SEARCH

SEARCH BY CITATION

Keywords:

  • Cataract;
  • heart transplant;
  • hyperlipidemia;
  • kidney transplant;
  • osteoporosis;
  • steroid withdrawal

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
  9. Appendix

A large prospective study of steroid withdrawal was performed within the framework of the Collaborative Transplant Study to analyze long-term graft and patient outcome in renal and heart transplant recipients. Steroids were withdrawn no earlier than 6 months posttransplantation. A comparison of 7-year outcomes in renal transplant recipients (94% receiving cyclosporine; 97% Caucasian) showed a benefit of steroid withdrawal versus steroid continuation in retrospectively matched controls, for graft survival (81.9%± 1.8% vs. 75.3%± 1.2%, p = 0.0001), patient survival (88.8%± 1.5% vs. 84.3 ± 1.0%; p = 0.0016) and death-censored graft survival (91.8%± 1.3% vs. 87.9%± 1.0%: p = 0.0091). Steroid withdrawal was associated with improved graft survival in heart recipients also (76.2%± 2.4% vs. 66.9%± 1.7%, p = 0.0008). A total of 58.6% of renal recipients and 44.3% of heart recipients never required steroids during follow up. Rates of acute rejection and renal dysfunction did not differ between steroid-free and steroid-continuation groups. Steroid withdrawal was associated with significantly improved cardiovascular risk factors compared with steroid continuation. Rates of the development of osteoporosis and cataracts did not differ in the entire patient cohort, but were strikingly lower in patients taken off steroids during the first posttransplant year.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
  9. Appendix

Short-term transplantation outcomes have improved with advances in immunosuppression and posttransplantation care, and consequently attention has shifted to late allograft failure, which is attributed mainly to chronic rejection and death with a functioning graft. Many complications in the posttransplant period are the result of immunosuppressive agents (1). Corticosteroids, which have been used for more than four decades, lead to side effects including weight gain, cataracts and bone loss, and also enhance cardiovascular risk factors such as hypertension, hyperlipidemia and diabetes (2). Although the advent of triple therapy with cyclosporine (CYA), steroids and azathioprine (AZA) has allowed steroid doses to be reduced, steroid-induced morbidity is still a major problem in transplant recipients. Strategies of complete steroid avoidance or of steroid withdrawal in the posttransplantation period have therefore been evaluated and have been shown to avert several of the adverse effects of long-term steroid use (3,4).

Despite the advantages of this approach, steroid withdrawal from CYA-based regimens has been attempted in only a small number of patients. Retrospective data from the Collaborative Transplant Study (CTS) registry showed that steroids were withdrawn from fewer than 10% of renal transplant patients by 1 year after transplantation (5). Results from prospective steroid-withdrawal trials have been difficult to interpret because of widely varying protocols and small patient populations. In general, the risk of acute rejection is increased among patients in whom steroids have been withdrawn (6), particularly if the withdrawal occurs shortly and rapidly after transplantation (7). Although in an earlier meta-analysis an increased risk of acute rejection with steroid-free immunosuppression was not associated with poorer graft or patient outcomes (8), a more recent meta-analysis concluded that both acute rejection and graft failure after a mean of 28 months of follow up were increased with this strategy (6).

The long-term outcomes after steroid withdrawal remain controversial. Our retrospective analysis of more than 12 000 kidney transplant recipients in the CTS database showed that 5-year graft and patient survival were highest in patients maintained on CYA alone or in combination with AZA, compared with patients continuing on the triple-drug regimen that included steroids (5). By contrast, a prospective, randomized multicenter trial from Canada demonstrated significantly lower long-term survival in patients in whom steroids were withdrawn 3 months after renal transplantation (9).

These conflicting results prompted us to convene a panel of 14 experts in 1994 to reinvestigate the feasibility of long-term steroid-free immunosuppression. Based on a consensus protocol, we initiated within the CTS framework a prospective collaborative study of steroid withdrawal, the main objective of which was to determine whether steroids could be withdrawn prospectively in stable renal allograft recipients without a detrimental effect on long-term outcomes (10,11). Because the potential benefits of a steroid-free maintenance immunosuppressive regimen have spurred interest in withdrawing steroids in heart transplant recipients, we also analyzed the long-term effects in cardiac transplantation. Steroidal side effects were not a focus of the prospective study. However, as a secondary objective, we have analyzed the influence of steroid-free treatment on common steroid side effects in these patients using data reported to the CTS and compared the results with those of a matched control series from the general CTS database.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
  9. Appendix

Study design and patients

The protocol was devised by the expert panel (Appendix). This was a multicenter collaborative study of 30 kidney and 13 heart transplant centers (Appendix). Participating centers obeyed institutional ethics committee regulations and prospectively enrolled recipients who fulfilled eligibility criteria. The CTS office at the University of Heidelberg, Germany, served as study center. Patients were enrolled between 1994 and 2002, the majority during the first 3 years. Inclusion criteria were: serum creatinine level of <260 μmol/L for kidney recipients and <200 μmol/L for heart recipients; good graft function for at least 6 months posttransplantation; stable graft function for at least 3 months before enrollment. Patients with highly reactive (>80%) preformed lymphocytotoxic antibodies, rapid rejection of a previous graft and previous severe vascular or steroid-resistant rejection were excluded. Each patient in the prospective study was matched to three patients from the general CTS database for the following variables: recipient and donor age, race, year of transplant, first or retransplant, type of end-stage disease, ischemic preservation time, geographical origin (continent), number of HLA mismatches, percent panel-reactive antibodies and duration to enrollment. In addition, all controls for kidney recipients were selected to have a creatinine level of <130 μmol/L at the same time as that of the study patients at the time of enrollment, and controls for cardiac recipients had a clinical outcome evaluation of 'excellent with minimal immunosuppression,' as defined by individual centers. Follow-up information on graft and patient survival was obtained 6 months after enrollment and yearly thereafter. The median period of follow up was 5 years for kidney recipients and 6.3 years for heart recipients.

Although no strict guidelines were established for steroid tapering, steroids were reduced slowly and in a stepwise fashion, leading to steroid-free maintenance after 6 months. Withdrawal was delayed in the case of deterioration of function. Rejection episodes were treated according to each center's established protocol, and steroid withdrawal could be attempted a second time after a minimum of 3 months of stable function. A third attempt after two failures was not recommended. Close monitoring of creatinine and CYA levels was considered essential before, during and after steroid withdrawal. During the period of steroid withdrawal, creatinine measurements were recommended every other week and then monthly, after conversion. Whole blood CYA levels were maintained between 150 and 250 ng/mL during and for 3 months after withdrawal.

The patient population for analysis of side effects included all patients from the prospective study for whom these data were available in the general CTS database and control patients from the CTS database who were matched initially for the analysis of primary outcomes and on whom secondary outcome data were also available.

Outcome measures

The primary outcomes were patient and graft survival. Functional graft survival was also determined after censoring patients dying with a functioning graft. Rates of impaired renal function and treatment for rejection were analyzed, and the evaluation of secondary outcomes included the incidence after steroid withdrawal of new cases of osteonecrosis, osteoporosis, or cataract, patients with systolic blood pressure (SBP) higher than 150 mmHg, patients receiving antihypertensive medication, and patients with cholesterol levels higher than 300 mg/dL. A protocol for assessing secondary outcomes was not specified; these were evaluated according to each center's practice and the information was provided only by centers that deemed the reporting effort logistically manageable; all patients for whom this information was available were analyzed and no exclusions were made.

Statistical analysis

The Kaplan-Meier method was used to estimate graft and patient survival. The log-rank test was used for comparisons and a p value less than 0.05 was considered significant. Cumulative frequencies for achieving a creatinine level >130 μmol/L, of rejection treatment, and of reinstatement of steroids over the 5-year period were also analyzed by this method. In addition, a 'snapshot' analysis was performed at yearly intervals to capture the fraction of patients who exhibited these events at any given time.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
  9. Appendix

Prospective data on steroid withdrawal were available for 1110 cadaver kidney recipients (of whom 61 were retransplants) and 450 heart patients. Matched controls from the CTS database (3 per patient) were identified for 1015 kidney and 420 heart transplant patients. The clinical characteristics of the steroid withdrawal and control groups at the time of steroid withdrawal were similar, except that a serum creatinine level of 130–260 μmol/L was present in 16% of patients with renal transplants who underwent steroid withdrawal, compared with 0% of controls who were all selected to have a serum creatinine level of <130 μmol/L (Table 1). The median time from transplantation to study enrollment was 1.1 years in kidney recipients and 1.4 years in heart recipients. A vast majority of patients (94%) received CYA-based immunosuppression.

Table 1.  Clinical characteristics of study populations
CharacteristicRenal transplantsHeart transplants
Steroid withdrawal (n = 1015)Matched controls (n = 3045)Steroid withdrawal (n = 420)Matched controls (n = 1260)
Recipient age (yr) (mean ± SD)45.6 ± 13.445.1 ± 13.848.2 ± 11.448.8 ± 11.7
Male gender (%)55.553.582.982.7
Race (%)
 White97.497.496.696.6
 Black0.61.40.51.7
 Other2.01.32.91.7
Donor age (yr) (mean ± SD)35.0 ± 15.535.0 ± 15.631.7 ± 12.331.9 ± 12.2
Cold ischemia time (h) (mean ± SD)19.5 ± 7.120.4 ± 7.12.5 ± 1.32.6 ± 1.1
HLA
 0–19.014.02.00.6
 2–478.175.049.053.5
 5–612.911.049.045.8
Creatinine > 130 μmol/L (%)16.00.0--
Geographic origin (%)
 Europe75.577.135.553.4
 North America22.017.955.246.6
 Other2.65.09.30.0
Regraft (%)6.06.00.70.7
Receiving cylosporine (%)94.091.593.398.0

Long-term graft and patient outcomes after steroid withdrawal

Figure 1 shows that 7 years after steroid withdrawal, 81.3%± 1.7% of all kidney recipients and 76.9%± 2.3% of all heart recipients continued to have a functioning graft. When the results for kidney transplants were analyzed according to the immunosuppressive regimen at study entry, no significant differences in 5-year graft survival were noted between groups receiving CYA alone (87.0%± 2.5%) or with AZA (86.2%± 1.8%) or MMF (89.8%± 3.1%), although treatment with MMF appeared to have a slight advantage. Outcomes after steroid withdrawal were not influenced by antibody induction (data not shown).

image

Figure 1. Seven-year graft survival after steroid withdrawal in cadaver kidney and heart transplant recipients.

Download figure to PowerPoint

Our study included patients in whom steroids were withdrawn at any time beyond 6 months after transplantation. We therefore examined graft outcomes as a function of the duration of graft stability before withdrawal and found no significant differences in 5-year survival for steroid withdrawal conducted ≤1 year or >1 year after renal transplantation (88.5%± 1.8% vs. 87.4%± 1.4%, p = 0.7466) or heart transplantation (88.5%± 2.6% vs. 83.0%± 2.4%; p = 0.1533). Because the nature of the CTS database did not allow us to ascertain the exact date of rejection treatment, we were unable to match patients and controls according to whether rejections had been treated or not prior to study enrollment. However, analysis of a possible influence of pre-enrollment rejections on postenrollment outcomes did not reveal a significant effect in these 'good risk' patients. A total of 22.9% of kidney recipients and 48.0% of heart recipients had been treated for at least one acute rejection prior to enrollment for steroid withdrawal. The 5-year graft survival rates after withdrawal were 86.8 ± 2.3% and 87.9 ± 1.3% (p = 0.428) for kidney recipients with or without prior rejection treatment, respectively, and the corresponding survival rates in heart transplant recipients were 84.6 ± 2.7% and 86.8 ± 2.4%, respectively (p = 0.499). Neither did pre-enrollment rejections have a significant effect on the rate of de novo rejection during the first year after steroid withdrawal. Among kidney recipients, 4.4% of patients without and 6.4% of patients with previous rejections required treatment for rejection during the first year (p = 0.161), and among heart recipients the corresponding rates were 15.3% and 18.8%, respectively (p = 0.200). Separate analysis of patients who were enrolled for steroid withdrawal during the first posttransplant year or after the first year also did not show a significant effect of pre-enrollment rejection treatment on postenrollment outcome in either subset (data not shown).

When 7-year outcomes after steroid withdrawal in renal recipients were compared with those in matched control patients after steroid continuation, a clear benefit for steroid withdrawal was shown for graft survival (81.9%± 1.8% vs. 75.3%± 1.2%, p = 0.0001), patient survival (88.8%± 1.5% vs. 84.3%± 1.0%; p = 0.0016) and death-censored graft survival (91.8%± 1.3% vs. 87.9%± 1.0%: p = 0.0091) (Figure 2). Although only patients with matching controls were included in this analysis, graft survival was virtually identical to that obtained with the series as a whole. An analysis of the causes of death did not reveal significant differences between steroid withdrawal and control groups. In heart recipients, 7-year graft survival also was significantly better after steroid withdrawal (76.2%± 2.4% vs. 66.9%± 1.7%, p = 0.0008) (Figure 3).

image

Figure 2. Seven-year graft (A), patient (B) and functional graft (C) survival in renal transplant recipients after steroid withdrawal (study patients) or steroid continuation (matched controls).

Download figure to PowerPoint

image

Figure 3. Seven-year graft survival in cardiac transplant recipients after steroid withdrawal (study patients) or steroid continuation (matched controls).

Download figure to PowerPoint

Renal function after steroid withdrawal

At enrollment, all controls and 84% of renal patients in the steroid-withdrawal group had a serum creatinine <130 μmol/L. Over 5 years, creatinine levels increased de novo to >130 μmol/L in 37.3%± 1.9% of patients who received steroid-free treatment, as compared with 35.1%± 1.0% of control patients who continued to receive steroids (p = 0.4527) (Figure 4A). As expected, in the steroid-withdrawal group, creatinine levels deteriorated to >130 μmol/L in significantly fewer patients who always remained steroid free (33.6%± 2.6%) compared with patients who required steroids at any time (50.4%± 3.0%) (p < 0.0001) (Figure 4B).

image

Figure 4. Renal function in cadaver kidney recipients over 5 years after steroid withdrawal (study patients) or steroid continuation (matched controls) (A) and after steroid resumption (steroids any year) or steroid-free maintenance (5 yr steroid free) (B).

Download figure to PowerPoint

Acute rejection

The occurrence of acute rejection over 5 years after steroid withdrawal was analyzed as the cumulative likelihood of kidney and heart recipients requiring treatment for acute rejection during this period (Figure 5). The frequency of patients requiring rejection treatment was similar regardless of steroid withdrawal or continuation for both kidney (8.6%± 1.1% vs. 10.2%± 0.7%; p = 0.2067) and heart transplants (35.3%± 2.8% vs. 30.6%± 2.3%; p = 0.1487). The rate of treatment for heart transplants was much higher than for kidney transplants, a reflection possibly of a lower threshold for treatment of suspected cardiac rejection.

image

Figure 5. Cumulative 5-year incidence of patients treated for acute rejection after steroid withdrawal (study patients) or steroid continuation (matched controls).

Download figure to PowerPoint

Five years after steroid withdrawal, the cumulative rate of patients requiring steroids at any time was 41.4%± 1.5% for renal transplant recipients and 55.7%± 2.5% for cardiac transplant recipients. However, when the frequency of steroid use was analyzed on a yearly basis, steroid use did not increase over successive years (Table 2). The trend was similar in heart recipients, although frequencies of steroid use were higher.

Table 2.  Long-term steroid use
Type of transplantPrevalence of steroid use (%)
Year 1Year 2Year 3Year 4Year 5
Kidney36.326.024.723.023.2
Heart54.944.838.138.937.8

Long-term influence of steroid-free maintenance on secondary parameters

Because of the paucity of data on secondary parameters in heart transplants, this analysis is confined to renal transplants. As explained earlier, this analysis was not part of the original prospective study, hence data were available only for a subset of study patients and matched controls and were obtained from the general CTS file. Outcomes for secondary parameters are shown in Table 3.

Table 3.  Effect of steroid withdrawal on secondary parameters in kidney recipients
Parameter Frequency at study entry (%)Cumulative frequency of new cases after 5 years of follow up (%)
Steroid withdrawalMatched controls p valueSteroid withdrawalMatched controls p value
Hypertension
 Receiving antihypertensive agents79.178.90.904880.282.60.2908
 Systolic BP >150 mmHg28.831.00.458522.125.90.0570
Cholesterol
 >200 mg/dL70.471.30.784070.673.20.1835
 >300 mg/dL7.17.60.82185.38.40.0078
Osteonecrosis6.71.1<0.00014.63.30.1039
Osteoporosis27.415.10.000220.219.50.5752
Cataracts17.45.9<0.000111.79.70.1241

Steroid withdrawal did not reduce the number of new patients requiring antihypertensive therapy over 5 years, when compared with patients continuing on steroids. Steroid withdrawal reduced somewhat the cumulative 5-year frequency of new patients who experienced SBP >150 mmHg (22.1%± 1.6% vs. 25.9%± 1.1%; p = 0.0635). The frequencies of patients with cholesterol levels higher than certain threshold values were similar in both groups at the start of the study, but after steroid withdrawal, significantly fewer patients developed a de novo cholesterol level >300 mg/dL. The cumulative 5-year rates of patients exceeding 300 mg/dL were 5.3%± 0.9% in patients in whom steroids were withdrawn, as compared with 8.4%± 0.7% in matched controls (p = 0.0078). Statins were used by 51.3% of the steroid-withdrawal group and 59.6% of the control group (p = 0.1353).

At enrollment, patients in the steroid-withdrawal group had significantly higher frequencies of osteonecrosis, osteoporosis or cataracts, compared with the control patients, suggesting that patients with evidence of steroid-associated conditions were selectively enrolled for steroid withdrawal. When the entire series of study patients was examined, the development of new cases of these three conditions was not affected by steroid withdrawal (Table 3). However, there was a distinct difference in emergence of new cases of osteoporosis or cataract in patients in whom steroids were withdrawn ≤1 year or >1 year after transplantation. Steroid withdrawal more than 1 year after transplantation had no influence on the development of new cases of osteoporosis or cataract, and moreover, no benefit was demonstrable in patients who remained steroid free compared with those who required steroids during follow up. By contrast, steroid withdrawal during the first posttransplant year resulted in strikingly lower rates of osteoporosis and cataract, compared with steroid continuation (Figure 6). The 5-year cumulative rates of de novo osteoporosis in these patients were 13.6%± 2.3% in study patients versus 24.3%± 1.9% in matched controls (p = 0.0020), and the corresponding rates of cataract formation were 7.2%± 1.8% vs. 13.6%± 1.5% (p = 0.0092). There was no difference, however, in the rates of osteonecrosis (5.0%± 1.4% vs. 4.9%± 0.9%, p = 0.8624).

image

Figure 6. Cumulative 5-year incidence of new cases of osteoporosis (A) or cataract (B) in cadaver kidney recipients after steroid withdrawal ≤1 year after transplantation (study patients) or steroid continuation (matched controls).

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
  9. Appendix

The main aim of this study was to determine whether long-term steroid-free maintenance could be achieved without detrimental effect on graft and patient survival. Previous studies of steroid withdrawal have led to conflicting results (3,9,13). This large prospective analysis shows that steroid withdrawal after 6 months posttransplantation leads to superior 7-year graft and patient outcomes in stable renal transplant recipients, compared with steroid continuation. More than 95% of patients enrolled were Caucasians and the study did not address whether steroid withdrawal would be equally successful in patients belonging to other ethnical groups.

Our findings are at variance with those in the literature showing steroid weaning to place patients at risk of poorer long-term outcomes (9) and must therefore be interpreted with caution. Certainly, we enrolled patients for steroid withdrawal only if considered to be low risk, and controls were not studied prospectively. However, these factors should not undermine the validity of our results, because the analysis was designed to be more favorable to the control group. Each kidney recipient in the prospective steroid-withdrawal group was matched by various criteria to three concurrent controls, all selected to have a creatinine level of <130 μmol/L; by contrast, 16% of the study group had a creatinine level of 130–260 μmol/L. A higher serum creatinine level at the time of steroid withdrawal has been linked to a higher risk of acute rejections and failure of steroid withdrawal (7,12). Thus despite poorer baseline renal function in the steroid-withdrawal group, graft and patient survival surpassed that in the steroid maintenance group. The results from this prospective study concur with previous results obtained from a retrospective analysis of steroid withdrawal (5). Single-center studies have also shown that steroid withdrawal is not detrimental to the graft in the long term (3,13). However, in the large Canadian multicenter trial of steroid withdrawal 3 months after renal transplantation, there was increased graft loss that was noted only after 5 years of follow up (9). A drawback of that study was that when risk factors confounding graft survival were included in the analysis, there was no significant influence of assigned treatment on graft survival.

Early discontinuation may have contributed to poorer outcomes after steroid withdrawal in the Canadian study, as multivariate analyses have shown that discontinuation in less than 6 months after transplantation is a risk factor for the failure of steroid withdrawal (7). In our study, steroids were withdrawn only after 6 months posttransplantation, which could be a factor in the low rate of rejection observed after withdrawal. Another critical factor for the success of steroid withdrawal is the selection of appropriate patients. Our study excluded patients recognized to be at increased risk of graft loss, such as those with unsatisfactory renal function or with high immunologic risk (14). Furthermore, we tapered steroids very slowly, over a 6-month period, as slow weaning off steroids reduces the rate of acute rejection.

With 94% of our patients receiving CYA, our study shows that steroids can be withdrawn successfully in CYA-treated patients with excellent long-term survival. Also, graft survival in CYA-treated patients was similar regardless of adjunctive immunosuppression with AZA. It has been suggested that inclusion of newer, more potent immunosuppressive agents will make steroid-free maintenance safer. Initial results with regimens using MMF with CYA to allow steroid withdrawal showed mixed results after 1 year, with an increased incidence of postwithdrawal rejection, which however did not translate into increased graft loss (15,16). In our study, steroid-free maintenance with CYA plus MMF offered slightly improved graft survival.

The incidence of acute rejection in our study, as measured by the rate of treatment for rejection, was low and did not differ significantly between patients in whom steroids were withdrawn and matched controls who continued on steroid maintenance. In our kidney recipients, the cumulative rate of acute rejection was 8.6%. The incidence of acute rejection in published studies of steroid withdrawal has ranged between 7% and 60% (17,18), and a recent meta-analysis of steroid-withdrawal trials found the risk of acute rejection to be 14% higher after withdrawal (6).

Although 16% of patients in the steroid-withdrawal group had increased creatinine levels at the start of the study, subsequent deterioration of renal function was similar in steroid-free and steroid continuation patients, with an approximately 35% cumulative incidence of new patients in each group exhibiting a serum creatinine level of >130 μmol/L over the 5-year period. Thus, overall, steroid removal was not detrimental to renal function, a finding at odds with that of Ratcliffe et al. (19) who noted a progressive increase in serum creatinine levels over 3 years in patients after steroid withdrawal, compared with patients who continued on triple therapy. The frequencies of patients with an increased creatinine level of >130 μmol/L at the end of each year remained relatively stable, suggesting a lack of progressive renal dysfunction over time. As expected, not all patients had good long-term renal function, and serum creatinine levels were higher in patients in whom steroids were resumed, compared with those who remained steroid free, reflecting the effect of acute rejection episodes.

Approximately 36% of kidney recipients and 53% of heart recipients required reintroduction of steroids during the first year; subsequently the requirement for steroids leveled off, paralleling the frequency of treatment for acute rejection. In the long-term, 59% of kidney recipients and 44% of heart recipients could be maintained completely steroid free. Other studies reported steroid-free maintenance rates in kidney recipients of 49% and 73% (20,21).

An advantage of avoiding maintenance steroids should be a reduction in the frequency of steroid-related side effects. A potentially important finding in this study was that early steroid withdrawal significantly reduced the occurrence of osteoporosis and cataracts. These benefits of earlier steroid withdrawal may be explained by rapid bone loss in the early posttransplant period (22) and the influence of the cumulative steroid dose on both bone density and cataract formation after renal transplantation (23,24). It has been suggested that even short-term use of steroids may trigger pathologic processes that are irreversible (25). Approximately 60% of our kidney recipients had steroids withdrawn 1 year or more after transplantation, and complications were present at a significantly higher frequency among the steroid-withdrawal group at study entry, signifying selection of these patients for steroid withdrawal.

Avoidance of corticosteroids may also reduce the risk factors for cardiovascular disease, one of the most common causes of death in transplant recipients (26). The results of our study suggested a trend toward more effective control of hypertension in steroid-free patients. Hyperlipidemia is another common occurrence after transplantation, and decreases in total cholesterol, LDL-cholesterol, and HDL-cholesterol have been documented in patients undergoing steroid withdrawal (27). Although current cholesterol guidelines recommend a cutoff level of 200 mg/dL, the cutoff of 300 mg/dL in this study is more appropriate since we have shown previously that graft outcomes are adversely affected only at cholesterol levels of >300 mg/dL (28). Thus our finding that steroid withdrawal significantly reduced the frequency of hypercholesterolemia >300 mg/dL provides a possible link to the improved outcomes noted with this approach. The improved cholesterol values after steroid withdrawal cannot be ascribed to preferential treatment of patients with statins after steroid withdrawal, as more patients in the control group were receiving statins.

In cardiac transplantation, triple-drug therapy has improved short-term outcomes but has not influenced the development of posttransplantation coronary artery disease (29,30). Steroid withdrawal has been attempted in heart recipients, and in patients weaned late after transplantation, short-term follow up showed good results (31,32). Our study, with 450 cardiac recipients overall, showed a 7-year survival after steroid-free maintenance of 76.9%, and an improvement in survival of 9% compared with matched patients maintained on steroids. All controls were selected for 'excellent graft function', an assessment that in our experience is well correlated with subsequent outcome (33).

Some shortcomings of the study must be discussed. A randomized study would have been the best strategy, but this was not feasible because very few participants opted for randomization. Given the unfavorable results of the Canadian study, most participants considered it more important to study a large cohort of patients in whom steroids were withdrawn. Hence we selected our controls from the database. However, as discussed earlier, these were controls matched to have lower risk (because of better renal function) than the study group; in the heart transplant arm all controls were reported to have excellent graft function. We could not match the study groups and controls for previous acute rejection episodes due to technical limitations in the CTS database. However, our analysis showed that pre-enrollment rejections did not significantly affect rates of graft survival or rejection post study enrollment. This result is not surprising since it is in line with our previous observation that the effect of acute graft rejection on subsequent outcome is very small, provided successful rejection treatment resulted in a return to normal graft function (34). At the time the study was initiated, long-term graft outcomes were the main concern, and hence the prospective study did not focus on other adverse effects of steroids, which were expected to improve with steroid withdrawal. Using side effect data from the CTS database may be a strength of the analysis rather than a weakness because of a smaller potential of reporting bias from a database unrelated to the study. Although the data set was not complete, the results reflect all available data.

In conclusion, this large prospective study demonstrates good long-term graft outcomes and no worsening of allograft function after steroid withdrawal in low risk renal and cardiac transplant recipients on CYA-based immunosuppression. The results show that steroids can be successfully withdrawn in a group of transplant patients without increasing the risk of acute rejection or having a deleterious impact on renal function. Early steroid withdrawal has a significant positive influence on the emergence of de novo osteoporosis and cataract. Further studies are needed to better identify clinical characteristics predictive of successful long-term steroid withdrawal.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
  9. Appendix

We thank the centers participating in the Collaborative Transplant Study for providing the data on which this analysis was based. The contributions by doctors and staff at centers enrolling patients in the steroid-withdrawal study are gratefully acknowledged. The cost for the initial consensus committee meeting was defrayed by Novartis AG, Basel, Switzerland. The study itself was not supported by any pharmaceutical company.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
  9. Appendix
  • 1
    Gonin JM. Maintenance immunosuppression: new agents and persistent dilemmas. Adv Renal Repl Ther 2000; 7: 95116.
  • 2
    Citterio F. Steroid side effects and their impact on transplantation outcome. Transplantation 2001; 72 (Suppl): S75S80.
  • 3
    Tarantino A, Montagnino G, Ponticelli C. Corticosteroids in kidney transplant recipients. Safety issues and timing of discontinuation. Drug Saf 1995; 13: 145156.
  • 4
    Lo A, Alloway RR. Strategies to reduce toxicities and improve outcomes in renal transplant recipients. Pharmacotherapy 2002; 22: 316328.DOI: 10.1592/phco.22.5.316.33198
  • 5
    Opelz G. Effect of the maintenance immunosuppressive drug regimen on kidney transplant outcome. Transplantation 1994; 58: 443446.
  • 6
    Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000; 11: 19101917.
  • 7
    Hricik DE, Whalen CC, Lautman J et al. Withdrawal of steroids after renal transplantation—Clinical predictors of outcome. Transplantation 1992; 53: 4145.
  • 8
    Hricik DE, O'Toole MA, Schulak JA, Herson J. Steroid-free immunosuppression in cyclosporine-treated renal transplant recipients: a meta-analysis. J Am Soc Nephrol 1993; 4: 13001305.
  • 9
    Sinclair NR. Low-dose steroid therapy in cyclosporine-treated renal transplant recipients with well-functioning grafts. The Canadian Multicentre Transplant Study Group. CMAJ 1992; 147: 645657.
  • 10
    Collaborative Transplant Study. Newsletter No. 3, 1994. Available at http://www.ctstransplant.org/. Accessed on August 26, 2004.
  • 11
    Collaborative Transplant Study. Newsletter No. 4, 1994. Available at http://www.ctstransplant.org/. Accessed on October 25, 2004.
  • 12
    Hricik DE, Seliga RM, Fleming-Brooks S, Bartucci MR, Schulak JA. Determinants of long-term allograft function following steroid withdrawal in renal transplant recipients. Clin Transplant 1995; 9: 419423.
  • 13
    Hillebrand G, Schneeberger H, Schleibner S et al. Ten years experience with cyclosporine monotherapy after renal transplantation. Transplant Proc 1993; 25: 513514.
  • 14
    Touchard G, Hauet T, Cogny Van Weydevelt F et al. Maintenance cyclosporine monotherapy after renal transplantation—clinical predictors of long-term outcome. Nephrol Dial Transplant 1997; 12: 19561960.DOI: 10.1093/ndt/12.9.1956
  • 15
    Lebranchu Y. Comparison of two corticosteroid regimens in combination with CellCept and cyclosporine A for prevention of acute allograft rejection: 12 month results of a double-blind, randomized, multi-center study. M 55002 Study Group. Transplant Proc 1999; 31: 249250.DOI: 10.1016/S0041-1345(98)01522-X
  • 16
    Ahsan N, Hricik D, Matas A et al. Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil—a prospective randomized study. Steroid Withdrawal Study Group. Transplantation 1999; 68: 18651874.
  • 17
    Hollander AA, Hene RJ, Hermans J, Van Es LA, Van Der Woude FJ. Late prednisone withdrawal in cyclosporine-treated kidney transplant patients: a randomized study. J Am Soc Nephrol 1997; 8: 294301.
  • 18
    Gulanikar AC, Belitsky P, MacDonald AS, Cohen A, Bitter-Suerman H. Randomized controlled trial of steroids versus no steroids in stable cyclosporine-treated renal graft recipients. Transplant Proc 1991; 23: 990991.
  • 19
    Ratcliffe PJ, Dudley CR, Higgins RM, Firth JD, Smith B, Morris PJ. Randomised controlled trial of steroid withdrawal in renal transplant recipients receiving triple immunosuppression. Lancet 1996; 348: 643648.DOI: 10.1016/S0140-6736(96)02510-X
  • 20
    Sivaraman P, Nussbaumer G, Landsberg D. Lack of long-term benefits of steroid withdrawal in renal transplant recipients. Am J Kidney Dis 2001; 37: 11621169.
  • 21
    Offermann G, Schwarz A, Krause PH. Long-term effects of steroid withdrawal in kidney transplantation. Transpl Int 1993; 6: 290292.DOI: 10.1007/BF00336030
  • 22
    Julian BA, Laskow DA, Dubovsky J, Dubovsky EV, Curtis JJ, Quarles LD. Rapid loss of vertebral mineral density after renal ransplantation. N Engl J Med 1991; 325: 544550.
  • 23
    Wolpaw T, Deal CL, Fleming-Brooks S, Bartucci MR, Schulak JA, Hricik DE. Factors influencing vertebral bone density after renal transplantation. Transplantation 1994; 58: 11861189.
  • 24
    Matsunami C, Hilton AF, Dyer JA, Rumbach OW, Hardie IR. Ocular complications in renal transplant patients. Aust N Z J Ophthalmol 1994; 22: 5357.
  • 25
    Ponticelli C. Withdrawal of steroids from a cyclosporine-based regimen: pro. Transplant Proc 1998; 30: 17821784.DOI: 10.1016/S0041-1345(98)00430-8
  • 26
    Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000; 57: 307313.DOI: 10.1046/j.1523-1755.2000.00816.x
  • 27
    Hricik DE, Bartucci MR, Mayes JT, Schulak JA. The effects of steroid withdrawal on the lipoprotein profiles of cyclosporine-treated kidney and kidney-pancreas transplant recipients. Transplantation 1992; 54: 868871.
  • 28
    Collaborative Transplant Study. Newsletter No. 2, 2003. Available at http://www.ctstransplant.org/. Accessed on August 26, 2004.
  • 29
    Olivari MT, Homans DC, Wilson RF, Kubo SH, Ring WS. Coronary artery disease in cardiac transplant patients receiving triple-drug immunosuppressive therapy. Circulation 1989; 80(suppl): III111III115.
  • 30
    Olivari MT, Kubo SH, Braunlin EA, Bolman RM, Ring WS. Five-year experience with triple-drug immunosuppressive therapy in cardiac transplantation. Circulation 1990; 82(suppl): IV276IV280.
  • 31
    Kobashigawa JA, Stevenson LW, Brownfield ED et al. Initial success of steroid weaning late after heart transplantation. J Heart Lung Transplant 1992; 11: 428430.
  • 32
    Miller LW, Wolford T, McBride LR, Peigh P, Pennington DG. Successful withdrawal of corticosteroids in heart transplantation. J Heart Lung Transplant 1992; 11: 431434.
  • 33
    Collaborative Transplant Study. Archive CTS-H-85501-Aug2004, CTS-H-85601-Aug2004, CTS-H-85701-Aug2004, CTS-H85801-Aug2004. Available at http://www.ctstransplant.org/. Accessed on October 25, 2004.
  • 34
    Opelz G for the Collaborative Transplant Study. Critical evaluation of the association of acute with chronic graft rejection in kidney and heart transplant recipients. Transplant Proc 1997; 29: 7376.DOI: 10.1016/S0041-1345(96)00013-9

Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
  9. Appendix

Members of the Consensus Protocol Committee:

J. Andreu, D. Holt, R. Johnson, W. Land, J. Lloveras, D. Niese, G. Opelz, C. Ponticelli, D. Roth, J-P. Soulillou, A. Tejani, G. Thiel, G. Tufveson, D. van Buren.

The following transplant centers participated in this study:

Kidney Transplants: Barcelona, Spain, Hospital del Mar (Dr. Lloveras); Hospital Vall D' Hebron (Dr. Callis); Belo Horizonte, Brazil (Dr. Salamao Filho); Botucato, Brazil (Dr. Carvalho); Buenos Aires, Argentina, Cemic (Dr. Moreno), Instituto de Nefrologia (Dr. Casadei), Sanatorio Mitre (Dr. Agost Carreno); Cardiff, UK (Dr. Moore); Cologne, Germany (Dr. Arns); Heidelberg, Germany (Dr. Tönshoff); Izmir, Turkey (Dr. Gurkan); Jena, Germany (Dr. Sperschneider); Ljubljana, Slovenia (Dr. Kandus); Mannheim, Germany (Dr. Schnülle); Marburg, Germany (Dr. Lange); Munich, Germany (Dr. Kuhlmann); New Lambton, Australia (Dr. Hibberd); Nottingham, UK (Dr. Rigg); Oviedo, Spain (Dr. Gomez); Pato Branco, Brazil (Dr. Engel); Portland, Oregon, USA (Dr. Norman); Prague, Czechia (Dr. Ivaskova); Quebec, Canada (Dr. Lachance); Santander, Spain (Dr. Arias); St. Gallen, Switzerland (Dr. Garzoni); Szeged, Hungary (Dr. Szenohradszki); Tours, France (Dr. Lebranchu); Ulm, Germany (Dr. Abendroth); Valencia, Spain (Dr. Sanchez-Plumed); Zürich, Switzerland (Dr. Binswanger, Dr. Weber).

Heart Transplants: Edmonton, Canada (Dr. Modry); Essen, Germany (Dr. Jakob); Lausanne, Switzerland (Dr. Seydoux); London, Canada (Dr. McKenzie); Melbourne, Australia (Dr. Esmore); Montreal, Canada (Dr. Carrier); Oklahoma City, USA (Dr. Nelson); Paris, France (Dr. Amrein); Perth, Australia (Dr. O Driscoll); Prague, Czechia (Dr. Malek); Sydney, Australia (Dr. Keogh); Vancouver, Canada (Dr. Ignaszewski); Zürich, Switzerland (Dr. Turina).