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
particular CNIs, tend to exacerbate this condition.34,35
Immunosuppressive drugs, in 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
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.
Mean systolic and diastolic blood pressures were significantly lower in both belatacept groups compared with the CsA group (p≤0.002) 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 pivotal trials described above26,27 trial.25
and patients recruited in the phase II 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 Epstein–Barr 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
1. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B, Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era, Am J Transplant, 2004;4:378–83.
including patients from the two
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 belatacept–MMF, belatacept–SRL or tacrolimus–MMF. 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 belatacept–MMF, belatacept–SRL and tacrolimus–MMF 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 8–10 ml/min higher with either belatacept regimen than with tacrolimus–MMF. 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 belatacept–SRL 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
2. Chapman JR, Chronic calcineurin inhibitor use is nephrotoxic, Clin Pharmacol Ther, 2011;90:207–9.
3. Matas AJ, Calcineurin inhibitors: short-term friend, long-term foe?, Clin Pharmacol Ther, 2011;90:209–11.
4. Lebranchu Y, Can we eliminate both calcineurin inhibitors and steroids?, Transplant Proc, 2010;42:S25-8.
5. Mulay AV, Hussain N, Fergusson D, Knoll GA, Calcineurin inhibitor withdrawal from sirolimus-based therapy in kidney
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