Early extracorporeal photopheresis treatment is associated with better survival in patients with chronic or recurrent acute lung allograft dysfunction.

BACKGROUND: Due to development of chronic lung allograft dysfunction (CLAD), prognosis for patients undergoing lung transplantation (LTx) is still worse compared to other solid organ transplant recipients. Treatment options for slowing down CLAD progression are scarce with extracorporeal photopheresis (ECP) as an established rescue therapy. The aim of the study was to identify characteristics of responders and non-responders to ECP treatment, assess their survival, lung function development and by that define the subset of patients who should receive early ECP treatment. METHODS: We performed a retrospective study of all LTx patients receiving ECP treatment at the University Hospital Zurich between January 2010 and March 2020. Patients were followed-up for a maximum period of 5 years. Mortality and lung function development were assessed by CLAD stage and by CLAD subtype before initiation of ECP treatment. RESULTS: Overall, 105 patients received at least one ECP following LTx. A total of 57 patients (61.3%) died within the study period with a median survival of 15 months. Mortality was 57% for patients who started ECP at CLAD1, 39% for CLAD2, 93% for CLAD3, and 90% for CLAD4 (p < 0.001). Survival and lung function development was best in young patients at early CLAD stages 1 and 2. Response to ECP treatment was worst in patients with CLAD-RAS/mixed subtype (14.3%) and patients with ECP initiation in CLAD stages 3 (7.1%) and 4 (11.1%). Survival was significantly better in a subset of patients with recurrent acute allograft dysfunction and earlier start of ECP treatment (105 vs 15 months). CONCLUSION: In this retrospective analysis of a large group of CLAD patients treated with ECP after LTx, early initiation of ECP was associated with better long-term survival. Besides a subset of patients suffering of recurrent allograft dysfunction, especially a subset of patients defined as responders showed an improved response rate and survival, suggesting that ECP should be initiated in early CLAD stages and young patients. ECP might therefore prevent long-term disease progression even in patients with CLAD refractory to other treatment options and thus prevent or delay re-transplantation.

Epicardial placement of human placental membrane allografts in coronary artery bypass graft surgery is associated with reduced postoperative atrial fibrillation: a pilot study for a future multi-center randomized controlled trial.

BACKGROUND: Post-operative atrial fibrillation (POAF) occurs in up to 40% of patients following coronary artery bypass grafting (CABG) and is associated with a higher risk of stroke and mortality. This study investigates how POAF may be mitigated by epicardial placement of aseptically processed human placental membrane allografts (HPMAs) before pericardial closure in CABG surgery. This study was conducted as a pilot feasibility study to collect preliminary for a forthcoming multi-center randomized controlled trial. METHODS: This retrospective observational study of patients undergoing CABG surgery excluded patients with pre-operative heart failure, chronic kidney disease, or a history of atrial fibrillation. The "treatment" group (n = 24) had three HPMAs placed epicardially following cardiopulmonary bypass decannulation but before partial pericardial approximation and chest closure. The only difference in clinical protocol for the control group (n = 54) was that they did not receive HPMA. RESULTS: HPMA-treated patients saw a significant, greater than four-fold reduction in POAF incidence compared to controls (35.2-8.3%, p = 0.0136). Univariate analysis demonstrated that HPMA treatment was associated with an 83% reduction in POAF (OR = 0.17, p = 0.0248). Multivariable analysis yielded similar results (OR = 0.07, p = 0.0156) after controlling for other covariates. Overall length of stay (LOS) between groups was similar, but ICU LOS trended lower with HPMA treatment (p = 0.0677). Post-operative inotrope and vasopressor requirements were similar among groups. There was no new-onset post-operative heart failure, stroke, or death reported up to thirty days in either group. CONCLUSIONS: Epicardial HPMA placement can be a simple intervention at the end of CABG surgery that may provide a new approach to reduce post-operative atrial fibrillation by modulating local inflammation, possibly reducing ICU and hospital stay, and ultimately improving patient outcomes.

IL-6 inhibition prevents costimulation blockade-resistant allograft rejection in T cell-depleted recipients by promoting intragraft immune regulation in mice.

The efficacy of costimulation blockade with CTLA4-Ig (belatacept) in transplantation is limited due to T cell-mediated rejection, which also persists after induction with anti-thymocyte globulin (ATG). Here, we investigate why ATG fails to prevent costimulation blockade-resistant rejection and how this barrier can be overcome. ATG did not prevent graft rejection in a murine heart transplant model of CTLA4-Ig therapy and induced a pro-inflammatory cytokine environment. While ATG improved the balance between regulatory T cells (Treg) and effector T cells in the spleen, it had no such effect within cardiac allografts. Neutralizing IL-6 alleviated graft inflammation, increased intragraft Treg frequencies, and enhanced intragraft IL-10 and Th2-cytokine expression. IL-6 blockade together with ATG allowed CTLA4-Ig therapy to achieve long-term, rejection-free heart allograft survival. This beneficial effect was abolished upon Treg depletion. Combining ATG with IL-6 blockade prevents costimulation blockade-resistant rejection, thereby eliminating a major impediment to clinical use of costimulation blockers in transplantation.

Clinicopathologic Spectrum and Outcomes of Infections Diagnosed on Graft Biopsies and Nephrectomy in Live Renal Allograft Recipients: An Institutional Experience.

OBJECTIVES: Modern immunosuppressive regimens have reduced rejection episodes in renal allograft recipients but have increased the risk of opportunistic infections. Infections are considered to be the second leading cause of death after cardiovascular complications in renal allograft recipients. Data on opportunistic infections affecting the allograft itself are scarce. The present study describes the spectrum of renal opportunistic infections and their outcomes diagnosed on renal allograft biopsies and nephrectomy specimens. MATERIALS AND METHODS: Our retrospective observational study was conducted from December 2011 to December 2021. We analyzed infectious episodes diagnosed on renal allograft biopsies or graft nephrectomy specimens. We obtained clinical, epidemiological, and laboratory details for analyses from hospital records. RESULTS: BK virus nephropathy was the most common opportunistic infection affecting the allograft, accounting for 47% of cases, followed by bacterial graft pyelonephritis (25%). Mucormycosis was the most common fungal infection. The diagnosis of infection from day of transplant ranged from 14 days to 39 months. Follow-up periods ranged from 1 to 10 years. Mortality was highest among patients with opportunistic fungal infection (62%), followed by viral infections, and graft failure rate was highest in patients with graft pyelonephritis (50%). Among patients with BK polyomavirus nephropathy, 45% had stable graft function compared with just 33% of patients with bacterial graft pyelonephritis. CONCLUSIONS: BK polyoma virus infection was the most common infection affecting the renal allograft in our study. Although fungal infections caused the highest mortality among our patients, bacterial graft pyelonephritis was responsible for maximum graft failure. Correctly identifying infections on histology is important so that graft and patient life can be prolonged.

Impact of surgical risk factors for non-union on lumbar spinal fusion outcomes using cellular bone allograft at 24-months follow-up.

BACKGROUND: The current report investigates fusion rates and patient-reported outcomes following lumbar spinal surgery using cellular bone allograft (CBA) in patients with risk factors for non-union. METHODS: A prospective, open label study was conducted in subjects undergoing lumbar spinal fusion with CBA (NCT02969616) to assess fusion success rates and patient-reported outcomes in subjects with risk factors for non-union. Subjects were categorized into low-risk (≤ 1 risk factors) and high-risk (> 1 risk factors) groups. Radiographic fusion status was evaluated by an independent review of dynamic radiographs and CT scans. Patient-reported outcome measures included quality of life (EQ-5D), Oswestry Disability Index (ODI) and Visual Analog Scales (VAS) for back and leg pain. Adverse event reporting was conducted throughout 24-months of follow-up. RESULTS: A total of 274 subjects were enrolled: 140 subjects (51.1%) were categorized into the high-risk group (> 1 risk factor) and 134 subjects (48.9%) into the low-risk group (≤ 1 risk factors). The overall mean age at screening was 58.8 years (SD 12.5) with a higher distribution of females (63.1%) than males (36.9%). No statistical difference in fusion rates were observed between the low-risk (90.0%) and high-risk (93.9%) groups (p > 0.05). A statistically significant improvement in patient-reported outcomes (EQ-5D, ODI and VAS) was observed at all time points (p < 0.05) in both low and high-risk groups. The low-risk group showed enhanced improvement at multiple timepoints in EQ-5D, ODI, VAS-Back pain and VAS-Leg pain scores compared to the high-risk group (p < 0.05). The number of AEs were similar among risk groups. CONCLUSIONS: This study demonstrates high fusion rates following lumbar spinal surgery using CBA, regardless of associated risk factors. Patient reported outcomes and fusion rates were not adversely affected by risk factor profiles. TRIAL REGISTRATION: NCT02969616 (21/11/2016).

Mucormycosis in Liver Allograft Following Transplant for Secondary Biliary Cirrhosis.

Mucormycosis, a group of opportunistic mycoses caused by Mucorales, present a significant threat to immunocompromised patients. In this report, we present the case of a 57-year-old male patient who underwent liver transplant for secondary biliary cirrhosis following inadvertent bile duct injury. Despite initial satisfactory postoperative evolution, the patient developed fever, and imaging revealed a suspicious lesion. Preliminary culture growth suggested a filamentous fungus, leading to initiation of liposomal amphotericin B. However, the lesion progressed, and a surgical debridement was necessary. During surgery, involvement of the liver dome and diaphragm was observed, and a nonanatomical hepatectomy was performed. Despite efforts, the patient's condition deteriorated, ultimately resulting in multiple organ failure and mortality. This case emphasizes the challenging nature of mucormycosis in livertransplant recipients.

Rictor/mTORC2 signalling contributes to renal vascular endothelial-to-mesenchymal transition and renal allograft interstitial fibrosis by regulating BNIP3-mediated mitophagy.

BACKGROUND: Renal allograft interstitial fibrosis/tubular atrophy (IF/TA) constitutes the principal histopathological characteristic of chronic allograft dysfunction (CAD) in kidney-transplanted patients. While renal vascular endothelial-mesenchymal transition (EndMT) has been verified as an important contributing factor to IF/TA in CAD patients, its underlying mechanisms remain obscure. Through single-cell transcriptomic analysis, we identified Rictor as a potential pivotal mediator for EndMT. This investigation sought to elucidate the role of Rictor/mTORC2 signalling in the pathogenesis of renal allograft interstitial fibrosis and the associated mechanisms. METHODS: The influence of the Rictor/mTOR2 pathway on renal vascular EndMT and renal allograft fibrosis was investigated by cell experiments and Rictor depletion in renal allogeneic transplantation mice models. Subsequently, a series of assays were conducted to explore the underlying mechanisms of the enhanced mitophagy and the ameliorated EndMT resulting from Rictor knockout. RESULTS: Our findings revealed a significant activation of the Rictor/mTORC2 signalling in CAD patients and allogeneic kidney transplanted mice. The suppression of Rictor/mTORC2 signalling alleviated TNFα-induced EndMT in HUVECs. Moreover, Rictor knockout in endothelial cells remarkably ameliorated renal vascular EndMT and allograft interstitial fibrosis in allogeneic kidney transplanted mice. Mechanistically, Rictor knockout resulted in an augmented BNIP3-mediated mitophagy in endothelial cells. Furthermore, Rictor/mTORC2 facilitated the MARCH5-mediated degradation of BNIP3 at the K130 site through K48-linked ubiquitination, thereby regulating mitophagy activity. Subsequent experiments also demonstrated that BNIP3 knockdown nearly reversed the enhanced mitophagy and mitigated EndMT and allograft interstitial fibrosis induced by Rictor knockout. CONCLUSIONS: Consequently, our study underscores Rictor/mTORC2 signalling as a critical mediator of renal vascular EndMT and allograft interstitial fibrosis progression, exerting its impact through regulating BNIP3-mediated mitophagy. This insight unveils a potential therapeutic target for mitigating renal allograft interstitial fibrosis.

Transplantation of cryopreserved cardiovascular homografts.

Due to degeneration, homografts were since the 1950s only used strictly for replacement of complex arterial segments and lesions incl. the aortic valve, replacement of infected arterial prostheses, and vascular access for patients on haemodialysis. During the 1990s, rate-differentiated freezing methods and anti-crystallization agents proved to prevent crystallisation, and more widespread use with expanded indications incl. coronary and lower limb bypasses began justified by promising midterm results. In 2021, the first Scandinavian homograft biobank was founded in Odense in Denmark. This review summarises the history and the experiences from this biobank.

Machine Perfusion Enables 24-h Preservation of Vascularized Composite Allografts in a Swine Model of Allotransplantation.

The current gold standard for preserving vascularized composite allografts (VCA) is 4°C static cold storage (SCS), albeit muscle vulnerability to ischemia can be described as early as after 2 h of SCS. Alternatively, machine perfusion (MP) is growing in the world of organ preservation. Herein, we investigated the outcomes of oxygenated acellular subnormothermic machine perfusion (SNMP) for 24-h VCA preservation before allotransplantation in a swine model. Six partial hindlimbs were procured on adult pigs and preserved ex vivo for 24 h with either SNMP (n = 3) or SCS (n = 3) before heterotopic allotransplantation. Recipient animals received immunosuppression and were followed up for 14 days. Clinical monitoring was carried out twice daily, and graft biopsies and blood samples were regularly collected. Two blinded pathologists assessed skin and muscle samples. Overall survival was higher in the SNMP group. Early euthanasia of 2 animals in the SCS group was linked to significant graft degeneration. Analyses of the grafts showed massive muscle degeneration in the SCS group and a normal aspect in the SNMP group 2 weeks after allotransplantation. Therefore, this 24-h SNMP protocol using a modified Steen solution generated better clinical and histological outcomes in allotransplantation when compared to time-matched SCS.

Impact of donor-specific antibody with low mean fluorescence intensity on allograft outcomes in kidney transplant.

BACKGROUND: Immune-mediated rejection is the most common cause of allograft failure in kidney transplant (KT) patients. Exposure to alloantigen, including human leukocyte antigen (HLA), results in the production of donor-specific antibodies (DSA). There are limited data about low levels of mean fluorescence intensity (MFI) DSA, especially post-transplantation. This study evaluated allograft outcomes in KT patients with low MFI DSA. METHODS: From January 2007 to December 2021, KT patients who were tested for post-transplant DSA at Ramathibodi Hospital, Bangkok, Thailand, with the DSA MFI ≤ 1000 were evaluated. These KT patients were categorized into two groups: very low DSA (VLL; MFI = 1-500) and low DSA (LL; MFI = 501-1000). All KT patients were evaluated for the primary outcomes, such as the incidence of acute rejection, serum creatinine levels at one and five years after transplantation as well as allograft and patient survivals. RESULTS: Among 36 KT patients 25 were included as those with VLL and 11 as those with LL. The LL group had significantly higher T-cell mediated allograft rejection (TCMR) than the VLL group (45% vs. 12%, P = 0.04). In addition, 10 patients, 5 in the VLL group and 5 in the LL group developed antibody-mediated allograft rejection (ABMR). Both TCMR and ABMR were confirmed by biopsy results. There was a trend toward higher MFI in KT patients with ABMR than without ABMR (P = 0.22). At 5 post-transplant years, serum creatinine, allograft and patient survivals were comparable between these two groups. Furthermore, the univariate and multivariate analyzes revealed that the LL group was a high risk for rejection. CONCLUSION: Low MFI DSA values after transplantation may be associated with a higher incidence of rejection, but this finding did not show differences in allograft and patient survival in this study's analysis.

Biomarkers from subcutaneous engineered tissues predict acute rejection of organ allografts.

Invasive graft biopsies assess the efficacy of immunosuppression through lagging indicators of transplant rejection. We report on a microporous scaffold implant as a minimally invasive immunological niche to assay rejection before graft injury. Adoptive transfer of T cells into Rag2-/- mice with mismatched allografts induced acute cellular allograft rejection (ACAR), with subsequent validation in wild-type animals. Following murine heart or skin transplantation, scaffold implants accumulate predominantly innate immune cells. The scaffold enables frequent biopsy, and gene expression analyses identified biomarkers of ACAR before clinical signs of graft injury. This gene signature distinguishes ACAR and immunodeficient respiratory infection before injury onset, indicating the specificity of the biomarkers to differentiate ACAR from other inflammatory insult. Overall, this implantable scaffold enables remote evaluation of the early risk of rejection, which could potentially be used to reduce the frequency of routine graft biopsy, reduce toxicities by personalizing immunosuppression, and prolong transplant life.

Chronological Changes in the Histology of Infection-Related Glomerulonephritis in Renal Allograft: A Case Report.

We report the histological changes over time for a patient with infection-related glomerulonephritis (IRGN) that developed in a transplanted kidney. A 47-year-old man had undergone renal transplantation 3 years ago for end-stage kidney disease (ESKD). After several episodes of acute rejection, the patient was in a stable CKD condition. The abrupt development of severe microscopic hematuria and renal dysfunction was observed approximately 2 weeks after the onset of a phlegmon in his right leg. An allograft biopsy showed prominent glomerular endocapillary proliferation on light microscopy, granular C3 deposition on immunofluorescent microscopy, and subepithelial electron-dense deposits on electron microscopy, suggesting IRGN accompanied by moderate interstitial fibrosis and tubular atrophy (IFTA). Positive glomerular staining for nephritis-associated plasmin receptor (NAPlr) and plasmin activity, which are biomarkers of bacterial IRGN, supported the diagnosis. Although the infection was completely cured with antibiotic therapy, renal dysfunction persisted. A re-biopsy of the allograft 2 months later revealed resolution of the glomerular endocapillary proliferation and negative staining for NAPlr/plasmin activity, with worsening IFTA. We showed, for the first time, the chronological changes in infiltrating cells and histological markers of IRGN in transplanted kidneys. Glomerular changes, including NAPlr/plasmin activity staining, almost disappeared after the cessation of infection, while interstitial changes continuously progressed, contributing to ESKD progression.

Normothermic Preservation of the Intestinal Allograft.

Intestinal allotransplantation was first described in the 1960s and successfully performed in the 1980s. Since that time, less progress has been made in the preservation of the allograft before transplantation and static cold storage remains the current standard. Normothermic machine perfusion represents an opportunity to simultaneously preserve, assess, and recondition the organ for transplantation and improve the procurement radius for allografts. The substantial progress made in the field during the last 60 years, coupled with the success of the preclinical animal model of machine perfusion-preserved intestinal transplantation, suggest we are approaching the point of clinical application.

Extracorporeal photopheresis (ECP) in the treatment of chronic lung allograft dysfunction (CLAD): a prospective, multicentre, open-label, randomised controlled trial studying the addition of ECP to standard care in the treatment of bilateral lung transplant patients with CLAD (E-CLAD UK).

BACKGROUND: Long-term survival after lung transplantation is limited compared with other organ transplants. The main cause is development of progressive immune-mediated damage to the lung allograft. This damage, which can develop via multiple immune pathways, is captured under the umbrella term chronic lung allograft dysfunction (CLAD). Despite the availability of powerful immunosuppressive drugs, there are presently no treatments proven to reverse or reliably halt the loss of lung function caused by CLAD. The aim of the E-CLAD UK trial is to determine whether the addition of immunomodulatory therapy, in the form of extracorporeal photopheresis (ECP), to standard care is more efficacious at stabilising lung function in CLAD compared with standard care alone. METHODS AND ANALYSIS: E-CLAD UK is a Phase II clinical trial of an investigational medicinal product (Methoxsalen) delivered to a buffy coat prepared via an enclosed ECP circuit. Target recruitment is 90 bilateral lung transplant patients identified as having CLAD and being treated at one of the five UK adult lung transplant centres. Participants will be randomised 1:1 to intervention plus standard of care, or standard of care alone. Intervention will comprise nine ECP cycles spread over 20 weeks, each course involving two treatments of ECP on consecutive days. All participants will be followed up for a period of 24 weeks.The primary outcome is lung function stabilisation derived from change in forced expiratory volume in one second and forced vital capacity at 12 and 24 weeks compared with baseline at study entry. Other parameters include change in exercise capacity, health-related quality of life and safety. A mechanistic study will seek to identify molecular or cellular markers linked to treatment response and qualitative interviews will explore patient experiences of CLAD and the ECP treatment.A patient and public advisory group is integral to the trial from design to implementation, developing material to support the consent process and interview materials. ETHICS AND DISSEMINATION: The East Midlands-Derby Research Ethics Committee has provided ethical approval (REC 22/EM/0218). Dissemination will be via publications, patient-friendly summaries and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT number 2022-002659-20; ISRCTN 10615985.

Clinical Outcomes of Medial Meniscal Allograft Transplantation With or Without High Tibial Osteotomy: A Case-Control Study Up to 8 Years of Follow-up.

BACKGROUND: Satisfactory clinical results of meniscal allograft transplantation (MAT) have been reported in recent years. However, it remains unclear whether the clinical outcomes of MAT when combined with an osteotomy are inferior to those of isolated MAT. PURPOSE: To compare the survival rates and clinical outcomes of patients who received isolated medial MAT with those of patients undergoing medial MAT combined with high tibial osteotomy (HTO). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 55 patients underwent arthroscopic medial MAT using the soft tissue technique and HTO (mean age, 41.3 ± 10.4 years; 9 female); after fuzzy case-control matching on demographics, 55 controls who underwent isolated medial MAT were also included. Survival analyses were performed using the Kaplan-Meier method with surgical failure, clinical failure (Lysholm score, <65), and reoperation as endpoints. Subjective clinical scores were collected preoperatively and at the final follow-up. RESULTS: The mean follow-up time was 5.4 years, up to 8 years. All outcomes significantly improved at the last follow-up (P < .001). No differences were identified between MAT and MAT + HTO groups preoperatively and at the last follow-up (P > .05). At the final follow-up, 8 of 55 (14.5%) of the MAT + HTO patients and 9 of 55 (16.4%) of the MAT patients had a Lysholm score <65 (P = .885). Overall, 90% of the patients declared they would repeat the surgery regardless of the combined procedure. Surgical failure was identified in 6 of 110 (5.5%) patients: 5 of 55 (9.1%) in the MAT + HTO group and 1 of 55 (1.8%) in the MAT group (P = .093). Clinical failure was identified in 19 of 110 (17.3%) patients: 11 of 55 (20%) in the MAT + HTO group and 8 of 55 (14.5%) in the MAT group (P = .447). A significantly lower survivorship from surgical failure was identified in the MAT + HTO group (hazard ratio, 5.1; P = .049), while no differences in survivorship from reoperation and clinical failure were identified (P > .05). CONCLUSION: Patients undergoing medial MAT + HTO showed similar clinical results to patients undergoing isolated medial MAT at midterm follow-up, and thus a surgically addressed malalignment does not represent a contraindication for medial MAT. However, the need for a concomitant HTO is associated with a slightly higher failure rate over time.

Comparison Between Corticocancellous Allograft and Bovine Xenograft for Sinus Augmentation: A Radiographic, Histologic, and Histomorphometric Clinical Study.

Sinus floor augmentation is one of the most common approaches to obtain sufficient bone availability for placing implants in cases with severe bone atrophy in the posterior maxilla. Several bone substitutes are indicated for sinus augmentation, but they may achieve different clinical outcomes. This study aims to compare bovine bone mineral (BBM) with freeze-dried bone allograft (FDBA) in a two-stage lateral window sinus grafting approach. Twenty patients received a lateral window sinus elevation with either FDBA or BBM. Postoperative graft height was measured with CBCT. Implants were placed 6 months later, at which time biopsy samples were taken for histologic analysis and new CBCT scans were performed to measure graft height. The mean height reduction at 6 months was 20.27% ± 4.94% for FDBA samples and 5.36% ± 2.41% for BBM samples. The histologic analysis revealed a mean ratio of newly formed bone of 43.70% ± 5.29% for the FDBA group and 38.11% ± 4.03% for the BBM group. The FDBA group also showed a higher amount of residual biomaterial (17.25% ± 10.10%) and connective tissue (14.63% ± 4.38%) compared to the BBM group (15.53% ± 5.42% and 13.11% ± 4.42%, respectively). The differences between groups were statistically significant for the height reduction and newly formed bone (P ≤ .05) but not for the amounts of residual biomaterial and nonmineralized connective tissue (P ≥ .05). Six months after performing a lateral window sinus elevation, the percentage of newly formed bone was significantly higher when using FDBA than when using BBM, although the graft height reduction was also significantly higher for the FDBA group.