Meta-analysis of Bailing Capsule After Renal Transplantation

Keliang Chen The Forth A liated Hospital Zhejiang University School of Medicine Zuohua Yu Fujian University of Traditional Chinese Medicine Guangyi Huang The Forth A liated Hospital Zhejiang University School of Medicine Dongye Liu The Forth A liated Hospital Zhejiang University School of Medicine Zhongpan Zhang The Forth A liated Hospital Zhejiang University School of Medicine Kai Qi The Forth A liated Hospital Zhejiang University School of Medicine Hao Zhou (  haozhou@zju.edu.cn ) First A liated Hospital of Nanjing Medical University

with the control group, Bailing Capsule treatment group has obvious advantages in Improvement of liver and kidney function after renal transplantation1,but did not show good clinical results in reducing the incidence of acute rejection.

Background
With the increasing number of kidney transplantation patients, how to prevent and treat the complications after kidney transplantation better and improve the postoperative life quality of patients have drawn highly attention in the field of kidney transplantation. As the commonly clinical used alternative to natural cordyceps sinensis, Bailing capsule has the function of tonifying kidney and strengthening essence. [1] While after kidney transplantation, the etiology and pathogenesis of various complications mainly attribute to the deficiency of kidney, so the clinical usually used the adjuvant therapy. In the meantime, studies have found that the capsule could decrease the occurrence of transplanted renal rejection and improve the function of liver and kidney in the application after renal transplantation [2]. This article collected the clinical study of bailing capsule applied in post-renal transplantation, and used the data for meta-analysis, in order to promote the treatment of bailing capsule transforming from empirical medicine to evidence-based medicine after kidney transplantation. In addition, it could provide the theoretical basis for the application of bailing capsule after kidney transplantation.

Literature search
China journal full-text database (CNKI), Chinese science and technology journal full-text database, wanfang database, PubMed, EMBase, Cochrane were comprehensively searched until January, 2019. "Bailing Capsule", "Bailing Jiaonang", "Corbrin Capsule", "CS-C-Q80", "Kidney transplant", "Renal transplant" were for the search term. Relevant clinical literature was screened out for research. At the same time, in order to prevent the occurrence of missed detection, we additional check the corresponding article references.

Research type
Bailing capsule was used for clinical study after kidney transplantation.

Research object
This study was performed on the basis of routine western medicine group added in plus bailing capsule after renal transplantation. The dose of bailing capsule was not limited, and the patient's race, nationality, age and gender were not limited.
The number of samples in the literature was sufficient, and the comparison of indicators between groups had statistical significance

exclusion criteria
Experimental research, data and related information were similar or studies with insufficient data for pooling were excluded. Combined application of 2 or more traditional Chinese medicines.

Data extraction and quality assessment
Two investigators extracted data from all potentially relevant studies independently. The following characteristics were recorded: first author's name, year of publication, ethnicity and number of included patients, number of male and female patients, divided into groups, results of efficacy and safety. Missing data were also examined by contacting the first or corresponding author. Conflicting evaluations were resolved by discussion.

Methods quality assessment
The quality of the included literature was evaluated with indicators including random sequence generation, allocation hiding, implementation and double blindness of participants, blindness in result evaluation, integrity of result data, selective reporting, and other biases. And the index data were graded (high risk, low risk, unclear).

Statistical analysis
The latest RevMan5.3 software provided by the Cochrane collaboration was used for meta-analysis.
The pooled data were used to assess efficacy and safety by the standard mean difference (SMD) with 95% confidence intervals (95%CIs). P < 0.05 was considered statistically significant. Heterogeneity among trials was determined by I2, which was defined as 100% × (Q − df)/Q, where Q is Cochran's heterogeneity statistic and df is the degrees of freedom, using a fixed-effect model set at low statistical inconsistency (I2 < 50%); otherwise, we used a random-effects model, which is better adapted to clinical and statistical variations.
Subgroup analysis should be considered if there was statistical heterogeneity. Subgroup analysis should be conducted from the perspective of clinical medicine to analyze the factors that may cause heterogeneity, so as to explore the sources of heterogeneity as far as possible. The Z test was used to compare whether there was a statistical difference between the experimental group and the control group. The inverted funnel plot was used to test whether there was publication bias. [3] Results

Quality evaluation and basic information of included literature
The included studies were published between 1998 and 2016. A total of 1,580 patients participated in the 10 studies, including 990 in the bailing capsule treatment group and 590 in the control group.
Among them, 1 document of "liang fangfang 2016" mentioned the use of random number table method, 1 document of "li. Y 2009" mentioned the use of lottery random method, and 3 documents of "Chen wu 2012, Zhang Zhihong 2008, Zhang Zhihong 2011" only mentioned random method, the rest did not list the random scheme. Table 3-1 for the quality evaluation of the included literature, Table 3-2 for the basic information of the included literature.

Effect of bailing capsule on serum creatinine level after kidney transplantation
Eight studies reported changes in SCr levels after treatment, and performed the meta-analysis on the SCr levels of bailing capsules after renal transplantation. [4][5][6][7][8][9][10][11] The results showed that there was statistical heterogeneity between the two groups P < 0.00001 I² = 97% (figure 3-2). The random effects model was used to combine the effect size, and subgroup analysis was considered. The results showed that there was still statistical heterogeneity in the 6.0g/day group P < 0.00001 I² = 99% .
There was no statistical heterogeneity in the 3.0g/day group P = 0.85 I² = 0% . The dose 3.6g/day,

Effect of bailing capsule on blood urea nitrogen level after kidney transplantation
Eight studies reported the data of BUN level changes after treatment, conducted the meta-analysis on the BUN levels of bailing capsules after renal transplantation, and adopted WMD for statistical analysis. [4][5][6][7][8][9][10][11] The results showed that there was statistical heterogeneity between the two groups P = 0.02 I² = 57% ( figure 3-4). The random effects model was adopted and subgroup analysis was considered. The results showed that there was no statistical heterogeneity between the 3.0g/day group P = 0.41 I² = 0% and the 6.0g/day group P = 0.56 I² = 0% . The dose 3.6g/day, 9.0g/day was only one literature and was meaningless. Thus, it was considered that different doses of oral bailing capsules might be one of the sources of heterogeneity (figure [3][4][5]. It could be considered that bailing capsule treatment group is better than control group in reducing BUN level, the difference had statistical significance. (WMD= -0.72 95%CI[-1.18 -0.25] Z= 3.02 P=0.003). Figure 3-4

Effect of bailing capsule on the level of alanine transaminase after kidney transplantation
Six studies reported changes in ALT levels after treatment. [4,5,8,9,12,13]

Discussion
Patients with end-stage nephropathy, whether undergoing dialysis or renal transplantation, the duration of the disease from onset to end-stage nephropathy is prolonged. It would be leading to the decline of viscera function eventually if failed to nurse. After kidney transplantation, the etiology can be attributed to long time illness and loss of condition and drug invasion generally, the pathogenesis is kidney deficiency, develop for viscera declining. [1] The constituents of the bailing capsule mainly include D-mannitol (cordyceps acid), ergosterol, polysaccharide, carrier alkaloids, 18 amino acids, vitamins and trace elements [14,15]. Among them, D-mannitol has the effect of diuretic, dehydration, free radical scavenging, anti-oxidation, antiasthmatic and expectorant. It can treat edema and urinary retention caused by kidney diseases, and can prevent organ and tissue fibrosis. Ergosterol can inhibit the proliferation of mesangial cells, delay renal interstitial and glomerular fibrosis.Nucleosides (alkaloids) has the effect of inhibiting the increase of serum cholesterol and prevent atherosclerosis. Adenosine (one of alkaloids) is the main quality control index, which can regulate renin release, glomerular filtration rate, mesangial and vascular smooth muscle growth. Bailing capsule contains 8 essential amino acids and 10 nonessential amino acids, which can improve glomerular function, prevent glomerular sclerosis, and remove free radicals and antioxidants [16].

Effect and mechanism of bailing capsule in protecting renal function after kidney transplantation.
How to better protect renal function is the key to success after renal transplantation. Bailing capsule has the function of tonifying kidney and strengthening essence. Firstly, Bailing capsule can dilate renal arteries, increase renal blood flow, and thereby improve glomerular filtration rate, which is conducive to reduce the re-absorption of SCr and BUN by renal tubules [17]. Our study also revealed that Bailing capsule has statistical significance in reducing SCr and BUN. Secondly, Bailing capsule can inhibit renal tubulointerstitial lesion and apoptosis of renal tubular epithelial cells and reduce the destruction of renal tubule tissue, so as to protect the integrity of its structure and function, reduce the damage of renal parenchymal cells, and thus improve renal function [17].

Effect and mechanism of bailing capsule on anti-rejection after renal transplantation
There is no unified opinion as to whether bailing capsule is an immunosuppressant or an immunoregulator. Ding Chenguang et al. believed that bailing capsule is more suitable as an immune regulator, which has a two-way regulating effect on the body's immune system [8]. It would not reduce the body's systemic immune defense while suppressed the parenchymal organs selectively. It also has a regulatory effect on humoral immunity, which can increase serum IgG and reduce the incidence of infection. However, our study showed that there was no statistical significance of bailing capsule in alleviating acute rejection after renal transplantation.

The characteristics and limitations of this study
This meta analysis combined the bailing capsule with conventional western medicine group therapy for patients after renal transplantation, collecting all eligible controlled trials published at home and abroad, expanding the clinical sample size, to obtain further test results, guide clinical medication usage better and more objective, and then provide objective and meaningful theoretical basis for the application of bailing capsule in the treatment of kidney transplantation. The study found that took the capsule combined with conventional western medicine compared with the group using western medicine only was much more effective in protection of the renal and liver function after renal transplantation, but there was no statistical significance in reducing acute rejection. We hope this research can avoid misunderstanding of clinical workers in this respect, at the same time we hope that more scholars conducted mutual discussion and syndrome differentiation.
This study has some limitations, such as the number of the standard literatures included is relatively small, experimental study population is lack, the study time is short In addition, some documents have been published for so long time that the probability of publication bias and the statistical heterogeneity was higher, thus the accuracy of the research results may be affected. If we expanded the sample content, unified the dosage and time, extend the test time, or have more high-quality literatures in recent years, we will get more stable and reliable test results. Therefore, more largesample, multicenter, high-quality studies should be conducted in the future to guide clinical treatment better.