tacrolimus and Weight-Gain

Weight gain early after transplant is a risk factor for posttransplant metabolic syndrome (PTMS), cardiovascular events, and renal insufficiency. The impact of mammalian target of rapamycin inhibition on posttransplant weight gain and the development of PTMS components postliver transplantation were examined in a randomized, controlled study.. After a run-in period, patients (N = 719) were randomized at 30 ± 5 days posttransplant in a 1:1:1 ratio to 3 treatment groups: (i) everolimus (EVR) + reduced tacrolimus (TAC) (n = 245); (ii) TAC control (n = 243) or (iii) TAC elimination (n = 231). In this post hoc analysis, weight change at 12 and 24 months was compared between groups. Vital signs, lipids, and laboratory parameters at 12 and 24 months and rates of PTMS were assessed.. Mean increase in weight from baseline was higher at month 12 in the TAC control arm (8.15 ± 9.27 kg) than in the EVR + reduced TAC (5.88 ± 12.60 kg, P = 0.056) and the TAC elimination arms (4.76 ± 9.94 kg, P = 0.007). At month 24, the TAC control arm displayed a significantly greater weight increase (9.54 ± 10.21 kg) than either the EVR + reduced TAC (6.69 ± 8.37 kg, P = 0.011) or the TAC elimination groups (6.01 ± 9.98 kg, P = 0.024). Rates of PTMS were similar for the EVR + reduced TAC (71.8%), TAC elimination (70.3%) and TAC control (67.4%) arms (P = NS).. EVR with reduced-exposure TAC attenuated weight gain at 1 and 2 years posttransplant compared with a standard TAC immunosuppression regimen. Rates of PTMS were comparable between EVR-containing and TAC control regimens.

Topics: Adult; Aged; Cardiovascular Diseases; Everolimus; Female; Follow-Up Studies; Glycosylation; Graft Rejection; Graft Survival; Hemoglobins; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Male; Metabolic Syndrome; Middle Aged; Obesity; Prospective Studies; Risk Factors; Signal Transduction; Tacrolimus; Weight Gain

Topics: Adult; Body Mass Index; Cholesterol; Cyclosporine; Follow-Up Studies; Humans; Liver Transplantation; Obesity; Tacrolimus; Time Factors; Triglycerides; United States; Weight Gain

The purpose of the present study was to evaluate the difference in BMI pattern between patients with persistent new-onset diabetes after transplantation (P-NODAT) and without new-onset diabetes after transplantation (N-NODAT) in a retrospective matched case-control (1:3) analysis. Thirty-six patients who developed P-NODAT were identified among 186 adult renal transplant recipients with no evidence of pretransplant diabetes mellitus who underwent kidney transplantation from September 1997 to March 2008 and were treated with a triple regimen including tacrolimus. The controls were selected to match the patients for pretransplant BMI, age at transplantation (± 5 yr), and date of transplantation (± 12 months). Finally, 20 P-NODAT patients and 60 N-NODAT patients were selected. The pre- and posttransplant BMI data were collected every 16 weeks for up to 80 weeks. The clinical characteristics did not differ between the P-NODAT group and N-NODAT group. BMI increased faster in the P-NODAT group than in the N-NODAT group. The mixed-model analysis showed that patients with P-NODAT exhibited a faster increase in BMI. P-NODAT is associated with posttransplant weight gain. The risk of P-NODAT should be considered in patients with rapid weight gain after transplantation.

Topics: Adult; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Time Factors; Weight Gain

We investigated clinical factors that affected the clearance of tacrolimus (FK506) administered by continuous drip infusion to children who had received allogeneic hematopoietic SCT. Blood FK506 levels were measured every day in 27 patients in an attempt to adjust the dose to maintain the target range (10-15 ng/mL). Patients who developed engraftment syndrome (ES) and acute GVHD and patients less than 7 years of age showed a higher FK506 clearance calculated from body weight (BW) for 5 or more consecutive days compared with the control groups. A time-course study showed that the occurrence of ES, but not acute GVHD, was related to increased clearance of FK506. When calculated from body surface area (BSA), a significant increase in FK506 clearance was observed in patients with ES, but not in those less than 7 years of age. FK506 clearance was not influenced by CYP3A5, multidrug resistance 1 or ABCG2 genotypes. None of the clinical parameters affected blood FK506 levels. Determination of the FK506 dose on the basis of frequent monitoring of the blood concentration seems to minimize the serious adverse effects induced by the immunosuppressant. It may be more accurate to dose FK506 according to BSA rather than BW for pediatric patients.

Topics: Adolescent; Aging; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Child; Child, Preschool; Cytochrome P-450 CYP3A; Drug Dosage Calculations; Erythema; Female; Fever; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Hypoxia; Immunosuppressive Agents; Infant; Male; Metabolic Clearance Rate; Neoplasm Proteins; Polymorphism, Genetic; Pulmonary Eosinophilia; Syndrome; Tacrolimus; Weight Gain

Excessive weight gain that leads to obesity is quite common after kidney transplantation. This is often attributed to immunosuppression. The aim of this retrospective study was to assess the effect of calcineurin inhibitors on post-transplant weight gain.. A total of 99 patients were studied. The patients were divided into cyclosporine A (CyA) and tacrolimus (Tac) groups and were evaluated for weight changes and risk factors related to weight gain.. The weights of patients in both groups significantly increased after the sixth month. The median weight gain at 12 months was 3.5 and 8.0 kg compared with pretransplant dry weight in the Tac and CyA groups, respectively. The increases in the CyA group were significant compared with those of the Tac group. The prevalences of obese and overweight patients in both groups did not differ during a 12-month follow-up. The frequencies of diabetes mellitus, hypertension and dyslipidemia were comparable in both groups. The decrease in systolic blood pressure (BP) of the Tac group was significant compared with the decrease in the CyA group at the 12th month. In the 12-month follow-up period, the increases in triglyceride, total- and low-density lipoprotein-cholesterol values of the CyA group were significantly higher than those of the Tac group. The weight change between 0 and 12 months was negatively correlated with pretransplant body mass index (BMI) and positively with cumulative corticosteroid doses, total-cholesterol and BP changes.. Only pretransplant BMI, creatinine clearance, CyA usage, being hypertensive and dyslipidemic were independent predictors of weight gain at the 12th month. Our results suggested that the type of immunosuppression may affect post-transplant weight gain.

Topics: Adult; Body Mass Index; Calcineurin Inhibitors; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Retrospective Studies; Risk Factors; Tacrolimus; Weight Gain

Posttransplant diabetes mellitus (PTDM) is common post transplantation and is associated with tacrolimus (TAC) and steroid therapy. The aim of the present study was to analyze the incidences of PTDM and associated risk factors.. We selected renal transplant recipients treated with TAC, mycophenolate mofetil (MM), and steroids. Exclusion criteria were recipients <18 years old, history of diabetes, recipients of kidney/pancreas, and/or those receiving cyclosporine or sirolimus. PTDM was defined as glucose >126 mg/dL, with or without drug therapy.. Among 67 patients who fulfilled the inclusion criteria, 18 (26.8%) developed PTDM within 2 months of transplantation. Compared with normal glucose patients, the PTDM group was older, male, received a kidney from deceased donors, and showed higher pretransplant glucose levels. No differences were noticed in renal function or daily dose of TAC or steroids. However, TAC trough levels in the first month were higher among the PTDM group, despite the lower dose per kilogram. After 1 year of follow-up, weight gain as well as daily TAC per kilogram dose was less among PTDM patients. Analysis of potential risk factors showed a higher incidence of hepatitis C virus infection in the PTDM group, as well as a higher frequency of HLA DR13.. The incidence of PTDM diagnosed in the early posttransplant period in the present series was 26.8%. Risk factors included older age, male gender, recipients of kidneys from deceased donors, hepatitis C virus infection, higher pretransplant glucose levels, and higher TAC trough levels during the first month posttransplant.

Topics: Adult; Diabetes Mellitus; Female; Follow-Up Studies; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus; Time Factors; Weight Gain

Excessive weight gain is common after liver transplantation and frequently leads to obesity. This has been attributed to immunosuppression. The aim of the present study was to assess the extent of weight gain and the risk factors for weight gain after liver transplantation. Height and estimated dry weight were collected prospectively in consecutive adult liver-transplant patients, transplanted between January 1996 and October 2001. A total of 597 patients (45% female, median age of 50 years; range 16-73) was studied. Eighty-six percentage was transplanted for chronic liver disease. The median weight gain at 1 and 3 years was 5.1 and 9.5 kg above dry weight pretransplant. By 1 and 3 years, 24% and 31% had become obese (defined as a body mass index (BMI) >30 kg/m(2)). There was no significant difference in weight gain between the sexes, those who were obese before transplantation or those who received corticosteroids for >3 months. Weight gain was significantly greater (P < 0.05) in patients aged >50 years and those transplanted for chronic liver disease compared with fulminant liver failure. A pretransplant BMI >30 was a strong indicator that the patient would still have a BMI >30 at 3 years. There was no effect of the type of immunosuppression on weight gain. Obesity is common in the liver transplant population, but it seems to be unrelated to any specific immunosuppressive drug. The greatest weight gain occurs after the first 6 months and intervention with dietary advice at this point could be implemented to minimize the long-term morbidity and mortality risks associated with obesity.

Topics: Adolescent; Adult; Aged; Cyclosporine; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Obesity; Prospective Studies; Tacrolimus; Weight Gain

Posttransplantation diabetes mellitus (PTDM) is a common complication of kidney transplantation, associated with poorer graft and patient outcomes. Tacrolimus is a strong immunosuppressive drug associated with low acute rejection rates, but a higher risk for PTDM. High trough levels of tacrolimus during the first month after transplantation have been found to be a significant risk factor for the development of PTDM. The aim of this single-center study was to identify the risk factors for the development of PTDM among kidney transplant recipients under tacrolimus therapy. We examined 73 cadaveric kidney transplant recipients receiving tacrolimus between 1994 and 2003. Age, donor and recipient gender, dialysis method, body mass index (BMI), first year weight gain, mismatches, incidence of acute rejection and delayed graft function, hepatitis C serology, first year cumulative steroid dose, first tacrolimus blood level, first tacrolimus blood level <15 ng/mL, and corresponding tacrolimus daily doses and concentration/dose ratios (CDR) were also collected. PTDM was defined as at least 2 fasting blood glucose values > or =126 mg/dL, according to the World Health Organization criteria. Incidence of first year PTDM was 27.4%. Patients with PTDM showed significantly higher age, BMI, first tacrolimus blood level, first tacrolimus CDR, and CDR with tacrolimus blood level <15 ng/mL as well as less 1-year weight gain. After logistic regression, age (relative risk [RR] 1.060, confidence interval [CI] 95%, 1.001-1.122; P = .043) and first tacrolimus blood level (RR 1.154; CI 95%, 1.038-1.283; P = .008) remain significant risk factors for developing PTDM. Older age and initial tacrolimus blood levels were the main risk factors for PTDM among our group of patients. Kidney transplant recipients who develop PTDM maintain a high CDR of tacrolimus.

Topics: Adult; Body Mass Index; Diabetes Mellitus; Female; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Tissue Donors; Weight Gain

Segmental small intestinal transplantation (SIT) using living related donors (LRD) is being evaluated as a therapy, clinically. Advantages of this technique include an increase in the donor pool, optimization of the timing of transplants, and potential immunologic benefits. However, the ability of a short segment of intestine to function after transplantation has not been investigated in large animal models. This study evaluates the impact of immunosuppression on the adaptive process and the ability of a transplanted segment of intestine to adapt. A pig model of segmental SIT was used. Animals were resected, leaving 150 cm of distal ileum (n = 5), resected and treated with FK506 (n = 4), or steroids (n = 4), or with FK506 + steroids (n = 7), or transplanted using a similar segment of ileum and treated with FK506 + steroid immunosuppression (n = 9). Animals undergoing resection, or resection plus steroid treatment, did well, gaining weight post-operatively (37% and 15% of preoperative weight, respectively). However, animals undergoing resection and treated with FK506 or FK506 + steroids did poorly, losing weight (-14% and -22% of preoperative weight, respectively) and showing significant impairment of intestinal adaptation, morphologically and functionally. Furthermore, FK506-treated animals developed inflammatory changes in the intestinal mucosa, mimicking rejection. Segmental SIT animals had a high rate of rejection (66%) and showed a similar impairment in adaptation. Hence, segmental SIT is a stringent physiological test of intestinal adaptation. FK506 appears to impair gut function after resection, either directly, or by interfering with the adaptive process. In this model of segmental SIT, FK506 and steroids at the doses tested did not provide adequate immunosuppression to prevent rejection and the graft did not function adequately to allow growth. Further studies are required to evaluate the mechanisms underlying these findings, and to determine if similar effects occur in humans.

Topics: Adaptation, Physiological; Animals; Female; Glucocorticoids; Graft Rejection; Ileum; Immunosuppressive Agents; Intestinal Mucosa; Living Donors; Methylprednisolone; Permeability; Swine; Tacrolimus; Weight Gain

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

Topics: Abdomen; Animals; Drug Administration Schedule; Drug Therapy, Combination; Fingolimod Hydrochloride; Graft Survival; Heart Transplantation; Immunosuppressive Agents; Intraoperative Period; Kidney Function Tests; Liver Function Tests; Propylene Glycols; Rats; Rats, Inbred Lew; Rats, Inbred Strains; Regression Analysis; Sphingosine; Tacrolimus; Transplantation, Heterotopic; Transplantation, Homologous; Weight Gain

Under normal physiological conditions, the intestine presents an adenosine triphosphate (ATP)-dependent barrier to luminal contents. Disruption of this barrier function can occur when cellular metabolism is compromised. This study examined the effects of FK506 on intestinal permeability and enterocyte metabolic function in Lewis rats.. Rats were administered FK506 at a dose of 0.1, 0.5, or 2 mg/kg on alternate days for 6 weeks. Intestinal permeability was assessed by measuring urinary recovery of 99mTc-diethylenetriamine pentacetate, and electrophysiological conductance measurements were performed in Ussing chambers. Metabolic function was assessed in isolated enterocytes by measuring total ATP and CO2 release from [14C]pyruvate and [14C]glucose.. Rats treated with FK506 showed a dose-dependent reduction in weight gain as well as increased in vivo and in vitro intestinal permeability. There was no difference in plasma creatinine or urinary output. Changes in permeability correlated with reduced ATP levels and CO2 release because of diminished mitochondrial function. Lactate production, as a measure of glycolytic activity, was not altered by FK506.. In a dose-dependent manner, FK506 treatment in rats reduces weight gain, increases intestinal permeability, and decreases the ability of the small intestine to use glucose as an energy source.

Topics: Adenosine Triphosphate; Analysis of Variance; Animals; Carbon Monoxide; Dose-Response Relationship, Drug; Electric Conductivity; Electrophysiology; Intestine, Small; Lactates; Male; Mitochondria; Permeability; Rats; Rats, Inbred Lew; Tacrolimus; Technetium Tc 99m Pentetate; Weight Gain

We have previously shown that blood concentrations of tacrolimus, a new immunosuppressive agent, were greater when it was administered orally at 10 pm than when it was administered at 10 am in rats. The present study was undertaken to examine whether the toxic effects of tacrolimus show administration time-dependent variations. Male Wistar rats were maintained under conditions of light from 7 am to 7 pm and dark from 7 pm to 7 am. Tacrolimus (1 and 4 mg/kg) was given orally at 10 am (day trial) or 10 pm (night trial) for 14 days. Blood samples were obtained at 24 hours after the final dosage of the agent. Weight gain was smaller in the night trial than in the day trial. Plasma concentrations of urea and creatinine increased significantly in the night trial while the elevations in these parameters were not observed in the day trial. These results suggest that the toxic effects of tacrolimus also vary with its time of oral dosage.

Topics: Animals; Creatinine; Male; Rats; Rats, Wistar; Tacrolimus; Time Factors; Urea; Weight Gain

Topics: Administration, Oral; Adult; Child; Child, Preschool; Enteral Nutrition; Female; Follow-Up Studies; Growth; Humans; Intestinal Absorption; Intestine, Small; Liver Transplantation; Male; Nutritional Physiological Phenomena; Parenteral Nutrition, Total; Retrospective Studies; Tacrolimus; Weight Gain; Xylose

The purpose of this study was to investigate two promising immunosuppressive agents, didemnin B (DB) and FK506 (FK), during pregnancy to assess potential adverse maternal or fetal effects. Pregnant C3H mice were randomized into control and high- and low-dose treatment groups for each drug. Animals received daily injections from day 1 to day 16, and on day 17 of gestation the maternal condition, litter size, fetal resorption rates, and fetal/placental unit weights were determined. Immunoglobulin (IgG) levels were obtained for DB treatment groups. Delayed type hypersensitivity was assessed in virgin females. Both DB and FK had dose-dependent immunosuppressive activity in the DTH assay, and DB caused elevated IgG concentrations. High doses of DB caused diarrhea and maternal wasting with no fetal survival; with low-dose DB, maternal weight gain was depressed, but pregnancy outcome was not different from control animals. High-dose FK had no obvious detrimental effects on maternal health but caused resorption of all fetuses; administration of low-dose FK resulted in a higher number of resorptions, but fetuses that survived did not appear different from controls. We conclude that these immunosuppressive drugs can have adverse effects on pregnancy, but the maternal and fetal toxicity are dose-dependent.

Topics: Animals; Anti-Bacterial Agents; Depsipeptides; Dose-Response Relationship, Drug; Female; Fetal Viability; Fetus; Hypersensitivity, Delayed; Immunoglobulin G; Immunosuppressive Agents; Maternal-Fetal Exchange; Mice; Mice, Inbred C3H; Organ Size; Peptides, Cyclic; Placenta; Pregnancy; Pregnancy, Animal; Respiration; Tacrolimus; Weight Gain