Donation After Cardiac Death Liver Research Articles

Transplant Candidate Outcomes After Declining a DCD Liver in the United States.

In the context of the organ shortage, donation after circulatory death (DCD) provides an opportunity to expand the donor pool. Although deceased-donor liver transplantation from DCD donors has expanded, DCD livers continue to be discarded at elevated rates; the use of DCD livers from older donors, or donors with comorbidities, is controversial. Using US registry data from 2009 to 2020, we identified 1564 candidates on whose behalf a DCD liver offer was accepted ("acceptors") and 16 981 candidates on whose behalf the same DCD offers were declined ("decliners"). We characterized outcomes of decliners using a competing risk framework and estimated the survival benefit (adjusted hazard ratio [95% confidence interval]) of accepting DCD livers using Cox regression. Within 10 y of DCD offer decline, 50.9% of candidates died or were removed from the waitlist before transplantation with any type of allograft. DCD acceptors had lower mortality compared with decliners at 10 y postoffer (35.4% versus 48.9%, P < 0.001). After adjustment for candidate covariates, DCD offer acceptance was associated with a 46% reduction in mortality (0.54 [0.49-0.61]). Acceptors of older (age ≥50), obese (body mass index ≥30), hypertensive, nonlocal, diabetic, and increased risk DCD livers had 44% (0.56 [0.42-0.73]), 40% (0.60 [0.49-0.74]), 48% (0.52 [0.41-0.66]), 46% (0.54 [0.45-0.65]), 32% (0.68 [0.43-1.05]), and 45% (0.55 [0.42-0.72]) lower mortality risk compared with DCD decliners, respectively. DCD offer acceptance is associated with considerable long-term survival benefits for liver transplant candidates, even with older DCD donors or donors with comorbidities. Increased recovery and utilization of DCD livers should be encouraged.

Beneficial Effects of Combined Use of Extracorporeal Membrane Oxygenation and Hypothermic Machine Perfusion in Porcine Donors after Cardiac Death for Liver Transplantation.

Grafts from donors after cardiac death (DCD) have greatly contributed to expanding the donor organ pool. This study aimed to determine the benefits of subnormothermic extracorporeal membrane oxygenation (ECMO) and hypothermic machine perfusion (HMP) in a porcine model of DCD liver. Female domestic crossbred Large Yorkshire and Landrace pigs weighing approximately 20 kg were used. The abdominal aorta and inferior vena cava were cannulated and connected to an ECMO circuit for in situ perfusion of the abdominal organs at 22 °C for 60 min, 45 min after cardiac death. The pigs were divided into the cold storage (CS) group (n = 3), where liver grafts were preserved at 4 °C, and the HMP group (n = 3), where liver grafts were preserved by HMP at 8-10 °C. After 4 h of preservation, liver function was evaluated using an isolated liver reperfusion model for 2 h. Although the difference was insignificant, the liver effluent enzyme levels in the HMP group were lower than those in the CS group. Furthermore, morphological findings showed fewer injured hepatocytes in the HMP group than in the CS group. The combined use of in situ subnormothermic ECMO and HMP was beneficial for the functional improvement of DCD liver grafts.

Hypothermic oxygenated perfusion attenuates DCD liver ischemia–reperfusion injury by activating the JAK2/STAT3/HAX1 pathway to regulate endoplasmic reticulum stress

BackgroundHepatic ischemia–reperfusion injury (IRI) in donation after cardiac death (DCD) donors is a major determinant of transplantation success. Endoplasmic reticulum (ER) stress plays a key role in hepatic IRI, with potential involvement of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and the antiapoptotic protein hematopoietic-lineage substrate-1-associated protein X-1 (HAX1). In this study, we aimed to investigate the effects of hypothermic oxygenated perfusion (HOPE), an organ preservation modality, on ER stress and apoptosis during hepatic IRI in a DCD rat model.MethodsTo investigate whether HOPE could improve IRI in DCD livers, levels of different related proteins were examined by western blotting and quantitative real-time polymerase chain reaction. Further expression analyses, immunohistochemical analyses, immunofluorescence staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and transmission electron microscopy were conducted to analyze the effects of HOPE on ER stress and apoptosis. To clarify the role of the JAK2/STAT3 pathway and HAX1 in this process, AG490 inhibitor, JAX1 plasmid transfection, co-immunoprecipitation (CO-IP), and flow cytometry analyses were conducted.ResultsHOPE reduced liver injury and inflammation while alleviating ER stress and apoptosis in the DCD rat model. Mechanistically, HOPE inhibited unfolded protein responses by activating the JAK2/STAT3 pathway, thus reducing ER stress and apoptosis. Moreover, the activated JAK2/STAT3 pathway upregulated HAX1, promoting the interaction between HAX1 and SERCA2b to maintain ER calcium homeostasis. Upregulated HAX1 also modulated ER stress and apoptosis by inhibiting the inositol-requiring enzyme 1 (IRE1) pathway.ConclusionsJAK2/STAT3-mediated upregulation of HAX1 during HOPE alleviates hepatic ER stress and apoptosis, indicating the JAK2/STAT3/HAX1 pathway as a potential target for IRI management during DCD liver transplantation.Graphical

Combined Use of Subnormothermic Extracorporeal Support and Hypothermic Oxygenated Machine Perfusion for Liver Graft After Cardiac Death in Pigs

The use of grafts from donors after cardiac death (DCD) would greatly contribute to the expansion of the donor organ pool. This study aims to determine the benefits of extracorporeal membrane oxygenation (ECMO) and hypothermic oxygenated machine perfusion (HOPE) in a large animal model of DCD liver. After cardiac arrest, the abdominal aorta and the inferior vena cava were cannulated and connected to an ECMO circuit. Porcine livers were perfused in situ with ECMO at 22°C for 60 minutes after 45 minutes of cardiac death. Then, the livers were perfused for 4 hours by cold storage (CS) or HOPE. In group 1, non-in situ ECMO and grafts were preserved by HOPE. In group 2, in situ ECMO and grafts were preserved by HOPE. In group 3, in situ ECMO and grafts were preserved by CS. After preservation, all grafts were evaluated using an isolated reperfusion model (IRM) with autologous blood for 2 hours. During HOPE, aspartate aminotransferase (AST) levels and hepatic arterial pressure in group 2 tended to be lower than in group 1. Hematoxylin-eosin staining findings after HOPE showed more massive sinusoidal congestion and hepatocyte cytoplasmic vacuolization in group 1 than in group 2. The AST and LDH levels in group 2 at the start-up of IRM tended to be lower than in group 1. The combined use of in situ subnormothermic ECMO and HOPE is essential for the functional recovery of DCD liver grafts.

Charged multivesicular body protein 2B ameliorates biliary injury in the liver from donation after cardiac death rats via autophagy with air-oxygenated normothermic machine perfusion

Normothermic machine perfusion (NMP) could provide a curative treatment to reduce biliary injury in donation after cardiac death (DCD) donor livers; however, the underlying mechanisms remain poorly understood. In a rat model, our study compared air-oxygenated NMP to hyperoxygenated NMP and found that air-oxygenated NMP improved DCD functional recovery. Here, we found that the charged multivesicular body protein 2B (CHMP2B) expression was substantially elevated in the intrahepatic biliary duct endothelium of the cold-preserved rat DCD liver after air-oxygenated NMP or in biliary endothelial cells under hypoxia/physoxia. CHMP2B knockout (CHMP2B−/−) rat livers showed increased biliary injury after air-oxygenated NMP, indicated by decreased bile production and bilirubin level, elevated biliary levels of lactate dehydrogenase and gamma-glutamyl transferase. Mechanically, we demonstrated that CHMP2B was transcriptionally regulated by Kruppel-like transcription factor 6 (KLF6) and alleviated biliary injury through decreasing autophagy. Collectively, our results suggested that air-oxygenated NMP regulates CHMP2B expression through the KLF6, which reduces biliary injury by inhibiting autophagy. Targeting the KLF6-CHMP2B autophagy axis may provide a solution to reducing biliary injury in DCD livers undergoing NMP.

What's in a name? Higher risks with donation after cardiac death than public health service increased risk livers

Background: Public health service increased risk donor(IRD) and donation after cardiac death (DCD) livers are utilized to address the organ shortage in liver transplantation, particularly during the opioid epidemic. “Increased risk donor” terminology implies greater risk than DCD by its name, but without direct risk comparison.Objective: The aim of this study was to examine the risks of accepting IRD livers compared to DCD livers during the opioid epidemic.Methods: Retrospective, single center study of 92 recipients of IRD donors and 21 DCD donors(22% and 5% of adult transplants) between 1/2013-5/2017. Median post transplant follow-up was 2.6 years. The primary outcome was the composite of post-transplant risks likely to be greatest in IRD donor and DCD livers, namely, donor viral transmission (HBV, HCV, HIV) and ischemic cholangiopathy. Secondary outcomes were patient and graft survival, biopsy-proven rejection, CMV and EBV viremia. Categorical variables were analyzed using chi square and continuous variables Kruskal-Wallis techniques. Propensity score matched sensitivity analysis was conducted using logistic regression. Cox proportional hazard regression models were used for survival analyses.Results: Ischemic cholangiopathy and graft failure leading to retransplantation occurred in 40% and 14% of DCD recipients but did not occur among IRD recipients(p<0.0001). There were no occurrences of HBV, HCV, HIV transmission. Survival was similar between DCD and IRD groups(90% vs 84% respectively, p=0.23).Conclusion Despite its name, increased risk donors are less risky than DCD livers given lower rates of ischemic cholangiopathy and retransplantation, supporting the recent decision to rename this group of donors to encourage utilization.

400.5: Outcomes After Declining a Donation After Cardiac Death (DCD) Liver for Transplant Candidates in the United States

Introduction: In the context of the deceased-donor liver shortage, donation after cardiac death (DCD) provides an opportunity to expand the donor pool, but DCD organs confer higher risk of biliary complications and graft loss. Patients and clinicians who are offered a DCD liver must choose whether to accept the higher risk or remain on the waitlist in hopes of a better offer. We explored outcomes of candidates who declined a DCD offer, and investigated the survival benefit accepting vs declining the offer of a DCD liver. In addition, we estimated the number of additional liver transplants that could be achieved if DCD livers were utilized at the same rate as livers from otherwise-comparable DBD donors. Methods: Using national registry data from the United States (SRTR) 2009-2020, we identified 1,564 candidates who accepted DCD offers (“acceptors”) and 16,981 candidates who declined the same DCD offers (“decliners”). We characterized outcomes of decliners using a competing risk framework. In addition, we compared patient survival of acceptors vs. decliners using Cox regression. We used Poisson regression to compare observed discard of DCD livers to the number of discards expected based on donor characteristics other than DCD. Results: Among DCD decliners, 50.9% died/dropped out from waitlist; only 43.1% were transplanted with a donation after brain death (DBD) liver. DCD acceptors had lower mortality compared to decliners at 10 years post-offer (35.4% vs. 48.9%, p<0.001) (Fiigure 1). After adjustment, DCD acceptors had 46% lower mortality risk compared to DCD decliners (aHR= 0.49 0.54 0.61). The survival benefit of DCD LT varied by MELD stratum. DCD acceptors and decliners with MELD 6-14 at offer had comparable risk of mortality (aHR= 0.56 0.89 1.42, p=0.6). DCD offer acceptors had 55%, 34% and 52% lower risk of mortality compared to DCD offer decliners within MELD strata 15-24 (aHR= 0.39 0.45 0.54, p<0.001), 25-34 (aHR= 0.55 0.66 0.79, p<0.001) and 35 or higher (aHR= 0.29 0.48 0.78, p=0.004), respectively (Figure 2). Out of 1005 recovered DCD livers, 298 were discarded in 2019. If DCD livers were utilized at the same rate as comparable DBD livers, we estimated that 235 (78.9%) of them would have been transplanted. Conclusions: Despite risk of biliary complications, DCD offer acceptance is associated with considerable long-term survival benefit for liver transplant candidates. Increased utilization of DCD livers should be encouraged. This work was supported by grant number K01DK101677 (Massie), 5T32DK007713-23 (Eagleson), and K24DK101828 (Segev) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The analyses described here are the responsibility of the authors alone and do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. The data reported here have been supplied by the Hennepin Healthcare Research Institute (HHRI) as the contractor for the Scientific Registry of Transplant Recipients (SRTR). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy of or interpretation by the SRTR or the U.S. Government.

Single Center Experience with Incidence, Impact and Predictors of Biliary Complications in Donation After Circulatory Death Liver Transplantation.

Introduction: Utilizing allografts from donors after cardiac death (DCD) has improved organ availability, and DCD livers comprise a growing proportion of transplantations. However, it has been suggested that DCD transplantations have worse outcomes. Research Questions: We aimed to characterize outcomes in a large cohort of DCD transplantations, identify trends in outcomes over time, and identify factors associated with the development of biliary complications. Design: We conducted an observational retrospective cohort study of patients receiving DCD liver allografts within a large academic teaching hospital with a high transplantation volume. Consecutive patients who underwent Type III DCD liver transplantation from 2006-2016 were included in our cohort. Re-transplantations and multi-organ transplant recipients were excluded. Results: Ninety-six type III DCD transplantations occurred between 2006-2016. We report a 1one-year patient survival of 90.6% (87) and a 5five-year patient survival of 69.8% (67). Twenty-nine (30.2%) patients experienced any biliary complication in the first year following discharge, with 17 (17.7%) experiencing ischemic cholangiopathy. Five-year patient (P = 0.04) and graft (P = 0.005) survival improved over time. Post-operative biliary complications experienced during index admission and prior to discharge were found to be associated with the development of biliary complications (P = 0.005) and ischemic cholangiopathy (P = 0.01) following discharge. Conclusion: Our data suggested that outcomes using DCD allografts have improved, however biliary complications remain a significant issue in DCD transplantation. Patients who experienced post-operative biliary complications during index admission may require more frequent screening to allow the initiation of earlier treatment for biliary complications.

Optimal Conditions for Oxygenated Subnormothermic Machine Perfusion for Liver Grafts Using a Novel Perfusion Device

Liver transplantation from donors after cardiac death (DCD) resolves donor shortages. We investigated the optimal time for subnormothermic oxygenated perfusion in DCD liver transplantation. Ten F1 pigs (body weight: 27-32 kg) were allocated to 2 groups: the heart beating group (n=6), from which livers were retrieved while the heart was beating, and the donation after cardiac death (DCD) group (n=4), in which liver retrieval was performed on pigs under apnea-induced cardiac arrest for 20 minutes. In both groups, the livers were kept in cold storage for 2 hours after retrieval and perfused with a subnormothermic oxygenated Krebs-Henseleit buffer for 120 minutes. We used a novel perfusion device, which can set maximum perfusion pressures of arteries and portal vein, developed by Asahikawa Medical University and Chuo Seiko Co. Bile production, liver enzymes, and inflammatory cytokines were measured and the sinusoidal space, using tissue specimens taken from liver grafts, was measured at 30, 60, 90, and 120 minutes after the start of perfusion. Bile production peaked at 90 minutes. Significantly higher levels of liver enzymes and inflammatory cytokines were found in the DCD group (P < .05). The release of liver enzymes peaked at 60 minutes and that of inflammatory cytokines peaked at 90 minutes. The hepatic sinusoidal space was wide at 90 minutes and narrowed after 120 minutes. The results suggest that subnormothermic oxygenation perfusion may maintain optimal graft condition until around 90 minutes and perfusion for more than 120 minutes may be counterproductive.

Liver allograft findings of donation after cardiac death versus brain death in recipients with hepatitis C related cirrhosis: a matched histologic comparison

As the demand for organ transplantation increases, utilization of liver allografts of donation after cardiac death (DCD) is becoming increasingly necessary. Althoughthe clinical outcomes of DCD allografts have been well described, the histologic features are not well characterized. Liver biopsies (n=131) from age-matched DCD (n=60) and donation after brain death (DBD; n=71) recipients with hepatitis C virus were compared. Histologic features were studied in a blinded fashion, subgrouped into time 0, 0-6 months, and >6 months. In time 0 biopsies, more DCD cases had zone 3 (43.8 vs 29%) and bridging necrosis (19 vs 0%), albeit not statistically significant. At 0-6 months, more DCD cases had portal edema (p=0.01). Pericholangitis (30.4% vs 18.8%) and acute cholestasis (21.7% vs 12.5%) were more common in DCD, but not statistically significant. At >6 months, pericholangitis (19% vs 4.5%) persisted in DCD, although not statistically significant. Overall, both groups had similar bile duct injury, portal inflammation, and fibrosis. Postoperative biliary complications were more common in DCD (19% vs 0%). Three-year and 10-year graft survival and patient outcomes were similar in both cohorts. Biliary alterations were more prevalent in the 0-6 month time period DCD biopsies, reflecting increased vulnerability of this group to biliary complications in the early post-orthotopic liver transplant (OLT) period. This finding may suggest poor graft perfusion despite comparable cold ischemia times. However, these features improved and DCD recipients have similar graft and overall survival compared to DBD recipients, indicating that carefully selected DCD liver allografts are a viable option for transplantation.

HO-1/BMMSC perfusion using a normothermic machine perfusion system reduces the acute rejection of DCD liver transplantation by regulating NKT cell co-inhibitory receptors in rats

BackgroundLiver transplantation (LT) is required in many end-stage liver diseases. Donation after cardiac death (DCD) livers are often used, and treatment of acute rejection (ACR) requires the use of immunosuppressive drugs that are associated with complications. Bone marrow mesenchymal stem cells (BMMSCs) are used in treatment following LT; however, they have limitations, including low colonization in the liver. An optimized BMMSC application method is required to suppress ACR.MethodsBMMSCs were isolated and modified with the heme oxygenase 1 (HO-1) gene. HO-1/BMMSCs were perfused into donor liver in vitro using a normothermic machine perfusion (NMP) system, followed by LT into rats. The severity of ACR was evaluated based on liver histopathology. Gene chip technology was used to detect differential gene expression, and flow cytometry to analyze changes in natural killer (NK) T cells.ResultsNMP induced BMMSCs to colonize the donor liver during in vitro preservation. The survival of HO-1/BMMSCs in liver grafts was significantly longer than that of unmodified BMMSCs. When the donor liver contained HO-1/BMMSCs, the local immunosuppressive effect was improved and prolonged, ACR was controlled, and survival time was significantly prolonged. The application of HO-1/BMMSCs reduced the number of NKT cells in liver grafts, increased the expression of NKT cell co-inhibitory receptors, and reduced NKT cell expression of interferon-γ.ConclusionsNK cell and CD8+ T cell activation was inhibited by application of HO-1/BMMSCs, which reduced ACR of transplanted liver. This approach could be developed to enhance the success rate of LT.

Pharmacological Activating Transcription Factor 6 Activation Is Beneficial for Liver Retrieval With ex vivo Normothermic Mechanical Perfusion From Cardiac Dead Donor Rats.

Background: Normothermic machine perfusion (NMP) could be beneficial for organ retrieval from donors after cardiac death (DCD). Activating transcription factor 6 (ATF6) was recently shown to mitigate liver ischemia/reperfusion injury and confer protection. The aims of this study were to assess the implication of ATF6 in liver retrieval from DCD rat livers with NMP and explore the effect of pharmacologic ATF-6 activation on liver retrieval.Methods: The livers from DCD rats were exposed to 30 min of warm ischemia and 8 h cold preservation followed by 2 h NMP with or without an ATF6 activator in the perfusate. Perfusates and livers were harvested to detect ATF6 expression, liver function, and inflammation.Results: DCD livers with NMP were associated with ATF6 overexpression and activation based on IHC and WB (P < 0.05). The ATF6 activator downregulated perfusate aminotransferases, decreased the Suzuki score, downregulated CD68 and MPO based on IHC, induced the expression of cytochrome c in mitochondria and inhibited the expression of cytochrome c in cytoplasm based on WB, reduced TNFα and IL-6 levels based on ELISA, decreased levels of MDA, GSSG and ATP, and increased SOD activity and GSH levels in the perfused livers (P < 0.05).Conclusion: ATF6 is important for liver retrieval, and an exogenous ATF6 activator accelerates liver retrieval from DCD rats in an ex vivo NMP model.

Liver transplantation using grafts from donors after circulatory death - the first Czech Republic experience.

Liver transplantation is established as alifesaving procedure for patients with acute and chronic liver failure, as well as certain selected malignancies. Due to acontinuing organ shortage and ever-growing patient waiting lists, donation after cardiac death (DCD) is becoming more frequently utilized in order to close the gap between &#8220;supply and demand&#8221;. Aretrospective analysis of DCD and subsequent liver transplantations was performed. From May 2016 to September 2019, atotal of 9 DCD liver transplantations were performed in our institution. All cases except one were primary liver transplantations. The recipients comprised 5 (56%) males and 4 (44%) females. The mean DCD donor age was 41±12 (22-57) years, with ventilation duration of 7±1 days and warm ischemia time 19±3 minutes. The average recipient age was 51±22 (4-73) years, with an average cold ischemia 3h:59m±27m and manipulation time of 23±5 minutes. Periprocedural mortality was 1 (11%). Hepatitis C recurrence was documented in 1 (11%) patient. The mean follow-up time was 19±13 (7-37) months. Until now, we have not observed any signs of ischemic cholangiopathy. DCD liver transplantation allows us to enlarge the pool of potential liver grafts, thus decreasing the time spent on the liver recipient waiting list. This paper documents the first series of DCD liver transplantations in the Czech Republic.

Novel oxygenation technique for hypothermic machine perfusion of liver grafts: Validation in porcine Donation after Cardiac Death (DCD) liver model

BackgroundHypothermic oxygenated machine perfusion improves outcomes in Liver Transplantation, but application is limited as O2 is supplied by a stationary circuit. A novel technique of O2 “pre-charge” in a portable pump would broaden use and further mitigate ischemia damage from organ transport. MethodsPorcine DCD livers were randomized to static cold storage (SCS, n = 8) or hypothermic machine perfusion (HMP). HMP was stratified into HMP-O2 (n = 5), non-O2 open to air HMP-RA (n = 5), and non-O2 with sealed lids or no air HMP-NA (n = 5). HMP-O2 was “pre-charged” using 100% O2 delivered at 10 L/min over 15 min. Perfusate and tissue O2 tension (pO2), liver biopsies, and fluid chemistries were analyzed. Results“Pre-charge” achieves sustained tissue and perfusate pO2 vs others. HMP-O2 results in decreased markers of hepatocyte injury: ALT (p < 0.05) and LDH (p < 0.05), lower expression of CRP and higher expression of SOD1 vs SCS. This suggests decreased inflammation and improved ROS scavenging. Conclusions“Pre-charge” is an effective technique, which allows portability and transport without an O2 source and improves graft parameters.

Effects of Short-Term Normothermic and Subnormothermic Perfusion After Cold Preservation on Liver Transplantation From Donors After Cardiac Death

BackgroundLiver transplantation from donors after cardiac death (DCD) could increase the pool of organs. We previously reported that oxygenated subnormothermic (20°C-25°C) ex vivo liver perfusion (SELP) improved the graft viability in rats. This study aimed to compare the effectiveness of SELP and normothermic (37°C) ex vivo liver perfusion (NELP) after cold storage (CS) in DCD liver grafts. MethodsMale Wistar rats were used, and grafts were retrieved 30 minutes after cardiac arrest. We performed oxygenated NELP and SELP with a Krebs-Henseleit buffer for different time points and durations: Group 0, donation performed from heart-beating donors (control); Group 1 (DCD group), donation performed from DCD donors with no treatments; Group 2, NELP performed before CS (30 minutes); Group 3, NELP performed after CS (30 minutes); Group 4, SELP performed after CS (30 minutes); Group 5, SELP performed after CS (60 minutes); and Group 6, SELP performed after CS (90 minutes). After 15 minutes of incubation at room temperature, the grafts were reperfused under normothermic conditions for 60 minutes as a model of liver transplantation. ResultsNo significant differences in body and liver weight were observed between all groups. In the SELP after CS groups, even 30 minutes of perfusion improved bile production, tumor necrosis factor-α, and interleukin-1β significantly compared with the DCD group (P < .05), comparable with NELP groups. ConclusionSELP rescued DCD livers from ischemia-reperfusion injury the same as the normothermic perfusion before or after CS groups. SELP after CS is more convenient than normothermic perfusion; hence, this technique may increase the organ pool.

Cytoprotective Effects of Mesenchymal Stem Cells During Liver Transplantation From Donors After Cardiac Death in Swine

BackgroundLiver transplantation from donors after cardiac death (DCDs) can increase the pool of available organs. Recently, mesenchymal stem cells (MSCs) have been used to treat various diseases. Some studies have reported that MSCs improve the outcome of liver transplantation from DCDs in mice. The aim of this study was to evaluate the cytoprotective effects and safety of MSC transplantation on liver grafts from DCDs in swine. MethodsFor the MSCs, we used swine adipose-derived stem cells (ADSCs). Landrace swine were divided into 3 groups (n = 5) as follows: 1. the heart-beating (HB) group, from which liver grafts were retrieved and transplanted; 2. the DCD group, from which liver grafts were retrieved 10 minutes after apnea-induced cardiac arrest and transplanted; and 3. the ADSC group, from which liver grafts were retrieved as with the DCD group, transplanted, and then infused with 1.0 × 107 ADSCs 2 hours after reperfusion. ResultsIn the HB group, all 5 recipients survived for >7 days, whereas all 5 recipients in the DCD group died within 24 hours after transplantation. In the ADSC group, 3 recipients survived for >7 days, whereas 2 recipients died within 4 days after transplantation. The survival rate was significantly higher in the ADSC group than in the DCD group. ConclusionsMSCs could protect the function of liver grafts from warm ischemia-reperfusion injury and improve the viability of DCD liver grafts.

Recipient gender and body mass index are associated with early acute rejection in donation after cardiac death liver transplantation

Early acute rejection (EAR) is a common complication after liver transplantation (LT). The aim of this study was to evaluate the incidence and risk factors of EAR in donation after cardiac death (DCD) liver transplantation recipients. We retrospectively analysed the data of 461 DCD liver transplants performed during the period from January 2010 to June 2016 to study the relationship between EAR and various clinical factors. EAR was defined as histologically proven acute cellular rejection occurring less than 90 days after transplantation. The median follow-up time for this study was 33.1 months (range: 0.03-92.8 months). Thirty-two (6.9%) patients developed EAR with a median period of 20.5 days (5-88 days) after transplantation. A multivariate analysis revealed that female recipient (hazard ratio: 2.801; P=0.024) and high recipient body mass index (BMI) (hazard ratio: 1.005; P=0.049) were two independent risk factors for early acute rejection. In DCD liver transplantation, recipient female gender and high BMI were associated with a higher incidence of EAR, while the use of CD25-Ab and/or MMF had a protective effect.

Results in liver transplantation using grafts from donors after controlled circulatory death: A single-center experience comparing donor grafts harvested after controlled circulatory death to those harvested after brain death.

In recent years, interest in donation after cardiac death (DCD) has increased. Although DCD liver transplantation (LT) has demonstrated satisfactory long-term outcomes, different studies have shown poorer patient and graft survival after DCD than after donation after brain death (DBD). This study aimed to evaluate the results of LT using controlled DCD (cDCD) donors, specifically the incidence of primary non-function and ischemic cholangiopathy (IC), and to compare these results with those of LT using DBD in the same time period. Between June 2012 and July 2018, we performed 66 transplants using cDCD and 258 with DBD grafts. The incidence of IC was similar in both groups (2% in DBD, 1.5% in DCD; P=.999). No significant differences were found for overall graft and patient survival rates between the groups at 1 and 2years post-transplantation. This study provided evidence that cDCD donors exhibit excellent graft and patient survival outcomes. When the warm ischemia time is <30minutes and cold ischemia time is <6hours, the graft and patient survival rates and the incidence of IC in DCD are similar to those in DBD, even when using donors without age restrictions.

Impact of human-derived hemoglobin based oxygen vesicles as a machine perfusion solution for liver donation after cardiac death in a pig model.

The recent clinical application of perfusion technology for the machine preservation of donation after cardiac death (DCD) grafts has some advantages. Oxygenation has been proposed for the preservation of DCD liver grafts. The aim of this study is to clarify whether the use of HbV-containing preservation solution during the subnormothermic machine perfusion (SNMP) of the liver graft improves the graft function of DCD porcine livers in an ex vivo reperfusion model. Pig livers were excised after 60 minutes of warm ischemic time and were preserved under one of three preservation conditions for 4 hours. The preservation conditions were as follows: 4°C cold storage (CS group; N = 5), Hypothermic machine preservation (HMP) with UW gluconate solution (HMP group; N = 5), SNMP (21°C) with UW gluconate solution (SNMP group; N = 5), SNMP (21°C) with HbVs (Hb; 1.8 mg/dl) perfusate (SNMP+HbV group; N = 5). Autologous blood perfusion was performed for 2 hours in an isolated liver reperfusion model (IRM). The oxygen consumption of the SNMP and SNMP+HbV group was higher than the HMP groups (p < 0.05). During the reperfusion, the AST level in the SNMP+HbV group was lower than that in the CS, HMP and SNMP groups. The changes in pH after reperfusion was significantly lower in SNMP+HbV group than CS and HMP groups. The ultrastructural findings indicated that the mitochondria of the SNMP+HbV group was well maintained in comparison to the CS, HMP and SNMP groups. The SNMP+HbVs preservation solution protected against metabolic acidosis and preserved the liver function after reperfusion injury in the DCD liver.

Continuous Resuscitation for Porcine Liver Transplantation From Donor After Cardiac Death

BackgroundTo solve the serious donor shortage, the demand is increasing for developing a new method to use the marginal donors, including donors after cardiac death (DCD). Continuous machine perfusion from ex vivo to in situ is a novel technique to overcome warm ischemia during organ grafting as an ischemia-free transplantation. Herein, we tested orthotopic and heterotopic ischemia-free liver transplantation in pigs and evaluated the perfusion characteristics of DCD grafts from ex vivo preservation to implantation. Materials and MethodsThe demonstration of ischemia-free transplantation was conducted using both orthotopic and heterotopic transplantation models. Warm ischemia time (WIT) was set at 60 minutes or 120 minutes in the DCD models. Recipients were humanely killed 3 days after transplant. Flow rates of portal vein and hepatic artery were set to 0.06 to 0.15 mL/min/g and 0.04 to 0.06 mL/min/g for the liver weight ratio, respectively. ResultsUnder the stable perfusion rate by machine perfusion, the average hepatic artery pressure of the liver graft after a WIT of 120 minutes was approximately 80 mm Hg higher than after WIT of 60 minutes. The recipient with liver graft of WIT of 60 minutes could not survive overnight. In heterotopic model, the recipient with 1 hour DCD liver survived until humanely killed. ConclusionsThe results of pressure monitoring in our DCD liver graft model indicate that pressures are influenced not only by thrombus formation but also by postmortem rigidity at 2 hours after cardiac death.