Long-term outcomes after conversion to belatacept

Calcineurin inhibitors (CNIs) are key components of maintenance immunosuppression in transplantation medicine. However, CNIs are associated with nephrotoxicity and post-transplant diabetes and may contribute to delayed graft function, which can particularly affect organs from marginal donors.

When CNI-based standard of care immunosuppression is not tolerated after kidney transplantation, one strategy involves converting patients to belatacept-based immunosuppression. Small-scale studies have suggested that this improves kidney function, but may result in a higher incidence of acute rejection and opportunistic infections. 

The aim of the present study was, therefore, to investigate the long-term kidney allograft efficacy and safety outcomes in a population of kidney transplant recipients who underwent conversion to belatacept.

Between 2007 and 2020, 311 kidney transplant recipients were prospectively enrolled from two French transplant centres. Participants were converted to belatacept for CNI nephrotoxicity at any time post-transplantation. All patients received a kidney allograft evaluation before conversion to belatacept or continuation with standard CNI triple therapy (CNI, antiproliferative, steroid).

Patients converted to belatacept received a 5 mg/kg dose, initially every fortnight for the first five doses, and then monthly thereafter. During this time, the CNI was decreased by 25% after each belatacept infusion and discontinued after the fourth dose; the antiproliferative dose was uptitrated over the same period, and steroids were maintained at current doses.

Following kidney allograft evaluation, a total of 243 participants on belatacept were matched to a well-balanced control cohort of 243 patients maintained on CNI-based regimen (standardised mean difference, <0.05). There were no significant differences between the groups by mean recipient age (52; SD 16), gender (64% male) or mean eGFR (33; 13).

The primary end point was death-censored allograft survival at 7 years post-conversion. There was a significantly higher rate of allograft survival in the belatacept group compared to the CNI control group (78% [95% CI, 71–84] vs 63% [56–70]; log rank P<0.001). There were 43 (18%) graft failures in the belatacept group and 86 (35%) in the control group. The causes of failure were similar between the two groups, with the majority due to chronic antibody-mediated rejection. At 7 years, the mean eGFR was higher in the belatacept group than the CNI group (26 mL/min/1.73 m² [15–25] vs 20.2 mL/min/1.73 m² [21–31]; P=0.04).

There were similar rates of patient death between the belatacept and control groups (28% vs 36%; P=0.34), with similar distribution of the causes of death. The leading cause was infectious diseases, including COVID-19. There was no significant difference in the rates of active antibody-mediated rejection (6% vs 7%; P=0.58), T-cell-mediated rejection (4% vs 4%; P=0.82). Cardiovascular complications, the development of post-transplant diabetes and the incidence of cancer were also very similar. The belatacept group had a significantly higher rate of de novo proteinuria (37% vs 21%; P<0.001); however, de novo circulating anti-HLA DSA incidence was significantly lower in the belatacept group (10% vs 21%; P=0.002).

The authors concluded that, compared to those treated with a CNI-based immunosuppression, conversion to belatacept post-transplant is associated with greater long-term graft survival and acceptable safety outcomes, and might be considered in kidney recipients suffering from CNI nephrotoxicity, or with prolonged delayed or impaired graft function. 

It is disappointing that ethnicity for the recipients and donors was not recorded, but the authors should be commended on conducting such a large long-term clinical trial in transplant patients, especially through the duration of the COVID-19 pandemic.

The full article can be read here.