Frontiers in transplantation最新文献

Objective: Cardiac Allograft Vasculopathy (CAV), a process of vascular damage accelerated by antibody-mediated rejection (AMR), is one of the leading causes of cardiac transplant failure. Proteasome inhibitors (PIs) are utilized to treat AMR, however PI-associated toxicity limits their therapeutic utility. Novel immunoproteasome inhibitors (IPIs) have higher specificity for immune cells and have not been investigated for AMR in cardiac transplant patients. We sought to evaluate IPI effect on AMR in a murine cardiac transplant model.

Methods: Fully MHC mismatched C57BL/6 to huCD52Tg heterotopic heart transplantations were performed. Recipients were treated with alemtuzumab (10 µg, IP) on days -2, -1, 2, and 4 and anti-CD25mAb (PC61, 100 µg, IP) on day 7 to accelerate AMR with or without IPI (ONX-0914,15 mg/kg, SQ), administered on transplant day and three times a week thereafter.

Results: Animals without IPI gradually developed post-transplant donor-specific antibody (DSA) and showed a significantly elevated DSA level compared to animals receiving IPI. (TFXM 48.86 vs. 14.17; p = 0.0291, BFXM 43.53 vs. 6.114; p = 0.0031). Accordingly, H&E staining of allograft showed reduced evidence of AMR with IPI compared to controls (P = 0.0410). Notably, increased mortality was observed in the IPI treated group.

Conclusion: This study demonstrated the ability of ONYX-0914, an IPI, to control post-transplant DSA production and the AMR development in a heart transplant model. However, IPI-resistant DSA production was also observed and increased mortality with IPI therapy raises concerns about potential toxicity. Further investigation is warranted to assess the utility and potential risk associated with the use of IPI as a post-transplant maintenance immunosuppression.

Purpose: The purpose of this study was to evaluate the correlation between longitudinal monitoring of donor-derived cell free DNA (dd-cfDNA) in lung transplant recipients and a "gold standard" of existing tools (pulmonary function testing, radiographic imaging, laboratory and bronchoscopy data, clinical judgment) to assess allograft function.

Methods: 24 consecutive transplant recipients were prospectively enrolled in this study measuring dd-cfDNA levels monthly in the first year after bilateral lung transplant. Blinded clinical adjudications were performed at the same timepoints to categorize allograft function as stable (FEV1 within 10% of prior value or when compared to best two averaged post-transplant values) or unstable. When deemed unstable, etiology of unstable graft function was elicited based on available clinical data. We then evaluated the association between dd-cfDNA and the clinical impression of allograft function using linear mixed models which adjusted for patient-level covariates and time since transplant.

Results: Unstable allografts were associated with 54.4% higher measures of dd-cfDNA, controlling for time since transplant and demographic covariates [adjusted mean ratio (aMR) = 1.54, 95% CI: 1.25-1.91]. Females tended to have higher measures of dd-cfDNA (aMR = 1.90 95%CI: 1.14-3.16). A two-fold increase in dd-cfDNA was associated with declines in FEV1 and FVC of 0.047 and 0.066 L, respectively, controlling for time since transplant and demographic covariates (slope: -0.047 95%CI: -0.076 to -0.019, and slope: -0.066 95%CI: -0.097 to -0.035, respectively). Discussion: Donor derived cell free DNA presents a potential additional minimally invasive clinical tool in lung transplant allograft monitoring within the first year of transplant, with unstable allografts correlating with higher dd-cfDNA values.

Background: Adoptive therapy with umbilical cord blood (UCB) T-regulatory (Treg) cells can prevent graft vs. host disease (GVHD). We hypothesize that UCB Tregs can treat GVHD and synergize with ruxolitinib, Jak2 inhibitor, to improve outcomes.

Methods: UCB Treg potency and efficacy was examined using cell suppression assay and xenogeneic GVHD model, respectively. Ruxolitinib was fed continuously in presence or absence of CellTraceViolet tagged UCB Tregs on days +4, +7, +11, +18. Mice were followed for survival, GVHD score, hematology parameters and inflammation.

Results: Addition of ruxolitinib to UCB Tregs exerted synergistic suppressor function in vitro and improved persistence of UCB Tregs in vivo. Lower GVHD score, improved survival, increased hemoglobin level and platelet count, decreased inflammatory cytokines and decrease in CD3⁺ T cell lung infiltrate was observed in UCB Tregs+ruxolitinib recipients.

Conclusion: UCB Treg+Ruxolitinib combination improves outcomes in xenogeneic GVHD and should be explored in a clinical setting.

Introduction: As research advances in vascularized composite allotransplantation (VCA), large animal models are essential for translational studies related to immune rejection and graft survival. However, procurement of large flaps can cause significant defects, complicating wound closure and increasing postoperative risks. This study details the surgical techniques and outcomes of autologous vertical rectus abdominis myocutaneous (VRAM) flap transplantation and neck flap isolation with induced ischemia in a swine model. The purpose of this study was to identify the most effective control procedure for use in future VRAM flap allotransplantation research.

Methods: We performed two left heterotopic autologous VRAM flap transplants and two right anterolateral neck flap isolations using female Yucatan pigs. Postoperatively, animals were monitored for complications and flap healing, with punch biopsies taken on POD1, 5, and at the end of the study for histological analysis. Transcutaneous oxygen and temperature were also recorded.

Results: Both autologous flaps survived after vessel anastomosis, with effective closure of abdominal defects using suturable mesh, and no postoperative complications were observed. Histology revealed mild dermal edema and perivascular inflammation on POD5. In the neck flap group, both flaps survived temporary ischemia, however, postoperative complications included dorsal flap necrosis and wound dehiscence, requiring reoperation. No gross inflammation or edema was observed following surgery and histologically there was only mild dermal edema on POD5.

Discussion: We have developed a low-risk, technically feasible porcine autologous VRAM flap transplantation model and our findings support its use in future VCA studies.

Introduction: In living donor kidney transplantation (LDKT), vascular anastomosis is more difficult due to missing arterial patches and shorter renal veins. The surgical challenge is even more demanding in kidneys with multiple arteries. Although renal transplantation is feasible in most cases of complex donor vascular anatomy and similar results compared with standard LDKT are reported, the discussion on potentially increased complication rates and graft function continues. This prompted us to review our results of LDKT with multiple renal artery (MRA) grafts with a special concentration on complications and long-term function.

Patients and methods: We reviewed the records of all LDKT in our center from the beginning of the program in 2005 until 2022 for arterial vascular reconstructions. The cohort was divided into two groups: transplantation with vascular reconstruction (VR) and standard transplantation. These groups were compared for operative parameters and short- and long-term results.

Results: From 2005 to 2022, 211 LDKT were completed in our unit. In 32 (15.2%), a VR was performed, including single ostium side-to-side anastomosis, end-to-side anastomosis, patch reconstruction, and vein interposition. There was no significant difference in operative time (169 min vs. 180 min; p = 0.118) and time for anastomosis (28 min vs. 26 min; p = 0.59) between both groups. Postoperative complications (5.7% vs. 7.4%; p = 0.72) were not significantly different. During the follow-up period (110 months, range 10-204), the risk of organ loss was comparable after VR (13.625% vs. 11.56% p = 0.69).

Conclusion: In LDKT, arterial vascular reconstructions for kidneys with MRA provide similar results compared to grafts with a single renal artery (SRA). Short- and long-term results are comparable with standard procedures.

Background: Health system websites are important resources to guide health care decisions and may be useful tools to improve racial equity in access to living donor kidney transplant (LDKT).

Methods: We performed a cross-sectional study of adult LDKT programs in the United States. We created an assessment tool for website quality across three domains: accessibility (access to LDKT specific information from the transplant center website), readability (ease of reading and clarity), and educational content (appropriateness and presentation of information, LDKT-specific content, program-specific characteristics, and adherence to equity-centered principles of web design).

Results: Among the 185 transplant center websites reviewed, only 14.6% of LDKT sites could be accessed directly from the transplant center webpage. The median suitability assessment of materials (SAM)-a validated measure of website content for chronic kidney disease (CKD)-was 45 out of 86 (IQR 4) and the median Flesch-Kincaid grade level and ease score were 9.1 (IQR 0.8) on a scale of 0-18 and 51.2 (IQR 5) on a scale of 0-100, respectively.

Conclusion: These results indicate that LDKT websites are currently not available, accessible, and understandable for many potential transplant candidates and donors. Optimizing the content and design of transplant center websites may be a promising and effective strategy for improving equity in access to LDKT.

Background: Despite advances in immunosuppressive therapies, chronic rejection and immunosuppression-related complications remain significant challenges in transplantation. Developing transplantation tolerance through thymus transplantation may offer a solution. This paper details our technique for procuring and transplanting porcine vascularized thymic lobes (VTL), which can be utilized to study and research allogeneic and xenogeneic transplantation models in large animals.

Methods: GalT-KO miniature swine (n = 16) and baboons (n = 12) were used for VTL transplantation. The right or left cervical thymic lobe was dissected, harvested with its artery and veins, and flushed with cold lactated Ringer's solution. VTL graft was transplanted intraabdominally in all animals.

Results: We performed non-survival (n = 2) and survival (n = 2) VTL autotransplants in pigs and xeno-VTL and kidney transplants in baboons (n = 12). All grafts immediately turned pink after reperfusion and had good blood inflow and outflow. Pigs in the survival autotransplant group were euthanized immediately post-operatively due to complications related to VTL donation. One baboon lost its graft due to antibody-mediated rejection, and another lost it due to venous thrombosis. Other baboons had no complications and survived until the endpoint.

Conclusion: Here, we describe our approach and experience in swine vascularized thymic lobe procurement and transplantation. The technique requires moderate surgical skills to achieve reproducible results. Living-donor VTL donation in pigs is not recommended due to the high risk of surgical complications related to the harvesting procedure.

Background: Liver transplantation (LT) improves survival in end-stage liver disease. Several reports have addressed the impact of LT on patients' lives, beyond purely medical outcomes. Although the quality of life and mental health have been demonstrated to improve with this procedure, such studies are still missing in Latin America.

Methods: Patients who received LT at the Fundación Santa Fe de Bogotá between 2017 and 2019 were assessed for quality of life (QoL), anxiety, and depression and they were followed up for one year after the procedure. Pre-transplant data were gathered at inclusion on the waiting list, while post-transplant data at 3- and 12 months after LT. European Quality of Life-5 Dimensions (EQ-5D) and European Quality of Life-Visual Analog Scale (EQ-VAS) instruments were used to evaluate QoL. The Hospital Anxiety and Depression Scale (HADS) was used for evaluating anxious and depressive symptoms.

Results: 115 recipients met the inclusion criteria. Mean pre-transplant EQ-VAS was 70.78, rising to 87.16 and 92.56 at 3- and 12-months, respectively. Improvements in all EQ-5D dimensions were found in response to LT. According to the HADS questionnaire, anxiety was reduced by 2.35 points and depression by 1.63 points after LT.

Conclusion: in the short term, LT is a successful strategy for enhancing QoL, anxiety, and depression in patients with liver disease. Long-term benefits must be assessed.

Introduction: Circulating cell-free DNA (cfDNA) is emerging as a non-invasive biomarker in solid organ transplantation (SOT) monitoring and data on its diagnostic potential have been increasing in recent years. This review aims to summarize the main advances in technologies, clinical applications and future perspectives of cfDNA for transplantation, and to approach the contribution of epigenetics to improve the specific detection of rejection.

Methods: Published literature investigating cfDNA as a biomarker for the diagnosis of transplant rejection was systematically reviewed, specifically clinical trials evaluating the test performance of algorithms predicting rejection based on cfDNA fraction. Literature highlighting epigenetic features in transplant rejection was also reviewed to outline the potential contribution of the epigenomic analysis to the needs of rejection-specific diagnosis.

Results: 40 articles were reviewed, and results were extracted and summarized. 16 met the inclusion criteria by evaluating the diagnostic performance of a predictive test for the discrimination of rejection vs. non-rejection patients (2 heart, 3 liver, 4 kidney, and 7 lung transplantations). The recurring conclusion is the kinetics of dd-cfDNA levels, strongly increasing immediately after transplantation and reaching basal levels after days to weeks and remaining stable in non-rejection patients. On the other hand, rejection is characterized by an increase in dd-cfDNA levels, depending on the transplanted organs. In addition, the epigenetic signature can help improve the specificity of the diagnosis of rejection by searching for specific epigenetic features that are by the clinical status of patients.

Conclusion: Cell-free DNA is a promising non-invasive biomarker but still needs standardization of technologies and protocols to be used for diagnostic purposes. Moreover, the lack of specificity of this marker can be compensated by the contribution of epigenetic analysis for which data are growing, although progress is still needed for its use in a clinical context.