Use of donation after circulatory death (DCD) donor livers for transplantation has remained cautious in the United States. The aim of this study was to demonstrate the expansion of a DCD liver transplantation (LT) program with the use of extended criteria donor (ECD) DCD livers. After institutional review board approval, 135 consecutive DCD LTs were retrospectively studied. ECD DCD livers were defined as those with 1 of the following factors: donor age >50 years, donor body mass index >35 kg/m2, donor functional warm ischemia time >30 minutes, and donor liver macrosteatosis >30%. An optimization protocol was introduced in July 2011 to improve outcomes of DCD LT, which included thrombolytic donor flush and efforts to minimize ischemia times. The impact of this protocol on outcomes was evaluated in terms of graft loss, ischemic cholangiopathy (IC), and change in DCD LT volume. Of 135 consecutive DCD LTs, 62 were ECD DCDs. In total, 24 ECD DCD LTs were performed before (era 1) and 38 after the institution of optimization protocol (era 2), accounting for an increase in the use of ECD DCD livers from 39% to 52%. Overall outcomes of ECD DCD LT improved in era 2, with a significantly lower incidence of IC (5% versus 17% in era 1; P = 0.03) and better 1‐year graft survival (93% versus 75% in era 1; P = 0.07). Survival outcomes for ECD DCD LT in era 2 were comparable to matched deceased donor LT. With the expansion of the DCD donor pool, the number of DCD LTs performed at our center gradually increased in era 2 to account for >20% of the center's LT volume. In conclusion, with the optimization of perioperative conditions, ECD DCD livers can be successfully transplanted to expand the donor pool for LT.
Formation of de novo donor-specific antibodies (dn-DSAs) has been associated with longterm immunologic complications after liver transplantation (LT). We hypothesized that human leukocyte antigen (HLA) epitope/eplet mismatch (MM) is a marker of immunogenicity and a risk factor for dn-DSA formation. Sera from 80 LT recipients were prospectively screened for dn-DSA by a Luminex single-antigen test (One Lambda, Inc., Canoga Park, CA) at 1, 2, 3, 6, 12, 18, 24, and 36 months after LT. HLA typing of the recipients and donors was performed using polymerase chain reaction (PCR)-SSP and PCR-SSOP Luminex low-resolution methods (One Lambda, Inc.). The HLAMatchmaker computer algorithm was used for identification of MM eplets at HLA-DRB1 and -DQA1/B1 loci. Luminex single-antigen bead solid phase assay was used for antibody analysis. Standard immunosuppression included thymoglobulin-rituximab induction and tacrolimus maintenance. There were 27 (34%) patients who developed dn-DSA. There were no episodes of antibody-mediated rejection, and 9 (11%) developed acute cellular rejection (ACR). A positive crossmatch status and a higher number of HLA-A, -B, -DR, and -ABDR MMs were not associated with dn-DSA formation. Patients developing dn-DSA had a significantly higher number of total (38 ± 2.7 versus 28 ± 2.3; P = 0.01) and antibody-verified (AbVer; 14 ± 1.1 versus 10 ± 1; P = 0.015) class II MM eplets. By a multivariate regression analysis, the number of class II MM eplets was strongly associated with risk of class II dn-DSA formation (odds ratio [OR], 1.2; P < 0.01). Patients with ACR had a significantly higher number of total (20.2 ± 1.3 versus 13.9 ± 0.9; P < 0.01) as well as AbVer (10.7 ± 1.1 versus 7.5 ± 0.6; P = 0.03) class I MM eplets. In conclusion, donor-recipient HLA epitope MM is associated with a risk of dn-DSA formation and rejection after LT. However, further studies are required to evaluate the clinical utility of epitope matching in LT.
The vagus nerve provides motor, sensory, and autonomic innervation of multiple organs, and electrical vagus nerve stimulation (VNS) provides an adjunctive treatment option for e.g. medication-refractory epilepsy and treatment-resistant depression. The mechanisms of action for VNS are not known, and high-resolution anatomical mapping of the human vagus nerve is needed to better understand its functional organization. Electron microscopy (EM) is required for the detection of both myelinated and unmyelinated axons, but access to well-preserved human vagus nerves for ultrastructural studies is sparse. Intact human vagus nerve samples were procured intra-operatively from deceased organ donors, and tissues were immediately immersion fixed and processed for EM. Ultrastructural studies of cervical and sub-diaphragmatic vagus nerve segments showed excellent preservation of the lamellated wall of myelin sheaths, and the axolemma of myelinated and unmyelinated fibers were intact. Microtubules, neurofilaments, and mitochondria were readily identified in the axoplasm, and the ultrastructural integrity of Schwann cell nuclei, Remak bundles, and basal lamina was also well preserved. Digital segmentation of myelinated and unmyelinated axons allowed for determination of fiber size and myelination. We propose a novel source of human vagus nerve tissues for detailed ultrastructural studies and mapping to support efforts to refine neuromodulation strategies, including VNS.
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