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American Journal of Kidney Diseases

Treatment of Atypical Hemolytic Uremic Syndrome and Thrombotic Microangiopathies: A Focus on Eculizumab

Published:November 09, 2012DOI:https://doi.org/10.1053/j.ajkd.2012.07.028
      Uncontrolled complement activation is central to the occurrence of atypical hemolytic uremic syndrome (aHUS) and can result in thrombotic microangiopathies (TMAs).These terms encompass a group of heterogenic inherited or acquired diseases that recent research suggests may be triggered by the complement cascade. Pathogenetic triggers of complement activation include immunologic disorders, genetics, infections, systemic diseases, pregnancy, drug administration, metabolic diseases, transplantation, or triggers of mixed cause. Hallmarks of aHUS and other TMAs include increased vascular endothelium thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, coagulation abnormalities, and vascular shear stress, whereas common end points of these mechanisms include hemolytic anemia, thrombocytopenia with microvascular infarction, and predisposition for decreased kidney function and other organ involvement. The central role of the complement cascade as a disease trigger suggests a possible therapeutic target. Eculizumab, a first-in-class humanized monoclonal anti-C5 antibody that has been successful in the treatment of paroxysmal nocturnal hemoglobinuria, a disorder of complement-induced hemolytic anemia, received approval for the treatment of aHUS in the United States and Europe in late 2011. We review the treatment of aHUS and other TMAs, focusing on the role of eculizumab, including its pharmacology, mechanism of action, and approved dosing recommendations and health economic considerations. Finally, the potential for future indications for eculizumab use in other complement-driven diseases is discussed.

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      Linked Article

      • Beneficial Effect of Eculizumab on Thrombotic Microangiopathies: Another Point of View
        American Journal of Kidney DiseasesVol. 63Issue 1
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          We read with great interest the contribution by Schmidtko et al.1 The authors reviewed the treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies (TMAs), focusing on the role of eculizumab, a high-affinity humanized monoclonal antibody that binds to and blocks the cleavage of C5 into the inflammatory, prothrombotic, and lytic C5a and C5b-9 terminal complement component. However, the authors did not explain how C5 inhibition halts systemic TMAs. Thus, we present another potential mechanism of eculizumab in the treatment of TMAs.
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