NDT Advance Access originally published online on July 28, 2006
Nephrology Dialysis Transplantation 2006 21(11):3243-3251; doi:10.1093/ndt/gfl397
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Conversion of ciclosporin A to tacrolimus in kidney transplant recipients with chronic allograft nephropathy
Division of Nephrology, Department of Medicine, University of Hong Kong and Queen Mary Hospital, Hong Kong, China
Correspondence and offprint requests to: Prof. T. M. Chan, Department of Medicine, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China. Email: dtmchan{at}hku.hk
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Abstract |
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Background. Tacrolimus and ciclosporin might have different effects on intra-renal fibrosis and allograft function in chronic allograft nephropathy (CAN). It is difficult to predict the response to calcineurin inhibitor minimization in patients with CAN.
Methods. This prospective randomized study compared ciclosporin A (CsA)-to-tacrolimus conversion (group A, target tacrolimus trough level 6–8 ng/ml) vs CsA minimization (group B, target CsA trough level 80–100 ng/ml) with regard to efficacy and safety in patients with CAN and deteriorating allograft function. The primary efficacy endpoint was improvement in the slope of inverse serum creatinine (1/SCr) vs time plot.
Results. There were 34 evaluable patients (n = 16 in group A; n = 18 in group B), with similar baseline characteristics. Both groups reached target drug levels after a 3-month run-in period. Over the ensuing 12 months, nine (56.3%) subjects in group A and 10 (55.6%) in group B reached the primary end point (P = 0.968). Both groups showed considerable improvement in the slope of 1/SCr vs time plot. There was no significant difference in the slope between groups before and after intervention. Graft survival was 87% in group A and 100% in group B (P = 0.121). Acute rejection was encountered in two group A subjects. There was no significant change or difference in blood glucose, lipids, and blood pressure between groups.
Conclusion. Our results suggest that in patients with CAN and deteriorating allograft function, CsA-to-tacrolimus conversion or CsA minimization achieved comparable efficacies in retarding the decline of graft function. Such contention may be biased by the low patient number. Further studies with a larger cohort are needed for validation.
Keywords: chronic allograft nephropathy; ciclosporin A; minimization; tacrolimus conversion
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Introduction |
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Despite improvements in immunosuppressive protocols for kidney transplantation, chronic allograft nephropathy (CAN) remains one of the most important causes of graft loss in the first post-transplant decade [1]. CAN is characterized clinically by progressive graft failure associated with variable degrees of hypertension and proteinuria, and histologically by non-specific chronic changes in the vascular (afferent arteriosclerosis), glomerular (glomerulosclerosis) and tubulointerstitial (tubular atrophy and interstitial fibrosis) compartments of the kidney [2]. Five years after transplantation, up to two-thirds of allografts have been shown to demonstrate features of moderate to severe CAN [3]. The aetiology of CAN is not well understood, and a variety of immunological and nonimmunological factors, including histo-incompatibility, acute rejection, preservation injury, donor status, hypertension, hyperlipidaemia and the use of calcineurin inhibitors (CNI), notably ciclosporin A (CsA), have been incriminated [1].
To date, there is no specific treatment for CAN. Emerging evidence indicates that growth factors, such as transforming growth factor-ß (TGF-ß), are critically important in both CAN and chronic CsA toxicity, suggesting that these two entities share common pathophysiological pathways, and chronic CsA nephrotoxicity may contribute significantly to CAN [4–7]. Because of this, several studies have investigated the role of an alternative immunosuppressive agent, such as mycophenolate mofetil (MMF), and found that the introduction of MMF with reduction or withdrawal of CsA had a favourable outcome on post-transplantation graft function and survival [8,9]. However, such strategy, although safe in most instances, may be offset by the potentially increased risk of acute rejection and graft loss [10,11], and it may not be entirely desirable to withdraw CNI altogether. Tacrolimus is a newer CNI that is more potent than CsA in rejection prophylaxis [12], and has been associated with reduced intrarenal expression of TGF-ß [13,14] and other profibrotic genes [15], and less allograft fibrosis [16] compared with patients treated with CsA. These observations suggest that tacrolimus substitution for CsA may be beneficial for patients with documented CAN without compromising immunosuppressive efficacy.
In this study, we prospectively compared CsA-to-tacrolimus conversion with CsA minimization, with regard to renal function preservation in patients with CAN and progressive loss of graft function.
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Methods |
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Study design and patients
This was a randomized, controlled, open-label, prospective study conducted in five major renal transplant centres in Hong Kong between July 2001 and June 2004. The study protocol was approved by the Institutional Review Board and Research Ethics Committee of the Hong Kong Hospital Authority, and all participating subjects gave written, informed consent before study entry. Cadaveric or living-related renal transplant recipients of either gender between age 18 and 65, at least 12 months post-transplant and maintained on a CsA-based immunosuppressive regimen with steady-state whole blood trough levels not exceeding 150 ng/ml and serum creatinine (SCr) between 100 and 400 µmol/l, histologically proven CAN within the preceding 12 months, and deteriorating graft renal function as evidenced by a negative slope of 1/SCr plotted against time, were eligible. A regression line plotted with at least six SCr values over the preceding 12 months had to demonstrate a negative slope that had a significant P-value <0.05 and an adjusted R2 > 0.35. All biopsies were independently reviewed and scored by a single pathologist in accordance with the Banff 97 criteria [2]. Patients with alternative causes of graft dysfunction (de novo or recurrent disease, obstruction or transplant renal artery stenosis detected by Doppler ultrasonography during the preceding 12 months), biopsy proven acute rejection of Banff 97 grades I, II or III within 3 months prior to study entry, and patients who were receiving tacrolimus or rapamycin before recruitment were excluded. Additional exclusion criteria were systemic infection, introduction of angiotensin converting enzyme inhibitor or receptor blocker within 3 months before recruitment, receipt of other solid organ transplant, concurrent participation in other investigational immunosuppressive protocol, and women lactating, pregnant or of childbearing potential not using, or who were unwilling to use a reliable contraceptive method during and for 6 weeks following the study.
Randomization and intervention protocol
Eligible and consenting subjects were assigned by simple randomization using a computer-generated sequence into either the tacrolimus conversion (group A) or the CsA minimization (group B) arm (Figure 1). Patients randomized to group A underwent a clean conversion to tacrolimus at a dose of 0.16 mg/kg/day in two divided doses 12 h after the last dose of CsA. The dose of tacrolimus was then titrated during a 3-month run-in phase to attain a 12-h trough whole blood level of 6–8 ng/ml using a microparticle enzyme immunoassay on a Viva analyser (Dade Behring, UK). Other concomitant medications remained unchanged according to individual centre protocol. Patients randomized to group B continued to receive CsA with dosages adjusted to maintain a 12-h trough blood level of 80–100 ng/ml using the Dade–Behring Emit Enzyme Immunoassay, and other medications according to centre protocol. All patients were followed-up every 2 weeks for the first month, then at 4-weekly intervals till 6 months, and then at 2-monthly intervals till the study end. The total follow-up duration for both groups was 15 months. Pertinent clinical data including body weight, blood pressure, urine dipstick test, complete blood count, liver and renal function panels, blood glucose and 12-h trough blood levels of tacrolimus (for group A) or CsA (for group B), were recorded on each visit. Fasting blood glucose, haemoglobin A1C level, full lipid profile, and 24-h urine for protein and creatinine were assayed every 2 months. All adverse events and medication log were carefully documented throughout the study.
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Study end points
The primary end point was the rate of a significant improvement in graft function defined as a stabilization or reduction of SCr observed from 3–15 months of conversion as reflected by a flattening or positive slope of the 1/SCr against time plot, absence of any major event necessitating premature termination of the randomized therapy, and the absence of graft loss.
Secondary end points were graft and patient survival, incidence of acute rejection, SCr and calculated creatinine clearance, blood pressure, salient laboratory parameters, incidence of de novo post-transplant diabetes mellitus, use of medications for hypertension, diabetes mellitus and hyperlipidaemia.
Statistical analysis
Statistical analyses and sample size calculations were performed using SPSS for windows (version 12.0) and SAS for windows (version 9.1). Our crude estimate indicated that the enrolment of 46 patients would achieve 80% power to detect a 20% difference in SCr at 1 year between the two groups with a two-sided significance level (
) of 0.05 using an independent two-sample t-test. Assuming a dropout rate of 10%, the study aimed to enrol 50 patients. Due to the stringent inclusion criteria, the final sample size achieved (n = 34) resulted in a power of 
67%. Data were presented as mean ± SD unless otherwise specified. Continuous variables between groups were compared using either unpaired t-test or Mann–Whitney U-test. Paired t-test or Wilcoxon signed rank test was used for within group comparison where appropriate. Comparisons of categorical variables were performed using either 
2 test or Fisher's exact test. Linear regression analysis was used to estimate the slope of the 1/SCr vs time plot for individual subjects. SCr values within the first 3 months after randomization were not included in the calculation of slope of 1/SCr vs time in view of the blood level titration during this period. Differences in the slopes of 1/SCr vs time before (calculated from SCr values in the 12 months before randomization) and after intervention (calculated from SCr values over the 3–15 months interval following randomization) and between the two treatment groups, were sought [17]. Mixed linear model was used in the calculation of least squares means of SCr and in the comparison of the trends of 1/SCr vs time plots between the two groups. Treatment group and time were treated as fixed effects in the mixed linear model analysis. Akaike's information criterion was used to assess model fitness. Two-tailed P-values of <0.05 were considered statistically significant.
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Results |
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Baseline characteristics
All participating subjects were ethnic Chinese. The baseline demographic and clinical characteristics of the two groups were well matched except for a higher proportion of subjects with a history of allograft rejection and concomitant use of MMF or azathioprine in group A (Table 1). There was no difference in the overall distribution of the Banff 97 grades for CAN between groups (P = 1.000). The underlying renal diseases were IgA nephropathy in three, chronic glomerulonephritis in three, crescentic glomerulonephritis in one, and unknown in nine for group A; IgA nephropathy in four, membranoproliferative glomerulonephritis in one, focal segmental glomerulosclerosis in one, hypertensive nephrosclerosis in one, chronic pyelonephritis in one, chronic glomerulonephritis in two, and unknown in eight for group B.
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Immunosuppressive treatment
The dose and trough blood level of CsA decreased significantly in group B after the first 3 months, while the dose of prednisolone was comparable between the two groups (Table 2). There was no significant within-group difference in steroid dosage before and after intervention. Most of the patients randomized to CsA-to-tacrolimus conversion required a reduction in tacrolimus dose during titration, so that there was a significant reduction of tacrolimus dose for the group as a whole during the first 3 months. The final stable dose of tacrolimus was in the range of 0.066–0.08 mg/kg/day.
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Primary outcome
Nine (56.3%) patients in group A and 10 (55.6%) patients in group B (P = 0.968) showed a significant improvement in 1/SCr vs time slope, indicating a reduction in the rate of renal function deterioration, following intervention (Figure 2). There was a significant reduction in 1/SCr vs time slope in group A (overall trend for the whole group before and after intervention, –0.123 vs –0.050 l/µmol/month, P = 0.029) (Figure 3). The corresponding values in group B were –0.090 and –0.045 l/µmol/month (P = 0.096). Between-group comparison showed that their difference in 1/SCr vs time slope was not statistically significant both before (difference in slope of mixed linear model regression –0.033 l/µmol/month, P = 0.196) and after intervention (difference in slope of mixed linear model regression –0.010 l/µmol/month, P = 0.724).
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Secondary outcomes
Changes in other salient clinical and laboratory parameters are listed in Table 3. Both treatment groups showed a significant and sustained reduction in systolic blood pressure compared with baseline values within the first 6 months. Proteinuria and creatinine clearance did not change significantly and remained similar between the two groups. Triglyceride level in group B was significantly lower after 6 months, but the lipid profile, blood glucose and uric acid levels did not differ between the two groups throughout the study. The reduction in uric acid level in both groups did not reach statistical significance. None of the subjects developed de novo diabetes mellitus, and there was no change in the requirement for anti-hypertensive or lipid-lowering medications.
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Graft survival in the study period was 87% in group A and 100% in group B (P = 0.121, Figure 4). Two group A patients reached end-stage renal failure, one due to progression of CAN and the other one followed an episode of delayed acute rejection. Acute rejection occurred in two patients, both from group A. One patient developed acute rejection 2 months after entering this study, which was related to suboptimal tacrolimus blood levels. His baseline SCr was 300 µmol/l. Despite treatment with pulse corticosteroid he became dialysis dependent four weeks later. Another group A subject developed Banff 97 grade IA acute rejection one week after entering this study, when the trough tacrolimus blood level was 8.9 ng/ml. He responded to pulse corticosteroid treatment and SCr returned to baseline level. The incidence of adverse events did not differ between the two groups (Table 4). Four patients in group A and one in group B developed infection (P = 0.164). There was no mortality. Apart from the two patients who reached end-stage renal failure, none required premature discontinuation of study.
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Discussion |
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The results from this study showed that in renal transplant recipients of CsA-based immunosuppression with deteriorating allograft function due to CAN, conversion to tacrolimus or reduction of CsA alone are equally effective in improving the subsequent course of CAN, as evidenced by a significant flattening of the negatively sloping 1/SCr vs time plot in the ensuing 12 months after therapeutic intervention. This beneficial effect was observed in over half of the patients in each group. When the overall trend for the whole group was analysed, a significant improvement was observed only in the CsA-to-tacrolimus group (group A) but not with CsA minimization. This discrepancy could be related to the more negative slope in group A subjects at baseline compared with group B, although the between-group difference did not reach statistical significance both before and after intervention. These findings bear clinical importance. Firstly, gradual minimization of CsA is both safe and effective without the need to introduce another immunosuppressive agent. None of the subjects in the CsA arm experienced acute rejection after blood levels of CsA were reduced by an average of 29% at 12 months. The final drug levels were similar to those in a recent study [18] of 13 subjects with CAN who benefited from a 24% dose reduction in CsA. However, the investigators in this study had also introduced MMF prior to CsA reduction. Our results suggest that this may not be necessary in all patients, which has obvious financial implications.
Secondly, tacrolimus conversion or CsA reduction yielded comparable profiles of SCr regression and, more importantly, obviated the potentially heightened risk of acute rejection observed with CNI-withdrawing protocols. Although the addition of MMF followed by complete CNI withdrawal has been reported to achieve success for CAN [8,19], the risk of acute rejection is significantly higher following CsA withdrawal either in stable patients receiving MMF [20], or during the early post-transplant period in patients receiving regimens that contain MMF [21] or sirolimus [22]. Indeed, a meta-analysis of 10 clinical trials including data from over 1000 subjects demonstrated an 11% increase in the odds of acute rejection after CsA withdrawal [11]. Thus, while the safety of complete CNI withdrawal is still debatable, a minimization approach may be a viable alternative option that alters the course of CAN without compromising safety.
Thirdly, although there have been several reports favouring the conversion of CsA to tacrolimus for CAN [18,23–27], these studies were often uncontrolled or retrospective in nature. The recommended tacrolimus dose and target trough blood levels from two recent randomized controlled trials were 0.15 mg/kg/day and 5–15 ng/ml [23], and 0.10 mg/kg/day and 5–10 ng/ml [18], respectively, while the corresponding values in 2 non-randomized trials were even higher at 0.15 mg/kg/day and 10–15 ng/ml [27,28], respectively. Here, we showed that much lower doses of 0.066–0.08 mg/kg/day and trough levels within 6–8 ng/ml produced comparable results without compromising safety. The feasibility of such low blood levels is supported by a recent observational study [24] in which conversion of CsA to tacrolimus with trough levels of 6–7 ng/ml in 133 renal transplant recipients was adequate and not associated with increased rejection risk after 4 years of follow-up. The immediate advantages of low-dose tacrolimus include reduced risk of side effects, notably new-onset diabetes which is dose-dependent [12], and lowering of drug budget. Indeed, the incidence of de novo diabetes approached 8.5% in 107 patients who underwent tacrolimus conversion when the drug level was aimed high [28]. On the other hand, patients converted to tacrolimus from CsA in the present study were at no greater risk for developing diabetes or glucose intolerance, which concurs with observations made in the Caucasian population employing lower drug targets [18,29,30]. Furthermore, the long term metabolic and organ-specific benefits of reduced cumulative exposure to CNI may be even more far-reaching. In addition to diabetes, lipid profiles were consistently reported to be improved after CsA was switched to tacrolimus [23,24]. However, we and others [26] have not reproduced this phenomenon. The discrepancy could be related to the confounding effect of variable doses of corticosteroid in different series.
One drawback of this study is the low patient number which could bias our conclusions. This arises from the stringent inclusion criteria that resulted in a slow take-on rate. In addition, randomization of low patient numbers resulted in an imbalance in concomitant immunosuppressants and historical rejection rates at baseline. Nevertheless, such differences, even if real, would only be in favour of a stabilizing effect of CsA-FK506 conversion. More importantly, there was no difference in the Banff 97 score distribution between groups. Herein, around 55% of subjects randomized to either treatment arm reached primary endpoint. To our knowledge, there is only one published study that also employs 1/SCr vs time trend as the primary end point in tacrolimus-converted subjects [18], and the response rates were slightly higher, being 62% (8 of 13 subjects by intention-to-treat analysis) in the conversion arm and 69% (9 of 13 subjects) in the CsA reduction plus MMF arm. On the other hand, absolute SCr values were used as the primary outcome measure in two recently published trials of tacrolimus conversion in which SCr decreased after 2 years [23] and 4 years [24] of conversion. Here, we only demonstrated a slower pace of SCr rise rather than a decline in the absolute SCr value. Such discrepancy may be partly due to the exclusion of subjects who lost their grafts in those two studies, and partly related to the shorter follow-up duration in this study. Nevertheless, a potential disadvantage of using SCr alone as the treatment end point is that it only reflects graft function at a pre-selected time point rather than its true evolution over time. We believe that it is clinically pertinent to compare the rate of renal function deterioration in individual patients before and after intervention, since SCr value can be affected by a change in muscle mass, and the rate of progression of renal failure varies between patients.
Graft survival and the pattern of adverse events were comparable between the two treatment groups although two patients developed acute rejection in group A. One patient developed delayed acute rejection that was probably precipitated by a short period of suboptimal tacrolimus blood levels. Thus, from a practical viewpoint, a minimization protocol is more convenient than a switch in CNI, since the latter entails starting with an empirical dose that may not always be adequate. This does not mean our empirical starting dose of tacrolimus at 0.16 mg/kg/day was inadequate, since the majority of patients required a subsequent downward adjustment so that by 12 months there was a 49% dose reduction. Another patient experienced rejection just one week after entering the study, which was likely to be related to the preceding low CsA blood levels in view of the concomitant tacrolimus level of 8.9 ng/ml. In a series that compared 126 patients who underwent CsA-to-tacrolimus conversion with 60 patients who remained on CsA, the incidence of acute rejection in the first 2 years was 4.8 and 5%, respectively [23].
Apart from CsA minimization or conversion to tacrolimus or MMF, there is an emerging trend to combine CNI minimization or withdrawal with mammalian target of rapamycin (mTOR) inhibitors such as sirolimus or everolimus [31]. Absence of nephrotoxicity is a distinct advantage of mTOR inhibitors, but they were not available at the inception of this study. In a recent report of 43 patients with CAN, conversion from CNI to sirolimus was associated with improved renal function, yet up to a third of the subjects developed overt proteinuria [32]. The long-term safety and efficacy of this approach requires further validation.
In summary, this study indicates comparable safety and efficacy of CsA-to-tacrolimus conversion and CsA minimization in patients with CAN and deteriorating graft function. Its validity remains to be confirmed in a larger cohort of subjects.
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Appendix |
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Membership of the Hong Kong Nephrology Study Group includes: Queen Mary Hospital—Sydney CW Tang, Sing Leung Lui, Angela YM Wang, Kwok Wah Chan, Colin SO Tang, Man Fai Lam, Kai Chung Tse, Terence PS Yip, Kar Neng Lai, Tak Mao Chan; United Christian Hospital—Anthony Tang, Yiu Wing Ho, Chung Ying Leung; Princess Margaret Hospital—Ernest WK Tsang, Matthew KL Tong; Queen Elizabeth Hospital—Francis KM Wong, Ka Foon Chau, Chun Sang Li; Kwong Wah Hospital—Kin Yee Lo, Siu Ka Mak, Andrew KM Wong; Tuen Mun Hospital—Tze Hoi Kwan, Tak Cheung Au.
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Acknowledgements |
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This study was partially supported by a grant from Fujisawa HK Ltd. The authors thank Ms Emily W. L. Liu for accurately recording all clinical data from the participating centres.
Conflict of interest statement. None declared.
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Notes |
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Please refer to Appendix for participants in the Study Group. 
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References |
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[Abstract/Free Full Text]
Accepted in revised form: 6. 6.06
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