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Background: Survival of kidney transplant recipients (KTR) is low compared with the general population. Low muscle mass and muscle strength may contribute to lower survival, but practical measures of muscle status suitable for routine care have not been evaluated for their association with long-term survival and their relation with each other in a large cohort of KTR. Methods: Data of outpatient KTR ≥ 1 year post-transplantation, included in the TransplantLines Biobank and Cohort Study (ClinicalTrials.gov Identifier: NCT03272841), were used. Muscle mass was determined as appendicular skeletal muscle mass indexed for height2 (ASMI) through bio-electrical impedance analysis (BIA), and by 24-h urinary creatinine excretion rate indexed for height2 (CERI). Muscle strength was determined by hand grip strength indexed for height2 (HGSI). Secondary analyses were performed using parameters not indexed for height2. Cox proportional hazards models were used to investigate the associations between muscle mass and muscle strength and all-cause mortality, both in univariable and multivariable models with adjustment for potential confounders, including age, sex, body mass index (BMI), estimated glomerular filtration rate (eGFR) and proteinuria. Results: We included 741 KTR (62% male, age 55 ± 13 years, BMI 27.3 ± 4.6 kg/m2), of which 62 (8%) died during a median [interquartile range] follow-up of 3.0 [2.3–5.7] years. Compared with patients who survived, patients who died had similar ASMI (7.0 ± 1.0 vs. 7.0 ± 1.0 kg/m2; P = 0.57), lower CERI (4.2 ± 1.1 vs. 3.5 ± 0.9 mmol/24 h/m2; P < 0.001) and lower HGSI (12.6 ± 3.3 vs. 10.4 ± 2.8 kg/m2; P < 0.001). We observed no association between ASMI and all-cause mortality (HR 0.93 per SD increase; 95% confidence interval [CI] [0.72, 1.19]; P = 0.54), whereas CERI and HGSI were significantly

Background: RNA interference (RNAi) is a natural gene modulation process that was recently approved for clinical use and has great potential for treatment of many pathological conditions. The surface receptor FAS and tumor suppressor p53 are implicated in ischemic liver damage. Both may be silenced via RNAi with limited off-target effects. We determined the efficiency of FAS siRNA delivery with lipid nanoparticles during normothermic (37°C) and hypothermic (4°C) ex vivo machine perfusion. We also show silencing p53 via siRNA reduces inflammation and caspase expression during liver ischemia. Methods: Rat portal veins were cannulated (Fig. 1A) and perfused at 10mmHg on a closed-loop pump circuit regulated by circulating water bath (Fig. 1B). Controls were perfused with Williams E+10U insulin and lipid nanoparticles (Fig. 1C). Normothermic livers were perfused with medium plus nanoparticle/FAS-siRNA complex with 3‘-AlexaFluor-555 modification at 37°C. Hypothermic livers were perfused similarly at 4°C. Biopsies were collected at 4 hours, formalin fixed, stained, then imaged with confocal microscopy. For p53 studies, siRNA was delivered 24 hours before hilum clamping. Tissue/blood was collected 3 days after siRNA injection. Results: Compared to empty vector controls (Fig. 2A-D), normothermic (Fig. 2E-H) and hypothermic livers (Fig. 2I-L) perfused with FAS siRNA demonstrate diffuse uptake in sinusoids and surrounding central veins. SiRNA is observed together in sinusoid membranes and in hepatocyte cytoplasm. Livers pretreated with p53 siRNA showed reduced cellular infiltration, vacuolization, and fewer caspase-3 positive cells. Conclusions: By incorporating RNAi into preservation solutions or delivering before procurement, we may reliably improve the quality of livers during the ischemic period. It will be important to determine the ideal perfusion temperature. Further studies will quantify uptake with peptide-nucleic acid hybridization at both perfusion temperatures and

Background: The major concern in liver transplantation of grafts from donation after circulatory death (DCD) donors remains the high incidence of non-anastomotic biliary strictures (NAS). Machine perfusion has been proposed as an alternative strategy for organ preservation which reduces ischemia-reperfusion injury (IRI). Experimental studies have shown that dual hypothermic oxygenated machine perfusion (DHOPE) is associated with less IRI, improved hepatocellular function, and better preserved mitochondrial and endothelial function compared to conventional static cold storage (SCS). Moreover, DHOPE was safely applied with promising results in a recently performed phase-1 study. The aim of the current study is to determine the efficacy of DHOPE in reducing the incidence of NAS after DCD liver transplantation. Methods: This is an international multicenter randomized controlled trial. Adult patients (≥18 yrs. old) undergoing transplantation of a DCD donor liver (Maastricht category III) will be randomized between the intervention and control group. In the intervention group, livers will be subjected to two hours of end-ischemic DHOPE after SCS and before implantation. In the control group, livers will be subjected to care as usual with conventional SCS only. Primary outcome is the incidence of symptomatic NAS diagnosed by a blinded adjudication committee. In all patients, magnetic resonance cholangiography will be obtained at six months after transplantation. Discussion: DHOPE is associated with reduced IRI of the bile ducts. Whether reduced IRI of the bile ducts leads to lower incidence of NAS after DCD liver transplantation can only be examined in a randomized controlled trial. Trial registration: The trial was registered in Clinicaltrials.gov in September 2015 with the identifier NCT02584283.