Meta-analysis of the effectiveness and safety of Shenyankangfu tablets combined with losartan potassium in the treatment of chronic glomerulonephritis.

OBJECTIVE: To conduct a systematic review of the efficacy and safety of Shenyankangfu tablets in combination with losartan potassium in the treatment of chronic glomerulonephritis.
METHOD: We searched PubMed, Embase, Cochrane Library, CNKI, WanFang Data, and WeiPu for comparative studies on Shenyankangfu tablets in combination with losartan potassium in the treatment of chronic glomerulonephritis. The search period runs from the establishment of the database until September 2021. Data extraction and quality evaluation were carried out on the documents that met the inclusion criteria, and a meta-analysis of the included literature was conducted using the RevMan5.3 software.
RESULTS: A total of 17 randomized controlled trials that met the inclusion criteria were included, with a total sample size of 1680 patients (841 patients in the study group and 839 in the control group). The effective rate was significantly higher in the study group than in the control group [RR = 1.22, 95% CI (1.16, 1.27), P < 0.00001]. In addition, 24-hour urine protein levels [SMD = -1.11, 95% CI (-1.40, -0.83), P < 0.00001], urine NAG enzyme [SMD = -0.99, 95% CI (-1.27, -0.72), P < 0.00001], leukotactin-1 [SMD = -2.43, 95% CI (-3.50, -1.35), P < 0.00001], and the incidence of adverse reactions [RR = 0.43, 95% CI (0.28, 0.66), P < 0.00001] were lower in the study group when compared to the control group.
CONCLUSION: It is safer to treat chronic glomerulonephritis with Shyenyankangfu tablets in combination with losartan potassium. At the same time, it alleviates disease-related symptoms, reduces the influence of cytokine levels, and has fewer adverse reactions, making it more conducive to disease recovery. However, additional multi-center, randomized, control trials with large sample sizes must be conducted to confirm the findings.

1. Introduction

Chronic glomerulonephritis (CGN) is a relatively common primary glomerular disease with a high prevalence [1, 2]. CGN is a primary glomerular disease, mainly due to the influence of various causes with the main clinical manifestations of proteinuria, hematuresis, edema, and hypertension [3, 4]. It has an insidious onset and a delayed course, and the majority of patients progress to chronic renal failure. CGN is characterized by interstitial fibrosis, glomerulosclerosis, and tubular atrophy and is the final common pathway of most glomerular disorders (primary or secondary) when poorly managed or unresponsive to therapies. Since CGN is prone to recurrent episodes, if the disease progresses and is not effectively treated, it can result in life-threatening complications such as renal failure.

Because proteinuria and hypertension are independent risk factors influencing the prognosis of chronic nephritis, controlling them is an important measure to delay renal failure [5]. Currently, clinical treatment methods primarily involve the use of angiotensin II receptor blockers (ARBs) to reduce glomerular intravascular pressure and proteinuria, thereby delaying chronic renal function changes. However, when used alone, ARBs have poor therapeutic effects.

Although studies conducted in China have shown that the combination of traditional Chinese medicine (Shenyankangfu tablets, SYKF tablets) and losartan potassium tablets has a greater clinical benefit than losartan potassium tablets alone in the treatment of CGN, no systematic analysis has yet been conducted in this area. Therefore, we intend to conduct a meta-analysis to investigate the efficacy and safety of the combination of SYKF tablets and losartan potassium tablets in the treatment of CGN.

2. Materials and methods

2.1 Search strategy

Registration: Based on the Cochrane Handbook criteria and Preferred Reporting Items for System Reviews and Meta-Analyses (PRISMA statement), our meta-analysis was registered with PROSPERO (CRD42022345149). Searcher: The literature search and information extraction were carried out independently by two searchers. Database: PubMed, Embase, Web of Science, CNKI, WanFang database (WANFANG), and VIP database (VIP). Search terms: "Shenyankangfu tablets," "losartan potassium tablets," and "chronic glomerulonephritis." Search time range: From the date of establishment of each database until September 2021.

2.2 Inclusion and exclusion criteria

2.2.1 Inclusion criteria

Study type: All prospective randomized controlled trials, whether blinded or not, were included. Study patients: All patients meet the criteria for the diagnosis of chronic nephritis set by the World Health Organization (WHO). Intervention measurements: The control group was treated with SYKF or losartan potassium alone, while the experimental group was treated with the combination of SYKF and losartan potassium (50 mg, Po, qd). Outcome indicators: The primary indicators include the effective rate. The efficacy criteria are as follows: Significantly effective, clinical signs and symptoms are significantly alleviated, 24 h urine protein quantitative decrease > 40% or urine protein decrease 2 "+", urine sediment count red blood cell decrease > 40% or urine red blood cell decrease 2 "+"; Effective, clinical signs and symptoms are relieved, 24 h urine protein quantitative decrease ≤ 40% or urine protein decrease 1 "+"; Invalid, clinical signs, symptoms, and related indicators aggravated or not alleviated. Total effective rate = Significant effective rate + effective rate. The secondary indicators include serum creatinine (Scr), Blood urea nitrogen (BUN), 24-hour urinary protein quantity, urine NAG enzyme, and LKN-1.

2.2.2 Exclusion criteria

1: Reviews, animal experiments, case reports, and expert experience reports; 2: Repeated publications; 3: Studies where full-text data cannot be extracted for statistical analysis.

2.3 Data extraction and bias risk assessment

The literature screening and data extraction were carried out independently by two researchers. A unified extraction table was used for data extraction. Where there was a disagreement, it was resolved through discussion or with the assistance of a third researcher. The bias risk of included studies was assessed according to the Cochran Handbook. The evaluation content includes random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. Each item was classified as low, high, or unclear risk.

2.4 Statistical analysis

Statistical analysis was performed using RevMan5.3 software. The evaluation indicators of the study are binary variables, such as effective rate and incidence of adverse reactions. Relative risk (Risk ratio, RR) was used as the analysis statistic, and its 95% confidence interval (CI) was calculated. Continuous variables include 24-hour urine protein, urine N-Acetyl-D-glucosamine (NAG) enzyme, blood urea nitrogen, blood creatinine, and leukotactin-1 (LKN-1). The standardized mean difference (SMD) was used as the analysis statistic, and its 95% CI was calculated. A Z-test was used to analyze RR; P < 0.05 indicates that the two evaluation indices are statistically different; otherwise, there is no statistical difference. The χ2 test was used to analyze heterogeneity. If statistical heterogeneity existed between studies (P < 0.1, I2 > 50%), the random effects model was used for analysis; otherwise, the fixed effects model was employed.

3. Results

3.1 Basic characteristics of included studies

The literature search and screening process is shown in Fig 1. Initially, 63 kinds of related literature were retrieved. After reading the title and abstract and excluding irrelevant or repetitive articles, read the full text and standard evaluation of the remaining 36 kinds of literature. 23 non-core literature in China, drug inconsistencies, data loss, and non-detailed literature were deleted. Finally, 17 kinds of literature (abstract could be obtained in Supplementary material abstract) that met the criteria were included in the meta-analysis [6-22]. A total of 841 patients in the study group and 839 patients in the control group were included. The basic characteristics of each study are summarized in Table 1.

Fig 1

Summary of the process for identifying candidate studies.

Table 1

The characteristics of clinical studies.

Study (years)	Number(n = male/female) Age(years)		Treatments		Outcome index	Intergroup difference
	Study group	Control group	Study group	Control group
Chen SY 2021	40(23/17) 41.4±3.7	40(21/19) 41.5±3.4	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective rate2. Urine NAG enzyme3. 24-hour urinary protein quantity4. Cytokines5. Adverse Reaction6. Scr7. BUN	1. P<0.052. P<0.053. P<0.054. P<0.055. P<0.056. P<0.057. P<0.05
Guo YM 2018	63(35/28) 45.3±8.2	63(36/27) 46.5±9.5	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. 24-hour urinary protein quantity2. Cytokines3. T cell subsets	1. P<0.052. P<0.053. P<0.05
Li HX 2017	120(58/62) 43.9±7.7	120(56/64) 43.6±7.5	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective rate2. 24-hour urinary protein quantity3. Urine NAG enzyme4. BUN5. Scr6. Adverse Reaction	1. P<0.052. P<0.053. P<0.054. P>0.055. P>0.056. P<0.05
Li MB 2017	34(20/14) 42.6±14.9	34(21/13) 42.1±15.2	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	SYKF tablet (5 tablets, tid)	1. Effective rate2. Adverse Reaction	1. P<0.052. P<0.05
Li XD 2017	34(19/15) 35.0±4.6	34(18/16) 34.8±5.3	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective rate2. Symptom score3. 24-hour urinary protein quantity4. IL-6,85. BUN6. Scr	1. P<0.052. P<0.053. P<0.054. P<0.055. P>0.056. P>0.05
Lv TH 2020	44(24/20) 50.5±5.3	44(23/21) 51.0±5.5	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective rate2. 24-hour urinary protein quantity3. IL-6,84. Adverse Reaction	1. P<0.052. P<0.053. P<0.054. P<0.05
Pan HX 2016	50(26/24) 48.5±3.2	50(27/23) 47.3±3.5	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective rate2. 24-hour urinary protein quantity3. GFR4. Adverse Reaction5. Scr	1. P<0.052. P<0.053. P<0.054. P<0.055. P<0.05
Qiu H 2017	60(31/29) 42.9±2.7	60(32/28) 43.4±3.4	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective rate2. 24-hour urinary protein quantity3. Urine NAG enzyme4. Adverse Reaction5. BUN6. Scr	1. P<0.052. P<0.053. P<0.054. P<0.055. P>0.056. P>0.05
Qiu J 2018	30(18/12) 52±3	30(13/17) 52±3	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective rate2. 24-hour urinary protein quantity3. BUN4. Scr	1. P<0.052. P<0.053. P<0.054. P<0.05
Su Y 2019	60(45/15) 34.3±3.2	60(42/18) 35.6±4.1	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective rate2. 24-hour urinary protein quantity3. BUN4. Scr5. GFR	1. P<0.052. P<0.053. P<0.054. P<0.055. P>0.05
Wang XL 2018	40(21/19) 49.5±9.4	40(22/18) 49.7±9.8	SYKF tablet (8 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective rate2. 24-hour urinary protein quantity3. Scr4. LKN-15. IL-86. TNFα	1. P<0.052. P<0.053. P<0.054. P<0.055. P<0.056. P<0.05
	35.6±9.4
Wu Y 2016	50(31/19) 54.4±3.2	50(33/17) 55.4±3.3	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective Rate2. LKN-13. IL-334. TNFα5. BUN6. Scr7. GFR	1. P<0.052. P<0.053. P<0.054. P<0.055. P>0.056. P>0.057. P>0.05
Xu ZY 2016	50(30/20) 35.2±4.3	50(32/18) 35.1±4.1	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective Rate2. Adverse Reaction	1. P<0.052. P>0.05
Yan H 2018	30(18/12) 52±3	30(1317) 52±3	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective Rate2. 24-hour urinary protein quantity3. BUN4. Scr	1. P<0.052. P<0.053. P>0.054. P>0.05
Yu GA 2017	46(30/16) 46.5±3.8	44(26/18) 47.3±4.1	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. 24-hour urinary protein quantity2. IL-6,8	1. P<0.052. P<0.05
Zhao D 2017	49(29/20) 42±6	49(28/21) 42±5	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective rate2. Urine NAG enzyme3. 24-hour urinary protein quantity4. BUN5. Scr6. Systolic blood pressure	1. P<0.052. P<0.053. P<0.054. P<0.055. P<0.056. P<0.05
Zheng BL 2014	41	41	SYKF tablet (5 tablets, tid) + Losartan Potassium tablet (1 tablets, qd))	Losartan Potassium tablet (1 tablets, qd)	1. Effective rate2. Urine NAG enzyme3. 24-hour urinary protein quantity4. IL-6,85. BUN6. Scr	1. P<0.052. P<0.053. P<0.054. P<0.055. P>0.056. P>0.05

SYKF tablet: Shenyankangfu tablet Scr: Serum creatinine GFR:Glomerular filtration rate BUN: Blood urea nitrogen

3.2 Quality evaluation results of included studies

The articles included are all Chinese literature. There are 12 kinds of literature mentioning specific random methods [6, 9, 11, 13–18, 20–22], and the remaining 5 kinds of literature only mention the use of random grouping [7, 8, 10, 12, 19], with no specific random methods described. All the reported research data are complete. None of the studies provided information on blinding, sample size estimation, or random allocation concealment. The risk of bias assessment is shown in Fig 2.

Fig 2

Risk of bias.

(A): Risk of bias graph indicating the review authors’ rating regarding the risk of bias, presented as percentages, across all of the included studies; (B):Risk of bias summary indicating the review authors’ judgments on each risk of bias item for each included study. Green color, low risk of bias; yellow color, unclear risk of bias; red color, high risk of bias.

3.3 Results of Meta-analysis

3.3.1 Effective rate

The total effective rate was reported in 15 studies [6, 8–19, 21, 22]. There was no statistical heterogeneity among the studies (P = 0.42, I2 = 3%), and the fixed effect model was used for the meta-analysis. The meta-analysis results revealed that the total effective rate of patients in the study group was significantly higher than that of the control group [RR = 1.22, 95% CI (1.16, 1.27), P < 0.00001]. The results are shown in Fig 3.

Fig 3

Forest plot of effects of Shenyankangfu tablets and Losartan potassium in the treatment of chronic glomerulonephritis on effective rate.

3.3.2 24-h urine protein levels

14 studies [6–8, 10–16, 19–22] reported changes in 24-h urine protein levels, and there was statistical heterogeneity between the studies (P < 0.00001, I2 = 84%). The random effects model was used for the meta-analysis. The results are shown in Fig 4 and S1 Table in S1 File. The study group had significantly lower 24-h urine protein levels than the control group [SMD = -1.11, 95% CI (-1.40, -0.83), P < 0.00001].

Fig 4

Forest plot of effects of Shenyankangfu tablets and Losartan potassium in the treatment of chronic glomerulonephritis on 24-hour urine protein quantification.

3.3.3 Serum creatinine (Scr)

12 studies [6, 8, 10, 12–17, 19, 21, 22] reported changes in Scr, and statistical heterogeneity (P < 0.00001, I2 = 91%) existed between the studies. The random effects model was used for the meta-analysis. The results are shown in Fig 5 and S2 Table in S1 File. The value of Scr did not change significantly in the study group compared to the control group.

Fig 5

Forest plot of effects of Shenyankangfu tablets and Losartan potassium in the treatment of chronic glomerulonephritis on Serum creatinine.

3.3.4 Blood urea nitrogen (BUN)

10 studies [6, 8, 10, 13–15, 17, 19, 21, 22] reported changes in blood urea nitrogen, and there was statistical heterogeneity between the studies (P < 0.00001, I2 = 91%). The random effects model was used for meta-analysis. The results are shown in Fig 6 and S3 Table in S1 File. The value of BUN did not change significantly in the study group compared to the control group [SMD = -0.42, 95% CI (-0.85, 0), P = 0.05].

Fig 6

Forest plot of effects of Shenyankangfu tablets and Losartan potassium in the treatment of chronic glomerulonephritis on blood urea nitrogen.

3.3.5 Urine NAG enzyme

5 studies [6, 8, 13, 21, 22] reported changes in urine NAG enzyme, and there was statistical heterogeneity between the studies (P = 0.04, I2 = 60%). The random effects model was used for the meta-analysis. The urine NAG enzyme was significantly lower in the experimental group than in the control group [SMD = -0.99, 95% CI (-1.27, -0.72), P < 0.00001]. The results are shown in Fig 7 and S4 Table in S1 File.

Fig 7

Forest plot of effects of Shenyankangfu tablets and Losartan potassium in the treatment of chronic glomerulonephritis on urine NAG enzyme.

3.3.6 Leukotactin-1 (LKN-1)

5 studies [6, 7, 15–17] reported changes in leukotactin-1, and there was statistical heterogeneity between the studies (P < 0.00001, I2 = 95%). The random effects model was used for the meta-analysis. The experimental group had a significantly lower LKN-1 than the control group [SMD = -2.43, 95% CI (-3.50, -1.35), P < 0.00001]. The results are shown in Fig 8 and S5 Table in S1 File.

Fig 8

Forest plot of effects of Shenyankangfu tablets and Losartan potassium in the treatment of chronic glomerulonephritis on leukotactin-1.

3.3.7 Adverse reaction

6 studies [6, 8, 9, 11–13] reported changes in the rate of adverse reactions. There was no statistical heterogeneity between the studies (P = 0.69, I2 = 0%), and the fixed-effect model was used for the meta-analysis. The meta-analysis results showed that the rate of adverse reaction in patients in the study group was significantly lower than that in the control group [RR = 0.43, 95% CI (0.28, 0.66), P < 0.00001]. The results are shown in Fig 9.

Fig 9

Forest plot of effects of Shenyankangfu tablets and Losartan potassium in the treatment of chronic glomerulonephritis on adverse reaction.

3.3.8 Analysis of publication bias

The effective rate was used as an indicator to draw an inverted funnel chart, as shown in Fig 10. The scatter points of each study are within the scope of the inverted funnel chart, and the distribution is symmetrical. It suggests that the possibility of publication bias in this study is low.

Fig 10

Inverted funnel plots of effective rate.

4. Discussion

CGN is a primary glomerular disease characterized by diffuse inflammation and limited glomerular fibrosis with clinical manifestations of proteinuria, hematuria, hypertension, and varying degrees of edema. Since CGN is prone to recurrent episodes, if the disease progresses and is not effectively treated, it can result in life-threatening complications such as renal failure, severely affecting the patient’s health and quality of life. Although the pathogenesis of chronic glomerulonephritis is not completely understood, most clinical research scholars believe that it is closely related to humoral immunity. When chronic glomerulonephritis is taken into account, the main goal of clinical treatment is to reduce proteinuria.

Losartan potassium, which is an angiotensin II receptor antagonist can selectively compete for angiotensin receptor 2 binding that dilates renal arteries and blood vessels throughout the body, reducing proteinuria and blood pressure [20]. Following treatment, the patient’s glomerular hypermetabolic state significantly improves, thereby protecting renal function and reducing the degree of renal function damage. However, it was found during clinical trials that long-term use affects blood pressure, increases the burden on the kidneys, and causes a variety of adverse reactions. In addition, the patient is prone to recurring attacks after discontinuing the drug, which affects the patient’s treatment effect.

Modern pharmacological studies have found that Shenyankangfu tablets have anti-inflammatory properties, promote liver protein synthesis, prevent protein loss, regulate immune function, and lower blood pressure [23]. Considering that GN is primarily associated with infection or autoimmune abnormalities, SYKFT tablets may have therapeutic effects by regulating pathways involved in immunity, inflammation, and oxidative stress [24], thereby reducing the occurrence of proteinuria, and hematuria, and delaying the deterioration of renal function. In addition, treatment of CKD relies on effective control of proteinuria and protection of kidney function. In previous research, SYKFT was shown to provide a greater advantage in improving CKD clinical symptoms, controlling proteinuria, protecting kidney function, and reducing Western medicine side effects [25].

A meta-analysis was conducted to assess the efficacy and safety of the combination of Shenyankangfu tablets and losartan potassium in the treatment of chronic glomerulonephritis. The results showed that using Shenyankangfu tablets in combination with losartan potassium significantly improved the total effective rate of the patients in the study group. The 24-hour urine protein, NAG enzyme, and LKN-1 levels were significantly lower in the study group when compared to the control group. Scr and BUN were reduced to varying degrees in both groups of patients, but the difference was insignificant. All raw data could be obtained in study’s minimal underlying data in supporting information. The overall incidence of adverse reactions was lower in the study group than in the control group. This indicates that treating chronic glomerulonephritis with the combination of Sheyanyankangfu tablets and losartan potassium is safer. At the same time, it alleviates disease-related symptoms, reduces the influence of cytokine levels, and has fewer adverse reactions, making it more conducive to disease recovery.

This study has the following limitations: 1. The random method of some studies is not clearly stated, and there is no mention of double-blind, which diminishes the reliability of the evidence and may introduce selection bias; 2. The literature is composed solely of Chinese sources, which may result in publication bias. Additional multi-center, randomized, controlled trials with large sample sizes must be conducted to confirm the findings.

PRISMA 2020 checklist.

(DOCX)

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Study’s minimal underlying data: Raw data involved in meta-analysis.

(XLSX)

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This file consists of the supporting tables for this submission.

(DOCX)

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Supplementary material (abstract): Abstracts of the literature used in the meta-analysis.

(DOCX)

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6 Jul 2022

Meta-analysis of the effectiveness and safety of Shenyankangfu tablets combined with losartan potassium in the treatment of Chronic glomerulonephritis

PLOS ONE

Dear Dr. Zhu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The manuscript focuses on a topic of potential interest. However, the study has major pitfalls that should be addressed to support the conclusion. To mention few of them, i) need to elaborate on the mechanism of action of the drug, as it is not known in western medicine world; ii) need to be more specific on the losartan mechanisms of action; iii) concern about the presentation  of Table 1, where intergroup difference is hard to read and is not self-explanatory; iv) need to add in the limitations that, since the study was conducted in Chinese population, this drug needs to be studied in other populations before it can become mainstream; v) concern about the fact that many of the studies cited are unavailable to non-Chinese readers and this is a problem for making context of this meta-analysis. Would it be possible to have at least the abstract of these studies translated in English to be added as supplementary material?; vii) unclear why they kept mentioning chronic glomerulonephritis as the most common glomerular disease worldwide. The introduction and early parts of the discussion should be re-written to reflect the actual report of worldwide literature on glomerular diseases; viii) need to clarify how chronic glomerulonephritis was defined in the included studies; ix) concern about the fact that the results presented in the abstract and section 3.3.1 of the Results seem to say the opposite of those reported in Figure 3; x) need to provide kidney function reported in the studies included; xi) need to support with references several statements made in the discussion; xii) need to improve the manuscript by a more detailed discussion into the main findings including, for instance, why the control group did better than the main group (Figure 3); xiii) need to provide the number (and percentage) of studies that were low-, moderate-, and high-risk of bias; xiv) need to provide the dose of losartan in the included studies.

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Feng et al. conducted meta-analysis of the effectiveness and safety of Shenyankangfu tablets combined with losartan potassium in the treatment of Chronic glomerulonephritis. The results showed that the total effective rate of patients in the study group was significantly improved after using the Shenyankangfu tablets in combination with losartan potassium. 24-hour urine protein, urine NAG enzyme, LKN-1 are lower than the control group. BUN and Cr were not very different between the groups and adverse reactions were less frequent in the study group.

1. Would recommend elaborating on the mechanism of action of the drug as it is not known in western medicine world. Also I would recommend being more specific in losartan's MOA (decrease glomerular hypertension from efferent dilatation, some direct podocyte effects and less fibrosis through TGF-B).

2.Table 1 intergroup difference is hard to read and is not self explanatory.

3. Would check for spelling and grammatical errors.

4. Since the study was conducted in Chinese population, this drug needs to be studied in other population before it can become mainstream.

Reviewer #2: Feng et al have conducted this meta-analysis on the effectiveness and safety of Shenyankangfu tablet combined with Losartan potassium in the treatment of chronic glomerulonephritis (CGN). Please see my comments on this manuscript:

MAJOR:

1. My main problem with this paper submitted to PLOS ONE with largely English readership (and the authors have listed this as a limitation to this study) is the inclusion of only Chinese studies (or studies published in Chinese literature). Many of the studies cited are unavailable to non-Chinese readers and this is a problem for making context of this meta-analysis.

2. It is unclear to me why the authors kept mentioning CGN as the most common glomerular disease worldwide. This is not substantiated in any report of worldwide literature on glomerular diseases. IgAN is the commonest GN in European and Asian countries (including China - See Nephrol Dial Transplant. 2010 Feb;25(2):334-6.) while MCD / FSGS is common in Latin Americans and Africa (see Nephrol Dial Transplant. 2010 Feb;25(2):490-6; and PLoS One. 2016 Mar 24;11(3):e0152203.). CGN represents the final common pathway of most glomerular disorders (primary or secondary) if not well treated or does not respond to therapies and is characterized by interstitial fibrosis, glomerulosclerosis and tubular atrophy. The introduction and early parts of the discussion should therefore be re-written to reflect this.

3. How was chronic glomerulonephritis defined in the included studies? Was this from the same type of primary or secondary GN?

4. Figure 3 clearly shows that the "Total effective rate" was higher (favors) the control group. The results you presented in the abstract and section 3.3.1 of the results seems to say the opposite. This should be clarified.

5. It is unclear about kidney function of the studies included. I think the authors should at least summarize baseline and end-of study serum creatinine, eGFR and ACR (and other tests) in a Table (main or supplementary) to improve context and understanding of the included studies.

6. Several statements were made in the discussion that were not backed up with references (e.g. "Modern pharmacological studies have found that Shenyankangfu tablets have the functions of anti-inflammatory, promoting liver protein synthesis, preventing protein loss, regulating immune function, and lowering blood pressure." Can you provide references to back up this statement as well as others?"

7. I think the study can be improved by a more detailed discussion into the main findings including, for instance, why the control group did better than the main group (Figure 3) amongst others to be discussed.

8. Based on the risk of bias analysis carried out, please clearly provide the number (and percentage) of studies that were low-, moderate- and high-risk of bias.

9. Did the included studies provide dose of Losartan? This should be provided as it has implications on the results provided.

MINOR

1. Please expand the abbreviations before first use (e.g. SMD; urine NAG, etc)

2. Provide the PROSPERO registration number for this study protocol

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Ikechi Okpechi

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2 Aug 2022

Reviewer #1: Feng et al. conducted meta-analysis of the effectiveness and safety of Shenyankangfu tablets combined with losartan potassium in the treatment of Chronic glomerulonephritis. The results showed that the total effective rate of patients in the study group was significantly improved after using the Shenyankangfu tablets in combination with losartan potassium. 24-hour urine protein, urine NAG enzyme, LKN-1 are lower than the control group. BUN and Cr were not very different between the groups and adverse reactions were less frequent in the study group.

1.Would recommend elaborating on the mechanism of action of the drug as it is not known in western medicine world. Also I would recommend being more specific in losartan's MOA (decrease glomerular hypertension from efferent dilatation, some direct podocyte effects and less fibrosis through TGF-B).

Response: We sincerely appreciate the valuable comments. the Shenyankangfu Tablet (SYKFT) treatment of GN primarily involved infection, inflammation, or immunity processes. Considering that GN was primarily correlated with infection or autoimmune abnormalities, SYKFT may exert therapeutic effects by regulating pathways involved in immunity, inflammation, and oxidative stress [1]. We have added the mechanism of action of SYKFT in the section of discussion in the manuscript. The aim of this study was to systematically review the efficacy and safety of Shenyankangfu tablets combined with losartan potassium in the treatment of chronic glomerulonephritis. Our next research will focus on losartan's MOA.

1.Jin M, Ren W, Zhang W, et al. Exploring the Underlying Mechanism of Shenyankangfu Tablet in the Treatment of Glomerulonephritis Through Network Pharmacology, Machine Learning, Molecular Docking, and Experimental Validation. Drug Des Devel Ther. 2021;15:4585-4601.

2.Table 1 intergroup difference is hard to read and is not self explanatory.

Response: Thanks for your professional suggestion. We have made adjustments to the way we write of Table 1 intergroup difference. The numbers in intergroup difference are in one-to-one correspondence with the numbers in outcome index.

3. Would check for spelling and grammatical errors.

Response: Thanks for your professional suggestion. We have made corrections to spelling and grammar mistakes in the manuscript.

4.Since the study was conducted in Chinese population, this drug needs to be studied in other population before it can become mainstream.

Response: Thanks for this suggestion. Shenyankangfu Tablet (SYKFT) is a Chinese patent medicine that has been used widely to decrease proteinuria and the progression of chronic kidney disease. Its safety has been confirmed by a multicenter randomized controlled trial [1]. Of course, the next step is to conduct research in other population to make it mainstream

1.Wu J, Duan SW, Yang HT, et al. Efficacy and safety of Shenyankangfu Tablet, a Chinese patent medicine, for primary glomerulonephritis: A multicenter randomized controlled trial. J Integr Med. 2021;1:009.

Reviewer #2: Feng et al have conducted this meta-analysis on the effectiveness and safety of Shenyankangfu tablet combined with Losartan potassium in the treatment of chronic glomerulonephritis (CGN). Please see my comments on this manuscript:

MAJOR:

1. My main problem with this paper submitted to PLOS ONE with largely English readership (and the authors have listed this as a limitation to this study) is the inclusion of only Chinese studies (or studies published in Chinese literature). Many of the studies cited are unavailable to non-Chinese readers and this is a problem for making context of this meta-analysis.

Response: Thank you for this constructive suggestion. We have provided the abstract of these studies translated in English as supplementary material (abstract).

2. It is unclear to me why the authors kept mentioning CGN as the most common glomerular disease worldwide. This is not substantiated in any report of worldwide literature on glomerular diseases. IgAN is the commonest GN in European and Asian countries (including China - See Nephrol Dial Transplant. 2010 Feb;25(2):334-6.) while MCD / FSGS is common in Latin Americans and Africa (see Nephrol Dial Transplant. 2010 Feb;25(2):490-6; and PLoS One. 2016 Mar 24;11(3):e0152203.). CGN represents the final common pathway of most glomerular disorders (primary or secondary) if not well treated or does not respond to therapies and is characterized by interstitial fibrosis, glomerulosclerosis and tubular atrophy. The introduction and early parts of the discussion should therefore be re-written to reflect this.

Response: Thank you for this constructive suggestion. We have re-written the introduction and early parts of the discussion.

3. How was chronic glomerulonephritis defined in the included studies? Was this from the same type of primary or secondary GN?

Response: Thanks for your professional suggestion. Chronic glomerulonephritis is mainly a disease with clinical symptoms such as renal dysfunction, proteinuria, hematuria, hypertension and other clinical symptoms caused by various etiologies. It was from the same type of primary GN.

4. Figure 3 clearly shows that the "Total effective rate" was higher (favors) the control group. The results you presented in the abstract and section 3.3.1 of the results seems to say the opposite. This should be clarified.

Response: Thanks for your professional suggestion. In Fig.3, the effective rate in experiment group was 92.08% (674/732). In control group, the effective rate was 75.68% (554/732). The experimental group was more effective. The results I presented in the abstract and section 3.3.1 of the results was that the effective rate in experimental group were significantly higher than that of control group. This conclusion is consistent with the results expressed in Fig.3

5.It is unclear about kidney function of the studies included. I think the authors should at least summarize baseline and end-of study serum creatinine, eGFR and ACR (and other tests) in a Table (main or supplementary) to improve context and understanding of the included studies.

Response: Thanks for your professional suggestion. We have summarized baseline and end-of study 24-hour urine protein quantification, Serum creatinine, blood urea nitrogen, Urine NAG enzyme and leukotactin-1 in the supplementary materials (table).

6. Several statements were made in the discussion that were not backed up with references (e.g. "Modern pharmacological studies have found that Shenyankangfu tablets have the functions of anti-inflammatory, promoting liver protein synthesis, preventing protein loss, regulating immune function, and lowering blood pressure." Can you provide references to back up this statement as well as others?"

Response: Thanks for your professional suggestion. We have added the reference in appropriate place in the manuscript.

7. I think the study can be improved by a more detailed discussion into the main findings including, for instance, why the control group did better than the main group (Figure 3) amongst others to be discussed.

Response: Thanks for your professional suggestion. In Fig.3, the effective rate in experiment group was 92.08% (674/732). In control group, the effective rate was 75.68% (554/732). The experimental group was more effective. The results I presented in the abstract and section 3.3.1 of the results was that the effective rate in experimental group were significantly higher than that of control group. This conclusion is consistent with the results expressed in Fig.3

8. Based on the risk of bias analysis carried out, please clearly provide the number (and percentage) of studies that were low-, moderate- and high-risk of bias.

Response: Thanks for your professional suggestion. The bias risk of included studies was assessed according to the Cochran Handbook. The evaluation content includes: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias. The low risk, high risk, and unclear risk were used to describle each item. For random sequence generation, there are 12 studies (70.58%) in low risk of bias and 5 studies (29.41%) in unclear risk. As for allocation concealment, blinding of participants and personnel, blinding of outcome assessment and other bias, all studies (100%) were unclear risk. In addition, all studies (100%) were low risk in incomplete outcome data and selective reporting.

9.Did the included studies provide dose of Losartan? This should be provided as it has implications on the results provided.

Response: Thanks for your professional suggestion. The dose of Losartan was 50mg, Po, qd. We have added the dose of Losartan in Inclusion criteria in the section of Materials and Methods

MINOR

1. Please expand the abbreviations before first use (e.g. SMD; urine NAG, etc)

Response: Thanks for your professional suggestion. SMD: standardized mean difference. NAG:N acetyl β-D Glucosaminidase. We have assed the full name of SMD and NAG in the manuscript.

2. Provide the PROSPERO registration number for this study protocol

Response: Thanks for your suggestion. The PROSPERO registration number for this study protocol is CRD42022345149. We have added the PROSPERO registration number in the section of search strategy in the manuscript.

7 Sep 2022

13 Sep 2022

The revised manuscript is improved. However, few points remain to be addressed,

namely, i) need to elaborate more on RAAS blockers on lowering intraglomerular hypertension, direct podocyte effects by blocking ATII receptors;

Response: Thanks for your professional suggestion. Losartan potassium, which is an angiotensin II receptor antagonist can selectively compete for angiotensin receptor 2 binding that dilates renal arteries and blood vessels throughout the body, reducing proteinuria and blood pressure.

ii) need to provide more in depth details about the mechanism of action of Shenyankangfu tablets;

Response: Thanks for your professional suggestion. We have provided more in depth details about the mechanism of action of Shenyankangfu tablets. the Shenyankangfu Tablet (SYKFT) treatment of GN primarily involved infection, inflammation, or immunity processes. Considering that GN was primarily correlated with infection or autoimmune abnormalities, SYKFT may exert therapeutic effects by regulating pathways involved in immunity, inflammation, and oxidative stress [1]. In addition, treatment of CKD relies on effective control of proteinuria and protection of kidney function. In previous research, SYKFT was shown to provide a greater advantage in improving CKD clinical symptoms, controlling proteinuria, protecting kidney function, and reducing Western medicine side effects [2].

1.Jin M, Ren W, Zhang W, et al. Exploring the Underlying Mechanism of Shenyankangfu Tablet in the Treatment of Glomerulonephritis Through Network Pharmacology, Machine Learning, Molecular Docking, and Experimental Validation. Drug Des Devel Ther. 2021;15:4585-4601.

2.Lu H, Tang S, Su B. Clinical observation on treating 50 cases of chronic nephritis by Shenyan Kangfu tablets plus valsartan. Clin J Chin Med. 2012;4:79–80. doi: 10.4236/cm.2013.43012.

iii) need minor revision regarding grammatical errors.

Response: We sincerely appreciate the valuable comments. We found a professional language editing company to revise grammatical errors of the manuscript, and the proof is as follows:

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

22 Sep 2022

Meta-analysis of the effectiveness and safety of Shenyankangfu tablets combined with losartan potassium in the treatment of Chronic glomerulonephritis

PONE-D-21-37134R2

Dear Dr. Zhu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

The re-revised version of the manuscript is definitely improved. The authors have now properly addressed all the reviewers’ comments and criticisms.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Combination of Shenyankangfu tablets combined with losartan potassium in the treatment of Chronic glomerulonephritis alleviates disease-related symptoms, reduces the influence of cytokine levels, and has fewer adverse reactions compared to losartan alone. This needs to be verified in other populations other than Han Chinese.

Reviewer #2: The authors have shown in their paper that it is safer to treat CGN with Shyenyankangfu tablets combined with losartan potassium. They also show that this compound alleviates disease-related symptoms, reduces the influence of cytokine levels, and has fewer adverse reactions. I have no further comments for the authors who have now responded to all queries.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

29 Sep 2022

PONE-D-21-37134R2

Meta-analysis of the effectiveness and safety of Shenyankangfu tablets combined with losartan potassium in the treatment of chronic glomerulonephritis

Dear Dr. Zhu:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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Thank you for submitting your work to PLOS ONE and supporting open access.

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on behalf of

Prof. Giuseppe Remuzzi

Academic Editor

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