Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased risk of cardiovascular disease contributes significantly to the higher rate of mortality seen in kidney transplant patients compared to the general population. New-onset diabetes mellitus (NODM) is a major risk factor for cardiovascular disease, as well as being associated with significantly increased graft loss and higher health care costs compared to the nondiabetic transplant population. Evidence from large-scale analyses of registry databases has shown that the calcineurin inhibitor, tacrolimus, is associated with approximately a 50% increase in the risk of NODM compared to the microemulsion formulation of cyclosporine (CsA); but to date, little robust evidence is available from clinical trials. The DIRECT (Diabetes Incidence after REnal transplantation: Neoral C2 monitoring versus Tacrolimus) study will be the first prospective trial to compare directly the impact of tacrolimus and CsA microemulsion on glucose metabolism in kidney transplant recipients. DIRECT is a 6-month, parallel-group, open-label, randomized trial for which approximately 700 patients will be recruited at around 70 transplant centers worldwide. Patients will be randomized to tacrolimus or CsA microemulsion (using C2 monitoring), with mycophenolate mofetil or enteric-coated mycophenolic acid, steroids, and basiliximab. Primary endpoints are: (a) a composite of NODM or impaired fasting glucose among patients who are nondiabetic at time of transplantation; and (b) combined incidence of biopsy-proven acute rejection, graft loss, or death with CsA microemulsion C2 monitoring compared to tacrolimus trough monitoring . Full results are expected in 2006, with interim results available by the end of 2004, and will be awaited with interest by the transplant community.
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PMID:Rationale and design of the DIRECT study: a comparative assessment of the hyperglycemic effects of tacrolimus and cyclosporine following renal transplantation. 1583 49

New-onset diabetes mellitus (NODM) is associated with increased risk of graft failure and death in renal transplant recipients. Some clinical studies have indicated that NODM risk is higher with tacrolimus than cyclosporine, but no comparative trial has used American Diabetic Association (ADA)/World Health Organization (WHO) criteria for diagnosis of diabetes mellitus. The Diabetes Incidence After Renal Transplantation, Neoral C2 Monitoring Versus Tacrolimus (DIRECT) study is a 6-month open-label, multicenter trial comparing the impact of tacrolimus and Neoral (cyclosporine microemulsion) on glucose metabolism in 700 de novo kidney transplant recipients, based on ADA/WHO criteria. Patients are randomized to tacrolimus (C0 monitoring) or Neoral (C2 monitoring), stratified by baseline diabetic status and ethnicity. All patients receive basiliximab, corticosteroids, and mycophenolate mofetil or enteric-coated mycophenolate acid (myfortic). Pooled interim 3-month results from a subset of 115 patients receiving either tacrolimus or Neoral showed that the primary efficacy end-point (biopsy-proven acute rejection [BPAR], graft loss or death) occurred in 11 patients (10%). There were four graft losses and only one death, which occurred after graft loss. Eight patients experienced BPAR (7.3%). Among 99 patients who were nondiabetic at baseline, 14 developed NODM by month 3, 17 developed impaired fasting glucose or impaired glucose tolerance, and another 5 patients received hypoglycemic treatment for at least 14 consecutive days or at the month 3 visit, resulting in a 36% incidence of impaired glucose metabolism. At 3 months, median GFR (Nankivell) was 63.7 mL/min; median serum creatinine was 137 micromol/L. Full complete results are expected in December 2005.
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PMID:Prospective, multicenter, randomized trial to compare incidence of new-onset diabetes mellitus and glucose metabolism in patients receiving cyclosporine microemulsion versus tacrolimus after de novo kidney transplantation. 1584 4

We evaluate 5-year results of a prospective randomized trial that compared cyclosporine microemulsion (CsA-me) and Tacrolimus (Tac) for primary immunosuppression. One hundred one adult patients undergoing liver transplantation were randomized to receive Tac (n = 50) or CsA-me (n = 51). The most frequent indication for the procedure was cirrhosis due to virus C followed by alcoholism. Survival rates at 1, 3, and 5 years were 86%, 75%, and 72%, respectively; there was no significant difference between CsA-me versus Tac arms. Acute rejection occurred in 30 cases (30%), independent of the type of primary immunosuppression. Serious adverse events were reported significantly more among patients under CsA-me (48 episodes) than under Tac (32 episodes). Nineteen patients were switched to the other calcineurin inhibitor. The switch was much more frequent from CsA-me to Tac (n = 15; 29.4%), mainly because of lack of efficacy (n = 10; 19.6%). There were no cases of chronic rejections in the Tac arm. Four patients were switched from Tac to CsA-me for side effects; only 1 remains alive, after treatment was changed from CsA-me to an antimetabolite. There were no statistical differences in renal dysfunction, diabetes, hypertension, neurologic disorders, new-onset malignancies, or infections. There were no differences in survival or rejection among the intention-to-treat groups. Serious adverse events, total patients with switch of calcineurin inhibitor, as well as switches due to lack of efficacy, were statistically more frequent under CsA-me. Tacrolimus seems to be a more appropriate drug to be used for primary immunosuppression in liver transplantation.
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PMID:Five-year follow-up of a trial comparing Tacrolimus and cyclosporine microemulsion in liver transplantation. 1591 41

Tacrolimus was approved in Japan in April 1996 for the prevention of allograft rejection in patients receiving kidney transplants. There has been a concern that immunosuppressive therapy may be associated with cardiovascular and metabolic complications, including hyperlipidemia, hypertension, and posttransplant diabetes mellitus. A multicenter (59 institutions) study was conducted in Japan in patients who underwent renal transplantation and received tacrolimus immunosuppression. Patients were followed for >5 years, from April 1996 to December 2002. Of the 1569 patients enrolled, 1542 were evaluated. In this analysis, graft survival rate and medication usage patterns of antihyperlipidemics, antihypertensives, insulin, and oral hypoglycemics were observed for >5 years in patients receiving tacrolimus immunosuppression. The graft survival rates of patients requiring antihyperlipidemic therapy and experiencing acute rejection were significantly lower compared with all other patients (P < .05). The risk of graft rejection was significantly greater in patients with cardiovascular complications requiring antihyperlipidemics or antihypertensives. Graft survival was significantly lower in patients with acute rejection and antihyperlipidemic therapy than in other patients.
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PMID:Safety analysis after tacrolimus immunosuppression in renal transplant recipients in Japan: 5-year results in >1500 patients. 1591 58

Recent clinical trials have documented the short-term safety of steroid avoidance (SA) in kidney transplant recipients. Since July 2003, we have used a SA immunosuppression protocol for low-risk kidney transplant recipients. Eligibility criteria are age > or = 18, primary transplant (living or deceased donor), and tacrolimus started by postoperative day 3. Recipients were excluded if peak/current PRA was >50%/20%, or if they had a positive flow crossmatch, or if they had the recent use of corticosteroids (<6 months). All recipients received induction with rabbit anti-thymocyte globulin, total dose 6 mg/kg, or basiliximab. Recipients received 5 daily doses of corticosteroid and mycophenolate mofetil 1 gm twice daily starting on the day of transplantation. Tacrolimus was started when the serum creatinine level decreased by 20%, or by postoperative day 3. The goal for trough tacrolimus levels was 10-15 ng/mL for the first month, 8-12 ng/mL for months 2-3, and 5-10 ng/mL after month 3. Protocol biopsies (bx) were performed at reperfusion, 1 month, 4 months, and 12 months. Ninety-four kidney transplantations were performed during the study period. Sixty-seven recipients (71%) were eligible and enrolled in SA. Characteristics of the 67 SA recipients: mean age, 53 years (range, 26-70); 41% female; 67% Caucasian; 24% Hispanic; 15% African American; and 5% Native American. Also, 77% received a living donor kidney. The mean follow-up was 180 days (range, 10-360). At last follow-up, 91% remained steroid-free. Biopsy-proven acute rejection (BPAR) occurred in 5 recipients (7.5%). Three recipients (4.5%) had clinical BPAR and 2 had subclinical. One recipient died with pneumonia 4 months following transplantation. Posttransplantation diabetes mellitus (PTDM) occurred in 2 (5%) of 38 recipients. In the initial 41 recipients, 27 had protocol bx at 1 month and 13 at 4 months available for analysis. Chronic allograft nephropathy (CAN) was present on protocol bx in 48% at 1 month and 69% at 4 month. Actuarial (Kaplan-Meier method) patient and graft survival rates at 351 days were 97.8% and 96.8%, respectively. SA with anti-thymocyte globulin induction in low-immunologic risk kidney transplant recipients is safe and is associated with a low risk of BPAR. The incidence of PTDM appears to be lower.
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PMID:Steroid avoidance immunosuppression in low-risk kidney transplant recipients. 1591 66

Posttransplantation diabetes mellitus (PTDM) is a complication arising mostly during the first 6 months after kidney transplantation. Considering the serious outcomes of chronic hyperglycemia in kidney transplant patients, the recognition of factors that contribute to the onset of PTDM is of particular relevance. A retrospective analysis was performed to document the incidence of and the risk factors for diabetes mellitus occurring in the first year after kidney transplantation among 177 adult patients, without previously known diabetes transplanted between January 1998 and December 2000. PTDM, defined as fasting plasma glucose > or = 126 mg/dL confirmed by repeat testing on a different day, occurred in 48 (27.12%) patients of whom 36 showed transient changes during the first year after transplantation. Univariate analysis identified variables to be associated with the onset of PTDM: older recipient age (P = .05), male gender (P = .03), family history of diabetes (P = .04), advanced donor age (P = .008), absence of induction immunosuppression (P = .04), use of tacrolimus (vs cyclosporine; P = .01), one or more than one (steroid-treated) acute rejection episode(s) (P = .000001), cytomegalovirus infection (P = .02), and use of beta-blockers or diuretics (P = .05). By multivariate analysis, five factors were independently associated with the onset of PTDM: two episodes of rejection (odds ratio = 42.69, P = .000025), one episode of rejection (5.01, P = .007), older recipient age (1.06, P = .017), family history of diabetes (7.24, P = .011), and weight at transplantation (1.03, P = .048). Tacrolimus treatment remained of borderline significance (2.77, P = .05). In addition to traditional risk factors predisposing to the development of type 2 diabetes in the general population, episodes of acute rejection significantly influence the incidence of PTDM.
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PMID:Factors influencing the onset of diabetes mellitus after kidney transplantation: a single French center experience. 1591 84

Cardiovascular morbidity, including coronary artery disease and left ventricular hypertrophy, and mortality are high in patients following renal transplantation. Cardiovascular disease is thought to be due to traditional (hypertension, hyperlipidemia, diabetes mellitus and smoking) as well as nontraditional cardiovascular risk factors (microinflammation). Furthermore, immunosuppressive drugs, namely, calcineurin inhibitors, sirolimus, and steroids, have been reported to adversely affect cardiovascular risk factors (e.g., hypertension, hyperlipidemia, hyperglycemia). Evidence from comparative trials and from conversion studies suggest that blood pressure, hyperlipidemia, and hyperglycemia after renal transplantation may be differentially affected by the calcineurin inhibitors cyclosporine and tacrolimus. In the European Tacrolimus versus Cyclosporin A Microemulsion Renal Transplantation Study, 557 patients were randomly allocated to therapy with tacrolimus (n = 286) versus cyclosporine (n = 271). In addition, to blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose, we estimated the 10-year risk of coronary heart disease (Framingham risk score). Tacrolimus resulted in a significantly lower time-weighted average of serum cholesterol (P < .001), and mean arterial blood pressure (P < .05), but a higher time-weighted average of blood glucose (P < .01) than cyclosporine. Mean 10-year coronary artery disease risk estimate was significantly lower in men treated with tacrolimus, (10.0% versus 13.2%; P < .01) but was unchanged in women (4.7% versus 7.0%). Tacrolimus and cyclosporine microemulsion have compound-specific effects on cardiovascular risk factors that differentially affect the predicted rate of coronary artery disease.
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PMID:Cardiovascular risk estimates and risk factors in renal transplant recipients. 1591 88

Early steroid discontinuation (ESD) has been associated with a lower incidence of post-transplant diabetes mellitus (PTDM). We retrospectively reviewed the incidence of PTDM in relation to racial groups in kidney transplant recipients treated with ESD. Between January 2002 and September 2003, 125 consecutive primary adult kidney transplants were performed. Group A (n = 91) had steroids discontinued on postoperative day 6 and maintenance immunosuppression of Tacrolimus and mycophenolate mofetil. Group B (n = 34), received the same immunosuppression but was maintained on steroids indefinitely. Induction consisted of thymoglobulin in African-Americans; all others received Simulect. At 1 yr, patient/graft survival, serum creatinine and rate of acute rejection were similar in both groups. The incidence of PTDM was significantly lower in group A (7%) compared with group B (26%, p = 0.0209). The incidence of PTDM in group A was limited to Hispanic patients with a family history of diabetes mellitus. African-Americans and Caucasians in group A did not experience PTDM (p = 0.005 compared with African-American in group B). Our steroid free protocol nearly eliminated the incidence of PTDM in African-Americans and Caucasians, but was still associated with significant rate of PTDM in Hispanic recipients. Alternative immunosuppression may benefit this population.
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PMID:Increased risk of post-transplant diabetes mellitus despite early steroid discontinuation in Hispanic kidney transplant recipients. 1600

Relaxation of the upper age limits for solid organ transplantation coupled with improvements in post-transplant survival have resulted in greater numbers of elderly patients receiving immunosuppressant drugs such as tacrolimus. Tacrolimus is a potent agent with a narrow therapeutic window and large inter- and intraindividual pharmacokinetic variability. Numerous physiological changes occur with aging that could potentially affect the pharmacokinetics of tacrolimus and, hence, patient dosage requirements. Tacrolimus is primarily metabolised by cytochrome P450 (CYP) 3A enzymes in the gut wall and liver. It is also a substrate for P-glycoprotein, which counter-transports diffused tacrolimus out of intestinal cells and back into the gut lumen. Age-associated alterations in CYP 3A and P-glycoprotein expression and/or activity, along with liver mass and body composition changes, would be expected to affect the pharmacokinetics of tacrolimus in the elderly. However, interindividual variation in these processes may mask any changes caused by aging. More investigation is needed into the impact aging has on CYP and P-glycoprotein activity and expression. No single-dose, intense blood-sampling study has specifically compared the pharmacokinetics of tacrolimus across different patient age groups. However, five population pharmacokinetic studies, one in kidney, one in bone marrow and three in liver transplant recipients, have investigated age as a co-variate. None found a significant influence for age on tacrolimus bioavailability, volume of distribution or clearance. The number of elderly patients included in each study, however, was not documented and may have been only small. It is likely that inter- and intraindividual pharmacokinetic variability associated with tacrolimus increase in elderly populations. In addition to pharmacokinetic differences, donor organ viability, multiple co-morbidity, polypharmacy and immunological changes need to be considered when using tacrolimus in the elderly. Aging is associated with decreased immunoresponsiveness, a slower body repair process and increased drug adverse effects. Elderly liver and kidney transplant recipients are more likely to develop new-onset diabetes mellitus than younger patients. Elderly transplant recipients exhibit higher mortality from infectious and cardiovascular causes than younger patients but may be less likely to develop acute rejection. Elderly kidney recipients have a higher potential for chronic allograft nephropathy, and a single rejection episode can be more devastating. There is a paucity of information on optimal tacrolimus dosage and target trough concentration in the elderly. The therapeutic window for tacrolimus concentrations may be narrower. Further integrated pharmacokinetic-pharmacodynamic studies of tacrolimus are required. It would appear reasonable, based on current knowledge, to commence tacrolimus at similar doses as those used in younger patients. Maintenance dose requirements over the longer term may be lower in the elderly, but the increased variability in kinetics and the variety of factors that impact on dosage suggest that patient care needs to be based around more frequent monitoring in this age group.
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PMID:Pharmacokinetic considerations relating to tacrolimus dosing in the elderly. 1603 70

Cyclosporin (CsA) therapy is associated with side effects such as hypertension, hyperlipidemia and nephrotoxicity. Tacrolimus (Tac) has been shown to be more favourable in this respect. We retrospectively analysed office blood pressure (BP), serum total cholesterol (TC) and fasting glucose levels, and estimated graft function profiles in paediatric (n =56) and young adult (n =14) renal transplant recipients whose maintenance immunosuppressive regimen was based upon CsA (n =38) or Tac (n =32) given with mycophenolate mofetil and corticosteroids. The analysis was performed at four different time-points: at 1, 6, 12, and 24 months post-transplant, respectively. Baseline characteristics were comparable between treatment groups. Differences for both systolic and diastolic BP, and graft function between treatment groups became significant from month 1 and throughout the 2-year period. Values (mean +/- SD) for CsA-treated and Tac-treated recipients at 2 years were 118.8+/-11.1 / 74.6+/-7.4 mmHg vs 109.3+/-11.2 / 67.2+/-7.8 mmHg for systolic and diastolic BP, respectively, p <0.005/0.005; and 72.0+/-18.5 ml/min vs 84.0+/-22.4 ml/min per 1.73 m(2) for graft function, respectively, p <0.01. Office hypertension, defined as the use of antihypertensive medication at month 24, was significantly associated with CsA-therapy (chi(2), p <0.01). TC levels became significantly lower at months 6, 12, and 24 in the Tac group compared with the CsA group. Hypercholesterolemia, defined as TC>or=200 mg/dl, was significantly associated with CsA-based immunosuppressive regimen at months 6, 12, and 24 post-transplant (chi(2), p <0.05, p <0.001, and p <0.01, respectively). Although Tac therapy was associated with higher glucose levels, no recipient developed post-transplant diabetes mellitus. The number of recipients who experienced acute rejections was comparable in both groups. In conclusion, Tac-based immunosuppressive therapy was found to be associated with more favourable potential risk-factor profiles for cardiovascular disease and better graft function at 2 years post-transplant compared with CsA-therapy.
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PMID:Potential cardiovascular risk factors in paediatric renal transplant recipients. 1625 6


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