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Steroid Sparing in Kidney Transplantation: Changing Paradigms, Improving Outcomes, and Remaining Questions

Department of Medicine, Case Western Reserve University, and Division of Nephrology and Hypertension, University Hospitals of Cleveland, Cleveland, Ohio

Address correspondence to: Dr. Donald E. Hricik, University Hospitals of Cleveland, 11100 Euclid Avenue, Room 8124 Lakeside Building, Cleveland, OH 44106. Phone: 216-844-8060; Fax: 216-844-5204; dhricik{at}aol.com

	Abstract

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The widely known adverse effects of long-term therapy with corticosteroids have motivated increasing interest in steroid-free immunosuppression for kidney transplant recipients. Results from recent trials that used newer immunosuppressants to facilitate elimination of steroids suggest better short-term results than were achieved in an earlier era. However, the best results have been reported in uncontrolled trials of low-risk patients or in randomized trials with relatively short periods of follow-up. Increasingly, the therapeutic paradigm has shifted from late withdrawal of steroids to very early withdrawal after transplantation or even complete avoidance. Induction antibody therapy has been used routinely in the most successful trials that involved early steroid withdrawal or avoidance. Although the outcomes of kidney transplant recipients who are treated with steroid-free immunosuppression are improving steadily, there still is room for concern in recommending this strategy as a standard of practice.

	Introduction and Historical Background

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During the early years of kidney transplantation, it became clear that long-term maintenance therapy with corticosteroids was responsible for a great deal of morbidity. Widely recognized adverse effects of steroid therapy include an increased susceptibility to infection; weight gain with cushingoid changes; cataracts; glucose intolerance; myopathy; sodium retention manifested by edema and hypertension; hyperlipidemia; and a number of skeletal effects, including osteopenia, aseptic necrosis, and impaired growth. These morbid adverse effects translate into an economic cost. We used Markov modeling to calculate the cost of steroid-related adverse effects in a theoretical cohort of 50 kidney transplant recipients with 10 yr of follow-up and estimated a cost of $5300 (1996 US dollars) per patient per year (1).

Even before the availability of cyclosporine (CsA) in the early 1980s, a trend had begun toward lowering steroid dosages that were used both for maintenance immunosuppression (2–4) and for the treatment of acute rejection (5,6) to minimize adverse effects. Since the introduction of CsA, each new development in immunosuppressive therapy has been accompanied by further interest in steroid-free immunosuppression. Both physician (7) and patient (8,9) surveys indicate that, increasingly, steroid-free protocols are a goal in organ transplantation. When asked which class of drugs they would choose if monotherapy were risk-free, only 10% of patients who participated in one recent survey chose corticosteroids (9). Conversely, 65% chose corticosteroids when asked which class of agents they would prefer to eliminate if withdrawal of that therapy were risk-free (9).

Traditionally, elimination of steroids has not been free of risk. Collective data accrued during the CsA/azathioprine era (roughly 1983 to 1994) and summarized in older reviews (7,10) indicated that steroid avoidance protocols were associated with an incidence of acute rejection that ranged from 15 to 79% (10). In reported experiences with steroid withdrawal protocols from that era, the incidence of acute rejection ranged from 3 to 81% (10). A meta-analysis of seven randomized trials from that era indicated a 48% incidence of acute rejection associated with steroid-free immunosuppression, compared with a 30% incidence in steroid-treated control subjects (11). An ongoing question in the field is whether an incremental risk for acute rejection, however small, can be justified on the basis of benefits that are accrued by the majority of patients who are weaned successfully off of steroids. In our previously cited economic analysis that weighed the costs of steroid effects against the costs of diagnosing and treating acute rejection, an economic break-even point was predicted with an 11% incremental risk for acute rejection in patients who were withdrawn from steroids (1).

One axiom that emerged from the CsA/azathioprine era was the notion that complete avoidance or early withdrawal of steroid therapy was associated with a higher risk for acute rejection than that observed when steroids were withdrawn later (>3 mo after transplantation). This axiom was promulgated, in part, from data that were generated at our own center (12,13) but supported by other reports (14). In a small randomized study of 59 patients who were treated with polyclonal induction antibody therapy, CsA, and azathioprine, acute rejection occurred in 81% of patients who were withdrawn from steroids 2 wk after transplantation, compared with 54% in steroid-treated control subjects (12). Moreover, 58% of the rejection episodes that occurred in the steroid withdrawal group were considered clinically severe, requiring treatment with OKT3. In a multivariate analysis of clinical factors that are associated with acute rejection after withdrawal of steroids in our patient population, relatively early timing of steroid withdrawal was the strongest risk factor for rejection, followed, in order, by donor–recipient racial mismatch and an elevated serum creatinine concentration at the time of steroid withdrawal (13).

Even more concerning than the risk for acute rejection were observations from the CsA/azathioprine era to suggest that elimination of steroids might increase the risk for long-term graft loss. Results of a large, randomized, placebo-controlled Canadian study of 523 patients showed a significant reduction in graft survival at 5 yr in patients who were withdrawn from steroids 3 mo after transplant and maintained on CsA monotherapy (15). Although the study has been criticized because of a high rate of patient dropout and inadequate immunosuppression (16), it was the first large trial to suggest that at least 5 yr of follow-up may be needed to judge the wisdom of steroid-free protocols in kidney transplantation. A subsequent, updated meta-analysis of 10 randomized trials from that era (but including two studies that used mycophenolate mofetil [MMF] instead of azathioprine) confirmed the outcome of the Canadian trial, suggesting that elimination of steroids was associated with a statistically significant risk for both acute rejection and long-term graft loss (17).

At least two studies from the CsA/azathioprine era suggested that long-term allograft survival after steroid withdrawal was optimized in patients who received relatively high dosages of CsA (18,19). These studies provided the first hint that use of more potent residual immunosuppression might enhance the safety of steroid-free immunosuppression. With the introduction of tacrolimus, MMF, sirolimus, and newer antibodies that are used for induction therapy, the short-term safety of steroid-free regimens generally has improved. However, a recent meta-analysis of six randomized trials of patients who were withdrawn from steroids while receiving MMF-based immunosuppression (with CsA in four studies and tacrolimus in two studies) demonstrated a relative risk for acute rejection of 2.28 (P < 0.00001) in patients who were withdrawn from steroids compared with steroid-treated control subjects (Figure 1) (20). In this analysis, the pooled risk for graft loss was not significantly different between groups, but the duration of follow-up in the six studies ranged from 3 mo to only 24 mo.

View larger version (14K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Cumulative incidence of acute rejection based on randomization (maintenance, maintained on steroids; withdrawal, withdrawn from steroids) and ethnicity in a trial of late steroid withdrawal in patients who were maintained on cyclosporine and mycophenolate mofetil (MMF) (54).

In critically appraising the recent literature on steroid-free immunosuppression, it is important, as in any review, to judge studies on the basis of their size and design (i.e., nonrandomized versus randomized with a steroid-treated control group). Other important considerations include the incremental risk for rejection that is attributable to elimination of steroids (compared with a steroid-treated control group) and the immunologic risk status of the study population, perhaps best judged by ethnic heterogeneity and the ratio of deceased- to live-donor transplants. Finally, on the basis of lessons from the Canadian study, it is particularly important to judge each study on the basis of duration of follow-up. In the remainder of this review, we focus on studies that were reported in the past 10 yr and are classified on the basis of nonrandomized versus randomized study designs, residual immunosuppression, and the timing of steroid cessation. A discussion of steroid-free protocols would not be complete without mention of a number of uncontrolled experiences with the use of T cell–depleting induction antibodies (either alemtuzumab or high dosages of polyclonal anti-lymphocyte antibodies) to facilitate minimal maintenance immunosuppression, most often consisting of monotherapy with a noncorticosteroid immunosuppressant (24–27). We consider these protocols to be more experimental than steroid-free protocols that use more conventional forms of maintenance immunosuppression, thus falling beyond the scope of this review.

	Nonrandomized Studies

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Late Steroid Withdrawal with CsA-Based Immunosuppression
Opelz et al. (28) reported the outcomes of 1110 recipients of deceased-donor kidneys in whom steroids were discontinued no earlier than 6 mo after transplantation. Notably, 97% of the patients were white and 94% received CsA either alone or in combination with either azathioprine or MMF. Outcomes were compared with retrospectively matched control subjects who were selected on the basis of relatively low serum creatinine concentrations at posttransplantation time intervals that were comparable to the enrollment times for study patients. With a median follow-up of 5 yr, late steroid withdrawal was associated with improved graft survival (81.9 versus 75.3%; P = 0.0001) and patient survival (88.8 versus 84.3%; P = 0.0016) compared with continued steroid therapy. The cumulative incidence of acute rejection after steroid withdrawal was only 8%, although 40% of patients who were enrolled in the study ultimately renewed steroid therapy, often for unclear reasons.

Rama et al. (29) reported the extended follow-up of an earlier pilot study of late steroid withdrawal in a Spanish population of 91 recipients of first or second deceased-donor kidney transplants (30). All patients received CsA and MMF. Induction antibody therapy was not used. The timing of steroid withdrawal was variable, and outcomes of patients who were withdrawn <6 mo after transplantation (n = 35) were compared with those who were withdrawn >6 mo after transplantation (n = 56). Remarkably, no episodes of acute rejection were reported after steroid withdrawal. The two groups had comparable long-term patient and graft survivals. However, a rise in urine protein excretion during 10 yr of follow-up was noted only in the patients who were withdrawn from steroids after 6 mo after transplantation.

Hocker et al. (31) described the outcomes of 20 German children who were withdrawn from steroids an average of 1.5 yr after transplantation and maintained on CsA and MMF. Compared with retrospective case control subjects, growth was improved in both pubertal and prepubertal children who were withdrawn from steroids. In addition, mean arterial BP was lower than that observed in the control group.

Laouad et al. (32) performed multivariate analyses to determine risk factors for graft loss in 223 low-risk patients who were withdrawn from steroid therapy at variable time intervals during the first year after transplantation after treatment with a polyclonal antilymphocyte antibody and heterogeneous maintenance immunosuppression. Fifteen-year actuarial graft survival was 83.9%. Risk factors for graft loss included age <35 yr, proteinuria, and the lack of treatment with MMF.

Early Steroid Withdrawal or Steroid Avoidance with CsA-Based Immunosuppression
A number of published reports have described the outcomes of early elimination of steroids in patients who receive CsA-based immunosuppression. It is noteworthy that induction antibody therapy of some kind was used in each study. In an uncontrolled, multicenter pilot study that was performed in Canada, complete avoidance of corticosteroids was attempted in 57 patients who were treated with daclizumab induction therapy, MMF, and CsA (33). Fourteen (25%) patients experienced acute rejection episodes, 13 of which were readily reversed with steroids. At last follow-up, serum creatinine concentration among patients who experienced acute rejection was not significantly different from patients without acute rejection. In a similar uncontrolled Danish study, 68 patients were treated with antithymocyte globulin induction, CsA, and MMF with complete avoidance of corticosteroids. The incidence of acute rejection was 15% after a median follow-up of 488 d (34) and was similar to the incidence of rejection that was reported in an extended cohort of patients from the same center (35).

One of the largest uncontrolled experiences with early steroid withdrawal has been described in a series of publications from the University of Minnesota (36–41). All patients in this experience received induction therapy with rabbit antithymocyte globulin. The original report from this group was limited to recipients of living-donor kidney transplants who were withdrawn from steroids after 5 d and maintained on CsA and MMF (36). More recently, the group described the 5-yr outcomes of 589 patients who were subjected to this protocol but with heterogeneous combinations of residual immunosuppressants (40). Notably, 72% of the patients were recipients of living-donor transplants, and 89% were white. Compared with historical control patients who were treated with steroids, prednisone-free patients had a significantly lower rate of cytomegalovirus infection, posttransplantation diabetes, cataracts, avascular necrosis, and fractures. At 5 yr, actuarial patient survival was 91%, graft survival was 84%, and acute rejection–free graft survival was 84%. Similar excellent outcomes were reported in a subset of 78 patients who were deemed to be immunologically "high risk" on the basis of some combination of black (n = 6) or Native American ethnicity, delayed graft function, elevated panel reactive antibodies, or nonprimary transplantation (39). Among the patients from this large series, 239 were randomly assigned to one of three steroid-free maintenance immunosuppression regimens: CsA and MMF (n = 85), high-level tacrolimus and low-level sirolimus (n = 72), or low-level tacrolimus and high-level sirolimus (n = 82) (41). At 24 mo, the groups exhibited no statistically significant differences in patient, graft, or acute rejection–free graft survival or in kidney function.

Late Steroid Withdrawal with Tacrolimus-Based Immunosuppression
In a large study from Poland, 489 patients were randomly assigned to receive either azathioprine (n = 246) or MMF (n = 243) together with tacrolimus and steroids (42). Steroids were withdrawn in each group after 3 mo, leaving no steroid-treated control group. Steroids were withdrawn only in patients who were free of acute rejection for the first 3 mo and who exhibited serum creatinine concentrations <1.4 mg/dl (48.8 and 60.5% of the two groups, respectively). Biopsy-proven rates of acute rejection were 18.9% in the MMF-treated group compared with 26.8% in the azathioprine-treated group (P = 0.038), suggesting that MMF may increase the safety of steroid withdrawal.

Early Steroid Withdrawal or Steroid Avoidance with Tacrolimus-Based Immunosuppression
In one of the few recent reports of steroid avoidance in pediatric patients, Sarwal et al. (43) described the outcomes of 57 children. All patients received an extended course (nine doses) of daclizumab and maintenance immunosuppression with tacrolimus and MMF. After a mean follow-up of 20 mo, the incidence of acute rejection was 8%, and both patient and graft survival rates were 98%. Compared with historical controls, children who were maintained off steroids exhibited better linear growth and less hypertension.

Investigators at Northwestern University have accrued a large uncontrolled experience with early steroid withdrawal (after 3 d) in kidney and kidney-pancreas transplant recipients who were treated with induction antibody therapy and either tacrolimus and MMF or tacrolimus and sirolimus (44,45). Recently, they reported the outcomes of patients who underwent early steroid withdrawal after receiving induction therapy with either alemtuzumab (n = 123) or basiliximab (n = 155), followed by maintenance therapy with tacrolimus and MMF (45). Sixty-nine percent of the patients were recipients of living-donor transplants, but 32% of the patients were either black or Hispanic. Although rejection rates in the first 3 mo after transplantation were lower in the group that was treated with alemtuzumab, after 1 yr of follow-up, the cumulative incidence of rejection was 14.9% in alemtuzumab-treated patients versus 13.5% in basiliximab-treated patients (NS). Most recently, this group of investigators retrospectively measured rates of decline in GFR in 116 patients who were treated with early steroid withdrawal and found no significant differences with the rates of decline measured in 96 patients who were maintained on steroids after a median follow-up of 5 yr (46).

Ciancio et al. (47) also reported a small series of 44 kidney transplant recipients who were treated with alemtuzumab, MMF, and low-dosages of tacrolimus. Prednisone was discontinued after 1 wk. With a median follow-up of 9 mo, patient and graft survival each were 100%, and biopsy-proven acute rejection occurred in four patients.

Late Steroid Withdrawal with Sirolimus-Based Immunosuppression
To date, use of sirolimus to facilitate steroid-free immunosuppression has been reported only in nonrandomized studies. We reported excellent short-term outcomes in 30 black kidney transplant recipients who were subjected to late withdrawal of prednisone (between 3 and 5 mo after transplantation) while receiving sirolimus and tacrolimus (48). No induction therapy was administered. With a mean follow-up of 14 mo, the cumulative incidence of acute rejection was only 6.7%. However, after a mean follow-up of 48.5 mo, the cumulative incidence of acute rejection was 41%, and graft loss occurred in 25% of patients. Nine of 13 episodes of acute rejection were related to noncompliance with other immunosuppressants (unpublished observations, 2006).

Mahalati and Kahan (49) described 156 patients who were treated with sirolimus and CsA and withdrawn from steroids at varying times after transplantation that ranged from 1 wk to >2 yr. The overall incidence of acute rejection after steroid withdrawal was 6.4%, and the incidence of chronic rejection was 5.1%. Two years after attempted steroid withdrawal, approximately three quarters of patients from this ethnically heterogeneous population remained steroid-free.

Early Steroid Withdrawal with Sirolimus-Based Immunosuppression
In an uncontrolled, multicenter, pilot study, Woodle et al. (50) reported the outcomes of 77 "low-risk" kidney transplant recipients in whom steroids were withdrawn 4 d after transplantation in primary kidney transplant recipients who were treated with basiliximab, sirolimus, and tacrolimus. Blacks and highly sensitized patients were excluded from the study. After 1 yr of follow-up, the incidence of biopsy-proven acute rejection was 13% with an additional 10.5% incidence of presumed rejection. Patient and graft survival were 100% after 1 yr.

Two nonrandomized experiences with early steroid withdrawal in black kidney transplant recipients have been reported. Boardman et al. (51) reported the outcomes of early steroid withdrawal in 56 black kidney transplant recipients who were treated with polyclonal antibody induction therapy, either tacrolimus or CsA, and either MMF or sirolimus. The incidence of acute rejection after 1 yr of follow-up was 23% and was comparable to that observed in a concurrent group of nonblack patients. Using similar regimens but substituting basiliximab for a polyclonal induction antibody, Kumar et al. (52) reported a 16% cumulative incidence of clinically overt acute rejection 1 yr after early steroid withdrawal in black patients who also were treated with routine surveillance kidney biopsies.

	Randomized Studies

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Late Steroid Withdrawal with CsA-Based Immunosuppression
Two large randomized trials have examined the benefits and risks of late steroid withdrawal (approximately 3 mo after transplantation) in patients who were maintained on CsA and MMF (53,54). In each of these studies, the use of induction antibody therapy was optional. In the first study, performed at multiple centers in Europe, Australia, and South Africa, patients (n = 500) were enrolled at the time of transplantation and randomly assigned to low-dosage steroids for 3 mo followed by discontinuation or to regular dosages in the control group (53). At 12 mo, the incidence of acute rejection in the low/stop group was 25 versus 15% in the control arm (P = 0.008). The difference in acute rejection rates at 6 mo was NS among the 30% of patients who were treated with induction antibody therapy (15% in the low/stop group versus 14% in the control group). It is interesting that the majority of acute rejection episodes occurred during the first 3 mo after transplantation, before prednisolone actually was discontinued in the low/stop group. In fact, beyond day 84, only 4% of patients in the low/stop group and 0.4% of patients in the control group experienced acute rejection. There were no significant differences in patient or allograft survival rates at 12 mo. Follow-up of patients beyond 1 yr has not been reported.

The smaller American study (n = 266), aborted by a data safety monitoring board, differed from the European-based study in that patients were enrolled and randomly assigned at 3 mo after transplantation when they met inclusion criteria, including freedom from acute rejection before enrollment (54). At 12 mo after randomization, the incidence of acute rejection was 22% in the steroid withdrawal group versus 5% in the steroid-treated group (P = 0.0007). As shown in Figure 2, the cumulative incidence of acute rejection was particularly high among black participants (approximately 60% within 12 mo of randomization). Notably, use of induction antibody therapy was variable but had no statistically discernible impact on the incidence of acute rejection. Follow-up beyond 12 mo will never be reported from this study because investigators were advised by the data safety monitoring board to individualize treatment decisions.

View larger version (14K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Relative risks (RR) of acute rejection from a meta-analysis of randomized steroid withdrawal trials in patients who received MMF-based immunosuppression (20).

Early Steroid Withdrawal with CsA-Based Immunosuppression
Results from a small, multicenter, randomized trial reported by Vincenti et al. (56) indicate that the use of induction therapy with basiliximab followed by maintenance treatment with CsA and MMF could facilitate early withdrawal of prednisone without a statistically significant increase in the risk for acute rejection over relatively short periods of follow-up. The incidence of acute rejection in patients who were withdrawn from steroids after 5 d (n = 40) was 20% within 12 mo versus 16% in steroid-treated control subjects (n = 43; NS).

Late Steroid Withdrawal with Tacrolimus-Based Immunosuppression
In a Spanish study, 92 kidney transplant recipients who were treated initially with tacrolimus, MMF, and steroids were randomly allocated to continue triple therapy or withdrawal of steroids beginning 3 mo after transplantation (57). Inclusion criteria included stable renal function, freedom from acute rejection, and panel reactive antibodies <50%. After 2 yr of follow-up, the incidence of acute rejection was 6% in patients who were withdrawn from steroids and 3% in those who were maintained on steroids (NS).

Early Steroid Withdrawal or Steroid Avoidance with Tacrolimus-Based Immunosuppression
Two large European randomized trials of early steroid withdrawal or steroid avoidance were published recently. Roistang et al. (58) published the preliminary results of a European trial (the Carbohydrate Ratio Management in European National Diets [CARMEN] study) of early steroid withdrawal in patients who were receiving tacrolimus/MMF and either a single preoperative dose of methylprednisolone (n = 260) or standard doses of steroids without daclizumab induction (n = 278). The incidence of acute rejection was 16.5% in each group, but duration of follow-up was only 6 mo. Reported benefits included a significantly reduced incidence of new-onset diabetes in the steroid-free group (0.4 versus 5.4%; P = 0.003) and lower mean cholesterol levels at last follow-up.

A three-arm European trial (the ATLAS study) underscores the importance of induction antibody therapy in steroid avoidance trials (59). In this large study, a control group of patients received tacrolimus/MMF/steroids (n = 147) and were compared with patients who were randomly assigned to receive either basiliximab and tacrolimus monotherapy (n = 153) or tacrolimus/MMF/no steroids without induction antibody therapy (n = 151). The incidence of acute rejection was significantly higher in both experimental groups compared with the steroid-treated control group (8.2% in the control group versus 26.5% in the basiliximab/tacrolimus group and 30.5% in the tacrolimus/MMF group; P < 0.001). Again, duration of follow-up was limited to 6 mo.

One of the best designed randomized trials of early steroid withdrawal in patients who were receiving tacrolimus and MMF will not be published for several years owing to its admirable 5-yr, double-blinded, placebo-controlled study design. However, an interim analysis of this trial was presented recently (60). A total of 396 patients were enrolled and randomly assigned to receive either tacrolimus/MMF/steroids (n = 195) or tacrolimus/MMF and 7 d of steroids (n = 191). All patients received induction antibody therapy, although the choice of antibody was optional and center dependent. A total of 43% of the study population received deceased-donor transplants, and 20% were black. After 12 mo of follow-up, the incidence of biopsy-proven acute rejection was 6% in steroid-treated patients and 12% in the steroid withdrawal group (P = 0.04). There were no significant differences in graft or patient survival.

Randomized Trials with Complex Study Designs
A Dutch trial that involved 364 kidney transplant recipients was somewhat unique in that early steroid withdrawal (after 3 d; n = 186) was compared with late steroid withdrawal (at 16 wk; n = 178) in patients who were treated with tacrolimus and MMF (61). Patients in the early steroid withdrawal group also received induction therapy with daclizumab. There was no difference in the incidence of acute rejection (12% versus 15%), renal function, or graft or patient survival at 1 yr.

Smak Gregoor et al. (62) described a three-arm trial in which patients were randomly assigned at 6 mo after transplantation to continued treatment with CsA, MMF, and steroids (n = 73); CsA withdrawal (n = 63); or steroid withdrawal (n = 76). After 18 mo of follow-up, the incidence of biopsy-proven acute rejection was 1.4 versus 22 versus 4%, respectively. Compared with the other two groups, patients who were withdrawn from steroids exhibited lower mean arterial BP and lower total cholesterol levels.

In another large trial that was conducted in 47 European centers, 851 primary kidney transplant recipients who were treated initially with tacrolimus, MMF, and steroids were randomly allocated to continue tripe therapy (n = 277), discontinue steroids (n = 279), or discontinue MMF (n = 277) (63). The 6-mo incidence of biopsy-proven acute rejection was similar in all groups (17.0 versus 15.1 versus 14.8%, respectively). Mean total and LDL cholesterol levels were lower in the group of patients who were withdrawn from steroids.

The FREEDOM trial (64) is one of the more interesting recent studies of steroid-free immunosuppression in which 338 kidney transplant recipients were randomly assigned to maintenance steroid therapy; early steroid withdrawal after 7 d; or true steroid avoidance together with treatment with basiliximab, CsA, and enteric-coated mycophenolic acid. Preliminary results from this open-label, multicenter trial after 3 mo of follow-up indicate the lowest incidence of acute rejection in patients who were maintained on steroids (5.9%), the highest incidence in patients who were treated with steroid avoidance (20.9%) and intermediate rates in patients who underwent early steroid withdrawal (15.6%).

	Reexamining the Benefits of Steroid-Free Immunosuppression

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To the extent that corticosteroids are known to exacerbate hypertension, hyperlipidemia, and glucose intolerance, a major rationale for eliminating steroids in kidney transplant recipients is the desire to minimize these risk factors for cardiovascular disease. However, data on the effects of eliminating steroids on these risk factors have been mixed. Many of the randomized trials cited herein have demonstrated some benefit of steroid-free immunosuppression on BP, lipid levels, and/or glycemic control. However, a number of investigators have questioned whether similar benefits can be achieved with low maintenance dosages of steroids. A retrospective study of 58 patients who were followed for >7 yr showed that decreasing prednisone dosage from 17.5 to 10 mg/d resulted in significant improvements in weight, BP, and glycosylated hemoglobin level (65). However, no further improvement in these parameters could be demonstrated after complete elimination of steroids. A study of insulin resistance in kidney transplant recipients who underwent steroid withdrawal demonstrated a beneficial effect of lowering prednisolone dosage to 5 mg but no further improvement after complete withdrawal (66). Although we reported "cure" of new-onset diabetes in eight patients within a few months of steroid withdrawal (67), others have shown that this benefit often is short-lived, with diabetes ultimately recurring in a majority of patients despite the absence of steroid therapy (68). In our experience with steroid withdrawal in black kidney transplant recipients, new-onset diabetes has not resolved in any patient after elimination of steroids (48). Although many studies demonstrate that steroid withdrawal is associated with a decrease in total and LDL cholesterol concentrations, they often fail to note that withdrawal of steroid therapy is associated regularly with a concomitant decrease in HDL cholesterol levels (69), raising questions about any beneficial impact on cardiovascular risk.

Some studies suggest that steroid-free immunosuppression reduces weight gain after transplantation (70). However, in a Dutch study, weight gain during the first posttransplantation year was no different in patients who underwent early steroid withdrawal than in patients who were maintained on 5 mg/d prednisolone (71). In the 24-mo interim analysis of a randomized, placebo-controlled trial in which all patients received induction antibody therapy, tacrolimus, and MMF, a comparison of patients who were withdrawn from prednisone with those who were maintained on 5 mg/d revealed no differences in mean BP, number of BP medications, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, or the percentage of patients who were on lipid-lowering therapy (59). Moreover, there was no difference in the incidence of new-onset diabetes using strict criteria based on fasting blood sugars (60), although new-onset diabetes that required treatment with insulin was less common in the steroid withdrawal group.

Corticosteroids often are invoked as a major cause of posttransplantation osteopenia. However, comparisons of patients who were treated with early steroid withdrawal with those who were maintained on low dosages of steroids have demonstrated only a modest benefit that seems to be restricted to the lumbar spine (72,73). In fact, in the large study by ter Meulen et al. (72), bone density measured in the femoral neck and lumbar spine decreased to a similar degree within 3 mo of transplantation, irrespective of whether the patients were withdrawn from prednisone early or maintained on steroids.

Finally, the observation that prednisone favorably alters the nephrotoxic effects of CsA in an animal model (74) has raised concerns that steroids may protect against calcineurin inhibitor–mediated nephrotoxicity and, alternatively, that elimination of steroids might increase this toxicity. Supporting this hypothesis, a recent study that used protocol biopsies found a 10% incidence of calcineurin inhibitor toxicity among patients who were randomly assigned to early steroid withdrawal (n = 35) compared with a 3% incidence in patients who were maintained on steroids (n = 34) (75).

	Conclusion

Top Abstract Introduction and Historical... Nonrandomized Studies Randomized Studies Reexamining the Benefits of... Conclusion References

 
On the basis of this review of recent studies of steroid-free immunosuppression in kidney transplantation, it is impossible not to conclude that short-term results in steroid-free protocols using modern immunosuppressants have improved greatly over results that were obtained in the CsA-azathioprine era. However, some of the largest and most favorable experiences have been described in nonrandomized studies of patients who were at low immunologic risk for rejection. Moreover, virtually all of the most recent randomized trials continue to show trends for higher rates of acute rejection in patients who are withdrawn from steroids when compared with patients who are maintained on steroid therapy. In addition, many of the randomized trials are flawed by relatively short durations of follow-up, and even the largest of the studies lack the statistical power to demonstrate meaningful effects on graft or patient survival over short periods of time. There is a particular lack of long-term follow-up of high-risk patients (e.g., black patients) who are subjected to steroid-free immunosuppression. However, the incremental short-term risk for acute rejection that is associated with steroid-free immunosuppression in the most recent randomized trials generally has fallen below the "break-even" point, at least from an economic point of view.

Recent analyses of the Scientific Registry of Transplant Recipients (SRTR) database suggest that the studies cited in this review have had an impact on clinical practice (76). As seen in Figure 3, steroid withdrawal became increasingly common among recipients of a first kidney transplant between 1999 and 2003, especially in living versus deceased donor recipients Paralleling the paradigm shift in the timing of steroid withdrawal incorporated in clinical trials, data from the SRTR analyses indicate that steroid avoidance is more prevalent than steroid withdrawal in clinical practice (Figure 4). In 2004, 23% of all first transplant recipients were discharged from the hospital without steroids. Virtually all of the modern studies of steroid avoidance or early steroid withdrawal have used some kind of induction antibody therapy, making it almost axiomatic that induction therapy be used for optimal results.

View larger version (27K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Steroid withdrawal rates at 1 yr after transplantation for deceased- and living-donor kidney transplants, 1999 through 2003. Adapted from reference (76), with permission.

View larger version (25K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 4. Steroid avoidance rates for deceased- and living-donor kidney transplants, 1999 through 2004. Adapted from reference (76), with permission.

	Footnotes

 
Published online ahead of print. Publication date available at www.cjasn.org.

	References

Top Abstract Introduction and Historical... Nonrandomized Studies Randomized Studies Reexamining the Benefits of... Conclusion References

 

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