Challenges in early clinical drug development for ischemia-reperfusion injury in kidney transplantation

Abstract

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.

Keywords:

• ischemia-reperfusion injury
• kidney
• transplantation

Acknowledgments

JA Ross and EM Harrison contributed equally to this work.

Declaration of interest

S O’Neill is supported by the Medical Research Council. Furthermore, J Hughes, EM Harrison and SJ Wigmore have served on the advisory board for GlaxoSmithKline. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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