Personalized Tacrolimus Dosing After Liver Transplantation: A Randomized Clinical Trial.

Background: Inter- and intra-individual variability in tacrolimus dose requirements mandates empirical clinician-titrated dosing that frequently results in deviation from a narrow target range. Improved methods to individually dose tacrolimus are needed. Our objective was to determine whether a quantitative, dynamically-customized, phenotypic-outcome-guided dosing method termed Phenotypic Personalized Medicine (PPM) would improve target drug trough maintenance. Methods: In a single-center, randomized, pragmatic clinical trial ( NCT03527238 ), 62 adults were screened, enrolled, and randomized prior to liver transplantation 1:1 to standard-of-care (SOC) clinician-determined or PPM-guided dosing of tacrolimus. The primary outcome measure was percent days with large (>2 ng/mL) deviation from target range from transplant to discharge. Secondary outcomes included percent days outside-of-target-range and mean area-under-the-curve (AUC) outside-of-target-range per day. Safety measures included rejection, graft failure, death, infection, nephrotoxicity, or neurotoxicity. Results: 56 (29 SOC, 27 PPM) patients completed the study. The primary outcome measure was found to be significantly different between the two groups. Patients in the SOC group had a mean of 38.4% of post-transplant days with large deviations from target range; the PPM group had 24.3% of post-transplant days with large deviations; (difference -14.1%, 95% CI: -26.7 to -1.5 %, P=0.029). No significant differences were found in the secondary outcomes. In post-hoc analysis, the SOC group had a 50% longer median length-of-stay than the PPM group [15 days (Q1-Q3: 11-20) versus 10 days (Q1-Q3: 8.5-12); difference 5 days, 95% CI: 2-8 days, P=0.0026]. Conclusions: PPM guided tacrolimus dosing leads to better drug level maintenance than SOC. The PPM approach leads to actionable dosing recommendations on a day-to-day basis. Lay Summary: In a study on 62 adults who underwent liver transplantation, researchers investigated whether a new dosing method called Phenotypic Personalized Medicine (PPM) would improve daily dosing of the immunosuppression drug tacrolimus. They found that PPM guided tacrolimus dosing leads to better drug level maintenance than the standard-of-care clinician-determined dosing. This means that the PPM approach leads to actionable dosing recommendations on a day-to-day basis and can help improve patient outcomes.

Portosystemic shunts versus endoscopic intervention with or without medical treatment for prevention of rebleeding in people with cirrhosis.

BACKGROUND: People with liver cirrhosis who have had one episode of variceal bleeding are at risk for repeated episodes of bleeding. Endoscopic intervention and portosystemic shunts are used to prevent further bleeding, but there is no consensus as to which approach is preferable. OBJECTIVES: To compare the benefits and harms of shunts (surgical shunts (total shunt (TS), distal splenorenal shunt (DSRS), or transjugular intrahepatic portosystemic shunt (TIPS)) versus endoscopic intervention (endoscopic sclerotherapy or banding, or both) with or without medical treatment (non-selective beta blockers or nitrates, or both) for prevention of variceal rebleeding in people with liver cirrhosis. SEARCH METHODS: We searched the CHBG Controlled Trials Register; CENTRAL, in the Cochrane Library; MEDLINE Ovid; Embase Ovid; LILACS (Bireme); Science Citation Index - Expanded (Web of Science); and Conference Proceedings Citation Index - Science (Web of Science); as well as conference proceedings and the references of trials identified until 22 June 2020. We contacted study investigators and industry researchers. SELECTION CRITERIA: Randomised clinical trials comparing shunts versus endoscopic interventions with or without medical treatment in people with cirrhosis who had recovered from a variceal haemorrhage. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. When possible, we collected data to allow intention-to-treat analysis. For each outcome, we estimated a meta-analysed estimate of treatment effect across trials (risk ratio for binary outcomes). We used random-effects model meta-analysis as our main analysis and as a means of presenting results. We reported differences in means for continuous outcomes without a meta-analytic estimate due to high variability in their assessment among all trials. We assessed the certainty of evidence using GRADE. MAIN RESULTS: We identified 27 randomised trials with 1828 participants. Three trials assessed TSs, five assessed DSRSs, and 19 trials assessed TIPSs. The endoscopic intervention was sclerotherapy in 16 trials, band ligation in eight trials, and a combination of band ligation and either sclerotherapy or glue injection in three trials. In eight trials, endoscopy was combined with beta blockers (in one trial plus isosorbide mononitrate). We judged all trials to be at high risk of bias. We assessed the certainty of evidence for all the outcome review results as very low (i.e. the true effects of the results are likely to be substantially different from the results of estimated effects). The very low evidence grading is due to the overall high risk of bias for all trials, and to imprecision and publication bias for some outcomes. Therefore, we are very uncertain whether portosystemic shunts versus endoscopy interventions with or without medical treatment have effects on all-cause mortality (RR 0.99, 95% CI 0.86 to 1.13; 1828 participants; 27 trials), on rebleeding (RR 0.40, 95% CI 0.33 to 0.50; 1769 participants; 26 trials), on mortality due to rebleeding (RR 0.51, 95% CI 0.34 to 0.76; 1779 participants; 26 trials), and on occurrence of hepatic encephalopathy, both acute (RR 1.60, 95% CI 1.33 to 1.92; 1649 participants; 24 trials) and chronic (RR 2.51, 95% CI 1.38 to 4.55; 956 participants; 13 trials). No data were available regarding health-related quality of life. Analysing each modality of portosystemic shunts individually (i.e. TS, DSRS, and TIPS) versus endoscopic interventions with or without medical treatment, we are very uncertain if each type of shunt has effect on all-cause mortality: TS, RR 0.46, 95% CI 0.19 to 1.13; 164 participants; 3 trials; DSRS, RR 0.93, 95% CI 0.65 to 1.33; 352 participants; 4 trials; and TIPS, RR 1.10, 95% CI 0.92 to 1.31; 1312 participants; 19 trial; on rebleeding: TS, RR 0.28, 95% CI 0.14 to 0.56; 127 participants; 2 trials; DSRS, RR 0.26, 95% CI 0.11 to 0.65; 330 participants; 5 trials; and TIPS, RR 0.44, 95% CI 0.36 to 0.55; 1312 participants; 19 trials; on mortality due to rebleeding: TS, RR 0.25, 95% CI 0.06 to 0.96; 164 participants; 3 trials; DSRS, RR 0.31, 95% CI 0.13 to 0.74; 352 participants; 5 trials; and TIPS, RR 0.65, 95% CI 0.40 to 1.04; 1263 participants; 18 trials; on acute hepatic encephalopathy: TS, RR 1.66, 95% CI 0.70 to 3.92; 115 participants; 2 trials; DSRS, RR 1.70, 95% CI 0.94 to 3.08; 287 participants; 4 trials, TIPS, RR 1.61, 95% CI 1.29 to 1.99; 1247 participants; 18 trials; and chronic hepatic encephalopathy: TS, Fisher's exact test P = 0.11; 69 participants; 1 trial; DSRS, RR 4.87, 95% CI 1.46 to 16.23; 170 participants; 2 trials; and TIPS, RR 1.88, 95% CI 0.93 to 3.80; 717 participants; 10 trials. The proportion of participants with shunt occlusion or dysfunction was overall 37% (95% CI 33% to 40%). It was 3% (95% CI 0.8% to 10%) following TS, 7% (95% CI 3% to 13%) following DSRS, and 47.1% (95% CI 43% to 51%) following TIPS. Shunt dysfunction in trials utilising polytetrafluoroethylene-covered stents was 17% (95% CI 11% to 24%). Length of inpatient hospital stay and cost were not comparable across trials. Funding was unclear in 16 trials; 11 trials were funded by government, local hospitals, or universities. AUTHORS' CONCLUSIONS: Evidence on whether portosystemic shunts versus endoscopy interventions with or without medical treatment in people with cirrhosis and previous hypertensive portal bleeding have little or no effect on all-cause mortality is very uncertain. Evidence on whether portosystemic shunts may reduce bleeding and mortality due to bleeding while increasing hepatic encephalopathy is also very uncertain. We need properly conducted trials to assess effects of these interventions not only on assessed outcomes, but also on quality of life, costs, and length of hospital stay.

Utility of a routine bench cholangiogram for ex situ split liver procedure.

BACKGROUND: Biliary complications can result in a significant morbidity for split liver graft recipients. Biliary drainage for segment 1 and 4 is highly variable and could be the source of bile leaks. Use of a bench cholangiogram (BCH) can accurately define the segmental biliary system and identify any significant biliary radicles that need retention or repair during bench preparation of split grafts. This study evaluates the clinical relevance of routine BCH in split liver transplantation (SLT). METHODS: Retrospective review of 100 BCH images performed during ex situ deceased donor SLT between January 2009 and January 2015. The radiographs were reviewed by two surgeons and the biliary anatomy was compared using Huang and Reichert classification. RESULTS: 100 BCH images were reviewed. Variant anatomy was frequently identified in the intrahepatic bile duct system, the number and drainage patterns of segment 1&4 duct was diverse. BCH results guided the line of parenchymal transection to obtain a single segment 2&3 duct in 15 cases. A surgical intervention in the form of suture ligation of significant segment 1 or 4 duct at bench preparation was performed in 6 cases. BCH images guided surgical control of post-operative bile leak in 3 patients. CONCLUSION: Bench cholangiogram is a useful tool to guide liver parenchymal transection and potentially reduce the incidence of biliary complications.

Obtaining Optimal Long-Term Outcomes from Liver Transplantation for Hepatocellular Cancer.

Liver transplantation is the definitive treatment for patients with end-stage liver disease. Liver transplantation is also the optimal treatment for patients with hepatocellular carcinoma (HCC), especially in the setting of chronic liver disease. Unfortunately, due to the worldwide shortage of organs, this treatment is not available for all patients with HCC. Strict selection criteria have been developed in order to obtain optimal results. A surgical perspective of the preoperative selection, perioperative management, and postoperative care of patients is reviewed in depth and provides an overview for obtaining optimal long-term results from liver transplantation for HCC. With rigorous selection and patient management, excellent long-term outcomes can be obtained with liver transplantation for patients with HCC.

Intention to Split Policy: A Successful Strategy in a Combined Pediatric and Adult Liver Transplant Center.

OBJECTIVE: The primary aim of this study is to evaluate the role of split liver transplantation (SLT) in a combined pediatric and adult liver transplant center. The secondary aim is to reflect on our clinical practice and discuss strategies to build a successful split program using an "intention to split policy." BACKGROUND: SLT is an established procedure to expand the organ pool and reduce wait list mortality; however, technical and logistic issues are limiting factors. METHODS: Prospectively collected data and outcomes of SLT procedures performed between November 1992 and March 2014 were analyzed retrospectively. To assess the effect of standardization and learning curve, the experience was divided into 2 time periods. RESULTS: Out of 3449 liver transplant procedures performed, 516(15%) were SLT. The recipients included 266 children (290 grafts; 56%) and 212 adults (226 grafts; 44%). The median donor age was 25(7-63 years) and the median weight was 70(22-111 kg). The cold and warm ischemic times improved significantly during the second period (SP) (2001-2014). With experience, there was a significant reduction in the biliary complications for both grafts. The introduction of "intention to split policy" resulted in a significantly increased usage of SLT. There was no mortality on the pediatric wait list for last 4 years. Over the last decade 65% of our pediatric transplants were SLT. The overall 1-, 5-, 10-year patient and graft survival of left graft recipients was 91%, 90%, and 89% and 90%, 87%, and 86%. For right grafts it was 87%, 82%, and 81% and 82%, 81%, and 79%, respectively. CONCLUSIONS: SLT is an effective surgical strategy to meet the demands in a combined adult and pediatric transplant center. Good outcomes can be achieved with a standardized technique.

Acute renal failure in patients with ischemic heart disease: causes and novel approaches in breaking the cycle of self-perpetuating insults abrogated by surgery.

At present, there seems to be diametrically opposing views on the causes of acute renal insufficiency in patients with ischemic heart disease (IHD) elective for cardiac revascularization. In this review, we examined recent advances in the understanding of the pathophysiology of acute renal failure in patients with IHD and surgery-induced acute phase reaction. Emphasis is given to the cellular and molecular mechanisms that contribute to the initiation and progression of inflammation. We evaluated the different pharmacological, technical, and surgical strategies used to improve the outcome of patients with IHD with impaired renal dysfunction and analyzed the influence of renal insufficiency on long-term results after surgery.