Potential Benefits of Adding Low-dose Tacrolimus to a Belatacept-based Regimen After Kidney Transplantation

We read with interest the article by Yamauchi et al1 in the April 2025 issue of Transplantation. In this retrospective registry analysis using the Organ Procurement and Transplant Network database between July 2011 and April 2022, the authors compared the outcomes of patients who underwent transplantation of kidneys from deceased donors who sustained acute kidney injury (AKI) and were discharged on a belatacept-based versus tacrolimus-based maintenance immunosuppression. The recipients were matched for covariates. Graft and patient survivals were similar between the groups despite significantly higher treated rejection in the belatacept group (13% versus 7%, P < 0.001). The 6-mo estimated glomerular filtration rate (eGFR) was significantly higher in the belatacept versus tacrolimus group, but 12-mo eGFRs were similar.1 Because of the increased risk for acute rejection (AR) with belatacept, many programs using the de novo belatacept protocol also include concomitant low-dose tacrolimus for variable periods. The belatacept and low-dose tacrolimus combination has dual theoretical benefits of lower nephrotoxicity compared with standard-dose tacrolimus and lower rejection risk compared with belatacept. The study by Yamauchi et al excluded patients who were discharged on belatacept with tacrolimus. Recently, we published the findings from the United Network for Organ Sharing database analysis comparing the outcomes of kidney transplant recipients between January 2010 and December 2022 who were discharged on a tacrolimus-based versus belatacept-based maintenance immunosuppression.2 In this propensity-matched adjusted model, overall patient death (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.92-1.14; P = 0.648), all-cause graft failure (HR, 1.07; 95% CI, 0.97-1.17; P = 0.195), and death-censored graft failure (HR, 1.11; 95% CI, 0.98-1.25; P = 0.096) were similar for belatacept (n = 2612) versus tacrolimus (n = 12760) groups. However, patient death (HR, 0.87; 95% CI, 0.76-1; P = 0.043) and graft failure (HR, 0.73; 95% CI, 0.64-0.83; P < 0.001) were significantly lower in patients discharged on belatacept along with tacrolimus (n = 2033) compared with tacrolimus (n = 9004) arm. Twelve-month serum creatinine was significantly lower in belatacept arms. In the long-term extension study of the original BENEFIT trial (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial), patients randomly assigned to belatacept arms had a 43% reduction in the risk of death or graft loss at 7 y and higher mean eGFR, when compared with patients randomly assigned to cyclosporine.3 Although donor kidney with AKI by itself may not be a risk factor for AR, AKI can increase the odds for developing delayed graft function (DGF) which in turn could possibly increase the risk for developing AR.4 As expected, the incidence of DGF was much higher (tacrolimus arm at 44% and belatacept arm at 45%) in the study by Yamauchi et al1 analyzing recipients of kidneys with AKI when compared with a DGF rate of 23%–27% with tacrolimus and 31%–32% with belatacept use in our analysis.2 There was a numerically lower AR in the belatacept plus tacrolimus arm in our study at 9.4% compared with 10.6% in belatacept without tacrolimus arm. However, the capture of AR in databases is suboptimal, with missing data points. Based on these observations, we believe that it would be useful to analyze the outcomes, especially 12-mo eGFR and patient survival for recipients of donor kidneys with AKI discharged on belatacept with tacrolimus versus tacrolimus alone.