A clinical research consortium sponsored by NIAID and JDRF
Kawai T, Sachs DH, Spitzer T, Tolkoff-Rubin N, Wong W, Williams W, Saidman S, Colvin RB, Sykes M, Cosimi AB, Ko DSC, LoCascio S
Transplant Center, Massachusetts General Hospital, Boston, MA Transplant Biology Research Center, Massachusetts General Hospital, Charlestown, MA Pathology, Massachusetts General Hospital, Boston, MA, United States Hematology, Massachusetts General Hospital, Boston, MA Immune Tolerance Network, University of California, San Francisco, CA
BACKGROUND: We previously reported successful induction of renal allograft tolerance (off all immunosuppression (IS) for 2-5 years) by the mixed chimerism approach in 4/5 haploidentical recipients of combined kidney and bone marrow transplantation (CKBMT). Five additional subjects have now been enrolled in a slightly revised, ongoing protocol.
METHODS: The initial four subjects have been followed for an additional 2 years. The 5 new subjects, age 22-43, also received CKBMT from HLA mismatched donors. The revised preparative regimen added more intensive anti-CD20 mAb treatment, a short post-transplant course of steroids, and tacrolimus in place of cyclosporine.
RESULTS: The previously reported 4 subjects continue to be stable with normal kidney function off all IS for 4-7 years. Two of these subjects developed anti-donor HLA class II antibody shortly after IS discontinuation, but have had no functional impairment, nor evidence of rejection on sequential protocol biopsies. In all 5 new subjects, mixed chimerism was detected on days 7-13, and undetectable after day 14. All five subjects developed derangement of renal function between days 10-20, which was attributed to cytokine release ( engraftment syndrome ) associated with engraftment and/or loss of donor hematopoietic cells, as described in our previous report. One subject developed thrombotic microangiopathy, thought to be due to tacrolimus toxicity concomitant with this cytokine syndrome, and continues to have impaired renal function. The other four subjects recovered normal kidney function. IS was discontinued successfully in the first two of these subjects at 8 months after transplantation and is currently being weaned in the other two.
CONCLUSIONS: Renal allograft function in recipients of CKBMT remains stable in 6 of 8 subjects, at 1 month to 7 years after discontinuing IS and in 2 subjects currently being weaned. Understanding and appropriate treatment for the transient renal dysfunction seen regularly at about day 10 remain to be clarified.
