Transplantation Reports最新文献

The availability of thoracic organ transplantation as the treatment of choice for end-stage cardiac or pulmonary diseases is limited by the insufficient number of donor organs from brain dead donors, especially for organs where live-donation is not an option. Patients, who have not progressed to brain death, but have exhausted therapeutic options and life sustaining therapies are withdrawn can become donors with circulatory determination of death (DCD) when they meet criteria for the definition of this state. This approach can fulfill the wish of a patient to become an organ donor and also help to increase the number of donor organs. The DCD process exposes organs to prolonged warm ischemia that increases the possibility of primary graft dysfunction and failure. However, new technologies help in protecting the organs from cold preservation-related ischemia and facilitate resuscitation and monitoring of viability after the occurrence of the DCD-related ischemic insult. Herein, we review the opportunities and challenges in DCD thoracic organ transplantation, emerging techniques in preservation and monitoring of these organs and the potential effect of DCD thoracic organ transplantation on expanding the donor pool.

The sociocultural perception of Cardiopulmonary Death Donation by the population is an important issue, especially at this time when this type of donation is growing. However, the data that are currently available are insufficient to draw definitive conclusions on public reactions. Controlled organ donation after cardiocirculatory determination of death has generated an ethical and social debate since its implementation. The objective is to analyze the most relevant ethical-moral and social issues that involve this type of donation.

We were selected the 30 articles about this area with the PRISMA methodology. 72.2% of the articles that analyze the ethical conflicts on the withdrawal of life support treatment state that the staff that carries it out must be separate from the donation staff. 38.9% believe that it should be done in the ICM and 44.4% that it should be done by the ICM staff themselves. Regarding who should suggest controlled organ donation after cardiocirculatory determination of death, they all agree that it should be totally unrelated to ICM staff. 71.4% of the articles that analyze the use of premortem procedures justify their use based on scientific evidence and declare that they do not harm the potential donor. 42.1% accept the use of permanent circulatory cessation in determining death and 78.9% believe that a consensus should be reached on the waiting time in asystole. Despite some detractors, the use of ECMO is fully justified. Christian and Jewish culture are in favor of non-heart beating donation, but religious and economic objections continue to be raised in the Middle East. 80% of the articles that mention euthanasia classify it as a subject completely unrelated to controlled organ donation after cardiocirculatory determination of death

In conclusion, Organ donation after cardiocirculatory determination of death has experienced a boom in recent years and continues to lead to ethical-moral and social debate.

At the early days of organ transplantation before the diagnosis of brain death came in use only organs of non-heart-beating persons - who were the first donors after cardiac death (DCD) - could be taken for organ transplantation beside the living donors.

Organs from the first brain-dead donor were transplanted in 1963 in Belgium, five years later the famous Harvard Committee criteria were published. Following that in the Western world DCD was not used for organ transplantation, just in exceptional cases for several decades.

However, organ scarceness lead the way back to the idea of DCD. The original Maastricht classification discerns uncontrolled and controlled DCD in 4 categories from dead upon arrival through unsuccessful resuscitation attempt and awaiting cardiac death to cardiac arrest of a brain-dead person.

The time between the cessation of the of the circulation and the perfusion of the organ with the specific storage fluid is crucial for the possible use of the organs as transplants.

The recent studies explore the possibilities of the reconditioning of the organs to allow more and more of them to use for transplantation. The applicability is mostly needed in DCD cases. It is still open whether cold or warm perfusion, static or machine perfusion in continuous or pulsatile form would be the best for which organ.

Despite the evidence of the usefulness of this donor category, DCD is still not used universally. For example in Europe only one-third of the countries use DCD, the main reason is the underdevelopment of the infrastructural criteria in some of the countries, and the unsolved ethical and organizational challenges in others.

Background

Graft-versus-host disease (GVHD) continues to emerge as the topmost causative factor of the morbidity and mortality rate post hematopoietic stem cell transplantation. The graft cells attack the recipient host tissues resulting in acute or chronic GVHD that affect organs, including the lung, liver, skin, and gastrointestinal tract. Certain factors are considered to play a crucial role in the progression of the disease, such as antibodies produced by B cells, reduction in regulatory T cells, and immune tolerance disruption to self-antigen.

Main body

This review highlighted the pathophysiology of GVHD, clinical manifestation, stages of GVHD in different organs, and the significant role played by Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) in cytokine signalling, development, and function of several immune cells. Furthermore, we discussed the clinical efficacy of drugs, which comprises JAK inhibitors, monoclonal antibodies, and proteasome inhibitors that are widely used to treat GVHD.

Conclusion

Considering the progress recorded in identifying the therapeutic regimens for GVHD, novel and effective therapeutic approaches are much needed to alleviate the complication that arises post hematopoietic stem cell transplantation and reduce the morbidity and mortality rate of the disease.

Introduction

Organ shortage represents one of the main issues associated with lung transplantation (LTx). Over the years, in an attempt to increase the donor pool, the use of donors after cardiac death (DCDs) has gradually increased, with good results that bode well for their wider use in the future.

Methods

In this work, our experience with DCDs is presented. In addition, a brief literature review on controlled (c) and uncontrolled (u) DCDs was performed on the studies published in the last four years.

Results

From 2018 to 2022 our center performed three LTx with DCDs. All the donors were uDCDs (Maastricht class II). The median warm ischemic time of the graft was 160 min. In all the three LTx, lungs were reconditioned using portable Ex-Vivo-Lung-Perfusion (EVLP) system (Organ Care System, OCS, TransMedics) for a median time of 535 min. All the three LTx were performed with an intraoperative veno-arterial extra-corporeal membrane oxygenation (V-A ECMO), which was prolonged postoperatively in one patient.

Grade 3 primary graft disfunction (PGD) at 72 h was observed in one patient. No signs of acute rejection were observed in any patient at the surveillance transbronchial biopsies. One patient died 317 after LTx for consequences of a lung adenocarcinoma diagnosed in the native lung, while the other two are still alive with a preserved graft function.

Summary

The most recent studies confirm similar results between DCDs and DBDs in terms of survival and graft function. Good results can also be achieved in uDCDs if standardized protocols are followed and graft function is monitored by EVLP.

Hence, the use of DCDs represents a valid solution to expand the donor pool.

Chronic immunosuppressive therapy is critical to all transplant patients to help prevent rejection, chronic injury and loss of allograft. Tacrolimus is used as immunosuppression in more than ninety percent of kidney transplant recipients, and requires drug level monitoring. It is known that many prescribed medications can alter tacrolimus metabolism and lead to unpredictable levels that may expose patients to the above-mentioned complications. However, the use of over-the-counter medications is often overlooked. Here, we present a case report in which over-the-counter calcium carbonate significantly affected the patient's tacrolimus metabolism leading to unpredictable levels.

Allogeneic blood and marrow transplant (BMT) is used to transplant a new immune system in patients with hematologic malignancies or immune-mediated disease. BMT patients require initial immune suppression to prevent graft rejection and graft versus host disease (GVHD). Tacrolimus and cyclosporine are calcineurin inhibitors (CNI) and methotrexate is an antimetabolite used to mitigate this immune response. Tacrolimus has data supporting oral dose variation based on pharmacogenomic (PGx) studies for Intermediate Metabolizers (IM) and Poor Metabolizers (PM) on studies done in kidney transplant patients. There are fewer studies on BMT patients in this field, and even less on the variability of IV to oral conversion dosing and first pass metabolism effect based on PGx profiles. Methotrexate has been shown to have PGx mutations affecting its metabolism at higher dosing used for chemotherapy, but its impact on BMT patient dosing is not well-defined. Based on our study, we found statistically significant variability in Tacrolimus concentration based on drug assay levels compared with dosing for Intravenous (IV) and oral formulation based on PGx predicted phenotypes. We further noted a profound effect on first pass metabolism when transitioning between IV and oral dosing of Tacrolimus based on PGx predicted phenotypes. The average oral dose in predicted IM phenotypes divided by the IV dose was 2.68. For the predicted PM phenotype, the average oral dose divided by the IV dose was 1.18. The p-value in a two-tailed nonparametric T-test with equal variance assessing the conversion factor from IV to oral dosing in predicted IM versus PM phenotypes was significant with a p-value of 0.002. Methotrexate metabolism did not seem to be affected by PGx mutations at the doses used for BMT GVHD prevention.

With the continued deficit of available organs for transplantation, optimal care of the brain-dead and cardiac death donor is essential to optimize quality and quantity of precious organs. Anesthesiologists are a critical part of the perioperative surgical retrieval process, although individually, may rarely care for a donor. Prospective data to inform specific clinical practices is sparse although educational resources exist to guide anesthesiologists with ethical or clinical questions and protocols from intensive care units and organ procurement organizations serve as useful templates for maintenance of organ function. Pre-surgical resuscitation, optimization and homeostatic strategies should be continued into the operating room. Cautious titration of low dose anesthetic and analgesic agents may be required to blunt sympathetic and spinal reflexes but should not aggravate hypotension and muscle relaxation is recommended to facilitate surgical exposure. Anesthesiologists should be aware of procedural and pharmaceutical aspects of the donation process, including re-intubation of a deceased donor after death is confirmed when lung retrieval is planned.