Early calcineurin-inhibitor to belatacept conversion in steroid-free kidney transplant recipients
Belatacept (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.
METHODS:At 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.
RESULTS:The 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.
CONCLUSIONS:Our 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.
CET Conclusion
| Reviewer: | Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford |
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| Conclusion: | This small single-centre study randomised kidney transplant recipients with early steroid withdrawal three months post-transplant to one of three immunosuppressive regimens – Belatacept and MPA, Belatacept and low-dose tacrolimus, or Tacrolimus and MPA. In keeping with previous studies, the acute rejection rate was high in the belatacept/MPA arm, which was discontinued. Outcomes in the other two arms were statistically similar. The study is underpowered, with only 27 patients recruited across the three arms, and so any real conclusions are difficult to make. No sample size calculation is reported, and the original study protocol suggests planned recruitment of 43 patients. Significantly more patients would be required to show a clinically meaningful difference in the primary endpoint of change in eGFR. Of interest, 395 patients were screened for recruitment with only 27 patients consented and enrolled. Inclusion/exclusion criteria were not particularly restrictive, and no explanation is provided as to why recruitment rates were so poor. |
Methodological quality
| Jadad score | 3 |
|---|---|
| Allocation concealment | NO |
| Data analysis | INTENTION TO TREAT |
Study Details
| Aims: | This study aimed to investigate the impact of early tacrolimus to Belatacept (Bela) conversion for maintenance immunosuppressive therapy in kidney transplant recipients. |
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| Interventions: | Participants were randomised to convert to Bela+mycophenolate (MPA), Bela+low dose Tac or to continue with Tac+MPA. |
| Participants: | 27 kidney transplant recipients. |
| Outcomes: | The primary outcome was the estimated glomerular filtration rate (eGFR). The secondary outcomes were patient survival, graft survival, incidence of de novo donor specific antibodies (DSA), incidence of biopsy proven acute rejection (BPAR), and incidence of adverse events such as posttransplant diabetes mellitus, infections, malignancies, and hyperlipidemia. |
| Follow Up: | 24 months |
Metadata
| Funding: | No funding was received for this study |
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| Publication type: | Randomized Controlled Trial, Randomised Controlled Trial |
| Trial registration: | ClinicalTrials.gov - NCT02213068 |
| Organ: | Kidney |
| Language: | English |
| Author email: | l-gallon@northwestern.edu |
| MeSH terms: | Humans; Abatacept; Calcineurin; Calcineurin Inhibitors; CD28 Antigens; CD8-Positive T-Lymphocytes; Immunosuppressive Agents; Kidney Transplantation; Leukocytes, Mononuclear; Mycophenolic Acid; Steroids; Tacrolimus; Drug Substitution; 7D0YB67S97 (Abatacept); EC 3-1-3-16 (Calcineurin); 0 (Calcineurin Inhibitors); 0 (CD28 Antigens); 0 (Immunosuppressive Agents); HU9DX48N0T (Mycophenolic Acid); 0 (Steroids); WM0HAQ4WNM (Tacrolimus) |