Lower tacrolimus trough levels in the late period after living donor liver transplantation contribute to improvements in long-term clinical outcomes.

BACKGROUND: Previous studies have emphasized the need to reduce tacrolimus (TAC) trough levels in the early post-liver transplantation (LT) period. However, whether late-period TAC trough levels influence the long-term outcomes of liver recipients is not clear. METHODS: We enrolled 155 adult liver recipients survived more than 3 years after living donor liver transplantation because of non-malignant liver diseases. The maintenance immunosuppressive regimens were TAC monotherapy and combined therapy with mycophenolate mofetil. Patients were divided into three groups according to their late-period TAC trough levels: < 3 ng/mL group, 3-5 ng/mL group, and  >5 ng/mL group. The complications and adverse effects of TAC were analyzed. RESULTS: Each group showed similar rejection, graft loss and mortality. Patients achieved the < 5 ng/mL state in less than 4 years had fewer new-onset diabetes, hyperlipidemia, de novo malignancies, and hepatitis B virus recurrence; the complications of renal dysfunction and hypertension rates were the same among these 3 groups. CONCLUSIONS: Collectively, our findings indicated that lower TAC trough levels in the late period of liver transplantation are safe, improve the long-term outcomes.

Role of [18F] fludeoxyglucose positron emission tomography in the selection of liver transplantation candidates in patients with hepatocellular carcinoma.

BACKGROUND: The Milan criteria are widely accepted among many centers. However, patients with hepatocellular carcinoma beyond the Milan criteria might still benefit from liver transplantation (LT) when tumor itself is not aggressive. [18F] fluorodeoxyglucose positron emission tomography/computed tomography imaging could provide useful information of tumor behaviors, which is helpful to predict the prognosis for many tumors. METHOD: In order to determine its role in candidate selection for LT, we therefore retrospectively analyzed 103 recipients with preoperative positron emission tomography (PET) findings. RESULTS: Positive PET findings (PET+) were significantly associated with tumor nodule numbers (P=0.013), tumor grade (P=0.025), macro- (P=0.002) and micro-vascular invasion (P=0.002), as well as the Milan criteria (P=0.018). PET+ patients had significantly increased risk of tumor recurrence post-LT compared to PET negative (PET-) patients (P=0.007). The 1-, 3-, and 5-year overall survival rate of PET- patients were 96.0%, 87.2% and 76.2%, compared to 74.7%, 55.4% and 49.9% in PET+ patients, respectively (P<0.05). The 1-, 3-, and 5-year recurrence-free survival rate of PET- patients were 91.8%, 81.9% and 76.0%, compared to 70.1%, 39.3% and 21.9% in PET+ patients, respectively (P<0.05). Recipients within the Milan criteria showed comparable 1-, 3-, and 5-year survival rates in comparison with those beyond the Milan criteria with a PET- findings (1-, 3-, and 5-year overall survival rates, 97.5%, 83.3%, and 83.3% vs 90.0%, 80.0%, and 66.7%, P= 0.123; 1-, 3-, and 5-year recurrence-free survival rates, 95.1%, 73.1%, and 73.1% vs 90.0%, 78.8%, and 65.6%, P=0.148). CONCLUSIONS: Certain patients with hepatocellular carcinoma and negative PET findings, who have exceeded the Milan criteria, are also eligible candidates for LT. Preoperative PET/CT imaging is an important marker, which should be incorporated in extended candidate selection criteria for LT.

Anti-virus prophylaxis withdrawal may be feasible in liver transplant recipients whose serum HBeAg and HBV DNA are negative.

Anti-virus prophylactic therapy may be not necessary for the prevention of hepatitis B virus (HBV) recurrence after HBV-related liver transplantation (LT). However, studies on completely stopping the hepatitis B immune globulin (HBIG) and nucleos(t)ide analogs (NUC) after LT are few. The aim of the current study was to evaluate the safety of anti-virus prophylaxis withdrawal in liver recipients whose serum hepatitis B e antigen (HBeAg) and HBV DNA are negative. We analyzed 190 patients undergone LT for HBV-related liver disease from 2006 to 2012 and found that 10 patients completely stopped the HBIG and NUC due to poor compliance. These patients were liver biopsied and checked monthly with serum HBV markers, HBV DNA and liver function. Among the 10 patients, 9 did not show the signs of HBV recurrence after a mean follow-up of 51.6 months (range 20-73) after withdrawal of the HBIG and NUC. The average time from LT to the withdrawal of the anti-virus drug was 23.8 (13-42) months; one patient showed hepatitis B surface antigen-positive and detectable HBV DNA after stopping anti-virus drugs and this patient was successfully treated with entecavir. Our data suggested that complete withdrawal of anti-virus prophylaxis was safe and feasible for patients whose serum HBeAg and HBV DNA were negative at the time of LT.

''Minimizing tacrolimus'' strategy and long-term survival after liver transplantation.

AIM: To investigate the effect of the ''minimizing tacrolimus'' strategy on long-term survival of patients after liver transplantation (LT). METHODS: We conducted a retrospective study of 319 patients who received LT between January 2009 and December 2011 at the First Affiliated Hospital of Zhejiang University School of Medicine. Following elimination of ineligible patients, 235 patients were included in the study. The relationship between early tacrolimus (TAC) exposure and survival period was analyzed by Kaplan Meier curves. Adverse effects related to TAC were evaluated by the χ(2) test. Routine monitoring of blood TAC concentration (TC) was performed using the PRO-Trac(TM) II Tacrolimus Elisa Kit (Diasorin, United States). RESULTS: Of 235 subjects enrolled in the study, 124 (52.8%) experienced adverse effects due to TAC. When evaluating mean TC, the survival time of patients with a mean TC < 5 ng/mL was significantly shorter than that in the other groups (911.3 ± 131.6 d vs 1381.1 ± 66.1 d, 911.3 ± 131.6 d vs 1327.3 ± 47.8 d, 911.3 ± 131.6 d vs 1343.2 ± 83.1 d, P < 0.05), while the survival times of patients with a mean TC of 5-7, 7-10 and 10-15 ng/mL were comparable. Adverse effects due to TAC in all four groups were not significantly different. When comparing the standard deviation (SD) of TC among the groups, the survival time of patients with a SD of 2-4 was significantly longer than that in the other groups (1388.8 ± 45.4 d vs 1029.6 ± 131.3 d, 1388.8 ± 45.4 d vs 1274.9 ± 57.0 d, P < 0.05), while in patients with a SD < 2 and SD > 4, the survival time was not statistically different. Adverse effects experienced in all three groups were not statistically different. In Cox regression analysis, male patients and those with a primary diagnosis of benign disease, mean TC > 5 ng/mL and TC SD 2-4 had better outcomes. CONCLUSION: The early ''minimizing tacrolimus'' strategy with a mean TC of 5-10 ng/mL and SD of 2-4 was beneficial in terms of long-term survival after LT.

Kupffer cells contribute to concanavalin A-induced hepatic injury through a Th1 but not Th17 type response-dependent pathway in mice.

BACKGROUND: Increasing evidence suggests that a close interaction of Kupffer cells with T cells plays a central role in concanavalin A-induced hepatic injury in mice, but the underlying mechanisms remain obscure. The present study aimed to determine the relative roles of Th1 and Th17 type responses in concanavalin A-induced hepatic injury in mice, and to investigate whether or not Kupffer cells contribute to hepatic injury via a Th1 or Th17 type response-dependent pathway. METHODS: Immune-mediated hepatic injury was induced in C57BL/6 mice by intravenous injection of concanavalin A. Kupffer cells were inactivated by pretreatment with gadolinium chloride 24 hours before the concanavalin A injection. The interferon-gamma (IFN-gamma) and interleukin-17 (IL-17) pathways were blocked by specific neutralizing antibodies. Hepatic injury was assessed using serum transferase activity and pathological analysis. Expression of inflammatory cytokines within the liver was detected by real-time polymerase chain reaction and immunohistochemistry. RESULTS: Neutralization of IFN-gamma significantly attenuated concanavalin A-induced hepatic injury. However, neutralization of IL-17 failed to suppress the injury. Inactivation of Kupffer cells by gadolinium chloride pretreatment protected against concanavalin A-induced injury and significantly reduced hepatic cytokine levels including TNF-alpha, IL-6 and IFN-gamma but not IL-17. CONCLUSION: Our findings suggest that Kupffer cells contribute to concanavalin A-induced hepatic injury via a Th1 type response-dependent pathway and production of inflammatory cytokines including TNF-alpha, IL-6 and IFN-gamma.

Th17 promotes acute rejection following liver transplantation in rats.

T help cell 17 (Th17), recently identified as a new subset of CD4(+) T cells, has been implicated in autoimmune diseases, tumor immunity, and transplant rejection. To investigate the role of Th17 in acute hepatic rejection, a rat model of allogeneic liver transplantation (Dark Agouti (DA) to Brown Norway (BN)) was established and isogeneic liver transplantation (BN to BN) was used as controls in the study. The expression of Th17-related cytokines in the liver and peripheral blood was determined by immunohistochemistry, flow cytometry, enzyme-linked immunosorbent assay (ELISA), or real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Strong expression of interleukin-17A (IL-17A), IL-6, transforming growth factor-ß (TGF-ß), IL-8, and myeloperoxidase (MPO) was observed in liver allografts. The ratios of Th17 to CD4(+) lymphocytes in the liver and peripheral blood were dramatically increased in the allograft group compared with the control (P<0.01). Secreted IL-17 and IL-6 in liver homogenate and serum were significantly elevated in the allograft group, while secreted TGF-ß was increased in liver homogenate and decreased in serum compared with the control (P<0.01). The messenger RNA (mRNA) levels of IL-17, IL-21, and IL-23 were enhanced in the allografts compared with the control (P<0.01). Correlation analysis showed significant correlations between IL-17 and IL-6 and TGF-ß and between IL-17 and IL-21 and IL-23. The present study demonstrates that Th17 plays a role in promoting rat liver allograft rejection.