Human Tracheal Transplantation.

Long-segment tracheal airway defects may be congenital or result from burns, trauma, iatrogenic intubation damage, or tumor invasion. Although airway defects <6 cm in length may be reconstructed using existing end-to-end reconstructive techniques, defects >6 cm continue to challenge surgeons worldwide. The reconstruction of long-segment tracheal defects has long been a reconstructive dilemma, and these defects are associated with significant morbidity and mortality. Many of these defects are not compatible with life or require a permanent extended-length tracheostomy that is fraught with complications including mucus plugging and tracheoesophageal fistula. Extensive circumferential tracheal defects require a reconstructive technique that provides a rigid structure able to withstand the inspiratory pressures, a structure that will biologically integrate, and contain functional ciliated epithelium to allow for normal mucociliary clearance. Tracheal transplantation has been considered the reconstructive "Holy Grail;" however, there has been a long-held scientific dogma that revascularization of the trachea was not possible. This dogma stifled research to achieve single-staged vascularized tracheal transplantation and prompted the introduction of many creative and inventive alternatives. Throughout history, alloplastic material, nonvascularized allografts, and homografts have been used to address this dilemma. However, these techniques have largely been unsuccessful. The recent introduction of a technique for single-staged vascularized tracheal transplantation may offer a solution to this dilemma and potentially a solution to management of the fatal tracheoesophageal fistula.

Viral Enteritis in Solid-Organ Transplantation.

Solid organ transplant recipients are at increased risk for infections due to chronic immunosuppression. Diarrhea is a commonly encountered problem post transplantation, with infectious causes of diarrhea being a frequent complication. Viral infections/enteritides in solid organ transplant recipients often result from frequently encountered pathogens in this population such as cytomegalovirus, adenovirus, and norovirus. However, several emerging viral pathogens are increasingly being recognized as more sensitive diagnostic techniques become available. Treatment is often limited to supportive care and reduction in immunosuppression, though antiviral therapies mayplay a role in the treatment in certain diseases. Viral enteritis is an important entity that contributes to morbidity and mortality in transplant recipients.

Cellular Therapies in Solid Organ Allotransplantation: Promise and Pitfalls.

Donor specific transfusions have been the basis of tolerance inducing protocols since Peter Medawar showed that it was experimentally feasible in the 1950s. Though trials of cellular therapies have become increasingly common in solid organ transplantation, they have not become standard practice. Additionally, whereas some protocols have focused on cellular therapies as a method for donor antigen delivery-thought to promote tolerance in and of itself in the correct immunologic context-other approaches have alternatively focused on the intrinsic immunosuppressive properties of the certain cell types with less emphasis on their origin, including mesenchymal stem cells, regulatory T cells, and regulatory dendritic cells. Regardless of intent, all cellular therapies must contend with the potential that introducing donor antigen in a new context will lead to sensitization. In this review, we focus on the variety of cellular therapies that have been applied in human trials and non-human primate models, describe their efficacy, highlight data regarding their potential for sensitization, and discuss opportunities for cellular therapies within our current understanding of the immune landscape.

Transplantation and immunosuppression: a review of novel transplant-related immunosuppressant drugs.

Immunosuppressive drugs used in the transplantation period are generally defined as induction and maintenance therapy. The use of immunosuppressants, which are particularly useful and have fewer side effects, decreased both mortality and morbidity. Many drugs such as steroids, calcineurin inhibitors (cyclosporine-A, tacrolimus), antimetabolites (mycophenolate mofetil, azathioprine), and mTOR inhibitors (sirolimus, everolimus) are used as immunosuppressive agents. Although immunosuppressant drugs cause many side effects such as hypertension, infection, and hyperlipidemia, they are the agents that should be used to prevent organ rejection. This shows the importance of individualized drug use. The optimal immunosuppressive therapy post-transplant is not established. Therefore, discovering less toxic but more potent new agents is of great importance, and new experimental and clinical studies are needed in this regard.Our review discussed the mechanism of immunosuppressants, new agents' discovery, and current therapeutic protocols in the transplantation.

Use of cryopreserved ovarian tissue in the Danish fertility preservation cohort.

OBJECTIVE: To evaluate the use of cryopreserved ovarian tissue in the Danish fertility preservation cohort. DESIGN: Retrospective cohort study. SETTING: University hospitals and fertility clinics. PATIENT(S): Ovarian tissue cryopreservation (OTC) was performed for 1,186 Danish girls and women from 1999-2020, of whom 117 subsequently underwent ovarian tissue transplantation (OTT). Subgroup 1 included 759 patients with a follow-up period of >5 years. Out of these, OTT rates were further analyzed for those patients who were alive and aged >24 years in July 2020 (subgroup 2; n = 554). INTERVENTION(S): OTC and OTT. MAIN OUTCOME MEASURE(S): OTT, death, donation of tissue. RESULT(S): In subgroup 1, 14% of the patients had undergone OTT, 18% had died, 9% had donated their tissue for research, and 59% still had their tissue stored. In subgroup 2, 19% had undergone OTT and for most diagnoses the OTT rates ranged from 15% to 22% with benign hematologic diseases having the highest OTT rate (35%). On the basis of the entire cohort, stratified age analysis indicated that women aged ≥30 years at OTC were more likely to return for OTT than women aged 18-29 years at OTC; mean storage times were 3.7 and 3.6 years, respectively. Only 4% of the girls aged <18 years at OTC had undergone OTT. CONCLUSION(S): The OTT rates depended on the diagnosis, age at OTC, and follow-up time. Specific criteria are needed for reporting and comparing OTT rates. Six out of 10 patients still had their cryopreserved tissue stored and longer follow-up is needed, especially for younger girls.

Donor-derived Cell-free DNA in Solid-organ Transplant Diagnostics: Indications, Limitations, and Future Directions.

The last few years have seen an explosion in clinical research focusing on the use of donor-derived cell-free DNA (dd-cfDNA) in solid-organ transplants (SOT). Although most of the literature published so far focuses on kidney transplants, there are several recent as well as ongoing research studies on heart, lung, pancreas, and liver transplants. Though initially studied as a noninvasive means of identifying subclinical or acute rejection in SOT, it is rapidly becoming clear that instead of being a specific marker for allograft rejection, dd-cfDNA is more appropriately described as a marker of severe injury, although the most common cause of this injury is allograft rejection. Multiple studies in kidney transplants have shown that although sensitivity for the diagnosis of antibody-mediated rejection is excellent, it is less so for T-cell-mediated rejection. It is possible that combining dd-cfDNA with other novel urine- or blood-based biomarkers may increase the sensitivity for the diagnosis of rejection. Irrespective of the cause, though, elevated dd-cfDNA seems to portend adverse allograft prognosis and formation of de novo donor-specific antibody. Although current data do not lend themselves to a clear conclusion, ongoing studies may reveal the utility of serial surveillance for the management of SOT as following levels of dd-cfDNA over time may provide windows of opportunity to intervene early and before irreversible allograft injury. Finally, cost-effectiveness studies will be needed to guide the ideal incorporation of dd-cfDNA into routine clinical practice.

Impact of COVID-19 in solid organ transplant recipients.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exploded onto the world stage in early 2020. The impact on solid organ transplantation (SOT) has been profound affecting potential donors, candidates, and recipients. Importantly, decreased donations and the pressure of limited resources placed on health care by the pandemic also disrupted transplant systems. We address the impact of COVID-19 on organ transplantation globally and review current understanding of the epidemiology, outcomes, diagnosis, and treatment of COVID-19 in SOT recipients.

Chimerism as the basis for organ repair.

Organ and tissue repair are complex processes involving signaling molecules, growth factors, and cell cycle regulators that act in concert to promote cell division and differentiation at sites of injury. In embryonic development, progenitor fetal cells are actively involved in reparative mechanisms and display a biphasic interaction with the mother; and there is constant trafficking of fetal cells into maternal circulation and vice versa. This phenomenon of fetal microchimerism may have significant impact considering the primitive, multilineage nature of these cells. In published work, we have reported that fetal-derived placental cells expressing the homeodomain protein CDX2 retain all "stem" functional proteins of embryonic stem cells yet are endowed with additional functions in areas of growth, survival, homing, and immune modulation. These cells exhibit multipotency in vitro and in vivo, giving rise to spontaneously beating cardiomyocytes and vascular cells. In mouse models, CDX2 cells from female placentas can be administered intravenously to male mice subjected to myocardial infarction with subsequent homing of the CDX2 cells to infarcted areas and evidence of cellular regeneration with enhanced cardiac function. Elucidating the role of microchimeric fetal-derived placental cells may have broader scientific potential, as one can envision allogeneic cell therapy strategies targeted at tissue regeneration for a variety of organ systems.

Declínio nas doações e transplantes de órgãos no Ceará durante a pandemia da COVID-19: estudo descritivo, abril a junho de 2020 / Disminución de donaciones y trasplantes de órganos en Ceará durante la pandemia COVID-19: un estudio descriptivo, abril - junio de 2020 / Fall in organ donations and transplants in Ceará in the COVID-19 pandemic: a descriptive study, April - June 2020

Objetivo Descrever as doações e os transplantes de órgãos no Ceará, Brasil, após a declaração da pandemia da COVID-19. Métodos Estudo descritivo, com dados da Associação Brasileira de Transplantes de Órgãos. O número de doadores e transplantes do período de abril a junho de 2020 foi comparado ao mesmo período de 2019 e ao primeiro trimestre de 2020. Resultados No primeiro semestre de 2020, o estado registrou 72 doadores efetivos. Destes, 17 (23,6%) no segundo trimestre. Dos 352 transplantes do primeiro semestre de 2020, 37 (10,7%) foram realizados no segundo trimestre. Em comparação ao período de abril a junho de 2019, houve redução de 67,9% e 89,3% no número de doadores e transplantes, respectivamente, no mesmo período de 2020. Conclusão Os números de doadores e transplantes do Ceará apresentaram importante declínio nos três meses seguintes ao decreto da pandemia da COVID-19, especialmente os das modalidades de rim, coração e córneas.

Objetivo Describir las donaciones y trasplantes de órganos en Ceará, Brasil, después de la declaración de la pandemia COVID-19. Métodos estudio descriptivo con datos de la Asociación Brasileña de Trasplantes de Órganos. Se comparó el número de donantes y trasplantes de abril a junio de 2020 con el mismo período de 2019 y el primer trimestre de 2020. Resultados El primer semestre de 2020, Ceará registró 72 donantes efectivos. De estos, 17 (23,6%) en el segundo trimestre. De 352 trasplantes realizados en el primer semestre de 2020, 37 (10.7%) fueron realizados en el segundo trimestre. En comparación al período de abril a junio de 2019, hubo reducción de 67,9% y 89,3% en el número de donantes y trasplantes, respectivamente, en el mismo período de 2020. Conclusión El número de donantes y trasplantes en Ceará mostró importante disminución en los tres meses siguientes al decreto pandémico COVID-19, especialmente las modalidades renal, cardíaca y córneas.

Objective To describe organ donations and transplants in Ceará state, Brazil, following the declaration of the COVID-19 pandemic. Methods This was a descriptive study using data from the Brazilian Organ Transplantation Association. The number of donors and transplants from April to June 2020 was compared to the same period in 2019 and to the first quarter of 2020. Results In the first half of 2020, the state registered 72 effective donors, just 17 (23.6%) of whom related to the second quarter. Of the 352 transplants in the first half of 2020, 37 (10.7%) were performed in the second quarter. Compared with the period from April to June 2019, there was a reduction of 67.9% and 89.3% in the number of donors and transplants, respectively, in the same period of 2020. Conclusion The number of donors and transplants in Ceará showed an important fall in the three months following the declaration of the COVID-19 pandemic, especially for kidney, heart and cornea transplants.

Evolving Impact of COVID-19 on Transplant Center Practices and Policies in the United States.

In our first survey of transplant centers in March 2020, >75% of kidney and liver programs were either suspended or operating under restrictions. To safely resume transplantation, we must understand the evolving impact of COVID-19 on transplant recipients and center-level practices. We therefore conducted a six-week follow-up survey May 7-15, 2020, and linked responses to the COVID-19 incidence map, with a response rate of 84%. Suspension of live donor transplantation decreased from 72% in March to 30% in May for kidneys and from 68% to 52% for livers. Restrictions/suspension of deceased donor transplantation decreased from 84% to 58% for kidneys and from 73% to 42% for livers. Resuming transplantation at normal capacity was envisioned by 83% of programs by August 2020. Exclusively using local recovery teams for deceased donor procurement was reported by 28%. Respondents reported caring for a total of 1166 COVID-19-positive transplant recipients; 25% were critically ill. Telemedicine challenges were reported by 81%. There was a lack of consensus regarding management of potential living donors or candidates with SARS-CoV-2. Our findings demonstrate persistent heterogeneity in center-level response to COVID-19 even as transplant activity resumes, making ongoing national data collection and real-time analysis critical to inform best practices.

Pediatric transplantation in Europe during the COVID-19 pandemic: Early impact on activity and healthcare.

The current pandemic SARS-CoV-2 has required an unusual allocation of resources that can negatively impact chronically ill patients and high-complexity procedures. Across the European Reference Network on Pediatric Transplantation (ERN TransplantChild), we conducted a survey to investigate the impact of the COVID-19 outbreak on pediatric transplant activity and healthcare practices in both solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). The replies of 30 professionals from 18 centers in Europe were collected. Twelve of 18 centers (67%) showed a reduction in their usual transplant activity. Additionally, outpatient visits have been modified and restricted to selected ones, and the use of telemedicine tools has increased. Additionally, a total of 14 COVID-19 pediatric transplanted patients were identified at the time of the survey, including eight transplant recipients and six candidates for transplantation. Only two moderate-severe cases were reported, both in HSCT setting. These survey results demonstrate the limitations in healthcare resources for pediatric transplantation patients during early stages of this pandemic. COVID-19 disease is a major worldwide challenge for the field of pediatric transplantation, where there will be a need for systematic data collection, encouraging regular discussions to address the long-term consequences for pediatric transplantation candidates, recipients, and their families.

Deceased Organ Donation in Syria: Challenges and Solutions.

The first living-donor kidney transplant in Syria was performed 41 years ago; by 2019, 5407 renal transplants had been performed there. Three heart transplants from deceased donors were performed in the late 1980s; cardiac transplant activities have since discontinued. In 2003, a new, national Syrian legislation was enacted authorizing the use of organs from living unrelated donors and from deceased donors. This important law was preceded by another big stride in this regard: the acceptance by the higher Islamic religious authorities in Syria in 2001 of the principle of procurement of organs from deceased donors, provided that consent is given by a first- or second-degree relative. After the enactment of this law, kidney transplant rates increased from 7 per million population in 2002 to 17 per million population in 2007. Kidney transplants performed abroad for Syrian patients declined from 25% in 2002 to < 2% in 2007. Kidney transplants continued at comparable rates until 2010, before the beginning of the political crisis in 2011. Four decades after the first successful kidney transplant in Syria, however, patients needing an organ transplant must rely on living donors only. Moreover, 17 years after the law authorizing use of organs from deceased donors, a program is still not in place in Syria, and additional improvement of the legal framework is needed. The war, limited resources, and lack of public awareness about the importance of organ donation and transplant appear to be major factors inhibiting initiation of a deceased-donor program in Syria. A concerted and ongoing education campaign is needed to increase awareness of organ donation, change negative public attitudes, and gain societal acceptance. Every effort must be made to initiate a deceased-donor program to lessen the burden on living donors and to enable national self-sufficiency in organs for transplant.

Evolution of surgical steps in robotics-assisted donor surgery for uterus transplantation: results of the eight cases in the Swedish trial.

OBJECTIVE: To perform a stepwise development of the surgical method for robotics-assisted laparoscopy in donor hysterectomy for uterus transplantation (UTx), a unique treatment for absolute uterine-factor infertility. DESIGN: Prospective observational study. SETTING: University hospital. PATIENT(S): Eight donors, aged 38-62 years, underwent surgery for retrieval of the uterus and vasculature. INTERVENTION(S): Robotics-assisted laparoscopy was performed in donors for 6-7 h with video recording. Conversion to laparotomy was performed for last parts of retrieval surgery. MAIN OUTCOME MEASURE(S): Description, evaluation, and timing of 12 specific surgical steps, as well as surgical outcomes and complications. RESULT(S): There was a progression during the course of eight surgeries. In the initial two cases, seven and six items were completed with robotics compared with all 12 items in the last three procedures. The passive surgical time decreased from ∼20% in the first four cases to ∼8% in the last three procedures. The estimated median (range) blood loss, total surgical time, and length of hospital stay were, respectively, 125 mL (100-600), 11.25 h (10-13), and 5.5 days (5-6). Two reversible complications occurred: One patient acquired pressure alopecia, and one developed pyelonephritis. CONCLUSION(S): The study demonstrates a clear evolution of a strategy toward fully robotic donor surgery in UTx. This is likely to become the main approach in donor surgery of live UTx donors. CLINICAL TRIAL REGISTRATION NUMBER: NCT02987023.

Early Impact of COVID-19 on Solid Organ Transplantation in the United States.

BACKGROUND: The regional impact of coronavirus disease 2019 on solid organ transplantation in the United States has not been fully evaluated. METHODS: A retrospective analysis of month-to-month trends on waitlist additions, waitlist deaths, and transplant surgeries between all United Network for Organ Sharing (UNOS) regions was performed. A linear regression model trained on historical data was used to estimate anticipated transplantation volume. RESULTS: All UNOS regions reported a decrease in total waitlist additions and transplant surgeries. The largest decreases in total transplants were identified in regions 1, 2, 6, and 9, with regions 2, 7, 8, and 9 noting the largest decrease in waitlist additions. Six of the 11 regions noted increases in waitlist deaths, with UNOS regions 9, 1, and 2, all located within the Northeast, noting the highest percent increase in waitlist deaths at 170%, 89%, and 54%, respectively. The largest reductions in solid organ transplantation and waitlist deaths were seen in kidney and lung transplantation. Current transplantation volume is significantly lower than the low range of the 95% confidence interval derived from the linear regression model (2182 versus 3110; P < 0.05). CONCLUSIONS: Significant decreases in total waitlist additions and transplant surgeries with increases in waitlist deaths were noted in the majority of US transplant domains. The impact was especially prevalent in areas with high burden of coronavirus disease 2019 infection. National and regional strategies aimed at minimizing disruptions in transplantation are needed.

Recent advances in precision medicine for individualized immunosuppression.

PURPOSE OF REVIEW: The current tools to proactively guide and individualize immunosuppression in solid organ transplantation are limited. Despite continued improvements in posttransplant outcomes, the adverse effects of over-immunosuppression or under-immunosuppression are common. The present review is intended to highlight recent advances in individualized immunosuppression. RECENT FINDINGS: There has been a great focus on genomic information to predict drug dose requirements, specifically on single nucleotide polymorphisms of CYP3A5 and ABCB1. Furthermore, biomarker studies have developed ways to better predict clinical outcomes, such as graft rejection. SUMMARY: The integration of advanced computing tools, such as artificial neural networks and machine learning, with genome sequencing has led to intriguing findings on individual or group-specific dosing requirements. Rapid computing allows for processing of data and discovering otherwise undetected clinical patterns. Genetic polymorphisms of CYP3A5 and ABCB1 have yielded results to suggest varying dose requirements correlated with race and sex. Newly proposed biomarkers offer precise and noninvasive ways to monitor patient's status. Cell-free DNA quantitation is increasingly explored as an indicator of allograft injury and rejection, which can help avoid unneeded biopsies and more frequently monitor graft function.