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      Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders : Complement and eculizumab monitoring

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          Abstract

          <p id="d98286e493">Various complement‐mediated renal disorders are treated currently 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 haemolytic uraemic syndrome (aHUS, <i>n</i> = 12), C3 glomerulopathies (C3G, <i>n</i> = 9) and acute antibody‐mediated renal graft rejection (AMR, <i>n</i> = 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 analysing the haemolytic 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 enzyme‐linked immunosorbent assay (ELISA). Serum eculizumab concentrations up to 1082 μg/ml point to drug accumulation, especially in paediatric patients. Loss of the therapeutic antibody via urine with concentrations up to 56 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 reduced significantly 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 for a patient‐orientated tailored therapy. </p>

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          Most cited references45

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          An international consensus approach to the management of atypical hemolytic uremic syndrome in children.

          Atypical hemolytic uremic syndrome (aHUS) emerged during the last decade as a disease largely of complement dysregulation. This advance facilitated the development of novel, rational treatment options targeting terminal complement activation, e.g., using an anti-C5 antibody (eculizumab). We review treatment and patient management issues related to this therapeutic approach. We present consensus clinical practice recommendations generated by HUS International, an international expert group of clinicians and basic scientists with a focused interest in HUS. We aim to address the following questions of high relevance to daily clinical practice: Which complement investigations should be done and when? What is the importance of anti-factor H antibody detection? Who should be treated with eculizumab? Is plasma exchange therapy still needed? When should eculizumab therapy be initiated? How and when should complement blockade be monitored? Can the approved treatment schedule be modified? What approach should be taken to kidney and/or combined liver-kidney transplantation? How should we limit the risk of meningococcal infection under complement blockade therapy? A pressing question today regards the treatment duration. We discuss the need for prospective studies to establish evidence-based criteria for the continuation or cessation of anticomplement therapy in patients with and without identified complement mutations.
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            Dynamics of complement activation in aHUS and how to monitor eculizumab therapy.

            Atypical hemolytic-uremic syndrome (aHUS) is associated with genetic complement abnormalities/anti-complement factor H antibodies, which paved the way to treatment with eculizumab. We studied 44 aHUS patients and their relatives to (1) test new assays of complement activation, (2) verify whether such abnormality occurs also in unaffected mutation carriers, and (3) search for a tool for eculizumab titration. An abnormal circulating complement profile (low C3, high C5a, or SC5b-9) was found in 47% to 64% of patients, irrespective of disease phase. Acute aHUS serum, but not serum from remission, caused wider C3 and C5b-9 deposits than control serum on unstimulated human microvascular endothelial cells (HMEC-1). In adenosine 5'-diphosphate-activated HMEC-1, also sera from 84% and 100% of patients in remission, and from all unaffected mutation carriers, induced excessive C3 and C5b-9 deposits. At variance, in most patients with C3 glomerulopathies/immune complex-associated membranoproliferative glomerulonephritis, serum-induced endothelial C5b-9 deposits were normal. In 8 eculizumab-treated aHUS patients, C3/SC5b-9 circulating levels did not change posteculizumab, whereas serum-induced endothelial C5b-9 deposits normalized after treatment, paralleled or even preceded remission, and guided drug dosing and timing. These results point to efficient complement inhibition on endothelium for aHUS treatment. C5b-9 endothelial deposits might help monitor eculizumab effectiveness, avoid drug overexposure, and save money considering the extremely high cost of the drug.
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              Eculizumab for dense deposit disease and C3 glomerulonephritis.

              The principle defect in dense deposit disease and C3 glomerulonephritis is hyperactivity of the alternative complement pathway. Eculizumab, a monoclonal antibody that binds to C5 to prevent formation of the membrane attack complex, may prove beneficial. In this open-label, proof of concept efficacy and safety study, six subjects with dense deposit disease or C3 glomerulonephritis were treated with eculizumab every other week for 1 year. All had proteinuria >1 g/d and/or AKI at enrollment. Subjects underwent biopsy before enrollment and repeat biopsy at the 1-year mark. The subjects included three patients with dense deposit disease (including one patient with recurrent dense deposit disease in allograft) and three patients with C3 glomerulonephritis (including two patients with recurrent C3 glomerulonephritis in allograft). Genetic and complement function testing revealed a mutation in CFH and MCP in one subject each, C3 nephritic factor in three subjects, and elevated levels of serum membrane attack complex in three subjects. After 12 months, two subjects showed significantly reduced serum creatinine, one subject achieved marked reduction in proteinuria, and one subject had stable laboratory parameters but histopathologic improvements. Elevated serum membrane attack complex levels normalized on therapy and paralleled improvements in creatinine and proteinuria. Clinical and histopathologic data suggest a response to eculizumab in some but not all subjects with dense deposit disease and C3 glomerulonephritis. Elevation of serum membrane attack complex before treatment may predict response. Additional research is needed to define the subgroup of dense deposit disease/C3 glomerulonephritis patients in whom eculizumab therapy can be considered.
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                Author and article information

                Journal
                Clinical & Experimental Immunology
                Clin Exp Immunol
                Wiley
                00099104
                February 2017
                February 2017
                November 25 2016
                : 187
                : 2
                : 304-315
                Affiliations
                [1 ]Institute of Immunology; University of Heidelberg; Heidelberg Germany
                [2 ]Department of Pediatric Nephrology; University Hospital Tübingen; Germany
                [3 ]Department of Hematology and Oncology; ALB FILS Hospital Göppingen; Germany
                [4 ]Department of Pediatric Nephrology; University Hospital Bonn; Germany
                [5 ]Department of Pediatric Immunology; University Hospital Jena; Germany
                [6 ]Department of Pediatric Nephrology; University Children's Hospital Zurich; Switzerland
                [7 ]Department of Internal Medicine; University of Giessen; Germany
                [8 ]Department of Nephrology and Hypertension; University Hospital Erlangen; Germany
                [9 ]Division of Nephrology, Department of Internal Medicine III; University Hospital Carl Gustav Carus; Dresden Germany
                [10 ]Department of Pediatrics I; University Children's Hospital Heidelberg; Germany
                [11 ]Department of Pediatric Nephrology; University Hospital Essen; Germany
                [12 ]Department of Pediatric Nephrology; Hospital Memmingen; Germany
                [13 ]Department of Internal Medicine IV; University Hospital Freiburg; Germany
                Article
                10.1111/cei.12890
                5217898
                27784126
                4b343c89-ae4d-4e57-9fdd-827e91b78c98
                © 2016

                http://doi.wiley.com/10.1002/tdm_license_1

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