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In this ancillary study of the CONCEPT trial, we studied the role of CsA withdrawal at 3 months (3M) post-transplant on the intensity of epithelial phenotypic changes (EPC, an early marker for kidney fibrogenesis) on the 12 M surveillance biopsy. Although conversion from CsA to sirolimus (SRL) at 3M was reported to have improved mean graft function at 12 M, it did not reduce the score of EPC (1.73 ± 1.15 in the SRL group vs. 1.87 ± 1 in the CsA group, P = 0.61). Acute rejection, which had occurred twice more frequently in SRL-converted patients included here, was associated with 12 M EPC. Interestingly, we observed that the patients durably exposed to CsA and who developed 12 M EPC had a significant progression of blood pulse pressure (pp) from 1 to 6M post-transplantation (Δpp = +12.3 mmHg, P = 0.0035). Pulse pressure at 4, 6, and 9 M and pp progression from 1 to 6M were significantly associated with the development of EPC at 12 M in renal grafts. Logistic regression analysis revealed that a high 6M pp (≥ 60 mmHg) was an independent risk factor for 12 M EPC with an odds ratio of 2.25 per additional 10 mmHg pp (95%CI: 1.14-4.4, P = 0.02) after adjustment with recipient's and donor's age, acute rejection incidence and immunosuppressive regimen. A post hoc analysis of the data collected in the whole population CONCEPT study revealed that pp was significantly higher at 6 months in patients maintained on CsA and that at this time point pp correlated negatively with GFR at 1 year., (© 2013 Steunstichting ESOT.)

Background: There have been few prospective studies on the natural history of nonadherence (NA) in kidney transplant recipients (KTRs) over time. The objective of this study was to prospectively evaluate the rate of and risk factors for NA in a French cohort of KTRs., Method: A total of 312 KTRs from eight French transplantation centers were included in this prospective, noninterventional cohort study. A computer-learning software package (the Organ Transplant Information System) was made available to all patients., Results: Using the four-item Morisky scale, we showed that 17.3%, 24.1%, 30.7%, and 34.6% of patients were nonadherent at posttransplant month 3 (M3), M6, M12, and M24, respectively. Young age was predictive of NA at M6, M12, and M24. Surprisingly, simple treatment regimens including a small number of doses per day and a small number of tablets per day were associated with NA at M3 and M12, respectively. Other factors predictive of NA included failure to use the Organ Transplant Information System software package at M6 and patient reports of adverse events at M12 and M24. Importantly, we observed that physicians underestimated the prevalence of adverse events when compared to patient self-reporting., Conclusion: Our observed rate of medication NA in France is consistent with rates reported in previous studies. We found variability in NA risk factors over time as well as an unexpected risk factor (simple treatment regimens). These findings will be useful in developing effective adherence-promoting interventions.

Background: Sirolimus (SRL) is a potent immunosuppressant used in organ transplantation. It is known to decrease vascular endothelial growth factor (VEGF) synthesis, making it an interesting treatment option for transplant patients who develop Kaposi sarcoma or other malignant diseases. Because VEGF plays a key role in glomerular function and vascular remodelling, we determined the effect of SRL on renal VEGF expression., Methods: Using immunohistochemistry and quantitative image analysis, we examined renal VEGF expression in routine kidney biopsies performed at 1 year post-transplant in the CONCEPT study, a prospective randomized study comparing a cyclosporine (CsA)-based regimen to a SRL-based regimen in association with mycophenolate mofetil (MMF)., Results: A total of 74 patients were included in this substudy; 35 were randomized to the CsA group and 39 to the SRL group. Using continuous variables, the mean percentage of glomerular VEGF expression at Week 52 was significantly lower in the SRL group (14.7 ± 13%) compared to CsA group (21.2 ± 14%: P = 0.02). The percentage of glomerular VEGF expression at Week 52 was not influenced by recipient or donor age, gender, renal function, CsA dose, CsA blood level, SRL dose or SRL blood level. It was significantly lower in patients with a proteinuria over versus below 0.5 g/day (11.58 ± 7.9 versus 19.45 ± 15.53; P = 0.036)., Conclusions: There is emerging evidence that the VEGF system can play either a beneficial or a detrimental role depending on the specific pathologic situations. Therefore, modulating the renal VEGF axis by using an SRL-based regimen may influence the evolution of kidney injury associated with renal transplantation.

Whether or not a cyclosporine A (CsA)-free immunosuppressant regimen based on sirolimus (SRL) prevents aortic stiffening and improves central hemodynamics in renal recipients remains unknown. Forty-four patients (48 ± 2 years) enrolled in the CONCEPT trial were randomized at week 12 (W12) to continue CsA or switch to SRL, both associated with mycophenolate mofetil. Carotid systolic blood pressure (cSBP), pulse pressure (cPP), central pressure wave reflection (augmentation index, AIx) and carotid-to-femoral pulse-wave velocity (PWV: aortic stiffness) were blindly assessed at W12, W26 and W52 together with plasma endothelin-1 (ET-1), thiobarbituric acid-reactive substances (TBARS) and superoxide dismutase (SOD) and catalase erythrocyte activities. At W12, there was no difference between groups. At follow-up, PWV, cSBP, cPP and AIx were lower in the SRL group. The difference in PWV remained significant after adjustment for blood pressure and eGFR. In parallel, ET-1 decreased in the SRL group, while TBARS, SOD and catalase erythrocyte activities increased in both groups but to a lesser extent in the SRL group. Our results demonstrate that a CsA-free regimen based on SRL reduces aortic stiffness, plasma endothelin-1 and oxidative stress in renal recipients suggesting a protective effect on the arterial wall that may be translated into cardiovascular risk reduction., (©2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function. We previously reported that conversion from cyclosporine A (CsA) to sirolimus (SRL) 3 months after transplantation significantly improved renal function at 1 year. In the Postconcept trial, 77 patients in the SRL group and 85 in the CsA group were followed for 48 months. Renal function (Cockcroft and Gault) was significantly better at month 48 (M48) in the SRL group both in the intent-to-treat population (ITT): 62.6 mL/min/1.73 m(2) versus 57.1 mL/min/1.73 m(2) (p = 0.013) and in the on-treatment population (OT): 67.5 mL/min/1.73 m(2) versus 57.4 mL/min/1.73 m(2) (p = 0.002). Two biopsy proven acute rejection episodes occurred after M12 in each group. Graft and patient survival were comparable (graft survival: 97.4 vs. 100%; patient survival: 97.4 vs. 97.6%, respectively). The incidence of new-onset diabetes was numerically increased in the SRL group (7 vs. 2). In OT, three cancers occurred in the SRL group versus nine in the CsA group and mean proteinuria was increased in the SRL group (0.42 ± 0.44 vs. 0.26 ± 0.37; p = 0.018). In summary, the renal benefits associated with conversion of CsA to SRL, at 3 months posttransplantation, in combination with MMF were maintained for 4 years posttransplantation., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)