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*
Department of Medicine, Hennepin County Medical Center, Minneapolis,
Minnesota
Division of Biostatistics, University of Minnesota, Minneapolis,
Minnesota
Department of Biostatistics, University of Tennessee, Memphis,
Tennessee.
Correspondence to Dr. Bertram L. Kasiske, Department of Medicine, Hennepin County Medical Center, 701 Park Avenue South, Minneapolis, MN 55415. Phone: 612-347-6088; Fax: 612-347-2003; E-mail: kasis001{at}tc.umn.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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2 test (P >
0.05). In 10 CsA withdrawal trials (n = 1049), the proportion of
patients with acute rejection was increased by 0.11 (0.07 to 0.15, P
< 0.001). In 12 trials (n = 1151), the RR of graft failure after
CsA withdrawal was 1.06 (95% confidence interval, 0.82 to 1.29, P =
0.646), but a 2 test indicated that there was study
heterogeneity. However, there was no evidence of heterogeneity in the six
studies (n = 632) with at least 4.0 yr (5.8 ± 1.7) of
follow-up (RR = 0.92; range, 0.64 to 1.20, P = 0.569) or in the seven
trials (n = 962) published in peer-reviewed journals (RR = 0.95;
range, 0.70 to 1.20 P = 0.682). Finally, in three trials (n
= 259) that compared CsA and prednisone withdrawal, there was a nonsignificant
trend for less graft failure with CsA withdrawal (RR = 0.63; range, 0.08 to
1.16, P = 0.190). Thus, unlike prednisone withdrawal, CsA withdrawal
in select patients seems to impart little risk of long-term graft failure. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Corticosteroids are effective in reducing the incidence of acute rejection but are a major cause of morbidity and mortality. Like all immunosuppression, corticosteroids contribute to the increased risk of infection and possibly cancer in the late posttransplantation period. In addition, corticosteroids have adverse effects on cardiovascular disease risk factors, such as diabetes, hypertension, and hyperlipidemia. Cardiovascular disease is a major cause of death in the late posttransplantation period. As a result, a number of clinical trials have examined whether prednisone can be safely withdrawn after renal transplantation. A meta-analysis of randomized, controlled trials of prednisone withdrawal and avoidance was published in 1993 (1). However, since that time, several additional prednisone withdrawal trials have been conducted, including two large, multicenter, randomized, controlled trials (2,3).
Cyclosporin A (CsA) also adversely affects several cardiovascular disease risk factors; CsA not only may contribute to mortality after renal transplantation but also may cause nephrotoxicity that is histologically and clinically indistinguishable from chronic allograft nephropathy. A number of randomized controlled trials have been conducted to examine whether CsA can be safely withdrawn after renal transplantation. We published a meta-analysis of these trials in 1993 (4). Although CsA withdrawal caused an increased incidence of acute rejection, graft survival did not seem to be adversely affected. However, the length of follow-up was relatively short. Since that time, several groups have reported the results of long-term follow-up and several additional CsA withdrawal trials have been conducted.
Despite that a number of randomized, controlled trials have been conducted, withdrawal of either prednisone or CsA remains controversial. Therefore, we conducted a meta-analysis of randomized, controlled trials that examined either prednisone or CsA withdrawal. In addition, we included trials that compared withdrawal of prednisone with withdrawal of CsA. Our purpose was not only to enhance statistical power by increasing sample size but also to examine possible reasons for differences in the results of the clinical trials that underlie this ongoing controversy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Study Selection
We included only published, randomized, controlled trials in which either
prednisone or CsA was withdrawn or randomized trials comparing prednisone
withdrawal with CsA withdrawal. We included only trials that reported the
incidence of acute rejection and/or renal allograft failure. All end points
were analyzed by intent to treat. We did not exclude reports on the basis of
language, but all studies were published in English. In several instances,
results from some or all patients in a clinical trial were reported more than
once. In these instances, we extracted data on end points from the publication
with the longest duration of follow-up. We did not include studies of
prednisone or CsA avoidance, i.e., studies in which patients in one
arm never received prednisone or CsA. Studies that compared prednisone
withdrawal or CsA withdrawal with the withdrawal of other immunosuppression,
e.g., azathioprine, also were excluded.
Data Extraction
Two investigators (B.L.K. and H.A.C.) independently reviewed all studies.
We extracted data on study quality, including whether (1) the study
was published in a peer-reviewed journal, (2) it had been stated that
institutional review board approval had been obtained, (3) the source
of funding was indicated, (4) the study design included a statistical
assessment of the sample size needed, (5) inclusion and exclusion
criteria were clearly stated, (6) possible differences in patients
allocated to treatment and control were examined, (7) a placebo was
used to mask investigators and subjects, (8) the allocation process
was truly random (compared with a pseudo-random allocation whereby, for
example, every other patient was allocated to treatment or control),
(9) the randomization technique was clearly described (envelopes,
central randomization, etc.), (10) the statistical methods used to
analyze the results were described, (11) patient withdrawals were
described, (12) results were analyzed by intention to treat, and
(13) the study end points were clearly defined. We derived an
arbitrary quality index using a formula whereby each of the above quality
indices were given one point if the criterion was completely fulfilled, one
half of a point if the criterion seemed to be only partially fulfilled, or (in
the case of publication in a peer-reviewed journal) two points. The composite
study quality index was the total number of points (maximum = 14).
We also extracted data on the proportion of study patients who were first transplants, the proportion who were recipients of cadaveric donor kidneys, whether patient selection was based on the absence of acute rejection and/or stable graft function, and what other immunosuppressive agents were used, e.g., azathioprine and mycophenolate mofetil. In addition, we tabulated the time withdrawal was begun, the time it was completed, and the duration of follow-up (from the time of transplantation to the time of last follow-up or loss of the allograft).
Statistical Techniques
For acute rejection, the duration of follow-up was often relatively short,
because most acute rejection episodes occurred soon after withdrawal. Indeed,
some studies failed to report the exact duration of follow-up. Therefore, we
examined the difference in the proportion of withdrawal and control patients
who had acute rejection following randomization: Di =
Pti - Pci, where
Pti = rti/nti,
Pci = rci/nci,
rti and rci are the number of patients
with an acute rejection episode, and nti and
nci are the numbers of patients allocated to the treatment
and control groups respectively for the ith study. The variance of
Di was calculated as
 |
Weighted means and confidence intervals (CI) were then calculated for the
combined differences between treatment and control groups using a
fixed-effects model. The weighted mean treatment effect was calculated as
 |
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We looked for homogeneity of treatment effects with the test statistic:
 |
We also examined the relative risk (RR) of graft failure (defined as either
return to dialysis or death with a functioning allograft) between
immunosuppression withdrawal and nonwithdrawal control groups. Some studies
reported results over a specific time interval, e.g., the proportions
of patients with graft survival in withdrawal and control groups after an
exact (or mean) period of follow-up. In other words, these studies reported
two proportions—the proportion of patients who survived in the
withdrawal group and the proportion of patients who survived in the control
group—and reported the exact (or mean) duration of follow-up. For these
studies, we estimated the RR of graft survival between withdrawal and control
as
 |
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For other studies, data were presented in more detail using tables and/or
figures that indicated the proportions of the withdrawal and control groups
that survived after two or more discrete time intervals. For these studies, we
estimated the RR of graft failure as
 |
2 test for homogeneity were calculated as described
above. We also examined potential reasons for heterogeneity in study results using linear regression analysis weighted by inverse variance. In this analysis, differences in the proportions of patients with acute rejection and differences in the RR for graft failure were used as dependent variables. Study quality and other study characteristics were used as independent variables. All differences were considered significant for P < 0.05 (two-tail). Analysis was carried out using the Statistical Package for the Social Sciences.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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For acute rejection, the pooled mean difference between treatment and
control was 0.14 (95% CI = 0.10 to 0.17, P < 0.001), indicating
that the proportion of patients with acute rejection after prednisone
withdrawal was significantly greater compared with controls
(Figure 1). The test for
homogeneity (2 = 13.7, P > 0.05) indicated that
the individual studies were relatively homogeneous. The RR for graft failure
was 1.40 (1.09 to 1.71, P = 0.012), indicating that significantly
more patients lost their grafts in the prednisone withdrawal group compared
with controls (Figure 2). The
test for homogeneity (2 = 12.0, P > 0.05)
indicated that the individual study results were relatively homogeneous.
Although the results were relatively homogeneous, we nevertheless sought
possible reasons for differences in results using regression analysis. There
were no statistically significant correlations between the differences in
acute rejection and any of the study or patient characteristics. None of the
patient or study characteristics correlated with the effect of prednisone
withdrawal on graft survival.
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CsA Withdrawal
Thirteen studies examined CsA withdrawal
(Table 2)
(5,6,7,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36).
Seven had been published in peer-reviewed journals, and six had not. The 10
studies that examined the effects of CsA withdrawal on acute rejection
included 1049 (mean, 105 ± 83) patients with 50.7 ± 33.9 mo of
follow-up. The 12 studies that provided adequate data on graft survival after
CsA withdrawal included 1151 (mean, 96 ± 80) patients with 45.1
± 32.9 mo of follow-up.
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For acute rejection, the pooled mean difference between CsA withdrawal and
control was 0.11 (0.07 to 0.15, P < 0.001), indicating that the
proportion of patients with acute rejection after CsA withdrawal was 11%
higher than that of controls (Figure
3). The test for homogeneity (2 = 64.9, P
< 0.001) indicated that the individual study results were heterogeneous. To
explore possible reasons for this heterogeneity in results, weighted,
univariate regression analysis was carried out to determine which, if any,
patient or study characteristics correlated with the effect of CsA withdrawal
on acute rejection. The study quality index (r = -0.698, P =
0.025), whether the study was published in a peer-reviewed journal (r
= -0.696, P = 0.025), and the number of patients studied (r
= -0.823, P = 0.003) each correlated inversely with the difference in
the rate of acute rejection. However, these characteristics were significantly
correlated with each other. It is difficult to tell whether study quality and
sample size were independent correlates to the study results. However, in a
multivariate analysis, sample size was a better predictor and study quality
did not correlate with differences in acute rejection once sample size was
taken into account (data not shown).
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The RR for graft failure was 1.06 (0.82 to 1.29, P = 0.646),
indicating no difference in the risk for graft failure in the CsA withdrawal
group compared with controls (Figure
4). However, the test for homogeneity (2 = 43.0,
P < 0.001) again indicated that the individual study results were
heterogeneous. In an unweighted regression analysis, the study quality index
was inversely proportional to the RR for graft failure (r = -0.645,
P = 0.024), suggesting that in studies of lower quality, CsA
withdrawal had a more adverse effect on graft survival. Whether studies were
published in peer-reviewed journals also correlated inversely with the RR of
graft failure from CsA withdrawal (r = -0.721, P = 0.008) in
unweighted regression analysis. However, when the regression analysis was
weighted by inverse variance, neither study quality (r = -0.367,
P = 0.241) nor peer review (r = -0.416, P = 0.178)
significantly influenced the results of studies that examined the effects of
CsA withdrawal on graft survival. Thus, it seems that the influence of study
quality and peer review on the results was largely abolished when the
variability in results was accounted for by weighting with inverse
variance.
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Studies that were or were not peer-reviewed were combined separately
(Figure 5). The pooled RR for
graft failure among five studies (n = 189 patients) that were not
published in peer-reviewed journals was 2.07 (1.30 to 2.83, P =
0.006; 2 test for homogeneity = 39.4, P < 0.001),
indicating that these study results were heterogeneous. In contrast, the
pooled RR for graft failure among the seven studies (n = 962
patients) published in peer-reviewed journals was only 0.95 (0.70 to 1.20,
P = 0.682). The 2 test for homogeneity = 3.5
(P > 0.05), indicating that the results in these seven studies
were more homogeneous. Thus, the heterogeneity in results seemed to be found
in studies that were not published in peer-reviewed journals, which also
correlated with a low study quality index.
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We also compared the pooled results of studies with less than 48 or more
than 48 mo of follow-up. The pooled RR of graft failure for the six studies
(n = 519 patients) with less than 48 mo (17 ± 7 mo) of
follow-up was 1.43 (0.97 to 1.89, P = 0.066). The 2
was 34.9 (P < 0.001), indicating significant heterogeneity. The
pooled RR of graft failure for the six studies (n = 632 patients)
with at least 48 mo (70 ± 20 mo) of follow-up was 0.92 (0.64 to 1.20,
P = 0.569). The 2 was 5.1 (P > 0.05),
indicating that these studies with longer follow-up were relatively
homogeneous. Thus, the studies of short duration seemed to contribute to the
heterogeneity of results and were more likely to report that CsA withdrawal
negatively influenced graft survival compared with studies of longer
duration.
CsA Versus Prednisone Withdrawal
Three studies compared CsA withdrawal with prednisone withdrawal, and two
of these were published in peer-reviewed journals
(Table 3) (5,6,7,37,38).
The three studies included 259 (86 ± 35) patients who were followed for
43.9 ± 6.0 mo. Each examined both acute rejection and graft survival.
There was no difference in the proportion of patients with acute rejection
between CsA and prednisone withdrawal; pooled difference = 0.04 (-0.07 to
0.144, P = 0.516). The 2 was 6.2 (P >
0.05), indicating that the results were homogeneous. There was a
nonsignificant trend for graft failure to be less for CsA withdrawal compared
with prednisone withdrawal (0.63 [range, 0.08 to 1.18], P = 0.190;
2 = 3.5, P > 0.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The results of prednisone withdrawal trials have suggested not only that the risk of acute rejection after withdrawal is high (Figure 1) but also that the risk of graft failure tends to be increased (Figure 2). The results seem to be fairly homogeneous, at least by a crude statistical test of homogeneity. It was hoped that the use of mycophenolate mofetil would allow prednisone to be discontinued safely. Mycophenolate mofetil seems to be more effective than azathioprine in preventing acute rejection early after renal transplantation, so it is possible that withdrawal of prednisone may be more successful in patients who are treated with mycophenolate mofetil than in patients who receive azathioprine. Two of the prednisone withdrawal trials used mycophenolate mofetil (2,3). In both trials, the difference in acute rejection between withdrawal and control did not seem to be different compared with trials that did not use mycophenolate mofetil (Figure 1). Both trials reported only 12 mo of follow-up to date, so it may be too early to tell whether the effect of prednisone withdrawal on graft survival will be different in these studies.
The need for long-term follow-up was demonstrated when decreased graft survival after prednisone withdrawal first became evident after 5 yr of follow-up (18). Although this trial has been criticized because of the large number of crossovers and other design flaws, it is nevertheless the largest randomized controlled trial of prednisone withdrawal published to date. Because the mean follow-up of all of the prednisone withdrawal trials is only 28 mo, it is important for investigators to report long-term follow-up results (>5 yr) in the future.
The results of CsA withdrawal seem to be different from those of prednisone withdrawal. Like prednisone withdrawal, acute rejection is increased after withdrawing CsA (Figure 3). However, unlike prednisone withdrawal, CsA withdrawal does not seem to increase the rate of graft failure (Figure 4). The results of the prednisone withdrawal trials seem to be homogeneous, whereas those of CsA withdrawal are relatively heterogeneous. In particular, CsA withdrawal trials of lower study quality (indicated by failure to publish results in a peer-reviewed journal) seem to report a higher incidence of graft failure than trials of higher study quality (Figure 5). Studies of longer duration (>4 yr of follow-up) also tended to be studies of higher quality and reported no adverse effect of CsA withdrawal on graft survival.
We can only speculate on why the increased rate of acute rejection after CsA withdrawal did not produce an increased incidence of graft failure. Acute rejection, especially acute rejection occurring more than 3 to 6 mo posttransplantation, has been linked to graft failure in several observational studies (39,40). However, we are not aware of studies comparing the effects on graft survival of acute rejections that occur on regular maintenance immunosuppression versus acute rejections that occur after CsA withdrawal. It is possible that acute rejections that occur after CsA withdrawal resemble those that occur in the early posttransplantation period and have minimal effect on graft survival. It is also possible that the deleterious effects of acute rejection after CsA withdrawal are balanced by the beneficial effects of reduced nephrotoxicity. In fact, it is tempting to speculate that the difference in the effects on graft survival of prednisone versus CsA withdrawal may be due to the fact that CsA is nephrotoxic, whereas prednisone is not. In any case, it is possible that the results with both prednisone and CsA withdrawal may be different with longer follow-up, and it is hoped that investigators will continue to report long-term follow-up results of these trials.
For both prednisone and CsA withdrawal, we could find no effects on acute rejection or graft survival attributable to whether withdrawal was early or late after transplantation. Similarly, we could find no effects on outcomes attributable to how patients were selected, e.g., whether only "stable" patients were selected for withdrawal. However, the numbers of patients studied were relatively small, so it is possible that an effect of the timing of withdrawal or of how patients were selected for withdrawal could have gone undetected in our analysis. Similarly, the duration of the taper period did not seem to influence the results, but the small numbers and differences in how prednisone and CsA were withdrawn may have precluded our ability to detect significant differences.
No two clinical trials are the same. Many reported and unreported differences in patient populations and/or study design may have influenced these results. For example, uncontrolled observations have indicated that CsA withdrawal may be associated with a higher rate of graft failure in black patients compared with Caucasian patients (41). Race also influenced the rate of acute rejection after prednisone withdrawal (11). Individuals with a greater degree of major histocompatibility mismatching and individuals who were younger tended to have a higher incidence of acute rejection after CsA withdrawal (42). The real possibility that these or other risk factors can help in determining patients in whom CsA or prednisone can be safely withdrawn has not been adequately studied in controlled trials.
In summary, the results of this meta-analysis indicate that prednisone withdrawal after renal transplantation is associated with a higher incidence of acute rejection and graft failure. A higher incidence of acute rejection is also seen after CsA withdrawal, but CsA withdrawal does not adversely affect graft survival, even in studies with long-term follow-up. Some of the controversy over the results of CsA withdrawal may be due to differences in trial results attributable to a greater incidence of postwithdrawal graft failure in studies of low quality and/or shorter duration of follow-up.
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Acknowledgments |
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References |
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) and the pooled results
of all studies (
). The area to the right of the vertical dashed line
indicates a greater proportion of patients with acute rejection after
withdrawal compared with control. Horizontal lines indicate 95% confidence
intervals (CI), and failure of 95% CI to cross the vertical dashed line
indicates P < 0.05. The number of patients uniquely identifies
each study (see 
