Effect of mycophenolate mofetil on blood pressure: a meta-analysis

Background: Long-term treatment of immunosuppressive agent have been proved to induce hypertension. The relative efficacy of mycophenolate mofetil (MMF) on blood pressure (BP) is not well known. Identifying the performance of this drug will help to reduce the incidence of the adverse reactions. Methods: We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library for relevant studies published up to December, 2017. We compared blood pressure levels before and after the MMF treatment including systolic blood pressure and diastolic blood pressure. We used the Newcastle Ottawa scale for the assessment of the quality of studies. Analysis was performed using the statistical software Review Manager Version 5.0 and STATA 14.0. Result: We retrieved 6 studies with 208 patients. The data extracted were systolic BP (SBP) and diastolic BP (DBP). Study quality was assessed using the method of Jadad, and data were synthesized using a random-effects model and weight mean difference. MMF caused a small reduce in DBP (0.79mmHg, 95% CI, 0.03 to 1.55, P=0.043), with no obvious effect on SBP (0.12mmHg, 95%CI -0.41 to 0.64). In meta-regression, country (china vs. other country), duration of follow-up, percentage of men, and mean age of study participants were proved to be not the contributing factors. Conclusion: The MMF treatment can slightly reduce DBP, but not affect the SBP, which indicated the cardiovascular safety of this immunosuppressive agent.

3 response [1]. It is proved to be efficient for inflammatory conditions such as IgA nephropathy or systemic lupus erthematodes [1]. It is also recognized as an anti-rejection drug, which is wildly used in preventing solid organ rejection and in vascularized composite allotransplantation.
MMF has become the most common used calcineurin inhibitor after kidney transplantation in the many countries. Many studies have revealed that this long-term treatment of immunosuppressive agent could induce hypertension, therefore increase the risk of cardiovascular diseases [2]. There were many reasons for immunosuppressive agent induced hypertension, including direct cytotoxic effects induced endothelial impairment and dysfunction, and direct contractile effects on vascular smooth muscle cells [3][4][5]. The clinical trials with most centres also proved that, immunosuppressive agent decreases in effective blood pressure control and subsequent increases in antihypertensive treatments in patients on immunosuppressive regimens. However, the relationship between MMF and blood pressure is not well studied. Therefore, we preformed this meta-analysis to clarify this question.

Methods
Standard of systematic reviews.
This study is designed and performed according to the "Transparent reporting of systematic reviews and meta-analyses" (PRISMA) guidelines.
Systematic search and study selection.
The systematic literature searches of PubMed, Embase, and Cochrane Library database was conducted from inception to December, 2017 with no language restrictions. We use the following search strategy: (mycophenolate mofetil or mycophenolate sodium or mycophenolic acid or cellcept or myfortic or MMF) AND (hypertension or hypertensive or blood pressure or high blood pressure). All searched articles were carefully examined for 4 additional article to avoid search missing. Articles identified as randomized controlled trials will be read throughout to further screen.
Data extraction and quality assessment.
Two reviewer (Guilan Cao and Qianqian Fan) extracted data from included trials independently. Disagreements were resolved by a third reviewer (Xiaoguang Li). The following data were extracted: first author's names, years of publication, country, study population, sample size, mean age, year, patient male%, patient BMI and follow-up.
Methodological quality of included studies was assessed by the Newcastle-Ottawa Scale (NOS).

Statistical analysis.
The information including study year, country, treatment characteristics (dose, duration, type of formulation), gender ratio, number of participants enrolled, follower-up and outcomes were collected. Besides, the level of SBP and DBP pretherapy and posttreatment were also abstracted. Differences of SBP between before and after MMF treatment were calculated as: SBP Δ = SBP post-treatm ent -SBP pre-treatm ent ; Differences of DBP between before and after MMF treatment were calculated as: DBP Δ = DBP post-treatm ent -DBP pre-treatm ent ; Standard deviations (SDs) of SBP Δ and DBP Δ were calculated using the following formula: SD = square root [(SD pre-treatm ent )²+(SD post-treatm ent )²-(2R×SD pretreatm ent ×SD post-treatm en ), assuming a correlation coefficient (R SBP = 0.399,R DBP = 0.337).
If SD was not showed directly, SD was estimated using the following formula: SD = SEM×sqrt(n). Heterogeneity among the included studies was assessed by Cochran's Q statisticc and by calculating the heterogeneity (I 2 ). Using reported cut-off values (>50% mild, 51% to 75% moderate, and >75% significant), the random-effects model is used when significant heterogeneity was obtained on analysis.

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The effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). The sensitivity analysis was performed by leave-one-out method to assess the influence of each study on the overall effect size.
Statistical software.
All analyses were conducted using Review Manager 5.3 (Cochrane Editorial Unit, London, UK) software or STATA 14.0 (Stata Corporation, College Station, TX, USA) software.

Study Selection
Based on an initial search with the review of articles and abstracts, a total of 1702 studies were enrolled. After selection of potentially relevant articles, articles were evaluated in detail. Of these studies, only 25 were clinical trials to evaluate the effect of MMF.

Study Characteristics
The characteristics of the included studies were presented in Table S1. Our meta-analysis finally identified 6 articles that included a total of 208 patients from 4 different countries (USA, Belgium, Spain, and China). Mean patient age was 48 years old, and 60% of patients were men.

Quality Evaluation
All selected studies were assessed quality evaluation according to the NOS. The minimum score of them was eight, while the maximum was nine. For selection, all the studies could obtain four stars (100%). In relation to comparability, two stars were also awarded for all studies (100%). For exhibition, more than half of the studies (65.0%) got more than two stars. All the studies got more than 7 stars, showing high scientific quality (Table S2) (Table S3 and Table S4).

Discussion
In the present meta-analysis, we included available data on the relationship between blood pressure and MMF treatment. As we know, there are lots of researches have studied the possible benefits of MMF therapy in cardiovascular risks [2], the effect of MMF treatment on blood pressure still unclear. This review demonstrates that MMF cause slightly decrease in DBP, with no significant effects on SBP. As far as we know, this study is the first systematic review and meta-analysis about the effect of MMF on blood pressure. The present review suggested that MMF therapy could help to slightly reduce DBP and not affect the SBP.

Immunosuppressive agent in cardiovascular risks
More than half of patients who received solid organ transplantation may develop hypertension [2]. Hypertension should be taken seriously, because it is a risk factor for decreased allograft survival, cardiovascular disease and stroke [12,13] This study had several limitations. First, the enrolled subjects of all studies was 208 participants, which may be too few to detect complications of hypertension and other cardiac events, we only evaluated the effect of MMF on BP. Second, not all the author offered the initial blood pressure before and after the MMF treatment, our results should consider these problems. Furthermore, the conclusion of our study on the effect of MMF therapy on blood pressure is not very powerful, due to the limited enrolled RCT trails, more high-quality RCTs with larger sample sizes were needed. In spite of this, we are sure 8 that we study is meaningful to side effects of MMF treatment.
Conclusions this meta-analysis suggests that MMF treatment could only slightly reduce DBP and not affect the SBP. We believed that these could provide some evidence for the effect of MMF therapy on blood pressure. The MMF treatment not increases the risk of hypertension,

Declarations
Ethics approval and consent to participate Not applicable.

Consent for publication
Not applicable.

Availability of data and materials
All data generated or analysed during this study are included in this published article.

Competing interests
The authors declare that they have no competing interests.  15 Effect of MMF on systolic blood pressure (SBP). Data are given as mean (95% confidence interval CI).

Figure 4
Funnel plot for studies of systolic blood pressure.
16 Figure 5 Funnel plot for studies of diastolic blood pressure.

Supplementary Files
This is a list of supplementary files associated with the primary manuscript. Click to download. Tables.docx