Facteurs de risque d’insuffisance rénale chronique chez les greffés cardiaques : du phénotype aux tests pharmacogénomiques

Chronic kidney disease (CKD) is a major problem frequently observed in cardiac transplant recipients. Calcineurin inhibitors, which have become the cornerstone of immunosuppressive treatments in solid organ transplantation, are considered a major cause of post-transplant renal dysfunction. Several other factors such as recipients’ demographic, clinical and genetic characteristics also contribute to this phenomenon, but it remains rather difficult to determine which patients present the highest risk of CKD after transplantation. Discovery of new genetic markers of renal dysfunction could one day lead to individualization of immunosuppressive therapy according to each patient’s genetic profile. However, transplant patients’ opinions towards pharmacogenomic testing remain unknown, and it is unclear whether these differ from healthy individuals’ opinions. This doctoral thesis thus aims: 1- To describe the very long-term evolution of renal function after transplantation and to identify demographic and phenotypic markers associated with postheart transplant CKD; 2- To identify genetic markers associated with calcineurin inhibitor-induced nephrotoxicity; 3- To assess and to compare the attitudes of patients and healthy individuals concerning the potential integration of pharmacogenomic markers in clinical practice. Three projects have been conducted to answer these questions. The first one relies on a retrospective analysis of the evolution of renal function in patients who received a heart transplantation at our institution between 1983 and 2008. We discovered that deterioration of renal function continues up to 20 years after transplant and that risk factors of CKD include, among others, advanced age, female gender, pretransplant renal dysfunction, hypertension, hyperglycemia and use of prednisone. The second project is a pharmacogenomic study looking at genetic determinants of calcineurin inhibitor-induced nephrotoxicity. We were able to illustrate for the first time that a genetic polymorphism related to PRKCB (gene encoding protein kinase C-β) is associated with renal function in heart transplant patients, whereas it is probably not the case for polymorphisms in TGFB1 (gene encoding transforming growth factor-β1). The third section of this thesis reports the results of a questionnaire whose purpose was to compare the attitudes towards pharmacogenomic testing in a group of healthy volunteers, cardiac transplant recipients and heart failure patients. This study demonstrated that, although enthusiasm regarding pharmacogenomics is shared equally among these individuals, preoccupations related to confidentiality and potential impacts on employment and insurance are more important in healthy volunteers. In summary, the work presented in this thesis showed that early identification of heart transplant patients who are most likely to develop renal dysfunction as well as adoption of an individualized therapeutic approach involving clinical applications of pharmacogenomics could potentially help to prevent this post-transplant complication.

Keyphrases: Cyclosporine, Tacrolimus, Cardiac transplantation, Renal insufficiency, Risk factors, Nephrotoxicity, Cyclosporine, Tacrolimus, Heart failure, Pharmacogenomics, Public opinion