Corticosteroids form part of the immunosuppressive regimen used in many transplant centers. However, the long-term use of even low doses of corticosteroids has been associated with considerable morbidity, with adverse effects including hypertension, hyperlipidemia, diabetes mellitus, osteoporosis, fractures, Cushing syndrome, serious infections, and gastrointestinal events (1–3). Studies in various patient groups have reported that prednisolone use (even at low doses) significantly increased the risk of developing hypertension, diabetes, fractures (e.g., hip or spine), cataracts, bruising, and muscle weakness, as well as more risk for hospitalization for pneumonia (4–7). Furthermore, increasing duration of low-dose corticosteroid use (≤7.5-mg prednisolone) has been shown to be associated with acne, skin bruising, weight gain, and cataracts, whereas escalating dose was associated with fractures and sleep disturbances (8).
As a consequence of the detrimental effects of long-term corticosteroid use, research has been undertaken to evaluate the effects of corticosteroid avoidance or early withdrawal in renal transplant recipients. Most meta-analyses and reviews of published data have shown that steroid avoidance at transplantation or early withdrawal of steroids after transplantation was associated with increased rate or risk of acute rejection but without adversely affecting patient or graft survival (9–14). Moreover, a large prospective study of steroid withdrawal at least 6 months after transplantation in renal transplant recipients showed significantly improved patient and graft survival, as well as significantly improved cardiovascular risk factors, and similar rates of acute rejection compared with steroid continuation in retrospectively matched control patients (15). However, the data are not completely consistent because an earlier review of steroid-withdrawal studies in renal transplant recipients found that the increased risk of acute rejection also was accompanied by an increase in graft failure (16).
Tacrolimus is well established as a mainstay of immunosuppressive treatment after renal transplantation (17–19), but this agent also allows corticosteroid-sparing strategies to be implemented. For example, substituting cyclosporine with tacrolimus enables lower doses of maintenance corticosteroids to be used (20–22), and growing evidence indicates that combining tacrolimus with mycophenolate mofetil (MMF) or antibody induction therapy may allow early steroid withdrawal or complete avoidance of steroids in the posttransplantation setting (23, 24). However, long-term data investigating the effects of corticosteroid-free regimens are lacking.
The antibody, tacrolimus, and steroid withdrawal (ATLAS) study evaluated the feasibility of two corticosteroid-free immunosuppressive regimens (basiliximab induction therapy followed by tacrolimus monotherapy, and tacrolimus plus MMF) compared with a standard tacrolimus-based triple regimen after renal transplantation. The 6-month and 1-year follow-up data showed the rate of acute rejection was higher with both steroid-free regimens, but patient and graft survival was similar across the groups (25, 26). The present analysis reports the 3-year follow-up data for the ATLAS study, including patient and graft survival, incidence of acute rejection, renal function and tolerability.
Of the 451 patients included in the full 6-month analysis set, 3-year follow-up data were available for 421 (93.3%) patients: tacrolimus/basiliximab (Tac/Bas), 143 (93.5%) of 153; tacrolimus/MMF (Tac/MMF), 139 (92.1%) of 151; and tacrolimus/MMF/steroids (triple therapy), 139 (94.6%) of 147. These rates of follow-up were only slightly lower than at 1 year with 432 (95.8%) patients. Demographics and baseline characteristics for patients included in the 3-year analysis were similar across treatment groups. Most patients were male (61.5%, 64.7%, and 61.2%) and the mean ages (SD) were 46.1 (11.5), 47.2 (11.8), and 45.7 (12.9) years in the Tac/Bas, Tac/MMF, and triple therapy groups, respectively.
At the 3-year visit, the mean doses of tacrolimus were similar in the Tac/MMF (4.5 mg) and triple therapy arms (4.4 mg) but were slightly higher in the Tac/Bas group (4.9 mg) (see Table, SDC,http://links.lww.com/TP/A679). Mean (SD) tacrolimus trough levels were 8.3 (3.01), 7.9 (2.46), and 8.1 (2.69) ng/mL in the Tac/Bas, Tac/MMF, and triple therapy groups, respectively.
At 3 years, 48.5% in the Tac/Bas group, 57.9% in the Tac/MMF group, and 42.6% in the triple therapy group remained on their original randomized immunosuppressive regimen (from 1 year proportions of 58.2%, 63.7%, and 69.7%, respectively). High numbers of patients remained on the components of their original randomized study treatments, largely preserving the steroid-free nature of the two test treatment arms (Fig. 1). At 3 years, 64.0% in the Tac/Bas group, 77.6% in the Tac/MMF group, and 33.7% of patients in the triple therapy group were not receiving corticosteroids. Compared with the results at 1 year, the proportions for the Tac/Bas and Tac/MMF groups were slightly lower (71.0% and 74.8%, respectively), whereas the proportion in the triple therapy group increased considerably (22.1%); the changes from baseline in the use of corticosteroids were statistically significant at 1 year (P<0.0001) (see Table, SDC,http://links.lww.com/TP/A679). The proportions of patients on tacrolimus monotherapy at 3 years were 48.5% in the Tac/Bas group, 9.3% in the Tac/MMF group, and 3.0% in the triple therapy group (see Table, SDC,http://links.lww.com/TP/A679); the equivalent proportions at 1 year were 58.2%, 5.6%, and 0.8%, respectively.
Acute and Chronic Rejection
Biopsy-proven acute rejection (BPAR) incidence in all three groups was similar and infrequent at 3 years. Between the 6-month and 3-year visits, there were three BPAR episodes in the Tac/Bas group (2.1%), three episodes in the Tac/MMF (2.2%), and four episodes in the triple therapy group (2.2%). Most acute rejection episodes occurred during the main 6-month study, when the incidence was higher in the corticosteroid-free groups (26.1% in the Tac/Bas group and 30.5% in the Tac/MMF group vs. 8.2% in the triple therapy group; P<0.001).
The Kaplan-Meier estimates for the number of patients free from acute rejection were similar at 3 years to those at 1 year and 6 months within each treatment group: 71.7% versus 71.7% and 73.1% in the Tac/Bas group, 67.6% versus 67.6% and 69.1% in the Tac/MMF group, and 89.8% versus 91.5% and 91.5% and in the triple group, respectively (P=not significant at 3 years, Fig. 2). Of the total acute rejection episodes that occurred after the main 6-month study during the 3-year follow-up, four were in the Tac/Bas treatment group (one corticosteroid-resistant and three corticosteroid-sensitive episodes), five were in the Tac/MMF treatment group (four corticosteroid-sensitive episodes and one episode classified as “other”), and four in the triple therapy group (all corticosteroid-sensitive).
Between 6 months and 3 years, chronic rejection was bioptically diagnosed in 3 (2.1%), 6 (4.3%), and 5 patients (3.6%) in the Tac/Bas, Tac/MMF, and triple therapy groups, respectively.
Graft and Patient Survival
Three-year graft survival (Kaplan-Meier estimate) was almost identical across the treatment groups at 92.7% in the Tac/Bas group and 92.5% in both the Tac/MMF and triple therapy groups (P=not significant, Fig. 3A). These rates were similar to those observed at 1 year (93.4%, 95.3%, and 95.9%, respectively) and 6 months (93.4%, 96.0%, and 95.9%, respectively).
In total, 10 graft losses occurred between the 6-month and 3-year visits, 2 in the Tac/Bas group (one due to recurrence of the primary disease and one with unknown cause), 4 in the Tac/MMF group (three due to chronic rejection and one due to recurrence of the primary disease), and 4 in the triple therapy group (one due to acute refractory rejection, one due to chronic rejection, one due to recurrence of the primary disease and one with unknown cause).
There were no significant differences between the three treatment groups in patient survival rates (Kaplan-Meier estimates) at 3 years (Fig. 3B): 93.1% in the Tac/Bas group, 96.4% in the Tac/MMF group, and 97.0% in the triple therapy group. Similar patient survival rates were also seen at 1 year (99.3%, 98.6%, and 98.6%) and 6 months (all 99.3%) in the Tac/Bas, Tac/MMF, and triple therapy groups, respectively.
There were 12 deaths between the 6-month and 3-year visits: 5 in the Tac/Bas group (pulmonary edema, liver cirrhosis, acute myocardial infarction, lymphoma, and B-cell lymphoma); 2 in the Tac/MMF group (cerebral vascular accident and myocardial infarction); and 5 in the triple therapy group (breast cancer, melanoma, carcinoma of the lung, and unknown in two cases).
Renal function was similar between the three treatment groups throughout the study. Mean serum creatinine level at 3 years was 137.6 μM in the Tac/Bas group, 141.9 μM in the Tac/MMF group, and 139.1 μM in the triple therapy group. The respective mean serum creatinine levels were 137.8 μM, 137.5 μM, and 129.8 μM at 1 year and 176.2 μM, 145.3 μM, and 141.8 μM at 6 months in the Tac/Bas, Tac/MMF, and triple therapy groups.
Mean estimated glomerular filtration rate was similar across the treatment groups at each assessment visit. Mean estimated glomerular filtration rate at 3 years was 54.4 mL/min per 1.73m2 in the Tac/Bas group, 53.7 mL/min per 1.73m2 in the Tac/MMF group, and 55.4 mL/min per 1.73m2 in the triple therapy group; respective rates at 1 year were 53.4 mL/min per 1.73m2, 53.5 mL/min per 1.73m2, and 57.0 mL/min per 1.73m2 and at 6 months were 45.9 mL/min per 1.73m2, 50.8 mL/min per 1.73m2, and 53.6 mL/min per 1.73m2.
The treatment regimens were generally well tolerated. Adverse events (AEs) were similar in incidence, both overall and in the different categories, across the three treatment groups between the 1-year and 3-year follow-up visits (Table 1).
Laboratory parameters at the 3-year visit were generally similar across the three treatment groups and are summarized in Table 2. However, although total and LDL cholesterol levels decreased from baseline (transplantation) in all groups, a numerically higher decrease was seen in the Tac/Bas group compared with the other two groups (Tac/Bas vs. Tac/MMF, P<0.05). Similarly, antihyperlipidemic medication was administered to fewer patients in the Tac/Bas group (35 [24.5%]) compared with the Tac/MMF group (39 [28.1%]) and the triple therapy group (45 [32.4%])(P=not significant).
Blood pressure, both diastolic and systolic, was similar across the three treatment groups at the 3-year visit. At the same time point, 107 (74.8%), 111 (79.9%), and 108 (77.7%) patients were receiving antihypertensive medication in the Tac/Bas, Tac/MMF, and triple therapy groups (P=not significant).
Insulin use was reported in 8.4%, 19.4%, and 14.4% in the Tac/Bas, Tac/MMF, and triple therapy groups, respectively. New-onset insulin use between the 1-year and 3-year visits in patients who did not have diabetes at baseline (transplantation) was reported in 4 (3.0%), 9 (7.6%), and 6 (4.9%) patients, respectively, and oral antidiabetic medication use at the 3-year visit was reported in 4.9%, 3.6%, and 3.6% patients, respectively (P=not significant).
This observational, 3-year follow-up study in renal transplant recipients has shown that the two corticosteroid-free immunosuppressive regimens provided similar patient/graft survival and renal function compared with standard triple therapy, and all three strategies were generally well tolerated. Most patients in the Tac/Bas (64.0%) and Tac/MMF (77.6%) groups were corticosteroid-free at 3 years after transplantation, and 33.7% of patients in the triple therapy group remained steroid free at 3 years. The high number of patients becoming steroid-free in the original triple therapy group was unexpected and may dilute differences in efficacy or adverse effects between groups. In total, 42% to 58% of patients remained on their original randomized immunosuppression regimen. This is similar to a previous 3-year observational follow-up study investigating the withdrawal of steroids or MMF from tacrolimus-based triple therapy, in which 46% to 63% of patients remained on their original regimen (23). The trend for a notable proportion of patients initiated on triple therapy control arm to become steroid-free may be seen as a positive development for potentially reducing steroid-related morbidity.
Overall, the results of this 3-year study provide support for previous findings that steroid-free regimens are a feasible alternative to triple therapy in the long-term management of renal transplant recipients (23, 27). An observational, 3-year study of steroid withdrawal 3 months after transplantation (23) and a double-blind, randomized, 5-year trial of steroid withdrawal at 7 days after transplantation (27) demonstrated that similar rates of patient and graft survival were achieved, and renal function was well preserved compared with tacrolimus-based triple therapy (with or without antibody induction). Similar to the ATLAS study, both of these studies also showed that acute rejection occurred more frequently with the steroid-free immunosuppression regimens compared with triple therapy, with most episodes reported in the first 6 months after transplantation. Hence, the present study confirms prior observations that, although early higher rates of acute rejection may be seen with steroid-free regimens, this does not translate into poorer long-term outcomes, such as graft and patient survival and renal function.
In the present analysis, the Tac/Bas regimen offered a favorable cardiovascular risk factor profile, showing statistically nonsignificant trends for greater reduction in serum cholesterol and lower use of antihyperlipidemic and insulin medications compared with the Tac/MMF and triple therapy treatment arms. These findings are consistent with those observed at 6 months and 1 year (25, 26). A reduction in risk factors for posttransplantation cardiovascular disease, which is a leading cause of mortality in renal transplant recipients, is a key benefit of steroid-free immunosuppression regimens (28). This advantage of steroid avoidance has been demonstrated in several other studies of renal transplant patients, including the aforementioned 3- and 5-year studies, which have shown reductions compared with corticosteroid therapy in posttransplantation incidence of new-onset diabetes mellitus, new-onset metabolic syndrome, reduced serum cholesterol, and improved blood pressure (23, 24, 27, 29). Furthermore, several recent reviews of steroid withdrawal or avoidance that focused more on a contemporary immunosuppression (often including the use of mycophenolic acid and interleukin 2 receptor antibodies) confirmed the main findings of our study, that is, unaffected graft and patient survival rates, despite a higher rate of acute rejection, and decreased cardiovascular risk factors (10–14).
The main limitation of the study is that changes to the patients’ immunosuppression regimens could be made at the discretion of the investigator after the main 6-month study. Although it is very encouraging to see such high numbers of patients remaining on tacrolimus-based treatment at 3 years after transplantation, the degree of switching between regimens makes it difficult to draw firm conclusions or make comparisons between groups. Specifically, patients originally randomized to the steroid-free treatment groups may not have remained steroid-free throughout the follow-up period, and this undoubtedly complicates the interpretation of the long-term effects of each treatment regimen. Another limitation of the present analysis is the duration of follow-up. Three years is probably insufficient to clearly determine the long-term effects of steroid-free immunosuppression on renal allograft function and other efficacy and safety parameters. Further research in large, randomized, double-blind clinical trials of more than 5 years may be warranted to fully investigate this treatment strategy.
In conclusion, this analysis provides evidence that corticosteroid-free regimens are feasible and effective while preserving renal function in renal transplant recipients during the long term. In addition, the effects of acute rejection episodes on the health of the patient and the graft must be considered alongside the safety implications of long-term steroid use, that is, increased risk of cardiovascular and metabolic events. It may therefore be prudent to use low-dose immunosuppression coupled with steroid withdrawal or avoidance where possible, reserving steroid-based regimens for those patients at more risk of acute rejection, although treatment benefits of steroid-free protocols did not reach statistical significance.
MATERIALS AND METHODS
The methodology has been described in detail previously (25). Briefly, this study was conducted in 21 transplant centers in 10 European countries (Study ID: Cochrane Renal Group CRG020800135) in accordance with the Declaration of Helsinki and in compliance with the International Conference on Harmonization Good Clinical Practice (ICH-GCP) regulation and guidelines.
Adult patients (aged 18–65 years) with end-stage renal disease were eligible for inclusion if they were suitable candidates for primary renal transplantation from a deceased or living donor aged 5–65 years with a compatible ABO blood type. Patients were excluded from the study if they showed a panel reactive antibody grade 50% or higher in the previous 6 months or underwent retransplantation. Renal transplant recipients in the present trial showed a low immunologic risk as exemplified by being of white race, having a mean human leukocyte antigen mismatch of 2.7 to 2.9, having mean panel reactive antibody levels of 2%, and all receiving a primary renal transplant (cadaveric donor in 88%–89%). Full inclusion and exclusion criteria have been listed previously (25).
This was a 3-year follow-up study to an open-label, parallel-group, randomized, multicenter study designed to assess the efficacy and safety of corticosteroid avoidance with tacrolimus (Prograf; Astellas Pharma Europe Ltd., Staines, UK) monotherapy after Tac/Bas induction and from a dual Tac/MMF regimen without antibody induction, compared with triple therapy. In the 6-month study, patients were randomized 1:1:1, stratified by center (25).
After the 6-month period of the original study, all patients were managed according to the center preferences, and only routine data were collected. Data were collected throughout the main study, that is, up to 6 months and then at visits at 1 year (with an additional time window of up to 6 months) and at 3 years (±6 months).
In the original study, all patients received tacrolimus at an initial dosage of 0.2 mg/kg per day given in two divided doses of 0.1 mg/kg. The first dose was administered within 12 hr before reperfusion. Subsequent doses of tacrolimus were adjusted to maintain whole-blood trough levels of 10 to 20 ng/mL on days 0 to 28 and 5 to 15 ng/mL from months 1 to 6. For all treatments, dosing after the 6-month treatment period was at the discretion of the investigator.
The Tac/MMF and triple therapy groups received MMF at an initial oral dosage of 2 g/day with 1 g given within 12 hr before reperfusion. This was maintained up to day 14, after which 1 g/day was administered until the end of the main study. Patients in the Tac/Bas group received two 20 mg doses of basiliximab, one on day 0 within 2 hr of surgery, and one on day 4 after transplantation.
All patients received an intravenous perioperative dose of 500-mg methylprednisolone or more. For the corticosteroid-free groups, no further corticosteroid administration was planned after the day of surgery. Patients in the triple therapy group received an intravenous bolus of methylprednisolone 125 mg on day 1 and oral prednisolone (or equivalent) as follows: 20 mg/day on days 2 to 14, 15 mg/day on days 15 to 28, 10 mg/day on days 29 to 42, and 5 mg/day until the end of the main study.
Efficacy and Safety Assessments
The main efficacy endpoints in this 3-year follow-up were incidences of BPARs, patient and graft survival, renal function (measured by serum creatinine levels and glomerular filtration rates [calculated using the Modified Diet in Renal Disease equation]) (30). Criteria for efficacy endpoints have been described previously (25). Safety was assessed by monitoring AEs for specific body systems and parameters, recording comedications, changes in laboratory parameters (including serum lipids), and vital signs.
Statistical analysis of the data is considered as exploratory and based on observational data. Efficacy was analyzed using the intent-to-treat population, which included all randomized patients who were transplanted and received at least one dose of study medication (basiliximab and tacrolimus for the Tac/Bas group, tacrolimus and MMF for the Tac/MMF, and triple therapy groups). Safety was based on the intent-to-treat patients who provided data for the 3-year follow-up period.
Incidences of and times to first BPAR and first acute rejections, as well as patient and graft survival for the original 6-month study and up to 3 years after transplantation were analyzed using Kaplan-Meier survival procedures, with the standard error computed according to the Greenwood formula. Differences between treatment groups were analyzed using the Wilcoxon-Gehan test. No adjustment was carried out for multiple comparisons. The frequency of acute rejections, the proportion of corticosteroid-free patients, and the proportion of patients on specific medications at year 3 were analyzed using a chi-square statistic. Continuous parameters like renal function were compared globally among treatment groups using the Mann-Whitney U test. Fisher exact test was used to compare the incidence of AEs.
The authors would like to thank Caroline Anthony, a professional medical writer with Acumed, for her assistance in drafting and revising the article.
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