Detecting new-onset diabetes and the effect of prednisolone on glycaemia after renal transplantation

© 2013 Dr. Christopher James YatesBackground: A significant impediment to long-term graft survival after kidney transplantation has been the morbidity and mortality attributable to cardiovascular disease. New-onset diabetes after transplantation (NODAT) is an independent predictor of cardiovascular events and prednisolone immunosuppression is a major modifiable risk factor for NODAT. Aims: This study aimed to investigate the relationship between prednisolone and post-transplant glycaemia and to identify strategies to reduce the incidence and improve the detection of NODAT. Methods: In kidney transplant recipients 3-4 weeks post-transplant, the accuracy of limited sampling strategies for assessing exposure to biologically active free prednisolone was tested and the relationship between free prednisolone exposure and glycaemia was determined using continuous glucose monitoring (CGM). CGM was also used to compare the glycaemic effects of once daily and divided twice-daily prednisolone dosing. Finally, the sensitivities of screening tests for NODAT were compared at various time points during the first year after kidney transplantation. Results: Free prednisolone exposure was accurately predicted using limited sampling strategies that incorporated two concentration samples within four hours of dosing. There was significant inter-individual variability in free prednisolone exposure but minimal intra-individual variability, and no association between bodyweight and free prednisolone exposure was observed. Free prednisolone exposure correlated with hyperglycaemia, measured by peak glucose and exposure to glucose concentrations of 7.8mmol/L or greater. Dividing the total daily prednisolone dose into two equal doses 12 hours apart reduced hyperglycaemia and glycaemic variability. Once daily prednisolone administration resulted in a peak in plasma glucose 7-8 hours later and during the initial post-transplant hospitalisation 70% of patients without pre-existing diabetes developed diabetic range blood glucose levels. With moderate prednisolone doses six weeks post-transplant, 4pm blood glucose assessment was more sensitive than the oral glucose tolerance test in detecting NODAT. With low maintenance prednisolone doses from three months onwards, glycated haemoglobin (HbA1c) had comparable sensitivity to the oral glucose tolerance test in detecting NODAT. Fasting plasma glucose testing was inadequate for detecting NODAT at all stages in the first year post-transplantation. Conclusions: After kidney transplantation free prednisolone exposure correlates with glycaemia and divided twice-daily dosing reduces hyperglycaemia. Therefore therapeutic drug monitoring and divided daily dosing may reduce the incidence of NODAT. With morning prednisolone, hyperglycaemia is best detected by afternoon glucose testing early post-transplant, and either HbA1c or OGTT from three months post-transplant