Ischemic Preconditioning in Liver Transplantation: Lost in Translation?

This article refers to:

Impact of Three Methods of Ischemic Preconditioning on Ischemia-Reperfusion Injury in a Pig Model of Liver Transplantation

Advanced ischemia-reperfusion injury (IRI) is a serious complication following liver transplantation or after liver resections requiring the intraoperative clamping of the liver pedicle, as it can lead to liver failure or primary graft dysfunction or non-function. The duration of ischemia and the quality of liver parenchyma are its key determinants and risk factors. Given the increase in morbidity and mortality caused by liver IRI, a large volume of research was directed toward understanding its mechanisms and identifying protective strategies against it, including refinements in organ preservation strategies or various pharmacologic approaches. Another attractive option explored in various models of warm and cold ischemia as well as in several clinical trials is ischemic preconditioning (IP), an intriguing biological phenomenon shown to trigger several endogenous mechanisms of protection in different organs [1–3]. This cheap, straightforward and apparently safe approach where short episodes of non-lethal ischemia provided protection against the effects of a subsequent longer, more damaging ischemia spurred extensive animal and clinical investigations with encouraging yet often conflicting results [4].

Numerous experimental studies and several clinical trials have confirmed the value of IP as a protective strategy against warm liver IRI [4, 5]. However, the evidence diverges and the ischemic protection seems less consistent and effective when the conditioned liver is removed from its initial owner and transplanted into another individual. Whereas LTX in rodents has been repeatedly shown to result in milder biochemical and histologic injury and improved animal survival [1], the clinical experience shows a limited benefit as several studies reported an improved tolerance to IRI on based on transaminase leak or the histological findings of preconditioned grafts but no meaningful impact on graft function or graft and patient survival [6, 7] Moreover, some reports cautioned that in spite of biochemical improvements in IRI, recipients of IP livers showed inferior graft function, fueling the speculations about a differential response of IP between warm IRI and post-transplant IRI which may go as far as to adversely affect allograft function [6].

In this issue Belon et al. join the controversy and present the results of a porcine study where three different preconditioning strategies were applied in connection to liver transplantation [8]. The authors explored three IP protocols differing widely in the putative protective mechanisms, namely direct donor preconditioning, indirect, remote recipient preconditioning and, finally, combined direct donor and indirect recipient preconditioning. In all three IP groups the preconditioning protocol consisted of three cycles with 5 minutes of ischemia followed by 5 minutes of reperfusion. The “remote organ” used for preconditioning was the entire small intestine, a large and highly reactive territory expected to respond rapidly to the iterative ischemic stimulus.

Although it is unclear when remote IP was performed in relationship to graft reperfusion in the group combining donor and recipient conditioning (before recipient hepatectomy or after graft reperfusion), the graft was submitted to the remote stimulus after reperfusion, making this protocol to correspond to a post-conditioning approach. Hence, this the study explores 2 preconditioning strategies, combining pre- and post-conditioning. Intriguingly, the results show a trend toward a more advanced bile duct injury when splanchnic, remote, IP was attempted.

Interestingly, several similar molecular changes induced by preconditioning (upregulation of anti-apoptotic genes, alterations of the nitric oxide metabolism) were reported earlier in a small clinical trial, validating and linking this porcine experiment to clinical observations [9]. Although the French group claimed, somehow unsubstantiated, that ischemic preconditioning protects against liver IR, Belon et al. genuinely conclude that none of their preconditioning protocols appear suitable for further use in the clinic. This appears as a reasonable advice as no obvious benefit of IP nor a trend toward has become apparent, in spite of extending the observations beyond the target organ and examining the recipient lungs, intestine and kidneys.

Apart of the low number of animals in each groups, the study has several other limitations and caveats. The use of a without veno-venous by-pass may have resulted in up to two hours of splanchnic stasis which may have added a degree of intestinal injury to the model. The relatively short cold ischemia may have induced only a limited liver injury so that the effect of IP remained less evident.

Whereas transplant surgeons remain enthralled by the potential of a simple, straightforward method to prevent post-ischemic graft dysfunction, there is no experimental nor clinical consensus about the best method of ischemic conditioning as regarding the number of ischemic cycles, the effective ischemic time required to induce the protective stimulus, or the choice of the preconditioned organ to maximize the beneficial effects of IP. This study uses a “5 minutes x3” preconditioning protocol frequently used experimentally [4]. Moreover, it is clinically relevant and acceptable, as it would probably not induce excessive organ injury, it would not take too much time to apply and has been previously used in clinical trials [10]. However, the translation of preconditioning protocols that work satisfactorily in liver surgery into transplantation setting may prove disappointing [6, 10]. We speculate that part of the explanation is due to organ perfusion or cooling which may remove protective factors from the organ or may interfere with various intracellular signaling pathways or protein synthesis. In addition, an excessive ischemic injury due to prolonged cold ischemia may override any mild protection given by preconditioning.

Some additional answers could be offered by the ongoing Finnish RIPTRANS study, a multicentre trial using a remote ischemic preconditioning protocol similar to that presented herein and performed twice on the thigh of brain-dead organ donors before procurement [11]. As the trial will study the recipients of kidneys and livers as well as hearts and lungs from randomly preconditioned donors, a wealth of data should be available in the near future and should answer the question whether translating ischemic preconditioning in clinical transplantation is feasible or not.

Disclosure statement

No potential conflict of interest was reported by the author(s).