Transplantation
Mammalian Target of Rapamycin Inhibitor-based Regimens
On the other hand, CNI withdrawal or avoidance has been tested with mammalian target of rapamycin (mTOR) inhibitors, which are generally considered more potent immunosuppressants than MMF. A meta-analysis of CNI withdrawal in CNI-treated recipients showed a modest increase in the risk of rejection (less than 10 %) and a modest but significant improvement in renal function without additional risk of graft loss.5
Despite these data, CNI
withdrawal is not routinely practised in Europe. Interestingly, the European Medicines Agency authorised only a transient use of SRL plus CsA, because this drug combination was considered overtly nephrotoxic.12
Switching from CNIs to mTOR inhibitors has met with
The levels of proteinuria and allograft function have been identified as good predictors of a successful conversion.14
variable success.13 Thus
the selection of appropriate candidates is crucial for obtaining the benefits of CNI withdrawal with mTOR inhibitors.
CNI avoidance in patients receiving mTOR inhibitors has generally been used together with MMF and induction therapy. In this regard, numerous single-centre experiences with anti-interleukin-2R (IL2R) monoclonal antibodies or polyclonals have shown better preservation of renal function.15
In contrast, a previous controlled multicentre study was terminated because of a higher than expected rejection rate, and SRL-treated patients had more wound healing problems and no improved outcomes.17
A study mainly in transplant recipients from living donors demonstrated that a CNI-free immunosuppressive regimen may be feasible.16
A French multicentre trial evaluating the use of
SRL plus MMF even attempted CNI avoidance and steroid withdrawal, which was successfully achieved in more than 80 % of patients, but with higher proteinuria and a higher percentage of discontinuations in patients treated with SRL plus MMF.18
In favour of this drug
combination was the observed low incidence of cytomegalovirus infection. More recent trials looking at early discontinuation of CNIs after transplantation and induction with polyclonals or anti-IL2R monoclonal antibodies show effective prevention of acute rejection and improved renal function, but also a high rate of discontinuations (approximately 30 %) in patients receiving mTOR inhibitors.19,20
This is
considered one of the main limitations of this type of regimen, which may account for its low penetration in the clinical community.
The delayed use of mTOR inhibitors after transplantation aims to avoid wound healing problems and enhance the recovery of renal function in patients with delayed graft function. The Spare-the-Nephron trial21 explored the utility of the temporary use of a CNI in association with MMF and delayed conversion from CNI to SRL, in comparison with the permanent use of a CNI plus MMF. Data from this study initially appeared promising, with ameliorated renal function in patients receiving SRL versus CNI at one year after transplantation, but this difference was indistinguishable after two years. Low doses of tacrolimus and SRL for the first three months after transplantation may efficiently prevent the development of acute rejection and allow the subsequent elimination of the anti-calcineurin macrolide, which is followed by improvement in allograft function.22 deserve further investigation.
This strategy may
A recent large trial assessed the efficacy and safety of two regimens of everolimus plus reduced-exposure CsA compared with
66
In a multicentre phase II trial, therapy with CsA was compared with two regimens of belatacept in renal transplant recipients following induction therapy with basiliximab, MMF and corticosteroids.25
All the
treatment arms showed similar low incidences of acute rejection at six months (7 %, 6 % and 8 % for intensive belatacept, less intensive [LI] belatacept and CsA, respectively). Both belatacept regimens exhibited a lower incidence of chronic allograft nephropathy and a slightly more favourable cardiovascular (CV) risk profile relative to CsA.
Belatacept was used in more intensive (MI) and LI regimens and CsA was used as the control arm. These two studies were conducted in adult kidney transplant recipients of organs from conventional living or deceased donors (Belatacept evaluation of nephroprotection and efficacy as first-line immunosuppression trial [BENEFIT])26
The encouraging results of the above phase II trial, which showed an amelioration of renal function and reduction of chronic allograft damage with belatacept, were the basis for two pivotal Phase III trials.26,27
mycophenolic acid plus standard CsA over the course of 24 months in more than 800 de novo renal transplant recipients.23
This study
showed that the use of everolimus with progressive reduction in CsA exposure – up to 60 % reduction at one year – resulted in similar efficacy and renal function compared with standard CsA exposure plus mycophenolate sodium.
Belatacept-based Regimens
Moreover, histological studies revealed that the elimination of cyclosporine A (CsA) in sirolimus (SRL)-treated recipients does not increase the risk of chronic rejection.10,11
Beside small molecule immunosuppressants, new biological agents may also be used for the prevention of acute rejection in CNI-sparing regimens in order to preserve renal function. T-cell co-stimulation blockade with a second-generation cytotoxic T-lymphocyte antigen-4 (CTLA-4) immunoglobulin fusion protein, belatacept, which has a high avidity for CD86 and CD80 molecules on antigen-presenting cells, may help in the development of such regimens.24
or from extended criteria donors (Belatacept evaluation of nephroprotection and efficacy as first-line immunosuppression trial – extended criteria donors [BENEFIT-EXT]).27
At Month 12 of the BENEFIT study, both belatacept regimens had similar patient/graft survival compared to CsA (MI belatacept 95 %, LI belatacept 97 % and CsA 93 %) and were associated with superior glomerular filtration rates (GFR) than CsA (65, 63 and 50 ml/min for MI belatacept, LI belatacept and CsA, respectively; p≤0.001 both belatacept regimens versus CsA). Belatacept patients experienced a higher incidence (MI belatacept 22 % and LI belatacept 17 % versus CsA 7 %) and grade of acute rejection episodes, but with a modest impact on renal function.
In the BENEFIT-EXT study, patient/graft survival with belatacept was similar to CsA (MI belatacept 86 %, LI belatacept 89 % and CsA 85 %) at 12 months. As in the previous study, belatacept-treated patients had superior renal function and the incidence of acute rejection was similar between the three groups. The mean measured GFR was 4–7 ml/min higher with both belatacept regimens versus CsA (p=0.008 MI belatacept versus CsA; p=0.1039 LI belatacept versus CsA).
The one-year efficacy results of BENEFIT and BENEFIT-EXT have been supported for up to three years of treatment.28–31
Acute rejection
episodes beyond one year after transplantation were scarce and not associated with the development of anti-human leukocyte antigen antibodies. The prevalence of chronic allograft nephropathy in protocol
EUROPEAN NEPHROLOGY
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