Comparison of alternative arterial anastomosis site during liver transplantation when the recipient's hepatic artery is unusable.

Background: Few studies have analyzed outcomes of liver transplantation (LT) when the recipient hepatic artery (HA) was not usable. Methods: We retrospectively evaluated the outcomes of LT performed using the different alternative sites to HA. Results: Between 2002 and 2017, 1,677 LT were performed in our institution among which 141 (8.4%) with unusable recipient HA were analyzed. Four groups were defined according to the site of anastomosis: the splenic artery (SA group, n=26), coeliac trunk (CT group, n=12), aorta using or not the donor's vessel (Ao group, n=91) and aorta using a vascular prosthesis (Ao-P group, n=12) as conduit. The median number of intraoperative red blood cell transfusions was significantly increased in the Ao and Ao-P groups (5, 5, 8.5 and 16 for SA, CT, Ao and Ao-P group respectively, P=0.002), as well as fresh frozen plasma (4.5, 2.5, 10, 17 for the SA, CT, Ao and Ao-P groups respectively, P=0.001). Hospitalization duration was also significantly increased in the Ao and Ao-P groups (15, 16, 24, 26.5 days for the SA, CT, Ao and Ao-P groups respectively, P<0.001). The occurrence of early allograft dysfunction (EAD) (P=0.07) or arterial complications (P=0.26) was not statistically different. Level of factor V, INR, bilirubin and creatinine during the 7th postoperative days (POD) was significantly improved in the SA group. No difference was observed regarding graft (P=0.18) and patient (P=0.16) survival. Conclusions: In case of unusable HA, intraoperative and postoperative outcomes are improved when using the SA or CT compared to aorta.

Hypothermic Oxygenated Perfusion Improves Extended Criteria Donor Liver Graft Function and Reduces Duration of Hospitalization Without Extra Cost: The PERPHO Study.

Few studies have evaluated the efficacy or the cost of hypothermic oxygenated perfusion (HOPE) in the conservation of extended criteria donor (ECD) grafts from donation after brain death (DBD) donors during liver transplantation (LT). We performed a prospective, monocentric study (NCT03376074) designed to evaluate the interest of HOPE for ECD-DBD grafts. For comparison, a control group was selected after propensity score matching among patients who received transplants between 2010 and 2017. Between February and November 2018, the HOPE procedure was used in 25 LTs. Immediately after LT, the median aspartate aminotransferase (AST) level was significantly lower in the HOPE group (724UI versus 1284UI; P = 0.046) as were the alanine aminotransferase (ALT; 392UI versus 720UI; P = 0.01), lactate (2.2 versus 2.7; P = 0.01) There was a significant reduction in intensive care unit stay (3 versus 5 days; P = 0.01) and hospitalization (15 versus 20 days; P = 0.01). The incidence of early allograft dysfunction (EAD; 28% versus 42%; P = 0.22) was similar . A level of AST or ALT in perfusate >800UI was found to be highly predictive of EAD occurrence (areas under the curve, 0.92 and 0.91, respectively). The 12-month graft (88% versus 89.5%; P = 1.00) and patient survival rates (91% versus 91.3%; P = 1.00) were similar. The additional cost of HOPE was estimated at € 5298 per patient. The difference between costs and revenues, from the hospital's perspective, was not different between the HOPE and control groups (respectively, € 3023 versus € 4059]; IC, -€ 5470 and € 8652). HOPE may improve ECD graft function and reduce hospitalization stay without extra cost. These results must be confirmed in a randomized trial.

Tacrolimus Concentrations Measured in Excreted Bile in Liver Transplant Recipients: The STABILE Study.

PURPOSE: Tacrolimus (TAC) is the main immunosuppressive drug in liver transplantation. Despite intensive therapeutic drug monitoring (TDM) that relies on whole blood trough concentration (TACblood), patients still present with acute cellular rejection or TAC-related toxic effects with concentrations within the therapeutic range. TAC concentration in peripheral blood mononuclear cells (TACPBMC) is considered as an efficient surrogate marker of TAC efficacy. However, it is still not applicable in daily practice. New TDM methods are therefore needed, especially during the early postoperative period. TAC is metabolized in the liver and eliminated through biliary excretion. We therefore hypothesised that TAC concentration measured in excreted bile (TACbileC) could be a relevant surrogate marker of its efficacy. METHODS: The Therapeutic Drug Monitoring of Tacrolimus Biliary Concentrations for Liver-Transplanted Patients (STABILE) study is a prospective monocentric trial. During the 7 first days after TAC therapy initiation, TACbileC was measured. The correlation between TACbileC and TACPBMC as well as between TACblood and TACPBMC was assessed. The correlations between TACbileC and liver graft function parameter or with occurrence of neurologic toxic effects were also evaluated. FINDINGS: Between May 2016 and April 2017, 41 patients were analyzed. TACbileC was significantly correlated with TACPBMC (r = 0.25, P = 0.007). However, a better correlation was found between TACPBMC and TACblood (r = 0.53, P < 0.001) and was confirmed in multivariate analysis. However, only TACbileC was significantly correlated with liver graft function, such as factor V (r = 0.40, P = 0.009) or bilirubin level (r = 0.21, P = 0.01), and significantly lower in patients presenting with neurologic toxic effects (P < 0.001). Receiver operating characteristic curve analysis found that a TACbileC level lower than 0.20 ng/mL on day 2 after TAC therapy initiation was a good predictive marker of occurrence of neurotoxic effects (AUC = 0.81). IMPLICATIONS: TACbileC is not a better surrogate maker of TAC activity than TACblood. However, TACbileC could help predict the occurrence of TAC toxic effects when a T-tube is inserted. ClinicalTrials.gov identifier: NCT02820259.

High Intrapatient Variability of Tacrolimus Exposure in the Early Period After Liver Transplantation Is Associated With Poorer Outcomes.

BACKGROUND: Tacrolimus (TAC) is the cornerstone of immunosuppressive regimen in liver transplantation (LT). Its pharmacokinetics is characterized by a high interpatient and intrapatient variability (IPV) leading to an unpredictable dose-response relationship. The aim of our study was to evaluate the impact of TAC IPV (IPV) on graft and patient outcomes after LT. METHODS: We retrospectively analyzed 812 LT recipients treated with TAC. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of whole blood trough concentrations. Patients were categorized in 2 groups: low IPV (CV < 40%) and high IPV (CV ≥ 40%). RESULTS: There were significantly more neurologic complications (31.2% vs 16.6%, P < 0.001), cardiovascular complications (19.7% vs 9.7%, P < 0.001), and acute renal failure requiring dialysis (8.5% vs 2.2%, P < 0.001) in the high CV group than in the low CV group. Moreover, graft survival was significantly poorer in the high CV group (hazard ratio, 1.42; 95% confidence interval, 1.04-1.95; P = 0.03). A pretransplantation elevated Model for End-Stage Liver Disease score (P < 0.001) and Child-Pugh grade (P < 0.001) were identified as risk factors for presenting a high CV. CONCLUSIONS: A high CV of TAC concentrations was found to be predictive of TAC-related toxicity and poorer survival.

A high performance liquid chromatography tandem mass spectrometry for the quantification of tacrolimus in human bile in liver transplant recipients.

Tacrolimus whole-blood concentrations imperfectly reflect concentrations at the effect site. Tacrolimus concentrations in the transplanted organ could be more relevant to predict rejection events. Because liver biopsy cannot be repeatedly performed after liver transplantation, we suggested measuring tacrolimus in the bile to have a cost-effective and clinically implementable surrogate marker of intra-hepatic tacrolimus concentration. We developed and fully validated a liquid chromatography-tandem mass spectrometry method for the determination of tacrolimus in human bile. Sample purification was achieved using protein precipitation and liquid-liquid extraction with ethyl-acetate. Gradient elution was performed using a C18 analytical column with a 5min run-time. The method was linear from 0.5ng/mL to 20ng/mL. In this concentration range, within-day and between-day precisions as well as overall bias were within ±15%. Matrix effect was fully corrected by the internal standard (ascomycin). The assay was optimized to achieve good selectivity in this complex biological matrix. Tacrolimus was found to be stable in bile stored 6 months at -80°C, after 3 freeze and thaw cycles, 20h at room temperature and 24h in extracts kept at 15°C in the auto-sampler. The method was applied to quantify tacrolimus in bile from liver transplant recipients. It allowed getting preliminary data about tacrolimus excretion profile in bile and showed the lack of correlation between tacrolimus whole blood concentration and tacrolimus liver exposition. This alternative and innovative analytical approach of tacrolimus bio-analysis appears suitable for further studies evaluating relevance of biliary tacrolimus concentration as a new pharmacological marker of immunosuppressive activity.