Presented at:
2007 American Transplant Congress
San Francisco, CA, May 5-9, 2007
A Tolerance Trial in Kidney Transplantation Based on T-Cell Depletion, Tacrolimus, and Sirolimus
Knechtle S, Hu H, Janus C, Radke N, Sollinger H, Davis Z, Bloom D
University of Wisconsin, Madison, WI
To assess the ability of T-cell depletion in combination with a limited 2-month course of tacrolimus and a 1-year course of sirolimus to induce tolerance in well-matched renal allograft recipients, a pilot study was undertaken to assess the outcome of this strategy in 10 patients. Seven patients are currently beyond 1-year follow-up and 3 patients will reach that timepoint within the next 4 weeks.
All patients were primary renal transplants with at least 3 of 6 HLA antigen matches, including 9 living donor transplants and 1 0-antigen mismatch deceased donor transplant. HLA-identical combinations were excluded. All patients received 3 doses of alemtuzumab 30 mg on days 0, 1, and 2. All patients received 2 months of tacrolimus, maintaining levels of 4-8 ng/ml. All patients began sirolimus on day 1 post-transplant and continued sirolimus for at least 1 year targeting levels of 8-12 ng/ml. Alloantibody measured by Luminex, protocol biopsy, and cytokine kinetics tests (CKT) are done at 1 year. CKT measures T cell responses to donor vs. third-party vs. self.
One of 7 patients has chronic antibody-mediated rejection a 1 year (Cr=2.3 mg/dL). No other patient has had acute or chronic rejection. Two patients have started weaning from sirolimus based on GFR>50 ml/min, absence of alloantibody, and absence of rejection on 1-year protocol biopsy. Two eligible patients refused to be withdrawn. Three patients did not meet criteria for withdrawal: 1 due to development of alloantibody and positive C4d staining, clinically unsuspected and in the absence of graft injury by histology, and 2 patients due to GFR<50 ml/min. The CKTs performed on samples taken month 12 post-transplant have revealed that 2 patients have donor-specific unresponsiveness, as there was little or no production of IL-2, IFN-γ, IL-13, or IL-5 to donor antigen. The month 6 and month 9 CKTs for one patient likewise demonstrated unresponsiveness. Two other patients are hyporesponsive to donor antigen at month 12. The patient who has developed alloantibody and whose biopsy showed C4d+ staining definitive hyperresponsiveness to donor antigen. Two patients were hospitalized for infection (1 diabetic foot infection, 1 bacterial sepsis).
This pilot study reveals that this immunosuppressive protocol has been well tolerated, prevents rejection, and has permitted weaning of immunosuppression in some patients as is currently in progress. The CKT is being evaluated for correlation with clinical immune responsiveness.