Organs For Transplantation Research Articles

Existing Ethical Tensions in Xenotransplantation.

The genetic modification of pigs as a source of transplantable organs is one of several possible solutions to the chronic organ shortage. This paper describes existing ethical tensions in xenotransplantation (XTx) that argue against pursuing it. Recommendations for lifelong infectious disease surveillance and notification of close contacts of recipients are in tension with the rights of human research subjects. Parental/guardian consent for pediatric xenograft recipients is in tension with a child's right to an open future. Individual consent to transplant is in tension with public health threats that include zoonotic diseases. XTx amplifies concerns about justice in organ transplantation and could exacerbate existing inequities. The prevention of infectious disease in source animals is in tension with the best practices of animal care and animal welfare, requiring isolation, ethologically inappropriate housing, and invasive reproductive procedures that would severely impact the well-being of intelligent social creatures like pigs.

The View of the Three Monotheistic Religions Toward Cadaveric Organ Donation.

Religious concerns regarding the legitimacy of cadaveric organ donation have been found to be major inhibiting factors for people to consent to donate organs post-mortem for transplantation; this constitutes a major cause for the grave shortfall of available organs for transplantation. The purpose of this review is to explore the view of the three monotheistic religions, namely Christianity, Islam, and Judaism, toward cadaveric organ donation. The literature review reveals that all three monotheistic religions support cadaveric organ donation but within certain restrictions. We provide a detailed description of the approach of each religion and the inhibiting considerations as interpreted by religious authorities. Health professionals need to collaborate with faith leaders in order to optimize the education of the public of believers with regard to the benefits stemming from organ donation. Developing transplantation medicine does not depend solely on technical capabilities and expertise; rather, this development should go hand in hand with religious, traditional and cultural beliefs and rituals. Providing a believer with a religious authority about cadaveric organ donation is very effective in helping families and individuals cope with difficult and critical decisions.

Transplantation Medicine: An Historical Perspective

In the 68 years between the first human solid organ transplant and the present, the number of these transplanted organs has reached one million, tracking at about 40,000 more annually. Looking ahead are the prospects for growing transplantable organs outside the body. The arc of this story extends from Alexis Carrell and Charles Lindbergh’s experiments with tissue culture, to Joseph Murray and Thomas Starzl’s surgical trials, to Jean Dausset and Peter Medawar’s discoveries about immune tolerance and rejection, and pushing into the future of regenerative medicine, to bioengineers Shinya Yamanaka, James Thomson, Anthony Atala, and Toshiro Sato– highlighting a few among many.

Role of normothermic machine perfusion in liver transplantation: Current trends and outcomes

Liver transplantation is the only known curative treatment option for end-stage liver diseases and failure; however, there is an imbalance between the number of available liver organs for transplant and the number of patients as recipients due to a shortage of suitable organs. In recent years, ex vivo liver machine perfusion has been introduced to liver transplantation to expand the donor organ pool. Studies showed that using normothermic machine perfusion can increase the pool of transplantable discarded livers and is a promising strategy to improve graft resilience and performance further.

Development and Characterization of a Nonelectronic Versatile Oxygenating Perfusion System for Tissue Preservation.

Oxygenated machine perfusion of human organs has been shown to improve both preservation quality and time duration when compared to the current gold standard: static cold storage. However, existing machine perfusion devices designed for preservation and transportation of transplantable organs are too complicated and organ-specific to merit use as a solution for all organs. This work presents a novel, portable, and nonelectronic device potentially capable of delivering oxygenated machine perfusion to a variety of organs. An innovative pneumatic circuit system regulates a compressed oxygen source that cyclically inflates and deflates silicone tubes, which function as both theoxygenator and perfusion pump. Different combinations of silicone tubes in single or parallel configurations, with lengths ranging from 1.5 to 15.2 m, were evaluated at varying oxygen pressures from 27.6 to 110.3 kPa. The silicone tubes in parallel configurations produced higher peak perfusion pressures (70% increase), mean flow rates (102% increase), and oxygenation rates (268% increase) than the single silicone tubes that had equivalent total lengths. While pumping against a vascular resistance element that mimicked a kidney, the device achieved perfusion pressures (8.4-131.6mmHg), flow rates (2.0-40.2mLmin-1), and oxygenation rates (up to 388μmolmin-1) that are consistent with values used in previous kidney preservation studies. The nonelectronic device achieved those perfusion parameters using 4.4Lmin-1 of oxygen to operate. These results demonstrate that oxygenated machine perfusion can be successfully achieved without any electronic components.

The role of hypothermic machine perfusion in selecting renal grafts with advanced histological score.

BackgroundFew studies explored the role of hypothermic machine perfusion (HMP) in the sub‐group of non‐standard renal grafts with a biopsy‐proven advanced histological impairment. This study aimed to investigate the role of HMP in grafts with a Karpinski Score >3 in terms of the need for dialysis, creatinine reduction ratio at day‐7 (CRR7), and 3‐year graft survival.MethodsTwenty‐three perfused grafts with Karpinski Score >3 evaluated between November 2017 and December 2018 were retrospectively analyzed and compared with a control group of 32 non‐perfused grafts transplanted between January 2014 and October 2017.ResultsAfter transplantation, perfused grafts had fewer cases requiring dialysis (8.7% vs. 34.4%; p = 0.051), a better reduction in serum creatinine (median at 7 days: 2.2 vs. 4.3 mg/dl; p = 0.045), and shorter length of hospital stay (median 11 vs. 15 days; p = 0.01). Three‐year death‐censored graft survival was better in the perfused cases (91.3% vs. 77.0%; p = 0.16).In perfused grafts, initial renal resistance (RR) had the best predictive value for renal function recovery after the first week, as defined by CRR7 ≤ 70% (AUC = 0.83; p = 0.02). A cut‐off value of 0.5 mm Hg/ml/min showed a sensitivity of 82.4%, a specificity of 83.3%, and diagnostic odds ratio = 23.4. After dividing the entire population into a Low‐RR (n = 8) and a High‐RR Group (n = 15), more cases with CRR7 ≤ 70% were reported in the latter group (86.7 vs. 13.3%; p = 0.03).ConclusionHMP yielded promising results in kidneys with Karpinski Score >3. Initial RR should be of interest in selecting non‐standard organs for single kidney transplantation even in impaired histology.

Organ Donation Willingness Among Asian Americans: Results from a National Study.

Asian Americans are the fastest growing racial group in the USA, but their health disparities are often overlooked. Although their needs for transplantable organs are substantial, they have the lowest rates of organ donation per million compared to other Americans by race. To better understand Asian Americans' disposition toward organ donation, a self-administered survey was developed based on formative data collection and guidance from a Community Advisory Board composed of Asian American stakeholders. The instrument was deployed online, and quota sampling based on the 2017 American Community Survey was used to achieve a sample representative (N = 899) of the Asian American population. Bivariate tests using logistic regression and the chi-square test of independence were performed. Over half (58.1%) of respondents were willing to be organ donors. A majority (81.8%) expressed a willingness to donate a family member's organs, but enthusiasm depended on the family member's donor wishes. Only 9.5% of respondents indicated that the decision to donate their organs was theirs alone to make; the remainder would involve at least one other family member. Other key sociodemographic associations were found. This study demonstrates both the diversity of Asian Americans but also the centrality of the family's role in making decisions about organ donation. Practice and research considerations for the field are also presented.

Crosslinked alginate‐xanthan gum blends as effective hydrogels for 3D bioprinting of biological tissues

Abstract3D bioprinting has a high potential for directly printing customized tissues and organs for surgical transplantation. However, adequate bioink formulations, in which cells can be combined with proper fluids for bioprinting structures with complex architectures, are still needed. In this work, we have combined alginate and xanthan gum in different proportions, aiming at producing an effective noncytotoxic, shear‐thinning, and easily sterilizable hydrogel, crosslinkable by the addition of low amounts of strontium ions, which would lead to stronger structures than those crosslinked with calcium. The results attained show that increases in xanthan gum concentration improve the rheological behavior of the material regarding printability and that heat‐sterilized formulations can show adequate rheological performance for bioprinting. Stable and noncytotoxic structures were obtained with a hydrogel consisting of 1% (w/v) alginate and 2.5% (w/v) xanthan gum in α‐MEM supplemented culture medium crosslinked by immersion in 50 mmol L−1 strontium chloride solution for 10 min postprinting. In conclusion, this new hydrogel formulation, optimized for bioink production, is designed to mimic the extracellular matrix with significant potential to be used for a wide plethora of applications, from the production of simple cellularized structures useful in drug screening and as microtissue models to complex organ bioprinting.

Why Do Young Adults in the United States Have Such Low Rates of Organ Donation Registration?

The demand for transplantable organs has outpaced the supply. Thus, 20 Americans die every day while waiting for an organ. Although most adults support organ donation, 42% are not registered. The rate is even lower among young adults who are not enrolled in/never graduated from college. The aim of this study was to use the Integrated Behavior Model (IBM) to identify factors that predicted organ donation registration among a racially diverse sample of non-student young adults. The study was observational and cross-sectional. Proportional allocation was used to identify a racially diverse sample of 550 non-student, young adults from ten states in the U.S. with the lowest registration rates. A valid and reliable survey was designed, pilot-tested, and administered. A total of 407 young adults completed the survey (74%). Only 19% were registered donors. Caucasians were more likely to be registered donors than racial minorities, χ² (3, N = 407) = 15.19, p = 0.002. Those with more positive direct attitudes toward registration were 1.5 times more likely to be registered than those who had negative direct attitudes. Among non-registrants, indirect descriptive norm and direct attitude were statistically significant predictors of behavioral intention. Moreover, those who knew someone who donated an organ and knew someone who needed a transplant were nearly three times more likely to intend to register in the next year. The IBM proved useful in elucidating factors that predicted intention to register among non-student young adults. The IBM should be used by those who desire to increase registration rates.

Euthanasia and palliative care in pulmonology

Background: Currently, euthanasia is officially allowed only in a number of countries, in most countries, as well as in the Russian Federation, it is prohibited by law. However, in clinical practice, there are a large number of incurable patients who experience intractable pain, so the problem of euthanasia is relevant.
 Aim: to analyze the current state of the problem of euthanasia and palliative care in pulmonology.
 Material and methods: review of domestic and foreign literature on the problem of euthanasia over the past 10 years has been carried out. Literature search was carried out using the e-library and PubMed databases.
 Results: We present a medical and philosophical perspective. Currently, euthanasia (Greek "good death") is a way to quickly and painlessly die if there is a serious illness that is incurable, suffering and pain. The best and perhaps the only alternative to euthanasia is palliative care. In pulmonology, palliative care focuses on early detection of respiratory failure, dyspnea, fear and pain relief. The effective organization of palliative care in respiratory medicine depends on the well-coordinated work of pulmonologists, physiotherapists, nurses, and psychologists.
 Conclusion: The problem of euthanasia to date still remains controversial from both medical and ethical points of view. The adoption of euthanasia by law may be a deterrent to governments from funding research into new treatments. The risk of abuse of euthanasia in order to obtain organs for transplantation or to get rid of seriously ill burdensome relatives cannot be ruled out. It is necessary to consider the issue of introducing additional educational cycles on the issues of modern achievements in palliative medicine, technical means of rehabilitation and the peculiarities of their use in patients with various diseases in the terminal stage in the training of doctors and nurses.

Living kidney donation in a developing country.

Living kidney donation has been advocated as a means to ameliorate the chronic shortage of organs for transplantation. Significant rates of comorbidity and familial risk for kidney disease may limit this approach in the local context; there is currently limited data describing living donation in Africa. We assessed reasons for non-donation and outcomes following donation in a cohort of 1208 ethnically diverse potential living donors evaluated over a 32-year period at a single transplant centre in South Africa. Medical contraindications were the commonest reason for donor exclusion. Black donors were more frequently excluded (52.1% vs. 39.3%; p<0.001), particularly for medical contraindications (44% vs. 35%; p<0.001); 298 donors proceeded to donor nephrectomy (24.7%). Although no donor required kidney replacement therapy, an estimated glomerular filtration rate below 60 ml/min/1.73 m2 was recorded in 27% of donors at a median follow-up of 3.7 years, new onset albuminuria >300 mg/day was observed in 4%, and 12.8% developed new-onset hypertension. Black ethnicity was not associated with an increased risk of adverse post-donation outcomes. This study highlights the difficulties of pursuing live donation in a population with significant medical comorbidity, but provides reassurance of the safety of the procedure in carefully selected donors in the developing world.

Evaluation of equine xenogeneic mixed lymphocyte reactions using 5-ethynyl-2’-deoxyuridine (EdU)

Allogeneic solid organ transplantation is currently the only treatment option for end stage organ disease. The shortage of available donor organs has driven efforts to utilize xenogeneic organs for transplantation. In vitro methods for evaluating immune-compatibility are a quick and low cost means of screening novel tissue products prior to more involved, expensive, and invasive live animal studies. Recently, a new analog of the DNA base thymidine, 5-ethynyl-2’-deoxyuridine (EdU), was developed. It may be used in a fast, efficient and specific means of evaluating cell proliferation via flow cytometry. This study was designed to test and optimize this platform for assessing equine xenogeneic one-way mixed lymphocyte reaction (MLR) to porcine stimulator cells. Furthermore, it was hypothesized that an enriched T-lymphocyte (T-cell) population would generate a stronger proliferative response to stimulation, and higher levels of cytokine production when compared to unfractionated peripheral blood mononuclear cells (PBMCs). PBMCs and T-cells were isolated from 3 horses and 4 pigs. Equine xenogeneic MLRs were set up using porcine allogeneic MLRs as a reference for clinically acceptable levels of cell proliferation. Equine T-cells showed significantly greater EdU incorporation in one-way xenogeneic MLRs than equine PBMCs. However, there was no significant difference in cell proliferation between porcine T-cell and PBMC as responders in allogenic one-way MLRs. Given the results of this study, we consider that enriched equine T-cells should be used in preference to unfractionated PBMCs when attempting to evaluate the equine xenogeneic response using the EdU assay as an indicator of suitability for transplant in vivo.

MO1019: Sigma-1 Receptor Agonists are Protective in a Rat Model of Kidney Transplantation

Abstract BACKGROUND AND AIMS End-stage renal disease affects nearly 2 million people worldwide. The disease is associated with an irreversible deterioration in renal function and can only be treated by dialysis or kidney transplantation (KTx). KTx is associated with better long-term outcomes and quality of life compared with dialysis, but the shortage of donor organs is a serious and unsolved problem. Graft survival is highly dependent on the extent of cold and warm ischemic injury during Tx. We recently described the renoprotective effects of Sigma-1 receptor (S1R) agonist treatment in IRI. Thus, our aim was to develop a novel preservation solution that, with the addition of S1R agonist compounds, minimizes ischemic damage in order to improve the condition of grafts and so increase the number of organs suitable for Tx. METHOD Kidneys of male Wistar rats were perfused and placed in ice cold (i) custodiol preservation solution; custodiol containing S1R agonists, (ii) fluvoxamine or (iii) SA-4503 for 2 h, then autotransplanted and sacrificed 24 h after reperfusion. Sham-operated rats served as controls. In a second experiment, kidneys of wild-type and S1R knockout mice were perfused and placed in an ice-cold preservation solution containing an original, selective S1R agonist compound (VCC) for 24 h of cold ischemia and tissue samples were collected. Renal function parameters were determined. Renal expression of tubular injury markers (Kim-1, Ngal) and inflammatory cytokines (Il-1α, Il-6, Tnf-α, Mcp-1) were measured. Periodic acid-Schiff staining was performed on kidney tissue sections to evaluate structural changes. CD45 immunostaining was performed on kidney sections to determine the extent of leukocyte infiltration. DNA fragmentation resulted by apoptotic events in the kidney was evaluated by TUNEL-assay. RESULTS S1R agonists mitigated renal functional impairment and tubular dilatation following Tx. Expression of early and sensitive tubular injury markers was markedly less elevated in S1R agonist-treated kidneys. S1R agonists alleviated renal apoptosis as shown on TUNEL-stained kidney sections. Decreased numbers of CD45 + leukocytes and decreased inflammatory cytokine expressions confirmed the anti-inflammatory effect of S1R agonists. The S1R agonist VCC compound mitigated cold ischemic structural kidney damage in wild-type but not in S1R KO mice, which confirms the protective role of the receptor. CONCLUSION The addition of S1R agonists to the preservation solution during Tx improves graft function and alleviates structural damage, thus improving long-term outcomes. S1R agonists reduce graft injury during cold storage, therefore the number of transplantable donor organs can be increased. FUNDING OTKA PD-131 637; FK-124 491; 2020–4.1.1.-TKP2020-6 183 069 269; 2020–4.1.1.-TKP2020-6 183 169 273; KDP-2020/1 019 145.

Kidney Transplantation From Hepatitis-C Viraemic Donors:Considerations for Practice in the United Kingdom.

Background: Donor hepatitis-C (HCV) infection has historically represented a barrier to kidney transplantation (KT). However, direct-acting antiviral (DAA) medications have revolutionised treatment of chronic HCV infection. Recent American studies have demonstrated that DAA regimes can be used safely peri-operatively in KT to mitigate HCV transmission risk. Methods: To formulate this narrative review, a comprehensive literature search was performed to analyse results of existing clinical trials examining KT from HCV-positive donors to HCV-negative recipients with peri-operative DAA regimes. Results: 13 studies were reviewed (11 single centre, four retrospective). Outcomes for 315 recipients were available across these studies. A sustained virological response at 12 weeks (SVR12) of 100% was achieved in 11 studies. One study employed an ultra-short DAA regime and achieved an SVR12 of 98%, while another achieved SVR12 of 96% due to treatment of a missed mixed genotype. Conclusion: HCV+ KT is safe and may allow increased utilisation of organs for transplantation from HCV+ donors, who often have other favourable characteristics for successful donation. Findings from US clinical trials can be applied to the United Kingdom transplant framework to improve organ utilisation as suggested by the NHSBT vision strategy “Organ Donation and Transplantation 2030: meeting the need”.

Response to American College of Physician’s statement on the ethics of transplant after normothermic regional perfusion

This paper responds to the position statement released by the American College of Physicians (ACP) entitled "Ethics, Determination of Death, and Organ Transplantation in Normothermic Regional Perfusion (NRP) with Controlled Donation after Circulatory Determination of Death (cDCD): American College of Physicians Statement of Concern." The ACP's statement engages with critical ethical issues surrounding cDCD NRP, but several of their conclusions are flawed. Contrary to the statement, the practice respects the dead donor rule and the legal definition of death while honoring the wishes of the deceased and their loved ones to help save the lives of those in need of organ transplants. cDCD NRP is well established in many countries, it can enhance trust in medical practice and organ donation, and will increase the availability of optimal organs for life-saving transplants.

Immunological microenvironment at the maternal-fetal interface

The immune cells, especially innate immune cells (Natural Killer cells and Macrophages) residing at the maternal-fetal interface are playing critical roles during pregnancy. Here we discuss the immunological characteristic at the maternal-fetal interface during normal pregnancy. These key decidual immune cells are reshaped of their uterus-specific homeostatic functions within this uterus microenvironment. Through emphasizing the similarities and differences between decidua immune microenvironments with tumor or transplantation immune microenvironments, distinctive immune cell niche with activated, tolerant, proangiogenic and nurturing characteristic at the maternal interface is exhibited. Deeper understanding of the immunological microenvironment during pregnancy yield important insight not only into the pathogenesis of various human pregnancy complications, but also suggest ways to better manipulate these immune cells in cancer and transplant organs.

Survey on Knowledge, Attitude and Practice of Organ Donation Among Dental Students in Chennai

Organ donation is the procedure when an individual permits their very own organ to be expelled and transplanted to someone else, legitimately, either by assent while the contributor is alive or dead with the consent of the closest relative. Donation might be for research or, all the more ordinarily, solid transplantable organs and tissues might be given to be transplanted into another person. Common transplantations include kidneys, heart, liver, pancreas, digestive tracts, lungs, bones, bone marrow, skin, and corneas. Some organs and tissues can be given by living contributors, for example, a kidney or part of the liver, some portion of the pancreas, some portion of the lungs or part of the intestines,however most donations happen after the giver has died.In 2017 Spain had the most elevated contributor rate on the planet at 46.9 per million individuals, trailed by Portugal (34.0 per million), Belgium (33.6 per million), Croatia (33.0 per million) and the US (32.0 per million). As of February 2, 2019, there were 120,000 individuals sitting tight forever sparing organ transplants in the US. Of these, 74,897 individuals were dynamic up-and-comers hanging tight for a donor.While perspectives on organ gift are certain, there is an enormous hole between the quantities of enrolled contributors contrasted with those anticipating organ gifts on a worldwide level.

Lessons from nature: Leveraging the freeze-tolerant wood frog as a model to improve organ cryopreservation and biobanking

The freeze-tolerant wood frog, Rana sylvatica, is one of the very few vertebrate species known to endure full body freezing in winter and thaw in early spring without any significant sign of damage. Once frozen, wood frogs show no cardiac or lung activity, brain function, or physical movement yet resume full physiological and biochemical functions within hours after thawing. The miraculous ability to tolerate such extreme stresses makes wood frogs an attractive model for identifying the molecular mechanisms that can promote freeze/thaw endurance. Recapitulating these pro-survival strategies in transplantable human cells and organs could improve viability post-thaw leading to better post-transplant outcomes, in addition to providing more time for adequate distribution of these transplantable materials across larger geographical areas. Indeed, several laboratories are beginning to mimic the pro-survival responses observed in wood frogs to preservation of human cells, tissues and organs and, to date, a few trials have been successful in extending preservation time prior to transplantation. In this review, we discuss the biology of the freeze-tolerant wood frog, current advances in biobanking based on these animals, and extend our discussion to future prospects for cryopreservation as an aid to regenerative medicine.

Heart transplantation: focus on donor recovery strategies, left ventricular assist devices, and novel therapies.

Heart transplantation is advocated in selected patients with advanced heart failure in the absence of contraindications. Principal challenges in heart transplantation centre around an insufficient and underutilized donor organ pool, the need to individualize titration of immunosuppressive therapy, and to minimize late complications such as cardiac allograft vasculopathy, malignancy, and renal dysfunction. Advances have served to increase the organ donor pool by advocating the use of donors with underlying hepatitis C virus infection and by expanding the donor source to use hearts donated after circulatory death. New techniques to preserve the donor heart over prolonged ischaemic times, and enabling longer transport times in a safe manner, have been introduced. Mechanical circulatory support as a bridge to transplantation has allowed patients with advanced heart failure to avoid progressive deterioration in hepato-renal function while awaiting an optimal donor organ match. The management of the heart transplantation recipient remains a challenge despite advances in immunosuppression, which provide early gains in rejection avoidance but are associated with infections and late-outcome challenges. In this article, we review contemporary advances and challenges in this field to focus on donor recovery strategies, left ventricular assist devices, and immunosuppressive monitoring therapies with the potential to enhance outcomes. We also describe opportunities for future discovery to include a renewed focus on long-term survival, which continues to be an area that is under-studied and poorly characterized, non-human sources of organs for transplantation including xenotransplantation as well as chimeric transplantation, and technology competitive to human heart transplantation, such as tissue engineering.

A transplant compatible with all patients: A salvage underway

A transplant compatible with all patients: A salvage underway