Transplantation Liver Research Articles

Association of COVID-19 With Risk of Posttransplant Diabetes Mellitus

Background. Posttransplant diabetes mellitus (PTDM) is an important complication for solid organ transplant recipients (SOTRs). COVID-19 has been associated with an increased risk of incident diabetes in the general population. However, the association between COVID-19 and new-onset PTDM has not been explored. Methods. Using the National COVID Cohort Collaborative Enclave, we conducted a cohort study of adults without diabetes receiving a solid organ transplant (heart, lung, kidney, or liver) in the United States between April 1, 2020, and March 31, 2023, with and without a first diagnosis of COVID-19 (COVID+ versus COVID–) within 180 d of SOT. We propensity score matched a single COVID+ SOTR with a COVID– SOTR who was diabetes free at the same point posttransplant. Within this matched cohort, we used multivariable Cox proportional hazards models to examine the adjusted risk of PTDM associated with COVID+. Results. Among 1342 COVID+ SOTRs matched to 1342 COVID– SOTRs, the crude rate of newly diagnosed PTDM in the 2 y post-COVID was 17% in those with versus 13% in those without COVID-19 (P = 0.007). COVID-19 was significantly associated with new PTDM (adjusted hazard ratio, 1.37; 95% confidence interval, 1.12-1.68 at 2 y). Conclusions. Similar to other viral infections, COVID-19 is associated with an increased risk of PTDM in SOTRs.

Chemical approaches targeting the hurdles of hepatocyte transplantation: mechanisms, applications, and advances

Hepatocyte transplantation (HTx) has been a novel cell-based therapy for severe liver diseases, as the donor livers for orthotopic liver transplantation are of great shortage. However, HTx has been confronted with two main hurdles: limited high-quality hepatocyte sources and low cell engraftment and repopulation rate. To cope with, researchers have investigated on various strategies, including small molecule drugs with unique advantages. Small molecules are promising chemical tools to modulate cell fate and function for generating high quality hepatocyte sources. In addition, endothelial barrier, immune responses, and low proliferative efficiency of donor hepatocytes mainly contributes to low cell engraftment and repopulation rate. Interfering these biological processes with small molecules is beneficial for improving cell engraftment and repopulation. In this review, we will discuss the applications and advances of small molecules in modulating cell differentiation and reprogramming for hepatocyte resources and in improving cell engraftment and repopulation as well as its underlying mechanisms.

Mesenteric Vein to Gonadal Vein Shunt Embolization in Patients with Portal Hypertension: Technical Considerations and Clinical Outcomes.

To assess the technical and clinical outcomes of percutaneous embolization for high-flow mesenteric vein to gonadal vein (MGV) portosystemic shunts. In this HIPPA-compliant, review board-approved study, patients who underwent embolization of MGV shunts between 2011 and 2023 were included. Patient demographic data, embolization technique, clinical outcomes, and complications were retrieved from the electronic health records. Technical success was defined as complete occlusion of the shunt on follow-up imaging. Clinical outcomes assessed were resolution/improvement of hepatic encephalopathy, improvement in liver function, changes to liver volumes, and occurrence of adverse events. Eight patients (mean age 59.5, 75% female) with nine MGV shunts were included. The indications for shunt embolization included medically refractory hepatic encephalopathy, bleeding duodenal varices, and transplant liver dysfunction. The mean maximum shunt diameter was 23.3mm. Embolization was most commonly performed with a combination of coils and N-butyl cyanoacrylate or vascular plugs. Complete MGV shunt thrombosis was achieved in 7/9 shunts post-embolization, and symptom improvement was noted in 7/8 patients. Child-Pugh scores improved post-embolization in 6/9 patients by a median of 3 points. Liver volumes also increased by a mean of 20.8 ± 17.7% post-embolization. Minor adverse events included new onset ascites, partial mesenteric/portal vein thrombosis, and new gastroesophageal varices without bleeding in four patients. Embolization of MGV shunts is technically feasible and effective for treatment of hepatic encephalopathy and increasing hepatopetal portal perfusion. There was an improvement in Child-Pugh scores and an increase in liver volumes in the majority of patients post-embolization.

Ultra-Small Copper-Based Multienzyme-Like Nanoparticles Protect Against Hepatic Ischemia-Reperfusion Injury Through Scavenging Reactive Oxygen Species in Mice.

Hepatic ischemia-reperfusion injury (IRI) is a severe complication that occurs in the process of liver transplantation, hepatectomy, and other end-stage liver disease surgery, often resulting in the failure of surgery operation and even patient death. Currently, there is no effective way to prevent hepatic IRI clinically. Here, it is reported that the ultra-small copper-based multienzyme-like nanoparticles with catalase-like (CAT-like) and superoxide dismutase-like (SOD-like) catalytic activities significantly scavenge the surge-generated endogenous reactive oxygen species (ROS) and effectively protects hepatic IRI. Density functional theory calculations confirm that the nanoparticles efficiently scavenge ROS through their synergistic effects of the ultra-small copper SOD-like activity and manganese dioxides CAT-like activity. Furthermore, the results show that the biocompatible CMP NPs significantly protected hepatocytes from IRI in vitro and in vivo. Importantly, their therapeutic effect is much stronger than that of N-acetylcysteamine acid (NAC), an FDA-approved antioxidative drug. Finally, it is demonstrated that the protective effects of CMP NPs on hepatic IRI are related to suppressing inflammation and hepatocytic apoptosis and maintaining endothelial functions through scavenging ROS in liver tissues. The study can provide insight into the development of next-generation nanomedicines for scavenging ROS.

Awake prone positioning in an infant following living donor liver transplantation

BackgroundProne position has been proven to improve ventilation and oxygenation in infants. Currently, there are few reports of early prone position ventilation after pediatric liver transplantation. Here, we present our experience with prone position in an infant following living donor liver transplantation, in an attempt to improve oxygenation.Case presentationAn 8-month-old boy, 7.5 kg, experienced two failed extubations that presented with Type II respiratory failure due to dyspnea, potentially caused by consolidation and airway secretions. To prevent the third failure of extubation, prone position ventilation was implemented after the third extubation on the 11th postoperative day. Oxygenation increased after each prone position session with no signs of transplant liver ischemia or other adverse outcomes. Following two days of continuous prone position, airway secretions decreased, and the infant was discharged from the ICU. The third extubation procedure was successful.ConclusionsProne position ventilation may be effective in this infant without adverse events, indicating that early prone position is not absolutely contraindicated after pediatric liver transplantation. Therefore, more reasonable prone position strategies should be sought in infants undergoing liver transplantation.

Comparative Evaluation of 0.9% Normal Saline Versus Acetate-Gluconate-Based Balanced Solution on Acid-Base Status and Postoperative Liver Function in Donor Hepatectomy Patients.

Background Live donor liver transplantation, a widely practiced procedure, involves resecting a portion of a healthy donor's liver for transplantation. Despite advancements, it poses challenges like cardiovascular instability and electrolyte imbalances, with maintaining acid-base balance being critical. This study compares the effects of 0.9% normal saline and PlasmaLyte A® on acid-base status and postoperative liver function. Methodology This prospective observational study was conducted over one year among 40 healthy adults aged 18-60 years undergoing donor hepatectomy. Patients were alternately allocated to receive either 0.9% saline (Group 1; n = 20) or PlasmaLyte A® (Group 2; n = 20). Key parameters, including acid-base status, hemodynamic parameters, and postoperative liver function, were monitored at various intervals. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 25.0 (Released 2017; IBM Corp., Armonk, NY, USA), with appropriate statistical tests. A p-value <0.05 was considered statistically significant. Results The study included 40 patients, with 20 in each group. No significant differences were observed between the groups concerning age, gender, weight, hemodynamic parameters, and urine output. However, significant differences were found in acid-base parameters. Group 2 showed better preservation of acid-base balance with higher pH and HCO₃ levels. Patients in Group 1 exhibited a significant decrease in HCO₃ levels during surgery, while those in Group 2 maintained a more stable metabolic profile. Furthermore, nine patients in Group 1 required sodium bicarbonate supplementation for metabolic acidosis, compared to only three in Group 2. Postoperative liver function tests revealed no significant differences between the two groups, although a trend toward better outcomes was observed in Group 2. Conclusions PlasmaLyte A® demonstrated superior preservation of acid-base balance compared to 0.9% normal saline, with less need for bicarbonate supplementation. While liver function outcomes were similar, the balanced solution showed a trend toward better metabolic stability, suggesting it may offer safer and more effective fluid management in liver transplantation surgery.

Targeted Broader Sharing for Liver Continuous Distribution.

In recent years, changes to US organ allocation have aimed to improve equity and accessibility across regions. The Organ Procurement and Transplantation Network plans to adopt continuous liver distribution, prioritizing candidates based on a weighted composite allocation score (CAS) incorporating proximity, ABO types, medical urgency, and pediatric priority. The Liver Committee has requested research on CAS variations that account for geographical heterogenicity. We describe a method for designing a geographically heterogeneous CAS with targeted broader sharing (CAS-TBS) to balance the highly variable geographic distributions of liver transplant listings and liver donations. CAS-TBS assigns each donor hospital to either broader sharing or nearby sharing, adjusting donor-candidate distance allocation points accordingly. We found that to reduce geographic disparity in the median Model for End-stage Liver Disease at transplant (MMaT), >75% of livers recovered in regions 2 and 10 should be distributed with broader sharing, whereas 95% of livers recovered in regions 5 and 1 should be distributed with nearby sharing. In a 3-y simulation of liver allocation, CAS-TBS decreased MMaT by 2.1 points in high-MMaT areas such as region 5 while increasing MMaT only by 0.65 points in low-MMaT areas such as region 3. CAS-TBS significantly decreased median transport distance from 202 to 167 nautical miles under acuity circles and decreased waitlist deaths. Our CAS-TBS design methodology could be applied to design geographically heterogeneous allocation scores that reflect transplant community values and priorities within the continuous distribution project of the Organ Procurement and Transplantation Network. In our simulations, the incremental benefit of CAS-TBS over CAS was modest.

Potential of Raman-Reflectance Combination in Quantifying Liver Steatosis and Fat Droplet Size: Evidence From Monte Carlo Simulations and Phantom Studies.

This study explores a combined strategy of Raman and reflectance spectroscopy for quantifying liver fat content and fat droplet size, crucial in assessing donor livers. By using Monte Carlo simulations and experimental setups with oil-in-water phantoms, our findings indicate that Raman scattering can solely differentiate between varying fat contents. At the same time, reflectance intensity is influenced by both fat content and oil droplet size, with a more pronounced sensitivity to fat droplet size. This study demonstrates the efficacy of combined Raman and reflectance spectroscopy in assessing liver steatosis and fat droplet size, potentially aiding in assessing donor livers for transplantation.

P.348: Split left and right liver transplantation plus domino liver transplantation: one donor liver and three recipients at the same time, a complex but feasible allocation scheme to alleviate donor liver shortage.

P.348: Split left and right liver transplantation plus domino liver transplantation: one donor liver and three recipients at the same time, a complex but feasible allocation scheme to alleviate donor liver shortage.

413.1: Factors influencing the use of non-ideal deceased donor livers for transplantation: A qualitative study of U.S. transplant center leaders.

413.1: Factors influencing the use of non-ideal deceased donor livers for transplantation: A qualitative study of U.S. transplant center leaders.

Deceased donor non-composite split liver and intestinal transplantation for children.

Children with intestinal failure suffer liver damage associated with parenteral nutrition: a condition known as intestinal failure-associated liver disease (IFALD), which requires transplantation of both liver and intestine. In many countries, simultaneous transplantation of these two organs is performed using grafts from a deceased donor, but there have been no such cases in Japan, and the details of the procedure are not clear. Recently, we performed simultaneous split liver and intestinal transplantation in two premature infants with IFALD, using organs from identical deceased donors and achieved good results. These are the first two cases of this procedure being performed in Japan. We report these cases and discuss the important aspects of the surgical and perioperative management.

Identification and validation of ferroptosis-related hub genes and immune infiltration in liver ischemia-reperfusion injury

Ischemia–reperfusion injury (IRI) is a cumulation of pathophysiological processes that involves cell and organelle damage upon blood flow constraint and subsequent restoration. However, studies on overall immune infiltration and ferroptosis in liver ischemia-reperfusion injury (LIRI) are limited. This study explored immune cell infiltration and ferroptosis in LIRI using bioinformatics and experimental validation. The GSE151648 dataset, including 40 matched pairs of pre- and post- transplant liver samples was downloaded for bioinformatic analysis. Eleven hub genes were identified by overlapping differentially expressed genes (DEGs), iron genes, and genes identified through weighted gene co-expression network analysis (WGCNA). Subsequently, the pathway enrichment, transcription factor-target, microRNA-mRNA and protein-protein interaction networks were investigated. The diagnostic model was established by logistic regression, which was validated in the GSE23649 and GSE100155 datasets and verified using cytological experiments. Moreover, several drugs targeting these genes were found in DrugBank, providing a more effective treatment for LIRI. In addition, the expression of 11 hub genes was validated using quantitative real-time polymerase chain reaction (qRT-PCR) in liver transplantation samples and animal models. The expression of the 11 hub genes increased in LIRI compared with the control. Five genes were significantly enriched in six biological process terms, six genes showed high enrichment for LIRI-related signaling pathways. There were 56 relevant transcriptional factors and two central modules in the protein-protein interaction network. Further immune infiltration analysis indicated that immune cells including neutrophils and natural killer cells were differentially accumulated in the pre- and post-transplant groups, and this was accompanied by changes in immune-related factors. Finally, 10 targeted drugs were screened. Through bioinformatics and further experimental verification, we identified hub genes related to ferroptosis that could be used as potential targets to alleviate LIRI.

Disease progression of side-branch intraductal papillary mucinous neoplasms following solid organ transplant

BackgroundBranch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) are becoming more prevalent with advanced medical imaging and account for most of pancreatic cystic neoplasms (PCNs). Most incidental lesions should be surveyed, with resection reserved for specific, high-risk cases. Solid organ transplantation candidates may be high risk of resection before transplant and will require systemic immunosuppression after transplant, which has been theorized to alter the natural history of the IPMN. We aimed to describe the progression in surveilled cysts after solid organ transplantation. MethodsA prospectively maintained database of PCNs was queried for patients with IPMN. Patients who had received a previous solid organ transplantation and with ≥2 imaging studies >6 months apart after transplantation were included. Clinically relevant (CR) progression was defined as symptoms, worrisome/high-risk stigmata, or invasive carcinoma (IC). Growth ≥5 mm in 2 years is considered CR progression; size ≥3 cm alone is not. ResultsBetween 1997 and 2023, 252 patients received solid organ transplantation (liver, 86; kidney, 113; and lung, 54) and were diagnosed as having an IPMN. This cohort was compared with a set of 770 patients surveilled for IPMN who did not have previous transplantation. Median follow-up period was 3.7 years (IQR, 1.6–6.8). Moreover, 2 transplant patients (0.8%) developed IC, and 4 developed (1.6%) high-grade dysplasia (HGD). Both were less common in transplant patients than the nontransplant population (IC, 3.3%; HGD, 2.9%), although this was not significant on time-to-event analysis (IC, P = .152; HGD, P = .352). The rate of CR progression was high in the transplant cohort (n = 118; 47%). Features of CR progression included size growth (n = 79; 67%), other worrisome/high-risk stigmata (n = 25; 21%), and new main duct involvement (n = 14; 12%). Compared with the nontransplant (n = 128; 17%), transplant patients had a higher rate of CR progression (P < .001), which was mostly explained by a more frequent size growth (31% vs 9%; P < .001). However, no transplant patients with size growth CR progression developed IC. Moreover, 17 (6.7%) required pancreatic surgery for CR progression after transplant vs 58 (7.5%) in the nontransplant population. Furthermore, 6 resected cysts (35%) harbored high-risk pathology after transplant (IC, 2; HGD, 4) vs 40 (69%) in the general population (P < .001; IC, 29; HGD, 11). ConclusionMalignant transformation of BD-IPMNs is rare despite systemic immunosuppression in solid organ transplant patients. This supports transplantation in patients with IPMN without fear of worsening their risk of pancreatic cancer, although it was associated with a higher risk of disease progression. Patients with IPMNs should be surveilled with yearly scans after transplant, with pancreatic resection reserved for only high-risk features as we continue to define the optimal criteria for those with CR progression.

Primary Team Versus Local Recovery in Liver Transplantation in the Modern Era: A National Analysis of the United Network for Organ Sharing Database.

The implementation of acuity circles (AC) in 2020 and the COVID-19 pandemic increased the use of local surgeons to recover livers for transplant; however, the impact on liver transplant (LT) outcomes is unknown. Deceased donor adult LT recipients from the UNOS database were identified. Recipients were grouped by donor surgeon: local versus primary recovery. Patient and graft survival as well as trends in local recovery in the 2 years pre-AC and post-AC were assessed. The utilization of local recovery in LT increased from 22.3% to 37.9% post-AC (p<0.01). LTs with local recovery had longer cold ischemia times (6.5 h [5.4-7.8] vs. 5.3 h [4.4-6.5], p<0.01) and traveled further (210 miles [89-373] vs. 73 miles [11-196], p<0.01) than those using primary recovery. Multivariate analyses revealed no differences in patient or graft survival between local and primary recovery, and between OPO and local surgeon. There was no difference in survival when comparing simultaneous liver-kidney, donation after circulatory death, MELD ≥ 30, or redo-LT by recovery team. Recovery and utilization rates were also noted to be higher post-AC (51.4%vs. 48.6% pre-AC, p<0.01) as well as when OPO surgeons recovered the allografts (72.5%vs. 66.0%, p<0.01). Nearly 40% of LTs are performed using local recovery, and utilization rates and trends continue to change with changing organ-sharing paradigms such as AC. This practice appears safe with outcomes similar to recovery by the primary team in appropriately selected recipients and may lead to increased access and the ability to transplant more livers.

Perioperative management in pediatric domino liver transplantation for metabolic disorders: A narrative review.

Domino liver transplantation and domino-auxiliary partial orthotopic liver transplantation are emerging techniques that can expand the liver donor pool and provide hope for children with liver disease. The innovative technique of domino liver transplantation has emerged as a pioneering strategy, capitalizing on structurally preserved livers from donors exhibiting single enzymatic defects within a morphologically normal context, effectively broadening the donor pool. Concurrently, the increasingly prevalent domino-auxiliary partial orthotopic liver transplantation method assumes a critical role in bolstering available donor resources. These advanced transplantation methods present a unique opportunity for pediatric patients who, despite having structurally and functionally intact livers and lacking early signs of portal hypertension or extrahepatic involvement, do not attain priority on conventional transplant lists. Utilizing optimal clinical conditions enhances posttransplant outcomes, benefiting patients who would otherwise endure extended waiting periods for traditional transplantation. The perioperative management of children undergoing these procedures is complex and requires careful consideration of some factors, including clinical and metabolic conditions of the specific metabolic disorder, and the need for tailored perioperative management planning. Furthermore, the prudent consideration of de novo disease development in the recipient assumes paramount significance when selecting suitable donors for domino liver transplantation, as it profoundly influences prognosis, mortality, and morbidity. This narrative review of domino liver transplantation will discuss the pathophysiology, clinical evaluation, perioperative management, and prognostic expectations, focusing on perioperative anesthetic considerations for children undergoing domino liver transplantation.

Blood Supply of Caudate Lobe and Its Significance in Transplantation of Liver

Blood Supply of Caudate Lobe and Its Significance in Transplantation of Liver

Long-term outcomes after hypothermic oxygenated machine perfusion and transplantation of 1,202 donor livers in a real-world setting (HOPE-REAL study)

Despite strong evidence for improved preservation of donor livers by machine perfusion, longer post-transplant follow-up data are urgently needed in an unselected patient population. We aimed to assess long-term outcomes after transplantation of hypothermic oxygenated machine perfusion (HOPE)-treated donor livers based on real-world data (i.e., IDEAL-D stage 4). In this international, multicentre, observational cohort study, we collected data from adult recipients of HOPE-treated livers transplanted between January 2012 and December 2021. Analyses were stratified by donation after brain death (DBD) and donation after circulatory death (DCD), sub-divided by their respective risk categories. The primary outcome was death-censored graft survival. Secondary outcomes included the incidence of primary non-function (PNF) and ischaemic cholangiopathy (IC). We report on 1,202 liver transplantations (64% DBD) performed at 22 European centres. For DBD, a total number of 99 benchmark (8%), 176 standard (15%), and 493 extended-criteria (41%) cases were included. For DCD, 117 transplants were classified as low risk (10%), 186 as high risk (16%), and 131 as futile (11%), with significant risk profile variations among centres. Actuarial 1-, 3-, and 5-year death-censored graft survival rates for DBD and DCD livers were 95%, 92%, and 91%, vs. 92%, 87%, and 81%, respectively (log-rank p= 0.003). Within DBD and DCD strata, death-censored graft survival was similar among risk groups (log-rank p= 0.26, p= 0.99). Graft loss due to PNF or IC was 2.3% and 0.4% (DBD), and 5% and 4.1% (DCD). This study shows excellent 5-year survival after transplantation of HOPE-treated DBD and DCD livers with low rates of graft loss due to PNF or IC, irrespective of their individual risk profile. HOPE treatment has now reached IDEAL-D stage 4, which further supports its implementation in routine clinical practice. ClinicalTrials.gov Identifier: NCT05520320. This study demonstrates the excellent long-term performance of hypothermic oxygenated machine perfusion (HOPE) treatment of donation after circulatory and donation after brain death liver grafts irrespective of their individual risk profile in a real-world setting, outside the evaluation of randomised-controlled trials. While previous studies have established safety, feasibility, and efficacy against the current standard, according to the IDEAL-D evaluation framework, HOPE treatment has now reached the final IDEAL-D stage 4, which further supports its implementation in routine clinical practice.

Effect of Remote Ischemic Conditioning on Organ Transplantation: A Meta-Analysis of Randomized Controlled Trials

BackgroundRemote ischemic conditioning (RIC) has shown great advantages in protecting organs from ischemia-reperfusion loss and applied research on RIC continues to increase. We performed a systematic review and meta-analysis to comprehensively investigate the value of RIC for different organ transplantation. MethodsWe searched PubMed, EMBASE, and the Cochrane Library from inception to November 1, 2023, for randomized controlled trials investigating whether RIC has an advantage in organ transplantation (including heart, lung, liver, and kidney) compared with controls. The primary outcomes varied according to the transplanted organ, including liver transplantation (graft loss, early allograft dysfunction, acute kidney injury, days in hospital, and mortality); kidney transplantation (delayed graft function, acute rejection (AR), graft loss, 50% decrease in serum creatinine, glomerular filtration rate, days in hospital, and mortality); heart and lung transplantation (AR, mortality). Two investigators independently selected suitable trials, assessed trial quality, and extracted the data. ResultsA total of 11 randomized controlled trials were included in this study, including six kidney transplants, three liver transplants, and one heart and lung transplant each, with 561 RIC cases and 564 controls, and a total of 1125 patients. The results showed that RIC did not reduce mortality in transplant patients compared with controls (liver transplant: RR0.9, 95% confidence interval [0.31-2.66]; kidney transplant: RR 0.76, 95% confidence interval [0.17-3.33]), graft failure rate (liver transplantation: RR 0.3, 95% confidence interval [0.07, 1.19]; kidney transplantation: RR 0.89, 95% confidence interval [0.35, 2.27]), length of hospital stay (liver transplantation: standard mean difference [SMD] 0.14, 95% confidence interval [−0.15, 0.42]; kidney transplantation: SMD −0.1, 95% confidence interval [−0.3, 0.11]). In addition, RIC did not improve early liver function after liver transplantation (RR 0.97, 95% confidence interval [0.55,1.7]), acute kidney injury after liver transplantation (RR 1.17 95% confidence interval [0.9, 1.54]), delayed functional recovery after renal transplantation (RR 0.84, 95% confidence interval [0.62, 1.15]), AR rate (RR 1.04, 95% confidence interval [0.72, 1.49]), 50% serum creatinine decline rate (RR 1.1, 95% confidence interval [0.88, 1.37]), glomerular filtration rate 3 months after surgery (SMD 0.13, 95% confidence interval [−0.05, 0.31]) and postoperative 12 months glomerular filtration rate (SMD 0.13, 95% confidence interval [−0.06, 0.31]). ConclusionRemote ischemic modulation does not improve clinical outcomes in patients undergoing organ transplantation (heart, lung, liver, and kidney).

Viability assessment and transplantation of extended criteria donor liver grafts using normothermic machine perfusion

BackgroundThe scarcity of available liver grafts necessitates the use of organs from extended criteria donors, a practice associated with an increased risk of graft failure. A notable percentage of deceased donor liver allografts are rejected due to subjective criteria. Normothermic machine perfusion holds promise for introducing objective parameters into this decision-making process. The aim of this study was to compare the outcomes of standard criteria and extended criteria donor allografts after liver transplantation, following viability assessment, using normothermic machine perfusion. MethodsLiver allografts preserved by normothermic machine perfusion before liver transplantation at the University Hospital of Münster were retrospectively analyzed. Organs were stratified according to the Eurotransplant Donor Risk Index. In total, 101 liver grafts were included in this study and divided into 2 groups: (1) standard criteria donors with a Donor Risk Index <1.8 (DRI-low) and (2) extended criteria donors with a Donor Risk Index ≥1.8 (DRI-high). ResultsAn increased risk profile of donor livers, as assessed by the Eurotransplant Donor Risk Index, did not correlate with patient or graft survival. High-risk liver grafts were effectively transplanted into recipients with different risk levels after viability assessment by normothermic machine perfusion. However, the recipients’ model for end-stage liver disease scores showed a significant association with both overall patient and graft survival. ConclusionThe use of normothermic machine perfusion for viability assessment allows safe transplantation of high-risk donor livers and effectively addresses the disparity between donor liver availability and transplantation demand.

Defatting of donor transplant livers during normothermic perfusion—a randomised clinical trial: study protocol for the DeFat study

BackgroundLiver disease is the third leading cause of premature death in the UK. Transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs. As a result, up to 20% of patients on liver transplant waiting lists die before receiving a transplant. A third of donated livers are not suitable for transplant, often due to steatosis. Hepatic steatosis, which affects 33% of the UK population, is strongly associated with obesity, an increasing problem in the potential donor pool. We have recently tested defatting interventions during normothermic machine perfusion (NMP) in discarded steatotic human livers that were not transplanted. A combination of therapies including forskolin (NKH477) and L-carnitine to defat liver cells and lipoprotein apheresis filtration were investigated. These interventions resulted in functional improvement during perfusion and reduced the intrahepatocellular triglyceride (IHTG) content. We hypothesise that defatting during NMP will allow more steatotic livers to be transplanted with improved outcomes.MethodsIn the proposed multi-centre clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim to test the safety and feasibility of the defatting intervention and will explore efficacy by comparing ex-situ and post-reperfusion liver function between the groups. The primary endpoint will be the proportion of livers that achieve predefined functional criteria during perfusion which indicate potential suitability for transplantation. These criteria reflect hepatic metabolism and injury and include lactate clearance, perfusate pH, glucose metabolism, bile composition, vascular flows and transaminase levels. Clinical secondary endpoints will include proportion of livers transplanted in the two arms, graft function; cell-free DNA (cfDNA) at follow-up visits; patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); non-anastomotic biliary strictures and recurrence of steatosis (determined on MRI at 6 months).DiscussionThis study explores ex-situ pharmacological optimisation of steatotic donor livers during NMP. If the intervention proves effective, it will allow the safe transplantation of livers that are currently very likely to be discarded, thereby reducing waiting list deaths.Trial registrationISRCTN ISRCTN14957538. Registered in October 2022.