Calcineurin inhibitor (CNI)-based immunosuppression after kidney transplantation remains the standard of care after kidney transplantation; however, CNIs result in endothelial activation which can result in vasoconstriction, and in some cases, ischemic tissue damage.1-4 It has been hypothesized that this process contributes to chronic vascular and tubular-interstitial damage in kidney transplant recipients treated long term with CNIs.5 In addition, although 1-year graft survivals have improved significantly with CNI-based immunosuppression, long-term graft survival and allograft half-life have improved very little.
More recently, belatacept-based immunosuppression has offered an alternative that may result in better glomerular filtration rate (GFR) and perhaps better long-term graft survival.6 Belatacept is the first clinically available costimulatory pathway blocking agent for preventing T-cell activation to replace CNI-based immunosuppression for kidney transplantation. The phase 3 BENEFIT trial of de novo belatacept-based immunosuppression after kidney transplant showed an early and sustained 15 mL/min per 1.73 m2 better GFR compared with the CNI-treated control group.7-9 More recently, Vincenti et al10 reported on the 7-year outcomes in this cohort and showed better graft survival and renal function in the belatacept- treated group.
Low GFR after kidney transplantation is associated with inferior graft survival.11,12 Different strategies to address this problem have included running lower CNI levels; however, this strategy may increase the risk for immune activation resulting in rejection or the development of de novo donor-specific antibody (DSA). Conversion to mammalian target of rapamycin inhibitor therapy is another strategy, which has been used to manage kidney transplant patients with low GFR; however, this strategy is associated with poor patient tolerance resulting in 25% or more abandoning of the therapy because of adverse effects.13,14 In addition, this strategy has not uniformly resulted in an improvement in GFR.
Because belatacept is not associated with endothelial injury or chronic ischemic damage, it is reasonable to hypothesize that converting kidney transplant patients with low GFR after kidney transplantation on CNI-based therapy will increase GFR.
Although there are reports on conversion to belatacept in patients with a suboptimal GFR, none to our knowledge have used a control group either prospectively or as in this study a direct matched cohort.15-17
At our center, we adapted a clinical protocol to switch to belatacept-based immunosuppression in kidney transplant recipients on tacrolimus-based immunosuppression with stable but low estimated GFR (eGFR) during the first few months after kidney transplant.
The aim of this study was to analyze the change in eGFR after conversion from tacrolimus- to belatacept-based immunosuppression in kidney transplant recipients with stable low eGFR compared with a matched control group. We hypothesize that we would see a significant increase in eGFR after conversion to belatacept when compared with the control group.
MATERIALS AND METHODS
This is a retrospective observation study of patient converted from CNI therapy to belatacept for low GFR early after kidney transplantation. We included all patients converted from tacrolimus to belatacept between 2012 and 2016. This study was approved by the Mayo Clinic Institutional Review Board.
During this study period, we had a clinical protocol to convert patients to belatacept if they had a stable but low GFR, and they were at least 1-month posttransplant. Eligible patients had low eGFR with no improvement in the absence of prerenal or postrenal causes or severe CNI toxicity. The majority of patients had eGFR < 40 mL/min per 1.73 m2. Recipients of either deceased or living donor kidney were eligible. Most eligible patients had a biopsy with no evidence of rejection or glomerulonephritis. Patients were excluded if they had a current DSA with a mean fluorescent intensity greater than 1000. All converted patients had positive serology for Epstein-Barr virus.
Our clinical protocol calls for a surveillance biopsy at 4, 12, and 24 months posttransplant. Our protocol also calls for a biopsy if delayed graft function (DGF) lasts more than 14 days.
All patients received induction immunosuppression. Before 2011, patients received induction with rabbit antithymocyte globulin. After 2011, induction was with alemtuzumab. Patients older than 65 years received basiliximab, which did not change during the study period. Patients receiving induction with the depleting agents had complete withdrawal of corticosteroids by posttransplant day 5, whereas those receiving basiliximab induction continued maintenance corticosteroids. Maintenance immunosuppression was typically with tacrolimus and mycophenolate mofetil. Tacrolimus was started on posttransplant day 1 or 2, irrespective of DGF. Goals for trough tacrolimus levels were 8 to 10 ng/mL for the first month and then, 6 to 8 ng/mL.
Belatacept Conversion Protocol
The protocol for belatacept conversion started with a belatacept infusion of 5 mg/kg weekly for 4 weeks, then 5 mg/kg every 2 weeks for 4 weeks, and then 5 mg/kg monthly. The tacrolimus was reduced to 50% of the original dose after 2 weeks, to 25% original dose after 3 weeks and stopped after 4 weeks. After initiation of belatacept, all patients were maintained on mycophenolate mofetil and prednisone at a minimal dose of 5 mg/day.
Four patients who received belatacept were excluded: 1 patient had early allograft failure secondary atypical hemolytic uremic syndrome, 1 patient refused additional doses after first dose, 1 patient had 50% cortical necrosis on biopsy, and 1 patient was enrolled in a prospective, multicenter institutional review board–approved protocol for belatacept conversion.
All continuous data are given as mean (SD) unless otherwise stated.
We used direct matching to select 1 control case for each patient converted to belatacept from a pool of 2359 possible control patients. Factors that were matched on include recipient age, sex, race, donor source (living versus deceased), retransplant, on dialysis pretransplant, DGF, time 0 biopsy luminal stenosis Banff score (cv) greater than 0, Kidney Donor Profile Index (KDPI) greater than 85%, rejection before conversion, DSA before transplant, transplant date, and eGFR at conversion. For example, patients converted at 4 months would be matched to controls based on those controls with 4 months eGFR.
To perform the matching, a genetic algorithm approach was used (through the “matching” package in R). This algorithm is neither completely exhaustive (every match tested) or greedy, but rather uses a stochastic process to iteratively generate sets of matches and then selects the best at each iteration. The criterion for a good match was a minimal average treatment effect (as a test statistic) across all variables. Additionally, calipers were set to restrict the maximal differences that are acceptable for matches. This assures that any mismatching is spread over the variables rather than loaded on a single variable. Calipers were set by matching patients several times and adjusting them until an acceptable spread is achieved.
The primary outcome was the change in eGFR from the point of conversion to belatacept to 4 months postconversion (delta eGFR). eGFR was calculated using the chronic kidney disease epidemiology collaboration formula.18 Secondary outcomes include graft survival, rejection postconversion, and the slope of the inverse serum creatinine for 12 months after conversion. The primary outcome was tested with a paired t test, whereas the secondary outcomes and match performance were tested using appropriate paired analyses (t tests for continuous variables, McNemar test for discrete variables, and log-rank tests with a random effect for pairing for survival data).
To model the change in eGFR over time, we used a piecewise mixed effects model.
This model accounts for the intervention with a change in slope postconversion (given by c).19 If belatacept conversion had a positive impact, we would expect the slope to increase significantly postconversion relative to the control group. We use a generalized estimating equation with an autocorrelative variance structure (AR1) to compare the differences between converted and control patients within matches across this piecewise model (c versus c' in the equation below). To this end, the model produces the effect of conversion as the mean difference in the postconversion change in slope. The overall model may then be written as
All analyses were carried out using the R software package (R foundation for statistical computing, Vienna, Austria). The generalized estimating equation was fit using the “geepack” library.
There were 30 patients in the conversion group and 30 in the matched control group (Table 1). The median time to belatacept conversion was 107 days (interquartile range [IQR], 46-129). The baseline recipient, donor, and transplant characteristics were well matched (Table 1). The mean age for the conversion group was 54.1 (12.7) years, and 40.0% of conversion group were women. 10.0% were retransplanted, and 73.3% were on dialysis before transplantation. 83.3% received a deceased donor, and the mean KDPI for the deceased donor kidneys was 72.7%. All patients received induction therapy. More patients in the belatacept group were on steroid avoidance immunosuppression before conversion (70% vs 40%; P =0.019); however, at the time of conversion to belatacept, all patients were started on low-dose prednisone.
The biopsy rate before belatacept conversion was similar in the groups. Before conversion, 22 (73%) in the belatacept group and 23 (77%) of the control group had a biopsy (P = 0.766) (Table 2). There were no significant differences in the Banff scores between the groups; however, there is a trend toward more chronic changes in the belatacept group and more inflammatory changes in the control group.
Graft survival using the Kaplan-Meier method was similar in the 2 groups (Figure 1). The estimated graft survival, including death with functioning graft, at 2 years posttransplant was 88.7% in the belatacept group and 93.2% in the control group (log rank, P = 0.961).
The median preconversion eGFR for the entire cohort was 23.0 mL/min per 1.73 m2 with an IQR of 15.7 to 31.4. The mean baseline eGFR at the time of conversion was not different between the conversion and control group (Table 3). At the time of conversion, the trough tacrolimus level was lower in the belatacept group (6.28 [2.14] vs 7.71 [2.43]; P = 0.019). The delta eGFR at 4 months postconversion was 11.0 (12.9) mL/min per 1.73 m2 in belatacept conversion group and 4.8 (10.5) mL/min per 1.73 m2 in the control group (P = 0.045). The trough tacrolimus level in the control group was 7.71 (2.43) at time of conversion and 6.10 (2.47) at 4 months postconversion (P = 0.015). We also analyzed the eGFR at 12 months after conversion. The delta eGFR from conversion to 12 months postconversion was 13.7 (12.4) mL/min per 1.73 m2 in the Belatacept conversion group and 7.2 (11.7) mL/min per 1.73 m2 in the control group (P = 0.075) (Table 3).
We also analyzed the difference in the slope of the inverse of the serum creatinine for all creatinine values obtained during the year after belatacept conversion (Figure 2). After adjusting for the slope of inverse creatinine for the 4-month preconversion period, there was no significant difference in the slope of inverse creatinine during the 12-month period after conversion between the 2 groups.
Acute rejection postconversion occurred in 5 (16.7%) patients in the conversion group and none of the control group (P = 0.052). Time to rejection postconversion was a median 86 days with the range of 63 to 114 days. The Banff classification20 of the rejections was 2 borderline, 2 IIa, and 1 IB. De novo DSA developed postconversion in 4 in the belatacept group and 2 in the control group (P = 0.67).
The BENEFIT trial demonstrated that in kidney transplant recipients treated with de novo belatacept-based immunosuppression, there was a 10- to 15-mL/min per 1.73 m2 better eGFR as compared with the control group on cyclosporine.9,21 This difference in eGFR was seen as early as 1-month posttransplant after kidney transplant and was sustained throughout the first year and beyond. However, there are less data available on the impact of conversion from CNI-based therapy to belatacept on GFR.
In the current study, we report on the effect of converting patients with stable low GFR after kidney transplantation to belatacept compared with a carefully matched control group. In this analysis, we saw an 11.0 (SD, 12.9) mL/min per 1.73 m2 increase in the eGFR in the belatacept group as compared with 4.8 (SD 10.5) mL/min per 1.73 m2 increase in the control group, which was significant (P = 0.045). The observation of a small increase in GFR in the control group is noteworthy, because without the control group, one might conclude that the change in eGFR was entirely related to the conversion to belatacept. The slight improvement in eGFR in the control group is probably multifactorial; however, it is possible that the lower trough tacrolimus level at 4 months postconversion may have contributed (Table 3). We also analyzed the slope of the inverse creatinine during the year after conversion. After controlling for the slope of inverse creatinine during a preconversion period, we did not see a significant difference in the slope during the first year after conversion between the 2 groups. So although we did demonstrate a significant better eGFR at the solitary timepoint at 4 months postconversion, after controlling for the slope during the 4-month preconversion period, the slope of the inverse creatinine for 12 months postconversion was not significantly higher in the belatacept conversion group. This discordant finding suggests caution in interpreting the delta-eGFR improvement seen at 4 months postconversion alone. Thus, the absolute delta eGFR may overestimate the direct impact of the belatacept intervention.
We used direct matching to select the control group. In this process, we systematically controlled for multiple covariates that could influence the decision to convert to belatacept or might have had an impact on the outcome. This assiduous matching process should reduce the selection bias because of the confounding variables and result in a better estimate of the treatment effects.
Similar to the BENEFIT trial and other reports, we also saw more acute cellular rejection after conversion to belatacept.9,21-25 Some of these early rejections were severe with higher Banff grade rejection. In our cohort converted to belatacept 16.7% (P = 0.052) had acute rejection after conversion. All of our patients were on tacrolimus-based immunosuppression before belatacept conversion. In addition, all patients received induction therapy, and the majority received induction with a lymphocyte depleting agent (Table 1). Recent studies have suggested that there is a unique population of CD57-positive CD4 T cells that are resistant to the costimulatory pathway blockade by belatacept which might help explain the higher risk of rejection that occurs with belatacept-based therapy.26
Rostaing et al27 reported the results of multicenter randomized controlled trail of converting from CNI-based immunosuppression to belatacept in stable kidney transplant recipients. The study showed that 12 months after conversion there was a 7.0-mL/min per 1.73 m2 increase in eGFR in the conversion group and 2.1 mL/min per 1.73 m2 increase in the control group (P = 0.0058). This study enrolled patients between 6 and 36 months posttransplant regardless of GFR and the mean baseline eGFR in the conversion group was 53.5 (SD, 11.01) mL/min per 1.73 m2. In our study, we enrolled patients with low stable eGFR for belatacept conversion. In our study cohort, the mean eGFR at conversion was 22.6 (SD, 12.5) mL/min per 1.73 m2. We hypothesized that converting to belatacept would improve the GFR and improve the long-term outcomes. The magnitude of the delta eGFR after conversion to belatacept in the study by Rostaing et al was similar to result in our study. This study cohort also had acute rejection in 6 (7.1%) of 84 patients after belatacept conversion. In the 2-year extension of this study, the improvement in eGFR was well maintained at 2 years follow-up (7.8 mL/min), and there were no additional rejections during the second year.28
One might not expect much change in the GFR after conversion to belatacept with modest tacrolimus levels, thus the benefits are limited. Rostaing et al27 showed little difference in those with a GFR less than 45, so our results are in keeping with this subanalysis. Much like the studies of conversion to mammalian target of rapamycin inhibitors, impaired function seems to attenuate the hemodynamic improvement.29-31 The BENEFIT trial used cyclosporine for the control group. The impact of tacrolimus and cyclosporine on GFR are not the same.9 GFR is consistently about 10% better with tacrolimus.32,33 Our data do not allow us to determine the mechanisms; however, our study strongly indicated very modest improvement at 1 year. Whether any metabolic improvements after conversion to Belatacept might outweigh poor GFR and show any signal will need a longer period of study.34,35
Most of our patients were converted to belatacept during the first 4 months after kidney transplantation. The median time to belatacept conversion was 107 days (IQR, 46-129). This early period is where there is the best chance for this strategy to be effective before the progression to more chronic and fixed chronic vascular and tubular-interstitial changes has occurred. Our data do not address the impact on belatacept conversion at later period after kidney transplantation.
There are several weaknesses to this study. Although we carefully matched the control group for multiple variables, it is possible that there were unmeasured bias in the selection of patients to convert to belatacept which might influence the outcome. We also had a relatively small study cohort, thus making the study vulnerable to a type II (false negative) statistical error. Preconversion biopsies were not available in all patients. This is a single-center study, and therefore, the findings may not be generalizable.
We conclude that conversion from tacrolimus-based immunosuppression to belatacept-based immunosuppression during the first several months after kidney transplantation in recipients with low stable eGFR may only result in a modest increase in GFR, but is associated with a trend toward more acute cellular rejection. More studies on the risks and benefits of converting kidney transplant patients on CNI-based immunosuppression with low GFR to belatacept are needed.
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