Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with Thymoglobulin or Campath

Abstract

Background: Multiple drug immunosuppression has allowed the near elimination of rejection, but without commensurate improvements in longterm graft survival and at the cost of quality of life. We have suggested that transplantation outcomes can be improved by modifying the timing and dosage of immunosuppression to facilitate natural mechanisms of alloengraftment and acquired tolerance.

Study design: Two therapeutic principles were applied for kidney transplantation: pretransplant recipient conditioning with antilymphoid antibody preparations (Thymoglobulin [Sangstat] or Campath [ILEX Pharmaceuticals]), and minimal posttransplant immunosuppression with tacrolimus monotherapy including "spaced weaning" of maintenance doses when possible. The results in Thymoglobulin- (n = 101) and Campath-pretreated renal transplantation recipients (n = 90) were compared with those in 152 conventionally immunosuppressed recipients in the immediately preceding era.

Results: Spaced weaning was attempted in more than 90% of the kidney transplant recipients after pretreatment with both lymphoid-depleting agents, and is currently in effect in two-thirds of the survivors. Although there was a much higher rate of acute rejection in the Thymoglobulin-pretreated recipients than in either the Campath-pretreated or historic control recipients, patient and graft survival in both lymphoid depletion groups is at least equivalent to that of historic control patients. In the Thymoglobulin-conditioned patients for whom followups are now 24 to 40 months, chronic allograft nephropathy (CAN) progressed at the same rate as in historic control patients. Selected patients on weaning developed donor-specific nonreactivity.

Conclusions: After lymphoid depletion, kidney transplantation can be readily accomplished under minimal immunosuppression with less dependence on late maintenance immunosuppression and a better quality of life. Campath was the more effective agent for pretreatment. Guidelines for spaced weaning need additional refinement.

Figure 1

Patient and graft survival in historic control (○○), Thymoglobulin-pretreated (×), and Campath-pretreated (black squares) kidney recipients.

Figure 2

Incidence and time to first acute rejection in historic control (○○), Thymoglobulin-pretreated (×), and Campath-pretreated (black squares) recipients.

Figure 3

Variable preweaning courses and weaning outcomes in Thymoglobulin-pretreated kidney recipients. Solid shade = daily tacrolimus (Tac) dosing, Spaced weaning represented by spikes that indicate frequency and dose. (A) Uncomplicated weaning from daily to once weekly doses of tacrolimus between 4 and 10 posttransplant mo in a cadaver kidney recipient who has been rejection free for more than 3 y. (B) Spaced weaning begun after 7 mo after a difficult rejection at 2½ mo. Tacrolimus doses have been three times per week for the past year in this recipient of a kidney from a live unrelated donor. (C) Reweaning in a patient who developed a mild rejection after 9 mo on one dose of tacrolimus per week. The eventual (and current) dose is three times per week. (D) Irreversible rejection of a cadaver kidney 4 wk after an attempt to reduce tacrolimus doses to every other day. The patient’s original disease was lupus nephritis.