Immunogenicity of meningococcus C vaccination in a patient with atypical hemolytic uremic syndrome (aHUS) on eculizumab therapy
ABSTRACT We report successful kidney transplantation in a 10-yr-old boy with aHUS and heterozygous factor H mutation using the terminal complement inhibitor eculizumab to avoid recurrence of aHUS in the renal graft. Vaccination against meningococcus C (Men C) is essential in patients with dysfunction of the complement system, as induced by eculizumab. In our patient, we report waning SBA titers but maintenance of protective SBA titers (≥1:8) after kidney transplantation under immunosuppressive therapy with mycophenolate mofetil, tacrolimus, steroids, and eculizumab over a 27-month observational period. Our case illustrates that a humoral immune response to conjugate Men C vaccination may be mounted and maintained despite chronic renal disease, kidney transplantation, immunosuppressive drugs, and immunomodulatory therapy with eculizumab. However, it remains unclear whether serologically defined protective SBA titers mediate true protection from invasive meningococcal disease in an immunocompromised patient, particularly under treatment with a complement inhibitor. Thus, close monitoring of SBA titers seems mandatory in this patient.
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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.Nephrology Dialysis Transplantation 07/2012; 27(7):2673-85. DOI:10.1093/ndt/gfs279 · 3.49 Impact Factor
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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.01/2013; 1(2). DOI:10.1517/21678707.2013.750579
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ABSTRACT: The complement system plays a vital role in mediating disease processes within renal allografts. Eculizumab is a humanized monoclonal antibody that targets complement protein C5, inhibiting cleavage into C5a and C5b, and therefore preventing formation of the membrane attack complex (MAC). It has been used primarily within renal transplantation to treat atypical hemolytic-uremic syndrome (aHUS) and antibody-mediated rejection (AMR) post-transplant, and also as prophylaxis in transplants at high risk for these conditions. Eculizumab appears to be effective in protecting renal allografts when post-transplant aHUS or AMR occur, although the published cases report relatively short follow-up. It is unclear how long treatment should continue (a particularly important issue given the expense of the drug), or whether eculizumab contributes to the development of accommodation in humans. When used for prophylaxis, eculizumab also appears to be effective. Some highly sensitized patients have developed either acute AMR or features of chronic AMR despite administration of the drug - this suggests that complement activation is not the only mechanism responsible for AMR. All patients should receive vaccination against Neisseria meningitidis prior to receiving eculizumab. Clinical trials, predominantly in antibody-incompatible renal transplantation, are ongoing to determine the optimal use of C5 inhibition.Clinical Transplantation 03/2013; 27(3). DOI:10.1111/ctr.12102 · 1.49 Impact Factor