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1.
Front Transplant ; 3: 1353124, 2024.
Article in English | MEDLINE | ID: mdl-38993754

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.

2.
Transplant Direct ; 10(4): e1609, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38481967

ABSTRACT

Background: Brief normothermic machine perfusion is increasingly used to assess and recondition grafts before transplant. During normothermic machine perfusion, metabolic activity is typically maintained using red blood cell (RBC)-based solutions. However, the utilization of RBCs creates important logistical constraints. This study explored the feasibility of human kidney normothermic perfusion using William's E-based perfusate with no additional oxygen carrier. Methods: Sixteen human kidneys declined for transplant were perfused with a perfusion solution containing packed RBCs or William's E medium only for 6 h using a pressure-controlled system. The temperature was set at 37 °C. Renal artery resistance, oxygen extraction, metabolic activity, energy metabolism, and histological features were evaluated. Results: Baseline donor demographics were similar in both groups. Throughout perfusion, kidneys perfused with William's E exhibited improved renal flow (P = 0.041) but similar arterial resistance. Lactic acid levels remained higher in kidneys perfused with RBCs during the first 3 h of perfusion but were similar thereafter (P = 0.95 at 6 h). Throughout perfusion, kidneys from both groups exhibited comparable behavior regarding oxygen consumption (P = 0.41) and reconstitution of ATP tissue concentration (P = 0.55). Similarly, nicotinamide adenine dinucleotide levels were preserved during perfusion. There was no evidence of histological damage caused by either perfusate. Conclusions: In human kidneys, William's E medium provides a logistically convenient, off-the-shelf alternative to packed RBCs for up to 6 h of normothermic machine perfusion.

3.
J Clin Med ; 9(1)2020 Jan 18.
Article in English | MEDLINE | ID: mdl-31963739

ABSTRACT

Ex situ machine perfusion is a promising technology to help improve organ viability prior to transplantation. However, preclinical studies using discarded human livers to evaluate therapeutic interventions and optimize perfusion conditions are limited by significant graft heterogeneity. In order to improve the efficacy and reproducibility of future studies, a split-liver perfusion model was developed to allow simultaneous perfusion of left and right lobes, allowing one lobe to serve as a control for the other. Eleven discarded livers were surgically split, and both lobes perfused simultaneously on separate perfusion devices for 3 h at subnormothermic temperatures. Lobar perfusion parameters were also compared with whole livers undergoing perfusion. Similar to whole-liver perfusions, each lobe in the split-liver model exhibited a progressive decrease in arterial resistance and lactate levels throughout perfusion, which were not significantly different between right and left lobes. Split liver lobes also demonstrated comparable energy charge ratios. Ex situ split-liver perfusion is a novel experimental model that allows each graft to act as its own control. This model is particularly well suited for preclinical studies by avoiding the need for large numbers of enrolled livers necessary due to the heterogenous nature of discarded human liver research.

4.
PLoS One ; 15(1): e0228011, 2020.
Article in English | MEDLINE | ID: mdl-31978172

ABSTRACT

There continues to be a significant shortage of donor livers for transplantation. One impediment is the discard rate of fatty, or steatotic, livers because of their poor post-transplant function. Steatotic livers are prone to significant ischemia-reperfusion injury (IRI) and data regarding how best to improve the quality of steatotic livers is lacking. Herein, we use normothermic (37°C) machine perfusion in combination with metabolic and lipidomic profiling to elucidate deficiencies in metabolic pathways in steatotic livers, and to inform strategies for improving their function. During perfusion, energy cofactors increased in steatotic livers to a similar extent as non-steatotic livers, but there were significant deficits in anti-oxidant capacity, efficient energy utilization, and lipid metabolism. Steatotic livers appeared to oxidize fatty acids at a higher rate but favored ketone body production rather than energy regeneration via the tricyclic acid cycle. As a result, lactate clearance was slower and transaminase levels were higher in steatotic livers. Lipidomic profiling revealed ω-3 polyunsaturated fatty acids increased in non-steatotic livers to a greater extent than in steatotic livers. The novel use of metabolic and lipidomic profiling during ex situ normothermic machine perfusion has the potential to guide the resuscitation and rehabilitation of steatotic livers for transplantation.


Subject(s)
Fatty Liver/metabolism , Lipidomics , Metabolomics , Perfusion , Resuscitation , Temperature , Adenosine Triphosphate/biosynthesis , Bile Acids and Salts/metabolism , Fatty Acids/metabolism , Fatty Liver/pathology , Fatty Liver/physiopathology , Glucose/metabolism , Hemodynamics , Humans , Liver/pathology , Liver/physiopathology , Liver Function Tests , Oxidation-Reduction , Oxidative Stress , Vascular Resistance
5.
Artif Organs ; 44(1): 81-90, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31368159

ABSTRACT

Gradual rewarming from hypothermic to normothermic is a novel perfusion modality with superior outcome to sudden rewarming to normothermic. However, the identification of an oxygen carrier that could function at a temperature range from 4 to 7°C or whether it is necessary to use oxygen carrier during kidney rewarming, remains unresolved. This study was designed to test the use of a hemoglobin-based oxygen carrier (HBOC) during gradual kidney rewarming as an alternative to simple dissolved oxygen. In this study, 10 rat kidneys were randomly divided into the control and the HBOC group. In the control group, no oxygen carrier was used during rewarming perfusion and the perfusion solution was oxygenated only by applying diffused carbogen flow. The protocol mimicked a donor after circulatory death (DCD) kidney transplantation, where after 30 minutes warm ischemia and 120 minutes cold storage in University of Wisconsin solution, the DCD kidneys underwent gradual rewarming from 10 to 37°C during 90 minutes with or without HBOC. This was followed by 30 minutes of warm ischemia in room temperature to mimic the anastomosis time and 120 minutes of reperfusion at 37°C to mimic the early post-transplant state of the graft. The HBOC group demonstrated superior kidney function which was highlighted by higher ultrafiltrate production, better glomerular filtration rate and improved sodium reabsorption. There was no significant difference between the 2 groups regarding the hemodynamics, tissue injury, and adenosine triphosphate levels. In conclusion, this study suggests better renal function recovery in DCD kidneys after rewarming with HBOC compared to rewarming without an oxygen carrier.


Subject(s)
Blood Substitutes/pharmacology , Hemoglobins/pharmacology , Kidney/physiology , Organ Preservation/methods , Animals , Equipment Design , Kidney/drug effects , Kidney/ultrastructure , Male , Organ Preservation/instrumentation , Oxygen Consumption/drug effects , Perfusion/instrumentation , Perfusion/methods , Rats , Rats, Inbred Lew , Rewarming/instrumentation , Rewarming/methods
6.
Am J Transplant ; 20(4): 977-987, 2020 04.
Article in English | MEDLINE | ID: mdl-31823520

ABSTRACT

Through multiple mechanisms, regulatory B cells (Breg) have been shown to play an important role in the development of allograft tolerance. However, a careful understanding of the role of antigen-specificity in Breg-mediated allograft tolerance has remained elusive. In experimental models of islet and cardiac transplantation, it has been established that Bregs can be induced in vivo by anti-CD45RB ± anti-TIM1antibody treatment, resulting in prolonged, Breg-dependent allograft tolerance. The importance of Breg antigen recognition has been suggested but not confirmed through adoptive transfer experiments, using tolerant WT C57BL/6 animals challenged with either BALB/c or C3H grafts. However, the importance of receptor-specificity has not been formally tested. Here, we utilize the novel ovalbumin-specific B cell receptor transnuclear (OBI) mice in multiple primary tolerance and adoptive transfer experiments to establish that Breg-dependent allograft tolerance relies on antigen recognition by B cells. Additionally, we identify that this Breg-dependent tolerance relies on the function of transforming growth factor-ß. Together, these experiments mark important progress toward understanding how best to improve Breg-mediated allograft tolerance.


Subject(s)
B-Lymphocytes, Regulatory , Transplantation Tolerance , Animals , Immune Tolerance , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred C57BL , T-Lymphocytes, Regulatory
7.
Am J Transplant ; 19(10): 2814-2824, 2019 10.
Article in English | MEDLINE | ID: mdl-30938927

ABSTRACT

Normothermic machine perfusion presents a novel platform for pretransplant assessment and reconditioning of kidney grafts. Maintaining the metabolic activity of a preserved graft at physiologic levels requires an adequate oxygen supply, typically delivered by crystalloid solutions supplemented with red blood cells. In this study, we explored the feasibility of using a synthetic hemoglobin-based oxygen carrier (HBOC) in human kidney normothermic perfusion. Fourteen discarded human kidneys were perfused for 6 hours at a mean temperature of 37°C using a pressure-controlled system. Kidneys were perfused with a perfusion solution supplemented with either HBOC (n = 7) or packed red blood cells (PRBC) (n = 7) to increase oxygen-carrying capacity. Renal artery resistance, oxygen extraction, metabolic activity, energy stores, and histological features were evaluated. Throughout perfusion, kidneys from both groups exhibited comparable behavior regarding vascular flow (P = .66), oxygen consumption (P = .88), and reconstitution of tissue adenosine triphosphate (P = .057). Lactic acid levels were significantly higher in kidneys perfused with PRBC (P = .007). Histological findings were comparable between groups, and there was no evidence of histological damage caused by the HBOC. This feasibility experiment demonstrates that a HBOC solution can offer a logistically more convenient off-the-shelf alternative to PRBC in normothermic machine perfusion of human kidneys.


Subject(s)
Blood Substitutes/pharmacology , Hemoglobins/pharmacology , Kidney/drug effects , Organ Preservation Solutions/chemistry , Organ Preservation/methods , Oxygen/metabolism , Reperfusion Injury/prevention & control , Adult , Aged , Cells, Cultured , Erythrocytes/chemistry , Extracorporeal Circulation , Female , Follow-Up Studies , Humans , Male , Middle Aged , Oxygen Consumption , Perfusion , Tissue Survival , Tissue and Organ Harvesting/methods
8.
Annu Int Conf IEEE Eng Med Biol Soc ; 2018: 3128-3131, 2018 Jul.
Article in English | MEDLINE | ID: mdl-30441057

ABSTRACT

This paper introduces a non-invasive, contrastenhanced ultrasound (CEUS) infusion method to quantify the health of viable donor livers. The method uses the infusion of microbubbles and their destruction and subsequent replenishment to measure the perfusion rate in the liver microvasculature. The proposed method improves on the previous parameter extraction approaches applied to the flashreplenishment technique by addressing the effects of the microbubble mixing within the perfusate bath and destruction rate. By doing so, the tissue perfusion rate can be extracted from the data even though the microbubble concentration is not constant throughout image acquisition. The measured changes in the tissue perfusion rate showed that CEUS infusion is a viable biomarker for assessing liver health.


Subject(s)
Liver , Animals , Contrast Media , Microbubbles , Perfusion , Swine , Ultrasonography
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