Addressing the Donor Liver Shortage with <i>EX VIVO</i> Machine Perfusion

Izamis, Maria-Louisa; Berendsen, Tim; Uygun, Korkut; Yarmush, Martin L.

doi:10.1260/2040-2295.3.2.279

Cited by 6 publications

(4 citation statements)

References 145 publications

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“…Machine perfusion (MP) has been employed at the end of ischemia to recover organs prior to transplantation, improving both the quality of organs after preservation and transplant outcome (5–8). In addition, MP allows the realtime measurement of parameters that correlate with graft quality, which facilitates more informed and objective decision making in the organ allocation process (9, 10). As a result, MP potentially reduces the unnecessary discarding of viable livers.…”

Section: Introductionmentioning

confidence: 99%

Determination and Extension of the Limits to Static Cold Storage using Subnormothermic Machine Perfusion

et al. 2013

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Purpose Static cold storage (SCS) of the liver for transplantation is limited by time. Continuation of metabolic activity leads to depletion of energy stores and loss of cellular function, which results in poor post-transplant function. Machine perfusion (MP) applied at the end of preservation may improve the viability of marginal liver grafts and provides information on the quality of the organ. We attempt to define the limits to SCS in terms of easily measurable perfusion parameters and investigate whether MP can improve liver viability. Methods Rat livers were cold-stored for 0, 24, 48, 72, and 120 hours, after which they were treated with subnormothermic machine perfusion (SNMP). Livers cold-stored for 48 and 72 hours were transplanted orthotopically with or without SNMP. During SNMP easily measurable parameters were monitored and adenosine triphosphate (ATP) content was measured following preservation and SNMP. Results ATP increased significantly during SNMP, but the recovered ATP content deteriorated with increased duration of SCS, with minimal improvement after 72 hours of SCS. Vascular resistance during SNMP increased with extended preservation. After 48 hours of SCS, orthotopic transplantation survival increased significantly from 50% to 100% with SNMP, but did not improve after 72 hours. Conclusions Vascular resistance and ATP recovery suggest a decrease in viability after 48 hours of SCS. Survival data confirms the loss of post-transplant graft function and supports the use of ATP and vascular resistance as useful indicators. Further, we show that the recoverability of a liver using SNMP is limited to 48 hours of SCS.

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Section: Introductionmentioning

confidence: 99%

Determination and Extension of the Limits to Static Cold Storage using Subnormothermic Machine Perfusion

et al. 2013

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“…While NMP is ideal for mimicking physiological parameters, from a clinical applicability perspective it is more complicated compared to SCS, creating a bottleneck for wide-spread adoption [13]. Sub-normothermic (~20°C) machine perfusion (SNMP) preservation is an alternative that is simpler in practice [6;7].…”

Section: Introductionmentioning

confidence: 99%

Perfusion Defatting at Subnormothermic Temperatures in Steatotic Rat Livers

Liu¹,

Berendsen²,

Izamis³

et al. 2013

Transplantation Proceedings

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Hepatic steatosis is a major risk factor in liver transplantation. Use of machine perfusion to reduce steatosis has been reported previously at normothermic (37°C) temperatures, with minimal media as well as specialized defatting cocktails. In this work, we tested if sub-normothermic (room temperature) machine perfusion, a more practical version of machine perfusion approach that does not require temperature control or oxygen carriers could also be employed to reduce fat content in steatotic livers. Steatotic livers recovered from obese Zucker rats were perfused for 6 hours. A significant increase of very-low density protein (VLDL) and triglyceride (TG) content in perfusate, with or without a defatting cocktail, was observed although the changes in histology were minimal and changes in intracellular TG content were not statistically significant. The differences in oxygen uptake rate, VLDL secretion, TG secretion, venous resistance were similar in both groups. This study confirms lipid export during sub-normothermic machine perfusion, however the duration of perfusion necessary appears much higher than required in normothermic perfusion.

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“…An area of keen investigation is into the use of machine perfusion (MP) as a means of resuscitating presently non-transplantable donor organs after cardiac death (DCD), thereby significantly increasing the donor organ pool [1], [2]. Porcine and murine models of DCD livers are significantly improved by MP compared to organs preserved by the gold standard of static cold storage [3], and furthermore, normothermic machine perfusion (NMP) is necessary for their successful transplantation [4], [5], [6], [7].…”

Section: Introductionmentioning

confidence: 99%

Resuscitation of Ischemic Donor Livers with Normothermic Machine Perfusion: A Metabolic Flux Analysis of Treatment in Rats

et al. 2013

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Normothermic machine perfusion has previously been demonstrated to restore damaged warm ischemic livers to transplantable condition in animal models. However, the mechanisms of recovery are unclear, preventing rational optimization of perfusion systems and slowing clinical translation of machine perfusion. In this study, organ recovery time and major perfusate shortcomings were evaluated using a comprehensive metabolic analysis of organ function in perfusion prior to successful transplantation. Two groups, Fresh livers and livers subjected to 1 hr of warm ischemia (WI) received perfusion for a total preservation time of 6 hrs, followed by successful transplantation. 24 metabolic fluxes were directly measured and 38 stoichiometrically-related fluxes were estimated via a mass balance model of the major pathways of energy metabolism. This analysis revealed stable metabolism in Fresh livers throughout perfusion while identifying two distinct metabolic states in WI livers, separated at t = 2 hrs, coinciding with recovery of oxygen uptake rates to Fresh liver values. This finding strongly suggests successful organ resuscitation within 2 hrs of perfusion. Overall perfused livers regulated metabolism of perfusate substrates according to their metabolic needs, despite supraphysiological levels of some metabolites. This study establishes the first integrative metabolic basis for the dynamics of recovery during perfusion treatment of marginal livers. Our initial findings support enhanced oxygen delivery for both timely recovery and long-term sustenance. These results are expected to lead the optimization of the treatment protocols and perfusion media from a metabolic perspective, facilitating translation to clinical use.

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Addressing the Donor Liver Shortage with EX VIVO Machine Perfusion

Cited by 6 publications

References 145 publications

Determination and Extension of the Limits to Static Cold Storage using Subnormothermic Machine Perfusion

Determination and Extension of the Limits to Static Cold Storage using Subnormothermic Machine Perfusion

Perfusion Defatting at Subnormothermic Temperatures in Steatotic Rat Livers

Resuscitation of Ischemic Donor Livers with Normothermic Machine Perfusion: A Metabolic Flux Analysis of Treatment in Rats

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