Long-Term Outcomes of Everolimus Therapy in De Novo Liver Transplantation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

BACKGROUND: Risk of nephrotoxicity in liver transplant patients on calcineurin inhibitors (CnIs) is a concern. Several controlled trials reported benefit of everolimus (EVR) in minimizing this risk when combined with a reduced CnI dose. BACKGROUND: To systematically review the efficacy and safety of EVR, alone or with reduced CnI dose, as compared to CnI alone post-liver transplantation. METHODS: We searched MEDLINE, Scopus, and the Cochrane Library for randomized controlled trials comparing EVR- and CnI-based regimens post-liver transplantation. Assessment of studies and data extraction were undertaken independently. RESULTS: Eight studies were selected, describing 769 patients. Cockcroft-Gault GFR was higher at one (P = .05), 3, and 5 years (P = .030) in patients on EVR compared to those receiving CnI therapy. The composite endpoint of efficacy failure was similar between the 2 arms after 1, 3, and 5 years of study. More patients discontinued EVR due to adverse effects in 1 year; however, no difference was noted after 3 or 5 years. A higher rates of proteinuria, peripheral edema, and incisional hernia occurred in patients on EVR. CONCLUSIONS: The analysis confirms noninferiority of EVR and reduced CnI combination. Combination regimen resulted in better renal function compared to standard CnI therapy

Indocyanine green clearance reflects reperfusion injury following liver transplantation and is an early predictor of graft function

Background/Aims: Primary graft dysfunction is difficult to predict. We have previously shown that indocyanine green clearance measured at 24 h following orthotopic liver transplantation predicts graft survival and outcome. We prospectively evaluated the use of indocyanine green clearance (with a cut-off value of 200 ml/min) as a marker of graft function following orthotopic liver transplantation and investigated its relationship with the markers of reperfusion injury during orthotopic liver transplantation.Methods: In all patients indocyanine green clearance was measured at 24 h. Repeated blood samples were taken before, during the anhepatic and reperfusion phase and up to 12 h following orthotopic liver transplantation to measure the levels of neutrophil elastase and reactive oxygen intermediates. All patients studied had normal hepatic arterial pulse on Doppler-ultrasound post orthotopic liver transplantation.Results: All patients with indocyanine green clearance >200 ml/min recovered following orthotopic liver transplantation and remained well up to 3 months of follow up. Four patients had an indocyanine green clearance <200 ml/min; three were re-transplanted for graft failure within 3 days of the transplant, while one survived after prolonged intensive support and hospitalization. Indocyanine green clearance significantly correlated with reactive oxygen intermediates production and neutrophil elastase during orthotopic liver transplantation (r=-0.61, p<0.002 and r=-0.66, p<0.0009, respectively), Indocyanine green clearance was also significantly correlated,vith alanine aminotransferase and prothrombin time at 24 h post-transplantation (r=-0.35, p<0.02 and r=-0.4, p<0.0077, respectively).Conclusion: Indocyanine green reflects the degree of reperfusion injury and is a good early marker of primary graft function. Indocyanine green clearance over 200 ml/min is associated with favorable outcome

Hydrogen peroxide mobilizes Ca2+ through two distinct mechanisms in rat hepatocytes

AIM: Hydrogen peroxide (H(2)O(2)) is produced during liver transplantation. Ischemia/reperfusion induces oxidation and causes intracellular Ca(2+) overload, which harms liver cells. Our goal was to determine the precise mechanisms of these processes. METHODS: Hepatocytes were extracted from rats. Intracellular Ca(2+) concentrations ([Ca(2+)](i)), inner mitochondrial membrane potentials and NAD(P)H levels were measured using fluorescence imaging. Phospholipase C (PLC) activity was detected using exogenous PIP(2). ATP concentrations were measured using the luciferin-luciferase method. Patch-clamp recordings were performed to evaluate membrane currents. RESULTS: H(2)O(2) increased intracellular Ca(2+) concentrations ([Ca(2+)](i)) across two kinetic phases. A low concentration (400 μmol/L) of H(2)O(2) induced a sustained elevation of [Ca(2+)](i) that was reversed by removing extracellular Ca(2+). H(2)O(2) increased membrane currents consistent with intracellular ATP concentrations. The non-selective ATP-sensitive cation channel blocker amiloride inhibited H(2)O(2)-induced membrane current increases and [Ca(2+)](i) elevation. A high concentration (1 mmol/L) of H(2)O(2) induced an additional transient elevation of [Ca(2+)](i), which was abolished by the specific PLC blocker U73122 but was not eliminated by removal of extracellular Ca(2+). PLC activity was increased by 1 mmol/L H(2)O(2) but not by 400 μmol/L H(2)O(2). CONCLUSION: H(2)O(2) mobilizes Ca(2+) through two distinct mechanisms. In one, 400 μmol/L H(2)O(2)-induced sustained [Ca(2+)](i) elevation is mediated via a Ca(2+) influx mechanism, under which H(2)O(2) impairs mitochondrial function via oxidative stress, reduces intracellular ATP production, and in turn opens ATP-sensitive, non-specific cation channels, leading to Ca(2+) influx. In contrast, 1 mmol/L H(2)O(2)-induced transient elevation of [Ca(2+)](i) is mediated via activation of the PLC signaling pathway and subsequently, by mobilization of Ca(2+) from intracellular Ca(2+) stores