Effective immunosupression management is central to achieving optimal outcomes in liver transplant recipients. Current immunosuppression regimens and agents are highly effective in minimizing graft loss due to acute and chronic rejection but can also produce a substantial array of toxicities. The utilization of immunosuppression varies widely, contributing to the wide disparities in posttransplant outcomes reported between transplant centers. The International Liver Transplantation Society (ILTS) convened a consensus conference, comprised of a global panel of expert hepatologists, transplant surgeons, nephrologists, and pharmacologists to review the literature and experience pertaining to immunosuppression management to develop guidelines on key aspects of immunosuppression. The consensus findings and recommendations of the ILTS Consensus guidelines on immunosuppression in liver transplant recipients are presented in this article.

The 6-minute walk distance (6MWD) is a simple test measuring global physical function. It is commonly used to predict mortality in patients with cardiac and pulmonary diseases, but it is also useful in assessing the functional status of patients with a variety of other medical conditions. We sought to determine (1) the characteristics of the 6MWD in patients listed for liver transplantation (LT), (2) the existence of a relationship between the 6MWD and the quality of life, and (3) the relationship between the 6MWD and survival in LT candidates. The 6MWD was prospectively measured in all patients listed for LT. The 6MWD was determined when the listed Model for End-Stage Liver Disease (MELD) score was !15. Patients were followed until LT, death, removal from the wait list, or the end of the study period. Quality of life was assessed with the Short Form 36 (SF-36). In 121 patients, the mean 6MWD was 369 6 122 m; it was not related to age, height, weight, body mass index, albumin level, or etiology of liver disease and showed a moderate correlation with the physical component score (PCS) on the SF-36 (r ¼ 0.4) and a moderate inverse correlation with the native MELD score (r ¼ À0.61). In an unadjusted analysis, a high native MELD score, a low 6MWD, and a low PCS were associated with mortality, with only the 6MWD retaining significance after adjustment for covariates. Each 100-m increase in the 6MWD was significantly associated with increased survival (hazard ratio ¼ 0.48, P ¼ 0.0001), with 6MWD < 250 m being associated with an increased risk of death (P ¼ 0.0001). In conclusion, the 6MWD is significantly reduced in patients awaiting LT and is inversely correlated with the native MELD score. A pretransplant 6MWD < 250 m is a risk for death on the wait list. Liver Transpl 16:1373-1378, 2010. V C 2010 AASLD.Received May 24, 2010; accepted July 30, 2010.The 6-minute walk distance (6MWD) is a simple and practical test that evaluates the global and integrated responses of all the systems involved in exercise: cardiopulmonary systems, systemic and peripheral circulation, neuromuscular function, and muscle metabolism. It is not an exertional test and does not measure specific information for each organ system. However, because most activities of daily living are performed at submaximal levels of exertion, it is felt to better reflect the functional exercise level for daily physical activities. The 6MWD predicts mortality in patients with heart failure, chronic obstructive pulmonary disease, or pulmonary hypertension and in candidates for lung transplantation.

Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

Treatment with an all-oral interferon-free antiviral regimen using simeprevir and sofosbuvir with or without ribavirin (RBV) for 12 weeks resulted in high sustained virologic response (SVR) rates along with minimal adverse events in non-liver transplant (LT) patients with hepatitis C virus (HCV) genotype 1 infection. This is the first multicenter report on the efficacy, safety, and tolerability of this regimen in LT recipients. A total of 123 patients (76% male, 74% white, 60% genotype 1a, 30% METAVIR F3-F4, 4% decompensation, 11% cholestatic recurrence, 7% had kidney transplant, and 82% previously failed pegylated interferon/RBV-based regimens) received treatment and were followed for a median of 30 weeks (range 12-53 weeks). The median time from LT to treatment was 32 months (range 2-317 months). Tacrolimus was the primary immunosuppression in 91% of patients. Minimal immunosuppression dose adjustments were required. An SVR 12 weeks after treatment completion (SVR12) was achieved in 90% of patients (95% confidence interval 84%-96%). In patients with genotype 1a infection, the SVR12 rate was significantly lower in those with METAVIR F3-F4 (71%) compared to those with F0-F2 (91%). Half of the patients achieved undetected HCV RNA at treatment week 4, and their SVR12 rate was significantly higher (96%) compared to those with detectable HCV RNA (83%). Treatment was very well tolerated with mild degrees of adverse events, except for one death possibly due to drug-induced lung injury. In the 25 patients who received RBV, 72% developed anemia requiring intervention. Conclusion: An all-oral interferon-free antiviral regimen using simeprevir and sofosbuvir with or without RBV for 12 weeks was very well tolerated and resulted in excellent SVR12 rates in LT recipients with HCV genotype 1 infection. (HEPATOLOGY 2015;61:1880-1886 H epatitis C viral (HCV) infection is the leading indication for liver transplant (LT) worldwide. Recurrence of HCV is universal among recipients with viremia at the time of transplant and occurs immediately after LT. 1,2 Although the clinical course of HCV recurrence is variable, severe histological recurrence is the most common cause of graft loss and death, which accounts for approximately 60% of graft losses and nearly 50% of deaths by 10 years after LT. 3,4 Liver allograft and recipient survival can be substantially improved with successful eradication of HCV. 5,6 Treatment with pegylated interferon (Peg-IFN) and ribavirin (RBV) was not effective and poorly tolerated in the post-LT setting, with reported sustained virologic response (SVR) rates ranging 24%-45% for patients with HCV genotype 1. 7,8 The combination of direct-acting antiviral agents, in the form of a firstgeneration protease inhibitor (PI), telaprevir or boceprevir, with Peg-IFN and RBV improved SVR rates to