|Year : 2018 | Volume
| Issue : 6 | Page : 1376-1385
|Comparison of tacrolimus and cyclosporine for immunosuppression after renal transplantation: An updated systematic review and meta-analysis
Anoush Azarfar1, Yalda Ravanshad2, Hassan Mehrad-Majd3, Mohammad Esmaeeli1, Shapour Badiei Aval4, Maryam Emadzadeh5, Maryam Salehi6, Ali Moradi7, Mohadese Golsorkhi8, Mahmood Reza Khazaei9
1 Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Community Medicine, Mashhad Medical Science Branch, Islamic Azad University, Mashhad, Iran
3 Department of Molecular Medicine, Clinical Research Unit, Mashhad University of Medical Sciences, Mashhad, Iran
4 Department of Acupuncture, Clinical Research Unit, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
5 Department of Community Medicine, Clinical Research Unit, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
6 Department of Community Medicine, Kidney Transplantation Complications Research Center; Clinical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
7 Department of Orthopedics, Orthopedic Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
8 Department of Pediatrics, Mashhad University of Medical Sciences, Mashhad, Iran
9 Department of Pediatrics, Mashhad Medical Science Branch, Islamic Azad University, Mashhad, Iran
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|Date of Submission||28-Sep-2017|
|Date of Decision||02-Jan-2018|
|Date of Acceptance||02-Jan-2018|
|Date of Web Publication||27-Dec-2018|
| Abstract|| |
Kidney transplantation is usually followed by immunosuppressive therapy to prevent early rejection and prolong graft survival. The calcineurin inhibitors (CNIs) represent the most commonly used agents. However, available evidence suggests the poor outcome over the long term, maybe be due to the potential nephrotoxicity associated with CNIs. Several randomized trials have compared tacrolimus (TAC) with cyclosporine, to find the optimal agent for renal transplantation; however, studies have shown conflicting results. The aim of this study was to systematically review and update the evidence for the benefits and harm of TAC versus cyclosporine as the primary immunosuppression after renal transplantation. The study was a systematic review and meta-analysis. An electronic literature search was conducted to identify appropriated trial studies. The outcomes were presented as relative risk (RR), with 95% confidence intervals (CI). Statistical analysis used was meta-analysis. Twenty-one eligible randomized controlled trials were included in this systematic review. TAC was significantly superior to cyclosporine considering the total effect size of graft loss (RR 0.089; 95% CI0.057–0.122, P <0.001), acute rejection (RR 0.638; 95% CI 0.571–0.713, P <0.001) and hypercholeste-rolemia (RR 0.634; 95% CI, 0.539–0.746, P <0.001). On the contrary, cyclosporine seemed to be significantly superior to TAC with regard to diabetes (RR 1.891; 95% CI 1.522–2.350, P <0.001). However, no significant differences between the two CNIs were found with regard to mortality, infection, and hypertension. The review indicates that TAC is significantly superior to cyclosporine regarding graft loss, acute rejection, and hypercholesterolemia, but cyclosporine seems to be significantly superior to TAC regarding diabetes. However, further large randomized trials are suggested.
|How to cite this article:|
Azarfar A, Ravanshad Y, Mehrad-Majd H, Esmaeeli M, Aval SB, Emadzadeh M, Salehi M, Moradi A, Golsorkhi M, Khazaei MR. Comparison of tacrolimus and cyclosporine for immunosuppression after renal transplantation: An updated systematic review and meta-analysis. Saudi J Kidney Dis Transpl 2018;29:1376-85
|How to cite this URL:|
Azarfar A, Ravanshad Y, Mehrad-Majd H, Esmaeeli M, Aval SB, Emadzadeh M, Salehi M, Moradi A, Golsorkhi M, Khazaei MR. Comparison of tacrolimus and cyclosporine for immunosuppression after renal transplantation: An updated systematic review and meta-analysis. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2019 Jan 17];29:1376-85. Available from: http://www.sjkdt.org/text.asp?2018/29/6/1376/248292
| Introduction|| |
Kidney transplantation is the treatment of choice for most patients with end-stage renal disease (ESRD), which is also called chronic renal failure. For patients with ESRD, renal transplantation can improve survival and quality of life, and cause cost reduction in health-care. At present, the reported one-year patient and graft survival rates are 94% and 82%, respectively. At the time of transplantation, cyclosporine A (CyA) and tacrolimus (TAC), as calcineurin inhibitors, are used to achieve adequate immunosuppression and to prevent acute rejection episodes. CyA was discovered in 1971, and in 1983, this drug was approved for prevention of organ transplant rejection. TAC (Prograf) was discovered in the early 1980s and from 1989, used for the prevention of liver transplant rejection. After that, the usage of this drug developed rapidly for the transplantation of other organs.
Some randomized trials have compared TAC with CyA in transplant recipients. However, the results have been conflicting, and hence the immunosuppressive therapy for kidney transplant continues to be debated, and the evidence on its efficacy and safety is incon-clusive. Therefore, the aim of this study was to compare the efficacy of TAC and CyA for immunosuppressive therapy after renal transplantation.
| Subjects and Methods|| |
We searched PubMed, The Cochrane Library, Science Direct, Scopus, and Web of Science (updated up to January 2017). Search term was (c*closporin* or CyA or Neoral* or Sandimmun*) and (TAC or FK506 or FK506 or Prograf) and “kidney transplantation” and (random* or blind* or placebo* or meta-analysis). We scanned bibliographies in relevant articles and conference proceedings. Studies by the same author were checked for possible overlapping participant groups. If the study was reported as duplicate, only the most recent or complete study was included in this study. The following selection criteria were applied: we included all randomized trials comparing TAC with CyA as initial immuno-suppressive therapy, with combination of any additional immunosuppressive treatments in the intervention and control arms. We excluded trials in which participants received another solid organ in addition to a kidney transplant (such as kidney with pancreas). Studies that failed to meet the inclusion criteria were excluded from the study.
Data extraction and quality assessment
Two independent reviewers extracted data from the articles according to the selection criteria. Disagreements were resolved by discussion between two reviewers and where necessary taking the opinion of one-third reviewer. The quality of randomized trials was assessed using the Jaded score system. The following information was abstracted from each included study: first author and year of publication, design of study, sample size, mean age of patients, intervention regime, follow-up duration, concomitant treatment, and outcome measures for each group. All the analyses were based on previously published studies, thus no ethical approval or patient consent was required.
Quantitative data synthesis and data analysis
We extracted data and then used comprehensive meta-analysis to pool them for summary estimates. We expressed the results’ relative risk (RR), with 95% confidence intervals (CIs). Heterogeneity among our studies was checked by the Chi-square-based Cochran’s Q and / statistics to measure the proportion of total variation due to heterogeneity beyond chance.
If I2 was >50%, heterogeneity was considered statistically significant, and data were analyzed using a random effect model. Otherwise, the fixed-effects model was applied as the preferred method; P <0.05 was considered as statistically significant.
| Results|| |
Search results and characteristics
The literature search yielded 867 potential relevant articles. We excluded 59 articles because of duplication. We also excluded 775 articles after reviewing the titles and abstracts because they were books, book sections or, review papers and therefore not relevant. We then reviewed full text of selected articles and a total of 21 studies were included in the systematic review (all of them were clinical trials (CT)].,,,,,,,,,,,,,,,,,,,, The flow diagram of study selection is given in [Figure 1]. Characteristics and the details of the studies are summarized in [Table 1].
|Table 1: General characteristics of trials included in this systematic review.|
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The summary of outcomes of this study, comparing the two groups, TAC and CyA are provided in [Table 2].
Sixteen trials reported on mortality, and between TAC and CyA no significant difference was found, as shown in [Figure 2] (RR 1.072; 95% CI 0.792–1.452, P = 0.651).
|Figure 2: Forest plot of mortality comparing two groups of intervention; tacrolimus versus cyclosporine.|
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Eighteen trials reported on graft loss. There was a significant difference, and higher graft loss was seen in the CyA group compared with TAC as shown in [Figure 3] (RR 0.089; 95% CI 0.057–0.122, P <0.001).
|Figure 3: Forest plot of graft loss comparing two groups of intervention; tacrolimus versus cyclosporine.|
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Eighteen trials reported on acute rejection. There was a lower frequency of acute rejection with TAC therapy (RR 0.638; 95% CI 0.571–0.713, P <0.001; [Figure 4]).
|Figure 4: Forest plot of acute rejection comparing two groups of intervention; tacrolimus versus cyclosporine.|
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Eighteen trials reported on diabetes. An insignificant trend toward more diabetes was seen in the TAC group compared with the CyA group (RR 1.891; 95% CI 1.522–2.350, P <0.001; [Figure 5]).
|Figure 5: Forest plot of diabetes comparing two groups of intervention; tacrolimus versus cyclosporine.|
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The observed frequency and type of infections were similar in the two treatment groups throughout the study (RR 1.053; 95% CI 0.924–1.94, P = 0.11, [Figure 6]).
|Figure 6: Forest plot of infection comparing two groups of intervention; tacrolimus versus cyclosporine.|
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The incidence of hypertension was reported in 10 studies. No significant difference was found between the TAC and CyA groups in the incidence of hypertension (RR 0.958; 95% CI, 0.849–1.081, P = 0.489, [Figure 7]).
|Figure 7: Forest plot of hypertension comparing two groups of intervention; tacrolimus versus cyclosporine.|
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Pooled results failed to show statistically significant differences between the TAC and CyA groups in the incidence of hypercholes-terolemia (RR 0.634; 95% CI 0.539–0.746, P <0.001 [Figure 8]).
|Figure 8: Forest plot of hypercholesterolemia comparing two groups of intervention; tacrolimus vs cyclosporine.|
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| Discussion|| |
This meta-analysis showed that TAC was significantly superior to CyA in reducing graft loss, acute rejection, and hypercholestero-lemia, and CyA was significantly superior regarding diabetes. The results of another meta-analysis regarding TAC versus CyA are different from this review. In that study, TAC was significantly superior to CyA with regard to causing hypertension (RR 0.8; 95% CI 0.69–0.93, P = 0.003), and hyperlipidemia (RR 0.57; 95% CI 0.44–0.74, P <0.0001).
Another meta-analysis study showed that TAC was a more cost-effective treatment than CyA for the prevention of adverse events of renal transplant. They concluded that TAC is an effective and safe immunosuppressive agent, and for the primary prevention of graft rejection in renal transplant, it may be more cost-effective than CyA; however, new-onset diabetes should be considered during the medication period. Their results were approximately similar to our results. Another meta-analysis was made on the bioavailability, efficacy and safety of generic immunosuppressive drugs for kidney transplantation. They concluded that all the generic immunosuppressive drugs did not have equivalent relative bio-availability, and it depended on their brands. We did not investigate this issue in our study.
A meta-analysis compared TAC with CyA as primary immunosuppression after heart transplantation and showed that TAC was preferred over CyA considering the increased occurrence of hypertension, hyperlipidemia (similar to our study), gingival hyperplasia, and hirsutism. They suggested more trials with a low risk of bias.
In one study conducted by Liu et al on Chinese de novo kidney transplant recipients who were CYP3A5 expressers, CyA-based maintenance therapy was found to be safe with respect to acute rejection, patient, and graft survival. In fact, CyA was a more beneficial agent for this particulr population, meaning that the place of origin of subjects should be taken into account while choosing the optimal drug.
Although CNIs constitute the first-line immu-nosuppressive agents for maintenance therapy, the optimal maintenance immunosuppressive therapy in renal transplantation is not yet established. Combination therapy regimen in which anti-rejection medications are typically given in combination with antiproliferative agents (e.g., mycophenolate mofetil (MMF), mycophenolate sodium, and azathioprine), has attracted more attention as a new approach to limit CNIs-specific nephrotoxicity. However, despite such therapeutic and interventional strategies that lead to a significant decline of acute rejection in the first year, posttransplant chronic rejection remains an ongoing challenge, and new treatment options with appropriate long-term cases continue to be researched and developed, with the hope of minimizing the risk of rejection and adverse outcomes.
| Conclusion|| |
Acknowledging the limitations of the study due to the size and nature of the trials included, our review shows that TAC seems to be significantly superior to CyA regarding graft loss, acute rejection, and hypercholestero-lemia, but CyA seems to be significantly superior considering diabetes. However, further large randomized trials are suggested.
Conflict of interest: None declared.
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. [Last accessed on 2017 Apr 12].
Dr. Yalda Ravanshad
Department of Community Medicine, Mashhad Medical Science Branch, Islamic Azad University, Mashhad
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2]
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