tacrolimus and Arteriosclerosis

Cyclosporine and tacrolimus are potent inhibitors of the calcineurin-dependent cytokine synthesis in activated lymphocytes. In renal transplant patients tacrolimus is more powerful in preventing severe and refractory rejections, even when compared with the new cyclosporine microemulsion formulation. Both drugs are equally nephrotoxic, but tacrolimus induces less hypertension and less pronounced hyperlipidaemia. Especially in some categories of patients, a higher incidence of de-novo diabetes mellitus is seen with tacrolimus therapy.

Topics: Arteriosclerosis; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Tacrolimus; Time Factors

Topics: Adult; Arteriosclerosis; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Lipids; Male; Pancreas Transplantation; Risk Factors; Tacrolimus

Topics: Adult; Arteriosclerosis; Cyclosporine; Diabetes Mellitus; Dose-Response Relationship, Drug; Female; Glucose Tolerance Test; Graft Rejection; Humans; Liver Transplantation; Male; Middle Aged; Risk Factors; Tacrolimus

Calcineurin inhibitors reduce the acute rejection rate and greatly improve renal allograft survival. However, they are associated with some adverse events, including nephrotoxicity, a risk factor for allograft failure. Chronic calcineurin inhibitor-induced nephrotoxicity causes irreversible damage to renal components, such as arteriolar hyaline thickening. The aim of this study is to investigate the risk factors for tacrolimus-induced chronic nephrotoxicity using zero-time biopsy specimens.. Between January 2001 and December 2010, 483 patients who underwent living-related kidney transplantation and had also been placed on a tacrolimus-based regimen were enrolled in this study. There were 1859 specimens evaluated comprising 483 zero-time biopsy specimens and 1376 protocol and for-cause biopsy specimens. De novo arteriolar hyaline thickening due to tacrolimus-induced chronic nephrotoxicity was scored according to the Banff classification aah score. In this study, tacrolimus-induced nephrotoxicity was defined as a positive aah score.. Of the 483 patients, 108 patients (22.4%) had biopsy-proven tacrolimus-induced chronic nephrotoxicity. Multivariate analysis showed that interlobular arteriosclerosis proven by zero-time biopsy (OR: 2.23, 95%CI: 1.38-3.58, P < 0.01) and acute rejection episodes (OR: 1.58, 95%CI: 1.00-2.47, P = 0.04) were independent risk factors for tacrolimus-induced chronic nephrotoxicity. However, tacrolimus-induced chronic nephrotoxicity did not affect long-term graft survival.. This is the first report showing that arteriosclerosis in zero-time biopsy specimens is a risk factor for histological tacrolimus-induced chronic nephrotoxicity.

Topics: Acute Disease; Adult; Allografts; Arterioles; Arteriosclerosis; Biopsy; Calcineurin Inhibitors; Chi-Square Distribution; Chronic Disease; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney; Kidney Diseases; Kidney Transplantation; Living Donors; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Predictive Value of Tests; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

Oxidized low-density lipoprotein (oxLDL)-induced apoptosis of vascular endothelial cells may contribute to plaque erosion and rupture. We aimed to clarify the relationship between the oxLDL-induced calcium signal and induction of apoptotic pathways.. Apoptosis was evaluated by biochemical methods, including studies of enzyme activities, protein processing, release of proapoptotic factors, chromatin cleavage, and especially by morphological methods that evaluate apoptosis/necrosis by SYTO-13/propidium iodide fluorescent labeling. The oxLDL-induced sustained calcium rise activated 2 distinct calcium-dependent mitochondrial apoptotic pathways in human microvascular endothelial cells. OxLDLs induced calpain activation and subsequent Bid cleavage and cytochrome C release, which were blocked by calpeptin. Cyclosporin-A inhibited cytochrome C release, possibly by inhibiting the opening of the mitochondrial permeability transition pore (mPTP). Calcineurin, another cyclosporin-sensitive step, was not implicated, because oxLDLs inhibited calcineurin and FK-506 treatment was ineffective. Cytochrome C release in turn induced caspase-3 activation. In addition, oxLDLs triggered release and nuclear translocation of mitochondrial apoptosis-inducing factor through a mechanism dependent on calcium but independent of calpains, mPTP, and caspases.. OxLDL-induced apoptosis involves 2 distinct calcium-dependent pathways, the first mediated by calpain/mPTP/cytochrome C/caspase-3 and the second mediated by apoptosis-inducing factor, which is cyclosporin-insensitive and caspase-independent.

Topics: Apoptosis; Apoptosis Inducing Factor; Arteriosclerosis; BH3 Interacting Domain Death Agonist Protein; Calcium; Calpain; Carrier Proteins; Caspase 3; Caspase Inhibitors; Caspases; Cells, Cultured; Cyclosporine; Cysteine Proteinase Inhibitors; Cytochromes c; Endothelium, Vascular; Flavoproteins; Humans; Immunosuppressive Agents; Lipoproteins, LDL; Membrane Proteins; Microcirculation; Mitochondria; Tacrolimus

Since atherosclerosis is a chronic inflammatory disease, we tested the hypothesis that the immunosuppressive drug FK506 would attenuate the development of atherosclerosis using a mouse model of collar-induced atherosclerosis. ApoE-/- mice were treated for 4 weeks with the immunosuppressive drug FK506 (0.05 mg/kg/day), yielding sustained blood levels (approximately 0.2 ng/mL) without systemic side effects. Atherosclerotic plaque development of FK506-treated mice was significantly reduced (63%) while plaque cell density was increased (52%) compared to controls. Importantly, FK506 also blocked progression of pre-existing atherosclerotic plaques. Plaque area of pre-existing plaques was 35% reduced by FK506. Cell density (35%) and collagen content (51%) were significantly increased, whereas necrotic core content was decreased (42%), indicating a more stable plaque morphology. Similar results were found during spontaneous atherosclerotic plaque development in ApoE-/- mice (treatment 17-25 weeks of age). Flow-cytometric analysis showed no peripheral effects on blood cell count or T-cell activation after FK506-treatment. In vitro, FK506 decreased vascular smooth muscle cell (VSMC) apoptosis and inhibited nuclear factor of activated T cells (NFAT)-luciferase reporter activity at concentrations in the range of the in vivo concentration. Low-dose FK506 inhibits collar-induced atherosclerotic plaque development and progression and induces more stable plaque phenotypes in ApoE-/- mice without any peripheral side effects.

Topics: Animals; Apolipoproteins E; Apoptosis; Arteriosclerosis; Blood Cell Count; Disease Models, Animal; Immunosuppressive Agents; Luciferases; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; NF-kappa B; Plaque, Amyloid; Tacrolimus

The main rheological properties of red blood cells (RBC) are deformability and aggregability. Deformability is one of the most important factors of RBC flow in high-shear rate areas, especially in the microcirculation. Aggregability of erythrocytes can impair circulation in low-shear rate areas. Both deformability and aggregability of RBC are abnormal in patients with renal insufficiency and after kidney transplantation. Cyclosporine (CsA) and less frequently tacrolimus (Tc) may cause hyperlipidemia and hypertension. Dobiasova et al proposed the term Atherogenic Index of Plasma (AIP), defined as a log (TG/HDL-C). Subjects with high AIP have and higher risk of cardiovascular complications due to atherosclerosis. Hence the aim of this study was to compare aggregability and deformability of RBC from kidney transplant recipients on CsA or Tc-based immunosuppression with healthy volunteers and subjects with dyslipidemia (control groups). Both control and transplant recipient groups were arbitrarily divided by value of AIP as < or = 0 (AIP-) or >0 (AIP+). Deformability and aggregability of erythrocytes were measured using Rheodyn SSD and Myrenne Aggregometer, respectively.. We observed a significant increase in aggregation index at stasis in CsA-treated patients and an increased deformability in Tc-treated patients with negative AIP. Deterioration of hemorheological properties of RBC in kidney transplant recipients was confined to an increased aggregability in CsA-treated patients regardless of AIP value. An increased deformability of RBC in Tc-treated patients with normal lipid profiles may suggest a positive effect of Tc on mechanical properties of RBC.

Topics: Adult; Arteriosclerosis; Creatinine; Cyclosporine; Erythrocytes; Female; Hematocrit; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Middle Aged; Postoperative Complications; Rheology; Risk Factors; Tacrolimus

A number of studies have reported a lower atherogenic lipid profile in liver transplant recipients under tacrolimus (FK506) than in those under cyclosporine A (CyA) immunosuppression. This has mainly been attributed to the steroid-saving effect of FK506. However, the effects of converting CyA to FK506 monotherapy on lipid metabolism have not been specifically investigated. In 20 patients with stable graft function, immunosuppressive monotherapy was switched from CyA to FK506 because of CyA-related side-effects (hypertension, nephrotoxicity, hypercholesterolaemia). Serum lipid levels were measured before and 3, 6 and 12 months after conversion. In 5 patients, a modification of immunosuppression became necessary during the study period (4 were reconverted to CyA, 1 to glucocorticoids). In the remaining 15 patients on FK506 monotherapy, 12 months after conversion, a slight decrease in mean serum cholesterol, a slight increase in LDL, but a significant decrease in mean serum HDL were observed, resulting in a significant increase in Chol/HDL and LDL/HDL ratios. Conversion of immunosuppressive monotherapy from CyA to FK506 had no beneficial effect on the atherogenic lipid profile in this selected study population of long-term liver transplant survivors.

Topics: Arteriosclerosis; Cyclosporine; Female; Humans; Immunosuppressive Agents; Lipids; Liver; Liver Transplantation; Male; Middle Aged; Postoperative Period; Retreatment; Tacrolimus; Time Factors

Data indicate that tacrolimus and cyclosporine A (CsA) differentially affect the risk of atherosclerosis. The results of our recent in vitro studies of clinically relevant CsA concentrations demonstrated the modulation of macrophage scavenger receptors (MSRs) involved in atherogenesis. This work evaluated the effects of clinically relevant tacrolimus concentrations on the expression of the MSR genes CD36 and CD68, SR-A and SR-BII, lectin-like oxidized low-density lipoprotein receptor-1, the nuclear hormone receptors peroxisome proliferator-activated receptor (PPAR)gamma and liver-X-receptor-alpha, and the cholesterol efflux pump ABCA1 in the in vitro human THP-1 macrophage model.. The cells were cultured and differentiated into macrophages. Macrophages were treated with the tacrolimus to assess gene expression in a time-dependent (1, 2, 4, 8, and 24 hr) and dose-dependent (concentrations [micrograms/liter] corresponding to the trough [15], peak [30], and 4 x peak [120]) manner using reverse-transcriptase polymerase chain reactions. The gene expression levels of interest were normalized to GAPDH expression in each sample to provide semiquantitative reverse-transcriptase polymerase chain reaction results. Additional immunoblotting studies demonstrated protein expression of CD36, PPARgamma, and ABCA1. RESULTS.: The gene expression of CD36, SR-BII, and lectin-like oxidized low-density lipoprotein receptor-1 were down-regulated, and ABCA1 was up-regulated. CD68, SR-AI, liver-X-receptor-alpha, and PPARgamma were regulated in a dose-dependent manner. Protein expression of CD36 was down-regulated, and PPARgamma and ABCA1 were relatively unchanged.. Tacrolimus seems to regulate MSRs, nuclear hormone receptors, and ABCA1 in THP-1 macrophages. These results differ from previous findings with CsA and may provide insight into the mechanisms of posttransplant atherosclerosis.

Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Arteriosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; CD36 Antigens; Cell Line; Cyclosporine; Gene Expression; Humans; Immunosuppressive Agents; Macrophages; Receptors, Cytoplasmic and Nuclear; Receptors, Immunologic; Receptors, LDL; Receptors, Scavenger; RNA, Messenger; Scavenger Receptors, Class A; Tacrolimus

Cyclosporin A is a lipogenic immunosuppressor that can induce posttransplant hyperlipidaemia. Oxidation of low-density lipoprotein (LDL) has been recognized as a major atherogenic factor. Tacrolimus seems to be less lipogenic with an apparently better cardiovascular profile than CsA.. We have studied the lipidic profile and the oxidation of HDL and LDL in 20 renal transplant patients, 12 male and 8 female, mean age 45 +/- 10 year, who where switched from CsA to tacrolimus due to CsA adverse effects. LDL were determined by ultracentrifugation. Oxidation study before and 6 months after conversion to tacrolimus was performed by adding CuSO4.. After conversion, systolic blood pressure (BP) decreased from 154 +/- 21 to 133 +/- 21 mm Hg (p = 0.008), diastolic BP from 97 +/- 13 to 77 +/- 15 mm Hg (p = 0.016), total cholesterol from 6.08 +/- 0.9 to 5.68 +/- 1.1 mmol/l (p = 0.02), LDL-chol from 3.29 +/- 1.01 to 2.96 +/- 0.3 mmol/l (p = 0.04) and apo-B lipoprotein from 1.42 +/- 0.28 to 1.15 +/- 0.34 mg/dl (p = 0.003). The oxidation of LDL improved after conversion: the initial dienic compounds decreased from 95 +/- 20 to 63 +/- 12 umol/g and the final DC from 207 +/- 56 to 107 +/- 35 umol/g. Lag-phase increased from 33 +/- 21 to 45 +/- 17 min (p < 0.05).. Tacrolimus has improved hyperlipidaemia in our cyclosporin previously treated patients and increased the resistance to oxidation of high and low-density lipoproteins.

Topics: Adult; Antihypertensive Agents; Apolipoproteins B; Arteriosclerosis; Azathioprine; Cholesterol; Cyclosporine; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Prednisone; Retrospective Studies; Tacrolimus; Triglycerides

Topics: Arteriosclerosis; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lipoproteins, LDL; Male; Middle Aged; Reference Values; Risk Factors; Tacrolimus

The aim of this study was to compare the effects of cyclosporine, tacrolimus, mycophenolate mofetil and SDZ RAD on an animal model of transplant arteriosclerosis involving alloantigen dependent and independent mechanisms.

Topics: Animals; Aorta, Abdominal; Arteriosclerosis; Chronic Disease; Cyclosporine; Disease Models, Animal; Everolimus; Graft Rejection; Immunosuppressive Agents; Isoantigens; Male; Mycophenolic Acid; Rats; Rats, Inbred F344; Rats, Inbred Lew; Sirolimus; Tacrolimus

Endothelial dysfunction is an early key event in the development of arteriosclerotic cardiovascular disease (ASCVD), thus an early marker of subclinical ASCVD. Endothelial function is impaired in renal transplant recipients (RTR) treated with cyclosporine (CyA). Tacrolimus is associated with less hyperlipidemia and hypertension than CyA, however, there are no data on endothelial function in tacrolimus-treated RTR.. High-resolution brachial ultrasonography was used to assess endothelium-dependent dilatation (EDD), and endothelium-independent dilatation (EID) in 20 stable RTR and a control group of 10 healthy subjects without clinical evidence of ASCVD. The RTR group included patients receiving CyA (n=10) and tacrolimus (n=10). EDD and EID were measured as percent increase in brachial artery diameter in response to reactive hyperemia and nitroglycerin, respectively.. EDD was significantly lower in RTR versus controls (1.7+/-0.7 vs. 7.3+/-0.7%, P<0.0001), whereas EID was similar in the two groups. No significant differences were found in EDD or in EID between CyA- and tacrolimus-treated RTR. Glomerular filtration rate, plasma homocysteine, blood pressure, and lipid profiles were similar in CyA- and tacrolimus-treated RTR.

Topics: Adult; Arteriosclerosis; Cyclosporine; Endothelium, Vascular; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Risk Factors; Tacrolimus; Vasodilation

Although the introduction of cyclosporine A (CyA) and FK506 for immunosuppressive therapy has dramatically enhanced the early survival of organ transplant recipients, administration of these immunosuppresants is correlated with high incidence of transplant arteriosclerosis. Transplant-associated arteriosclerosis is believed to result from recipient inflammatory responses to the allograft, as it is characterized by early mononuclear cell infiltration of the transplanted vessel. We reported that vascular endothelial cells naturally express a death factor, Fas ligand, that may function to inhibit detrimental leukocyte infiltration. Here, we show that CyA or FK506 downregulates FasL expression on endothelial cells with accompanying decrease in the cytotoxicity toward Fas-bearing cells. Our findings not only demonstrate a novel biological action of these drugs, but also suggest a mechanism by which immunosupressive treatment contributes to atherogenesis.

Topics: Arteriosclerosis; Cyclosporine; Down-Regulation; Endothelium, Vascular; Fas Ligand Protein; Immunosuppressive Agents; Membrane Glycoproteins; Organ Transplantation; Tacrolimus

Tacrolimus (TAC) is an effective primary immunosuppressive agent in kidney transplantation. Acute nephrotoxicity due to TAC in kidney transplant patients is either similar to, or significantly more frequent than that of cyclosporin A (CsA). In this study we describe the clinico-morphologic characteristics of acute TAC nephrotoxicity in kidney transplant recipients.. We studied retrospectively the clinical courses of 67 patients who underwent kidney transplantation under TAC immunosuppression at Tokyo Women's Medical University between July 1990 and January 1997. We compared the recipient's characteristics with and without acute TAC nephrotoxicity. We also studied retrospectively the clinico-morphologic profiles of the acute TAC nephrotoxicity with 16 kidney transplant recipients under TAC immunosuppression, who were diagnosed with acute TAC nephrotoxicity by allograft biopsies between January 1996 and January 1997.. There were no significant differences between acute TAC nephrotoxicity and non-nephrotoxicity groups about age, sex, donor source, age of donor, the proportion of ABO incompatible and the number of human leukocyte antigen (HLA) mismatches. Of 27 acute TAC nephrotoxicity recipients, 7 patients (26%) had moderate-to-severe grade arteriosclerosis in their allograft arteries. The onset of TAC nephrotoxicity occurred 8-69 days post-operatively. The baseline creatinine level was 1.92 mg/dL (range 0.4-5.1 mg/dL) and rose by 38.4% (range 0-84.6) during episodes of nephrotoxicity. The mean peak of the whole blood TAC trough level during the toxic episodes was 32.5 ng/mL (range 21.2-58.5 ng/mL). The rise in creatinine level preceded the highest TAC level in 10 cases. A mean reduction in TAC dosage of 18.9% (range 0-50% led to a fall of 17.2% (range 0-43%) in serum creatinine levels. The moderate-to-severe arteriosclerosis in allograft arteries was seen in 5 (31%) patients.. The high trough level of the whole blood TAC and the existence of moderate-to-severe arteriosclerosis in allograft arteries have the potential of causing TAC nephrotoxicities. A reduction of TAC dosage may be effective in improving allograft functions.

Topics: Adult; Arteriosclerosis; Creatinine; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Living Donors; Male; Middle Aged; Retrospective Studies; Tacrolimus; Time Factors

Topics: Animals; Antibodies; Arteriosclerosis; Graft Survival; Heart Transplantation; Immunosuppression Therapy; Lymphocyte Depletion; Male; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptors, Antigen, T-Cell, alpha-beta; T-Lymphocytes; Tacrolimus; Transplantation, Heterotopic; Transplantation, Homologous; Transplantation, Isogeneic

To investigate the role of activated T lymphocytes in the formation of atherosclerotic lesions, we studied the influence of FK506, an immunosuppressant, on the development of atherosclerosis in cholesterol-fed rabbits. New Zealand White rabbits fed on a 1.5% cholesterol diet were administered FK506 at 0.05 mg/kg (n = 12), 0.1 mg/kg (n = 12) or isotonic saline (as the control, n = 12) intramuscularly three times a week for 12 weeks. Although FK506 treatment did not affect plasma lipid levels, it caused an increase in the development of atherosclerotic lesions in a dose-dependent manner. Immunohistochemical analysis of the aorta after 8 weeks on the diet revealed that the ratio of T lymphocytes to the total number of cells in the plaques decreased significantly in the FK506 treated rabbits compared to the control rabbits. In culture, FK506 did not affect smooth muscle cell proliferation and cholesteryl ester formation in the macrophages. In contrast, culture medium from lymphocytes stimulated by concanavalin A decreased the accumulation of cholesteryl ester in the macrophages. This effect was inhibited by the culture medium in the presence of FK506. These findings suggest that activated T lymphocytes may inhibit intracellular cholesterol accumulation in atherosclerotic plaque.

Topics: Animals; Arteriosclerosis; Cell Division; Cholesterol Esters; Cholesterol, Dietary; Immunosuppressive Agents; Lipids; Lymphocyte Activation; Macrophages, Peritoneal; Muscle, Smooth, Vascular; Rabbits; T-Lymphocytes; Tacrolimus; Weight Gain

After allogenic transplantations a dramatic increase in the development of arteriosclerotic plaques can be observed, which might be due to metabolic alterations, influenced by changes of the transplant organ or immunosuppression. In this study the effects of FK 506 in kidney transplant patients on cardiovascular risk factors were compared to cyclosporin A (CsA) immunosuppression. Both groups showed no statistical differences in number, kidney function, age, body weight, sex distribution, steroid dosage and follow-up time after transplantation. Total cholesterol was similar in FK 506-treated patients (231 +/- 22 vs. 278 +/- 52 mg/dl) as compared with patients with CsA immunosuppression. Furthermore, there were no differences in triglycerides (220 +/- 72 vs. 210 +/- 67 mg/dl), HDL-cholesterol (67 +/- 14 vs. 52 +/- 18 mg/dl) and fasting glucose (112 +/- 36 vs. 116 +/- 17 mg/dl). However, the concentration of LDL-cholesterol (114 +/- 21 vs. 167 +/- 37 mg/dl), the independent risk factor Lp(a) (11 +/- 9 vs. 27 +/- 8 mg/dl) and fibrinogen (216 +/- 71 vs. 297 +/- 47) was lower in FK 506-treated patients. Our results indicate that FK 506 immunosuppression offers some advantages in cardiovascular risk factors.

Topics: Adult; Age Factors; Arteriosclerosis; Blood Glucose; Body Weight; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cyclosporine; Fasting; Female; Fibrinogen; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Transplantation; Lipid Metabolism; Lipids; Male; Prednisolone; Risk Factors; Sex Factors; Tacrolimus; Transplantation, Homologous; Triglycerides

Topics: Animals; Arteriosclerosis; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Creatinine; Graft Survival; Heart Transplantation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Rats; Rats, Inbred BN; Rats, Inbred Lew; Simvastatin; Tacrolimus; Transplantation, Homologous; Transplantation, Isogeneic

Topics: Animals; Arteriosclerosis; Cyclosporine; Heart Transplantation; Male; Rats; Rats, Inbred F344; Rats, Inbred Lew; Tacrolimus; Time Factors; Transplantation, Homologous; Transplantation, Isogeneic