Frontiers in transplantation最新文献

Background: Kidney perfusion is a tool that allows organs to be assessed before transplantation. After brain death (BD), hormonal dysfunction can compromise graft quality. Hormonal treatment of donors has shown positive outcomes, and treatment during ex vivo perfusion may be advantageous. The combination of 17β-estradiol (E2) and methylprednisolone (MP) has been shown to modulate inflammation in donors. Therefore, this study aims to evaluate treatment with E2 and MP during isolated perfusion of kidneys in brain-dead male and female rats.

Methods: Female and male Wistar rats were submitted to BD and maintained for 4 h. In the same animal, the right kidney [RK-no isolated perfusion of kidney (IPK)] was removed and stored, while the left kidney (LK-with IPK) had the ureter and the renal artery cannulated and flushed with 5 ml of cold saline. The LK was then taken directly to the IPK system for 90 min. Experimental groups were performed in both male and female: IPK (without treatment) and IPK + Treat (MP and E2 added to the perfusate). Perfusion was performed with a constant pressure of 100 mmHg, using William's Medium E supplemented with HEPES, creatinine, and albumin as perfusate. Perfusate and urine were collected, and flow measurements were recorded. After IPK, the LK was stored.

Results: IL-6 was reduced in all perfused groups, regardless of treatment. In female IPK + Treat, there was a reduction in perfusion flow, followed by reduced creatinine clearance and Na⁺ excretion. No difference was observed in males in regards to treatment.

Conclusion: The combined treatment of E2 and MP during isolated kidney perfusion compromised kidney function in females. In males, no detrimental effects were observed. These results show a sex-dependent action of the proposed treatment.

Background: Long-term survival after lung transplantation is significantly shorter compared with other solid organ transplantations. Chronic lung allograft dysfunction (CLAD), including bronchiolitis obliterans syndrome (BOS), remains the major barrier to survival. CLAD is diagnosed according to ISHLT's guidelines: a 20% drop in FEV₁ using spirometry for CLAD grade 1. Given the difficulties of confounders using spirometry, other methods for precise diagnostics are being explored. Exhaled breath particles (EBP) measured as particle flow rate (PFR) from the airways have been explored as a potential method to diagnose lung injury in preclinical and clinical settings of acute respiratory distress syndrome (ARDS) and primary graft dysfunction (PGD). In fact, PFR has been shown to indicate early signs of lung injury in both ARDS and PGD settings. In the present study, we explored whether PFR could be used as a marker for BOS.

Methods: Lung transplant patients with different BOS grades were included. All patients were in stable condition without ongoing infections and >2 years posttransplantation. PFR (in particles per liter) was measured using a Particles in Exhaled Air (PExA) 2.0 device (PExA, Gothenburg, Sweden), containing an optical particle counter, at the start of the study and then 1 year out, in total two time points (0 and 1 year). Particles in the diameter range of 0.41-4.55 µm were measured.

Results: At both the start of the study and 1 year out, patients with BOS grade 0 had significantly higher PFR than patients with BOS grades 2-3. During the study period, patients who progressed in their BOS grade all expressed lower PFR as they progressed in BOS grade, while patients who remained stable in BOS grade did not. The particle distribution between the different BOS grades had a similar pattern; however, it significantly decreased PFR with severity in the BOS grade.

Conclusions: EBP expressed as PFR could be used to distinguish severity in BOS grade and could be used to follow the progression of BOS over time. PFR could be used as a new diagnostic tool for BOS and to follow the development of lung function over time.

The porous structure can effectively reduce the stress shielding effect in the process of implanting prostheses in the treatment of bone defects, but the performance of different types of porous structures directly affects the treatment effect, so it is necessary to evaluate a variety of different porous structures and select the most suitable structure type for implantation to improve the treatment effect. Based on the three-dimensional model of porous structure, this paper uses numerical analysis to evaluate the mechanical properties of porous structure and completes the primary selection of porous structure; secondly, the indexes and weights affecting the performance of porous structure are clarified, the calculation method of evaluation value is determined, and the evaluation system of implanted prosthesis with porous structure is constructed; then, through mechanical experiments and animal experiments, the machinability index and bone ingrowth index of the primary structure and commonly used clinical structure are studied; finally, according to the evaluation system, the most suitable type of porous structure for implantation is selected. The results of this study found that the tetrahedral body-centered structure [diamond structure] is the optimal structure type for the preparation of implanted prostheses with porous structures. The implantation of tetrahedral body-heart structure is of great significance for the treatment of segmental bone defects and can improve the quality of life of patients.

Background: Respiratory viruses can impact the allograft function in lung transplant recipients, but it is unknown if this occurs with SARS-CoV-2 infection. We studied the long-term outcomes of lung transplant recipients infected with SARS-CoV-2.

Methods: This single-center retrospective study compared lung transplant recipients with SARS-CoV-2 between June 2020 and April 2021 with a matched control group. Within the SARS-CoV-2 cohort, univariable associations between clinical factors and outcomes were tested. Changes in pulmonary function tests were analyzed. Primary endpoints included acute cellular rejection and all-cause mortality within 12 months.

Results: Fifty-three lung transplant recipients were infected with SARS-CoV-2. The median age was 64 years. 29 (54.7%) were managed outpatient, and 24 (45.3%) required hospitalization, with 13 intensive care unit admissions. All-cause mortality was 24.5%. Within the SARS-CoV-2 cohort, older age was significantly associated with all-cause mortality (p-value 0.017) as was ICU admission (p = 0.009) and an A1C > 6.5 (p = 0.033). The mean change in FEV1 was -1.1% at 3 months with minimal change at 6 and 12 months (-2.6% and -1% respectively), all compared to baseline. Acute cellular rejection was identified in 13.7% of the SARS-CoV-2 cohort compared to 11.8% in the matched control group; it was not significantly associated with the infection status (p = 0.706). However, all-cause mortality was significantly associated with infection status (p = 0.019).

Conclusion: Long-term outcomes of SARS-CoV-2 in lung transplant recipients are widely variable. Within the SARS-CoV-2 cohort, all-cause mortality was 24.5%, and older age was significantly associated with mortality. We did not observe significant declines in FEV1 in this group.

Introduction: Catheter-related bloodstream infections (CRBSI) incidence is well-studied in general hemodialysis patients. There is a lack of data on CRBSI rates specifically in solid organ transplant (SOT) recipients requiring hemodialysis. This study aims to investigate CRBSI incidence in this population at a single center.

Methods: This retrospective, single-center cohort study at Massachusetts General Hospital (MGH) investigated CRBSI incidence in non-kidney SOT (i.e., heart, lung, liver) who required hemodialysis via a tunneled dialysis catheter (TDC). Data was collected from January 2016 to October 2024, with patients followed for up to two years post-transplant or until death/end of study.

Results: 42 individuals met the study's inclusion criteria. The mean age of this cohort was 57 years, 50% were male, and 81% were White. The group consisted of 17 liver transplant recipients (40.5%), 13 heart transplant recipients (31.0%), and 12 lung transplant recipients (28.6%). Among the 12 lung transplant recipients, 8 received basiliximab induction, and 4 received no antibody induction therapy. 97% of the patients received mycophenolate mofetil, tacrolimus, and prednisone, while 3% received steroid-free maintenance. The median follow-up was 51.5 days (interquartile range 16-233). During this period, six individuals developed CRBSI, resulting in an incidence rate of 0.86 infections per 1,000 catheter-days. No deaths were attributed to CRBSI.

Conclusions: Our findings suggest that intense immunosuppression in the setting of SOT is not associated with an increased risk of CRBSI in patients with renal failure utilizing TDC especially when a consistent and standardized protocol for the access and care of these catheters is utilized.

Current screening practices have significantly reduced the transmission of donor-derived infections through organ transplantations. However, in exceptional cases, a deceased donor may harbor an undetected active infection, or abnormal blood test results may be mistakenly attributed to the dying process, resulting in missed infections. These ongoing infections can then be transmitted through the grafts. This report presents a case of confirmed donor-derived herpes simplex virus type 1 (HSV-1) hepatitis following kidney transplantation. The HSV-1 infection in the recipient was initially overlooked and misattributed to a probable mycophenolate mofetil-induced etiology, which led to a delay in initiating antiviral therapy. The recipient subsequently developed HSV-1 hepatitis, which progressed to liver failure and multiorgan failure, ultimately resulting in death. As a result of this case, our transplant center promptly revised its screening and prophylactic antiviral treatment protocols. All kidney transplant recipients who are herpes simplex virus (HSV) antibody-negative now receive valaciclovir until the donor's HSV DNA PCR status is confirmed to be negative.

Allograft dysfunction is a major limitation of survival in organ transplant recipients including those who have received lung transplantation. Early detection of allograft dysfunction is thus crucial to improve outcomes in these patients. However, there are several causes of allograft dysfunction with allograft infection and rejection being the two important causes. It is often difficult to distinguish between those causes as the presentation can be similar. Allograft rejection, especially antibody-mediated rejection (AMR) and chronic lung allograft dysfunction (CLAD) are often identified too late where progression has already occurred. Biomarkers like anti-HLA antibodies including donor-specific antibodies (DSA), donor-derived cell-free DNA (dd-cfDNA), immune cell function (ICF) assays and next-generation sequencing for microorganisms allow for early identification of allograft dysfunction as well as differentiate rejection from other processes such as infection. This in turn allows for early intervention and, ideally, improved long-term allograft outcomes. Greater evidence exists for these biomarkers in other solid organ transplantations including kidney and heart transplantation, but application to lung transplant recipients is increasing and seems equally promising. In this review, we evaluate existing evidence for using these biomarkers and share our center practice in utilizing a combination of these biomarkers post-transplantation to assess for allograft dysfunction.

Background: Renal dysfunction is a common and serious complication in patients with end-stage liver diseases. While some patients recover renal function after liver transplantation (LT), others do not. Additionally, patients with normal kidney function (Normal-KF) before LT may develop post-transplant renal dysfunction. Early identification of patients at risk for impaired kidney function (Impaired-KF) post-LT is critical to improving outcomes. This study integrated metabolomic and proteomic analyses to investigate molecular profiles distinguishing Normal-KF from Impaired-KF post-LT.

Methods: Nine LT recipients were classified into Normal-KF (n = 5) and Impaired-KF (n = 4) groups. One additional recipient with pre-transplant renal function impairment who recovered renal function after LT, was analyzed separately. Serum samples were collected at 2- and 5-weeks post-LT. The metabolomic and proteomic profiles were assessed by untargeted liquid chromatography-tandem mass spectrometry.

Results: Metabolomic analysis identified 29 significantly altered metabolites between Normal-KF and Impaired-KF (fold change > 2, p < 0.05). Proteomic analysis revealed 45 differentially expressed proteins (fold change > 1.25, p < 0.05). For the recovered patient, the metabolomic profile closely resembled Normal-KF, whereas the proteomic profile remained aligned with Impaired-KF at both 14- and 35-days post-LT. From week 2 to week 5, both the metabolomic and proteomic profiles of the recovered patient showed trends toward the Normal-KF.

Conclusion: This study revealed distinct metabolomic and proteomic signatures associated with renal dysfunction post-LT. Proteomic profiles indicated a delayed recovery compared to metabolomic profiles, suggesting a dynamic and muti-layered renal recovery process. Further research is warranted to elucidate the functional implications of the differential proteins and metabolites for improved monitoring and therapeutic strategies.

Background: Kidney transplantation is associated with an increased risk of severe COVID-19 disease. Additionally, cells of the kidney express ACE-2 making them a potential target of the SARS-CoV-2 virus. Both uncontrolled viral replication and T-cell receptor (TCR) mediated cellular immunity towards the infected cells could lead to tissue destruction in the kidney. In cases where pathological findings are not always capable of providing definitive diagnosis, insights into the TCR repertoire could offer valuable information. Here we present a case of potentially infection driven tubulitis in a kidney transplant patient.

Methods: The source of kidney infiltrating T-cells was assessed through next generation TCR sequencing. Using cells from the living donor and overlapping peptide pool of SARS-CoV-2 S-, N-, and M-protein (Wuhan variant), antigen specific T-cells were isolated from peripheral blood by overnight stimulation and subsequent isolation using antibodies and magnetic beads against CD154 and CD137. The clonotypes of these two samples were compared to the clonotypes in a single kidney biopsy cylinder.

Results: We found that 11.1% of the repertoire of the kidney infiltrating T cells were identical to SARS-CoV-2 specific T-cells in the periphery, and only 3.1% of the repertoire was identical to allo-specific TCRs. We also observed substantial overlap between the TCR repertoires of virus-specific and donor-specific T cells, with high similarity and even identical TCR sequences present in both populations. The TCRs with dual specificity constituted a larger proportion of the allo-specific than the virus specific population. These results indicate that SARS-CoV-2 specific T-cells may directly spill into an allo-specific T cell response and that either class of T-cells may cause the observed tubulitis.

Conclusion: TCR-seq of whole biopsies is a method to evaluate the ingragraft TCR repertoire can complement routine pathology and provide further insights into the mechanisms underlying a diagnosis.

This Part 2 of a bipartite review commences with the delineation of a conceptual model outlining the fundamental role of injury-induced regulated cell death (RCD) in the release of DAMPs that drive innate immune responses involved in early inflammation-related allograft dysfunction and alloimmune-mediated allograft rejection. In relation to this topic, the focus is on the divergent role of donor and recipient dendritic cells (DCs), which become immunogenic in the presence of DAMPs to regulate alloimmunity, but in the absence of DAMPs acquire tolerogenic properties to promote allotolerance. With respect to this scenario, proposals are then made for leveraging RCD and DAMPs as biomarkers during normothermic regional perfusion (NRP) and normothermic machine perfusion (NMP) of transplant organs from DCD donors, a strategy poised to significantly enhance current policies for assessing donor organ quality. The focus is then on the ambitious goal to target RCD and DAMPs therapeutically during NRP and NMP, aiming to profoundly suppress subsequently early allograft inflammation and alloimmunity in the recipient. This strategic approach seeks to prevent the activation of intragraft innate immune cells including DCs during donor organ reperfusion in the recipient, which is driven by ischemia/reperfusion injury-induced DAMPs. In this context, available inhibitors of various types of RCD, as well as scavengers and inhibitors of DAMPs are highlighted for their promising therapeutic potential in NRP and NMP settings, building on their proven efficacy in other experimental disease models. If successful, this kind of therapeutic intervention should also be considered for application to organs from DBD donors. Finally, drawing on current global insights into the critical role of RCD and DAMPs in driving innate inflammatory and (allo)immune responses, targeting their inhibition and/or prevention during normothermic perfusion of transplant organs from DCD donors - and potentially DBD donors - holds the transformative potential to not only alleviate transplant dysfunction and suppress allograft rejection but also foster allograft tolerance.