Transplant International最新文献

Xenotransplantation of porcine hearts has become a promising alternative to human allotransplantation, where organ demand still greatly surpasses organ availability. Before entering the clinic, however, feasibility of cardiac xenotransplantation needs to be proven, ideally in the life supporting orthotopic pig-to-nonhuman primate xenotransplantation model. In this review, we shortly outline the last three decades of research and then discuss in detail its most recent advances. These include the genetic modifications of donor pigs to overcome hyperacute rejection and coagulation dysregulation, new organ preservation methods to prevent perioperative xenograft dysfunction, experimental immunosuppressive and immunomodulatory therapies to inhibit the adaptive immune system and systemic inflammation in the recipient, growth control concepts to avoid detrimental overgrowth of the porcine hearts in nonhuman primates, and lastly, the avoidance of porcine cytomegalovirus infections in donor pigs. With these strategies, consistent survival of 6-9 months was achieved in the orthotopic xenotransplantation model, thereby fulfilling the prerequisites for the initiation of a clinical trial.

Patients undergoing kidney transplant are at risk of severe COVID-19. Our single-center retrospective analysis evaluated the outcomes of kidney transplant outpatients with COVID-19 who were managed with reduced immunosuppression and treatment with molnupiravir. Between January 2022 and May 2023, we included 93 patients (62 men, average age 56 years), serum creatinine 127 (101-153) µmol/L. Molnupiravir was administered, and immunosuppressive therapy was reduced immediately following the confirmation of SARS-CoV-2 infection by PCR, which was 2 (1-3) days after the onset of symptoms. Only three (3.2%) patients required hospitalization, and one patient died. Acute kidney injury was observed in two patients. During the follow-up period of 19 (15-22) months, there was no significant increase in proteinuria, no acute or new chronic graft rejection, and kidney graft function remained stable; serum creatinine was 124 (106-159) µmol/L post-COVID-19 infection and 128 (101-161) µmol/L at the end of the follow-up period. Our results demonstrate that early initiation of molnupiravir treatment combined with a temporary reduction in immunosuppressive therapy results in favorable clinical outcomes in patients with COVID-19, with preservation of good graft function and no episodes of graft rejection.

Duodenal leaks (DL) contribute to most graft losses following pancreas transplantation. However, there is a paucity of literature comparing graft preservation approach versus upfront graft pancreatectomy in these patients. We reviewed all pancreas transplants performed in our institution between 2000 and 2020 and identified the recipients developing DL to compare based on their management: percutaneous drainage vs. operative graft preservation vs. upfront pancreatectomy. Of the 595 patients undergoing pancreas transplantation, 74 (12.4%) developed a duodenal leak with a median follow up of 108 months. Forty-five (61%) were managed by graft preservation strategies, with the rest being treated with upfront graft pancreatectomy. DL managed by graft preservation strategies had similar graft survival rates at 1 and 5-year compared to the matched cohort of population without DL (95% and 59% vs. 91% and 62%; p = 0.78). Multivariate analysis identified male recipient (OR: OR: 6.18; CI95%: 1.26-41.09; p = 0.04) to have higher odds of undergoing an upfront graft pancreatectomy. In appropriately selected recipients with DL, graft preservation strategies utilizing either interventional radiology guided percutaneous drainage or laparotomy with/without repair of leak can achieve comparable long-term graft survival rates compared to recipients without DL.

Previous solid organ transplantation has been associated with worse survival among colorectal cancer (CRC) patients. This study investigates the contribution of CRC characteristics and treatment-related factors to the differential survival. Using the Swedish register-linkage CRCBaSe, all patients with solid organ transplantation before CRC diagnosis were identified and matched with non-transplanted CRC patients. Associations between transplantation history and clinical CRC factors and survival were estimated using the Kaplan-Meier estimator and logistic, multinomial, and Cox regression, respectively. Ninety-eight transplanted and 474 non-transplanted CRC patients were followed for 5 years after diagnosis. Among patients with stage I-III cancer, transplanted patients had lower odds of treatment with abdominal surgery [odds ratio (OR):0.27, 95% confidence interval (CI):0.08-0.90], than non-transplanted patients. Among those treated with surgery, transplanted colon cancer patients had lower odds of receiving adjuvant chemotherapy (OR:0.31, 95% CI:0.11-0.85), and transplanted rectal cancer patients had higher rate of relapse (hazard ratio:9.60, 95% CI:1.84-50.1), than non-transplanted patients. Five-year cancer-specific and overall survival was 56% and 35% among transplanted CRC patients, and 68% and 57% among non-transplanted. Accordingly, transplanted CRC patients were treated less intensely than non-transplanted patients, and had worse cancer-specific and overall survival. These patients might benefit from multidisciplinary evaluation including transplantation specialists.

Given the increasing frequency of simultaneous pancreas-kidney transplants performed in recipients with Type II diabetes and CKD, we sought to evaluate possible differences in the rates of allograft rejection, infection, and surgical complications in 298 Type I (T1D) versus 47 Type II (T2D) diabetic recipients of simultaneous pancreas-kidney transplants between 2006-2017. There were no significant differences in patient or graft survival. The risk of biopsy-proven rejection of both grafts was not significantly different between T2D and T1D recipients (HR_pancreas = 1.04, p = 0.93; HR_kidney = 0.96; p = 0.93). Rejection-free survival in both grafts were also not different between the two diabetes types (p_pancreas = 0.57; p_kidney = 0.41). T2D had a significantly lower incidence of de novo DSA at 1 year (21% vs. 39%, p = 0.02). There was no difference in T2D vs. T1D recipients regarding readmissions (HR = 0.77, p = 0.25), infections (HR = 0.77, p = 0.18), major surgical complications (HR = 0.89, p = 0.79) and thrombosis (HR = 0.92, p = 0.90). In conclusion, rejection, infections, and surgical complications after simultaneous pancreas-kidney transplant are not statistically significantly different in T2D compared to T1D recipients.

Human leukocyte antigen (HLA) mismatches (MM) between donor and recipient lead to eplet MM (epMM) in lung transplantation (LTX), which can induce the development of de-novo donor-specific HLA-antibodies (dnDSA), particularly HLA-DQ-dnDSA. Aim of our study was to identify risk factors for HLA-DQ-dnDSA development. We included all patients undergoing LTX between 2012 and 2020. All recipients/donors were typed for HLA 11-loci. Development of dnDSA was monitored 1-year post-LTX. EpMM were calculated using HLAMatchmaker. Differences in proportions and means were compared using Chi2-test and Students' t-test. We used Kaplan-Meier curves with LogRank test and multivariate Cox regression to compare acute cellular rejection (ACR), chronic lung allograft dysfunction (CLAD) and survival. Out of 183 patients, 22.9% patients developed HLA-DQ-dnDSA. HLA-DQ-homozygous patients were more likely to develop HLA-DQ-dnDSA than HLA-DQ-heterozygous patients (p = 0.03). Patients homozygous for HLA-DQ1 appeared to have a higher risk of developing HLA-DQ-dnDSA if they received a donor with HLA-DQB1*03:01. Several DQ-eplets were significantly associated with HLA-DQ-dnDSA development. In the multivariate analysis HLA-DQ-dnDSA was significantly associated with ACR (p = 0.03) and CLAD (p = 0.01). HLA-DQ-homozygosity, several high-risk DQ combinations and high-risk epMM result in a higher risk for HLA-DQ-dnDSA development which negatively impact clinical outcomes. Implementation in clinical practice could improve immunological compatibility and graft outcomes.

Biliary complications are still a major cause for morbidity and mortality after liver transplantation (LT). Ischemia/reperfusion injury (IRI) leads to disruption of the biliary epithelium. We introduce a novel model to study the effect of IRI on human cholangiocytes using extrahepatic cholangiocyte organoids (ECOs). Extrahepatic bile duct tissue was collected during LT at static cold storage and after reperfusion (n = 15); gallbladder tissue was used for controls (n = 5). ECOs (n = 9) were cultured from extrahepatic biliary tissue, with IRI induced in an atmosphere of 95% air (nitrogen), 1% O₂ and 5% CO₂for 48 h, followed by 24 h of reoxygenation. Qualitative and quantitative histology and qRT-PCR were performed to discern phenotype, markers of hypoxia, programmed cell death and proliferation. ECOs self-organized into circular structures resembling biliary architecture containing cholangiocytes that expressed EpCAM, CK19, LGR5 and SOX-9. After hypoxia, ECOs showed increased expression of VEGF A (p < 0.0001), SLC2A1 (p < 0.0001) and ACSL4 (p < 0.0001) to indicate response to hypoxic damage and subsequent programmed cell death. Increase in cyclin D1 (p < 0.0001) after reoxygenation indicated proliferative activity in ECOs. Therefore, ECO structure and response to IRI are comparable to that found in-vivo, providing a suitable model to study IRI of the bile duct in-vitro.

Heart transplant patients have an increased risk of developing cancer. Patients who underwent HTx between 1985 and 2017 were included. Detection of cancer was obtained by cross-checking the study population with the Swedish Cancer-Registry and the Cause-of-Death-Registry. A total of 664 patients were followed for a median of 7.7 years. In all, 231 malignancies were diagnosed in 138 patients. Compared to the general population the excess risk of cancer following HTx was 6.2-fold calculated as the standardized incidence ratio (SIR) and 2.9-fold after exclusion of non-melanoma skin cancer (NMSC). The most common malignancies were NMSC, non-Hodgins lymphoma, and lung cancer. There was no significant difference in overall survival between those with and without a history of cancer before HTx (p = 0.53). During a median follow-up of 7.7 years, 19% of HTx recipients developed cancer, 6.2-fold higher relative to the general population, and 2.9-fold higher when excluding NMSC. Risk factors for malignancies (excluding NMSC) included previous smoking, hypertension and prolonged ischemic time; and for NMSC, increasing age, seronegative CMV-donors, and azathioprine. A previous cancer in selected recipients results in similar survival compared to those without cancer prior to HTx.

Ex situ lung perfusion (ESLP) is used for organ reconditioning, repair, and re-evaluation prior to transplantation. Since valid preclinical animal models are required for translationally relevant studies, we developed a 17 mL low-volume ESLP for double- and single-lung application that enables cost-effective optimal compliance "reduction" of the 3R principles of animal research. In single-lung mode, ten Fischer344 and Lewis rat lungs were subjected to ESLP and static cold storage using STEEN or PerfadexPlus. Key perfusion parameters, thermal lung imaging, blood gas analysis (BGA), colloid oncotic pressure (COP), lung weight gain, histological work-up, and cytokine analysis were performed. Significant differences between perfusion solutions but not between the rat strains were detected. Most relevant perfusion parameters confirmed valid ESLP with homogeneous lung perfusion, evidenced by uniform lung surface temperature. BGA showed temperature-dependent metabolic activities with differences depending on perfusion solution composition. COP is not decisive for pulmonary oedema and associated weight gain, but possibly rather observed chemokine profile and dextran sensitivity of rats. Histological examination confirmed intact lung architecture without infarcts or hemorrhages due to optimal organ procurement and single-lung application protocol using our in-house-designed ESLP system.