Published ahead of print on June 25, 2008
Clin J Am Soc Nephrol 3: 938-940, 2008
© 2008 American Society of Nephrology
doi: 10.2215/CJN.02190508
Renal Transplantation: What's New?
Suzanne El-Sayegh*,
Mohamed H. Sayegh
, and
William M. Bennett
* Renal Division, Staten Island University Hospital, Staten Island, New York; Renal Division, Brigham & Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts; and Northwest Renal Clinic, Portland, Oregon
Correspondence: Dr. William M. Bennett, Legacy Transplant Services, 1040 NW 22nd Avenue, Suite 480, Portland, OR 97210-3025. Phone: 503-413-7349; Fax: 503-413-6563; E-mail: bennettw{at}lhs.org
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Antibodies against MICA antigens and kidney-transplant rejection. N Engl J Med 357: 1293–1300, 2007 Zou Y, Stastny P, Susal C, Dohler B, Opelz G
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It has been known for many years that patients with well-matched kidney transplants, even those who are matched at HLA-A, -B, and -DR, do not have indefinite allograft survival, and some kidneys fail as a result of rejection. In an attempt to understand the mechanism for rejection with graft loss in the face of excellent HLA matching, Zou et al. took pretransplantation sera from 1910 kidney transplant recipients and tested these sera for antibodies to MHC class I–related chain A (MICA) antigens. These antigens are expressed on the surface of epithelial cells, endothelial cells, fibroblasts, and monocytes. The MICA antigens are ligands of an activating receptor on natural killer cells and CD8+ T lymphocytes. Genes for these antigens are located close to the HLA-A and -B loci.
Findings.
Antibodies against these MICA antigens were detected in 11.4% of the 1910 patients. More important, the presence of these antibodies was associated with inferior graft survival compared with transplant centers without such antibodies (88 versus 93%; P = 0.01). In patients with good HLA matching (zero or one antigen mismatch of HLA-A plus HLA-B plus HLA-DR), sensitization to MICA was associated with even worse graft survival (83 versus 95% in individuals without such antibodies; P = 0.002).
Commentary.
This study provides a mechanism by which some allografts can be rejected, despite excellent matching and without anti-HLA antibodies. An editorial accompanying this article suggested that anti-MICA antibodies might be surrogate markers for a fundamental mechanism that mediates graft rejection, specifically, natural killer cell alloreactivity, which is due to these antigens’ binding to an activating ligand (1). It is possible that exploring this further may lead to better screening and cross-matching and further understanding of the role that these antigens may play in development of chronic allograft nephropathy.
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Footnotes
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Published online ahead of print. Publication date available at www.cjasn.org.
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References
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- Flegel WA: Will MICA glitter for recipients of kidney transplants?
N Engl J Med357
:1337
–1339,2007[Free Full Text]
A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard therapy in kidney transplant recipients. Am J Transplant 8: 307–316, 2008 Vincenti F, Schena FP, Paraskevas S, Hauser IA, Walker RG, Grinyo J, FREEDOM Study Group
Renal transplant physicians have discussed the avoidance of steroid therapy or its withdrawal repeatedly over many decades. Some previous studies found that withdrawal of steroid therapy even in ideal candidates is associated with an increased rate of acute rejection episodes. In fact, a National Institutes of Health–sponsored study was stopped because of the high rate of rejection in steroid withdrawal patients who are of African American descent (1). This study was a randomized, open-label, multicenter study of patients who received no steroids, steroids for 1 wk followed by withdrawal, or standard steroids. This was done together with cyclosporine and enteric-coated mycophenolate sodium. Induction with the anti-CD25 antibody basiliximab was given to all patients.
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Findings.
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The incidence of biopsy-proven acute rejection, graft loss, or death was 36% in the group that was steroid-free. This was statistically worse than standard steroids. With steroid withdrawal after 1 wk, the incidence of these end points was 29.6%. This difference was NS compared with the 19.3% incidence of this combined end point with standard steroids. Biopsy-proven rejection was less frequent with standard steroids than with either of the other two groups. The benefits of the steroid withdrawal and the steroid-free group were less use of medication for posttransplantation diabetes and hyperlipidemia.
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Commentary.
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The study of Vincenti et al. was interesting in that it confirmed older observations that steroid avoidance or withdrawal is associated with increased risk for biopsy-proven rejection. In this study, the total avoidance of steroids resulted in inferior outcomes. Although the 1-wk withdrawal of steroids was noninferior to standard steroid therapy, the biopsy-proven rejection rate was higher, and this group showed a trend toward worse outcomes than with standard steroids. The take-home message for transplant recipients seems clear. Most patients can certainly get away with less steroids than they used to be given, and most transplant centers in the United States now reduce steroids to 
0.1 ml/g during the first few months after transplantation. Other studies have shown that late withdrawal is beneficial in carefully selected rejection-free patients, although deterioration of renal function and calcineurin inhibitor nephrotoxicity are risks when steroids are withdrawn. Perhaps the result of this study would have been different if a more potent induction agent such as thymoglobulin had been used. This might have allowed more success with the steroid-free or steroid-withdrawal arms of the study. In current clinical practice, it has not yet been shown that steroid removal is beneficial for the average patient in view of the increased risk for acute rejection episodes. More studies are clearly needed, and strategies using more potent induction may be in order. The steroid adverse effects that were often notable in the past have been markedly reduced by low-dosage steroid protocols, and it is rare these days to see a patient who is overtly cushingoid because of his or her posttransplantation immunosuppression. It seems most prudent to withdraw steroids or minimize steroids in patients who are the most at risk for steroid complications, including weight gain, metabolic bone disease, and posttransplantation diabetes; however, despite the theoretical appeal, data on the efficacy of steroid reduction in avoiding these complications are remarkably sparse. At this time, it is our opinion that the low-dosage steroid protocol should remain the standard of care for most renal transplant recipients.
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References
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- Steroid Withdrawal Study Group: Steroid withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil: A prospective randomized study.
Transplantation68
:1865
–1874,1999[CrossRef][Medline]
Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 357: 2562–2575, 2007 Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, Margreiter R, Hugo C, Grinyo JM, Frei U, Vanrenterghem Y, Daloze P, Halloran PF, ELITE-Symphony Study
Most commonly used modern immunosuppressive regimens for renal transplantation reduce the incidence of acute rejection compared with historical controls; however, selecting the optimal regimen with the fewest adverse effects is the source of some controversy. The Efficacy Limiting Toxicity Elimination (ELITE)-Symphony Study was designed to evaluate common therapeutic combinations to ascertain the best regimen for minimizing renal toxicity. A total of 1645 renal transplant recipients were randomly assigned to receive cyclosporine, mycophenolate mofetil, and corticosteroids as the standard immunosuppressive regimen. This was compared with the anti–IL-2 receptor antibody daclizumab; mycophenolate mofetil; corticosteroids; and low-dosage cyclosporine, low-dosage tacrolimus, or low-dosage sirolimus. Kidney function as estimated by the Cockroft-Gault formula 1 yr after transplantation was the primary study end point. Acute rejection and allograft survival were also examined as secondary end points.
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Findings.
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The best renal function was observed in the low-dosage tacrolimus arm of the study compared with the other three groups. Estimated creatinine clearance in the low-dosage tacrolimus group was 65.4 ml/min. The other groups ranged from 56.7 to 59.4 ml/min. Biopsy-proven acute rejection was also markedly reduced in the low-dosage tacrolimus group (12.3%) compared with standard-dosage cyclosporine (26%), low-dosage cyclosporine (24%), and low-dosage sirolimus (27.2%). This translated into better graft survival favoring low-dosage tacrolimus. Adverse effects were common but were more common in the low-dosage sirolimus group. In this large, well-done study, induction with an anti-CD25 mAb, mycophenolate mofetil, and steroid used in combination with low-dosage tacrolimus was a superior regimen to the others studied.
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Commentary.
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Picking an immunosuppressive regimen that maximizes efficacy and reduces the percentage of acute rejection episodes while limiting nephrotoxicity is the goal of most renal transplant programs. This large study carried out in 83 centers around the world used conventional dosages of cyclosporine in combination with corticosteroids and mycophenolate mofetil without induction compared with induction with an anti-IL receptor mAb plus mycophenolate; steroids; and lower than the usual starting dosages of cyclosporine, tacrolimus, and sirolimus. At 1 yr, the study end points of improved renal function and reduced rejection were observed primarily in the induction plus low-dosage tacrolimus group. This study was well done, and the regimens mirror clinical practice. Although it is appealing to translate the results of this study directly to practice, there are a few caveats that need to be considered. The study end points were observed 1 yr after transplantation. As pointed out by the editorialist, 1 yr may be too short of a follow-up time, because most nephrotoxicity is evident at times more remote from transplantation (1). Major concerns resulting from effect of immunosuppressive agents usually arise beyond the first year. The primary end point used in this study is an estimated creatinine clearance from the serum creatinine calculated from the Cockroft-Gault formula. Although this is convenient, it may not reflect true kidney function as well as other available formulas or actual GFR measurements. In the short term, sirolimus-based regimens had the most adverse effects and were not particularly effective in preventing acute rejection; however, the combination of mycophenolate mofetil together with tacrolimus results in more gastrointestinal adverse effects than cyclosporine-based regimens, and new-onset diabetes is clearly more frequent in tacrolimus-based regimens. At the end of the day, the question still remains about which is the best long-term regimen for most patients to maximize efficacy and limit toxicity, particularly nephrotoxicity. The long-term follow-up of these ELITE-Symphony patients will be critical in helping to answer this question.
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References
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- Leichtman AB: Balancing efficacy and toxicity in kidney-transplant immunosuppression.
N Engl J Med357
:2625
–2627,2007[Free Full Text]
HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 358: 353–361, 2008 Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman SL, Shaffer J, Preffer FI, Ding R, Sharma V, Fishman JA, Dey B, Ko DS, Hertl M, Goes NB, Wong W, Williams WW Jr, Colvin RB, Sykes M, Sachs DH
During the past few decades, short-term renal graft survival has dramatically improved with the introduction of new immunosuppressive medications; however, chronic rejection leading to graft loss and serious adverse effects from global immunosuppression or specific drug toxicities of current immunosuppressive regimens remain the major obstacle for long-term success of solid organ transplantation (1). Hence, the ideal strategy to treat patients with organ transplants should focus on the induction of immune tolerance, thereby leading to an improvement in long-term graft survival and elimination of toxic immunosuppressive drugs. Kawai et al. recently reported on five kidney transplant recipients who received a regimen of combined bone marrow and kidney transplants from HLA single-haplotype–mismatched living-related donors. The first three patients were treated with cyclophosphamide, anti–CD-2 mAb, cyclosporine, and thymic irradiation before their transplant. The protocol was modified after the third patient by adding rituximab and prednisone. The patients were subsequently withdrawn from maintenance immunosuppression.
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Findings.
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All five patients developed a transient chimerism (presence of donor bone marrow–derived cells in the recipient) by day 7; however, this chimerism was not detected on and after day 14. It is interesting that this is different from what has been previously reported in mice that develop permanent chimerism but somewhat similar to the primate data. One patient developed humoral rejection with anti-donor HLA class II antibodies and was treated with thymoglobulin, intravenous immunoglobulin, and rituximab without any improvement in his kidney function, leading to graft loss. The immunosuppressive medications were tapered off and discontinued in the other four patients who maintained a GFR 
60 ml/min. When tested in vitro, the T cells that were derived from stable patients without immunosuppressive therapy demonstrated unresponsiveness to the donor, with a higher level of intragraft FOXP3 mRNA (regulatory T cells) despite a similar level of mRNA for granzyme B (effector cytotoxic T cells), when compared with stable patients who were on immunosuppressive therapy. Upregulation of FOXP3, a marker of regulatory T cells, suggested that active regulatory mechanisms may be operating to maintain the tolerant state.
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Commentary.
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The authors reported the results of a pilot study that is funded by the National Institute of Health Immune Tolerance Network (http://www.immunetolerance.org) to induce tolerance in kidney transplant recipients and is based on extensive small and large animal studies showing that creation of mixed allogeneic chimerism results in induction of a tolerant state in subsequent solid organ transplant recipients. In 2006, Fudaba et al. (2) reported six patients who had ESRD as a result of multiple myeloma and received simultaneous kidney and bone marrow transplant from HLA-identical siblings to cure the myeloma and induce tolerance. This new article extends these initial observations to one-haplotype–matched kidney transplant recipients who do not have a hematologic malignancy. They reported five patients who developed transient chimerism after receiving combined bone marrow and kidney transplants from HLA single-haplotype–mismatched living-related donors without the development of graft-versus-host disease. Despite the withdrawal of the immunosuppressive medications, four of the five patients remained rejection-free and maintained a stable GFR, at least up until the end of the reported follow-up period. The development of humoral rejection and one graft loss resulted in modification of the protocol to include B cell depletion in two recipients. Although it has been demonstrated that clonal deletion is the main mechanism of tolerance in animals, it seems that maintenance of tolerance in humans may depend on active regulatory mechanisms.
Achieving transplantation tolerance, defined immunologically as the absence of a pathologic alloimmune response against donor transplant antigens (3), has been difficult in humans. Clinically, tolerance is defined as protection from acute and chronic rejection and indefinite allograft survival in the absence of chronic maintenance immunosuppression in an immunocompetent host. Although there have been scattered reports of kidney transplant recipients who have stopped taking or were intentionally withdrawn from immunosuppressive drugs without rejection, only recently intentional trials evaluating feasibility of tolerance-inducing regimens have been initiated (http://www.immunetolerance.org). The article described here sets the stage for expanding tolerance trials of human transplant recipients. There are several scientific and nonscientific challenges to achieving tolerance in the clinic (reviewed reference [3]). The pilot study by Kawai et al. sets the stage to overcome these challenges and expand pilot trials to achieve this elusive goal.
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References
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- Sayegh MH, Carpenter CB: Transplantation 50 years later: Progress, challenges and promises.
N Engl J Med351
:2761
–2766,2004[Free Full Text]
- Fudaba Y, Spitzer TR, Shaffer J, Kawai T, Fehr T, Delmonico F, Preffer F, Tolkoff-Rubin N, Dey BR, Saidman SL, Kraus A, Bonnefoix T, McAfee S, Power K, Kattleman K, Colvin RB, Sachs DH, Cosimi AB, Sykes M: Myeloma responses and tolerance following combined kidney and nonmyeloablative marrow transplantation: In vivo and in vitro analyses.
Am J Transplant2121
–2133,2006
- Salama AD, Womer KL, Sayegh MH: Clinical transplantation tolerance: Many rivers to cross.
J Immunol178
:5419
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