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Meszaros 2022 Abstract Bioblast

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6.6. «5 min»
Meszaros Andras
Meszaros Andras T, Hofmann J, Gnaiger E, Oberhuber R, Hautz T, Öfner D, Schneeberger S (2022) Pre-transplant mitochondrial respiration as a clinical prognostic marker during static cold storage and machine perfusion of the liver.
Bioblast 2022: BEC Inaugural Conference. In: »Watch the presentation«

Link: Bioblast 2022: BEC Inaugural Conference

Meszaros Andras, Hofmann Julia, Gnaiger Erich, Oberhuber R, Hautz T, Oefner D, Schneeberger Stefan (2022)

Event: Bioblast 2022

The growing demand for liver grafts promotes the use of extended criteria organs, but donor and organ biomarkers with strong predictive value in liver transplantation are lacking. To assure optimal clinical outcome, pre-transplantation evaluation of organ quality is needed. Bioenergetic performance during static cold storage (SCS) or machine perfusion (MP) may correlate with organ function after liver transplantation (LT) [1]. Martins et al. described a relationship between mitochondrial respiration, membrane potential and postoperative aminotransferase values and outcome of LT [2]. Flavin mononucleotide (FMN) in the perfusate as a damage marker during hypothermic MP has been proposed as biomarker by other groups [3]. We aimed at using a high-resolution approach to assess mitochondrial respiratory capacities during SCS and normothermic MP (NMP) and test for their predictive value towards the outcome in clinical liver transplantation.

High-resolution respirometry (HRR, O2k, Oroboros Instruments) was chosen to maximize resolution with minimal amount of tissue sample required (< 20 mg wet weight liver wedge biopsy) [4]. Mitochondrial respiration was characterized in tissue homogenates by assessing the succinate-linked coupling control. Mitochondrial parameters were then correlated with clinical outcome (“early allograft dysfunction”, EAD and “liver graft assessment following transplantation”, L-GrAFT scores). 43 liver allografts were enrolled in the SCS cohort, and 71 liver allografts were enrolled in the NMP cohort of prospective clinical studies. In the latter cohort, livers underwent NMP (OrganOx Metra) for up to 24 h, of which 47 livers were transplanted. Biopsy samples were collected at the end of SCS, at 1 h, 6 h and end of NMP.

HRR allowed the assessment of mitochondrial respiration within 2 h after sample collection. We observed a considerable variability in mitochondrial respiration between grafts after SCS and during NMP. In the cohort of SCS livers without NMP, P-L control efficiency correlated with EAD (0.8 in the group of initial function compared to 0.7 in EAD-livers; p = 0.02). For the NMP cohort, in the multivariate analysis, area-under-the-curve (AUC) values of LEAK respiration, cytochrome c and P-L control efficiencies during the first 6 h of NMP correlated with L-GrAFT.

There is a clear relationship between mitochondrial function/damage of the liver and clinical outcome upon transplantation, as was shown previously. FMN can be readily assessed in the perfusate during MP but not in SCS organs. Based on our results, in SCS livers, P-L control efficiency measured before transplantation correlates with EAD. During NMP, AUC values for markers of outer mitochondrial membrane damage, ATP synthesis efficiency and dissipative respiration during the first 6 h of NMP predict clinical outcome (L-GrAFT). Assessment of mitochondrial respiratory capacities by HRR is therefore a promising tool to select optimal grafts with or without machine perfusion.

  1. Hofmann J, Otarashvili G, Meszaros A, Ebner S, Weissenbacher A, Cardini B, Oberhuber R, Resch T, Öfner D, Schneeberger S, Troppmair J, Hautz T (2020) Restoring mitochondrial function while avoiding redox stress: the key to preventing ischemia/reperfusion injury in machine perfused liver grafts?
  2. Martins RM, Teodoro JS, Furtado E, Rolo AP, Palmeira CM, Tralhão JG (2019) Evaluation of bioenergetic and mitochondrial function in liver transplantation.
  3. Muller X, Schlegel A, Kron P, Eshmuminov D, Würdinger M, Meierhofer D, Clavien PA, Dutkowski P (2019) Novel real-time prediction of liver graft function during hypothermic oxygenated machine perfusion before liver transplantation.
  4. Doerrier C, Garcia-Souza LF, Krumschnabel G, Wohlfarter Y, Mészáros AT, Gnaiger E (2018) High-Resolution FluoRespirometry and OXPHOS protocols for human cells, permeabilized fibers from small biopsies of muscle, and isolated mitochondria.

Keywords: transplantation, liver, mitochondria, respiration, outcome

O2k-Network Lab: AT Innsbruck Schneeberger S

Affiliations and support

Meszaros AT1, Hofmann J1, Gnaiger E2, Oberhuber R1, Hautz T1, Öfner D1, Schneeberger S1
  1. organLife, Organ Regeneration Center of Excellence and Daniel Swarovski Research Laboratory, Dept Visceral, Transplant and Thoracic Surgery, Medical Univ Innsbruck, Innsbruck, Austria - [email protected]
  2. Oroboros Instruments, Innsbruck, Austria

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