LONG-TERM RESULTS OF THE REDUCTION OF EXPOSURE TO CALCINEURIN INHIBITORS ASSOCIATED WITH MTOR INHIBITORS IN KIDNEY TRANSPLANTATION

Introduction:

The use of mTOR inhibitors (mammalian Target Of Rapamycin, rapamycin or everolimus) has been proposed to reduce the nephrotoxicity of calcineurin inhibitors (CNIs) and their influence on chronic graft dysfunction and renal, cardiovascular and infectious comorbidities. The results of the initial mTOR studies to evaluate its efficacy and safety were designed with complete suspension of CNIs and showed lower efficacy in rejection control and graft survival, which is why, since 1995, we initiated a protocol with reduced doses of CNIs associated with full doses of mTOR-I and steroids in order to reduce nephrotoxicity without reducing efficacy. In a selected group of patients, mTOR was used with reduced doses of mycophenolate without CNI. We present the results of this treatment regimen.

Methods:

We conducted a retrospective cross-sectional and analytical study including consecutive isolated or combined kidney transplant (KT) patients who were converted to mTOR inhibitors as part of their immunosuppressive regimen between January 2010 and December 2020. All patients (P) received induction with thymoglobulin and were biopsied prior to mTOR conversion to exclude rejection. Categorical variables were compared using the X2 test and reported as proportions and absolute values, while continuous variables were analyzed using the t-test or Wilcoxon test, as appropriate. Time-to-event analysis was performed using the Kaplan-Meier method and Cox regression, with group comparisons using the Mantel-Cox test. A 5% alpha was considered significant. Statistical analysis was performed using R (R Core Team (2023)).

Results:

A total of 647 isolated or combined KTs were performed during the study period; 207 P (31.9%) received mTOR-based immunosuppression with a median follow-up of 6.6 years (IQR 4.5-8.8). Baseline characteristics of the recipients and donors in the study are summarized in Table 1. 88.9% (n=189) were treated with mTORi plus low-dose CNI regimen (Table 1). Switching scenarios and times are described in Table 2. Patient survival at 1, 5 and 10 years was 97.6%, 88.1% and 73.3%, respectively. Graft survival at 1, 5, and 10 years was 96%, 84%, and 65%, respectively. In Cox regression analysis, living donor was a protective factor for patient survival with HR 0.11 (CI 0.02-0.53) p-value 0.006 (Graph 1). No protective effect of the living donor on graft survival was observed. The initial and final CKDe GFR rates were 53.6 ml/min (SD 22.2) and 55.9 ml/min (SD 25.1), respectively. The prevalence of acute rejection after switching to mTOR-I was 3.4% (n=7). De novo DSA was detected in 12 of 207 patients (5.8%) at a mean time of 2.80 ± 1.65 years after mTOR-I conversion. Of the 44 patients who underwent conversion due to viral reactivation, 42 had a negative BK and/or CMV viral load after switching to mTOR.

Conclusions:

The use of ImTOR in renal transplantation is safe in the conversion scenarios described. Good efficacy was observed with reduced rejection rates, low incidence of de novo DSA and viral replication with good long-term patient and graft survival. Larger randomized controlled trials are needed to confirm these findings and clarify the long-term benefits of mTORi in kidney transplantation.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.