A proof of concept study on real-time LiMAx CYP1A2 liver function assessment of donor grafts during normothermic machine perfusion

AbstractNo single reliable parameter exists to assess liver graft function of extended criteria donors during ex-vivo normothermic machine perfusion (NMP). The liver maximum capacity (LiMAx) test is a clinically validated cytochromal breath test, measuring liver function based on 13CO2 production. As an innovative concept, we aimed to integrate the LiMAx breath test with NMP to assess organ function. Eleven human livers were perfused using NMP. After one hour of stabilization, LiMAx testing was performed. Injury markers (ALT, AST, miR-122, FMN, and Suzuki-score) and lactate clearance were measured and related to LiMAx values. LiMAx values ranged between 111 and 1838 µg/kg/h, and performing consecutive LiMAx tests during longer NMP was feasible. No correlation was found between LiMAx value and miR-122 and FMN levels in the perfusate. However, a significant inverse correlation was found between LiMAx value and histological injury (Suzuki-score, R = − 0.874, P < 0.001), AST (R = − 0.812, P = 0.004) and ALT (R = − 0.687, P = 0.028). Furthermore, a significant correlation was found with lactate clearance (R = 0.683, P = 0.043). We demonstrate, as proof of principle, that liver function during NMP can be quantified using the LiMAx test, illustrating a positive correlation with traditional injury markers. This new breath-test application separates livers with adequate cytochromal liver function from inadequate ones and may support decision-making in the safe utilization of extended criteria donor grafts.

Download Full-text

Twenty-four hour ex-vivo normothermic machine perfusion in rat livers

TECHNOLOGY ◽

10.1142/s2339547820500028 ◽

2020 ◽

pp. 1-10

Author(s):

Omar Haque ◽

Casie A. Pendexter ◽

Stephanie E.J. Cronin ◽

Siavash Raigani ◽

Reiner J. de Vries ◽

...

Keyword(s):

Rat Liver ◽

Ex Vivo ◽

Liver Perfusion ◽

Therapeutic Interventions ◽

Liver Graft ◽

Large Animal ◽

Machine Perfusion ◽

Normothermic Machine Perfusion ◽

Organ Quality ◽

Rat Livers

Ex-vivo liver perfusion (EVLP) is an ideal platform to study liver disease, therapeutic interventions, and pharmacokinetic properties of drugs without any patient risk. Rat livers are an ideal model for EVLP due to less organ quality variability, ease of hepatectomy, well-defined molecular pathways, and relatively low costs compared to large animal or human perfusions. However, the major limitation with rat liver normothermic machine perfusion (NMP) is maintaining physiologic liver function on an ex-vivo machine perfusion system. To address this need, our research demonstrates 24-hour EVLP in rats under normothermic conditions. Early (6 hour) perfusate transaminase levels and oxygen consumption of the liver graft are shown to be good markers of perfusion success and correlate with viable 24-hour post-perfusion histology. Finally, we address overcoming challenges in long-term rat liver perfusions such as rising intrahepatic pressures and contamination, and offer future directions necessary to build upon our work.

Download Full-text

Improving Liver Graft Function Using CD47 Blockade in the Setting of Normothermic Machine Perfusion

Transplantation Journal ◽

10.1097/tp.0000000000003688 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Sandra Garcia-Aroz ◽

Min Xu ◽

Ola Ahmed ◽

Joshua Hollingshead ◽

Xuanchuan Wang ◽

...

Keyword(s):

Graft Function ◽

Liver Graft ◽

Machine Perfusion ◽

Normothermic Machine Perfusion

Download Full-text

Hyperspectral imaging for ex-vivo organ characterization during normothermic machine perfusion

European Urology Supplements ◽

10.1016/s1569-9056(18)31366-6 ◽

2018 ◽

Vol 17 (2) ◽

pp. e767 ◽

Cited By ~ 1

Author(s):

W. Markgraf ◽

M.W.W. Janssen ◽

J. Lilienthal ◽

P. Feistel ◽

C. Thiele ◽

...

Keyword(s):

Hyperspectral Imaging ◽

Ex Vivo ◽

Machine Perfusion ◽

Normothermic Machine Perfusion

Download Full-text

Assessment of liver function: pre- and peritransplant evaluation

Clinical Chemistry ◽

10.1093/clinchem/43.8.1539 ◽

1997 ◽

Vol 43 (8) ◽

pp. 1539-1545 ◽

Cited By ~ 20

Author(s):

Abraham Shaked ◽

Fredrick A Nunes ◽

Kim M Olthoff ◽

Michael R Lucey

Keyword(s):

Liver Function ◽

Graft Function ◽

Terminal Condition ◽

High Rate ◽

Liver Graft ◽

Therapeutic Modality ◽

Donor Liver ◽

Laboratory Assessment ◽

Residual Liver Function ◽

End Stage

Abstract Liver transplantation has been demonstrated to be a successful therapeutic modality for patients with end-stage liver disease. The high rate of survival for an otherwise terminal condition has resulted in significant expansion of the indications and diseases treated by this procedure, and is hampered only by the limited numbers of organs available for transplantation. Efforts in clinical and laboratory medicine should be directed to identify candidates who would benefit most from this procedure, to provide better means for accurate assessment of liver reserve and the appropriate timing for transplantation, to identify quality liver grafts that would have the potential to tolerate cold preservation and reperfusion injury, and to assist in accurate monitoring of graft function immediately after transplantation. The aim of this manuscript is to describe the existing pathways for clinical and laboratory assessment of pretransplant residual liver function, the donor liver graft, and immediate posttransplantation function.

Download Full-text

Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts?

International Journal of Molecular Sciences ◽

10.3390/ijms21093132 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3132 ◽

Cited By ~ 3

Author(s):

Julia Hofmann ◽

Giorgi Otarashvili ◽

Andras Meszaros ◽

Susanne Ebner ◽

Annemarie Weissenbacher ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ex Vivo ◽

Ischemia Reperfusion ◽

Graft Function ◽

Ros Production ◽

Machine Perfusion ◽

Redox Stress ◽

Molecular Events ◽

Regulate Cell Death

Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.

Download Full-text