Belatacept with time-limited tacrolimus coimmunosuppression modifies the 3-year risk of eplet mismatch in kidney transplantation

Abstract

Solid organ transplant donor-recipient eplet mismatch has been correlated with donor-specific antibody (DSA) formation, antibody-mediated rejection, and overall rejection rates. However, studies have been predominantly in patients on tacrolimus-based immunosuppression regimens and have not fully explored differences in ethnically and racially diverse populations. Evidence indicates that patients on belatacept have lower rates of DSA formation, suggesting mediation of the immunogenicity of mismatched human leukocyte antigen polymorphisms. We performed a retrospective, single-center analysis of class II eplet disparity in a cohort of kidney transplant recipients treated using belatacept with tacrolimus induction (Bela/Tac_TL) or tacrolimus regimens between 2016 and 2019. Bela/Tac_TL (n = 294) and tacrolimus (n = 294) cohorts were propensity score-matched with standardized difference <0.15. Single-molecule eplet risk level was associated with immune event rates for both groups. In Cox regression analysis stratified by eplet risk level, Bela/Tac_TL immunosuppression was associated with a decreased rate of DSA (hazard ratio [HR] = 0.4), antibody-mediated rejection (HR = 0.2), and rejection (HR = 0.45). In the low-risk group, cumulative graft failure was lower for patients on Bela/Tac_TL (P < .02). Analysis of eplet mismatch burden may be a useful adjunct in identifying high-risk populations with increased immunosuppression requirements and should encourage the design of allocation rules to incentivize lower-risk pairings without negatively impacting equity in access.

Keywords: HLA; antibody; belatacept; costimulation; eplet; immunosuppression; rejection.

Figure 1:. Patient selection diagram.

Patients transplanted at Emory University between 2016–2019 were evaluated for inclusion. Those who met eligibility criteria were propensity score matched into balanced tacrolimus and Bela/Tac_TL cohorts.

Figure 2.. Eplet risk stratification of tacrolimus cohort.

Single molecule DR/DQ eplet risk scoring was applied to the tacrolimus cohort, resulting in 128 high-risk, 99 intermediate-risk, and 67 low-risk patients. Stratification of DR/DQ DSA development was statistically significant, with AMR and acute rejection also showing a trend towards association.

Figure 3.. Eplet risk stratification of Bela/Tac_TL cohort.

Single molecule DR/DQ eplet risk scoring was applied to the Bela/Tac_TL cohort, resulting in 141 high-risk patients, 96 intermediate-risk, and 57 low-risk patients. Stratification of DR/DQ DSA-free survival and survival from death or graft loss was statistically significant.

Figure 4.. Modification of eplet risk by immunosuppression regimen.

Bela/Tac_TL was associated with improvements in DSA and AMR, particularly for intermediate-risk patients. Rejection rates were lower for Bela/Tac_TL patients across risk levels. Rates of patient and graft survival were improved for low-risk patients on Bela/Tac_TL when compared to those on tacrolimus regimens.

Figure 5.. Immunogenicity of specific eplets.

The event rate (A) and enrichment (B) of immune events between the tacrolimus cohort (average event rate = 0.38, average frequency enrichment in cases = 0.03) and Bela/Tac_TL cohort (average event rate 0.21, average frequency enrichment in cases = 0.04) for individual eplets is shown. Communities of mismatched eplets identified in our cohort (C) are shown colored by association with DR/DQ specific DSA.