Sirolimus versus cyclosporine therapy increases circulating regulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft injury

Abstract

Background: In kidney transplant recipients with alemtuzumab induction maintained on mycophenolate mofetil (MMF) immunosuppression, sirolimus (SRL) promotes significant expansion of circulating CD4+CD25high regulatory T cells (Treg). This might translate into more effective protection against chronic graft injury compared to cyclosporin A (CsA), which, in the same clinical setting, does not affect Treg.

Methods: To assess this hypothesis, in the extension of a single-center, prospective, randomized, open, blind endpoint study aimed to assess the effect of low-dose SRL or CsA on circulating Treg, we compared the outcomes of renal transplant recipients on SRL (n=11) or CsA (n=10) by per-protocol biopsies and serial measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), and 24-hour proteinuria over 30 months posttransplant.

Results: Despite 4-fold higher CD4+CD25high Treg counts (22.1+/-12.2% vs. 5.7+/-4.2% of CD3+CD4+ T cells), SRL-treated patients, compared to CsA-treated patients, had a significantly higher tubular C4d staining score (1.1+/-0.6 vs. 0.2+/-0.3, P<0.01), with nonsignificant trends to higher chronic allograft damage index score (5.6+/-2.4 vs. 3.7+/-3.3), faster GFR (-2.92+/-0.33 vs. -0.28+/-0.44 ml/min/1.73 m2 per year), and RPF (-10.80+/-5.45 vs. -1.86+/-3.09 ml/min/1.73 m2 per year) decline, and more clinical proteinuria (n=6 vs. 4). There was no significant correlation between Treg counts and any considered outcome variable in the study group as a whole and within each cohort.

Conclusions: These data suggest that, despite enhanced Treg expression, low-dose SRL combined to alemtuzumab induction and MMF-based steroid-free maintenance therapy, does not appreciably protect renal transplant recipients from chronic allograft injury and dysfunction.