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. 2024 Jul 1:3:1353124.
doi: 10.3389/frtra.2024.1353124. eCollection 2024.

Gradual rewarming with a hemoglobin-based oxygen carrier improves viability of donation after circulatory death in rat livers

Paria Mahboub  1   2   3 , Mohamed Aburawi  3   4 , O Sila Ozgur  2   3 , Casie Pendexter  2   3 , Stephanie Cronin  2   3 , Florence Min Lin  3 , Rohil Jain  2   3 , Murat N Karabacak  2   3 , Negin Karimian  2   3 , Shannon N Tessier  2   3 , James F Markmann  4 , Heidi Yeh  4 , Korkut Uygun  2   3
Affiliations

Gradual rewarming with a hemoglobin-based oxygen carrier improves viability of donation after circulatory death in rat livers

Paria Mahboub et al. Front Transplant. .

Abstract

Background: Donation after circulatory death (DCD) grafts are vital for increasing available donor organs. Gradual rewarming during machine perfusion has proven effective in mitigating reperfusion injury and enhancing graft quality. Limited data exist on artificial oxygen carriers as an effective solution to meet the increasing metabolic demand with temperature changes. The aim of the present study was to assess the efficacy and safety of utilizing a hemoglobin-based oxygen carrier (HBOC) during the gradual rewarming of DCD rat livers.

Methods: Liver grafts were procured after 30 min of warm ischemia. The effect of 90 min of oxygenated rewarming perfusion from ice cold temperatures (4 °C) to 37 °C with HBOC after cold storage was evaluated and the results were compared with cold storage alone. Reperfusion at 37 °C was performed to assess the post-preservation recovery.

Results: Gradual rewarming with HBOC significantly enhanced recovery, demonstrated by markedly lower lactate levels and reduced vascular resistance compared to cold-stored liver grafts. Increased bile production in the HBOC group was noted, indicating improved liver function and bile synthesis capacity. Histological examination showed reduced cellular damage and better tissue preservation in the HBOC-treated livers compared to those subjected to cold storage alone.

Conclusion: This study suggests the safety of using HBOC during rewarming perfusion of rat livers as no harmful effect was detected. Furthermore, the viability assessment indicated improvement in graft function.

Keywords: HBOC; cold storage; donation after cardiac death (DCD); gradual rewarming; machine perfusion.

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Conflict of interest statement

KU is inventor on pending patents relevant to this study, has a financial interest in Sylvatica Biotech, a company focused on developing organ preservation technology, whose interests are managed by the MGH and Mass General Brigham in accordance with their conflict of interest policies. ST and KU have several patent applications disclosures on extended organ preservation that may be relevant to this study. The HOBC-201 used in this study was provided by HBO2 Therapeutics LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Graphic representation of the rodent liver perfusion system: (A) solution reservoir, (B) roller pump, (C,D) oxygenator containing silicon tubing and providing Carbogen and a heat exchanger with a thermoregulator, (E) bubble trap, (F) pressure probe, (G) organ chamber, and (H) bile Eppendorf.
Figure 2
Figure 2
Liver profile during the 90-min gradual rewarming phase of the rewarm&HBOC group after CS: (A) temperature and (B,C) flow was increased and portal resistance slightly reduced during gradual rewarming. (D) pH normalized by the end of the gradual rewarming procedure. (E) Bicarbonate levels in perfusate. (F) Decrease in lactate levels.
Figure 3
Figure 3
Livers undergoing gradual rewarming showed improved function and recovery compared to CS controls during the 2-h reperfusion with HBOC. (A) pH was better in the rewarm&HBOC group compared to the CS group, with a significant difference at t = 60 (p = 0.016). (B) Bicarbonate levels were better in the rewarm&HBOC group with a significant difference at t = 30 (p = 0.05) and t = 60 (p = 0.032). (C) In contrast to the CS group, the lactate level was significantly lower in the rewarm&HBOC group between t = 30 and t = 120 (p ≤ 0.05). (D) Glucose concentration remained significantly lower in the rewarm&HBOC group compared to the CS group between t = 30 and t = 120 (p = ≤0.05). * represents individual time point significances of the experimental group.
Figure 4
Figure 4
Graphical presentation of oxygen concentration, ATP level, and bile fluid in both the rewarming and CS groups. (A) There was a lower trend of ALT in the rewarm&HBOC group compared to the CS group during 120 min of reperfusion (p = 0.056). (B) Oxygen consumption remained higher in the CS group in comparison with the rewarming group, and this difference was significant at t = 90 (p = 0.024). (C) There was no significant difference in ATP levels between both groups (p = 0.55). (D) The total volume of bile production measured at the end of 120 min of reperfusion was meaningfully higher in the rewarm&HBOC group compared to the CS group. (E) There was no difference in the level of bicarbonate and (F) bile pH in bile samples of the rewarm&HBOC and CS groups during 120 min of reperfusion. * represents individual time point significances.
Figure 5
Figure 5
Vascular injury parameters and H&E staining from the rewarming and CS groups at the end of reperfusion. (A) Flow was significantly higher in the rewarm&HBOC group compared to the CS group from t = 30 to t = 120 (p ≤ 0.05). (B) Resistance was lower in the rewarm&HBOC group compared to the CS group during 120 min of reperfusion with a significant difference at t = 90 (p = 0.02). CS liver tissues (D) demonstrated higher venous congestion (stasis of fluid in parenchyma shown by arrows) compared to the rewarm&HBOC liver grafts (C).
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