Rewarming Injury after Cold Preservation

Thomas Minor,Charlotte Von Horn

doi:10.3390/ijms20092059

Thomas Minor, Charlotte Von Horn

Open Access

https://doi.org/10.3390/ijms20092059

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Abstract

Organ dysfunction pertinent to tissue injury related to ischemic ex vivo preservation during transport from donor to recipient still represents a pivotal impediment in transplantation medicine. Cold storage under anoxic conditions minimizes metabolic activity, but eventually cannot prevent energetic depletion and impairment of cellular signal homeostasis. Reoxygenation of anoxically injured tissue may trigger additional damage to the graft, e.g., by abundant production of oxygen free radicals upon abrupt reactivation of a not yet equilibrated cellular metabolism. Paradoxically, this process is driven by the sudden restoration of normothermic conditions upon reperfusion and substantially less pronounced during re-oxygenation in the cold. The massive energy demand associated with normothermia is not met by the cellular systems that still suffer from hypothermic torpor and dys-equilibrated metabolites and eventually leads to mitochondrial damage, induction of apoptosis and inflammatory responses. This rewarming injury is partly alleviated by preceding supply of oxygen already in the cold but more effectively counteracted by an ensuing controlled and slow oxygenated warming up of the organ prior to implantation. A gentle restitution of metabolic turnover rates in line with the resumption of enzyme kinetics and molecular homeostasis improves post transplantation graft function and survival.

Highlights

Preservation/reperfusion injury still represents a major denominator of graft dysfunction after transplantation
We will give a synoptic perspective on emerging knowledge concerning the role of this “rewarming injury” in the context of organ preservation, molecular backgrounds and first strategies to minimize its repercussions in clinical routine
Oxidative stress is recognized as a trigger to apoptotic transformation and cell death [6]. This so-called oxygen paradox [6] mainly acts on three sources of oxygen free radicals (OFR) generation: Breakdown products like xanthine or hypoxanthine, that unnaturally accumulate during anoxic catabolism of high energy phosphates [7] can be metabolized at very high rates by xanthine oxidase (XOD), a radical generating isoform of the enzyme xanthine dehydrogenase (XDH) induced during ischemia [8]

Summary

Introduction

Preservation/reperfusion injury still represents a major denominator of graft dysfunction after transplantation. Limited quality of grafts from extended criteria donors, warm ischemia upon donation after cardiac standstill and extended times of preservation are frequent exponents that adversely affect the functional resilience of the organ during the period of ex vivo storage. It seems likely, that the existing preservation technology should be further developed to comply with the future requirements in the evolving field of graft preservation and conditioning. That the existing preservation technology should be further developed to comply with the future requirements in the evolving field of graft preservation and conditioning To this prospect, a thorough understanding of pathophysiologic issues pertinent to preservation/reperfusion injury will be crucial. We will give a synoptic perspective on emerging knowledge concerning the role of this “rewarming injury” in the context of organ preservation, molecular backgrounds and first strategies to minimize its repercussions in clinical routine

Cold Ischemic Preservation

Reoxygenation Injury

Mitigation of Rewarming Injury

Conclusions