Glucocorticosteroid-free versus glucocorticosteroid-containing immunosuppression for liver transplanted patients.
Ontology highlight
ABSTRACT:
SUBMITTER: Fairfield C
PROVIDER: S-EPMC6494590 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundThe potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.Methods/designThe study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.DiscussionIf our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.Trial registerTrial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36).
| S-EPMC2889889 | biostudies-literature
Project description:The shortage of transplant organs remains a serious issue worldwide, and using liver grafts from extended criteria donors could expand the donor pool. Extended criteria donor liver allografts have a high chance of complications such as primary nonfunction, early allograft dysfunction, and ischemic-type biliary lesions. How to employ these extended criteria donors safely and effectively warrants further investigation. Herein, we report the successful use of a marginal donor liver with hyperbilirubinemia to save the life of an acute-on-chronic liver failure recipient using a new surgical technique: ischemia-free liver transplantation (IFLT). The graft was retrieved for transplantation due to the following reasons: (I) the recipient was in a life-threatening situation and no living donor donation candidate was available; (II) the graft was considered transplantable except for cholestasis; and (III) IFLT could reduce ischemia/reperfusion injury (IRI), resuscitate the allograft ex situ, and maintain organ viability before transplantation. The graft was transplanted successfully using the IFLT procedure. Although anatomic biliary stricture occurred after surgery, no IRI-related complications were found during the follow-up. The use of liver grafts from extended criteria donors is safe and effective under IFLT. Additional IFLT clinical studies need to be performed, particularly concerning donor management, graft selection, and ex situ resuscitation.
| S-EPMC8033382 | biostudies-literature
Project description:BackgroundChronic deterioration of kidney graft function is related to inadequate immunosuppression (IS). A novel tool to assess the individual net state of IS in transplanted patients might be the monitoring of Torque teno virus (TTV) viral load. TTV is a non-pathogen virus detectable in almost all individuals. TTV level in the peripheral blood has been linked to the immune-competence of its host and should thus reflect IS after solid organ transplantation.MethodsTTV plasma load was quantified monthly by RT-PCR for a period of 1 year in 45 kidney-transplanted children. Post-transplant time was at least 3 months. The relation of the virus DNA levels to IS and transplant-specific clinical and laboratory parameters was analysed longitudinally.ResultsTTV DNA was detectable in 94.5% of the plasma samples. There was a significant association with the post-transplant follow-up time as well as with the type of IS regimen, with lower virus loads in patients after longer post-transplant time and mTOR inhibitor-based IS. Furthermore, a significant positive correlation with the dose of prednisolone and mycophenolate mofetil was found.ConclusionsTTV levels show an association/correlation with the strength of IS. Further studies are needed in order to evaluate TTV measurement as a tool for IS monitoring for hard clinical outcomes such as presence of donor-specific antibodies, rejections or infections-common consequences of insufficient or too intense IS.
| S-EPMC7701084 | biostudies-literature
Project description:Background. Efavirenz (EFV), an antiretroviral medication used to treat human immunodeficiency virus (HIV) infection, can increase lipid levels. Because hyperlipidemia is associated with increased risk for cardiovascular (CV) events, this study compared the risk of CV events in patients initiating EFV-containing vs EFV-free antiretroviral regimens. Methods. Antiretroviral-naive HIV-positive (HIV+) patients ages 18-64 were selected from commercial and Medicaid insurance claims databases. Patients with ≥1 claim for antiretroviral medications between January 1, 2007 and December 31, 2013 were classified into 2 cohorts: EFV-containing or EFV-free regimens. Patients were required to have 6 months of continuous enrollment before initiation, with no evidence of a CV event during this time. Patients were observed from initiation until the occurrence of a CV event, disenrollment, or study end. Cardiovascular events were identified through diagnosis or procedure codes for myocardial infarction, stroke, percutaneous coronary intervention, or coronary artery bypass graft. We calculated unadjusted incidence rates (IRs) and fit propensity-score-weighted Cox proportional hazards models. Results. There were 22 212 patients (11 978 EFV-containing and 10 234 EFV-free) identified in the commercial database and 7400 patients identified (2943 EFV-containing and 4457 EFV-free) in the Medicaid database. Cardiovascular events were rare (commercial IR = 396 per 100 000 person-years; Medicaid IR = 973 per 100 000 person-years). In propensity-score-weighted models, hazards of CV events were significantly lower for EFV-containing regimens in the commercial database (hazard ratio [HR] = 0.68; 95% confidence interval [CI], .49-.93) No significant difference was found in the Medicaid database (HR = 0.83; 95% CI, .58-1.19). Conclusions. This analysis found no evidence of increased risk of CV events among HIV+ patients initiating EFV-containing regimens.
| S-EPMC4866551 | biostudies-literature
Project description:BackgroundMost liver transplant recipients receive calcineurin inhibitors (CNIs), especially tacrolimus and cyclosporine, as immunosuppressant agents to prevent rejection. A controversy exists as to whether the outcomes of hepatitis C virus (HCV)-infected liver transplant patients differ based on the CNIs used. This meta-analysis compares the clinical outcomes of tacrolimus-based and cyclosporine-based immunosuppression, especially cases of HCV recurrence in liver transplant patients with end-stage liver disease caused by HCV infection.MethodsRelated articles were identified from the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Medline, and Embase. Meta-analyses were performed for the results of homogeneous studies.ResultsNine randomized or quasi-randomized controlled trials were included. The total effect size of mortality (RR = 0.98, 95% CI: 0.77-1.25, P = 0.87) and graft loss (RR = 1.05, 95% CI: 0.83-1.33, P = 0.67) showed no significant difference between the two groups irrespective of duration of immunosuppressant therapy after liver transplantation. In addition, the HCV recurrence-induced mortality (RR = 1.11, 95% CI: 0.66-1.89, P = 0.69), graft loss (RR = 1.62, 95% CI: 0.64-4.07, P = 0.31) and retransplantation (RR = 1.40, 95% CI: 0.48-4.09, P = 0.54), as well as available biopsies, confirmed that histological HCV recurrences (RR =? 0.92, 95% CI: 0.71-1.19, P = 0.51) were similar.ConclusionThese results suggested no difference in posttransplant HCV recurrence-induced mortality, graft loss and retransplantation, as well as histological HCV recurrence in patients treated with tacrolimus-based and cyclosporine-based immunosuppresion.
| S-EPMC4157850 | biostudies-literature
Project description:Background and aimsSeveral meta-analyses comparing ciclosporin with tacrolimus have been conducted since the 1994 publication of the tacrolimus registration trials, but most captured data from randomized controlled trials (RCTs) predating recent improvements in waiting list prioritization, induction protocols and concomitant medications. The present study comprised a systematic review and meta-analysis of ciclosporin and tacrolimus in liver transplant recipients using studies published since January 2000.MethodsSearches of PubMed, the Cochrane Library and EMBASE identified RCTs of tacrolimus and ciclosporin as the immunosuppressant in adult primary liver transplant recipients, published between January 2000 and August 6, 2014. A random effects meta-analysis was conducted to evaluate the relative risk of death, graft loss, acute rejection (AR), new-onset diabetes after transplantation (NODAT) and hypertension with tacrolimus relative to ciclosporin at 12 months.ResultsThe literature search identified 11 RCTs comparing ciclosporin with tacrolimus. Relative to ciclosporin, tacrolimus was associated with significantly improved outcomes in terms of patient mortality (risk ratio [RR] with ciclosporin of 1.26; 95% confidence interval [95%CI] 1.01-1.58). Tacrolimus was superior to ciclosporin in terms of hypertension (RR with ciclosporin 1.26; 95%CI 1.07-1.47), but inferior in terms of NODAT (RR with ciclosporin 0.60; 95%CI 0.47-0.77). There were no significant differences between ciclosporin and tacrolimus in terms of graft loss or AR.ConclusionsMeta-analysis of RCTs published since 2000 showed tacrolimus to be superior to ciclosporin in terms of patient mortality and hypertension, while ciclosporin was superior in terms of NODAT. No significant differences were identified in terms of graft loss or AR. These findings provide further evidence supporting the use of tacrolimus as the cornerstone of immunosuppressive therapy in liver transplant recipients.
| S-EPMC5094765 | biostudies-literature
Project description:Corticosteroids remain the mainstay of immunosuppression for liver transplant recipients despite several serious complications including infection, hepatitis C virus (HCV) recurrence, diabetes mellitus (DM), and hypertension. We attempted to compare the safety and efficacy of T-cell specific antibody induction with complete corticosteroid avoidance. We searched MEDLINE, EMBASE, and Cochrane central library. Randomized controlled trials comparing T-cell specific antibody induction with corticosteroid induction immunosuppression were included. Our primary outcome was the incidence of biopsy-proven acute rejection. Eleven trials involving 1683 patients were included. The incidence of acute rejection was not significantly different between the antibody and steroid induction groups (risk ratio [RR] 0.85, 95% confidence interval [CI] 0.72, 1.01, P = 0.06, I2 = 0%). However, T-cell specific antibody induction significantly reduced the risk of cytomegalovirus infection (RR 0.48, 95% CI 0.33, 0.70, P = 0.0002, I2 = 3%), HCV recurrence (RR 0.89, 95% CI 0.80, 0.99, P = 0.03, I2 = 0%), DM (RR 0.41, 95% CI 0.32, 0.54, P < 0.0001, I2 = 0%) and hypertension (RR 0.71, 95% CI 0.55, 0.90, P = 0.005, I2 = 35%). Trial sequential analysis for acute rejection showed that the cumulative z-curve did not cross the Trial sequential boundary and the required information size was not reached. T-cell specific antibody induction compared to corticosteroid induction seems to significantly reduce opportunistic infections including cytomegalovirus infection and HCV recurrence and metabolic complications including DM and hypertension. However, given the insufficient study power, low quality of evidence, and heterogeneous immunosuppressive regimens, our results should be cautiously appreciated.
| S-EPMC10147598 | biostudies-literature
Project description:Background and objectivesHypophosphatemia is commonly observed in patients receiving continuous KRT. Patients who develop hypophosphatemia may be at risk of respiratory and neuromuscular dysfunction and therefore subject to prolongation of ventilator support. We evaluated the association of phosphate-containing versus phosphate-free continuous KRT solutions with ventilator dependence in critically ill patients receiving continuous KRT.Design, setting, participants, & measurementsOur study was a single-center, retrospective, pre-post cohort study of adult patients receiving continuous KRT and mechanical ventilation during their intensive care unit stay. Zero-inflated negative binomial regression with and without propensity score matching was used to model our primary outcome: ventilator-free days at 28 days. Intensive care unit and hospital lengths of stay as well as hospital mortality were analyzed with a t test or a chi-squared test, as appropriate.ResultsWe identified 992 eligible patients, of whom 649 (65%) received phosphate-containing solutions and 343 (35%) received phosphate-free solutions. In multivariable models, patients receiving phosphate-containing continuous KRT solutions had 12% (95% confidence interval, 0.17 to 0.47) more ventilator-free days at 28 days. Patients exposed to phosphate-containing versus phosphate-free solutions had 17% (95% confidence interval, -0.08 to -0.30) fewer days in the intensive care unit and 20% (95% confidence interval, - 0.12 to -0.32) fewer days in the hospital. Concordant results were observed for ventilator-free days at 28 days in the propensity score matched analysis. There was no difference in hospital mortality between the groups.ConclusionsThe use of phosphate-containing versus phosphate-free continuous KRT solutions was independently associated with fewer ventilator days and shorter stay in the intensive care unit.
| S-EPMC9269583 | biostudies-literature
Project description:Ornithine transcarbamylase deficiency (OTCD) is a metabolic and genetic disease caused by dysfunction of the hepatocytic urea cycle. To develop new drugs or therapies for OTCD, it is ideal to use models that are more closely related to human metabolism and pathology. Primary human hepatocytes (HHs) isolated from two patients (a 6-month-old boy and a 5-year-old girl) and a healthy donor were transplanted into host mice (hemi-, hetero-OTCD mice, and control mice, respectively). HHs were isolated from these mice and used for serial transplantation into the next host mouse or for in vitro experiments. Histological, biochemical, and enzyme activity analyses were performed. Cultured HHs were treated with ammonium chloride or therapeutic drugs. Replacement rates exceeded 80% after serial transplantation in both OTCD mice. These highly humanized OTCD mice showed characteristics similar to OTCD patients that included increased blood ammonia levels and urine orotic acid levels enhanced by allopurinol. Hemi-OTCD mice showed defects in OTC expression and significantly low enzymatic activities, while hetero-OTCD mice showed residual OTC expression and activities. A reduction in ammonium metabolism was observed in cultured HHs from OTCD mice, and treatment with the therapeutic drug reduced the ammonia levels in the culture medium. In conclusion, we established in vivo OTC mouse models with hemi- and hetero-patient HHs. HHs isolated from the mice were useful as an in vitro model of OTCD. These OTC models could be a source of valuable patient-derived hepatocytes that would enable large scale and reproducible experiments using the same donor.
| S-EPMC8247293 | biostudies-literature
Project description: Not available
| S-EPMC8330141 | biostudies-literature