Traditionally, high immunological risk patients, including hypersensitized patients, have never been enrolled in prospective trials during drug development. This was the case for mycophenolate mofetil (MPA) and tacrolimus (TAC), the drug combination considered the current standard of care since the publication of the Symphony trial.1
The number of hypersensitized patients on the waiting list is growing worldwide. Although allocation policies may increase the transplant rate of these patients, alternative immunosuppressive strategies with improved efficacy, safety, and tolerability are necessary to fulfill individual needs. Yet, regardless of the definition of immunological high risk, these patients receive effective induction therapy, generally with anti-thymocyte globulin, followed by the standard of care TAC, MPA, and steroid (P) combination, and do not routinely undergo any minimization strategies.
The development of mammalian target of rapamycin (mTOR) inhibitors (mTORi) followed the same path, avoiding enrollment of hypersensitized patients in pivotal clinical trials. Interestingly, even after the approval of sirolimus (SRL) and everolimus (EVR) by regulatory agencies, their use in high-risk hypersensitized kidney transplant recipients is still consistently avoided.
The inherent question then is “Why do we avoid using mTORi in hypersensitized patients?” The answer is not straightforward. When SRL was approved, the high expectations for an SRL-based calcineurin inhibitor (CNI)-free immunosuppressive regimens were soon frustrated, clearly associated with insufficient efficacy and poor tolerability of these immunosuppressive strategies. Yet, are mTORi less effective for the prevention of acute rejection in comparison with MPA in the absence of a CNI? The answer is probably no. In the Caesar trial, 535 kidney transplant recipients received daclizumab induction followed by CsA/MPA/P. At 12 months, the incidence of acute rejection was 38% after CsA withdrawal and 25.4% after CsA dose reduction 6 months after kidney transplantation compared to 27.5% in the triple-drug regimen.2 In a multicenter trial involving 430 kidney transplant recipients receiving CsA/SRL/P, withdrawal of CsA 3 months after kidney transplantation was associated with an increase in the incidence of acute rejection compared to the triple regimen (9.8% versus 4.2%) at 12 months.3 Finally, in a multicenter trial involving 224 kidney transplant recipients receiving CsA/MPA/P, conversion of eligible patients to CsA/P, EVR/P, or MPA/P 6 months after transplantation was associated with a higher incidence of acute rejection in the MPA/P group leading to premature termination of the MPA group (9% versus 3% versus 22%), respectively.4 Despite the differences in inclusion and exclusion criteria and study design, altogether, these studies suggest that the maintenance of a CNI is associated with the lowest incidence of acute rejection. When CNI is withdrawn, maintenance of mTORi provides at least comparable efficacy to MPA for the prevention of acute rejection.
The second question is whether mTORi are associated with an increased risk of development of de novo donor-specific antibodies (DSA). In a subanalysis of 2 prospective randomized trials involving 127 kidney transplant recipients receiving CsA/MPA/P, conversion from CsA to EVR at 3–4.5 months was associated with higher incidence de novo DSA (23% versus 10.8%, P = 0.048) and antibody-mediated rejection (AMR) (8 versus 2, P = 0.036) compared to patients maintained on CsA/MPA/P.5 Importantly, similar findings were observed after a 50% reduction in TAC dose at 4 months6 or withdrawal of TAC7 at 6 months in 2 cohorts of stable low immunological risk kidney transplant recipients receiving MPA/P. Altogether, these data suggest that a minimal effective CNI concentration is required for the prevention of acute rejection and the development of DSA.
The third question is whether the lower TAC concentrations routinely used in combination with mTORi, a requirement to avoid overt nephrotoxicity, are effective for the prevention of DSA. Recently, the Transform trial, which also excluded hypersensitized patients, showed comparable efficacy between EVR and MPA for the prevention of acute rejection and DSA formation, despite a significant lower mean TAC concentration in the EVR compared to the MPA group during the first 2 years (4.1 versus 6.9 ng/mL at 1 y and 3.9 versus 6.8 ng/mL at 2 y).8
In this issue of Transplantation, Cucchiari et al9 performed a retrospective cohort analysis comparing clinical outcomes of 71 consecutive kidney transplant recipients with cPRA ≥50% receiving induction therapy followed by TAC/P and MPA (n = 38) or mTORi (n = 33). The incidence of biopsy-proven acute rejection, including AMR, was lower in the mTORi group with 2 graft losses occurring in the MPA group. There were no differences in 1-year renal function, Banff chronicity score at 3- and 12-month protocol biopsies, and development of de novo DSAs.
Whilst this work provides initial data suggesting that mTORi are at least as effective as MPA in hypersensitized patients in combination with CNI, caution is necessary when interpreting and extrapolating these results to other populations. First, given the retrospective nature of the study, the small sample size, and short follow-up time, selection biases and residual unaccounted confounding factors may influence the described outcomes. In fact, according to the local immunosuppressive protocol, patients with exclusion criteria to receive mTORi, namely, obesity, focal and segmental glomerulosclerosis, previous adverse reaction, and chronic lung disease, and all blood group ABO-incompatible living donor recipients were treated with MPA. Second, the incidence of AMR in the MPA group, higher than expected, might be associated with unaccounted demographic risk factors. Particularly interesting in this analysis is that TAC trough concentrations along the first year were not different between the 2 groups (12-mo concentrations were 8.72 ± 2.93 ng/mL and 7.85 ± 3.07 ng/mL for MPA and mTORi groups, respectively, P = 0.277), raising a few concerns. Could similar outcomes be achieved with reduced TAC concentrations as in the Transform trial? Despite the lack of difference in renal function and histology at the end of the first year, could this higher TAC exposure be associated with increased risk of chronic nephrotoxicity? Can we safely reduce TAC concentrations after the first year without comproising the efficacy for the prevention of DSA and AMR? Would this strategy provide similar results in recipients of high kidney donor profile index kidneys, inherently more susceptible to acute and chronic nephrotoxicities? What is the short-and long-term tolerability of mTORi in such a population considering the baseline demographic characteristics? In the recent Athena trial, kidney transplant recipients receiving TAC/EVR/P showed similar TAC concentrations (around 6 ng/mL by mo 12) but inferior renal function, compared to those receiving TAC/MPA/P at 12 months after transplantation.10 Finally, are there sufficient benefits to use this immunosuppressive regimen over the standard of care regimen? While short-term benefits may include limitation of viral replication, the long-term benefits are still uncertain, including tolerability, renal function stability, and the incidence of malignancies.
Although there are several experimental mechanistic biological evidences behind the possible differential effect of mTORi and MPA on T and B cells, these preliminary data provide further insight for the design of prospective clinical trials aiming to improve the long-term outcomes of an increasing population of patients at high risk for graft loss.
1. Ekberg H, Tedesco-Silva H, Demirbas A, et al.; ELITE-Symphony StudyReduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007; 357:2562–2575
2. Ekberg H, Grinyó J, Nashan B, et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR study. Am J Transplant. 2007; 7:560–570
3. Johnson RW, Kreis H, Oberbauer R, et al. Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation. 2001; 72:777–786
4. Bemelman FJ, de Fijter JW, Kers J, et al. Early conversion to prednisolone/everolimus as an alternative weaning regimen associates with beneficial renal transplant histology and function: the randomized-controlled MECANO trial. Am J Transplant. 2017; 17:1020–1030
5. Liefeldt L, Brakemeier S, Glander P, et al. Donor-specific HLA antibodies in a cohort comparing everolimus with cyclosporine after kidney transplantation. Am J Transplant. 2012; 12:1192–1198
6. Gatault P, Kamar N, Büchler M, et al. Reduction of extended-release tacrolimus dose in low-immunological-risk kidney transplant recipients increases risk of rejection and appearance of donor-specific antibodies: a randomized study. Am J Transplant. 2017; 17:1370–1379
7. Hricik DE, Formica RN, Nickerson P, et al.; Clinical Trials in Organ Transplantation-09 ConsortiumAdverse outcomes of tacrolimus withdrawal in immune-quiescent kidney transplant recipients. J Am Soc Nephrol. 2015; 26:3114–3122
8. Berger SP, Sommerer C, Witzke O, et al. Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from TRANSFORM study. Am J Transplant. 2019; 19:3018–3034
9. Cucchiari D, Molina-Andujar A, Montagud-Marrahi E, et al. Use of de-novo mTOR inhibitors in hypersensitzed kidney transplant recipients: experience from clinical practice. Transplantation this issue
10. Sommerer C, Suwelack B, Dragun D, et al.; Athena Study GroupAn open-label, randomized trial indicates that everolimus with tacrolimus or cyclosporine is comparable to standard immunosuppression in de novo kidney transplant patients. Kidney Int. 2019; 96:231–244