Belatacept Versus Tacrolimus for Kidney Transplant Recipients of Deceased Donors With Acute Kidney Injury: Glass Half-Full?

Yamauchi et al reported the outcomes of a retrospective cohort study using the US Organ Procurement and Transplantation Network database of deceased donor kidneys with acute kidney injury (AKI) for transplant recipients who received de novo belatacept compared with a calcineurin inhibitor (CNI)-based regimen. Patients who received belatacept (N = 567) were closely matched with those on CNI (N = 2268) in a 1:4 fashion. They analyzed the differences in graft function, patient survival, graft survival, and rejection between the 2 groups.1 Donor AKI was defined on the basis of change in creatinine from admission to the time of procurement and staged using the Kidney Disease: Improving Global Outcomes international consensus guidelines.2 All stages of AKI were reasonably well represented in the belatacept cohort (AKI stage 1: 41%, stage 2: 19%, and stage 3: 40%).1 Graft function was statistically superior in the belatacept group compared with the tacrolimus group at 6 mo (58.2 ± 24.2 versus 54.6 ± 21.6 mL/min/1.73 m2, P < 0.001), but this difference was not sustained at 12 mo posttransplant (57.2 ± 24.3 versus 55.7 ± 22.2 mL/min/1.73 m2, P = 0.057). Death-censored graft survival at 1 y was not different and was >95% in both groups. At a median follow-up of ~3 y, there was no difference in mortality between the groups.1 Consistent with prior published data with de novo belatacept use,3,4 the rejection rates were higher in the belatacept group (13% versus 7%, P < 0.001) but did not impact graft function or survival at 12 mo posttransplant. The findings of this study are largely consistent with previously published studies on de novo belatacept use with regards to a higher early rejection risk with a lack of subsequent effect on early graft and patient survival.3-5 There are several significant aspects with important implications that need to be pointed out. First, there has been an increasing focus on increasing organ utilization and reducing discard in the United States after the passage of the Advancing American Kidney Health executive order.6 These data provide yet another reassuring piece of evidence that AKI kidneys should be used and have acceptable risks of delayed graft function, length of stay, and short-term graft survival. It is also noteworthy that no obvious “CNI effect” with a detrimental impact on short-term graft function due to presumed nephrotoxicity or hemodynamic effect could be identified. Nevertheless, these data do provide reassuring evidence for clinicians who would like to have a de novo CNI-sparing strategy available for deceased donor kidney transplantation with AKI kidneys. There are limitations to this study that need to be considered in appropriate interpretation of these data. Belatacept use data were gathered from 57 centers, but only 2 centers accounted for 50% of the belatacept patients, so matching could not be done at the center level. Although the results were still consistent with the general cohort when the authors addressed the potential for “center effect” by performing a multivariate regression analysis as a sensitivity analysis and adjusted for all matched covariates and transplant centers, the variability in center-specific protocols and practices may affect the generalizability of these findings. Although the authors confirmed de novo belatacept use and excluded those with a CNI overlap based on immunosuppression at discharge, at 12 mo only 77% of patients were still on belatacept as compared with 94% remained on tacrolimus at 1 y. Furthermore, only about 3% of transplant centers in the United States currently report using de novo belatacept in kidney transplant recipients, further affecting generalizability.7 The details of rejection, such as type, severity, treatment, and association with the type of induction, are understandably missing in this registry analysis. However, the rejection rates and their lack of impact on graft function in the short term are reassuring and consistent with previously published data.3-5 The lack of mortality and graft survival benefit with de novo belatacept use with a follow-up of approximately 3 y needs to be considered in the context of a possible inadequate observation period. Previous evidence from the original “BENEFIT” studies with de novo belatacept versus cyclosporine showed a graft and patient survival benefit at the end of 7 y of observation.4 Thus, it would be appropriate to say that the maximal short-term mortality benefit to the patient in this study lies in the early acceptance/allocation of a donor with AKI and liberation from dialysis rather than the choice of posttransplant immunosuppressive regimen. In contrast, the transplant community needs to focus on immunosuppression strategies that enhance long-term outcomes of kidney transplantation with prolonged graft survival and decreased mortality. A future analysis of these data may help us interpret these questions. This analysis is also important because it lays the groundwork for future studies. A registry study inherently does not allow for the granularity that can be achieved with a multicenter prospective approach. Variables to use in the future to determine which patients will benefit from an early “CNI-sparing” approach use could include biopsy information,8 donor risk factors that predispose to chronic kidney disease, hypothermic perfusion parameters, and donor urine output before procurement.