Reduced exposure to calcineurin inhibitors in renal transplantation.
BACKGROUND
Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens.


METHODS
We randomly assigned 1645 renal-transplant recipients to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. The primary end point was the estimated glomerular filtration rate (GFR), as calculated by the Cockcroft-Gault formula, 12 months after transplantation. Secondary end points included acute rejection and allograft survival.


RESULTS
The mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 ml per minute) than in the other three groups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%). Allograft survival differed significantly among the four groups (P=0.02) and was highest in the low-dose tacrolimus group (94.2%), followed by the low-dose cyclosporine group (93.1%), the standard-dose cyclosporine group (89.3%), and the low-dose sirolimus group (89.3%). Serious adverse events were more common in the low-dose sirolimus group than in the other groups (53.2% vs. a range of 43.4 to 44.3%), although a similar proportion of patients in each group had at least one adverse event during treatment (86.3 to 90.5%).


CONCLUSIONS
A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction. (ClinicalTrials.gov number, NCT00231764 [ClinicalTrials.gov].).
Ekberg
Henrik
H
Lund University, Malmö, Sweden. henrik.ekberg@med.lu.se
Tedesco-Silva
Helio
H
Demirbas
Alper
A
Vítko
Stefan
S
Nashan
Björn
B
Gürkan
Alp
A
Margreiter
Raimund
R
Hugo
Christian
C
Grinyó
Josep M
JM
Frei
Ulrich
U
Vanrenterghem
Yves
Y
Daloze
Pierre
P
Halloran
Philip F
PF
D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage; D000077561:Daclizumab; D003920:Diabetes Mellitus / Q000209:etiology; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009894:Opportunistic Infections; D011241:Prednisone / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects; D016559:Tacrolimus / Q000008:administration & dosage*; D017211:Treatment Failure
D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000077561:Daclizumab; D009173:Mycophenolic Acid; D011241:Prednisone; D020123:Sirolimus; D016559:Tacrolimus