Transplantation

Kidney Transplantation Prophylaxis of Organ Rejection and Preservation of Renal Function

Josep M Griny,1 Oriol Bestard,2 Josep M Cruzado2 and Joan Torras2
1. Professor and Chief of Nephrology Department; 2. Nephrologist, Nephrology Department, University Hospital Bellvitge, University of Barcelona

Abstract
Immunosuppressive regimens used in renal transplantation during the last two decades have been very successful in reducing acute rejection and the cumulative doses of steroids employed. However, these improvements have not resulted in a clear amelioration of long-term allograft outcomes. Immune and non-immune factors induce permanent graft attrition. Among them, chronic calcineurin inhibitor (CNI) nephrotoxicity may contribute to renal damage. CNI-sparing/avoidance regimens to minimise or avoid nephrotoxicity have been attempted with different drug combinations. Mycophenolic acid-related agents seem to be useful in minimising CNI use, but are not potent enough for complete CNI avoidance. CNI reduction or elimination appears to be feasible with macrolide mammalian target of rapamycin inhibitors. However, the intolerability to these macrolides has limited their success and introduction into the renal transplantation setting. Belatacept, a co-stimulatory blocker with minimal nephrotoxicity, has been used in CNI-free regimens, with acceptable rates of acute rejection and significant amelioration of renal function and structure in the medium term after transplantation.

Keywords
Kidney transplantation, acute rejection, renal function, chronic allograft damage, calcineurin inhibitor nephrotoxicity, mammalian target of rapamycin inhibitors, mycophenolic acid, belatacept
Disclosure: Josep M Griny has served as an advisor for Novartis, Roche, Bristol-Myers Squibb SA and Life Cycle Pharma. The remaining authors have no conflicts of interest to declare. Received: 12 January 2012 Accepted: 1 February 2012 Citation: European Nephrology, 2012;6(1):658 Correspondence: Josep M Griny, Department of Nephrology, University Hospital Bellvitge, University of Barcelona, LHospitalet 08907, Barcelona, Spain. E: jgrinyo@bellvitgehospital.cat

Support: The publication of this article was funded by Bristol-Myers Squibb SA. The views and opinions expressed are those of the authors and not necessarily those of Bristol-Myers Squibb SA.

In the renal transplantation setting, continuous improvements in immunosuppressive regimens have led to low rates of acute rejection, but without a clear increase in graft survival.1 The usual nephrotoxic regimens derived from the almost universal use of calcineurin inhibitors (CNIs) have been considered to contribute to long-term graft losses due to the progression of renal fibrosis and function deterioration,2 although there is a debate on the role of these immunosuppressants in the development of chronic graft damage.3 Hence an ongoing challenge in renal transplantation is how to reconcile the effective prevention of acute rejection with the preservation of renal function, especially in the medium to long term. CNI-based immunosuppressive regimens have probably provided their best results in renal transplantation. New refinements in the last few years have apparently optimised renal function, attenuated CNI-related adverse effects and consolidated widely used regimens, with slight variations between centres. Triple therapies combining CNIs, mycophenolic acid drugs and steroids are the current standard in the vast majority of institutions.4 Despite the knowledge that CNI nephrotoxicity is almost inevitable in the long term, attempts to minimise CNI use are usually cautiously addressed, and these are more popular than CNI withdrawal or CNI avoidance.

Mycophenolate-based Regimens
The balance between the prevention of immunological allograft losses and the management of CNI-related toxicities is still hard to find. CNI reduction or elimination may increase the risk of acute and chronic rejection.5 Because of these concerns, in most instances, CNIs have been used at conventional doses in induction and maintenance therapy. The introduction of mycophenolate mofetil (MMF) has further enhanced CNI dose reduction and may thus improve renal function in stable patients.6 In patients with progressive deterioration of renal function, CNI minimisation in conjunction with MMF use has been considered a useful strategy to stabilise renal function without increasing the risk of rejection.7 To attenuate the nephrotoxic effects of CNIs, many low-dose regimens have been attempted. One of the most successful has been studied in the so-called Symphony trial,8 which showed that low-dose tacrolimus in combination with MMF and steroids with daclizumab induction resulted in a rejection rate of less than 15 % and improved renal function at one year after transplantation. However, in a long-term follow-up, the renal benefit of low-dose tacrolimus was more modest in comparison with conventional and reduced doses of cyclosporine.9

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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 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 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 variable success.13 The levels of proteinuria and allograft function have been identified as good predictors of a successful conversion.14 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 A study mainly in transplant recipients from living donors demonstrated that a CNI-free immunosuppressive regimen may be feasible.16 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 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 This strategy may deserve further investigation. A recent large trial assessed the efficacy and safety of two regimens of everolimus plus reduced-exposure CsA compared with 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
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 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. 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 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 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; p0.001 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 47 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.2831 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

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Kidney Transplantation Prophylaxis of Organ Rejection and Preservation of Renal Function

biopsies were 18%, 24% and 32% in the MI belatacept, LI belatacept and CsA groups, respectively, in the BENEFIT study,26 and 45 %, 46% and 52% in the corresponding groups in the BENEFIT-EXT study.27 The differences observed between the two studies probably reflect the presence of pre-existing lesions in kidneys from extended criteria donors in the BENEFIT-EXT study. In the BENEFIT study, the renal function in belatacept-treated patients, as evaluated by estimated GFR, showed a positive slope to the end of Year 3, in contrast with a negative slope in patients receiving CsA. In the BENEFIT-EXT study, all three therapeutic arms displayed negative slopes to the end of Year 3, but these were attenuated in belatacept-treated patients compared with those receiving CsA. This better preservation of renal function and parenchyma with belatacept might have a positive impact on long-term graft survival, which should be assessed in extended follow-up. Another likely benefit of avoiding CNI immunosuppressants through maintenance immunosuppression with belatacept is the potential amelioration of the CV and metabolic risk profiles of patients. CV disease is the most common cause of death among kidney transplant recipients provided the graft is functioning and thus is an important issue that requires attention. 32,33 Immunosuppressive drugs, in particular CNIs, tend to exacerbate this condition.34,35 Secondary endpoints of the phase III BENEFIT and BENEFIT-EXT trials evaluated changes in blood pressure, changes in serum lipids and the incidence of new-onset diabetes after transplant (NODAT) at Month 12 following treatment. 36 Mean systolic and diastolic blood pressures were significantly lower in both belatacept groups compared with the CsA group (p0.002) in both studies. Similarly, non-high-density lipoprotein cholesterol was lower in patients receiving belatacept than CsA in both studies (p<0.01). Serum triglycerides were significantly reduced (p<0.02) and NODAT less common (p<0.05) in the belatacept groups relative to CsA. While the CV and metabolic risk profiles of belatacept will continue to be assessed in the future, these findings suggest a substantial improvement in CV and metabolic risks with belatacept versus other available drugs.36 The safety profile of belatacept-based immunosuppression was addressed in a pooled safety analysis37 including patients from the two pivotal trials described above26,27 and patients recruited in the phase II trial.25 This analysis included 1,425 patients (MI belatacept 477, LI belatacept 472 and cyclosporine 476) with a median follow-up of approximately 2.4 years. The conclusions were that belatacept was generally well tolerated and that the frequency of deaths (MI belatacept 7 %, LI belatacept 5 % and CsA 7 %) and serious infections (MI belatacept 37 %, LI belatacept 32 % and CsA 36 %) were lower in the LI belatacept group versus CsA. The frequency of malignancies was 10%, 6% and 7% in the MI belatacept, LI belatacept and CsA groups, respectively, but more post-transplant lymphoproliferative disorder (PTLD) was observed in the belatacept groups. A total of 16 cases of PTLD occurred (n=8 for MI belatacept, n=6 for LI belatacept and n=2 for CsA), including nine cases involving the central nervous system (CNS) (n=6 for MI belatacept and n=3 for LI belatacept). The risk of PTLD was highest in EpsteinBarr virus (EBV)-negative recipients and more CNS PTLD cases were reported in the MI belatacept group; one case of progressive multifocal leukoencephalopathy was also reported in this group. These safety data indicate that EBV serostatus should be routinely checked in

listed patients and that belatacept should be avoided in patients who are EBV-seronegative and those with unknown EBV serology. According to the reported data, the best benefit:risk ratio was observed with the LI regimen, considering its similar efficacy but superior safety profile relative to the MI regimen. This LI belatacept regimen has recently been approved for renal transplantation by the regulatory agencies in Europe and the US.38 The stability of renal function and the absence of late acute rejection in patients under maintenance immunosuppression with belatacept suggest that it may be sensible to switch established patients from a CNI to belatacept. The feasibility of this strategy was explored in a phase II trial.39,40 Conversion from CNI to belatacept resulted in improved renal function. At Year 2 following conversion, mean GFR was 62.0 ml/min with belatacept and 55.4 ml/min with a CNI; the mean change in GFR from baseline was +8.8 ml/min versus +0.3 ml/min, respectively. The results of this study may open the door to a non-nephrotoxic immunosuppression option for established renal transplant patients. The so-called low-toxicity regimens usually address CNI or steroid sparing and it is difficult to reconcile both in a single immunosuppressive protocol. In this regard, the combination of T-cell depletion with polyclonal anti-thymocyte globulin (ATG) under co-stimulatory blockade with belatacept was used to explore the feasibility of CNI- and steroid-free therapies in a single regimen.41 A randomised controlled open-label exploratory study assessed two belatacept-based regimens compared with a tacrolimus-based, steroid-avoiding regimen.41 A total of 89 EBV-seropositive recipients of living and deceased donor renal allografts were randomised to receive belataceptMMF, belataceptSRL or tacrolimusMMF. Both macrolide immunosuppressants were dosed to reach conventional levels. All patients received induction with four doses of thymoglobulin (6 mg/kg maximum cumulative dose) and an associated short course of corticosteroids the first week after surgery. Acute rejection occurred in four, one and one patients in the belataceptMMF, belataceptSRL and tacrolimusMMF groups, respectively, and most acute rejection occurred within the first three months. Interestingly, more than two-thirds of patients in the belatacept groups remained on CNI- and steroid-free regimens at 12 months and the GFR was 810 ml/min higher with either belatacept regimen than with tacrolimusMMF. Overall safety was comparable between all groups and no cases of PTLD were observed. This exploratory trial suggests that primary immunosuppression with belatacept may enable the simultaneous avoidance of both CNIs and corticosteroids without an increased rate of acute rejection. On the contrary, and despite the small number of patients, it is interesting to note the very low incidence of acute rejection in the belataceptSRL arm. This might suggest potential immunosuppressive mechanisms of the drug combination enhancing graft acceptance.

Summary
With the introduction of new agents, regimens able to prevent acute rejection and at the same time better preserve renal function seem feasible. Additional fine-tuning in order to optimise new drug combinations will be an interesting challenge to be addressed in the next few years. n
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Chapman JR, Chronic calcineurin inhibitor use is nephrotoxic, Clin Pharmacol Ther, 2011;90:2079. Matas AJ, Calcineurin inhibitors: short-term friend, long-term foe?, Clin Pharmacol Ther, 2011;90:20911.

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