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Keywords:

  • Acute rejection;
  • calcineurin inhibitors;
  • graft survival;
  • hypertension;
  • kidney transplantation;
  • meta-analysis;
  • sirolimus;
  • systematic review;
  • withdrawal

Abstract

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

Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function, however, it also carries risk of acute rejection. We conducted a systematic review of randomized trials that involved CNI withdrawal from a sirolimus-based immunosuppressive regimen. The search strategy yielded six trials (n = 1047 patients) reported in eight publications. CNI withdrawal from sirolimus-based therapy, was associated with an increased risk of acute rejection (risk difference, 6%; 95% CI 2–10%, p = 0.002) but a higher creatinine clearance (mean difference, 7.49 mL/min; 95% CI 5.08–9.89 mL/min, p < 0.00001) at 1 year compared to continued CNI and sirolimus therapy. Graft loss (relative risk, 0.87; 95% CI 0.46–1.64, p = 0.66) and death (relative risk, 0.88; CI 0.40–1.96, p = 0.76) were similar in both groups at 1 year. Hypertension was significantly reduced in the CNI withdrawal group (relative risk, 0.56; 95% CI 0.40–0.78, p = 0.0006). CNI withdrawal from sirolimus-based therapy is associated with an increased risk of acute rejection in the short term with a significant improvement in renal function and a reduction in hypertension. Longer follow-up is needed to determine if these changes will result in a significant improvement in patient and graft survival.


Introduction

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

Calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, are potent medications that have become the cornerstone of immunosuppressive therapy following kidney transplantation. The early pivotal trials with cyclosporine showed a significant reduction in acute rejection and improvement in 1-year allograft survival (1,2). Subsequent studies with tacrolimus showed a significant reduction in acute rejection rates (3,4). Recent studies have shown that over 85% of kidney transplant recipients receive either cyclosporine or tacrolimus as part of their maintenance immunosuppressive regimen (5).

Although the era of CNI use brought about dramatic improvements in allograft survival, concern about acute and chronic nephrotoxicity quickly emerged (6,7). In order to overcome the long-term toxicity associated with immunosuppression, withdrawal strategies involving different medications has been attempted (8,9). Individual studies of CNI withdrawal have produced conflicting results (8). In a systematic review of 13 trials, cyclosporine withdrawal following renal transplantation was associated with a significant increase in acute rejection but no difference in allograft survival (8). However, in all of these trials, azathioprine and prednisone were used for immunosuppression after cyclosporine was withdrawn (8).

Sirolimus is a newer immunosuppressive agent whose mechanism of action differs from that of calcineurin inhibitors. Two large trials showed that combination of sirolimus with cyclosporine resulted in a significant reduction in acute rejection compared to either azathioprine or placebo (10,11). However, in both of these trials the sirolimus treated patients had a significantly lower creatinine clearance compared to the placebo or azathioprine groups. This finding suggested that sirolimus could potentiate the known nephrotoxicity of calcineurin inhibitors. A similar reduction in creatinine clearance was found when sirolimus was combined with tacrolimus (12). The finding of enhanced nephrotoxicity has prompted investigators to evaluate sirolimus in combination with low dose CNI as well as study CNI withdrawal in an effort to improve renal function (13). Immunosuppressive withdrawal strategies often carry a risk of acute rejection, which may or may not impact long-term graft survival (8). The potential risks and benefits of CNI withdrawal from a sirolimus-based regimen are not clearly known. Accordingly, the objective of this study was to systematically review all trials evaluating CNI withdrawal from a sirolimus-based immunosuppressive regimen in kidney transplant recipients. Endpoints to be studied include acute rejection, renal function, blood pressure, lipid parameters, patient and graft survival.

Materials and Methods

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

Search strategy

We searched Medline (1966 to July 2004) by combining the MeSH term ‘kidney transplantation’ with text words (cyclosporine or tacrolimus or FK506) and (sirolimus or rapamycin). We then applied a highly sensitive search filter designed to identify randomized controlled trials (14). The search was not restricted to studies published in English. A similar search strategy was used for Embase (1980 to week 32, 2004) and Cochrane Central Register of Clinical Trials (2nd quarter, 2004). In addition, the following key journals were hand-searched for relevant publications from 2001 to August 2004: Journal of American Society of Nephrology, American Journal of Kidney Diseases, Kidney International, Transplantation and American Journal of Transplantation. Abstracts presented at the American Transplant Congress between 2001 and 2004 were also hand-searched for relevant studies. The time frame of the hand-search was chosen based on the introduction of sirolimus into practice. Reference lists of eligible studies were examined for relevant trials and the authors of eligible studies were contacted in an attempt to identify unpublished completed trials or ongoing studies.

Study selection and data abstraction

Two investigators (AM, NH) independently assessed all titles and abstracts identified in the literature search for potentially eligible studies. All potentially eligible studies were then independently reevaluated by AM, NH. To be included in the review, the following criteria had to be met: the study was a randomized controlled trial; the study population consisted of adult patients receiving primary or repeat renal transplant (deceased or living donor); initial immunosuppression consisted of sirolimus and a CNI (cyclosporine or tacrolimus) and was followed by planned withdrawal of the CNI in the intervention group; the control group continued to receive both sirolimus and a calcineurin inhibitor; and the study reported one of the following outcomes: acute rejection, serum creatinine or creatinine clearance, blood pressure, total cholesterol, triglycerides, allograft survival or patient survival. We excluded studies involving complete CNI avoidance and studies involving dual-organ transplants (e.g. combine liver–kidney transplantation). If multiple articles from the same trial were found, the report presenting 1-year data was used in the primary analysis. A sensitivity analysis was performed to see if the results differed when the longest follow-up report was included in the analysis, instead of the 1-year data from the same study. To determine if the results differed, based on the CNI or the publication type, we repeated the analyses first by including only those trials that used cyclosporine followed by those that were published in peer-review journal. Disagreement about study inclusion was resolved by consensus.

Two investigators independently abstracted data from eligible studies using a standardized form. The following data were abstracted: patient demographic details, concomitant immunosuppression, target drug levels, length of follow-up, time of CNI withdrawal post-transplant, proportion of patients achieving complete withdrawal and the outcomes noted above. Differences on the data abstracted were resolved by consensus. The authors were contacted if any specific data were missing (e.g. standard deviation) from the report. The methodological quality of all included studies was assessed with the Jadad scale, which measures blinding, randomization, withdrawals and dropouts (15). A maximum score of 5 represents the highest quality trial.

Analysis

The primary outcome measures were acute rejection following CNI withdrawal, renal function (measured using serum creatinine or creatinine clearance), allograft and patient survival. Secondary outcomes included total cholesterol, triglycerides, blood pressure and post-transplant diabetes mellitus. To summarize dichotomous outcomes, the number of events (acute rejection, diabetes, graft loss, death and hypertension) reported in each trial and total number of patients randomized were used to calculate the relative risk and absolute risk difference. To summarize continuous outcomes (creatinine clearance, serum creatinine, total cholesterol, triglycerides, systolic and diastolic blood pressure), the mean and standard deviation reported in the individual trials at the end of follow-up was used to calculate weighted mean difference. Results of intention-to-treat analysis were included. All effect measures were calculated for the CNI withdrawal arm compared to CNI continuation arm (control group). For dichotomous variables, a value of 0.5 was imputed if no events occurred in a particular study so the relative risk could be calculated (16). Heterogeneity across the studies was assessed using the Q-statistic with p < 0.1 considered significant (16). In the absence of significant heterogeneity, individual study effects were pooled using a fixed effects model by inverse variance method (16). If there was evidence of heterogeneity, the outcomes were pooled using the random effects model of DerSimonian and Laird (16). All reported p-values are two-tailed and p < 0.05 was considered statistically significant. The analysis was performed using an Excel spreadsheet (Microsoft® Excel 2000) and RevMan software package (Version 4.2, Cochrane Collaboration software).

Results

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

The search strategy identified 162 articles from Medline, 272 from Embase, 61 from Cochrane Central, 2 from journal hand-search and 1 from conference proceedings hand-search (Figure 1). Of these, 12 were potentially eligible and reviewed as full articles (13,17–27). Four studies were excluded (13,17–19) for the following reasons: review article (n = 1), control group did not receive sirolimus (n = 1) and no outcome of interest (n = 2). Of the eight studies that met the inclusion criteria, three articles reported 1-, 2- and 3-year follow-up data of the same trial (Rapamune Maintenance Regimen Study) (22–24). The 1-year follow-up report (22) was used for the primary analysis and the 3-year report (24) was used in sensitivity analyses. Therefore, the primary analysis included six trials involving 1047 patients. There was 100% agreement among reviewers about the included studies.

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Figure 1. Search results and selection of randomized trials for analysis.

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Table 1 summarizes the baseline characteristics of the studies included in the analysis. Only one trial was performed in the United States (20) with the remainder from Canada, Europe and Australia (21,22,25–27). Five trials were published as full articles in peer-reviewed journals (20–22,25,26) while only one report was in abstract form (27). Three trials had a sample size of less than 100 patients (21,25,26). Five studies used cyclosporine (20–22,25,27) and only one used tacrolimus (26) as the CNI. Most trials involved low risk patients with a large proportion of Caucasians, very few diabetics and the majority undergoing primary transplantation (Table 1). Planned antibody induction, delayed graft function or highly sensitized patients were specifically excluded in some of the trials (Table 1). Four studies reported specific eligibility criteria to proceed with CNI withdrawal (20–22,26). Most trials required that the patient had adequate and stable renal function with no significant acute rejection in the preceding month (20–22,26). Calcineurin inhibitor withdrawal was completed in 75 to 93% of randomized patients (Table 1). The methodological quality scores were generally low with a median value of 2 (Table 1). None of the six trials was reported as double blind. Table 2 outlines the target drug levels for sirolimus, cyclosporine and tacrolimus as well as lists the other immunosuppression used in the six included trials.

Table 1.  Baseline characteristics of studies included in analysis. Figures are given for withdrawal/control group as appropriatea
CharacteristicsJohnson22Gonwa20Baboolal21Stallone25Jardine27Grinyo26
  1. aNR, not reported; CyA, cyclosporine; DGF, delayed graft function; PRA, panel reactive antibody; Cr, serum creatinine.

Year200120022003200320042004
RegionEurope, Australia, CanadaEurope, USAUnited Kingdom, IrelandItalyUnited KingdomSpain
Sample size215/215100/9742/4520/20101/10544/43
Primary transplant (%)90/92100/100NRNRNR89/93
Caucasian (%)94/9580/7393/98100/100NR93/98
Male (%)62/6758/5774/58NRNR71/70
Mean recipient age (years)45/4645/4545/4540/47NR42/47
Diabetes (%)8/78/95/0NRNR7/5
Deceased donor (%)88/88100/10085/91100/100NR100/100
Mean donor age (years)42/44NRNR40/46NR41/43
Calcineurin inhibitorCyACyACyACyACyATacrolimus
Follow-up (months)12126121212
Time of randomization post-transplantation3 monthsWithin 48 h3 months3 months3 monthsWithin 24 h
Criteria for calcineurin inhibitor withdrawal Cr < 400; absence of severe rejection in 4 weeksStable function; absence of rejection in 3 weeksCr < 400; absence of severe rejectionNRNRStable function; absence of rejection in 3 weeks
Exclusion criteriaPlanned antibody inductionDGF > 7 days, repeat transplant or live donorPlanned antibody inductionNRNRPRA > 50, repeat transplant if early first loss
Time of withdrawal post-transplantation (months)323333
Completed withdrawal (%)937881NRNR75
Quality score322213
Table 2.  Target drug levels and other immunosuppression of the studies included in the analysisa
StudyTarget sirolimus levels (ng/mL)Target calcineurin inhibitor levels (ng/mL)Other immunosuppression
Before withdrawalAfter withdrawalBefore withdrawalAfter withdrawal
  1. aNR, not reported; N/A, not applicable.

Gonwa20
 Withdrawal10–2010–20100–175 then 100–150N/AInduction: NR Both groups: prednisone
 ControlFixed dose (6 mg load then 2 mg/day)Fixed dose (6 mg load then 2 mg/day)200–400 then 200–300150–250 
Baboolal21
 Withdrawal4–128–16200–400 then 125–250N/AInduction: not used Both groups: prednisone
 Control4–128–16200–400 then 125–25050–100 
Johnson22
 Withdrawal>520–30200–400 then 150–300N/AInduction: Not used Both groups: prednisone
 Control>5>5200–400 then 150–30075–200 
Stallone25
 WithdrawalFixed dose (15 mg load then 2 mg/day)10–15150–250N/AInduction: NR Both groups: prednisone
 ControlFixed dose (15 mg load then 2 mg/day)Fixed dose (2 mg/day)150–250150–250 
Jardine27
 Withdrawal4–128–16125–250N/AInduction: NR Both groups: prednisone
 Control4–128–16125–25050–100 
Grinyo26
 Withdrawal8–1612–203–8N/AInduction: Not used Both groups: prednisone
 Control4–84–88–125–10 

Acute rejection

Three studies reported acute rejection occurring after CNI withdrawal (20–22). The studies were homogeneous (Q = 0.08, p = 0.96) and all showed a trend toward a higher incidence of acute rejection following CNI withdrawal. The pooled estimate showed that CNI withdrawal significantly increased the risk of acute rejection (relative risk 2.36; 95% CI, 1.34–4.15; p = 0.003). The absolute risk difference in acute rejection was 6.0% (95% CI, 2–10%; p = 0.002) (Figure 2). This implies that CNI withdrawal is associated with an incremental risk of acute rejection of 6%. A sensitivity analysis using the 3-year data instead of the 1-year data from the Rapamune Maintenance Regimen Study (24) had little impact on the relative or absolute risk of rejection given that very few rejections occurred after the first year (relative risk 2.04; 95% CI, 1.2–3.46; p = 0.009 and absolute risk difference 6%; 95% CI, 2–10%; p = 0.006).

image

Figure 2. Absolute risk difference of acute rejection after calcineurin inhibitor withdrawal compared to the control group receiving combined calcineurin inhibitor and sirolimus therapy. RD, risk difference; 95% CI, 95% confidence interval.

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All six of the included trials reported the total rejection rate from the time of transplantation to the end of follow-up. The studies were homogeneous (Q = 3.4, p = 0.64) and most showed a nonsignificant trend toward more overall acute rejection in the CNI withdrawal group (Figure 3). Pooling of the trials showed that the overall risk of acute rejection (includes rejection occurring before and after CNI withdrawal) was increased in the withdrawal group (relative risk 1.59; 95% CI, 1.2–2.1%; p = 0.001). The CNI withdrawal group had an 8% (95% CI, 3–12%; p = 0.0006) absolute increase in total acute rejection since transplantation compared to the control group (Figure 3). A sensitivity analysis using the 3-year data from the Rapamune Maintenance Regimen Study (24) had no significant impact on the risk of total rejection following transplantation (relative risk 1.55; 95% CI, 1.18–2.04; p = 0.002). Similarly, the overall risk of rejection following transplantation did not significantly change if the analysis was repeated using the five studies (20–22,25,26) published in a peer-reviewed journal (relative risk 1.48; 95% CI, 1.09–2.02; p = 0.01). A sensitivity analysis involving only trials that used cyclosporine (i.e. the one tacrolimus trial (26) was excluded) did not significantly change the relative (relative risk 1.56; 95% CI, 1.17–2.07, p = 0.003) or absolute (absolute risk difference 7%; 95% CI, 3–12%, p = 0.002) risk of acute rejection. In the three studies (20–22) that reported acute rejection before and after withdrawal, there was no increased risk of rejection prior to CNI withdrawal (relative risk 1.0; 95% CI, 0.64–1.56; p = 1.0).

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Figure 3. Absolute risk difference of acute rejection since transplantation for the calcineurin inhibitor withdrawal group compared to the control group receiving combined calcineurin inhibitor and sirolimus therapy. RD, risk difference; 95% CI, 95% confidence interval.

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Graft and patient survival

All six of the included trials reported both patient death and allograft loss. There was no evidence of heterogeneity for the outcome of graft loss (Q = 2.42, p = 0.79) or patient death (Q = 0.57, p = 0.99). CNI withdrawal had no significant effect on the relative (relative risk 0.87; 95% CI, 0.46–1.64; p = 0.66) (Figure 4) or absolute risk of graft loss (absolute risk difference 0%; 95% CI, −3–2%; p = 0.32) at 1 year. The results did not change when the study with only 6-month follow-up (21) was included. When a sensitivity analysis using the 3-year data from the Rapamune Maintenance Regimen Study (24) was performed, there was a trend toward decreased graft loss in the CNI withdrawal group (relative risk 0.70; 95% CI, 0.45–1.10; p = 0.12). This trend was more pronounced when the trial reported in abstract form (27) was excluded from analysis (relative risk 0.69; 95% CI, 0.43–1.05; p = 0.08). CNI withdrawal had no effect on patient death (relative risk 0.88; 95% CI, 0.40–1.96; p = 0.76).

image

Figure 4. Relative risk of graft loss since transplantation for the calcineurin inhibitor withdrawal group compared to the control group receiving combined calcineurin inhibitor and sirolimus therapy. RR, relative risk; 95% CI, 95% confidence interval.

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Renal function

Creatinine clearance was reported by all studies; however, one study (25) only reported median and inter-quartile range and thus could not be included in the pooled analysis. We estimated the mean difference in creatinine clearance between the withdrawal and control group at the end of follow-up. There was no evidence of heterogeneity between the studies (Q = 2.58, p = 0.63). CNI withdrawal was associated with a significant increase in the creatinine clearance (weighted mean difference 7.49 mL/min; 95% CI, 5.08–9.89; p < 0.00001) (Figure 5). A sensitivity analysis involving only trials that used cyclosporine (i.e. the one tacrolimus trial (26) was excluded) did not rsignificantly change the effect on creatinine clearance (weighted mean difference 7.78 mL/min; 95% CI, 5.31–10.24; p < 0.00001). Similarly, serum creatinine, which was reported in four studies (20–22,27) was significantly lower in the CNI withdrawal group (weighted mean difference −0.19 mg/dL; 95% CI, −0.28 to −0.10; p < 0.0001) compared to control arm at the end of follow-up.

image

Figure 5. Weighted mean difference in creatinine clearance since transplantation for the calcineurin inhibitor withdrawal group compared to the control group receiving combined calcineurin inhibitor and sirolimus therapy. WMD, weighted mean difference; 95% CI, 95% confidence interval.

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Blood pressure, lipids and post-transplant diabetes mellitus

Three studies reported on the proportion of patients with hypertension (21,22,25) and there was no evidence of heterogeneity between the studies (Q = 2.92, p = 0.23). CNI withdrawal was associated with a significant reduction in the risk of hypertension (relative risk 0.56; 95% CI, 0.40–0.78; p = 0.0006). Mean systolic blood pressure was reported in three studies (20,22,26) and mean diastolic blood pressure was reported in two studies (22,26). There was no evidence of study heterogeneity for either systolic blood pressure (Q = 0.01, p = 1.0) or diastolic blood pressure (Q = 0, p = 1.0). CNI withdrawal was associated with a significant reduction in both systolic (weighted mean difference −7.02 mmHg; 95% CI, −10.25 to −3.79; p < 0.0001) and diastolic blood pressure (weighted mean difference −3.2 mmHg; 95% CI, −5.29 to −1.11%; p = 0.003).

Four studies reported total cholesterol and triglycerides (20–22,25). There was significant heterogeneity for the outcome of total cholesterol (Q = 63.1, p < 0.001) as well as for triglycerides (Q = 16.9, p < 0.001). Pooling of the studies was therefore conducted using a random effects model. CNI withdrawal was not associated with any significant effect on total cholesterol (weighted mean difference 0.53 mmol/L; 95% CI, −0.26 to 1.31; p = 0.19) or triglycerides (weighted mean difference 0.17 mmol/L; 95% CI, −0.33 to 0.68; p = 0.5). However, there was a trend toward more statin use in the CNI withdrawal group (relative risk 1.09; 95% CI, 0.97–1.21; p = 0.14) in the two studies that reported medication usage (20,22). The use of fibrates was not significantly different between the two groups (relative risk 0.95; 95% CI, 0.68–1.31; p = 0.73).

Four studies reported incidence of post-transplant diabetes mellitus (20,22,25,26). The studies were homogeneous (Q = 1.85, p = 0.60). There was no significant effect of CNI withdrawal on the risk of post-transplant diabetes mellitus (relative risk 0.93; 95% CI, 0.49–1.78; p = 0.83).

Discussion

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

This systematic review has demonstrated that compared to the continued use of a CNI and sirolimus, CNI withdrawal early post-transplantation is associated with a significant increase in the risk of acute rejection. However, despite the increase in rejection the strategy of CNI withdrawal was associated with a significant improvement in creatinine clearance, less hypertension and no unfavorable effect on patient or graft survival.

The incremental rejection risk from CNI withdrawal found in this study was slightly lower than a previous meta-analysis on cyclosporine withdrawal (8). Kasiske et al. found that patients undergoing cyclosporine withdrawal had an 11% increase in acute rejection compared to the control patients (8). They also found that the studies were heterogeneous and smaller studies tended to a report of higher risk of rejection after cyclosporine withdrawal (8). In our analysis, the studies were clinically homogeneous with respect to acute rejection and a relationship with sample size was not obvious. The higher rejection risk in the Kasiske meta-analysis may also reflect the era of the included trials and the other immunosuppression (azathioprine) used. Nonetheless, we still found that CNI withdrawal was associated with an increased risk of rejection even when a more potent immunosuppressant, such as sirolimus was used instead of azathioprine. In addition, most of the studies in this analysis included relatively low-risk patients. Had more high-risk patients been included, the incremental risk of rejection might have been even greater. This suggests that patients undergoing CNI withdrawal require close monitoring for rejection and a degree of caution is required before generalizing this strategy to higher risk populations.

Despite the increased risk of rejection, we found that CNI withdrawal had no deleterious effect on graft survival. Our sensitivity analysis using 3-year follow-up data even suggested a trend toward improved graft survival in the withdrawal arm. This finding was similar to previous trials of CNI withdrawal. Studies with short duration of follow-up tended to show that cyclosporine withdrawal was associated with an increased risk of allograft failure, whereas studies with more than 48-months follow-up tended to show a beneficial effect on graft outcome (8). It is not clear why the increased rate of acute rejection does not seem to negatively effect graft survival in the setting of cyclosporine withdrawal. It may be that the rejection episodes are mild and easily treated in the setting of controlled immunosuppression withdrawal. In the five studies that reported rejection grade in this analysis, only one Banff III acute rejection was reported and the majority of rejection events were mild (21,22,25–27).

We found that CNI withdrawal was associated with a significant increase in the creatinine clearance. This improvement in renal function occurred despite the increase in rejection noted above. This suggests that reducing the nephrotoxicity of CNIs may be more advantageous to overall function than a rejection episode in the setting of medication withdrawal. Experimental data have shown that a pharmacokinetic interaction with sirolimus leads to increased blood and renal tissue levels of cyclosporine, thereby increasing CNI toxicity (28). Meier–Kriesche et al. recently showed that the combination of cyclosporine and sirolimus was associated with worse 4-year graft survival (74.6% vs. 79.3%) compared to the combination of cyclosporine and mycophenolate mofetil (29). Thus, the improvement in renal function found in our study is consistent with the known nephrotoxicity of the sirolimus–CNI combination. Histological data from two studies included in this analysis appear to support the functional improvement we have shown (19,25). In both of these studies, the incidence of new cases of chronic allograft nephropathy was significantly lower in the CNI withdrawal group (19,25). In addition, one study showed that the vascular lesions were significantly more severe in the group that remained on the CNI (25). Although long-term data are currently lacking, it appears that early functional and structural changes are seen with CNI withdrawal from a sirolimus-based regimen that may prove beneficial to long-term allograft survival.

Recent studies have found the 1-year serum creatinine (30–33) and creatinine clearance (34,35) to be strong predictors of long-term graft survival. Hariharan et al. showed that a 1.0 mg/dL increase in the serum creatinine at 1 year was associated with a 63% increased risk of graft failure (30). Using this data, the difference in serum creatinine of 0.19 mg/dL we found, would result in a 12% reduction in graft failure with CNI withdrawal. Following renal transplantation, the average decline in creatinine clearance is approximately 1.5 mL/min/year (36,37). Therefore, the increase in creatinine clearance of 7.49 mL/min found in this analysis is clinically important. Such an increase in function would be expected to improve graft survival by several years (36,37).

The effect of CNI withdrawal on cardiac risk profile is important, given that cardiovascular disease is the most common cause of death following renal transplantation (38,39). We have found that the effect of CNI withdrawal on total cholesterol and triglycerides was heterogeneous across studies. One study (21) showed a trend toward lower cholesterol and triglyceride levels in the withdrawal arm, while the other studies showed a trend toward increased lipid levels (20,22,25). Different target levels for sirolimus may help explain some of the variability in the lipid levels. In addition, the use of lipid lowering medications was reported in only two studies. Differences in the use of statins and fibrates between the withdrawal arm and the control arm could also explain some of the heterogeneity. In contrast, the effect of CNI withdrawal on blood pressure was uniform across the studies in this analysis. The lower systolic and diastolic blood pressures were both statistically significant and clinically meaningful. We found that the systolic blood pressure was 7.02 mmHg lower in the CNI withdrawal group compared to the control patients. Mange et al. showed that for every 10 mmHg increase in the systolic blood pressure the rate of renal allograft survival fell by 15% (40). Although unproven in this situation, the effect of CNI withdrawal on blood pressure may prove beneficial in the long term.

Limitations to this study should be noted. First, there were only six trials that could be included in the analysis. The number of available trials is a potential limitation for any meta-analysis; however, the clinical outcomes were homogeneous, which gave confidence to the pooled results. Second, none of the studies was blinded and therefore diagnostic suspicion bias could have occurred contributing to the increased risk of rejection seen in the CNI withdrawal group. This bias could have occurred if investigators felt that the withdrawal arm should be monitored more closely and undergo biopsy for smaller changes in renal function. Third, only one study examined the withdrawal of tacrolimus (26). Although the change in renal function and risk of acute rejection in this study was in the same direction as the cyclosporine trials, no firm conclusion can be made about the effect of tacrolimus withdrawal from a sirolimus-based therapy. Finally, this analysis generally involved trials with low risk patients who remained stable in the month before withdrawal. This limits the generalizability of our findings to other potentially higher risk populations.

In conclusion, CNI withdrawal from a sirolimus-based therapy is associated with an increased risk of acute rejection with a significant improvement in renal function, reduction in hypertension and no harmful effect on short-term graft survival. Based on this analysis, however, no firm conclusion can be drawn on long-term outcomes. Longer follow-up of the studies in this analysis is needed to determine if this strategy, which has important short-term risks and benefits, will result in a significant improvement in long-term patient and graft survival.

References

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