Transplantation最新文献

Background: Heart failure, a leading global health challenge, affects over 23 million people worldwide, with heart transplantation being the gold standard for end-stage disease. However, the scarcity of viable donor hearts presents a significant barrier, with only one-third of available grafts being used because of stringent selection criteria. Machine perfusion technologies, particularly normothermic machine perfusion (NMP), offer promise for improving graft preservation and assessment, yet their full potential for predicting transplantability remains underexplored.

Methods: This study investigates 3 assessment methods to enhance human heart evaluation during NMP, focusing on mitochondrial function, left ventricular performance, and inflammatory markers. First, resonance Raman spectroscopy is used to assess mitochondrial redox state as a proxy for metabolic competency, offering a noninvasive and dynamic evaluation of mitochondrial function during ex vivo preservation. Second, left ventricular function is quantified using intraventricular balloons, providing critical insights into graft viability and performance. Third, inflammatory markers and endothelial activation are assessed from the perfusate to aid the prediction of posttransplant outcomes.

Results: These methods were successfully tested on human donor hearts that were declined for transplantation, preserved via static cold storage, and subsequently assessed with NMP in Langendorff mode.

Conclusions: The results demonstrate that these parameters can be easily integrated into existing clinical perfusion workflows and hold potential for improving heart transplantation outcomes by enhancing graft selection and optimizing donor heart use. Future studies will further validate these biomarkers across different preservation techniques and evaluate their clinical applicability.

Background: Acute kidney injury resulting from ischemia/reperfusion injury (IRI) remains a significant clinical challenge, with limited therapeutic options. This study investigated the renoprotective mechanisms of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), in nondiabetic mice, focusing on neutrophil dynamics and adenosine signaling pathways.

Methods: Nondiabetic mice were pretreated with dapagliflozin before bilateral renal IRI. Some groups received concurrent treatment with an adenosine A2A receptor antagonist. We used novel multiphoton intravital imaging, complemented by comprehensive molecular and metabolomic analyses, to visualize neutrophil trafficking during early reperfusion.

Results: Dapagliflozin significantly attenuated renal dysfunction ( P  < 0.01) and histological damage ( P  < 0.01). Real-time imaging revealed that dapagliflozin markedly suppressed neutrophil infiltration into the glomeruli and peritubular capillaries during early reperfusion, and this effect was partially reversed by coadministration of an A2A receptor antagonist. Molecular analyses demonstrated reduced matrix metalloproteinase-9 expression and activity, with decreased levels of endothelial adhesion molecules, including intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Kidney adenosine levels were significantly increased in dapagliflozin-treated mice and were inversely correlated with matrix metalloproteinase-9 activity. Metabolome analysis revealed significant metabolic reprogramming characterized by suppressed glycolysis, enhanced tricarboxylic acid cycle activity, and elevated adenosine pathway components.

Conclusions: Dapagliflozin protects against renal IRI through the adenosine-mediated inhibition of neutrophil infiltration and inflammatory activation. This novel mechanism, involving metabolic reprogramming and enhanced adenosine signaling, extends our understanding of the pleiotropic effects of sodium-glucose cotransporter 2 inhibitors beyond glycemic control and suggests potential therapeutic applications for preventing acute kidney injury in high-risk clinical settings, including kidney transplantation.

Background: Extracorporeal membrane oxygenation (ECMO) is an important intraoperative support strategy in lung transplantation, particularly for high-risk patients. Although ECMO offers theoretical advantages such as controlled reperfusion and hemodynamic stabilization, its impact on postoperative outcomes compared with off-pump techniques remains debated. This study aimed to evaluate evidence comparing ECMO and off-pump approaches.

Methods: Three databases were assessed. The primary outcome was overall survival. Secondary outcomes included time until extubation, intensive care unit and hospital length of stay (LOS), primary graft dysfunction at postoperative day 3, and need for renal replacement therapy. Hazard ratio, odds ratio, and mean difference (MD) with 95% confidence interval (CI) were calculated. Time-to-event data reconstruction and sensitivity analyses were performed. A subgroup analysis compared planned versus unplanned ECMO to address treatment allocation bias.

Results: Six retrospective studies with 1008 patients were included. ECMO was associated with lower overall survival (hazard ratio, 1.555; 95% CI, 1.13-2.15; P  = 0.007). ECMO also resulted in longer time until extubation (MD, 1.24 d; 95% CI, 0.38-2.09; P  = 0.005), intensive care unit LOS (MD, 2.40 d; 95% CI, 1.20-3.61; P  < 0.001), hospital LOS (MD, 3.61 d; 95% CI, 0.81-6.40; P  = 0.011), and higher primary graft dysfunction incidence at day 3 (odds ratio, 2.18; 95% CI, 1.34-3.53; P  = 0.002). No significant difference was observed for renal replacement therapy ( P  = 0.054). Landmark analysis showed poorer survival for patients supported with ECMO during the first 6 mo but not beyond.

Conclusions: ECMO is associated with poorer early survival and adverse outcomes but remains crucial for high-risk patients, underscoring the need for optimized selection and standardized management.

Background: Cirrhotic cardiomyopathy (CCM) has been redefined and linked to major adverse cardiovascular events (MACEs) after liver transplantation (LT). However, its impact on post-LT heart failure (HF) and survival remains unclear. This study assessed the association between CCM and MACE post-LT.

Methods: We conducted a retrospective cohort study of adults with cirrhosis undergoing deceased-donor LT at a state-wide center between 2010 and 2022. CCM was defined using the Cirrhotic Cardiomyopathy Consortium (CCC-2020) criteria. The primary outcome was new-onset MACE, including HF, within 12-mo post-LT. The secondary outcome was long-term survival.

Results: Among 362 patients, 57 (16%) had CCM. MACE occurred in 46 (13%) of 362, including 15 cases of HF. Patients with CCM had higher MACE incidence than non-CCM (33% versus 9%; P  < 0.001), driven by HF (21% versus 1%; P  < 0.001). CCM independently predicted MACE (odds ratio 4.5 [95% CI, 2.3-9.0]; P  < 0.001) and HF (odds ratio 22.8 [95% CI, 6.0-86.2]; P  < 0.001); age was also independently associated with MACE. Late-onset HF (>30 d) was more severe than perioperative HF (≤30 d). CCM was associated with a 2.1-d longer intensive care unit length of stay (95% CI, 0.1-4.1; P  = 0.04), but not other perioperative outcomes, graft loss, or mortality for the 4.7-year follow-up (interquartile rang 2.5-6.9 y).

Conclusions: Pre-LT CCM, by CCC-2020 criteria, was associated with a 4-fold higher risk of post-LT MACE, primarily because of HF. Other MACE and survival were not impacted. Further research is required to identify which patients with CCM are at the greatest risk of HF, the impact of age, and whether targeted intervention or surveillance can mitigate this.

Background: Long-term kidney graft monitoring still relies on delayed clinical indicators such as eGFR and proteinuria, which change only after substantial injury. To investigate biological processes not captured by standard metrics, we hypothesized that plasma proteomics could identify biomarkers and reveal the pathways underlying the pathological process, thereby providing independent prognostic value for late graft failure.

Methods: In this retrospective matched case-control study, we analyzed pre-event plasma samples from 29 kidney transplant recipients who later experienced late, death-censored graft failure (DCGF; occurring ≥1 y posttransplant) and 49 matched recipients without DCGF from the TransplantLines Biobank. We quantified 800 proteins by label-free liquid chromatography with tandem spectrometry, followed by differential expression analysis and survival-related feature selection. Independent survival markers were evaluated using random survival forests. Biological context was analyzed via STRING network and enrichment analyses.

Results: The cohort (n = 78) had a baseline age of 49.8 ± 14.1 y and estimated glomerular filtration rate of 36.9 ± 13.2 mL/min/1.73 m2. Median time between transplantation and baseline was 2.7 (0.7-7.8) y with 4.6 (2.1-5.8) y of follow-up. Seventeen proteins differed at baseline between cases and controls, including HLA-A and lipopolysaccharide-binding protein. Feature selection identified a 113-protein signature enriched in lipid metabolism, coagulation, and immunity. This signature provided significant prognostic value independent of clinical parameters such as estimated glomerular filtration rate and proteinuria (C-index 0.878 versus 0.851, P < 0.001). After accounting for confounders, apolipoprotein L1 and C1 were the most prominent.

Conclusions: Proteomic profiling may provide novel biological insights into the pathogenesis of DCGF and may complement existing clinical metrics.

Background: With clinical xenotransplantation now underway, optimal patient selection is critical for achieving successful outcomes. Candidates with antibodies targeting Bw4 and Bw6 epitopes on HLA molecules often experience prolonged wait times for allotransplantation because of high calculated panel reactive antibody levels. We investigated whether these antibodies cross-react with class I swine leukocyte antigen (SLA) molecules and could therefore pose a barrier to xenotransplantation.

Methods: We performed sequence alignment and structural modeling to assess the presence of Bw4 and Bw6 epitopes in class I SLA proteins. Human sera containing anti-Bw4 or anti-Bw6 antibodies were tested for reactivity against SLA molecules encoded by 5 haplotypes from pigs we study in xenotransplantation. Genetically engineered pig renal endothelial cells and a prototype panel of SLA-coated beads served as antigenic targets in flow cytometry assays.

Results: Structural analysis confirmed the absence of Bw4 and the presence of modified Bw6 motifs in SLA molecules. Despite the potential epitope conservation, anti-Bw6 sera showed no significant IgG binding to SLA, possibly because of residues adjacent to the canonical epitope. One anti-Bw4 patient showed IgG reactivity to SLA alleles lacking Bw4 or Bw6, implicating a distinct epitope. IgM reactivity was broadly observed across sera.

Conclusions: These findings indicate that the SLA of at least some pigs will not exhibit cross-reactivity with anti-Bw4 and anti-Bw6 antibodies. Incorporating detailed, epitope-level histocompatibility testing may allow these highly sensitized patients, access to xenotransplantation.