Donor-specific tolerance has been a goal in clinical organ transplantation since the 1950s. Despite significant advancements in immunosuppressive strategies, recipients of organ allografts still require nonspecific immunosuppression to prevent graft loss. Unfortunately, this requisite therapy is often associated with adverse side effects (such as nephrotoxicity, neurotoxicity, gastrointestinal symptoms, etc.) and, more importantly, increased incidences of life-threatening opportunistic infections and neoplasia. Despite the description more than 45 years ago of acquired tolerance to allogeneic skin grafts in mice (1), this same phenomenon in human solid organ transplantation remains elusive. Acceptance of a transplanted organ without indefinite immunosuppression has been reported (2) but clearly remains the exception rather than the rule.
Five previous cases of allogeneic bone marrow transplantation (BMT) followed by living-related renal transplantation in the same donor/recipient combination have been reported in the scientific literature (3–6)), and we are aware of a more recent sixth patient (7). All scientifically reported recipients received some degree of post-kidney transplant pharmacological immunosuppression, although the indication in some was for post-BMT pulmonary complications and not for prophylaxis against renal rejection (3). We report another patient with longer follow-up and the only case (to our knowledge) of a renal transplant after BMT with a postoperative course completely devoid of pharmacological immunosuppression.
Our patient, a Caucasian woman (originally blood type B+) with longstanding type I diabetes mellitus, was diagnosed with chronic myelogenous leukemia (CML) in 1986 at 28 years of age. She was unsuccessfully treated with hydroxyurea and busulfan and developed bilateral blindness from thrombocytopenia-related retinal hemorrhage. Her thrombocytopenia was refractory to platelet transfusions secondary to splenomegaly and sequestration. Her CML progressed, and an HLA-identical sister (blood type 0+) was identified as a suitable bone marrow donor. A splenectomy was performed in March 1988 to lessen the risk of critical thrombocytopenia resulting from her BMT preconditioning chemotherapy and total body irradiation. She underwent BMT from her sister in May 1988 at another institution. She received cyclosporine A and methotrexate during the first year post-BMT, but these medications were discontinued thereafter. Her course during this time was remarkable for mild graft-versus-host disease (GVHD) involving the skin and liver, which did not require an increase in her immunosuppression. Glucocorticoids were not used because of the mild nature of the GVHD and the potential to worsen her glucose control. She developed end-stage renal disease and began maintenance hemodialysis in August 1993. We were asked to evaluate her in January 1995 for renal transplantation. The etiology of her renal disease was likely a combination of the nephrotoxic pre- and post-BMT regimen and diabetic nephropathy, and we found her to be a suitable transplant recipient. The same sister who had given bone marrow to her was found to be an acceptable renal donor. The recipient’s blood type had converted to O, indicating successful long-term marrow replacement. There was no evidence of CML recurrence or chronic GVHD. Pertinent pretransplant donor data included: (1) estimated renal plasma flow 562 ml·min−1, with 41% contributed by the right kidney; (2) creatinine clearance 147 ml·min−1 based on a 12-hr urine collection (theoretically 60 ml·min−1 from the right kidney); and (3) multiple left renal arteries and a single right renal artery on arteriography.
We concluded that immunosuppressive therapy would be unnecessary after kidney transplantation, and, after the appropriately detailed discussions with the entire family, tested our prediction with full-thickness skin grafts from the sister on January 20, 1995. The skin grafts were accepted without pharmacological immunosuppression, and living-related renal transplantation using the right donor kidney was performed on February 20, 1995. There was prompt renal function, and no induction or maintenance immunosuppression was given. A radionuclide renal scan on posttransplant day 1 showed an estimated renal plasma flow of 331 ml·min−1; this increased to 407 ml·min−1 on day 8 and is currently 402 ml·min−1 (November 2000). She has experienced no episodes of GVHD or renal rejection after kidney transplantation. A urinary tract infection in July 1996 increased her serum creatinine to 1.5 mg·dl−1, but antibiotic therapy successfully restored it to baseline. She has no proteinuria, her serum creatinine is 1.0 mg·dl−1, and her creatinine clearance is 64 ml·min−1. She remains in remission from her CML, and there is no evidence of chronic GVHD.
The clinical appearance of the skin grafts 6 days after grafting and 6 weeks after grafting (2 weeks after renal transplantation) is shown in Figure 1. Punch biopsies of the skin “allo”grafts after 2 years showed no histologic abnormality (Fig. 2).
We have described a patient who developed chronic renal failure 5 years after undergoing BMT from an HLA-identical, ABO non-identical sister. After 1.5 years of maintenance hemodialysis she received a living-related kidney from the same sister and has enjoyed a 6-year posttransplant course free from GVHD—which did occur after renal transplantation in one other patient (3) —or rejection without pharmacological immunosuppression. Tolerance to the kidney transplant was expected, based on the acceptance of a previous full-thickness skin graft from the same donor. However, we cannot state this tolerance is donor-specific without testing with a third-party graft. A bone marrow chimera from a MHC-disparate donor/recipient combination is known to be at least partially immunodeficient (8) because the positive thymic selection of T lymphocytes is restricted by the MHC of the recipient, whereas peripheral antigen presentation is restricted by donor MHC (on donor-derived antigen-presenting cells). That the donor and recipient were HLA-identical siblings eliminates this possible source of nonspecific T lymphocyte dysfunction in the recipient. It is also unlikely that prior splenectomy was sufficiently immunosuppressive to obviate pharmacological immunosuppression after renal transplantation more than 5 years later.
Investigators have attempted to enhance the presumed beneficial transfer of passenger leukocytes via bone marrow augmentation after organ transplantation (9,10). This presumption is predicated on the idea that establishment of microchimerism in the recipient confers an immunological benefit (11) and is supported by the observation that some recipients with prolonged graft survival exhibit donor microchimerism and donor-specific hyporesponsiveness (12). There is, however, no proof that microchimerism, either graft-derived or marrow-derived, leads to indefinite allograft survival in humans in the absence of chronic immunosuppression, and late rejection of a liver allograft has been documented despite the presence of donor microchimerism (13).
The present and other reports of living-related renal transplantation after BMT in the same donor/recipient combination are examples of graft acceptance without maintenance immunosuppression in the setting of true chimerism, which differs altogether from microchimerism. Admittedly, BMT followed by renal transplantation from the same donor is not a strategy we can duplicate on a routine basis. These unusual reports are important, however, in that they may provide a basis for studying the mechanism(s) involved in tolerance, and they prove that genetically disparate solid organs can co-exist and function well without chronic immunosuppression.
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