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Atypical hemolytic uremic syndrome

Hemolytic uremic syndrome is characterized by the triad of Coombs negative microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Most cases of the hemolytic uremic syndrome occur after infection with Shiga toxin–producing Escherichia coli. Less commonly,the syndrome can occur as a complication of invasive infection with Streptococcus pneumoniae.Other cases of the hemolytic uremic syndrome are classified as atypical and are usually disorders of complement regulation that can be either sporadic or familial. 

The complement system is part of the innate immune system, which provides immediate defense against infection and does not evolve as does the adaptive immune system. The classic complement pathway is activated by the C1 antibody-antigen complex. The alternative complement pathway leads to the same pathway via C3. Both pathways lead to the formation of C5 through C9 membrane attack complexes, which form channels across the membranes of target cells, leading to cell lysis and death.

The alternate pathway does not require an antibody trigger so is always active at low levels. Inhibitory factors (factor H, factor I, membrane cofactor protein, and factor H-related proteins) regulate the activity of the alternate pathway. Uncontrolled activation of the alternative complement system is the hallmark of aHUS. Several genetic mutations and polymorphisms involving complement regulatory proteins have been implicated in the pathogenesis of the disease.

Loss of function variants in genes encoding inhibitors of the complement system, including factor H (CFH), complement factor I (CFI), membrane cofactor protein (MCP/CD46), complement factor H-related proteins (CFHRI, CFHR3, CFHR4, CFHR5) thrombomodulin (THBD) and C4b binding protein (C4BP), as well as gain of variants in genes encoding complement factor B, (CFB) and complement 3 (C3) are associated with aHUS. A molecular defect has been detected in approximately 60% of cases of aHUS.  Complement factor H (CFH) mutations are the most frequent.

 

Acquired complement dysregulation due to CFH autoantibodies are reported in 6-10% cases. Other patients may have as yet unidentified complement mutations. Infection, pregnancy and even drugs may trigger clinical disease in the presence of these mutations.

The disease affects both adults and children, with more than 40% of cases first reported after 18 years of age. More than 50% of patients progress to end-stage renal disease. About 60% of aHUS patients have at least one complication outside of the kidney, including neurological, cardiovascular, and gastrointestinal. During the first year, 65% of all patients die, require dialysis, or have permanent kidney injury.

Atypical HUS needs to be differentiated from the other TMAs such as thrombotic thrombocytopenic purpura (TTP), Shiga-toxin-producing E.coli hemolytic uremic syndrome (STEC-HUS) and anti-phospholipid antibody syndrome. All four diseases have overlapping clinical presentations. Though neurologic dysfunction is thought to indicate TTP, about 48% aHUS cases report neurologic dysfunction. Similarly, diarrhea is not specific for STEC-HUS, as up to 30% of aHUS cases present with diarrhea. Patients with aHUS have normal levels of ADAMTS13 and have no evidence of Shiga toxin-producing E coli or lupus anticoagulant.

Previously, aHUS was treated with plasma exchange, which replaces defective complement regulatory proteins and removes inhibitory antibodies. More recently, eculizumab was approved by the FDA for treatment of aHUS. It is a recombinant humanized monoclonal antibody that binds with high affinity to C5 and prevents formation of the membrane attack complex. It is now considered to be the treatment of choice for aHUS. Renal function improves and platelet counts increase within a couple of weeks after initiation of treatment. For a patient with atypical hemolytic uremic syndrome on dialysis, treatment with eculizumab should continue for 4 to 6 months if there are no extrarenal manifestations. But many patients continue to have the defect in the complement system, so the problem may recur.

The biggest drawback to eculizumab is its exorbitant price. A regimen of treatment can cost hundreds of thousands of dollars. Patients treated with Eculizumab may have increased susceptibility to infections, especially with encapsulated bacteria like Neisseria meningitidis, Streptococcus pneumonia, and Haemophilus influenza type b. Vaccination is recommended prior to treatment.

References:

• Schwartz J et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue. J Clin Apher. 2013 Jul;28(3):145-284.
• Campistol JM, Arias M, Ariceta G, Blasco M, et al. An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document. Nefrologia. 2013 Jan 18;33:27-45.
• Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol. 2012 Nov; 8:622-33.
• Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009;361:1676-1687.
• Tanimoto T, Oshima Y, kami M. Eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013;369:1378-9.
• Kelly R, Richards S, Hillmen P, Hill A. The pathophysiology of paroxysmal nocturnal hemoglobinuria and treatment with eculizumab. Ther Clin Risk Manag 2009;5: 911-921.
•  Tanimoto T, Oshima Y, kami M. Eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013;369:1378-9.
• Kao AY, et al. Case 19-2018: A 15-year old girl with acute kidney injury, N Engl J Med 2018;378:2421-29.