#4045 Immunosuppression and Post-Transplant Hyperglycemia (original) (raw)
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Transplantation, 2006
Background. The aim of this study was to evaluate the incidence and risk factors for posttransplant diabetes mellitus (PTDM; defined as new insulin use and/or new hyperglycemia) in 528 kidney recipients using different immunosuppressive agents. Methods. Maintenance therapy included mycophenolate mofetil or azathioprine plus glucocorticoids in combination with Group I cyclosporine (263); Group II tacrolimus (60); or Group III sirolimus (205). Results. The mean follow-up was 39.2 (range 9.0-103.8) months. Overall, the number of patients needing insulin was 7.4% (39/528). The incidences for Groups I, II, and III of 7.6%, 11.7%, and 5.9%, respectively, were not statistically different. Characteristics of patients with PTDM included older age (Pϭ0.007); greater body weight (kg) at transplant, 6 months, and 12 months, respectively (PϽ0.001); greater BMI (kg/m 2) at transplant, 6 months, and 12 months, respectively (PϽ0.001); more acute rejection episodes 28.2% vs. 13.5% (Pϭ0.012); and increased incidence in African Americans (Pϭ0.03). Multivariable analysis demonstrated increased risk for PTDM (defined as new insulin use) for tacrolimus, (hazard ratio [HR] 3.794, Pϭ0.007); treated rejections (HR 2.491, Pϭ0.0115); age (HR 1.407, Pϭ0.0116); and BMI (HR 1.153, PϽ0.0001). New insulin use occurred sooner and with less total glucocorticoid dose for tacrolimus patients. If PTDM is defined as all cases of new hyperglycemia, then no immunosuppressive drug group demonstrated an increased risk. Conclusion. The risk for developing PTDM is greatest among older recipients, and those obese at the time of transplant; those given steroid pulse therapy were at exceptionally high-risk. PTDM risk reduction should focus on weight loss in the obese end-stage renal disease population prior to transplant.
Kidney International Reports
Introduction: Despite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization. Methods: We conducted an open-label, multicenter, randomized trial testing whether a tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) or cyclosporine A (CsA) with steroid minimization (SM) (CsA-SM), decreased the incidence of PTDM compared with tacrolimus with SM (Tac-SM). All arms received basiliximab and mycophenolate mofetil. High risk was defined by age >60 or >45 years plus metabolic criteria based on body mass index, triglycerides, and high-density lipoprotein-cholesterol levels. The primary endpoint was the incidence of PTDM after 12 months. Results: The study comprised 128 de novo renal transplant recipients without pretransplant diabetes (Tac-SW: 44, Tac-SM: 42, CsA-SM: 42). The 1-year incidence of PTDM in each arm was 37.8% for Tac-SW, 25.7% for Tac-SM, and 9.7% for CsA-SM (relative risk [RR] Tac-SW vs. CsA-SM 3.9 [1.2-12.4; P ¼ 0.01]; RR Tac-SM vs. CsA-SM 2.7 [0.8-8.9; P ¼ 0.1]). Antidiabetic therapy was required less commonly in the CsA-SM arm (P ¼ 0.06); however, acute rejection rate was higher in CsA-SM arm (Tac-SW 11.4%, Tac-SM 4.8%, and CsA-SM 21.4% of patients; cumulative incidence P ¼ 0.04). Graft and patient survival, and graft function were similar among arms. Conclusion: In high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence.
Evaluating mechanisms of post-transplant diabetes mellitus
Nephrology Dialysis Transplantation, 2004
Post-transplant diabetes mellitus (PTDM) is a frequent complication in renal transplantation. While both tacrolimus and ciclosporin are known to be associated with PTDM, the mechanisms underlying this metabolic disturbance and the relative contribution of concomitant corticosteroids have been unclear. At the University Hospital Maastricht, a series of studies have been conducted to investigate these issues. Administering tacrolimus to nondiabetic, dialysis patients was shown to result in a dose-related reduction in insulin secretion without altering insulin resistance. The patients who developed diabetes after transplantation already had impaired glucose metabolism pre-transplant. In a second study, corticosteroid withdrawal from tacrolimus-based immunosuppression reduced insulin resistance without changing insulin secretion. Moreover, reducing tacrolimus blood levels by 30% within the therapeutic window increased both insulin and C-peptide secretion by 24 and 36%, respectively. Accordingly, the effects of tacrolimus on insulin secretion are both dose dependent and reversible. A comparison of the effects of tacrolimus and ciclosporin on glucose metabolism revealed reduced insulin release with tacrolimus at week 3 post-transplant, but for the remainder of the 3 year follow-up there were no significant differences between the two treatment arms. Also, no difference was reported in glucose metabolism following conversion of stable renal recipients from ciclosporin to tacrolimus. Therefore, replacing tacrolimus with ciclosporin in patients experiencing glucose metabolism disturbances is unlikely to be helpful. In a recent study, early corticosteroid withdrawal from tacrolimus-based therapy resulted in a significantly lower incidence of new-onset diabetes mellitus than that achieved with a corticosteroid dose-tapering regimen. In conclusion, corticosteroid minimization plus dose-optimized tacrolimus immunosuppression is likely to be the best option for patients at risk of developing PTDM.
Background: Corticosteroids and calcineurin inhibitors (CNIs) are included in renal transplantation immunosuppressive protocols around the world. Well-known side effects are associated with the use of these drugs, including new onset of diabetes after transplantation (NODAT). Long-term patient survival rates are lower among patients with NODAT. The optimal immunosuppressive protocol would therefore include not using corticosteroids and minimization of CNI use. Methods/Design: This is a prospective, multi-centre, controlled, randomized, parallel group, open-label study involving kidney transplant patients. The study compares a steroid-free immunosuppressive protocol (study arm A), which is based on low-dose tacrolimus and mycophenolate mofetil (MMF) maintenance therapy together with antithymocyte globulin (ATG) induction, with the conventional immunosuppressive protocol (study arm B), being based on low-dose tacrolimus, MMF and steroids together with interleukin-2 receptor (IL2-R) induction. The study is designed to include most normal-risk patients. It will exclude patients seen as at a high risk of rejection. The primary objective of the study is to assess the cumulative incidence of NODAT in the two study arms 12 months after transplantation using the American Diabetes Association type 2 diabetes diagnostic criteria. The composite measure of freedom from acute rejection, graft survival and patient survival will be evaluated. Renal function and chronic changes in the transplanted kidney will be assessed. Discussion: If this study confirms conceptual expectations, namely decreased incidence of NODAT, the steroid-free study protocol could be used with all patients. The regimen could be especially beneficial for patients at a high risk of diabetes mellitus. Trial registration: Trial registration: EudraCT 2012-000451-13.
Posttransplantation diabetus mellitus under calcineurin inhibitor
Transplantation Proceedings, 2003
The development of postransplantation diabetes mellitus (PTDM) is a serious complication of kidney transplantation. PTDM has a major impact on quality of life decreasing rates of patient and graft survival. It is well known that some currently used immunosuppressants are diabetogenic. Greater diabetogenicity of FK-506 has been reported in multicenter trials. We initiated a study of conversion from tacrolimus (FK-506) to cyclosporine (CsA) among kidney allograft recipients presenting with PTDM to evaluate whether this maneuver would ameliorate a diabetic state. This analysis of 20 adult, renal allograft recipients presenting with PTDM assumed the need for insulin therapy or oral hypoglycemics before and after conversion of the immunosuppressive regimen. The criteria for evaluating the outcome were as follows: dose reduction of insulin or oral hypoglycemic agents, adequacy of glucose control, C-peptide levels, and insulin concentration. During the follow-up, we observed an improvement in the control of blood glucose in the converted group. In 13 patients, satisfactory glucose control was obtained without insulin or any other agent. In 3 patients a significant dose reduction of required insulin was possible. In another 2 patients who were insulin-dependent, the switch to oral hypoglycemic treatment was clinically possible after conversion. After conversion we observed significantly lowered fasting blood glucose levels and increased C-peptide levels. The conversion from a tacrolimus to a CsA-based immunosuppressive regimen resulted in better glucose metabolism. We demonstrated a positive effect of conversion on the diabetic state of patients with PTDM.
Emerging treatments for post-transplantation diabetes mellitus
Nature Reviews Nephrology, 2015
| Post-transplantation diabetes mellitus (PTDM), also known as new-onset diabetes mellitus (NODM), occurs in 10-15% of renal transplant recipients and is associated with cardiovascular disease and reduced lifespan. In the majority of cases, PTDM is characterized by β-cell dysfunction, as well as reduced insulin sensitivity in liver, muscle and adipose tissue. Glucose-lowering therapy must be compatible with immunosuppressant agents, reduced glomerular filtration rate (GFR) and severe arteriosclerosis. Such therapy should not place the patient at risk by inducing hypoglycaemic episodes or exacerbating renal function owing to adverse gastrointestinal effects with hypovolaemia. First-generation and secondgeneration sulphonylureas are generally avoided, and caution is currently advocated for the use of metformin in patients with GFR <60 ml/min/1.73 m 2 . DPP-4 inhibitors do not interact with immunosuppressant drugs and have demonstrated safety in small clinical trials. Other therapeutic options include glinides and glitazones. Evidence-based treatment regimens used in patients with type 2 diabetes mellitus cannot be directly implemented in patients with PTDM. Studies investigating the latest drugs are required to direct the development of improved treatment strategies for patients with PTDM. This Review outlines the modern principles of glucose-lowering treatment in PTDM with specific reference to renal transplant recipients.
ptdm in kidney allograft recipients current concept.pdf
The number of kidney allograft recipients has been increasing worldwide and along with that is a proportional rise in the number of individuals who develop posttransplantation diabetes mellitus (PTDM). It is therefore necessary that physicians who render care to transplant recipients, be conversant with the current issues that relate to this relatively common complication. We searched the Medline using the keywords diabetes, transplantation, kidney and PTDM, and retrieved all relevant articles that were published in the last 15 years up to 2008. Post-transplantation diabetes mellitus is a common complication following renal transplantation affecting approximately 10 to 20% of such patients. In the majority of the studies we reviewed, PTDM was similar to diabetes in non-transplant patients and the risk factors included older age at transplantation, family history of diabetes, obesity, elevated body mass index, nonwhite ethnicity and the use of steroids and several immunosuppressive agents. Curtailment of the heavy disease burden associated with PTDM should lay emphasis on pro-active preventive measures that are aimed at modifying the known risk factors and the individualized use of immunosuppressive agents determined by the pre-transplant risk profile of the patient.
DIABETES MELLITUS AFTER RENAL TRANSPLANTATION
Transplantation, 1996
T ACROLIMUS, a potent immunosuppressive drug, has been associated with improved kidney graft survival, although there is an increased incidence of posttransplant diabetes mellitus (PTDM). PTDM is a serious complication of immunosuppressive drugs that increases the risk of both graft loss and patient death, and predisposes patients to diabetic complications, including retinopathy and neuropathy. We reported here two cases of PTDM under a tacrolimus-based immunosuppression.