title: Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders.
abstract: 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, 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 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.
authors: Institute of Immunology, University of Heidelberg, Heidelberg, Germany.
authors: C
authors: C
authors: Wehling
authors: Department of Pediatric Nephrology, University Hospital Tübingen, Germany.
authors: O
authors: O
authors: Amon
authors: Department of Hematology and Oncology, ALB FILS Hospital Göppingen, Germany.
authors: M
authors: M
authors: Bommer
authors: Department of Pediatric Nephrology, University Hospital Bonn, Germany.
authors: B
authors: B
authors: Hoppe
authors: Department of Pediatric Immunology, University Hospital Jena, Germany.
authors: K
authors: K
authors: Kentouche
authors: Department of Pediatric Nephrology, University Children's Hospital Zurich, Switzerland.
authors: G
authors: G
authors: Schalk
authors: Department of Internal Medicine, University of Giessen, Germany.
authors: R
authors: R
authors: Weimer
authors: Department of Nephrology and Hypertension, University Hospital Erlangen, Germany.
authors: M
authors: M
authors: Wiesener
authors: Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany.
authors: B
authors: B
authors: Hohenstein
authors: Department of Pediatrics I, University Children's Hospital Heidelberg, Germany.
authors: B
authors: B
authors: Tönshoff
authors: Department of Pediatric Nephrology, University Hospital Essen, Germany.
authors: R
authors: R
authors: Büscher
authors: Department of Pediatric Nephrology, Hospital Memmingen, Germany.
authors: H
authors: H
authors: Fehrenbach
authors: Department of Internal Medicine IV, University Hospital Freiburg, Germany.
authors: Ö-N
authors: ÖN
authors: Gök
authors: Institute of Immunology, University of Heidelberg, Heidelberg, Germany.
authors: M
authors: M
authors: Kirschfink
mesh_terms: D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D065766:Atypical Hemolytic Uremic Syndrome / Q000188:drug therapy*; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003167:Complement Activation / Q000187:drug effects; D003176:Complement C3 / Q000276:immunology*; D003182:Complement C5 / Q000276:immunology; D005260:Female; D015433:Glomerulonephritis, Membranous / Q000188:drug therapy*; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007223:Infant; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D003176:Complement C3; D003182:Complement C5; D007166:Immunosuppressive Agents; C481642:eculizumab
keywords: biomarker; complement; drug monitoring; eculizumab; renal disease