title: Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters.
abstract: Approximately 350,000 individuals in the United States rely on maintenance hemodialysis treatment because of end-stage renal disease. Despite improvements in dialysis technology, the mortality rate for patients treated with maintenance dialysis is still exceptionally high, with a 5-year survival rate of only 35%. Many patients succumb to conditions resulting at least in part from the chronic induction of inflammation. Among the triggers of inflammation, the complement system is of particular importance, being a well-appreciated mediator of inflammatory processes that is involved in many pathologic states. Here we used a refined pre-clinical model of hemodialysis in cynomolgus monkeys to confirm that even modern, polymer-based hemodialysis filters activate complement and to evaluate the potential of Cp40, a peptidic C3 inhibitor, to attenuate hemodialysis-induced complement activation. Our data show marked induction of complement activation even after only a single session of hemodialysis. Importantly, complete inhibition of complement activation was achieved in response to two distinct Cp40 treatment regimens. Further, we show that application of Cp40 during hemodialysis resulted in increased levels of the anti-inflammatory cytokine IL-10, indicating that Cp40 may be a potent and cost-effective treatment option for attenuating chronic inflammatory conditions in dialysis-dependent patients.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, USA.
authors.forename: Edimara S
authors.initials: ES
authors.lastname: Reis
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: DeAngelis
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Simian Conservation Breeding and Research Center (SICONBREC), Makati City, Philippines.
authors.forename: Ranillo R G
authors.initials: RR
authors.lastname: Resuello
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricklin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, USA. Electronic address: lambris@upenn.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
mesh_terms: D000818:Animals; D003167:Complement Activation / Q000187:drug effects* / Q000276:immunology; D003176:Complement C3 / Q000037:antagonists & inhibitors* / Q000276:immunology; D016753:Interleukin-10 / Q000097:blood; D008252:Macaca fascicularis; D008851:Micropore Filters / Q000009:adverse effects*; D023421:Models, Animal; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D006435:Renal Dialysis / Q000009:adverse effects*
chemical_list: D003176:Complement C3; D010455:Peptides; D016753:Interleukin-10
keywords: C3; Complement; Compstatin; Cp40; Hemodialysis