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Effect of sirolimus on carotid atherosclerosis in kidney transplant recipients: data derived from a prospective randomized controlled trial.

ABSTRACT: Background:In animal models, the mammalian target of rapamycin inhibitors (mTORIs) may prevent atherogenesis by the regulation of homeostasis of cholesterol and by a reduced inflammatory response. The aim of this study is to compare the carotid intima-media thickness (cIMT) between de novo tacrolimus/mycophenolate and tacrolimus/sirolimus at low doses. The cIMT is considered a surrogate marker of atherosclerosis. Methods:We evaluated cIMT at baseline and at 6 and 12?months after kidney transplantation in a database derived from a previously published trial. That trial had prospectively randomly assigned kidney transplant recipients older than 60?years of age to one of two groups: tacrolimus/sirolimus (n?=?21) or tacrolimus/mycophenolate (n?=?23). The cIMT was evaluated by using ultrasound in the common carotid artery wall on both sides. Results:The total and high-density lipoprotein cholesterol levels were higher in the sirolimus group at 6 and 12?months. The cIMT decreased over time at 6 and 12?months in the sirolimus group (P?=?0.012); this decrease continued to be significant in a model adjusted for age, sex, presence of diabetes, statin use and smoking. Conclusions:The use of sirolimus plus tacrolimus de novo in kidney transplantation is associated with a reduction in cIMT after 12?months, a decrease more significant than seen with the combination of mycophenolate plus tacrolimus. This suggests a class effect of mTORI in the prevention of atherosclerosis.

SUBMITTER: Silva AL

PROVIDER: S-EPMC6275445 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Effect of sirolimus on carotid atherosclerosis in kidney transplant recipients: data derived from a prospective randomized controlled trial.

Silva Andre L AL Fusco Daniéliso R DR Nga Hong S HS Takase Henrique M HM Bravin Ariane M AM Contti Mariana M MM Valiatti Mariana F MF de Andrade Luis Gustavo M LGM

Clinical kidney journal 20180606 6

<h4>Background</h4>In animal models, the mammalian target of rapamycin inhibitors (mTORIs) may prevent atherogenesis by the regulation of homeostasis of cholesterol and by a reduced inflammatory response. The aim of this study is to compare the carotid intima-media thickness (cIMT) between <i>de novo</i> tacrolimus/mycophenolate and tacrolimus/sirolimus at low doses. The cIMT is considered a surrogate marker of atherosclerosis.<h4>Methods</h4>We evaluated cIMT at baseline and at 6 and 12 months ...[more]

PMID: 30524720

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Project description:Background and aimsAs conversion from calcineurin inhibitor to sirolimus (SRL), a mechanistic target of rapamycin inhibitor (mTOR-I), has been shown to enhance immunoregulatory profiles in liver transplant (LT) recipients (LTRs), mTOR-I therapy might allow for increased success of immunosuppression (IS) withdrawal. Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal.Approach and resultsWe performed a prospective trial of SRL monotherapy withdrawal in nonimmune, nonviremic LTRs > 3 years post-LT. SRL was weaned over ~6 months, and biopsies were performed 12 months postweaning or at concern for acute rejection. Twenty-one LTRs consented; 6 were excluded due to subclinical acute rejection on baseline biopsy or other reasons, and 15 underwent weaning (age 61.3 ± 8.8 years; LT to SRL weaning 6.7 ± 3 years). Eight (53%) achieved operational tolerance (TOL). Of the 7 who were nontolerant (non-TOL), 6 had mild acute rejection on biopsy near the end of weaning or at study end; 1 was removed from the trial due to liver cancer recurrence. At baseline preweaning, there were statistically increased blood tolerogenic dendritic cells and cell phenotypes correlating with chronic antigen presentation in the TOL versus non-TOL groups. A previously identified biopsy gene signature accurately predicted TOL versus non-TOL in 12/14 LTRs before weaning. At study end, biopsy staining revealed statistically significant increases in antigen-presenting cell:leukocyte pairings, FOXP3+ /CD4+ T cells, Tbet+ /CD8+ T cells, and lobular dendritic cells in the non-TOL group.ConclusionsThis study evaluated IS withdrawal directly from mTOR-I therapy in LTRs and achieved > 50% operational tolerance. Preweaning gene expression and peripheral blood mononuclear cell profiling may be useful as predictors of successful mTOR-I therapy withdrawal. NCT02062944.

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Effect of sirolimus on carotid atherosclerosis in kidney transplant recipients: data derived from a prospective randomized controlled trial.

Publications

Effect of sirolimus on carotid atherosclerosis in kidney transplant recipients: data derived from a prospective randomized controlled trial.

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