[Show abstract][Hide abstract] ABSTRACT: Thrombotic microangiopathy (TMA) is a pathological process involving thrombocytopenia, microangiopathic haemolytic anaemia and microvascular occlusion. TMA is common to haemolytic uraemic syndrome (HUS) associated with shiga toxin or invasive pneumococcal infection, atypical HUS (aHUS), thrombotic thrombocytopenic purpura (TTP) and other disorders including malignant hypertension. HUS complicating infection with shiga toxin-producing Escherichia coli (STEC) is a significant cause of acute renal failure in children worldwide, occurring sporadically or in epidemics. Studies in aHUS have revealed genetic and acquired factors leading to dysregulation of the alternative complement pathway. TTP has been linked to reduced activity of the ADAMTS13 cleaving protease (typically with an autoantibody to ADAMTS13) with consequent disruption of von Willebrand factor multimer processing. However, the convergence of pathogenic pathways and clinical overlap create diagnostic uncertainty, especially at initial presentation. Furthermore, recent developments are challenging established management protocols. This review addresses the current understanding of molecular mechanisms underlying TMA, relating these to clinical presentation with an emphasis on renal manifestations. A diagnostic and therapeutic approach is presented, based on international guidelines, disease registries and published trials. Early treatment remains largely empirical, consisting of plasma replacement/exchange with the exception of childhood STEC-HUS or pneumococcal sepsis. Emerging therapies such as the complement C5 inhibitor eculizumab for aHUS and rituximab for TTP are discussed, as is renal transplantation for those patients who become dialysis-dependent as a result of aHUS.
[Show abstract][Hide abstract] ABSTRACT: Introduction: This review focuses on the use of an orphan drug eculizumab (Soliris®; Alexion Pharmaceuticals Inc.), for the treatment of an extremely rare disease, atypical hemolytic uremic syndrome (aHUS). aHUS is associated with very high mortality and morbidity rates. Current therapies (plasma therapy, liver transplant) are imperfect and fraught with complications. The authors briefly describe the clinical features and diagnosis of aHUS. The pathogenesis is the result of mutations in genes encoding alternative complement regulators. This results in unregulated activity of the alternate complement pathway, endothelial injury, and thrombotic microangiopathy (TMA). Eculizumab is a humanized monoclonal antibody that inhibits the production of the terminal complement components C5a and the membrane attack complex (C5b-9) by binding to complement protein C5a. This blocks the proinflammatory and cytolytic effects of terminal complement activation.
Areas covered: Eculizumab use is described in many case reports and in two prospective Phase II open-label clinical trials in adolescent and adult patients with aHUS. There is also a retrospective study in children, adolescents and adults with aHUS. There are few serious side-effects and no reports of tachphylaxis or drug resistance.
Expert opinion: The results are very encouraging and more information is being obtained regarding the optimal timing of initiation, doses and maintenance protocols. Cost and availability may be important limitations to its widespread use. In summary, eculizumab therapy is now the standard of care in the prevention and treatment of episodes of aHUS. Prophylactic eculizumab should be used for renal transplant candidates with a genetically determined risk of post-transplantation aHUS recurrence.
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