Genomic and Cellular Markers and Chronic Renal Allograft Function

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DESCRIPTION (provided by applicant): Chronic renal allograft survival is poorer in African Americans than Caucasians which may be due to medication non-adherence, racial differences in immunosuppressive pharmacokinetics, genomic factors, increased immunoreactivity, and racial variation in immunodynamic responses. This proposal describes a pilot study that is based on our preliminary findings that indicate race and gender impact on the interpatient variability in drug transport (gene and protein) and immunodynamic responses with immunosuppressive drug exposure within a dosing interval after renal transplantation. The hypothesis of this application is that individual renal allograft recipients receiving chronic, dose-adjusted immunosuppressives exhibit a time-dependent drug transporter dynamics and immunologic responses over a dosing interval that are influenced by race and gender. The specific aims are to: 1) Examine race and gender influence on time-dependent extracellular/intracellular immunodynamic responses and their relationship to extracellular/intracellular immunosuppressive concentrations; 2) Investigate interpatient and intrapatient, time-dependent patterns of P- glycoprotein expression (gene and protein) and function in relation to race, gender and drug concentrations. These aims will extend our initial four-hour studies of time-dependent responses of MDR1 gene expression, intracellular cytokines (IL-2 and IL-4) and extracellular immunodynamic responses of CD4+ and CD8+ T regulatory cells, T Helper 1 and T Helper 2 lymphocytes to include an entire twelve-hour dosing interval in renal transplant recipients. This study will also investigate the relationship of the P-gp transport protein and immunodynamic responses to race, gender, age, drug exposure, renal function, time post-transplant, HLA compatibility and concurrent medications. The results of this study will provide preliminary data to create a bridge from the non-specific clinical monitoring methods that are currently used to create a novel approach that incorporates cellular and genomic biomarkers. This patient specific approach will allow clinicians to provide more individualized immunosuppressive therapy and enhance allograft survival. PUBLIC HEALTH RELEVANCE: The significance of this project is related to the growing need for strategies that will increase allograft survival and function following renal transplantation due to the rising incidence of end stage renal disease in the United States. A primary concern is the observed racial disparity with regard to suboptimal renal allograft outcomes in spite of improved drug therapy. The results of this study will lead to the development of new therapeutic guidelines as well as potential biomarkers that incorporate race and gender differences in response to immunosuppression and facilitate individualization of drug treatment and improved allograft survival and function.