The rocky road of limited immunosuppression for renal transplantation in African Americans.

What do we know about renal transplantation in African Americans? A lot, but still not enough. An excellent summary of many of the issues involved has recently been published (1). Since the 1970s it has been noted that “black Americans are at significantly greater risk of end-stage renal disease (ESRD) than whites . although they represent less than 13% of the general population, blacks make up almost a third of those with ESRD” (2). Once African Americans reach ESRD, they have more difficulty getting a renal transplant (2–5). When African Americans come to renal transplantation, they do so with a higher set point for pretransplant immune reactivity demonstrated in both nonspecific and specific immunologic tests: increased percentage of activated T cells, higher spontaneous blastogenesis, greater donor-specific mixed lymphocyte culture (MLC) responsiveness, increased costimulatory responses, and heightened primed cellular alloimmunity by ELISPOT (6, 7a). Suthanthiran et al. reported higher concentrations of transforming growth factor (TGF)but not of interleukin (IL)-6 or tumor necrosis factor (TNF)in African Americans (8). Although TGFis rather notorious as a fibrogenic molecule and held responsible for the infamous striped fibrosis occurring with cyclosporine A (CSA) nephrotoxicity, TGFhas also been reported to be a potent endogenous immunosuppressant as well as a factor in the immunosuppressant effects of CSA, whose immunosuppressive capacity in a murine model was blunted when anti-TGFantibodies were given (9). Another possible indication of the heightened immune responsiveness of African Americans is the fact that immunologically mediated renal diseases such as lupus nephritis and vasculitis have poorer outcomes in African Americans (10, 11). The possible roles of Lewis red cell antigen and Duffy antigen receptor have also been explored with suggestive and/or unconfirmed beneficial effects (12, 13). After renal transplantation African Americans have progressively worse renal allograft survival (1995–2002) when compared to whites (88.0% vs. 91.5% at one year; 74.0% vs. 82.8% at three years; and 59.1% vs. 72.5% at five years, respectively) (14). These unfavorable outcomes reflect the increased risk that African Americans have for acute rejection and chronic renal allograft failure both in the pre and post CSA era (15–19). There was no convincing evidence that human leukocyte antigen (HLA) mismatching, except for zero-mismatched deceased donor (DD) kidney survivals and their distinctly better outcomes, could explain the lower graft survival in African American (AA) recipients (18, 20). Even in two-haplotype-matched living-related AA renal transplant recipients, there was both a higher frequency of acute rejection during the initial transplant hospitalization and worse five-year graft survival with or without early acute rejection (21). Although early noncompliance was clearly ruled out, as was the role of major HLA mismatching, later noncompliance with and/or lower bioavailability of immunosuppressant medications remained possible (21). Recently, however, the seven-year actuarial graft survival of living donor (LD) renal transplants in 238 African Americans was found to be comparable to that in 211 non-African Americans, whereas the outcomes in DD kidney recipients were inferior (64% vs. 79%; P 0.03) (22). The inferior outcome was ascribed to a significantly greater frequency of ESRD caused by hypertension and longer dialysis periods when compared to either AA recipients of LD kidneys or non-AA recipients of DD kidneys (22). All patients received thymoglobulin or anti-CD25, prednisone, tacrolimus (TAC), and mycophenolate mofetil (MMF) (22). Even before attempts were made to eliminate certain immunosuppressant medications, such as prednisone and calcineurin inhibitors, it was known that “African-American patients required a 37% mean higher dose of TAC than white patients to achieve comparable blood concentrations” (19). Subsequent studies focused on augmented immunosuppression protocols in AA renal transplant recipients. Substitution of MMF for azathioprine (AZA) significantly (P 0.001) improved both patient and death-censored graft survival at 3 years in AA primary renal transplant recipients (96.3% vs. 93.2%, and 85.8% vs. 75.2%, respectively), similar to its effect in whites; about 40% of these patients received induction therapy and essentially all received a calcineurin inhibitor and prednisone (though not specified) (23). In a small, nonrandomized prospective study of 29 African Americans and 20 high-risk Hispanic renal transplant recipients, the addition of the IL-2 receptor antibody daclizumab to CSA, MMF, and prednisone was associated with a reduction in acute rejection rates to 26.4% per patient-years vs. 49.3% in 56 similar controls who did not receive daclizumab with average follow-up of approximately 13 and 17 months, respectively (24). In a retrospective study of 88 AA renal transplant recipients, induction with thymoglobulin (n 36) or basiliximab (n 52) resulted in comparable graft survival and function at approximately 20 months, though the treatment groups had different composition (25). AA renal transplant recipients treated either with CSA/prednisone (n 90) or sirolimus (SIR)/CSA/ prednisone (n 86) were compared with 148 white recipients receiving SIR/CSA/prednisone (26). Acute rejection episodes within two years were reduced in African Americans from 43.3% to 17.0% (P 0.004) in the SIR/CSA/prednisone group, comparable to an acute rejection frequency of 18% in whites (26). The same group had a two-year graft survival of Department of Hypertension and Nephrology, Cleveland Clinic, Cleveland, OH. Address correspondence to: William E. Braun, M.D., Department of Hypertension and Nephrology, Cleveland Clinic, 9500 Euclid Avenue, Desk A51 Cleveland, OH, 44195. E-mail: braunw@ccf.org Received 13 October 2006. Accepted 20 October 2006. Copyright © 2007 by Lippincott Williams & Wilkins ISSN 0041-1337/07/8303-267 DOI: 10.1097/01.tp. 0000251654.84774. 5a