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

Background. In kidney transplant recipients with alemtuzumab induction maintained on mycophenolate mofetil (MMF) immunosuppression, sirolimus (SRL) promotes significant expansion of circulating CD4(+)CD25(high) 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(+)CD25(high) Treg counts (22.1 +/- 12.2% vs. 5.7 +/- 4.2% of CD3+CD4+ T cells), SRLtreated 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 mi/min/1.73m(2) per year), and RPF (- 10.80 +/- 5.45 vs. -1.86 3.09 ml/min/ 1.73 m(2) 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.