The Efficacy and Safety of Integrated Chinese Plus Western Medicine Compared with Western Medicine Alone in the Treatment for Purpuric Nephritis: A Meta-Aalysis

Objective: This research is aimed to systematically evaluate the efficacy and safety of Chinese plus Western Medicine treatment for Childhood purpuric nephritis by Meta-analysis, in order to improve the cure rate and reduce adverse reactions of this disease, then provide guidance for clinical medication. Methods: There are six major databases including CNKI, Pubmed, Embase, World Wide Database, Web of science and Science Direct retrieved through the Internet, and the randomized-controlled trials of the combined therapy for Childhood purpuric nephritis published both in Chinese and English from the 1999 to October 2019 were collected. Meta-analysis by R software 3.5.0 was adopted to analyze the effective index and adverse effect. Results: In total 92 papers of randomized-controlled clinical studies were enrolled. HSPN children treated with combined therapy demonstrated a significant increase in total effective rate (RR=1.19; 95%CI (1.16–1.21), P<0.001) when compared with Western medicine alone. Our study also found that Chinese plus Western medicine had an advantage on decreasing 24-hour urine protein (WMD=-0.47; 95%CI (-0.53,-0.41); p<0.001) and urine erythrocyte count (WMD=-8.88; 95%CI (-9.80,-7.96); p<0.001) when compared with Western medicine. Children seemed to benefit more from combined treatment in the adverse effect (RR=0.64; 95%CI (0.46, 0.87); p<0.01). Conclusions: Integrated Chinese plus Western medicine treatment was effective for Childhood purpuric nephritis, which may be a superior alternative for HSPN. Nevertheless, long-term, high-quality and multicenter RCTs are required to make the results more convincing.


Introduction
Henoch-Schonlein purpura nephritis (HSPN) is a disease of kidney which damage the kidney within 6 months after the onset of Henoch-Schonlein purpura (HSP) [1]. At present, the specific pathogenesis of HSPN is not completely identified. It is generally accepted that some virus, bacteria, specific substances and other factors lead to allergic reactions, the disorder of cellular and humoral immunity. Eventually, the IgA immune complex deposits in the glomerulus can be seriously damaged. As a result, those substance damage the kidney [2,3]. There are also domestic studies which point out that the disorder of intestinal microflora in children is also related to the pathogenesis of this disease [4]. Most children with HSPN have a good prognosis. However, the report demonstrated that around15% to 20% of children will eventually develop chronic renal failure. Thus, it is of great importance to pay enough attention to it. There is no unified treatment plan for this disease because of the diverse clinical manifestations and complex pathological classification of HSPN. At present, the treatment mainly includes symptomatic treatment, immunosuppressant and glucocorticoid application [5,6]. In recent years, more and more papers revealed that the integrated treatment of children HSPN with traditional Chinese and Western medicine has achieved excellent result. They determined the treatment program of Western medicine according to the clinical manifestation and pathological classification of children. At the same time, the individualized dialectical treatment combined with Chinese medicine classification. Many academic reports showed that the traditional Chinese medicine have the function of synergistic detoxification for glucocorticoid and it can be quite favorable [7,8]. In this paper, a meta-analysis is conducted on the randomized controlled trials (RCT) of the combined treatment for children HSPN with traditional Chinese and Western medicine. The aim of the research is to objectively evaluate the effectiveness and possible advantages of the treatment so as to provide a basis for the guidance of rational clinical medication.

Search Strategy
The research articles were searched on the CNKI, Pubmed, Embase, World Wide Database, Web of science and Science Direct databases (1999-October 2019; key words: "purpura nephritis" and" integrated Traditional/Chinese and/plus Western Medicine" or" combined Chinese and Western Medicine). The academic materials was limited to the published studies that focused on RCT or clinical trials of integrated Chinese and Western Medicine therapy for Childhood/children HSPN. The publications are in both English-language and Chinese-language. In order to ensure complete literature retrieval, Chinese and English keywords were used to carry out secondary search on traditional Chinese medicine, Chinese and western medicine, integrated Chinese and western medicine. Meanwhile, retrospective research was conducted on the related literature references.

Inclusion and Exclusion Criteria
The inclusion and exclusion criteria were formulated according to the PICOS features which were included in the RCT: P (patient, research object), I (intervention method), C (control, comparative intervention method), O (outcomes, measurement outcomes), S (studies, research design).
The inclusion criteria were as follows. (a) P: children with HSPN and all met the diagnostic criteria of the evidence-based guidelines for the diagnosis and treatment of HSPN in the kidney disease group of the Chinese Medical Association in 2009 [9]

Study Selection and Data Extraction
A unified table was developed by two evaluators to extract data from the included literature, based on the inclusive and exclusive criteria through titles and abstracts. The parts expressed in tabular from were the first author, publication year, study design, demographic characteristics, number and intervention measures of patients enrolled in trial and control group, duration of intervention and follow-up, main outcome measures (the total effective rate/24-hour urine protein ration/Urine erythrocyte count), side-effects. The consensus was reached by consulting the third investigator when disagreements happened.

Outcome Measurements
To evaluate the efficacy and safety of Chinese plus Western medicine, the ratio of recovery significant effect, effective rate is called total effective rate.
Effective: clinical symptoms and signs decreased in 50% ~ 75%, urine sediment erythrocyte decreased ≥2 /HP and/or 24-hour urine protein ration decreased by 25% to 50%. Different studies had their own definition of complete and partial remission, but all of them used the reduction of urinary protein as the indicator.
(3) The safety index were the incidence of adverse reactions during treatment and follow-up.

Quality Assessment and Data Synthesis
Since the selected articles were all involved Chinese medicine, the JADAD Scale, which considered the randomization, blinding, follow-up, was used to assess the quality of studies that was scored from 0 to 5 by two investigators. At the same time, the Distribution of hidden is evaluated. 0-2 was classified as low quality, 3-5 were classified as high quality studies. All scores were over 2, suggesting that their outcomes were convictive.
Risk ratios (RR) with its 95% confidence interval (CI) were analyzed for dichotomous outcomes, while the mean difference (MD) was chosen for continuous variables, described with a 95%CI. R version 3.5.0 was used to conduct meta-analysis. We applied a random-effect model or a fixed-effect analysis depending on I 2 and P which was to measure the heterogeneity. The effective and adverse rate are combined and tested with the escalc and rma. uni functions of the R metafor. 24-hour urine protein ration and Urine erythrocyte count mean with the metacont function of the R metafor. If the results show a statistical difference, the potential publication bias will be analyzed by "funnel plot". Funnel plot are tested by regtest function. If the graph is symmetrical, there will be no effect of publication bias. If the graph is asymmetric, there is publication bias. At last, mixed effect models were used to analyze heterogeneity in studies with high heterogeneity. Studies with high heterogeneity were analyzed for heterogeneity.

Basic Characteristics of Included Studies
A total of 7,394 children in the 92 studies were included in the systematic evaluation, all of whom were aged from 2 to 15 years old. All studies described and compared the baseline conditions of children in the experimental group and the control group in terms of age, sex ratio, disease course, with statistical significance between the two groups (P>0.05). On the whole, the study showed good inter-group equilibrium and comparability (P>0.05). The experimental group of 44 studies was treated with proprietary Chinese medicine capsules, tablets and injections, and the remaining 48 studies were treated with traditional Chinese medicine decoction. Western medicine in the control group was treated with glucocorticoids, including 11 studies that added CTX and other immunosuppressor, with the basic treatment measures in all studies were basically the same.

Effect of Combine Therapy on Total Effective Rates
89 studies described efficiency, we combined and tested the results by the escalc functions of the R metafor. As presented in figure 2, the forestplot showed the heterogeneity of each study (P<0.01, I 2 =38.98%), and the random effect model was used for analysis. Children treated with Chinese plus Western medicine demonstrated a significant increase in total effective rates [ Figure 2 RR=1.19; 95%CI (1.16-1.21), P<0.001] when compared with Western medicine alone. Taking total effective rate as an evaluation index, children seemed to benefit more from combined therapy. Then the 91 studies were analyzed by funnel plot with regtest function, as presented in Figure 3, P<0.01, the plot is not completely symmetrical, indicating publication bias.

Effect of Combined Therapy on 24-hour Urine
Protein Ration Level 37 studies described 24-hour urine protein ration level, we combined and tested the results by the metacont function of the R metafor. As presented in figure 4, the forestplot showed the heterogeneity of each study (I 2 =98%), and the random effect model was used for analysis. Our study also found that Chinese plus Western medicine had an advantage on decreasing 24-hour urine protein [ Figure 4 WMD=-0.47; 95%CI (-0.53,-0.41); p<0.001] when compared with Western medicine alone. We conducted funnel plot analysis of the 37 studies, as presented in Figure 5, P<0.001, the plot is not completely symmetrical, indicating publication bias.

Effect of Combined Therapy on Urine Erythrocyte Count Level
We combined and tested the Urine erythrocyte count of 28 studies by the metacont function of the R metafor. Our study found combined therapy could significantly reduce the urine erythrocyte count [ Figure 6 WMD=-8.88; 95%CI (-9.80,-7.96); p<0.001, random effects model] compared with the western medicine alone. Funnel plot shows that the graph is not completely symmetrical (P=0.0119), Figure 7, with publication bias.

Adverse Effects of the Combine Therapy
30 studies reported adverse effect in the course of treatment. Heterogeneity exists in each study (P<0.01), the random effect model was adopted. It is proved that Chinese plus Western medicine could decrease adverse effects more effectively [ Figure 8 RR=0.64; 95%CI (0.46, 0.87); p<0.01] than Western medicine alone. The funnel plot also shows the graph is basically symmetrical (P=0.71>0.05), figure 9, with no publication bias.

Heterogeneity Analysis
The main indicators, 24-hour urine protein ration, urine erythrocyte count, and adverse effect all showed high heterogeneity. We used the ratio of the number of men in the experimental group to the control group and the year of publication to fit the mixed effect model. 24-hour urine protein ration indicator shows two concomitant variables did not contribute to heterogeneity; urine erythrocyte count indicator shows two concomitant variables can explain the total heterogeneity of 5.78%, but two concomitant variable are meaningless in the model; adverse effect indicator shows two concomitant variables can explain the total heterogeneity of 4.06%, but two concomitant variables are also meaningless in the model. We tried unsuccessfully to find the source of heterogeneity. But the age and disease course of each experimental patient were basically the same between the two groups, the cause of heterogeneity is not clear, and it is preliminarily inferred that heterogeneity comes from the variation in the study.

Conclusion
The analysis in this study found that the integrated Chinese and Western medicine treatment for children who have HSPN was more superior in the total effective rate. Our studies also found the combined therapy could reduce the 24-hour urine protein ration level, Urine erythrocyte count and adverse rate, children could seemed to benefit more from combined treatment than the Western medicine alone. Integrated Chinese plus Western medicine treatment was effective for Childhood purpuric nephritis, which may be a superior alternative for HSPN. Nevertheless, the funnel plots of the total effective rate, 24-hour urine protein ration level and Urine erythrocyte count showed that the graphs are not completely symmetrical, with publication bias. So the long-term and high-quality RCTs are required to make the results more convincing.
At last, the main indicators, 24-hour urine protein ration, urine erythrocyte count and adverse effect all showed high heterogeneity. We performed a heterogeneity analysis from the ratio of the number of men and the year of publication using the mixed effect model, but the cause of heterogeneity is not clear, it is preliminarily inferred that heterogeneity comes from the variation in the study.

Discussion
The cause of HSPN is still unknown. At present, the etiology of HSPN is mainly attributive to infection factors and genetic factors. For example, viruses, bacteria, especially streptococcus and helicobacter pylori are more inclined to cause HSPN. The rubella, hepatitis virus, mycoplasma pneumoniae and parasitic infection may cause HSPN morbidity. In addition, HLA gene, IgA are also involved in the pathogenesis of HSPN [102]. In the theory of Chinese medicine, HSPN belongs to the category of "purpura, blood disorder". The clinical physicians are intended to type the HSPN into syndrome of heat in blood, the syndrome of qi deficiency, the syndrome of yin deficiency, the syndrome of dampness-heat blocking collaterals, the syndrome of deficiency of both qi and yin, the syndrome of wind-heat hurting collaterals and so on. Blood stasis blocks collaterals, abdominal pain and joint pain, blood stasis blocks renal collaterals, urine and urine, proteinuria can be seen in renal sealing function and loss of function, and the course of pathogenesis is lingering, which suggests that blood stasis blocks collaterals can be indispensable to the pathogenesis of HSPN [103]. However, it is not enough to grasp the syndrome dynamics of children HSPN and the clinical physicians is not sufficient in the relationship between the syndromes and impact of some factors. Therefore, to some extent, the study on the children HSPN has its limitations.
At the present stage, since the pathogenesis of children HSPN has not been clearly understood, there are various kinds of drugs for clinical treatment of children HSPN, and there is insufficient in uniform standards for clinical treatment and the treatment effect is also different. Clinical medical workers have been constantly exploring and studying [104]. However, there is no recognized standard of treatment both domestically and overseas. In many oversea countries, medical researchers advocated clinical observation following up to the child with light illness but there is no consensus in China. They assume that Hormone combined with Immunosuppressor should be used. It is reported that the total effective rate of Cyclosporine A and hormone therapy for children HSPN is 97.4% [105]. Numerous studies manifested that Glucocorticoid has anti-inflammatory and anti-allergic effects are one of the first choice drugs for clinical treatment of children HSPN. However, clinical observation shows that the effect of glucocorticoid alone is limited and can easily lead to a variety of adverse reactions, such as hormone resistance, hormone dependence and so on. Therefore, the discussion of new therapeutic regimen can be crucial to the treatment of children HSPN. Along with the continuous inheritance and development of Traditional Chinese Medicine, scholars tried best to apply Traditional Chinese Medicine in the clinical treatment of children HSPN.
Individualized drug used according to TCM syndrome differentiation improves the therapeutic efficiency of children's HSPN to some extent. At present, the treatment of children HSPN is mainly based on the combination of Chinese and Western medicine in China, which is a kind of mature treatment. At present, they apply western medicine to rapidly control the deterioration of the condition and then the traditional Chinese Medicine is to treat in a safe and comprehensive way. In a sense, this can be the most safe and effective way to treat school-age children HSPN.
According to the above studies, domestic scholars have adopted RCT design in the clinical research on the combined treatment for children HSPN to be treated with traditional Chinese medicine and Western medicine. However, the implementation of operation process and matters needing attention were not rigorous enough so that there is a high possibility of implementation bias, which is also a serious problem confronted by the application of traditional Chinese medicine in clinical practice. Therefore, the research should attach great importance to the implementation of the RCT research principle in the future so that it can get more reliable, accurate and instructive data for clinical practice. What's more important, it can provide reliable evidence-based support for the treatment in children with HSPN and treated with the combination of Chinese and Western medicine to the International market. Finally, it can improve the curative effect of the treatment of diseases and benefit the general patients.