title: Randomized trial comparing late concentration-controlled calcineurin inhibitor or mycophenolate mofetil withdrawal.
abstract: BACKGROUND
  Early calcineurin inhibitor (CNI) withdrawal with mycophenolate mofetil (MMF) has not become routine practice, due to concerns about excess acute rejection. Therapeutic drug monitoring may be advantageous when the CNI or MMF is withdrawn.
  
  
  METHODS
  This prospective, randomized, concentration-controlled withdrawal study enrolled 177 stable renal transplant recipients on maintenance CNI-based immunosuppression, combined with steroids and MMF. After the feasibility phase of the study, patients were randomized to MMF-withdrawal (target area under the time-concentration curve-cyclosporine: 3250 ng·hr/mL or tacrolimus: 120 ng·hr/mL) or CNI-withdrawal (target area under the time-concentration curve-mycophenolic acid: 75 μg·hr/mL).
  
  
  RESULTS
  The estimated glomerular filtration rate (modification of diet in renal disease) remained significantly better after CNI elimination (59.5±2.1 mL/min vs. 51.1±2.1 mL/min, P = 0.006) up to 3 years and resulted in less functional decline, including the subgroup with an estimated glomerular filtration rate less than 50 mL/min at baseline (P = 0.03). At 6 months, one patient in the MMF-withdrawal group (1.3%) and three in the CNI-withdrawal group (3.8%) experienced acute rejection (P = 0.62). The defined higher mycophenolic acid exposure was well tolerated.
  
  
  CONCLUSIONS
  These data indicate that with time the large majority of stable renal transplant recipients can be safely reduced to dual therapy with MMF or CNIs, applying concentration-controlled dosing. CNI-free patients, including those with moderate renal allograft dysfunction, have the benefit of improved renal function, whereas the risk of acute rejection after late withdrawal is low.
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jacqueline S
authors.initials: JS
authors.lastname: Mourer
authors.forename: Jan den
authors.initials: Jd
authors.lastname: Hartigh
authors.forename: Erik W
authors.initials: EW
authors.lastname: van Zwet
authors.forename: Marko J K
authors.initials: MJ
authors.lastname: Mallat
authors.forename: Jeroen
authors.initials: J
authors.lastname: Dubbeld
authors.forename: Johan W
authors.initials: JW
authors.lastname: de Fijter
mesh_terms: D000208:Acute Disease; D001706:Biopsy; D065095:Calcineurin Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006085:Graft Survival; D006801:Humans; D007676:Kidney Failure, Chronic / Q000503:physiopathology / Q000628:therapy; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D009173:Mycophenolic Acid