Normothermic ex situ liver perfusion (NEsLP) offers the opportunity to assess biomarkers of graft function and injury. We investigated NEsLP parameters (biomarkers and markers) for the assessment of liver viability in a porcine transplantation model. Grafts from heart‐beating donors (HBD), and from donors with 30 minutes (donation after cardiac death [DCD]30′), 70 minutes (DCD70′), and 120 minutes (DCD120′) of warm ischemia were studied. The HBD, DCD30′, and DCD70′‐groups had 100% survival. In contrast, 70% developed primary nonfunction (PNF) and died in the DCD120′‐group. Hepatocellular function during NEsLP showed low lactate (≤1.1 mmol/L) in all the groups except the DCD120′‐group (>2 mmol/L) at 4 hours of perfusion (P = .04). The fold‐urea increase was significantly lower in the DCD120′‐group (≤0.4) compared to the other groups (≥0.65) (P = .01). As for cholangiocyte function, bile/perfusate glucose ratio was significantly lower (<0.6) in all the groups except the DCD120′‐group (≥0.9) after 3 hours of perfusion (<0.01). Bile/perfusate Na+ ratio was significantly higher (≥1.2) after 3 hours of perfusion in all the groups except for the DCD120′‐group (≤1) (P < .01). Three hours after transplantation, the DCD120′‐group had a significantly higher international normalized ratio (>5) compared to the rest of the groups (≤1.9) (P = .02). Rocuronium levels were higher at all the time‐points in the animals that developed PNF during NEsLP and after transplantation. This study demonstrates that biomarkers and markers of hepatocellular and cholangiocyte function during NEsLP correlate with the degree of ischemic injury and posttransplant function.

The prevalence of obesity in the United States and the world is increasing to unprecedented levels. Obesity is defined as a body mass index (BMI) ≥30 kg/m 2 , severe obesity as a BMI ≥35 kg/m 2 , and extreme obesity as ≥40 kg/m 2 . 1 In 2015-2016, approximately 93.3 million or 39.8% of the USA adult population was obese, and by 2030 this is estimated to increase to more than 50%. 2 Obesity is also increasing in the dialysis and renal transplant population; the proportion of patients undergoing kidney transplantation who are obese (BMI ≥30 kg/m 2 ) is currently 60%. 3 This increased prevalence of obesity has posed new challenges to accessing, delivering, and maintaining optimal care of patients with chronic kidney disease, including those treated with hemodialysis (HD), peritoneal dialysis (PD), and kidney transplant. [3][4][5][6] Obesity is associated with a multitude of complications in the transplant recipient including delayed graft function, acute rejection, wound complications, prolonged hospitalization, new onset diabetes mellitus, cardiovascular complications, [7][8][9] and reduced graft survival. 4-6,10-17 Recognition of these associated complications has led many centers to limit transplant candidacy at a BMI of 35-40 kg/m 2 . Singularly, obesity has become a major obstacle to life-saving kidney transplant and is the third-most common reason for patients to be inactive on the kidney transplant waitlist. 18In this review, we discuss the morbidity associated with obesity and strategies to prevent and manage these complications, as well as medical and surgical treatment of obesity in the end-stage kidney disease (ESKD) population. | THE OB E S IT Y PAR ADOXParadoxically, obesity has been associated with increased survival in the HD population, while a normal or low BMI has been associated with worse outcomes. 19,20 In a meta-analysis of over 190 000 patients, obese patients were 34% less likely to die than those of normal BMI, 21 while the lowest all-cause and cardiovascular mortality was associated with a BMI of 40-45 kg/m 2 . 22 Multiple theories have been proposed to explain the 'obesity paradox'. First and foremost, it remains unclear that this represents a true 'cause and effect' relationship. Rather, this may reflect confounding by comorbid illness and/or inflammation, or survivor bias, that obese patients reaching ESKD are a highly atypical subgroup of the general obese population, most of which has died before reaching ESKD. This may also be a result of competing risks that the dialysis patient does not survive long enough for the increase in cardiovascular and other disease processes that are directly caused by obesity to manifest. 20,[23][24][25][26][27][28][29][30]

Background. Normothermic ex situ liver perfusion (NEsLP) reduces reperfusion injury of donation after circulatory death (DCD) grafts and optimizes graft function. The goal of our study was to elucidate how NEsLP impacts global metabolism in DCD grafts using high-throughput metabolomics. Methods. Pig livers were preserved by 2 different techniques: static cold storage and NEsLP. Grafts obtained from heart-beating donors were compared with donation after circulatory death (DCD) grafts with either 30 minutes (DCD30) or 60 minutes (DCD60) ischemia time. Liver tissues were collected at the end of preservation period (T0) with either cold storage or NEsLP (n = 5 per group). Grafts were transplanted into recipient pigs and a second liver biopsy was collected 2 hours following liver transplantation (T1). Snap-frozen tissue was processed and analyzed by Sciex 6600 Q-TOF high-resolution mass spectrometer. Data analysis was performed using MetaboAnalyst 4.0 software. Results. Prolonged ischemia resulted in 38 out of 81 metabolites being differentially abundant over time. Mitochondrial metabolism was significantly affected, with disruption in oxidative phosphorylation capacity i.e the Warburg effect (P = 3.62E-03) and urea cycle (P = 7.95E-0.4). NEsLP resulted in improved mitochondrial metabolism and glycolysis (4.20E-02) oxidation of branched chain fatty acids (P = 4.07E-02). Conclusions. This unbiased, high-throughput metabolomics study reveals that mitochondrial function is globally rescued with NEsLP, associated with improvement in DCD graft function. NEsLP is able to rescue DCD grafts, improving their metabolic function to that of livers not exposed to DCD procurement.