Primary cilia as a targetable node between biliary injury, senescence and regeneration in liver transplantation.

BACKGROUND & AIMS: Biliary complications are a major cause of morbidity and mortality in liver transplantation. Up to 25% of patients that develop biliary complications require additional surgical procedures, re-transplantation or die in the absence of a suitable regraft. Here, we investigate the role of the primary cilium, a highly-specialised sensory organelle, in biliary injury leading to post-transplant biliary complications. METHODS: Human biopsies were used to study the structure and function of primary cilia in liver transplant recipients that develop biliary complications (N=7) in comparison with recipients without biliary complications (N=12). To study the biological effects of the primary cilia during transplantation, we generated murine models that recapitulate liver procurement and cold storage, and assessed the elimination of the primary cilia in biliary epithelial cells in the K19CreERTKif3aflox/flox mouse model. To explore the molecular mechanisms responsible for the observed phenotypes we used in vitro models of ischemia, cellular senescence and primary cilia ablation. Finally, we used pharmacological and genetic approaches to target cellular senescence and the primary cilia, both in mouse models and discarded human donor livers. RESULTS: Prolonged ischemic periods before transplantation result in ciliary shortening and cellular senescence, an irreversible cell cycle arrest that blocks regeneration. Our results indicate that primary cilia damage results in biliary injury and a loss of regenerative potential. Senescence negatively impacts primary cilia structure and triggers a negative feedback loop that further impairs regeneration. Finally, we explore how targeted interventions for cellular senescence and/or the stabilisation of the primary cilia improve biliary regeneration following ischemic injury. CONCLUSIONS: Primary cilia play an essential role in biliary regeneration and we demonstrate that senolytics and cilia-stabilising treatments provide a potential therapeutic opportunity to reduce the rate of biliary complications and improve clinical outcomes in liver transplantation. IMPACT AND IMPLICATIONS: Up to 25% of liver transplants result in biliary complications, leading to additional surgery, retransplants, or death. We found that the incidence of biliary complications is increased by damage to the primary cilium, an antenna that protrudes from the cell and is key to regeneration. Here, we show that treatments that preserve the primary cilia during the transplant process provide a potential solution to reduce the rates of biliary complications.

Machine perfusion preservation highlights from the Congress of the European Society of Organ Transplantation 2023.

The 21st Congress of the European Society of Organ Transplantation (ESOT), held on September 17-20th, 2023, in Athens, Greece, was a pivotal event in transplantation, focusing on the theme "Disruptive Innovation, Trusted Care." The congress attracted a global audience of 2 826 participants from 82 countries, emphasizing its international significance. Machine perfusion, as a groundbreaking technology in organ transplantation, was one of the central focuses of the conference. This year's meeting had a remarkable increase in accepted abstracts on machine perfusion, evidencing its growing prominence in the field. The collective findings from these abstracts highlighted the efficacy of machine perfusion in improving organ viability and transplant outcomes. Studies demonstrated improvements in graft survival and reduction in complications, as well as novel uses and techniques. Furthermore, the integration of machine perfusion with regenerative medicine and its application across multiple organ types were significant discussion points. The congress also highlighted the challenges and solutions in implementing machine perfusion in clinical settings, emphasizing the importance of practical training and international collaboration for advancing this technology. ESOT 2023 served as a crucial platform for disseminating scientific advancements, fostering practical learning, and facilitating international collaborations in organ transplantation. The congress underscored the evolution and importance of machine perfusion technology, marking a significant step forward in enhancing patient outcomes in the field of organ transplantation.

Recent outcomes of liver transplantation for Budd-Chiari syndrome: A study of the European Liver Transplant Registry (ELTR) and affiliated centers.

BACKGROUND AND AIMS: Management of Budd-Chiari syndrome (BCS) has improved over the last decades. The main aim was to evaluate the contemporary post-liver transplant (post-LT) outcomes in Europe. APPROACH AND RESULTS: Data from all patients who underwent transplantation from 1976 to 2020 was obtained from the European Liver Transplant Registry (ELTR). Patients < 16 years, with secondary BCS or HCC were excluded. Patient survival (PS) and graft survival (GS) before and after 2000 were compared. Multivariate Cox regression analysis identified predictors of PS and GS after 2000. Supplemental data was requested from all ELTR-affiliated centers and received from 44. In all, 808 patients underwent transplantation between 2000 and 2020. One-, 5- and 10-year PS was 84%, 77%, and 68%, and GS was 79%, 70%, and 62%, respectively. Both significantly improved compared to outcomes before 2000 ( p < 0.001). Median follow-up was 50 months and retransplantation rate was 12%. Recipient age (aHR:1.04,95%CI:1.02-1.06) and MELD score (aHR:1.04,95%CI:1.01-1.06), especially above 30, were associated with worse PS, while male sex had better outcomes (aHR:0.63,95%CI:0.41-0.96). Donor age was associated with worse PS (aHR:1.01,95%CI:1.00-1.03) and GS (aHR:1.02,95%CI:1.01-1.03). In 353 patients (44%) with supplemental data, 33% had myeloproliferative neoplasm, 20% underwent TIPS pre-LT, and 85% used anticoagulation post-LT. Post-LT anticoagulation was associated with improved PS (aHR:0.29,95%CI:0.16-0.54) and GS (aHR:0.48,95%CI:0.29-0.81). Hepatic artery thrombosis and portal vein thrombosis (PVT) occurred in 9% and 7%, while recurrent BCS was rare (3%). CONCLUSIONS: LT for BCS results in excellent patient- and graft-survival. Older recipient or donor age and higher MELD are associated with poorer outcomes, while long-term anticoagulation improves both patient and graft outcomes.

Choroidal and retinal thinning in chronic kidney disease independently associate with eGFR decline and are modifiable with treatment.

In patients with chronic kidney disease (CKD), there is an unmet need for novel biomarkers that reliably track kidney injury, demonstrate treatment-response, and predict outcomes. Here, we investigate the potential of retinal optical coherence tomography (OCT) to achieve these ends in a series of prospective studies of patients with pre-dialysis CKD (including those with a kidney transplant), patients with kidney failure undergoing kidney transplantation, living kidney donors, and healthy volunteers. Compared to health, we observe similar retinal thinning and reduced macular volume in patients with CKD and in those with a kidney transplant. However, the choroidal thinning observed in CKD is not seen in patients with a kidney transplant whose choroids resemble those of healthy volunteers. In CKD, the degree of choroidal thinning relates to falling eGFR and extent of kidney scarring. Following kidney transplantation, choroidal thickness increases rapidly (~10%) and is maintained over 1-year, whereas gradual choroidal thinning is seen during the 12 months following kidney donation. In patients with CKD, retinal and choroidal thickness independently associate with eGFR decline over 2 years. These observations highlight the potential for retinal OCT to act as a non-invasive monitoring and prognostic biomarker of kidney injury.

Liquid biopsy for early detection of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly prevalent and lethal cancer globally. Over 90% of HCC cases arise in the context of liver cirrhosis, and the severity of the underlying liver disease or advanced tumor stage at diagnosis significantly limits treatment options. Early diagnosis is crucial, and all guidelines stress the importance of screening protocols for HCC early detection as a public health objective. As serum biomarkers are not optimal for early diagnosis, liquid biopsy has emerged as a promising tool for diagnosis, prognostication, and patients' stratification for personalized therapy in various solid tumors, including HCC. While circulating tumor cells (CTCs) are better suited for personalized therapy and prognosis, cell-free DNA (cfDNA) and extracellular vesicle-based technologies show potential for early diagnosis, HCC screening, and surveillance protocols. Evaluating the added value of liquid biopsy genetic and epigenetic biomarkers for HCC screening is a key goal in translational research. Somatic mutations commonly found in HCC can be investigated in cfDNA and plasma exosomes as genetic biomarkers. Unique methylation patterns in cfDNA or cfDNA fragmentome features have been suggested as innovative tools for early HCC detection. Likewise, extracellular vesicle cargo biomarkers such as miRNAs and long non-coding RNAs may serve as potential biomarkers for early HCC detection. This review will explore recent findings on the utility of liquid biopsy for early HCC diagnosis. Combining liquid biopsy methods with traditional serological biomarkers could improve the overall diagnostic accuracy for early HCC detection.

Immunosuppression of HLA identical living-donor kidney transplant recipients: A systematic review.

BACKGROUND: Kidney transplant (KT) recipients of HLA identical siblings (HLAid) have lower immunological risk, but there are no specific recommendations for immunosuppression. Our aim was to analyze evidence about results from HLAid living-donor recipients under different immunosuppression in the current era of immunological risk assessment. METHODS: Systematic review of studies describing associations between outcomes of HLAid living-donor KT recipients according to their immunological risk and applied immunosuppression. RESULTS: From 1351 studies, 16 (5636 KT recipients) were included in the analysis. All studies were retrospective, ten comparing immunosuppression strategies, and six immunological risk strata. Of those ten, six studies were published in 1990 or earlier and only three included tacrolimus. The evidence is poor, and the inclusion of calcineurin inhibitors does not demonstrate better results. Furthermore, only few studies describe different immunosuppression regimens according to the patient immunological risk and, in general, they do not include the assessment with new solid phase assays. CONCLUSIONS: There are no studies analyzing the association of outcomes of HLAid KT recipients with current immunological risk tools. In the absence of evidence, no decision or proposal of immunosuppression adapted to modern immunological risk assessment can be made currently by the Descartes Working Group.

European Society for Organ Transplantation (ESOT) Consensus Statement on the Role of Pancreas Machine Perfusion to Increase the Donor Pool for Beta Cell Replacement Therapy.

The advent of Machine Perfusion (MP) as a superior form of preservation and assessment for cold storage of both high-risk kidney's and the liver presents opportunities in the field of beta-cell replacement. It is yet unknown whether such techniques, when applied to the pancreas, can increase the pool of suitable donor organs as well as ameliorating the effects of ischemia incurred during the retrieval process. Recent experimental models of pancreatic MP appear promising. Applications of MP to the pancreas, needs refinement regarding perfusion protocols and organ viability assessment criteria. To address the "Role of pancreas machine perfusion to increase the donor pool for beta cell replacement," the European Society for Organ Transplantation (ESOT) assembled a dedicated working group comprising of experts to review literature pertaining to the role of MP as a method of improving donor pancreas quality as well as quantity available for transplant, and to develop guidelines founded on evidence-based reviews in experimental and clinical settings. These were subsequently refined during the Consensus Conference when this took place in Prague.

Normothermic machine perfusion versus static cold storage in donation after circulatory death kidney transplantation: a randomized controlled trial.

Kidney transplantation is the optimal treatment for end-stage renal disease, but it is still severely limited by a lack of suitable organ donors. Kidneys from donation after circulatory death (DCD) donors have been used to increase transplant rates, but these organs are susceptible to cold ischemic injury in the storage period before transplantation, the clinical consequence of which is high rates of delayed graft function (DGF). Normothermic machine perfusion (NMP) is an emerging technique that circulates a warmed, oxygenated red-cell-based perfusate through the kidney to maintain near-physiological conditions. We conducted a randomized controlled trial to compare the outcome of DCD kidney transplants after conventional static cold storage (SCS) alone or SCS plus 1-h NMP. A total of 338 kidneys were randomly allocated to SCS (n = 168) or NMP (n = 170), and 277 kidneys were included in the final intention-to-treat analysis. The primary endpoint was DGF, defined as the requirement for dialysis in the first 7 d after transplant. The rate of DGF was 82 of 135 (60.7%) in NMP kidneys versus 83 of 142 (58.5%) in SCS kidneys (adjusted odds ratio (95% confidence interval) 1.13 (0.69-1.84); P = 0.624). NMP was not associated with any increase in transplant thrombosis, infectious complications or any other adverse events. A 1-h period of NMP at the end of SCS did not reduce the rate of DGF in DCD kidneys. NMP was demonstrated to be feasible, safe and suitable for clinical application. Trial registration number: ISRCTN15821205 .

Research and Innovation in Organ Donation: Recommendations From an International Consensus Forum.

This report provides recommendations from the Research and Innovation domain as part of the International Donation and Transplantation Legislative and Policy Forum (hereafter the Forum) to provide expert guidance on the structure of an ideal organ and tissue donation and transplantation system. The recommendations focus on deceased donation research and are intended for clinicians, investigators, decision-makers, and patient, family, and donor (PFD) partners involved in the field. Methods: We identified topics impacting donation research through consensus using nominal group technique. Members performed narrative reviews and synthesized current knowledge on each topic, which included academic articles, policy documents, and gray literature. Using the nominal group technique, committee members discussed significant findings, which provided evidence for our recommendations. The Forum's scientific committee then vetted recommendations. Results: We developed 16 recommendations in 3 key areas to provide stakeholders guidance in developing a robust deceased donor research framework. These include PFD and public involvement in research; donor, surrogate, and recipient consent within a research ethics framework; and data management. We highlight the importance of PFD and public partner involvement in research, we define the minimum ethical requirements for the protection of donors and recipients of both target and nontarget organ recipients, and we recommend the creation of a centrally administered donor research oversight committee, a single specialist institutional review board, and a research oversight body to facilitate coordination and ethical oversight of organ donor intervention research. Conclusions: Our recommendations provide a roadmap for developing and implementing an ethical deceased donation research framework that continually builds public trust. Although these recommendations can be applied to jurisdictions developing or reforming their organ and tissue donation and transplantation system, stakeholders are encouraged to collaborate and respond to their specific jurisdictional needs related to organ and tissue shortages.

Utilization of livers donated after circulatory death for transplantation - An international comparison.

BACKGROUND & AIMS: Liver graft utilization rates are a hot topic due to the worldwide organ shortage and the increasing number of transplant candidates on waiting lists. Liver perfusion techniques have been introduced in several countries, and may help to increase the organ supply, as they potentially enable the assessment of livers before use. METHODS: Liver offers were counted from donation after circulatory death (DCD) donors (Maastricht type III) arising during the past decade in eight countries, including Belgium, France, Italy, the Netherlands, Spain, Switzerland, the UK, and the US. Initial type-III DCD liver offers were correlated with accepted, recovered and implanted livers. RESULTS: A total number of 34,269 DCD livers were offered, resulting in 9,780 liver transplants (28.5%). The discard rates were highest in the UK and US, ranging between 70 and 80%. In contrast, much lower DCD liver discard rates, e.g. between 30-40%, were found in Belgium, France, Italy, Spain and Switzerland. In addition, we observed large differences in the use of various machine perfusion techniques, as well as in graft and donor risk factors. For example, the median donor age and functional donor warm ischemia time were highest in Italy, e.g. >40 min, followed by Switzerland, France, and the Netherlands. Importantly, such varying risk profiles of accepted DCD livers between countries did not translate into large differences in 5-year graft survival rates, which ranged between 60-82% in this analysis. CONCLUSIONS: Overall, DCD liver discard rates across the eight countries were high, although this primarily reflects the situation in the Netherlands, the UK and the US. Countries where in situ and ex situ machine perfusion strategies were used routinely had better DCD utilization rates without compromised outcomes. IMPACT AND IMPLICATIONS: A significant number of Maastricht type III DCD livers are discarded across Europe and North America today. The overall utilization rate among eight Western countries is 28.5% but varies significantly between 18.9% and 74.2%. For example, the median DCD-III liver utilization in five countries, e.g. Belgium, France, Italy, Switzerland, and Spain is 65%, in contrast to 24% in the Netherlands, UK and US. Despite this, and despite different rules and strategies for organ acceptance and preservation, 1- and 5-year graft survival rates remain fairly similar among all participating countries. A highly varying experience with modern machine perfusion technology was observed. In situ and ex situ liver perfusion concepts, and application of assessment tools for type-III DCD livers before transplantation, may be a key explanation for the observed differences in DCD-III utilization.

The 3-Step Model of informed consent for living kidney donation: a proposal on behalf of the DESCaRTES Working Group of the European Renal Association.

Living donation challenges the ethical principle of non-maleficence in that it exposes healthy persons to risks for the benefit of someone else. This makes safety, informed consent (IC) and education a priority. Living kidney donation has multiple benefits for the potential donor, but there are also several known short- and long-term risks. Although complete standardization of IC is likely to be unattainable, studies have emphasized the need for a standardized IC process to enable equitable educational and decision-making prospects for the prevention of inequities across transplant centers. Based on the Three-Talk Model of shared decision-making by Elwyn et al., we propose a model, named 3-Step (S) Model, where each step coincides with the three ideal timings of the process leading the living donor to the decision to pursue living donation: prior to the need for kidney replacement therapy (team talk); at the local nephrology unit or transplant center, with transplant clinicians and surgeons prior to evaluations start (option talk); and throughout evaluation, after having learned about the different aspects of donation, especially if there are second thoughts or doubts (decision talk). Based on the 3-S Model, to deliver conceptual and practical guidance to nephrologists and transplant clinicians, we provide recommendations for standardization of the timing, content, modalities for communicating risks and assessment of understanding prior to donation. The 3-S Model successfully allows an integration between standardization and individualization of IC, enabling a person-centered approach to potential donors. Studies will assess the effectiveness of the 3-S Model in kidney transplant clinical practice.

External Validation of the United Kingdom Transplant Benefit Score in Australia and New Zealand.

Introduction: In Australia and New Zealand, liver allocation is needs based (based on model for end-stage liver disease score). An alternative allocation system is a transplant benefit-based model. Transplant benefit is quantified by complex waitlist and transplant survival prediction models. Research Questions: To validate the UK transplant benefit score in an Australia and New Zealand population. Design: This study analyzed data on listings and transplants for chronic liver disease between 2009 and 2018, using the Australia and New Zealand Liver and Intestinal Transplant Registry. Excluded were variant syndromes, hepatocellular cancer, urgent listings, pediatric, living donor, and multi-organ listings and transplants. UK transplant benefit waitlist and transplant benefit score were calculated for listings and transplants, respectively. Outcomes were time to waitlist death and time to transplant failure. Calibration and discrimination were assessed with Kaplan-Meier analysis and C-statistics. Results: There were differences in the UK and Australia and New Zealand listing, transplant, and donor populations including older recipient age, higher recipient and donor body mass index, and higher incidence of hepatitis C in the Australia and New Zealand population. Waitlist scores were calculated for 2241 patients and transplant scores were calculated for 1755 patients. The waitlist model C-statistic at 5 years was 0.70 and the transplant model C-statistic was 0.56, with poor calibration of both models. Conclusion: The UK transplant benefit score model performed poorly, suggesting that UK benefit-based allocation would not improve overall outcomes in Australia and New Zealand. Generalizability of survival prediction models was limited by differences in transplant populations and practices.

A Home Education Service to Increase Knowledge of Treatment Options and Improve Attitudes to Living Donor Kidney Transplantation.

Introduction: Lack of knowledge about living donor kidney transplant and difficulties in approaching potential donors constitute barriers for many patients and may contribute to inequality of access. Project Aims: Renal Education and Choices at Home was a UK single-centre pilot of home education; an initiative aiming to overcome barriers by increasing knowledge among patients and support networks and by facilitating living donation discussion in the patient's home. Design: This was a pre-post comparison of knowledge, attitude, and ability to communicate about transplant. Pre-visit knowledge about treatment options and attitudes towards transplant were measured using a validated questionnaire, repeated 4-6 weeks post-visit, to assess the session's impact, along with an evaluation survey, to determine how patients perceived the session. Results: From November 2018 to February 2020, a nurse specialist delivered living donor transplant education sessions in the homes of 86 patients, attended by 141 additional invitees. Home visits led to a significant improvement in knowledge about renal therapies, including living donor transplantation. The evaluation of the home visits by patients and invitees was overwhelmingly positive. Of the 86 patients visited, 46 (53%) had at least one potential donor initiating the assessment process following the visit. Overall, 78 potential donors initiated the assessment process. Conclusion: Home education contributed to addressing recognised barriers, in a way that was well received by patients and was novel in our health system. Home education may be particularly beneficial for patients affected by known barriers to living donor transplantation such as socio-economic deprivation.

Improved Organ Utilization and Better Transplant Outcomes With In Situ Normothermic Regional Perfusion in Controlled Donation After Circulatory Death.

BACKGROUND: . We evaluated whether the use of normothermic regional perfusion (NRP) was associated with increased organ recovery and improved transplant outcomes from controlled donation after circulatory death (cDCD). METHODS: . This is a retrospective analysis of UK adult cDCD donors' where at least 1 abdominal organ was accepted for transplantation between January 1, 2011, and December 31, 2019. RESULTS: . A mean of 3.3 organs was transplanted when NRP was used compared with 2.6 organs per donor when NRP was not used. When adjusting for organ-specific donor risk profiles, the use of NRP increased the odds of all abdominal organs being transplanted by 3-fold for liver ( P < 0.0001; 95% confidence interval [CI], 2.20-4.29), 1.5-fold for kidney ( P = 0.12; 95% CI, 0.87-2.58), and 1.6-fold for pancreas ( P = 0.0611; 95% CI, 0.98-2.64). Twelve-mo liver transplant survival was superior for recipients of a cDCD NRP graft with a 51% lower risk-adjusted hazard of transplant failure (HR = 0.494). In risk-adjusted analyses, NRP kidneys had a 35% lower chance of developing delayed graft function than non-NRP kidneys (odds ratio, 0.65; 95% CI, 0.465-0.901)' and the expected 12-mo estimated glomerular filtration rate was 6.3 mL/min/1.73 m 2 better if abdominal NRP was used ( P < 0.0001). CONCLUSIONS: . The use of NRP during DCD organ recovery leads to increased organ utilization and improved transplant outcomes compared with conventional organ recovery.

European Society for Organ Transplantation (ESOT) Consensus Statement on Outcome Measures in Liver Transplantation According to Value-Based Health Care.

Liver transplantation is a highly complex, life-saving, treatment for many patients with advanced liver disease. Liver transplantation requires multidisciplinary teams, system-wide adaptations and significant investment, as well as being an expensive treatment. Several metrics have been proposed to monitor processes and outcomes, however these lack patient focus and do not capture all aspects of the process. Most of the reported outcomes do not capture those outcomes that matter to the patients. Adopting the principles of Value-Based Health Care (VBHC), may provide an opportunity to develop those metrics that matter to patients. In this article, we present a Consensus Statement on Outcome Measures in Liver Transplantation following the principles of VBHC, developed by a dedicated panel of experts under the auspices of the European Society of Organ Transplantation (ESOT) Guidelines' Taskforce. The overarching goal is to provide a framework to facilitate the development of outcome measures as an initial step to apply the VMC paradigm to liver transplantation.