Efficacy and Safety of Early Mammalian Target of Rapamycin Inhibitors with Minimization of Calcineurin Inhibitors in Kidney Transplant Recipients

Abstract

Background To improve the long-term results of kidney transplantation, interstitial fibrosis and renal tubular atrophy should be suppressed. Purpose To investigate the effect of interstitial fibrosis/renal tubular atrophy (IF/TA) in a protocol that involves calcineurin inhibitor (CNI) reduction and everolimus (EVL) addition in kidney transplant patients. Materials and Methods In 96 cases of kidney transplantation performed at the Tokyo Medical University Hachioji Medical Center between November 2012 and December 2016, we examined 78 patients who underwent renal biopsy 3 (pre-transplantation) and 12 months (post-transplantation). The introductory immunosuppressant treatments combined 4 agents (CNI + MPSL + MMF + basiliximab). We performed a protocol-based renal biopsy for the patients 90 days post transplantation. For patients who did not show signs of organ rejection, we reduced the doses of CNI and MMF, and then added EVL to the regimen. We grouped the patients according to the presence/absence of EVL administrations and examined renal function, organ rejection, and IF/TA 3 and 12 months later. Results The mean ages of the patients in the EVL (n=39) and non-EVL groups (n=39) were 48.2 and 48.2 years, respectively. In the EVL group, 16 patients (16/39: 41.0%) received cyclosporine (CyA), whereas 19 patients (19/39: 48.7%) received the same in the non-EVL group. Organ rejection (acute T-cell-mediated rejection, ATMR) prior to the 90-day protocol was observed in 8 patients in the EVL group and in 14 patients in the control group. IF/TA was observed in 2 patients in the EVL group and in 4 patients in the control group. During the 1-year protocol, organ rejection (ATMR) was observed in 4 patients in the EVL group and in 5 patients in the control group. IF/TA occurred in 20 patients in the EVL group and in 20 patients in the control group. The change in IF/TA score in the EVL group was ci;4/2 (mean: 2.0), ct;4/2 (mean: 2.0) after 3 months and ci;15/20 (mean: 0.75), ct;13/20 (mean: 0.65) after 12 months. In the control group, the change in IF/TA score was ci;4/4 (mean: 1.0), ct;4/4 (mean: 1.0) after 3 months and ci;17/20 (mean: 0.85), ct; 20/20 (mean: 1.0) after 12 months. The risk factors of pre-ATMR were CyA (2.6 times) and HLA mismatch (2.4 times). The risk factor of post-ATMR was pre-ATMR. The risk factors of post-IF/TA were donor age (2.3 times) and presence of donor-specific antibody I (DSA-I; 1.6 times). Conclusion CyA and HLA mismatch were found to be risk factors of ATMR during the early phase post transplantation. History of ATMR was a risk factor of post-ATMR. By adding EVL to CyA, the manifestation of ATMR was suppressed. We observed no difference in renal function between the two groups. Post-administration CNI reduction and EVL addition did not contribute to the suppression of IF/TA.