Search

Introduction and Objectives: Epigenetic changes represent a mechanism connecting external stresses with long-term modifications of gene expression programs. In solid organ transplantation, ischemia-reperfusion injury (IRI) appears to induce epigenomic changes in the graft, although the currently available data are extremely limited. The present study aimed to characterize variations in DNA methylation and their effects on the transcriptome in liver transplantation from brain-dead donors. Patients and Methods: 12 liver grafts were evaluated through serial biopsies at different timings in the procurement-transplantation process: T0 (warm procurement, in donor), T1 (bench surgery), and T2 (after reperfusion, in recipient). DNA methylation (DNAm) and transcriptome profiles of biopsies were analyzed using microarrays and RNAseq. Results: Significant variations in DNAm were identified, particularly between T2 and T0. Functional enrichment of the best 1000 ranked differentially methylated promoters demonstrated that 387 hypermethylated and 613 hypomethylated promoters were involved in spliceosomal assembly and response to biotic stimuli, and inflammatory immune responses, respectively. At the transcriptome level, T2 vs. T0 showed an upregulation of 337 and downregulation of 61 genes, collectively involved in TNF-α, NFKB, and interleukin signaling. Cell enrichment analysis individuates macrophages, monocytes, and neutrophils as the most significant tissue-cell type in the response. Conclusions: In the process of liver graft procurement-transplantation, IRI induces significant epigenetic changes that primarily act on the signaling pathways of inflammatory responses dependent on TNF-α, NFKB, and interleukins. Our DNAm datasets are the early IRI methylome literature and will serve as a launch point for studying the impact of epigenetic modification in IRI.

Background: Simultaneous pancreas-kidney transplantation (SPK) is an established therapy for diabetes mellitus (DM) patients with associated end stage renal disease. We report the initial results of SPK in our institution after qualification as transplantation program. Patients and methods: Between September 2017 and July 2018, we performed 3 SPK in type 1 diabetic patients with end-stage renal disease. All grafts were procured from brain-dead marginal donors according Pittsburg criteria. Results: The recipients were 2 men and 1 woman with a mean age of 43 ± 5.4 years. Mean time from DM diagnosis and time on dialysis were 25.7 ± 3.9 years and 19.7 ± 9.1 months. The mean age and HbA1C value of donor were 56.7 ± 0.5 years and 5.67 ± 0.05%. The pancreatic grafts were transplanted intraperitoneally in the right iliac fossa. Two patients required a relaparotomy due to arterial anastomotic hemorrhage and two patients developed acute cellular rejection. With a median follow-up of 13 (6–15) months, patient's and graft's survival rate were 100%. All patients showed HbA1C within normal range, but oral glucose tolerance test showed DM pattern in two patients at 3 months after transplantation. Conclusions: In our initial experience with SPK, mid-term grafts and patient survival appear comparable to the results reported in literature. Despite the limited availability of donors and the use of grafts from marginal donors, a quality pancreas transplantation program can be established even in a small-volume centers. Nonetheless further improvement in surgical techniques and meticulous management appear mandatory. Keywords: Simultaneous pancreas-kidney transplantation, Initial experience, Postoperative bleeding, Acute cellular rejection