Kidney transplantation under a tolerogenic regimen of recipient pretreatment and low-dose postoperative immunosuppression with subsequent weaning.
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.
Shapiro
Ron
R
Thomas E Starzl Transplantation Institute, University of Pittsburgh medical Center, Pittsburgh, PA 15213, USA. shapiror@msx.upmc.edu
Jordan
Mark L
ML
Basu
Amit
A
Scantlebury
Velma
V
Potdar
Santosh
S
Tan
Henkie P
HP
Gray
Edward A
EA
Randhawa
Parmjeet S
PS
Murase
Noriko
N
Zeevi
Adriana
A
Demetris
Anthony J
AJ
Woodward
Jennifer
J
Marcos
Amadeo
A
Fung
John J
JJ
Starzl
Thomas E
TE
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*
D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D016559:Tacrolimus