Monitoring of complement activation biomarkers and eculizumab in complement‐mediated renal disorders
2017
Various complement-mediated renal disorders are currently treated with the complement inhibitor eculizumab. By blocking the cleavage of C5 this monoclonal antibody prevents cell damage caused by complement-mediated inflammation. We included 23 patients with atypical hemolytic uremic syndrome (aHUS, n=12), C3 glomerulopathies (C3G, n=9) and acute antibody-mediated renal graft rejection (AMR, n=2), treated with eculizumab in 12 hospitals in Germany. We explored the course of complement activation biomarkers and the benefit of therapeutic drug monitoring of eculizumab. Complement activation was assessed by analyzing the hemolytic complement function of the classical (CH50) and the alternative pathway (APH50), C3, and the activation products C3d, C5a and sC5b-9 prior to, 3 and 6 months after eculizumab treatment. Eculizumab concentrations were determined by a newly established specific ELISA. Serum eculizumab concentrations up to 1082 μg/mL point to drug accumulation especially in pediatric patients. Loss of the therapeutic antibody via urine with concentrations up to 56.0 μg/mL correlated with proteinuria. In aHUS patients, effective complement inhibition was demonstrated by significant reductions of CH50, APH50, C3d, and sC5b-9 levels, whereas C5a levels were only significantly reduced after 6 months treatment. C3G patients presented increased C3d and consistently low C3 levels, reflecting ongoing complement activation and consumption at the C3 level, despite eculizumab treatment. A comprehensive complement analysis together with drug monitoring is required to distinguish mode of complement activation and efficacy of eculizumab treatment in distinct renal disorders. Accumulation of the anti-C5 antibody points to the need of a patient-oriented tailored therapy. This article is protected by copyright. All rights reserved.
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