With the introduction of more potent immunosuppressive agents, such as MMF, Tac, sirolimus, and newer induction agents such as anti-thymocyte globulin and anti-IL2 receptor antibodies in the 1990s, the overall incidence of acute rejection has decreased during this time span in patients treated with steroid-containing immunosuppressive regimens.13–16
At the same time, there has been a renewed enthusiasm in steroid-free immunosuppression. This is shown by the continuous increase in the numbers of patients on a steroid-free immunosuppressive regimen at the time of discharge from the hospital after transplant surgery ().17
The trend of the use of steroid-free immunosuppression at discharge within the US transplant centers between 2000 and 2006.
Ahsan et al
presented the results of a multicenter, randomized, and double-blind steroid withdrawal trial at 3 months after transplant, in patients receiving a combination of CsA and MMF. Although patient and graft survival were no different at 1 year, there was a significant increase in acute rejection or treatment failure (9.8% with steroids and 30.8% without steroids, P
<0.001). In particular, the risk of treatment failure was much higher for blacks (39.6%) than for non-blacks (16.0%). Furthermore, patients withdrawn successfully from steroids had a higher serum creatinine. Vanrenterghem et al
conducted a similar trial in Europe involving 500 patients, with half of them having steroids discontinued at 3 months. The rate of biopsy-proven acute rejection was higher in the steroid withdrawal group at 6 months (23 vs 14%, respectively, P
=0.008) and 12 months (25 vs 15%, respectively), although the graft loss at 12 months was similar (5 vs 4%, respectively). Neither of these studies involved a universal use of antibody induction.
In the late 1990s, it was increasingly recognized that late posttransplant steroid withdrawal was associated with an increased incidence in acute rejection in some recipients. It was also recognized that the chronic use of steroids may have sensitized lymphocytes by upregulating the expression of cytokine receptors in the surface membrane so that withdrawal in a late stage would have resulted in the stimulation of those lymphocytes.20
Finally, late steroid withdrawal may not prevent steroid-related complications, at least in some aspects. With these considerations in mind, Matas et al
. from the University of Minnesota conducted a pilot study of rapid discontinuation of steroids within the first 5 days. Thymoglobulin was the induction agent; CsA and MMF were maintenance medications.21
Compared with the historical controls of CsA/AZA/P and CsA/MMF/P regimens without the use of an induction agent, there was no difference in 1-year patient and graft survival. Only 10% of patients had a biopsy-proven acute rejection that was not different from that of historical controls. However, 25% of patients returned to steroids 5 to 17 months after transplant.
In a multicenter, randomized early steroid withdrawal trial reported by Vincenti et al
., anti-IL2 receptor antibody was used as the induction agent, followed by CsA and MMF as the maintenance regimen. It yielded results comparable with those of the steroid-containing regimen regarding the incidence of acute rejection at 12 months (20 vs 16%, non significant).22
Patient and graft survival were similarly good in both groups, but 28% of patients from the steroid withdrawal group returned to steroid-containing regimens at 6 months after transplantation.
Most recently, the Freedom trial compared steroid-free and early steroid withdrawal with a standard chronic steroid-containing regimen using an anti-IL2 receptor antibody as the induction agent and a combination of CsA/MPA as maintenance therapy.23
At 12 months, biopsy-proven acute rejection occurred significantly more often and earlier in steroid-free and steroid withdrawal groups (31.5% in steroid-free, 26.1% in steroid withdrawal and 14.7% in standard steroid groups, P
=0.007 and P
=0.046 for steroid-free and steroid withdrawal groups vs standard steroid group, respectively). Patient and graft survival were no different among the groups. Renal function was no different.
On the other hand, the experience using a combination of CsA and sirolimus suggested that lower rates of acute rejection could be achieved without the use of steroids. Rajab et al
reported their experience with this combination in 301 primary kidney transplant patients. The first year incidence of acute rejection was 4.9% in the steroid-free group compared with 9.4% in a historical cohort of primary kidney transplant patients with a steroid-containing regimen (P
<.05). Patient and death censored graft survival at 1 year were 93.1% and 98.1%, respectively.
Since the introduction of Tac into the armamentarium of maintenance immunosuppressive medications, several clinical trials have shown a lower rate of acute rejection compared with CsA regimens.25–28
Rostaing et al
reported the outcome of a multicenter European study comparing the regimens of Tac and MMF with and without maintenance steroids. After 6 months of follow-up, the incidence of acute rejection was identical at 16.5% in both groups, involving a total of 538 patients. The severity of acute rejection was also identical. However, the steroid withdrawal group received induction therapy with an anti-IL2 receptor antibody, whereas the steroid-containing group did not. The major drawback of this study was a too short follow-up time and the differential use of induction agent.
After initially reporting their pilot experience with rapid steroid withdrawal in CsA- and MMF-treated patients, Matas et al
further extended their experience into a large cohort of patients to include Tac and sirolimus. In spite of not being randomized and uncontrolled, their experience clearly showed that, with the use of induction therapy, early steroid withdrawal produced acceptable short- and intermediate-term outcomes with regard to both patient and graft survival, as well as the incidence of acute rejection during the 5-year study period. Furthermore, compared with historical controls, steroid withdrawal patients experienced significantly fewer complications related to the long-term use of steroids such as cataracts, new-onset diabetes, avascular necrosis, and fractures.
Kumar et al
reported their experience with steroid withdrawal 2 days after transplant, using an anti-IL2 receptor antibody as the induction agent and Tac, combined either with MMF or sirolimus, as the maintenance regimen. More than half of their patients were African-American. A surveillance biopsy was performed on all their patients at 1, 6, 12, 24, and 36 months after transplant. Patient and graft survival were similar at 3 years. Clinical acute rejection was diagnosed in 14% of steroid-treated and in 16% of steroid withdrawal patients at 1 year (P
=NS). Subclinical acute rejection and chronic allograft nephropathy, diagnosed by surveillance biopsies, were higher in both groups. However, no difference existed between steroid-treated and steroid withdrawal patients over 3 years. Weight gain and incidence of new-onset diabetes were significantly lower in steroid withdrawal patients (change in body mass index 0.3 vs 4.4, respectively, over 3 years, P
=0.04, and new-onset diabetes (NODAT) 4 vs 21%, respectively, at 3 years, P
<.01). Similarly, a serious infection requiring hospitalization was lower in the steroid withdrawal group (18 vs 35%, P
African-American kidney transplant patients are traditionally considered to be at high risk for immunological complications. Steroid withdrawal in this group of patients was typically complicated by a higher rejection rate and poorer graft survival.18,34
However, African-American patients may benefit more from steroid withdrawal-related improvement in cardiovascular risk reduction, such as a reduced incidence of new-onset diabetes and weight gain. By using the combination of Tac and sirolimus, Hricik et al
have shown that steroids could be successfully withdrawn with a low incidence of acute rejection. Gruber et al
. achieved a similar outcome using a combination of Tac and MMF.36
More recently, Woodle et al
published their experience of early steroid withdrawal in patients receiving Tac and MMF. Their study involved 386 patients from multiple centers, randomized to rapid steroid withdrawal (191 patients) and to chronic low-dose steroids (195 patients) with a 5-year follow-up. They excluded highly sensitized patients (pPRA≥50% and/or cPRA≥25%). Steroid withdrawal was completed within 7 days after transplant. Induction was used but the choice of agents, an anti-IL2 receptor antibody or thymoglobulin, was determined by individual centers. After a 5-year follow-up, they found no difference between the two study groups in the composite primary end point of death, graft loss, and moderate–severe acute rejection. Biopsy-proven acute rejection, however, was higher in the steroid withdrawal group (17.8 vs 10.8%, respectively, over 5 years, Kaplan–Meier analysis, log-rank P
=0.042). When sub-analysis was performed to determine the effects of the induction agents used, the magnitude in the difference of acute rejection was higher in patients who received an anti-IL2 receptor antibody (24.2% in steroid withdrawal and 11.9% in chronic steroids use group, P
=0.105) than in patients who received thymoglobulin (14.4% in steroid withdrawal and 10.3% in chronic steroid group, P
=NS). Renal function was no different between the groups after 5 years. Serious infectious events were more common in chronic steroid users (16.4 vs 9.4%, P
=0.04). Post hoc
analysis did reveal a 5.8% increase in chronic allograft nephropathy in the steroid withdrawal group over 5 years (9.9 vs 4.1%, P
=0.028). However, this last observation needs to be interpreted cautiously, as neither baseline nor protocol biopsies were part of the study protocol. Thus, a possibility of preexisting donor disease and/or overdetection bias could not be excluded, as a greater proportion of patients from the steroid withdrawal group underwent biopsy (46.1 vs 32.8%, respectively, P
=0.009). The impact of chronic allograft nephropathy on the outcome remains unknown from this study. A longer follow-up may help further delineate this aspect.
Finally, Tan et al
reported their 3-year experience with steroid-free Tac monotherapy under alemtuzumab induction. They reported 3-year patient and graft survival at 93.3 and 86.3%, respectively. The incidence of acute cellular rejection was low within the first year (9.0%). However, the cumulative incidence of acute cellular rejection increased to as high as 24% within 3 years after transplantation. Late occurrence of acute cellular rejection, particularly within the second year, was especially detrimental to patient and graft survival. It is important to point out that, in addition to being steroid free, their protocol also incorporated a spaced weaning of Tac.
Two important questions remain with regard to all these clinical trials, randomized or not. First, what is the impact of the increased incidence of acute rejection in steroid withdrawal patients on long-term graft and patient survival? Second, are patients who experienced acute rejection systematically different from patients who did not experience acute rejection after steroid withdrawal? Many centers have established certain criteria for selecting patients for steroid-free immunosuppression. The criteria became more inclusive in some centers as they gained experience.23,31,33,39
The risk factors for acute rejection seemed similar for patients in steroid-free regimens as for those in steroid-containing regimens. Certain patients started on steroid-free regimens would have benefited from steroids once they experienced an episode of acute rejection.40,41