Transplant Community Research Articles

Monkeypox a Concern for Donor-derived Infection?

Monkeypox a Concern for Donor-derived Infection?

Counselling, Research Gaps, and Ethical Considerations Surrounding Pregnancy in Solid Organ Transplant Recipients.

Survival after solid-organ transplantation has improved significantly, and many contemporary transplant recipients are of childbearing potential.There are limited data to guide decision-making surrounding pregnancy after transplantation, variations in clinical practice, and significant knowledge gaps, all of which raise significant ethical issues.Post-transplant pregnancy is associated with an increased risk of maternal and fetal complications. Shared decision-making is a central aspect of patient counselling but is complicated by significant knowledge gaps.Stakeholder interests can be in conflict; exploring these tensions can help patients to evaluate their options and inform their deliberations. We argue that uniform, evidence-based recommendations for pregnancy after solid organ transplantation are needed.Conducting research, including patient-engaged studies, in this area should be priority for the transplant community.

The Value of Upper Extremity, face, and uterus transplantation: A Summit Conference

A panel of over 60 experts in the field of vascular composite allotransplantation from around the United States gathered on November 8, 2019 at the Uniformed Services University of the Health Sciences, in Bethesda MD. Experts in the field were recruited and invited through a collaborative effort of the American Society for Reconstructive Transplantation, the American Society of Transplantation, the American Society for Reproductive Medicine, and the American Society of Transplant Surgeons in order to discuss The Value of Upper Extremity, Face, and Uterus Transplantation: A Summit Conference . All sessions were directed by a moderator and focused on indications and contraindications, outcomes and costs of vascular composite allotransplantations in order to evaluate and discuss the state of the art science in the field. Representatives of major vascular composite allotransplantation centers in North America (Cleveland Clinic, University of Pennsylvania, Brigham and Women’s Health, New York University, the Mayo Clinic, Baylor, John Hopkins University, the University of Louisville) collaborated in order to present the combined experience of the major transplant centers in the United States. The panel members developed consensus guidelines for publication demonstrating success and unity amongst the vascular composite allotransplantation and solid organ transplantation communities. • A panel of 60 vascular composite allotransplantation experts from around the United States met in Bethesda, MD on November 8, 2019. • Indications, contraindication, outcomes and complications of face, hand and uterus transplantation were discussed. • This consensus meeting served to propel the field of vascular allograft transplantation through unity.

Effect of Covid-19 on Eye Banks and Corneal Transplantations: Current Perspectives.

The coronavirus disease 2019 (COVID-19) pandemic exerted a great impact on medical practice, which was reframed according to the actual needs. Ophthalmological services and procedures including corneal transplantation did not represent an exception. The adoption and implementation of new standard operating procedures as well as of new technologies for remote consultation and smart-working reshaped daily activities of both eye bankers, physicians, researchers, and patients. Regulatory restrictions were issued redefining corneal donor eligibility criteria, as well as handling and harvesting procedures of donor ocular tissues. Surgical schedules underwent an abrupt contraction with prioritization of urgent procedures. Local lockdowns and confinement strategies resulted in both a reduction and redirection of research activities. The evaluation of SARS-CoV-2 colonization of ocular tissues, long-term corneal storage techniques, new disinfection strategies, split corneal transplants and cell-based therapies for the treatment of corneal disease peaked in the pipeline. Aim of this article is to summarizes the overall impact of the pandemic on the corneal transplantation machinery, and the current and future perspectives for the corneal transplant community.

Adapting the HCT-CI Definitions for Children, Adolescents, and Young Adults with Hematologic Malignancies Undergoing Allogeneic Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation is a curative procedure for hematologic malignancies but is associated with a significant risk of non-relapse mortality (NRM). The Hematopoietic Cell Transplantation–Comorbidity Index (HCT-CI) is a prognostic tool that discriminates this risk in all age groups. A recent survey of transplant physicians demonstrated that 79% of pediatric providers used the HCT-CI infrequently, and most reported concerns about its applicability in the younger population. We conducted a retrospective study using the Center for International Blood and Marrow Transplant Research database to examine the impact of expanded HCT-CI definitions on NRM in pediatric and young adult patients with hematologic malignancies. We included 5790 patients <40 years old receiving allogeneic transplants between 2008 and 2017 to examine broader definitions of comorbidities in the HCT-CI, including history of mechanical ventilation and fungal infection, estimated glomerular filtration rate, and body mass index (BMI) percentiles. Multivariable Fine-Gray models were created to determine the effect of each HCT-CI defining comorbidity and its modification on NRM and were used to develop 2 novel risk scores. We next developed the expanded HCT-CI for children and young adults (youth with malignancies; expanded ymHCT-CI), where 23% patients had an increased comorbidity score, compared to the HCT-CI. Comorbidities with hazard ratio < 1.2 were then removed to create the simplified HCT-CI for children and young adults (youth with malignancies; simplified ymHCT-CI), which demonstrated higher scores corresponded to a greater risk of NRM (P < .001). These novel comorbidity indexes with broader definitions are more relevant to pediatric and young adult patients, and prospective studies are needed to validate these in the younger patient population. It remains to be seen whether the development of these pediatric-specific and practical risk indexes increases their use by the pediatric transplant community.

COVID-19 in kidney transplantation-implications for immunosuppression and vaccination.

COVID-19 pandemic continues to challenge the transplant community, given increased morbidity and mortality associated with the disease and poor response to prevention measures such as vaccination. Transplant recipients have a diminished response to both mRNA and vector-based vaccines compared to dialysis and the general population. The currently available assays to measure response to vaccination includes commercially available antibody assays for anti-Spike Ab, or anti- Receptor Binding Domain Ab. Positive antibody testing on the assays does not always correlate with neutralizing antibodies unless the antibody levels are high. Vaccinations help with boosting polyfunctional CD4+ T cell response, which continues to improve with subsequent booster doses. Ongoing efforts to improve vaccine response by using additional booster doses and heterologous vaccine combinations are underway. There is improved antibody response in moderate responders; however, the ones with poor response to initial vaccination doses, continue to have a poor response to sequential boosters. Factors associated with poor vaccine response include diabetes, older age, specific immunosuppressants such as belatacept, and high dose mycophenolate. In poor responders, a decrease in immunosuppression can increase response to vaccination. COVID infection or vaccination has not been associated with an increased risk of rejection. Pre- and Post-exposure monoclonal antibodies are available to provide further protection against COVID infection, especially in poor vaccine responders. However, the efficacy is challenged by the emergence of new viral strains. A recently approved bivalent vaccine offers better protection against the Omicron variant.

The Medawar Prize Acceptance Speech 2022.

The Medawar Prize Acceptance Speech 2022.

"Creating Blue Skies Overhead for All" Introduction of the 2022 Recipient of the Medawar Prize of the Transplantation Society: Professor Jeremy Chapman.

"Creating Blue Skies Overhead for All" Introduction of the 2022 Recipient of the Medawar Prize of the Transplantation Society: Professor Jeremy Chapman.

DCD kidney transplantation in Italy: Past, present, and future

The disproportion between the number of patients on the kidney transplant waiting list and the actual donors pool represents a primary issue for the international Transplant community. The development of donation after circulatory death (DCD) programs has been associated with a remarkable increase in organs procurement and transplants activities across the globe. However, effective DCD donation and transplantation require the resolution of several legal, ethical, deontological, logistical, and technical issues. In Italy, the major obstacle to this very specific type of dation was represented by the 20-minute no-touch period for the declaration of death by cardio-circulatory criteria established by the Italian legislation. Following the encouraging results obtained with the use of in situ Normothermic Regional Perfusion in the setting of a single-center exploratory trial performed between 2008 and 2013 (Alba project), the Comitato Nazionale per la Bioetica and the Centro Nazionale Trapianti eventually managed to start a national-scale controlled and uncontrolled DCD program. We herein describe the Italian DCD KT program with a special focus on the most crucial and peculiar aspects of the national organ donation and allocation process.

Pancreas Transplantation: Current Challenges, Considerations, and Controversies.

Pancreas transplantation (PTx) reestablishes an autoregulating source of endogenous insulin responsive to normal feedback controls. In addition to achieving complete β-cell replacement that frees the patient with diabetes from the need to monitor serum glucose and administer exogenous insulin, successful PTx provides counterregulatory hormone secretion and exocrine function. A functioning PTx mitigates glycemic variability, eliminates the daily stigma and burden of diabetes, restores normal glucose homeostasis in patients with complicated diabetes, and improves quality of life and life expectancy. The tradeoff is that it entails a major surgical procedure and requisite long-term immunosuppression. Despite the high likelihood of rendering patients euglycemic independent of exogenous insulin, PTx is considered a treatment rather than a cure. In spite of steadily improving outcomes in each successive era coupled with expansion of recipient selection criteria to include patients with a type 2 diabetes phenotype, a decline in PTx activity has occurred in the new millennium related to a number of factors including: (1) lack of a primary referral source and general acceptance by the diabetes care community; (2) absence of consensus criteria; and (3) access, education, and resource issues within the transplant community. In the author's experience, patients who present as potential candidates for PTx have felt as though they needed to circumvent the conventional diabetes care model to gain access to transplant options. PTx should be featured more prominently in the management algorithms for patients with insulin requiring diabetes who are failing exogenous insulin therapy or experiencing progressive diabetic complications regardless of diabetes type. Furthermore, all patients with diabetes and chronic kidney disease should undergo consideration for simultaneous pancreas-kidney transplantation independent of geography or location.

Functional Human iPSC-Derived Thymic Epithelial Progenitor Cells Reconstitute T Cell Development and Function in an In Vivo Model of Thymic Aplasia

The thymus is an essential primary lymphoid organ in which T cells mature, proliferate, and acquire a broad and self-tolerant T cell receptor repertoire. In the thymus, specialized thymic epithelial cells (TECs) select T cells capable of recognizing foreign antigens, and eliminate self-reactive T cells to prevent autoimmunity. In addition, the thymus also contributes to the differentiation of regulatory T cells which confine immune responses to actively preserve central tolerance. During thymic development, the interactions between hematopoietic lymphoid progenitor cells and thymic epithelial progenitor cells (TEPCs) provides indispensable signals to the development of the thymic epithelium. In humans, unlike in mice, the development of the thymus is completed before birth. There is no evidence of thymic stem cells that could contribute to a sustained regeneration of the thymic epithelium throughout life. Accordingly, the thymus has no endogenous capacity to regenerate. The thymus peaks in size during infancy and involutes with age, leading to the weakened immune function of the elderly known as immune senescence. Allogeneic hematopoietic stem cell transplant (HSCT) is a curative strategy for many malignant and non-malignant hematopoietic diseases, however, often at the cost of causing severe thymic dysfunction due to conditioning medications and graft-versus-host disease (GVHD). This can severely impair T cell immune reconstitution post-HSCT leading to life-threatening complications. In addition, genetic forms of congenital athymia (e.g. 22q11 Deletion Syndrome, TBX1, TBX2, PAX1, and CHD7 deficiency) can result in absence of T cell development. Complete congenital athymia is fatal early in life unless immune reconstitution is achieved by allogeneic thymus transplantation. However, the shortage of transplantable donor thymus tissue and lack of HLA-matching between donor and recipient limits the use of allogeneic thymus transplantation to a small number of children with complete congenital athymia. Thus, there is a critical unmet clinical need to provide HLA-matched thymic tissues for a larger group of patients with irreversible thymic injury and severe thymic dysfunction. Creating a regenerative thymus replacement therapy by generating functional TEPCs from induced-pluripotent stem cells (iPSCs) has been a longstanding aspiration of the transplant community. We have taken a novel approach by developing a robust in vitro TEPC differentiation protocol that sequentially induces all stages of human thymic ontogeny including bipotent third (III) pharyngeal pouch endoderm (PPEIII), ventralization of the PPE (PPEv), and TEPC commitment, usually lymphoid dependent. Here, we show that TEPCs from various iPSC-lines (tissue source, donor age and sex) express key markers of thymic epithelial fate and function, including FOXN1, PAX1, PAX9, HLA-DR. To examine their functional capacity, we transplanted iPSC-derived TEPCs under the kidney capsule of humanized (hCD34+ HSCs engrafted) athymic NSG-nude mice (NOD.scid.Il2Rγcnull, Foxn1null knockout allele). We observed robust hCD3+ development (40-60% out of hCD45 population) with CD4+ and CD8+ T cells (±70% and ±25%, respectively) at different stages of maturation (17% CD45RA+ CD45RO-, naïve; 80% CD45RA- CD45RO+, memory). Similar levels of T cells were found in mice that received human fetal thymus transplants, while T cells were not detected in NSG-nude mice without any thymus graft (primary or iPSC-derived). Mice with iPSC-derived thymus grafts had no clinical signs of autoimmunity or GVHD. In vivo matured grafts express levels of FOXN1, PAX1, PAX9, DLL4, PSMB11 and CD205 protein that are comparable to primary thymus tissue grafts. Altogether, our protocol reliably produces functional TEPCs from a diverse set of iPSCs that support T cell differentiation in vivo. We are currently characterizing the transcriptomic and epigenomic profile of iPSC-derived TEPCs on a single cell level before and after transplant. In addition, we are examining in vivo T cell function by analyzing the TCR repertoire and response to T-cell dependent antigens. We foresee that iPSC-derived TEPCs will offer a safe alternative as an HLA-matched thymic replacement therapy that will benefit a large cohort of patients, i.e. patients undergoing HSCT and patients receiving solid organ transplants in addition to patients with congenital thymic aplasia.

Preexisting Coronary Artery Disease in Liver Transplant Candidates: Risk Factor or Risk Marker?

Preexisting Coronary Artery Disease in Liver Transplant Candidates: Risk Factor or Risk Marker?

Living Liver Donation Does not Significantly Affect Long-Term Life, Disability, or Medical Insurability.

The growing practice of living liver donation requires comprehensive understanding of the financial implications for living liver donors. While obtaining and maintaining insurance is important to financial health, little is known about the impact of liver donation on future insurability. The purpose of this study was to evaluate the donors' experiences with insurance following donation and identify the insurance provider-driven factors that contribute to donor insurability. A two center cohort of living donors with donation between January 2000 and December 2018 (N = 442) were surveyed about postdonation insurance experiences. To understand insurance provider practices towards liver donors, life (n = 11) and disability (n = 4) insurance underwriters were asked to provide policy quotes for a standardized living liver donor profile. Responses (N = 101) were received by August 2020 (response rate = 22.9%). Living liver donors reported owning life (58%), disability (35%), and medical (87%) insurance at rates comparable to the general population with low proportions reporting difficulty obtaining these insurance types (9%, 9%, 4%, respectively). Post-donation life insurance ownership was associated with post-donation employment (P = 0.01). Underwriter responses indicate life and disability insurability were adversely affected up to 12 months following donation. Living liver donors did not have difficulty maintaining insurance in the long-term but should be counseled to purchase insurance prior to surgery as short-term insurability may be affected. Perception of difficulty obtaining insurance following donation remains of significant concern among living donors. Further collaboration between the transplant community and insurance companies is warranted.

COVID-19 Vaccines and Solid Organ Transplantation: More Doses, More Protection.

COVID-19 Vaccines and Solid Organ Transplantation: More Doses, More Protection.

Impact of COVID-19 on Organ Donation and Transplantation in the UK

The COVID-19 pandemic has placed considerable strain on the allocation of healthcare resources. In this research, we explored the views of healthcare professionals in the UK on the countrywide management of organ donation and transplantation during the first COVID-19 surge in the spring of 2020.&#x0D; Methods: An internet-based survey was developed and distributed over a 2-week period in May/June 2020.&#x0D; Results: Three hundred and fourteen professionals responded, covering all organ donation and transplant regions across the UK. Data suggest a considerable degree of scaling back of activity in all but one region (Northern Ireland). A range of absolute criteria for organ donation and transplantation were highlighted that have since been implemented in practice.&#x0D; Notable strengths of the countrywide response included the donation and transplant community acting responsibly and proportionately (51.6%), providing access to up-to-date information and data (43.9%,) and communicating risk (40.8%). Mixed views were expressed on equity in resource allocation, with 32% aligning with inequity, 28% with equity and 17% of respondents stating that equity issues are not relevant in a crisis.&#x0D; Conclusion: Findings highlight that managing scarcity is complex during a pandemic. Embedding ethical values in recovery and future threats preparedness should be prioritised.

Klotho in Kidney Transplantation: A New and Important Target?

Klotho in Kidney Transplantation: A New and Important Target?

COVID-19 Severity in Kidney Transplant Recipients According to Their Postvaccination Serological Assessment

Susceptibility of kidney transplant recipients (KTRs) to COVID-19 has been acutely apparent because of their increased risk of developing severe pneumonia1 and also, due to their lower vaccination response, conducing the transplant community to perform vaccine booster injections. Despite this, about 30% to 35% of patients remained seronegative after the third injection.2,3 Multiple reports highlighted the possibility of COVID-19 outbreak despite vaccination among KTRs,4 and the threshold of 264 BAU/ml antispike IgG has been initially determined to correlate with a protective neutralizing activity against symptomatic COVID-19 by the Alpha variant of concern (VOC).

Hepatocellular Carcinoma, Alpha Fetoprotein, and Liver Allocation for Transplantation: Past, Present and Future.

Hepatocellular carcinoma (HCC) is one of the leading indications for liver transplantation and has been the treatment of choice due to the oncologic benefit for patients with advanced chronic liver disease (AdvCLD) and small tumors for the last 25 years. For HCC patients undergoing liver transplantation, alpha fetoprotein (AFP) has increasingly been applied as an independent predictor for overall survival, disease free recurrence, and waitlist drop out. In addition to static AFP, newer studies evaluating the AFP dynamic response to downstaging therapy show enhanced prognostication compared to static AFP alone. While AFP has been utilized to select HCC patients for transplant, despite years of allocation policy changes, the US allocation system continues to take a uniform approach to HCC patients, without discriminating between those with favorable or unfavorable tumor biology. We aim to review the history of liver allocation for HCC in the US, the utility of AFP in liver transplantation, the implications of weaving AFP as a biomarker into policy. Based on this review, we encourage the US transplant community to revisit its HCC organ allocation model, to incorporate more precise oncologic principles for patient selection, and to adopt AFP dynamics to better stratify waitlist dropout risk.

Novel strategies in liver graft preservation-The French perspective.

Given the increasing graft shortage, the transplant community is forced to use so called marginal liver grafts with a higher susceptibility to ischemia-reperfusion injury. This exposes the recipient to a higher risk of graft failure and post-transplant complications. While static cold storage remains the gold standard in low-risk transplant scenarios, dynamic preservation strategies may allow to improve outcomes after transplantation of marginal liver grafts. Two dynamic preservation strategies, end-ischemic hypothermic oxygenated perfusion (HOPE) and continuous normothermic machine perfusion (cNMP), have been evaluated in randomized clinical trials. The results show improved preservation of liver grafts after cNMP and reduction of post-transplant biliary complications after HOPE. In comparison to cNMP, HOPE has the advantage of requiring less logistics and expertise with the possibility to return to default static cold storage. Both strategies allow to assess graft viability prior to transplantation and may thus contribute to optimizing graft selection and reducing discard rates. The use of dynamic preservation is rapidly increasing in France and results from a national randomized trial on the use of HOPE in marginal grafts will soon be available. Future applications should focus on controlled donation after circulatory death liver grafts, split grafts and graft treatment during perfusion. The final aim of dynamic liver graft preservation is to improve post-transplant outcomes, increase the number of transplanted grafts and allow expansion of transplant indications.

Outpatient and peri-operative antibiotic stewardship in solid organ transplantation.

The consequences of inappropriate antimicrobial use including resistance are increasingly recognized as a global public health threat and many steps have been taken over the last few decades to advance antimicrobial stewardship initiatives with most organ transplant centers currently part of institutions with active antimicrobial stewardship programs. A review of the literature was conducted and articles were categorized according to the topic and relevance in the judgment of the two authors. A summary review of the currently available literature was created with a focus on periprocedural and outpatient antimicrobial stewardship. Limitations in the data were significant and discussed in the review. The principles of antimicrobial stewardship remain important throughout all phases starting with periprocedural prophylactic antimicrobial selection all the way through to discharge and subsequent healthcare encounters. Despite the broad advances in stewardship initiatives and the rapidly progressing supportive data overall there continue to be significant opportunities for additional research within various special patient populations including recipients of solid organ transplantation (SOT). The recent white paper published in the American Journal of Transplantation called to action the transplant and stewardship communities to have an increased focus and awareness of the issues that antimicrobial overuse can present in the SOT patient population. This is an important step that will hopefully generate more data in this group of patients that arguably faces the greatest vulnerability to the consequences of increased antimicrobial resistance.