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+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.
Ruggenenti
Piero
P
Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo, Mario Negri Institute for Pharmacological Research, Transplant Research Center Chiara Cucchi De Alessandri e Gilberto Crespi, Bergamo, Italy. ruggenenti@marionegri.it
Perico
Norberto
N
Gotti
Eliana
E
Cravedi
Paolo
P
D'Agati
Vivette
V
Gagliardini
Elena
E
Abbate
Mauro
M
Gaspari
Flavio
F
Cattaneo
Dario
D
Noris
Marina
M
Casiraghi
Federica
F
Todeschini
Marta
M
Cugini
Daniela
D
Conti
Sara
S
Remuzzi
Giuseppe
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D002908:Chronic Disease; D016572:Cyclosporine / Q000627:therapeutic use*; D005260:Female; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D020123:Sirolimus / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D007166:Immunosuppressive Agents; D000074323:Alemtuzumab; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus