tacrolimus and Hypercholesterolemia

HMG-CoA reductase inhibitors (statins) have effects beyond lipid lowering, including immunomodulatory and anti-inflammatory properties. Statins are frequently combined with immunosuppressive agents in transplant recipients to modulate the hyperlipidemic side effects of the immunosuppressants. However, the role of statins in the immunosuppressive response that is achieved in individual patients remains to be assessed.. The aim of this study was to evaluate the immunomodulatory effect of atorvastatin given alone and in combined treatment with tacrolimus and mycophenolate mofetil.. Two patient groups were studied: renal transplant recipients receiving tacrolimus and mycophenolate mofetil therapy, and hypercholesterolemic patients (the control group). Fasting blood samples were taken from participants before and 1 month after atorvastatin treatment was started to study a small battery of biomarkers that are able to reflect the range of the effects of immunosuppressive therapy and atorvastatin.. All patients in the study were enrolled at the Hospital Clinic of Barcelona.. All patients enrolled in the study were candidates for treatment with atorvastatin because of high cholesterol levels. One group consisted of 25 stable renal transplant recipients with low-density lipoprotein (LDL) cholesterol levels above 100 mg/dL after 3 months of therapeutic lifestyle changes, according to the guidelines of the National Kidney Foundation - Kidney Disease Outcomes Quality Initiative. The other group included 25 hypercholesterolemic patients with LDL cholesterol levels above target values for the patients' overall risk, as derived from the National Cholesterol Education Program Adult Treatment Panel III criteria.. Atorvastatin (Lipitor®) treatment was started at a fixed dose of 20 mg daily.. The studied biomarkers were lymphocyte proliferation, intracellular adenosine triphosphate (ATP) synthesis in CD4+ T cells, intralymphocytary cytokine expression (interleukin [IL]-2, interferon [IFN]-γ), soluble cytokine production (IL-2, IFN-γ, IL-10, IL-17, and transforming growth factor-β) and regulatory T (T(reg)) cells.. Atorvastatin proved to be an immunomodulatory agent, significantly decreasing lymphocyte proliferation by 15% (p = 0.001), increasing ATP levels by 16% (p = 0.0004), and showing a trend toward increasing T(reg) cells in hypercholesterolemic patients (p = 0.09). In the renal transplant recipients, atorvastatin therapy did not modify any of the biomarkers of immunosuppression that were studied.. Atorvastatin showed immunoregulatory effects on T cells in hypercholesterolemic patients. These effects were absent in renal transplant recipients, suggesting that the beneficial effects of atorvastatin in this patient group do not relate to immunoregulation. Therefore, statin treatment cannot be considered as a means to reduce the dose of immunosuppressive agents.

Topics: Adenosine Triphosphate; Adult; Aged; Atorvastatin; Biomarkers; Cell Proliferation; Culture Media, Conditioned; Cytokines; Female; Gene Expression Regulation; Heptanoic Acids; Humans; Hypercholesterolemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pyrroles; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Tacrolimus; Transplantation

The aim of this prospective, randomized, double-blinded, placebo-controlled single center study was to evaluate an early steroid-free immunosuppression in liver transplant patients.. From March 2000 to October 2004, 110 patients were included. All patients received tacrolimus and steroids during the first 2 weeks after orthotopic liver transplantation (OLT). Thereafter, patients in the steroid group (n=54) received steroids and the remaining 56 a placebo. After 6 months, the immunosuppression for all was steroid free. Thirty patients were hepatitis C positive. Five years after inclusion, patient survival, organ survival, steroid side effects, and recirrhosis in hepatitis C virus (HCV) patients were reevaluated.. After 5 years, the following parameters were comparable in both groups: patient survival (P=0.236), organ survival (P=0.509), and acute rejections (P=0.409). Steroid-free immunosuppression lead to a higher rate of chronic rejections (P=0.023). Six months after OLT, there was a difference in rates of posttransplant diabetes mellitus (PTDM) (P=0.024) and hypercholesterolemia (P=0.002). However, 5 years after OLT, there was no difference in hypertension (P=0.647), PTDM (P=0.453), hypercholesterolemia (P=0.412), and osteoporosis (P=0.624). In HCV patients, we could not find any differences in patient survival (P=0.096), organ survival (P=0.424), time free from recirrhosis (P=0.647). The rate of recirrhosis was influenced by steroid bolus therapy (P=0.01) but not by avoiding continuous steroid therapy.. Early tapering down of steroids to a tacrolimus monotherapy is possible with comparable acute rejection rates. During steroid therapy, PTDM and hypercholesterolemia are cumulative. These side effects are reversible. The recirrhosis in HCV patients is not influenced by continuous steroid therapy but more frequent in HCV patients receiving a steroid bolus therapy.

Topics: Adrenal Cortex Hormones; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Graft Survival; Hepatitis C; Humans; Hypercholesterolemia; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Postoperative Complications; Recurrence; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

We investigated prospectively the efficacy of ezetimibe in addition to statin therapy in stable renal transplant patients in whom hypercholesterolemia was not sufficiently treated. Eighteen renal transplant patients received 10 mg ezetimibe once daily in addition to high-dose statin therapy for uncontrolled hypercholesterolemia. Total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, Tacrolimus (Tac)- and Cyclosporine A (CsA) blood levels, creatinine, urea, liver enzymes, electrolytes and creatinkinase (CK) were measured before initiation of ezetimibe therapy, after 7 days, 6 weeks and 3 months. Cholesterol concentrations decreased significantly (p < 0.005) from 264 +/- 46 mg/dL at baseline to 205 +/- 48 mg/dL after 1 week to 202 +/- 48 mg/dL after 6 weeks and 212 +/- 40 mg/dL after 3 months (reduction after 3 months 21 +/- 10%). LDL-concentrations decreased significantly (p < 0.005) from 178 +/- 41 mg/dL at baseline to 129 +/- 35 mg/dL after 1 week to 123 +/- 25 after 6 weeks and to 117 +/- 40 mg/dL after 3 months (reduction after 3 months 37 +/- 14%). Two patients stopped ezetimibe therapy due to nausea and muscle pain without CK elevation. Significant changes of CsA and Tac blood levels, liver and muscle enzymes were not observed. Ezetimibe seems to be an effective therapy for uncontrolled hypercholesterolemia in renal transplant patients when combined with high-dose statin therapy.

Topics: Adult; Aged; Anticholesteremic Agents; Azetidines; Cholesterol; Cyclosporine; Drug Therapy, Combination; Ezetimibe; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Kidney Transplantation; Liver; Male; Middle Aged; Muscle, Skeletal; Pravastatin; Simvastatin; Tacrolimus

Few studies used paired kidneys for comparison between tacrolimus and cyclosporine in renal transplantation. Most of the published data used whole blood trough levels for drug monitoring. However, the use of limited sampling strategy and abbreviated formula to estimate the 12-h area under concentration-time curve (AUC(0-12)) allowed better prediction of drug exposure. Sixty-six first cadaveric renal transplant recipients receiving paired kidneys were randomized to receive either tacrolimus-based (n = 33) or cyclosporine microemulsion (Neoral)-based therapies (n = 33). Abbreviated AUC(0-12) was used for drug monitoring and dose titration. Mean follow-up duration was 2.8 +/- 2 years. The patient and graft survival were comparable. Fewer incidence of acute rejection was observed in tacrolimus group (15% vs. 27.3%) though the difference was not significant (P = 0.23). The absolute value and the rate of decline of creatinine clearance were both significantly better in tacrolimus-treated patients. Prevalence of hypertension, post-transplant diabetes mellitus, infection, and malignancy were similar in both groups. Prevalence of hypercholesterolemia (11/33 vs. 4/33) and gum hypertrophy (6/33 vs. 1/33) was more common in cyclosporine-treated patients (P = 0.04 in both parameters). This was the first prospective, randomized study with paired kidney analysis showing the renal function was significantly better in tacrolimus-treated patients than in cyclosporine-treated patients.

Topics: Acute Disease; Adult; China; Cyclosporine; Emulsions; Female; Graft Rejection; Graft Survival; Humans; Hypercholesterolemia; Hypertension; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Survival Rate; Tacrolimus

Hypercholesterolemia is a frequent complication in renal transplant patients treated with cyclosporine A (CsA). Whether it is preferable to treat hypercholesterolemia with statins or to switch patients from CsA to tacrolimus (TRL) has not been investigated.. Twelve CsA-treated kidney transplant recipients with hypercholesterolemia were successively crossed over from CsA alone to: CsA plus atorvastatin; TRL alone; and TRL plus atorvastatin. Total cholesterol (C), Low density lipoprotein (LDL)-C, high density lipoprotein (HDL)-C, LDL and HDL alpha-tocopherol content, lag-time of LDL oxidation, plasma levels of oxidized LDL and the percentage of small dense LDL were assayed at the end of each treatment period. Endothelial function was assessed by high resolution ultrasound measurement of flow-mediated brachial artery vasodilatation (FMD).. Atorvastatin therapy was more efficient in reducing total cholesterol and LDL-C levels than conversion from CsA to TRL. Combining TRL with atorvastatin further reduced LDL-C levels as compared to TRL alone, but was no more efficient than the CsA-statin combination. Neither atorvastatin therapy nor conversion to TRL significantly changed the proportion of dense LDL, lipoprotein alpha-tocopherol contents or the lag time of LDL oxidation. Addition of atorvastatin to CsA increased FMD from 4.0+/-1.8% to 6.5+/-4.0% (P<0.05 vs. CsA). Conversion from CsA to TRL caused a slight improvement in FMD (5.1+/-2.1%, P<0.05 vs. CsA). Adding atorvastatin to TRL had no detectable effect on FMD (5.5+/-2.3%, P=NS vs. TRL).. Atorvastatin was more efficient in reducing total and LDL cholesterol levels of CsA-treated renal transplant patients than conversion to TRL and significantly improved endothelial dysfunction.

Topics: Adult; Apolipoproteins; Atorvastatin; Body Mass Index; Creatinine; Cross-Over Studies; Drug Therapy, Combination; Endothelium, Vascular; Female; Follow-Up Studies; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Middle Aged; Pyrroles; Tacrolimus; Triglycerides

The aim of this prospective multicenter study was to evaluate the effect of conversion from cyclosporine (CsA) to tacrolimus (Tac) on cardiovascular risk factors in stable kidney transplant patients with hyperlipidemia. Twenty-six patients were switched from CsA to Tac at 81.7 +/- 44.4 months after transplantation. Tac was started at 0.15 mg/kg/d. Patient outcomes were evaluated up to 6 months after conversion. Significant reductions were seen in systolic blood pressure (143 +/- 13 baseline to 136 +/- 9 mm Hg at 6 months, P = .026) as well as the need for antihypertensive medication, with no changes in diastolic blood pressure. There was a significant reduction in total cholesterol (247 +/- 41 to 221 +/- 35 mg/dL, P = .003), low-density lipoprotein cholesterol (150 +/- 24 to 127 +/- 27 mg/dL, P = .001), total cholesterol/high-density lipoprotein (HDL) cholesterol ratio (4.9 +/- 1.9 to 3.9 +/- 1, P = .02), and triglyceride levels (228 +/- 175 to 148 +/- 71 mg/dL, P = .026). No significant modifications in HDL cholesterol, Apo A1 and Apo-B levels, or in the need for lipid-lowering medication were observed. Glucose levels did not change, but an increase in HbAC1 took place (5.8 +/- 1.1 to 6.2 +/- 1, P = .002). In men Framingham risk score significantly decreased from 11.5 +/- 11.3 to 8.4 +/- 7.2. (P = .0023). In conclusion, elective conversion from CsA to Tac in stable kidney transplant patients with hyperlipidemia was related to an improved blood pressure and lipid profile, both suggesting a decrease in the estimated 10-year coronary heart disease risk in men.

Topics: Adult; Aged; Antihypertensive Agents; Cardiovascular Diseases; Cyclosporine; Emulsions; Female; Glomerular Filtration Rate; Humans; Hypercholesterolemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Risk Factors; Tacrolimus

The administration of sirolimus has been reported to be associated with high serum cholesterol and high triglyceride values. In a large prospective, multicenter 6-month study in renal transplantation, basic parameters of lipid metabolism (total serum cholesterol and triglycerides) were systematically assessed in patients who received tacrolimus/mycophenolate mofetil/steroids (Tac/MMF), tacrolimus/0.5 mg sirolimus (SIR)/steroids (Tac/0.5SIR) on tacrolimus/2 mg sirolimus/steroids (Tac/2SIR).. For purposes of analysis, lipid parameters were classified using the National Kidney Foundation Dyslipidemia Classification definitions.. Complete sets of data at all visits (baseline, months 1, 3, and 6) were available for 211 Tac/MMF, 210 Tac/0.5SIR, and 203 Tac/2SIR patients. Total serum cholesterol in the Tac/MMF group was 193.4 at baseline and 202.9 mg/dL at month 6. Values increased from 196 mg/dL to 212.5 mg/dL in Tac/0.5SIR and from 200 mg/dL to 230.5 mg/dL in Tac/2SIR. Differences in parameters between treatment groups were statistically significant (P < .05). Serum triglycerides decreased from baseline to 6 months in Tac/MMF, increased from 176.3 mg/dL (baseline) to 191.4 mg/dL (6 months) in Tac/0.5SIR and from 203 mg/dL to 255.3 mg/dL in Tac/2SIR. Parameters differed significantly between Tac/0.5SIR versus Tac/2SIR at P = .0069, and between Tac/MMF versus Tac/2SIR at P = .0013. In the Tac/2SIR group 36.5% had "high" serum cholesterol and 8.3% had "very high" triglyceride levels at 6 months.. Total serum cholesterol levels were relatively stable and serum triglycerides decreased between baseline and month 6 using a Tac/MMF regimen. Contrastingly, the Tac/SIR combinations led to increased total cholesterol values (at both sirolimus dose levels) and Tac/2SIR also led to increased triglyceride levels.

Topics: Cholesterol; Drug Therapy, Combination; Follow-Up Studies; Humans; Hypercholesterolemia; Immunosuppressive Agents; Mycophenolic Acid; Sirolimus; Tacrolimus; Triglycerides

Topics: Adult; Drug Therapy, Combination; Follow-Up Studies; Graft Survival; Humans; Hypercholesterolemia; Immunosuppressive Agents; Incidence; Liver Transplantation; Postoperative Complications; Prednisone; Tacrolimus; Time Factors

Tacrolimus-based immunosuppression seems safe and effective in liver and kidney transplantation. To assess the safety and efficacy of tacrolimus (TAC)-based immunosuppression after cardiac transplantation as well as the relative impact of tacrolimus on immunosuppression-related side effects such as hypertension and hyperlipidemia, we conducted a prospective, randomized, open-label, multicenter study of otherwise identical tacrolimus- and cyclosporine-based immunosuppressive regimens in adult patients undergoing cardiac transplantation.. Eighty-five adult patients (pts) at six United States cardiac transplant centers, undergoing their first cardiac transplant procedure, were prospectively randomized to receive either TAC-based (n = 39) or cyclosporine (CYA)-based (n = 46) immunosuppression. All pts received a triple-drug protocol with 15 pts (18%) receiving peri-operative OKT3 to delay TAC/CYA due to pre-transplant renal dysfunction. Endomyocardial biopsies were performed at Weeks 1, 2, 3, 4, 6, 8, 10, 12, 24, and 52. The study duration was 12 months.. Patients were mostly male (87%) Caucasian (90%) with a mean age of 54 years and primary diagnoses of coronary artery disease (55%) and idiopathic dilated cardiomyopathy (41%). There were no significant demographic differences between groups. Patient and allograft survival were not different in the two groups. The probability and overall incidence of each grade of rejection, whether treated or not, and the types of treatment required did not differ between the groups. At baseline and through 12 months of follow-up, chemistry and hematology values were similar between the groups except serum cholesterol was higher in the CYA group at 3, 6, and 12 months (239 vs 205 mg/dL, 246 vs 191 mg/dL, 212 vs 186 mg/dL, respectively, p < 0.001). Likewise, LDL-cholesterol, HDL-cholesterol and triglycerides were significantly higher in the CYA group. More CYA patients received therapy for hypercholesterolemia (71% vs 41% at 12 months, p = 0.01). There were no significant differences in renal function, hyperglycemia, hypomagnesemia, or hyperkalemia during the first 12 months. More CYA patients developed new-onset hypertension requiring pharmacologic treatment (71% vs 48%, p = 0.05). The incidence of infection was the same for the two groups (2.6 episodes/pt/12 month follow-up).. Tacrolimus-based immunosuppression seems effective for rejection prophylaxis during the first year after cardiac transplantation and is associated with less hypertension and hyperlipidemia and no difference in renal function, hyperglycemia or infection incidence when compared to cyclosporine-based immunosuppression.

Topics: Adult; Biopsy; Cardiomyopathy, Dilated; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Incidence; Male; Middle Aged; Muromonab-CD3; Prospective Studies; Tacrolimus; Triglycerides

Topics: Blood Pressure; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cyclosporine; Diabetes Mellitus, Type 1; Follow-Up Studies; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Lipids; Prevalence; Tacrolimus

Over the years, survival after liver transplantation has increased and metabolic complications are becoming more common, contributing to patients' morbidity and mortality. The objectives of this study were to describe a population of patients with hepatic transplantation and diabetes mellitus (DM), evaluate the frequency of metabolic complications, and assess the impact of a multidisciplinary team on DM management.. This was a retrospective study involving interview and medical record analysis of 46 consecutive patients followed at the diabetes mellitus and liver transplantation unit of a tertiary university hospital, all evaluated by a multidisciplinary team.. Of all patients, 76.1% were men, with a median age 60 years old (interquartile range: 56 to 65 years) and liver transplantation time of 5 years (interquartile range: 0.6-9 years). Hypertension, hypercholesterolemia, hypertriglyceridemia, alcoholism, and smoking were present in 47.8%, 34.8%, 23.9%, 34.8%, and 30.4% of the patients, respectively. The most frequent immunosuppressant in use was tacrolimus (71.1%). Regarding nutritional status, 37.9% of patients were classified as overweight according to body mass index, and 41.2% were considered overweight according to the triceps skin fold. The median glycosylated hemoglobin and weight before and after intervention of the multidisciplinary team in all 46 patients were, respectively, 7.6% (5.7% to 8.8%) versus 6.5% (5.7% to 7.7%); P = .022 and 70.5 kg (64.7 to 82.0 kg) versus 71.6 kg (65.0 to 85.0 kg); P = .18.. Hypertension and dyslipidemia were common in transplanted patients with DM. Intervention of the multidisciplinary team resulted in a significant improvement in glycosylated hemoglobin without significant weight gain.

Topics: Aged; Body Mass Index; Body Weight; Diabetes Mellitus; Female; Glycated Hemoglobin; Humans; Hypercholesterolemia; Hypertension; Hypertriglyceridemia; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Nutritional Status; Patient Care Team; Postoperative Complications; Postoperative Period; Retrospective Studies; Risk Factors; Tacrolimus

Cystic fibrosis (CF) is an inherited condition that causes progressive respiratory failure and is the third most common indication for adult bilateral lung transplantation. Post-transplant hyperlipidemia commonly affects lung transplant recipients, but the impact of lung transplantation on serum lipids in the adult CF population is not well studied. The aim of this study was to examine the impact of lung transplantation on the prevalence of hyperlipidemia in CF adults.. We retrospectively analyzed prospectively collected data in 108 CF adults undergoing bilateral sequential lung transplantation from 1996 to 2007 at our institution.. The prevalence of hypercholesterolemia (>5.2 mmol/liter) and hypertriglyceridemia (>2.2 mmol/liter) increased significantly after lung transplant (14.8% vs 32.4%, p = 0.002; 8.3% vs 41.7%, p < 0.0001, respectively). Cyclosporine A (CsA) use was associated with significantly higher post-transplant total and LDL cholesterol compared with tacrolimus use. Post-transplant calculated Framingham risk score was <10% in all but 1 subject.. Hyperlipidemia was common in our cohort of post-lung transplant CF adults, with a higher prevalence in those receiving CsA. Despite these findings, calculated cardiovascular risk remained low and none of these subjects developed clinically evident cardiovascular disease.

Topics: Adult; Cohort Studies; Cyclosporine; Cystic Fibrosis; Female; Graft Rejection; Humans; Hypercholesterolemia; Hypertriglyceridemia; Immunosuppressive Agents; Lipids; Lung Transplantation; Male; Prevalence; Prospective Studies; Retrospective Studies; Tacrolimus

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

Among the adverse effects of different calcineurin inhibitors (CIs), nephrotoxicity is the most common (incidence: 18.1% at 13 y from liver transplantation) and depends on a variable degree of tubular-interstitial injury accompanied by focal glomerular sclerosis. A new immunosuppressive drug was introduced in solid organ transplant management, Sirolimus (SRL). It is a nonnephrotoxic immunosuppressor.. Twenty-six patients who developed nephrotoxicity owing to CIs, showing an increment of serum creatinine levels (>1.8 mg/dL) were switched to SRL monotherapy, initially at a dosage between 3 and 5 mg/d, and subsequently adapted to achieve trough level between 8 to 10 ng/mL.. Patients were followed-up for a mean period of 40.3 months (range, 8.4 to 76.7) from liver transplantation. Mean follow-up after switch was 27.5 months (range, 2 to 71.2). Immunosuppression therapy was converted after a mean period of 12.8 months (range, 0.2 to 43.4). Serum creatinine, urea, and estimated glomerular filtration rate were significantly improved.. Patients developing renal dysfunction after liver transplantation may be successfully treated by conversion from CI to SRL. Hypertriglyceridemia and hypercholesterolemia represent the principal side effects from SRL, but are treatable. Furthermore, SRL can significantly improve glucose tolerance.

Topics: Adult; Aged; Blood Glucose; Calcineurin Inhibitors; Cohort Studies; Creatinine; Cyclosporine; Glomerular Filtration Rate; Humans; Hypercholesterolemia; Hypertriglyceridemia; Immunosuppressive Agents; Kidney; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Sirolimus; Tacrolimus; Treatment Outcome

Immunosuppression has improved graft and recipient survival in transplantation but is accompanied by several adverse effects like dyslipidemia and cardiovascular disease. Herein, we performed an observational, descriptive study to analyze the relationship of dyslipemia (hypercholesterolemia [hypercho] and hypertriglyceridemia [hypertg]) and cardiovascular disease with two different immunosuppressive regimens in liver transplantation: cyclosporine treatment based upon C2 levels (CsA2) and tacrolimus (Tac), both in combination with steroids. Seventy-four liver transplantation patients were included during a 2-year period: 35 with CsA2 and 39 with Tac. The mean follow-up was 40 months. There were no significant differences between the groups in terms of age, gender, Model for End-stage Liver Disease Score, Child stage, and indication for transplantation. The distribution of patients with HyperCho and HyperTg was independent of the immunosuppressive agent (P = NS), both in a global and in a stratified analysis at 6, 12, 24, and 60 months. The analysis of cardiovascular events revealed no differences between the groups (CsA2 14.3%; Tac 18.9%; P = NS). We suggest that CsA monitoring using C2 levels shows a safety profile similar to that of Tac with regard to the development of dyslipidemia and cardiovascular events.

Topics: Cyclosporine; Dyslipidemias; Female; Humans; Hypercholesterolemia; Hypertriglyceridemia; Immunosuppressive Agents; Lipids; Liver Transplantation; Male; Tacrolimus

Tacrolimus has been shown to be an important immunosuppressive agent in organ and bone marrow transplantation. Previously, we reported that there were no statistically significant differences between the pharmacokinetic parameters of the oral formulation of generic tacrolimus (TacroBell) and the conventional formulation (Prograf). This study was designed to evaluate the efficacy and safety of oral capsules of TacroBell in de novo renal transplantation.. Ninety-six renal transplant recipients from 9 transplantation centers in South Korea were enrolled between November 2005 and July 2007. De novo renal recipients ranged from 19-65 years old. Ninety-four patients who underwent renal transplantation were administered study drug at least one time in the intent-to-treat (ITT) analysis. This phase 4 clinical trial was a 26-week, open-label, noncomparative, multicenter study.. An acute rejection episode developed in 10/94 recipients (10.6%, 95% confidence interval, 4.4%-16.9%). There were no patient deaths during the study. The 6-month graft survival rate was 96.8%.. Based on this study, treatment with TacroBell is considered to be efficient and safe after primary renal transplantation.

Topics: Adult; Creatinine; Drugs, Generic; Graft Rejection; Humans; Hypercholesterolemia; Hypertriglyceridemia; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Pilot Projects; Postoperative Complications; Safety; Tacrolimus

Hyperlipidemia following successful renal transplantation is a frequent and persistent complication. Several immunosuppressive agents including cyclosporine A (CyA), corticosteroids, and tacrolimus appear to have a significant pathogenetic role. The aim of this study is to investigate the differential effects of different immunosuppressive agents on lipids in renal transplant patients.. Two groups of renal transplant recipients, each treated with a different combination of immunosuppressive agents, were studied: Group A (n = 13), cyclosporine A, mycophenolate mofetil (MMF), steroids, and basiliximab; Group B (n = 13), tacrolimus, MMF, steroids, and daclizumab). Plasma lipids [cholesterol (CHOL), low-density lipoprotein (LDL)-CHOL, high-density lipoprotein (HDL)-CHOL, and triglycerides (TG)] were examined before transplantation and 1 and 6 months posttransplantation.. The patients treated with cyclosporine A-MMF showed a significant increase in mean cholesterol and mean LDL-cholesterol values at the 1-month posttransplantation follow-up compared with pretransplant levels (CHOL: 208.9 +/- 47.4 vs. 268.7 +/- 42.2 mg/dl, P = 0.004; LDL: 118.4 +/- 49.9 vs. 198.7 +/- 40.7 mg/dl, P = 0.002; pretransplant vs. 1 month, respectively). At 6 months, LDL-cholesterol levels were significantly elevated compared with pretransplant levels (LDL: 118.4 +/- 49.9 vs. 148.3 +/- 48.5 mg/dl, P = 0.034), whereas there was no significant change in the cholesterol level during the same period. In cyclosporine A-MMF-treated patients, plasma triglyceride levels were reduced at the 1- and 6-month follow-up (TG: 293.9 +/- 59.2 vs. 182.9 +/- 48.7 mg/dl, P = 0.03; 293.9 +/- 59.2 vs. 178.6 +/- 74.2 mg/dl, +/- = 0.023; pretransplant vs. 1 and 6 months, respectively). Patients receiving combined therapy with tacrolimus-MMF showed no significant changes in LDL-CHOL levels during the trial. Cholesterol levels at 6 months posttransplantation were significantly lower than the pretransplant measurements (CHOL: 182.9 +/- 44.4 vs. 162.3 +/- 37.2 mg/dl, P = 0.024; pretransplant vs. 6 months). A significant reduction in triglyceride level was documented at the 1-month follow-up followed by a subsequent decrease within 6 months (TG: 228.5 +/- 61.6 vs. 147.6 +/- 51.5 mg/dl, P = 0.005; TG: 228.5 +/- 61.6 vs. 130.4 +/- 54.7 mg/dl, P = 0.011; pretransplant vs. 1 and 6 months, respectively).. In posttransplant patients with stable renal function cyclosporine therapy is associated with increased cholesterol and LDL-cholesterol levels. Hyperlipidemia is less pronounced in patients given tacrolimus. Tacrolimus appears to an immunosuppressant agent with fewer and less severe adverse effects on lipid metabolism.

Topics: Adult; Cholesterol, LDL; Creatinine; Cyclosporine; Female; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus

Nephrotoxicity caused by CNI may adversely affect long-term graft outcomes. For this reason, we have adopted a protocol for withdrawing TAC and converting to SRL at three months post-renal transplantation. All recipients received basiliximab induction and TAC, MMF, and prednisone. Patients without acute rejection by surveillance biopsy at three months were eligible for SRL conversion.. From August 2004 to September 2006, TAC was withdrawn and replaced by SRL in 30 first transplant recipients, who were followed for six to 39 months (mean 18 +/- 8). Renal function did not improve significantly after SRL conversion (p = 0.25). Acute rejection occurred in three patients (10%) at five to 12 months after CNI withdrawal. There were no occurrences of wound healing problems, pneumonitis or post-transplant lymphoproliferative disease. Thrombocytopenia and diabetes each occurred in one patient. Four patients received treatment for hypercholesterolemia. CNI withdrawal and replacement with SRL was an effective regimen in children who did not display biopsy evidence of acute rejection at three months post-transplant. While these early results are promising, the ultimate benefit of this protocol to enhance the long-term renal function and graft survival requires ongoing follow-up.

Topics: Biopsy; Child; Child, Preschool; Female; Graft Rejection; Humans; Hypercholesterolemia; Immunosuppressive Agents; Kidney Transplantation; Male; Retrospective Studies; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adult; Brain Edema; Cerebral Hemorrhage; Fatal Outcome; Female; Graft Rejection; Humans; Hypercholesterolemia; Hypertension; Liver Cirrhosis, Alcoholic; Liver Transplantation; Magnetic Resonance Imaging; Myelin Sheath; Postoperative Complications; Seizures; Tacrolimus

Topics: Adolescent; Adult; Aged; Body Weight; Cardiovascular Diseases; Creatinine; Cyclosporine; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Hypertension; Immunosuppressive Agents; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; Transplantation, Homologous

The use of cyclosporine for immunosuppression in renal transplantation allograft recipients is associated with hypertrichosis, gingival hyperplasia, and hypercholesterolemia. Conversion of patients to tacrolimus may lead to an improvement in these effects with minimal risk of rejection or allograft dysfunction.. Sixteen renal transplant recipients were prospectively converted from CsA to tacrolimus and followed for 1 year. Gingival hyperplasia index, total cholesterol, and blood pressure were recorded at the outset, 4-, 8-, and 12-month intervals. Glomerular filtration rate was checked before conversion and 1 year later. Photographs documenting hypertrichosis were taken before conversion and 1 year later. Adverse effects from tacrolimus were recorded at 4, 8, and 12 months.. Twelve patients with hypertrichosis noted rapid improvement. Mean gingival hyperplasia index decreased from 24 to 6; mean total cholesterol decreased from 237 to 195. Glomerular filtration rate was essentially unchanged (56 to 54). One episode of rejection occurred, three patients developed diarrhea, three noted headaches, and one had a tremor.. If carefully monitored, patients suffering adverse effects secondary to cyclosporine may be converted to tacrolimus with minimal risk of allograft dysfunction or rejection.

Topics: Adolescent; Adult; Cyclosporine; Diarrhea; Female; Gingival Hyperplasia; Humans; Hypercholesterolemia; Hypertrichosis; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus; Time Factors

Topics: Adult; Azathioprine; Cholesterol; Cholesterol, HDL; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Immunosuppressive Agents; Incidence; Japan; Kidney Transplantation; Male; Methylprednisolone; Postoperative Complications; Retrospective Studies; Ribonucleosides; Risk Factors; Tacrolimus; Triglycerides

The aim of this study was to compare the long-term effect of tacrolimus and cyclosporine therapies on serum cholesterol levels in liver transplant recipients. We retrospectively studied 127 consecutive adult liver transplant recipients who survived for at least 1 year after transplantation. Basal immunosuppression consisted of cyclosporine plus prednisone in 100 patients and tacrolimus plus prednisone in 27 patients. Hypercholesterolemia was defined as a fasting serum cholesterol level greater than 220 mg/dL. Mean follow-up was 39 months. No statistical significance was found between cyclosporine- and tacrolimus-treated patients regarding age, sex, diagnosis, and previous cholesterol levels; both groups were similar. Significantly more tacrolimus-treated patients were steroid free in the first and second year of follow-up (tacrolimus, 37% and 63%; cyclosporine, 13% and 32%, respectively; P <.01). In the third year of follow-up, this difference was not significant (77% v 56%). The overall incidence of hypercholesterolemia was 34.6% (44 patients). At the end of the study, hypercholesterolemia was found in 24 of 51 and 14 of 70 patients with and without steroids, respectively (P <.002). Also, mean cholesterol levels were 224 +/- 70 and 191 +/- 48 mg/dL before and after steroid withdrawal, respectively, P <.001. Hypercholesterolemia was found in 43.7% of the patients during cyclosporine plus prednisone therapy compared with 46.1% of the patients during tacrolimus plus prednisone therapy (P <.9). Greater mean cholesterol levels were found in the cyclosporine group, particularly in the second and third years of follow-up (P <.01). Hypercholesterolemia was found in 22% of the patients during cyclosporine monotherapy compared with 15% during tacrolimus monotherapy (P <.5). No differences were found in mean cholesterol levels during follow-up when both monotherapy groups were compared. In conclusion, a lower incidence of hypercholesterolemia was achieved in tacrolimus-treated patients, mainly when steroids were still part of the immunosuppressive treatment.

Topics: Cholesterol; Cyclosporine; Female; Follow-Up Studies; Humans; Hypercholesterolemia; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Middle Aged; Prednisone; Retrospective Studies; Tacrolimus; Time Factors

In this study, we compare cholesterol levels during the first year after renal transplantation in FK506 (Prograf)- and cyclosporine-treated patients matched for cumulative first-year steroid dose and hypercholesterolemia risk factors. All patients had pretransplant cholesterol levels < 200 mg/dl. At 3 months posttransplant, 68% of the cyclosporine-treated patients had at least one cholesterol level greater than 200 mg/dl compared with 30% of the FK506-treated patients (P < 0.05). At the end of the year, 26% of FK506- and 67% of cyclosporine-treated patients remained hypercholesterolemic (P < 0.05). We conclude that cyclosporine has inherently more effect on cholesterol levels than FK506 during the first year after kidney transplantation.

Topics: Adult; Age Factors; Cholesterol; Cyclosporine; Diabetes Mellitus, Type 1; Female; Furosemide; Humans; Hypercholesterolemia; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sex Factors; Tacrolimus

Topics: Cyclosporine; Follow-Up Studies; Humans; Hypercholesterolemia; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Retrospective Studies; Survivors; Tacrolimus; Time Factors

In a retrospective study the records of 302 adult patients (167 male, 135 female) after orthotopic liver transplantation (OLT) with a minimum follow-up of 6 months (median follow-up 18 months, maximum 5 yr) were reviewed with regard to cardiovascular risk factors. In 197 patients data concerning the occurrence of arterial hypertension, hyperglycemia, or hypercholesterolemia prior to OLT were available. We found a highly significant increase of cardiovascular risk factors following OLT. Obesity was found in 17.4% of male and 22.2% of female recipients after OLT. Hypercholesterolemia was evident in 66.2% of liver graft recipients. Hypertriglyceridemia occurred in 49.7% of all male patients. In females there was a significantly different prevalence of hypertriglyceridemia comparing patients with a follow-up period up to 2 yr and more than 2 yr (50% vs. 24.6%, p = 0.018). Nearly 45% of all patients met the criteria for arterial hypertension, with a slight increase in male patients beyond the second year of survival (p = 0.094). Hyperglycemia had a significantly higher frequency in male than in female patients (30.5% vs. 10.4%, p < 0.005). Furthermore we observed a clear trend towards reduction of occurrence of hyperglycemia more than 24 months after OLT, but not reaching statistical significance. No correlation was detected when serum levels of triglycerides, and cholesterol, body-mass-index, and arterial blood pressure were compared with applied dosages of immunosuppressive agents [cyclosporin A (CyA), tacrolimus, and prednisolone]. Only decreasing tacrolimus application was significantly correlated with decreasing glucosemia (p = 0.041). Patients receiving tacrolimus instead of CyA as primary immunosuppressant showed a significantly lower prevalence of hypercholesterolemia. Even hypertension, hyperglycemia, hypertriglyceridemia, and obesity had a lower occurrence in patients treated with tacrolimus although not reaching statistical significance.

Topics: Adolescent; Adult; Aged; Blood Glucose; Cardiovascular Diseases; Cyclosporine; Female; Follow-Up Studies; Glucocorticoids; Humans; Hypercholesterolemia; Hypertension; Hypertriglyceridemia; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Obesity; Prednisolone; Retrospective Studies; Risk Factors; Tacrolimus

The development of atherosclerotic cardiovascular complications is a common and serious problem for the long-term survivors of organ transplantation. Cyclosporine A plus steroid-based immuno-suppression regimens in these patients are associated with the development of hypertension, hyperlipidemia, obesity, and diabetes mellitus. Whether the new immunosuppressive agent tacrolimus (FK506) confers any advantage in terms of these cardiovascular risk factors has been less well studied. We compared serial changes in blood pressure, lipids, body weight, and glucose levels during the first 12 months after liver transplantation in patients using either cyclosporine A (n = 39) or tacrolimus (n = 24)-based immunosuppression. By 12 months, the prevalence of hypertension, hypercholesterolemia, and obesity was increased in the cyclosporine A group compared to tacrolimus: 82% versus 33%, 33% versus 0%, and 46% versus 29%, respectively (all p < .05). Triglyceride and total cholesterol levels were 196 +/- 23 versus 125 +/- 13 mg/dL and 225 +/- 9 versus 159 +/- 7 mg/dL for the cyclosporine A versus tacrolimus groups, respectively (p < .05). Cumulative posttransplant steroid dose was not related to the observed lipid changes in either group, although the increase in triglycerides was positively correlated to weight gain and diuretic use in the cyclosporine A group. The incidence of diabetes mellitus was not increased from baseline in either group. These results indicate that tacrolimus, compared to cyclosporine A, is associated with a less adverse cardiovascular risk profile in the first year after liver transplantation. Whether these differences persist and become clinically relevant to a liver transplant recipient population that is increasingly older and has more preexisting cardiovascular disease remains to be determined.

Topics: Adult; Benzothiadiazines; Blood Glucose; Blood Pressure; Body Weight; Cyclosporine; Diabetes Mellitus; Diuretics; Female; Humans; Hypercholesterolemia; Hypertension; Hypertriglyceridemia; Lipids; Liver Transplantation; Male; Middle Aged; Obesity; Prednisone; Risk Factors; Sex Factors; Sodium Chloride Symporter Inhibitors; Tacrolimus

Topics: Animals; Cholesterol; Coronary Disease; Drug Therapy, Combination; Graft Rejection; Heart Transplantation; Hypercholesterolemia; Immunosuppressive Agents; Male; Rabbits; Ribonucleosides; Tacrolimus; Time Factors

Topics: Anti-Bacterial Agents; Diabetes Complications; Follow-Up Studies; Graft Survival; Humans; Hypercholesterolemia; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Risk Factors; Tacrolimus

Topics: Animals; Cholesterol; Cholesterol, Dietary; Hypercholesterolemia; Male; Rabbits; Reference Values; Tacrolimus