Dataset Information

Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis.

ABSTRACT:

Background

Interleukin-2 (IL-2) antagonist has been used as an induction therapy in many centres in calcineurin inhibitor-sparing regimens. Tacrolimus has overwhelmingly replaced cyclosporine in the maintenance immunosuppressive protocols in many transplant centres. The aim of our study and meta-analysis is to explore the effect of IL-2 induction therapy on the rate of rejection and patient and graft survival in standard-risk renal transplant patients with tacrolimus-based maintenance immunotherapy. Secondary aims included assessment of the effect of IL-2 induction therapy on creatinine change and the risk of cytomegalovirus (CMV) infection.

Methods

We conducted a systematic review in different databases to identify studies and research work that assessed the effect of IL-2 antibody induction therapy on renal transplant outcomes. Inclusion criteria for our meta-analysis were all studies that compared IL-2 induction therapy with placebo or no induction therapy in standard-risk renal transplant recipients on tacrolimus-based maintenance immunosuppressive therapy. Data collected were the name of the first author, journal title, year of publication, country where the study was conducted, number of patients in the IL-2 induction therapy arm and in the placebo arm, number of patients who had biopsy-proven rejection and graft survival in each arm. A random effects model was used for the meta-analysis.

Results

Of the 470 articles found in different databases, 7 were included in the meta-analysis. Forest plot analysis for rate of rejection during the follow-up period post-transplant showed no significant difference between the groups. There was no evidence of heterogenicity between included studies (I ²?=?21.8%, P?=?0.27). The overall risk difference was -0.02 [95% confidence interval (CI) -0.05-0.01]. A random effects meta-analysis for patient and graft survival was performed using forest plot analysis and showed no significant effect of IL-2 receptor (IL-2R) antibody induction on patient or graft survival compared with placebo. The overall risk difference was -0.01 (95% CI -0.04-0.01) and 0.00 (95% CI -0.00-0.01), respectively. Three of the included studies showed no effect of basiliximab on creatinine change, two showed no effect on risk of CMV infection and two showed less risk of post-transplant diabetes in the basiliximab group.

Conclusion

IL-2R antibody induction therapy has no significant effect on the rate of rejection or patient or graft survival in standard-risk renal transplant recipients on tacrolimus-based maintenance immunotherapy. More randomized controlled studies are needed.

SUBMITTER: Ali H

PROVIDER: S-EPMC6671558 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis.

Ali Hatem H Mohiuddin Atif A Sharma Ajay A Shaheen Ihab I Kim Jon Jin JJ El Kosi Mohsen M Halawa Ahmed A

Clinical kidney journal 20190114 4

<h4>Background</h4>Interleukin-2 (IL-2) antagonist has been used as an induction therapy in many centres in calcineurin inhibitor-sparing regimens. Tacrolimus has overwhelmingly replaced cyclosporine in the maintenance immunosuppressive protocols in many transplant centres. The aim of our study and meta-analysis is to explore the effect of IL-2 induction therapy on the rate of rejection and patient and graft survival in standard-risk renal transplant patients with tacrolimus-based maintenance im ...[more]

PMID: 31384453

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Project description:ImportanceMedian survival after lung transplant is less than 6 years. Standard maintenance therapy typically includes tacrolimus and an antimetabolite (mycophenolate mofetil or azathioprine). Replacing the antimetabolite with sirolimus after postoperative wound healing may improve long-term survival due to antifibrotic, antiproliferative, and antiaging effects of sirolimus.ObjectivesTo compare survival between patients receiving sirolimus?plus?tacrolimus vs mycophenolate mofetil plus tacrolimus (the most common maintenance therapy) and to identify the combination of induction and maintenance therapy associated with the highest survival.Design, setting, and participantsThis cohort study of US recipients of lung transplants from January 1, 2003, through August 31, 2016, analyzed United Network for Organ Sharing (UNOS) data from January 1 through September 13, 2018. Because initiation of sirolimus therapy is usually delayed 3 to 12 months after lung transplant, primary analyses were based on patients alive and free of chronic rejection and malignant disease at 1 year in all groups, whereas sensitivity analyses used appropriate methods to include all patients from transplant time. Regression models adjusted for available potential confounders, including transplant center performance.ExposuresCell cycle inhibitor maintenance therapies, including sirolimus (n?=?219), mycophenolate mofetil (n?=?5782), mycophenolate sodium (n?=?408), azathioprine (n?=?2556), and concurrent sirolimus plus mycophenolate mofetil (n?=?54), were compared within a tacrolimus-based regimen. Combinations of each induction (basiliximab, daclizumab, antithymocyte globulin, alemtuzumab, or none) and maintenance (tacrolimus plus sirolimus, mycophenolate mofetil, or azathioprine) therapy were also compared.Main outcomes and measuresSurvival was the primary outcome; chronic rejection incidence and subsequent mortality were secondary outcomes.ResultsAmong this population of 9019 patients (median age, 57 years [interquartile range {IQR}, 46-63 years]; 5194 men [57.6%]), sirolimus?plus?tacrolimus was associated with better survival than mycophenolate mofetil plus tacrolimus (median, 8.9 years [IQR, 4.4-12.7 years] vs 7.1 years [IQR, 3.6-12.1 years]; adjusted hazard ratio [aHR],?0.71; 95% CI, 0.56-0.89; P?=?.003). Chronic rejection incidence (aHR,?0.75; 95% CI, 0.61-0.92) and mortality after chronic rejection (aHR,?0.52; 95% CI, 0.31-0.81) were lower with sirolimus?plus?tacrolimus. Compared with mycophenolate mofetil plus tacrolimus, survival differences for sirolimus plus mycophenolate mofetil plus tacrolimus (aHR,?1.14; 95% CI, 0.79-1.65), mycophenolate sodium plus tacrolimus (aHR,?0.95; 95% CI, 0.77-1.17), and azathioprine?plus?tacrolimus (aHR,?0.93; 95% CI, 0.84-1.02) were not significant. The induction-maintenance combination with the highest survival was sirolimus?plus?tacrolimus without induction therapy (median survival, 10.7 years [IQR, 7.3-12.7 years]; aHR,?0.48; 95% CI, 0.31-0.76; P?=?.002) compared with mycophenolate mofetil plus tacrolimus with induction therapy (median survival, 7.4 years [IQR, 3.9-12.6 years]).Conclusions and relevanceSirolimus?plus?tacrolimus was associated with improved patient survival after lung transplant compared with mycophenolate mofetil plus tacrolimus; no antibody induction therapy with sirolimus?plus?tacrolimus was associated with maximal survival.

Project description:BackgroundThe gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined.MethodsWe employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group), and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group).ResultsA statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity) at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05). Flagellar motor switch protein (fliNY) and type IV pilus assembly protein pilM (pilM) were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA) was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity.ConclusionsOur study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this objective.

Project description:BackgroundTacrolimus is the first-line immunosuppressant after organ transplantation. It is mainly metabolized by cytochrome P450, family 3, subfamily A (CYP3A) enzymes, but there are large individual differences in metabolism. Interleukin 6 (IL6) has been shown to cause a pan-suppression of mRNA levels of ten major CYP enzymes in human hepatocyte cultures. IL6 has been shown to provide hepatoprotection in various models of liver injury. Rs1800796 is a locus in the IL6 gene promoter region which regulates cytokine production. We speculated that IL6 rs1800796 polymorphisms may lead to individual differences in tacrolimus metabolism by affecting CYP3A enzymes levels and liver function after liver transplantation.Methodology/principal findingsNinety-six liver transplant patients receiving tacrolimus were enrolled in the study. Two single nucleotide polymorphisms (SNP), CYP3A5 rs776746 and IL6 rs1800796, were genotyped in both donors and recipients. The effects of SNPs on tacrolimus concentration/dose (C/D ratio) at four weeks after transplantation were studied, as well as the effects of donor IL6 rs1800796 polymorphisms on liver function. Both donor and recipient CYP3A5 rs776746 allele A showed association with lower C/D ratios, while donor IL6 rs1800796 allele G showed an association with higher C/D ratios. Donor CYP3A5 rs776746 allele A, IL6 rs1800796 allele C, and recipient CYP3A5 rs776746 allele A were associated with fast tacrolimus metabolism. With increasing numbers of these alleles, patients were found to have increasingly lower tacrolimus C/D ratios at time points after transplantation. Donor IL6 rs1800796 allele G carriers showed an association with higher glutamic-pyruvic transaminase (GPT) levels.ConclusionsCombined analysis of donor CYP3A5 rs776746, IL6 rs1800796, and recipient CYP3A5 rs776746 polymorphisms may distinguish tacrolimus metabolism better than CYP3A5 rs776746 alone. IL6 may lead to individual differences in tacrolimus metabolism mainly by affecting liver function.

Project description:Background and objectiveThe association between the CYP3A4*1B single nucleotide polymorphism (SNP) and tacrolimus pharmacokinetics in different studies is controversial. Therefore, a meta-analysis was employed to evaluate the correlation between the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics at different post-transplantation times in adult renal transplant recipients.MethodsStudies evaluating the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics were retrieved through a systematical search of Embase, PubMed, the Cochrane Library, ClinicalTrials.gov and three Chinese literature databases (up to Sept. 2014). The pharmacokinetic parameters (weight-adjusted tacrolimus daily dose and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio) were extracted, and the meta-analysis was performed using Stata 12.1.ResultsSeven studies (involving 1182 adult renal transplant recipients) were included in this meta-analysis. For the weight-adjusted tacrolimus daily dose, in all included renal transplant recipients (European & Indian populations), CYP3A4*1/*1 recipients required a significantly lower weight-adjusted tacrolimus daily dose than did CYP3A4*1B carriers at 7 days (WMD -0.048; 95% CI -0.083 ~ -0.014), 6 months (WMD -0.058; 95% CI -0.081 ~ -0.036) and 12 months (WMD - 0.061; 95% CI -0.096 ~ -0.027) post-transplantation. In light of the heterogeneity, the analysis was repeated after removing the only study in an Indian population, and CYP3A4*1/*1 European recipients (mostly Caucasian) required a lower weight-adjusted tacrolimus daily dose within the first year post-transplantation. The tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio (C0/Dose ratio) was significantly higher in CYP3A4*1/*1 recipients than in CYP3A4*1B carriers at 6 months (WMD 52.588; 95% CI 22.387 ~ 82.789) and 12 months (WMD 62.219; 95% CI 14.218 ~ 110.221) post-transplantation. When the only study in an Indian population was removed to examine European recipients (mostly Caucasian), the significant difference persisted at 1 month, 6 months and 12 months post-transplantation.ConclusionBased on our meta-analysis, the CYP3A4*1B genetic polymorphism affects tacrolimus dose requirements and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio within the first year post-transplantation in adult renal transplant recipients, especially in European recipients (mostly Caucasian).

Dataset Information

Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis.

Background

Methods

Results

Conclusion

Publications

Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis.

Similar Datasets

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