#4045 IMMUNOSUPPRESSION AND POST-TRANSPLANT HYPERGLYCEMIA
Authors: Oliveras Laia , Coloma Ana , Lino Luis , Favà Alexandre , Manonelles Anna , Codina Sergi , Couceiro Carlos , Melilli Edoardo , Cruzado Josep , Pascual Julio , Montero Nuria 
Published: June 2023

Abstract

Background and Aims
Post-transplant diabetes mellitus (PTDM) is a frequent complication after kidney transplantation (KT), with an incidence between 20-30%. PTDM increases the risk of cardiovascular disease, which is one of the main causes of death with functioning grafts. The pathophysiology of PTDM involves beta-cell dysfunction, with impaired insulin secretion and insulin resistance overlaid immunosuppression accelerating preexisting damage.
The major risk factor in the post-transplant period is immunosuppression therapy, such as steroids, calcineurin inhibitors (CNI), and mTOR inhibitors (mTORi). It is also a major modifiable risk but must be balanced with rejection risk. This systematic review aims to investigate the effect of different immunosuppressive regimens on the risk of PTDM incidence.

Methods
Relevant studies were obtained from a systematic literature search. We searched MEDLINE and CENTRAL (Cochrane Central Register of Controlled Trials) until 1st May 2022. We searched randomized controlled trials (RCT) including KT recipients receiving any immunosuppression and reporting PTDM outcomes. The definition of PTDM was whatever was used by the authors. Meta-analysis was done by pooling data for calculating the relative risks (RR) of the outcome by comparing different immunosuppression strategies.

Results
We identified 1,848 reports. After removing duplicates and screening titles and abstracts 156 full-text reports were assessed. We finally included 52 studies. Eight RCTs reported the outcome of PTDM using different induction therapies at ≤7 years after KT, with a total included a population of 1,495 recipients. The meta-analysis of all studies did not show differences in the risk of post-transplant diabetes mellitus in any of the comparisons. 49 RCTs evaluated mTORi use: 32 at de novo KT and 17 long-term follow-up conversions. When comparing mTORi vs antimetabolite there was a higher risk of PTDM in the mTORi group at ≤5 years postKT (22 studies, 8,178 participants, RR 1.25, 95%CI [1.05-1.49], p = 0.01). When comparing mTORi vs CNI there were no differences in PTDM risk at ≤5 years postKT (12 studies, 2,537 participants, RR 0.81, 95%CI [0.48-1.40], p = 0.46). Conversions from CNI to mTORi at ≤2 years postKT showed an increased risk of PTDM (15 studies, 3,200 participants, RR 1.60, 95%CI [1.14-2.23], p&lt;0.01). We found 39 RCTs that reported PTDM outcomes in KT receiving CNI. In de novo KT, there was an increased risk of developing PTDM with tacrolimus rather than with ciclosporin (26 studies, 5,635 patients, RR 1.71, 95%CI [1.38-2.11], p&lt;0.01) after ≤5 years postKT. There were no differences comparing different doses or tacrolimus formulations. When belatacept was compared to CNI we found a 38% reduction at 1-year post-KT in the risk of developing PTDM (6 studies, 2,100 participants, RR 0.62, 95% CI [0.42-0.91], p = 0.02).

Conclusion
A higher risk of PTDM was observed in patients receiving TAC vs CsA, and mTORi inhibitors. Belatacept showed a 38% reduction in PTDM compared to CNI. However, the risk of PTDM should be balanced with the risk of rejection.