tacrolimus and Hyperglycemia

Post-transplant diabetes mellitus is a significant risk factor for cardiovascular disease in solid organ transplantation. The main underlying pathophysiological mechanism of PTDM is pancreatic beta cell dysfunction in the context of insulin resistance, but the relative importance of each of these important components of glycemic metabolism is under intense debate.. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials to January 15, 2015. We selected systematic reviews and meta-analyses and randomized clinical trials. When no such reports were found for a given topic or drug, observational studies were included in the assessment.. There are agents with known diabetogenic effects: corticosteroids, calcineurin inhibitors including tacrolimus and cyclosporine, as well as the mammalian target of rapamycin inhibitors (sirolimus and everolimus). The association between the use of induction agents and PTDM is very scarce. No diabetogenic effects have been found with the use of azathioprine, mycophenolate mofetil and its derivatives.. Immunosuppression is the major modifiable risk factor for development of PTDM but risk versus benefit analysis is required to balance risk of developing PTDM versus rejection. Caution is advisable in immunosuppressant adjustments in the event that PTDM develops based on current evidence. Physicians should choose and use immunosuppression regimens shown to have the best outcome for patient and graft survival, irrespective of PTDM risk.

Topics: Adrenal Cortex Hormones; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Everolimus; Graft Rejection; Humans; Hyperglycemia; Immunosuppressive Agents; Mycophenolic Acid; Postoperative Complications; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases; Transplantation

Tacrolimus (FK506) is a macrolide lactone with potent immunosuppressive activity 100 times that of cyclosporine by weight. The molecular mechanism of action is mediated via an inhibition of the phosphorylase activity of calcineurin by drug-immunophilin complex, resulting in the inhibition of IL-2 gene expression. There are emerging studies now showing significant efficacy of tacrolimus in GVHD prevention in both related and unrelated donor transplantation. Three multicenter randomized studies comparing tacrolimus to cyclosporine have been completed, one each in related and unrelated donor transplantation; the remaining study involved both related and unrelated donor transplantation. All three studies showed a significantly lower incidence of grade II-IV acute GVHD in patients who received tacrolimus. One study in sibling donor transplantation showed that patients with advanced disease who received tacrolimus had a poorer survival than patients who received cyclosporine, but the survival was similar in patients with non-advanced disease. The remaining two studies, one in unrelated donors and the other combining both related and unrelated donors did not show any survival difference between the tacrolimus and cyclosporine groups. In addition, this review also highlights some of the critical questions regarding the role of this agent in allogeneic stem cell transplantation: (1) the contribution of methotrexate in combination with tacrolimus; (2) the starting i.v. dose of tacrolimus; (3) the suggested whole blood level of tacrolimus and its effect on nephrotoxicity; and (4) whether tacrolimus should be used in patients with advanced malignancy. Future studies using tacrolimus in combination with other immunosuppressants, and its use in patients with advanced malignancy will be warranted.

Topics: Acute Disease; Bone Marrow Transplantation; Drug Interactions; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Hyperglycemia; Hypertension; Immunosuppressive Agents; Kidney; Multicenter Studies as Topic; Nervous System; Randomized Controlled Trials as Topic; Tacrolimus; Transplantation, Homologous

To determine how well tacrolimus (FK506) and cyclosporin A (CsA) are tolerated after HLA-identical blood stem cell transplantation, we performed a retrospective review of 87 adults transplanted consecutively who received FK506 (n = 40) or CsA (n = 47) in a nonrandomized fashion in combination with methylprednisolone for graft-versus-host disease (GVHD) prophylaxis and compared the incidences of complications potentially related to the immunosuppressive agents. Pre-transplant demographic characteristics, drug compliance and rates of acute GVHD were comparable for the two groups. Following first discharge, fewer patients in the FK506 group required antihypertensive therapy (32 vs 59%, P = 0.022), but more required insulin (34 vs 10%, P = 0.014). There was also a trend for more hyperkalemia and less moderate-to-severe venoocclusive disease in the FK506 group. However, nephrotoxicity, neurotoxicity, hemolytic-uremic syndrome, and cytomegaloviral or fungal infections through the first 100 days post-transplant did not differ significantly between the two groups. We conclude that for allogeneic blood stem cell transplant recipients, the incidence of complications related to FK506 and CsA in equally effective dose schedules in combination with methylprednisolone are similar with the exception of the risks of hypertension and hyperglycemia.

Topics: Acute Kidney Injury; Adolescent; Adult; Chemical and Drug Induced Liver Injury; Cyclosporine; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Hyperglycemia; Hyperkalemia; Hypertension; Immunosuppressive Agents; Incidence; Infections; Male; Methylprednisolone; Middle Aged; Patient Compliance; Retrospective Studies; Seizures; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation

The sensitivity of fasting plasma glucose (FPG) in screening for new-onset diabetes after transplantation (NODAT) has been questioned, particularly in the presence of moderate-dose prednisolone, where peak plasma glucose occurs 7 to 8 hr after administration. Oral glucose tolerance testing (OGTT) has been mooted as an alternative but is inconvenient for patients.. We compared sensitivity of screening tests for NODAT at 6 weeks, 3 months, and 12 months after kidney transplantation in recipients receiving prednisolone, mycophenolate, and tacrolimus.. At 6 weeks, NODAT (capillary blood glucose [CapBG] ≥11.1 mmol/L, FPG ≥7.0 mmol/L, 2-hr plasma glucose ≥11.1 mmol/L, or glycated hemoglobin [HbA1c] ≥6.5%) was detected in 46% with CapBG versus 12% with OGTT (P=0.013), 4% with HbA1c (P<0.001), and 0% with FPG (P<0.001; n=26). At 3 months, NODAT was present in 14% with HbA1c versus 20% with OGTT (P=0.600) and 2% with FPG (P=0.059; n=50), whereas, at 12 months, NODAT was found in 4% with HbA1c versus 6% with OGTT (P=1.00) and 2% with FPG (P=0.618; n=51). Combining 3- and 12-month data, OGTT recorded NODAT in 14% and impaired glucose tolerance in 28%, whereas HbA1c detected NODAT in 10% and impaired glucose tolerance (from ≥5.7 to <6.5%) in 51%. Employing HbA1c as a screening test and reserving OGTT for those with impaired glucose tolerance would detect NODAT with a sensitivity more than 94%, avoiding the need for OGTT in 49% of patients.. This study confirms the inadequacy of FPG screening for NODAT in the first 6 weeks after transplantation, at which time 4 p.m. CapBG also outperformed OGTT. From 3 months, HbA1c had similar sensitivity to OGTT and represents a convenient alternative.

Topics: Adult; Blood Glucose; Circadian Rhythm; Cross-Sectional Studies; Fasting; Female; Glucocorticoids; Glucose Tolerance Test; Glycated Hemoglobin; Graft Rejection; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Male; Mass Screening; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisolone; Sensitivity and Specificity; Tacrolimus

The aim of this study was to prospectively evaluate the efficacy and safety of tacrolimus for treating rheumatoid arthritis (RA) patients in clinical practice. Fifty-five active RA patients who had been resistant or intolerant to other disease-modifying antirheumatic drugs were enrolled in this open-label trial. Patients were administered tacrolimus at a dosage of 1, 2 or 3 mg once daily, and followed up for 24 weeks. They were divided into three groups according to their dosage. Efficacy and safety were evaluated utilizing clinical and laboratory findings. Eighty percent of the patients had moderate or high disease activity; 55% were elderly and 53% had complications; 65% of the patients were started on tacrolimus as a monotherapy. Moderate or good response rates were achieved as follows: 38.2% (4 weeks); 41.8% (12 weeks); and 45.6% (24 weeks). Adverse events were observed in seven cases (12.7%). Only one case required hospitalization due to severe hyperglycemia caused by a high tacrolimus concentration (24.2 ng/ml); we suspected a drug interaction in this subject. Mean concentrations were dose-dependent in the 1, 2, and 3 mg/day groups (2.96, 4.29, and 8.32 ng/ml, respectively). Four cases of high concentration (over 10 ng/ml), without any signs or symptoms, were observed in the 3 mg/day group; in these cases, doses were decreased and no severe adverse events occurred. Tacrolimus was found to be both effective and safe in treating active RA patients with complicated backgrounds in clinical practice. Blood concentration measurements and dose adjustments should be performed to prevent severe adverse events in a 3 mg/day group.

Topics: Administration, Oral; Aged; Arthritis, Rheumatoid; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hyperglycemia; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Alternative measures to trough concentrations [non-trough concentrations and limited area under the concentration-time curve (AUC)] have been shown to better predict tacrolimus AUC. The aim of this study was to determine if these are also better predictors of adverse outcomes in long term liver transplant recipients.. The associations between tacrolimus trough concentrations (C(0)), non-trough concentrations (C(1), C(2), C(4), C(6/8)), and AUC(0-12) and the occurrence of hypertension, hyperkalaemia, hyperglycaemia and nephrotoxicity were assessed in 34 clinically stable liver transplant patients.. The most common adverse outcome was hypertension, prevalence of 36%. Hyperkalaemia and hyperglycaemia had a prevalence of 21% and 13%, respectively. A sequential population pharmacokinetic/pharmacodynamic approach was implemented. No significant association between predicted C(0), C(1), C(2), C(4), C(6/8) or AUC(0-12) and adverse effects could be found. Tacrolimus concentrations and AUC measures were in the same range in patients with and without adverse effects.. Measures reported to provide benefit, preventing graft rejection and minimizing acute adverse effects in the early post-transplant period, were not able to predict adverse effects in stable adult liver recipients whose trough concentrations were maintained in the notional target range.

Topics: Adult; Area Under Curve; Female; Humans; Hyperglycemia; Hyperkalemia; Hypertension; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Male; Models, Theoretical; Tacrolimus

Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus (TAC) + mycophenolate mofetil (MMF), TAC + azathioprine (AZA), or cyclosporine (Neoral; CsA) + MMF. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function (DGF). Patients were followed-up for 3 years.. The results at 3 years corroborate and extend the findings of the 2-year results. Patients with DGF treated with TAC+MMF experienced an increase in 3-year allograft survival compared with patients receiving CsA+MMF (84.1% vs. 49.9%, P=0.02). Patients randomized to either treatment arm containing TAC exhibited numerically superior kidney function when compared with CsA. During the 3 years, new-onset insulin dependence occurred in 6, 3, and 11 patients in the TAC+MMF, CsA+MMF, and TAC+AZA treatment arms, respectively. Furthermore, patients randomized to TAC+MMF received significantly lower doses of MMF as compared with those who received CsA+MMF.. All three immunosuppressive regimens provided excellent safety and efficacy. However, the best results overall were achieved with TAC+MMF. The combination may provide particular benefit to kidney allograft recipients with DGF. In patients who experienced DGF, graft survival was better at 3 years in those patients receiving TAC in combination with either MMF or AZA as compared with the patients receiving CsA with MMF.

Topics: Acute Disease; Azathioprine; Cadaver; Creatinine; Cyclosporine; Drug Therapy, Combination; Florida; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperglycemia; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Probability; Racial Groups; Survival Analysis; Tacrolimus; Time Factors; Tissue Donors

To assess the safety of tacrolimus used in combination with oral methotrexate (MTX) to control the signs and symptoms of rheumatoid arthritis (RA) in patients whose disease remains active despite treatment with MTX.. This was a multicenter open-label study conducted at 13 US sites. Eighty patients who at baseline had active RA (mean tender/painful joint count 29.4, mean swollen joint count 17.4, mean erythrocyte sedimentation rate 25.1 mm/hour) despite treatment for >/=1 month with a stable, maximally tolerated dosage of oral MTX (/=30% maximum increase in the Cr level from baseline during the study, with the Cr level in 3 patients (3.8%) exceeding the range considered normal for their age and sex. The maximum Cr level during the study was 1.8 mg/dl. The ACR20 clinical response rate at the end of treatment was 52.5% (95% confidence interval 41.6-63.4%).. In patients whose active RA persists despite treatment with MTX, tacrolimus in combination with MTX is safe and well-tolerated and provides clinical benefit.

Topics: Administration, Oral; Arthritis, Rheumatoid; Creatinine; Drug Therapy, Combination; Female; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney; Male; Methotrexate; Middle Aged; Tacrolimus; Treatment Outcome

The long-term effects of tacrolimus and cyclosporine on pancreatic islet cell function in renal transplant recipients are unclear. Therefore, a prospective, randomized, longitudinal study was performed that compared glucose metabolism in adult kidney allograft recipients on tacrolimus versus cyclosporine-based immunosuppression. Twenty-three white renal allograft recipients, randomized for either therapy with cyclosporine or tacrolimus, underwent intravenous glucose tolerance tests 6 times during the first 3 yr after transplantation. Concomitant therapy (low-dose steroids and azathioprine) was the same in both groups. Insulin sensitivity index (kG), insulin resistance (insulin/glucose ratio and homeostasis model assessment), and C-peptide and insulin secretion were calculated. Trough levels of tacrolimus and cyclosporine were measured. The occurrence of posttransplantation diabetes mellitus was prospectively monitored. Statistical analysis was performed by ANOVA for repeated measures, and parametric and nonparametric tests were also performed. Although only one patient treated with cyclosporine developed posttransplantation diabetes mellitus, kG levels were below normal in up to one-third of both patients who received tacrolimus and cyclosporine. The only significant difference between patients who received tacrolimus and those who received cyclosporine was in pancreatic secretion capacity at week 3 after transplantation, when the increment of C-peptide secretion was 57% lower and the increment of insulin secretion was 48% lower for patients receiving tacrolimus. In both groups, from week 3 to month 6, there was a tendency toward an increase in kG, despite a significant increase in fasting glucose and insulin resistance calculated by homeostasis model assessment. After month 6, there were no significant changes in any of the parameters of glucose metabolism, indicating that long-term use of either tacrolimus or cyclosporine does not cause chronic, cumulative pancreatic toxicity.

Topics: Adult; Aged; Cyclosporine; Diabetes Mellitus; Female; Glucose; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Period; Tacrolimus; Time Factors

The introduction of the potent immunosuppressive drugs tacrolimus (FK) and cyclosporine (CSA) has markedly improved the outcome of solid organ transplantation. However, these drugs can cause posttransplantation diabetes mellitus. Abnormalities in the glucose metabolism are of particular significance in pancreas transplantation.. We studied 26 pancreas allograft biopsies, performed 1-8 months posttransplantation, from 20 simultaneous kidney-pancreas transplant recipients, randomized to receive either FK or CSA. The biopsies were studied by light microscopy, immunoperoxidase stains for insulin and glucagon, in situ DNA-end labeling for detection of apoptosis, and electron microscopy. The islet morphology was correlated with the mean and peak levels of CSA and FK in serum, with corticosteroid administration and with glycemia.. On light microscopy cytoplasmic swelling, vacuolization, apoptosis, and abnormal immunostaining for insulin were seen in biopsies from patients receiving either FK or CSA. The islet cell damage was more frequent and severe in the group receiving FK than in the group receiving CSA (10/13 and 5/13, respectively) but the differences were not statistically significant. Significant correlation was seen between the presence of islet cell damage and serum levels of CSA or FK during the 15 days previous to the biopsy, as well as with the peak level of FK. Toxic levels of CSA or FK and administration of pulse steroids were associated with hyperglycemia when these occurred concurrently (P=0.005). Toxic levels of CSA or FK by themselves were associated with hyperglycemia in a minority of cases (8 and 26%, respectively). Electron microscopy showed cytoplasmic swelling and vacuolization, and marked decrease or absence of dense-core secretory granules in beta cells; the changes were more pronounced in patients on FK. Serial biopsies from two hyperglycemic patients receiving FK and evidence of islet cell damage demonstrated reversibility of the damage when FK was discontinued.. The structural damage to beta cells demonstrated in this study is similar to morphological and functional abnormalities previously described in experimental animal models and can at least partially account for the glucose metabolism abnormalities seen in patients receiving these drugs. Toxic levels of CSA or FK and higher steroid doses potentiate each others' diabetogenic effects.

Topics: Adult; Biopsy; Cyclosporine; Female; Follow-Up Studies; Humans; Hyperglycemia; Hyperplasia; Immunosuppressive Agents; Islets of Langerhans; Male; Microscopy, Electron; Middle Aged; Pancreas Transplantation; Tacrolimus; Time Factors; Transplantation, Homologous; Vacuoles

Topics: Adrenal Cortex Hormones; Antilymphocyte Serum; Cadaver; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperglycemia; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Tacrolimus; Tissue Donors

We report the results of a phase III open-label, randomized, multicenter trial comparing tacrolimus/methotrexate to cyclosporine/methotrexate for graft-versus-host disease (GVHD) prophylaxis after HLA-identical sibling marrow transplantation in patients with hematologic malignancy. The primary objective of this study was to compare the incidence of moderate to severe (grade II-IV) acute GVHD. Secondary objectives were to compare the relapse rate, disease-free survival, overall survival, and the incidence of chronic GVHD. Patients were stratified according to age (<40 v >/=40) and for male recipients of a marrow graft from an alloimmunized female. There was a significantly greater proportion of patients with advanced disease randomized to tacrolimus arm (P = . 02). The incidence of grade II-IV acute GVHD was significantly lower in patients who received tacrolimus than patients in the cyclosporine group (31.9% and 44.4%, respectively; P = .01). The incidence of grade III-IV acute GVHD was similar, 17.1% in cyclosporine group and 13.3% in the tacrolimus group. There was no difference in the incidence of chronic GVHD between the tacrolimus and the cyclosporine group (55.9% and 49.4%, respectively; P = .8). However, there was a significantly higher proportion of patients in the cyclosporine group who had clinical extensive chronic GVHD (P = . 03). The relapse rates of the two groups were similar. The patients in the cyclosporine arm had a significantly better 2-year disease-free survival and overall survival than patients in the tacrolimus arm, 50.4% versus 40.5% (P = .01) and 57.2% versus 46.9% (P = .02), respectively. The significant difference in the overall and disease-free survival was largely the result of the patients with advanced disease, 24.8% with tacrolimus versus 41.7% with cyclosporine (P = .006) and 20.4% with tacrolimus versus 28% with cyclosporine (P = .007), respectively. There was a higher frequency of deaths from regimen-related toxicity in patients with advanced disease who received tacrolimus. There was no difference in the disease-free and overall survival in patients with nonadvanced disease. These results show the superiority of tacrolimus/methotrexate over cyclosporine/methotrexate in the prevention of grade II-IV acute GVHD with no difference in disease-free or overall survival in patients with nonadvanced disease. The survival disadvantage in advanced disease patients receiving tacrolimus warrants further investigation.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Cyclosporine; Disease-Free Survival; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematologic Neoplasms; Histocompatibility; Humans; Hyperglycemia; Hypertension; Immunosuppressive Agents; Incidence; Male; Methotrexate; Middle Aged; Nuclear Family; Recurrence; Survival Analysis; Tacrolimus; Tissue Donors; Transplantation, Homologous; Treatment Outcome

Initial studies of FK506 combined with methotrexate (MTX) in patients receiving unrelated donor BMT have demonstrated a possible-decrease in the incidence of severe GVHD but high rates of severe stomatitis and nephrotoxicity. With this background, we undertook a pilot study evaluating FK506 in combination with a lower than usual dose of MTX in an attempt to improve the tolerability of this immunoprophylaxis regimen. Between July 1993 and October 1994, 26 consecutive adults receiving unrelated donor BMT at Emory University Hospital were enrolled on this study. All patients received FK506 intravenously at an initial dose of 0.03 mg/kg/day beginning day -1 and continuing until oral FK506 was tolerated. Patients also received MTX intravenously at 5 mg/m2 on days 1, 3, 6, and 11. The preparative regimen administered to all but one patient included cyclophosphamide at 200 mg/kg over 4 days followed by total body irradiation (TBI) at 1400 cGy in twice daily fractions over 4 days. The median age of patients was 31 years (range: 19 to 52). Sixteen donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing. Ten paris were minor mismatches at either class I or class II. Twenty-two of 26 patients (85%) completed four doses of MTX on schedule. Nephrotoxicity was the most common adverse event associated with the administration of FK506: 88% of patients experienced a doubling of their serum creatinine. One patient died of central nervous system hemorrhage prior to engraftment. Twenty-four of the remaining 25 patients (96%) engrafted. Fourteen of 24 patients (50%) evaluable developed grades 2-4 acute GVHD. The rate of severe (grades 3-4) acute GVHD was 25%. Chronic GVHD developed in 11 of 20 (55%) evaluable patients. At a median follow-up of 461 days, 14 patients (54%) are alive. All are relapse-free with a median Karnofsky performance status of 90% (range: 70-100%). The cumulative probability of 2-year disease-free survival is 50% (95% confidence interval [CI]: 0.33 to 0.77); for low risk patients 67% (95% CI: 0.47 to 0.95) and for high risk patients 23% (95% CI: 0.049 to 1.00). These preliminary data indicate that FK506-based immunosuppression following unrelated donor BMT is effective in preventing severe acute GVHD and warrants comparison to CSA-based regimens.

Topics: Adult; Bone Marrow Transplantation; Disease-Free Survival; Drug Therapy, Combination; Female; Graft Survival; Graft vs Host Disease; Hematologic Neoplasms; Histocompatibility; Humans; Hyperglycemia; Hypertension; Immunosuppressive Agents; Infections; Kidney Diseases; Life Tables; Liver Diseases; Male; Methotrexate; Middle Aged; Pilot Projects; Safety; Survival Analysis; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Topics: Amylases; Cholesterol; Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperglycemia; Kidney; Kidney Transplantation; Potassium; Prednisolone; Survival Rate; Tacrolimus; Time Factors; Triglycerides; Uric Acid

Topics: Drug Monitoring; Family; Graft Rejection; Humans; Hyperglycemia; Kidney Transplantation; Metabolic Clearance Rate; Prednisolone; Tacrolimus; Tissue Donors

From September 1990 to January 1992, 545 liver transplant patients were randomised to treatment with either FK506 and prednisolone or a conventional cyclosporin-based immunosuppressive regimen (CBIR). Eight European centres participated in the study. Adverse events were reported as defined by each centre. Hyperglycaemia was reported as an adverse event in 30.7% of patients receiving FK 506 compared with 20.5% in the CBIR group (P < 0.01). Diabetes mellitus was reported in 17.2% of patients treated with FK 506 and 9.5% of CBIR-treated patients (P < 0.05). Treatment with insulin was required in 12.0% of patients in the DK 506 treatment group and in 5% in the CBIR group at 6 months. Initially, higher doses of FK 506 were used. During the study, the protocol was changed to allow a lower dose of FK 506. When the early and late cohorts of patients were compared, the incidence of diabetes mellitus fell from 23.9% to 10.5% in FK 506-treated patients but remained relatively constant in the CBIR group (10.4% to 8.7%). The median cumulative doses of i.v. and p.o. corticosteroids were significantly greater in the CBIR group. Thus, in the overall series, the incidence of diabetes mellitus was significantly greater in the FK 506 group as compared with the CBIR group. However, when a lower FK 506 dose was used during the second half of the study, the difference in the incidence of diabetes mellitus disappeared.

Topics: Adolescent; Adult; Aged; Blood Glucose; Cyclosporine; Drug Therapy, Combination; Europe; Female; Glucose; Humans; Hyperglycemia; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Tacrolimus; Time Factors

Metabolic-related markers are novel tools for assessing insulin resistance. Early identification of post-transplantation diabetes mellitus (PTDM) before hyperglycemia can be helpful to attenuate the rapid development of diabetic complications. This article aims to explore the convenient and inexpensive values of metabolic-related markers, including TyG, TyG-BMI, TG/HDL-C, and non-HDL-C/HDL-C for predicting PTDM. The data of 191 kidney transplant recipients in our center were collected retrospectively. The association between TyG, TyG-BMI, TG/HDL-C, non-HDL-C/HDL-C and the risk of PTDM was examined by the area under the curve and logistic regression analyses. During 6 months follow-up, 12.04% of KT recipients developed PTDM, and significantly higher values of TyG-BMI, TyG, and non-HDL-C/HDL-C was found in patients with PTDM than in nondiabetic patients, especially among the recipients taking tacrolimus, regardless of gender. The incidence of PTDM increased along with the values of TyG or TyG-BMI. After adjusting for multiple potential factors, recipients with the highest trisector of TyG or TyG-BMI still had a higher risk of PTDM morbidity. In conclusion, TyG, TyG-BMI, TG/HDL-C and non-HDL-C/HDL-C can be used as cost-effective and promising monitors to identify individuals at high risk of PTDM, and TyG-BMI was the best alternative marker among the four markers.

Topics: Diabetes Mellitus; Humans; Hyperglycemia; Kidney Transplantation; Retrospective Studies; Risk Factors; Tacrolimus

Approximately 33.6% of nondiabetic solid organ transplant recipients who received tacrolimus developed hyperglycemia. Whether the tacrolimus-induced gut microbiota is involved in the regulation of hyperglycemia has not been reported. Hyperglycemia was observed in a tacrolimus-treated mouse model, with reduction in taxonomic abundance of butyrate-producing bacteria and decreased butyric acid concentration in the cecum. This tacrolimus-induced glucose metabolic disorder was caused by the gut microbiota, as confirmed by a broad-spectrum antibiotic model. Furthermore, oral supplementation with butyrate, whether for remedy or prevention, significantly increased the butyric acid content in the cecum and arrested hyperglycemia through the regulation of glucose-regulating hormones, including glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and insulin, in serum. The butyrate-G-protein-coupled receptor 43-GLP-1 pathway in the intestinal crypts may be involved in the pathogenesis of normalization of hyperglycemia caused by the tacrolimus. Therefore, tacrolimus affects glucose metabolism through the butyrate-associated GLP-1 pathway in the gut, and oral supplementation with butyrate provides new insights for the prevention and treatment of tacrolimus-induced hyperglycemia in transplant recipients.

Topics: Animals; Butyric Acid; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Hyperglycemia; Mice; Tacrolimus

Hyperglycemia promotes podocyte apoptosis and plays an important role in the pathogenesis of diabetic nephropathy (DN). Calcium/calcineurin (CaN) signaling is critical for podocyte apoptosis. Therefore, it is essential to elucidate the mechanisms underlying the regulation of CaN signaling. Recent studies reported that histone deacetylase 4 (HDAC4) is involved in podocyte apoptosis in DN. The aim of this study was to determine whether HDAC4 mediates the regulation of CaN and to elucidate the function of HDAC4 in high glucose (HG)-induced podocyte apoptosis. First, we identified the expression of HDAC4 was upregulated in podocytes of patients with DN. In vitro, the results also indicate that the mRNA and protein expression levels of HDAC4 were increased in HG-cultured podocytes. Silencing and overexpression of HDAC4 markedly decreased and increased CaN expression, respectively. Meanwhile, HG-induced podocyte apoptosis was abrogated by HDAC4-knockdown with subsequent decreased Bax expression and increased Bcl-2 expression. In contrast, overexpression of HDAC4 increased podocyte apoptosis and Bax expression, as well as decreased Bcl-2 expression. In addition, podocyte apoptosis induced by HDAC4 overexpression was effectively rescued by FK506, a pharmacological inhibitor of CaN, which was accompanied by decreased Bax and increased Bcl-2 expression. As a novel finding, HG-induced podocyte apoptosis is mediated by the HDAC4/CaN signaling pathway, which presents a promising target for therapeutic intervention in DN.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Calcineurin; Calcineurin Inhibitors; Cell Line; Diabetic Nephropathies; Gene Knockdown Techniques; Gene Silencing; Glucose; Histone Deacetylases; Humans; Hyperglycemia; Mice; Podocytes; Proto-Oncogene Proteins c-bcl-2; Repressor Proteins; RNA, Small Interfering; Signal Transduction; Tacrolimus; Up-Regulation

Posttransplantation diabetes mellitus (PTDM) is a frequent metabolic complication following solid organ transplantation and was proven to be associated with adverse outcome. This study aimed to identify the incidence and risk factors of PTDM under the background of relative-living renal transplantation in China.. We conducted a retrospective cohort study that included 358 recipients who underwent relative-living donor kidney transplantation in the Organ Transplant Institute of 309th Hospital of People's Liberation Army between January 1, 2010, and December 31, 2014. PTDM was defined based on American Diabetes Association criteria. Demographics and laboratory results were compared between patients with PTDM and non-PTDM; multivariate analysis was performed using a logistic regression model.. One hundred ten out of a total of 358 recipients were diagnosed with PTDM (30.72%) within 3 years after transplantations. Seven risk factors for PTDM were identified in multivariate analysis: body mass index ≥25 (odds ratio [OR] 1.905, 95% confidence interval [CI]: 1.114-3.258), family history of diabetes (OR 1.898, CI: 1.051-3.258), hypomagnesemia pretransplantation (OR 1.871, CI: 1.133-3.092), acute rejection episodes in 3 months posttransplantation (OR 2.312, CI: 1.015-5.268), tacrolimus use (OR 1.952, CI: 1.169-3.258), impaired fasting glucose diagnosed pretransplantation (OR 1.807, CI: 1.091-2.993), and hyperglycemia in the first week posttransplantation (OR 1.856, CI: 1.133-3.043).. Our study suggests high body mass index, family diabetes history, hypomagnesemia pretransplantation, acute rejection episodes within the first 3 months after transplantation, tacrolimus use, impaired fasting glucose diagnosed pretransplantation, and hyperglycemia within the first week after transplantation are independent risk factors of PTDM in relative-living donor transplantation.

Topics: Adult; Body Mass Index; China; Cohort Studies; Diabetes Mellitus; Female; Humans; Hyperglycemia; Immunosuppressive Agents; Incidence; Kidney Transplantation; Living Donors; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus

Solid organ transplantation (SOT) outcomes have continued to improve, although long-term use of immunosuppressants can lead to complications such as diabetes, compromising post-transplant outcomes. In this study, we have characterized the intestinal microbiome (IM) composition at the metagenomic level in the context of hyperglycemia induced by immunosuppressants. Sprague-Dawley rats were subjected to doses of tacrolimus and sirolimus that reliably induce hyperglycemia and an insulin-resistant state. Subsequent exposure to probiotics resulted in reversal of hyperglycemia. 16S rRNA and metagenomic sequencing of stool were done to identify the bacterial genes and pathways enriched in immunosuppression. Bacterial diversity was significantly decreased in sirolimus-treated rats, with 9 taxa significantly less present in both immunosuppression groups: Roseburia, Oscillospira, Mollicutes, Rothia, Micrococcaceae, Actinomycetales and Staphylococcus. Following probiotics, these changes were reversed to baseline. At the metagenomic level, the balance of metabolism was shifted towards the catabolic side with an increase of genes involved in sucrose degradation, similar to diabetes. Conversely, the control rats had greater abundance of anabolic processes and genes involved in starch degradation. Immunosuppression leads to a more catabolic microbial profile, which may influence development of diabetes after SOT. Modulation of the microbiome with probiotics may help in minimizing adverse long-term effects of immunosuppression.

Topics: Animals; Computational Biology; Diabetes Mellitus; Gastrointestinal Microbiome; Gene Ontology; Humans; Hyperglycemia; Immunosuppression Therapy; Immunosuppressive Agents; Insulin Resistance; Male; Metagenome; Metagenomics; Rats; RNA, Ribosomal, 16S; Sirolimus; Systems Biology; Tacrolimus; Transplantation

We evaluated the clinical efficacy of tailoring tacrolimus dosage to cytochrome P450 (CYP) 3A5 genotype in liver transplant patients. One hundred patients who received tacrolimus-based therapy were included in the retrospective study in which the relationship between the tacrolimus blood trough concentration/dosage ratio and the CYP3A5 genotype of both donors and recipients was determined. Subsequently, 106 patients were continuously enrolled in a prospective study and followed-up for 6 months; the relationship between tacrolimus dosage and CYP3A5 genotype was also determined. Rates of acute rejection, hepatotoxicity, renal toxicity, neurotoxicity, hypertension, and hyperglycemia were compared between the groups. During the 6 months following liver transplantation, the mean tacrolimus concentration/dosage ratio among patients who did not have the CYP3A5*1 genotype and who received a transplant from a donor with the same genotype (24/100, 24% of patients) was higher than that among patients who did have the CYP3A5*1 genotype and/or had a donor with the same genotype (76/100, 76% of patients). In the second part of the study, the tacrolimus dosage was tailored to CYP3A5 genotype and 24 patients (22.64%) received a lower dose. There was an obvious decrease in acute rejection, hepatotoxicity, renal toxicity, neurotoxicity, hypertension, hyperglycemia, and Pneumocystis carinii infection among the latter group. A lower tacrolimus dose was suitable for about 25% of the liver transplant patients, as these patients did not have the CYP3A5*1 genotype and received a transplant from a donor with the same genotype. Tailoring the tacrolimus dosage according to the CYP3A5 genotype could reduce rejection and adverse effects.

Topics: Adult; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Female; Gene Frequency; Genotype; Graft Rejection; Humans; Hyperglycemia; Hypertension; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Outcome Assessment, Health Care; Polymorphism, Genetic; Prospective Studies; Retrospective Studies; Tacrolimus; Time Factors; Tissue Donors

Hyperglycemia following solid organ transplant is common among patients without pre-existing diabetes mellitus (DM). Post-transplant hyperglycemia can occur once or multiple times, which if continued, causes new-onset diabetes after transplantation (NODAT).. To study if the first and recurrent incidence of hyperglycemia are affected differently by immunosuppressive regimens, demographic and medical-related risk factors, and inpatient hyperglycemic conditions (i.e., an emphasis on the time course of post-transplant complications).. We conducted a retrospective analysis of 407 patients who underwent kidney transplantation at Mayo Clinic Arizona. Among these, there were 292 patients with no signs of DM prior to transplant. For this category of patients, we evaluated the impact of (1) immunosuppressive drugs (e.g., tacrolimus, sirolimus, and steroid), (2) demographic and medical-related risk factors, and (3) inpatient hyperglycemic conditions on the first and recurrent incidence of hyperglycemia in one year post-transplant. We employed two versions of Cox regression analyses: (1) a time-dependent model to analyze the recurrent cases of hyperglycemia and (2) a time-independent model to analyze the first incidence of hyperglycemia.. Age (P = 0.018), HDL cholesterol (P = 0.010), and the average trough level of tacrolimus (P<0.0001) are significant risk factors associated with the first incidence of hyperglycemia, while age (P<0.0001), non-White race (P = 0.002), BMI (P = 0.002), HDL cholesterol (P = 0.003), uric acid (P = 0.012), and using steroid (P = 0.007) are the significant risk factors for the recurrent cases of hyperglycemia.. This study draws attention to the importance of analyzing the risk factors associated with a disease (specially a chronic one) with respect to both its first and recurrent incidence, as well as carefully differentiating these two perspectives: a fact that is currently overlooked in the literature.

Topics: Cohort Studies; Female; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Recurrence; Risk Factors; Sirolimus; Steroids; Tacrolimus; Transplant Recipients

Kidney transplant recipients may develop new-onset diabetes after transplantation (NODAT) and transplant-associated hyperglycemia (TAH) (NODAT or new-onset impaired glucose tolerance-IGT). We studied 251 consecutive renal transplant South Asian recipients for incidence of NODAT and its risk factors between June 2004 and January 2009. Pre-transplant glucose tolerance test (GTT) identified non-diabetics (n = 102, IGT-24, NGT-78) for analysis. Baseline immunosuppression along with either cyclosporine (CsA) (n = 70) or tacrolimus (Tac) (n = 32) was given. Patients underwent GTT 20 days (mean) post-transplant to identify NODAT, normal (N) or IGT. TAH was observed in 40.2% of the patients (40% in CsA and 40.6% in Tac) (P = 0.5). NODAT developed in 13.7% of the patients (12.9% in CsA and 15.6% in Tac) (P = 0.5). Overall, Hepatitis C (P = 0.007), human leukocyte antigen (HLA) B52 (P = 0.03) and lack of HLA A28 (A68/69) (P = 0.03) were associated with TAH. In the Tac group, higher Day 1 dosage (P <0.001), HLA A1 (P = 0.04), B13 (P = 0.03) and lack of DR2 (P = 0.004) increased the risk of TAH. In the CsA group, HLA A10 (P = 0.03), failure of triglyceride (P = 0.001) or low-density lipoprotein (LDL) (P = 0.03) to lower or high-density lipoprotein to rise (P = 0.001), and higher post-transplant LDL (P <0.001) and cholesterol levels (P = 0.02) were associated with NODAT or TAH. Post-transplant fasting plasma glucose on Day 1 had sensitivity-54.5%, specificity-50.1%, positive predictive value-18.1% and negative predictive value-84.8% for detecting NODAT. In conclusion, there is a genetic predisposition to NODAT and TAH in South Asia as seen by the HLA associations, and a predisposition exists to the individual diabetogenic effects of Tac and CsA based on HLA type. This could lead to more careful selection of calcineurin inhibitors based on HLA types in the South Asian population.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Female; Genetic Predisposition to Disease; Graft Rejection; HLA Antigens; Humans; Hyperglycemia; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Tacrolimus

Although the contribution of the immunosuppressants tacrolimus (TAC) and sirolimus (SIR) to the development of posttransplant diabetes mellitus (PTDM) are being increasingly recognized, the mechanisms of immunosuppressant-induced hyperglycemia are unclear. SIR induces insulin resistance predominantly, but is associated with β-cell dysfunction in rodents. TAC affects islet function but is associated with worsening insulin sensitivity in a few, and improvement in some, clinical studies. We sought to clarify the contributions of TAC and SIR to insulin resistance and islet function. Four groups of male and female Sprague-Dawley rats received TAC, SIR, TAC and SIR, or control for 2 weeks. All rats were administered an oral glucose challenge at the end of treatment. Half the groups were sacrificed 10 minutes after administration of regular insulin whereas the other half did not receive insulin before sacrifice. Liver, pancreas, fat, and muscle were harvested subsequently. Quantification of Western blots revealed that SIR and TAC plus SIR suppressed the phospho-Akt (pAkt)-to-Akt ratios in liver, muscle, and fat compared with control, regardless of sex. TAC alone did not impair the pAkt-to-Akt ratios in any of the tissues in male and female rats. β-Cell mass was reduced significantly after TAC treatment in male rats. SIR did not affect β-cell mass, regardless of sex. Our study demonstrated very clearly that SIR impairs insulin signaling, without any effect on β-cell mass, and TAC does not impair insulin signaling but reduces β-cell mass. Our efforts are key to understanding the mechanisms of immunosuppressant-induced hyperglycemia and to tailoring treatments for PTDM.

Topics: Adipose Tissue; Animals; Female; Hyperglycemia; Immunosuppressive Agents; Insulin; Liver; Male; Mice; Mice, Inbred C57BL; Pancreas; Rats; Rats, Sprague-Dawley; Sex Factors; Signal Transduction; Sirolimus; Tacrolimus; Transplants

New onset of diabetes after transplantation (NODAT) is a known complication of renal transplantation, but early glycaemic status after transplantation has not been described prospectively. This study aimed to assess blood glucose (BG) levels immediately following kidney transplantation in non-diabetic subjects and to explore their relationship to later graft outcomes and NODAT occurrence.. Over a 9-month period, 43 consecutive non-diabetic patients who received a kidney transplant were prospectively investigated. During the first 4 days after transplantation, fasting BG was measured and the 24-h BG profile assessed by continuous glucose monitoring (CGM). Capillary BG was measured on hospital admittance and at least four times a day for CGM calibration thereafter. All adverse events were recorded, and fasting BG and HbA1c were assessed at 3, 6 and 12 months and at the last visit to our centre.. Immediately following renal transplantation, capillary BG was 12.2 ± 3.8 mmol/L. On day 1 (D1), fasting BG was 9.9 ± 4.3 mmol/L and decreased to 6.0 ± 1.5 mmol/L on D3. The CGM-reported mean 24-h BG (mmol/L) was 10.2±2.4 on D1, 7.7 ± 1.3 on D2 and 7.5 ± 1.1 on D3. From D1 to D4, 43% of patients spent>12h/day with BG levels>7.7 mmol/L. While morbidity during the 3 months following transplantation appeared unrelated to BG, the first post-transplantation capillary BG measurement and fasting BG on D1 tended to be higher in patients who developed diabetes 3 months later. Tacrolimus treatment was associated with a higher incidence of dysglycaemia at 3 and 6 months. After a mean follow-up of 72 months, NODAT was frequently seen (18.6%), and was associated with tacrolimus medication (P<0.01) and a higher rate of renal transplantation failure (RR: 3.6, P<0.02).. Hyperglycaemia appears to be a nearly constant characteristic immediately following transplantation in non-diabetic kidney recipients. Higher BG values could identify patients at risk for later post-transplant diabetes and graft failure.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; Body Mass Index; Critical Care; Diabetes Mellitus; Female; Follow-Up Studies; France; Glycated Hemoglobin; Graft Rejection; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Monitoring, Physiologic; Predictive Value of Tests; Prospective Studies; Risk Factors; Tacrolimus

Immunosuppressants are an important cause of posttransplantation diabetes mellitus. We have shown that tacrolimus and sirolimus induce hyperglycemia and hyperinsulinemia in normal rats. We hypothesized that metformin, given concurrently with tacrolimus and/or sirolimus, prevents disturbances in glucose and insulin metabolism.. Eight groups (n=6) of normal Sprague-Dawley rats were studied: four groups received tacrolimus, sirolimus, tacrolimus/sirolimus, or control for 14 days, and four more groups received similar treatments along with metformin. Daily glucoses were measured. All rats were administered an oral glucose challenge before sacrifice. Pancreata were analyzed by terminal deoxynucleotide tranferase-mediated dUTP nick-end labeling staining and immunohistochemistry.. Tacrolimus, sirolimus, and tacrolimus/sirolimus impaired glucose tolerance compared to control. Sirolimus and tacrolimus/sirolimus also increased random blood glucose levels. Sirolimus alone resulted in hyperinsulinemia after oral glucose challenge compared to control. In the sirolimus/metformin and tacrolimus/sirolimus/metformin groups, mean daily random glucose was no longer increased, although the response to glucose challenge was still impaired. Metformin decreased pancreatic exocrine and trended to decrease endocrine apoptosis in tacrolimus/sirolimus group and reduced islet insulin content in sirolimus group.. This is the first study to show that metformin can improve immunosuppressant-induced hyperglycemia, when administered concurrently, and reduces exocrine apoptosis (reducing the impact on potential islet progenitor cells).

Topics: Animals; Apoptosis; Biomarkers; Blood Glucose; Disease Models, Animal; Glucose Tolerance Test; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Immunohistochemistry; Immunosuppressive Agents; In Situ Nick-End Labeling; Insulin; Male; Metformin; Pancreas, Exocrine; Rats; Rats, Sprague-Dawley; Sirolimus; Tacrolimus; Time Factors

Topics: Area Under Curve; Blood Glucose; C-Peptide; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Hyperglycemia; Hypoglycemia; Immune Tolerance; Immunosuppressive Agents; Islets of Langerhans; Islets of Langerhans Transplantation; Middle Aged; Tacrolimus

Diabetic ketoacidosis in patients receiving tacrolimus in the post-transplant setting is rare. We describe two such cases in solid-organ transplant recipients. The first patient, a 17-year-old male, presented with severe diabetic ketoacidosis and was managed with intravenous fluids and insulin infusion. He was a known case of Laurence-Moon-Bardet-Biedl syndrome and had received a renal transplant 2 years ago and was receiving tacrolimus since then. Although diabetic ketoacidosis resolved in 24 hours, large doses of subcutaneous insulin (upto 130 units per day) were needed to keep serum glucose within the normal range. Substitution of tacrolimus with cyclosporine obviated the need for insulin or oral hypoglycaemics. The second patient, a 55-year-old woman, presented with a history of polyuria for 3 days. She had received a hepatic transplant 2 years ago and tacrolimus was being used since then. Mild diabetic ketoacidosis was managed with fluid resuscitation and subcutaneous insulin. Her insulin requirement after an uneventful recovery has been 54 - 70 units per day. Clinicians should be cognizant of the possibility of hyperglycaemic crisis presenting as sudden onset of diabetic ketocidosis in patients receiving tacrolimus. Use of an alternative calcineurin inhibitor may provide a safer solution to minimize future morbidity in such patients.

Topics: Adolescent; Diabetic Ketoacidosis; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Immunosuppressive Agents; Injections, Subcutaneous; Insulin; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Treatment Outcome

New-onset diabetes after transplantation may be associated with the use of tacrolimus (Tac) causing impaired insulin release or reduced insulin sensitivity. Such effects have not been studied in renal transplant recipients receiving traditional twice-daily tacrolimus (TacBID) and then compared to the new once-daily prolonged release formulation of tacrolimus (TacOD).. We performed a prospective crossover study of 20 stable non-diabetic renal transplant recipients. All patients underwent one hyperglycaemic clamp on TacBID (3.8 ± 2.2 mg/day) and a new clamp 4-6 weeks after a 1:1 mg/day switch to TacOD (4.0 ± 2.8 mg/day).. Tac trough concentrations decreased from 6.6 ± 2.9 to 5.4 ± 1.4 μg/mL (P = 0.037) and Tac max from 21.3 ± 8.4 to 15.2 ± 3.5 μg/L (P = 0.001). Tac AUC(0-24) was reduced from 265 ± 112 to 218 ± 47 μg × h/L (P = 0.12). The hyperglycaemic clamp did not detect any change in insulin sensitivity index after conversion [0.26 ± 0.21 versus 0.26 ± 0.25 μmol/min/kg/(pmol/L insulin), P = 0.99] nor any change in first (334 ± 274 versus 353 ± 248 μIU × min/mL, P = 0.41) or second phase insulin secretion (224 ± 155 versus 263 ± 210 μIU × min/mL/mmol glucose, P = 0.60) on TacBID versus TacOD.. Conversion from standard TacBID to TacOD on a 1:1 mg basis is safe. In spite of a reduced Tac exposure, there was no change in insulin release or sensitivity in renal transplant recipients.

Topics: Adult; Aged; Blood Glucose; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hyperglycemia; Immunosuppressive Agents; Insulin Resistance; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Prognosis; Prospective Studies; Tacrolimus; Tissue Distribution

Immunosuppression medications contribute to posttransplant diabetes mellitus in patients and can cause insulin resistance in male rats. Tacrolimus (TAC)-sirolimus (SIR) immunosuppression is also associated with appearance of ovarian cysts in transplant patients. Because insulin resistance is observed in patients with polycystic ovary syndrome, we hypothesized that TAC or SIR may induce reproductive abnormalities.. We monitored estrus cycles of adult female rats treated daily with TAC, SIR, and combination of TAC-SIR, or diluent (control) for 4 weeks. Animals were then challenged with oral glucose to determine their glucose and insulin responses, killed, and their blood and tissues, including ovaries and uteri harvested.. TAC and TAC-SIR treatments increased mean random glucose concentrations (P<0.05). TAC, SIR, and TAC-SIR treatments also increased the glucose response to oral glucose challenge (P<0.05). The insulin response to glucose was significantly higher in rats treated with SIR compared with TAC (P<0.05). TAC, SIR and TAC-SIR treatments reduced number of estrus cycles (P<0.05). The ovaries were smaller after SIR and TAC-SIR treatment compared with controls. The TAC and TAC-SIR treatment groups had fewer preovulatory follicles. Corpora lutea were present in all groups. Ovarian aromatase expression was reduced in the SIR and TAC-SIR treatment groups. A significant (P<0.05) reduction in uterine size was observed in all treatment groups when compared with controls.. In a model of immunosuppressant-induced hyperglycemia, both TAC and SIR induced reproductive abnormalities in adult female rats, likely through different mechanisms.

Topics: Animals; Aromatase; Blood Glucose; Estrus; Female; Gene Expression Regulation, Enzymologic; Glucose; Hyperglycemia; Immunosuppressive Agents; Insulin Resistance; Ovary; Phenotype; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley; Sirolimus; Tacrolimus; Uterus

Intensive glycemic control has been shown to positively impact outcomes in an intensive care setting. Whether this practice is beneficial after liver transplantation (LT) is not known.. A retrospective review of patients undergoing LT from February 2002 to July 2007 was conducted to analyze the association between perioperative hyperglycemia and outcomes after LT. Covariates included preexisting diabetes, mean glucose 3 months pre-LT, need for insulin drip post-LT, mean total glucose during the post-LT hospitalization, age, sex, type of transplant, and model for end-stage liver disease score. Outcomes within 1 year of LT included rejection, infection, rehospitalization, prolonged ventilation, and patient/graft survival.. One hundred thirteen LT and 31 liver-kidney recipients were included. By multivariate logistic regression adjusting for covariates, the rejection rate was significantly lower for patients with postoperative glucose levels less than 200 mg/dL (n=114) vs. more than 200 mg/dL (n=30) (odds ratio: 0.055; 95% confidence interval: 0.0154-0.200; P<0.001). The need for prolonged ventilation was more common in patients with glucose less than 200 vs. more than 200 mg/dL (odds ratio: 4.30; 95% confidence interval: 1.284-14.388; P=0.018). Although other outcomes, infection, rehospitalization, patient/graft survival, were not different among the glucose control groups, rejection was associated with increased rehospitalizations and infections.. Our data demonstrate an association between the immediate posttransplant glycemic control and the development of subsequent rejection. Prospective trials investigating the effects of perioperative glycemic control on outcomes and morbidity after LT are warranted.

Topics: Adult; Aged; Blood Glucose; Female; Graft Rejection; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Patient Selection; Postoperative Complications; Postoperative Period; Prednisone; Preoperative Care; Regression Analysis; Retrospective Studies; Survival Rate; Tacrolimus; Treatment Outcome

The ability of supplemental islet infusions (SII) to restore insulin independence in islet transplant recipients with graft dysfunction has been attributed to the coadministration of exenatide. However, improving islet transplant outcomes could explain the success of SII. We aimed to determine the effect on islet graft function and insulin independence of SII using these new protocols, without the use of exenatide.. Seventeen islet transplant recipients underwent SIIs after developing graft dysfunction requiring insulin use. For induction therapy, four subjects received daclizumab induction therapy, whereas 13 subjects received thymoglobulin and etanercept. Maintenance immunosuppression consisted of sirolimus+tacrolimus or tacrolimus+cellcept.. SII was performed 49.3+/-4.8 months (mean+/-SEM) after the preceding islet transplant. Subjects received significantly lower islet mass with their SII compared with initial transplant(s) (6076+/-492 vs. 9071+/-796 IEQ/kg; P=0.003). Fifteen of the 17 subjects (88.2%) became insulin independent 2.4+/-0.5 months after SII. Insulin-independent duration after SII exceeded that of the initial transplant(s) (24.8+/-2.2 vs. 14.2+/-2.6 months by Kaplan-Meier analysis, P=0.009). Subjects show improved glycemic control after SII (HbA1c 7.0%+/-0.2% pre-SII vs. 6.1%+/-0.2% post-SII, P=0.005) and did not become immunosensitized.. Using current protocols, SII in the absence of exenatide results in impressive insulin-independence rates and the durability of insulin independence seems to be promising. However, a beneficial effect of exenatide should not be discounted until tested in randomized controlled studies.

Topics: Antilymphocyte Serum; Blood Glucose; C-Peptide; Drug Therapy, Combination; Etanercept; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Immunoglobulin G; Immunosuppressive Agents; Insulin; Islets of Langerhans Transplantation; Male; Postoperative Complications; Receptors, Tumor Necrosis Factor; Sirolimus; Tacrolimus

To probe into the effects of different doses of FK506 on endocrine function of pancreatic islets in Wistar rats.. Wistar rats were randomly divide into control group A (0mg/kg/d) and experimental group B (1mg/kg/d), C (3mg/kg/d), D (10mg/kg/d) treated with FK506. In an intraperitoneal glucose tolerance test, plasma glucose, insulin and C-peptide were measured with a glucose analyzer and ELISA. The ultra-structure of beta cells of pancreatic islets were assayed with an electric microscope.. In the intraperitoneal glucose tolerance test, the level of plasma glucose increased with an increasing of dose of FK506 and the level of plasma insulin and C-peptide decreased with an increasing of dose of FK506. The result of the plasma glucose level showed no significant difference among groups A, B, C, and D at 0 and 120 min P>or=0.05, and result of plasma glucose level show significant differences among groups A, B, C, D at 30, 60 and 90 min, P<0.05. The result of the plasma insulin level showed significant difference among groups A, B, C, and D at 0, 30, 60, 90 min P<0.05.The result of the plasma C-peptide level showed no significant difference among groups A, B, C, and D at 0 min P> 0.05, and the result of plasma C-peptide level showed significant differences in groups A, B, C, and D at 30, 60, 90 and 120 min, P<0.05.With electric microscope assay, the endocrine secretory granules decreased in experiment group. There is some vacuolization in the beta cells of pancreatic islets in group D.. It was shown in the study that disorders of glucose metabolism induced by FK506 were related to the dosage of FK506.

Topics: Animals; Blood Glucose; C-Peptide; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Glucose Tolerance Test; Hyperglycemia; Immunosuppressive Agents; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Microscopy, Electron, Transmission; Rats; Rats, Wistar; Tacrolimus

New-onset diabetes after transplantation (NODAT) is a frequent complication after liver transplantation and has a negative impact on both patient and graft survival. In analogy with the previous finding of an association between posttransplant hypomagnesemia and NODAT in renal transplant recipients, the relation between both pretransplant and posttransplant hypomagnesemia and NODAT was studied in liver transplant recipients (LTRs). One hundred sixty-nine adult LTRs (>18 years old) without diabetes who underwent transplantation between 2004 and 2009 were studied (mean age = 52.11 ± 12.6 years, proportion of LTRs who were male = 67.5%, body mass index = 25.5 ± 4.4 kg/m², proportion receiving tacrolimus = 90.0%). NODAT was defined according to the American Diabetes Association criteria. The association of NODAT with both pretransplant and posttransplant serum magnesium (Mg) was examined. Overall, 52 of 169 patients (30.8%) developed NODAT, and 57.7% of these (30 patients) were treated with antidiabetic drugs. Both pretransplant Mg levels and Mg levels in the first month after transplantation were lower in patients developing NODAT (P = 0.008 and P = 0.001, respectively). A multivariate regression model (adjusted for weight, pretransplant glucose levels, hyperglycemia in the first week after transplantation, gender, hepatitis C, and corticosteroid dosing) demonstrated both pretransplant Mg levels (hazard ratio = 0.844 per 0.1 mg/dL increase, 95% confidence interval = 0.764-0.932, P = 0.001) and posttransplant Mg levels (hazard ratio = 0.659, 95% confidence interval = 0.518-0.838, P = 0.001) to be independent predictors of NODAT together with age, biopsy-proven acute rejection, and cytomegalovirus (CMV) infection in the first year after transplantation. In conclusion, pretransplant hypomagnesemia and early posttransplant hypomagnesemia are independent predictors of new-onset diabetes after liver transplantation. Other risk factors are age, biopsy-proven acute rejection, and CMV infection.

Topics: Adult; Biomarkers; Case-Control Studies; Cytomegalovirus Infections; Diabetes Mellitus; Female; Graft Survival; Humans; Hyperglycemia; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Magnesium; Male; Metabolic Diseases; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Risk; Risk Factors; Tacrolimus; Young Adult

New-onset diabetes after transplantation (NODAT) has been associated with cardiovascular and thrombotic complications, acute rejection, and infection in transplant recipients. NODAT in kidney transplantation is well described; however, data are lacking in liver transplant recipients.. To evaluate the incidence of new-onset diabetes within 6 months postoperatively in adult liver transplant recipients. DESIGN, PARTICIPANTS, SETTING, AND INTERVENTIONS: Patients who underwent a liver transplantation at our institution between January 2004 and December 2005 were retrospectively evaluated. NODAT was defined according to the diagnostic criteria of the American Diabetes Association/World Health Organization, persistent hyperglycemia (serum glucose > or = 200 mg/dL occurring 2 weeks after initial steroid induction and persisting for more than 2 weeks), or the need for hypoglycemic agents upon discharge.. Incidence of NODAT within 6 months after transplantation in patients with poor glycemic control within the first 2 weeks after transplantation, acute rejection episodes, infections, hospital readmissions, and cardiovascular and thrombotic events.. Forty-five patients were evaluated. Within the first 6 months after transplantation, NODAT developed in 11 (24%). Acute rejection, infection, hospital readmissions, cardiovascular events, and thrombotic events did not differ between the groups.. Elevated fasting levels of blood glucose during the first 2 weeks after liver transplantation may be associated with an increased incidence of NODAT and may have predictive value. More studies are needed to determine the effects of recognition and treatment of hyperglycemia in recent transplant recipients.

Topics: Diabetes Mellitus; Dose-Response Relationship, Drug; Female; Glucocorticoids; Graft Rejection; Humans; Hyperglycemia; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Postoperative Complications; Postoperative Period; Prognosis; Retrospective Studies; Risk; Tacrolimus; United States

Post-transplant diabetes mellitus (PTDM) is a common and potentially serious complication after solid organ transplantation. There are only a few data, however, about the incidence of DM in patients undergoing lung transplantation.. The medical records of 119 consecutive patients who underwent lung transplantation from 1998 to September 2004 were reviewed. Patients were divided in three groups according to their diabetes status, including pre-transplant DM, the PTDM group and those without DM. Patient records and all laboratory data were reviewed and the clinical course of diabetes was monitored. All recipients were treated with tacrolimus based regimen.. Mean follow-up for all patients was 25+/-10. Twenty-three patients had DM in the pre-lung transplantation (LTX) DM group. PTDM developed in 34 of the remaining 96 patients (35.4%) with an incidence of 20%, 23% after 6 months and 12 months post-transplant. No significant difference was noted between 12 and 24 months post-LTX. The patients who developed DM were older (57+/-15 vs 53+/-13 years, p=0.009), had increased BMI (26+/-5 vs 24+/-4, p=0.0001), shorter time from diagnosis to LTX (21+/-13 vs 28+/-18 months, p=0.007) more cytomegalovirus infection and more acute rejection and hyperglycemia in the first month after LTX. Four patients died in the PTDM group compared to nine patients in the no-DM group (12% vs 14%; p=0.72).. Post-transplant diabetes is a common complication in lung transplant patients receiving tacrolimus-based immunosuppression. The risk for developing PTDM is greatest among older recipients, those obese, and among recipients with more rejections episodes.

Topics: Adult; Age Factors; Aged; Diabetes Mellitus; Female; Follow-Up Studies; Graft Rejection; Humans; Hyperglycemia; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Logistic Models; Lung Transplantation; Male; Middle Aged; Obesity; Risk; Risk Factors; Tacrolimus

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

Topics: Glucose; Humans; Hyperglycemia; Immunosuppressive Agents; Metabolic Diseases; Randomized Controlled Trials as Topic; Tacrolimus; Transplantation Immunology

Diabetes mellitus causes multiple cardiovascular complications. Previous studies have shown that prolonged exposure (96 h) of human umbilical vein endothelial cells (HUVECs) to hyperglycemia causes a significant increase in apoptosis. We report here that this increase in apoptosis is associated with an increase in Ca(2+) current (whole cell patch-clamp recorded) resulting from Ca(2+) entry mediated by store-operated channels (SOCs). The number of apoptotic cells after prolonged high glucose (HG, 30 mmol/L) exposure was significantly reduced in the presence of the SOC inhibitor 2-APB or of La(3+). A marked increase (approximately 80%) in Ca(2+)-dependent calcineurin (CN-A) phosphatase activity also occurred after prolonged HG exposure. Prolonged HG exposure-induced increase in CN-A activity was prevented by 2-APB, and selective CN-A phosphatase inhibition by FK506 or calmodulin inhibition by calmidazolium decreased HG-induced apoptosis. Blocking hydrogen peroxide production using catalase or inhibiting the tyrosine kinase pp60(src) during prolonged exposure to HG, resulted in a marked decrease in apoptosis and was further associated with a significant reduction in CN-A phosphatase activity. The results demonstrate a significant role for Ca(2+) entry in HG-induced apoptosis in HUVECs, and suggest that this role is mediated via H(2)O(2) generation and the action of the Ca(2+)-activated protein phosphatase calcineurin.

Topics: Apoptosis; Boron Compounds; Calcineurin; Calcium; Calcium Channels; Calmodulin; Catalase; Endothelium, Vascular; Glucose; Humans; Hydrogen Peroxide; Hyperglycemia; Imidazoles; Patch-Clamp Techniques; Phosphoric Monoester Hydrolases; Proto-Oncogene Proteins pp60(c-src); Tacrolimus; Umbilical Veins

To evaluate the long-term systemic toxicity of tacrolimus (FK-506) administered by various routes, and to assess the effect of dose reduction on toxicity.. The study animals were 120 experimentally naive adult female Wistar rats weighing 200-250 g each. The rats were randomly divided into 10 equal groups (n=12 in each) and treated with tacrolimus administered topically (in drops, 0.3%, q.i.d.), intravitreally (0.5 mg/kg bodyweight/week), intramuscularly (1 mg/kg bodyweight/week), low-dose intravenously (1 mg/kg bodyweight/week) and in high-dose intravenously (2 mg/kg bodyweight/week) for 3 months. The rats in the control groups (one for each different route of administration) were treated with 0.9% NaCl. The blood concentration of tacrolimus, complete blood count and biochemistry parameters were measured each month for the 3-month study period.. The rats in the control groups and experimental groups administered topical and intravitreal tacrolimus did not demonstrate any systemic toxic effects. The rats that developed certain toxic effects (hyperglycaemia, hyperkalaemia and nephrotoxicity) in the groups given low-dose or high-dose i.v. tacrolimus responded well to dose reduction. Following dose reduction, blood glucose concentrations decreased from 247.4 +/- 42.3 mg/dL to 189.6 +/- 37.9 mg/dL (P <0.05), and from 237.4 +/- 41.1 mg/dL to 182.3 +/- 22.7 mg/dL (P <0.05) in the low- and high-dose i.v. tacrolimus-treated rats, respectively. The rats that developed impaired hepatic function after high-dose tacrolimus did not respond to dose reduction. Baseline cholesterol concentrations for the intramuscular and low- and high-dose i.v. tacrolimus-treated groups, demonstrated decreases, respectively, from 87.4 +/- 14.0 mg/dL, 86.4 +/- 14.0 mg/dL and 90.4 +/- 14.3 mg/dL to 53.6 +/- 9.8 mg/dL, 52.1 +/- 12.5 mg/dL and 63.5 +/- 11.7 mg/dL by the end of the second month. The differences were found to be statistically significant (P <0.05 for each result).. Topical or intravitreal administration of tacrolimus seems to be systemically safe whereas parenteral administration can cause some systemic haematological changes such as dose-dependent decreased serum cholesterol concentrations. Dose reduction may prevent such adverse effects.

Topics: Administration, Topical; Animals; Blood Glucose; Dose-Response Relationship, Drug; Drug Administration Routes; Female; Hyperglycemia; Hyperkalemia; Immunosuppressive Agents; Injections, Intramuscular; Injections, Intravenous; Kidney; Liver; Rats; Rats, Wistar; Tacrolimus; Vitreous Body

The efficacy and safety of tacrolimus (FK506; Prograf) were determined in 28 adult kidney transplant patients (20 males and 8 females), aged 18-68 years (mean+/-S.D.: 46.9+/-4.03 years). Induction therapy was ATG-F (n=23), daclizumab (n=3), or none (n=2), and maintenance immunosuppression consisted of tacrolimus, combined with mycophenolate mofetil (MMF; n=26) or azathioprine (AZA; n=2) and prednisone (Pred). In seven patients, cyclosporine A microemulsion (Neoral) was replaced by tacrolimus for acute rejection (AR; three patients), slow graft function (SGF, two patients) and Neoral side effects (two patients). Acute rejection occurred in five patients (17.8%), three of whom were steroid-resistant treated with a second course of ATG-F. Infection occurred in 10 patients (35.7%) with a total of 15 infectious episodes, comprising bacterial (73%) and viral (27%) infections related to CMV. Other side effects related to tacrolimus were hypertension in four patients (14%) and post-transplantation hyperglycemia in nine patients (32%), three of whom required insulin therapy. In addition, hypercholesterolemia and hypertriglyceridemia occurred in six (21%) and eight patients (28.5%), respectively. The patient's hospital stay was 12.7+/-1.3 days (range: 8-24 days), and mean serum creatinine upon discharge, and at 1, 3 and 6 months following transplantation were: 2.1+/-0.5, 1.47+/-0.21, 1.41+/-0.53 and 1.23+/-0.11 mg/dl, respectively. The 6-month actuarial patient and graft survival rates were 100%. While tacrolimus is an effective calcineurin inhibitor for kidney transplantation (KT), severe acute rejection seen is related to highly sensitized patients, and the CMV infections noted were related to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. Longer follow-up with a larger patient sample is needed to fully assess both the efficacy and safety of tacrolimus, including its metabolic effects.

Topics: Acute Disease; Adolescent; Adult; Aged; Calcineurin Inhibitors; Cytomegalovirus Infections; Female; Graft Rejection; Humans; Hyperglycemia; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Safety; Tacrolimus

In a living renal transplantation, the recipients are administered an immunosuppressive agent preoperatively. The drug exhibits a high incidence of side effects of special note. We examined the side effects of tacrolimus to evaluate the postoperative management of living renal transplantation. Hypertension, hyperglycemia, tachycardia and chest pain were found as the side effects. The blood concentration should be measured frequently to maintain the effective blood concentration and to prevent the side effect.

Topics: Adult; Aged; Female; Humans; Hyperglycemia; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Monitoring, Physiologic; Perioperative Care; Tacrolimus

Post-transplant diabetes mellitus, a complication due to corticosteroids and the calcineurin inhibitors, cyclosporine and tacrolimus (FK506), is commonly regarded as a form of type-2 (adult-onset) diabetes mellitus. Diabetic ketoacidosis, which requires relative insulin deficiency to impair fatty acid metabolism, is a complication of type-1 diabetes mellitus. We report three patients who presented with diabetic ketoacidosis post-transplant. All three patients presented with severe hyperglycemia, significant ketosis and metabolic acidosis of variable severity. One patient was a renal transplant recipient on a cyclosporine-based regimen. The other two patients were liver transplant recipients receiving either cyclosporine or tacrolimus-based immunosuppression. Both of the liver transplant recipients were found to have moderate to high serum levels of calcineurin inhibitors on presentation. The liver recipient on cyclosporine (Neoral) had a 4 hour post-dose level of 388 ng/ml and the patient on tacrolimus was found to have a trough level of 21.2 ng/ml. Our experience suggests that post-transplant diabetes mellitus, in association with calcineurin inhibition, may result in ketoacidosis either secondary to relative beta cell dysfunction, peripheral insulin resistance, or a combination of the two effects. Post-transplant diabetes mellitus can be an atypical form of adult-onset diabetes with features of both type I and type II diabetes mellitus.

Topics: Adult; Calcineurin; Cyclosporine; Diabetic Ketoacidosis; Female; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus

Topics: Adult; Blood Glucose; Diabetes Mellitus; Drug Monitoring; Female; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Reoperation; Retrospective Studies; Tacrolimus

In the present experiments, we compared the anti-ischemic effects of the immunosuppressants cyclosporin A (CsA) and FK506 in hyperglycemic animals subjected to 30 min of middle cerebral artery (MCA) occlusion. Both immunosuppressants were given as pre-treatment, the effect of treatment being evaluated by 2,3, 5-triphenyltetrazolium (TTC) staining after 3 days of recovery. Both FK506 and CsA reduced the infarct volume to less than 1/3 of control. In spite of CsA's known effect as a blocker of the mitochondrial transition (MPT) pore, it failed to give a more robust effect than FK506. If anything, FK506, which lacks an effect on the MPT pore, had a more pronounced anti-ischemic effect. We conclude that, in this model of infarction, an MPT may not play a major pathogenetic role.

Topics: Analysis of Variance; Animals; Arterial Occlusive Diseases; Cerebral Infarction; Cyclosporine; Hyperglycemia; Immunosuppressive Agents; Ischemic Attack, Transient; Male; Neuroprotective Agents; Rats; Rats, Wistar; Tacrolimus; Treatment Outcome

Topics: Cyclosporine; Diabetes Complications; Diabetes Mellitus; Drainage; Female; Glucose; Graft Rejection; Humans; Hyperglycemia; Immunosuppressive Agents; Male; Pancreas Transplantation; Portal System; Tacrolimus; Transplantation, Homologous

Topics: Adolescent; Azathioprine; Child; Child, Preschool; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Heart Transplantation; Humans; Hyperglycemia; Immunosuppressive Agents; Infant; Lymphoproliferative Disorders; Male; Medical Records; Prednisone; Retrospective Studies; Tacrolimus

Topics: Administration, Oral; Adolescent; Blood Glucose; Child; Child, Preschool; Cyclosporine; Diabetes Mellitus, Type 1; Emulsions; Follow-Up Studies; Humans; Hyperglycemia; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Tacrolimus; Time Factors

This study was designed to (a) estimate the contribution of tacrolimus nephrotoxicity to episodes of renal allograft dysfunction investigated by needle biopsy, (b) describe the temporal evolution of nephrotoxicity and its response to therapy, and (c) ascertain how often renal dysfunction is associated with concurrent extra-renal toxicity. Patients were selected based on a rising serum creatinine, normal ultrasound, and biopsy findings leading to a reduction in the dose of tacrolimus and a fall in serum creatinine. Twenty two (17%) cases of nephrotoxicity were identified amongst 128 consecutive kidney transplant biopsies with sufficient clinical data for analysis. There were 13 males and 9 females, 17-75 yr in age. Tacrolimus was administered initially as a 0.075-0.1 mg/kg/d IV continuous infusion followed by an oral dose of 0.15 mg/kg twice daily. The onset of nephrotoxicity in this study occurred 1-156 wk post-operatively. The mean baseline creatinine was 212.2 +/- 168.0 mumol/l (range 88.4-875.2) and rose 40.6% +/- 14.2% (range 11-66) during episodes of nephrotoxicity (p < 0.001). The highest recorded plasma and whole-blood tacrolimus levels during the toxic episodes were respectively 2.7 +/- 0.8 ng/ml (range 1.1-3.5) and 31.6 +/- 10.6 ng/ml (range 14.5-50.5). The drug levels were considered to be beyond the therapeutic range in 18/22 (82%) patients. The highest tacrolimus level preceeded the rise in serum creatinine in 20 cases by an interval of 1.6 +/- 1.8 d. A mean reduction in tacrolimus dosage of 41% +/- 21% (range 11-89) led to a 86% +/- 18% (range 45-100) fall in the serum creatinine within 1-14 d (p < 0.001). Interactions between tacrolimus and clarithromycin, diltiazem, or itraconazole modified the pharmakokinetic parameters in three cases. Serum potassium > 5.0 mequiv/l was recorded in 9/22 (41%) cases. Three or more elevations in blood glucose > 7.7 mmol/l (140 mg/dl) were recorded in 4/11 (36%) non-diabetic patients. Hand tremors were seen in two (9%) cases and elevated diastolic blood pressure > 90 mmHg in seven (32%) patients. In conclusion, tacrolimus nephrotoxicity accounted for 17% of graft dysfunction episodes investigated by biopsy. Concurrent hyperglycemia, hyperkalemia, or tremors were noted in several patients. Nephrotoxicity responded well to reduction in the drug dosage.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Aged; Anti-Bacterial Agents; Antifungal Agents; Biopsy, Needle; Clarithromycin; Creatinine; Diltiazem; Drug Interactions; Female; Humans; Hyperglycemia; Hyperkalemia; Hypertension; Immunosuppressive Agents; Infusions, Intravenous; Itraconazole; Kidney; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Time Factors; Transplantation, Homologous; Tremor; Ultrasonography; Vasodilator Agents

Topics: Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Cyclosporine; Follow-Up Studies; Humans; Hyperglycemia; Hypertension; Hypertriglyceridemia; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Obesity; Prevalence; Retrospective Studies; Risk Assessment; Risk Factors; Survival Rate; Tacrolimus

FK506 (tacrolimus) is a strong immunosuppressant: it has been approved as a drug for liver transplantation in Japan, the United States, and the United Kingdom. One of its main adverse effects is hyperglycemia. Thus, in this study, we investigated the mechanism and the reversibility of the hyperglycemia caused by FK506. FK506 did not affect the glucose uptake by insulin into rat strio-muscle cell line, but suppressed insulin production in rat insulinoma cells. Two-week oral administration of FK506 at 10 mg/kg/day suppressed insulin production time-dependently at the transcriptional step in pancreatic beta-cells, while glucagon content in pancreatic alpha-cells was not affected. When FK506 administration was stopped in these rats, insulin mRNA transcription and insulin production returned to normal. This recovery indicates that the adverse effect of FK506 on the pancreas is reversible. A high content of FK506 binding protein-12 (FKBP-12) in the pancreatic beta-cells was confirmed by immunostaining with anti-human FKBP-12 mAb, but the content was less in the pancreatic alpha-cells and almost negligible in the acinar cells. In contrast, a high content of calcineurin in the pancreatic alpha-cells was confirmed by using anti-calcineurin polyclonal antibody, but this content was less in the pancreatic beta-cells and not found in the acinar cells. Thus, as in the case with NF-AT in T cells, these findings point to the reduction of unidentified nuclear factors for insulin mRNA transcription caused by the binding of FK506 to FKBP-12 and a subsequent inhibition of calcineurin in the beta-cells.

Topics: Animals; Carrier Proteins; DNA-Binding Proteins; Heat-Shock Proteins; Hyperglycemia; In Situ Hybridization; Insulin; Insulin Antagonists; Islets of Langerhans; L Cells; Mice; Rats; RNA, Messenger; Tacrolimus; Tacrolimus Binding Proteins; Tumor Cells, Cultured

Topics: Animals; Humans; Hyperglycemia; Immune Tolerance; Immunosuppressive Agents; Kidney; Rats; Tacrolimus

Topics: Cyclosporine; Glucose Intolerance; Graft Rejection; Humans; Hyperglycemia; Liver Transplantation; Tacrolimus

Hyperglycemia and new-onset diabetes mellitus is a well-recognized complication of solid organ transplantation. With the advent of FK-506 as a new immunosuppressive drug used in orthotopic liver transplantation (OLT), much attention has been paid to its diabetogenic effects. Currently, there are no data on the long term effects of FK-506 in glucose metabolism after OLT. In the present study, we determined the need for outpatient insulin in 52 American veterans who received 58 liver transplants using primary immunosuppression with FK-506 and PRED, with a mean follow-up of 467 days (range 17-952 days). We also analyzed their plasma glucose and FK-506 levels as well as the doses of PRED and FK-506 that they received at various intervals post-OLT. There were 7/52 (13.6%) patients who required insulin for the first time after OLT. Of these, the number of patients on insulin at 3, 6, and 12 months post-OLT was 5/47 (10.6%), 6/44 (13.6%), and 1/26 (3.8%), with none requiring insulin de novo at 18, 24, and 30 months post-OLT. Three patients required insulin temporarily but subsequently became normoglycemic without additional therapy. The need for insulin was not related to the dose of FK-506 administered nor the plasma level. Patients who required outpatient insulin were receiving higher doses of PRED than those not requiring insulin. The need for insulin did not affect the long-term graft or patient survival. In conclusion, the need for insulin with FK-506 compares favorably to that of previous immunosuppressive regimens, and FK-506 may have a reversible diabetogenic effect that is not dose dependent.

Topics: Actuarial Analysis; Adult; Aged; Blood Glucose; Diabetes Mellitus; Follow-Up Studies; Humans; Hyperglycemia; Insulin; Liver Transplantation; Middle Aged; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Experimental; Homeostasis; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans Transplantation; Kidney; Mice; Mice, Nude; Tacrolimus; Transplantation, Heterologous; Transplantation, Heterotopic

The effect of FK506 on glucose metabolism was studied in five cynomolgus monkeys after pancreatic transplantation and in 10 nontransplanted cynomolgus monkeys. We have clearly demonstrated that FK506 can induce hyperglycemia in these animals. In the orally treated nontransplanted animals the hyperglycemia was usually very mild (4.5-6.0 mmol/L). In one of the five transplanted animals, hyperglycemia was induced by the FK506 treatment, since histological signs of rejection were absent and since plasma glucose levels normalized on dose reduction. The glucose disappearance rates, as indicated by the K-values, decreased from a mean of 3.0 +/- 0.5%/min before FK506 treatment to 2.4 +/- 0.6%/min at one month and 1.5 +/- 0.4%/min at three months in the nontransplanted animals. In the transplant group, the K values decreased significantly from 4.2 +/- 0.6%/min in the donor animals to 1.4 +/- 0.4%/min at day 10 posttransplantation (P < 0.02). At one and three months postoperatively, the mean K-values were 1.4 +/- 0.2%/min and 1.2 +/- 0.6%/min, respectively. We conclude that FK506 is diabetogenic in the cynomolgus monkey. This side effect, however, was found to be reversible on dose reduction.

Topics: Animals; Glucose; Glucose Tolerance Test; Graft Rejection; Hyperglycemia; Macaca fascicularis; Pancreas Transplantation; Tacrolimus

Topics: Animals; Drug Evaluation, Preclinical; Graft Rejection; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Papio; Pyridines; Tacrolimus

Topics: Animals; Dogs; Drug Evaluation, Preclinical; Hyperglycemia; Immunosuppressive Agents; Kidney; Kidney Transplantation; Papio; Postoperative Complications; Pyridines; Tacrolimus; Vasculitis