Delivery of Mesenchymal Stem Cells during Hypothermic Machine Perfusion in a Translational Kidney Perfusion Study.

In transplantation, hypothermic machine perfusion (HMP) has been shown to be superior to static cold storage (SCS) in terms of functional outcomes. Ex vivo machine perfusion offers the possibility to deliver drugs or other active substances, such as Mesenchymal Stem Cells (MSCs), directly into an organ without affecting the recipient. MSCs are multipotent, self-renewing cells with tissue-repair capacities, and their application to ameliorate ischemia- reperfusion injury (IRI) is being investigated in several preclinical and clinical studies. The aim of this study was to introduce MSCs into a translational model of hypothermic machine perfusion and to test the efficiency and feasibility of this method. Methods: three rodent kidneys, six porcine kidneys and three human kidneys underwent HMP with 1-5 × 106 labelled MSCs within respective perfusates. Only porcine kidneys were compared to a control group of 6 kidneys undergoing HMP without MSCs, followed by mimicked reperfusion with whole blood at 37 °C for 2 h for all 12 kidneys. Reperfusion perfusate samples were analyzed for levels of NGAL and IL-ß by ELISA. Functional parameters, including urinary output, oxygen consumption and creatinine clearance, were compared and found to be similar between the MSC treatment group and the control group in the porcine model. IL-1ß levels were higher in perfusate and urine samples in the MSC group, with a median of 285.3 ng/mL (IQR 224.3-407.8 ng/mL) vs. 209.2 ng/mL (IQR 174.9-220.1), p = 0.51 and 105.3 ng/mL (IQR 71.03-164.7 ng/mL) vs. 307.7 ng/mL (IQR 190.9-349.6 ng/mL), p = 0.16, respectively. MSCs could be traced within the kidneys in all models using widefield microscopy after HMP. The application of Mesenchymal Stem Cells in an ex vivo hypothermic machine perfusion setting is feasible, and MSCs can be delivered into the kidney grafts during HMP. Functional parameters during mimicked reperfusion were not altered in treated kidney grafts. Changes in levels of IL-1ß suggest that MSCs might have an effect on the kidney grafts, and whether this leads to a positive or a negative outcome on IRI in transplantation needs to be determined in further experiments.

Post-transplant lymphoproliferative disorders following kidney transplantation: A literature review with updates on risk factors, prognostic indices, screening strategies, treatment and analysis of donor type.

Post-transplant lymphoproliferative disorders (PTLD) is a devastating complication of kidney transplantation with an insidious presentation and potential to disseminate aggressively. This review delineates the risk factors, prognostic indexes, screening, current management algorithm and promising treatment strategies for PTLD. Kidneys from both extended criteria donors (ECD) and living donors (LD) are being increasingly used to expand the donor pool. This review also delineates whether PTLD outcomes vary based on these donor sources. While Epstein-Barr virus (EBV) is a well-known risk factor for PTLD development, the use of T-cell depleting induction agents has been increasingly implicated in aggressive, monomorphic forms of PTLD. Research regarding maintenance therapy is sparse. The international prognostic index seems to be the most validate prognostic tool. Screening for PTLD is controversial, as annual PET-CT is most sensitive but costly, while targeted monitoring of EBV-seronegative patients was more economically feasible, is recommended by the American Society of Transplantation, but is limited to a subset of the population. Other screening strategies such as using Immunoglobulin/T-cell receptor require further validation. A risk-stratified approach is taken in the treatment of PTLD. The first step is the reduction of immunosuppressants, after which rituximab and chemotherapy may be introduced if unsuccessful. Some novel treatments have also shown potential benefit in studies: brentuximab vedotin, chimeric antigen receptor T-cell therapy and EBV-specific cytotoxic T lymphocytes. Analysis of LD v DD recipients show no significant difference in incidence and mortality of PTLD but did reveal a shortened time to development of PTLD from transplant. Analysis of SCD vs ECD recipients show a higher incidence of PTLD in the ECD group, which might be attributed to longer time on dialysis for these patients, age, and the pro-inflammatory nature of these organs. However, incidence of PTLD overall is still extremely low. Efforts should be focused on optimising recipients instead. Minimising the use of T-cell depleting therapy while encouraging research on the effect of new immunosuppressants on PTLD, screening for EBV status are essential, while enabling shared decision-making during counselling when choosing kidney donor types and individualised risk tailoring are strongly advocated.

The UEMS experience in continuous medical education accreditation process: a 'quo vadis' analysis of our global database.

Background: The authors systematically appraise a large database of continuous professional development (CPD) and continuous medical education (CME) events against the European Accreditation Council for Continuous Medical Education (EACCME) framework. Methods: The authors performed a retrospective observational study of all CPD or CME events within the European Union of Medical Specialists (UEMS) database between 2017 and 2019, including 91 countries and 6034 events. Assessment of event design, quality and outcomes was evaluated against a validated, expert-derived accreditation framework, using thematic analysis to extract distinct themes, and subsequent quantitative analysis. Results: The authors included 5649 live educational events (LEEs) and 385 e-learning materials (ELMs). Three thousand seven hundred sixty-two [3762 (62.3%)] of the events did not report clear justification in their needs assessment process. Most accreditation applications claimed covering a single educational need [1603/2277 (70.3%)]. Needs assessments were reported to be similar across conferences, courses and other types of events (P<0.01); 5642/6034 events (93.5%) had clearly documented expected learning outcomes; only 978/6034 (16.2%) reported a single expected learning outcome while the rest report 2-10 outcomes. Providers who declared more than one educational need also declared multiple learning outcomes (ρ=0.051, P<0.01). Conclusions: Despite EACCME providing a robust framework for the CPD/CME accreditation process, reporting quality can still be improved, as more than 1 in 2 events fail to provide a clear description of their needs assessment. To the authors' knowledge, this is the largest educational LEE/ELM database, which can be a starting to revisit the CME/CPD accreditation process.

Environmentally sustainable kidney care through transplantation: Current status and future challenges.

The environmental impact of healthcare is an issue currently examined with increased scrutiny and on a global scale with multiple stakeholders seeking to identify the appropriate interventions to reduce it. Interestingly, a significant portion of healthcare's environmental impact stems from intensive modalities of treatment for chronic disease. There is no better example than End-Stage Renal Disease (ESRD), where dialysis or transplantation are the modalities of treatment offered to the vast majority of these patients. Kidney transplantation (KTx) offers a longer life expectancy and improved quality of life in comparison to dialysis. Cost-effectiveness analyses have proven its financial superiority, as well. PubMed and EMBASE literature search using keywords "kidney transplantation", "carbon footprint", "sustainability" showed that there is no published work in the field of environmental sustainability in kidney transplantation. Relevant literature was identified for surgical services and applied to transplantation. Assuming its environmental superiority to dialysis, maximising KTx rate would be an important action towards "green" renal care services. That could be achieved through living organ donation, systematic use of machine perfusion for extended criteria deceased donors and individualised immune risk stratification techniques. All these measures aim towards implementing enhanced recovery protocols and two vital steps can be taken towards assessing their value. The first step is a detailed audit of the environmental impact of these novel techniques and secondly their impact in reducing the length of hospital stay and its subsequent environmental impact. Another key element is delivering appropriate post-operative care, substituting allograft biopsy with non-invasive techniques and reducing physical outpatient follow-up, using telemedicine. The gap in quantifying KTx services environmental impact needs to be addressed urgently, with development of strategies within the multidisciplinary transplant team. Introducing novel technologies can lead to donor pool expansion and improved organ utilisation rates, transforming transplant services in "green" hubs.

Microdialysis in Abdominal Organ Transplantation and the Potential for Integration with Dynamic Preservation Platforms and Post Transplant Monitoring.

The perpetual organ shortage crisis worldwide has meant a paradigm shift in global thinking with subsequent expansion of the accepted criteria for an organ donor to meet the demand. Robust pre-transplant organ viability assessment is the next great challenge in the field of transplantation today. Organ preservation in the nature of static cold storage has reached its limits, and machine perfusion both cold and warm offers theoretically superior preservation and the potential to assess organs. Microdialysis is a novel technique with proven ability to allow remote assessment of tissue biochemistry and metabolism. It has been used in various pre-clinical and clinical models of abdominal organ preservation and transplantation. This review focuses on the use of microdialysis in the assessment of the kidney, liver, and pancreas, and where this novel technology is heading in the context of the assessing organ viability prior to and after transplantation.

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.

The Medical Community's Role in Communication Strategies during Health Crises-Perspective from European Union of Medical Specialists (UEMS).

The COVID-19 pandemic was complicated by the spread of false information leading to what became widely called an "infodemic". The present opinion paper was written by an ad hoc international team united under the European Union of Medical Specialists (UEMS) umbrella and reflects the organizations' effort to contribute to the resolution of these issues, by highlighting and reflecting on them and by suggesting the medical community's necessary activities resulting in the formulation of effective future communication strategies. The importance of physicians' and other health workers' role and mission as educators and leaders in communities in critical situations should be reassessed and upgraded. We need to equip future doctors with strong and sustainable leadership and communication skills through relevant undergraduate and postgraduate education programs, in order that compliance with preventive medical advice is increased. To avoid possible politically and otherwise biased communication in health crises of the future, European nations should establish independent advisory bodies providing evidence-based advice and participate in communication campaigns. Medical and other health professional organizations should build organizational and personal capacities of their members to enable them to reliably inform and adequately educate governments, populations, civic society, employers' and employees' organizations, schools and universities, and other stakeholders.

A Conceptual Framework for Evaluating National Organ Donation and Transplantation Programs.

Conceptual frameworks are valuable resources that can be used to guide the planning, evaluation, and development of healthcare services. However, there are currently no comprehensive frameworks focused on organ donation and transplantation that identify the critical factors underlying a successful national program. To address this knowledge gap, we developed a conceptual framework that takes into account all major domains of influence, including political and societal aspects as well as clinical implementation. The framework was initially constructed based on a targeted review of the relevant medical literature. Feedback provided by a panel of international experts was incorporated into the framework via an iterative process. The final framework features 16 essential domains that are critical for initiating and maintaining a successful program and improving the health of patients with organ failure. Of particular note, these domains are subject to three overarching health system principles: responsiveness, efficiency, and equity. This framework represents a first attempt to develop a whole-system view of the various factors that contribute to the success of a national program. These findings provide a useful tool that can be adapted to any jurisdiction and used to plan, evaluate, and improve organ donation and transplantation programs.

Ten Lessons From the Spanish Model of Organ Donation and Transplantation.

The organ donation and transplantation program in Spain has long been considered the gold standard worldwide. An in-depth understanding of the Spanish program may promote the development and reform of transplant programs in other countries. Here, we present a narrative literature review of the Spanish organ donation and transplantation program supplemented by expert feedback and presented according to a conceptual framework of best practices in the field. Core features of the Spanish program include its three-tiered governing structure, close and collaborative relationships with the media, dedicated professional roles, a comprehensive reimbursement strategy, and intensive tailored training programs for all personnel. Several more sophisticated measures have also been implemented, including those focused on advanced donation after circulatory death (DCD) and expanded criteria for organ donation. The overall program is driven by a culture of research, innovation, and continuous commitment and complemented by successful strategies in prevention of end-stage liver and renal disease. Countries seeking ways to reform their current transplant systems might adopt core features and may ultimately aspire to include the aforementioned sophisticated measures. Countries intent on reforming their transplant system should also introduce programs that support living donation, an area of the Spanish program with potential for further improvement.

Lessons From the Portuguese Solid Organ Donation and Transplantation System: Achieving Success Despite Challenging Conditions.

Over the past two decades, Portugal has become one of the world leaders in organ donation and transplantation despite significant financial constraints. This study highlights how Portugal achieved success in organ donation and transplantation and discusses how this information might be used by other countries that are seeking to reform their national programs. To accomplish this goal, we performed a narrative review of relevant academic and grey literature and revised our results after consultation with two national experts. Our findings were then synthesized according to a conceptual framework for organ donation and transplantation programs. Our results revealed several key strategies used by the Portuguese organ donation and transplantation program, including collaboration with Spain and other European nations, a focus on tertiary prevention, and sustained financial commitment. This report also explores how cooperative efforts were facilitated by geographical, governmental, and cultural proximity to Spain, a world leader in organ donation and transplantation. In conclusion, our review of the Portuguese experience provides insight into the development of organ donation and transplantation systems. However, other countries seeking to reform their national transplant systems will need to adapt these policies and practices to align with their unique cultures and contexts.

Solid Organ Donation and Transplantation in the United Kingdom: Good Governance is Key to Success.

The United Kingdom (UK) supports a highly successful organ donation and transplantation program. While the UK originally had one of the lowest organ donation rates in Europe, sustained reforms have resulted in steady improvement. Of note, the UK nearly doubled its rate of deceased donations between 2008 and 2018. In this report, we present a case study of the UK organ donation and transplantation program as an example of a complete system with sound and inclusive governing structures that are strongly integrated with critical programs focused on training and research. This study was based on an initial targeted review of the literature led by a UK expert that included guidelines, national reports, and academic papers. Feedback solicited from other European experts was incorporated into our findings via an iterative process. Overall, the study highlights the stepwise evolution of the UK program that ultimately became successful largely due to ongoing collaborative efforts carried out at all levels. Centralized coordination of all aspects of the program remains a key driver of improved rates of organ donation and transplantation. The designation and empowerment of expert clinical leadership have helped to maintain focus and promote ongoing quality improvement.

The National Organ Donation and Transplantation Program in Greece: Gap Analysis and Recommendations for Change.

Greece has fallen far behind many comparable European countries in the field of organ donation and transplantation and has made little progress over the past decade. Despite efforts to improve its organ donation and transplantation program, systemic problems persist. In 2019, the Onassis Foundation commissioned a report to be prepared by the London School of Economics and Political Science that focused on the state of the Greek organ donation and transplantation program and proposed recommendations for its improvement. In this paper, we present our analysis of the Greek organ donation and transplantation program together with an overview of our specific recommendations. The analysis of the Greek program was undertaken in an iterative manner using a conceptual framework of best practices developed specifically for this project. Our findings were further developed via an iterative process with information provided by key Greek stakeholders and comparisons with case studies that featured successful donation and transplantation programs in Croatia, Italy, Portugal, Spain, and the United Kingdom. Because of their overall complexity, we used a systems-level approach to generate comprehensive and far-reaching recommendations to address the difficulties currently experienced by the Greek organ donation and transplantation program.

Organ Donation in Croatia: The Importance of a National Champion, a Comprehensive Plan, and International Collaborations.

The Republic of Croatia is a global leader in organ donation and transplantation despite having fewer resources and more modest healthcare expenditures than other countries in the European Union. The results of an extensive literature review were combined with expert input in an iterative multi-step data collection and evaluation process designed to assess trends in Croatian organ donation and transplantation and identify key elements, policy changes, and drivers of the system that have contributed to its success. Multiple sources of evidence were used in this study, including primary documents, national and international transplantation reports, and insights from critical informants and content experts. The results highlight several key organizational reforms that have substantially improved the performance of the Croatian transplant program. Our findings emphasize the importance of strong central governance led by an empowered national clinical leader acting under the direct auspices of the Ministry of Health and a comprehensive and progressive national plan. The Croatian transplant system is notable for its integrated approach and efficient manner of managing scarce health resources. Collectively, the results suggest that Croatia has become nearly self-sufficient due to its systematic implementation of the guiding principles for organ donation and transplantation.

How to Structure a Successful Organ Donation and Transplantation System in Eight (Not So Easy) Steps: An Italian Case Study.

Valuable information can be obtained from a systematic evaluation of a successful national transplant program. This paper provides an overview of Italy's solid organ transplantation program which is coordinated by the National Transplant Network (Rete Nazionale Trapianti) and The National Transplant Center (Centro Nazionale Trapianti). The analysis is based on a system-level conceptual framework and identifies components of the Italian system that have contributed to improving rates of organ donation and transplantation. A narrative literature review was conducted and the findings were validated iteratively with input from subject matter experts. The results were organized into eight critical steps, including 1) generating legal definitions of living and deceased donation, 2) taking steps to ensure that altruistic donation and transplantation become part of the national culture and a point of pride, 3) seeking out existing examples of successful programs, 4) creating a situation in which it is easy to become a donor, 5) learning from mistakes, 6) working to diminish risk factors that lead to the need for organ donation, 7) increasing the rate of donations and transplantations via innovative strategies and policies, and 8) planning for a system that supports growth.

Translational research and innovation in modern transplant practice: Paradigms from Greece and around the world.

The continuous clinical and technological advances, together with the social, health and economic challenges that the global population faces, have created an environment where the evolution of the field of transplantation is essentially necessary. The goal of this special issue is to provide a picture of the current status of transplantation in Greece as well as in many other countries in Europe and around the world. Authors from Greece and several other countries provide us with valuable insight into their respective areas of transplant expertise, with a main focus on the field of translational research and innovation. The papers that are part of this Special Issue "Translational Research and Innovation and the current status of Transplantation in Greece" have presented innovative and meaningful approaches in modern transplant research and practice. They provide us with a clear overview of the current landscape in transplantation, including liver transplantation in the context of a major pandemic, the evolution of living donor kidney transplantation or the evolution of the effect of hepatitis C virus infection in transplantation, while at the same time explore more recent challen ges, such as the issue of frailty in the transplant candidate and the changes brought by newer treatments, such as immunotherapy, in transplant oncology. Additionally, they offer us a glimpse of the effect that technological innovations, such as virtual reality, can have on transplantation, both in terms of clinical and educational aspects. Just as critical is the fact that this Special Issue emphasizes the multidisciplinary, collaborative efforts currently taking place that link transplant research and innovation with other cutting-edge disciplines such as bioengineering, advanced information technology and artificial intelligence. In this Special Issue, in addition to the clinical and research evolution of the field of transplantation, we are witnessing the importance of interdisciplinary collaboration in medicine.

Evaluation of the usefulness of the Clavien-Dindo classification of surgical complications.

The Clavien-Dindo (CD) classification is widely used in the reporting of surgical complications in scientific literature. It groups complications based on the level of intervention required to resolve them, and benefits from simplicity and ease of use, both of which contribute its to high inter-rater reliability. It has been validated for use in many specialties due to strong correlation with key outcome measures including length of stay, postsurgical quality of life and case-related renumeration. Limitations of the classification include concerns over differentiating grade III and IV complications and not classifying intraoperative complications. The Comprehensive Complication Index is an adaptation of the CD classification which generates a morbidity score from 0 to 100. It has been proposed as a more effective method of assessing the morbidity burden of surgical procedures. However, it remains less popular as calculations of morbidity are complicated and time-consuming. In recent years there have been suggestions of adaptations to the CD classification such as the Clavien-Dindo-Sink classification, while in some specialties, completely new classifications have been proposed due to evidence the CD classification is not reliable. Similarly, the Surgical Expertise and Validity Evaluation project aims to determine benchmarks against which surgeons may compare their own practice.

Pancreas Transplantation in Black, Asian and Minority Ethnic Patients-Single Centre Experience in the UK.

Ethnic disparities in the outcomes after simultaneous pancreas kidney (SPK) transplantation still exist. The influence of ethnicity on the outcomes of pancreas transplantation in the UK has not been reported and hence we aimed to investigate our cohort. A retrospective analysis of all pancreas transplant recipients (n = 171; Caucasians = 118/Black Asian Ethnic Minorities, BAME = 53) from 2006 to 2020 was done. The median follow-up was 80 months. Patient & pancreas graft survival, rejection rate, steroid free maintenance rate, HbA1c, weight gain, and the incidence of secondary diabetic complications post-transplant were compared between the groups. p < 0.003 was considered significant (corrected for multiple hypothesis testing). Immunosuppression consisted of alemtuzumab induction and steroid free maintenance with tacrolimus and mycophenolate mofetil. Pancreas graft & patient survival were equivalent in both the groups. BAME recipients had a higher prevalence of type-2 diabetes mellitus pre-transplant (BAME = 30.19% vs. Caucasians = 0.85%, p < 0.0001), and waited for a similar time to transplantation once waitlisted, although pre-emptive SPK transplantation rate was higher for Caucasian recipients (Caucasians = 78.5% vs. BAME = 0.85%, p < 0.0001). Despite equivalent rejections & steroid usage, BAME recipients gained more weight (BAME = 7.7% vs. Caucasians = 1.8%, p = 0.001), but had similar HbA1c (functioning grafts) at 3-,12-, 36-, and 60-months post-transplant.

Anaesthetic Approach to Enhanced Recovery after Surgery for Kidney Transplantation: A Narrative Review.

Enhanced recovery after surgery (ERAS) protocols are designed to reduce medical complications, the length of hospital stays (LoS), and healthcare costs. ERAS is considered safe and effective for kidney transplant (KTx) surgery. KTx recipients are often frail with multiple comorbidities. As these patients follow an extensive diagnostic pathway preoperatively, the ERAS protocol can ideally be implemented at this stage. Small singular changes in a long perioperative pathway can result in significant positive outcomes. We have investigated the current evidence for an ERAS pathway related to anaesthetic considerations in renal transplant surgery for adult recipients.

Risks for donors associated with living kidney donation: meta-analysis.

BACKGROUND: Living kidney donation risk is likely to differ according to donor's demographics. We aimed to analyse the effects of age, sex, body mass index (BMI) and ethnicity. METHODS: A systematic review and meta-analysis was undertaken of the effects of preoperative patient characteristics on donor kidney function outcomes, surgical complications, and hypertension. RESULTS: 5129 studies were identified, of which 31 met the inclusion criteria, mainly from the USA and Europe. The estimated glomerular filtration rate (eGFR) in donors aged over 60 years was a mean of 9.54 ml per min per 1.73 m2 lower than that of younger donors (P < 0.001). Female donors had higher relative short- and long-term survival. BMI of over 30 kg/m2 was found to significantly lower the donor's eGFR 1 year after donation: the eGFR of obese donors was lower than that of non-obese patients by a mean of -2.70 (95 per cent c.i. -3.24 to -2.15) ml per min per 1.73 m2 (P < 0.001). Obesity was also associated with higher blood pressure both before and 1 year after donation, and a higher level of proteinuria, but had no impact on operative complications. In the long term, African donors were more likely to develop end-stage renal disease than Caucasians. CONCLUSION: Obesity and male sex were associated with inferior outcomes. Older donors (aged over 60 years) have a larger eGFR decline than younger donors, and African donors have a higher incidence of ESRD than Caucasians.