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Comparison of Sirolimus Combined With Tacrolimus and Mycophenolate Mofetil Combined With Tacrolimus in Kidney Transplantation Recipients: A Meta-Analysis
Comparison of Sirolimus Combined With Tacrolimus and Mycophenolate Mofetil Combined With Tacrolimus in Kidney Transplantation Recipients: A Meta-Analysis L. Gaoa, F. Xub, H. Chengc, and J. Liud,* a
Department of Gynecology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China; Department of Gynecology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China; cDepartment of Urology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China; and dPeople’s Hospital of Hangzhou Medical College, Hangzhou, China b
ABSTRACT Purpose. The study was designed to compare the outcomes of sirolimus (SRL) combined with tacrolimus (TAC) and mycophenolate mofetil (MMF) combined with TAC in kidney transplantation recipients. Methods. A literature search of PubMed, Embase, and Web of Science was performed to identify relevant studies, and the last update was on February 1, 2018. All studies with appropriate data comparing the SRL group with the MMF group were included. SRL and MMF were used in sufficient doses. Relevant information was recorded and analyzed. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the effects of SRL and MMF. Relevant outcomes, including delayed graft function, acute rejection, graft survival, seroma, anemia, lymphocele, and hyperlipidemia, were compared. Results. Ten studies with a total of 2357 patients (n ¼ 1256 receiving SRL vs n ¼ 1101 receiving MMF) were ultimately included. Our results indicated that the SRL group experienced a higher rate of hyperlipidemia (OR: 1.864; 95% CI, 1.494e2.325) and lymphocele (OR: 2.58; 95% CI, 1.49e4.47). However, no significant differences were detected regarding the rates of delayed graft function, acute rejection, graft survival, infectious complications, anemia, or seroma. Conclusions. This meta-analysis suggested that SRL combined with TAC and MMF combined with TAC were equally safe and effective for the kidney transplantation recipients. However, the MMF group exhibited a marginally significant advantage of lower incidence of hyperlipidemia and lymphocele.
T
HE introduction of cyclosporine (CsA) in the 1980s greatly alleviated the rates of acute rejection (AR) and subsequently improved the short-term renal allograft survival. However, the use of calcineurin inhibitors (CNIs), CsA, and tacrolimus (TAC) has been associated with both acute and chronic nephrotoxicity, which contribute to the progression of interstitial fibrosis/tubular atrophy and late graft loss in renal transplant recipients [1e3]. Recent studies have indicated that minimizing or even eliminating CNIs from a regimen containing sirolimus (SRL) and mycophenolate mofetil (MMF) may be beneficial with regard to long-term renal allograft function [4,5], as SRL fails to exert 0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.08.056
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the same effect on kidneys that CNIs do. Inhibitors of the mammalian target of rapamycin, such as SRL, everolimus, and agents such as MMF are the principal antiproliferatives used in renal transplantation. Application of these new immunosuppressive drugs has reduced the rate of AR and
The People’s Hospital of Hangzhou Medical College. *Address correspondence to Jinwei Liu, People’s Hospital of Hangzhou Medical College, No. 158 Shangtang Road, Xiacheng District, 310000 Hangzhou, China. Tel: þ86 0571 85893339; Fax: 010-84832676-808. E-mail: [email protected] ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 3306e3313 (2018)
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increased the rate of graft survival after kidney transplantation [6e8]. SRL is a bacterial metabolic complex discovered in soil samples in the 1970s that can inhibit m-TOR. It is widely used as a safe drug to prevent and treat renal transplant rejection [9,10]. MMF is an ester derivative of mycophenolic acid, harboring a unique immunosuppressive effect and greater safety [11,12]. Kidney transplantation often demands the administration of immunosuppressive agents to reduce the incidence of rejection. TAC, in combination with MMF or SRL, is an effective immunosuppressive regimen for kidney transplantation recipients [13e16]. Several comparative studies of MMF and SRL in combination with TAC have been reported; however, no definite conclusions have been reached [17e27]. In consideration of the possible superiority of MMF over SRL in combination with TAC, this meta-analysis of the available published literature was conducted to compare the outcomes of the 2 immunosuppressive agents. METHODS This study aimed to compare the effectiveness of immunosuppressive agents, namely MMF and SRL, in kidney transplantation recipients. The present meta-analysis was performed in strict accordance with Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines [28].
Search Strategy A literature search of PubMed, Embase, and Web of Science was conducted to identify studies concerning the comparison of MMF combined with TAC to SRL combined with TAC. No time restriction was applied. The search keywords were (“kidney transplantation” OR “renal transplantation”) AND (“SRL” OR “rapamycin”) AND “MMF”. Only English-language studies were included in our meta-analysis. Moreover, the related articles listed in these databases and the references of the acquired articles were searched by hand. A flow diagram illustrating the details of the study selection process is presented in Fig 1.
Fig 1. Flow chart of the study selection process. independently extracted data from enrolled studies and discrepancies were resolved by consensus.
Statistical Analysis The meta-analyses were performed using STATA13. The ORs and their corresponding 95% CIs were used to assess the effects of SRL or MMF. Statistical heterogeneity was assessed using the Q test and a L’Abbe plot. The random-effect model was used for outcomes that displayed significant heterogeneity with P values < 10%; otherwise, the fixed-effect model was used [29e31]. Publication bias was assessed using a funnel plot.
Study Selection Process The key points of the quality assessment included clear definitions of the following: 1. clear definition of the study population and country of origin, 2. clear documentation of the immunosuppressive agent as SRL or MMF, 3. the study design, and 4. the outcome assessment. The exclusion criteria were as follows: 1. Transplant patients were all children, 2. Insufficient data provided, 3. The procedure involved pancreas and kidney transplantation.
Data Extraction The outcomes of interest were MMF combined with TAC and SRL combined with TAC in kidney transplantation recipients. The following fundamental variables were extracted from each study: name of the first author, year of publication, patient’s age and sex, donor source (deceased: living) (%), donor age (years), indication for transplantation, cold ischemia time (hours), HLA mismatch, and Panel Reactive Antibody. The major outcomes of interest included the rates of: 1. Delayed graft function, 2. AR, 3. Graft survival, 4. Infectious complications, 5. Anemia, 6. Hyperlipidemia, 7. Lymphocele, and 8. Seroma. Two reviewers (LL.G and F.X)
RESULTS Literature Search
A total of 10 officially published studies were included in this meta-analysis (Fig 1). A total of 1004 studies were identified, of which 107 were repetitive and 897 were excluded due to irrelevance based on titles and abstracts. After evaluation of the remaining manuscripts, 10 studies ultimately met the inclusion criteria. Characteristics of the Included Studies
A total of 2357 consecutive patients undergoing SRL (n ¼ 1256, 53.3%) combined with TAC and MMF combined with TAC (n ¼ 1101, 46.7%) were analyzed. Demographics and the basic information of patients, including age, sex, donor sourcedeceased living (%), donor age (years), indication for transplantation, cold ischemia time (hours), and HLA mismatch are summarized in Table 1. The relevant outcomes, including delayed graft function rate, AR rate, graft survival rate,
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GAO, XU, CHENG ET AL Table 1. Characteristics of the Enrolled Studies No of patients
Age
Donor source (deceased: living) (%)
Sex (M:F)
Author
Year
SRL
MMF
SRL
MMF
SRL
MMF
Joshua J Gaetano John F Flechner et al Gallon et al Thomas Jane Oleg Edison L Aneesh
2006 2006 2003 2011 2006 2003 2009 2016 2007 2009
79 50 74 152 37 185 307 282 50 40
19 50 84 139 45 176 211 287 50 40
47 NM 44.9 47.9 46.3 45.3 46 49.2 37.4 36
50 NM 48.9 48.4 42.3 47.8 47 49.6 42.6 38
38:40 NM 42:32 109:43 22:15 123:62 183:124 186:96 31:19 33:7
11:8 NM 49:35 81:58 28:17 123:53 124:87 179:108 38:12 32:8
SRL
63 NM 68.9 60.5 27 63.2 58 81.2 24 NM
MMF
37 NM 31.1 39.5 73 36.8 42 18.8 76 NM
58 NM 59.5 64 33 64.2 49 85.4 24 NM
42 NM 40.5 36 67 35.8 51 14.6 76 NM
Cold ischemia time (hours)
HLA mismatch
SRL
MMF
SRL
MMF
14 NM NM 17.7 NM 19.1 NM NM NM NM
13 NM NM 17.4 NM 19.8 NM NM NM NM
3.8 NM NM 3.38 3.1 3.4 NM NM 3.4 NM
2.7 NM NM 3.32 3.6 3.6 NM NM 3.3 NM
Indication for transplantation No. of patients
PRA
Hypertension (%)
Diabetic nephropathy (%)
Glomerulonephritis (%)
Hereditary kidney disease
Donor age (years)
Author
Year
SRL
MMF
SRL
MMF
SRL
MMF
SRL
MMF
SRL
MMF
SRL
MMF
SRL
MMF
Joshua J Gaetano John F Flechner et al Gallon et al Thomas Jane Oleg Edison L Aneesh
2006 2006 2003 2011 2006 2003 2009 2016 2007 2009
79 50 74 152 37 185 307 282 50 40
19 50 84 139 45 176 211 287 50 40
9 NM NM NM NM 2.7 5 0.77 NM NM
3 NM NM NM NM 2.4 9 0.75 NM NM
NM NM NM 14.5 NM 28.6 11 12.1 18 NM
NM NM NM 12.2 NM 30.7 12 11.2 12 NM
NM 18 NM 17.8 NM 22.7 31 NM 2 7.5
NM 28 NM 12.2 NM 22.7 22 NM 8 5
NM NM NM 25 NM 11.9 32 20.9 14 57.5
NM NM NM 19.4 NM 15.3 36 17.1 20 50
NM NM NM 7.2 NM 9.7 14 15.2 NM NM
NM NM NM 15.1 NM 8.5 16 21.6 NM NM
39 14 41 NM 43.2 13.6 39.9 12.9 NM NM 49.9 41.6 10.0 NM
40 17 35 NM 44.4 13.9 33.2 11.4 NM NM 48.2 41.9 10.5 NM
Abbreviations: MMF, mycophenolate mofetil; NM, not mentioned; PRA, panel reactive antibodies; SRL, sirolimus.
including AR rate (OR: 1.18; 95% CI, 0.90e1.54) (Fig 2C), delayed graft function rate (OR: 1.02; 95% CI, 0.91e1.14) (Fig 2D), anemia rate (OR: 1.20; 95% CI, 0.84e1.73) (Fig 2E), graft survival rate (OR: 0.60; 95% CI, 0.36e1.02) (Fig 2F), infectious complications rate (OR: 1.16; 95% CI, 0.82e1.66) (Fig 2G) or seroma rate (OR: 1.43; 95% CI, 0.60e3.43) (Fig 2H). In addition, a funnel plot indicated no publication bias (Fig 3), and L’Abbe plots of the outcomes of SRL and MMF did not show heterogeneity among the different studies (Fig 4).
infectious complications rate, anemia rate, hyperlipidemia rate, lymphocele rate, and seroma rate are listed in Table 2. Meta-analysis Results
Firstly, meta-analysis of the 10 officially published researches were conducted, which revealed that administration of MMF group exhibited a lower incidence of hyperlipidemia (OR: 1.864; 95% CI, 1.494e2.325) (Fig 2A) and of lymphocele (OR: 2.58; 95% CI, 1.49e4.47) (Fig 2B). However, other outcomes showed no significant differences,
Table 2. Main Outcomes of the Enrolled Studies No. of patients
Delayed graft function
Acute rejection
Graft survival rate
Infectious complications
Author
Year
SRL
MMF
SRL
MMF
SRL
MMF
SRL
MMF
SRL
MMF
Joshua J Gaetano John F Flechner et al Gallon et al Thomas Jane Oleg Edison L Aneesh
2006 2006 2003 2011 2006 2003 2009 2016 2007 2009
79 50 74 152 37 185 307 282 50 40
19 50 84 139 45 176 211 287 50 40
18 NM 19 36 3 42 21 NM 21 NM
61 NM 55 116 34 143 286 NM 29 NM
17 13 6 26 NM 24 44 10 7 6
3 5 10 17 NM 20 27 12 6 8
NM 41 NM 135 NM 172 NM NM 49 NM
NM 44 NM 133 NM 168 NM NM 46 NM
NM 32 10 NM 3 NM NM 21 20 5
NM 22 0 NM 7 NM NM 20 24 11
Abbreviations: MMF, mycophenolate mofetil; NM, not mentioned; SRL, sirolimus.
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Fig 2. Forest plots of the outcomes resulting from the use of SRL and MMF. (A) The OR and 95% CI of the hyperlipidemia rate; (B) The OR and 95% CI of the lymphocele rate; (C) The OR and 95% CI of the acute rejection; (D) The OR and 95% CI of the delayed graft function rate; (E) The OR and 95% CI of the anemia rate; (F) The OR and 95% CI of the graft survival rate; (G) The OR and 95% CI of the infectious complications rate; and (H) The OR and 95% CI of the seroma rate between the two immunosuppressive agents.
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GAO, XU, CHENG ET AL
Fig 3. Funnel plots of the outcomes of the SRL and MMF groups with regard to the rates of (A) Hyperlipidemia; (B) Lymphocele; (C) Acute rejection; (D) Delayed graft function; (E) Anemia; and (F) Infectious complications.
DISCUSSION
Rapamycin is a novel anti-rejection drug of macrolide, which is the latest powerful immunosuppressive agent globally, clinically used for organ transplantation antirejection and autoimmune diseases. In terms of immunosuppressive activity, it is 10 times stronger than cyclosporine, accompanied by low toxicity. A combination of rapamycin with CsA exerts synergistic immunosuppressive effect [32e34]. Similar to SRL, MMF also has been used in kidney
transplantation recipients; it is an ester derivative of mycophenolic acid and harbors unique immunosuppressive effects and greater safety. In terms of combination with other immunosuppressive drugs, MMF could be applied with CsA and adrenal cortical hormone [12,35,36]. Several studies have concluded that these 2 immunosuppressive agents are equally safe and effective for kidney transplantation [22,24]. However, some studies have demonstrated that MMF overwhelms SRL in some aspects, such as
TACROLIMUS IN KIDNEY TRANSPLANTATION
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Fig 4. L’Abbe plots of the outcomes of the SRL and MMF groups with regard to the rates of (A) Hyperlipidemia; (B) Lymphocele; (C) Acute rejection; (D) Delayed graft function; (E) Anemia; (F) Graft survival; (G) Infectious complications; and (H) Seroma.
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graft survival, complication rates, etc. [17e21,23,25e27]. Metaanalysis is a powerful tool to provide more reliable results than a single study, especially in explaining controversial conclusions, because it provides the most comprehensive information by pooling data from similar studies. Consequently, we used meta-analysis to clarify the role of immunosuppressive agents (SRL combined with TAC or MMF combined with TAC) in kidney transplantation recipients. Our results showed no significant differences between the SRL group and the MMF group in terms of the rates of delayed graft function, AR, graft survival, infectious complications, anemia, and seroma. However, the MMF group showed slightly lower rates of diabetes, hyperlipidemia, and lymphocele compared to the SRL group. Together, these results suggest that MMF combined with TAC may be superior to SRL combined with TAC in terms of longterm outcomes. Notably, there was no statistical difference in the most important indexes, including delayed graft function, AR or graft survival between the MMF group and the SRL group. In general, there were no significant differences between the SRL group and MMF group. Hence, they were equally safe and effective for kidney transplantation recipients. To the best of our knowledge, our study is the first metaanalysis to compare the immunosuppressive agents SRL combined with TAC and MMF combined with TAC. Moreover, there were some other advantages in our metaanalysis. First of all, our study covered a large number of patients, which made our conclusion more convincing. Secondly, a funnel plot revealed that there was no publication bias in our analysis. However, several limitations of this study must be acknowledged. First, all the enrolled studies were observational randomized controlled trials and high-quality observational cohort studies with large sample size, so long-term follow-ups are needed to update our findings. Second, adjusted estimates could not be performed in our analysis due to insufficient data for the adjustment by other covariates such as age, lifestyle, etc. Hence, more sufficient data are warranted when these 2 articles are formally published. CONCLUSIONS
In summary, this meta-analysis showed that SRL combined with TAC might lead to higher rates of diabetes, hyperlipidemia, and lymphocele compared to MMF combined with TAC, while no significant differences were found in terms of the rates of delayed graft function, AR, graft survival, infectious complications, anemia, or seroma (particularly delayed graft function, AR rate, and graft survival). Hence, we can draw the conclusion that both SRL and MMF, when widely applied in clinical conditions, have similar efficacy in important aspects. Regardless, further exploration is necessary in the future. REFERENCES [1] Bennett WM. Insights into chronic cyclosporine nephrotoxicity. Int J Clin Pharmacol Ther 1996;34:515e9.
GAO, XU, CHENG ET AL [2] Pescovitz MD, Govani M. Sirolimus and mycophenolate mofetil for calcineurin-free immunosuppression in renal transplant recipients. Am J Kidney Dis 2001;38:S16e21. [3] Goldfarb DA. Review: the natural history of chronic allograft nephropathy. J Urol 2005;173:2106. [4] Groth CG, Backman L, Morales JM, Calne R, Kreis H, Lang P, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999;67:1036e42. [5] Kreis H, Cisterne JM, Land W, Wramner L, Squifflet JP, Abramowicz D, et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000;69:1252e60. [6] Mycophenolate mofetil in renal transplantation: 3-year results from the placebo-controlled trial. European Mycophenolate Mofetil Cooperative Study Group. Transplantation 1999;68:391e6. [7] Nashan B. The role of Certican (everolimus, rad) in the many pathways of chronic rejection. Transplant Proc 2001;33:3215e20. [8] Flechner SM, Goldfarb D, Modlin C, Feng J, Krishnamurthi V, Mastroianni B, et al. Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation 2002;74:1070e6. [9] Tedesco Silva H, Rosso Felipe C, Medina Pestana JO. Reviewing 15 years of experience with sirolimus. Transplant Res 2015;4:6. [10] Zhao DQ, Li SW, Sun QQ. Sirolimus-based immunosuppressive regimens in renal transplantation: a systemic review. Transplant Proc 2016;48:3e9. [11] van Gelder T, Hesselink DA. Mycophenolate revisited. Transpl Int 2015;28:508e15. [12] Wagner M, Earley AK, Webster AC, Schmid CH, Balk EM, Uhlig K. Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2015:Cd007746. [13] Albano L, Banas B, Klempnauer JL, Glyda M, Viklicky O, Kamar N. OSAKA trial: a randomized, controlled trial comparing tacrolimus QD and BD in kidney transplantation. Transplantation 2013;96:897e903. [14] Gelens MA, Christiaans MH, van Heurn EL, van den BergLoonen EP, Peutz-Kootstra CJ, van Hooff JP. High rejection rate during calcineurin inhibitor-free and early steroid withdrawal immunosuppression in renal transplantation. Transplantation 2006;82:1221e3. [15] Mendez R, Gonwa T, Yang HC, Weinstein S, Jensik S, Steinberg S. A prospective, randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 1 year. Transplantation 2005;80:303e9. [16] Vitko S, Wlodarczyk Z, Kyllonen L, Czajkowski Z, Margreiter R, Backman L, et al. Tacrolimus combined with two different dosages of sirolimus in kidney transplantation: results of a multicenter study. Am J Transplant 2006;6:531e8. [17] Augustine JJ, Chang PC, Knauss TC, Aeder MI, Bodziak KA, Schulak JA, et al. Improved renal function after conversion from tacrolimus/sirolimus to tacrolimus/mycophenolate mofetil in kidney transplant recipients. Transplantation 2006;81: 1004e9. [18] Ciancio G, Burke GW, Gaynor JJ, Ruiz P, Roth D, Kupin W, et al. A randomized long-term trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate versus cyclosporine/sirolimus in renal transplantation: three-year analysis. Transplantation 2006;81:845e52. [19] Flechner SM, Glyda M, Cockfield S, Grinyo J, Legendre C, Russ G, et al. The ORION study: comparison of two sirolimusbased regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients. Am J Transplant 2011;11:1633e44. [20] Gallon L, Perico N, Dimitrov BD, Winoto J, Remuzzi G, Leventhal J, et al. Long-term renal allograft function on a
TACROLIMUS IN KIDNEY TRANSPLANTATION tacrolimus-based, pred-free maintenance immunosuppression comparing sirolimus vs. MMF. Am J Transplant 2006;6:1617e23. [21] Gonwa T, Mendez R, Yang HC, Weinstein S, Jensik S, Steinberg S, et al. Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months. Transplantation 2003;75:1213e20. [22] Gralla J, Wiseman AC. Tacrolimus/sirolimus versus tacrolimus/mycophenolate in kidney transplantation: improved 3-year graft and patient survival in recent era. Transplantation 2009;87: 1712e9. [23] Meier-Kriesche HU, Steffen BJ, Chu AH, Loveland JJ, Gordon RD, Morris JA, et al. Sirolimus with neoral versus mycophenolate mofetil with neoral is associated with decreased renal allograft survival. Am J Transplant 2004;4:2058e66. [24] Rummo OO, Carmellini M, Rostaing L, Oberbauer R, Christiaans MH, Mousson C, et al. ADHERE: randomized controlled trial comparing renal function in de novo kidney transplant recipients receiving prolonged-release tacrolimus plus mycophenolate mofetil or sirolimus. Transpl Int 2017;30:83e95. [25] Sampaio EL, Pinheiro-Machado PG, Garcia R, Felipe CR, Park SI, Casarini DE, et al. Mycophenolate mofetil vs. sirolimus in kidney transplant recipients receiving tacrolimus-based immunosuppressive regimen. Clin Transplant 2008;22:141e9. [26] Srivastava A, Muruganandham K, Vinodh PB, Singh P, Dubey D, Kapoor R, et al. Post-renal transplant surgical complications with newer immunosuppressive drugs: mycophenolate mofetil vs. m-TOR inhibitors. Int Urol Nephrol 2010;42:279e84. [27] Valente JF, Hricik D, Weigel K, Seaman D, Knauss T, Siegel CT, et al. Comparison of sirolimus vs. mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation. Am J Transplant 2003;3:1128e34.
3313 [28] Knobloch K, Yoon U, Vogt PM. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and publication bias. J Craniomaxillofac Surg 2011;39: 91e2. [29] DerSimonian R. Meta-analysis in the design and monitoring of clinical trials. Stat Med 1996;15:1237e48. discussion 49-52. [30] Fricton J, Look JO, Wright E, Alencar FG, Chen H, Lang M, et al. Systematic review and meta-analysis of randomized controlled trials evaluating intraoral orthopedic appliances for temporomandibular disorders. J Orofac Pain 2010;24:237e54. [31] Thorlund K, Anema A, Mills E. Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals. Clin Epidemiol 2010;2: 57e66. [32] Fine NM, Kushwaha SS. Recent advances in mammalian target of rapamycin inhibitor use in heart and lung transplantation. Transplantation 2016;100:2558e68. [33] Grimbert P, Thaunat O. mTOR inhibitors and risk of chronic antibody-mediated rejection after kidney transplantation: where are we now? Transplant Int 2017;30:647e57. [34] van Gelder T, Fischer L, Shihab F, Shipkova M. Optimizing everolimus exposure when combined with calcineurin inhibitors in solid organ transplantation. Transplant Rev 2017;31:151e7. [35] Montero N, Perez-Saez MJ, Pascual J, Abramowicz D, Budde K, Dudley C, et al. Immunosuppression in the elderly renal allograft recipient: a systematic review. Transplant Rev 2016;30: 144e53. [36] Zhang D, Chow DS. Clinical pharmacokinetics of mycophenolic acid in hematopoietic stem cell transplantation recipients. Eur J Drug Metab Pharmacokinet 2017;42:183e9.
Department of Gynecology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China; Department of Gynecology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China; cDepartment of Urology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China; and dPeople’s Hospital of Hangzhou Medical College, Hangzhou, China b
ABSTRACT Purpose. The study was designed to compare the outcomes of sirolimus (SRL) combined with tacrolimus (TAC) and mycophenolate mofetil (MMF) combined with TAC in kidney transplantation recipients. Methods. A literature search of PubMed, Embase, and Web of Science was performed to identify relevant studies, and the last update was on February 1, 2018. All studies with appropriate data comparing the SRL group with the MMF group were included. SRL and MMF were used in sufficient doses. Relevant information was recorded and analyzed. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the effects of SRL and MMF. Relevant outcomes, including delayed graft function, acute rejection, graft survival, seroma, anemia, lymphocele, and hyperlipidemia, were compared. Results. Ten studies with a total of 2357 patients (n ¼ 1256 receiving SRL vs n ¼ 1101 receiving MMF) were ultimately included. Our results indicated that the SRL group experienced a higher rate of hyperlipidemia (OR: 1.864; 95% CI, 1.494e2.325) and lymphocele (OR: 2.58; 95% CI, 1.49e4.47). However, no significant differences were detected regarding the rates of delayed graft function, acute rejection, graft survival, infectious complications, anemia, or seroma. Conclusions. This meta-analysis suggested that SRL combined with TAC and MMF combined with TAC were equally safe and effective for the kidney transplantation recipients. However, the MMF group exhibited a marginally significant advantage of lower incidence of hyperlipidemia and lymphocele.
T
HE introduction of cyclosporine (CsA) in the 1980s greatly alleviated the rates of acute rejection (AR) and subsequently improved the short-term renal allograft survival. However, the use of calcineurin inhibitors (CNIs), CsA, and tacrolimus (TAC) has been associated with both acute and chronic nephrotoxicity, which contribute to the progression of interstitial fibrosis/tubular atrophy and late graft loss in renal transplant recipients [1e3]. Recent studies have indicated that minimizing or even eliminating CNIs from a regimen containing sirolimus (SRL) and mycophenolate mofetil (MMF) may be beneficial with regard to long-term renal allograft function [4,5], as SRL fails to exert 0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.08.056
3306
the same effect on kidneys that CNIs do. Inhibitors of the mammalian target of rapamycin, such as SRL, everolimus, and agents such as MMF are the principal antiproliferatives used in renal transplantation. Application of these new immunosuppressive drugs has reduced the rate of AR and
The People’s Hospital of Hangzhou Medical College. *Address correspondence to Jinwei Liu, People’s Hospital of Hangzhou Medical College, No. 158 Shangtang Road, Xiacheng District, 310000 Hangzhou, China. Tel: þ86 0571 85893339; Fax: 010-84832676-808. E-mail: [email protected] ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 3306e3313 (2018)
TACROLIMUS IN KIDNEY TRANSPLANTATION
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increased the rate of graft survival after kidney transplantation [6e8]. SRL is a bacterial metabolic complex discovered in soil samples in the 1970s that can inhibit m-TOR. It is widely used as a safe drug to prevent and treat renal transplant rejection [9,10]. MMF is an ester derivative of mycophenolic acid, harboring a unique immunosuppressive effect and greater safety [11,12]. Kidney transplantation often demands the administration of immunosuppressive agents to reduce the incidence of rejection. TAC, in combination with MMF or SRL, is an effective immunosuppressive regimen for kidney transplantation recipients [13e16]. Several comparative studies of MMF and SRL in combination with TAC have been reported; however, no definite conclusions have been reached [17e27]. In consideration of the possible superiority of MMF over SRL in combination with TAC, this meta-analysis of the available published literature was conducted to compare the outcomes of the 2 immunosuppressive agents. METHODS This study aimed to compare the effectiveness of immunosuppressive agents, namely MMF and SRL, in kidney transplantation recipients. The present meta-analysis was performed in strict accordance with Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines [28].
Search Strategy A literature search of PubMed, Embase, and Web of Science was conducted to identify studies concerning the comparison of MMF combined with TAC to SRL combined with TAC. No time restriction was applied. The search keywords were (“kidney transplantation” OR “renal transplantation”) AND (“SRL” OR “rapamycin”) AND “MMF”. Only English-language studies were included in our meta-analysis. Moreover, the related articles listed in these databases and the references of the acquired articles were searched by hand. A flow diagram illustrating the details of the study selection process is presented in Fig 1.
Fig 1. Flow chart of the study selection process. independently extracted data from enrolled studies and discrepancies were resolved by consensus.
Statistical Analysis The meta-analyses were performed using STATA13. The ORs and their corresponding 95% CIs were used to assess the effects of SRL or MMF. Statistical heterogeneity was assessed using the Q test and a L’Abbe plot. The random-effect model was used for outcomes that displayed significant heterogeneity with P values < 10%; otherwise, the fixed-effect model was used [29e31]. Publication bias was assessed using a funnel plot.
Study Selection Process The key points of the quality assessment included clear definitions of the following: 1. clear definition of the study population and country of origin, 2. clear documentation of the immunosuppressive agent as SRL or MMF, 3. the study design, and 4. the outcome assessment. The exclusion criteria were as follows: 1. Transplant patients were all children, 2. Insufficient data provided, 3. The procedure involved pancreas and kidney transplantation.
Data Extraction The outcomes of interest were MMF combined with TAC and SRL combined with TAC in kidney transplantation recipients. The following fundamental variables were extracted from each study: name of the first author, year of publication, patient’s age and sex, donor source (deceased: living) (%), donor age (years), indication for transplantation, cold ischemia time (hours), HLA mismatch, and Panel Reactive Antibody. The major outcomes of interest included the rates of: 1. Delayed graft function, 2. AR, 3. Graft survival, 4. Infectious complications, 5. Anemia, 6. Hyperlipidemia, 7. Lymphocele, and 8. Seroma. Two reviewers (LL.G and F.X)
RESULTS Literature Search
A total of 10 officially published studies were included in this meta-analysis (Fig 1). A total of 1004 studies were identified, of which 107 were repetitive and 897 were excluded due to irrelevance based on titles and abstracts. After evaluation of the remaining manuscripts, 10 studies ultimately met the inclusion criteria. Characteristics of the Included Studies
A total of 2357 consecutive patients undergoing SRL (n ¼ 1256, 53.3%) combined with TAC and MMF combined with TAC (n ¼ 1101, 46.7%) were analyzed. Demographics and the basic information of patients, including age, sex, donor sourcedeceased living (%), donor age (years), indication for transplantation, cold ischemia time (hours), and HLA mismatch are summarized in Table 1. The relevant outcomes, including delayed graft function rate, AR rate, graft survival rate,
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GAO, XU, CHENG ET AL Table 1. Characteristics of the Enrolled Studies No of patients
Age
Donor source (deceased: living) (%)
Sex (M:F)
Author
Year
SRL
MMF
SRL
MMF
SRL
MMF
Joshua J Gaetano John F Flechner et al Gallon et al Thomas Jane Oleg Edison L Aneesh
2006 2006 2003 2011 2006 2003 2009 2016 2007 2009
79 50 74 152 37 185 307 282 50 40
19 50 84 139 45 176 211 287 50 40
47 NM 44.9 47.9 46.3 45.3 46 49.2 37.4 36
50 NM 48.9 48.4 42.3 47.8 47 49.6 42.6 38
38:40 NM 42:32 109:43 22:15 123:62 183:124 186:96 31:19 33:7
11:8 NM 49:35 81:58 28:17 123:53 124:87 179:108 38:12 32:8
SRL
63 NM 68.9 60.5 27 63.2 58 81.2 24 NM
MMF
37 NM 31.1 39.5 73 36.8 42 18.8 76 NM
58 NM 59.5 64 33 64.2 49 85.4 24 NM
42 NM 40.5 36 67 35.8 51 14.6 76 NM
Cold ischemia time (hours)
HLA mismatch
SRL
MMF
SRL
MMF
14 NM NM 17.7 NM 19.1 NM NM NM NM
13 NM NM 17.4 NM 19.8 NM NM NM NM
3.8 NM NM 3.38 3.1 3.4 NM NM 3.4 NM
2.7 NM NM 3.32 3.6 3.6 NM NM 3.3 NM
Indication for transplantation No. of patients
PRA
Hypertension (%)
Diabetic nephropathy (%)
Glomerulonephritis (%)
Hereditary kidney disease
Donor age (years)
Author
Year
SRL
MMF
SRL
MMF
SRL
MMF
SRL
MMF
SRL
MMF
SRL
MMF
SRL
MMF
Joshua J Gaetano John F Flechner et al Gallon et al Thomas Jane Oleg Edison L Aneesh
2006 2006 2003 2011 2006 2003 2009 2016 2007 2009
79 50 74 152 37 185 307 282 50 40
19 50 84 139 45 176 211 287 50 40
9 NM NM NM NM 2.7 5 0.77 NM NM
3 NM NM NM NM 2.4 9 0.75 NM NM
NM NM NM 14.5 NM 28.6 11 12.1 18 NM
NM NM NM 12.2 NM 30.7 12 11.2 12 NM
NM 18 NM 17.8 NM 22.7 31 NM 2 7.5
NM 28 NM 12.2 NM 22.7 22 NM 8 5
NM NM NM 25 NM 11.9 32 20.9 14 57.5
NM NM NM 19.4 NM 15.3 36 17.1 20 50
NM NM NM 7.2 NM 9.7 14 15.2 NM NM
NM NM NM 15.1 NM 8.5 16 21.6 NM NM
39 14 41 NM 43.2 13.6 39.9 12.9 NM NM 49.9 41.6 10.0 NM
40 17 35 NM 44.4 13.9 33.2 11.4 NM NM 48.2 41.9 10.5 NM
Abbreviations: MMF, mycophenolate mofetil; NM, not mentioned; PRA, panel reactive antibodies; SRL, sirolimus.
including AR rate (OR: 1.18; 95% CI, 0.90e1.54) (Fig 2C), delayed graft function rate (OR: 1.02; 95% CI, 0.91e1.14) (Fig 2D), anemia rate (OR: 1.20; 95% CI, 0.84e1.73) (Fig 2E), graft survival rate (OR: 0.60; 95% CI, 0.36e1.02) (Fig 2F), infectious complications rate (OR: 1.16; 95% CI, 0.82e1.66) (Fig 2G) or seroma rate (OR: 1.43; 95% CI, 0.60e3.43) (Fig 2H). In addition, a funnel plot indicated no publication bias (Fig 3), and L’Abbe plots of the outcomes of SRL and MMF did not show heterogeneity among the different studies (Fig 4).
infectious complications rate, anemia rate, hyperlipidemia rate, lymphocele rate, and seroma rate are listed in Table 2. Meta-analysis Results
Firstly, meta-analysis of the 10 officially published researches were conducted, which revealed that administration of MMF group exhibited a lower incidence of hyperlipidemia (OR: 1.864; 95% CI, 1.494e2.325) (Fig 2A) and of lymphocele (OR: 2.58; 95% CI, 1.49e4.47) (Fig 2B). However, other outcomes showed no significant differences,
Table 2. Main Outcomes of the Enrolled Studies No. of patients
Delayed graft function
Acute rejection
Graft survival rate
Infectious complications
Author
Year
SRL
MMF
SRL
MMF
SRL
MMF
SRL
MMF
SRL
MMF
Joshua J Gaetano John F Flechner et al Gallon et al Thomas Jane Oleg Edison L Aneesh
2006 2006 2003 2011 2006 2003 2009 2016 2007 2009
79 50 74 152 37 185 307 282 50 40
19 50 84 139 45 176 211 287 50 40
18 NM 19 36 3 42 21 NM 21 NM
61 NM 55 116 34 143 286 NM 29 NM
17 13 6 26 NM 24 44 10 7 6
3 5 10 17 NM 20 27 12 6 8
NM 41 NM 135 NM 172 NM NM 49 NM
NM 44 NM 133 NM 168 NM NM 46 NM
NM 32 10 NM 3 NM NM 21 20 5
NM 22 0 NM 7 NM NM 20 24 11
Abbreviations: MMF, mycophenolate mofetil; NM, not mentioned; SRL, sirolimus.
TACROLIMUS IN KIDNEY TRANSPLANTATION
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Fig 2. Forest plots of the outcomes resulting from the use of SRL and MMF. (A) The OR and 95% CI of the hyperlipidemia rate; (B) The OR and 95% CI of the lymphocele rate; (C) The OR and 95% CI of the acute rejection; (D) The OR and 95% CI of the delayed graft function rate; (E) The OR and 95% CI of the anemia rate; (F) The OR and 95% CI of the graft survival rate; (G) The OR and 95% CI of the infectious complications rate; and (H) The OR and 95% CI of the seroma rate between the two immunosuppressive agents.
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GAO, XU, CHENG ET AL
Fig 3. Funnel plots of the outcomes of the SRL and MMF groups with regard to the rates of (A) Hyperlipidemia; (B) Lymphocele; (C) Acute rejection; (D) Delayed graft function; (E) Anemia; and (F) Infectious complications.
DISCUSSION
Rapamycin is a novel anti-rejection drug of macrolide, which is the latest powerful immunosuppressive agent globally, clinically used for organ transplantation antirejection and autoimmune diseases. In terms of immunosuppressive activity, it is 10 times stronger than cyclosporine, accompanied by low toxicity. A combination of rapamycin with CsA exerts synergistic immunosuppressive effect [32e34]. Similar to SRL, MMF also has been used in kidney
transplantation recipients; it is an ester derivative of mycophenolic acid and harbors unique immunosuppressive effects and greater safety. In terms of combination with other immunosuppressive drugs, MMF could be applied with CsA and adrenal cortical hormone [12,35,36]. Several studies have concluded that these 2 immunosuppressive agents are equally safe and effective for kidney transplantation [22,24]. However, some studies have demonstrated that MMF overwhelms SRL in some aspects, such as
TACROLIMUS IN KIDNEY TRANSPLANTATION
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Fig 4. L’Abbe plots of the outcomes of the SRL and MMF groups with regard to the rates of (A) Hyperlipidemia; (B) Lymphocele; (C) Acute rejection; (D) Delayed graft function; (E) Anemia; (F) Graft survival; (G) Infectious complications; and (H) Seroma.
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graft survival, complication rates, etc. [17e21,23,25e27]. Metaanalysis is a powerful tool to provide more reliable results than a single study, especially in explaining controversial conclusions, because it provides the most comprehensive information by pooling data from similar studies. Consequently, we used meta-analysis to clarify the role of immunosuppressive agents (SRL combined with TAC or MMF combined with TAC) in kidney transplantation recipients. Our results showed no significant differences between the SRL group and the MMF group in terms of the rates of delayed graft function, AR, graft survival, infectious complications, anemia, and seroma. However, the MMF group showed slightly lower rates of diabetes, hyperlipidemia, and lymphocele compared to the SRL group. Together, these results suggest that MMF combined with TAC may be superior to SRL combined with TAC in terms of longterm outcomes. Notably, there was no statistical difference in the most important indexes, including delayed graft function, AR or graft survival between the MMF group and the SRL group. In general, there were no significant differences between the SRL group and MMF group. Hence, they were equally safe and effective for kidney transplantation recipients. To the best of our knowledge, our study is the first metaanalysis to compare the immunosuppressive agents SRL combined with TAC and MMF combined with TAC. Moreover, there were some other advantages in our metaanalysis. First of all, our study covered a large number of patients, which made our conclusion more convincing. Secondly, a funnel plot revealed that there was no publication bias in our analysis. However, several limitations of this study must be acknowledged. First, all the enrolled studies were observational randomized controlled trials and high-quality observational cohort studies with large sample size, so long-term follow-ups are needed to update our findings. Second, adjusted estimates could not be performed in our analysis due to insufficient data for the adjustment by other covariates such as age, lifestyle, etc. Hence, more sufficient data are warranted when these 2 articles are formally published. CONCLUSIONS
In summary, this meta-analysis showed that SRL combined with TAC might lead to higher rates of diabetes, hyperlipidemia, and lymphocele compared to MMF combined with TAC, while no significant differences were found in terms of the rates of delayed graft function, AR, graft survival, infectious complications, anemia, or seroma (particularly delayed graft function, AR rate, and graft survival). Hence, we can draw the conclusion that both SRL and MMF, when widely applied in clinical conditions, have similar efficacy in important aspects. Regardless, further exploration is necessary in the future. REFERENCES [1] Bennett WM. Insights into chronic cyclosporine nephrotoxicity. Int J Clin Pharmacol Ther 1996;34:515e9.
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