Use of De Novo mTOR Inhibitors in Hypersensitized Kidney Transplant Recipients: Experience From Clinical Practice

Abstract

Background. It is commonly believed that mTOR inhibitors (mTORi) should not be used in high-immunological risk kidney transplant recipients due to a perceived increased risk of rejection. However, almost all trials that examined the association of optimal-dose mTORi with calcineurin inhibitor (CNI) have excluded hypersensitized recipients from enrollment. Methods. To shed light on this issue, we examined 71 consecutive patients with a baseline calculated panel reactive antibody (cPRA) ≥50% that underwent kidney transplantation from June 2013 to December 2016 in our unit. Immunosuppression was based on CNI (tacrolimus), steroids and alternatively mycophenolic acid (MPA; n = 38), or mTORi (either everolimus or sirolimus, n = 33, target trough levels 3–8 ng/mL). Results. Demographic and immunological risk profiles were similar, and almost 90% of patients in both groups received induction with lymphocyte-depleting agents. Cox-regression analysis of rejection-free survival revealed better results for mTORi versus MPA in terms of biopsy-proven acute rejection (hazard ratio [confidence interval], 0.32 [0.11-0.90], P = 0.031 at univariable analysis and 0.34 [0.11-0.95], P = 0.040 at multivariable analysis). There were no differences in 1-year renal function, Banff chronicity score at 3- and 12-month protocol biopsy and development of de novo donor-specific antibodies. Tacrolimus trough levels along the first year were not different between groups (12-mo levels were 8.72 ± 2.93 and 7.85 ± 3.07 ng/mL for MPA and mTORi group respectively, P = 0.277). Conclusions. This single-center retrospective cohort analysis suggests that in hypersensitized kidney transplant recipients receiving tacrolimus-based immunosuppressive therapy similar clinical outcomes may be obtained using mTOR inhibitors compared to mycophenolate.

Immunogenic and immunotolerogenic effects of extracorporeal photopheresis in high immunological risk kidney recipients. A single center case series

“…Finally, ECP should not be considered as a unique therapeutic action, but should be conceived as a complementary technique that must be accompanied by concomitant actions in the management of rejection or infections. 43,44 In summary, ECP is a safe procedure that could have a role for the treatment of KT rejection in highly immunosuppressed patients with concomitant active infection or at high risk of developing it.…”

“…More studies are needed to determine the best time to start this treatment and the most appropriate frequency to obtain the best outcome of the treatment. Finally, ECP should not be considered as a unique therapeutic action, but should be conceived as a complementary technique that must be accompanied by concomitant actions in the management of rejection or infections 43,44 …”

The impact of functional delayed graft function in the modern era of kidney transplantation – A retrospective study

“…A key aspect in this kind of studies is the immunosuppressive regimen of the included patients, which in most cases was not specified in terms of type of immunosuppressants or its distribution among the studied groups [9,15]. This is an important issue taking into account that cyclosporine has been associated with higher nephrotoxicity and poorer eGFR than tacrolimus [13,20–22] in the long‐term follow‐up, as well as the increasing use of CNI‐minimization strategies with mTORi [13,20–22].…”

Medical Aspects of mTOR Inhibition in Kidney Transplantation

“…In a sub-analysis of the same population focused on high immunological risk patients, defined as a baseline cPRA ≥ 50% ( n = 71), the combination TAC + mTORi was associated with better results in terms of 1-year rejection-free survival compared to TAC + MPA (incidence of biopsy-proven acute rejection was 15.2% versus 36.8%, respectively) [ 81 ]. This striking difference in results in comparison with the US92 trial [ 78 ] is probably attributed to the higher TAC trough levels employed [ 80 , 81 ]. This probably indicatesthat in the high immunological risk population, TAC should not be minimized as in the low-risk population studied in the TRANSFORM trial.…”