tacrolimus and Atherosclerosis

Magnesium (Mg) is key in diabetes mellitus, hyperlipidemia, and cardiovascular disease.. This is a retrospective cross-sectional study including 103 kidney transplant recipients. Patients aged under 18 years, patients treated with Mg supplementation, antihyperlipidemic agents, or diuretics, and patients with active infection or malignancy were not enrolled. Patients were divided into 2 groups according to median serum Mg level. The atherogenic index of plasma was calculated by a logarithmic transformation of the number acquired by dividing the molar concentrations of serum triglyceride by high-density lipoprotein value.. The mean serum Mg level was 1.91 ± 0.28 mg/dL. Six patients (5.8%) had hypomagnesemia (Mg <1.5 mg/dL), and 2 (1.9%) had hypermagnesemia (Mg >2.6 mg/dL). Serum Mg level was negatively correlated with body mass index, estimated glomerular filtration rate (eGFR), and tacrolimus trough level and positively correlated with levels of phosphorus, total cholesterol, and low-density lipoprotein (LDL-C). There was no correlation between serum Mg and triglyceride, high-density lipoprotein, atherogenic index of plasma, and cyclosporin A trough level. Patients with Mg >1.87 mg/dL had lower eGFR, tacrolimus, and cyclosporin A trough level and higher total cholesterol and LDL-C compared to those with Mg ≤1.87 mg/dL. In adjusted ordinal analysis, eGFR (hazard ratio (HR): 0.981, 95% CI 0.964-0.999, P = .036) and total cholesterol (HR: 1.015, 95% CI 1.004-1.027, P = .008) were independently associated with serum Mg. In multivariate linear regression analysis, serum Mg level was independently associated with LDL-C (β = .296, t = 3.079, P = .003) and total cholesterol (β = .295, t = 3.075, P = .003).. Serum Mg level may have an important impact on dyslipidemia in kidney transplant recipients.

Topics: Adolescent; Aged; Atherosclerosis; Cholesterol, LDL; Cross-Sectional Studies; Cyclosporine; Humans; Hyperlipidemias; Kidney Transplantation; Lipoproteins, HDL; Magnesium; Retrospective Studies; Tacrolimus; Triglycerides

Leukocyte telomere length (LTL) is a marker for biological age. Pediatric liver transplant recipients show a high rate of subclinical atherosclerosis, indicated by elevated intima-media thickness (IMT). We hypothesized that atherosclerosis is associated with biological age in these patients and investigated the course of LTL over time. We measured LTL from peripheral blood leukocytes by quantitative polymerase chain reaction and IMT from 97 pediatric patients after liver transplantation in a prospective cohort study. Of the patients, 71% (n = 69) had two or more assessments (total, 228 observations; median follow-up, 1.1 years). Lower LTL was associated with higher IMT (β = -0.701, p = 0.01) and higher aspartate aminotransferase (β = -0.001, p = 0.02), adjusted for age, sex, and age at transplantation. Of the patients, 45% showed decreasing LTL over time, whereas 55% exhibited stable LTL. Patients with stable LTL showed a decrease in IMT (median, -0.02 mm/year) and a decrease of tacrolimus trough levels (median, -0.08 μg/L/year). LTL is associated with IMT independent of age in pediatric liver transplant patients, suggesting that early aging contributes to the high burden of subclinical cardiovascular damage and may furthermore negatively affect the graft.

Topics: Aspartate Aminotransferases; Atherosclerosis; Carotid Intima-Media Thickness; Child; Humans; Leukocytes; Liver Transplantation; Prospective Studies; Tacrolimus; Telomere

Although cardiovascular disease (CVD) is the leading cause of long-term mortality in liver transplant recipients (LTRs), the role of recently identified biomarkers of CVD risk in liver transplantation is unknown. We aimed to evaluate an extensive CVD risk profile in LTRs. Markers of CVD risk in 65 LTRs with no known history of diabetes mellitus (DM), dyslipidemia, or ischemic heart disease were compared to age-, sex-, and body mass index (BMI)-matched controls with no chronic medical disease. LTRs on corticosteroids or those with graft cirrhosis (GC) were excluded. The effect of calcineurin inhibitors on the CVD risk profile was separately analyzed in LTRs receiving either tacrolimus (Tac) or cyclosporine A (CsA). To evaluate the impact of GC, a comparison was made between LTRs with and without GC. Non-DM LTRs were matched to controls with respect to age, sex, and BMI. LTRs had similar serum high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and total cholesterol in comparison with BMI-matched controls. Proatherogenic small-dense (sd) LDL-C (33.6 ± 14 versus 25.9 ± 9.9 mg/dL; P < 0.001) and %sdLDL-C (30% ± 10% versus 26.4% ± 9%; P = 0.02) were significantly higher in LTRs. In comparison with controls, LTRs had higher apolipoprotein B (apoB; 98 ± 37 versus 88 ± 24 mg/dL; P < 0.01), very low density lipoprotein-particle concentration (VLDL-P; 7.7 ± 6.7 nmol/L versus 3.2 ± 9.1 nmol/L; P < 0.001), and VLDL size (51.1 ± 6.6 versus 46.5 ± 6.9 nm; P < 0.001). In LTRs, VLDL size and VLDL-P were directly related to serum CsA levels (r = 0.53, P = 0.09, and r = 0.63, P < 0.01, respectively) but not to Tac levels. In comparison with controls, LTRs had significantly lower total serum high-density lipoprotein-particle concentration. In comparison with those with preserved graft function, LTRs with GC had lower levels of serum atherogenic markers characterized by low sdLDL-C, apoB, triglycerides, LDL-C, and total cholesterol. In conclusion, LTRs have a proatherogenic lipoprotein profile that is not captured with a traditional lipid panel, and this suggests that a detailed serum atherogenic profile is needed to truly assess CVD risk in LTRs.

Topics: Aged; Atherosclerosis; Biomarkers; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Cross-Sectional Studies; Cyclosporine; Female; Humans; Immunosuppression Therapy; Inflammation; Lipoproteins; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Middle Aged; Prospective Studies; Risk; Tacrolimus; Transplant Recipients

Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immuno-inflammatory mechanisms are involved. Inflammatory cytokines are implicated in the development and progression of atherosclerotic lesions. Immunomodulatory therapies have been proposed for the treatment of atherosclerosis. Therefore, the aim of this study was to investigate the systemic anti-inflammatory and immunomodulatory effects of atorvastatin, cyclosporine A (CsA), and tacrolimus (FK506) on plasma inflammatory markers in atherosclerotic rabbits. Male New Zealand rabbits were randomized into five groups each of 12 animals. Standard diet-fed group served as control, and the cholesterol-fed group received a diet supplemented with 1% cholesterol alone, cholesterol + atorvastatin, cholesterol + FK506, and cholesterol + CsA. Serum levels of lipid profile parameters (triglycerides, cholesterol, and high-density lipoprotein) were measured using colorimetric methods. Serum levels of C-reactive protein (CRP), interleukin-6 (Il-6), and interferon-gamma (INF-γ) were measured in all studied groups using ELISA techniques. Our results revealed a significant decrease (p < 0.001) in the serum levels of lipid profile parameters, CRP, Il-6, and INF-γ in atorvastatin-treated group compared with the cholesterol-fed group. On the other hand, a non-significant difference was observed for the same parameters in either FK506- or CsA-treated groups compared with the cholesterol-fed group. In conclusion, atorvastatin has a systemic anti-inflammatory role that far surpassed the cholesterol reduction effect alone. FK506 or CsA failed to suppress elevated plasma inflammatory markers. Thus, low doses of these two immunomodulating drugs could not have generalized systemic anti-inflammatory or immunosuppressive effects.

Topics: Animals; Atherosclerosis; Atorvastatin; Biomarkers; C-Reactive Protein; Cholesterol; Cholesterol, Dietary; Cholesterol, HDL; Cholesterol, LDL; Cyclosporine; Heptanoic Acids; Immunologic Factors; Inflammation; Interferon-gamma; Interleukin-6; Male; Plasma; Pyrroles; Rabbits; Tacrolimus; Triglycerides

Previous studies showed both pro- and anti-atherogenic effects of immunosuppressant drug FK506 on atherosclerosis. As these divergent/paradoxical results of FK506 may at least in part be attributable to differences in FK506 dosing, we have, in the current study, assessed dose-dependent effects of FK506 on atherosclerotic lesion formation as well as on inflammatory parameters relevant to atherosclerosis. Unlike low-dose FK506, high-dose FK506 did not protect against atherosclerosis in ApoE-/- mice. The high-dose induced hypercholesterolaemia, whereas the low-dose did not. Both low- and high-dose FK506 treatment significantly reduced systemic CD3+ and CD4+CD25+ T-cell populations, and showed similar suppression of FoxP3 regulatory T-cell populations. Increased IL-4+ CD4+ T-cells and decreased IgG-MDA-LDL antibody titres pointed to a selective, albeit modest Th2 skewing in the high-dose treatment group, despite the advanced stage of atherosclerosis. Low concentrations of FK506, however, skewed bone marrow-derived macrophage polarisation towards a M2 macrophage phenotype, whereas high concentration did not. A low-dose FK506 treatment regime protected against atherosclerosis by suppressing T-cell activation and favouring (M2) macrophage polarisation. Although a high-dose FK506 treatment effected a similar T-cell suppressive effect, with an even more pronounced shift towards Th2 type immune responses, this did not translate in atheroprotection due to the hypercholesterolaemia and absent M2 skewing.

Topics: Animals; Antibodies; Apolipoproteins E; Atherosclerosis; Carotid Arteries; Cell Differentiation; Cells, Cultured; Cholesterol; Cytokines; Cytoprotection; Drug Dosage Calculations; Humans; Hypercholesterolemia; Immunosuppressive Agents; Lipoproteins, LDL; Lymphocyte Activation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Tacrolimus; Th2 Cells

Sirolimus (SIR) alone or in combination with cyclosporine (CsA) or tacrolimus (TAC) are used in solid organ transplantation, but uncertainty remains regarding their respective atherogenic potentials.. THP-1 cells were cultured as macrophages and then treated with plasma trough and peak concentration doses of SIR, SIR/CsA or SIR/TAC to assess the time- and dose-dependent mRNA or protein expression of selected atherogenic genes. The selected atherogenic genes included: the macrophage scavenger receptors (MSRs) CD36, CD68, scavenger receptor (SR)-A, SR-BII, and LOX-1; the nuclear hormone receptors peroxisome proliferator activated receptor gamma (PPARgamma) and liver-X-receptor alpha (LXRalpha); and the cholesterol efflux transporter (ABCA-1).. SIR-mediated changes in mRNA included the upregulation of ABCA1, downregulation of CD68, SR-A and SR-BII, and concentration- and/or time-dependent effects on CD36, LOX-1, PPARgamma, and LXRalpha that did not translate into significant protein changes. With SIR/CsA, the protein expressions of PPARgamma and ABCA-1 were downregulated at 8 h. In contrast, with SIR/TAC, PPARgamma, and ABCA-1 protein expressions were upregulated at 8 h.. Combination results differed from findings with SIR alone, supporting the observed clinical phenotype with calcineurin inhibitors. These findings may provide a rationale for the development of novel drug delivery strategies to mitigate adverse pharmacodynamic responses.

Topics: Atherosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Calcineurin Inhibitors; CD36 Antigens; Cell Line; Cyclosporine; DNA-Binding Proteins; Dose-Response Relationship, Drug; Drug Interactions; Gene Expression Regulation; Humans; Immunosuppressive Agents; Liver X Receptors; Macrophages; Orphan Nuclear Receptors; PPAR gamma; Receptors, Cytoplasmic and Nuclear; Receptors, Scavenger; RNA, Messenger; Sirolimus; Tacrolimus; Time Factors

Organ transplantation is a risk factor for atherogenesis that may be related to immunosuppressive therapy. Increased free radical generation may even aggravate atherogenesis. The aim of the study was to assess lipid metabolism in relation to risk factors for atherogenesis as well as carbohydrate metabolism and antioxidant status among children after liver transplantation. We studied 35 children at 3 to 5 years after liver transplant in whom the following parameters were assessed: total cholesterol; triglyceride; high-density lipoprotein cholesterol; low-density lipoprotein cholesterol (LDL-C); very low-density lipoprotein cholesterol; apolipoproteins B, AI, E, lipoprotein (a); vitamin E; glutathione; glucose; insulin; and glutathione peroxidase activity. Three subgroups of patients were assessed according to the immunosuppressive therapy: cyclosporine (CsA), tacrolimus (Tac), or mycophenolate mofetil (MMF) in combination with low-dose CsA or Tac. We observed differences among the subgroups only in total cholesterol (CsA: 131.6 to 285.6; Tac: 144.0 to 181.61; MMF: 132.1 to 181.2) and LDL-C (CsA: 79.4 to 126.9; Tac: 42.2 to 118.8; MMF: 74.2 to 117.3). Lipid metabolism was not significantly disturbed among children after liver transplantation, an observation that does not point to a high risk of atherogenesis. CsA seems to have the strongest untoward effect on cholesterol metabolism. Decreased GSH concentration after liver transplantation may be related to slightly impaired liver function, but GPx activity and vitamin E concentrations remained normal.

Topics: Antioxidants; Atherosclerosis; Child; Child, Preschool; Cyclosporine; Dietary Carbohydrates; Dietary Fats; Drug Therapy, Combination; Follow-Up Studies; Glutathione; Glutathione Peroxidase; Humans; Immunosuppressive Agents; Lipoproteins; Liver Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors