Age and Race Influences on Immunosuppression after Renal Transplant

ABSTRACT The incidence of end stage renal disease in the United States has continued to increase. The age-adjusted rate of end stage renal disease is 4x greater in African Americans than Caucasians with an increased incidence in elderly patients. Renal transplantation is the preferred renal replacement therapy due to cost efficiency and improved life expectancy, regardless of age, race or sex. Renal transplant has more than doubled in recipients = 65 years with a continued increase in African Americans. Tacrolimus and mycophenolic acid is the most common regimen prescribed to attenuate immunologic responses and avoid allograft rejection. Elderly renal transplant recipients may receive older, less functional organs. Increased age is an independent risk for chronic allograft failure suggesting the need for age-adjusted dosing regimens. In addition, chronic allograft survival is poorer in African Americans than Caucasians, which may be due to racial differences in immunosuppressive pharmacokinetics, genomic factors, co-morbidities and immunologic responses. Clinical pharmacology research in the area of age, race and sex differences in immunosuppressive pharmacokinetics and pharmacodynamics is lacking leading to a major knowledge gap that impedes evidence-based, individualization of immunosuppressives. This proposal will address this knowledge gap and determine the influence of age, race and sex on pharmacokinetics and pharmacodynamics of tacrolimus and mycophenolic acid. This study will enroll 216 stable African American and Caucasian male and female renal transplant recipients that will be stratified into young, middle age and elderly groups. We hypothesize that age, race and sex exert independent, and possible combined influences, on immunosuppressive pharmacokinetics and pharmacodynamic responses and this effect is potentiated in patients with certain genotypes that influence drug metabolism and membrane transport. The Specific Aims are: 1) To investigate the effect of age, race, and sex on the pharmacokinetics of tacrolimus and mycophenolic acid and the influence of pharmacogenomic variants associated with drug metabolism and tissue distribution. 2) To investigate the association of age, race and sex on intrapatient pharmacodynamic responses including adverse drug effects, T regulatory cells, cellular P-gp function, intracellular NFAT1 translocation and their relationship to immunosuppressive pharmacokinetics. 3) Utilize mechanism-based pharmacokinetic and pharmacodynamic system models to determine the relationship of age, race and sex to tacrolimus and MPA pharmacokinetics and pharmacodynamics using T regulatory cells, P-gp function, and NFAT1 translocation, adverse effects, renal function and gene variants. These aims will promote major progress in immunosuppression by providing a bridge from the non-specific clinical monitoring methods currently used and create novel dosing and monitoring approaches that integrate age, race and sex with cellular and clinical endpoints, pharmacokinetics and pharmacogenomics to attain personalized medicine.