Background: Over the past three decades, public attitudes to organ donation have been a subject of numerous studies focusing on donor motivation. Here, we present a fresh approach. We suggest focusing on public acceptability instead of motivation. The point is to understand public attitudes well enough to avoid risking public support for organ transplantation. We conducted the study in Denmark because there have been significant developments in public attitudes to organ donation in this country. In the 1990s, Denmark was a country with very low public support for organ donation and Denmark was the last country in Europe to introduce brain death as a legal criterion of death, whereas today Eurobarometer surveys rate Denmark as one of the European countries with the highest support for deceased organ donation from brain dead donors.Methods: We conducted a telephone survey in Denmark (N = 1195). A questionnaire was developed on the basis of preceding qualitative studies and pilot testing and included reuse of one item from earlier surveys to facilitate historical comparison. The analysis of the data was carried out using IBM SPSS Statistics 22 and focused on descriptive statistics.Results: A clear majority of 91.9 % are positive or very positive towards organ donation; 85.8 % like the idea of their body being used after their death, 85.0 % is willing to donate their own organs, 82.1 % to donate their tissue and only 2.3 % find that too much has been done to promote organ donation. There is limited support for monetary incentives for organ donation (5.8 %) and presumed consent (30.4 %), while a majority (63.9 %) supports making it mandatory to register a personal decision. Religious self-identification has limited impact on attitudes.Conclusions: We can identify a shift over the past three decades from marked opposition to organ transplantation to strong support as well as a pattern in the contemporary public attitudes, which can help explain what is central to public acceptability: self-determination. Policies fostering choice are met with a majority of positive attitudes, while presumed consent and monetary incentives are met with more negative attitudes. Our approach calls for comparative studies in other countries to generate a better overall understanding of the conditions of acceptability, which need to be in place to ensure the long-term social robustness of organ donation and thereby safeguard this important medical technology.
The aim of this study is to determine the feasibility of using nuclear magnetic resonance (NMR) tracer studies (13C-enriched glucose) to detect ex vivo de novo metabolism in the perfusion fluid and cortical tissue of porcine kidneys during hypothermic machine perfusion (HMP).
Ischaemic reperfusion (IR) injury is a major cause of graft loss, morbidity and mortality following orthotopic liver transplantation (OLT). Demand for liver transplantation has resulted in increasing use of marginal grafts that are more prone to IR injury. Remote ischaemic preconditioning (RIPC) reduces IR injury in experimental models, but recipient RIPC has not been evaluated clinically.
Tacrolimus is available as twice-daily Prograf® (Tac-BID) and the once-daily formulation, Advagraf® (Tac-OD). Although therapeutically equivalent, some transplant recipients require dose adjustments to achieve similar tacrolimus trough concentrations [Tac C0] after conversion between formulations. Tacrolimus is primarily metabolized by cytochrome P450 3A5 (CYP3A5). We sought to determine whether genetic polymorphisms in the CYP3A5 enzyme; CYP3A5 *1/*1 and CYP3A5 *1/*3 (expressers) compared to CYP3A5 *3/*3 (non-expressers) could account for discrepancies in dose requirements following conversion from Tac-BID to Tac-OD.
BACKGROUND:Silibinin has been shown to have anti-HCV activity and immune-modulating properties by regulating dendritic cell (DC) function. DCs are antigen-presenting cells that, together with regulatory T cells (Treg), play a pivotal role in controlling alloimmune, as well as anti-HCV immune responses.METHODS:Twelve liver transplant patients with HCV recurrence received iv infusion of Silibinin (iv-SIL) for 14 consecutive days. Using flow cytometry, before and at the end of treatment, we determined the frequencies of circulating myeloid (m) and plasmacytoid (p) DC and Treg and the expression of costimulatory/coregulatory molecules by the DC subsets and Treg. Statistical analysis was performed using the paired Student's t test and Pearson correlation test.RESULTS:After iv-SIL treatment, we observed an elevated plasmacytoid dendritic cell (pDC)/myeloid dendritic cell (mDC) ratio, while pDC displayed lower HLA-DR and higher immunoglobulin-like transcript 4 (ILT4), CD39, and HLA-G expression compared to the pretreatment baseline. In addition, after iv-SIL, mDC showed increased inducible costimulator ligand (ICOSL) expression. No changes were detected in Treg frequency or programed death (PD)-1 expression by these cells. Moreover, several correlations between DC/Treg markers and clinical parameters were detected.CONCLUSIONS:This descriptive study, in liver transplant patients with HCV recurrence, reveals the impact of iv-SIL on DC and Treg. The changes observed in circulating pDC and mDC that have previously been associated with tolerogenic conditions shed new light on how iv-SIL may regulate anti-viral and alloimmunity. We have also observed multiple clinical correlations that could improve the clinical management of liver transplant patients and that deserve further analysis.
Post-transplant lymphoproliferative disorder (PTLD) adversely affects patients’ long-term outcome.
BACKGROUND:The shortage of suitable organs and achieved tolerance are uncontested main concerns in transplantation. Long waiting lists for deceased donors and limited numbers of living donors are the current scenarios. Kidney grafts from living donors have better overall survival compared to cadaveric and require less aggressive immunosuppressive regimens. The human leukocyte antigen (HLA) labs have the key role to test the recipient and donors compatibility based on typing and antibody profile. The current standard molecular procedure in solid organ transplantation is low-resolution typing, at the antigen level.MAIN TEXT:In this commentary, the merits of high versus low degree of typing resolution in solid organ transplantation are discussed. Critical questions and reasons to bring high-resolution typing as a routine test in health system are considered. Specifically, with the introduction of the next-generation sequencing (NGS) in HLA, the pros and cons in living donation and benefits after deceased donation are critically evaluated.CONCLUSION:NGS has the potential to improve the transplant rates and the overall graft survival. Alternative strategies to increase in demanding the number of transplants are briefly highlighted.
Immunosuppressive therapy after kidney transplantation is based on calcineurin inhibitors (CNI). In most cases CNI therapy is combined with mycophenolate and steroids. In spite of good short-term results this therapy is associated with long-term toxicities, graft loss and patient death. Therefore, alternative immunosuppressive strategies are needed that combine excellent efficacy with low incidences of long-term adverse outcomes. This review focuses on the strategies based on mTOR- inhibitors in combination with minimized exposure to CNI.
While immunosuppressive agents are necessary to prevent the rejection of transplanted organs, and are a great medical success story for protecting against early allograft loss, graft and patient survival over the long term are diminished by side effects from these same drugs. One striking long-term side effect is a high rate of skin cancer development. The skin cancers that develop in transplant recipients tend to be numerous, as well as particularly aggressive, and are therefore a major contributor to morbidity and mortality in transplant recipients. An apparent reason for the high incidence of skin cancer likely relates to suppression of immune surveillance mechanisms, but other more direct effects of certain immunosuppressive drugs are also bound to contribute to cancers of UV-exposed skin. However, over the past few years, evidence has emerged to suggest that one class of immunosuppressants, mammalian target of rapamycin (mTOR) inhibitors, could potentially inhibit skin tumour formation through a number of mechanisms that are still being studied intensively today. Therefore, in light of the high skin cancer incidence in transplant recipients, it follows that clinical trials have been conducted to determine if mTOR inhibitors can significantly reduce these post-transplant skin malignancies. Here, the problem of post-transplant skin cancer will be briefly reviewed, along with the possible mechanisms contributing to this problem, followed by an overview of the relevant clinical trial results using mTOR inhibitors.
Commercial transplant tourism results in significant harm to both kidney donors and recipients. However, proponents of incentives for kidney donation assert that proper oversight of the process prevents these harms and also that transplant numbers can be safely increased so that the moral burden of poor end-stage kidney disease outcomes can be alleviated. In a moral dilemma analysis, the principle of preventing donor harm can be dissociated from the principles of providing benefits to the recipient and to society. It is plausible that an incentivized donor is fundamentally different from an uncompensated donor. Incentivized donors can experience harms unrelated to lack of regulation because their characteristics are determined by the incentive superimposed upon a poverty circumstance. Moreover, creating a system of incentivized donation without established national registries for capturing all long-term donor outcomes would be morally inconsistent, since without prior demonstration that donor outcomes are not income or wealth-dependent, a population of incentivized donors cannot be morally created in a clinical trial. Socioeconomic factors adversely affect outcome in other surgical populations, and interventions on income or wealth in these populations have not been studied. Coercion will be increased in families not affected by kidney disease, where knowledge of a new income source and not of a potential recipient is the incentive. In the case of elective surgery such as kidney donation, donor non-maleficence trumps donor autonomy, recipient beneficence, and beneficence to society when there is a conflict among these principles. Yet, we are still faced with the total moral burden of end-stage kidney disease, which belongs to the society that cannot provide enough donor kidneys. Acting according to one arm of the dilemma to prevent donor harm does not erase obligations towards the other, to provide recipient benefit. To resolve the moral burden, as moral agents, we must rearrange our institutions by increasing available donor organs from other sources. The shortage of donor kidneys creates a moral burden for society, but incentives for donation will only increase the total moral burden of end-stage kidney disease.
Background Determining eligibility for a kidney transplant is an important decision. Practice guidelines define contraindications to transplantation; however many are not evidence based. Canadian guidelines recommend that patients unlikely to survive the wait period not be evaluated. The purpose of this study was to evaluate what proportion of patients with a contraindication would survive the wait time. Methods Consecutive incident dialysis patients (January 2006 to December 2012) with a contraindication, defined using Canadian guidelines, were studied. Mortality rates were determined for each individual contraindication. Theoretical survival to the median wait time to transplantation was calculated. Results Of 746 incident patients, 435 (58 %) were deemed to have a contraindication at dialysis start. Nearly 80 % had a contraindication with a high mortality rate (dementia, multisystem disease, etc.). Patients with high mortality rates were less likely to survive the wait list than be transplanted. Patients with non-adherence, obesity, and potentially reversible disease had relatively low mortality rates, were more likely to survive, and possibly be transplanted at a time with the prospect of a better outcome. Conclusions This study gives some credence that many patients with a contraindication are not likely to benefit. A better framework of defining contraindications is needed to allow better decision-making.
Here, we review 15 years of clinical use of sirolimus in our transplant center, in context with the developing immunosuppressive strategies use worldwide. The majority of studies were conducted in de novo kidney transplant recipients, using sirolimus (SRL) in combination with calcineurin inhibitors (CNIs). We also explored steroid (ST) or CNI-sparing therapies, including CNI minimization, elimination, or conversion strategies in combination with mycophenolate (MMF/MPS). Pooled long-term outcomes were comparable with those obtained with CNI and antimetabolite combination. Surprisingly, there are still several areas that need further investigation to improve the risk/benefit profile of SRL in kidney transplantation, including pharmacokinetic/pharmacodynamic drug-to-drug interaction with cyclosporine (CsA) or tacrolimus (TAC), mechanisms of SRL-associated adverse reactions and combinations with other drugs such as belatacept and once-daily TAC, possibly leading to improved long-term adherence. These studies, along with others investigating the benefits of SRL associated lower viral infections and malignancies, are essential as we do not expect the introduction of new immunosuppressive drugs in the near future.
Cutaneous melanoma carries the potential for substantial morbidity and mortality in the solid organ transplant population. We systematically reviewed the literature published from January 1995 to January 2012 to determine the overall relative risk and prognosis of melanoma in transplant recipients. Our search identified 7,512 citations. Twelve unique non-overlapping studies reported the population-based incidence of melanoma in an inception cohort of solid organ transplant recipients. Compared to the general population, there is a 2.4-fold (95% confidence interval, 2.0 to 2.9) increased incidence of melanoma after transplantation. No population-based outcome data were identified for melanoma arising post-transplant. Data from non-population based cohort studies suggest a worse prognosis for late-stage melanoma developing after transplantation compared with the general population. For patients with a history of pre-transplant melanoma, one population-based study reported a local recurrence rate of 11% (2/19) after transplantation, although staging and survival information was lacking. There is a need for population-based data on the prognosis of melanoma arising pre- and post-transplantation. Increased incidence and potentially worse melanoma outcomes in this high-risk population have implications for clinical care in terms of prevention, screening and reduction of immunosuppression after melanoma development post-transplant, as well as transplantation decisions in patients with a history of pre-transplant melanoma.
Background The failure of a kidney transplant is now a common reason for initiation of dialysis therapy. Kidney transplant recipients commencing dialysis have greater morbidity and mortality than transplant-naïve, incident dialysis patients. This study aimed to identify variables associated with survival after graft failure. Methods All recipients of first, deceased donor kidney transplants performed in Northern Ireland between 1986 and 2005 who had a functioning graft at 12 months were included ( n = 585). Clinical and blood-derived variables (age, gender, primary renal disease, diabetic status, smoking status, human leukocyte antigen (HLA) mismatch, acute rejection episodes, immunosuppression, cardiovascular disease, graft survival, haemoglobin, albumin, phosphate, C reactive protein, estimated glomerular filtration rate (eGFR), rate of eGFR decline, dialysis modality, and access) were collected prospectively and investigated for association with re-transplantation and survival. The association between re-transplantation and survival was explored by modelling re-transplantation as a time-dependent covariate. Results Median follow-up time was 12.1 years. Recipients with a failing graft (158/585) demonstrated rapid loss of eGFR prior to graft failure, reducing the time available to plan for alternative renal replacement therapy. Median survival after graft failure was 3.0 years. In multivariate analysis, age and re-transplantation were associated with survival after graft failure. Re-transplantation was associated with an 88% reduction in mortality. Conclusions Optimal management of kidney transplant recipients with failing grafts requires early recognition of declining function and proactive preparation for re-transplantation given the substantial survival benefit this confers. The survival benefit associated with re-transplantation persists after prolonged exposure to immunosuppressive therapy.
Delayed graft function (DGF) remains a significant and detrimental postoperative phenomenon following living-related renal allograft transplantation, with a published incidence of up to 15%. Early therapeutic vasodilatory interventions have been shown to improve DGF, and modifications to immunosuppressive regimens may subsequently lessen its impact. This pilot study assesses the potential applicability of perioperative non-invasive cardiac output monitoring (NICOM), transit-time flow monitoring (TTFM) of the transplant renal artery and pre-/perioperative thromboelastography (TEG) in the early prediction of DGF and perioperative complications.
We analyzed all PRA-negative patients who received a first kidney transplant from an HLA-identical living donor. The patients received no antibody induction. An intraoperative bolus of 500 mg of methylprednisolone was administered. Then, steroid therapy was withdrawn within one week. Tacrolimus and mycophenolate treatment were started 3 days before transplantation with tacrolimus target levels of 4 to 8 ng/mL. In the absence of rejection, tacrolimus was withdrawn between 3 and 12 months post-transplant to reach mycophenolate mofetil monotherapy of 2 g/day or equivalent.
Extracorporeal membranous oxygenation is proposed for abdominal organ procurement from donation after circulatory determination of death (DCD). In France, the national Agency of Biomedicine supervises the procurement of kidneys from DCD, specifying the durations of tolerated warm and cold ischemia. However, no study has determined the optimal conditions of this technique. The aim of this work was to develop a preclinical model of DCD using abdominal normothermic oxygenated recirculation (ANOR). In short, our objectives are to characterize the mechanisms involved during ANOR and its impact on abdominal organs.
Patients with renal transplant are at higher risk of mortality from cardiovascular disease (CVD) compared with the general population. Physical activity has been shown to reduce the risk of CVD mortality in these patients. Unfortunately, barriers such as the harsh Canadian climate prevent patients from engaging in and harvesting the health benefits of physical activity. This pilot study explored active video gaming (AVG) as a way for patients with renal transplant to obtain physical activity and examined its effect on their functional status and quality of life (QOL).
BACKGROUND:Premature cardiovascular (CV) death is the commonest cause of death in renal transplant recipients. Abnormalities of left ventricular (LV) structure (collectively termed uremic cardiomyopathy) and left atrial (LA) dilation, a marker of fluid status and diastolic function, are risk factors for reduced survival in patients with end stage renal disease (ESRD). In the present analysis, we studied the impact of pre-transplant LA and LV abnormalities on survival after successful renal transplantation (RT).METHODS:One hundred nineteen renal transplant recipients (first transplant, deceased donors) underwent cardiovascular MRI (CMR) as part of CV screening prior to inclusion on the waiting list. Data regarding transplant function and patient survival after transplantation were collected.RESULTS:Median post-transplant follow-up was 4.3 years (interquartile range (IQR) 1.9, 6.2). During the post-transplant period, 13 patients returned to dialysis after graft failure and 23 patients died with a functioning graft. Survival analyses, censoring for patients returning to dialysis, showed that pre-transplant LV hypertrophy and elevated LA volume were significantly associated with reduced survival after transplantation. Multivariate Cox regression analyses demonstrated that longer waiting time, poorer transplant function, presence of LV hypertrophy and higher LA volume on screening CMR and female sex were independent predictors of death in patients with a functioning transplant.CONCLUSIONS:Presence of LVH and higher LA volume are significant, independent predictors of death in patients who are wait-listed and proceed with renal transplantation.
