The promise of hypothermic machine perfusion for liver allografts

20 November 2014  //  News

As the gap between the supply and demand of available liver allografts for transplant continues to grow, technologies in place for organ preservation and organ resuscitation ahead of transplant continue to be explored and refined. The accepted methods of static cold storage (SCS) and hypothermic machine perfusion (HMP) remain the mainstay of clinical organ preservation for all vascularized organs including kidney, heart, lung, liver, pancreas, intestine, and pancreatic islets.1 And while SCS is an acknowledged approach for all of these organs, only in kidney preservation has HMP seen widespread clinical application.1 Nonetheless, HMP is proving to be an emerging technology for other allografts, with a growing body of work exploring and likely justifying its use in all of the non-renal solid organs.1 With liver allografts in particular, HMP offers the promise of substantial advantages over SCS, and its application may lead to transformational change in liver transplantation.1

The biggest potential impact of hypothermic machine perfusion use over the current standard of static cold storage is expansion of the donor pool.2,3 Marginal (expanded) allografts, either because of steatosis or advanced age, could be converted into allografts that transplant teams would accept with confidence. Data supporting the approach of “resuscitated” allografts have been most convincingly produced by the group at Columbia University Medical Center, New York, USA in terms of clinical performance of these grafts as well as biochemical proof of concept (HMP allografts are more resistant to ischemia-reperfusion injury, have increased levels of stored adenosine tri-phosphate (ATP), show lower levels of inflammatory cytokines, lower peak post-transplant transaminases, improved renal function, and shorter hospital stays).4 Moreover, HMP may be the tool to allow transplant teams to consistently transplant donation after circulatory death (DCD) livers, both controlled and, potentially, uncontrolled.

Hypothermic machine perfusion use for liver allografts may also confer substantial health economic advantages to the present transplant center structure. If the current practice of allowing increased cold ischemia times in the kidney allograft can safely be translated to the liver, the few extra hours gained would allow transplants to be performed during regular (non-emergency) hours, reducing personnel costs and providing rested surgical teams for these critical operations. Such a shift was observed in the transplant community when SCS shifted from Euro Collins to UW Solution for liver preservation. Extrapolating from the kidney experience, HMP of livers should be expected to lower delayed graft function (DGF) rates as well as improve graft survival rates at 12 months.4 With the protracted hospitalization often brought on by delayed liver allograft function, the advantages conferred by HMP would be expected to translate into quicker patient recoveries as well as shorter hospital stays.4 In some studies, machine preservation of kidneys was found to be cheaper and generated more quality-adjusted life years than SCS,1 an enticing possibility to consider for the liver transplant recipient.

In the United States, the liver transplant community is in under increasing regulatory pressure to allocate livers over broader geographic areas. Implementation of the “Share 35” rule in mid-2013 has meant allografts now travel greater distances prior to implantation. The current push to create larger geographic regions, with the goal of equalizing waiting time across the country, will inevitably stretch the limits of currently accepted cold ischemia times. Broad adoption of HMP, perhaps with livers traveling while being perfused, is the most likely of the existing or emerging technologies to be effective in support of this regulatory mandate.

Possibly the most enticing characteristics of HMP, as applied to liver allografts, are the ability to therapeutically modulate the graft as well as to enhance the diagnostic capabilities of the transplant teams as they struggle with the decision to use or discard a particular liver. The application of additional gases to the perfusion circuit (“persufflation” with either oxygen or nitrous oxide) has generated exciting experimental data supporting this approach to reduce damage from reperfusion injury to the liver. The addition of oxygen to persufflation may be critical in preserving or restoring mitochondrial ATP levels. This simple modification merits broader clinical testing. Hypothermic machine perfusion offers, for the first time, the possibility for the clinician to assess the quality and expected performance of an allograft after procurement but ahead of implantation beyond the very crude metrics of gross and histologic appearance of the organ. Real-time testing of the perfusion effluent for aspartate amino transferase (AST) concentration, tissue ATP, liver fatty-acid binding protein (L-FABP) as hepatic viability markers may become critical components of allograft assessment. The existing technology of microdialysis may be used to continually monitor the metabolic changes in an allograft, as has already been shown in large-animal studies. Finally, a perfused liver allograft may be the right environment to receive, while perfused, treatment with molecules that attenuate ischemia-reperfusion injury, such as ‘small interfering RNA’, currently being tested in kidney transplants.

In short, the liver transplant community worldwide is poised to benefit immensely from the extension of the proven technology of HMP previously applied extensively only in kidney transplants. Such an evolution will undoubtedly move the field forward and benefit the patients served by transplantation.

 

 Expected benefits of HMP1-4

  • Expansion of deceased-donor organ pool
  • Supply of nutrients and supplemental oxygen to meet energy needs
  • Elimination of toxic by-products of metabolism
  • Allows addition of cyto-protective medicinal and / or immune-modulating agents
  • Allows for real-time evaluation of suitability of allograft for transplant
  • May extend cold ischemic time without sacrificing allograft function, improving schedule logistics
  • May lead to decreased delayed allograft function with commensurate reduction in health care costs

 

  1. Taylor MJ, Simona CB. Current State of Hypothermic Machine Perfusion Preservation of Organs: The Clinical Perspective. Cryobiology 2010;60(3 Suppl):S20–35.
  2. Bond M et al. The Effectiveness and Cost-Effectiveness of Methods of Storing Donated Kidneys from Deceased Donors: a Systematic Review and Economic Model. Health Technol Assess 2009;13(38):iii-iv, xi-xiv, 1–156.
  3. Moers C et al. Machine Perfusion or Cold Storage in Deceased-Donor Kidney Transplantation. N Engl J Med 2009;360(1):7–19.
  4. Graham JA, Guarrera JV. Resuscitation of marginal Liver Allografts for Transplantation with Machine Perfusion Technology. Journal of Hepatology 2014 [Epub ahead of print].