

Organizations:

References

TEXTBOOKS
Kaplan BS.Inherited hemolytic-uremic syndrome. In: NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:690-91.

Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999;924-2225.

REVIEW ARTICLES
Noris M, Remuzzi G. Thrombotic microangiopathy after kidney transplantation. Am J Transplant. 2010;10(7):1517-23.

Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361(17):1676-87.

Ruggenenti P, Noris M, Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombocytopenic purpura. Kidney Int. 2001;60:831-46.

Bosch T, Wendler T. Extracorporeal plasma treatment in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: a review. Ther Apher. 2001;5:182-85.

Taylor Cm. Hemolytic-uremic syndrome and complement factor H deficiency: clinical aspects. Semin Thromb Hemost. 2001;27:185-90.

Ault BH. Factor H and the pathogenesis of renal diseases.Pediatr nephrol. 2000;14:1045-53.

Neuhaus TJ, Calonder S, Leumann EP. Heterogeneity of atypical hemolytic uraemic syndromes.Arch Dis Child. 1997;76:518-21.

JOURNAL ARTICLES
Noris M, Caprioli J, Bresin E, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol. 2010;5(10):1844-59.

Saland JM, Ruggenenti P, Remuzzi G; Consensus Study Group. Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2009;20(5):940-9.

Veyradier A, Obert B, Haddad E, et al. Severe deficiency of the specific von Willebrand factor-cleaving protease (ADAMTS 13) activity in a subgroup of children with atypical hemolytic uremic syndrome. J Pediatr. 2003;142(3):310-17.

Quan A, Sullivan EK, Alexander SR. Recurrence of hemolytic uremic syndrome after renal transplantation in children: a report of the North American Pediatric Renal Transplant Cooperative Study. Transplantation. 2001;72:742-45.

Magen D, Oliven A, Shechter Y, et al. Plasmapheresis in a very young infant with atypical hemolytic uremic syndrome. Pediatr Nephrol. 2001;16:87-90.

Richards A, Buddles MR, Donne RL, et al. Factor H mutations in hemolytic uremic syndrome cluster in exons 18-20, a domain important for host cell recognition. Am J Hum Genet. 2001; 68:485-90.

Buddles MR, Donne RL, Richards A, et al. Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome. Am J Hum Genet. 2000;66:1721-22.

Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J AM Soc Nephrol. 1998;9:1126-33.

INTERNET
Noris M, Bresin E, Mele C, Remuzzi G, Caprioli J. (Updated March 10, 2011). Atypical
Hemolytic-Uremic Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at http://www.genetests.org. Accessed March 1, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Complement Factor H; CFH. Entry No: 134370. Last Edited February 22, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 1, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Hemolytic
Uremic Syndrome, Atypical, Susceptibility to, 1; AHUS1. Entry No: 235400. Last Edited
November 28, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 1, 2012.

National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC)
http://kidney.niddk.nih.gov/kudiseases/pubs/childkidneydiseases/hemolytic_uremic_syndrome/index.aspx Last Updated September 2, 2010. Accessed March 1, 2012.

The Atypical HUS Website: http://atypicalhus.50megs.com/. Accessed March 1, 2012.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2012/03/19 00:00:00 GMT+0

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