Immunosuppression Minimization

The past decade has witnessed unprecedented advances in renal transplantation propelled by novel and effective immunosuppression drugs. The introduction of mycophenolate mofetil (MMF), tacrolimus, cyclosporine microemulsion, sirolimus, a new generation of monoclonal antibodies (the anti–interleukin-2 receptor blockers, daclizumab and basiliximab), and the depleting polyclonal biologic Thymoglobulin has provided transplant physicians with a wide choice in selecting effective immunosuppression regimens (1–5). The intensification of immunosuppression, however, results in over-immunosuppression–associated complications such as opportunistic infections and malignancies. This is exemplified by the emergence of a previously rare infection, BK virus nephropathy, which may account for irreversible graft loss in 3 to 5% of renal transplant recipients (6). The threat of malignancy is yet another risk confronting patients on long-term immunosuppression, reported to occur in up to 40% of patients by 20 yr after transplantation (7). Another factor limiting improvement in long-term outcome is the occurrence of cardiovascular disease, a major cause of death in renal transplant recipients (8,9). Many of the current immunosuppression drugs are associated with one or more risk factors that predispose to atherosclerotic cardiovascular disease. Of the current immunosuppressive agents in use, corticosteroids and calcineurin inhibitors (CNI) are the most pro-atherogenic drugs (9). The cardiovascular risk of sirolimus is unclear: it can induce hyperlipidemia, but it has also been shown to inhibit intimal and smooth muscle cell proliferation (10). The prospect for approval by the Food and Drug Administration of newer and more specific immunosuppressive drugs that lack nephrotoxicity and cardiovascular toxicities is several years away (4). No new drug or biologic agent is currently in phase III trial; it is thus unlikely that novel therapy for renal or solid organ transplantation will be approved before the latter part of the decade (4). In the interim, drug minimization regimens in select patient populations are being explored to improve the safety of immunosuppression regimens while preserving their efficacy. The two main classes of drugs that are targeted for drug minimization are corticosteroid and CNI. Drug minimization strategies are not safe for all patients, and patient selection is as important as the choice of the minimization protocol (11). This review will summarize current and emerging drug minimization strategies. Corticosteroid Minimization Regimens Because of the side effects associated with the long-term use of corticosteroids, several strategies have been used to minimize their use after renal transplantation (12). Several important issues, however, remain unresolved; timing of steroid withdrawal, advantages and risks associated with total steroid avoidance, optimal concomitant immunosuppression, requirement for biologic induction therapy, and the role of immune monitoring. Withdrawal of corticosteroids has been arbitrarily considered late when implemented beyond 3 mo after transplantation and early within 7 d after transplantation. Late withdrawal of corticosteroids has been considered safer than early withdrawal although results from recent studies with the use of the newer and more effective maintenance drugs (cyclosporine microemulsion, tacrolimus, MMF, and sirolimus) no longer support this notion (13–17). Two rigorous double blind randomized trials (one US and one global) of late steroid withdrawal with concomitant maintenance therapy consisting of cyclosporine and MMF demonstrate both the potential risks and benefits of these immunosuppression strategies (18,19). The inclusion criteria for the US study were first transplant recipients on cyclosporine, MMF (dose ≥ 2 g/d) and prednisone, who had no history of previous rejection and had a serum creatinine <2.4 mg/dl (18). Patients who fulfilled these criteria at 3 mo posttransplantation were randomized to continue prednisone therapy or withdrawal from prednisone over 2 mo. Two hundred sixty-six patients were enrolled when the study was stopped because of excess rejection in the prednisone-withdrawal group. At 12 mo after transplantation, the acute rejection rate was significantly higher in the withdrawal group compared with the group on maintenance steroids (30.8% versus 9.8%). However, the high rejection rate in the steroid withdrawal group was predominantly the result of a significantly higher rejection rate in African-American patients withdrawn from prednisone (Figure 1). Despite the increased risk of rejection, steroid withdrawal was associated with metabolic benefits; patients withdrawn from steroids with functioning grafts at 6 mo had significantly lower cholesterol levels and required less use of antihypertensive drugs. In the global second trial (Europe, South Africa, Australia), 500 renal transplant recipients were randomized in a double blind steroid regimen for 6 mo with an unblinded 6-mo follow-up (19). Table 1 shows the steroid regimen, rejection rate, and side effects of the two treatment arms. The investigators from these two trials concluded that late withdrawal of steroids with concomitant immunosuppression therapy consisting of cyclosporine and MMF may result in a slightly greater but acceptable risk of acute rejection (except in black patients) but is associated with a reduction in some corticosteroid-related side effects. Similar findings were reported from a randomized, open-label, parallel-group trial of corticosteroids withdrawal in patients treated with tacrolimus and MMF (20). The incidence of acute rejection at 6 mo in patients withdrawn from steroids 3 mo after transplantation (n = 279) was 5.9% compared with 0.9% in patients who were maintained on steroids (n = 277) (20). Recent strategies in corticosteroid minimization have favored immunosuppression regimens in which steroids are withdrawn very early after transplantation (usually in the first week) or completely avoided (14–17,21,22). The potential advantages of the newer approaches in corticosteroid sparing are listed in Table 2. Acute rejection in patients with short-term exposure (or avoidance) of steroids occurs early after transplantation when renal allograft recipients are monitored closely and frequently. In contrast, late corticosteroid withdrawal (>3 mo) is instituted at a time when the patients’ clinic visits are infrequent and the follow-up care may not be under the direct supervision of the transplant center. The design and the outcome of trials with early steroid withdrawal or avoidance are shown in Table 3. All these trials have in common the use of biologic induction therapy to provide more effective immunosuppression coverage in the early posttransplant period. It is evident that trials with corticosteroid minimization or avoidance are associated with excellent short-term outcome. Caution, however, should be used when these regimens are incorporated in clinical practice; these trials were less than rigorous with the infrequent use of controls, outcome based on statistically underpowered studies, and lack of long-term follow-up. Another unresolved issue is the optimum concomitant immunosuppression that allows for the safest and most effective corticosteroid minimization regimen. The maintenance drug combinations in use, cyclosporine-MMF, tacrolimus-MMF, cyclosporine-sirolimus, and more recently tacrolimus-sirolimus have not been tested against each other in the context of corticosteroid minimization. Finally, the safety and benefits of very early withdrawal versus complete avoidance of steroids have yet to be determined although steroids-free regimens have contributed to the success of islet cells transplantation (27). A study that may resolve this issue is the FREEDOM trial. In this study, 300 patients are being randomized to three treatment arms: no corticosteroids; 7 d of corticosteroid therapy; and standard maintenance corticosteroid therapy. All patients will be treated with two doses of basiliximab at day 0 and day 4, MMF, and cyclosporine. This trial started enrollment in 2003. In the interim, transplant physicians should consider using corticosteroid minimization regimens selectively for patients who are at high risk of complications from steroid therapy: (1) patients previously treated with corticosteroids; (2) children with low immunologic risk; (3) patients at risk for skeletal disease; (4) patients with atherosclerotic cardiovascular disease; (5) patients with susceptibility to metabolic disorders; or (6) obese patients. In summary, efforts to spare or eliminate corticosteroid therapy can be successful provided patients are carefully selected and closely monitored. Figure 1. : The cumulative incidence of biopsy proven acute rejection 3 mos after transplantation in African-American (AA) and non-AA patients maintained or withdrawn from prednisone. Adapted from reference 18.Table 1: Outcome of a double blind comparison of two corticosteroids regimens plus MMF and cyclosporineTable 2: Advantages of very early withdrawal or complete avoidance of corticosteroids in renal transplantationTable 3: Design and outcome of newer and more aggressive corticosteroid sparing trialsaCalcineurin Inhibitors Minimization Regimens The introduction of CNI in renal transplantation, cyclosporine 20 yr ago, and tacrolimus a decade later resulted in a dramatic decrease in acute rejection rates and improvement in graft survival. However CNI-based immunosuppression is associated with complications that result in posttransplant morbidities that may limit further improvement in long-term outcome (8,9). While nephrotoxicity has been amply documented and is frequently cited as the Achilles’ heel of the CNI representing toxicity-limiting efficacy, the proof of inexorable progression of CNI-induced nephrotoxicity remains controversial (28–31) In a recent review of data from the Scientific Registry of Transplant Recipients, Ojo et al. (30) reported that 15.7% of recipients of extrarenal organs developed renal insufficiency within 5 yr of transplantation. In contrast, a large study of 1663 renal transplant recipients, Burke et al. (31) found that the majority of patients tolerated long-term cyclosporine without progressive nephropathy; in fact, low doses of cyclosporine were associated with worse long-term outcome (31). In the recent 5-yr follow-up of the phase III cyclosporine versus tacrolimus trial, the median serum creatinine was unchanged or slightly improved (28). The importance of the level of renal function at 1 yr after transplantation as a risk factor for long-term graft outcome was recently highlighted in an analysis of data from the United Network of Organ Sharing registry by Hariharan et al. (32). Patients who had a serum creatinine of 1.5 mg/dl or lower at 1 yr (or had a <0.3 mg/dl rise in serum creatinine of between 6 and 12 mo) had the best long-term graft outcome. Hence patients who develop renal dysfunction from CNI nephrotoxicity (or for that matter acute rejection) are at greater risk of having a shortened graft half-life. However, the concern with the long-term use of CNI extends beyond their effect on renal function to their adverse effect on survival from deaths due to cardiovascular disease and malignancy. The most common cause of graft loss long-term is death with a functioning kidney (33). In a recent single-center study, cardiovascular events and malignancy were the most common causes of death after 5 yr of transplantation in patients with a functioning kidney (8). While there are differences in the side effect profile between cyclosporine and tacrolimus, therapy with CNI contributes to several cardiovascular risk factors, including hypertension, hyperlipidemia, and metabolic abnormalities such as hyperglycemia and hyperuricemia (9). In addition, nephrotoxicity from CNI may also contribute to cardiovascular disease. A recent study by Meire-Kriesche et al. (34) of 58,900 adult renal transplant recipients registered in the US Renal Data System showed that renal function at 1 yr was strongly associated with the incidence of cardiovascular death independent of many risk factors for cardiovascular disease. The third important risk associated with CNI use is malignancy (35–38). Cyclosporine has been shown to promote cancer progression by a direct cellular effect independent on its effect on the host immune cells (36). The effect of the dosage of cyclosporine on malignancy was explored in a prospective, open label randomized study by Dantal et al. (38). Two hundred thirty-one patients were randomized 1 yr after transplantation to either the continued use of the standard dose of cyclosporine or reduced dose of cyclosporine. With a 66-mo follow-up period, 37 patients in the standard dose group and 23 in the low-dose group developed cancers (P < 0.034); two thirds of the cancers were skin cancers. However the low-dose cyclosporine regimen was associated with a higher risk of rejection. A confounding aspect of this study, however, was that it was conducted in the azathioprine era before the introduction of the more powerful antiproliferative agents, MMF and sirolimus. Withdrawal of CNI in patients treated with azathioprine and prednisone has been associated with a high incidence of rejection and graft loss (39). The introduction of the newer, more powerful antiproliferative agents has prompted renewed interest and experimentation with CNI-sparing regimens, as well as CNI-free regimens. The purpose of this review is to evaluate the safety and potential benefits of the recent CNI–sparing/avoidance trials in renal transplantation. CNI sparing is defined as the initial use after transplantation of a standard or low dose of CNI with subsequent withdrawal. CNI-avoidance protocols consist of immunosuppression regimens that completely avoid the use of CNI. Trials with CNI-Sparing Regimens Five large, prospective, multicenter trials have evaluated the safety and efficacy of CNI withdrawal after renal transplantation. The first was reported by Smak Gregoor et al. (40) and was designed as a prospective randomized study in primary transplant recipients treated with an immunosuppression regimen consisting of cyclosporine, MMF, and prednisone. The objective of this study was to assess the safety of withdrawal of cyclosporine (50% reduction for 2 wk before discontinuation) or prednisone at 6 mo after transplantation compared with the continuation of triple therapy (Figure 2). Eighteen months after drug withdrawal, the patients withdrawn from cyclosporine had a significantly higher incidence of biopsy-proven rejection compared with the patients withdrawn from prednisone or maintained on triple therapy. The second study reported by Abramowicz et al. (41) is a European multicenter trial that enrolled 187 renal transplant recipients treated with triple therapy (cyclosporine-MMF-prednisone) and randomized at 3 mo to either cyclosporine withdrawal or to continue cyclosporine therapy. Cyclosporine withdrawal was gradual over 3 mo. The primary end point was creatinine clearance 6 mo after complete withdrawal of cyclosporine. In the per-protocol population (the withdrawal group), which excluded patients with acute rejections, there was a statistically significant increase in creatinine clearance (7.5 ml/min, P = 0.02) and improvement in serum creatinine (−11 versus +4 μmol/L, P = 0.0003). Reversible acute rejections, the majority of which were mild, occurred in nine cyclosporine withdrawal patients versus two cyclosporine continuation patients (10.6% versus 2.4% of each group, P = 0.03), with no graft loss. The lower rejection rate following CNI withdrawal reported by Abramowicz et al. (41) may have been achieved because of the more gradual withdrawal of cyclosporine. The next two trials (42,43) were designed to evaluate the efficacy of a maintenance regimen of following cyclosporine withdrawal. trials were to minimize the nephrotoxicity that was when sirolimus was used in with cyclosporine two studies (the first conducted in the United and and the second conducted United have slightly design but the the safety and the potential benefits of cyclosporine withdrawal from a sirolimus and steroid regimen. The specific design of each trial and the immunosuppressive regimens are shown in 3 and In both of these studies, cyclosporine was withdrawn over a of 1 mo. In the trial, cyclosporine was withdrawn at the end of 2 after transplantation in patients who had been rejection of patients were for cyclosporine The incidence of acute rejection at 1 yr was not statistically significant versus between patients who continued therapy with cyclosporine versus patients who were withdrawn from cyclosporine. Patients withdrawn from cyclosporine a significant increase in the In the design of the global trial, cyclosporine be withdrawn in patients who had previously had a rejection it was not a 3 rejection) Patients were excluded from the study an acute rejection in the wk or patients with renal function creatinine The incidence of acute rejection was in the first 3 mo before the (Figure between months 3 and patients withdrawn from cyclosporine had a significantly higher incidence of acute rejection compared to patients maintained on cyclosporine versus P = Figure However, the cumulative rejection rate at 1 and 3 yr in the cyclosporine withdrawal group, although was not statistically significant versus and versus than the group maintained on cyclosporine. The cyclosporine withdrawal group a significant and increase in after of cyclosporine (Figure In fact, on the of data of continued improvement in renal function by and serum the Food and Drug Administration on approved the use of sirolimus with in regimens that cyclosporine 2 to mo after renal transplantation in patients at low to immunologic In addition, there was a concomitant and significant improvement in versus at mo) and hyperuricemia versus at mo) in patients withdrawn from CNI the sirolimus levels were increased in the cyclosporine withdrawal patients, no significant differences were in levels at 1 yr between the two treatment At total serum cholesterol was higher in cyclosporine withdrawal group, predominantly due to an increase in between months 3 and the patients maintained on cyclosporine had a incidence of skin cancer compared with in the patients withdrawn from cyclosporine. The from these trials was that of cyclosporine from a sirolimus and steroids regimen was associated with a increase in rejection but resulted in statistically significant and improvement in renal this is acceptable in clinical in patients remains to be A to drug withdrawal is the lack of immune to patients at the risk of rejection. The trial of CNI withdrawal, the trial has enrolled patients in three treatment as shown in Figure The purpose of this study is to evaluate a very low dose of cyclosporine and without late cyclosporine in with anti–interleukin-2 receptor and MMF is safe and effective the important end of this study are acute rejection, and analysis of protocol biopsy at 1 The results of this trial will be reported in Figure 2. : The immunosuppression regimen and outcome following drug withdrawal (cyclosporine or or continuation of triple therapy. MMF, biopsy-proven acute rejection. P = and P = versus triple therapy and steroid withdrawal, 3. : design of the trial. and 6 by 2 and 20 for 3 by for 6 d dose at 1 with who were treated with biologic induction therapy be randomized at day 7 acute graft : design and outcome of the global trial. were not randomized had a history of 3 acute rejection, a rejection wk to or renal function creatinine acute : The in patients treated with cyclosporine, sirolimus, and prednisone to and following to either continuation of the triple therapy or of cyclosporine remain on double therapy with sirolimus and prednisone. significant : design of the study consisting of three treatment arms. Patients are randomized to transplant one of three treatment daclizumab and 1 2 wk for MMF, mycophenolate corticosteroids; cyclosporine. to to 300 to 3 mo) and to more immunosuppression regimens completely avoid the use of CNI. are more protocols and should be considered with within the context of rigorous Two recent trials that have with CNI-free regimens were reported by et al. and et al. The first study was a multicenter trial with an immunosuppressive regimen that of induction therapy with the and maintenance therapy with MMF and steroids The for CNI avoidance in this study was that the by to its be for CNI that inhibit in the early posttransplant period, when there is increased risk of rejection. patients were enrolled in the study and for 1 Patients who acute rejection were started on CNI. All patients were primary with and from The biopsy proven rejection rate at 1 yr was Despite the high rejection rate, the outcome was with a patient survival of and graft survival of the of findings that acute rejection the receptor on and were with that rejection may have been by such which can induce cell from the common a receptor that to several including and provide greater efficacy to CNI-free regimens The study by et al. a CNI-free regimen two antiproliferative agents, sirolimus and MMF, in with steroids but without induction therapy. At European renal allograft recipients were randomized to sirolimus (n = or cyclosporine (n = in an open label All patients MMF 2 and The dosage of sirolimus and cyclosporine were At 12 graft survival and patient survival were between the two treatment The incidence of biopsy-proven acute rejection was in the sirolimus versus in the cyclosporine not statistically The was higher in the patients compared with cyclosporine. A major concern with this trial was the very high doses of sirolimus that were required to the sirolimus levels for 2 mo and In addition, of patients in the sirolimus treatment group were from the protocol for a of while this trial the potential efficacy of a regimen two antiproliferative drugs in the of it of being The to this regimen of induction therapy with a biologic agent may improve its decrease the dose and sirolimus levels required to provide efficacy, and the acute rejection In an initial study evaluated a protocol consisting of daclizumab MMF 2 and sirolimus to 20 enrolled nine primary renal transplant recipients in this At 3 one of nine patients had an of acute rejection. While the immunosuppression regimen was well and were the most common side effects. Two trials have tested a immunosuppression regimen in a prospective randomized design et al. treated patients randomized to either cyclosporine or sirolimus with a protocol design consisting of induction therapy the and At 1 patient and graft survival were not significantly between the two treatment The patients had a rejection rate of compared with in the cyclosporine treatment group. At 6 and 12 the patients had a significantly lower serum creatinine levels than the patients, mg/dl and mg/dl versus and (P = and P = At 1 there were no significant differences in levels between the two treatment A multicenter trial by the a design but with a choice of the depleting polyclonal agent and tacrolimus of cyclosporine The study will 300 patients, and the results in patients are shown in Table The results of trials with the of the two antiproliferative agents, sirolimus and MMF, corticosteroids, and induction with a biologic agent that this immunosuppression regimen to be effective and be considered an from CNI-based However the long-term and of this regimen a more Table months outcome of the randomized emerging CNI-free are being developed for use in renal transplantation. novel protocols avoid CNI because the of of CNI not MMF or sirolimus) of to that also and the of patients to a of immunosuppression therapy with The most therapy is with a receptor consisting of the of with high to and and required for cell to the of can induce or graft survival A large multicenter prospective randomized study is the efficacy and safety of a regimen consisting of therapy with and maintenance immunosuppression consisting of MMF and corticosteroids versus a standard regimen of cyclosporine, MMF, and prednisone. This study enrollment of patients in The trial a in immunosuppression therapy; CNI and their for drug with therapy at or other In the effective of the with one or more biologic agents may both the use of CNI and A recently study by et al. showed that that were with cells with an immunosuppression therapy that of induction with an of and sirolimus. these their in clinical have at the time to immunosuppression therapy and selectively consider corticosteroids or CNI sparing regimens for patients who from drug minimization. The to from and