Early calcineurin-inhibitor to belatacept conversion in steroid-free kidney transplant recipients

Abstract

BackgroundBelatacept (Bela) was developed to reduce nephrotoxicity and cardiovascular risk that are associated with the chronic use of Calcineurin inhibitors (CNIs) in kidney transplant recipients. The use of Bela with early steroid withdrawal (ESW) and simultaneous CNI avoidance has not been formally evaluated.MethodsAt 3 months post-transplant, stable kidney transplant recipients with ESW on Tacrolimus (Tac) + mycophenolate (MPA) were randomized 1:1:1 to: 1) Bela+MPA, 2) Bela+low-dose Tac (trough goal <5 ng/mL), or 3) continue Tac+MPA. All patients underwent surveillance graft biopsies at enrollment and then at 12, and 24 months post-transplant. Twenty-seven recipients were included; 9 underwent conversion to Bela+MPA, 8 to Bela+low-dose Tac and 10 continued Tac+MPA. Serial blood samples were collected for immune phenotyping and gene expression analyses.ResultsThe Bela+MPA arm was closed early due to high rate of biopsy proven acute rejection (BPAR). The incidence of BPAR was 4/9 in Bela+MPA, 0/8 in Bela+low dose Tac and 2/10 in Tac+MPA, P= 0.087. The Bela+low-dose Tac regimen was associated with +8.8 mL/min/1.73 m2 increase in eGFR compared to -0.38 mL/min/1.73 m2 in Tac+MPA, P= 0.243. One graft loss occurred in the Bela+MPA group. Immunophenotyping of peripheral blood monocyte count (PBMC) showed that CD28+CD4+ and CD28+CD8+ T cells were higher in Bela+MPA patients with acute rejection compared to patients without rejection, although the difference did not reach statistical significance.ConclusionsOur data indicate that, in steroid free regimens, low-dose Tac maintenance is needed to prevent rejection when patients are converted to Bela, at least when the maneuver is done early after transplant.

Evaluation of Torque Teno Virus DNA Load as a Predictive Biomarker in Kidney Transplant Recipients Converted from Calcineurin Inhibitors to Belatacept

“…Recent studies show an increased risk of OPI in late-conversion from tacrolimus to belatacept. 29 The main risk factors were a low eGFR at conversion, older recipient age, and steroid use. Current recommendation for early belatacept use in KT is in association with low-dose tacrolimus.…”

Costimulatory Blockade and Solid Organ Transplantation: The Past, Present, and Future

“… 115 A randomized trial of early protocol belatacept conversion in patients with early steroid withdrawal also found a prohibitive rate of ACR associated with early belatacept conversion, resulting in the early closure of that treatment arm (interestingly, the group receiving belatacept and low-dose tacrolimus had no episodes of rejection and an 8.8 ml/min per 1.73 m 2 increase in eGFR compared to a −0.38 ml/min per 1.73 m 2 drop in the group maintained on tacrolimus + MMF). 116 Therefore, the timing of belatacept conversion likely must balance the risk of a higher ACR rate associated with early conversions against the risks of late conversion, namely that more time on CNI risks the development of irreversible histologic changes in the kidney. Based on our published experience at Emory with de novo belatacept and transient CNI therapy, 38 we have observed that early CNI withdrawal (less than 6 months posttransplant) is associated with prohibitively higher rates of ACR; thus, we begin to wean off the low-dose tacrolimus we provide our belatacept-treated patients at 9 months posttransplant.…”

Overview of pregnancy in solid-organ transplantation

“…Belatacept was developed to improve long-term outcomes by avoiding the potentially toxic effects of CNIs, mainly CNI-induced nephrotoxicity [35]. This medication selectively inhibits T-cell costimulation by binding to CD80/CD86 receptors on antigen-presenting cells (APCs) and thereby blocking the necessary CD28 costimulation of T cells [33,34].…”

“…Studies have shown that belatacept has similar patient and allograft survival in addition to improved renal function when compared to CNIbased treatment plans, but there is an increased risk of early allograft rejection and posttransplantation lymphoproliferative disease (PTLD) [34][35][36].…”

“…Studies have shown that belatacept has similar patient and allograft survival in addition to improved renal function when compared to CNI-based treatment plans, but there is an increased risk of early allograft rejection and posttransplantation lymphoproliferative disease (PTLD) [34–36]. Although it was originally being used in kidney transplantation, it has since started to be used in other SOT including liver and lung [37].…”