title: Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS.
abstract: Atypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening disease characterized by uncontrolled complement activation, systemic thrombotic microangiopathy (TMA), and vital organ damage. We evaluated the effect of terminal complement blockade with the anti-C5 monoclonal antibody eculizumab on biomarkers of cellular processes involved in TMA in patients with aHUS longitudinally, during up to 1 year of treatment, compared with in healthy volunteers. Biomarker levels were elevated at baseline in most patients, regardless of mutational status, plasma exchange/infusion use, platelet count, or lactate dehydrogenase or haptoglobin levels. Eculizumab reduced terminal complement activation (C5a and sC5b-9) and renal injury markers (clusterin, cystatin-C, β2-microglobulin, and liver fatty acid binding protein-1) to healthy volunteer levels and reduced inflammation (soluble tumor necrosis factor receptor-1), coagulation (prothrombin fragment F1+2 and d-dimer), and endothelial damage (thrombomodulin) markers to near-normal levels. Alternative pathway activation (Ba) and endothelial activation markers (soluble vascular cell adhesion molecule-1) decreased but remained elevated, reflecting ongoing complement activation in aHUS despite complete terminal complement blockade. These results highlight links between terminal complement activation and inflammation, endothelial damage, thrombosis, and renal injury and underscore ongoing risk for systemic TMA and progression to organ damage. Further research regarding underlying complement dysregulation is warranted. This trial was registered at www.clinicaltrials.gov as #NCT01194973.
authors.affiliation: Alexion Pharmaceuticals, Inc., Cheshire, CT.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Cofiell
authors.affiliation: Alexion Pharmaceuticals, Inc., Cheshire, CT.
authors.forename: Anjli
authors.initials: A
authors.lastname: Kukreja
authors.affiliation: Alexion Pharmaceuticals, Inc., Cheshire, CT.
authors.forename: Krystin
authors.initials: K
authors.lastname: Bedard
authors.affiliation: Alexion Pharmaceuticals, Inc., Cheshire, CT.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Alexion Pharmaceuticals, Inc., Cheshire, CT.
authors.forename: Angela P
authors.initials: AP
authors.lastname: Mickle
authors.affiliation: Alexion Pharmaceuticals, Inc., Cheshire, CT.
authors.forename: Masayo
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Alexion Pharmaceuticals, Inc., Cheshire, CT.
authors.forename: Camille L
authors.initials: CL
authors.lastname: Bedrosian
authors.affiliation: Alexion Pharmaceuticals, Inc., Cheshire, CT.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Faas
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000209:etiology; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D065766:Atypical Hemolytic Uremic Syndrome / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D003167:Complement Activation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D008297:Male; D013927:Thrombosis / Q000188:drug therapy / Q000209:etiology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; C481642:eculizumab
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