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Saudi Journal of Kidney Diseases and Transplantation
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SHORT REVIEW ARTICLE  
Year : 2018  |  Volume : 29  |  Issue : 6  |  Page : 1376-1385
Comparison of tacrolimus and cyclosporine for immunosuppression after renal transplantation: An updated systematic review and meta-analysis


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 Submission28-Sep-2017
Date of Decision02-Jan-2018
Date of Acceptance02-Jan-2018
Date of Web Publication27-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 Mar 18];29:1376-85. Available from: http://www.sjkdt.org/text.asp?2018/29/6/1376/248292

   Introduction Top


Kidney transplantation is the treatment of choice for most patients with end-stage renal disease (ESRD), which is also called chronic renal failure.[1] For patients with ESRD, renal transplantation can improve survival and quality of life, and cause cost reduction in health-care.[2] At present, the reported one-year patient and graft survival rates are 94% and 82%, respectively.[3] 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.[3] CyA was discovered in 1971, and in 1983, this drug was approved for prevention of organ transplant rejection.[4] 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.[4]

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,[4] and the evidence on its efficacy and safety is incon-clusive.[2] Therefore, the aim of this study was to compare the efficacy of TAC and CyA for immunosuppressive therapy after renal transplantation.


   Subjects and Methods Top


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 Top


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)].[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25] The flow diagram of study selection is given in [Figure 1]. Characteristics and the details of the studies are summarized in [Table 1].
Figure 1: Flowchart of study selection process.

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Table 1: General characteristics of trials included in this systematic review.

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Outcome

The summary of outcomes of this study, comparing the two groups, TAC and CyA are provided in [Table 2].
Table 2: Outcome of trials.

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Quantitative synthesis

Mortality

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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Graft loss

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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Acute rejection

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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Diabetes

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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Infection

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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Hypertension

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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Hypercholesterolemia

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 Top


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).[4]

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.[3] 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.[2] They concluded that all the generic immunosuppressive drugs did not have equivalent relative bio-availability, and it depended on their brands.[2] We did not investigate this issue in our study.

A meta-analysis[4] 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.[4]

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.[24] 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.[26] 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 Top


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.

 
   References Top

1.
Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: Meta-analysis and meta-regression of randomised trial data. BMJ 2005;331:810.  Back to cited text no. 1
    
2.
Tsipotis E, Gupta NR, Raman G, Zintzaras E, Jaber BL. Bioavailability, efficacy and safety of generic immunosuppressive drugs for kidney transplantation: A systematic review and meta-analysis. Am J Nephrol 2016;44:206-18.  Back to cited text no. 2
    
3.
Liu JY, You RX, Guo M, et al. Tacrolimus versus cyclosporine as primary immunosup-pressant after renal transplantation: A meta-analysis and economics evaluation. Am J Ther 2016;23:e810-24.  Back to cited text no. 3
    
4.
Penninga L, Møller CH, Gustafsson F, Steinbrüchel DA, Gluud C. Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: Systematic review with meta-analyses and trial sequential analyses of randomised trials. Eur J Clin Pharmacol 2010;66:1177-87.  Back to cited text no. 4
    
5.
Shapiro R, Jordan M, Scantlebury V, et al. FK 506 in clinical kidney transplantation. Transplant Proc 1991;23:3065-7.  Back to cited text no. 5
    
6.
Mayer AD, Dmitrewski J, Squifflet JP, et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: A report of the European Tacrolimus Multicenter Renal Study Group. Transplantation 1997;64:436-43.  Back to cited text no. 6
    
7.
Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 kidney transplant study group. Transplantation 1997; 63:977-83.  Back to cited text no. 7
    
8.
Morris-Stiff G, Ostrowski K, Balaji V, et al. Prospective randomised study comparing tacrolimus (Prograf) and cyclosporin (Neoral) as primary immunosuppression in cadaveric renal transplants at a single institution: Interim report of the first 80 cases. Transpl Int 1998;11 Suppl 1 :S334-6.  Back to cited text no. 8
    
9.
Radermacher J, Meiners M, Bramlage C, et al. Pronounced renal vasoconstriction and systemic hypertension in renal transplant patients treated with cyclosporin A versus FK 506. Transpl Int 1998;11:3-10.  Back to cited text no. 9
    
10.
Raofi V, Holman DM, Coady N, et al. A prospective randomized trial comparing the efficacy of tacrolimus versus cyclosporine in black recipients of primary cadaveric renal transplants. Am J Surg 1999;177:299-302.  Back to cited text no. 10
    
11.
Yang HC, Holman MJ, Langhoff E, et al. Tacrolimus/”low-dose” mycophenolate mofetil versus microemulsion cyclosporine/”low-dose” mycophenolate mofetil after kidney transplantation –1-year follow-up of a prospective, randomized clinical trial. Transplant Proc 1999;31:1121-4.  Back to cited text no. 11
    
12.
Wang XH, Tang XD, Xu D. Tacrolimus vs. cyA neoral in combination with MMF and steroids after cadaveric renal transplantation. Transplant Proc 2000;32:1702-3.  Back to cited text no. 12
    
13.
White SA, Jain S, Williams ST, et al. Randomized trial comparing neoral and tacrolimus immunousuppression for recipients of renal transplants procured from different donor groups. Transplant Proc 2000;32:600.  Back to cited text no. 13
    
14.
Ahsan N, Johnson C, Gonwa T, et al. Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclo-sporine oral solution (modified) plus mycophenolate mofetil after cadaveric kidney transplantation: Results at 2 years. Transplantation 2001;72:245-50.  Back to cited text no. 14
    
15.
Campos HH, Abbud Filho M; Brazilian Tacrolimus Study Group. One-year follow-up of a Brazilian randomized multicenter study comparing tacrolimus versus cyclosporine in kidney transplantation. Transplant Proc 2002; 34:1656-8.  Back to cited text no. 15
    
16.
Charpentier B; European Tacrolimus vs. Microemulsified Cyclosporin Study Group. A three arm study comparing immediate tacrolimus therapy with ATG induction therapy followed by either tacrolimus or cyclosporine in adult renal transplant recipients. Transplant Proc 2002;34:1625-6.  Back to cited text no. 16
    
17.
Margreiter R; European Tacrolimus vs. Ciclosporin Microemulsion Renal Transplantation Study Group. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: A randomised multicentre study. Lancet 2002;359: 741-6.  Back to cited text no. 17
    
18.
Trompeter R, Filler G, Webb NJ, et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol 2002;17:141-9.  Back to cited text no. 18
    
19.
Jarzembowski T, Panaro F, Raofi V, et al. Long-term results of a prospective randomized trial comparing tacrolimus versus cyclosporine in African-American recipients of primary cadaver renal transplant. Transpl Int 2005;18: 419-22.  Back to cited text no. 19
    
20.
Cheung CY, Wong KM, Chan HW, et al. Paired kidney analysis of tacrolimus and cyclosporine microemulsion-based therapy in Chinese cadaveric renal transplant recipients. Transpl Int 2006;19:657-66.  Back to cited text no. 20
    
21.
Krämer BK, Del Castillo D, Margreiter R, et al. Efficacy and safety of tacrolimus compared with ciclosporin A in renal transplantation: Three-year observational results. Nephrol Dial Transplant 2008;23:2386-92.  Back to cited text no. 21
    
22.
Cheung CY, Chan HW, Liu YL, Chau KF, Li CS. Long-term graft function with tacrolimus and cyclosporine in renal transplantation: Paired kidney analysis. Nephrology (Carlton) 2009;14:758-63.  Back to cited text no. 22
    
23.
Lee YJ, Kim B, Lee JE, al. Randomized trial of cyclosporine and tacrolimus therapy with steroid withdrawal in living-donor renal transplantation: 5-year follow-up. Transpl Int 2010;23:147-54.  Back to cited text no. 23
    
24.
Liu LS, Li J, Chen XT, et al. Comparison of tacrolimus and cyclosporin A in CYP3A5 expressing Chinese de novo kidney transplant recipients: A 2-year prospective study. Int J Clin Pract Suppl 2015;183:43-52.  Back to cited text no. 24
    
25.
Krämer BK, Montagnino G, Krüger B, et al. Efficacy and safety of tacrolimus compared with ciclosporin – A in renal transplantation: 7-year observational results. Transpl Int 2016; 29:307-14.  Back to cited text no. 25
    
26.
Hardinger K, Brennan DC. Maintenance immunosuppressive therapy in renal transplantation in adults. UpToDate. Waltham, MA: UpToDate Inc.; 2017. Available from: http://www.uptodate.com. [Last accessed on 2017 Apr 12].  Back to cited text no. 26
    

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Correspondence Address:
Dr. Yalda Ravanshad
Department of Community Medicine, Mashhad Medical Science Branch, Islamic Azad University, Mashhad
Iran
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DOI: 10.4103/1319-2442.248292

PMID: 30588970

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
 
 
    Tables

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