Pharmacological targeting of C5a receptors during organ preservation improves kidney graft survival
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Updated: Jul 5, 2026
Normothermic Ex Vivo Kidney Perfusion for the Preservation of Kidney Grafts prior to Transplantation
Published on: July 15, 2015
1Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, OH 45229, USA.
Insights
Targeting the complement 5a receptor (C5aR) during cold ischemia improved kidney graft survival by reducing damage and inflammation. This suggests C5aR inhibitors could enhance outcomes for cadaveric kidney transplants.
Area of Science:
- Nephrology
- Immunology
- Transplantation Biology
Background:
- Delayed graft function (DGF) is a significant complication in cadaveric renal transplants, increasing long-term graft survival loss.
- Current organ preservation solutions have limited efficacy, with one-third of stored kidney grafts experiencing DGF.
- Complement activation plays a crucial role in the complex process of ischemic graft injury.
Purpose of the Study:
- To investigate the protective effect of pharmacologically targeting the complement 5a receptor (C5aR) during cold ischemia on kidney graft survival.
- To evaluate the impact of C5aR inhibition on inflammation and apoptosis in a mouse model of kidney transplantation.
- To assess C5aR expression in human kidney allografts and its correlation with graft function and ischemia time.
Main Methods:
- Utilized a mouse model of syngeneic kidney transplantation, storing grafts in University of Wisconsin solution with or without a C5aR antagonist.
- Assessed graft survival, tubular damage, apoptosis, C5aR expression, and inflammatory markers (TNF-α, MIP-2).
- Analyzed C5aR expression in human pediatric living-related and cadaveric kidney allografts, correlating findings with cold ischemia time and renal dysfunction.
Main Results:
- Graft survival increased from 29% to 57% in kidneys treated with a C5aR antagonist during cold storage.
- Treatment reduced tubular damage, apoptosis, sustained C5aR expression, and production of TNF-α and MIP-2.
- Cadaveric allografts exhibited significantly higher C5aR expression than living-related allografts, correlating positively with cold ischemia time, dysfunction, and apoptosis.
Conclusions:
- Pharmacological targeting of C5aR during cold ischemia offers a protective effect on early kidney graft survival.
- C5aR plays a significant role in the pathogenesis of DGF, particularly in cadaveric kidney transplantation.
- Supplementing organ preservation solutions with C5aR inhibitors represents a promising strategy to improve outcomes for kidney transplant recipients.
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.
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