Sirolimus In Liver Transplant Recipients Research Articles

Branched chain amino acids are associated with metabolic complications in liver transplant recipients

BackgroundObesity, dyslipidemia and type 2 diabetes (T2D) contribute substantially to increased cardiovascular morbidity and mortality in patients after orthotopic liver transplantation (OLTx). Elevated plasma branched chain amino acids (BCAA) are linked to metabolic disturbances and cardiovascular disease (CVD) risk profiles in several non-OLTx populations. MethodsCross-sectional analysis of liver transplant recipients from TransplantLines, a single-center biobank and cohort study. BCAA plasma levels were measured by means of nuclear-magnetic resonance spectroscopy. CVD and cardiometabolic factors were collected by using data from electronic patient records. Associations were determined between BCAA plasma levels and T2D, Metabolic Syndrome (MetS), CVD as well as mTOR inhibition in liver transplant recipients. Results336 Patients were divided into sex-stratified tertiles of total BCAA. MetS (P < 0.001) and T2D (P = 0.002) were significantly more frequent in subjects in the highest BCAA tertile. In logistic regression analyses, the multivariable adjusted odds ratio (OR) per 1 standard deviation increase in BCAA was 1.68 (95%CI: 1.18–2.20, P = 0.003) for MetS and 1.60 (95%CI: 1.14–2.23, P = 0.006) for T2D. Use of Sirolimus (mTOR inhibitor) was significantly associated with higher BCAA plasma levels, independent of age, sex, time after OLTx, MetS and other immunosuppressive medication (adjusted P = 0.002). ConclusionElevated BCAA plasma levels are associated with T2D, MetS and use of Sirolimus in liver transplant recipients. BCAA plasma levels may represent a valuable biomarker for cardiometabolic complications after OLTx.

S1006 Long-Term Safety of Sirolimus in Liver Transplant Recipients

INTRODUCTION: Sirolimus (SRL) has been used as an alternative to calcineurin inhibitors (CI) to spare renal function in liver transplant (LT) recipients. SRL received a black-box warning in LT because of concerns about hepatic artery thrombosis (HAT). Prior to this, we initiated a large number of LT patients on SRL. This study assesses the long-term safety of SRL in LT recipients. METHODS: This is a retrospective, single-center study of all LT recipients who initiated SRL from 2001-2006. A group that remained on SRL was compared to a group that discontinued SRL for adverse events (CNI group). Groups were compared for demographics, and LT outcomes. Kaplan-Meier analyses with Cox regression models were done to determine risk factors (RF), including SRL use, for death or end-stage renal disease (ESRD). RESULTS: 159 patients were included. 109 (68.5%) remained on SRL and 50 (31.4%) discontinued (CNI). There were no differences between groups in age at transplant, gender, race, etiology of liver disease or time after LT to SRL initiation. In SRL vs. CNI, there were no differences in HAT (2.8 vs. 2.0%), CAD (6.4 vs. 10%) or CVA (5.7% vs. 11.9%) (Table 1). Fewer patients on SRL died (47.7% vs. 58.0%) or developed ESRD (19.3 vs. 32.0%) though neither difference was significant at P = 0.228 and P = 0.078. No significant differences were noted in GFR between the two groups up to 10 years after LT. In the evaluation of risk factors to time to ESRD, CNI (SRL discontinuation) trended towards earlier onset of ESRD on univariate analysis (HR: 1.56, CI: 0.78, 3.23, P = 0.207 but not on multivariate analysis (HR:1.366, CI:0.675–2.763) (Figure 1). In the evaluation of RF for time of death, CNI was associated with greater mortality from time of transplant (HR: 1.46, CI: 1.06–2.03, P = 0.023) and from time of SRL initiation (HR: 1.64, CI: 1.06–2.55, P = 0.026). However, when including age, diabetes and GFR at LT in a multivariate analysis, the effect of CNI was no longer significant. CONCLUSION: The results describe one of the longest follow-up periods for SRL use in LT patients including 35 patients followed for over a decade. The results demonstrate that patients receiving SRL after LT did not have an increased risk of developing diabetes, CAD, CVA or HAT. Furthermore, SRL was at least equivalent to CNI in terms of ESRD and mortality. This suggests that SRL, in appropriate LT patients, is safe and that LT patients currently receiving SRL can continue to do so.Table 1.: showing baseline demographic variables and clinical characteristicsFigure 1.: Overall survival between groups from time of SRL conversion. End of SRL used as time varying variable.Figure 2.: Overall survival between groups from time of SRL conversion. End of SRL used as time varying variable.

Sirolimus in Liver Transplant Recipients with Hepatocellular Carcinoma: An Updated Meta-Analysis

ABSTRACTPrevious studies have indicated that sirolimus (SRL) may be effective for HCC patients undergoing liver transplantation (LT). However, the following results are still contradictory and do not have a clear conclusion. Therefore, we conducted an updated meta-analysis by retrieving published data in EMBASE, PubMed, and the Cochrane Library up to October 2017. Both efficiency and safety of SRL were analyzed using pooled odds ratio (ORs) with 95% confidence interval (CIs). A total of 11 studies involving 7,695 HCC patients were included. Compared with control group, SRL prolonged 1-year (OR = 2.44; CI = 1.66–3.59), 3 year (OR = 1.67; CI = 1.08–2.58) and 5-year (OR = 1.68; CI = 1.21–2.33) overall survival, as well as 1-year (OR = 2.13; CI = 1.19–3.81) disease-free survival. Pooled results found that SRL-treated patients had lower recurrence (OR = 0.60; CI = 0.37–0.98), lower recurrence-related mortality (OR = 0.58; CI = 0.42–0.81) and lower overall mortality (OR = 0.62; CI = 0.44–0.89). Moreover, fewer SRL-treated patients suffered from portal vein thrombosis (OR = 0.29; CI, 0.09–0.91) and diabetes (OR = 0.23; CI = 0.12–0.47), while SRL-treated patients were more vulnerable to acne compared with the control group (OR = 4.44; CI = 1.56–12.60). No significant differences in other adverse effects were found between two groups. Taken together, SRL-based immunosuppression is safe and effective in improving survival, as well as reducing recurrence and mortality for HCC patients following LT.

Effect of telaprevir on the pharmacokinetics of sirolimus in liver transplant recipients

Effect of telaprevir on the pharmacokinetics of sirolimus in liver transplant recipients

End of the Line for Sirolimus in Liver Transplant Recipients With Hepatitis C Virus?

We read with interest the article by Watt et al.1 about the impact of sirolimus (SRL)-based immunosuppression on patient and graft survival among recipients of liver transplantation (LT) with hepatitis C virus (HCV), and we commend their efforts in trying to shed some light on the mechanisms linking immunosuppression to the risk of HCV-related graft failure. However, we are convinced that the results of their analysis do not provide evidence against the use of SRL and mammalian target of rapamycin (mTOR) inhibitors in general in HCV-positive LT recipients. Despite Watt et al.'s attempt,1 capturing the complexity of posttransplant immunosuppression is a challenging task that cannot be remedied by the use of propensity score matching analysis alone. Concerns about the use of propensity score matching have been raised recently: hidden bias may increase because the matching of patient samples by observed variables (ie, HCV versus non-HCV) may generate further bias on account of latent, unobserved, and/or underestimated confounders.2 Because of the Food and Drug Administration's black-box warning for SRL in LT, its use may deliberately have been reserved for patients with poorer prognoses and/or multiple risk factors beyond HCV infection, such as renal failure, expanded criteria donors, hepatocellular carcinoma (eg, grade, stage, and microvascular invasion), de novo and recurrent malignancies, and cardiovascular/metabolic complications at any time during the posttransplant period. Furthermore, information on SRL trough levels, overall patient exposure, and the mode of calcineurin inhibitor withdrawal is missing in Watt et al.'s analysis, as are histological data on the severity of HCV recurrence. Evidence against the dismissal of mTOR inhibitors in HCV-positive LT recipients is accumulating in the international literature. A recent retrospective analysis of HCV patients on SRL showed significantly less advanced fibrosis (stage ≥ 2) in comparison with an HCV control group at 1 and 2 years (30.1% versus 50.5%, P = 0.001), with no difference in patient survival at 1 year (92.5% versus 87.9%, P = 0.15) and 5 years.3 A recent prospective randomized controlled trial of using everolimus (EVR) to minimize tacrolimus (TAC) in de novo LT recipients has shown that the use of EVR is associated with fewer and less severe acute rejection episodes, similar patient and graft survival, and superior renal function at 12 months in comparison with standard-exposure TAC.4 HCV-positive patients on EVR fared as the overall population did with respect to efficacy and renal function, and there were comparable changes in the viral load from the time of randomization to month 12 in comparison with the TAC group. EVR with minimized TAC was also associated with numerically (but not statistically) more stable liver fibrosis and comparable necroinflammatory scores.4, 5 Altogether, these results challenge Watt et al.'s conclusions1 and argue for cautiously interpreting data derived from large databases and for addressing the need for more properly designed longitudinal studies before the use of mTOR inhibitors in HCV-positive patients is dismissed. We believe that transplant physicians have acquired experience with mTOR inhibitors over the last years and that the results of Watt et al.'s study reflect a learning-curve effect and an initial misuse of mTOR inhibitors in the patients with poorest outcomes. Paolo De Simone, M.D.1 Faouzi Saliba, M.D., Ph.D.2 Lutz Fischer, M.D.3 1Hepato-Biliary Surgery and Liver Transplantation University of Pisa Medical School Hospital Pisa, Italy 2Hepato-Biliary Center Paul Brousse Hospital (Public Hospital System of Paris) University of Paris-Sud Villejuif, France 3Department of Hepatobiliary and Transplant Surgery University Medical Center Hamburg-Eppendorf, Germany

Use of sirolimus in liver transplant recipients with renal insufficiency: A systematic review and meta-analysis

Sirolimus is used in patients with renal insufficiency after liver transplantation (LT) and especially in those with calcineurin inhibitor (CNI)-associated nephrotoxicity. We conducted a systematic review of all randomized controlled trials and observational studies to test the hypothesis that the use of sirolimus is associated with an improvement in renal function at 1 year in LT recipients with renal insufficiency [glomerular filtration rate (GFR) < 60 mL/minute or creatinine level ≥ 1.5 mg/dL]. We performed a search of all major databases, conference proceedings, and relevant journals through December 2009 and contacted content experts, corresponding authors, and the pharmaceutical manufacturer. A random effects model was used to determine the pooled estimate of the change in renal function and pooled risk estimates of adverse events that may be associated with sirolimus-based therapy at 1 year. Eleven studies (three randomized controlled trials and eight observational studies) met the final inclusion criteria. A nonsignificant improvement of 3.38 mL/minute [95% confidence interval (CI) = -2.93 to 9.69] was observed in methodologically sound observational studies and controlled trials reporting the primary outcome. In controlled trials, baseline GFR >50 mL/min sirolimus use was associated with an improvement of 10.35 mL/minute (95% CI = 3.98-16.77) in GFR or creatinine clearance. Sirolimus was not significantly associated with death [relative risk (RR) = 1.12, 95% CI = 0.66-1.88] or graft failure (RR = 0.80, 95% CI = 0.45-1.41), although reporting was incomplete. It was associated with a statistically significant risk of infection (RR = 2.47, 95% CI = 1.14-5.36), rash (RR = 7.57, 95% CI = 1.75-32.70), ulcers (RR = 7.44, 95% CI = 2.03-27.28), and discontinuation of therapy (RR = 3.61, 95% CI = 1.32-9.89). Conversion to sirolimus from CNIs is associated with a nonsignificant improvement in renal function in LT recipients with renal insufficiency, although the results are limited by heterogeneity, a risk of bias, and a lack of standardized reporting.

Safety of an Immunosuppressant Protocol Based on Sirolimus in Liver Transplant Recipients With Malignancies or High Risk of Tumor Recurrence

Background The mammalian target of rapamycin inhibitors are immunosuppressive agents with antiproliferative effects and consequent potential application as anticancer agents. The safety and tolerance of calcineurin inhibitor (CNI)-free sirolimus-based immunosuppressant protocols in liver transplant recipients with malignancies or high risk of tumor recurrence has been scarcely evaluated. Patients and methods Fourteen liver transplant recipients, including 12 men, of overall mean age of 57.4 ± 12.4 years were distributed into two groups: group I, corresponding to 11 patients with malignant neoplasia, eight de novo neoplasia, and three recurrent hepatocarcinoma and; group II, three patients with high risk of tumor recurrence due to cholangiocarcinoma. Sirolimus was initiated at 2 mg od, with target levels of 3 to 9 ng/mL. Withdrawal of CNI was performed after reaching target levels of sirolimus. Periodic examinations of weight, arterial pressure, liver function tests, serum creatinine, triglycerides, cholesterol, sirolimus blood levels, and creatinine clearance were performed at 30, 60, 90, 180, and 360 days. Results After a median follow-up of 221.5 days, eight group I patients (72.7%) were alive, including six with stable disease. All group II patients were alive without evidence of tumor recurrence after a median follow-up of 560 days. CNI was withdrawn in 11 patients (78.6%). Sirolimus was withdrawn in only one case due to severe symptomatic oral ulcers. No vascular complications or rejection episodes were observed. Conclusions A sirolimus-based immunosuppressant protocol was well tolerated and safe in liver transplant recipients with malignancies or a high risk of recurrence of neoplastic disease.

Sirolimus in liver transplant recipients with renal dysfunction offers no advantage over low-dose calcineurin inhibitor regimens

The purpose of this study is to review the clinical experience with sirolimus immunosuppression in liver transplant patients with calcineurin inhibitor-induced chronic renal insufficiency. The study design is a case-control retrospective series. Fifty-seven liver transplant patients with renal insufficiency that were started on sirolimus at greater than 90 days postoperatively and treated for more than 90 days were identified. A control group of 57 patients maintained on low-dose calcineurin inhibitors, matched for gender, year of transplant, and baseline creatinine clearance, was also identified. There were no significant differences in the absolute creatinine clearance values between the sirolimus and control groups from 6 months before sirolimus conversion to 12 months after sirolimus conversion. Patients exposed to calcineurin inhibitors for more than 5 years or those with an initial creatinine clearance of less than 30 mL/minute who were converted to sirolimus did worse than control patients maintained on low-dose calcineurin inhibitors. Progression to renal replacement therapy, episodes of acute and chronic rejection, and death were similar between the sirolimus and control groups. The overall prevalence of side effects was significantly higher in the sirolimus group compared with the control group, although these were generally tolerable in most patients. In conclusion, this study suggests that conversion to sirolimus in liver transplant patients with chronic renal insufficiency is associated with stabilization of renal function but confers no additional benefit to low-dose calcineurin inhibitor regimens and may in fact be disadvantageous in patients with a creatinine clearance of less than 30 mL/minute.

The role of sirolimus in liver transplantation

Purpose of review Side effects of immunosuppressants contribute to long-term morbidity and impact quality of life following liver transplantation. In this article, recent publications on the potential role and side effects of sirolimus in liver transplant recipients will be reviewed. Recent findings Early reports of hepatic artery thrombosis associated with sirolimus led to the cessation of a multicenter trial and a ‘black box’ warning by the Food and Drug Administration. Interest in the agent remained, however, as several single center studies reported improvement in renal function and decreased neurotoxicities with sirolimus-based immunosuppression. Attention has been drawn to its antineoplastic characteristics for patients with hepatocellular carcinoma and the antiproliferative properties for patients with hepatitis C virus infection. In addition to the well known side effects, there have been recent reports of proteinuria and pulmonary complications associated with sirolimus. Summary Sirolimus appears to be a safe alternative to calcineurin inhibitors when used after the immediate postoperative period, benefiting patients with calcineurin inhibitor-induced toxicities. Larger randomized control trials comparing calcineurin inhibitor with sirolimus-based regimens are needed to determine which is best for specific patient populations.

Sirolimus Conversion in Liver Transplant Recipients With Renal Dysfunction: A Prospective, Randomized, Single-Center Trial

This pilot trial was designed to assess the safety and efficacy of SRL in liver transplant recipients with renal dysfunction. Forty patients with renal dysfunction (24-hr CrCl 40-80 mL/min) were randomized to be withdrawn from the calcineurin inhibitor (CNI) and receive sirolimus (SRL) or to continue CNI (control arm). Improvement in 24-hour CrCl was seen in the SRL arm at 3 months (75 mL/min SRL vs. 56 mL/min control, P=0.012), whereas at 12 months there was a trend toward improvement in the SRL arm (72 mL/min SRL vs. 58 mL/min control, P=0.09). Two patients, one in each arm, developed steroid-sensitive rejection. Side effects of SRL were limited and included hyperlipidemia requiring treatment (15%), pruritus (5%), and mouth sores (25%). In this trial, SRL-based immunosuppression was a safe alternative to CNI. Although early improvements were observed, withdrawing CNI and replacing it with SRL did not result in a statistically significant improvement in renal function at 12 months of follow-up.

Ascites and Edema Associated with the Use of Sirolimus in Liver Transplant Recipients Can Mimic Complications of Cirrhosis with Portal Hypertension

Ascites and Edema Associated with the Use of Sirolimus in Liver Transplant Recipients Can Mimic Complications of Cirrhosis with Portal Hypertension

Ten years of sirolimus therapy in orthotopic liver transplant recipients

Background Sirolimus therapy has been used in orthotopic liver transplant (OLT) recipients diagnosed with a variety of diseases; chronic graft rejection (CR), calcineurin associated renal toxicity, preemptive immune suppression, calcineurin related neurotoxicity, preemptive therapy in transplant recipients with history of hepatocellular carcinoma, and steroid resistant allograft rejection. Methods A search for the medical literature and experiences involving sirolimus was done. Results Several animal and human reports evaluating the use sirolimus in liver transplant recipients are found and discussed. Conclusion Sirolimus has been used for multitude of indications, primarily based on anecdotal experiences. However, reports of sirolimus related side effects have decreased the transplant communities’ enthusiasm towards promoting this agent as a safe immune suppression agent.

Sirolimus in liver transplantation

Since its introduction in renal transplantation in 1999, sirolimus is being used by an increasing number of liver transplant centers. Compared to the calcineurin inhibitors, sirolimus acts through a separate signal transduction pathway and has a myriad of important biologic effects including: inhibition of lymphocyte proliferation, inhibition of fibrosis and fibroblast proliferation, and antineoplastic effects. The clinical side-effect profile of this drug is also different than calcineurin inhibitors. Most important, sirolimus does not cause glucose intolerance, hypertension, or renal insufficiency. As a result, this drug offers significant potential advantages over conventional immunosuppressive agents. However, sirolimus may cause hyperlipidemia and has also been associated with hepatic artery thrombosis in liver transplant recipients. This review will summarize the published data on sirolimus in liver transplantation, focusing on the potential advantages and disadvantage of the use of this drug in liver transplant recipients. Finally, the potential benefits of antifibrosis and antineoplastic effects of sirolimus in liver transplant recipients will be discussed.