Reduced exposure to calcineurin inhibitors in renal transplantation

N Engl J Med. 2007 Dec 20;357(25):2562-75. doi: 10.1056/NEJMoa067411.

Abstract

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].).

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / administration & dosage
  • Adrenal Cortex Hormones / therapeutic use*
  • Adult
  • Aged
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal, Humanized
  • Calcineurin Inhibitors*
  • Cyclosporine / administration & dosage
  • Daclizumab
  • Diabetes Mellitus / etiology
  • Drug Therapy, Combination
  • Enzyme Inhibitors / administration & dosage*
  • Female
  • Glomerular Filtration Rate
  • Graft Rejection / prevention & control*
  • Humans
  • Immunoglobulin G / administration & dosage
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / therapeutic use*
  • Kaplan-Meier Estimate
  • Kidney Transplantation*
  • Male
  • Middle Aged
  • Mycophenolic Acid / administration & dosage
  • Mycophenolic Acid / analogs & derivatives*
  • Opportunistic Infections
  • Prednisone / administration & dosage
  • Sirolimus / administration & dosage
  • Sirolimus / adverse effects
  • Tacrolimus / administration & dosage*
  • Treatment Failure

Substances

  • Adrenal Cortex Hormones
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Calcineurin Inhibitors
  • Enzyme Inhibitors
  • Immunoglobulin G
  • Immunosuppressive Agents
  • Cyclosporine
  • Daclizumab
  • Mycophenolic Acid
  • Prednisone
  • Sirolimus
  • Tacrolimus

Associated data

  • ClinicalTrials.gov/NCT00231764