Progression of Arterial Pulse Pressure After Transplantation, a Potential Mechanism and Biomarker for CsA Associated Nephrotoxicity and Renal Graft Fibrosis.

Abstract

The benefits of cyclosporine A (CsA) are partly counterbalanced by its chronic vascular nephrotoxicity, which compromises renal graft outcome in the long term. In a previous clinical trial, 108 de novo renal transplanted patients were randomized, at 3 months post graft, to be withdrawn, either from CsA or mycophenolate mofetil (MMF). Then, they were maintained on a dual immunosuppressive therapy associating CsA + steroids (CsA group, n=54) or MMF + steroid (MMF group, n=54). All of them had protocol biopsies at 3 and 12 month post transplantation. We retrospectively analyzed the influence of pulse blood pressure progression (Δpp) from 3 months to 1 year after transplantation on two tubular epithelial phenotypic change (EPC) markers (β catenin and vimentin) expression, which are predictive of graft fibrogenesis and renal dysfunction. Δpp from 3 to 12 months was significantly higher in the CsA group of patients than in MMF group (Δpp= +4.5±2.2 vs -2±2.6mmHg, p<0.05). In the patients expressing EPC markers on their 12-month protocol biopsy, we found a significant pp progression (52.6±12 to 61±15mmHg, p=0.0061). Conversely, the patients without EPC marker expression at 12 months had a slight pp regression during this period (57.5±13 to 53±12 p=0.09). It is noteworthy that pp increased from 54.7±11 to 62±15mmHg (p=0.028) in the patients who displayed a significant cv progression (Δcv ≥1), but remained stable (from 55.5±13 to 55±13, p=0.8) in the patients without cv progression. These results suggest that the association between Δpp and EPC markers could be mediated by the development of arteriolosclerosis. Indeed, Δcv was significantly correlated with ΔEPC scores between 3 and 12 months post graft (r=0.32, p=0.01). A logistic regression model confirmed that CsA based therapy, Δpp and donor's age were 3 independent risk factors for EPC marker expression at 1 year and Δpp appeared to be a reliable predictive factor of renal function up to 4 years post transplantation. Conclusion: pp progression post transplantation could be a useful tool to predict the development of renal chronic vascular lesions and graft fibrosis, and to detect patients at risk for CsA nephrotoxicity.