Cyclosporin A-induced gingival overgrowth in renal transplant patients : a clinical, histological and experimental study

Abstract: Cyclosporine A (CsA) is widely used as an effective immunosuppressive agent to prevent rejection of organ transplants, as well as in the treatment of patients with various autoimmune diseases. The clinical use of CsA, however, is associated with adverse side effects, including nephrotoxicity, hepatotoxicity, hypertension, and neurotoxicity as well as gingival overgrowth. The present thesis is based on a series of clinical, histological, and experimental studies of CsA-induced gingival overgrowth in renal transplant recipients. The main findings from these series of studies are as follows. In a group of renal transplant pediatric recipients who had been under CsA therapy for at least 12 months, about 51% of the children exhibited gingival enlargement to varying degrees. The occurrence of gingival overgrowth in the adult renal transplant recipients who have been under CsA medication for 12 months was estimated to be about 40%. The vehicle in which CsA is administered orally significantly affects the duration and concentration of the drug in the oral cavity. The oral exposure for CsA during the dosage interval was approximately 130 times higher when the drug was administered in mixture form compared with capsule form. The development of CsA-induced gingival overgrowth was more rapid and the severity of the lesion was more pronounced in patients who were administered the drug in mixture form especially in the regions of the upper front and lower molar compared to capsule patients. Patients with CsA-induced gingival overgrowth exhibited increased plaque accumulation and gingival inflammation compared to those without gingival overgrowth. The occurrence and the development of CsA-induced gingival overgrowth was positively related to the total amount of CsA dose, administered to the patients during the first 6 posttransplant months. Furthermore, the occurrence of gingival overgrowth was significantly higher among patients who were concomitantly administered nifedipine than among those treated with CsA alone. The risk for developing gingival overgrowth was 22 times higher in these patients compared to patients who did not use nifedipine. The CsA-induced gingival overgrowth represents a tissue with an altered composition characterized by an increased thickness of the oral epithelium and relatively increased amounts of cells, vessels, non-collagenous matrix and decreased collagenous matrix in the non-infiltrated connective tissue. Evaluation of the renal function of renal transplant pediatric recipients showed that there is a positive correlation between the degree of gingival enlargement and changes in renal function expressed as filtration fraction. CsA, which by itself does not stimulate PGE2 biosynthesis, potentiates in a dose-dependent manner PGE2 formation in human gingival fibroblasts challenged with the inflammatory mediator TNFalpha.