In this randomized study, where stable renal transplant patients were converted from a CNI-based maintenance immunosuppressive regimen to belatacept, no difference in calculated 7-year risk of MACE or all-cause mortality could be demonstrated after 1 year of follow-up. We were unable to find a significant effect on any of the three modifiable cardiovascular risk factors which were used as input-variables in the risk calculator (serum LDL-cholesterol, diabetes-prevalence, and serum creatinine). The belatacept arm had significantly lower diastolic blood pressure, measured both centrally (SphygmoCor® method) and peripherally. We found a similar improvement for systolic pressure (Table 4, 5), but this difference was not statistically significant.
Of the three modifiable risk factors in the calculator, the expectations regarding effect on lipid profile were limited. While CsA has been implicated in dyslipidemia28, TAC seems to be less detrimental to lipid status. In our study, 94% of the participants were on TAC before randomization. Ferguson et al. 29 compared three steroid-avoiding regimens of immunosuppression: belatacept with MMF vs belatacept with sirolimus vs TAC with MMF. Both belatacept-arms had lower LDL (23.9 mg/ml and 25.0 mg/ml vs 34.0 mg/ml for TAC with MMF) after one year, but the difference was non-significant, possibly related to the limited sample-size of the study. Another observational study focusing on the metabolic effects of conversion from TAC to belatacept found improvement in GFR and acid-base status, but not in blood lipids 30. Our findings are in line with these reports, as we found no effect on LDL-cholesterol (Table 3).
However, we are surprised by the lack of effect on GFR, which is in contrast to the BENEFIT studies, as well as other conversion studies reported in the literature 24,31−33. In those studies, there was a consistent improvement in graft function by converting to belatacept. One possible explanation for this was the predominant use of TAC by our study participants with relatively low trough levels (Table 1) at baseline. In the Symphony trial 34, the low-dose TAC group had an average trough-level of 6.7 ng/ml 1 year after transplantation and achieved an eGFR on average 5.7 ml/min/1.73m2 higher than the other 3 comparator groups. A belatacept conversion study by Grinyo et al. 35 examined 173 patients with a mean time after transplantation to randomization of 19 months, baseline eGFR of 54 ml/min/1.73m2, and a low immunologic risk profile, making the population reasonably comparable to ours. Belatacept patients in that study showed an average improvement in eGFR of 4.9 ml/m/1.73m2 compared to CNI-patients. At baseline, patients using TAC (56%) had an average trough level of 7.2 ng/mL, while patients on CsA (44%) had an average trough level of 160.2 ng/mL. In our study, the mean trough levels of TAC (5.7 ng/ml) and CsA (91 ng/ml, 4 patients only) at the time of randomization were lower compared to both these studies 34,35. The lower CNI trough levels may have already significantly decreased the nephrotoxic side-effects and explain why our belatacept patients only experienced a non-significant gain in eGFR of 0.7 ml/m/1.73m2.
The third element of the calculator is the diabetes status. Multiple studies have corroborated the diabetogenicity of TAC in transplantation 36–38. Furthermore, reversibility of beta cell dysfunction and of PTDM after TAC-withdrawal has been established in both animal studies and in clinical experience 39–42. Thus, we expected to improve glycemic metabolism in converting from TAC to belatacept. However, no subject in our study reversed diabetes mellitus or developed PTDM in either study arm (Table 3). Also, triglycerides, serum ApoB, and serum ApoA1 did not improve (Table 4), which is of interest, since all three of these parameters are mentioned as risk factor for developing PTDM. 43,44
Beside trough levels, we also need to consider another bias. All patients were already treated with CNI for a median of 26 months since transplantation. Serious negative side effects of CNI-treatment could be less likely found in the control group, as patients suffering from these side effects could have been converted to alternative immunosuppression earlier on and thus not be eligible for this study.
The only positive effect that we found for belatacept was a significant improvement in diastolic blood pressure, measured both centrally (SphygmoCor® method) and peripherally. For systolic pressure, a similar improvement was found (Table 4), but it was not statistically significant (p = 0.09), most likely due to the relatively small sample size of this study. Although not included in the calculator, blood pressure is of course an established risk factor for cardiovascular disease. Moreover, high blood pressure is strongly associated with risk of graft failure and finding an improvement in this parameter could still indicate an advantage for belatacept-treatment 45.
Regarding safety, AEs occurred in both groups, but SAEs were reported almost twice as often in belatacept-treated patients (29.6% vs 15.7%), and the latter were more likely (5.6% vs 2.0%) to discontinue their study treatment than patients treated with CNI. Rejection was seen more often in the belatacept-patients. Four episodes of biopsy-proven acute rejections occurred in the belatacept-group vs one single episode in the CNI-group (7.4% vs 2.0%). Three patients showed signs of vascular inflammation in the biopsy, corresponding to Banff grade II, two of which were in the belatacept-group. All three patients were treated according to local protocol with high-dose steroids (4) and T-cell depleting antibodies (1), despite which one belatacept-patient suffered graft loss and re-initiated dialysis treatment. The other two recovered with treatment.
The rate of rejection in this study is in line with earlier reports. For example, in the trial by Grinyo et al. 35, 7.1% of belatacept-patients experienced rejection versus none in the CNI-group. In another trial by Adams et al. 46, 1-year rejection rates were around 50% when belatacept was used right after transplantation, declining to 33% when TAC was tapered off 3-5 months after transplantation. When TAC was tapered after 11 months, the rejection rates between TAC- and belatacept-treated patients were similar, around 16%. Other reports have described varying (0-11%) rates of rejection, but these are data from non-randomized ‘rescue’-settings after even longer time post-transplantation and are therefore not comparable with our results 47,48.
Beside rejection, urinary tract infections (UTIs), nasopharyngitis and other respiratory tract infections (RTIs) were more often seen in the belatacept arm (Table 7). The present study’s planned visits could have led to a bias in the reporting of uncomplicated infections, since a study visit was planned every month for belatacept-patients, instead of every 3 months for the CNI-continuation group.
Not a single case of pneumocystis-jirovecii pneumonia, cytomegalovirus- (CMV), polyoma- or EBV-associated disease was seen in the belatacept-patients. Three cases of CMV-infection were seen in CNI-patients. Previous reports have been inconclusive on opportunistic infections (OPIs) in belatacept-treatment. The follow-up study to the first belatacept-conversion trial noted a slightly higher incidence of viral infection (11% vs 14%) 35. In a recent study by Bertrand e.a. 50 OPI’s were noted in 453 patients treated with belatacept (9.8%) 49. In a multivariate analysis of that study, the authors concluded that patients with low GFR (<25 ml/min) and patients converted early after transplantation (within six months) were more likely to develop OPIs.
There was one case of lung cancer in the belatacept group in the present study. Previous studies have not indicated a higher risk of malignancy in belatacept beyond post-transplant-lymphoproliferative disorder 24,35.
A major strength of the current study is the international multicenter-approach, making it representative for European transplantation practice. However, this study also has important limitations which must be taken into account. The study duration of 1 year was most likely too short to reveal a significant difference in renal function between the two study groups. We have overestimated the potential reduction in MACE and mortality for patients that use low-dose TAC instead of CsA. Another limitation was the heterogeneous time from transplantation to trial enrollment, and the small number of patients on CsA and the relatively large span of eGFR also contributed to the heterogeneity. Patients with severely diminished graft function were less likely to benefit from conversion.
In conclusion, we have shown no effect on calculated cardiovascular risk or renal function in this study comparing late conversion to belatacept with continuation of CNI-based immunosuppression. We did show a significant difference in diastolic blood pressure. We re-confirmed the increased chance of rejection when converting to belatacept. After more than 10 years of clinical experience, the place of belatacept in kidney transplantation is still not fully established, but it may be an attractive option when patients suffer from significant side effects of CNI, like nephrotoxicity or PTDM. However, it is hard to define a significant benefit of belatacept for patients that are doing well on low-dose TAC-based therapy without severe CNI-related side-effects. Further studies are needed to define the place of belatacept in kidney transplantation.