Transplantation Liver Research Articles

Environmental eustress modulates \u03b2-ARs/CCL2 axis to induce anti-tumor immunity and sensitize immunotherapy against liver cancer in mice

Although psycho-social stress is a well-known factor that contributes to the development of cancer, it remains largely unclear whether and how environmental eustress influences malignant diseases and regulates cancer-related therapeutic responses. Using an established eustress model, we demonstrate that mice living in an enriched environment (EE) are protected from carcinogen-induced liver neoplasia and transplantable syngeneic liver tumors, owning to a CD8+ T cell-dependent tumor control. We identify a peripheral Neuro-Endocrine-Immune pathway in eustress, including Sympathetic nervous system (SNS)/β-adrenergic receptors (β-ARs)/CCL2 that relieves tumor immunosuppression and overcomes PD-L1 resistance to immunotherapy. Notably, EE activates peripheral SNS and β-ARs signaling in tumor cells and tumor infiltrated myeloid cells, leading to suppression of CCL2 expression and activation of anti-tumor immunity. Either blockade of CCL2/CCR2 or β-AR signaling in EE mice lose the tumor protection capability. Our study reveales that environmental eustress via EE stimulates anti-tumor immunity, resulting in more efficient tumor control and a better outcome of immunotherapy.

Machine Learning Prediction of Liver Allograft Utilization From Deceased Organ Donors Using the National Donor Management Goals Registry.

Several machine learning classifiers were trained to predict transplantation of a liver graft. We utilized 127 variables available in the DMG dataset. We included data from potential deceased organ donors between April 2012 and January 2019. The outcome was defined as liver recovery for transplantation in the operating room. The prediction was made based on data available 12-18 h after the time of authorization for transplantation. The data were randomly separated into training (60%), validation (20%), and test sets (20%). We compared the performance of our models to the Liver Discard Risk Index. Of 13 629 donors in the dataset, 9255 (68%) livers were recovered and transplanted, 1519 recovered but used for research or discarded, 2855 were not recovered. The optimized gradient boosting machine classifier achieved an area under the curve of the receiver operator characteristic of 0.84 on the test set, outperforming all other classifiers. This model predicts successful liver recovery for transplantation in the operating room, using data available early during donor management. It performs favorably when compared to existing models. It may provide real-time decision support during organ donor management and transplant logistics.

Post-operative outcomes in anonymous living liver donors: What motivates individuals to donate to strangers.

Anonymous living donor liver transplantation (LDLT) is a strategy to address the shortage of available transplantable livers; however, few studies have been conducted on this population. The objective of this study was to describe the motivations and medical, psychosocial, and financial outcomes of anonymous living liver donors. Between 2010-2019, 116 anonymous living liver donors were evaluated, 59 (51.7%) of whom proceeded to surgery. A subset of 21 anonymous donors were matched to biologically/emotionally related donors according to age, gender, race, and duration since surgery. A medical chart review and post-surgical interviews were performed to assess medical and financial outcomes. The primary motivation for donors was an unselfish desire to help others (43, 72.9%). A total of 13 (22%) anonymous donors experienced complications. Of these, 7 (11.9%) were grade I Clavien-Dindo classification, 5 (8.5%) grade II, 1 was grade III (1.7%); and no patients had grade IV-V Clavien-Dindo complications. Increased anxiety was reported by 3 (5.1%) donors, and one donor reported clinical levels of depression (1.7%). Within the matched controls, anonymous donors were not significantly different to biologically/emotionally related donors with regard to surgical complications, psychosocial, or financial outcomes. Allowing a greater number of anonymous donors may facilitate the reduction of the waitlist for liver transplant candidates.

TRANSTHYRETIN AMYLOIDOSIS THERAPIES: GUIDING THE FUTURE.

Transthyretin (TTR) amyloidosis (ATTR) is a progressive condition characterized by multiorgan accumulation of amyloid deposits composed of transthyretin (TTR) fibrils. Over the past decades, despite being a rare disease, ATTR amyloidosis has enabled top-tier therapeutics. In the 90s, organ transplantation was the mainstream therapeutic option and fostered distinct approaches, such as combined liver-heart transplant and domino (sequential) liver transplantation. Likewise, several TTR molecule stabilizers were developed successfully. Over the past decade, oriented genetic therapies emerged to prevent, control, and, surprisingly, reverse amyloid deposition. Silencing the TTR gene using different strategies is flourishing, and ongoing trials continue to evaluate diverse approaches to optimize their application. The following perspective describes the currently available treatments for ATTR amyloidosis and the prospects on the potential application of these strategies in other medical fields.

Ex situ machine preservation of donor livers for transplantation: HOPE for all?

Hypothermic oxygenated machine perfusion (HOPE) reduces ischaemia–reperfusion injury of donor livers and thereby improves outcomes after transplantation. End-ischaemic normothermic machine perfusion (NMP) enables assessment of hepatobiliary viability and selection of livers that would otherwise have been declined for transplantation. We advocate the combined use of (dual) HOPE and NMP for livers that are considered high risk, but may still be transplanted safely after ex situ resuscitation and assessment of hepatobiliary viability. Combined dual HOPE–NMP has the potential to substantially decrease the high rates of deceased donor liver discard.

Single-cell profiling reveals distinct immune phenotypes that contribute to ischaemia-reperfusion injury after steatotic liver transplantation.

ObjectivesThe discrepancy between supply and demand of organ has led to an increased utilization of steatotic liver for liver transplantation (LT). Hepatic steatosis, however, is a major risk factor for graft failure due to increased susceptibility to ischaemia‐reperfusion (I/R) injury during transplantation.Materials and methodsTo assess the plasticity and phenotype of immune cells within the microenvironment of steatotic liver graft at single‐cell level, single‐cell RNA‐sequencing (scRNA‐Seq) was carried out on 23 675 cells from transplanted rat livers. Bioinformatic analyses and multiplex immunohistochemistry were performed to assess the functional properties, transcriptional regulation, phenotypic switching and cell‐cell interactions of different cell subtypes.ResultsWe have identified 11 different cell types in transplanted livers and found that the highly complex ecosystem was shaped by myeloid‐derived cell subsets that transit between different states and interact mutually. Notably, a pro‐inflammatory phenotype of Kupffer cells (KCs) with high expression of colony‐stimulating factor 3 (CSF3) that was enriched in transplanted steatotic livers was potentially participated in fatty graft injury. We have also detected a subset of dendritic cells (DCs) with highly expressing XCR1 that was correlated with CD8+ T cells, mediating the severer steatotic liver damage by I/R injury.ConclusionsThe findings of our study provide new insight into the mechanisms by which steatosis exacerbates liver damage from I/R injury. Interventions based on these observations create opportunities in attenuating fatty liver graft injury and expanding the donor pool.

Ischaemia-free liver transplantation in humans: a first-in-human trial.

SummaryBackground Ischaemia-reperfusion injury is considered an inevitable component of organ transplantation, compromising organ quality and outcomes. Although several treatments have been proposed, none has avoided graft ischaemia and its detrimental consequences.Methods Ischaemia-free liver transplantation (IFLT) comprises surgical techniques enabling continuous oxygenated blood supply to the liver of brain-dead donor during procurement, preservation, and implantation using normothermic machine perfusion technology. In this non-randomised study, 38 donor livers were transplanted using IFLT and compared to 130 conventional liver transplants (CLT).Findings Two recipients (5•3%) in the IFLT group experienced early allograft dysfunction, compared to 50•0% in patients receiving conventional transplants (absolute risk difference, 44•8%; 95% confidence interval, 33•6-55•9%). Recipients of IFLT had significantly reduced median (IQR) peak aspartate aminotransferase levels within the first week compared to CLT recipients (365, 238-697 vs 1445, 791-3244 U/L, p<0•001); likewise, median total bilirubin levels on day 7 were significantly lower (2•34, 1•39-4•09 mg/dL) in the IFLT group than in the CLT group (5•10, 1•90-11•65 mg/dL) (p<0•001). Moreover, IFLT recipients had a shorter median intensive care unit stay (1•48, 0•75-2•00 vs 1•81, 1•00-4•58 days, p=0•006). Both one-month recipient (97•4% vs 90•8%, p=0•302) and graft survival (97.4% vs 90•0%, p=0•195) were better for IFLT than CLT, albeit differences were not statistically significant. Subgroup analysis showed that the extended criteria donor livers transplanted using the IFLT technique yielded faster post-transplant recovery than did the standard criteria donor livers transplanted using the conventional approach.Interpretation IFLT provides a novel approach that may improve outcomes, and allow the successful utilisation of extended criteria livers.Funding This study was funded by National Natural Science Foundation of China, Guangdong Provincial Key Laboratory Construction Projection on Organ Donation and Transplant Immunology, and Guangdong Provincial international Cooperation Base of Science and Technology.Panel: Research in context

Spectroscopic label-free microscopy of changes in live cell chromatin and biochemical composition in transplantable organoids.

Organoids formed from human induced pluripotent stem cells (hiPSCs) could be a limitless source of functional tissue for transplantations in many organs. Unfortunately, fine-tuning differentiation protocols to form large quantities of hiPSC organoids in a controlled, scalable, and reproducible manner is quite difficult and often takes a very long time. Recently, we introduced a new approach of rapid organoid formation from dissociated hiPSCs and endothelial cells using microfabricated cell-repellent microwell arrays. This approach, when combined with real-time label-free Raman spectroscopy of biochemical composition changes and confocal light scattering spectroscopic microscopy of chromatin transition, allows for monitoring live differentiating organoids without the need to sacrifice a sample, substantially shortening the time of protocol fine-tuning. We used this approach to both culture and monitor homogeneous liver organoids that have the main functional features of the human liver and which could be used for cell transplantation liver therapy in humans.

Early Allograft Dysfunction and Complications in DCD Liver Transplantation: Expert Consensus Statements From the International Liver Transplantation Society.

Livers for transplantation from donation after circulatory death donors are relatively more prone to early and ongoing alterations in graft function that might ultimately lead to graft loss and even patient death. In consideration of this fact, this working group of the International Liver Transplantation Society has performed a critical evaluation of the medical literature to create a set of statements regarding the assessment of early allograft function/dysfunction and complications arising in the setting of donation after circulatory death liver transplantation.

Noninvasive assessment of steatosis and viability of cold-stored human liver grafts by MRI.

PurposeA shortage of suitable donor livers is driving increased use of higher risk livers for transplantation. However, current biomarkers are not sensitive and specific enough to predict posttransplant liver function. This is limiting the expansion of the donor pool. Therefore, better noninvasive tests are required to determine which livers will function following implantation and hence can be safely transplanted. This study assesses the temperature sensitivity of proton density fat fraction and relaxometry parameters and examines their potential for assessment of liver function ex vivo.MethodsSix ex vivo human livers were scanned during static cold storage following normothermic machine perfusion. Proton density fat fraction, T1, T2, and were measured repeatedly during cooling on ice. Temperature corrections were derived from these measurements for the parameters that showed significant variation with temperature.ResultsStrong linear temperature sensitivities were observed for proton density fat fraction (R2 = 0.61, P < .001) and T1 (R2 = 0.78, P < .001). Temperature correction according to a linear model reduced the coefficient of repeatability in these measurements by 41% and 36%, respectively. No temperature dependence was observed in T2 or measurements. Comparing livers deemed functional and nonfunctional during normothermic machine perfusion by hemodynamic and biochemical criteria, T1 differed significantly: 516 ± 50 ms for functional versus 679 ± 60 ms for non-functional, P = .02.ConclusionTemperature correction is essential for robust measurement of proton density fat fraction and T1 in cold-stored human livers. These parameters may provide a noninvasive measure of viability for transplantation.

Collagen proportionate area correlates with histological stage and predicts clinical events in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease in need of accurate biomarkers for stratification and as surrogates for clinical endpoints in trials. Quantitative liver fibrosis assessment by collagen proportionate area (CPA) measurement has been demonstrated to correlate with clinical outcomes in chronic hepatitis C, alcohol-related and non-alcoholic fatty liver disease. We aimed to investigate the ability of CPA to quantify liver fibrosis and predict clinical events in PSC. Biopsies from 101 PSC patients from two European centres were retrospectively assessed by two expert pathologists in tandem, using grading (Ishak and Nakanuma) and staging (Ishak, Nakanuma, Ludwig) systems recently validated to predict clinical events in PSC. CPA was determined by image analysis of picro-Sirius red-stained sections following a standard protocol. We assessed the correlations between CPA, staging and grading and their associations with three outcomes: (1) time to PSC-related death, liver transplant or primary liver cancer; (2) liver transplant-free survival; (3) occurrence of cirrhosis-related clinical manifestations. CPA correlated strongly with histological stage determined by each scoring system (P<.001) and was significantly associated with the three endpoints. Median time to endpoint-1, endpoint-2 and endpoint-3 was shorter in patients with higher CPA, on Kaplan-Meier analyses (P=.011, P=.034 and P=.001, respectively). Quantitative fibrosis assessment by CPA has utility in PSC. It correlates with established histological staging systems and predicts clinical events. CPA may be a useful tool for staging fibrosis and for risk stratification in PSC and should be evaluated further within prospective clinical trials.

Cholangiocyte Epithelial to Mesenchymal Transition (EMT) is a potential molecular mechanism driving ischemic cholangiopathy in liver transplantation.

Donation after circulatory death (DCD) has expanded the donor pool for liver transplantation. However, ischemic cholangiopathy (IC) after DCD liver transplantation causes inferior outcomes. The molecular mechanisms of IC are currently unknown but may depend on ischemia-induced genetic reprograming of the biliary epithelium to mesenchymal-like cells. The main objective of this study was to determine if cholangiocytes undergo epithelial to mesenchymal transition (EMT) after exposure to DCD conditions and if this causally contributes to the phenotype of IC. Human cholangiocyte cultures were exposed to periods of warm and cold ischemia to mimic DCD liver donation. EMT was tested by assays of cell migration, cell morphology, and differential gene expression. Transplantation of syngeneic rat livers recovered under DCD conditions were evaluated for EMT changes by immunohistochemistry. Human cholangiocytes exposed to DCD conditions displayed migratory behavior and gene expression patterns consistent with EMT. E-cadherin and CK-7 expressions fell while N-cadherin, vimentin, TGFβ, and SNAIL rose, starting 24 hours and peaking 1–3 weeks after exposure. Cholangiocyte morphology changed from cuboidal (epithelial) before to spindle shaped (mesenchymal) a week after ischemia. These changes were blocked by pretreating cells with the Transforming Growth Factor beta (TGFβ) receptor antagonist Galunisertib (1 μM). Finally, rats with liver isografts cold stored for 20 hours in UW solution and exposed to warm ischemia (30 minutes) at recovery had elevated plasma bilirubin 1 week after transplantation and the liver tissue showed immunohistochemical evidence of early cholangiocyte EMT. Our findings show EMT occurs after exposure of human cholangiocytes to DCD conditions, which may be initiated by upstream signaling from autocrine derived TGFβ to cause mesenchymal specific morphological and migratory changes.

Quality of life in patients after liver transplantation: A literature of review

Liver Transplantation is one of the therapies that increases every year because it contributes to the improvement of patient survival. However, healing or control of the disease is often not accompanied by a full recovery of quality of life (QoL). This study aimed to reviews analyze various of the quality of life of patients Liver Transplantation. Ten articles were selected based on the articles which published which using the Model for End-stage Liver Disease (MELD), Short Form-36 (SF-36) Health Survey, NIDDK Liver Transplantation QoL survey, and European Organisation for Research and Treatment of Cancer QoL Questionnaire (5 studies) in measuring the quality of life of patients after transplantation. The collection of indicator in each article was used to see the factors that significantly influence the quality of life of patients. The results showed the quality of life of patients based on all analysis have improved after transplantation Liver. The global health, physical, emotional, cognitive, role and social function improved after transplantation. Indicator of financial difficulties also showed decrease after transplantation. At the start of the year there were changes that improved after the transplant. However, in the long term, the quality of life of people with liver disease will decline, especially they often experience fatigue and physical weakness. So that there needs to be exercises that can be used so that the quality of life for people with liver after transplantation is getting better.

The future of liver transplantation: Ex-vivo machine perfusion

Long-term preservation of liver grafts outside of the body (ex vivo) may enable treatment, repair, assessment of poor-quality livers currently declined for transplantation and regeneration of partial livers, thereby mitigating global donated liver shortage. The challenge, however, is to keep injured or resected human livers viable for multiple days, a time window necessary for expanded therapeutic interventions. Here, we present a liver perfusion technology that maintains ex vivo human liver function for seven days. The perfusion apparatus was engineered recapitulating core endocrine, renal, pulmonary, cardiac, diaphragmatic, and other physiologic functions for the liver, which are prerequisite for successful long-term liver preservation. The machine was developed in a stepwise fashion using swine livers and eventually tested in injured human livers declined for transplantation and in partial livers from patients, who have undergone formal hepatectomy. Perfused human livers, discarded for poor quality and predicted failure after transplantation, as well as the partial livers unveiled preserved function during ex vivo machine perfusion, as indicated by bile production, synthesis of coagulation factors and maintained cellular energy, among many others. Histological examinations of serial biopsies confirmed an intact liver structure at day seven. This data demonstrates, first, that injured human livers may recover from lethal injury and maintain function for one week outside of the body and second, that the availability of this machine perfusion system may provide an important tool for assessment of liver quality, to induce liver regeneration in partial livers, and to perform therapeutic interventions prior to transplantation.

Salvage living donor liver transplantation versus repeat liver resection for patients with recurrent hepatocellular carcinoma and liver cirrhosis: A propensity score-matched comparison

Following curative liver resection (LR), resectable tumor recurrence in patients with preserved liver function leads to deciding between a repeat LR and a salvage liver transplantation (LT), if a donor liver is available. This retrospective study compared survival outcomes following salvage living donor LT (LDLT) and repeat LR in patients with recurrent hepatocellular carcinoma (HCC). We also analyzed the risk factors associated with survival outcomes after salvage LDLT. We reviewed the medical records of patients who underwent repeat LR (n = 163) or LDLT (n = 84) for recurrent HCC following curative resections, between January 2005 and December 2017 at a single institution; 1:1 propensity score matching led to 49 patients in each group. Overall survival (OS) and recurrence-free survival (RFS) were significantly better in the salvage LDLT group than in the repeat LR group (both, p = 0.000). Multivariate analysis revealed that the number of HCCs in explants obtained during salvage LDLT was an independent risk factor for both OS (p = 0.043) and RFS (p = 0.014). The results indicate that salvage LDLT is superior to repeat LR for treating patients with transplantable, intrahepatic HCC recurrence, including those with Child-Pugh class A liver cirrhosis.

Laparoscopic living donor hepatectomy using the left liver - pushing the limits further

With the accumulation of experience in both living donor liver transplantation (LDLT) and laparoscopic liver surgery, efforts have been made to minimize the surgical trauma to the donor and many institutions are now using minimally invasive approach for donor surgery. Nevertheless, the overwhelming majority of the grafts used for adult LDLT are right lobe grafts. Right lobe, which usually consist of 2/3 of the liver, provides a larger size grafts, facilitating the recovery of the recipient but this comes at the price of the increase risk of the donor. It is known that utilization of right lobe has a higher complication and mortality rate compared to the left, but the utilization of the left lobe has not been practiced widely. In this talk, I'll provide the early results of our program using laparoscopic approach for left lobe and describe the detailed techniques through video presentation.

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection.

Liver allograft recipients are more likely to develop transplantation tolerance than those that receive other types of organ graft. Experimental studies suggest that immune cells and other non-parenchymal cells in the unique liver microenvironment play critical roles in promoting liver tolerogenicity. Of these, liver interstitial dendritic cells (DCs) are heterogeneous, innate immune cells that appear to play pivotal roles in the instigation, integration and regulation of inflammatory responses after liver transplantation. Interstitial liver DCs (recruited in situ or derived from circulating precursors) have been implicated in regulation of both ischemia/reperfusion injury (IRI) and anti-donor immunity. Thus, livers transplanted from mice constitutively lacking DCs into syngeneic, wild-type recipients, display increased tissue injury, indicating a protective role of liver-resident donor DCs against transplant IRI. Also, donor DC depletion before transplant prevents mouse spontaneous liver allograft tolerance across major histocompatibility complex (MHC) barriers. On the other hand, mouse liver graft-infiltrating host DCs that acquire donor MHC antigen via “cross-dressing”, regulate anti-donor T cell reactivity in association with exhaustion of graft-infiltrating T cells and promote allograft tolerance. In an early phase clinical trial, infusion of donor-derived regulatory DCs (DCreg) before living donor liver transplantation can induce alterations in host T cell populations that may be conducive to attenuation of anti-donor immune reactivity. We discuss the role of DCs in regulation of warm and liver transplant IRI and the induction of liver allograft tolerance. We also address design of cell therapies using DCreg to reduce the immunosuppressive drug burden and promote clinical liver allograft tolerance.

Evolution of Monoclonal Gammopathy of Undetermined Significance in Kidney Transplant Recipients at the CHUM (Centre Hospitalier de l'Université de Montréal) — a Single-Institution Retrospective Study

IntroductionRecommendations guiding the care of patients with monoclonal gammopathy of undetermined significance (MGUS) in the setting of kidney transplant are scarce. Nevertheless, monoclonal gammopathies carry a risk of neoplastic progression to hematologic malignancies and may induce renal injury from their deposition in the kidney (monoclonal gammopathy of renal significance - MGRS). However, it remains largely uncertain if these considerations translate into adverse outcomes in the setting of transplantation, as immunosuppression might favor malignant evolution of MGUS or, alternatively, a nephrotoxic paraprotein could lead to graft loss.MethodsWe conducted a retrospective review of the medical records of patients who received a kidney transplant at our institution between Jan 1, 2000 and Jan 1, 2016. We included patients with at least one available serum protein electrophoresis at any time before or after transplantation. Exclusion criteria consisted of age < 18 years at the time of transplant, no follow-up at our center, multiorgan transplant (liver, lung, pancreas, heart), as well as first transplant prior to study period or presence of any plasma cell malignancy before transplant. Outcomes of interest included paraprotein evolution, appearance of hematologic malignancy, graft rejection and loss. Chi-square tests and Fischer's exact probability test for categorical data and Student's t test for continuous variables were used to assess statistical significance.ResultsOut of 1009 eligible transplant recipients, 755 patients were included in our study based on our inclusion and exclusion criteria. Thirteen patients were found to have MGUS prior to transplant and a monoclonal gammopathy appeared in 43 patients after transplant corresponding to a 5-year incidence rate of 2.7%. Median patient follow-up was 7.5 years. Of the patients with MGUS prior to transplant, 2 developed light chain deposition disease (LCDD) after a follow-up of 1 and 2 years and 2 evolved to smoldering multiple myeloma (SMM) at 1 month and 4 years post-transplant. Of the 43 patients who developed MGUS after transplant, 1 transformed into multiple myeloma (MM) 8 years later and 1 progressed to LCDD 2 months after transplant. None of the 6 patients who evolved to malignancy after transplantation had a systematic hematologic workup prior to allograft implantation questioning whether SMM or MGRS may have already been present before transplant. Figure 1 summarizes the evolution of monoclonal gammopathies in our study population. Of monoclonal gammopathies appearing after transplantation, most remained stable (n=26, 60%) and 9 (21%) were found to be transient. Median size was 0.76 g/L (range 0.1 - 21.6 g/L). Twenty-two (74%) were of IgG isotype and an abnormal kappa/lambda ratio was present in 6 cases (14%). We conducted a univariate analysis to compare allograft outcomes between patients who developed post-transplant MGUS (n=43) and patients who did not (n=699). No differences in induction immunosuppression, occurrence of graft loss (18% and 11%, p=0.14) and acute rejection rates (26% and 27%, p=0.866) were observed between these two groups, respectively. However, the former were found to have an increased risk of CMV (26% and 12%, p=0.01) and polyoma BK virus (26% and 14%, p=0.04). Of note, 7 cases of post-transplant lymphoproliferative disorder (PTLD) were identified in our study population and none was preceded by MGUS.ConclusionOur study suggests a reassuring evolution of true MGUS in the setting of renal transplantation. Indeed, the cases of plasma cell malignancies diagnosed in transplant recipients may have already been present before transplant, yet undetected from lack of systematic investigation. We therefore highlight the importance of identifying and diligently investigating monoclonal immunoglobulins in transplant candidates. If a paraprotein is found before transplant, further investigations with bone marrow biopsy and review of native kidney biopsy appear warranted in order to identify cases of plasma cell dyscrasias (such as SMM) and MGRS prior to transplant. Additionally, MGUS arising after transplant appear to carry a favorable evolution. They also tend to be transient and their appearance may be related to prior CMV and BK virus infections. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Machine Perfusion of Donation After Circulatory Death Liver and Lungs Before Combined Liver-lung Transplantation.

Shortage of deceased donor organs for transplantation has led to the increased use of organs from donation after circulatory death (DCD) donors. There are currently no reports describing outcomes after multiorgan transplantation with DCD livers. The use of DCD organs for multiorgan transplantation can be enhanced if the detrimental effects of prolonged cold ischemia and subsequent ischemia-reperfusion injury are overcome. We present a case in which the liver and lungs of a DCD donor were preserved using ex situ machine perfusion for combined liver-lung transplantation. The recipient was a 19-year-old male patient requiring bilateral lung transplantation for severe progressive pleural parenchymal fibroelastosis and portal hypertension with portal vein thrombosis. The donor liver was preserved with dual hypothermic oxygenated machine perfusion, whereas the lungs were perfused using ex vivo lung perfusion. With ex vivo lung perfusion, total preservation time of right and left lung reached 17 and 21 h, respectively. Now, 2 y after transplantation, liver function is normal and lung function is improving. To conclude, we suggest that combined transplantation of DCD liver and lungs is feasible when cold ischemia is reduced with ex situ machine perfusion preservation.

Thrombolytic Therapy During ex-vivo Normothermic Machine Perfusion of Human Livers Reduces Peribiliary Vascular Plexus Injury.

Background: A major limitation in expanding the use of donation after circulatory death (DCD) livers in transplantation is the increased risk of graft failure secondary to ischemic cholangiopathy. Warm ischemia causes thrombosis and injury to the peribiliary vascular plexus (PVP), which is supplied by branches of the hepatic artery, causing higher rates of biliary complications in DCD allografts.Aims/Objectives: We aimed to recondition discarded DCD livers with tissue plasminogen activator (tPA) while on normothermic machine perfusion (NMP) to improve PVP blood flow and reduce biliary injury.Methods: Five discarded DCD human livers underwent 12 h of NMP. Plasminogen was circulated in the base perfusate prior to initiation of perfusion and 1 mg/kg of tPA was administered through the hepatic artery at T = 0.5 h. Two livers were split prior to perfusion (S1, S2), with tPA administered in one lobe, while the other served as a control. The remaining three whole livers (W1-W3) were compared to seven DCD control liver perfusions (C1-C7) with similar hepatocellular and biliary viability criteria. D-dimer levels were measured at T = 1 h to verify efficacy of tPA. Lactate, total bile production, bile pH, and difference in biliary injury scores before and after perfusion were compared between tPA and non-tPA groups using unpaired, Mann-Whitney tests.Results: Average weight-adjusted D-dimer levels were higher in tPA livers in the split and whole-liver model, verifying drug function. There were no differences in perfusion hepatic artery resistance, portal vein resistance, and arterial lactate between tPA livers and non-tPA livers in both the split and whole-liver model. However, when comparing biliary injury between hepatocellular and biliary non-viable whole livers, tPA livers had significantly lower PVP injury scores (0.67 vs. 2.0) and mural stroma (MS) injury scores (1.3 vs. 2.7).Conclusion: This study demonstrates that administration of tPA into DCD livers during NMP can reduce PVP and MS injury. Further studies are necessary to assess the effect of tPA administration on long term biliary complications.