A systematic review and meta-analysis of integrated traditional Chinese medicine and Western medicine in treating glomerulosclerosis

Abstract Background: The combination of Traditional Chinese medicine and Western medicine (TCM+WM) has been widely used in the treatment of glomerulosclerosis, but the results are still controversial. This study will assess the clinical efficacy of TCM+WM for glomerulosclerosis and provide evidence-based medical data via meta-analysis. Method: The MEDLINE, EMBASE, PubMed, Cochrane Central Registry of Controlled Trials, and multiple Chinese databases (Wan Fang, CNKI, and VIP) were searched for randomized controlled trials (RCT) that compared the effects of WM and TCM+WM. Review Manager 5.3 software was used for the meta-analysis of selected studies, and appropriate tests were performed to determine the quality, heterogeneity and sensitivity of these studies. Results: Sixteen RCTs met the inclusion criteria and were selected for the analysis. Compared with the placebo or WM-treated glomerulosclerosis patients, TCM+WM intervention significantly improved renal function indices including 24-hour urine protein quantity (24 h U-Pro), serum creatinine (Scr), blood urea nitrogen (BUN), creatinine clearance (Ccr). In addition, the serum albumin (ALB), triglyceride (TG), and cholesterol (CHOL) levels were also significantly improved (P < .05) in patients receiving the combination therapy. Finally, the combination of TCM+WM reduced the indices of glomerulosclerosis more effectively compared with WM alone. Conclusion: The combination of TCM+WM can significantly improve the renal function and prognosis of patients with glomerulosclerosis.


Introduction
Glomerulosclerosis is the primary pathological basis for the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD), [1] and the direct cause of 25.8% of the ESRD cases. [2] Although the incidence rate varies depending on the race, sex, age, primary disease etc, it places a considerable socioeconomic burden on the patients. The most common symptom of glomerulosclerosis is proteinuria, along with hematuria, hypertension, renal insufficiency, etc. [3] It is currently treated with hormones, angiotensin converting enzyme inhibitor (ACEI), and immunosuppressants, [4] which can be supplemented with lipidlowering, anticoagulation, and hypotensive drugs. Nevertheless, the high recurrence rate and adverse reactions have greatly limited the outcomes of these strategies. [5,6] Traditional Chinese medicine classifies glomerulosclerosis as "consumptive disease," "urine turbid" etc, and the herbal preparations have been very effective in mitigating the symptoms. [7,8] We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared the therapeutic effects of Western medicine (WM) and TCM+WM on patients with glomerulosclerosis.

Methods
The Cochrane Handbook for Systematic Review of Interventions and Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [9] were followed for all steps.

Search strategy
The Cochrane library, EMBASE, PubMed and MEDLINE databases, and Chinese language databases including VIP, Wan Fang, and CNKI were searched for relevant RCTs published from June 2001 to November 2019. The following keywords were used to search the English-language databases: "traditional Chinese medicine," "TCM," "glomerulosclerosis," "Western medicine," "combination," "RCT," "Formulas of Chinese medicine," and "clinical trials." The Chinese databases were searched using the following keywords: "Shen Xiao Qiu Ying Hua," "Zhong Xi Yi Jie He," "Fang," "Lian He," "Sui Ji Dui Zhao Shi Yan," and "Lin Chuang Yan Jiu." The retrieved papers were screened by 2 authors based on the title and abstract, and the bibliography of the selected papers was further screened manually to identify additional RCTs. In case of any issues with the trial design or results or other ambiguities, the corresponding authors were contacted for clarification. Ethical approval was not necessary since animal models or human subjects were not involved.

Inclusion and exclusion criteria
The studies were selected based on the following inclusion criteria: confirmed diagnosis of glomerulosclerosis, RCT design, comparison of WM-treated (control) and TCM+WM-treated (treatment group) patients, minimum treatment duration of 4 weeks, evaluation of renal function (24-

Study selection and quality assessment
After excluding the irrelevant papers, 2 reviewers independently screened the RCTs according to the established inclusion criteria. The results were compared and any differences are resolved through discussion or a third reviewer. The Jadad scale was used for quality assessment based on randomization, blinding, controlled, withdrawals, and dropouts. [10] Studies with a score of 1 to 3 were of low-quality and a score of 4 to 7 indicated high-quality.

Data extraction
The following data were extracted: authors, year of publication, mean age of treatment group and control group, the number of patients (treatment group/control group), diagnostic criteria, interventions, and duration of treatment.
The main evaluation indices were as follows: (1) renal function indicators: 24-h U-Pro, Scr, BUN; (2) serological indicators: ALB; (3) Drug safety evaluation: number of patients with adverse event relative to the total number of patients.

Sensitivity analysis
Sensitivity analysis was performed for each variable by eliminating one study and recalculating the data of the remaining studies to determine the effect of the variable on the results. The absence of any major changes indicates stable results. [11] 2.6. Heterogeneity analysis I 2 was used to determine the heterogeneity of the included studies, with P < .05 indicating statistical significance. [12] Fixed effects model was used for I 2 < 50% and P ≥ .05, otherwise a randomeffects model was used.

Subgroup analysis
The heterogeneity between studies was evaluated by the I 2 index.
The following subgroups were analyzed to identify the potential sources of heterogeneity: Nephrotic syndrome (NS is defined as proteinuria >3.5 g/d and serum albumin <30 g/L), glomerulonephritis (proteinuria <3.5 g/d and serum albumin >30 g/L), and other (no clear description of proteinuria or serum albumin) stages based on the clinical manifestation, [13] and based on the TCM treatment focus and the severity of Qi deficiency and blood stasis syndrome, [14] invigorate Qi (Qi deficiency > blood stasis), dispel blood stasis (blood stasis > Qi deficiency), or both (blood stasis = Qi deficiency).

Publishing bias
Begg test and funnel plot were used to determine publication bias with the State software. A roughly symmetrical funnel plot, or a Begg test with P > .05 indicated lack of publication bias. [15] 2.9. Statistical analysis RevMan software v5.3 was used for meta-analysis and statistical analysis (The Cochrane Collaboration, Oxford, UK). Standard mean difference (SMD) and 95% confidence interval (CI) were calculated, and P < .05 was considered statistically significant. [16] 3. Results

Study selection and literature search
A total of 1710 articles were retrieved, of which 1565 were excluded based on their titles and abstracts. After excluding 129 articles based on the criteria mentioned in the methods, 16 articles that met the inclusion criteria were finally selected for meta-analysis (Fig. 1). The RCTs are summarized in Table 1. As shown in Table 2, the highest Jadad score was 5, and the average score was 3.63. [19,20,[22][23][24][25][26][28][29][30]32] compared the 24-h U-Pro levels in the treatment (374 patients) and control groups (368 patients). As shown in the forest plot in Fig. 2 Table 1 Characteristics of the RCTs included for the meta-analysis.

Author
Year of publication

Randomized Randomization hide
Blinding Withdrawal and exit

Sensitivity analysis
Sensitivity analysis of 7 indicators (24 h U-Pro, Scr, BUN, ALB, TG, Ccr, and CHOL) did not show any significant change following elimination of single studies, indicating that the results were stable (Fig. 10).

The assessment of publication bias
The funnel plot of the 7 indicators (24 h U-Pro, Scr, BUN, ALB, TG, Ccr, and CHOL) did not show any significant publication bias in the meta-analysis (Fig. 11).

Discussion
Glomerulosclerosis frequently progresses to end-stage renal disease, which is highly recalcitrant to treatment. [33] Although hormone therapy can improve remission rate for 16 weeks, prolonged treatment may result in serious adverse reactions, such as blood pressure fluctuations, faster heart rate, decreased immune function, and secondary diabetes. In addition, immunosuppressants like FK506, cyclosporine A etc. are more expensive and cannot be prescribed often. [31] Traditional Chinese medicine based on natural herbs has gained considerable attention in recent years due to the lower toxicity and side effects. However, the TCM formulations are not well defined and rarely validated by clinical studies. To this end, we performed a meta-analysis of 16 RCTs [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] to compare the therapeutic effect of WM alone or in combination with TCM on 1082 patients with glomerulosclerosis. He et al [18] applied selfmade Qingxue Xiaobai decoction to mitigate the side effects caused by long-term hormone therapy, improve immunity, and reduce the recurrence of glomerulosclerosis, thereby delaying renal deterioration. Yan et al [26] found that the Pishen Tongyu decoction can reduce renal protein levels and block connective tissue growth factor (CTGF) expression or inhibit its activity, thereby inhibiting renal fibrosis and delaying the progression of glomerulosclerosis. Hai [27] used the Shenzong Huoxue decoction to increase the appetite of patients by restoring renal function, which increased protein intake and restored ALB and Hb levels. Modern pharmacological studies have demonstrated the renoprotective effects of TCM formulations. [24] For example, rhubarb, Chuanxiong, and Tripterygium can relieve renal tubular hypermetabolism by inhibiting cell proliferation, reduce extracellular matrix accumulation, and resist platelet aggregation. In addition, Astragalus has a diuretic effect and can significantly reduce proteinuria. This meta-analysis showed that integrating TCM with conventional WM drugs can significantly improve renal function indices, improve treatment outcomes, and reduce recurrence. TCM+WM effectively reduced U-Pro, Scr, BUN, CHOL, and TG levels, and increased that of ALB and Ccr compared with WM alone.   The ideal meta-analysis should be able to include all highquality, homogeneous studies. However, since it is practically difficult to include all studies, publication bias is unavoidable. In this study, funnel plots of the 24-h U-Pro, Scr, BUN, Ccr, TG, CHOL, and ALB showed incomplete symmetry, suggesting possible bias. The quality evaluation and risk bias analysis showed that the 16 included RCTs were very limited, and the amount of included studies was relatively less, which may lead to a result bias. Therefore, our conclusions need further validation through higher quality RCTs.

Conclusion
Integrated TCM+WM can significantly improve renal function, prognosis, and the quality of life of patients with glomerulosclerosis compared with WM alone, and should considered in clinical practice.