Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation.
BACKGROUND
The adoption of calcineurin inhibitors (CNI) as the mainstay of immunosuppression has resuited in a significant decrease of acute rejection and improvement of short-term graft survival. However, because of the irreversible nephrotoxicity associated with the chronic use of the CNI, the magnitude of the improvement of long-term graft survival has been more modest. Therefore, an effective immunosuppression regimen that does not rely on CNI may result in improvement of long-term outcome and simplification of the management of transplant recipients.


METHODS
Ninety-eight patients of primary cadaver or living donor kidneys at low immunologic risk were enrolled in a CNI avoidance study. The immunosuppression regimen consisted of daclizumab, a humanized monoclonal antibody that binds to the alpha chain of the interleukin-2 receptor (IL-2Ralpha), administered for a total of five doses at biweekly intervals; 3 gm/day mycophenolate mofetil for the first 6 month and 2 gm thereafter; and conventional corticosteroid therapy. Patients who underwent rejection episodes could be started on CNI. The primary efficacy end-point was biopsy-proven rejection during the first 6 months posttransplant.


RESULTS
Biopsy-proven rejection was diagnosed in 48% of patients during the first 6 months after transplantation. The majority of rejection episodes were Banff grade I and IIA and were fully reversed with corticosteroid therapy. The median time to the first biopsy-proven rejection among patients who experienced this event during the first 6 months was 39 days. In 22 patients with delayed graft function, the proportion of patients with biopsy-proven rejection was 50% at 6 months. However in the first 2 weeks posttransplant, only 1 of 22 patients with delayed graft function developed biopsy-proven rejection. At 1 year, patient survival was 97% and graft survival was 96%. Only two grafts were lost secondary to rejection. At 1-year posttransplant, 62% of patients had received CNI for more than 7 days. At 1-year posttransplant, the mean serum creatinine in the nonrejectors with no CNI use was 113 micromol/L (95%, confidence interval [CI], 100.7 to 125.3 micromol/L) and in the rejectors or patients with CNI use (more than 7 days) was 154 micromol/L (95% CI, 135.0 to 173.0 micromol/L). In selected patients with rejection, analysis of circulating and intragraft lymphocytes revealed complete IL-2Ralpha saturation.


CONCLUSIONS
This CNI avoidance study in immunologic low-risk patients, while only partially successful in preventing acute rejection, provided benefits to a sizable minority of patients who have not required chronic CNI therapy. However, wide acceptance of a CNI-sparing immunosuppression regimen may require a lower rate of acute rejection, possibly through the addition of a non-nephrotoxic dose of CNI. However, because complete IL-2Ralpha blockade was present during rejection, it can be assumed that alternative pathways, such as IL-15, may be responsible for the rejection; thus, the incorporation of non-nephrotoxic immunosuppressive agents, such as sirolimus, may provide a more strategic approach.
Vincenti
F
F
University of California, San Francisco, USA.
Ramos
E
E
Brattstrom
C
C
Cho
S
S
Ekberg
H
H
Grinyo
J
J
Johnson
R
R
Kuypers
D
D
Stuart
F
F
Khanna
A
A
Navarro
M
M
Nashan
B
B
D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001706:Biopsy; D065095:Calcineurin Inhibitors; D000077561:Daclizumab; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors; D013997:Time Factors; D014184:Transplantation, Homologous / Q000473:pathology; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D000077561:Daclizumab; D009173:Mycophenolic Acid