ENvarsus for Impaired Glucose Tolerance Post REnal transplAnT

Renal Transplant Failure

Our hypothesis is that switching from the current standard of care twice daily Adoport (Tacrolimus) to once daily Envarsus (tacrolimus) in patients who have impaired glucose tolerance post-transplant will lead to an improvement in their glucose tolerance, and may reduce the subsequent incidence of PTDM.

Kidney transplantation is widely held to be the optimal form of renal replacement therapy for patients with end-stage renal disease, leading to a longer survival and improved quality of life in patients receiving a renal transplant compared to those that remain on dialysis. However renal transplantation brings with it a new set of challenges for the clinician. One of the most important of these is post-transplant diabetes mellitus (PTDM). The prevalence of PTDM has increased over time and may occur in up to a third of all post-transplant patients making it a critical challenge for transplant physicians. PTDM represents a significant risk factor to both patient and graft survival, with some studies suggesting an increase of 60% in graft failure and an almost 90% increase in mortality. This morbidity and mortality is due to the greatly increased risk of cardiovascular disease associated with PTDM. In addition to the clinical consequences of PTDM for patients, there is also a huge economic impact on healthcare, with a diagnosis of PTDM doubling the cost of healthcare for a transplant patient. Important risks factors for PTDM include: Black/Asian race, male sex, older patients, receipt of a 'Donation after cardiac death' kidney, family history of diabetes, BP, raised body-mass index, Hepatitis C disease, Cytomegalovirus (CMV) viraemia, hyperparathyroidism, low HDL cholesterol, and hypomagnesaemia. In addition, PTDM is caused by multiple factors associated with renal transplantation. Steroid use impairs pancreatic beta-cell function, induces gluconeogenesis and glycolysis, inhibits glycogenesis and leads to insulin resistance. Tacrolimus, a calcineurin inhibitor (CNI), has been associated with increased rates of PTDM when compared to other CNIs (i.e. cyclosporine). It leads to hyperglycaemia via reduction of pancreatic insulin secretion and a reduction of GLUT-4 mediated glucose uptake into cells. In addition, it may directly cause beta cell toxicity and down regulate insulin gene expression. High tacrolimus concentrations have been associated with the development of PTDM; however, due to its enhanced efficacy in prevention of acute and chronic rejection, it has become the most widely used immunosuppressive medication in renal transplantation. Over 30% of patients post renal transplant have evidence of impaired glucose tolerance (IGT). IGT is a key step in the development of PTDM and an opportunity for intervention to prevent the development of PTDM. Higher peak tacrolimus levels have been associated with islet cell damage leading to hyperglycaemia, with evidence that this damage may be reversible with changing tacrolimus exposure . Not all tacrolimus based regimens may have the same side effects. Envarsus is a newer tacrolimus formulation, which has significantly altered pharmacokinetic properties and bioavailability compared to other tacrolimus based regimens. Envarsus has significantly lower peak to trough ratios and a 30% lower peak concentration. Both of these unique properties may reduce the beta cell toxicity seen with older tacrolimus based regimens and lead to an improvement in impaired glucose tolerance.

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