Transplantation最新文献

Background: We aimed to assess contemporary transplant outcomes among kidney recipients with amyloidosis, as the treatment and prognosis of amyloidosis have shown improvement over time.

Methods: Using the US Organ Procurement and Transplantation Network database, we initially evaluated the changes in patient and graft survival among kidney recipients with amyloidosis from 2002 to 2021. We then compared transplant outcomes between recipients with amyloidosis versus those with diabetic and nondiabetic causes of kidney failure, creating 1:4 matches with highly similar characteristics separately for deceased donor kidney transplant (DDKT) and living donor kidney transplant (LDKT) during the last decade (2012-2021).

Results: We identified 643 kidney recipients with amyloidosis during 2002-2021. Patient and death-censored graft survival improved over time. In the matching analysis for 207 DDKT and 166 LDKT recipients with amyloidosis during 2012-2021, patient survival was not significantly different between amyloidosis and diabetes groups in both DDKT (log-rank, P  = 0.057) and LDKT ( P  = 0.99). Compared with the nondiabetes group, patient survival in the amyloidosis group was not significantly different for DDKTs ( P  = 0.56) but was significantly lower for LDKTs ( P  = 0.04). Death-censored graft failure risk was not significantly different between amyloidosis and diabetes or nondiabetes groups for both DDKTs ( P  = 0.78 and 0.75) and LDKTs ( P  = 0.40 and 0.24).

Conclusions: In this well-matched cohort study, we found no significant differences in patient and graft survival between kidney recipients with amyloidosis and those with diabetes. Similarly, these outcomes were not significantly different between those with amyloidosis versus nondiabetic causes, except for patient survival of LDKT recipients.

Chronic graft-versus-host disease (cGVHD) is an immune-mediated, heterogeneous, multiorgan complication affecting allogeneic hematopoietic cell transplantation recipients, leading to increased morbidity, mortality, and decline in health-related quality-of-life. Advances in understanding the complex disease pathophysiology, and collaborative efforts lead by the National Institutes of Health to standardize criteria for clinical trials, led to bench-to-bedside efforts resulting in the development of 4 US Food and Drug Administration-approved agents for the treatment steroids-refractory cGVHD since 2017. Despite the remarkable advances in the field of hematopoietic cell transplantation in prevention of cGVHD, and more treatment options, the outcome of patients with moderate-severe cGVHD remains suboptimal. Essential to successful cGVHD management is to recognize the disease at early stages before the onset of irreversible damage, allowing for personalized multidisciplinary specialized interventions that include pharmacologic therapies and additional supportive care measures. The aim of this review is to summarize key areas of active clinical research and new developments in cGVHD therapeutic approaches, with focus on (1) preemptive therapy, (2) upfront therapy beyond corticosteroids, (3) treatment refractory cGVHD novel agents, role of combination therapies, and organ-specific approaches, and (4) challenges, gaps, and future directions.

Background: Current investigation indicates that nuclear factor (erythroid-derived 2)-like 2 (NRF2) possesses both proinflammatory and anti-inflammatory capabilities in T cells, yet its exact function in acute graft-versus-host disease (aGVHD) CD4+ T cells remains unexplored.

Methods: This study aims to determine NRF2 levels within CD4+ T cells of patients with or without aGVHD and analyze the correlation between T-cell receptor activation and NRF2 expression. RNA sequencing was used to detect changes in the expression profile of CD4+ T cells after overexpression of NRF2, and functional enrichment analysis was performed on the sequencing results. Finally, after treating aGVHD CD4+ T cells with NRF2 inhibitor, the expression of related pathway molecules was detected.

Results: Our findings demonstrated a significant upregulation of NRF2 expression in CD4+ T cells from patients in the aGVHD group compared with patients in the non-aGVHD group, and its expression level is correlated with the severity of aGVHD. Additionally, T-cell receptor activation in CD4+ T cells elevates NRF2 expression. Postactivation of NRF2-inhibited CD4+ T cells, the expression levels of T-cell activation markers were notably lower than those in non-NRF2-inhibited CD4+ T cells. Sequencing analysis identified 904 genes that changed after NRF2 overexpression. These genes were categorized into 288 gene subsets, encompassing pathways such as T-cell receptor signaling transduction, Janus kinase 1/signal transducer and activator of transcription 1 (JAK1-STAT1) signaling, T helper cell 17 (Th17) cell differentiation, etc. Ultimately, treating CD4+ T cells of aGVHD patients with an NRF2 inhibitor led to a significant downregulation of JAK1-STAT1 signaling and Th17 cells.

Conclusions: Elevated NRF2 expression in CD4+ T cells of patients with aGVHD initiates and exacerbates aGVHD by potentiating T-cell activation, amplifying JAK1/STAT1 signaling, and instigating Th17/regulatory T-cell ratio imbalance.

In September 2022, in Banff, Alberta, Canada, the XVIth Banff meeting, corresponding to the 30th anniversary of the Banff classification, was held, leading to 2 recent publications. Discussions at the Banff meeting focused on proposing improvements to the Banff process as a whole. In line with this, a unique opportunity was offered to a selected group of 16 representatives from the pathology and transplant nephrology community, experts in the field of kidney transplantation, to review these 2 Banff manuscripts. The aim was to provide an insightful commentary, to gauge any prospective influence the proposed changes may have, and to identify any potential areas for future enhancement within the Banff classification. The group expressed its satisfaction with the incorporation of 2 new entities, namely "microvascular inflammation/injury donor-specific antibodies-negative and C4d negative" and "probable antibody-mediated rejection," into category 2. These changes expand the classification, facilitating the capture of more biopsies and providing an opportunity to explore the clinical implications of these lesions further. However, we found that the Banff classification remains complex, potentially hindering its widespread utilization, even if a degree of complexity may be unavoidable given the intricate pathophysiology of kidney allograft pathology. Addressing the histomorphologic diagnosis of chronic active T cell-mediated rejection (CA TCMR), potentially reconsidering a diagnostic-agnostic approach, as for category 2, to inflammation in interstitial fibrosis and tubular atrophy and chronic active T cell-mediated rejection was also an important objective. Furthermore, we felt a need for more evidence before molecular diagnostics could be routinely integrated and emphasized the need for clinical and histologic context determination and the substantiation of its clinical impact through rigorous clinical trials. Finally, our discussions stressed the ongoing necessity for multidisciplinary decision-making regarding patient care.

Background: Concern of ischemia-reperfusion injury reduces utilization of donor lungs. We hypothesized adding L-alanyl-L-glutamine (L-AG) to preservation solution may protect donor lungs from ischemia-reperfusion injury through its multiple cytoprotective effects.

Methods: A lung transplantation cell culture model was used on human lung epithelial cells and pulmonary microvascular endothelial cells, and the effects of adding different concentrations of L-AG on basic cellular function were tested. Rat donor lungs were preserved at 4 °C with 8 mmol/L L-AG for 12 h followed by 4 h reperfusion or monitored for 3 d. Lung function, lung histology, inflammation, and cell death biomarker were tested. Computerized tomography scan was used and metabolomic analysis was performed on lung tissues.

Results: Cold preservation with L-AG improved cell viability and inhibited apoptosis in cell culture. Rat donor lungs treated with L-AG during cold storage showed decreased peak airway pressure, higher dynamic compliance and oxygenation ability, reduced lung injury, apoptosis, and oxidative stress during reperfusion. L-AG treatment significantly changed 130 metabolites during reperfusion, with enhanced amino acid biosynthesis and tricarboxylic acid cycle. Furthermore, cold storage with L-AG decreased primary graft dysfunction grade, improved oxygenation, reduced pulmonary atelectasis, sign of infection, and pneumothorax in a rat left lung transplant 3-d survival model.

Conclusions: Adding L-AG to cold preservation solution reduced lung injury and alleviated primary graft dysfunction by inhibiting inflammation, oxidative stress, and cell death with modified metabolic activities.

Background: To overcome organ shortages, donation after circulatory death (DCD) kidneys are being increasingly used for transplantation. Prior research suggests that DCD kidneys have inferior outcomes compared with kidneys donated after brain death. Normothermic machine perfusion (NMP) and normothermic regional perfusion (NRP) may enhance the preservation of DCD kidneys and improve transplant outcomes. This study aimed to review the evidence surrounding NMP and NRP in DCD kidney transplantation.

Methods: Two independent reviewers conducted searches for all publications reporting outcomes for NMP and NRP-controlled DCD kidneys, focusing on delayed graft function, primary nonfunction, graft function, graft survival, and graft utilization. Weighted means were calculated for all relevant outcomes and controls. Formal meta-analyses could not be conducted because of significant heterogeneity.

Results: Twenty studies were included for review (6 NMP studies and 14 NRP studies). Delayed graft function rates seemed to be lower for NRP kidneys (24.6%) compared with NMP kidneys (54.3%). Both modalities yielded similar outcomes with respect to primary nonfunction (NMP 3.3% and NRP 5.6%), graft function (12-mo creatinine 149.3 μmol/L for NMP and 129.9 μmol/L for NRP), and graft utilization (NMP 83.3% and NRP 89%). Although no direct comparisons exist, our evidence suggests that both modalities have good short- and medium-term graft outcomes and high graft survival rates.

Conclusions: Current literature demonstrates that both NMP and NRP are feasible strategies that may increase donor organ utilization while maintaining acceptable transplant outcomes and likely improved outcomes compared with cold-stored DCD kidneys. Further research is needed to directly compare NRP and NMP outcomes.

Background: The global shortage of solid organs for transplantation is exacerbated by high demand, resulting in organ deficits and steadily growing waiting lists. Diverse strategies have been established to address this issue and enhance organ availability, including the use of organs from individuals who have undergone extracorporeal cardiopulmonary resuscitation (eCPR). The main aim of this work was to examine the outcomes for both graft and recipients of solid organ transplantations sourced from donors who underwent eCPR.

Methods: We performed a systematic literature review using a combination of the terms related to extracorporeal life support and organ donation. Using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, PubMed and Scopus databases were searched up to February 2024.

Results: From 1764 considered publications, 13 studies comprising 130 donors and 322 organ donations were finally analyzed. On average, included patients were 36 y old, and the extracorporeal life support was used for 4 d. Kidneys were the most often transplanted organs (68%; 220/322), followed by liver (22%; 72/322) and heart (5%; 15/322); with a very good short-term graft survival rate (95% for kidneys, 92% for lungs, 88% for liver, and 73% for heart). Four studies with 230 grafts reported functional outcomes at the 1-y follow-up, with graft losses reported for 4 hearts (36%), 8 livers (17%), and 7 kidneys (4%).

Conclusions: Following eCPR, organs can be successfully used with very high graft and recipient survival. In terms of meeting demand, the use of organs from patients after eCPR might be a suitable method for expanding the organ donation pool.

Background: Strategies to minimize ischemic damage during heart transplantation (HTX) by donation after circulatory death (DCD) are warranted because the inevitable ischemic injury linked to DCD HTX deteriorates mitochondrial respiratory capacity and ultimately graft quality. This study aimed to examine the myocardial mitochondrial function during DCD HTX with hypothermic oxygenated machine perfusion (HOPE) and compare the effect of normothermic regional perfusion (NRP) with that of direct procurement and perfusion (DPP).

Methods: A porcine DCD HTX model was used with hearts subjected to either DPP (n = 6) or NRP (n = 7) followed by HOPE and orthotopic HTX. Mitochondrial respiratory function was analyzed by high-resolution respirometry in left ventricle biopsies at baseline, after 180 min of HOPE, and after 60 min of reperfusion post-HTX.

Results: Mitochondrial oxidative phosphorylation ( P  = 0.0008), respiratory control ratio ( P  = 0.04), and coupling efficiency ( P  = 0.04) declined during DCD HTX. Fatty acid oxidation was preserved after 3 h of HOPE with a modest, statistically nonsignificant decline after reperfusion ( P  = 0.2). Oxidative phosphorylation was inversely correlated with troponin-T levels ( r  = -0.70, P  = 0.0004). No statistically significant difference in mitochondrial respiratory capacity was observed between participants exposed to NRP and DPP.

Conclusions: Mitochondrial respiratory capacity declined gradually throughout the course of DCD HTX and correlated with the degree of myocardial damage. Following HOPE, the extent of mitochondrial deterioration was comparable between NRP and DPP.