title: Challenges in early clinical drug development for ischemia-reperfusion injury in kidney transplantation.
abstract: BACKGROUND
  In an effort to expand the donor pool, kidneys from donation after cardiac death (DCD) donors are increasingly utilised in renal transplantation. These kidneys suffer greater ischemia-reperfusion injury (IRI) and have a higher incidence of delayed graft function. In the last 25 years, relatively few pharmacological therapies to reduce IRI have been tested in randomised controlled trials in renal transplantation and currently no pharmacological agents are routinely utilised for this purpose.
  
  
  METHODS
  The authors look at why promising treatments in pre-clinical studies have not translated to significant clinical benefit in human trials. This may reflect a translational disconnect between the pre-clinical models used and clinical problems that are encountered in the transplant population. They also discuss the issues in conducting clinical trials and its implication on drug development.
  
  
  CONCLUSIONS
  Translating pharmacological strategies for reducing IRI is highly challenging at every stage of development from pre-clinical studies to clinical trials. Scientific knowledge of the complexity of IRI is rapidly evolving and new treatments are expected to emerge. There are ethical barriers that prevent donor treatments, particularly in the DCD setting. However, new clinical techniques such as normothermic regional and ex-vivo perfusion represent exciting opportunities to utilise pharmacological agents earlier in the process of transplantation.
authors.affiliation: University of Edinburgh, Chancellor's Building, MRC Centre for Inflammation Research, Tissue Injury and Repair Group, Royal Infirmary of Edinburgh , 49 Little France Crescent, Edinburgh EH16 4SA , UK +44 78 4959 2113 ; +44 13 1242 6520 ; stephenoneill@doctors.org.uk.
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Neill
authors.forename: Kevin
authors.initials: K
authors.lastname: Gallagher
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hughes
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Wigmore
authors.forename: James A
authors.initials: JA
authors.lastname: Ross
authors.forename: Ewen M
authors.initials: EM
authors.lastname: Harrison
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D016030:Kidney Transplantation / Q000379:methods*; D016032:Randomized Controlled Trials as Topic; D015427:Reperfusion Injury / Q000517:prevention & control*; D057170:Translational Research, Biomedical / Q000458:organization & administration
keywords: ischemia-reperfusion injury; kidney; transplantation