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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/TacTL) or tacrolimus regimens between 2016 and 2019. Bela/TacTL(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/TacTLimmunosuppression 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/TacTL(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.

Belatacept results in improved kidney transplant outcomes, but utilization has been limited by logistical barriers related to monthly (q1m) intravenous infusions. Every 2-month (q2m) belatacept has potential to increase utilization, therefore we conducted a randomized noninferiority trial in low immunologic risk renal transplant recipients greater than 1-year posttransplant. Patients on belatacept were randomly assigned to q1m or q2m therapy. The primary objective was a noninferiority comparison of renal function (eGFR) at 12 months with a noninferiority margin (NIM) of 6.0 ml/min/1.73 m2. One hundred and sixty-six participants were randomized to q1m (n= 82) or q2m (n= 84) belatacept, 163 patients received treatment, and 76 q1m and 77 q2m subjects completed the 12-month study period. Every 2-month belatacept was noninferior to q1m, as the difference in mean eGFR adjusted for baseline renal function did not exceed the NIM. Two-month dosing was safe and well tolerated, with no patient deaths or graft losses. Four rejection episodes and three cases of donor-specific antibodies (DSAs) occurred among q2m subjects; however, only one rejection and one instance of DSA were observed in subjects adherent to the study protocol. Every 2-month belatacept therapy may facilitate long-term utilization of costimulation blockade, but future multicenter studies with long-term follow-up will further elucidate immunologic risk. (ClinicalTrials.govNCT02560558).

Belatacept results in improved kidney transplant outcomes, but utilization has been limited by logistical barriers related to monthly (q1m) intravenous infusions. Every 2‐month (q2m) belatacept has potential to increase utilization, therefore we conducted a randomized noninferiority trial in low immunologic risk renal transplant recipients greater than 1‐year posttransplant. Patients on belatacept were randomly assigned to q1m or q2m therapy. The primary objective was a noninferiority comparison of renal function (eGFR) at 12 months with a noninferiority margin (NIM) of 6.0 ml/min/1.73 m2. One hundred and sixty‐six participants were randomized to q1m (n= 82) or q2m (n= 84) belatacept, 163 patients received treatment, and 76 q1m and 77 q2m subjects completed the 12‐month study period. Every 2‐month belatacept was noninferior to q1m, as the difference in mean eGFR adjusted for baseline renal function did not exceed the NIM. Two‐month dosing was safe and well tolerated, with no patient deaths or graft losses. Four rejection episodes and three cases of donor‐specific antibodies (DSAs) occurred among q2m subjects; however, only one rejection and one instance of DSA were observed in subjects adherent to the study protocol. Every 2‐month belatacept therapy may facilitate long‐term utilization of costimulation blockade, but future multicenter studies with long‐term follow‐up will further elucidate immunologic risk. (ClinicalTrials.gov NCT02560558). This single‐center trial randomized stable kidney transplant recipients more than one year posttransplant to every 2 months versus standard monthly belatacept dosing shows noninferiority, as determined by renal function 12 months after randomization.

Cytomegalovirus (CMV) remains associated with poor outcomes after kidney transplantation (kTx). The impact of belatacept on CMV infection remains understudied. In this study, we assessed the impact of belatacept on patient and graft survivals. CMV seronegative kTx recipients were included. Patient and graft survival were studied using Kaplan‐Meier method, log‐rank test. Cox models were used to compare outcomes by CMV risk and immunosuppressive regimen. Incidence and persistence of CMV viremia under belatacept vs tacrolimus were compared. Among 308 CMV seronegative recipients, 168 CMV high‐risk and 203 belatacept‐treated patients were included. High‐risk CMV status was associated with lower patient survival and graft survival. Among the CMV high‐risk group, patients treated with belatacept presented a higher incidence of CMV viremia, a higher rate of first‐line treatment failure and a longer time to virus clearance. They had a nonsignificant trend toward a lower graft survival. Belatacept‐based maintenance immunosuppression is associated with an increased risk of CMV primary‐infection and a prolonged course of viral replication in CMV high‐risk patients. Further studies are needed to confirm the nonsignificant trend towards a lower graft survival in CMV high‐risk patients treated with belatacept and whether it is explained by the higher risk of CMV reactivation and infection. A retrospective comparison of high CMV–risk kidney transplant recipients treated with de novo belatacept versus tacrolimus shows a higher risk of CMV viremia in belatacept‐treated patients.

Multidrug-resistant organism (MDRO) colonization is a fundamental challenge in antimicrobial resistance. Limited studies have shown that fecal microbiota transplantation (FMT) can reduce MDRO colonization, but its mechanisms are poorly understood. We conducted a randomized, controlled trial of FMT for MDRO decolonization in renal transplant recipients called PREMIX (NCT02922816). Eleven participants were enrolled and randomized 1:1 to FMT or an observation period followed by delayed FMT if stool cultures were MDRO positive at day 36. Participants who were MDRO positive after one FMT were treated with a second FMT. At last visit, eight of nine patients who completed all treatments were MDRO culture negative. FMT-treated participants had longer time to recurrent MDRO infection versus PREMIX-eligible controls who were not treated with FMT. Key taxa (Akkermansia muciniphila, Alistipes putredinis, Phocaeicola dorei, Phascolarctobacterium faecium, Alistipesspecies, Mesosutterella massiliensis, Barnesiella intestinihominis, and Faecalibacterium prausnitzii) from the single feces donor used in the study that engrafted in recipients and metabolites such as short-chain fatty acids and bile acids in FMT-responding participants uncovered leads for rational microbiome therapeutic and diagnostic development. Metagenomic analyses revealed a previously unobserved mechanism of MDRO eradication by conspecific strain competition in an FMT-treated subset. Susceptible Enterobacteralesstrains that replaced baseline extended-spectrum β-lactamase–producing strains were not detectable in donor microbiota manufactured as FMT doses but in one case were detectable in the recipient before FMT. These data suggest that FMT may provide a path to exploit strain competition to reduce MDRO colonization.

A majority of kidney transplant recipients receive calcineurin inhibitor-based immunosuppression. However, some do not tolerate calcineurin inhibitors and require other immunosuppressive strategies. Until recently, alternative approaches have been associated with inferior outcomes, but recent methods have effectively utilized belatacept in calcineurin inhibitor-intolerant patients. Though promising, belatacept uptake has been limited by higher acute rejection rates, unavailability due to production shortages, and logistical challenges as a result of intravenous infusion requirements. Interestingly, its predecessor abatacept is clinically available in subcutaneous formulation to treat autoimmune disorders but has not been used in clinical transplantation. Here we report on a series of 9 calcineurin inhibitor-intolerant transplant recipients converted to abatacept early after transplant as rescue immunosuppression during periods of belatacept unavailability. Retrospective review revealed successful allograft salvage and 100% patient and graft survival (median 115 months) after conversion to abatacept. Patients received abatacept for a median duration of 82 months with stable, long-term renal allograft function, a single cellular rejection episode, and no clinically apparent protective immunity concerns. Hence our findings suggest that future clinical studies utilizing abatacept either de novo or as conversion therapy in transplant recipients should be considered.

A majority of kidney transplant recipients receive calcineurin inhibitor‐based immunosuppression. However, some do not tolerate calcineurin inhibitors and require other immunosuppressive strategies. Until recently, alternative approaches have been associated with inferior outcomes, but recent methods have effectively utilized belatacept in calcineurin inhibitor‐intolerant patients. Though promising, belatacept uptake has been limited by higher acute rejection rates, unavailability due to production shortages, and logistical challenges as a result of intravenous infusion requirements. Interestingly, its predecessor abatacept is clinically available in subcutaneous formulation to treat autoimmune disorders but has not been used in clinical transplantation. Here we report on a series of 9 calcineurin inhibitor‐intolerant transplant recipients converted to abatacept early after transplant as rescue immunosuppression during periods of belatacept unavailability. Retrospective review revealed successful allograft salvage and 100% patient and graft survival (median 115 months) after conversion to abatacept. Patients received abatacept for a median duration of 82 months with stable, long‐term renal allograft function, a single cellular rejection episode, and no clinically apparent protective immunity concerns. Hence our findings suggest that future clinical studies utilizing abatacept either de novo or as conversion therapy in transplant recipients should be considered. This retrospective review of nine kidney transplant recipients converted to abatacept as rescue immunosuppression due to calcineurin inhibitor intolerance reveals successful allograft salvage with 100% patient and graft survival, and stable, long‐term renal allograft function.