The Unified Brain-Based Determination of Death Conceptually Justifies Death Determination in DCDD and NRP Protocols.

Organ donation after the circulatory determination of death requires the permanent cessation of circulation while organ donation after the brain determination of death requires the irreversible cessation of brain functions. The unified brain-based determination of death connects the brain and circulatory death criteria for circulatory death determination in organ donation as follows: permanent cessation of systemic circulation causes permanent cessation of brain circulation which causes permanent cessation of brain perfusion which causes permanent cessation of brain function. The relevant circulation that must cease in circulatory death determination is that to the brain. Eliminating brain circulation from the donor ECMO organ perfusion circuit in thoracoabdominal NRP protocols satisfies the unified brain-based determination of death but only if the complete cessation of brain circulation can be proved. Despite its medical and physiologic rationale, the unified brain-based determination of death remains inconsistent with the Uniform Determination of Death Act.

The novel HLA-A*02:1152 and HLA-B*40:566 alleles identified in Russian bone marrow donors.

Identification of two novel HLA alleles in Russian bone marrow donors.

Post-transplant de novo anti-HLA donor specific antibodies may contribute to poor graft function after haploidentical haematopoietic stem cell transplantation.

De novo anti-HLA donor-specific antibodies (DSAs) were rarely reported in stem cell transplantation patients. We present a case of 39-year-old acute myelogenous leukaemia patient who developed de novo DSAs only 16 days after transplantation with the highest mean fluorescence intensity (MFI) of 7406.23, which were associated with poor graft function (PGF). We used plasma exchange (PE) and intravenous immunoglobulin (IVIg) to reduce DSA level. A series of treatment including mesenchymal stem cells and donor cell transfusion were used to help recover graft function. On day 130, the patient achieved a successful engraftment.

Advantages of pooling of human bone marrow-derived mesenchymal stromal cells from different donors versus single-donor MSCs.

Mesenchymal stromal cells (MSC) from adult bone marrow are the most commonly used cells in clinical trials. MSCs from single donors are the preferred starting material but suffer from a major setback of being heterogeneous that results in unpredictable and inconsistent clinical outcomes. To overcome this, we developed a method of pooling MSCs from different donors and created cell banks to cater clinical needs. Initially, the master cell banks (MCBs) were created at passage 1 (P1) from the bone marrow MSCs isolated from of nine different donors. At this stage, MCBs from three different donors were mixed in equal proportion and expanded till P3 to create working cell banks. Further, the pooled cells and individual donor MSCs were expanded till P5 and cryopreserved and extensively characterised. There was a large heterogeneity among the individual donor MSCs in terms of growth kinetics (90% Coefficient of variation (CV) for cell yield and 44% CV for population doubling time at P5), immunosuppressive ability (30% CV at 1:1 and 300% CV at 1:10 ratio), and the angiogenic factor secretion potential (20% CV for VEGF and71% CV for SDF-1). Comparatively, the pooled cells have more stable profiles (60% CV for cell yield and 7% CV for population doubling time at P5) and exhibit better immunosuppressive ability (15% CV at 1:1 and 32% CV at 1:10 ratio ) and consistent secretion of angiogenic factors (16% CV for VEGF and 51% CV for SDF-1). Further pooling does not compromise the trilineage differentiation capacity or phenotypic marker expression of the MSCs. The senescence and in vitro tumourigenicity characteristics of the pooled cells are also similar to those of individual donor MSCs. We conclude that pooling of MSCs from three different donors reduces heterogeneity among individual donors and produces MSCs with a consistent secretion and higher immunosuppressive profile.

Abigail Levin replies.

This letter responds to the letter "The Open Donor View and Procreative Beneficence," by Daniel Groll, in the same, May-June 2024, issue of the Hastings Center Report.

The Open Donor View and Procreative Beneficence.

This letter responds to the article "What Do Prospective Parents Owe to Their Children?," by Abigail Levin, in the March-April 2024 issue of the Hastings Center Report.

A systematic review of assisted and third-party reproduction guidelines regarding management and care of donors.

BACKGROUND: Gamete and embryo donors face complex challenges affecting their health and quality of life. Healthcare providers need access to well-structured, evidence-based, and needs-based guidance to care for gamete and embryo donors. Therefore, this systematic review aimed to synthesize current assisted and third-party reproduction guidelines regarding management and care of donors. METHODS: The databases of ISI, PubMed, Scopus, and websites of organizations related to the assisted reproduction were searched using the keywords of "third party reproduction", "gamete donation", "embryo donation", "guidelines", "committee opinion", and "best practice", without time limit up to July 2023. All the clinical or ethical guidelines and best practice statements regarding management and care for gamete and embryo donors written in the English language were included in the study. Quality assessment was carried using AGREE II tool. Included documents were reviewed and extracted data were narratively synthesized. RESULTS: In this systematic review 14 related documents were reviewed of which eight were guidelines, three were practice codes and three were committee opinions. Five documents were developed in the United States, three in Canada, two in the United Kingdom, one in Australia, and one in Australia and New Zealand. Also, two guidelines developed by the European Society of Human Reproduction and Embryology were found. Management and care provided for donors were classified into four categories including screening, counseling, information provision, and ethical considerations. CONCLUSION: While the current guidelines include some recommendations regarding the management and care of gamete/embryo donors in screening, counseling, information provision, and ethical considerations, nevertheless some shortcomings need to be addressed including donors' psychosocial needs, long-term effects of donation, donors' follow-up cares, and legal and human rights aspects of donation. Therefore, it is needed to conduct robust and well-designed research studies to fill the knowledge gap about gamete and embryo donors' needs, to inform current practices by developing evidence-based guidelines.

Gamete and embryo donors face complex challenges affecting their health and quality of life. To manage these challenges, healthcare providers need guidelines that are based on evidence and donors' real needs. In order to develop a comprehensive guideline that meets the needs of donors; it is important to review the current guidelines. So, in this study we reviewed the current assisted and third-party reproduction guidelines regarding management and care of donors. We searched databases and relevant websites and found 14 related documents. The main topics recommended for management and care of donors in these guidelines included screening, counseling, information provision, and ethical considerations. We recognized that some of donors' needs are neglected in these documents including donors' psychosocial needs, long-term effects of donation on donors, their follow-up cares, and legal and human rights aspects of donation. Therefore, there is need for further research to develop guidelines based on donors' unmet needs.

Ethical and Equity Guidance for Transplant Programs Considering Thoracoabdominal Normothermic Regional Perfusion (TA-NRP) for Procurement of Hearts.

Donation after circulatory determination of death (DCDD) is an accepted practice in the United States, but heart procurement under these circumstances has been debated. Although the practice is experiencing a resurgence due to the recently completed trials using ex vivo perfusion systems, interest in thoracoabdominal normothermic regional perfusion (TA-NRP), wherein the organs are reanimated in situ prior to procurement, has raised many ethical questions. We outline practical, ethical, and equity considerations to ensure transplant programs make well-informed decisions about TA-NRP. We present a multidisciplinary analysis of the relevant ethical issues arising from DCDD-NRP heart procurement, including application of the Dead Donor Rule and the Uniform Definition of Death Act, and provide recommendations to facilitate ethical analysis and input from all interested parties. We also recommend informed consent, as distinct from typical "authorization," for cadaveric organ donation using TA-NRP.

An Ethics Committee's Evaluation of Normothermic Regional Perfusion (NRP) in 2018-Unsatisfactory Answers Then-and Now.

An adult university hospital ethics committee evaluated a proposed TA-NRP protocol in the fall of 2018. The protocol raised ethical concerns about violation of the Uniform Determination of Death Act and the prohibition known as the Dead Donor Rule, with potential resultant legal consequences. An additional concern was the potential for increased mistrust by the community of organ donation and transplantation. The ethics committee evaluated the responses to these concerns as unable to surmount the ethical and legal boundaries and the ethics committee declined to endorse the procedure. These concerns endure.

Restoring the Organism as a Whole: Does NRP Resurrect the Dead?

The introduction of normothermic regional perfusion (NRP) in controlled donation after circulatory determination of death (cDCDD) protocols is by some regarded as controversial and ethically troublesome. One of the main concerns that opponents have about introducing NRP in cDCDD protocols is that reestablishing circulation will negate the determination of death by circulatory criteria, potentially resuscitating the donor. In this article, I argue that this is not the case. If we take a closer look at the concept of death underlying the circulatory criterion for determination of death, we find that the purpose of the criterion is to show whether the organism as a whole has died. I argue that this purpose is fulfilled by the circulatory criterion in cDCDD protocols, and that applying NRP does not negate the determination of death or resuscitate the donor.

Donor Blood Tests do Not Predict Pancreas Graft Survival After Simultaneous Pancreas Kidney Transplantation; a National Cohort Study.

Simultaneous pancreas-kidney (SPK) transplantation improves quality of life and limits progression of diabetic complications. There is reluctance to accept pancreata from donors with abnormal blood tests, due to concern of inferior outcomes. We investigated whether donor amylase and liver blood tests (markers of visceral ischaemic injury) predict pancreas graft outcome using the UK Transplant Registry (2016-2021). 857 SPK recipients were included (619 following brainstem death, 238 following circulatory death). Peak donor amylase ranged from 8 to 3300 U/L (median = 70), and this had no impact on pancreas graft survival when adjusting for multiple confounders (aHR = 0.944, 95% CI = 0.754-1.81). Peak alanine transaminases also did not influence pancreas graft survival in multivariable models (aHR = 0.967, 95% CI = 0.848-1.102). Restricted cubic splines were used to assess associations between donor blood tests and pancreas graft survival without assuming linear relationships; these confirmed neither amylase, nor transaminases, significantly impact pancreas transplant outcome. This is the largest, most statistically robust study evaluating donor blood tests and transplant outcome. Provided other factors are acceptable, pancreata from donors with mild or moderately raised amylase and transaminases can be accepted with confidence. The use of pancreas grafts from such donors is therefore a safe, immediate, and simple approach to expand the donor pool to reach increasing demands.

Basiliximab Treatment for Patients With Steroid-Refractory Acute Graft-Versus-Host Disease Following Matched Sibling Donor Hematopoietic Stem Cell Transplantation.

Basiliximab is an important treatment for steroid-refractory acute graft-versus-host disease (SR-aGVHD). We performed this retrospective study to evaluate the efficacy and safety of basiliximab treatment in SR-aGVHD patients following matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) (n = 63). Overall response rate (ORR) was 63.5% and 54% at any time and at day 28 after basiliximab treatment. Grade III-IV aGVHD before basiliximab treatment predicted a poor ORR after basiliximab treatment. The rates of virus, bacteria, and fungi infections were 54%, 23.8%, and 3.1%, respectively. With a median follow-up of 730 (range, 67-3,042) days, the 1-year probability of overall survival and disease-free survival after basiliximab treatment were 58.6% (95% confidence interval [CI] = 47.6%-72.2%) and 55.4% (95% CI = 44.3%-69.2%), respectively. The 3-year cumulative incidence of relapse and non-relapse mortality after basiliximab treatment were 18.9% (95% CI = 8.3%-29.5%) and 33.8% (95% CI = 21.8%-45.7%), respectively. Comorbidities burden before allo-HSCT, severity of aGVHD and liver aGVHD before basiliximab treatment showed negative influences on survival. Thus, basiliximab was safe and effective treatment for SR-aGVHD following MSD-HSCT.

Characterisation of the novel HLA-C*15:274 allele using short and long-read sequencing technologies.

The novel HLA-C*15:274 allele, first described in a potential bone marrow donor from Brazil.

Multi-centre analytical performance verification of an IVD assay to quantify donor-derived cell-free DNA in solid organ transplant recipients.

Donor-derived cell-free DNA (dd-cfDNA) has been widely studied as biomarker for non-invasive allograft rejection monitoring. Earlier rejection detection enables more prompt diagnosis and intervention, ultimately improving patient treatment and outcomes. This multi-centre study aims to verify analytical performance of a next-generation sequencing-based dd-cfDNA assay at end-user environments. Three independent laboratories received the same experimental design and 16 blinded samples to perform cfDNA extraction and the dd-cfDNA assay workflow. dd-cfDNA results were compared between sites and against manufacturer validation to evaluate concordance, reproducibility, repeatability and verify analytical performance. A total of 247 sample libraries were generated across 18 runs, with completion time of <24 h. A 96.0% first pass rate highlighted minimal failures. Overall observed versus expected dd-cfDNA results demonstrated good concordance and a strong positive correlation with linear least squares regression r2 = 0.9989, and high repeatability and reproducibility within and between sites, respectively (p > 0.05). Manufacturer validation established limit of blank 0.18%, limit of detection 0.23% and limit of quantification 0.23%, and results from independent sites verified those limits. Parallel analyses illustrated no significant difference (p = 0.951) between dd-cfDNA results with or without recipient genotype. The dd-cfDNA assay evaluated here has been verified as a reliable method for efficient, reproducible dd-cfDNA quantification in plasma from solid organ transplant recipients without requiring genotyping. Implementation of onsite dd-cfDNA testing at clinical laboratories could facilitate earlier detection of allograft injury, bearing great potential for patient care.

Active Donor Management Goals in Serial Donors After Brain Death.

OBJECTIVES: Management of potential organ donors is crucial in the donation process, considering that hemodynamic instability is quite common. MATERIALS AND METHODS: In the this single-center retrospective observational study, we analyzed 87 utilized brain death donors consecutively admitted to our intensive care unit from January 1, 2019, to December 31, 2022. We assessed the achievement of donor management goals during the observation period, and we also evaluated whether the achieve-ment of donor goals differed between younger and older donors (arbitrary age cutoff of 65 years). RESULTS: In our series, mean age of donors was 67 ± 18 y, and organ-per-donor ratio was 2.3. The number of donor goals significantly increased during the 6-hour observation period (P < .001) and all donor goals were achieved in most donors (84/87) at the end of the observation period with no changes in the use and dose of vasoactive drugs. With respect to age, the number of donor goals was significantly higher in older donors at first evaluation, but goals significantly increased in both age subgroups of donors at the end of the 6-hour observation period. CONCLUSIONS: Our data strongly suggested that a strict hemodynamic monitoring schedule allows the achievement of donor goals both in older and in younger brain death donors. We confirmed our previous findings that hemodynamic management in brain death donors is influenced by age. A strict hemodynamic monitoring schedule of brain death donors is useful to consistently achieve donor goals.

Outcomes of Kidneys Transplanted From Hepatitis C Viremic Donors to Naive Recipients From an Appalachian Rural Kidney Transplant Program.

OBJECTIVES: Before the advent of direct-acting antiviral therapy for hepatitis C virus, a large proportion of kidneys from donors with hepatitis C viremia were discarded. Hepatitis C virus is now amenable to effective treatment with excellent seronegativity rates. In this study, we review the outcomes of hepatitis C viremic kidneys transplanted into hepatitis C-naive recipients. MATERIALS AND METHODS: In this retrospective observational study, we examined 6 deceased donor kidneys with hepatitis C viremia that were transplanted into hepatitis C-naive recipients between March 2020 and April 2021 at a single center. Because of health insurance constraints, patients were treated for hepatitis C virus with glecaprevir/pibrentasvir for 8 weeks following seroconversion posttransplant. Primary outcome measured was viral seroconversion; secondary outcomes included graft function, posttransplant complications, and all-cause mortality. RESULTS: On average, patients seroconverted 6 days (range, 4-10 d) after transplant and began treatment 26 days (range, 15-37 d) after seroconversion. An 8-week course of antiviral treatment was successful in preventing acute hepatitis C virus infection in all patients. Posttransplant median creatinine was 1.96 mg/dL (range, 1-4.55 mg/dL), whereas median estimated glomerular filtration rate was 41.33 mL/min/1.73 m2 (range, 17-85 mL/min/1.73 m2). Patient survival rate was 66.7%, and death-censored graft survival rate was 100%. Two patients died from unrelated reasons: 1 from acute respiratory failure secondary to SARS-CoV-2 infection and 1 from posttransplant lymphoproliferative disorder. Two patients developed allograft rejection posttransplant (1 developed antibody mediated rejection, 1 developed borderline T-cell-mediated cellular rejection). Other major complications included neutropenia, fungal rash, SARS-CoV-2 infection, cytomegalovirus, BK virus, and Epstein-Barr virus reactivation. CONCLUSIONS: Use of hepatitis C-viremic donor kidneys for transplant is a safe option and has great potential to increase the kidney donor pool, as long as high index of suspicion is maintained for allograft rejection and opportunistic infections.