# Efficacy and Safety ofSalvia miltiorrhiza for Treating Chronic Kidney Diseases: A Systematic Review and Meta-Analysis

Authors: Wei Zhang; Jun Li; Pan Yang; Gaoqiang Wang; Yanli Yue; Yuanfang Zhong; Hanyin Liu; Dingkun Gui; Youhua Xu; Niansong Wang
Journal: Evidence-Based Complementary and Alternative Medicine
 (2022)

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## Abstract

Objective. This meta-analysis evaluated the effects and potential harms of Salvia miltiorrhiza or its extracts Salvianolate and Tanshinone for the treatment of population with a chronic kidney disease (CKD). Methods. We searched for the randomized clinical trials (RCTs) through databases including the Cochrane Library, PubMed, Embase, Web of Science, Current Controlled Trials, China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform (Wanfang Data), China Biology Medicine Disc (SinoMed), and Chinese Clinical Trial Registry (ChiCTR). Meta-analysis was performed with STATA 16 software after data extraction. The risk of bias was assessed with the Cochrane risk-of-bias tool (RoB 2.0), and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was employed to evaluate the quality of evidence. Result. A total of 32 studies were included involving 2264 participants. Compared to the control group, the treatment group significantly decreased serum creatinine (SCr) (SMD −0.60, 95% CI −0.79 to −0.41, P<0.0001), blood urea nitrogen (BUN) (SMD −0.66, 95% CI −0.81 to −0.50, P<0.0001), Cystatin C (CysC) (SMD −5.16, 95% CI −14.84 to 4.53, P=0.297), 24 hour urine protein (24 h UPE) (SMD −0.70, 95% CI −1.21 to −0.19, P=0.008), time to initiation of dialysis (Log RR 0.43, 95% CI 0.23 to 0.81, P=0.0089), serum total cholesterol (TC) (SMD −0.53, 95% CI −0.88 to −0.17, P=0.0042, P=0.0035), plasma fibrinogen (FIB) (SMD −0.79, 95% CI −1.12 to −0.46, P<0.0001), C-reactive protein (CRP) (SMD −0.56, 95% CI −0.93 to −0.19, P=0.0029); increased creatinine clearance (Ccr) (SMD 0.92, 95% CI 0.43 to 1.41, P=0.0002), glomerular filtration rate (GFR) (SMD 0.56, 95% CI 0.30 to 0.83, P<0.001), effective rate (Log RR 0.30, 95% CI 0.23 to 0.37, P<0.0001), and hemoglobin (Hb) (SMD 0.42, 95% CI 0.13 to 0.71, P=0.0042). Moreover, the incidences of adverse effects were similar between the two groups. Conclusions. Salvia miltiorrhiza or its extracts Salvianolate and Tanshinone, as a complementary therapy to conventional medicine, presents potential impacts to improve kidney functions and delay the progression of CKD without obvious adverse effects. However, the certainty of the evidence and the risk of bias are suboptimal and further clinical studies are still required to determine the underlying effects.


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## Body

## 1. Introduction

A chronic kidney disease (CKD) arises from various heterogeneous diseases. The diagnosis of CKD rests on establishing a chronic reduction in the kidney function and structural damage.The prevalence of CKD for stages 1–5 is 13.4% and 10.6% for stages 3–5 [1]. Contrary to diabetes or other metabolic diseases as prevalent as CKD, renal function impairment is often asymptomatic until very late stages [2]. According to the National Kidney Foundation, 30 million adults in the United States had CKD in 2017, and only 10 percent knew they had it, at a medical cost of $103 billion. In addition, CKD ranks fourteenth in the list of leading causes of death, which accounts for 12.2 deaths per 1,00,000 people, and the death rate of CKD will continue to increase to reach 14 per 1,00,000 people by 2030 [3]. In short, CKD has the characteristics of high incidence, high cost, high mortality, and low recognition rate.Patients with CKD need efficient treatments to delay disease progression and improve the quality of life and the survival rate. In China, Chinese herbal medicines (CHMs) are widely used for the treatment of CKD. There are many prescriptions containing varieties or single CHM for CKD. It could also be said that every doctor’s prescription may be different and is constantly modified during patients’ followup. Hence, comparing the efficacy of diverse prescriptions is inherently heterogeneous and is not conducive to promotion outside China. Furthermore, according to the traditional Chinese medicine (TCM) theory, promoting blood circulation and removing blood stasis should be adopted throughout the treatment of CKD.Salvia miltiorrhiza (Danshen) is one of the most commonly used CHMs. Studies have demonstrated that Salvia miltiorrhiza is the top single CHM prescribed for CKD in China [4]. Medicinal parts of Salvia miltiorrhiza (Danshen) is the dried root and rhizomes of Salvia miltiorrhiza Bge. Salvia miltiorrhiza has specific preparations for clinical applications, such as Salvia miltiorrhiza tablet or injection and its extracts Salvianolate injection as well as Tanshinone injection, which all have strict quality control standards and the procedures are fully reproducible. Salvia miltiorrhiza and its extracts Salvianolate and Tanshinone are extensively used for CKD.Clinically, a number of studies have displayed thatSalvia miltiorrhiza can improve kidney function in CKD patients by increasing the glomerular filtration rate (GFR) and creatinine clearance (Ccr) and reducing serum creatinine (SCr) and proteinuria, but this conclusion is yet to be verified [5]. Research studies also reveal that Salvia miltiorrhiza could alleviate kidney injury via inhibiting oxidative stress and apoptosis [6] and exerting prominent renal protective effects in iron-overloaded mice by decreasing of iron deposition and suppression of lipid peroxidation and apoptosis in the kidney [7]. Tanshinone IIA significantly attenuates kidney fibrosis by inhibiting the recruitment of fibrocytes into the kidney [8] and decreases renal damage in diabetic rats via inhibiting oxidative stress and inflammation [9]. Salvianolate might alleviate the renal damage in chronic renal failure rats through antioxidant stress [10], accordingly attenuating glomerular injury, including albuminuria secretion, mesangial matrix expansion, foot process effacement in the kidneys of db/db mice, and ameliorated oxidative podocyte injury [11].There is one previous meta-analysis that evaluated the efficacy and safety of Tanshinone for CKD [12], which includes 21 studies published before June 1, 2019. In our meta-analysis, we include Salvia miltiorrhiza and its extracts Salvianolate besides Tanshinone because they have a strong connection with each other and they are all widely used in China for CKD. All of the studies we included were published before November 9th, 2021. The subjects in the previous meta-analysis were diagnosed with diabetic nephropathy (3 studies), hypertensive renal damage (4 studies), renal vascular hypertension (1 study), and cardiorenal syndrome (1 study) rather than CKD (12 studies). Whereas, we focused on the subjects of patients diagnosed with CKD. The inclusion of subjects was more rigorous, whereas we may miss some patients with CKD who were diagnosed with hypertensive nephropathy or other diagnoses.The current meta-analysis was performed to comprehensively evaluate the efficacy and safety ofSalvia miltiorrhiza and its extracts Salvianolate and Tanshinone for the treatment of patients with CKD, with a view to provide substantial evidence for supporting its clinical application in CKD patients.


## 2. Methods

### 2.1. Protocol and Registration

This meta-analysis had been registered in PROSPEPO with registration number CRD42021291786.


### 2.2. Eligibility Criteria

#### 2.2.1. Types of Studies

All randomized controlled trials (RCTs) evaluating the efficacy ofSalvia miltiorrhiza for CKD were included.


#### 2.2.2. Types of Participants

(1) Inclusion Criteria. Adults and children with CKD at all stages.(2) Exclusion Criteria. Studies stating that participants had renal damage, but without baseline GFR, Ccr, or SCr; participants with diabetic nephropathy. These issues had been investigated in a previous study [13]; studies involving Salvia miltiorrhiza as one of several active components in a compound recipe were not included.


#### 2.2.3. Types of Interventions

Treatment group receivedSalvia miltiorrhiza or its extracts Salvianolate and Tanshinone. The control group received placebo, no treatment, or conventional treatment.


#### 2.2.4. Outcomes

(1) Primary outcomes. Kidney function measured by SCr, Ccr, GFR, blood urea nitrogen (BUN) cystatin C (CySC), or effective rate, proteinuria measured by 24 hour urinary protein excretion (24 h UPE), time to initiation of dialysis, and adverse effects.(2) Secondary outcomes. Nutritional status assessed by serum albumin (ALB) and serum total cholesterol (TC), anemia measured by hemoglobin (Hb), hemorheology index measured by plasma fibrinogen (FIB), and inflammatory factor measured by C-reactive protein (CRP).


### 2.3. Search Methods

This meta-analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020 [14,15]) (Supplementary Table S1). We searched the Cochrane Library, PubMed, Embase, Web of Science, Current Controlled Trials, and Chinese databases including China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform (Wanfang Data), China Biology Medicine Disc (SinoMed), and Chinese Clinical Trial Registry (ChiCTR) from inception until November 9th, 2021 (Supplementary Table S2).


### 2.4. Study Selection

The search strategy described was used to obtain titles and abstracts of studies that may be relevant to this review. Titles, abstracts, and full texts were screened independently by two authors who determined which met the inclusion criteria and excluded studies that were not appropriate.


### 2.5. Data Collection Process

Data extraction was carried out independently by the same two authors using a pre-tested data extraction form. If more than one publication of one study existed, the publication with the most complete data was used. Any discrepancy between published versions was to be highlighted. Disagreements between authors were resolved by consensus and with a third author.


### 2.6. Quality Assessment and Statistical Methods

The publications included in this meta-analysis were subject to quality assessment according to the Cochrane criteria [15]. The risk of bias was assessed using the Cochrane risk-of-bias tool (RoB. 2.0) [16]. In addition, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was employed to evaluate the quality of evidence contributing to each estimate [15].The STATA 16 software was used for data analysis. For dichotomous outcomes, results were expressed as Log risk ratio (Log RR) with 95% confidence intervals (CI). For continuous outcomes, the standard mean difference (SMD) was presented with 95% confidence intervals (CI).Heterogeneity was analyzed using a Chi2 test on N − 1 degrees of freedom, with an alpha of 0.1 used for statistical significance and with the I2-test [15]. I2 > 50% corresponds to high levels of heterogeneity, respectively. A subgroup or sensitivity analysis was conducted to explore the underlying causes of heterogeneity in treatment outcomes.To assess small-study effects, we generated Egger’s test or funnel plots [15] including at least 10 trials of varying size. If asymmetry was detected in the funnel plot, a contour-enhanced funnel plot was generated to assess whether the asymmetry was likely due to publication bias or other factors of the trials.


### 2.7. Additional Analyses

We conducted subgroup analyses to explore the impact ofSalvia miltiorrhiza and its extracts Salvianolate and Tanshinone preparations.


## 2.1. Protocol and Registration

This meta-analysis had been registered in PROSPEPO with registration number CRD42021291786.


## 2.2. Eligibility Criteria

### 2.2.1. Types of Studies

All randomized controlled trials (RCTs) evaluating the efficacy ofSalvia miltiorrhiza for CKD were included.


### 2.2.2. Types of Participants

(1) Inclusion Criteria. Adults and children with CKD at all stages.(2) Exclusion Criteria. Studies stating that participants had renal damage, but without baseline GFR, Ccr, or SCr; participants with diabetic nephropathy. These issues had been investigated in a previous study [13]; studies involving Salvia miltiorrhiza as one of several active components in a compound recipe were not included.


### 2.2.3. Types of Interventions

Treatment group receivedSalvia miltiorrhiza or its extracts Salvianolate and Tanshinone. The control group received placebo, no treatment, or conventional treatment.


### 2.2.4. Outcomes

(1) Primary outcomes. Kidney function measured by SCr, Ccr, GFR, blood urea nitrogen (BUN) cystatin C (CySC), or effective rate, proteinuria measured by 24 hour urinary protein excretion (24 h UPE), time to initiation of dialysis, and adverse effects.(2) Secondary outcomes. Nutritional status assessed by serum albumin (ALB) and serum total cholesterol (TC), anemia measured by hemoglobin (Hb), hemorheology index measured by plasma fibrinogen (FIB), and inflammatory factor measured by C-reactive protein (CRP).


## 2.2.1. Types of Studies

All randomized controlled trials (RCTs) evaluating the efficacy ofSalvia miltiorrhiza for CKD were included.


## 2.2.2. Types of Participants

(1) Inclusion Criteria. Adults and children with CKD at all stages.(2) Exclusion Criteria. Studies stating that participants had renal damage, but without baseline GFR, Ccr, or SCr; participants with diabetic nephropathy. These issues had been investigated in a previous study [13]; studies involving Salvia miltiorrhiza as one of several active components in a compound recipe were not included.


## 2.2.3. Types of Interventions

Treatment group receivedSalvia miltiorrhiza or its extracts Salvianolate and Tanshinone. The control group received placebo, no treatment, or conventional treatment.


## 2.2.4. Outcomes

(1) Primary outcomes. Kidney function measured by SCr, Ccr, GFR, blood urea nitrogen (BUN) cystatin C (CySC), or effective rate, proteinuria measured by 24 hour urinary protein excretion (24 h UPE), time to initiation of dialysis, and adverse effects.(2) Secondary outcomes. Nutritional status assessed by serum albumin (ALB) and serum total cholesterol (TC), anemia measured by hemoglobin (Hb), hemorheology index measured by plasma fibrinogen (FIB), and inflammatory factor measured by C-reactive protein (CRP).


## 2.3. Search Methods

This meta-analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020 [14,15]) (Supplementary Table S1). We searched the Cochrane Library, PubMed, Embase, Web of Science, Current Controlled Trials, and Chinese databases including China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform (Wanfang Data), China Biology Medicine Disc (SinoMed), and Chinese Clinical Trial Registry (ChiCTR) from inception until November 9th, 2021 (Supplementary Table S2).


## 2.4. Study Selection

The search strategy described was used to obtain titles and abstracts of studies that may be relevant to this review. Titles, abstracts, and full texts were screened independently by two authors who determined which met the inclusion criteria and excluded studies that were not appropriate.


## 2.5. Data Collection Process

Data extraction was carried out independently by the same two authors using a pre-tested data extraction form. If more than one publication of one study existed, the publication with the most complete data was used. Any discrepancy between published versions was to be highlighted. Disagreements between authors were resolved by consensus and with a third author.


## 2.6. Quality Assessment and Statistical Methods

The publications included in this meta-analysis were subject to quality assessment according to the Cochrane criteria [15]. The risk of bias was assessed using the Cochrane risk-of-bias tool (RoB. 2.0) [16]. In addition, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was employed to evaluate the quality of evidence contributing to each estimate [15].The STATA 16 software was used for data analysis. For dichotomous outcomes, results were expressed as Log risk ratio (Log RR) with 95% confidence intervals (CI). For continuous outcomes, the standard mean difference (SMD) was presented with 95% confidence intervals (CI).Heterogeneity was analyzed using a Chi2 test on N − 1 degrees of freedom, with an alpha of 0.1 used for statistical significance and with the I2-test [15]. I2 > 50% corresponds to high levels of heterogeneity, respectively. A subgroup or sensitivity analysis was conducted to explore the underlying causes of heterogeneity in treatment outcomes.To assess small-study effects, we generated Egger’s test or funnel plots [15] including at least 10 trials of varying size. If asymmetry was detected in the funnel plot, a contour-enhanced funnel plot was generated to assess whether the asymmetry was likely due to publication bias or other factors of the trials.


## 2.7. Additional Analyses

We conducted subgroup analyses to explore the impact ofSalvia miltiorrhiza and its extracts Salvianolate and Tanshinone preparations.


## 3. Results

### 3.1. Study Selection

Our initial search found 332 records. After excluding 47 duplicate reports and 232 irrelevant records based on identification of titles and abstracts, we reviewed 53 full-text studies for inclusion and then 21 studies were further excluded. Finally, a total of 32 studies were included in the meta-analysis (Figure1).Figure 1
Flow of information through the different phases of the meta-analysis.


### 3.2. Study Characteristics

32 included studies involved 2264 participants and were conducted in hospitals of China and published in Chinese. All studies were parallel arm. Participants’ age ranged from 18–96 years. Authors, year of publication, treatment plan, sample size, duration of treatment, and index of evaluation of each study are presented in Table1.Table 1
Characteristics of included studies.
Study YearTreatmentControlNumber (T/C)DurationResults reportBao et al. 2002 [17]Salvia miltiorrhiza injection (6–10 ml ivgtt qd) + conventional steroid treatmentConventional steroid treatment24/202 weeksScr, BUN, 24 h UPE, ALBHuang 2009 [18]Salvia miltiorrhiza injection (20 ml ivgtt qd) + conventional treatmentConventional treatment46/462 weeksEffective rateWang et al. 2015 [19]Salvia miltiorrhiza Injection (1 ml ivgtt qd) + Huang qi injection (2.5 ml) + conventional treatmentConventional treatment30/292 monthsScr, BUN, CcrWang and Zhao [20]Salvia miltiorrhiza injection (400 mg ivgtt qd) + conventional treatmentConventional treatment53/4535 daysEffective rate, SCrWang et al. 2008 [21]Salvianolate injection (200 mg ivgtt qd) + alprostadil Injection (30μg ivgtt qd) + reduced glutathione injection (2.4 g ivgtt qd) conventional treatmentConventional treatment42/427 daysBUN SCr, BUN, GFRLiu 2017 [22]Salvianolate injection (200 mg ivgtt qd) + conventional treatmentConventional treatment30/302 weeksCySC, adverse effectFu et al. 2012 [23]Salvianolate Injection (200 mg ivgtt qd) + alprostadil Injection (20μg ivgtt qd) + reduced glutathione Injection (2.4 g ivgtt qd) + conventional treatmentConventional treatment15/1512 to 64 monthsEffect time to initiation ofLiu 2015 [24]Salvianolate injection (100 mg ivgtt qd) + conventional treatmentConventional treatment16/162 weeksDialysis, adverse effect of SCr, BUNHu et al. 2011 [25]Salvianolate injection (200 mg ivgtt qd) + conventional treatmentConventional treatment27/274 weeksSCr, 24 h UPESun and Luo 2012 [26]Salvianolate injection (200 mg ivgtt qd) + conventional treatmentConventional treatment40/382 weeksEffective rate, SCrXiong et al. 2007 [27]Salvia miltiorrhiza injection (80 mg ivgtt qd) + TCM decoction ((Rhubarb 20 g, calcined keel 20 g, calcined oyster 20 g, dandelion 20 g, Ligusticum chuanxiong 20 g) 300 ml retention enema for 1-2 h, qd) + conventional treatmentConventional treatment40/4030 daysBUN, Ccr, adverse effect effective rate, SCrWang et al. 2007 [28]Salvia miltiorrhiza injection (800 mg ivgtt qd) + conventional treatmentXueshuantong Injection (450 mg ivgtt qd) + conventional treatment24/2315 daysBUN, GFR, Hb, ALB, adverse effect effective rateXu et al. 2011 [29]Salvia miltiorrhiza injection (20 ml ivgtt qd) + Huang qi injection (40 g ivgtt qd) + conventional treatmentConventional treatment39/362 weeksEffective rate, SCrGuohua et al. 2009 [30]Salvia miltiorrhiza tablet (4 pills tid p.o.) + irbesartan (150 mg qd p.o.) + conventional treatmentIrbesartan (150 mg qd pop.o.) + conventional treatment32/316 monthsBUN, CysC, Hb, ALB, CRP effective rate, SCrWang 2012 [31]Salvia miltiorrhiza injection (800 mg ivgtt qd) + Valsartan (80 mg p. o. qd) + conventional treatmentValsartan (80 mg p.o. qd) + conventional treatment30/304 weeksBUN, 24 h UPE, TC SCr, 24 h UPE, TCXiang and Mo 2011 [32]Sodium Tanshinone II A sulfonate injection (40 mg ivgtt qd) + TCM decoction ((Rhubarb 10 g, Calcined oyster 20 g, Dandelion 30 g) 400 ml retention enema for 20–30 m, bid) + conventional treatmentTCM decoction [(Rhubarb 10 g, Calcined oyster 20 g, Dandelion 30 g) 400 ml retention enema for 20–30 m, bid] + conventional treatment31/308 weeksSCr, BUN, CcrWang and Xian-Qin 2007 [33]Sodium Tanshinone II A sulfonate Injection (20 ml ivgtt qd) + conventional treatmentConventional treatment31/282 monthsFIB effective rate, SCrGao and Gao 2011 [34]Sodium Tanshinone II A sulfonate injection (50 mgivgtt qd) + conventional treatmentConventional treatment48/424 weeksBUN, Ccr SCr, BUN, 24 hWang 2014 [35]Sodium Tanshinone II A sulfonate injection (40 mg ivgtt qd) + Alprostadil injection (10μg ivgtt qd) + conventional treatmentConventional treatment32/3228 daysUPE, CySC, CRP, FIB SCr, BUN, GFRTian et al. 2005 [36]Salvia miltiorrhiza injection (60 ml ivgtt qd) + conventional treatmentConventional treatment106/9610 daysAdverse effect SCr, CcrPeng et al. 2010 [37]Sodium tanshinone II A sulfonate injection (50 mg ivgtt qd) + Haikunshenxi capsule (2 pills p.o. tid) + conventional treatmentConventional treatment30/283 weeksSCr, BUN, CcrXu et al. 2012 [38]Salvia miltiorrhiza injection (1200 mg ivgtt qd) + Haikunshenxi capsule (2 pills p.o. tid) + conventional treatmentConventional treatment30/3015 daysEffective rate, SCr,BUN, 24 h, UPE, ALB, Ccr, HbPeng et al. 2010 [39]Salvianolate injection (200 mg ivgtt qd) + AlprostadilConventional treatment29/282 weeksSCr, BUN, CcrLiu et al. [40]Salvianolate injection (100 mg ivgtt qd) + alprostadil injection (20μg ivgtt qd) + conventional treatmentAlprostadil injection (20μgivgtt qd) + conventional treatment63/634 weeksEffective rate, SCr,BUN, CcrLv et al. 2006 [41]Salvia miltiorrhiza tablet (4 pills tid p.o.) + Jieduxiezhuo II decoction 150 ml retention enema qd + conventional treatmentJieduxiezhuo II decoction 150 ml retention enema qd + conventional treatment30/301 monthEffective rate, SCr, BUN, HbGuowei et al. 2016 [42]Sodium Tanshinone II A sulfonate injection (40 mg ivgtt qd) + alprostadil injection (10μg ivgtt qd) + conventional treatmentConventional treatment27/152 weeksEffective rate, SCrPang 2004 [43]Salvia miltiorrhiza injection (30 ml ivgtt qd) + TCM decoction 200 ml retention enema bid + low molecular levo-anhydride injection (250 ml ivgtt qd) + conventional treatmentConventional treatment20/2012BUN, effective rate, SCrChen 2016 [44]Salvianolate Injection (150 mg ivgtt qd + conventional treatmentConventional treatment32/3214 daysSCr, BUN, CcrWang 2015 [45]Salvianolate injection (100 mg ivgtt qd) + Valsartan (80 mg p.o. qd) + conventional treatmentValsartan (80 mg p.o. qd) + conventional treatment45/452 weeksSCr, BUN, 24 h UPE, CySCZhi et al. 2016 [46]Salvianolate injection (200 mg ivgtt qd) + Shenshuaining granules (1 bag p.o. 3–4 times/day) + conventional treatmentConventional treatment31/312 weeksSCr, BUN, Ccr, adverse effectChen and Lu 2012 [47]Salvia miltiorrhiza injection (0.8 g ivgtt qd) + sodium ferulate injection (0.3 g ivgtt qd) + conventional treatmentConventional treatment36/325 weeksEffective rate, SCr, BUN, Ccr, HbXie et al. 2020 [48]Sodium tanshinone II A sulfonate injection (50 mg ivgtt qd) + Corbrin capsule (2 g p.o. tid) + conventional treatmentCorbrin capsule (2 g p.o.tid) + conventional53/522 monthsEffective rate, SCr, BUN, 24 h UPET. treatment group; C. control group; p.o.: per os; qd: quaque die; tid: ter in die; ivgtt: injectio intiavenosus gutta; 24 h UPE: 24 hour urine protein excretion; GFR: glomerular filtration rate; Ccr. creatinine clearance; SCr: serum creatinine; BUN: Blood urea nitrogen; CysC. cystatin C; ALB: serum albumin; TC: serum total cholesterol; Hb: haemoglobin; FIB: plasma fibrinogen; and CRP: C-reactive protein.


### 3.3. Risk of Bias

The 32 studies included were all RCTs, yet only 9 had detailed descriptions of the methods. In one study, computer-generated random numbers were used in the sequence generation process, and in 6 studies, random number tables were adopted. Nevertheless, in another 2 studies, patient record numbers were used. Only one study specified the method of blinding, and that was single-blind. All studies were assessed according to the RoB. 2.0 tool, of which 8 (25%) were assessed as “low risk of bias,” 22 (68.75%) as “some concerns,” and 2 (6.25%) as “high risk” (Figure2).Figure 2
Risk of bias.


### 3.4. Results of Included Studies

#### 3.4.1. Kidney Function

(1) SCr. A total of 29 studies compared Scr levels between the treatment and control group. We classified these studies into following subgroups based on the different preparations: Salvia miltiorrhiza, Salvianolate, and Tanshinone. As indicated in Figure 3, the random-effect model was used due to the high heterogeneity. Scr levels in the treatment group were significantly reduced compared with the control group (SMD −0.60, 95% CI −0.79 to −0.41, P<0.0001, I2 = 77.82%). Subgroup analysis revealed that all of the 3 subgroups notably decreased SCr compared with control group (Salvia miltiorrhiza group: SMD −0.41, 95% CI −0.59 to −0.22, P<0.0001, I2 = 38.4%. Salvianolate group: SMD −0.97, 95% CI −1.42 to −0.52, P<0.0001, I2 = 80.49%. Tanshinone group: SMD −0.48, 95% CI −0.68 to −0.29, P<0.0001, I2 = 32.90%). The Salvianolate group was the main source of heterogeneity. Then, we divided the studies of the Salvianolate group into various subgroups based on bias, when we removed the RCT of Wang et al. [21] which had the highest Scr and the Liu [24] with the smallest sample size, both low risk group and some concerns group had low heterogeneity (I2 = 0 and I2 = 6.03%).Figure 3
Forest plot of meta-analysis of SCr.Egger’s test exhibited that there was no publication biasP<0.001.(2) Ccr. A total of 13 studies compared Ccr levels between the treatment group and control group. We classified studies into different subgroups based on the preparations: Salvia miltiorrhiza, Salvianolate and Tanshinone. As demonstrated in Figure 4, the random-effect model was used because of the high heterogeneity. Ccr levels in the treatment group were significantly increased compared to the control group (SMD 0.92, 95% CI 0.43 to 1.41, P=0.0002, I2 = 92.51%). Subgroup analysis indicated that Ccr levels in the Salvianolate subgroups was distinctly increased compared with control group (SMD 1.55, 95% CI 0.56 to 2.53, P=0.002, I2 = 94.30%). Ccr levels in the Salvia miltiorrhiza and Tanshinone groups were increased but not significant compared with control group (SMD 0.46, 95% CI 0.06 to 0.87, P<0.0249, I2 = 58.82%; SMD 0.61, 95% CI −0.02 to 1.20, P=0.0426, I2 = 85.39%).Figure 4
Forest plot of meta-analysis of Ccr.Egger’s test displayed that there was no publication biasP=0.2624.(3) GFR. A total of 3 studies compared GFR levels between the treatment group and control group. As shown in Figure 5, the heterogeneity was low (I2 = 0%) and the fixed-effect model was employed to analyze the data. GFR levels in the treatment group were significantly increased compared with the control group (SMD 0.56, 95% CI 0.30 to 0.83, P<0.001, I2 = 0%).Figure 5
Forest plot of meta-analysis of GFR.(4) BUN. A total of 26 studies reported BUN levels between the two groups. As presented in Figure 6, the random-effect model was used due to the high heterogeneity. BUN levels in the treatment group were significantly reduced compared with the control group (SMD −0.66, 95% CI −0.81 to −0.50, P<0.0001, I2 = 60.89%). Subgroup analysis indicated that all of the 3 subgroups had decreased BUN compared with the control group (Salvia miltiorrhiza group: SMD −0.52, 95% CI −0.70 to −0.34, P<0.0001, I2 = 30.29%; Salvianolate group: SMD −0.90, 95% CI −1.28 to −0.52, P<0.0001, I2 = 79.72%; Tanshinone group: SMD −0.63, 95% CI −0.81 to −0.45, P<0.0001, I2 = 0%). The Salvianolate group was the main cause of heterogeneity.Figure 6
Forest plot of meta-analysis of BUN.Egger’s test reflected that no publication bias existedP=0.9602.(5) CysC. A total of 4 studies recorded CysC levels between the treatment group and control group. As presented in Figure 7, CysC levels in the treatment group were decreased but without significance compared with the control group (SMD −5.16, 95% CI −14.84 to 4.53, P=0.297, I2 = 99.93%).Figure 7
Forest plot of meta-analysis of CysC.(6) Effective Rate. A total of 15 studies compared the effective rate between the two groups. As listed in Figure 8(a), the effective rate in the treatment group was significantly higher compared with the control group (Log RR 0.30, 95% CI 0.23 to 0.37, P<0.0001, I2 = 0%), and the heterogeneity was low. Subgroup analysis indicated that the effective rates were remarkably higher in Salvia miltiorrhiza and Tanshinone groups compared to the control group (Log RR 0.40, 95% CI 0.30 to 0.50, P<0.0001, I2 = 0%; Log RR 0.28 95% CI 0.11 to 0.44, P<0.001, I2 = 0%), the effective rate was higher in the Salvianolate group compared with the control group (Log RR 0.30, 95% CI -0.07 to 0.68, P=0.113, I2 = 76.77%). Liu et al. [40] used alprostadil injection combined Salvianolate injection in the treatment group, which might bias the heterogeneity. Furthermore, removal of this study resulted in a considerable reduced I2 (I2 = 0%).Figure 8
(a) Forest plot of meta-analysis of effective rate. (b) Contour-enhanced funnel plot of meta-analysis of the effective rate.
(a)(b)Egger’s test revealed that there was publication bias (P<0.05). As shown in Figure 8(b), 7 studies were imputed and 2 studies were in the area of 5% <P<10%.


#### 3.4.2. 24 h UPE

A total of 10 studies compared 24 h UPE levels between the treatment group and control group. As suggested in Figure9, 24 h UPE levels in the treatment group were observably reduced compared with the control group (SMD −0.70, 95% CI −1.21 to −0.19, P=0.008, I2 = 90.36%). We classified these studies into three subgroups based on the degrees of 24 h UPE: ≤1.0 g, 1.0–3.5 g, ≥3.5 g. Subgroup analysis indicated that the effect of Salvia miltiorrhiza was inversely proportional to the degree of proteinuria. (SMD −11.33, 95% CI −1.88 to −0.79, P<0.0001, I2 = 74.43%; SMD −0.49, 95% CI −1.16 to −0.19, P=0.159, I2 = 90.43%; SMD 0.03, 95% CI −0.55 to 0.62, P=0.912).Figure 9
Forest plot of meta-analysis of 24 h UPE.Egger’s test hinted that there was no publication biasP=0.5167.


#### 3.4.3. Time to Initiation of Dialysis

There was only one study [23] that reported the time to initiation of dialysis. As demonstrated in Figure 10, in comparison with the control group, there were less CKD patients into initiation of dialysis in the treatment group (Log RR 0.43, 95% CI 0.23 to 0.81, P=0.0089).Figure 10
Forest plot of meta-analysis of time to initiation of dialysis.


#### 3.4.4. Adverse Effects

In all, 13 studies reported adverse effects. As presented in Figure11(a), adverse effects in the treatment group did not differ significantly from that of the control group (Log RR −0.52, 95% CI: −1.16 to 0.12, P=0.1112, I2 = 0%).Figure 11
(a) Forest plot of meta-analysis of adverse effects. (b) Contour-enhanced funnel plot of meta-analysis of adverse effects.
(a)(b)Egger’s test indicated that there was publication biasP=0.0349. As shown in Figure 11(b), 7 studies were imputed, 2 studies were in the area of 1% < P < 5%, and one study was in the area of 5% < P < 10%.


#### 3.4.5. Nutritional Status

(1) ALB. A total of 4 studies documented ALB levels between the treatment group and control group. As displayed in Figure 12, there was no significance between the Salvia miltiorrhiza group and control group (SMD 0.23, 95% CI −0.28 to 0.75, P=0.3775, I2 = 76.82%).Figure 12
Forest plot of meta-analysis of ALB.(2) TC. A total of 2 studies recorded TC levels between the treatment group and control group. As expressed in Figure 13, TC levels in the treatment group were distinctly reduced compared with the control group (SMD −0.53, 95% CI−0.88 to −0.17, P=0.0035, I2 = 0%).Figure 13
Forest plot of meta-analysis of TC.


#### 3.4.6. Anemia Measured: Hb

A total of 6 studies reported HB levels. As manifested in Figure14, Hb levels in the treatment group were significantly enhanced compared with the control group (SMD 0.42, 95% CI 0.13 to 0.71, P=0.0042, I2 = 50.39%).Figure 14
Forest plot of meta-analysis of Hb.


#### 3.4.7. Hemorheology Index: FIB

A total of 2 studies had data of FIB levels. As presented in Figure15, FIB levels in the treatment group were significantly reduced compared with the control group (SMD −0.79, 95% CI −1.12 to −0.46, P<0.0001, I2 = 0%).Figure 15
Forest plot of meta-analysis of FIB.


#### 3.4.8. Inflammatory Factor: CRP

A total of 3 studies compared CRP levels between the treatment group and control group. As displayed in Figure16, CRP levels in the treatment group were notably reduced compared with the control group (SMD −0.56, 95% CI −0.93 to −0.19, P=0.0029, I2 = 56.31%).Figure 16
Forest plot of meta-analysis of CRP.


### 3.5. Certainty of Evidence

All outcome indicators were evaluated by GRADEpro GDT. The quality of evidence was downgraded for the risk of bias or publication bias. After comprehensive analysis, the summary table was formed, and it was found that 2 outcome indicators (14.29%) were of high quality, 12 outcome indicators (71.43%) were of moderate quality, and 2 outcome indicators (14.29%) were of low quality (Supplementary TableS3).


### 3.6. Publication Bias

Egger’s test declared that no publication bias in the indicators of SCr, CCr, BUN, and 24 h UPE were observed. Whereas, there was publication bias in the indicator of the effective rate; the contour-enhanced funnel plot suggested that 7 studies were imputed and 2 studies were in the area of 5% <P < 10%. In the indicator of adverse effects, Egger’s test hinted that there existed a publication bias, 7 studies were imputed, 2 studies were in the area of 1% < P < 5%, and another one study was in the area of 5% < P < 10%.


## 3.1. Study Selection

Our initial search found 332 records. After excluding 47 duplicate reports and 232 irrelevant records based on identification of titles and abstracts, we reviewed 53 full-text studies for inclusion and then 21 studies were further excluded. Finally, a total of 32 studies were included in the meta-analysis (Figure1).Figure 1
Flow of information through the different phases of the meta-analysis.


## 3.2. Study Characteristics

32 included studies involved 2264 participants and were conducted in hospitals of China and published in Chinese. All studies were parallel arm. Participants’ age ranged from 18–96 years. Authors, year of publication, treatment plan, sample size, duration of treatment, and index of evaluation of each study are presented in Table1.Table 1
Characteristics of included studies.
Study YearTreatmentControlNumber (T/C)DurationResults reportBao et al. 2002 [17]Salvia miltiorrhiza injection (6–10 ml ivgtt qd) + conventional steroid treatmentConventional steroid treatment24/202 weeksScr, BUN, 24 h UPE, ALBHuang 2009 [18]Salvia miltiorrhiza injection (20 ml ivgtt qd) + conventional treatmentConventional treatment46/462 weeksEffective rateWang et al. 2015 [19]Salvia miltiorrhiza Injection (1 ml ivgtt qd) + Huang qi injection (2.5 ml) + conventional treatmentConventional treatment30/292 monthsScr, BUN, CcrWang and Zhao [20]Salvia miltiorrhiza injection (400 mg ivgtt qd) + conventional treatmentConventional treatment53/4535 daysEffective rate, SCrWang et al. 2008 [21]Salvianolate injection (200 mg ivgtt qd) + alprostadil Injection (30μg ivgtt qd) + reduced glutathione injection (2.4 g ivgtt qd) conventional treatmentConventional treatment42/427 daysBUN SCr, BUN, GFRLiu 2017 [22]Salvianolate injection (200 mg ivgtt qd) + conventional treatmentConventional treatment30/302 weeksCySC, adverse effectFu et al. 2012 [23]Salvianolate Injection (200 mg ivgtt qd) + alprostadil Injection (20μg ivgtt qd) + reduced glutathione Injection (2.4 g ivgtt qd) + conventional treatmentConventional treatment15/1512 to 64 monthsEffect time to initiation ofLiu 2015 [24]Salvianolate injection (100 mg ivgtt qd) + conventional treatmentConventional treatment16/162 weeksDialysis, adverse effect of SCr, BUNHu et al. 2011 [25]Salvianolate injection (200 mg ivgtt qd) + conventional treatmentConventional treatment27/274 weeksSCr, 24 h UPESun and Luo 2012 [26]Salvianolate injection (200 mg ivgtt qd) + conventional treatmentConventional treatment40/382 weeksEffective rate, SCrXiong et al. 2007 [27]Salvia miltiorrhiza injection (80 mg ivgtt qd) + TCM decoction ((Rhubarb 20 g, calcined keel 20 g, calcined oyster 20 g, dandelion 20 g, Ligusticum chuanxiong 20 g) 300 ml retention enema for 1-2 h, qd) + conventional treatmentConventional treatment40/4030 daysBUN, Ccr, adverse effect effective rate, SCrWang et al. 2007 [28]Salvia miltiorrhiza injection (800 mg ivgtt qd) + conventional treatmentXueshuantong Injection (450 mg ivgtt qd) + conventional treatment24/2315 daysBUN, GFR, Hb, ALB, adverse effect effective rateXu et al. 2011 [29]Salvia miltiorrhiza injection (20 ml ivgtt qd) + Huang qi injection (40 g ivgtt qd) + conventional treatmentConventional treatment39/362 weeksEffective rate, SCrGuohua et al. 2009 [30]Salvia miltiorrhiza tablet (4 pills tid p.o.) + irbesartan (150 mg qd p.o.) + conventional treatmentIrbesartan (150 mg qd pop.o.) + conventional treatment32/316 monthsBUN, CysC, Hb, ALB, CRP effective rate, SCrWang 2012 [31]Salvia miltiorrhiza injection (800 mg ivgtt qd) + Valsartan (80 mg p. o. qd) + conventional treatmentValsartan (80 mg p.o. qd) + conventional treatment30/304 weeksBUN, 24 h UPE, TC SCr, 24 h UPE, TCXiang and Mo 2011 [32]Sodium Tanshinone II A sulfonate injection (40 mg ivgtt qd) + TCM decoction ((Rhubarb 10 g, Calcined oyster 20 g, Dandelion 30 g) 400 ml retention enema for 20–30 m, bid) + conventional treatmentTCM decoction [(Rhubarb 10 g, Calcined oyster 20 g, Dandelion 30 g) 400 ml retention enema for 20–30 m, bid] + conventional treatment31/308 weeksSCr, BUN, CcrWang and Xian-Qin 2007 [33]Sodium Tanshinone II A sulfonate Injection (20 ml ivgtt qd) + conventional treatmentConventional treatment31/282 monthsFIB effective rate, SCrGao and Gao 2011 [34]Sodium Tanshinone II A sulfonate injection (50 mgivgtt qd) + conventional treatmentConventional treatment48/424 weeksBUN, Ccr SCr, BUN, 24 hWang 2014 [35]Sodium Tanshinone II A sulfonate injection (40 mg ivgtt qd) + Alprostadil injection (10μg ivgtt qd) + conventional treatmentConventional treatment32/3228 daysUPE, CySC, CRP, FIB SCr, BUN, GFRTian et al. 2005 [36]Salvia miltiorrhiza injection (60 ml ivgtt qd) + conventional treatmentConventional treatment106/9610 daysAdverse effect SCr, CcrPeng et al. 2010 [37]Sodium tanshinone II A sulfonate injection (50 mg ivgtt qd) + Haikunshenxi capsule (2 pills p.o. tid) + conventional treatmentConventional treatment30/283 weeksSCr, BUN, CcrXu et al. 2012 [38]Salvia miltiorrhiza injection (1200 mg ivgtt qd) + Haikunshenxi capsule (2 pills p.o. tid) + conventional treatmentConventional treatment30/3015 daysEffective rate, SCr,BUN, 24 h, UPE, ALB, Ccr, HbPeng et al. 2010 [39]Salvianolate injection (200 mg ivgtt qd) + AlprostadilConventional treatment29/282 weeksSCr, BUN, CcrLiu et al. [40]Salvianolate injection (100 mg ivgtt qd) + alprostadil injection (20μg ivgtt qd) + conventional treatmentAlprostadil injection (20μgivgtt qd) + conventional treatment63/634 weeksEffective rate, SCr,BUN, CcrLv et al. 2006 [41]Salvia miltiorrhiza tablet (4 pills tid p.o.) + Jieduxiezhuo II decoction 150 ml retention enema qd + conventional treatmentJieduxiezhuo II decoction 150 ml retention enema qd + conventional treatment30/301 monthEffective rate, SCr, BUN, HbGuowei et al. 2016 [42]Sodium Tanshinone II A sulfonate injection (40 mg ivgtt qd) + alprostadil injection (10μg ivgtt qd) + conventional treatmentConventional treatment27/152 weeksEffective rate, SCrPang 2004 [43]Salvia miltiorrhiza injection (30 ml ivgtt qd) + TCM decoction 200 ml retention enema bid + low molecular levo-anhydride injection (250 ml ivgtt qd) + conventional treatmentConventional treatment20/2012BUN, effective rate, SCrChen 2016 [44]Salvianolate Injection (150 mg ivgtt qd + conventional treatmentConventional treatment32/3214 daysSCr, BUN, CcrWang 2015 [45]Salvianolate injection (100 mg ivgtt qd) + Valsartan (80 mg p.o. qd) + conventional treatmentValsartan (80 mg p.o. qd) + conventional treatment45/452 weeksSCr, BUN, 24 h UPE, CySCZhi et al. 2016 [46]Salvianolate injection (200 mg ivgtt qd) + Shenshuaining granules (1 bag p.o. 3–4 times/day) + conventional treatmentConventional treatment31/312 weeksSCr, BUN, Ccr, adverse effectChen and Lu 2012 [47]Salvia miltiorrhiza injection (0.8 g ivgtt qd) + sodium ferulate injection (0.3 g ivgtt qd) + conventional treatmentConventional treatment36/325 weeksEffective rate, SCr, BUN, Ccr, HbXie et al. 2020 [48]Sodium tanshinone II A sulfonate injection (50 mg ivgtt qd) + Corbrin capsule (2 g p.o. tid) + conventional treatmentCorbrin capsule (2 g p.o.tid) + conventional53/522 monthsEffective rate, SCr, BUN, 24 h UPET. treatment group; C. control group; p.o.: per os; qd: quaque die; tid: ter in die; ivgtt: injectio intiavenosus gutta; 24 h UPE: 24 hour urine protein excretion; GFR: glomerular filtration rate; Ccr. creatinine clearance; SCr: serum creatinine; BUN: Blood urea nitrogen; CysC. cystatin C; ALB: serum albumin; TC: serum total cholesterol; Hb: haemoglobin; FIB: plasma fibrinogen; and CRP: C-reactive protein.


## 3.3. Risk of Bias

The 32 studies included were all RCTs, yet only 9 had detailed descriptions of the methods. In one study, computer-generated random numbers were used in the sequence generation process, and in 6 studies, random number tables were adopted. Nevertheless, in another 2 studies, patient record numbers were used. Only one study specified the method of blinding, and that was single-blind. All studies were assessed according to the RoB. 2.0 tool, of which 8 (25%) were assessed as “low risk of bias,” 22 (68.75%) as “some concerns,” and 2 (6.25%) as “high risk” (Figure2).Figure 2
Risk of bias.


## 3.4. Results of Included Studies

### 3.4.1. Kidney Function

(1) SCr. A total of 29 studies compared Scr levels between the treatment and control group. We classified these studies into following subgroups based on the different preparations: Salvia miltiorrhiza, Salvianolate, and Tanshinone. As indicated in Figure 3, the random-effect model was used due to the high heterogeneity. Scr levels in the treatment group were significantly reduced compared with the control group (SMD −0.60, 95% CI −0.79 to −0.41, P<0.0001, I2 = 77.82%). Subgroup analysis revealed that all of the 3 subgroups notably decreased SCr compared with control group (Salvia miltiorrhiza group: SMD −0.41, 95% CI −0.59 to −0.22, P<0.0001, I2 = 38.4%. Salvianolate group: SMD −0.97, 95% CI −1.42 to −0.52, P<0.0001, I2 = 80.49%. Tanshinone group: SMD −0.48, 95% CI −0.68 to −0.29, P<0.0001, I2 = 32.90%). The Salvianolate group was the main source of heterogeneity. Then, we divided the studies of the Salvianolate group into various subgroups based on bias, when we removed the RCT of Wang et al. [21] which had the highest Scr and the Liu [24] with the smallest sample size, both low risk group and some concerns group had low heterogeneity (I2 = 0 and I2 = 6.03%).Figure 3
Forest plot of meta-analysis of SCr.Egger’s test exhibited that there was no publication biasP<0.001.(2) Ccr. A total of 13 studies compared Ccr levels between the treatment group and control group. We classified studies into different subgroups based on the preparations: Salvia miltiorrhiza, Salvianolate and Tanshinone. As demonstrated in Figure 4, the random-effect model was used because of the high heterogeneity. Ccr levels in the treatment group were significantly increased compared to the control group (SMD 0.92, 95% CI 0.43 to 1.41, P=0.0002, I2 = 92.51%). Subgroup analysis indicated that Ccr levels in the Salvianolate subgroups was distinctly increased compared with control group (SMD 1.55, 95% CI 0.56 to 2.53, P=0.002, I2 = 94.30%). Ccr levels in the Salvia miltiorrhiza and Tanshinone groups were increased but not significant compared with control group (SMD 0.46, 95% CI 0.06 to 0.87, P<0.0249, I2 = 58.82%; SMD 0.61, 95% CI −0.02 to 1.20, P=0.0426, I2 = 85.39%).Figure 4
Forest plot of meta-analysis of Ccr.Egger’s test displayed that there was no publication biasP=0.2624.(3) GFR. A total of 3 studies compared GFR levels between the treatment group and control group. As shown in Figure 5, the heterogeneity was low (I2 = 0%) and the fixed-effect model was employed to analyze the data. GFR levels in the treatment group were significantly increased compared with the control group (SMD 0.56, 95% CI 0.30 to 0.83, P<0.001, I2 = 0%).Figure 5
Forest plot of meta-analysis of GFR.(4) BUN. A total of 26 studies reported BUN levels between the two groups. As presented in Figure 6, the random-effect model was used due to the high heterogeneity. BUN levels in the treatment group were significantly reduced compared with the control group (SMD −0.66, 95% CI −0.81 to −0.50, P<0.0001, I2 = 60.89%). Subgroup analysis indicated that all of the 3 subgroups had decreased BUN compared with the control group (Salvia miltiorrhiza group: SMD −0.52, 95% CI −0.70 to −0.34, P<0.0001, I2 = 30.29%; Salvianolate group: SMD −0.90, 95% CI −1.28 to −0.52, P<0.0001, I2 = 79.72%; Tanshinone group: SMD −0.63, 95% CI −0.81 to −0.45, P<0.0001, I2 = 0%). The Salvianolate group was the main cause of heterogeneity.Figure 6
Forest plot of meta-analysis of BUN.Egger’s test reflected that no publication bias existedP=0.9602.(5) CysC. A total of 4 studies recorded CysC levels between the treatment group and control group. As presented in Figure 7, CysC levels in the treatment group were decreased but without significance compared with the control group (SMD −5.16, 95% CI −14.84 to 4.53, P=0.297, I2 = 99.93%).Figure 7
Forest plot of meta-analysis of CysC.(6) Effective Rate. A total of 15 studies compared the effective rate between the two groups. As listed in Figure 8(a), the effective rate in the treatment group was significantly higher compared with the control group (Log RR 0.30, 95% CI 0.23 to 0.37, P<0.0001, I2 = 0%), and the heterogeneity was low. Subgroup analysis indicated that the effective rates were remarkably higher in Salvia miltiorrhiza and Tanshinone groups compared to the control group (Log RR 0.40, 95% CI 0.30 to 0.50, P<0.0001, I2 = 0%; Log RR 0.28 95% CI 0.11 to 0.44, P<0.001, I2 = 0%), the effective rate was higher in the Salvianolate group compared with the control group (Log RR 0.30, 95% CI -0.07 to 0.68, P=0.113, I2 = 76.77%). Liu et al. [40] used alprostadil injection combined Salvianolate injection in the treatment group, which might bias the heterogeneity. Furthermore, removal of this study resulted in a considerable reduced I2 (I2 = 0%).Figure 8
(a) Forest plot of meta-analysis of effective rate. (b) Contour-enhanced funnel plot of meta-analysis of the effective rate.
(a)(b)Egger’s test revealed that there was publication bias (P<0.05). As shown in Figure 8(b), 7 studies were imputed and 2 studies were in the area of 5% <P<10%.


### 3.4.2. 24 h UPE

A total of 10 studies compared 24 h UPE levels between the treatment group and control group. As suggested in Figure9, 24 h UPE levels in the treatment group were observably reduced compared with the control group (SMD −0.70, 95% CI −1.21 to −0.19, P=0.008, I2 = 90.36%). We classified these studies into three subgroups based on the degrees of 24 h UPE: ≤1.0 g, 1.0–3.5 g, ≥3.5 g. Subgroup analysis indicated that the effect of Salvia miltiorrhiza was inversely proportional to the degree of proteinuria. (SMD −11.33, 95% CI −1.88 to −0.79, P<0.0001, I2 = 74.43%; SMD −0.49, 95% CI −1.16 to −0.19, P=0.159, I2 = 90.43%; SMD 0.03, 95% CI −0.55 to 0.62, P=0.912).Figure 9
Forest plot of meta-analysis of 24 h UPE.Egger’s test hinted that there was no publication biasP=0.5167.


### 3.4.3. Time to Initiation of Dialysis

There was only one study [23] that reported the time to initiation of dialysis. As demonstrated in Figure 10, in comparison with the control group, there were less CKD patients into initiation of dialysis in the treatment group (Log RR 0.43, 95% CI 0.23 to 0.81, P=0.0089).Figure 10
Forest plot of meta-analysis of time to initiation of dialysis.


### 3.4.4. Adverse Effects

In all, 13 studies reported adverse effects. As presented in Figure11(a), adverse effects in the treatment group did not differ significantly from that of the control group (Log RR −0.52, 95% CI: −1.16 to 0.12, P=0.1112, I2 = 0%).Figure 11
(a) Forest plot of meta-analysis of adverse effects. (b) Contour-enhanced funnel plot of meta-analysis of adverse effects.
(a)(b)Egger’s test indicated that there was publication biasP=0.0349. As shown in Figure 11(b), 7 studies were imputed, 2 studies were in the area of 1% < P < 5%, and one study was in the area of 5% < P < 10%.


### 3.4.5. Nutritional Status

(1) ALB. A total of 4 studies documented ALB levels between the treatment group and control group. As displayed in Figure 12, there was no significance between the Salvia miltiorrhiza group and control group (SMD 0.23, 95% CI −0.28 to 0.75, P=0.3775, I2 = 76.82%).Figure 12
Forest plot of meta-analysis of ALB.(2) TC. A total of 2 studies recorded TC levels between the treatment group and control group. As expressed in Figure 13, TC levels in the treatment group were distinctly reduced compared with the control group (SMD −0.53, 95% CI−0.88 to −0.17, P=0.0035, I2 = 0%).Figure 13
Forest plot of meta-analysis of TC.


### 3.4.6. Anemia Measured: Hb

A total of 6 studies reported HB levels. As manifested in Figure14, Hb levels in the treatment group were significantly enhanced compared with the control group (SMD 0.42, 95% CI 0.13 to 0.71, P=0.0042, I2 = 50.39%).Figure 14
Forest plot of meta-analysis of Hb.


### 3.4.7. Hemorheology Index: FIB

A total of 2 studies had data of FIB levels. As presented in Figure15, FIB levels in the treatment group were significantly reduced compared with the control group (SMD −0.79, 95% CI −1.12 to −0.46, P<0.0001, I2 = 0%).Figure 15
Forest plot of meta-analysis of FIB.


### 3.4.8. Inflammatory Factor: CRP

A total of 3 studies compared CRP levels between the treatment group and control group. As displayed in Figure16, CRP levels in the treatment group were notably reduced compared with the control group (SMD −0.56, 95% CI −0.93 to −0.19, P=0.0029, I2 = 56.31%).Figure 16
Forest plot of meta-analysis of CRP.


## 3.4.1. Kidney Function

(1) SCr. A total of 29 studies compared Scr levels between the treatment and control group. We classified these studies into following subgroups based on the different preparations: Salvia miltiorrhiza, Salvianolate, and Tanshinone. As indicated in Figure 3, the random-effect model was used due to the high heterogeneity. Scr levels in the treatment group were significantly reduced compared with the control group (SMD −0.60, 95% CI −0.79 to −0.41, P<0.0001, I2 = 77.82%). Subgroup analysis revealed that all of the 3 subgroups notably decreased SCr compared with control group (Salvia miltiorrhiza group: SMD −0.41, 95% CI −0.59 to −0.22, P<0.0001, I2 = 38.4%. Salvianolate group: SMD −0.97, 95% CI −1.42 to −0.52, P<0.0001, I2 = 80.49%. Tanshinone group: SMD −0.48, 95% CI −0.68 to −0.29, P<0.0001, I2 = 32.90%). The Salvianolate group was the main source of heterogeneity. Then, we divided the studies of the Salvianolate group into various subgroups based on bias, when we removed the RCT of Wang et al. [21] which had the highest Scr and the Liu [24] with the smallest sample size, both low risk group and some concerns group had low heterogeneity (I2 = 0 and I2 = 6.03%).Figure 3
Forest plot of meta-analysis of SCr.Egger’s test exhibited that there was no publication biasP<0.001.(2) Ccr. A total of 13 studies compared Ccr levels between the treatment group and control group. We classified studies into different subgroups based on the preparations: Salvia miltiorrhiza, Salvianolate and Tanshinone. As demonstrated in Figure 4, the random-effect model was used because of the high heterogeneity. Ccr levels in the treatment group were significantly increased compared to the control group (SMD 0.92, 95% CI 0.43 to 1.41, P=0.0002, I2 = 92.51%). Subgroup analysis indicated that Ccr levels in the Salvianolate subgroups was distinctly increased compared with control group (SMD 1.55, 95% CI 0.56 to 2.53, P=0.002, I2 = 94.30%). Ccr levels in the Salvia miltiorrhiza and Tanshinone groups were increased but not significant compared with control group (SMD 0.46, 95% CI 0.06 to 0.87, P<0.0249, I2 = 58.82%; SMD 0.61, 95% CI −0.02 to 1.20, P=0.0426, I2 = 85.39%).Figure 4
Forest plot of meta-analysis of Ccr.Egger’s test displayed that there was no publication biasP=0.2624.(3) GFR. A total of 3 studies compared GFR levels between the treatment group and control group. As shown in Figure 5, the heterogeneity was low (I2 = 0%) and the fixed-effect model was employed to analyze the data. GFR levels in the treatment group were significantly increased compared with the control group (SMD 0.56, 95% CI 0.30 to 0.83, P<0.001, I2 = 0%).Figure 5
Forest plot of meta-analysis of GFR.(4) BUN. A total of 26 studies reported BUN levels between the two groups. As presented in Figure 6, the random-effect model was used due to the high heterogeneity. BUN levels in the treatment group were significantly reduced compared with the control group (SMD −0.66, 95% CI −0.81 to −0.50, P<0.0001, I2 = 60.89%). Subgroup analysis indicated that all of the 3 subgroups had decreased BUN compared with the control group (Salvia miltiorrhiza group: SMD −0.52, 95% CI −0.70 to −0.34, P<0.0001, I2 = 30.29%; Salvianolate group: SMD −0.90, 95% CI −1.28 to −0.52, P<0.0001, I2 = 79.72%; Tanshinone group: SMD −0.63, 95% CI −0.81 to −0.45, P<0.0001, I2 = 0%). The Salvianolate group was the main cause of heterogeneity.Figure 6
Forest plot of meta-analysis of BUN.Egger’s test reflected that no publication bias existedP=0.9602.(5) CysC. A total of 4 studies recorded CysC levels between the treatment group and control group. As presented in Figure 7, CysC levels in the treatment group were decreased but without significance compared with the control group (SMD −5.16, 95% CI −14.84 to 4.53, P=0.297, I2 = 99.93%).Figure 7
Forest plot of meta-analysis of CysC.(6) Effective Rate. A total of 15 studies compared the effective rate between the two groups. As listed in Figure 8(a), the effective rate in the treatment group was significantly higher compared with the control group (Log RR 0.30, 95% CI 0.23 to 0.37, P<0.0001, I2 = 0%), and the heterogeneity was low. Subgroup analysis indicated that the effective rates were remarkably higher in Salvia miltiorrhiza and Tanshinone groups compared to the control group (Log RR 0.40, 95% CI 0.30 to 0.50, P<0.0001, I2 = 0%; Log RR 0.28 95% CI 0.11 to 0.44, P<0.001, I2 = 0%), the effective rate was higher in the Salvianolate group compared with the control group (Log RR 0.30, 95% CI -0.07 to 0.68, P=0.113, I2 = 76.77%). Liu et al. [40] used alprostadil injection combined Salvianolate injection in the treatment group, which might bias the heterogeneity. Furthermore, removal of this study resulted in a considerable reduced I2 (I2 = 0%).Figure 8
(a) Forest plot of meta-analysis of effective rate. (b) Contour-enhanced funnel plot of meta-analysis of the effective rate.
(a)(b)Egger’s test revealed that there was publication bias (P<0.05). As shown in Figure 8(b), 7 studies were imputed and 2 studies were in the area of 5% <P<10%.


## 3.4.2. 24 h UPE

A total of 10 studies compared 24 h UPE levels between the treatment group and control group. As suggested in Figure9, 24 h UPE levels in the treatment group were observably reduced compared with the control group (SMD −0.70, 95% CI −1.21 to −0.19, P=0.008, I2 = 90.36%). We classified these studies into three subgroups based on the degrees of 24 h UPE: ≤1.0 g, 1.0–3.5 g, ≥3.5 g. Subgroup analysis indicated that the effect of Salvia miltiorrhiza was inversely proportional to the degree of proteinuria. (SMD −11.33, 95% CI −1.88 to −0.79, P<0.0001, I2 = 74.43%; SMD −0.49, 95% CI −1.16 to −0.19, P=0.159, I2 = 90.43%; SMD 0.03, 95% CI −0.55 to 0.62, P=0.912).Figure 9
Forest plot of meta-analysis of 24 h UPE.Egger’s test hinted that there was no publication biasP=0.5167.


## 3.4.3. Time to Initiation of Dialysis

There was only one study [23] that reported the time to initiation of dialysis. As demonstrated in Figure 10, in comparison with the control group, there were less CKD patients into initiation of dialysis in the treatment group (Log RR 0.43, 95% CI 0.23 to 0.81, P=0.0089).Figure 10
Forest plot of meta-analysis of time to initiation of dialysis.


## 3.4.4. Adverse Effects

In all, 13 studies reported adverse effects. As presented in Figure11(a), adverse effects in the treatment group did not differ significantly from that of the control group (Log RR −0.52, 95% CI: −1.16 to 0.12, P=0.1112, I2 = 0%).Figure 11
(a) Forest plot of meta-analysis of adverse effects. (b) Contour-enhanced funnel plot of meta-analysis of adverse effects.
(a)(b)Egger’s test indicated that there was publication biasP=0.0349. As shown in Figure 11(b), 7 studies were imputed, 2 studies were in the area of 1% < P < 5%, and one study was in the area of 5% < P < 10%.


## 3.4.5. Nutritional Status

(1) ALB. A total of 4 studies documented ALB levels between the treatment group and control group. As displayed in Figure 12, there was no significance between the Salvia miltiorrhiza group and control group (SMD 0.23, 95% CI −0.28 to 0.75, P=0.3775, I2 = 76.82%).Figure 12
Forest plot of meta-analysis of ALB.(2) TC. A total of 2 studies recorded TC levels between the treatment group and control group. As expressed in Figure 13, TC levels in the treatment group were distinctly reduced compared with the control group (SMD −0.53, 95% CI−0.88 to −0.17, P=0.0035, I2 = 0%).Figure 13
Forest plot of meta-analysis of TC.


## 3.4.6. Anemia Measured: Hb

A total of 6 studies reported HB levels. As manifested in Figure14, Hb levels in the treatment group were significantly enhanced compared with the control group (SMD 0.42, 95% CI 0.13 to 0.71, P=0.0042, I2 = 50.39%).Figure 14
Forest plot of meta-analysis of Hb.


## 3.4.7. Hemorheology Index: FIB

A total of 2 studies had data of FIB levels. As presented in Figure15, FIB levels in the treatment group were significantly reduced compared with the control group (SMD −0.79, 95% CI −1.12 to −0.46, P<0.0001, I2 = 0%).Figure 15
Forest plot of meta-analysis of FIB.


## 3.4.8. Inflammatory Factor: CRP

A total of 3 studies compared CRP levels between the treatment group and control group. As displayed in Figure16, CRP levels in the treatment group were notably reduced compared with the control group (SMD −0.56, 95% CI −0.93 to −0.19, P=0.0029, I2 = 56.31%).Figure 16
Forest plot of meta-analysis of CRP.


## 3.5. Certainty of Evidence

All outcome indicators were evaluated by GRADEpro GDT. The quality of evidence was downgraded for the risk of bias or publication bias. After comprehensive analysis, the summary table was formed, and it was found that 2 outcome indicators (14.29%) were of high quality, 12 outcome indicators (71.43%) were of moderate quality, and 2 outcome indicators (14.29%) were of low quality (Supplementary TableS3).


## 3.6. Publication Bias

Egger’s test declared that no publication bias in the indicators of SCr, CCr, BUN, and 24 h UPE were observed. Whereas, there was publication bias in the indicator of the effective rate; the contour-enhanced funnel plot suggested that 7 studies were imputed and 2 studies were in the area of 5% <P < 10%. In the indicator of adverse effects, Egger’s test hinted that there existed a publication bias, 7 studies were imputed, 2 studies were in the area of 1% < P < 5%, and another one study was in the area of 5% < P < 10%.


## 4. Discussion

In this meta-analysis, we intended to explore potential effects ofSalvia miltiorrhiza for people with CKD on disease progression and complications. 32 studies that involved 2264 participants with CKD were included. In the aspects of kidney functions (SCr, Ccr, GFR, BUN, CySC, and effective rate), the comparison results revealed that the treatment group significantly reduced SCr, BUN and CysC, increased Ccr, GFR, and effective rate, indicating that this complementary therapy may have good effects for kidney functions. Proteinuria is a common clinical feature in patients with CKD, which is also an important factor in the CKD progression. The comparison demonstrated that the treatment group significantly reduced 24 h UPE. Furthermore, subgroup analysis indicated that the effect was inversely proportional to the degree of proteinuria, which confirmed that this complementary therapy may delay the CKD progression. In one study, time to initiation of dialysis was observed, the comparison uncovered that there were less CKD patients into initiation of dialysis in the treatment group. Unfortunately, the sample size of this study was too small (n = 30). 13 studies reported adverse effects. The incidence of adverse effects was similar between the two groups. Meanwhile, some indicators of complications were compared. The treatment group alleviated CKD-associated complications, and the complementary therapy may have effects on reducing TC, FIB, and CRP levels and increasing Hb levels.According to the TCM theory,Salvia miltiorrhiza (Danshen) is one of the most commonly used CHMs with the effect of promoting blood circulation to remove blood stasis, which should be used throughout the treatment of CKD. Studies have indicated that Salvia miltiorrhiza is the top single CHM prescribed for the treatment of CKD in China. A number of studies have testified that Salvia miltiorrhiza can improve kidney functions in CKD patients by increasing GFR and Ccr and reducing SCr and proteinuria [4]. Research studies also revealed that Salvia miltiorrhiza alleviated kidney injury via inhibiting oxidative stress and apoptosis [5]. Tanshinone IIA obviously attenuated kidney fibrosis by inhibiting the recruitment of fibrocytes into the kidney [7]. Besides, Salvianolate alleviated the renal damage and attenuated glomerular injury through antioxidant stress [9].There are certain limitations of the evidence that should be considered. According to the RoB 2.0 tool, 75% of the studies were assessed as “some concerns” or “high risk.” Although all of the included studies claimed to have a randomized controlled design, but only 9 had detailed descriptions of the methods. Methodological deficiencies are related to the lack of a clear description of randomization, allocation concealment, and binding. In 7 studies, computer-generated random numbers or random number tables were used. Whereas, patient record numbers were used in 2 studies. Only one study specified the method of blinding, whereas, that was single-blind. Egger’s test implied that there was publication bias in the indicator of effective rate and adverse effects.In addition, the heterogeneity was high in the results of some indicators. As for SCr, Salvianolate group was the main cause of heterogeneity. When we removed the RCT of Wang et al. [21] with the highest baseline Scr and the Liu et al. [24] with the smallest sample size, the heterogeneity significantly declined. In the indicator of the effective rate, Liu et al. [40] used alprostadil injection combined with Salvianolate injection for the treatment group, which could bias the heterogeneity. These abovementioned statements indicate that we should expand the sample size, to improve the quality of RCT. Meanwhile, limited by language barriers, only Chinese and English databases were searched, and all the included studies were conducted in China, which might affect the final results to a certain degree. Hence, there exist doubts about the applicability of evidence in other countries.


## 5. Conclusions

Current evidences indicate thatSalvia miltiorrhiza may have certain benefits for CKD patients as a complementary therapy, which could improve kidney functions, reduce proteinuria, delay the progression of CKD, and improve several complications resulting from CKD. However, the certainty of the evidence and the risk of bias are suboptimal and further clinical studies are still needed to determine the potential effects of Salvia miltiorrhiza for patients with CKD.



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*Source: 2117433-2022-06-14.xml*