title: Kidney transplantation under a tolerogenic regimen of recipient pretreatment and low-dose postoperative immunosuppression with subsequent weaning.
abstract: OBJECTIVE
  The purpose of this work was to perform kidney transplantation under a regimen of immunosuppression that facilitates rather than interferes with the recently defined mechanisms of alloengraftment and acquired tolerance.
  
  
  BACKGROUND
  In almost all centers, multiple immunosuppressive agents are given in large doses after kidney transplantation in an attempt to reduce the incidence of acute rejection to near zero. With the elucidation of the mechanisms of alloengraftment and acquired tolerance, it was realized that such heavy prophylactic immunosuppression could systematically subvert the clonal exhaustion-deletion that is the seminal mechanism of tolerance. In addition, it has been established that the rejection response can be made more readily treatable by pretransplant immunosuppression. Consequently, we conducted kidney transplantation in compliance with 2 therapeutic principles: recipient pretreatment and the least possible use of posttransplant immunosuppression.
  
  
  METHODS
  One-hundred fifty unselected renal transplant recipients with a mean age of 51 +/- 15 years and multiple risk factors had pretreatment with approximately 5 mg/kg of rabbit antithymocyte globulin (Thymoglobulin) in the hours before transplantation, under covering bolus doses of prednisone to prevent cytokine reactions. Minimal posttransplant immunosuppression was with tacrolimus monotherapy to which steroids or other agents were added only for the treatment of rejection. At or after 4 months after transplant, spaced-dose weaning from tacrolimus monotherapy was begun in patients who had exhibited a satisfactory course.
  
  
  RESULTS
  One-year actuarial patient and graft survival was 97% and 92%, respectively. Although the incidence of early acute rejection was 37%, only 7% required prolonged treatment with any agent other than tacrolimus. After a follow-up of 6 to 21 months, the mean serum creatinine in patients with functioning grafts is 1.8 +/- 1.0 mg/dL. Seventy-three percent of the patients met the criteria for spaced weaning. Although rejection episodes occasionally required restoration of daily treatment, 94 (63%) of the 150 patients currently receive tacrolimus in spaced doses ranging from every other day to once a week.
  
  
  CONCLUSIONS
  With this approach to immunosuppression, it has been possible to avoid early posttransplant overimmunosuppression and thereby to promote the evolution of a degree of partial tolerance sufficient to undertake substantial dose reduction. The strategy, which is applicable for all organ grafts, constitutes a paradigm shift in transplant management at our center.
authors.affiliation: Thomas E Starzl Transplantation Institute, University of Pittsburgh medical Center, Pittsburgh, PA 15213, USA. shapiror@msx.upmc.edu
authors.forename: Ron
authors.initials: R
authors.lastname: Shapiro
authors.forename: Mark L
authors.initials: ML
authors.lastname: Jordan
authors.forename: Amit
authors.initials: A
authors.lastname: Basu
authors.forename: Velma
authors.initials: V
authors.lastname: Scantlebury
authors.forename: Santosh
authors.initials: S
authors.lastname: Potdar
authors.forename: Henkie P
authors.initials: HP
authors.lastname: Tan
authors.forename: Edward A
authors.initials: EA
authors.lastname: Gray
authors.forename: Parmjeet S
authors.initials: PS
authors.lastname: Randhawa
authors.forename: Noriko
authors.initials: N
authors.lastname: Murase
authors.forename: Adriana
authors.initials: A
authors.lastname: Zeevi
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
authors.forename: Jennifer
authors.initials: J
authors.lastname: Woodward
authors.forename: Amadeo
authors.initials: A
authors.lastname: Marcos
authors.forename: John J
authors.initials: JJ
authors.lastname: Fung
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Starzl
mesh_terms: D000328:Adult; D000368:Aged; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology* / Q000379:methods; D008875:Middle Aged; D011184:Postoperative Period; D011300:Preoperative Care; D016559:Tacrolimus / Q000008:administration & dosage*
chemical_list: D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D016559:Tacrolimus