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Kidney Transplantation Under a Tolerogenic Regimen of Recipient Pretreatment and Low-Dose Postoperative Immunosuppression With Subsequent Weaning

Shapiro, Ron MD; Jordan, Mark L. MD; Basu, Amit MD; Scantlebury, Velma MD; Potdar, Santosh MD; Tan, Henkie P. MD, PhD; Gray, Edward A. BS; Randhawa, Parmjeet S. MD; Murase, Noriko MD; Zeevi, Adriana PhD; Demetris, Anthony J. MD; Woodward, Jennifer PhD; Marcos, Amadeo MD; Fung, John J. MD, PhD; Starzl, Thomas E. MD, PhD

doi: 10.1097/01.sla.0000089853.11184.53
Original Papers and Discussions

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.

Summary Background Data: 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.

Kidney transplantation was performed in 150 patients while observing the 2 principles of immunosuppression: recipient pretreatment and minimal posttransplant immunosuppression. A large proportion of the recipients could be weaned subsequently to spaced doses of monotherapeutic immunosuppression given from every other day to as infrequently as once per week.

From the Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA.

Present address of Velma Scantlebury: University of Southern Alabama, Mobile, AL.

Reprints: Ron Shapiro, MD, Thomas E. Starzl Transplantation Institute, 3459 5th Avenue, UPMC Montefiore, 7 South, Pittsburgh, PA 15213. E-mail:

© 2003 Lippincott Williams & Wilkins, Inc.