title: Pharmacological targeting of C5a receptors during organ preservation improves kidney graft survival.
abstract: Cadaveric renal transplants suffer frequently from delayed graft function, which is associated with increased risk for long-term graft survival loss. One-third of kidney grafts that are stored in current organ preservation solutions experience delayed graft function, demonstrating the urgent need for improvement. Although ischaemic graft injury is complex in nature, complement activation is considered important to the process. Here we show that pharmacological targeting of the complement 5a receptor (C5aR) during cold ischaemia has a protective effect on early kidney graft survival, inflammation and apoptosis in a mouse model of syngeneic kidney transplantation. Graft survival of kidneys that were stored in University of Wisconsin solution in the presence of a C5aR antagonist increased from 29% to 57%. Increased graft survival was associated with less tubular damage and apoptosis, protection from sustained C5aR expression and decreased production of tumour necrosis factor-alpha and macrophage inflammatory protein-2. In a translational approach, we determined C5aR expression in paediatric living-related and cadaveric allografts. C5aR expression was significantly higher in all compartments of kidneys from cadaveric compared with kidneys from living-related donors. C5aR expression in cadaveric kidneys correlated positively with cold ischaemia time, renal dysfunction and the frequency of apoptotic tubular cells, suggesting a novel role for C5a in delayed graft function pathogenesis. Supplementing organ preservation solutions with C5aR inhibitors may improve early graft function following cadaveric kidney transplantation.
authors.affiliation: Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Lewis
authors.forename: G
authors.initials: G
authors.lastname: Köhl
authors.forename: Q
authors.initials: Q
authors.lastname: Ma
authors.forename: P
authors.initials: P
authors.lastname: Devarajan
authors.forename: J
authors.initials: J
authors.lastname: Köhl
mesh_terms: D000818:Animals; D017209:Apoptosis; D002648:Child; D015936:Complement C5a / Q000378:metabolism; D006085:Graft Survival; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016030:Kidney Transplantation; D051379:Mice; D009926:Organ Preservation / Q000379:methods*; D019188:Organ Preservation Solutions / Q000494:pharmacology; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D013194:Staining and Labeling; D014185:Transplantation, Isogeneic
chemical_list: D019188:Organ Preservation Solutions; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a