Immunosuppression is now manageable in the

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1 EVOLVING STRATEGIES FOR IMMUNOSUPPRESSION IN RENAL TRANSPLANTATION: A REVIEW OF RECENT CLINICAL TRIALS* Stephen J. Tomlanovich, MD, Thomas C. Pearson, MD, DPhil, and Lorenzo Gallon, MD ABSTRACT When using immunosuppressant agents in renal transplantation, achieving low rejection rates while minimizing long-term toxicities (eg, nephrotoxicity and cardiovascular disease) associated with these agents is a primary goal. Strategies that reduce exposure to calcineurin inhibitors (CNIs) have demonstrated reasonable safety and efficacy in some targeted patient populations, but registry data and multicenter studies show that CNI-free regimens involving sirolimus and mycophenolate mofetil (MMF) generally have higher rejection rates and inferior graft outcomes. Longer term studies are needed to evaluate a possible learning curve with sirolimus and to study possible long-term toxicities such as wound healing, anemia, and hyperlipidemia. Converting to sirolimus and MMF after initial CNI therapy has also been studied. For example, results from the ongoing Spare the Nephron Trial demonstrate low rejection rates in stable transplant patients, short-term improvement in kidney function, and good safety results. In the future, *This article is based on presentations from the American Transplant Congress held May 5-9, 2007, in San Francisco, California. Clinical Professor of Medicine and Surgery, Medical Director, Renal Transplant Service, University of California at San Francisco, San Francisco, California. Professor of Surgery, Emory University School of Medicine, Co-Director Kidney/Pancreas Transplant Program, Emory University Hospital, Atlanta, Georgia. Associate Professor, Division of Nephrology/ Hypertension, Director, Transplant Nephrology Program, Northwestern University Medical School, Chicago, Illinois. Address correspondence to: Stephen J. Tomlanovich, MD, Clinical Professor of Medicine and Surgery, Medical Director Renal Transplant Service, University of California at San Francisco, Box 0780, 505 Parnassus Avenue, Moffitt 884, San Francisco, CA stomlanovich@surgery.ucsf.edu. agents such as belatacept may provide a nonnephrotoxic alternative to CNIs. Minimizing corticosteroid exposure is another worthy goal, and studies using induction protocols (eg, with lymphocyte-depleting agents or interleukin-2 receptor antagonists) and/or newer immunosuppressive agents (eg, MMF, sirolimus, and tacrolimus) have demonstrated that steroids can be withdrawn early in many patients without increasing the risk of acute rejection or long-term allograft problems. (Adv Stud Med. 2007;7(9): ) Immunosuppression is now manageable in the short term but it remains a major hurdle for long-term outcomes in renal transplantation. Specifically, current combinations of immunosuppressive agents lead to markedly reduced acute rejection rates in transplantation, but they do not provide a related increase in long-term graft survival. The reasons for this include cardiovascular disease, cancer, infections, bone fractures, and other toxicities related to the immunosuppressant agents themselves. Efforts to maintain low acute rejection rates and yet minimize longer term toxicity focus not only on creation and use of novel immunosuppressant agents but also improved employment of existing agents. In particular, as reviewed here, protocols to minimize exposure to calcineurin inhibitors (CNIs) and steroids have now been tested in many settings. CNI-FREE TRIALS Several CNI-free protocols for minimizing the cumulative toxicity of this class have now been tested. In one of the first single-arm CNI-free trials (n = 100), daclizumab/mycophenolate mofetil (MMF) provided Johns Hopkins Advanced Studies in Medicine n 275

2 acceptable 1-year patient and graft survival rates (97% and 96%, respectively) but unacceptable rejection rates (biopsy-proven acute rejection [BPAR] of 48% and 53% at 6 and 12 months, respectively), suggesting that interleukin-2 (IL-2) blockade was inadequate. 1 Similarly, in a trial (n = 78) comparing CNI/MMF/steroids with sirolimus/mmf/steroids, patients and graft survival were acceptable (97.5% and 92.5%, respectively) but BPAR was high (27.5%), and 43% of patients taking sirolimus discontinued because of side effects such as hyperlipidemia, thrombocytopenia, or anemia. 2 Induction with basiliximab reduced the 1-year BPAR (6.4%) when added to the sirolimus/mmf/steroid regimen (n = 61). 3 At 2 years, patients in the sirolimus group of this single-center prospective study had better renal function, both functionally and histologically, and a low complication rate and post-transplantation morbidity comparable to the CNI arm. 4 A larger follow-up trial (n = 260) testing 2 doses of MMF also showed the sirolimus-based immunosuppression with induction to be generally safe and effective (BPARs 9% and 13%). 5 In a single-center randomized trial involving living donor recipients (n = 132), the combination of sirolimus/mmf/steroids with induction also provided efficacy outcomes similar to and renal function better than a tacrolimus-based regimen. 6 More recently, in a trial involving thymoglobulin induction, low-dose MMF (1.5 g/day), and steroids (n = 166), the sirolimus and tacrolimus arms yielded identical rejection rates (19% BPAR) in addition to similar patient/graft survival and renal function. 7 Overall, these studies and a variety of other trials indicate that the regimen of anti IL-2 and sirolimus/mmf/steroids is reasonably safe and effective in targeted patients but that the rates of acute rejection may be higher than with CNI-based regimens Sirolimus also appears to have a learning curve that can significantly impact efficacy. In addition, the sirolimus/mmf combination may be trading one type of toxicity (nephrotoxicity) for a different type of long-term toxicity (eg, wound healing, anemia, and hyperlipidemia), a trade-off that only longer term studies can fully evaluate. Recent data from registries and large multicenter trials generally support these single-center study findings of higher rejection rates with CNI-free regimens and they also reveal inferior graft outcomes. For example, registry analysis shows that the 6-month acute rejection rate was significantly higher in patients discharged between 2000 and 2005 on sirolimus/mmf (n = 2040) compared to those discharged on CNI-based immunosuppressive regimens (n = ; overall 16.0% vs 11.2%; P <.001; Figure 1). 14 The sirolimus/mmf groups also had inferior outcomes in terms of graft survival rate and discontinuation rate. Note that patients in the sirolimus registry group may have had other clinical issues (eg, acute tubular necrosis and CNI intolerance) that necessitated sirolimus use at discharge. Data from the large SYMPHONY trial (n = 1645) also show increased 12- month BPAR with low-dose sirolimus (37.4%) versus low-dose tacrolimus (12.3%) and no benefits in terms of renal function. 15 Preliminary results from the ORION trial (n = 450) also document increased risk of acute rejection with sirolimus (30.3% BPAR) compared to tacrolimus, although the renal function was maintained. 16 As mentioned earlier in this article, outcomes may improve as centers become more experienced with sirolimus, but this learning curve effect is not reflected in these studies. Looking ahead, new agents such as belatacept, which inhibits T-cell activation via costimulation blockade, may eventually provide a level of immunosuppressive efficacy in renal transplantation similar to cyclosporine but without the nephropathy of the CNIs. In an ongoing randomized study comparing belatacept with cyclosporine in renal transplantation (n = 217), the 1-year acute rejection rates with this recombinant fusion protein were low (BPARs of 7% and 6% with 2 Figure 1. Increased Rate of Acute Rejection with CNI-Free Immunosuppression: Analysis of SRTR Registry Data n = CsA = cyclosporine; MMF = mycophenolate mofetil; SRL = sirolimus; SRTR = Scientific Registry of Transplant Recipients; TAC = tacrolimus. Reprinted with permission from Srinivas et al. Am J Transplant. 2007;7: Vol. 7, No. 9 n August 2007

3 different doses) and kidney function was preserved. 17 The future of CNI-free regimens may lie in the efficacy and toxicity profiles of such biologic agents. CNI CONVERSION TRIALS Several investigators have recently explored the benefits of late conversion to sirolimus and MMF in renal transplantation. These CNI conversion efforts are based on various lines of evidence, including previous studies documenting the efficacy of various non-cni combination therapies involving sirolimus 2,4,18 ; retrospective or single-center studies showing improved long-term glomerular filtration rate (GFR) with CNI conversion 19,20 ; and CNI conversion trials with cardiac 21 and liver 22 recipients showing preserved cardiac and hepatic function, in addition to improved renal function. Converting from CNIs to sirolimus is typically contemplated as a strategy to avoid nephrotoxicity and the related risk for chronic transplant nephropathy that is associated with CNIs while still allowing the early protection from acute rejection afforded by these agents. 23 Such a conversion might also avoid the early complications associated with inhibition of the mammalian target of rapamycin (mtor) inhibitors, such as wound healing and lymphocele. More theoretically, the switch might also avoid the reduction in CD4-CD25 regulatory T cells (Tregs) that has recently been associated with CNIs. 24 The potential drawbacks of such a CNI conversion to sirolimus include hyperlipidemia, proteinuria, 25 and possible altered glucose metabolism, including increased insulin resistance. 26 The largest multicenter prospective randomized clinical trial to test the safety and efficacy of CNI conversion to sirolimus has been the Spare the Nephron (STN) trial. In this trial, renal allograft recipients who were maintained on MMF and a CNI with or without corticosteroids for 14 days were randomized at 30 to 180 days post-transplant to continued MMF plus CNI or a switch to MMF plus sirolimus (2- to 10-mg loading dose and maintained for trough levels of 5 10 ng/ml). Patients with acute rejection, high lipids, or poor creatinine clearance at study entry were excluded. Interim STN results on 208 of 305 randomized patients as reported at the 2007 American Transplant Congress (ATC) are summarized here. The randomization produced groups that were similar in terms of gender, race, age, donor type, sensitization status, and form of induction therapy. Mean time to CNI conversion was approximately 4 months. In terms of the primary outcome, the mean percent change from baseline to 12 months of measured GFR (cold iothalamate), patients in the CNI conversion group had a higher mean increase in kidney function: 28.8% change (±75.0%) versus 8.2% (±56.0%; no P value because of interim nature of data; Figure 2). Rates of biopsy-proven acute rejection, death, and graft loss were similar. Safety outcomes were generally similar in the treatment groups. Overall, the preliminary STN results suggest that conversion to MMF plus sirolimus results in a low rejection rate in stable renal transplant patients and also suggests short-term improvement in estimated GFR. A definitive long-term assessment will require follow-up on all 305 patients for the full year and, moreover, continued tracking of clinical outcomes and safety over an even longer period. Another possible rationale for conversion from CNIs to sirolimus is the potential that this latter agent provides unique benefits for specific patient groups. At least one study has shown, for example, that maintenance immunosuppression with mtor inhibitors (with or without CNI) may reduce the incidence of de novo malignancies. 27 A randomized prospective study is now testing the efficacy of conversion to sirolimus (trough target levels 5 10 ng/ml) in renal transplant patients with a history of squamous cell carcinoma (SCC). The primary endpoint of this multicenter trial based in the Netherlands and the United Kingdom is Figure 2. Interim Results from the Spare the Nephron Trial: Mean Change in Glomerular Filtration Rates GFR = glomerular filtration rate; MMF/CNI = maintenance on mycophenolate mofetil and a calcineurin inhibitor; MMF/SRL = conversion to mycophenolate mofetil and sirolimus. Johns Hopkins Advanced Studies in Medicine n 277

4 the recurrence rate of biopsy-confirmed cutaneous SCC within 2 years of entry. In summary, based on single-center experiences and early results from STN, CNI conversion may be a good option for some renal transplantation recipients. However, the definitive role of CNI conversion remains to be defined by the results of ongoing multicenter prospective trials. STEROID-SPARING TRIALS The adverse effects of corticosteroids are well known, but the historical data strongly suggest that withdrawal of steroids in the months after renal transplant increases the rate of rejection. 28 Based on further scrutiny of that historical data and also based on growing use of induction protocols (eg, with lymphocyte-depleting agents or IL-2 receptor antagonists [IL-2-RA]) and newer immunosuppressive agents (eg, MMF, sirolimus, and tacrolimus), several investigators have recently explored new strategies to limit steroids as a maintenance agent. In one retrospective analysis, results with a rapid discontinuation protocol ( , n = 477) were compared to those from a more typical slow tapering of steroids over months ( , n = 388). In the rapid elimination group, thymoglobulin in 5 doses was the standard induction and prednisone was completely eliminated by day 5 after surgery. In this study, there were no significant differences in patient survival, graft survival, or creatinine clearance over 48 months. 29 Similarly, at Northwestern University we recently performed a retrospective analysis of 212 kidney transplant patients with or without prednisone as part of the maintenance immunosuppression. 30 All patients were managed with induction, including IL-2-RA (days 0 and 3) and methylprednisolone (days 0, 1, and 2) followed by maintenance with tacrolimus and MMF with (n = 96) or without (n = 116) prednisone (ie, rapid steroid elimination). The Kaplan-Meier analyses of patient and graft survival at 7 years after transplantation were not statistically different between the groups (Figure 3). Neither were there significant differences in acute rejection rates (P =.12), severity of rejection, or slope of GFR (P =.19). The prednisonetreated patients had a significantly higher incidence of hyperlipidemia (50% vs 30%; P =.001) and posttransplantation diabetes (15% vs 5%; P =.001). As reported at the 2007 ATC, histological evaluation of the allografts at 1 year post-transplant indicates a lack of differences between groups in terms of fibrosis, inflammation, or transplant glomerulopathy. 31 In another large retrospective analysis performed in our group, we focused on the impact of different induction agents on prednisone-free immunosuppression. 32 In this single-center study, kidney transplant patients received alemtuzumab (n = 123) or basiliximab (n = 155) induction along with brief methylprednisone (days 0, 1, 2) in combination with a tacrolimus/mmf maintenance regimen. Although early rejection rates (3 month) were lower in the alemtuzumab group, the 12-month patient graft and survival rates across an ethnically diverse population were equivalent in the 2 groups. The quality of renal function and the incidence of infectious complications were also similar. Maintenance regimens may also impact long-term outcomes with steroid-free immunosuppression; therefore, we prospectively compared outcomes following tacrolimus/mm (n = 45) or tacrolimus/sirolimus (n = 37) in renal transplant patients. 33 Patients randomized to the MMF group were younger (33.6 vs 39.4 years; P =.04) and also had a higher human leukocyte Figure 3. Effect of Prednisone Versus No Prednisone in Maintenance Immunosuppression on Long-Term Outcome After Renal Transplantation (A) Cumulative patient survival in PRED+ versus PRED- at 7 years after transplantation. The Kaplan-Meier curves are not significantly different (P =.06). Respectively, 77% and 74% of patients in the PRED+ and PRED- groups reached 5 years of post-transplantation follow-up. (B) Cumulative renal allograft survival in PRED+ versus PRED- at 7 years after transplantation. The Kaplan-Meier curves are not significantly different (P =.27). Adapted with permission from Gallon et al. Clin J Am Soc Nephrol. 2006;1: Vol. 7, No. 9 n August 2007

5 antigen mismatch (3.60 vs 3.10; P =.02). Over 3 years, graft loss was significantly higher in the sirolimus group (6 cases) versus the MMF group (1 case; P =.04). The GFR after transplantation was consistently and statistically better in the MMF group versus the sirolimus group, even after adjustment for patient age (Figure 4). The 4-year results of a blinded randomized trial with rapid steroid withdrawal was reported at ATC 2007 by Woodle et al. 34 Patients were treated with induction therapy and maintained on tacrolimus and mycophenolate mofetil. The rapid steroid withdrawal group had a significantly higher incidence of acute rejection, but they experienced some benefits in terms of reduced cardiovascular risk factors. Whether the modest benefits of steroid withdrawal outweigh the risk of increased rejection remains to be determined. 34 Several investigators have recently reported on early steroid withdrawal in special transplant populations. In African Americans, a retrospective analysis showed that one group of African American patients without steroid maintenance (n = 40) had 1-year graft survival and function and acute rejection rates that were essentially similar to African American patients with steroid maintenance (n = 33). 35 A larger (n = 160) and longer (3-year) comparison has now confirmed that kidney function and graft survival are comparable in African American patients with or without early steroid withdrawal. 36 The same author has reported comparable 5-year patient and graft outcomes, but higher 5-year serum creatinine and early (1 Figure 4. Impact of 2 Different Steroid-Free Maintenance Immunosuppression Regimens on Glomerular Filtration Rate GFR = glomerular filtration rate; Tac/MMF = tacrolimus/mycophenolate mofetil; Tac/SRL = tacrolimus/sirolimus. Adapted with permission from Gallon et al. Am J Transplant. 2006;6: month) subclinical acute rejection in African American recipients (n = 100) compared to non African American recipients (n = 100). 37 (See Selected Abstracts later in this monograph for descriptions of these 2 reports.) Experiences with early steroid withdrawal has now also been reported in ABO-incompatible patients, 38 crossmatch positive patients, 39 and retransplanted patients. 40 In summary, induction therapy with IL-2-RA or a T- cell depleting agent allows safe elimination of steroids in many patients without increasing the risk of acute rejection or long-term allograft problems. A steroid-free maintenance regimen has been shown to have significant health benefits in terms of fewer adverse events. In terms of a combination maintenance regimen in a steroid-free protocol, tacrolimus plus MMF may provide better graft survival and function than tacrolimus plus sirolimus. In African American patients, steroidfree immunosuppression can be safe, but increased rates of subclinical rejection suggest the need for an early biopsy. In patients with high levels of antiblood group antibodies, steroid therapy may need to continue for a longer period to avoid acute humoral rejection. REFERENCES 1. Vincenti F, Ramos E, Brattstrom C, et al. Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. Transplantation. 2001;71: Kreis H, Cisterne JM, Land W, et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation. 2000;69: Flechner SM, Goldfarb D, Modlin C, et al. Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation. 2002;74: Flechner SM, Kurian SM, Solez K, et al. De novo kidney transplantation without use of calcineurin inhibitors preserves renal structure and function at two years. Am J Transplant. 2004;4: Flechner SM, Feng J, Mastroianni B, et al. The effect of 2-gram versus 1-gram concentration controlled mycophenolate mofetil on renal transplant outcomes using sirolimus-based calcineurin inhibitor drug-free immunosuppression. Transplantation. 2005;79: Hamdy AF, El-Agroudy AE, Bakr MA, et al. Comparison of sirolimus with low-dose tacrolimus versus sirolimus-based calcineurin inhibitor-free regimen in live donor renal transplantation. Am J Transplant. 2005;5: Larson TS, Dean PG, Stegall MD, et al. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant. 2006;6: Flechner SM, Friend PJ, Brockmann J, et al. Alemtuzumab induction and sirolimus plus mycophenolate mofetil maintenance for CNI and steroid-free kidney transplant immunosuppression. Am J Transplant. 2005;5: Gelens MA, Christiaans MH, van Heurn EL, et al. High rejec- Johns Hopkins Advanced Studies in Medicine n 279

6 tion rate during calcineurin inhibitor-free and early steroid withdrawal immunosuppression in renal transplantation. Transplantation. 2006;82: Shaffer D, Kizilisik AT, Feurer I, et al. Calcineurin inhibitor avoidance versus steroid avoidance following kidney transplantation: postoperative complications. Transplant Proc. 2006;38: Oyen O, Strom EH, Midtvedt K, et al. Calcineurin inhibitorfree immunosuppression in renal allograft recipients with thrombotic microangiopathy/hemolytic uremic syndrome. Am J Transplant. 2006;6: Harmon W, Meyers K, Ingelfinger J, et al. Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation. J Am Soc Nephrol. 2006;17: Furian L, Baldan N, Margani G, et al. Calcineurin inhibitorfree immunosuppression in dual kidney transplantation from elderly donors. Clin Transplant. 2007;21: Srinivas TR, Schold JD, Guerra G, et al. 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Calcineurin inhibitorinduced chronic nephrotoxicity in liver transplant patients is reversible using rapamycin as the primary immunosuppressive agent. Clin Transplant. 2002;16: English J, Evan A, Houghton DC, Bennett WM. Cyclosporineinduced acute renal dysfunction in the rat. Evidence of arteriolar vasoconstriction with preservation of tubular function. Transplantation. 1987;44: Segundo DS, Ruiz JC, Izquierdo M, et al. Calcineurin inhibitors, but not rapamycin, reduce percentages of CD4+CD25+FOXP3+ regulatory T cells in renal transplant recipients. Transplantation. 2006;82: Ruiz JC, Campistol JM, Sanchez-Fructuoso A, et al. Increase of proteinuria after conversion from calcineurin inhibitor to sirolimus-based treatment in kidney transplant patients with chronic allograft dysfunction. Nephrol Dial Transplant. 2006;21: Teutonico A, Schena PF, Di Paolo S. Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus. 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Abstract Kaufman DB, Leventhal JR, Axelrod D, et al. Alemtuzumab induction and prednisone-free maintenance immunotherapy in kidney transplantation: comparison with basiliximab induction-- long-term results. Am J Transplant. 2005;5: Gallon L, Perico N, Dimitrov BD, et al. Long-term renal allograft function on a tacrolimus-based, pred-free maintenance immunosuppression comparing sirolimus vs. MMF. Am J Transplant. 2006;6: Woodle ES, Astellas Steroid Withdrawal Group. A randomized double blind, placebo-controlled trial of early corticosteroid cessation versus chronic corticosteroids: four-year results. Paper presented at: American Transplant Congress; May 5-9, 2007; San Francisco, Calif. 35. Haririan A, Sillix DH, Morawski K, et al. Short-term experience with early steroid withdrawal in African-American renal transplant recipients. Am J Transplant. 2006;6: Kumar M, Khan S, Malat G, et al. Early steroid withdrawal (SW) versus chronic steroid therapy (ST) in African American (AA) kidney recipients: 3 year outcome. Presented at: American Transplant Congress 2007; May 6, 2007; San Francisco, Calif. Abstract Kumar M, Khan S, Ranganna K, et al. Five-year outcome of early steroid withdrawal after kidney transplantation: African American (AA) vs. non African American recipients (non AA). Presented at: American Transplant Congress 2007; May 6, 2007; San Francisco, Calif. Abstract Galliford J, Chan K, Charif R, et al. Steroid sparing in ABO incompatible transplantation. Presented at: American Transplant Congress 2007; May 6, 2007; San Francisco, Calif. Abstract Stevens R, Wrenshall L, Grant W, et al. Successful early steroid withdrawal and calcineurin-inhibitor minimization in moderate to high immunological risk renal transplant recipients including ABO and cross match positive recipients. Presented at: American Transplant Congress 2007; May 6, 2007; San Francisco, Calif. Abstract Malat G, Khan S, Ranganna K, et al. One-year outcome of early steroid withdrawal and basiliximab induction in kidney recipients with retransplantation. Presented at: American Transplant Congress 2007; May 6, 2007; San Francisco, Calif. Abstract Vol. 7, No. 9 n August 2007