Immunosuppression Minimization: Current and Future Trends in Transplant Immunosuppression
Flavio Vincenti
Kidney Transplant Service, University of California, San Francisco, California.
Correspondence to Dr. Flavio Vincenti, University of California, San Francisco, Kidney Transplant Service, 505 Parnassus Avenue, M884, San Francisco, CA 94143-0780. Phone: 415-476-4496; Fax: 415-353-8974;E-mail: vincentif{at}surgery.ucsf.edu
The past decade has witnessed unprecedented advances in renaltransplantation propelled by novel and effective immunosuppressiondrugs. The introduction of mycophenolate mofetil (MMF), tacrolimus,cyclosporine microemulsion, sirolimus, a new generation of monoclonalantibodies (the anti–interleukin-2 receptor blockers,daclizumab and basiliximab), and the depleting polyclonal biologicThymoglobulin has provided transplant physicians with a widechoice in selecting effective immunosuppression regimens (1–5).The intensification of immunosuppression, however, results inover-immunosuppression–associated complications such asopportunistic infections and malignancies. This is exemplifiedby the emergence of a previously rare infection, BK virus nephropathy,which may account for irreversible graft loss in 3 to 5% ofrenal transplant recipients (6). The threat of malignancy isyet 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 outcomeis the occurrence of cardiovascular disease, a major cause ofdeath in renal transplant recipients (8,9). Many of the currentimmunosuppression drugs are associated with one or more riskfactors that predispose to atherosclerotic cardiovascular disease.Of the current immunosuppressive agents in use, corticosteroidsand calcineurin inhibitors (CNI) are the most pro-atherogenicdrugs (9). The cardiovascular risk of sirolimus is unclear:it can induce hyperlipidemia, but it has also been shown toinhibit intimal and smooth muscle cell proliferation (10). Theprospect for approval by the Food and Drug Administration ofnewer and more specific immunosuppressive drugs that lack nephrotoxicityand cardiovascular toxicities is several years away (4). Nonew drug or biologic agent is currently in phase III trial;it is thus unlikely that novel therapy for renal or solid organtransplantation will be approved before the latter part of thedecade (4). In the interim, drug minimization regimens in selectpatient populations are being explored to improve the safetyof immunosuppression regimens while preserving their efficacy.The two main classes of drugs that are targeted for drug minimizationare corticosteroid and CNI. Drug minimization strategies arenot safe for all patients, and patient selection is as importantas the choice of the minimization protocol (11). This reviewwill summarize current and emerging drug minimization strategies.
Corticosteroid Minimization Regimens
Because of the side effects associated with the long-term useof corticosteroids, several strategies have been used to minimizetheir use after renal transplantation (12). Several importantissues, however, remain unresolved; timing of steroid withdrawal,advantages and risks associated with total steroid avoidance,optimal concomitant immunosuppression, requirement for biologicinduction therapy, and the role of immune monitoring. Withdrawalof corticosteroids has been arbitrarily considered late whenimplemented beyond 3 mo after transplantation and early within7 d after transplantation. Late withdrawal of corticosteroidshas been considered safer than early withdrawal although resultsfrom recent studies with the use of the newer and more effectivemaintenance drugs (cyclosporine microemulsion, tacrolimus, MMF,and sirolimus) no longer support this notion (13–17).Two rigorous double blind randomized trials (one US and oneglobal) of late steroid withdrawal with concomitant maintenancetherapy consisting of cyclosporine and MMF demonstrate boththe potential risks and benefits of these immunosuppressionstrategies (18,19). The inclusion criteria for the US studywere first transplant recipients on cyclosporine, MMF (dose 2 g/d) and prednisone, who had no history ofprevious rejection and had a serum creatinine <2.4 mg/dl(18). Patients who fulfilled these criteria at 3 mo posttransplantationwere randomized to continue prednisone therapy or withdrawalfrom prednisone over 2 mo. Two hundred sixty-six patients wereenrolled when the study was stopped because of excess rejectionin the prednisone-withdrawal group. At 12 mo after transplantation,the acute rejection rate was significantly higher in the withdrawalgroup compared with the group on maintenance steroids (30.8%versus 9.8%). However, the high rejection rate in the steroidwithdrawal group was predominantly the result of a significantlyhigher rejection rate in African-American patients withdrawnfrom prednisone (Figure 1). Despite the increased risk of rejection,steroid withdrawal was associated with metabolic benefits; patientswithdrawn from steroids with functioning grafts at 6 mo hadsignificantly lower cholesterol levels and required less useof antihypertensive drugs. In the global second trial (Europe,South Africa, Australia), 500 renal transplant recipients wererandomized in a double blind steroid regimen for 6 mo with anunblinded 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 latewithdrawal of steroids with concomitant immunosuppression therapyconsisting of cyclosporine and MMF may result in a slightlygreater but acceptable risk of acute rejection (except in blackpatients) but is associated with a reduction in some corticosteroid-relatedside effects. Similar findings were reported from a randomized,open-label, parallel-group trial of corticosteroids withdrawalin patients treated with tacrolimus and MMF (20). The incidenceof acute rejection at 6 mo in patients withdrawn from steroids3 mo after transplantation (n = 279) was 5.9% compared with0.9% in patients who were maintained on steroids (n = 277) (20).Recent strategies in corticosteroid minimization have favoredimmunosuppression regimens in which steroids are withdrawn veryearly after transplantation (usually in the first week) or completelyavoided (14–17,21,22). The potential advantages of thenewer approaches in corticosteroid sparing are listed in Table 2.Acute rejection in patients with short-term exposure (oravoidance) of steroids occurs early after transplantation whenrenal allograft recipients are monitored closely and frequently.In contrast, late corticosteroid withdrawal (>3 mo) is institutedat a time when the patients’ clinic visits are infrequentand the follow-up care may not be under the direct supervisionof the transplant center. The design and the outcome of trialswith early steroid withdrawal or avoidance are shown in Table 3.All these trials have in common the use of biologic inductiontherapy to provide more effective immunosuppression coveragein the early posttransplant period. It is evident that trialswith corticosteroid minimization or avoidance are associatedwith excellent short-term outcome. Caution, however, shouldbe used when these regimens are incorporated in clinical practice;these trials were less than rigorous with the infrequent useof controls, outcome based on statistically underpowered studies,and lack of long-term follow-up. Another unresolved issue isthe optimum concomitant immunosuppression that allows for thesafest and most effective corticosteroid minimization regimen.The maintenance drug combinations in use, cyclosporine-MMF,tacrolimus-MMF, cyclosporine-sirolimus, and more recently tacrolimus-sirolimushave not been tested against each other in the context of corticosteroidminimization. Finally, the safety and benefits of very earlywithdrawal versus complete avoidance of steroids have yet tobe determined although steroids-free regimens have contributedto the success of islet cells transplantation (27). A studythat may resolve this issue is the FREEDOM trial. In this study,300 patients are being randomized to three treatment arms: nocorticosteroids; 7 d of corticosteroid therapy; and standardmaintenance corticosteroid therapy. All patients will be treatedwith two doses of basiliximab at day 0 and day 4, MMF, and cyclosporine.This trial started enrollment in 2003. In the interim, transplantphysicians should consider using corticosteroid minimizationregimens selectively for patients who are at high risk of complicationsfrom steroid therapy: (1) patients previously treated with corticosteroids;(2) children with low immunologic risk; (3) patients at riskfor skeletal disease; (4) patients with atherosclerotic cardiovasculardisease; (5) patients with susceptibility to metabolic disorders;or (6) obese patients. In summary, efforts to spare or eliminatecorticosteroid therapy can be successful provided patients arecarefully 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 3. Design and outcome of newer and more aggressive corticosteroid sparing trialsa
Calcineurin Inhibitors Minimization Regimens
The introduction of CNI in renal transplantation, cyclosporine20 yr ago, and tacrolimus a decade later resulted in a dramaticdecrease in acute rejection rates and improvement in graft survival.However CNI-based immunosuppression is associated with complicationsthat result in posttransplant morbidities that may limit furtherimprovement in long-term outcome (8,9). While nephrotoxicityhas been amply documented and is frequently cited as the Achilles’heel of the CNI representing toxicity-limiting efficacy, theproof of inexorable progression of CNI-induced nephrotoxicityremains controversial (28–31) In a recent review of datafrom the Scientific Registry of Transplant Recipients, Ojo etal. (30) reported that 15.7% of recipients of extrarenal organsdeveloped 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 toleratedlong-term cyclosporine without progressive nephropathy; in fact,low doses of cyclosporine were associated with worse long-termoutcome (31). In the recent 5-yr follow-up of the phase IIIcyclosporine versus tacrolimus trial, the median serum creatininewas unchanged or slightly improved (28). The importance of thelevel of renal function at 1 yr after transplantation as a riskfactor for long-term graft outcome was recently highlightedin an analysis of data from the United Network of Organ Sharingregistry by Hariharan et al. (32). Patients who had a serumcreatinine of 1.5 mg/dl or lower at 1 yr (or had a <0.3 mg/dlrise in serum creatinine of between 6 and 12 mo) had the bestlong-term graft outcome. Hence patients who develop renal dysfunctionfrom 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 theireffect on renal function to their adverse effect on survivalfrom deaths due to cardiovascular disease and malignancy. Themost common cause of graft loss long-term is death with a functioningkidney (33). In a recent single-center study, cardiovascularevents and malignancy were the most common causes of death after5 yr of transplantation in patients with a functioning kidney(8). While there are differences in the side effect profilebetween cyclosporine and tacrolimus, therapy with CNI contributesto several cardiovascular risk factors, including hypertension,hyperlipidemia, and metabolic abnormalities such as hyperglycemiaand hyperuricemia (9). In addition, nephrotoxicity from CNImay also contribute to cardiovascular disease. A recent studyby Meire-Kriesche et al. (34) of 58,900 adult renal transplantrecipients registered in the US Renal Data System showed thatrenal function at 1 yr was strongly associated with the incidenceof cardiovascular death independent of many risk factors forcardiovascular disease. The third important risk associatedwith CNI use is malignancy (35–38). Cyclosporine has beenshown to promote cancer progression by a direct cellular effectindependent on its effect on the host immune cells (36). Theeffect of the dosage of cyclosporine on malignancy was exploredin a prospective, open label randomized study by Dantal et al.(38). Two hundred thirty-one patients were randomized 1 yr aftertransplantation to either the continued use of the standarddose of cyclosporine or reduced dose of cyclosporine. With a66-mo follow-up period, 37 patients in the standard dose groupand 23 in the low-dose group developed cancers (P < 0.034);two thirds of the cancers were skin cancers. However the low-dosecyclosporine regimen was associated with a higher risk of rejection.A confounding aspect of this study, however, was that it wasconducted in the azathioprine era before the introduction ofthe more powerful antiproliferative agents, MMF and sirolimus.Withdrawal of CNI in patients treated with azathioprine andprednisone has been associated with a high incidence of rejectionand graft loss (39). The introduction of the newer, more powerfulantiproliferative agents has prompted renewed interest and experimentationwith CNI-sparing regimens, as well as CNI-free regimens. Thepurpose of this review is to evaluate the safety and potentialbenefits of the recent CNI–sparing/avoidance trials inrenal transplantation. CNI sparing is defined as the initialuse after transplantation of a standard or low dose of CNI withsubsequent withdrawal. CNI-avoidance protocols consist of immunosuppressionregimens that completely avoid the use of CNI.
Trials with CNI-Sparing Regimens
Five large, prospective, multicenter trials have evaluated thesafety and efficacy of CNI withdrawal after renal transplantation.The first was reported by Smak Gregoor et al. (40) and was designedas a prospective randomized study in primary transplant recipientstreated with an immunosuppression regimen consisting of cyclosporine,MMF, and prednisone. The objective of this study was to assessthe safety of withdrawal of cyclosporine (50% reduction for2 wk before discontinuation) or prednisone at 6 mo after transplantationcompared with the continuation of triple therapy (Figure 2).Eighteen months after drug withdrawal, the patients withdrawnfrom cyclosporine had a significantly higher incidence of biopsy-provenrejection compared with the patients withdrawn from prednisoneor maintained on triple therapy. The second study reported byAbramowicz et al. (41) is a European multicenter trial thatenrolled 187 renal transplant recipients treated with tripletherapy (cyclosporine-MMF-prednisone) and randomized at 3 moto either cyclosporine withdrawal or to continue cyclosporinetherapy. Cyclosporine withdrawal was gradual over 3 mo. Theprimary end point was creatinine clearance 6 mo after completewithdrawal of cyclosporine. In the per-protocol population (thewithdrawal group), which excluded patients with acute rejections,there was a statistically significant increase in creatinineclearance (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 cyclosporinewithdrawal 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 byAbramowicz et al. (41) may have been achieved because of themore gradual withdrawal of cyclosporine. The next two trials(42,43) were designed to evaluate the efficacy of a maintenanceregimen of sirolimus-prednisone following cyclosporine withdrawal.These trials were conceived to minimize the enhanced nephrotoxicitythat was observed when sirolimus was used in combination withfull-dose cyclosporine (2). These two studies (the first conductedin the United States and Europe, and the second conducted globallyminus United States) have slightly different design but thesame underlying rationale: assessing the safety and the potentialbenefits of cyclosporine withdrawal from a sirolimus and steroidregimen. The specific design of each trial and the immunosuppressiveregimens are shown in Figures 3 and 4. In both of these studies,cyclosporine was withdrawn gradually over a period of 1 mo.In the US-Europe trial, cyclosporine was withdrawn at the endof month 2 after transplantation only in patients who had beenrejection free (82% of patients were eligible for cyclosporineelimination). The incidence of acute rejection at 1 yr was notstatistically significant (18.6% versus 22.0%, respectively)between patients who continued therapy with cyclosporine versuspatients who were withdrawn from cyclosporine. Patients withdrawnfrom cyclosporine experienced a significant increase in thecalculated GFR (42). In the design of the global trial, cyclosporinecould be withdrawn in patients who had previously had a rejectionepisode (provided it was not a Banff grade 3 rejection) (43).Patients were excluded from the study if they suffered an acutevascular rejection in the 4 wk preceding randomization or patientswith poor renal function (serum creatinine > 4.4 mg/dl).The overall incidence of biopsy-confirmed acute rejection was13.1% in the first 3 mo before the randomization period (Figure 4).After randomization, between months 3 and 12, patients withdrawnfrom cyclosporine had a significantly higher incidence of acuterejection compared to patients maintained on cyclosporine (9.8%versus 4.2%, P = 0.035; Figure 4). However, the cumulative rejectionrate at 1 and 3 yr in the cyclosporine withdrawal group, althoughnumerically higher, was not statistically significant (20.2%versus 13.5% and 20.5% versus 14.9%) than the group maintainedon cyclosporine. The cyclosporine withdrawal group experienceda significant and sustained increase in calculated GFR soonafter discontinuation of cyclosporine (Figure 5). In fact, onthe basis of 3-yr data of continued improvement in renal function(as reflected by GFR and serum creatinine), the Food and DrugAdministration on April 11, 2003, approved the use of sirolimus(in combination with steroids) in regimens that withdraw cyclosporine2 to 4 mo after renal transplantation in patients at low tomoderate immunologic risk. In addition, there was a concomitantand significant improvement in hypertension (21.9% versus 8.8%at 24 mo) and hyperuricemia (14.4% versus 5.6% at 24 mo) inpatients withdrawn from CNI (44). Although the sirolimus targetblood levels were increased in the cyclosporine withdrawal patients,no significant differences were noted in lipid levels at 1 yrbetween the two treatment groups. At 24 mo, total serum cholesterolwas higher in cyclosporine withdrawal group, predominantly dueto an increase in HDL. After randomization between months 3and 24, the patients maintained on cyclosporine had a 4.7% incidenceof skin cancer compared with 2.3% in the patients withdrawnfrom cyclosporine. The conclusion from these trials was thatdiscontinuation of cyclosporine from a sirolimus and steroidsregimen was associated with a modest increase in rejection butresulted in statistically significant and clinically relevantimprovement in renal function. Whether this trade-off is deemedacceptable in clinical practice in stable patients remains tobe determined. A persistent deterrent to drug withdrawal isthe lack of validated immune assays to identify patients atthe greatest risk of rejection. The fourth trial of CNI withdrawal,the CAESAR (Cyclosporine Avoidance Eliminates Serious AdverseReactions) trial has enrolled 525 patients in three treatmentgroups as shown in Figure 6. The purpose of this study is toevaluate whether a very low dose of cyclosporine (with and withoutlate cyclosporine withdrawal) in combination with anti–interleukin-2receptor (IL-2R) blockade and MMF is safe and provides effectiveimmunosuppression. Among the important end points of this studyare acute rejection, measured GFR, and histologic analysis ofprotocol biopsy at 1 yr. The results of this trial will be reportedin 2004.
Figure 2. The immunosuppression regimen and outcome following randomization, drug withdrawal (cyclosporine or MMF), or continuation of triple therapy. CsA, Cyclosporine; MMF, Mycophenolate Mofetil; BPAR, biopsy-proven acute rejection. * P = 0.0001 and P = 0.001 versus triple therapy and steroid withdrawal, respectively.
Figure 3. Study design of the US-European sirolimus-based trial. (Group A) Standard steroids, full-dose CsA, and SRL 6 mg loading dose, followed by 2 mg/d. (Group B) Standard steroids, reduced-dose CSA, and SRL 20 mg/d for 3 d, followed by 10 mg/d for 6 d (mean dose at 1 yr, 6.4 ± 0.4 mg/d). (Group C) Patient with DGF who were treated with biologic induction therapy could be randomized at day 7 if off dialysis. CsA, Cyclosporine; SRL, Sirolimus; AR, acute rejection; DGF, delayed graft function.
Figure 4. Study design and outcome of the global sirolimus-based trial. *Patients were not randomized if they had a history of Banff grade 3 acute rejection, a vascular rejection 4 wk prior to randomization, or poor renal function (serum creatinine > 4.4 mg/dl). AR, acute rejection; CsA, Cyclosporine.
Figure 5. The calculated GFR in patients treated with cyclosporine, sirolimus, and prednisone (prior to randomization) and following randomization to either continuation of the triple therapy or elimination of cyclosporine (and remain on double therapy with sirolimus and prednisone). SRL, Sirolimus; CsA, Cyclosporine; P, prednisone. *Statistically significant results.
Figure 6. Study design of the CAESAR (Cyclosporine Avoidance Eliminates Serious Adverse Reactions) study consisting of three treatment arms. Patients are randomized prior to transplant into one of three treatment groups. Dac, daclizumab (2 mg/kg pre op and 1 mg/kg every 2 wk for four additional doses); MMF, mycophenolate mofetil; CS, corticosteroids; CsA, cyclosporine. * Target CsA blood levels, 50 to 100 ng/ml; ** target CsA blood levels, 150 to 300 ng/ml (up to 3 mo) and 100 to 200 ng/ml thereafter.
The more ambitious immunosuppression regimens completely avoidthe use of CNI. These are obviously more experimental protocolsand should be considered with caution, preferably within thecontext of rigorous trials. Two recent trials that have experimentedwith CNI-free regimens were reported by Vincenti et al. (45)and Kreis et al. (46) The first study was a multicenter US-Europetrial with an immunosuppressive regimen that consisted of inductiontherapy with the anti–IL-2R antibody, Daclizumab, andmaintenance therapy with MMF and steroids (45). The rationalefor CNI avoidance in this study was that the anti–IL-2Rantibody by blocking IL-2 binding to its receptor, could besubstituted for CNI that inhibit cytokine transcription, particularlyin the early posttransplant period, when there is increasedrisk of rejection. Ninety-eight patients were enrolled in thestudy and followed for 1 yr. Patients who experienced acuterejection were started on CNI. All patients were primary transplantswith 77% receiving cadaver kidneys and 33% receiving kidneysfrom living donors. The biopsy proven rejection rate at 1 yrwas 53%. Despite the high rejection rate, the overall 1-yr outcomewas excellent, with a patient survival of 97% and graft survivalof 96%. On the basis of our findings that during acute rejectionthe IL-2 receptor on circulating and intragraft lymphocyteswere fully saturated with daclizumab, we hypothesized that rejectionmay have been mediated by redundant cytokines such IL-15, whichcan induce T cell activation. Sirolimus blocks cytokine-mediatedproliferative signals from the common gamma chain, a receptorthat binds to several cytokines, including IL-15, and couldprovide greater efficacy to CNI-free regimens (47). The studyby Kreis et al. (46) utilized a CNI-free regimen combining twoantiproliferative agents, sirolimus and MMF, in conjunctionwith steroids but without antibody induction therapy. At 14European centers, cadaver renal allograft recipients were randomizedto receive sirolimus (n = 40) or cyclosporine (n = 38) in anopen label design. All patients received MMF 2 g/d and corticosteroid.The dosage of sirolimus and cyclosporine were concentration-controlled.At 12 mo, graft survival and patient survival were similar betweenthe two treatment groups. The incidence of biopsy-proven acuterejection was 27.5% in the sirolimus arm versus 18.4% in thecyclosporine arm, not statistically different. The calculatedGFR was consistently higher in the sirolimus-treated patientscompared with cyclosporine. A major concern with this trialwas the very high doses of sirolimus that were required to attainthe target sirolimus blood levels (30 ng/ml for 2 mo and 15ng/ml thereafter). In addition, 43% of patients in the sirolimustreatment group were discontinued from the protocol for a numberof reasons. Thus, while this trial demonstrated the potentialefficacy of a regimen combining two antiproliferative drugsin the absence of CNI, it fell short of being fully successful.The addition to this regimen of induction therapy with a biologicagent may improve its tolerability, decrease the dose and targetsirolimus levels required to provide efficacy, and possiblyreduce the acute rejection below 20%. In an initial pilot studywe evaluated a protocol consisting of daclizumab induction,MMF 2 g/d, and sirolimus (target blood levels, 10 to 20 ng/ml)(48). We enrolled nine primary renal transplant recipients inthis protocol. At 3 mo, only one of nine patients had an episodeof mild acute rejection. While the immunosuppression regimenwas well tolerated, anemia and hyperlipidemia were the mostcommon side effects. Two larger trials have tested a similarimmunosuppression regimen in a prospective randomized design(49–50). Flechner et al. (49) treated 61 patients randomizedto either cyclosporine or sirolimus with a protocol design consistingof induction therapy the chimeric anti–IL-2R antibodybasiliximab, MMF. and steroids. At 1 yr, patient and graft survivalwere not significantly different between the two treatment groups.The sirolimus-treated patients had a rejection rate of 6.4%compared with 16.6% in the cyclosporine treatment group. At6 and 12 mo, the sirolimus-treated patients had a significantlylower mean serum creatinine levels than the cyclosporine-treatedpatients, 1.29 mg/dl and 1.32 mg/dl versus 1.74 and 1.78 mg/dl,respectively (P = 0.008 and P = 0.004). At 1 yr, there wereno significant differences in lipid levels between the two treatmentgroups. A multicenter trial initiated by the Mayo Clinic usesa similar design but with a different choice of induction, thedepleting polyclonal agent Thymoglobulin, and tacrolimus insteadof cyclosporine (50). The study will ultimately enroll 300 patients,and the interim results in 126 patients are shown in Table 4.The results of trials with the combination of the two antiproliferativeagents, sirolimus and MMF, corticosteroids, and induction witha biologic agent allude that this immunosuppression regimenappears to be effective and could be considered an alternativeoption from CNI-based immunosuppression. However the long-termsafety, tolerability, and cost-effectiveness of this regimenrequires a more thorough analysis.
Table 4. Six months outcome of the Mayo Clinic randomized trial
Several emerging CNI-free therapies are being developed foruse in renal transplantation. These novel protocols avoid CNIbecause the mechanism of action of CNI (but not MMF or sirolimus)abrogates pathways of lymphocyte response to alloantigens thatalso block activation-induced apoptosis and the developmentof tolerance, relegating patients to a lifetime of immunosuppressiontherapy with considerable toxicities. The most promising therapyis co-stimulatory blockade with LEA29Y, a recombinant fusionreceptor protein consisting of the extracellular domain of CTLA4(which binds with high affinity to CD80 and CD86 and blocksco-stimulation signals required for T cell activation) linkedto the constant region of IgG1, can induce tolerance (in rodents)or indefinite graft survival (in non human primates) (51–53).A large multicenter prospective randomized study is testingthe efficacy and safety of a regimen consisting of chronic intermittentintravenous therapy with LEA29Y and maintenance immunosuppressionconsisting of MMF and corticosteroids versus a standard regimenof cyclosporine, MMF, and prednisone. This study finished enrollmentof 227 patients in December 2002. The LEA29Y trial representsa paradigm shift in immunosuppression therapy; replacing orallyadministered CNI and their requirements for therapeutic drugmonitoring with intermittent parenteral therapy (administeredat monthly or every other month intervals). In the future, effectiveblockade of the co-stimulatory pathway with one or more biologicagents may render unnecessary both the use of CNI and corticosteroids.A recently published study by Adams et al. (54) showed thatRhesus monkeys that underwent pancreatectomy were successfullytransplanted with allogeneic islets cells with an immunosuppressiontherapy that consisted of short induction with an anti-IL-2antibody, chronic intermittent administration of LEA29Y andsirolimus. Until these experimental therapies fulfill theirpromise in clinical trials, clinicians have flexibility at thepresent time to individualize immunosuppression therapy andselectively consider corticosteroids or CNI sparing regimensfor patients who could benefit from drug minimization.
Acknowledgments
The author would like to acknowledge research grants from NovartisPharmaceuticals, Hoffmann La Roche, Wyeth Ayerst Pharmaceuticals,and Bristol Myers Squibb.
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Top
Introduction
References
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. 
. In both of these studies, cyclosporine was withdrawn gradually over a period of 1 mo. In the US-Europe trial, cyclosporine was withdrawn at the end of month 2 after transplantation only in patients who had been rejection free (82% of patients were eligible for cyclosporine elimination). The incidence of acute rejection at 1 yr was not statistically significant (18.6% versus 22.0%, respectively) between patients who continued therapy with cyclosporine versus patients who were withdrawn from cyclosporine. Patients withdrawn from cyclosporine experienced a significant increase in the calculated GFR (42). In the design of the global trial, cyclosporine could be withdrawn in patients who had previously had a rejection episode (provided it was not a Banff grade 3 rejection) (43). Patients were excluded from the study if they suffered an acute vascular rejection in the 4 wk preceding randomization or patients with poor renal function (serum creatinine > 4.4 mg/dl). The overall incidence of biopsy-confirmed acute rejection was 13.1% in the first 3 mo before the randomization period (Figure 4). After randomization, between months 3 and 12, patients withdrawn from cyclosporine had a significantly higher incidence of acute rejection compared to patients maintained on cyclosporine (9.8% versus 4.2%, P = 0.035; Figure 4). However, the cumulative rejection rate at 1 and 3 yr in the cyclosporine withdrawal group, although numerically higher, was not statistically significant (20.2% versus 13.5% and 20.5% versus 14.9%) than the group maintained on cyclosporine. The cyclosporine withdrawal group experienced a significant and sustained increase in calculated GFR soon after discontinuation of cyclosporine (Figure 5). In fact, on the basis of 3-yr data of continued improvement in renal function (as reflected by GFR and serum creatinine), the Food and Drug Administration on April 11, 2003, approved the use of sirolimus (in combination with steroids) in regimens that withdraw cyclosporine 2 to 4 mo after renal transplantation in patients at low to moderate immunologic risk. In addition, there was a concomitant and significant improvement in hypertension (21.9% versus 8.8% at 24 mo) and hyperuricemia (14.4% versus 5.6% at 24 mo) in patients withdrawn from CNI (44). Although the sirolimus target blood levels were increased in the cyclosporine withdrawal patients, no significant differences were noted in lipid levels at 1 yr between the two treatment groups. At 24 mo, total serum cholesterol was higher in cyclosporine withdrawal group, predominantly due to an increase in HDL. After randomization between months 3 and 24, the patients maintained on cyclosporine had a 4.7% incidence of skin cancer compared with 2.3% in the patients withdrawn from cyclosporine. The conclusion from these trials was that discontinuation of cyclosporine from a sirolimus and steroids regimen was associated with a modest increase in rejection but resulted in statistically significant and clinically relevant improvement in renal function. Whether this trade-off is deemed acceptable in clinical practice in stable patients remains to be determined. A persistent deterrent to drug withdrawal is the lack of validated immune assays to identify patients at the greatest risk of rejection. The fourth trial of CNI withdrawal, the CAESAR (Cyclosporine Avoidance Eliminates Serious Adverse Reactions) trial has enrolled 525 patients in three treatment groups as shown in Figure 6. The purpose of this study is to evaluate whether a very low dose of cyclosporine (with and without late cyclosporine withdrawal) in combination with anti–interleukin-2 receptor (IL-2R) blockade and MMF is safe and provides effective immunosuppression. Among the important end points of this study are acute rejection, measured GFR, and histologic analysis of protocol biopsy at 1 yr. The results of this trial will be reported in 2004. 
to cultured human monocytes. J Immunol 137: 1577–1580, 1986[Abstract]
