The current state of the art with mTORi is the quest to discover the optimal immunosuppressive schedule that could guarantee kidney transplant recipients the lowest incidence of rejection and the best safety and long-term renal function. Thanks to all the basic, translational and clinical research achieved in the last twenty years, mTORi is now used as de novo immunosuppression in association with CNI at trough levels of 3–8 ng/mL. Another possibility is represented by the conversion of either CNI or mycophenolate (MPA) to an mTORi later on after transplantation. This can be beneficial in cases in which CNI- or MPA-related toxicity are evident, such as nephrotoxicity, tremor, leucopenia, diarrhea or CMV replication, which warrant a change in the immunosuppressive schedule. In these cases, late conversion can be carried out safely for most patients, especially from MPA to mTORi.
Moreover, different combinations of mTORi with the other immunosuppressive drugs have been investigated. Due to the narrow therapeutic index and the vast effects induced by mTORC1 and mTORC2 on human health and metabolism, management of side effects was challenging and hands-on experience was needed. Initially, it was not even clear that checking the trough level was necessary
[23], as some trials focused only on the oral dose and not on therapeutic drug monitoring
[24]. The general feeling about mTORi in the transplant community fluctuated from enthusiasm to disappointment, and vice-versa, given the brilliant discoveries and the frustrating failures. As a matter of fact, what is known about mTORi in kidney transplantation derives from the sum of pre-clinical and clinical data that have highlighted the strengths and the weaknesses of mTORi in this setting.
5. Real-Life Use of mTOR Inhibitors in Renal Transplantation
All the lessons learned by all these randomized clinical trials taught the transplant community how to take advantage of the benefits of mTORi (reduced rate of viral infections and cancer), without paying an excessive price for their side effects. It is also important to bear in mind the strict inclusion criteria of the TRANSFORM trial. Patients at high immunological risk were discarded, as well as recipients of a Donors after Circulatory Death (DCD), which represent a valuable source of donors in many countries. In this field, a single-center propensity score analysis published in 2020 by the researchers' group
[25] verified the real-life feasibility of using a TAC–mTORi combination scheme through 401 patients that were analyzed according to the baseline immunosuppression (TAC associated with either MPA or mTORi). mTORi were administered irrespective of the type of donor (non-heart beating or not) and the immunological risk of the recipient. Patients that would have not entered the TRANSFORM trial for these and other exclusion criteria accounted for 52.9% of the total population. Curiously, patients who met the TRANSFORM inclusion criteria (
n = 186) had very similar results to that of the original trial, with no differences in terms of 1-year and last follow-up graft rejection and survival between the MPA and mTORi group. On the other hand, patients that could not have participated in the trial (
n = 215), had better results for both outcomes. Another strong point in favor of mTORi was the evidence in all groups of better 1-year and last follow-up patient survival. A reduced rate of infection-related hospitalizations during the first year could partially justify this finding. On the other side, a higher incidence of drug discontinuation was observed in the mTORi group due to classical side effects, including hypercholesterolemia, proteinuria, surgical-associated complications, etc., as well as beneficial effects (reduced CMV reactivation and total number of infections requiring hospitalization).
A difference worthy to mention with respect to the TRANSFORM trial was the higher trough levels of TAC in patients treated with mTORi; this may also justify the decreased incidence of rejection in this group. This different attitude about TAC/mTORi trough levels was not associated with a worse 1-year renal function and higher chronicity scores at protocol renal biopsy
[25].
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)
[26]. This striking difference in results in comparison with the US92 trial
[27] is probably attributed to the higher TAC trough levels employed
[25][26]. 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.
6. Practical Use of mTOR Inhibitors in Kidney Transplantation—Troubleshooting
The two mTOR inhibitors commercially available and approved for use in kidney transplantation can be started soon after surgical intervention at a dose of 1–2 mg qd (Sirolimus, SRL) or 1–1.5 mg bid (Everolimus, EVL), with the aim to reach trough levels of 3–8 ng/mL. During the first weeks after kidney transplant, it is advisable, however, to maintain trough levels in the range of 3–5 ng/mL.
In the researchers' center, SRL and EVL are associated with TAC in order to reach a sum (TAC + mTORi) of trough levels of 8–12 ng/mL
[25][26]. This sum can be reduced to 8–10 ng/mL at 6–12 months after kidney transplantation, according to individual assessment of rejection risk. Particularly, TAC can be minimized to <5 ng/mL after 6–12 months in the low-risk population according to the TRANSFORM experience
[28]. In patients with high immunological risk, it is advisable not to minimize TAC during the first year after kidney transplantation and to consider reducing trough levels thereafter, according to local center policies and, preferably, to the results of per-indication or per-protocol kidney graft biopsies.
Induction should be based on individual risk assessment depending on the immunological risk (i.e., anti-CD25 antibodies for low-risk patients and anti-thymocyte globulins for the high-risk population).
Contraindications for the start of de novo mTOR inhibitors in kidney transplantation include: a previous history of intolerance or side effects with mTORi, chronic obstructive pulmonary disease, central obesity that could impair surgical wound healing, thrombotic microangiopathy as the cause of end-stage renal disease, and any patient at risk of surgical complications and possibly re-intervention. Patients that could benefit most from the use of mTOR inhibitors are those with a history of virally induced cancers and who are at risk of developing CMV disease or BK nephropathy.
Advantages for the use of mTOR inhibitors in comparison with MPA include, undoubtedly, less incidence of viral infections (especially, CMV and BK), less neutropenia and low blood platelets, and a possible reduction in long-term incidence of solid neoplasia, especially for non-melanoma skin cancer in which the evidence is more convincing
[29][30]. Moreover, in low immunological risk patients, mTORi could allow safe minimization of CNI, which in the long term could theoretically prolong graft survival.
The most common side effects associated with the use of mTOR inhibitors are listed in Table 1, along with a list of possible solutions.
Table 1. Most common side effects of mTOR inhibitors in kidney transplantation with a list of possible solutions.
Side Effect
|
Solution
|
Neumonitis
|
Discontinue mTORi.
|
Thrombotic microangiopathy
|
If clinically evident and in case of rejection, consider discontinuing mTORi.
If it is only a finding in renal biopsy without clinical deterioration, consider reducing trough levels of either CNI or mTORi or both. In low-risk patients consider conversion from CNI to MPA.
|
Surgical scar infection or late healing
|
Switch to MPA until resolved and then switch back to mTORi.
|
Lymphocele
|
Switch to MPA until resolved and then switch back to mTORi.
|
Productive surgical drainage
|
Switch to MPA until resolved and then switch back to mTORi.
|
Post-transplant diabetes mellitus
|
Start of oral antidiabetic agent and/or insulin.
Consider switching TAC to CsA.
|
Hypertriglicerydemia
|
Diet, weight loss, omega-3 fish oil.
|
Hypercolesterolemia
|
Diet, weight loss, statins, ezetimibe, fibrates.
|
Proteinuria
|
Consider using ACE inhibitors or Angiotensin Receptor Blockers.
|
Edemas
|
Consider using diuretics.
In patients taking vasodilators (such as amlodipine), consider switching to another anti-hypertensive agent.
|