Source Of Organs For Transplantation Research Articles

Tissue Injury Protection: The Other Face of Anticoagulant Treatments in the Context of Ischemia and Reperfusion Injury with a Focus on Transplantation.

Organ transplantation has enhanced the length and quality of life of patients suffering from life-threatening organ failure. Donors deceased after brain death (DBDDs) have been a primary source of organs for transplantation for a long time, but the need to find new strategies to face organ shortages has led to the broadening of the criteria for selecting DBDDs and advancing utilization of donors deceased after circulatory death. These new sources of organs come with an elevated risk of procuring organs of suboptimal quality. Whatever the source of organs for transplant, one constant issue is the occurrence of ischemia-reperfusion (IR) injury. The latter results from the variation of oxygen supply during the sequence of ischemia and reperfusion, from organ procurement to the restoration of blood circulation, triggering many deleterious interdependent processes involving biochemical, immune, vascular and coagulation systems. In this review, we focus on the roles of thrombo-inflammation and coagulation as part of IR injury, and we give an overview of the state of the art and perspectives on anticoagulant therapies in the field of transplantation, discussing benefits and risks and proposing a strategic guide to their use during transplantation procedures.

Organ donation: Key factors influencing the younger generation's decision-making in China.

The organ transplantation sector in China is facing a severe shortage of donors, and the organ donation rate needs to be increased. Since 2015, voluntary donation by citizens has become the only source of organs for transplantation in China. In recent years, there has been a relatively positive change in young people's attitudes toward organ donation after death. The aim of the study was to understand young people's perceptions and attitudes toward organ donation and the factors that influence them and can positively impact the promotion of organ donation. By analyzing relevant literature and legal texts, we developed a questionnaire. Information was obtained through questionnaires and interviews, and 501 valid questionnaires were returned from the target group. A chi-square test was used to examine whether there were significant differences in the willingness to organ donation among young people with different characteristics. A factor analysis was used to investigate the main factors influencing the different attitudes of young people toward organ donation, and a one-way ANOVA was used to examine whether young people with different characteristics were affected differently by different factors. In our survey of young people aged 18-30 years, 99.2% of respondents knew about organ donation, 47.1% were willing to donate organs, and 15.2% understood that there were corresponding laws and regulations for organ donation. The study's findings showed that urban residents are more willing to be organ donators than rural residents; people with higher education levels have better awareness and are more willing to donate an organ; and people with religious beliefs are more likely to donate organs. The main factors that support the willingness of young people to donate are the social environment that provides support, their optimism in dealing with death, and their desire to realize their final value after death. The main factors for those unwilling to donate were low awareness or misconceptions about organ donation among individuals and their families and their attitudes toward death. As the people who took the questionnaire are probably interested in organ donation, the sample results will show a higher percentage of people who know about organ donation. We hope to discuss further with a larger and broader sample coverage to improve the estimates' validity and reflect the overall picture more accurately in a future study. Young people knew about organ donation but had a low depth of awareness. Household registration type, education level, and religious affiliation significantly correlate with people's willingness to donate. The supportive environment for organ donation in society and the correct understanding of the organ donation process and laws and regulations can influence people's willingness to donate.

Do religious beliefs influence the acceptance of xenotransplantation? Veterinary students

Xenotransplantation could be a source of organs for transplantation given the global organ shortage. It is important to know the opinion and variables that influence the acceptance of xenotransplantation of the professionals who will work in the genetic manipulation, production, and care of animals to be used for this purpose. Analyze the influence of religious beliefs on the attitude toward xenotransplantation in veterinary students. The study population included 2683 veterinary students from different courses and Spanish Universities. Instrument evaluation included a validated self-administered and anonymously completed questionnaire (PCID-XENOTx-Ríos). The survey was self-administered and completed anonymously. Consent to collaborate in the study was requested. Variables for the study included attitude toward xenotransplantation and toward religion, considering the following options: practicing Catholic, nonpracticing Catholic, non-Catholic, and atheist/agnostic. Statistics were performed using descriptive analysis, Student t test, -X2, and Fisher's exact test. Of the total number of participants, 7 did not answer this question. Those in favor of xenotransplantation were 92.9% (n=247) of practicing Catholics, 92.8% (n=812) of nonpracticing Catholics, and 87.3% (n=69) of those professing another non-Catholic religion compared with 93.5% (n=1361) of those considering themselves agnostic/atheist (P=.037). Religion is an influential factor in attitudes toward organ xenotransplantation. Those who practice Catholicism and those who consider themselves agnostic/atheist are more accepting of organ procurement for transplantation than those who practice other religious doctrines.

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.

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.

Histopathology of pig kidney grafts with/without expression of the carbohydrate Neu5Gc in immunosuppressed baboons.

Pigs deficient in three glycosyltransferase enzymes (triple-knockout [TKO] pigs, that is, not expressing the three known carbohydrate xenoantigens) and expressing 'protective' human transgenes are considered a likely source of organs for transplantation into human recipients. Some human sera have no or minimal natural antibody binding to red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) from TKO pigs. However, all Old World monkeys exhibit natural antibody binding to TKO pig cells. The xenoantigen targets of Old World monkey natural antibodies are postulated to be carbohydrate moieties exposed when the expression of the carbohydrate N-glycolylneuraminic acid (Neu5Gc) is deleted. The aim of this study was to compare the survival in baboons and histopathology of renal grafts from pigs that either (a) expressed Neu5Gc (GTKO pigs; Group 1) or (b) did not express Neu5Gc (GTKO/CMAHKO [DKO] or TKO pigs; Group 2). Life-supporting renal transplants were carried out using GTKO (n=5) or DKO/TKO (n=5) pig kidneys under an anti-CD40mAb-based immunosuppressive regimen. Group 1 baboons survived longer than Group 2 baboons (median 237vs. 35 days; mean 196vs. 57 days; p<0.07) and exhibited histopathological features of antibody-mediated rejection in only two kidneys. Group 2 exhibited histopathological features of antibody-mediated rejection in all five grafts, with IgM and IgG binding to renal interstitial arteries and peritubular capillaries. Rejection-free survival was significantly longer in Group 1 (p<0.05). The absence of expression of Neu5Gc on pig kidney grafts is associated with increased binding of baboon antibodies to pig endothelium and reduced graft survival.

Evidence suggesting that deletion of expression of N-glycolylneuraminic acid (Neu5Gc) in the organ-source pig is associated with increased antibody-mediated rejection of kidney transplants in baboons.

Pigs deficient in three glycosyltransferase enzymes (triple-knockout [TKO] pigs) and expressing "protective" human transgenes are likely sources of organs for transplantation into human recipients. Testing of human sera against red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) from TKO pigs has revealed minimal evidence of natural antibody binding. However, unlike humans, baboons exhibit natural antibody binding to TKO pig cells. The xenoantigen specificities of these natural antibodies are postulated to be one or more carbohydrate moieties exposed when N-glycolylneuraminic acid (Neu5Gc) is deleted. The aim of this study was to compare the survival of renal grafts in baboons from pigs that either expressed Neu5Gc (GTKO pigs; Group1, n=5) or did not express Neu5Gc (GTKO/CMAHKO [DKO] or TKO pigs; Group2, n=5). An anti-CD40mAb-based immunosuppressive regimen was administered in both groups. Group1 kidneys functioned for 90-260days (median 237, mean 196days), with histopathological features of antibody-mediated rejection in two kidneys. Group2 kidneys functioned for 0-183days (median 35, mean 57), with all of the grafts exhibiting histologic features of antibody-mediated rejection. These findings suggest that the absence of expression of Neu5Gc on pig kidneys impacts graft survival in baboon recipients.

Effect on the donor lungs of using abdominal normothermic regional perfusion in controlled donation after circulatory death.

Controlled donation after circulatory death (cDCD) donors are becoming a common source of organs for transplantation globally. However, the graft survival rate of cDCD abdominal organs is inferior to that of organs from brain-dead donors. The rapid retrieval (RR) technique is used by most donor organ procurement teams. The abdominal normothermic regional perfusion (A-NRP) technique has been implemented to minimize warm ischaemic damage to the abdominal organs. However, there is limited information on the effect of A-NRP on the quality of the donor lungs. This study aimed to compare lung transplantation outcomes using lungs procured from cDCD donors using the A-NRP and abdominal RR techniques. A single-centre retrospective analysis of consecutive transplant recipients of cDCD lungs from June 2013 to December 2019 was performed. The recipients were divided into 2 cohorts according to the abdominal procurement technique used. The recipient and donor characteristics (age, sex, cause of brain injury, warm ischaemic time, diagnosis, lung allocation score and other factors), incidence of primary graft dysfunction and early survival were monitored. Twenty-eight consecutive lung transplantation recipients were identified (median age 59 years; 61% male); 14 recipients received lungs using the A-NRP and 14 using abdominal RR for abdominal organ retrieval. There were no significant differences in the baseline characteristics, primary graft dysfunction (P = 0.70), hospital mortality (P = 1.0) and 1-year survival rate (P = 1.0) between the 2 groups. No difference was observed in lung transplantation outcomes irrespective of the abdominal organ procurement technique used (A-NRP or abdominal RR).

EVIDENCE FOR GTKO/Β4GALNT2KO PIGS AS THE PREFERRED ORGAN-SOURCE FOR OLD WORLD MONKEYS AS A PRECLINICAL MODEL OF XENOTRANSPLANTATION INSTEAD OF TRIPLE-KNOCKOUT PIGS

Purpose: Triple-knockout pigs (TKO, in which expression of the three known pig xenoantigens has been deleted) are likely to be an optimal source of organs for transplantation into human recipients, some of whom do not have natural antibodies against TKO pig cells. However, Old World monkeys, e.g., baboons, have natural antibodies directed to TKO cells, i.e., to a ‘fourth’ xenoantigen that appears when N-glycolylneuraminic acid (Neu5Gc) is deleted. The aim of this study was to evaluate in vitro (i) anti-pig IgM/IgG binding, and (ii) complement-dependent cytotoxicity (CDC) to several kinds of pig peripheral blood mononuclear cells (PBMCs) using baboons sera. In addition, (iii) in vivo we compared the survival in baboons of renal grafts from pigs that either (a) expressed Neu5Gc (GTKO pigs) or (b) did not express Neu5Gc (GTKO/CMAHKO or TKO pigs) and therefore expressed the ‘fourth’ xenoantigen. Methods:In vitro, we measured (i) anti-pig IgM/IgG binding, and (ii) CDC by flow cytometry to GTKO, GTKO/β4GalNT2KO (that do not express the ‘fourth’ xenoantigen), and TKO pig PBMCs using 72 baboon sera. In vivo, life-supporting renal transplants were carried out in baboons using GTKO (n=6) or CMAHKO (TKO or GTKO/CMAHKO) (n=6) pig kidneys under an anti-CD40mAb-based regimen. Results:In vitro studies: Mean IgM antibody binding to GTKO/β4GalNT2KO pig PBMCs was significantly lower than to GTKO or TKO pig PBMCs (p<0.01). Mean IgG antibody binding to GTKO/β4GalNT2KO pig PBMCs was significantly lower than to TKO PBMCs (p<0.01). Mean CDC of GTKO/β4GalNT2KO pig PBMCs was significantly lower than of GTKO or TKO pig PBMCs (p<0.01) (Figure1). In vivo studies: One baboon in each group required early euthanasia for acute gastric dilatation, and were excluded from further analysis. GTKO pig kidneys functioned for 90-260 days (median 237 days, mean 196 days), with histopathological features of antibody-mediated rejection (AMR) being seen in only 2 of 5. The rejection-free survival of pig kidneys not expressing Neu5Gc (TKO or GTKO/CMAHKO) was significantly shorter (median 35 days; mean 57 days) (p<0.05) (Figure2). Four of 5 grafts failed from AMR within 1-61 days, and one baboon was euthanized for peripheral artery embolism at 183 days without features of rejection. Conclusions: Even though considered ideal for clinical xenotransplantation, the presence of natural antibodies to CMAHKO (TKO or GTKO/CMAHKO) pig cells in baboons complicates the survival of CMAHKO pig kidneys in baboons. Based on this vitro data, the use of GTKO/β4GalNT2KO (instead of TKO) pigs would be preferable for pig-to-baboon organ transplantation.

NEW WORLD MONKEYS AS MODELS FOR TESTING TRIPLE-KNOCKOUT (TKO) PIG RED BLOOD CELL OR SKIN TRANSPLANTS

Background: TKO pigs are an optimal source of organs for transplantation into human recipients, who do not commonly have high levels of preformed antibodies against TKO pig cells. However, Old World monkeys (OWMs), e.g., baboons, do have antibodies directed to TKO pig cells, associated with significant serum cytotoxicity. New World monkeys (NWMs), e.g., capuchins, have low or no antibodies to TKO pig cells. Our aims were (i) to measure anti-pig IgM/IgG binding and (ii) complement-dependent cytotoxicity (CDC) to GTKO and TKO pig cells using sera from humans, baboons, and capuchins, and (iii) to measure the efficacy of anti-thymocyte globulin (ATG) and Rituximab in these three species. Methods: (i) Sera from humans (n=9), baboons (n=6), and capuchins (n=9) were tested by flow cytometry for binding of IgM and IgG to peripheral blood mononuclear cells (PBMCs) from GTKO and TKO pigs. Binding intensity was presented as relative geometric mean (rGM). (ii) The sera (final concentration 25%) were also tested for CDC to the same pig cells by flow cytometry. (iii) The effect of ATG and Rituximab on human (n=2), baboon (n=2), and capuchin (n=3) PBMCs or B cells deletion was measured by flow cytometry. Results: Binding of serum IgM/IgG to pig cells (Figure1) Mean serum anti-GTKO IgM and IgG binding were both significantly lower in baboons than in humans and capuchins (p<0.01). Mean baboon anti-TKO IgM binding was significantly higher than in humans and capuchins (p<0.01). Mean capuchin anti-TKO IgG was significantly lower than in humans and baboons (p<0.01). Serum CDC to pig cells (Figure1) Mean serum CDC of GTKO PBMCs did not differ between the three species. Baboon serum CDC of TKO PBMCs was significantly greater than in humans and capuchins (p<0.01), but there was no difference between humans and capuchins. The CDC of ATG and Rituximab on PBMCs and B cells (Figure2) ATG (25-50µg/ml) depleted fewer PBMCs in capuchins and baboons than in humans, but the depletion in capuchins was not significantly different from that in baboons, except at high concentration (100µg/ml). In contrast, the effect of Rituximab in depleting B cells in capuchins was very limited, and significantly less than in humans and baboons (p<0.05 or 0.01). Conclusions: When TKO pig organs are transplanted, OWMs, e.g., baboons, would be less than ideal as recipients as they do not mimic the human immune response. NWMs, e.g., capuchins, are to be preferred. However, their small size and the reduced effect of ATG, and, particularly, Rituximab, limit their use as recipients of organs, though they would be ideal for studies of TKO pig red blood cell transfusion or skin transplantation, where immunosuppressive therapy is not required.Work on xenotransplantation at the University of Alabama at Birmingham is supported in part by NIH NIAID U19 grant AI090959 and in part by a grant to UAB from United Therapeutics.

Kidney transplantation with allografts from infant donors-Small organs, big value.

Although infant organ donors remain a rare source of organs for transplantation, technical challenges have resulted in increased rates of complications and inferior graft function. The aim of the present study was to investigate the outcomes of kidneys procured from juvenile and infant donors. We evaluated all kidney transplants from deceased donors<16years of age performed at our center between 01/2008 and 08/2019. We defined three groups based on quartiles of donor body weight: <13kg (infant donors), 13-40kg (juvenile donors), and>40kg (standard criteria donors). Clinical characteristics and outcomes were compared between groups. Ninety-two transplants were included in this study. Out of 92 recipients, there were 32 (34.8%) adult and 60 (65.2%) pediatric patients. All groups demonstrated excellent graft function and survival on both short and long-term follow-up. 1-year, 3-year, and 5-year graft survival rates for the standard criteria donor group were 100%, 95.2%, and 88.4%, respectively, compared with 95.8% for infant and 95% for juvenile donors at all times (P=.79). eGFR at 5years was 98.9±5.5, 74.1±6.2, and 81.6±6.9mL/min/1.73m2 for infant, juvenile, and standard criteria donors, respectively (P<.01). Infant donor allografts can be transplanted with excellent long-term outcomes in both pediatric and adult recipients. Implanting them as single allografts onto pediatric candidates allows for the transplantation of two patients. As such, pediatric recipients should be prioritized for these donor organs.

Evidence for GTKO/β4GalNT2KO Pigs as the Preferred Organ-source for Old World Nonhuman Primates as a Preclinical Model of Xenotransplantation.

Background.Triple-knockout (TKO) pigs (in which expression of the 3 known pig carbohydrate xenoantigens has been deleted) are likely to be an optimal source of organs for transplantation into human recipients, many of whom do not have natural antibodies against TKO pig cells. However, old world monkeys, for example, baboons, have natural antibodies directed to TKO cells (to a “fourth” xenoantigen that is exposed after TKO).Methods.We measured (1) anti-pig IgM/IgG binding, and (2) complement-dependent cytotoxicity (CDC), by flow cytometry to α1,3-galactosyltransfearse gene-knockout (GTKO), GTKO/β4GalNT2KO (that do not express the “fourth” xenoantigen), and TKO pig peripheral blood mononuclear cells (PBMCs) using 72 baboon sera (30 specific pathogen-free [SPF], and 42 non-SPF baboons).Results.Mean IgM antibody binding to GTKO/β4GalNT2KO pig PBMCs was significantly lower than to GTKO or TKO pig PBMCs (P < 0.01). Mean IgG antibody binding to GTKO/β4GalNT2KO pig PBMCs was significantly lower than to TKO PBMCs (P < 0.01). Mean CDC of GTKO/β4GalNT2KO pig PBMCs was significantly lower than of GTKO or TKO pig PBMCs (P < 0.01). SPF baboon serum IgM and IgG binding to, and CDC of, GTKO/β4GalNT2KO or TKO PBMCs were significantly lower than non-SPF baboon sera (P < 0.01).Conclusions.Although TKO pigs form the basis for proposed clinical trials of xenotransplantation, it is difficult to identify baboons with a low or negative CDC to TKO pigs. For pig-to-baboon organ transplantation, the use of GTKO/β4GalNT2KO pigs would be preferable. The use of SPF baboons as recipients might be a minor advantage.

Prediction Model for Timing of Death in Potential Donors After Circulatory Death (DCD III): Protocol for a Multicenter Prospective Observational Cohort Study.

BackgroundControlled donation after circulatory death (cDCD) is a major source of organs for transplantation. A potential cDCD donor poses considerable challenges in terms of identification of those dying within the predefined time frame of warm ischemia after withdrawal of life-sustaining treatment (WLST) to circulatory arrest. Several attempts have been made to develop models predicting the time between treatment withdrawal and circulatory arrest. This time window determines whether organ donation can occur and influences the quality of the donated organs. However, the selected patients used for these models were not always restricted to potential cDCD donors (eg, patients with cancer or severe infections were also included). This severely limits the generalizability of those data.ObjectiveThe objectives of this study are the following: (1) to develop a model predicting time to death within 60 minutes in potential cDCD patients; (2) to validate and update previous prediction models on time to death after WLST; (3) to determine timing and patient characteristics that are associated with prognostication and the decision-making process that leads to initiating end-of-life care; (4) to evaluate the impact of timing of family approach on organ donation approval; and (5) to assess the influence of variation in WLST processes on postmortem organ donor potential and actual postmortem organ donors.MethodsIn this multicenter observational prospective cohort study, all patients admitted to the intensive care unit of 3 university hospitals and 3 teaching hospitals who met the criteria of the cDCD protocol as defined by the Dutch Transplant Foundation were included. The target of enrolment was set to 400 patients. Previously developed models will be refitted in our data set. To further update previous prediction models, we will apply least absolute shrinkage and selection operator (LASSO) as a tool for efficient variable selection to develop the multivariable logistic regression model.ResultsThis protocol was funded in August 2014 by the Dutch Transplant Foundation. We expect to have the results of this study in July 2020. Patient enrolment was completed in July 2018 and data collection was completed in April 2020.ConclusionsThis study will provide a robust multimodal prediction model, based on clinical and physiological parameters, that can predict time to circulatory arrest in cDCD donors. In addition, it will add valuable insight in the process of WLST in cDCD donors and will fill an important knowledge gap in this essential field of health care.Trial RegistrationClinicalTrials.gov NCT04123275; https://clinicaltrials.gov/ct2/show/NCT04123275International Registered Report Identifier (IRRID)DERR1-10.2196/16733

Donation after circulatory death liver transplantation: consensus statements from the Spanish Liver Transplantation Society.

SummaryLivers from donation after circulatory death (DCD) donors are an increasingly more common source of organs for transplantation. While there are few high‐level studies in the field of DCD liver transplantation, clinical practice has undergone progressive changes during the past decade, in particular due to mounting use of postmortem normothermic regional perfusion (NRP). In Spain, uncontrolled DCD has been performed since the late 1980s/early 1990s, while controlled DCD was implemented nationally in 2012. Since 2012, the rise in DCD liver transplant activity in Spain has been considerable, and the great majority of DCD livers transplanted in Spain today are recovered with NRP. A panel of the Spanish Liver Transplantation Society was convened in 2018 to evaluate current evidence and accumulated experience in DCD liver transplantation, in particular addressing issues related to DCD liver evaluation, acceptance criteria, and recovery as well as recipient selection and postoperative management. This panel has created a series of consensus statements for the standard of practice in Spain and has published these statements with the hope they might help guide other groups interested in implementing new forms of DCD liver transplantation and/or introducing NRP into their clinical practices.

Recipient Outcomes From Nondirected Live Kidney Donors: A UK-based Cohort Study.

BackgroundIncreasing numbers of patients with end-stage renal failure are receiving kidneys from nondirected kidney donors (NKDs), also known as altruistic donors. Transplant outcomes for recipients of such kidneys are largely inferred from studies on specified kidney donors (SKDs), which may be inaccurate due to differences in donor, recipient and transplant specific factors. We report the outcomes for recipients of NKD in the United Kingdom.MethodsOutcomes for 6861 patients receiving a living donor kidney transplant between January 2007 and December 2014 were analyzed using both the National Health Service Blood and Transplant and the UK Renal Registry datasets. Graft and patient outcomes were compared for patients receiving NKD and SKD organs using univariable and multivariable analyses.ResultsThere was significant discordance between the NKD and SKD donors and recipients. These included increased donor age (median, 58 years vs 47 years; P < 0.001) and higher rates of hemodialysis and previous transplants in the NKD group (both P < 0.001). Despite such markers of increased risk among both donors and recipients of NKD kidneys, there was no difference in graft survival on univariable (hazard ratio, 1.20; 95% confidence interval, 0.77-1.86; P = 0.419) or multivariable analysis (hazard ratio, 1.13; 95% confidence interval, 0.65-1.95; P = 0.665).ConclusionsDespite some markers of transplant complexity, nondirected kidney donor organs are an excellent source of organs for transplantation.

Ectopic Pelvic Kidney with Anomalous Vascular Supply during Deceased Organ Procurement – Case Report

Even though renal ectopia is common, there have been very few reports of these kidneys being used for transplantation. The concerns with using such kidneys are subnormal function, ureteral anomalies and complications and anomalous arterial supply which makes arterial reconstruction challenging. Majority of reports are for use in living donor transplantation where good preoperative imaging is available. There is very scant literature reporting use of ectopic pelvic kidneys from deceased donors. We report a case of an ectopic pelvic kidney found during procurement, which could unfortunately not be used for transplantation due to vascular anomalies. It is important for procuring surgeons to anticipate these anomalies and know how to modify the procurement procedure in order to procure these kidneys. Ectopic kidneys can occasionally be used for transplantation if the vasculature can be reconstructed adequately. They can thus serve as an additional source of organs for transplantation. If known before the procurement, every attempt should be made to get a formal CT angiogram to assess the vascular and pelvi-ureteral anatomy of the ectopic kidney.

The Global Person: Pig-Human Embryos, Personhood, and Precision Medicine

Chimeras, in the form of pig-human embryos engineered by CRISPRCas9 and other biotechnologies, have been created as potential sources of organs for transplantation. Against that background, and in an era of "precision medicine," this Article examines the concept of the global genetically modified person and asks whether humanness and personhood are being eroded, or finding new boundaries in intellectual property and constitutional law.

Utilization of increased risk for transmission of infectious disease donor organs in solid organ transplantation: Retrospective analysis of disease transmission and safety.

The inadequate supply of transplantable organs necessitates new approaches to organ availability. Serologies and nucleic acid testing (NAT) for hepatitis C virus (HCV), hepatitis B virus (HBV), and human immunodeficiency virus (HIV) are used in microbiologic screening of potential organ donors. Organs from donors considered at "high risk" (Centers for Disease Control and Prevention, CDC 1994) or "increased risk" (U.S. Public Health Service, PHS 2013) for transmission of viral infection to recipients may provide an expanded source of organs for transplantation. We review a single-center experience with 257 adult organ recipients of organs from donors meeting either CDC 1994 or PHS 2013 risk criteria between 2011 and 2016. Tracking these transplants required modification of the Transplant Center electronic database to identify all recipients of increased-risk donor (IRD) organs, documentation of informed consent, and microbiologic testing data. No transmissions of HIV, HBV, or HCV were identified by NAT or clinically. Nine patients developed positive serologic assays for one of the tested viruses; all recipients were retested and remain negative by NAT. Notably, post-transplant HBV core serologies reverted to negative on re-testing; these positive serologies are likely false positives caused by receipt of blood products. Use of IRD organs can be performed safely with appropriate informed consent and rigorous pre- and post-transplant microbiological testing.

Deceased Organ Donors With a History of Increased Risk Behavior for the Transmission of Blood-Borne Viral Infection: The UK Experience.

Deceased organ donors are routinely screened for behaviors that increase the risk of transmissible blood-borne viral (BBV) infection, but the impact of this information on organ donation and transplant outcome is not well documented. Our aim was to establish the impact of such behavior on organ donation and utilization, as well transplant recipient outcomes. We identified all UK deceased organ donors from 2003 to 2015 with a disclosed history of increased risk behavior (IRB) including intravenous drug use (IVDU), imprisonment and increased risk sexual behavior. Of 17 262 potential donors, 659 (3.8%) had IRB for BBV and 285 (1.7%) were seropositive for BBV, of whom half had a history of IRB (mostly IVDU [78.5%]). Of actual donors with IRB, 393 were seronegative for viral markers at time of donation. A history of recent IVDU was associated with fewer potential donors proceeding to become actual organ donors (64% vs 75%, P = 0.007). Donors with IRB provided 1091 organs for transplantation (624 kidneys and 467 other organs). Transplant outcome was similar in recipients of organs from donors with and without IRB. There were 3 cases of unexpected hepatitis C virus transmission, all from an active IVDU donor who was hepatitis C virus seronegative at time of donation, but was found to be viremic on retrospective testing. Donors with a history of IRB provide a valuable source of organs for transplantation with good transplant outcomes and there is scope for increasing the use of organs from such donors.

Generation of CMAHKO/GTKO/shTNFRI-Fc/HO-1 quadruple gene modified pigs.

As an alternative source of organs for transplantation into humans, attention has been directed to pigs due to their similarities in biological features and organ size. However, severe immune rejection has prevented successful xenotransplantation using pig organs and tissues. To overcome immune rejection, recently developed genetic engineering systems such as TALEN coupled with somatic cell nuclear transfer (SCNT) to make embryos could be used to produce pigs compatible with xenotransplantation. We used the TALEN system to target the non-Gal antigen cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) gene in pigs that is naturally deleted in humans. Gal-deleted cells expressing both soluble human tumor necrosis factor receptor I IgG1-Fc (shTNFRI-Fc) and human hemagglutinin -tagged-human heme oxygenase-1 (hHO-1) were transfected with a TALEN target for CMAH. Cells lacking CMAH were negatively selected using N-glyconeuraminic acid (Neu5Gc)/magnetic beads and the level of Neu5Gc expression of isolated cells were analyzed by FACS and DNA sequencing. Cloned embryos using 3 different genetically modified cell clones were respectively transferred into 3 recipients, with 55.6% (5/9) becoming pregnant and three cloned pigs were produced. Successful genetic disruption of the CMAH gene was confirmed by sequencing, showing lack of expression of CMAH in tail-derived fibroblasts of the cloned piglets. Besides decreased expression of Neu5Gc in piglets produced by SCNT, antibody-mediated complement-dependent cytotoxicity assays and natural antibody binding for examining immuno-reactivity of the quadruple gene modified pigs derived from endothelial cells and fibroblasts were reduced significantly compared to those of wild type animals. We conclude that by combining the TALEN system and transgenic cells, targeting of multiple genes could be useful for generating organs for xenotransplantation. We produced miniature pigs with quadruple modified genes CMAHKO/GTKO/shTNFRI-Fc/hHO-1 that will be suitable for xenotransplantation by overcoming hyperacute, acute and anti-inflammatory rejection.