tacrolimus and Metabolic-Diseases

The occurrence of post-transplant diabetes mellitus (PTDM) is an important complication after renal transplantation associated with an increased risk of chronic transplant dysfunction and of cardiovascular morbidity and mortality. Both tacrolimus and cyclosporine have been associated with PTDM. In the initial studies, PTDM seemed to occur more often in tacrolimus treated patients than in cyclosporine treated patients. The mechanism by which tacrolimus could cause PTDM was unknown and the relative roles of tacrolimus and corticosteroids, which are often prescribed concomitantly with tacrolimus, were unknown. In several studies we used fasting glucose and insulin levels to assess (peripheral) insulin resistance, and intravenous glucose tolerance tests to assess insulin secretion by the pancreatic b-cells in response to a stimulus (glucose load). Thus, we evaluated the mechanism by which tacrolimus causes glucose metabolic disorders, risk factors for glucose metabolic disorders during tacrolimus treatment, the relative roles of corticosteroids and tacrolimus trough levels in glucose metabolic disorders, and also differences in glucose metabolism between patients using tacrolimus versus patients using cyclosporine. Based on the results of these studies and the available literature, the consequences for the choice of a primary immunosuppressive agent and guidelines for the treatment of PTDM during tacrolimus-based immunosuppression are discussed.

Topics: Adrenal Cortex Hormones; Clinical Protocols; Cyclosporine; Diabetes Mellitus; Glucose; Humans; Immunosuppressive Agents; Kidney Transplantation; Metabolic Diseases; Risk Factors; Tacrolimus

DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C(2) Monitoring Versus Tacrolimus) was a 6-month, open-label, randomized, multicenter study which used American Diabetes Association/World Health Organization criteria to define glucose abnormalities. De novo renal transplant patients were randomized to cyclosporine microemulsion (CsA-ME, using C(2) monitoring) or tacrolimus, with mycophenolic acid, steroids and basiliximab. The intent-to-treat population comprised 682 patients (336 CsA-ME, 346 tacrolimus): 567 were nondiabetic at baseline. Demographics, diabetes risk factors and steroid doses were similar between treatment groups. The primary safety endpoint, new-onset diabetes after transplant (NODAT) or impaired fasting glucose (IFG) at 6 months, occurred in 73 CsA-ME patients (26.0%) and 96 tacrolimus patients (33.6%, p = 0.046). The primary efficacy endpoint, biopsy-proven acute rejection, graft loss or death at 6 months, occurred in 43 CsA-ME patients (12.8%) and 34 tacrolimus patients (9.8%, p = 0.211). Mean glomerular filtration rate (Cockcroft-Gault) was 63.6 +/- 20.7 mL/min/1.73 m(2) in the CsA-ME cohort and 65.9 +/- 23.1 mL/min/1.73 m(2) with tacrolimus (p = 0.285); mean serum creatinine was 139 +/- 58 and 133 +/- 57 mumol/L, respectively (p = 0.005). Blood pressure was similar between treatment groups at month 6, but total cholesterol, LDL-cholesterol and triglyceride levels were significantly higher with CsA than with tacrolimus (total cholesterol:HDL remained unchanged). The profile and incidence of adverse events were similar between treatments. The incidence of NODAT or IFG at 6 months post-transplant is significantly lower with CsA-ME than with tacrolimus without a significant difference in short-term outcome.

Topics: Adolescent; Adult; Aged; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Glucose; Humans; Immunosuppressive Agents; Kidney Transplantation; Metabolic Diseases; Middle Aged; Tacrolimus; Treatment Outcome

Topics: Adult; Cyclosporine; Cytochrome P-450 CYP3A; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver-Specific Organic Anion Transporter 1; Male; Metabolic Diseases; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Organic Anion Transporters; Polymorphism, Genetic; Rhabdomyolysis; Tacrolimus; Treatment Outcome

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

We report on a 5-year-old boy with hyperzincemia and hypercalprotectinemia. Treatment began with Tacrolimus at the age of 4 years and 6 months. Despite an initial correction of clinical and biological symptoms, zincemia and calprotectinemia progressively worsened with secondary reappearance of symptoms.. Tacrolimus seems to have a transient effect in the treatment of Hyperzincemia and hyperprolactinemia.

Topics: Child, Preschool; Humans; Leukocyte L1 Antigen Complex; Male; Metabolic Diseases; Tacrolimus; Treatment Failure; Zinc

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

The incidence of glucose metabolism disturbances after transplantation often is based on the use of hypoglycemic agents and not on the results of glucose tolerance tests (GTTs), which may camouflage the real incidence. A lack of information also exists regarding the profile of glucose metabolism during the first year after transplant.. Oral GTT along with insulin measurements and drugs pharmacokinetics were prospectively performed at days 30, 60, 180, and 360 after transplant to diagnose disturbances of glucose metabolism after renal transplantation, in nonobese patients receiving either tacrolimus (n=55) or cyclosporine (n=29), along with mycophenolate mofetil and steroids.. The incidence of impaired glucose tolerance or diabetes mellitus reached a peak at 60 days and decreased at 1 year. It could not be adequately diagnosed using fasting plasma glucose in a decreased abnormal (>99 ng/mL) range. In both groups, insulin secretion, evaluated by the Homeostasis Model Assesment (HoMA-beta), decreased (P<0.005) from the condition of normal GTT (101+/-56%) to impaired glucose tolerance (72+/-35%) and diabetes mellitus (54+/-25%). In the cyclosporine group, insulin secretion was normal and stable throughout the study period, but in the tacrolimus group, insulin secretion recovered over time and was inversely correlated with tacrolimus exposure. Insulin resistance (HoMA-IR) did not change.. This study shows the need to perform an oral GTT at 60 days and at the end of the first year of renal transplantation to adequately diagnose impaired glucose metabolism.

Topics: Adult; Blood Glucose; Calcineurin Inhibitors; Cyclosporine; Fasting; Female; Glucose Tolerance Test; Homeostasis; Humans; Immunosuppressive Agents; Insulin; Insulin Resistance; Insulin Secretion; Kidney Transplantation; Male; Metabolic Diseases; Middle Aged; Mycophenolic Acid; Postoperative Period; Predictive Value of Tests; Prospective Studies; Steroids; Tacrolimus; Time Factors

FK506 (tacrolimus) and dexamethasone are potent immunosuppressants known to induce significant side effects on mineral homeostasis, including hypercalciuria and hypomagnesemia. However, the underlying molecular mechanisms remain unknown. The present study investigated the effects of FK506 and dexamethasone on the expression of proteins involved in active Ca(2+) reabsorption: the epithelial Ca(2+) channel TRPV5 and the cytosolic Ca(2+)-binding protein calbindin-D(28K). In addition, the renal expression of the putative Mg(2+) channel TRPM6, suggested to be involved in transcellular Mg(2+) reabsorption, was determined. Administration of FK506 to rats by daily oral gavage during 7 d significantly enhanced the urinary excretion of Ca(2+) and Mg(2+) and induced a significant hypomagnesemia. FK506 significantly decreased the renal mRNA expression of TRPV5 (62 +/- 7% relative to controls), calbindin-D(28K) (9 +/- 1%), and TRPM6 (52 +/- 8%), as determined by real-time quantitative PCR analysis. Furthermore, semiquantitative immunohistochemistry showed reduced renal protein abundance of TRPV5 (24 +/- 5%) and calbindin-D(28K) (29 +/- 4%), altogether suggesting that downregulation of these transport proteins is responsible for the FK506-induced Ca(2+) and Mg(2+) wasting. In contrast, dexamethasone significantly enhanced renal TRPV5 (150 +/- 15%), calbindin-D(28K) (177 +/- 23%), and TRPM6 (156 +/- 20%) mRNA levels along with TRPV5 (211 +/- 8%) and calbindin-D(28K) (176 +/- 5%) protein abundance in the presence of significantly increased Ca(2+) and Mg(2+) excretion. This indicated that these proteins are directly or indirectly regulated by dexamethasone. In conclusion, FK506 and dexamethasone induce renal Ca(2+) and Mg(2+) wasting, albeit by different mechanisms. Downregulation of specific Ca(2+) and Mg(2+) transport proteins provides a molecular mechanism for FK506-induced hypercalciuria and hypomagnesemia, whereas dexamethasone positively regulates these proteins.

Topics: Animals; Calbindins; Calcium; Calcium Channels; Calcium-Binding Proteins; Carrier Proteins; Down-Regulation; Immunosuppressive Agents; Kidney; Magnesium; Male; Metabolic Diseases; Rats; Rats, Wistar; S100 Calcium Binding Protein G; Tacrolimus; TRPV Cation Channels

Kidney transplant recipients require careful follow-up in both the early (< 6 months) and late posttransplant periods. Monitoring should focus on graft function and the most common complications of immunosuppression therapy. Infections, especially CMV infection, require particular attention in the first few months after transplantation, when immunosuppression is most intense. In both the early and the late posttransplant periods, an emphasis should be placed on intensive management of CVD risk factors (e.g., hypertension, hyperlipidemia, cigarette smoking). Screening for malignancies known to occur with a high incidence after transplantation is also important. With the improved short-term survival rates brought about by new, potent immunosuppressive agents, emphasis has now shifted to the prevention and treatment of posttransplant complications in kidney transplant recipients. A heightened awareness of these complications, along with a cooperative effort between primary care physicians and transplant programs, offers the best hope for further improvement in outcomes after kidney transplantation.

Topics: Cardiovascular Diseases; Cyclosporine; Cytomegalovirus Infections; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Transplantation; Metabolic Diseases; Monitoring, Physiologic; Neoplasms; Risk Assessment; Sirolimus; Tacrolimus; Transplantation, Homologous