Complement and atypical hemolytic uremic syndrome (aHUS)
Atypical hemolytic uremic syndrome (aHUS) is a very rare, life-threatening disease of genetic origin. Although the symptoms are similar, the underlying mechanism in aHUS is distinctly different from typical HUS, also called STEC-HUS, which is caused by infection of shiga toxin producing E. coli. aHUS accounts for ca 10% of all HUS cases and clear-cut diagnosis to distinguish between the two types is of greatest importance. The disease typically presents in childhood but only half of all aHUS patients are diagnosed before the age of 18. aHUS is caused by chronic, uncontrolled complement activation that leads to systemic thrombotic microangiopathy and, if left unchecked, such potentially catastrophic events as stroke, heart attack and renal failure (Ref 1, 2).
Mutations in genes encoding the complement regulators factor H, factor I, MCP and C3 are frequent in aHUS while some patients’ complement system is dysregulated by autoantibodies against e.g. factor H. The aberrant regulation causes complement attack on and destruction of both erythrocytes and endothelial cells via the alternative pathway. In the process, platelets and leukocytes are activated and thrombi are formed throughout the circulatory system. They cause particular damage in small blood vessels such as the ones in the glomeruli of the kidney, leading to glomerulonephritis and, ultimately, acute renal failure (Ref 2, 3).
aHUS often presents with malaise and fatigue, as well as hypertension and microangiopathic anemia, but rarely with the severe abdominal pain and bloody diarrhea associated with STEC-HUS. Onset of disease can also be abrupt and serious with sudden crises in the kidneys, heart and brain (Ref 1, 2).
Diagnosis of aHUS can be difficult due to the similarity of symptoms with other thrombotic microangiopathies such as STEC-HUS and thrombotic thrombocytopenic purpura (TTP). In suspected aHUS patients it is therefore recommended to test for complement pathway activity as well as screen for potential mutations in, initially, factor H, factor B, factor I and C3 (Ref 1, 4). Such careful analyses shed clear light on the molecular background of the illness of the specific patient.
Historically, plasma exchange to replace non-functioning complement components and remove autoantibodies against FH has been the most common treatment for aHUS patients. The efficacy of plasma exchange in aHUS has, however, never been scientifically proven and better therapy options have been sought for a long time. A major breakthrough came in 2011 with the approval of the antibody drug Eculizumab for the treatment of aHUS patients. Read more about Eculizumab in the Treatment section. Eculizumab targets C5 of the complement system, thereby inhibiting the terminal pathway and the consequent lysis of particularly sensitive cells in aHUS patients. There are several on-going clinical trials with complement targeted therapies designed to treat aHUS (Ref 1, 5). Hopefully, these will lead to the release of new drugs, with similar efficiacy, for the successful treatment of this serious and debilitating disease in the coming years.
1. Atypical hemolytic uremic syndrome: what is it, how is it diagnosed, and how is it treated? Nester & Thomas, Hematology Am Soc Hematol Educ Program 2012;2012:617-25.
2. Complement disorders and hemolytic uremic syndrome. Joesph & Gattineni, Curr Opin Pediatr 2013 Apr;25(2):209-15.
3. Thrombotic thrombocytopenic purpura and the atypical hemolytic uremic syndrome: an update. Tsai, Hematol Oncol Clin North Am 2013 Jun;27(3):565-84.
4. Complement Diagnostics: Concepts, Indications, and Practical Guidelines. Nilsson & Nilsson-Ekdahl, Clin Dev Immunol 2012;2012:962702.
5. Complement therapy in atypical haemolytic uraemic syndrome (aHUS). Wong et al, Mol Immunol 2013 Dec 15;56(3):199-212.