Transplantation Direct最新文献

Extracorporeal photopheresis (ECP) is a therapeutic intervention for modulating immune responses using an autologous apoptotic cell-based product, known as a photopheresate. The process of generating photopheresates offers attractive possibilities for manipulating distinct leukocyte subsets to either augment or dampen immune responses, depending on the disease context. This review discusses current uses of ECP as a cell-based therapy and introduces possible strategies to enhance the potency of photopheresates. In Europe, ECP is regulated under the European Union Tissue Directive, but innovative applications in solid organ transplantation, including modifications of the procedure, may force its reclassification as an Advanced Therapy Medicinal Product. Such modifications might include loading dendritic cells with antigens, polarizing dendritic cells toward immunogenic or tolerogenic states, or genetically manipulating leukocyte subsets. In conclusion, although ECP is a long-established, safe, and effective therapy, the more rigorous standards applied to Advanced Therapy Medicinal Product manufacture could help to ensure the quality of photopheresates applied to solid organ transplant recipients.

Extracorporeal photopheresis (ECP) is a well-established, safe, and effective immunomodulatory therapy currently used in clinics to decrease T cell-mediated immunity in various disorders, including autoimmune diseases and chronic rejection in organ transplantation. Although the ECP procedure has been shown to induce apoptotic cells that are reintroduced into the patient at the end of the treatment, the precise tolerogenic mechanisms mediated by ECP are not fully understood. Previous in vitro studies have demonstrated that early apoptotic cells express annexins on their cell surface, which suppress myeloid cell activation on stimulation with bacterial lipopolysaccharide through Toll-like receptors. Mechanistically, annexins prevent the upregulation of costimulatory molecules (CD40 and CD86) and decrease the secretion of proinflammatory cytokines (tumor necrosis factor and interferon-γ) through nuclear factor kappa B signaling pathways, altogether inhibiting antigen-specific T-cell responses in vivo. In human and mouse bone marrow-derived macrophages, binding of annexin to Dectin-1, a c-type lectin receptor, promotes peripheral tolerance through the spleen tyrosine kinase signaling pathway and NADPH oxidase 2 downstream activation. In animal models, the synergistic activation of Dectin-1 and Toll-like receptor 4 by damage-associated molecular patterns in graft-infiltrating monocytes leads to the induction of trained immunity. Because trained immunity prevents long-term allograft survival in organ transplant recipients, we hypothesize pretreatment with ECP represents a potential unexplored therapeutic option to favor transplantation tolerance. Specifically, ECP may serve as a prophylactic therapy to prevent trained immunity in contexts involving the activation of the Dectin-1 pathway.

Background: Ischemia/reperfusion injury after lung transplantation is a significant cause of morbidity. In the realm of ex vivo lung perfusion (EVLP), inflammation, edema formation, and reduced compliance have limited the durability of EVLP. Previous evidence has suggested that platelet activation and thrombosis may play a role in both conditions.

Methods: A literature search of PubMed and Embase was conducted, including all articles describing all human or animal investigations of platelet activation or the use of antiplatelet agents in the settings of EVLP or lung transplantation. Articles published from database inception to July 15, 2024, were analyzed.

Results: In total, 9 studies were included in the review. Studies on EVLP have found an association between platelet activation and adverse effects on lung function, whereas in lung transplantation, platelet activation appears to play a role in primary graft dysfunction. In both settings, the inhibition of platelets ameliorated these effects.

Conclusions: Platelet activation in EVLP and lung transplantation results in distal arterial thrombosis and has been associated with graft dysfunction. The use of antiplatelet agents in the included studies was associated with reduced lung injury and improved lung function on EVLP or during lung transplantation.

Background: Literature reports higher error rates in professions such as police officers and nurses during night shifts. Additionally, there is evidence of a higher rate of surgical complications and mortality rate if surgery is performed at night. Currently, kidney transplantations are performed at any time of day to minimize the cold ischemia time. Recent studies investigating the outcomes of kidney transplantation in relation to daytime have produced varying results.

Methods: A retrospective analysis was conducted on data from all patients who received a deceased donor kidney transplant at the University Medical Center Mannheim between January 1, 1997, and January 31, 2015. All recipients were followed for 2.5 y after the last kidney transplant. Daytime was divided into 2 categories: day (from 8 am to 7:59 pm) and night (from 8 pm to 7:59 am). Four operation intervals were defined on the basis of incision and suturing time (day/day, day/night, night/night, and night/day). Endpoints of primary interest were surgical complications, delayed onset of renal function requiring renal replacement therapy, transplant failure, and death.

Results: We analyzed 363 patients who underwent kidney transplantation during our study period. The incidence of surgical complications tended to be higher at night (P = 0.054). Rates of wound infections were significantly higher when the operation started at night (P = 0.018). The rate of wound infections (P = 0.007; Fisher test) and the incidence of DFG type 2 (P = 0.002) were highest in the night/day operation interval. The analysis of graft loss and patient survival showed no significant difference between day- and nighttime surgery but a positive trend toward operation started during the daytime.

Conclusions: In summary, the effect of the timing of transplant surgery on long- and short-term outcomes of kidney transplantation appears to be rather minor. Hence, reducing cold ischemia time should be the primary goal to improve the outcome of kidney transplantation.

Background: Sex differences in excess mortality risk (ie, above expected in the age-, sex-, and race-matched general population) among candidates waitlisted for transplant may reflect sex bias in access to the waitlist, disparities in allocation policies, and/or sex differences in care for patients with organ failure.

Methods: We used time-dependent relative survival models to determine the relative excess risk of mortality in females compared with males recorded in the Scientific Registry of Transplant Recipients who were waitlisted for kidney, heart, or liver transplant from 1988 to 2019, accounting for the modifying effects of candidate age and listing era.

Results: Among 644 262 kidney and 106 353 heart candidates, excess mortality was higher in female than male kidney candidates <60 y, but lower in female kidney candidates ≥60 y and heart candidates ≥12 y; patterns did not differ by era. Among 259 230 liver candidates, patterns differed by era of waitlisting. Excess mortality was lower for female than male liver candidates 0-12 and 25-44 y, and higher for females than males 13-24 y, without differences by era. Excess mortality was lower for female than male liver candidates 45-59 y waitlisted 1988-2011, but not different by sex for those waitlisted 2012-2019. Among liver candidates ≥60 y, excess mortality did not differ by sex for those waitlisted 1988-2011 but was higher for females than males waitlisted 2012-2019.

Conclusions: The patterns of sex differences in excess mortality observed among waitlisted transplant candidates likely reflect the selection of healthier, lower-risk females than males for waitlisting and higher mortality risks for females with organ failure.

Background: The allocation of a limited supply of donor organs remains a critical challenge for organ transplantation. The analytical tools that policymakers rely upon for improving allocation policy have seen little advancement since the introduction of computer simulation in 1995. In recent years, simulation has increasingly become a bottleneck in the policy design process. Partnering with the Organ Procurement and Transplantation Network Kidney Transplantation Committee, our team introduced new analytical techniques into the policy design process.

Methods: A new simulation algorithm was developed that reduces the time required to simulate 1 y of allocation from >6 h down to about 15 s while using the same simulation model as the preexisting simulator used by the Organ Procurement and Transplantation Network. This improvement enabled the simulation of thousands of allocation policies, allowing the introduction of multiobjective optimization as a primary method for policy design. An interactive website was created for committee members to analyze results and perform policy optimization.

Results: These techniques were applied to the development of new continuous distribution allocation policies for kidneys. We detail the policy design process, present graphical results from 50 000 policy simulations, and highlight 4 policies optimized to balance between multiple objectives differently.

Conclusions: Advances in analytical tools offer a path to improving organ transplantation through more effective and equitable organ allocation policies.

Background: The combined effects of age and sex impact important posttransplant outcomes. Despite key physiologic differences in metabolic and immune function, older women are often indiscriminately grouped with either young women or older men. We examined sex- and age-based differences in clinical markers of immunity in heart and kidney recipients, with specific attention to those of postmenopausal women.

Methods: Blood was prospectively collected before transplantation, and at 1 and 6 mo posttransplantation, alongside 12 mo of clinical data. Patients were stratified by age, biological sex, and menopause status. Absolute lymphocyte count (ALC), CD4⁺ and CD8⁺ lymphocyte subsets, total IgG, 4 selected cytokines, estradiol and progesterone, and cumulative incidence of infection were quantified within groups. The relationship between menopause category (premenopausal women, postmenopausal women, men) and 6-mo ALC was tested by linear regression, controlling for multiple confounding variables.

Results: The cohort included 40 heart, 23 kidney, and 3 heart-kidney recipients categorized as 10 women older than 50 y, 12 women 50 y and younger, 26 men older than 50 y, and 18 men 50 y and younger. At 6 mo posttransplant, mean ALC among older women (0.59 K/µL) fell to a far lower range of lymphopenia than in young women (0.9 K/µL), older men (0.85 K/µL), and younger men (0.82 K/µL). Postmenopausal women had significantly lower ALC compared with premenopausal women (P = 0.03) and men (P = 0.05). Women older than 50 y also had the greatest cumulative incidence of infection by 1 y compared with other groups.

Conclusions: These findings support the concern for increased risk of infection in postmenopausal organ transplant recipients.

Background: Normothermic machine perfusion (NMP) enables real-time assessment of liver graft viability through various biomarkers. Although lactate clearance during NMP has been associated with graft outcomes, its dynamic patterns and relationship with posttransplant biliary complications (PTBCs) remain poorly understood. We sought to evaluate whether dynamic lactate clearance patterns during NMP could predict PTBCs in both donations after circulatory death (DCD) and brain death (DBD) liver transplantation (LT).

Methods: We conducted a single-center retrospective study of 140 LT recipients (88 DCDs, 52 DBDs) undergoing NMP (2022-2024). K-means clustering analysis was applied to lactate clearance patterns during the first 3 h of NMP. The primary outcome was PTBCs. Multivariate logistic regression analysis was used to identify independent predictors for PTBC.

Results: K-means clustering revealed 3 distinct patterns: consistently low (cluster A), rapid clearance (cluster B), and prolonged elevation (cluster C). DCD grafts demonstrated more pronounced differences in lactate clearance and higher rates of persistent elevation than DBD grafts. For DCD grafts, the distribution was cluster A (26.1%, n = 23), cluster B (37.5%, n = 33), and cluster C (36.4%, n = 32), whereas DBD grafts showed cluster A (55.8%, n = 29), cluster B (17.3%, n = 9), and cluster C (26.9%, n = 14). In DCD grafts, PTBC rates were significantly higher in cluster C (37.5%) than in clusters A (13.0%, P = 0.045) and B (15.2%, P = 0.04). This association remained significant in multivariate analysis (adjusted odds ratio, 4.76; 95% confidence interval, 1.03-21.9; P = 0.045). No differences in recipient or donor variables were observed across clusters. Among DBD grafts, no intercluster differences in PTBC rates were found.

Conclusions: Dynamic lactate clearance patterns during NMP predict PTBCs in DCD LT. This novel approach may enable more precise risk stratification and guide posttransplant surveillance strategies for DCD grafts.

Background: Static cold storage (SCS) remains the standard method for organ preservation. The development of parenchymal edema during prolonged hypothermic machine perfusion (HMP) was a major barrier to the introduction of this technique for the preservation of pancreases. A short period of HMP could optimize the pancreas for reperfusion while minimizing the side effects related to perfusion. Our objective is to evaluate the impact of short-term HMP on the pancreatic reperfusion.

Methods: A preclinical study using a controlled donation after circulatory death porcine model was conducted. After procurement, the pancreases were preserved under hypothermic conditions for 2 h either by SCS (n = 4) or HMP (n = 4). After these 2 h of preservation, the pancreases were reperfused using a normothermic machine perfusion (NMP) for 2 h. During NMP, oxygenation, perfusion parameters, biochemical analyses, a glucose stimulation insulin secretion test, and an evaluation of ischemia/reperfusion injury by photoacoustic tomography were assessed.

Results: During NMP, resistance indices were significantly lower in the HMP group compared with the SCS group, even after 2 h of reperfusion. The tissue oxygen partial pressure was higher throughout NMP after HMP preservation. Lactate and amylase levels were equal between the 2 groups. Lipase levels were higher in the HMP group. The glucose stimulation test showed no difference between the 2 groups. Photoacoustic tomography assessment showed no endothelial damage in either group.

Conclusions: Our study suggests that a short-term HMP applied to pancreases for 2 h is effective in reducing resistance indexes and improving oxygenation.