Review ArticleCombined Therapy of Hypertensive Nephropathywith Breviscapine Injection and Antihypertensive DrugsA Systematic Review and a Meta-Analysis

LihuaWu 1 Ming Liu 2 and Zhuyuan Fang 2

1Affiliated Hospital of Nanjing University of Chinese Medicine Nanjing Jiangsu 210029 China2Institute of Hypertension Affiliated Hospital of Nanjing University of Chinese Medicine Nanjing Jiangsu 210029 China

Correspondence should be addressed to Ming Liu liumingxinghua163com and Zhuyuan Fang jsszyyfzy163com

Received 20 October 2018 Accepted 3 December 2018 Published 20 December 2018

Academic Editor Filippo Fratini

Copyright copy 2018 LihuaWu et alThis is an open access article distributed under the CreativeCommons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Objective To evaluate the beneficial and adverse effects of breviscapine injection in combination with antihypertensive drugs fortreating hypertensive nephropathy in clinical practiceMethodsWe searched PubMed the Cochrane Library Embase CNKI SinoMed VIP and Wanfang Data for relevant literatureThe timeframe of retrieval was set from the founding date of each database toSeptember 28 2018Results Fourteenpaperswere included in this studyThe quality of all the studies includedwas determined to below All studies were conducted with Chinese populations Meta-analysis showed that compared with single-use antihypertensivedrugs using breviscapine injection in combination with antihypertensive drugs to treat hypertensive nephropathy can reduceserum creatinine (Scr) [WMD = ndash3516 95 CI(ndash5001 ndash2031) 119875 le 0001] blood urea nitrogen (BUN) [WMD = ndash200 95CI(ndash307 ndash094) 119875 le 0001] 24-hour urinary total protein (24 h UTP) [WMD = ndash004 95 CI(ndash005 ndash002) 119875 le 0001] and thebeta-2-microglobulin (B2M) [WMD = ndash009 95 CI(ndash011 ndash007) 119875 le 0001] improve creatinine clearance rate (Ccr) [WMD= 784 95 CI(520 1049) 119875 le 0001] and increase the clinical efficacy [RR = 127 95 CI(105 153) 119875 = 0014] but does notlower systolic blood pressure (SBP) [WMD = ndash102 95 CI(ndash288 084) 119875 = 0281] There was no significant difference in adverseevents between experimental groups and control groups Conclusion Breviscapine injection in combination with antihypertensivedrugs can improve clinical efficacy and Ccr and reduce Scr BUN 24 h UTP and B2M in patients with hypertensive nephropathyThe present meta-analysis indicated that breviscapine injection can serve as a renal protective effect to patients with hypertensivenephropathy However the evidence of methodological quality and sample sizes is weak and thus further standardized research isrequired

1 Introduction

Hypertension is a risk factor for stroke coronary arterydisease heart failure peripheral vascular disease and chronickidney disease (CKD) [1 2] Elevated blood pressure (BP)wasthe leading global contributor to premature death in 2015accounting for almost 10 million deaths and over 200 milliondisability-adjusted life years [2] The main factors leadingto the development of hypertensive nephropathy include (1)inappropriately elevated sympathetic nervous activity (SNA)[3] (2) activation of the renin-angiotensin-aldosterone sys-tem (RAAS) [4] (3) increased arterial stiffness [5] (4) genetic

susceptibility [6] (5) impaired salt and water excretion bythe kidney [7] Hypertensive kidney disease is the secondleading cause of end-stage renal disease (ESRD) after dia-betes mellitus [8 9] In Europe according to the EuropeanDialysis and Transplant Association registry hypertensivenephropathy is accounted for 12 of new patients startingrenal replacement therapy However the reported incidencevaries among different countries with France Italy andUnited Kingdom reporting in 25 17 and 61 withboth Japanese and Chinese reporting in 6 and 7 respec-tively [10] Chronic kidney failure is a global disease atthe end of 2016 approximately 3 million patients were

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2018 Article ID 2958717 17 pageshttpsdoiorg10115520182958717

2 Evidence-Based Complementary and Alternative Medicine

on dialysis The incidence of chronic kidney failure variesbetween regions North America 0638million EuropeMid-dle East and Africa 0711 million Asia-Pacific 1343 millionand Latin America 0288 million [11] The diagnosis ofhypertension-induced renal damage is based on the finding ofreduced renal function andor the detection of albuminuria(ge300mgd or ge300mgg albuminuria to-creatinine ratioin the first morning void) CKD is classified according toestimated glomerular filtration rate (eGFR) calculated bythe 2009 CKD-Epidemiology Collaboration formula [12]Current evidence suggests that in patients with CKD BPshould be lowered to less than 14090mmHg and towards13080mmHgThe combination of renin-angiotensin systemblockers with calcium channel blockers (CCB) or diureticsshould be used to achieve recommended blood pressuretargets in CKD [9 13] A recent meta-analysis has shownthat BP lowering significantly reduced ESRD in patients withCKD but only in patients with albuminuria and had nobeneficial effect on cardiovascular events [14] In a largeretrospective cohort containing 398419 treated hypertensivepatients the nadir systolic blood pressure (SBP) and diastolicblood pressure (DBP) for the lowest risk of ESRD andmortality were 137 and 71mmHg respectively with a clearincrease in mortality risk at SBP less than 120mmHg [15]The evidence with respect to BP targets in patients with CKDis complex Lowering blood pressure may lead to a decreasein eGFR The reduction of albuminuria is also consideredto be a therapeutic target However there are also studiesin which treatment that was less effective at reducing albu-minuria was more effective at reducing cardiovascular events[16]

Breviscapine (Dengzhanhua) injection is extracted fromErigeron breviscapus (Vant) Erigeron breviscapus alsoknown as herba erigerontis or lamp chrysanthemum is atraditional Chinese herb that has been in use for more than600 years found in Yunnan Sichuan Guizhou and othersouthwest provinces of China Breviscapine as a purifiedflavonoid extract from this species was first isolated byZhanget al [17] Breviscapine mainly contains scutellarin (41015840567-tetrahydroxyflavone-7-O-glucuronide) and apigenin-7-O-glucuronide [18] Studies have shown that breviscapine hassignificant effects on vasodilation inhibition of platelet ag-gregation scavenging free radicals also has a protective effecton myocardial and endothelial structures because of its anti-inflammatory effects and improves microcirculationprotection against ischemiareperfusion (IR) anticoag-ulation and antithrombosis reduction of smooth musclecell migration and proliferation anticardiac remodelingantiarrhythmia and reduction of blood lipids [19ndash22]Breviscapine has been demonstrated to possess a number ofpharmacological functions in addition to its hemodynamiceffects it has been reported to serve as an antioxidativestress agent and a protein kinase C (PKC) inhibitor caninhibit the glycogen synthase kinase 3120573 (GSK3120573) signalingpathway to promote neurobehavioral function followingneurotrauma and can improve renal function and reduceurinary microalbuminuria [23ndash26] In the light of thesepharmacological activities an injection preparation ofbreviscapine (a traditional Chinese patent medicine)

has been wildly used in clinical treatment for cerebralinfarction cardiovascular disease diabetic nephropathyrenal impairment of essential hypertension and stroke inChina [18 25 27 28]

However in the past decades although numerous studieshave compared breviscapine injection with antihypertensivedrugs in the treatment of hypertensive nephropathy thecomparability of treatment protocols and evaluation method-ologies among these studies remains to be proven whichgreatly limits their clinical applicability Furthermore thecurrent state of evidence of breviscapine injection for hyper-tensive nephropathy has so far been unknown Therefore weconducted this systematic review to evaluate beneficial andadverse effects of breviscapine injection in the treatment ofhypertensive nephropathy

2 Methods and Analysis

21 Search Strategy We designed our systematic reviewand meta-analysis in accordance with the guidelines ofthe 2009 Preferred Reporting Items for Systematic Reviewsand Meta-analysis (PRISMA) statement Electronic networkdatabases were searched via computer Foreign databasessearched included PubMed Embase and the CochraneLibrary Chinese databases included the China NationalKnowledge Infrastructure (CNKI) China Biology MedicineDisc (Sino Med) the VIP information resource integrationservice platform (VIP) and the Wanfang Data knowledgeservice platform (Wanfang Data) The retrieval schemewas mainly based on a combination of subject words andfree words The searched words were ldquoDengzhanhuardquoldquoDengzhanhua preparationsrdquo ldquoDengzhanhua ZhusheyerdquoldquoZhusheyong Dengzhanhuardquo ldquoGaoxueya Shenbingrdquo ldquoGaox-ueya Shenyanrdquo ldquoGaoxueya Shenshunhairdquo while the searchedEnglish words were ldquoBreviscapinerdquo ldquoBreviscapine InjectionrdquoldquoBVPrdquo ldquoHypertensiveNephropathyrdquo ldquoHypertension RenalrdquoldquoHypertensive Kidney Lesionrdquo ldquoHypertensive Renal Dam-agerdquo and so on (Supplementary Tables S1 and S2 for the searchstrategy) The retrieval language was not limited and thetimeframe of the retrieval was from the founding date of eachdatabase to September 28 2018 There was no language lim-itation Manual searches of relevant literature supplementedthe electronic search

22 Inclusion and Exclusion Criteria

221 Types of Studies Randomized controlled trials (RCTs)that use breviscapine injection in combination with antihy-pertensive drugs to treat hypertensive nephropathy regard-less of blinding were used in this study Language was notrestricted as to minimize publication bias

222 Types of Participants There were no serious organicdiseases or complications in the selected cases The diagno-sis of hypertension-induced renal damage is based on thefinding of reduced renal function andor the detection ofalbuminuria CKD is classified according to eGFR calculatedby the 2009 CKD-Epidemiologyn Collaboration formula[12] Hypertension was defined as SBP ge 140mmHg or

Evidence-Based Complementary and Alternative Medicine 3

DBP ge 90mmHg based on the Chinese Guidelines for thePrevention and Treatment of Hypertension (2010) and the8th session of the Committee Report of the Joint Commis-sionJNC8 secondary hypertension and primary heart liverand brain disorder were excluded We did not limit inclusionbased on age sex case source disease course hypertensiveclassification or antihypertensives

223 Exclusion of Studies Studies were excluded if theywere (1) clinical trials from which no relevant data couldbe extracted (2) studies that were published repeatedly (3)populated with inconsistent baseline information (age sexcase source disease course hypertensive classification orantihypertensive drugs) (4) systematic review importantdata report and case reports no reply from correspondingauthors such that further data could not be obtained and(5) therapeutic measures failing to meet the predeterminedinclusion criteria

224 Intervention Experimental group received breviscap-ine injection combined with antihypertensive drugs [cap-topril amlodipine lisinopril benazepril losartan potas-sium felodipine and nifedipine (medication dose medi-cation time and frequency and treatment course)] Con-trol group received antihypertensive drugs including capto-pril amlodipine lisinopril benazepril losartan potassiumfelodipine nifedipine (medication dose medication timeand frequency and treatment course) Age sex and otherbaseline conditions of research subjects were well matched

225 Types of Outcome Measures Primary outcomes wereserum creatinine (Scr) and 24-hour urinary total pro-tein (24 h UTP) Secondary outcomes included blood ureanitrogen (BUN) creatinine clearance rate (Ccr) beta-2-microglobulin (B2M) systolic blood pressure (SBP) clinicalefficacy and adverse effects

226 Data Extraction Two evaluators independently per-formed a search according to the search strategy and pre-liminary screening was based on independent topics andabstracts of the search results excluding obviously unquali-fied documents A full-text methodology screening was con-ducted on the literature thatmightmeet the inclusion criteriaand the authors were contacted when there was incompleteinformation Then the studies were cross-checked by twoevaluators Any disagreement on the conclusion of twoevaluators was resolved by discussion If such disagreementcould not be resolved through discussion final judgment andarbitration were made by a third party Extracted contentsincluded authorsrsquo names year of publication number ofsamples intervention course of treatment and observedindicators

23 Quality Evaluation The investigators simultaneouslyevaluated the bias risk of the included studies based on theldquorisk of biasrdquo evaluation tool in the Cochrane Handbookfor Systematic Reviews [42] of interventions and relevantassessment guideline regulations This risk-evaluation toolcontains seven items (1) random sequence generation (2)

allocation concealment (3) blinding of the participants andpersonnel (4) blinding of the outcome data (5) incompleteoutcome data (6) selective reporting and (7) other biasand were evaluated as having a ldquohigh risk of biasrdquo ldquolow riskof biasrdquo or ldquounclear risk of biasrdquo according to assessmentcriteria

24 DataAnalysis (1) Stata 140 softwarewas used to performthe statistical analysis for the meta-analysis [43] (2) Selecteffect size if an index of the included documents is a binaryvariable the curative effect analysis statistics can be repre-sented by relative risk (RR) and expressed by its confidenceinterval (CI) mean difference (MD) and 95CI were used torepresent continuous changes (3) Homogeneity test it teststhe variation degree of original research results and clearlyincludes the degree of homogeneity of the experiment (4)Meta-analysis according to the result of the heterogeneitytest P ge 005 and 1198682 lt 50 indicate that the results havegood agreement and that the fixed effect model may be used119875 lt 005 and 1198682 ge 50 suggest that the heterogeneity of theresults cannot be ignored If the included studies still haveclinical significance the random effects model may be used(5) Sensitivity analysis in those meta-analyses of the compre-hensive factors combined with multiple outcomes possibleanomalous studies were ruled out before reevaluation Theresults were compared with those of meta-analysis beforethe exclusion to determine how the excluded studies wouldinfluence the combined effect size and the stability of meta-analysis If there is little difference between the two resultsthen the sensitivity of the results is relatively low and theresults are stable indicating high credibility (6) Subgroupanalysis subgroup analysis was conducted on some indexeswith high heterogeneity For events in which quantitativesynthesis was impossible and events with very low incidencequalitative evaluationmay be based on the description In thisstudy Stata 140 software was used to conduct a sensitivityanalysis and subgroup analysis and to create a sensitivityanalysis chart

25 Publication Bias Publication bias occurs when positivedata in similar research papers with statistical significanceare more likely to be published in journals This situationis hard to control The funnel plot method is often usedto detect publication bias Eggerrsquos test was performed todetect publication bias in the outcome measures If a largepublication bias was found in a particular research index theexact reason was identified

3 Results

31 Search Results A total of 411 documents [PubMed (n =125) the Cochrane Library (n= 29) Embase (n = 124) SinoMed (n = 28) CNKI (n = 47) Wanfang Data (n =27) andVIP (n = 31)] met the data collection and search strategyconditions NoteExpress a professional document manage-ment software was employed to check for duplication ofthe 411 obtained articles that met the relevance requirementThe majority of these trials were excluded because somepapers were found in more than one database and some

4 Evidence-Based Complementary and Alternative Medicine

Records identified through database searching PubMed= 125 the Cochrane Library= 29 Embase=124 Sino Med = 28 CNKI= 47Wanfang Data= 27 VIP= 31

Scre

enin

gIn

clud

edEl

igib

ility

Additional records identified through

other sources(n = 0)

Records aer duplicates removed(n = 159)

Records screened (n =159)

Records excluded (n = 57)Duplicate studies (n = 5)Case reports (n = 4)Animal experiments (n = 27)Conference abstracts (n = 10)Pharmacokinetic studies (n = 11)

Full-text articles assessedfor eligibility

(n = 102)

Full-text articles excluded Did not meet the inclusion criteria (n= 88)Nonrandomized controlledtrails (n = 15)Outcome measures did notmeet the inclusive criteria (n =68)other documents (n =5)

Studies included in meta-analysis (n = 14)

Iden

tifica

tion

PRISMA 2009 Flow Diagram

Figure 1 Flowchart of the process for literature retrieval

included irrelevant titles and abstracts Only 159 studies wereretrieved Following a review of the titles and abstractsseveral studies were excluded and only 102 studies remainedFive trials were excluded because of duplicated publicationsTwenty-seven trials were excluded for being animal studiesand twenty-five trials were excluded for being nonclinicaltrials including case reports pharmacokinetic studies andconference abstracts Eighty-eight out of the remaining 102articles were excluded based on the inclusion criteria leavingfourteen RCTs to be reviewed in Figure 1

32 Study Characteristics There were 14 randomized con-trolled trials [29ndash41 44] that were included in the presentresearch involving 1170 patients (593 in the research groupand 577 in the control group)These 14 RCTs are summarizedin Table 1

33 Summary of the Quality and Bias Risk of the TrialsIncluded The quality of all studies included was low Allstudies were carried out among the Chinese populationFourteen studies mention the use of random allocationAll studies failed to mention the specific grouping methodand none of the studies discussed allocation concealmentblinding or evaluator blinding The quality assessment isshown in Figures 2 and 3

34 Outcome Measures

341 Primary Outcome Serum Creatinine (Scr 120583moll)Twelve studies [30ndash40 44] involving 969 participants re-ported on the use of breviscapine injection plus antihy-pertensive drugs in the treatment of Scr for hypertensivenephropathy After the test for heterogeneity (1198682 = 959

Evidence-Based Complementary and Alternative Medicine 5

Table1Ch

aracteris

ticso

f14stu

dies

fulfilling

theinclusio

ncriteria

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Zhange

tal

2004

[29]

94(4747)

T1816

C

1713

T60plusmn8

C60plusmn8

GMY

(1999WHO-ISH

)

Brevisc

apine

injection(20m

livgttqd

)+control

Lisin

opril

(5-10m

gpo

tid)

25mgtid

2weeks

Guiding

principles

(2002)

24UA

ERSBP

DBP

B2M

TC

TGLDLLD

H-C

HctPAG

TFib

T2caseso

fdry

coug

hC

3caseso

fdry

coug

h

WeiandTan

2005[30]

76(4036)

T3010

C

288

T635

C64

3GMY

(1999WHO-ISH

)

Brevisc

apine

injection(20m

livgttqd

)+control

Amlodipine

(5mgpo

qd)+

Captopril(25m

gpo

tid)

4weeks

Guiding

principles

(2002)

24hUTP

BUN

Scrbloo

dB2

M

Urin

eB2M

T1sho

wed

mild

facialflu

shing

durin

ginfusion

CNon

e

RenandWu

2006[31]

60(3030)

T219

C228

T44

-75

C43-74

CGMY(200

4)

Brevisc

apine

injection(30m

livgttqd

)+control

Captopril

(25-75

mgpo

qd

)orN

ifedipine

(20-60

mgpo

qd

)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

24hUTP

BUN

Scr

T2caseso

fdry

coug

hC

1caseo

fmild

head

inflatio

n

Zheng2

006[32]

72(3735)

T2213

C

2314

T41-73

C42-71

GMY

(1999WHO-ISH

)

Brevisc

apine

injection(30m

livgttqd

)+control

Captopril

(25-75

mgpo

bidor

tid)o

rNifedipine

(10-60

mgpo

bidor

tid)

4weeks

Guiding

principles

(2002)

24hUTP

BUN

Scr

T2caseso

fcoug

hC

1caseo

fmild

head

inflatio

n

Chen

etal

2008[33]

57(2829)

T199

C209

T456plusmn203

C46

4plusmn211

CGMY(200

4)

Brevisc

apine

injection(20m

livgttqd

)+control

Benazepril(no

details)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

24hUTP

BUN

ScrCcr

T2caseso

fhead

swellin

gdizzinessd

uring

infusio

nC

1caseo

fcou

gh

Ye2009[34]

75(4035)

T2416

C

2015

T473plusmn

182

C46

9plusmn161

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Losartan

Potassium

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

24hUTP

Scr

CcrU

rineB

2M

SBPDBP

T1caseo

fdizziness

CNon

e

6 Evidence-Based Complementary and Alternative Medicine

Table1Con

tinued

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Hea

ndGen

2010[35]

168(8484)

T4935

C4836

T69plusmn11

C68plusmn11

CGMY(200

5)

Brevisc

apine

injection(20m

livgttqd

)+control

Captopril

(125-50

mgpo

tid

)30

days

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrB

UN

T5c

ases

ofdry

coug

hC

3caseso

fdry

coug

h

WangandLan

2012[36]

103(5251)

Unclear

T624plusmn48

C624plusmn48

GMY

(1999WHO-ISH

)andNephrology

(HaiyanWang)

Brevisc

apine

injection(10m

livgttqd

)+control

Lisin

opril

(20m

gpo

qd)

30days

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrB

UN

T1caseo

fdry

coug

hC

2caseso

fdry

coug

h

Liu2012[37]

50(2624)

T1214

C

1014

T55plusmn4

C53plusmn5

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(10m

livgttqd

)+control

Benazepril

(10m

gpo

bid)

2weeks

Guiding

principles

(2002)

SBPDBP

Urin

ary

microalbu

min

Not

repo

rted

Huang

etal

2013[38]

63(3330)

T249

C1911

Unclear

CGMY(200

4)

Brevisc

apine

injection(20m

livgttqd

)+control

Felodipine

(5mg

poqd)+As

pirin

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrBUN

TCT

Gblood

glucose

T2caseso

flim

bskin

redn

ess

CNon

e

Ye2013[39]

48(2424)

T168

C1410

T530plusmn93

C

490plusmn116

CGMY(2010)

Brevisc

apine

injection(12m

livgttqd

)+control

Antihypertensive

Drugs

(no

details)+

ProstaglandinE

injection(2ml

ivgttqd

)

30days

Guiding

principles

(2002)

Clinicaleffi

cacy

24hUTP

TC

TGScrBUN

Not

repo

rted

Qiao2015[40]

158(7979)

Unclear

T4801plusmn31

5C

4801plusmn31

5

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Captopril

(25-75

mgpo

tid

)orN

ifedipine

(10-60

mgpo

tid

)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

224

hUTP

ScrB

UN

Not

repo

rted

Zhao

andDon

g2016[41]

80(4040

)Unclear

T525plusmn

71

C525plusmn

71CG

MY(2010)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Benazepril(5mg

poqd)

4weeks

Guiding

principles

(2002)

Col-IVLN

PIII

PET

-1M

MP-9

NOE

ILAE

ISA

VOISB

PDBP

Non

e

Evidence-Based Complementary and Alternative Medicine 7

Table1Con

tinued

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Ma2

018[41]

66(3333)

T1914

C

2013

T4800plusmn

314

C4899plusmn

298

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Losartan

Potassium

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

Urin

eB2M

SBP

DBP

24h

UTP

ScrCcr

Not

repo

rted

Ttre

atmentgroup

Ccon

trolgroup

GMY(19

99WHO-ISH

)Th

e1999WHO-ISH

Guidelin

esforthe

Managem

ento

fHypertensionCG

MY(200

4)200

4Ch

ineseG

uidelin

esforthe

Managem

ento

fHypertension

CGMY(2010)2010Ch

ineseGuidelin

esfortheManagem

ento

fHypertension

CGMY(2014)2014Ch

ineseGuidelin

esfortheManagem

ento

fHypertension

Guiding

Principles

(2002)G

uiding

Principles

ofClinicalRe

search

onNew

Drugs

ofCh

ineseM

edicines

(2002)Scrserum

creatin

ineBU

Nblood

urea

nitro

genCcrcreatininec

learance

rate24h

UTP

24-ho

ururinarytotalproteinB

2Mbeta-2-microglob

ulin

SBP

systo

licbloo

dpressureD

BPd

iasto

licbloo

dpressureT

Ctotalcho

leste

rolTG

totaltriglycerid

esPAG

TplateletaggregationrateF

ibfi

brinogenH

cth

ematocritL

DL

low-densitylip

oproteinL

DH-C

lactatedehydrogenaseC

Col-IV

collagenIVL

Nlam

ininP

IIIP

procollagen-III-peptideET

-1end

othelin

1MMP-9matrix

metalloproteinase-9E

ILAelasticity

indexof

largearteryE

ISAelasticity

indexof

smallarteryVOIvascular

overload

index

8 Evidence-Based Complementary and Alternative Medicine

0 25 50 75 100

Low risk of bias

Unclear risk of bias

High risk of bias

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

Figure 2 Risk of bias

119875 le 0001) (Figure 4) we employed a random effectsmodel A funnel plot analysis of the 12 trials suggestedpossible publication bias and inclusion of low quality studiesas significant asymmetry is shown in Figure 5 We appliedEggerrsquos test to evaluate publication bias A p (P = 0634)value more than 005 was considered no publication bias(Supplementary Figure S1) The meta-analysis revealed thatthe experimental group performed better than the controlgroup in reducing Scr [WMD = ndash3516 95 CI(ndash5001ndash2031) 119875 le 0001] (Supplementary Figure S2)

342 Sensitivity Analysis We conducted a sensitivity analy-sis for Scr (Supplementary Figure S3) By seriatim excludingone trial each time and reperforming meta-analysis of theremaining trials we could observe whether the outcomeshave dramatically changed Sensitivity analysis indicated thatthe outcomes of Scr were very similar which had relativelygood stability

343 Subgroup Analysis Because of variability in evaluat-ing point of the serum creatinine we conducted subgroupanalysis among studies using different doses of breviscapineinjection (30ml 20ml 12ml 10ml and 5ml) Comparedwith the control groups the results of subgroup analysisshowed that there was no significant correlation between thedecrease of serum creatinine and the dose of breviscapineinjection (Figure 6)

344 24-Hour Urinary Total Protein (24h UTP gd) Twelvestudies [29ndash36 38ndash40 44] reported on the use of brevis-capine injection plus antihypertensive drugs in terms ofthe 24 h UTP for hypertensive nephropathy After the testfor heterogeneity (1198682 = 937 P le 0001) (Figure 7) weemployed a random effects modelWe conducted a sensitivity

analysis and applied Eggerrsquos test (P = 0586) to evaluatepublication bias for 24 h UTP (Supplementary Figures S4and S5) The meta-analysis revealed that the experimentalgroup performed better than the control group in reducing24 h UTP [WMD = ndash004 95 CI(ndash005 ndash002) 119875 le 0001](Figure S6)

345 Blood Urea Nitrogen (BUN mmolL) Ten studies [30ndash33 35ndash40] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of BUN forhypertensive nephropathy After the test for heterogeneity(1198682 = 923 119875 le 0001) (Figure 8) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (P = 0015) to evaluate publicationbias for BUN (Supplementary Figures S7 and S8) The meta-analysis revealed that the experimental group performedbetter than the control group in reducing BUN [WMD =ndash200 95 CI(ndash307 ndash094) 119875 le 0001] (SupplementaryFigure S9)

346 Creatinine Clearance Rate (Ccr mlmin) Three studies[33 34 44] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of Ccr forhypertensive nephropathy After the test for heterogeneity(1198682 = 00 119875 = 0903) (Figure 9) thus the fixed-effects model was used for data analysis The meta-analysisrevealed that the experimental group performed better thanthe control group in improving creatinine clearance rate[WMD = 784 95 CI(520 1049) 119875 le 0001] (Figure S10)

347 Beta-2-Microglobulin (B2M mgL) Three studies [3034 44] reported on the use of breviscapine injection plusantihypertensive drugs in the treatment of urine beta-2-microglobulin for hypertensive nephropathy After the test

Evidence-Based Complementary and Alternative Medicine 9

Rand

om se

quen

ce g

ener

atio

n (s

elec

tion

bias

)

Allo

catio

n co

ncea

lmen

t (se

lect

ion

bias

)

Blin

ding

of p

artic

ipan

ts an

d pe

rson

nel (

perfo

rman

ce b

ias)

Blin

ding

of o

utco

me a

sses

smen

t (de

tect

ion

bias

)

Inco

mpl

ete o

utco

me d

ata (

attr

ition

bia

s)

Sele

ctiv

e rep

ortin

g (r

epor

ting

bias

)

Oth

er b

ias

Chen et al 2008

He and Gen 2010

Huang et al 2013

Liu 2012

Ma 2018

Qiao 2015

Ren and Wu 2006

Wang and Lan 2012

Wei and Tan 2005

Ye 2009

Ye 2013

Zhang et al 2004

Zhao and Dong 2016

Zheng 2006

Figure 3 Risk of bias summary and graph

for heterogeneity (1198682 = 00 119875 = 0953) (Figure 10) thusthe fixed-effects model was used for data analysis The meta-analysis revealed that the experimental group performedbetter than the control group in reducing B2M [WMD =ndash009 95 CI(ndash011 ndash007) 119875 le 0001] (Figure S11)

348 Systolic Blood Pressure (SBP mmHg) Nine studies[29 34ndash38 40 41 44] reported on the use of breviscapineinjection plus antihypertensive drugs in the treatment of SBPfor hypertensive nephropathy After the test for heterogeneity(1198682 = 79 119875 le 0001) (Figure 11) we employed arandomeffectsmodelMeta-analysis showed anonsignificanttrend for reduction in systolic blood pressure between theexperimental group and the control group [WMD = ndash10295 CI(ndash288 084) 119875 = 0281] (Figure S12)

349 Comparison of Clinical Efficacy A total of 7 studies[31 33 35 36 38ndash40] reported the results of the total effectiverate involving 657 patients (330 in the experimental groupand 327 in the control group) After the test for heterogeneity(1198682 = 852 119875 le 0001) (Figure 12) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (119875 = 0181) to evaluate publicationbias for effective rate (Supplementary Figures S13 and S14)Meta-analysis indicated that the total clinical effective rateof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in treating for hypertensivenephropathy was higher than that in the control group whichshowed a statistically significant difference [RR = 127 95CI(105 153)119875 = 0014] (Figure S15) All included trials werepublished in Chinese academic journals Since trials withnegative or neutral results are less likely to be published

10 Evidence-Based Complementary and Alternative Medicine

Figure 4 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Scrfor hypertensive nephropathy

05

1015

se (W

MD

)

minus100 minus80 minus60 minus40 minus20 0WMD

Funnel plot with pseudo 95 confidence limits

Figure 5 Funnel plot for the publication bias of Scr

Evidence-Based Complementary and Alternative Medicine 11

Figure 6 Subgroup analysis of different doses of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone interms of Scr for hypertensive nephropathy

the efficacy of published studies might be overestimatedConsequently the possibility of publication bias could not beruled out

3410 Adverse Effects Nine of the included trials [29ndash36 38]described adverse effects in detail while the others did notmention adverse eventsOnly one showedmild facial flushingduring intravenous dripping of breviscapine [30] and afterthe speed of transfusion was slowed down the symptom gotremitted Two cases [38] showed redness of limb skin in theexperimental group There were two cases [31 32] of headinflation during the use of antihypertensive drugsTherewerethree cases [33 34] of head swelling and dizziness duringinfusion during the use of breviscapine injection Twenty-onecases showed dry cough due to the use of ACEI in six trials[29 31ndash33 35 36] None of the adverse events were seriousThese symptoms are self-limited and did not affect treatment

4 Discussion

Thismeta-analysis included 14 studies with 1170 total partici-pants comparing breviscapine injection plus antihypertensivedrugs versus antihypertensive drugs alone for hypertensivenephropathy Meanwhile the results demonstrated that theexpression levels of SCr and BUN were significantly lowerin patients treated with breviscapine injection in comparisonwith control subjects and the improvement of creatinineclearance was higher in patients treated with breviscapinein comparison with control subjects suggesting that thedrug serves as a protective role in the renal system ofpatients with hypertensive nephropathy Microalbuminuriais regarded as the earliest clinical sign of hypertensivenephropathy It is defined as a urinary albumin excretionrate ranging from 30 to 300mgday and the definitivemeasurement is based on a timed urine collection during

12 Evidence-Based Complementary and Alternative Medicine

Figure 7 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the 24 hUTP for hypertensive nephropathy

a 24-h period The present meta-analysis indicated thatbreviscapine injection can reduce 24-hour urinary proteinand the urinary beta-2-microglobulin a reduction in uri-nary protein may contribute towards the renal protectiveeffect of breviscapine injection in patients with hyperten-sive nephropathy Our analysis revealed that experimentalgroups showed better overall clinical efficacy than controlgroups

Erigeron breviscapus is a kind of traditional Chinesemedicine It was first recorded in the book of ldquoYunnan Mate-ria Medicardquo According to Chinese medicine theory erigeronbreviscapus is cold-natured sweet bitter and pungent intaste with the function of clearing heat relieving toxic-ity eliminating wind and dampness activating blood andremoving stasis expediting channel and activating meridianrelieving inflammation and alleviating pain The monomercomponent of Chinese herbal medicine (CHM) also knownas the natural pure compound drug has recently attractedmuch attention The natural extract artemisinin and itsderivatives are good examples of monomer components ofCHM that can treat diseases through various activities andcan be a good starting point to uncover the mechanism oftraditional Chinese medicine

Hypertensive renal injury is major target-organ damagedue to sustained high BP Long-term hypertension cancause renal sclerosis and gradually progress to chronic renalfailure Positive control of hypertension is the key to pre-venting hypertensive renal damage According to Chinesemedicine theory hypertensive renal injury is strongly relatedto fluid phlegm and dampness retention syndrome andliver-yang hyperactivity syndrome which are caused bydeficiency syndrome Chinese medicines which are usedto treat fluid phlegm and dampness retention syndromedeficiency syndrome and liver-yang hyperactivity syndromerespectively have certain advantages with regard to treatinghypertensive renal injury [45] Clinical research indicatesthat Chinese herbal medicine might control increased SBPinhibit the glomerular and tubular hyperplasia caused byhigh BP and significantly reduce urinary albumin and beta-2-microglobulin by increasing the activity of renal rennin andthe level of Ang II [46 47]

5 Limitations

Several limiting factors in this study should be consideredFirst the quality of the included randomized controlled trials

Evidence-Based Complementary and Alternative Medicine 13

Figure 8 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of theBUN for hypertensive nephropathy

Figure 9 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Ccrfor hypertensive nephropathy

was low All included trials showed high or undefined risk ofbias due to design reporting and methodology There wereno definitive randomized double-blind placebo-controlledtrials included in this meta-analysis No trials reporteddetailed randomization methods or allocation concealmentNo trial was double-blinded and unfortunately none ofRCT (randomized controlled trial) has a placebo in thetrial Therefore the reported strength of evidence should

be reevaluated and more rigorously designed placebo-controlled trials are warranted to give high-level evidencein future studies [48] Second five trials did not reportadverse reactions Therefore conclusions about safety can-not be made with confidence Furthermore certain activeingredients are chemically unstable which limits large-scalesynthesis These pressing issues should be resolved in futureresearch The safety of breviscapine injection needs to be

14 Evidence-Based Complementary and Alternative Medicine

Figure 10 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of beta-2-microglobulin for hypertensive nephropathy

Figure 11 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the SBPfor hypertensive nephropathy

strictly monitored and properly reported in future clinicaltrialsThird all tests produced positive results althoughmosttests were conducted with small samples We tried our best toavoid language bias and positional prejudice but cannot ruleout potential publication bias

Overall our results suggest that breviscapine injection iseffective and safe for the treatment of hypertensive nephropa-thy and this work has reference value for clinicians Morelarge-scale multicenter rigorously designed randomized

controlled trials are needed to provide accurate data tofurther validate the effectiveness and safety of breviscapineinjection

6 Conclusions

Evidence from this systematic review shows that breviscap-ine injection in combination with antihypertensive drugscan improve clinical efficacy and creatinine clearance rate

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

Evidence-Based Complementary and Alternative Medicine 3

DBP ge 90mmHg based on the Chinese Guidelines for thePrevention and Treatment of Hypertension (2010) and the8th session of the Committee Report of the Joint Commis-sionJNC8 secondary hypertension and primary heart liverand brain disorder were excluded We did not limit inclusionbased on age sex case source disease course hypertensiveclassification or antihypertensives

223 Exclusion of Studies Studies were excluded if theywere (1) clinical trials from which no relevant data couldbe extracted (2) studies that were published repeatedly (3)populated with inconsistent baseline information (age sexcase source disease course hypertensive classification orantihypertensive drugs) (4) systematic review importantdata report and case reports no reply from correspondingauthors such that further data could not be obtained and(5) therapeutic measures failing to meet the predeterminedinclusion criteria

224 Intervention Experimental group received breviscap-ine injection combined with antihypertensive drugs [cap-topril amlodipine lisinopril benazepril losartan potas-sium felodipine and nifedipine (medication dose medi-cation time and frequency and treatment course)] Con-trol group received antihypertensive drugs including capto-pril amlodipine lisinopril benazepril losartan potassiumfelodipine nifedipine (medication dose medication timeand frequency and treatment course) Age sex and otherbaseline conditions of research subjects were well matched

225 Types of Outcome Measures Primary outcomes wereserum creatinine (Scr) and 24-hour urinary total pro-tein (24 h UTP) Secondary outcomes included blood ureanitrogen (BUN) creatinine clearance rate (Ccr) beta-2-microglobulin (B2M) systolic blood pressure (SBP) clinicalefficacy and adverse effects

226 Data Extraction Two evaluators independently per-formed a search according to the search strategy and pre-liminary screening was based on independent topics andabstracts of the search results excluding obviously unquali-fied documents A full-text methodology screening was con-ducted on the literature thatmightmeet the inclusion criteriaand the authors were contacted when there was incompleteinformation Then the studies were cross-checked by twoevaluators Any disagreement on the conclusion of twoevaluators was resolved by discussion If such disagreementcould not be resolved through discussion final judgment andarbitration were made by a third party Extracted contentsincluded authorsrsquo names year of publication number ofsamples intervention course of treatment and observedindicators

23 Quality Evaluation The investigators simultaneouslyevaluated the bias risk of the included studies based on theldquorisk of biasrdquo evaluation tool in the Cochrane Handbookfor Systematic Reviews [42] of interventions and relevantassessment guideline regulations This risk-evaluation toolcontains seven items (1) random sequence generation (2)

allocation concealment (3) blinding of the participants andpersonnel (4) blinding of the outcome data (5) incompleteoutcome data (6) selective reporting and (7) other biasand were evaluated as having a ldquohigh risk of biasrdquo ldquolow riskof biasrdquo or ldquounclear risk of biasrdquo according to assessmentcriteria

24 DataAnalysis (1) Stata 140 softwarewas used to performthe statistical analysis for the meta-analysis [43] (2) Selecteffect size if an index of the included documents is a binaryvariable the curative effect analysis statistics can be repre-sented by relative risk (RR) and expressed by its confidenceinterval (CI) mean difference (MD) and 95CI were used torepresent continuous changes (3) Homogeneity test it teststhe variation degree of original research results and clearlyincludes the degree of homogeneity of the experiment (4)Meta-analysis according to the result of the heterogeneitytest P ge 005 and 1198682 lt 50 indicate that the results havegood agreement and that the fixed effect model may be used119875 lt 005 and 1198682 ge 50 suggest that the heterogeneity of theresults cannot be ignored If the included studies still haveclinical significance the random effects model may be used(5) Sensitivity analysis in those meta-analyses of the compre-hensive factors combined with multiple outcomes possibleanomalous studies were ruled out before reevaluation Theresults were compared with those of meta-analysis beforethe exclusion to determine how the excluded studies wouldinfluence the combined effect size and the stability of meta-analysis If there is little difference between the two resultsthen the sensitivity of the results is relatively low and theresults are stable indicating high credibility (6) Subgroupanalysis subgroup analysis was conducted on some indexeswith high heterogeneity For events in which quantitativesynthesis was impossible and events with very low incidencequalitative evaluationmay be based on the description In thisstudy Stata 140 software was used to conduct a sensitivityanalysis and subgroup analysis and to create a sensitivityanalysis chart

25 Publication Bias Publication bias occurs when positivedata in similar research papers with statistical significanceare more likely to be published in journals This situationis hard to control The funnel plot method is often usedto detect publication bias Eggerrsquos test was performed todetect publication bias in the outcome measures If a largepublication bias was found in a particular research index theexact reason was identified

3 Results

31 Search Results A total of 411 documents [PubMed (n =125) the Cochrane Library (n= 29) Embase (n = 124) SinoMed (n = 28) CNKI (n = 47) Wanfang Data (n =27) andVIP (n = 31)] met the data collection and search strategyconditions NoteExpress a professional document manage-ment software was employed to check for duplication ofthe 411 obtained articles that met the relevance requirementThe majority of these trials were excluded because somepapers were found in more than one database and some

4 Evidence-Based Complementary and Alternative Medicine

Records identified through database searching PubMed= 125 the Cochrane Library= 29 Embase=124 Sino Med = 28 CNKI= 47Wanfang Data= 27 VIP= 31

Scre

enin

gIn

clud

edEl

igib

ility

Additional records identified through

other sources(n = 0)

Records aer duplicates removed(n = 159)

Records screened (n =159)

Records excluded (n = 57)Duplicate studies (n = 5)Case reports (n = 4)Animal experiments (n = 27)Conference abstracts (n = 10)Pharmacokinetic studies (n = 11)

Full-text articles assessedfor eligibility

(n = 102)

Full-text articles excluded Did not meet the inclusion criteria (n= 88)Nonrandomized controlledtrails (n = 15)Outcome measures did notmeet the inclusive criteria (n =68)other documents (n =5)

Studies included in meta-analysis (n = 14)

Iden

tifica

tion

PRISMA 2009 Flow Diagram

Figure 1 Flowchart of the process for literature retrieval

included irrelevant titles and abstracts Only 159 studies wereretrieved Following a review of the titles and abstractsseveral studies were excluded and only 102 studies remainedFive trials were excluded because of duplicated publicationsTwenty-seven trials were excluded for being animal studiesand twenty-five trials were excluded for being nonclinicaltrials including case reports pharmacokinetic studies andconference abstracts Eighty-eight out of the remaining 102articles were excluded based on the inclusion criteria leavingfourteen RCTs to be reviewed in Figure 1

32 Study Characteristics There were 14 randomized con-trolled trials [29ndash41 44] that were included in the presentresearch involving 1170 patients (593 in the research groupand 577 in the control group)These 14 RCTs are summarizedin Table 1

33 Summary of the Quality and Bias Risk of the TrialsIncluded The quality of all studies included was low Allstudies were carried out among the Chinese populationFourteen studies mention the use of random allocationAll studies failed to mention the specific grouping methodand none of the studies discussed allocation concealmentblinding or evaluator blinding The quality assessment isshown in Figures 2 and 3

34 Outcome Measures

341 Primary Outcome Serum Creatinine (Scr 120583moll)Twelve studies [30ndash40 44] involving 969 participants re-ported on the use of breviscapine injection plus antihy-pertensive drugs in the treatment of Scr for hypertensivenephropathy After the test for heterogeneity (1198682 = 959

Evidence-Based Complementary and Alternative Medicine 5

Table1Ch

aracteris

ticso

f14stu

dies

fulfilling

theinclusio

ncriteria

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Zhange

tal

2004

[29]

94(4747)

T1816

C

1713

T60plusmn8

C60plusmn8

GMY

(1999WHO-ISH

)

Brevisc

apine

injection(20m

livgttqd

)+control

Lisin

opril

(5-10m

gpo

tid)

25mgtid

2weeks

Guiding

principles

(2002)

24UA

ERSBP

DBP

B2M

TC

TGLDLLD

H-C

HctPAG

TFib

T2caseso

fdry

coug

hC

3caseso

fdry

coug

h

WeiandTan

2005[30]

76(4036)

T3010

C

288

T635

C64

3GMY

(1999WHO-ISH

)

Brevisc

apine

injection(20m

livgttqd

)+control

Amlodipine

(5mgpo

qd)+

Captopril(25m

gpo

tid)

4weeks

Guiding

principles

(2002)

24hUTP

BUN

Scrbloo

dB2

M

Urin

eB2M

T1sho

wed

mild

facialflu

shing

durin

ginfusion

CNon

e

RenandWu

2006[31]

60(3030)

T219

C228

T44

-75

C43-74

CGMY(200

4)

Brevisc

apine

injection(30m

livgttqd

)+control

Captopril

(25-75

mgpo

qd

)orN

ifedipine

(20-60

mgpo

qd

)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

24hUTP

BUN

Scr

T2caseso

fdry

coug

hC

1caseo

fmild

head

inflatio

n

Zheng2

006[32]

72(3735)

T2213

C

2314

T41-73

C42-71

GMY

(1999WHO-ISH

)

Brevisc

apine

injection(30m

livgttqd

)+control

Captopril

(25-75

mgpo

bidor

tid)o

rNifedipine

(10-60

mgpo

bidor

tid)

4weeks

Guiding

principles

(2002)

24hUTP

BUN

Scr

T2caseso

fcoug

hC

1caseo

fmild

head

inflatio

n

Chen

etal

2008[33]

57(2829)

T199

C209

T456plusmn203

C46

4plusmn211

CGMY(200

4)

Brevisc

apine

injection(20m

livgttqd

)+control

Benazepril(no

details)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

24hUTP

BUN

ScrCcr

T2caseso

fhead

swellin

gdizzinessd

uring

infusio

nC

1caseo

fcou

gh

Ye2009[34]

75(4035)

T2416

C

2015

T473plusmn

182

C46

9plusmn161

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Losartan

Potassium

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

24hUTP

Scr

CcrU

rineB

2M

SBPDBP

T1caseo

fdizziness

CNon

e

6 Evidence-Based Complementary and Alternative Medicine

Table1Con

tinued

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Hea

ndGen

2010[35]

168(8484)

T4935

C4836

T69plusmn11

C68plusmn11

CGMY(200

5)

Brevisc

apine

injection(20m

livgttqd

)+control

Captopril

(125-50

mgpo

tid

)30

days

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrB

UN

T5c

ases

ofdry

coug

hC

3caseso

fdry

coug

h

WangandLan

2012[36]

103(5251)

Unclear

T624plusmn48

C624plusmn48

GMY

(1999WHO-ISH

)andNephrology

(HaiyanWang)

Brevisc

apine

injection(10m

livgttqd

)+control

Lisin

opril

(20m

gpo

qd)

30days

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrB

UN

T1caseo

fdry

coug

hC

2caseso

fdry

coug

h

Liu2012[37]

50(2624)

T1214

C

1014

T55plusmn4

C53plusmn5

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(10m

livgttqd

)+control

Benazepril

(10m

gpo

bid)

2weeks

Guiding

principles

(2002)

SBPDBP

Urin

ary

microalbu

min

Not

repo

rted

Huang

etal

2013[38]

63(3330)

T249

C1911

Unclear

CGMY(200

4)

Brevisc

apine

injection(20m

livgttqd

)+control

Felodipine

(5mg

poqd)+As

pirin

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrBUN

TCT

Gblood

glucose

T2caseso

flim

bskin

redn

ess

CNon

e

Ye2013[39]

48(2424)

T168

C1410

T530plusmn93

C

490plusmn116

CGMY(2010)

Brevisc

apine

injection(12m

livgttqd

)+control

Antihypertensive

Drugs

(no

details)+

ProstaglandinE

injection(2ml

ivgttqd

)

30days

Guiding

principles

(2002)

Clinicaleffi

cacy

24hUTP

TC

TGScrBUN

Not

repo

rted

Qiao2015[40]

158(7979)

Unclear

T4801plusmn31

5C

4801plusmn31

5

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Captopril

(25-75

mgpo

tid

)orN

ifedipine

(10-60

mgpo

tid

)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

224

hUTP

ScrB

UN

Not

repo

rted

Zhao

andDon

g2016[41]

80(4040

)Unclear

T525plusmn

71

C525plusmn

71CG

MY(2010)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Benazepril(5mg

poqd)

4weeks

Guiding

principles

(2002)

Col-IVLN

PIII

PET

-1M

MP-9

NOE

ILAE

ISA

VOISB

PDBP

Non

e

Evidence-Based Complementary and Alternative Medicine 7

Table1Con

tinued

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Ma2

018[41]

66(3333)

T1914

C

2013

T4800plusmn

314

C4899plusmn

298

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Losartan

Potassium

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

Urin

eB2M

SBP

DBP

24h

UTP

ScrCcr

Not

repo

rted

Ttre

atmentgroup

Ccon

trolgroup

GMY(19

99WHO-ISH

)Th

e1999WHO-ISH

Guidelin

esforthe

Managem

ento

fHypertensionCG

MY(200

4)200

4Ch

ineseG

uidelin

esforthe

Managem

ento

fHypertension

CGMY(2010)2010Ch

ineseGuidelin

esfortheManagem

ento

fHypertension

CGMY(2014)2014Ch

ineseGuidelin

esfortheManagem

ento

fHypertension

Guiding

Principles

(2002)G

uiding

Principles

ofClinicalRe

search

onNew

Drugs

ofCh

ineseM

edicines

(2002)Scrserum

creatin

ineBU

Nblood

urea

nitro

genCcrcreatininec

learance

rate24h

UTP

24-ho

ururinarytotalproteinB

2Mbeta-2-microglob

ulin

SBP

systo

licbloo

dpressureD

BPd

iasto

licbloo

dpressureT

Ctotalcho

leste

rolTG

totaltriglycerid

esPAG

TplateletaggregationrateF

ibfi

brinogenH

cth

ematocritL

DL

low-densitylip

oproteinL

DH-C

lactatedehydrogenaseC

Col-IV

collagenIVL

Nlam

ininP

IIIP

procollagen-III-peptideET

-1end

othelin

1MMP-9matrix

metalloproteinase-9E

ILAelasticity

indexof

largearteryE

ISAelasticity

indexof

smallarteryVOIvascular

overload

index

8 Evidence-Based Complementary and Alternative Medicine

0 25 50 75 100

Low risk of bias

Unclear risk of bias

High risk of bias

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

Figure 2 Risk of bias

119875 le 0001) (Figure 4) we employed a random effectsmodel A funnel plot analysis of the 12 trials suggestedpossible publication bias and inclusion of low quality studiesas significant asymmetry is shown in Figure 5 We appliedEggerrsquos test to evaluate publication bias A p (P = 0634)value more than 005 was considered no publication bias(Supplementary Figure S1) The meta-analysis revealed thatthe experimental group performed better than the controlgroup in reducing Scr [WMD = ndash3516 95 CI(ndash5001ndash2031) 119875 le 0001] (Supplementary Figure S2)

342 Sensitivity Analysis We conducted a sensitivity analy-sis for Scr (Supplementary Figure S3) By seriatim excludingone trial each time and reperforming meta-analysis of theremaining trials we could observe whether the outcomeshave dramatically changed Sensitivity analysis indicated thatthe outcomes of Scr were very similar which had relativelygood stability

343 Subgroup Analysis Because of variability in evaluat-ing point of the serum creatinine we conducted subgroupanalysis among studies using different doses of breviscapineinjection (30ml 20ml 12ml 10ml and 5ml) Comparedwith the control groups the results of subgroup analysisshowed that there was no significant correlation between thedecrease of serum creatinine and the dose of breviscapineinjection (Figure 6)

344 24-Hour Urinary Total Protein (24h UTP gd) Twelvestudies [29ndash36 38ndash40 44] reported on the use of brevis-capine injection plus antihypertensive drugs in terms ofthe 24 h UTP for hypertensive nephropathy After the testfor heterogeneity (1198682 = 937 P le 0001) (Figure 7) weemployed a random effects modelWe conducted a sensitivity

analysis and applied Eggerrsquos test (P = 0586) to evaluatepublication bias for 24 h UTP (Supplementary Figures S4and S5) The meta-analysis revealed that the experimentalgroup performed better than the control group in reducing24 h UTP [WMD = ndash004 95 CI(ndash005 ndash002) 119875 le 0001](Figure S6)

345 Blood Urea Nitrogen (BUN mmolL) Ten studies [30ndash33 35ndash40] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of BUN forhypertensive nephropathy After the test for heterogeneity(1198682 = 923 119875 le 0001) (Figure 8) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (P = 0015) to evaluate publicationbias for BUN (Supplementary Figures S7 and S8) The meta-analysis revealed that the experimental group performedbetter than the control group in reducing BUN [WMD =ndash200 95 CI(ndash307 ndash094) 119875 le 0001] (SupplementaryFigure S9)

346 Creatinine Clearance Rate (Ccr mlmin) Three studies[33 34 44] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of Ccr forhypertensive nephropathy After the test for heterogeneity(1198682 = 00 119875 = 0903) (Figure 9) thus the fixed-effects model was used for data analysis The meta-analysisrevealed that the experimental group performed better thanthe control group in improving creatinine clearance rate[WMD = 784 95 CI(520 1049) 119875 le 0001] (Figure S10)

347 Beta-2-Microglobulin (B2M mgL) Three studies [3034 44] reported on the use of breviscapine injection plusantihypertensive drugs in the treatment of urine beta-2-microglobulin for hypertensive nephropathy After the test

Evidence-Based Complementary and Alternative Medicine 9

Rand

om se

quen

ce g

ener

atio

n (s

elec

tion

bias

)

Allo

catio

n co

ncea

lmen

t (se

lect

ion

bias

)

Blin

ding

of p

artic

ipan

ts an

d pe

rson

nel (

perfo

rman

ce b

ias)

Blin

ding

of o

utco

me a

sses

smen

t (de

tect

ion

bias

)

Inco

mpl

ete o

utco

me d

ata (

attr

ition

bia

s)

Sele

ctiv

e rep

ortin

g (r

epor

ting

bias

)

Oth

er b

ias

Chen et al 2008

He and Gen 2010

Huang et al 2013

Liu 2012

Ma 2018

Qiao 2015

Ren and Wu 2006

Wang and Lan 2012

Wei and Tan 2005

Ye 2009

Ye 2013

Zhang et al 2004

Zhao and Dong 2016

Zheng 2006

Figure 3 Risk of bias summary and graph

for heterogeneity (1198682 = 00 119875 = 0953) (Figure 10) thusthe fixed-effects model was used for data analysis The meta-analysis revealed that the experimental group performedbetter than the control group in reducing B2M [WMD =ndash009 95 CI(ndash011 ndash007) 119875 le 0001] (Figure S11)

348 Systolic Blood Pressure (SBP mmHg) Nine studies[29 34ndash38 40 41 44] reported on the use of breviscapineinjection plus antihypertensive drugs in the treatment of SBPfor hypertensive nephropathy After the test for heterogeneity(1198682 = 79 119875 le 0001) (Figure 11) we employed arandomeffectsmodelMeta-analysis showed anonsignificanttrend for reduction in systolic blood pressure between theexperimental group and the control group [WMD = ndash10295 CI(ndash288 084) 119875 = 0281] (Figure S12)

349 Comparison of Clinical Efficacy A total of 7 studies[31 33 35 36 38ndash40] reported the results of the total effectiverate involving 657 patients (330 in the experimental groupand 327 in the control group) After the test for heterogeneity(1198682 = 852 119875 le 0001) (Figure 12) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (119875 = 0181) to evaluate publicationbias for effective rate (Supplementary Figures S13 and S14)Meta-analysis indicated that the total clinical effective rateof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in treating for hypertensivenephropathy was higher than that in the control group whichshowed a statistically significant difference [RR = 127 95CI(105 153)119875 = 0014] (Figure S15) All included trials werepublished in Chinese academic journals Since trials withnegative or neutral results are less likely to be published

10 Evidence-Based Complementary and Alternative Medicine

Figure 4 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Scrfor hypertensive nephropathy

05

1015

se (W

MD

)

minus100 minus80 minus60 minus40 minus20 0WMD

Funnel plot with pseudo 95 confidence limits

Figure 5 Funnel plot for the publication bias of Scr

Evidence-Based Complementary and Alternative Medicine 11

Figure 6 Subgroup analysis of different doses of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone interms of Scr for hypertensive nephropathy

the efficacy of published studies might be overestimatedConsequently the possibility of publication bias could not beruled out

3410 Adverse Effects Nine of the included trials [29ndash36 38]described adverse effects in detail while the others did notmention adverse eventsOnly one showedmild facial flushingduring intravenous dripping of breviscapine [30] and afterthe speed of transfusion was slowed down the symptom gotremitted Two cases [38] showed redness of limb skin in theexperimental group There were two cases [31 32] of headinflation during the use of antihypertensive drugsTherewerethree cases [33 34] of head swelling and dizziness duringinfusion during the use of breviscapine injection Twenty-onecases showed dry cough due to the use of ACEI in six trials[29 31ndash33 35 36] None of the adverse events were seriousThese symptoms are self-limited and did not affect treatment

4 Discussion

Thismeta-analysis included 14 studies with 1170 total partici-pants comparing breviscapine injection plus antihypertensivedrugs versus antihypertensive drugs alone for hypertensivenephropathy Meanwhile the results demonstrated that theexpression levels of SCr and BUN were significantly lowerin patients treated with breviscapine injection in comparisonwith control subjects and the improvement of creatinineclearance was higher in patients treated with breviscapinein comparison with control subjects suggesting that thedrug serves as a protective role in the renal system ofpatients with hypertensive nephropathy Microalbuminuriais regarded as the earliest clinical sign of hypertensivenephropathy It is defined as a urinary albumin excretionrate ranging from 30 to 300mgday and the definitivemeasurement is based on a timed urine collection during

12 Evidence-Based Complementary and Alternative Medicine

Figure 7 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the 24 hUTP for hypertensive nephropathy

a 24-h period The present meta-analysis indicated thatbreviscapine injection can reduce 24-hour urinary proteinand the urinary beta-2-microglobulin a reduction in uri-nary protein may contribute towards the renal protectiveeffect of breviscapine injection in patients with hyperten-sive nephropathy Our analysis revealed that experimentalgroups showed better overall clinical efficacy than controlgroups

Erigeron breviscapus is a kind of traditional Chinesemedicine It was first recorded in the book of ldquoYunnan Mate-ria Medicardquo According to Chinese medicine theory erigeronbreviscapus is cold-natured sweet bitter and pungent intaste with the function of clearing heat relieving toxic-ity eliminating wind and dampness activating blood andremoving stasis expediting channel and activating meridianrelieving inflammation and alleviating pain The monomercomponent of Chinese herbal medicine (CHM) also knownas the natural pure compound drug has recently attractedmuch attention The natural extract artemisinin and itsderivatives are good examples of monomer components ofCHM that can treat diseases through various activities andcan be a good starting point to uncover the mechanism oftraditional Chinese medicine

Hypertensive renal injury is major target-organ damagedue to sustained high BP Long-term hypertension cancause renal sclerosis and gradually progress to chronic renalfailure Positive control of hypertension is the key to pre-venting hypertensive renal damage According to Chinesemedicine theory hypertensive renal injury is strongly relatedto fluid phlegm and dampness retention syndrome andliver-yang hyperactivity syndrome which are caused bydeficiency syndrome Chinese medicines which are usedto treat fluid phlegm and dampness retention syndromedeficiency syndrome and liver-yang hyperactivity syndromerespectively have certain advantages with regard to treatinghypertensive renal injury [45] Clinical research indicatesthat Chinese herbal medicine might control increased SBPinhibit the glomerular and tubular hyperplasia caused byhigh BP and significantly reduce urinary albumin and beta-2-microglobulin by increasing the activity of renal rennin andthe level of Ang II [46 47]

5 Limitations

Several limiting factors in this study should be consideredFirst the quality of the included randomized controlled trials

Evidence-Based Complementary and Alternative Medicine 13

Figure 8 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of theBUN for hypertensive nephropathy

Figure 9 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Ccrfor hypertensive nephropathy

was low All included trials showed high or undefined risk ofbias due to design reporting and methodology There wereno definitive randomized double-blind placebo-controlledtrials included in this meta-analysis No trials reporteddetailed randomization methods or allocation concealmentNo trial was double-blinded and unfortunately none ofRCT (randomized controlled trial) has a placebo in thetrial Therefore the reported strength of evidence should

be reevaluated and more rigorously designed placebo-controlled trials are warranted to give high-level evidencein future studies [48] Second five trials did not reportadverse reactions Therefore conclusions about safety can-not be made with confidence Furthermore certain activeingredients are chemically unstable which limits large-scalesynthesis These pressing issues should be resolved in futureresearch The safety of breviscapine injection needs to be

14 Evidence-Based Complementary and Alternative Medicine

Figure 10 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of beta-2-microglobulin for hypertensive nephropathy

Figure 11 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the SBPfor hypertensive nephropathy

strictly monitored and properly reported in future clinicaltrialsThird all tests produced positive results althoughmosttests were conducted with small samples We tried our best toavoid language bias and positional prejudice but cannot ruleout potential publication bias

Overall our results suggest that breviscapine injection iseffective and safe for the treatment of hypertensive nephropa-thy and this work has reference value for clinicians Morelarge-scale multicenter rigorously designed randomized

controlled trials are needed to provide accurate data tofurther validate the effectiveness and safety of breviscapineinjection

6 Conclusions

Evidence from this systematic review shows that breviscap-ine injection in combination with antihypertensive drugscan improve clinical efficacy and creatinine clearance rate

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

4 Evidence-Based Complementary and Alternative Medicine

Records identified through database searching PubMed= 125 the Cochrane Library= 29 Embase=124 Sino Med = 28 CNKI= 47Wanfang Data= 27 VIP= 31

Scre

enin

gIn

clud

edEl

igib

ility

Additional records identified through

other sources(n = 0)

Records aer duplicates removed(n = 159)

Records screened (n =159)

Records excluded (n = 57)Duplicate studies (n = 5)Case reports (n = 4)Animal experiments (n = 27)Conference abstracts (n = 10)Pharmacokinetic studies (n = 11)

Full-text articles assessedfor eligibility

(n = 102)

Full-text articles excluded Did not meet the inclusion criteria (n= 88)Nonrandomized controlledtrails (n = 15)Outcome measures did notmeet the inclusive criteria (n =68)other documents (n =5)

Studies included in meta-analysis (n = 14)

Iden

tifica

tion

PRISMA 2009 Flow Diagram

Figure 1 Flowchart of the process for literature retrieval

included irrelevant titles and abstracts Only 159 studies wereretrieved Following a review of the titles and abstractsseveral studies were excluded and only 102 studies remainedFive trials were excluded because of duplicated publicationsTwenty-seven trials were excluded for being animal studiesand twenty-five trials were excluded for being nonclinicaltrials including case reports pharmacokinetic studies andconference abstracts Eighty-eight out of the remaining 102articles were excluded based on the inclusion criteria leavingfourteen RCTs to be reviewed in Figure 1

32 Study Characteristics There were 14 randomized con-trolled trials [29ndash41 44] that were included in the presentresearch involving 1170 patients (593 in the research groupand 577 in the control group)These 14 RCTs are summarizedin Table 1

33 Summary of the Quality and Bias Risk of the TrialsIncluded The quality of all studies included was low Allstudies were carried out among the Chinese populationFourteen studies mention the use of random allocationAll studies failed to mention the specific grouping methodand none of the studies discussed allocation concealmentblinding or evaluator blinding The quality assessment isshown in Figures 2 and 3

34 Outcome Measures

341 Primary Outcome Serum Creatinine (Scr 120583moll)Twelve studies [30ndash40 44] involving 969 participants re-ported on the use of breviscapine injection plus antihy-pertensive drugs in the treatment of Scr for hypertensivenephropathy After the test for heterogeneity (1198682 = 959

Evidence-Based Complementary and Alternative Medicine 5

Table1Ch

aracteris

ticso

f14stu

dies

fulfilling

theinclusio

ncriteria

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Zhange

tal

2004

[29]

94(4747)

T1816

C

1713

T60plusmn8

C60plusmn8

GMY

(1999WHO-ISH

)

Brevisc

apine

injection(20m

livgttqd

)+control

Lisin

opril

(5-10m

gpo

tid)

25mgtid

2weeks

Guiding

principles

(2002)

24UA

ERSBP

DBP

B2M

TC

TGLDLLD

H-C

HctPAG

TFib

T2caseso

fdry

coug

hC

3caseso

fdry

coug

h

WeiandTan

2005[30]

76(4036)

T3010

C

288

T635

C64

3GMY

(1999WHO-ISH

)

Brevisc

apine

injection(20m

livgttqd

)+control

Amlodipine

(5mgpo

qd)+

Captopril(25m

gpo

tid)

4weeks

Guiding

principles

(2002)

24hUTP

BUN

Scrbloo

dB2

M

Urin

eB2M

T1sho

wed

mild

facialflu

shing

durin

ginfusion

CNon

e

RenandWu

2006[31]

60(3030)

T219

C228

T44

-75

C43-74

CGMY(200

4)

Brevisc

apine

injection(30m

livgttqd

)+control

Captopril

(25-75

mgpo

qd

)orN

ifedipine

(20-60

mgpo

qd

)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

24hUTP

BUN

Scr

T2caseso

fdry

coug

hC

1caseo

fmild

head

inflatio

n

Zheng2

006[32]

72(3735)

T2213

C

2314

T41-73

C42-71

GMY

(1999WHO-ISH

)

Brevisc

apine

injection(30m

livgttqd

)+control

Captopril

(25-75

mgpo

bidor

tid)o

rNifedipine

(10-60

mgpo

bidor

tid)

4weeks

Guiding

principles

(2002)

24hUTP

BUN

Scr

T2caseso

fcoug

hC

1caseo

fmild

head

inflatio

n

Chen

etal

2008[33]

57(2829)

T199

C209

T456plusmn203

C46

4plusmn211

CGMY(200

4)

Brevisc

apine

injection(20m

livgttqd

)+control

Benazepril(no

details)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

24hUTP

BUN

ScrCcr

T2caseso

fhead

swellin

gdizzinessd

uring

infusio

nC

1caseo

fcou

gh

Ye2009[34]

75(4035)

T2416

C

2015

T473plusmn

182

C46

9plusmn161

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Losartan

Potassium

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

24hUTP

Scr

CcrU

rineB

2M

SBPDBP

T1caseo

fdizziness

CNon

e

6 Evidence-Based Complementary and Alternative Medicine

Table1Con

tinued

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Hea

ndGen

2010[35]

168(8484)

T4935

C4836

T69plusmn11

C68plusmn11

CGMY(200

5)

Brevisc

apine

injection(20m

livgttqd

)+control

Captopril

(125-50

mgpo

tid

)30

days

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrB

UN

T5c

ases

ofdry

coug

hC

3caseso

fdry

coug

h

WangandLan

2012[36]

103(5251)

Unclear

T624plusmn48

C624plusmn48

GMY

(1999WHO-ISH

)andNephrology

(HaiyanWang)

Brevisc

apine

injection(10m

livgttqd

)+control

Lisin

opril

(20m

gpo

qd)

30days

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrB

UN

T1caseo

fdry

coug

hC

2caseso

fdry

coug

h

Liu2012[37]

50(2624)

T1214

C

1014

T55plusmn4

C53plusmn5

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(10m

livgttqd

)+control

Benazepril

(10m

gpo

bid)

2weeks

Guiding

principles

(2002)

SBPDBP

Urin

ary

microalbu

min

Not

repo

rted

Huang

etal

2013[38]

63(3330)

T249

C1911

Unclear

CGMY(200

4)

Brevisc

apine

injection(20m

livgttqd

)+control

Felodipine

(5mg

poqd)+As

pirin

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrBUN

TCT

Gblood

glucose

T2caseso

flim

bskin

redn

ess

CNon

e

Ye2013[39]

48(2424)

T168

C1410

T530plusmn93

C

490plusmn116

CGMY(2010)

Brevisc

apine

injection(12m

livgttqd

)+control

Antihypertensive

Drugs

(no

details)+

ProstaglandinE

injection(2ml

ivgttqd

)

30days

Guiding

principles

(2002)

Clinicaleffi

cacy

24hUTP

TC

TGScrBUN

Not

repo

rted

Qiao2015[40]

158(7979)

Unclear

T4801plusmn31

5C

4801plusmn31

5

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Captopril

(25-75

mgpo

tid

)orN

ifedipine

(10-60

mgpo

tid

)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

224

hUTP

ScrB

UN

Not

repo

rted

Zhao

andDon

g2016[41]

80(4040

)Unclear

T525plusmn

71

C525plusmn

71CG

MY(2010)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Benazepril(5mg

poqd)

4weeks

Guiding

principles

(2002)

Col-IVLN

PIII

PET

-1M

MP-9

NOE

ILAE

ISA

VOISB

PDBP

Non

e

Evidence-Based Complementary and Alternative Medicine 7

Table1Con

tinued

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Ma2

018[41]

66(3333)

T1914

C

2013

T4800plusmn

314

C4899plusmn

298

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Losartan

Potassium

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

Urin

eB2M

SBP

DBP

24h

UTP

ScrCcr

Not

repo

rted

Ttre

atmentgroup

Ccon

trolgroup

GMY(19

99WHO-ISH

)Th

e1999WHO-ISH

Guidelin

esforthe

Managem

ento

fHypertensionCG

MY(200

4)200

4Ch

ineseG

uidelin

esforthe

Managem

ento

fHypertension

CGMY(2010)2010Ch

ineseGuidelin

esfortheManagem

ento

fHypertension

CGMY(2014)2014Ch

ineseGuidelin

esfortheManagem

ento

fHypertension

Guiding

Principles

(2002)G

uiding

Principles

ofClinicalRe

search

onNew

Drugs

ofCh

ineseM

edicines

(2002)Scrserum

creatin

ineBU

Nblood

urea

nitro

genCcrcreatininec

learance

rate24h

UTP

24-ho

ururinarytotalproteinB

2Mbeta-2-microglob

ulin

SBP

systo

licbloo

dpressureD

BPd

iasto

licbloo

dpressureT

Ctotalcho

leste

rolTG

totaltriglycerid

esPAG

TplateletaggregationrateF

ibfi

brinogenH

cth

ematocritL

DL

low-densitylip

oproteinL

DH-C

lactatedehydrogenaseC

Col-IV

collagenIVL

Nlam

ininP

IIIP

procollagen-III-peptideET

-1end

othelin

1MMP-9matrix

metalloproteinase-9E

ILAelasticity

indexof

largearteryE

ISAelasticity

indexof

smallarteryVOIvascular

overload

index

8 Evidence-Based Complementary and Alternative Medicine

0 25 50 75 100

Low risk of bias

Unclear risk of bias

High risk of bias

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

Figure 2 Risk of bias

119875 le 0001) (Figure 4) we employed a random effectsmodel A funnel plot analysis of the 12 trials suggestedpossible publication bias and inclusion of low quality studiesas significant asymmetry is shown in Figure 5 We appliedEggerrsquos test to evaluate publication bias A p (P = 0634)value more than 005 was considered no publication bias(Supplementary Figure S1) The meta-analysis revealed thatthe experimental group performed better than the controlgroup in reducing Scr [WMD = ndash3516 95 CI(ndash5001ndash2031) 119875 le 0001] (Supplementary Figure S2)

342 Sensitivity Analysis We conducted a sensitivity analy-sis for Scr (Supplementary Figure S3) By seriatim excludingone trial each time and reperforming meta-analysis of theremaining trials we could observe whether the outcomeshave dramatically changed Sensitivity analysis indicated thatthe outcomes of Scr were very similar which had relativelygood stability

343 Subgroup Analysis Because of variability in evaluat-ing point of the serum creatinine we conducted subgroupanalysis among studies using different doses of breviscapineinjection (30ml 20ml 12ml 10ml and 5ml) Comparedwith the control groups the results of subgroup analysisshowed that there was no significant correlation between thedecrease of serum creatinine and the dose of breviscapineinjection (Figure 6)

344 24-Hour Urinary Total Protein (24h UTP gd) Twelvestudies [29ndash36 38ndash40 44] reported on the use of brevis-capine injection plus antihypertensive drugs in terms ofthe 24 h UTP for hypertensive nephropathy After the testfor heterogeneity (1198682 = 937 P le 0001) (Figure 7) weemployed a random effects modelWe conducted a sensitivity

analysis and applied Eggerrsquos test (P = 0586) to evaluatepublication bias for 24 h UTP (Supplementary Figures S4and S5) The meta-analysis revealed that the experimentalgroup performed better than the control group in reducing24 h UTP [WMD = ndash004 95 CI(ndash005 ndash002) 119875 le 0001](Figure S6)

345 Blood Urea Nitrogen (BUN mmolL) Ten studies [30ndash33 35ndash40] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of BUN forhypertensive nephropathy After the test for heterogeneity(1198682 = 923 119875 le 0001) (Figure 8) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (P = 0015) to evaluate publicationbias for BUN (Supplementary Figures S7 and S8) The meta-analysis revealed that the experimental group performedbetter than the control group in reducing BUN [WMD =ndash200 95 CI(ndash307 ndash094) 119875 le 0001] (SupplementaryFigure S9)

346 Creatinine Clearance Rate (Ccr mlmin) Three studies[33 34 44] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of Ccr forhypertensive nephropathy After the test for heterogeneity(1198682 = 00 119875 = 0903) (Figure 9) thus the fixed-effects model was used for data analysis The meta-analysisrevealed that the experimental group performed better thanthe control group in improving creatinine clearance rate[WMD = 784 95 CI(520 1049) 119875 le 0001] (Figure S10)

347 Beta-2-Microglobulin (B2M mgL) Three studies [3034 44] reported on the use of breviscapine injection plusantihypertensive drugs in the treatment of urine beta-2-microglobulin for hypertensive nephropathy After the test

Evidence-Based Complementary and Alternative Medicine 9

Rand

om se

quen

ce g

ener

atio

n (s

elec

tion

bias

)

Allo

catio

n co

ncea

lmen

t (se

lect

ion

bias

)

Blin

ding

of p

artic

ipan

ts an

d pe

rson

nel (

perfo

rman

ce b

ias)

Blin

ding

of o

utco

me a

sses

smen

t (de

tect

ion

bias

)

Inco

mpl

ete o

utco

me d

ata (

attr

ition

bia

s)

Sele

ctiv

e rep

ortin

g (r

epor

ting

bias

)

Oth

er b

ias

Chen et al 2008

He and Gen 2010

Huang et al 2013

Liu 2012

Ma 2018

Qiao 2015

Ren and Wu 2006

Wang and Lan 2012

Wei and Tan 2005

Ye 2009

Ye 2013

Zhang et al 2004

Zhao and Dong 2016

Zheng 2006

Figure 3 Risk of bias summary and graph

for heterogeneity (1198682 = 00 119875 = 0953) (Figure 10) thusthe fixed-effects model was used for data analysis The meta-analysis revealed that the experimental group performedbetter than the control group in reducing B2M [WMD =ndash009 95 CI(ndash011 ndash007) 119875 le 0001] (Figure S11)

348 Systolic Blood Pressure (SBP mmHg) Nine studies[29 34ndash38 40 41 44] reported on the use of breviscapineinjection plus antihypertensive drugs in the treatment of SBPfor hypertensive nephropathy After the test for heterogeneity(1198682 = 79 119875 le 0001) (Figure 11) we employed arandomeffectsmodelMeta-analysis showed anonsignificanttrend for reduction in systolic blood pressure between theexperimental group and the control group [WMD = ndash10295 CI(ndash288 084) 119875 = 0281] (Figure S12)

349 Comparison of Clinical Efficacy A total of 7 studies[31 33 35 36 38ndash40] reported the results of the total effectiverate involving 657 patients (330 in the experimental groupand 327 in the control group) After the test for heterogeneity(1198682 = 852 119875 le 0001) (Figure 12) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (119875 = 0181) to evaluate publicationbias for effective rate (Supplementary Figures S13 and S14)Meta-analysis indicated that the total clinical effective rateof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in treating for hypertensivenephropathy was higher than that in the control group whichshowed a statistically significant difference [RR = 127 95CI(105 153)119875 = 0014] (Figure S15) All included trials werepublished in Chinese academic journals Since trials withnegative or neutral results are less likely to be published

10 Evidence-Based Complementary and Alternative Medicine

Figure 4 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Scrfor hypertensive nephropathy

05

1015

se (W

MD

)

minus100 minus80 minus60 minus40 minus20 0WMD

Funnel plot with pseudo 95 confidence limits

Figure 5 Funnel plot for the publication bias of Scr

Evidence-Based Complementary and Alternative Medicine 11

Figure 6 Subgroup analysis of different doses of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone interms of Scr for hypertensive nephropathy

the efficacy of published studies might be overestimatedConsequently the possibility of publication bias could not beruled out

3410 Adverse Effects Nine of the included trials [29ndash36 38]described adverse effects in detail while the others did notmention adverse eventsOnly one showedmild facial flushingduring intravenous dripping of breviscapine [30] and afterthe speed of transfusion was slowed down the symptom gotremitted Two cases [38] showed redness of limb skin in theexperimental group There were two cases [31 32] of headinflation during the use of antihypertensive drugsTherewerethree cases [33 34] of head swelling and dizziness duringinfusion during the use of breviscapine injection Twenty-onecases showed dry cough due to the use of ACEI in six trials[29 31ndash33 35 36] None of the adverse events were seriousThese symptoms are self-limited and did not affect treatment

4 Discussion

Thismeta-analysis included 14 studies with 1170 total partici-pants comparing breviscapine injection plus antihypertensivedrugs versus antihypertensive drugs alone for hypertensivenephropathy Meanwhile the results demonstrated that theexpression levels of SCr and BUN were significantly lowerin patients treated with breviscapine injection in comparisonwith control subjects and the improvement of creatinineclearance was higher in patients treated with breviscapinein comparison with control subjects suggesting that thedrug serves as a protective role in the renal system ofpatients with hypertensive nephropathy Microalbuminuriais regarded as the earliest clinical sign of hypertensivenephropathy It is defined as a urinary albumin excretionrate ranging from 30 to 300mgday and the definitivemeasurement is based on a timed urine collection during

12 Evidence-Based Complementary and Alternative Medicine

Figure 7 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the 24 hUTP for hypertensive nephropathy

a 24-h period The present meta-analysis indicated thatbreviscapine injection can reduce 24-hour urinary proteinand the urinary beta-2-microglobulin a reduction in uri-nary protein may contribute towards the renal protectiveeffect of breviscapine injection in patients with hyperten-sive nephropathy Our analysis revealed that experimentalgroups showed better overall clinical efficacy than controlgroups

Erigeron breviscapus is a kind of traditional Chinesemedicine It was first recorded in the book of ldquoYunnan Mate-ria Medicardquo According to Chinese medicine theory erigeronbreviscapus is cold-natured sweet bitter and pungent intaste with the function of clearing heat relieving toxic-ity eliminating wind and dampness activating blood andremoving stasis expediting channel and activating meridianrelieving inflammation and alleviating pain The monomercomponent of Chinese herbal medicine (CHM) also knownas the natural pure compound drug has recently attractedmuch attention The natural extract artemisinin and itsderivatives are good examples of monomer components ofCHM that can treat diseases through various activities andcan be a good starting point to uncover the mechanism oftraditional Chinese medicine

Hypertensive renal injury is major target-organ damagedue to sustained high BP Long-term hypertension cancause renal sclerosis and gradually progress to chronic renalfailure Positive control of hypertension is the key to pre-venting hypertensive renal damage According to Chinesemedicine theory hypertensive renal injury is strongly relatedto fluid phlegm and dampness retention syndrome andliver-yang hyperactivity syndrome which are caused bydeficiency syndrome Chinese medicines which are usedto treat fluid phlegm and dampness retention syndromedeficiency syndrome and liver-yang hyperactivity syndromerespectively have certain advantages with regard to treatinghypertensive renal injury [45] Clinical research indicatesthat Chinese herbal medicine might control increased SBPinhibit the glomerular and tubular hyperplasia caused byhigh BP and significantly reduce urinary albumin and beta-2-microglobulin by increasing the activity of renal rennin andthe level of Ang II [46 47]

5 Limitations

Several limiting factors in this study should be consideredFirst the quality of the included randomized controlled trials

Evidence-Based Complementary and Alternative Medicine 13

Figure 8 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of theBUN for hypertensive nephropathy

Figure 9 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Ccrfor hypertensive nephropathy

was low All included trials showed high or undefined risk ofbias due to design reporting and methodology There wereno definitive randomized double-blind placebo-controlledtrials included in this meta-analysis No trials reporteddetailed randomization methods or allocation concealmentNo trial was double-blinded and unfortunately none ofRCT (randomized controlled trial) has a placebo in thetrial Therefore the reported strength of evidence should

be reevaluated and more rigorously designed placebo-controlled trials are warranted to give high-level evidencein future studies [48] Second five trials did not reportadverse reactions Therefore conclusions about safety can-not be made with confidence Furthermore certain activeingredients are chemically unstable which limits large-scalesynthesis These pressing issues should be resolved in futureresearch The safety of breviscapine injection needs to be

14 Evidence-Based Complementary and Alternative Medicine

Figure 10 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of beta-2-microglobulin for hypertensive nephropathy

Figure 11 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the SBPfor hypertensive nephropathy

strictly monitored and properly reported in future clinicaltrialsThird all tests produced positive results althoughmosttests were conducted with small samples We tried our best toavoid language bias and positional prejudice but cannot ruleout potential publication bias

Overall our results suggest that breviscapine injection iseffective and safe for the treatment of hypertensive nephropa-thy and this work has reference value for clinicians Morelarge-scale multicenter rigorously designed randomized

controlled trials are needed to provide accurate data tofurther validate the effectiveness and safety of breviscapineinjection

6 Conclusions

Evidence from this systematic review shows that breviscap-ine injection in combination with antihypertensive drugscan improve clinical efficacy and creatinine clearance rate

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

Evidence-Based Complementary and Alternative Medicine 5

Table1Ch

aracteris

ticso

f14stu

dies

fulfilling

theinclusio

ncriteria

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Zhange

tal

2004

[29]

94(4747)

T1816

C

1713

T60plusmn8

C60plusmn8

GMY

(1999WHO-ISH

)

Brevisc

apine

injection(20m

livgttqd

)+control

Lisin

opril

(5-10m

gpo

tid)

25mgtid

2weeks

Guiding

principles

(2002)

24UA

ERSBP

DBP

B2M

TC

TGLDLLD

H-C

HctPAG

TFib

T2caseso

fdry

coug

hC

3caseso

fdry

coug

h

WeiandTan

2005[30]

76(4036)

T3010

C

288

T635

C64

3GMY

(1999WHO-ISH

)

Brevisc

apine

injection(20m

livgttqd

)+control

Amlodipine

(5mgpo

qd)+

Captopril(25m

gpo

tid)

4weeks

Guiding

principles

(2002)

24hUTP

BUN

Scrbloo

dB2

M

Urin

eB2M

T1sho

wed

mild

facialflu

shing

durin

ginfusion

CNon

e

RenandWu

2006[31]

60(3030)

T219

C228

T44

-75

C43-74

CGMY(200

4)

Brevisc

apine

injection(30m

livgttqd

)+control

Captopril

(25-75

mgpo

qd

)orN

ifedipine

(20-60

mgpo

qd

)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

24hUTP

BUN

Scr

T2caseso

fdry

coug

hC

1caseo

fmild

head

inflatio

n

Zheng2

006[32]

72(3735)

T2213

C

2314

T41-73

C42-71

GMY

(1999WHO-ISH

)

Brevisc

apine

injection(30m

livgttqd

)+control

Captopril

(25-75

mgpo

bidor

tid)o

rNifedipine

(10-60

mgpo

bidor

tid)

4weeks

Guiding

principles

(2002)

24hUTP

BUN

Scr

T2caseso

fcoug

hC

1caseo

fmild

head

inflatio

n

Chen

etal

2008[33]

57(2829)

T199

C209

T456plusmn203

C46

4plusmn211

CGMY(200

4)

Brevisc

apine

injection(20m

livgttqd

)+control

Benazepril(no

details)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

24hUTP

BUN

ScrCcr

T2caseso

fhead

swellin

gdizzinessd

uring

infusio

nC

1caseo

fcou

gh

Ye2009[34]

75(4035)

T2416

C

2015

T473plusmn

182

C46

9plusmn161

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Losartan

Potassium

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

24hUTP

Scr

CcrU

rineB

2M

SBPDBP

T1caseo

fdizziness

CNon

e

6 Evidence-Based Complementary and Alternative Medicine

Table1Con

tinued

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Hea

ndGen

2010[35]

168(8484)

T4935

C4836

T69plusmn11

C68plusmn11

CGMY(200

5)

Brevisc

apine

injection(20m

livgttqd

)+control

Captopril

(125-50

mgpo

tid

)30

days

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrB

UN

T5c

ases

ofdry

coug

hC

3caseso

fdry

coug

h

WangandLan

2012[36]

103(5251)

Unclear

T624plusmn48

C624plusmn48

GMY

(1999WHO-ISH

)andNephrology

(HaiyanWang)

Brevisc

apine

injection(10m

livgttqd

)+control

Lisin

opril

(20m

gpo

qd)

30days

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrB

UN

T1caseo

fdry

coug

hC

2caseso

fdry

coug

h

Liu2012[37]

50(2624)

T1214

C

1014

T55plusmn4

C53plusmn5

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(10m

livgttqd

)+control

Benazepril

(10m

gpo

bid)

2weeks

Guiding

principles

(2002)

SBPDBP

Urin

ary

microalbu

min

Not

repo

rted

Huang

etal

2013[38]

63(3330)

T249

C1911

Unclear

CGMY(200

4)

Brevisc

apine

injection(20m

livgttqd

)+control

Felodipine

(5mg

poqd)+As

pirin

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrBUN

TCT

Gblood

glucose

T2caseso

flim

bskin

redn

ess

CNon

e

Ye2013[39]

48(2424)

T168

C1410

T530plusmn93

C

490plusmn116

CGMY(2010)

Brevisc

apine

injection(12m

livgttqd

)+control

Antihypertensive

Drugs

(no

details)+

ProstaglandinE

injection(2ml

ivgttqd

)

30days

Guiding

principles

(2002)

Clinicaleffi

cacy

24hUTP

TC

TGScrBUN

Not

repo

rted

Qiao2015[40]

158(7979)

Unclear

T4801plusmn31

5C

4801plusmn31

5

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Captopril

(25-75

mgpo

tid

)orN

ifedipine

(10-60

mgpo

tid

)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

224

hUTP

ScrB

UN

Not

repo

rted

Zhao

andDon

g2016[41]

80(4040

)Unclear

T525plusmn

71

C525plusmn

71CG

MY(2010)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Benazepril(5mg

poqd)

4weeks

Guiding

principles

(2002)

Col-IVLN

PIII

PET

-1M

MP-9

NOE

ILAE

ISA

VOISB

PDBP

Non

e

Evidence-Based Complementary and Alternative Medicine 7

Table1Con

tinued

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Ma2

018[41]

66(3333)

T1914

C

2013

T4800plusmn

314

C4899plusmn

298

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Losartan

Potassium

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

Urin

eB2M

SBP

DBP

24h

UTP

ScrCcr

Not

repo

rted

Ttre

atmentgroup

Ccon

trolgroup

GMY(19

99WHO-ISH

)Th

e1999WHO-ISH

Guidelin

esforthe

Managem

ento

fHypertensionCG

MY(200

4)200

4Ch

ineseG

uidelin

esforthe

Managem

ento

fHypertension

CGMY(2010)2010Ch

ineseGuidelin

esfortheManagem

ento

fHypertension

CGMY(2014)2014Ch

ineseGuidelin

esfortheManagem

ento

fHypertension

Guiding

Principles

(2002)G

uiding

Principles

ofClinicalRe

search

onNew

Drugs

ofCh

ineseM

edicines

(2002)Scrserum

creatin

ineBU

Nblood

urea

nitro

genCcrcreatininec

learance

rate24h

UTP

24-ho

ururinarytotalproteinB

2Mbeta-2-microglob

ulin

SBP

systo

licbloo

dpressureD

BPd

iasto

licbloo

dpressureT

Ctotalcho

leste

rolTG

totaltriglycerid

esPAG

TplateletaggregationrateF

ibfi

brinogenH

cth

ematocritL

DL

low-densitylip

oproteinL

DH-C

lactatedehydrogenaseC

Col-IV

collagenIVL

Nlam

ininP

IIIP

procollagen-III-peptideET

-1end

othelin

1MMP-9matrix

metalloproteinase-9E

ILAelasticity

indexof

largearteryE

ISAelasticity

indexof

smallarteryVOIvascular

overload

index

8 Evidence-Based Complementary and Alternative Medicine

0 25 50 75 100

Low risk of bias

Unclear risk of bias

High risk of bias

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

Figure 2 Risk of bias

119875 le 0001) (Figure 4) we employed a random effectsmodel A funnel plot analysis of the 12 trials suggestedpossible publication bias and inclusion of low quality studiesas significant asymmetry is shown in Figure 5 We appliedEggerrsquos test to evaluate publication bias A p (P = 0634)value more than 005 was considered no publication bias(Supplementary Figure S1) The meta-analysis revealed thatthe experimental group performed better than the controlgroup in reducing Scr [WMD = ndash3516 95 CI(ndash5001ndash2031) 119875 le 0001] (Supplementary Figure S2)

342 Sensitivity Analysis We conducted a sensitivity analy-sis for Scr (Supplementary Figure S3) By seriatim excludingone trial each time and reperforming meta-analysis of theremaining trials we could observe whether the outcomeshave dramatically changed Sensitivity analysis indicated thatthe outcomes of Scr were very similar which had relativelygood stability

343 Subgroup Analysis Because of variability in evaluat-ing point of the serum creatinine we conducted subgroupanalysis among studies using different doses of breviscapineinjection (30ml 20ml 12ml 10ml and 5ml) Comparedwith the control groups the results of subgroup analysisshowed that there was no significant correlation between thedecrease of serum creatinine and the dose of breviscapineinjection (Figure 6)

344 24-Hour Urinary Total Protein (24h UTP gd) Twelvestudies [29ndash36 38ndash40 44] reported on the use of brevis-capine injection plus antihypertensive drugs in terms ofthe 24 h UTP for hypertensive nephropathy After the testfor heterogeneity (1198682 = 937 P le 0001) (Figure 7) weemployed a random effects modelWe conducted a sensitivity

analysis and applied Eggerrsquos test (P = 0586) to evaluatepublication bias for 24 h UTP (Supplementary Figures S4and S5) The meta-analysis revealed that the experimentalgroup performed better than the control group in reducing24 h UTP [WMD = ndash004 95 CI(ndash005 ndash002) 119875 le 0001](Figure S6)

345 Blood Urea Nitrogen (BUN mmolL) Ten studies [30ndash33 35ndash40] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of BUN forhypertensive nephropathy After the test for heterogeneity(1198682 = 923 119875 le 0001) (Figure 8) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (P = 0015) to evaluate publicationbias for BUN (Supplementary Figures S7 and S8) The meta-analysis revealed that the experimental group performedbetter than the control group in reducing BUN [WMD =ndash200 95 CI(ndash307 ndash094) 119875 le 0001] (SupplementaryFigure S9)

346 Creatinine Clearance Rate (Ccr mlmin) Three studies[33 34 44] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of Ccr forhypertensive nephropathy After the test for heterogeneity(1198682 = 00 119875 = 0903) (Figure 9) thus the fixed-effects model was used for data analysis The meta-analysisrevealed that the experimental group performed better thanthe control group in improving creatinine clearance rate[WMD = 784 95 CI(520 1049) 119875 le 0001] (Figure S10)

347 Beta-2-Microglobulin (B2M mgL) Three studies [3034 44] reported on the use of breviscapine injection plusantihypertensive drugs in the treatment of urine beta-2-microglobulin for hypertensive nephropathy After the test

Evidence-Based Complementary and Alternative Medicine 9

Rand

om se

quen

ce g

ener

atio

n (s

elec

tion

bias

)

Allo

catio

n co

ncea

lmen

t (se

lect

ion

bias

)

Blin

ding

of p

artic

ipan

ts an

d pe

rson

nel (

perfo

rman

ce b

ias)

Blin

ding

of o

utco

me a

sses

smen

t (de

tect

ion

bias

)

Inco

mpl

ete o

utco

me d

ata (

attr

ition

bia

s)

Sele

ctiv

e rep

ortin

g (r

epor

ting

bias

)

Oth

er b

ias

Chen et al 2008

He and Gen 2010

Huang et al 2013

Liu 2012

Ma 2018

Qiao 2015

Ren and Wu 2006

Wang and Lan 2012

Wei and Tan 2005

Ye 2009

Ye 2013

Zhang et al 2004

Zhao and Dong 2016

Zheng 2006

Figure 3 Risk of bias summary and graph

for heterogeneity (1198682 = 00 119875 = 0953) (Figure 10) thusthe fixed-effects model was used for data analysis The meta-analysis revealed that the experimental group performedbetter than the control group in reducing B2M [WMD =ndash009 95 CI(ndash011 ndash007) 119875 le 0001] (Figure S11)

348 Systolic Blood Pressure (SBP mmHg) Nine studies[29 34ndash38 40 41 44] reported on the use of breviscapineinjection plus antihypertensive drugs in the treatment of SBPfor hypertensive nephropathy After the test for heterogeneity(1198682 = 79 119875 le 0001) (Figure 11) we employed arandomeffectsmodelMeta-analysis showed anonsignificanttrend for reduction in systolic blood pressure between theexperimental group and the control group [WMD = ndash10295 CI(ndash288 084) 119875 = 0281] (Figure S12)

349 Comparison of Clinical Efficacy A total of 7 studies[31 33 35 36 38ndash40] reported the results of the total effectiverate involving 657 patients (330 in the experimental groupand 327 in the control group) After the test for heterogeneity(1198682 = 852 119875 le 0001) (Figure 12) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (119875 = 0181) to evaluate publicationbias for effective rate (Supplementary Figures S13 and S14)Meta-analysis indicated that the total clinical effective rateof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in treating for hypertensivenephropathy was higher than that in the control group whichshowed a statistically significant difference [RR = 127 95CI(105 153)119875 = 0014] (Figure S15) All included trials werepublished in Chinese academic journals Since trials withnegative or neutral results are less likely to be published

10 Evidence-Based Complementary and Alternative Medicine

Figure 4 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Scrfor hypertensive nephropathy

05

1015

se (W

MD

)

minus100 minus80 minus60 minus40 minus20 0WMD

Funnel plot with pseudo 95 confidence limits

Figure 5 Funnel plot for the publication bias of Scr

Evidence-Based Complementary and Alternative Medicine 11

Figure 6 Subgroup analysis of different doses of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone interms of Scr for hypertensive nephropathy

the efficacy of published studies might be overestimatedConsequently the possibility of publication bias could not beruled out

3410 Adverse Effects Nine of the included trials [29ndash36 38]described adverse effects in detail while the others did notmention adverse eventsOnly one showedmild facial flushingduring intravenous dripping of breviscapine [30] and afterthe speed of transfusion was slowed down the symptom gotremitted Two cases [38] showed redness of limb skin in theexperimental group There were two cases [31 32] of headinflation during the use of antihypertensive drugsTherewerethree cases [33 34] of head swelling and dizziness duringinfusion during the use of breviscapine injection Twenty-onecases showed dry cough due to the use of ACEI in six trials[29 31ndash33 35 36] None of the adverse events were seriousThese symptoms are self-limited and did not affect treatment

4 Discussion

Thismeta-analysis included 14 studies with 1170 total partici-pants comparing breviscapine injection plus antihypertensivedrugs versus antihypertensive drugs alone for hypertensivenephropathy Meanwhile the results demonstrated that theexpression levels of SCr and BUN were significantly lowerin patients treated with breviscapine injection in comparisonwith control subjects and the improvement of creatinineclearance was higher in patients treated with breviscapinein comparison with control subjects suggesting that thedrug serves as a protective role in the renal system ofpatients with hypertensive nephropathy Microalbuminuriais regarded as the earliest clinical sign of hypertensivenephropathy It is defined as a urinary albumin excretionrate ranging from 30 to 300mgday and the definitivemeasurement is based on a timed urine collection during

12 Evidence-Based Complementary and Alternative Medicine

Figure 7 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the 24 hUTP for hypertensive nephropathy

a 24-h period The present meta-analysis indicated thatbreviscapine injection can reduce 24-hour urinary proteinand the urinary beta-2-microglobulin a reduction in uri-nary protein may contribute towards the renal protectiveeffect of breviscapine injection in patients with hyperten-sive nephropathy Our analysis revealed that experimentalgroups showed better overall clinical efficacy than controlgroups

Erigeron breviscapus is a kind of traditional Chinesemedicine It was first recorded in the book of ldquoYunnan Mate-ria Medicardquo According to Chinese medicine theory erigeronbreviscapus is cold-natured sweet bitter and pungent intaste with the function of clearing heat relieving toxic-ity eliminating wind and dampness activating blood andremoving stasis expediting channel and activating meridianrelieving inflammation and alleviating pain The monomercomponent of Chinese herbal medicine (CHM) also knownas the natural pure compound drug has recently attractedmuch attention The natural extract artemisinin and itsderivatives are good examples of monomer components ofCHM that can treat diseases through various activities andcan be a good starting point to uncover the mechanism oftraditional Chinese medicine

Hypertensive renal injury is major target-organ damagedue to sustained high BP Long-term hypertension cancause renal sclerosis and gradually progress to chronic renalfailure Positive control of hypertension is the key to pre-venting hypertensive renal damage According to Chinesemedicine theory hypertensive renal injury is strongly relatedto fluid phlegm and dampness retention syndrome andliver-yang hyperactivity syndrome which are caused bydeficiency syndrome Chinese medicines which are usedto treat fluid phlegm and dampness retention syndromedeficiency syndrome and liver-yang hyperactivity syndromerespectively have certain advantages with regard to treatinghypertensive renal injury [45] Clinical research indicatesthat Chinese herbal medicine might control increased SBPinhibit the glomerular and tubular hyperplasia caused byhigh BP and significantly reduce urinary albumin and beta-2-microglobulin by increasing the activity of renal rennin andthe level of Ang II [46 47]

5 Limitations

Several limiting factors in this study should be consideredFirst the quality of the included randomized controlled trials

Evidence-Based Complementary and Alternative Medicine 13

Figure 8 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of theBUN for hypertensive nephropathy

Figure 9 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Ccrfor hypertensive nephropathy

was low All included trials showed high or undefined risk ofbias due to design reporting and methodology There wereno definitive randomized double-blind placebo-controlledtrials included in this meta-analysis No trials reporteddetailed randomization methods or allocation concealmentNo trial was double-blinded and unfortunately none ofRCT (randomized controlled trial) has a placebo in thetrial Therefore the reported strength of evidence should

be reevaluated and more rigorously designed placebo-controlled trials are warranted to give high-level evidencein future studies [48] Second five trials did not reportadverse reactions Therefore conclusions about safety can-not be made with confidence Furthermore certain activeingredients are chemically unstable which limits large-scalesynthesis These pressing issues should be resolved in futureresearch The safety of breviscapine injection needs to be

14 Evidence-Based Complementary and Alternative Medicine

Figure 10 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of beta-2-microglobulin for hypertensive nephropathy

Figure 11 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the SBPfor hypertensive nephropathy

strictly monitored and properly reported in future clinicaltrialsThird all tests produced positive results althoughmosttests were conducted with small samples We tried our best toavoid language bias and positional prejudice but cannot ruleout potential publication bias

Overall our results suggest that breviscapine injection iseffective and safe for the treatment of hypertensive nephropa-thy and this work has reference value for clinicians Morelarge-scale multicenter rigorously designed randomized

controlled trials are needed to provide accurate data tofurther validate the effectiveness and safety of breviscapineinjection

6 Conclusions

Evidence from this systematic review shows that breviscap-ine injection in combination with antihypertensive drugscan improve clinical efficacy and creatinine clearance rate

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

6 Evidence-Based Complementary and Alternative Medicine

Table1Con

tinued

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Hea

ndGen

2010[35]

168(8484)

T4935

C4836

T69plusmn11

C68plusmn11

CGMY(200

5)

Brevisc

apine

injection(20m

livgttqd

)+control

Captopril

(125-50

mgpo

tid

)30

days

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrB

UN

T5c

ases

ofdry

coug

hC

3caseso

fdry

coug

h

WangandLan

2012[36]

103(5251)

Unclear

T624plusmn48

C624plusmn48

GMY

(1999WHO-ISH

)andNephrology

(HaiyanWang)

Brevisc

apine

injection(10m

livgttqd

)+control

Lisin

opril

(20m

gpo

qd)

30days

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrB

UN

T1caseo

fdry

coug

hC

2caseso

fdry

coug

h

Liu2012[37]

50(2624)

T1214

C

1014

T55plusmn4

C53plusmn5

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(10m

livgttqd

)+control

Benazepril

(10m

gpo

bid)

2weeks

Guiding

principles

(2002)

SBPDBP

Urin

ary

microalbu

min

Not

repo

rted

Huang

etal

2013[38]

63(3330)

T249

C1911

Unclear

CGMY(200

4)

Brevisc

apine

injection(20m

livgttqd

)+control

Felodipine

(5mg

poqd)+As

pirin

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

24h

UTP

ScrBUN

TCT

Gblood

glucose

T2caseso

flim

bskin

redn

ess

CNon

e

Ye2013[39]

48(2424)

T168

C1410

T530plusmn93

C

490plusmn116

CGMY(2010)

Brevisc

apine

injection(12m

livgttqd

)+control

Antihypertensive

Drugs

(no

details)+

ProstaglandinE

injection(2ml

ivgttqd

)

30days

Guiding

principles

(2002)

Clinicaleffi

cacy

24hUTP

TC

TGScrBUN

Not

repo

rted

Qiao2015[40]

158(7979)

Unclear

T4801plusmn31

5C

4801plusmn31

5

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Captopril

(25-75

mgpo

tid

)orN

ifedipine

(10-60

mgpo

tid

)

4weeks

Guiding

principles

(2002)

Clinicaleffi

cacy

SBPDBP

224

hUTP

ScrB

UN

Not

repo

rted

Zhao

andDon

g2016[41]

80(4040

)Unclear

T525plusmn

71

C525plusmn

71CG

MY(2010)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Benazepril(5mg

poqd)

4weeks

Guiding

principles

(2002)

Col-IVLN

PIII

PET

-1M

MP-9

NOE

ILAE

ISA

VOISB

PDBP

Non

e

Evidence-Based Complementary and Alternative Medicine 7

Table1Con

tinued

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Ma2

018[41]

66(3333)

T1914

C

2013

T4800plusmn

314

C4899plusmn

298

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Losartan

Potassium

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

Urin

eB2M

SBP

DBP

24h

UTP

ScrCcr

Not

repo

rted

Ttre

atmentgroup

Ccon

trolgroup

GMY(19

99WHO-ISH

)Th

e1999WHO-ISH

Guidelin

esforthe

Managem

ento

fHypertensionCG

MY(200

4)200

4Ch

ineseG

uidelin

esforthe

Managem

ento

fHypertension

CGMY(2010)2010Ch

ineseGuidelin

esfortheManagem

ento

fHypertension

CGMY(2014)2014Ch

ineseGuidelin

esfortheManagem

ento

fHypertension

Guiding

Principles

(2002)G

uiding

Principles

ofClinicalRe

search

onNew

Drugs

ofCh

ineseM

edicines

(2002)Scrserum

creatin

ineBU

Nblood

urea

nitro

genCcrcreatininec

learance

rate24h

UTP

24-ho

ururinarytotalproteinB

2Mbeta-2-microglob

ulin

SBP

systo

licbloo

dpressureD

BPd

iasto

licbloo

dpressureT

Ctotalcho

leste

rolTG

totaltriglycerid

esPAG

TplateletaggregationrateF

ibfi

brinogenH

cth

ematocritL

DL

low-densitylip

oproteinL

DH-C

lactatedehydrogenaseC

Col-IV

collagenIVL

Nlam

ininP

IIIP

procollagen-III-peptideET

-1end

othelin

1MMP-9matrix

metalloproteinase-9E

ILAelasticity

indexof

largearteryE

ISAelasticity

indexof

smallarteryVOIvascular

overload

index

8 Evidence-Based Complementary and Alternative Medicine

0 25 50 75 100

Low risk of bias

Unclear risk of bias

High risk of bias

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

Figure 2 Risk of bias

119875 le 0001) (Figure 4) we employed a random effectsmodel A funnel plot analysis of the 12 trials suggestedpossible publication bias and inclusion of low quality studiesas significant asymmetry is shown in Figure 5 We appliedEggerrsquos test to evaluate publication bias A p (P = 0634)value more than 005 was considered no publication bias(Supplementary Figure S1) The meta-analysis revealed thatthe experimental group performed better than the controlgroup in reducing Scr [WMD = ndash3516 95 CI(ndash5001ndash2031) 119875 le 0001] (Supplementary Figure S2)

342 Sensitivity Analysis We conducted a sensitivity analy-sis for Scr (Supplementary Figure S3) By seriatim excludingone trial each time and reperforming meta-analysis of theremaining trials we could observe whether the outcomeshave dramatically changed Sensitivity analysis indicated thatthe outcomes of Scr were very similar which had relativelygood stability

343 Subgroup Analysis Because of variability in evaluat-ing point of the serum creatinine we conducted subgroupanalysis among studies using different doses of breviscapineinjection (30ml 20ml 12ml 10ml and 5ml) Comparedwith the control groups the results of subgroup analysisshowed that there was no significant correlation between thedecrease of serum creatinine and the dose of breviscapineinjection (Figure 6)

344 24-Hour Urinary Total Protein (24h UTP gd) Twelvestudies [29ndash36 38ndash40 44] reported on the use of brevis-capine injection plus antihypertensive drugs in terms ofthe 24 h UTP for hypertensive nephropathy After the testfor heterogeneity (1198682 = 937 P le 0001) (Figure 7) weemployed a random effects modelWe conducted a sensitivity

analysis and applied Eggerrsquos test (P = 0586) to evaluatepublication bias for 24 h UTP (Supplementary Figures S4and S5) The meta-analysis revealed that the experimentalgroup performed better than the control group in reducing24 h UTP [WMD = ndash004 95 CI(ndash005 ndash002) 119875 le 0001](Figure S6)

345 Blood Urea Nitrogen (BUN mmolL) Ten studies [30ndash33 35ndash40] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of BUN forhypertensive nephropathy After the test for heterogeneity(1198682 = 923 119875 le 0001) (Figure 8) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (P = 0015) to evaluate publicationbias for BUN (Supplementary Figures S7 and S8) The meta-analysis revealed that the experimental group performedbetter than the control group in reducing BUN [WMD =ndash200 95 CI(ndash307 ndash094) 119875 le 0001] (SupplementaryFigure S9)

346 Creatinine Clearance Rate (Ccr mlmin) Three studies[33 34 44] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of Ccr forhypertensive nephropathy After the test for heterogeneity(1198682 = 00 119875 = 0903) (Figure 9) thus the fixed-effects model was used for data analysis The meta-analysisrevealed that the experimental group performed better thanthe control group in improving creatinine clearance rate[WMD = 784 95 CI(520 1049) 119875 le 0001] (Figure S10)

347 Beta-2-Microglobulin (B2M mgL) Three studies [3034 44] reported on the use of breviscapine injection plusantihypertensive drugs in the treatment of urine beta-2-microglobulin for hypertensive nephropathy After the test

Evidence-Based Complementary and Alternative Medicine 9

Rand

om se

quen

ce g

ener

atio

n (s

elec

tion

bias

)

Allo

catio

n co

ncea

lmen

t (se

lect

ion

bias

)

Blin

ding

of p

artic

ipan

ts an

d pe

rson

nel (

perfo

rman

ce b

ias)

Blin

ding

of o

utco

me a

sses

smen

t (de

tect

ion

bias

)

Inco

mpl

ete o

utco

me d

ata (

attr

ition

bia

s)

Sele

ctiv

e rep

ortin

g (r

epor

ting

bias

)

Oth

er b

ias

Chen et al 2008

He and Gen 2010

Huang et al 2013

Liu 2012

Ma 2018

Qiao 2015

Ren and Wu 2006

Wang and Lan 2012

Wei and Tan 2005

Ye 2009

Ye 2013

Zhang et al 2004

Zhao and Dong 2016

Zheng 2006

Figure 3 Risk of bias summary and graph

for heterogeneity (1198682 = 00 119875 = 0953) (Figure 10) thusthe fixed-effects model was used for data analysis The meta-analysis revealed that the experimental group performedbetter than the control group in reducing B2M [WMD =ndash009 95 CI(ndash011 ndash007) 119875 le 0001] (Figure S11)

348 Systolic Blood Pressure (SBP mmHg) Nine studies[29 34ndash38 40 41 44] reported on the use of breviscapineinjection plus antihypertensive drugs in the treatment of SBPfor hypertensive nephropathy After the test for heterogeneity(1198682 = 79 119875 le 0001) (Figure 11) we employed arandomeffectsmodelMeta-analysis showed anonsignificanttrend for reduction in systolic blood pressure between theexperimental group and the control group [WMD = ndash10295 CI(ndash288 084) 119875 = 0281] (Figure S12)

349 Comparison of Clinical Efficacy A total of 7 studies[31 33 35 36 38ndash40] reported the results of the total effectiverate involving 657 patients (330 in the experimental groupand 327 in the control group) After the test for heterogeneity(1198682 = 852 119875 le 0001) (Figure 12) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (119875 = 0181) to evaluate publicationbias for effective rate (Supplementary Figures S13 and S14)Meta-analysis indicated that the total clinical effective rateof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in treating for hypertensivenephropathy was higher than that in the control group whichshowed a statistically significant difference [RR = 127 95CI(105 153)119875 = 0014] (Figure S15) All included trials werepublished in Chinese academic journals Since trials withnegative or neutral results are less likely to be published

10 Evidence-Based Complementary and Alternative Medicine

Figure 4 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Scrfor hypertensive nephropathy

05

1015

se (W

MD

)

minus100 minus80 minus60 minus40 minus20 0WMD

Funnel plot with pseudo 95 confidence limits

Figure 5 Funnel plot for the publication bias of Scr

Evidence-Based Complementary and Alternative Medicine 11

Figure 6 Subgroup analysis of different doses of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone interms of Scr for hypertensive nephropathy

the efficacy of published studies might be overestimatedConsequently the possibility of publication bias could not beruled out

3410 Adverse Effects Nine of the included trials [29ndash36 38]described adverse effects in detail while the others did notmention adverse eventsOnly one showedmild facial flushingduring intravenous dripping of breviscapine [30] and afterthe speed of transfusion was slowed down the symptom gotremitted Two cases [38] showed redness of limb skin in theexperimental group There were two cases [31 32] of headinflation during the use of antihypertensive drugsTherewerethree cases [33 34] of head swelling and dizziness duringinfusion during the use of breviscapine injection Twenty-onecases showed dry cough due to the use of ACEI in six trials[29 31ndash33 35 36] None of the adverse events were seriousThese symptoms are self-limited and did not affect treatment

4 Discussion

Thismeta-analysis included 14 studies with 1170 total partici-pants comparing breviscapine injection plus antihypertensivedrugs versus antihypertensive drugs alone for hypertensivenephropathy Meanwhile the results demonstrated that theexpression levels of SCr and BUN were significantly lowerin patients treated with breviscapine injection in comparisonwith control subjects and the improvement of creatinineclearance was higher in patients treated with breviscapinein comparison with control subjects suggesting that thedrug serves as a protective role in the renal system ofpatients with hypertensive nephropathy Microalbuminuriais regarded as the earliest clinical sign of hypertensivenephropathy It is defined as a urinary albumin excretionrate ranging from 30 to 300mgday and the definitivemeasurement is based on a timed urine collection during

12 Evidence-Based Complementary and Alternative Medicine

Figure 7 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the 24 hUTP for hypertensive nephropathy

a 24-h period The present meta-analysis indicated thatbreviscapine injection can reduce 24-hour urinary proteinand the urinary beta-2-microglobulin a reduction in uri-nary protein may contribute towards the renal protectiveeffect of breviscapine injection in patients with hyperten-sive nephropathy Our analysis revealed that experimentalgroups showed better overall clinical efficacy than controlgroups

Erigeron breviscapus is a kind of traditional Chinesemedicine It was first recorded in the book of ldquoYunnan Mate-ria Medicardquo According to Chinese medicine theory erigeronbreviscapus is cold-natured sweet bitter and pungent intaste with the function of clearing heat relieving toxic-ity eliminating wind and dampness activating blood andremoving stasis expediting channel and activating meridianrelieving inflammation and alleviating pain The monomercomponent of Chinese herbal medicine (CHM) also knownas the natural pure compound drug has recently attractedmuch attention The natural extract artemisinin and itsderivatives are good examples of monomer components ofCHM that can treat diseases through various activities andcan be a good starting point to uncover the mechanism oftraditional Chinese medicine

Hypertensive renal injury is major target-organ damagedue to sustained high BP Long-term hypertension cancause renal sclerosis and gradually progress to chronic renalfailure Positive control of hypertension is the key to pre-venting hypertensive renal damage According to Chinesemedicine theory hypertensive renal injury is strongly relatedto fluid phlegm and dampness retention syndrome andliver-yang hyperactivity syndrome which are caused bydeficiency syndrome Chinese medicines which are usedto treat fluid phlegm and dampness retention syndromedeficiency syndrome and liver-yang hyperactivity syndromerespectively have certain advantages with regard to treatinghypertensive renal injury [45] Clinical research indicatesthat Chinese herbal medicine might control increased SBPinhibit the glomerular and tubular hyperplasia caused byhigh BP and significantly reduce urinary albumin and beta-2-microglobulin by increasing the activity of renal rennin andthe level of Ang II [46 47]

5 Limitations

Several limiting factors in this study should be consideredFirst the quality of the included randomized controlled trials

Evidence-Based Complementary and Alternative Medicine 13

Figure 8 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of theBUN for hypertensive nephropathy

Figure 9 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Ccrfor hypertensive nephropathy

was low All included trials showed high or undefined risk ofbias due to design reporting and methodology There wereno definitive randomized double-blind placebo-controlledtrials included in this meta-analysis No trials reporteddetailed randomization methods or allocation concealmentNo trial was double-blinded and unfortunately none ofRCT (randomized controlled trial) has a placebo in thetrial Therefore the reported strength of evidence should

be reevaluated and more rigorously designed placebo-controlled trials are warranted to give high-level evidencein future studies [48] Second five trials did not reportadverse reactions Therefore conclusions about safety can-not be made with confidence Furthermore certain activeingredients are chemically unstable which limits large-scalesynthesis These pressing issues should be resolved in futureresearch The safety of breviscapine injection needs to be

14 Evidence-Based Complementary and Alternative Medicine

Figure 10 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of beta-2-microglobulin for hypertensive nephropathy

Figure 11 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the SBPfor hypertensive nephropathy

strictly monitored and properly reported in future clinicaltrialsThird all tests produced positive results althoughmosttests were conducted with small samples We tried our best toavoid language bias and positional prejudice but cannot ruleout potential publication bias

Overall our results suggest that breviscapine injection iseffective and safe for the treatment of hypertensive nephropa-thy and this work has reference value for clinicians Morelarge-scale multicenter rigorously designed randomized

controlled trials are needed to provide accurate data tofurther validate the effectiveness and safety of breviscapineinjection

6 Conclusions

Evidence from this systematic review shows that breviscap-ine injection in combination with antihypertensive drugscan improve clinical efficacy and creatinine clearance rate

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

Evidence-Based Complementary and Alternative Medicine 7

Table1Con

tinued

Stud

ySamplesize(TC)

SexMF

Age(years)

rang

emean

Diagn

osis

stand

ards

Interventio

nCon

trol

Cou

rseo

ftre

atment

Clinical

stand

ards

Outcomes

Adversereactions

Ma2

018[41]

66(3333)

T1914

C

2013

T4800plusmn

314

C4899plusmn

298

GMY

(1999WHO-ISH

)andCG

MY

(200

5)

Brevisc

apine

injection(5ml

ivgttqd

)+control

Losartan

Potassium

(100

mgpo

qd)

4weeks

Guiding

principles

(2002)

Urin

eB2M

SBP

DBP

24h

UTP

ScrCcr

Not

repo

rted

Ttre

atmentgroup

Ccon

trolgroup

GMY(19

99WHO-ISH

)Th

e1999WHO-ISH

Guidelin

esforthe

Managem

ento

fHypertensionCG

MY(200

4)200

4Ch

ineseG

uidelin

esforthe

Managem

ento

fHypertension

CGMY(2010)2010Ch

ineseGuidelin

esfortheManagem

ento

fHypertension

CGMY(2014)2014Ch

ineseGuidelin

esfortheManagem

ento

fHypertension

Guiding

Principles

(2002)G

uiding

Principles

ofClinicalRe

search

onNew

Drugs

ofCh

ineseM

edicines

(2002)Scrserum

creatin

ineBU

Nblood

urea

nitro

genCcrcreatininec

learance

rate24h

UTP

24-ho

ururinarytotalproteinB

2Mbeta-2-microglob

ulin

SBP

systo

licbloo

dpressureD

BPd

iasto

licbloo

dpressureT

Ctotalcho

leste

rolTG

totaltriglycerid

esPAG

TplateletaggregationrateF

ibfi

brinogenH

cth

ematocritL

DL

low-densitylip

oproteinL

DH-C

lactatedehydrogenaseC

Col-IV

collagenIVL

Nlam

ininP

IIIP

procollagen-III-peptideET

-1end

othelin

1MMP-9matrix

metalloproteinase-9E

ILAelasticity

indexof

largearteryE

ISAelasticity

indexof

smallarteryVOIvascular

overload

index

8 Evidence-Based Complementary and Alternative Medicine

0 25 50 75 100

Low risk of bias

Unclear risk of bias

High risk of bias

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

Figure 2 Risk of bias

119875 le 0001) (Figure 4) we employed a random effectsmodel A funnel plot analysis of the 12 trials suggestedpossible publication bias and inclusion of low quality studiesas significant asymmetry is shown in Figure 5 We appliedEggerrsquos test to evaluate publication bias A p (P = 0634)value more than 005 was considered no publication bias(Supplementary Figure S1) The meta-analysis revealed thatthe experimental group performed better than the controlgroup in reducing Scr [WMD = ndash3516 95 CI(ndash5001ndash2031) 119875 le 0001] (Supplementary Figure S2)

342 Sensitivity Analysis We conducted a sensitivity analy-sis for Scr (Supplementary Figure S3) By seriatim excludingone trial each time and reperforming meta-analysis of theremaining trials we could observe whether the outcomeshave dramatically changed Sensitivity analysis indicated thatthe outcomes of Scr were very similar which had relativelygood stability

343 Subgroup Analysis Because of variability in evaluat-ing point of the serum creatinine we conducted subgroupanalysis among studies using different doses of breviscapineinjection (30ml 20ml 12ml 10ml and 5ml) Comparedwith the control groups the results of subgroup analysisshowed that there was no significant correlation between thedecrease of serum creatinine and the dose of breviscapineinjection (Figure 6)

344 24-Hour Urinary Total Protein (24h UTP gd) Twelvestudies [29ndash36 38ndash40 44] reported on the use of brevis-capine injection plus antihypertensive drugs in terms ofthe 24 h UTP for hypertensive nephropathy After the testfor heterogeneity (1198682 = 937 P le 0001) (Figure 7) weemployed a random effects modelWe conducted a sensitivity

analysis and applied Eggerrsquos test (P = 0586) to evaluatepublication bias for 24 h UTP (Supplementary Figures S4and S5) The meta-analysis revealed that the experimentalgroup performed better than the control group in reducing24 h UTP [WMD = ndash004 95 CI(ndash005 ndash002) 119875 le 0001](Figure S6)

345 Blood Urea Nitrogen (BUN mmolL) Ten studies [30ndash33 35ndash40] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of BUN forhypertensive nephropathy After the test for heterogeneity(1198682 = 923 119875 le 0001) (Figure 8) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (P = 0015) to evaluate publicationbias for BUN (Supplementary Figures S7 and S8) The meta-analysis revealed that the experimental group performedbetter than the control group in reducing BUN [WMD =ndash200 95 CI(ndash307 ndash094) 119875 le 0001] (SupplementaryFigure S9)

346 Creatinine Clearance Rate (Ccr mlmin) Three studies[33 34 44] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of Ccr forhypertensive nephropathy After the test for heterogeneity(1198682 = 00 119875 = 0903) (Figure 9) thus the fixed-effects model was used for data analysis The meta-analysisrevealed that the experimental group performed better thanthe control group in improving creatinine clearance rate[WMD = 784 95 CI(520 1049) 119875 le 0001] (Figure S10)

347 Beta-2-Microglobulin (B2M mgL) Three studies [3034 44] reported on the use of breviscapine injection plusantihypertensive drugs in the treatment of urine beta-2-microglobulin for hypertensive nephropathy After the test

Evidence-Based Complementary and Alternative Medicine 9

Rand

om se

quen

ce g

ener

atio

n (s

elec

tion

bias

)

Allo

catio

n co

ncea

lmen

t (se

lect

ion

bias

)

Blin

ding

of p

artic

ipan

ts an

d pe

rson

nel (

perfo

rman

ce b

ias)

Blin

ding

of o

utco

me a

sses

smen

t (de

tect

ion

bias

)

Inco

mpl

ete o

utco

me d

ata (

attr

ition

bia

s)

Sele

ctiv

e rep

ortin

g (r

epor

ting

bias

)

Oth

er b

ias

Chen et al 2008

He and Gen 2010

Huang et al 2013

Liu 2012

Ma 2018

Qiao 2015

Ren and Wu 2006

Wang and Lan 2012

Wei and Tan 2005

Ye 2009

Ye 2013

Zhang et al 2004

Zhao and Dong 2016

Zheng 2006

Figure 3 Risk of bias summary and graph

for heterogeneity (1198682 = 00 119875 = 0953) (Figure 10) thusthe fixed-effects model was used for data analysis The meta-analysis revealed that the experimental group performedbetter than the control group in reducing B2M [WMD =ndash009 95 CI(ndash011 ndash007) 119875 le 0001] (Figure S11)

348 Systolic Blood Pressure (SBP mmHg) Nine studies[29 34ndash38 40 41 44] reported on the use of breviscapineinjection plus antihypertensive drugs in the treatment of SBPfor hypertensive nephropathy After the test for heterogeneity(1198682 = 79 119875 le 0001) (Figure 11) we employed arandomeffectsmodelMeta-analysis showed anonsignificanttrend for reduction in systolic blood pressure between theexperimental group and the control group [WMD = ndash10295 CI(ndash288 084) 119875 = 0281] (Figure S12)

349 Comparison of Clinical Efficacy A total of 7 studies[31 33 35 36 38ndash40] reported the results of the total effectiverate involving 657 patients (330 in the experimental groupand 327 in the control group) After the test for heterogeneity(1198682 = 852 119875 le 0001) (Figure 12) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (119875 = 0181) to evaluate publicationbias for effective rate (Supplementary Figures S13 and S14)Meta-analysis indicated that the total clinical effective rateof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in treating for hypertensivenephropathy was higher than that in the control group whichshowed a statistically significant difference [RR = 127 95CI(105 153)119875 = 0014] (Figure S15) All included trials werepublished in Chinese academic journals Since trials withnegative or neutral results are less likely to be published

10 Evidence-Based Complementary and Alternative Medicine

Figure 4 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Scrfor hypertensive nephropathy

05

1015

se (W

MD

)

minus100 minus80 minus60 minus40 minus20 0WMD

Funnel plot with pseudo 95 confidence limits

Figure 5 Funnel plot for the publication bias of Scr

Evidence-Based Complementary and Alternative Medicine 11

Figure 6 Subgroup analysis of different doses of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone interms of Scr for hypertensive nephropathy

the efficacy of published studies might be overestimatedConsequently the possibility of publication bias could not beruled out

3410 Adverse Effects Nine of the included trials [29ndash36 38]described adverse effects in detail while the others did notmention adverse eventsOnly one showedmild facial flushingduring intravenous dripping of breviscapine [30] and afterthe speed of transfusion was slowed down the symptom gotremitted Two cases [38] showed redness of limb skin in theexperimental group There were two cases [31 32] of headinflation during the use of antihypertensive drugsTherewerethree cases [33 34] of head swelling and dizziness duringinfusion during the use of breviscapine injection Twenty-onecases showed dry cough due to the use of ACEI in six trials[29 31ndash33 35 36] None of the adverse events were seriousThese symptoms are self-limited and did not affect treatment

4 Discussion

Thismeta-analysis included 14 studies with 1170 total partici-pants comparing breviscapine injection plus antihypertensivedrugs versus antihypertensive drugs alone for hypertensivenephropathy Meanwhile the results demonstrated that theexpression levels of SCr and BUN were significantly lowerin patients treated with breviscapine injection in comparisonwith control subjects and the improvement of creatinineclearance was higher in patients treated with breviscapinein comparison with control subjects suggesting that thedrug serves as a protective role in the renal system ofpatients with hypertensive nephropathy Microalbuminuriais regarded as the earliest clinical sign of hypertensivenephropathy It is defined as a urinary albumin excretionrate ranging from 30 to 300mgday and the definitivemeasurement is based on a timed urine collection during

12 Evidence-Based Complementary and Alternative Medicine

Figure 7 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the 24 hUTP for hypertensive nephropathy

a 24-h period The present meta-analysis indicated thatbreviscapine injection can reduce 24-hour urinary proteinand the urinary beta-2-microglobulin a reduction in uri-nary protein may contribute towards the renal protectiveeffect of breviscapine injection in patients with hyperten-sive nephropathy Our analysis revealed that experimentalgroups showed better overall clinical efficacy than controlgroups

Erigeron breviscapus is a kind of traditional Chinesemedicine It was first recorded in the book of ldquoYunnan Mate-ria Medicardquo According to Chinese medicine theory erigeronbreviscapus is cold-natured sweet bitter and pungent intaste with the function of clearing heat relieving toxic-ity eliminating wind and dampness activating blood andremoving stasis expediting channel and activating meridianrelieving inflammation and alleviating pain The monomercomponent of Chinese herbal medicine (CHM) also knownas the natural pure compound drug has recently attractedmuch attention The natural extract artemisinin and itsderivatives are good examples of monomer components ofCHM that can treat diseases through various activities andcan be a good starting point to uncover the mechanism oftraditional Chinese medicine

Hypertensive renal injury is major target-organ damagedue to sustained high BP Long-term hypertension cancause renal sclerosis and gradually progress to chronic renalfailure Positive control of hypertension is the key to pre-venting hypertensive renal damage According to Chinesemedicine theory hypertensive renal injury is strongly relatedto fluid phlegm and dampness retention syndrome andliver-yang hyperactivity syndrome which are caused bydeficiency syndrome Chinese medicines which are usedto treat fluid phlegm and dampness retention syndromedeficiency syndrome and liver-yang hyperactivity syndromerespectively have certain advantages with regard to treatinghypertensive renal injury [45] Clinical research indicatesthat Chinese herbal medicine might control increased SBPinhibit the glomerular and tubular hyperplasia caused byhigh BP and significantly reduce urinary albumin and beta-2-microglobulin by increasing the activity of renal rennin andthe level of Ang II [46 47]

5 Limitations

Several limiting factors in this study should be consideredFirst the quality of the included randomized controlled trials

Evidence-Based Complementary and Alternative Medicine 13

Figure 8 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of theBUN for hypertensive nephropathy

Figure 9 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Ccrfor hypertensive nephropathy

was low All included trials showed high or undefined risk ofbias due to design reporting and methodology There wereno definitive randomized double-blind placebo-controlledtrials included in this meta-analysis No trials reporteddetailed randomization methods or allocation concealmentNo trial was double-blinded and unfortunately none ofRCT (randomized controlled trial) has a placebo in thetrial Therefore the reported strength of evidence should

be reevaluated and more rigorously designed placebo-controlled trials are warranted to give high-level evidencein future studies [48] Second five trials did not reportadverse reactions Therefore conclusions about safety can-not be made with confidence Furthermore certain activeingredients are chemically unstable which limits large-scalesynthesis These pressing issues should be resolved in futureresearch The safety of breviscapine injection needs to be

14 Evidence-Based Complementary and Alternative Medicine

Figure 10 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of beta-2-microglobulin for hypertensive nephropathy

Figure 11 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the SBPfor hypertensive nephropathy

strictly monitored and properly reported in future clinicaltrialsThird all tests produced positive results althoughmosttests were conducted with small samples We tried our best toavoid language bias and positional prejudice but cannot ruleout potential publication bias

Overall our results suggest that breviscapine injection iseffective and safe for the treatment of hypertensive nephropa-thy and this work has reference value for clinicians Morelarge-scale multicenter rigorously designed randomized

controlled trials are needed to provide accurate data tofurther validate the effectiveness and safety of breviscapineinjection

6 Conclusions

Evidence from this systematic review shows that breviscap-ine injection in combination with antihypertensive drugscan improve clinical efficacy and creatinine clearance rate

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

8 Evidence-Based Complementary and Alternative Medicine

0 25 50 75 100

Low risk of bias

Unclear risk of bias

High risk of bias

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

Figure 2 Risk of bias

119875 le 0001) (Figure 4) we employed a random effectsmodel A funnel plot analysis of the 12 trials suggestedpossible publication bias and inclusion of low quality studiesas significant asymmetry is shown in Figure 5 We appliedEggerrsquos test to evaluate publication bias A p (P = 0634)value more than 005 was considered no publication bias(Supplementary Figure S1) The meta-analysis revealed thatthe experimental group performed better than the controlgroup in reducing Scr [WMD = ndash3516 95 CI(ndash5001ndash2031) 119875 le 0001] (Supplementary Figure S2)

342 Sensitivity Analysis We conducted a sensitivity analy-sis for Scr (Supplementary Figure S3) By seriatim excludingone trial each time and reperforming meta-analysis of theremaining trials we could observe whether the outcomeshave dramatically changed Sensitivity analysis indicated thatthe outcomes of Scr were very similar which had relativelygood stability

343 Subgroup Analysis Because of variability in evaluat-ing point of the serum creatinine we conducted subgroupanalysis among studies using different doses of breviscapineinjection (30ml 20ml 12ml 10ml and 5ml) Comparedwith the control groups the results of subgroup analysisshowed that there was no significant correlation between thedecrease of serum creatinine and the dose of breviscapineinjection (Figure 6)

344 24-Hour Urinary Total Protein (24h UTP gd) Twelvestudies [29ndash36 38ndash40 44] reported on the use of brevis-capine injection plus antihypertensive drugs in terms ofthe 24 h UTP for hypertensive nephropathy After the testfor heterogeneity (1198682 = 937 P le 0001) (Figure 7) weemployed a random effects modelWe conducted a sensitivity

analysis and applied Eggerrsquos test (P = 0586) to evaluatepublication bias for 24 h UTP (Supplementary Figures S4and S5) The meta-analysis revealed that the experimentalgroup performed better than the control group in reducing24 h UTP [WMD = ndash004 95 CI(ndash005 ndash002) 119875 le 0001](Figure S6)

345 Blood Urea Nitrogen (BUN mmolL) Ten studies [30ndash33 35ndash40] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of BUN forhypertensive nephropathy After the test for heterogeneity(1198682 = 923 119875 le 0001) (Figure 8) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (P = 0015) to evaluate publicationbias for BUN (Supplementary Figures S7 and S8) The meta-analysis revealed that the experimental group performedbetter than the control group in reducing BUN [WMD =ndash200 95 CI(ndash307 ndash094) 119875 le 0001] (SupplementaryFigure S9)

346 Creatinine Clearance Rate (Ccr mlmin) Three studies[33 34 44] reported on the use of breviscapine injectionplus antihypertensive drugs in the treatment of Ccr forhypertensive nephropathy After the test for heterogeneity(1198682 = 00 119875 = 0903) (Figure 9) thus the fixed-effects model was used for data analysis The meta-analysisrevealed that the experimental group performed better thanthe control group in improving creatinine clearance rate[WMD = 784 95 CI(520 1049) 119875 le 0001] (Figure S10)

347 Beta-2-Microglobulin (B2M mgL) Three studies [3034 44] reported on the use of breviscapine injection plusantihypertensive drugs in the treatment of urine beta-2-microglobulin for hypertensive nephropathy After the test

Evidence-Based Complementary and Alternative Medicine 9

Rand

om se

quen

ce g

ener

atio

n (s

elec

tion

bias

)

Allo

catio

n co

ncea

lmen

t (se

lect

ion

bias

)

Blin

ding

of p

artic

ipan

ts an

d pe

rson

nel (

perfo

rman

ce b

ias)

Blin

ding

of o

utco

me a

sses

smen

t (de

tect

ion

bias

)

Inco

mpl

ete o

utco

me d

ata (

attr

ition

bia

s)

Sele

ctiv

e rep

ortin

g (r

epor

ting

bias

)

Oth

er b

ias

Chen et al 2008

He and Gen 2010

Huang et al 2013

Liu 2012

Ma 2018

Qiao 2015

Ren and Wu 2006

Wang and Lan 2012

Wei and Tan 2005

Ye 2009

Ye 2013

Zhang et al 2004

Zhao and Dong 2016

Zheng 2006

Figure 3 Risk of bias summary and graph

for heterogeneity (1198682 = 00 119875 = 0953) (Figure 10) thusthe fixed-effects model was used for data analysis The meta-analysis revealed that the experimental group performedbetter than the control group in reducing B2M [WMD =ndash009 95 CI(ndash011 ndash007) 119875 le 0001] (Figure S11)

348 Systolic Blood Pressure (SBP mmHg) Nine studies[29 34ndash38 40 41 44] reported on the use of breviscapineinjection plus antihypertensive drugs in the treatment of SBPfor hypertensive nephropathy After the test for heterogeneity(1198682 = 79 119875 le 0001) (Figure 11) we employed arandomeffectsmodelMeta-analysis showed anonsignificanttrend for reduction in systolic blood pressure between theexperimental group and the control group [WMD = ndash10295 CI(ndash288 084) 119875 = 0281] (Figure S12)

349 Comparison of Clinical Efficacy A total of 7 studies[31 33 35 36 38ndash40] reported the results of the total effectiverate involving 657 patients (330 in the experimental groupand 327 in the control group) After the test for heterogeneity(1198682 = 852 119875 le 0001) (Figure 12) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (119875 = 0181) to evaluate publicationbias for effective rate (Supplementary Figures S13 and S14)Meta-analysis indicated that the total clinical effective rateof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in treating for hypertensivenephropathy was higher than that in the control group whichshowed a statistically significant difference [RR = 127 95CI(105 153)119875 = 0014] (Figure S15) All included trials werepublished in Chinese academic journals Since trials withnegative or neutral results are less likely to be published

10 Evidence-Based Complementary and Alternative Medicine

Figure 4 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Scrfor hypertensive nephropathy

05

1015

se (W

MD

)

minus100 minus80 minus60 minus40 minus20 0WMD

Funnel plot with pseudo 95 confidence limits

Figure 5 Funnel plot for the publication bias of Scr

Evidence-Based Complementary and Alternative Medicine 11

Figure 6 Subgroup analysis of different doses of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone interms of Scr for hypertensive nephropathy

the efficacy of published studies might be overestimatedConsequently the possibility of publication bias could not beruled out

3410 Adverse Effects Nine of the included trials [29ndash36 38]described adverse effects in detail while the others did notmention adverse eventsOnly one showedmild facial flushingduring intravenous dripping of breviscapine [30] and afterthe speed of transfusion was slowed down the symptom gotremitted Two cases [38] showed redness of limb skin in theexperimental group There were two cases [31 32] of headinflation during the use of antihypertensive drugsTherewerethree cases [33 34] of head swelling and dizziness duringinfusion during the use of breviscapine injection Twenty-onecases showed dry cough due to the use of ACEI in six trials[29 31ndash33 35 36] None of the adverse events were seriousThese symptoms are self-limited and did not affect treatment

4 Discussion

Thismeta-analysis included 14 studies with 1170 total partici-pants comparing breviscapine injection plus antihypertensivedrugs versus antihypertensive drugs alone for hypertensivenephropathy Meanwhile the results demonstrated that theexpression levels of SCr and BUN were significantly lowerin patients treated with breviscapine injection in comparisonwith control subjects and the improvement of creatinineclearance was higher in patients treated with breviscapinein comparison with control subjects suggesting that thedrug serves as a protective role in the renal system ofpatients with hypertensive nephropathy Microalbuminuriais regarded as the earliest clinical sign of hypertensivenephropathy It is defined as a urinary albumin excretionrate ranging from 30 to 300mgday and the definitivemeasurement is based on a timed urine collection during

12 Evidence-Based Complementary and Alternative Medicine

Figure 7 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the 24 hUTP for hypertensive nephropathy

a 24-h period The present meta-analysis indicated thatbreviscapine injection can reduce 24-hour urinary proteinand the urinary beta-2-microglobulin a reduction in uri-nary protein may contribute towards the renal protectiveeffect of breviscapine injection in patients with hyperten-sive nephropathy Our analysis revealed that experimentalgroups showed better overall clinical efficacy than controlgroups

Erigeron breviscapus is a kind of traditional Chinesemedicine It was first recorded in the book of ldquoYunnan Mate-ria Medicardquo According to Chinese medicine theory erigeronbreviscapus is cold-natured sweet bitter and pungent intaste with the function of clearing heat relieving toxic-ity eliminating wind and dampness activating blood andremoving stasis expediting channel and activating meridianrelieving inflammation and alleviating pain The monomercomponent of Chinese herbal medicine (CHM) also knownas the natural pure compound drug has recently attractedmuch attention The natural extract artemisinin and itsderivatives are good examples of monomer components ofCHM that can treat diseases through various activities andcan be a good starting point to uncover the mechanism oftraditional Chinese medicine

Hypertensive renal injury is major target-organ damagedue to sustained high BP Long-term hypertension cancause renal sclerosis and gradually progress to chronic renalfailure Positive control of hypertension is the key to pre-venting hypertensive renal damage According to Chinesemedicine theory hypertensive renal injury is strongly relatedto fluid phlegm and dampness retention syndrome andliver-yang hyperactivity syndrome which are caused bydeficiency syndrome Chinese medicines which are usedto treat fluid phlegm and dampness retention syndromedeficiency syndrome and liver-yang hyperactivity syndromerespectively have certain advantages with regard to treatinghypertensive renal injury [45] Clinical research indicatesthat Chinese herbal medicine might control increased SBPinhibit the glomerular and tubular hyperplasia caused byhigh BP and significantly reduce urinary albumin and beta-2-microglobulin by increasing the activity of renal rennin andthe level of Ang II [46 47]

5 Limitations

Several limiting factors in this study should be consideredFirst the quality of the included randomized controlled trials

Evidence-Based Complementary and Alternative Medicine 13

Figure 8 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of theBUN for hypertensive nephropathy

Figure 9 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Ccrfor hypertensive nephropathy

was low All included trials showed high or undefined risk ofbias due to design reporting and methodology There wereno definitive randomized double-blind placebo-controlledtrials included in this meta-analysis No trials reporteddetailed randomization methods or allocation concealmentNo trial was double-blinded and unfortunately none ofRCT (randomized controlled trial) has a placebo in thetrial Therefore the reported strength of evidence should

be reevaluated and more rigorously designed placebo-controlled trials are warranted to give high-level evidencein future studies [48] Second five trials did not reportadverse reactions Therefore conclusions about safety can-not be made with confidence Furthermore certain activeingredients are chemically unstable which limits large-scalesynthesis These pressing issues should be resolved in futureresearch The safety of breviscapine injection needs to be

14 Evidence-Based Complementary and Alternative Medicine

Figure 10 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of beta-2-microglobulin for hypertensive nephropathy

Figure 11 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the SBPfor hypertensive nephropathy

strictly monitored and properly reported in future clinicaltrialsThird all tests produced positive results althoughmosttests were conducted with small samples We tried our best toavoid language bias and positional prejudice but cannot ruleout potential publication bias

Overall our results suggest that breviscapine injection iseffective and safe for the treatment of hypertensive nephropa-thy and this work has reference value for clinicians Morelarge-scale multicenter rigorously designed randomized

controlled trials are needed to provide accurate data tofurther validate the effectiveness and safety of breviscapineinjection

6 Conclusions

Evidence from this systematic review shows that breviscap-ine injection in combination with antihypertensive drugscan improve clinical efficacy and creatinine clearance rate

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

Evidence-Based Complementary and Alternative Medicine 9

Rand

om se

quen

ce g

ener

atio

n (s

elec

tion

bias

)

Allo

catio

n co

ncea

lmen

t (se

lect

ion

bias

)

Blin

ding

of p

artic

ipan

ts an

d pe

rson

nel (

perfo

rman

ce b

ias)

Blin

ding

of o

utco

me a

sses

smen

t (de

tect

ion

bias

)

Inco

mpl

ete o

utco

me d

ata (

attr

ition

bia

s)

Sele

ctiv

e rep

ortin

g (r

epor

ting

bias

)

Oth

er b

ias

Chen et al 2008

He and Gen 2010

Huang et al 2013

Liu 2012

Ma 2018

Qiao 2015

Ren and Wu 2006

Wang and Lan 2012

Wei and Tan 2005

Ye 2009

Ye 2013

Zhang et al 2004

Zhao and Dong 2016

Zheng 2006

Figure 3 Risk of bias summary and graph

for heterogeneity (1198682 = 00 119875 = 0953) (Figure 10) thusthe fixed-effects model was used for data analysis The meta-analysis revealed that the experimental group performedbetter than the control group in reducing B2M [WMD =ndash009 95 CI(ndash011 ndash007) 119875 le 0001] (Figure S11)

348 Systolic Blood Pressure (SBP mmHg) Nine studies[29 34ndash38 40 41 44] reported on the use of breviscapineinjection plus antihypertensive drugs in the treatment of SBPfor hypertensive nephropathy After the test for heterogeneity(1198682 = 79 119875 le 0001) (Figure 11) we employed arandomeffectsmodelMeta-analysis showed anonsignificanttrend for reduction in systolic blood pressure between theexperimental group and the control group [WMD = ndash10295 CI(ndash288 084) 119875 = 0281] (Figure S12)

349 Comparison of Clinical Efficacy A total of 7 studies[31 33 35 36 38ndash40] reported the results of the total effectiverate involving 657 patients (330 in the experimental groupand 327 in the control group) After the test for heterogeneity(1198682 = 852 119875 le 0001) (Figure 12) we employed arandom effects model We conducted a sensitivity analysisand applied Eggerrsquos test (119875 = 0181) to evaluate publicationbias for effective rate (Supplementary Figures S13 and S14)Meta-analysis indicated that the total clinical effective rateof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in treating for hypertensivenephropathy was higher than that in the control group whichshowed a statistically significant difference [RR = 127 95CI(105 153)119875 = 0014] (Figure S15) All included trials werepublished in Chinese academic journals Since trials withnegative or neutral results are less likely to be published

10 Evidence-Based Complementary and Alternative Medicine

Figure 4 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Scrfor hypertensive nephropathy

05

1015

se (W

MD

)

minus100 minus80 minus60 minus40 minus20 0WMD

Funnel plot with pseudo 95 confidence limits

Figure 5 Funnel plot for the publication bias of Scr

Evidence-Based Complementary and Alternative Medicine 11

Figure 6 Subgroup analysis of different doses of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone interms of Scr for hypertensive nephropathy

the efficacy of published studies might be overestimatedConsequently the possibility of publication bias could not beruled out

3410 Adverse Effects Nine of the included trials [29ndash36 38]described adverse effects in detail while the others did notmention adverse eventsOnly one showedmild facial flushingduring intravenous dripping of breviscapine [30] and afterthe speed of transfusion was slowed down the symptom gotremitted Two cases [38] showed redness of limb skin in theexperimental group There were two cases [31 32] of headinflation during the use of antihypertensive drugsTherewerethree cases [33 34] of head swelling and dizziness duringinfusion during the use of breviscapine injection Twenty-onecases showed dry cough due to the use of ACEI in six trials[29 31ndash33 35 36] None of the adverse events were seriousThese symptoms are self-limited and did not affect treatment

4 Discussion

Thismeta-analysis included 14 studies with 1170 total partici-pants comparing breviscapine injection plus antihypertensivedrugs versus antihypertensive drugs alone for hypertensivenephropathy Meanwhile the results demonstrated that theexpression levels of SCr and BUN were significantly lowerin patients treated with breviscapine injection in comparisonwith control subjects and the improvement of creatinineclearance was higher in patients treated with breviscapinein comparison with control subjects suggesting that thedrug serves as a protective role in the renal system ofpatients with hypertensive nephropathy Microalbuminuriais regarded as the earliest clinical sign of hypertensivenephropathy It is defined as a urinary albumin excretionrate ranging from 30 to 300mgday and the definitivemeasurement is based on a timed urine collection during

12 Evidence-Based Complementary and Alternative Medicine

Figure 7 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the 24 hUTP for hypertensive nephropathy

a 24-h period The present meta-analysis indicated thatbreviscapine injection can reduce 24-hour urinary proteinand the urinary beta-2-microglobulin a reduction in uri-nary protein may contribute towards the renal protectiveeffect of breviscapine injection in patients with hyperten-sive nephropathy Our analysis revealed that experimentalgroups showed better overall clinical efficacy than controlgroups

Erigeron breviscapus is a kind of traditional Chinesemedicine It was first recorded in the book of ldquoYunnan Mate-ria Medicardquo According to Chinese medicine theory erigeronbreviscapus is cold-natured sweet bitter and pungent intaste with the function of clearing heat relieving toxic-ity eliminating wind and dampness activating blood andremoving stasis expediting channel and activating meridianrelieving inflammation and alleviating pain The monomercomponent of Chinese herbal medicine (CHM) also knownas the natural pure compound drug has recently attractedmuch attention The natural extract artemisinin and itsderivatives are good examples of monomer components ofCHM that can treat diseases through various activities andcan be a good starting point to uncover the mechanism oftraditional Chinese medicine

Hypertensive renal injury is major target-organ damagedue to sustained high BP Long-term hypertension cancause renal sclerosis and gradually progress to chronic renalfailure Positive control of hypertension is the key to pre-venting hypertensive renal damage According to Chinesemedicine theory hypertensive renal injury is strongly relatedto fluid phlegm and dampness retention syndrome andliver-yang hyperactivity syndrome which are caused bydeficiency syndrome Chinese medicines which are usedto treat fluid phlegm and dampness retention syndromedeficiency syndrome and liver-yang hyperactivity syndromerespectively have certain advantages with regard to treatinghypertensive renal injury [45] Clinical research indicatesthat Chinese herbal medicine might control increased SBPinhibit the glomerular and tubular hyperplasia caused byhigh BP and significantly reduce urinary albumin and beta-2-microglobulin by increasing the activity of renal rennin andthe level of Ang II [46 47]

5 Limitations

Several limiting factors in this study should be consideredFirst the quality of the included randomized controlled trials

Evidence-Based Complementary and Alternative Medicine 13

Figure 8 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of theBUN for hypertensive nephropathy

Figure 9 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Ccrfor hypertensive nephropathy

was low All included trials showed high or undefined risk ofbias due to design reporting and methodology There wereno definitive randomized double-blind placebo-controlledtrials included in this meta-analysis No trials reporteddetailed randomization methods or allocation concealmentNo trial was double-blinded and unfortunately none ofRCT (randomized controlled trial) has a placebo in thetrial Therefore the reported strength of evidence should

be reevaluated and more rigorously designed placebo-controlled trials are warranted to give high-level evidencein future studies [48] Second five trials did not reportadverse reactions Therefore conclusions about safety can-not be made with confidence Furthermore certain activeingredients are chemically unstable which limits large-scalesynthesis These pressing issues should be resolved in futureresearch The safety of breviscapine injection needs to be

14 Evidence-Based Complementary and Alternative Medicine

Figure 10 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of beta-2-microglobulin for hypertensive nephropathy

Figure 11 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the SBPfor hypertensive nephropathy

strictly monitored and properly reported in future clinicaltrialsThird all tests produced positive results althoughmosttests were conducted with small samples We tried our best toavoid language bias and positional prejudice but cannot ruleout potential publication bias

Overall our results suggest that breviscapine injection iseffective and safe for the treatment of hypertensive nephropa-thy and this work has reference value for clinicians Morelarge-scale multicenter rigorously designed randomized

controlled trials are needed to provide accurate data tofurther validate the effectiveness and safety of breviscapineinjection

6 Conclusions

Evidence from this systematic review shows that breviscap-ine injection in combination with antihypertensive drugscan improve clinical efficacy and creatinine clearance rate

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

10 Evidence-Based Complementary and Alternative Medicine

Figure 4 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Scrfor hypertensive nephropathy

05

1015

se (W

MD

)

minus100 minus80 minus60 minus40 minus20 0WMD

Funnel plot with pseudo 95 confidence limits

Figure 5 Funnel plot for the publication bias of Scr

Evidence-Based Complementary and Alternative Medicine 11

Figure 6 Subgroup analysis of different doses of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone interms of Scr for hypertensive nephropathy

the efficacy of published studies might be overestimatedConsequently the possibility of publication bias could not beruled out

3410 Adverse Effects Nine of the included trials [29ndash36 38]described adverse effects in detail while the others did notmention adverse eventsOnly one showedmild facial flushingduring intravenous dripping of breviscapine [30] and afterthe speed of transfusion was slowed down the symptom gotremitted Two cases [38] showed redness of limb skin in theexperimental group There were two cases [31 32] of headinflation during the use of antihypertensive drugsTherewerethree cases [33 34] of head swelling and dizziness duringinfusion during the use of breviscapine injection Twenty-onecases showed dry cough due to the use of ACEI in six trials[29 31ndash33 35 36] None of the adverse events were seriousThese symptoms are self-limited and did not affect treatment

4 Discussion

Thismeta-analysis included 14 studies with 1170 total partici-pants comparing breviscapine injection plus antihypertensivedrugs versus antihypertensive drugs alone for hypertensivenephropathy Meanwhile the results demonstrated that theexpression levels of SCr and BUN were significantly lowerin patients treated with breviscapine injection in comparisonwith control subjects and the improvement of creatinineclearance was higher in patients treated with breviscapinein comparison with control subjects suggesting that thedrug serves as a protective role in the renal system ofpatients with hypertensive nephropathy Microalbuminuriais regarded as the earliest clinical sign of hypertensivenephropathy It is defined as a urinary albumin excretionrate ranging from 30 to 300mgday and the definitivemeasurement is based on a timed urine collection during

12 Evidence-Based Complementary and Alternative Medicine

Figure 7 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the 24 hUTP for hypertensive nephropathy

a 24-h period The present meta-analysis indicated thatbreviscapine injection can reduce 24-hour urinary proteinand the urinary beta-2-microglobulin a reduction in uri-nary protein may contribute towards the renal protectiveeffect of breviscapine injection in patients with hyperten-sive nephropathy Our analysis revealed that experimentalgroups showed better overall clinical efficacy than controlgroups

Erigeron breviscapus is a kind of traditional Chinesemedicine It was first recorded in the book of ldquoYunnan Mate-ria Medicardquo According to Chinese medicine theory erigeronbreviscapus is cold-natured sweet bitter and pungent intaste with the function of clearing heat relieving toxic-ity eliminating wind and dampness activating blood andremoving stasis expediting channel and activating meridianrelieving inflammation and alleviating pain The monomercomponent of Chinese herbal medicine (CHM) also knownas the natural pure compound drug has recently attractedmuch attention The natural extract artemisinin and itsderivatives are good examples of monomer components ofCHM that can treat diseases through various activities andcan be a good starting point to uncover the mechanism oftraditional Chinese medicine

Hypertensive renal injury is major target-organ damagedue to sustained high BP Long-term hypertension cancause renal sclerosis and gradually progress to chronic renalfailure Positive control of hypertension is the key to pre-venting hypertensive renal damage According to Chinesemedicine theory hypertensive renal injury is strongly relatedto fluid phlegm and dampness retention syndrome andliver-yang hyperactivity syndrome which are caused bydeficiency syndrome Chinese medicines which are usedto treat fluid phlegm and dampness retention syndromedeficiency syndrome and liver-yang hyperactivity syndromerespectively have certain advantages with regard to treatinghypertensive renal injury [45] Clinical research indicatesthat Chinese herbal medicine might control increased SBPinhibit the glomerular and tubular hyperplasia caused byhigh BP and significantly reduce urinary albumin and beta-2-microglobulin by increasing the activity of renal rennin andthe level of Ang II [46 47]

5 Limitations

Several limiting factors in this study should be consideredFirst the quality of the included randomized controlled trials

Evidence-Based Complementary and Alternative Medicine 13

Figure 8 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of theBUN for hypertensive nephropathy

Figure 9 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Ccrfor hypertensive nephropathy

was low All included trials showed high or undefined risk ofbias due to design reporting and methodology There wereno definitive randomized double-blind placebo-controlledtrials included in this meta-analysis No trials reporteddetailed randomization methods or allocation concealmentNo trial was double-blinded and unfortunately none ofRCT (randomized controlled trial) has a placebo in thetrial Therefore the reported strength of evidence should

be reevaluated and more rigorously designed placebo-controlled trials are warranted to give high-level evidencein future studies [48] Second five trials did not reportadverse reactions Therefore conclusions about safety can-not be made with confidence Furthermore certain activeingredients are chemically unstable which limits large-scalesynthesis These pressing issues should be resolved in futureresearch The safety of breviscapine injection needs to be

14 Evidence-Based Complementary and Alternative Medicine

Figure 10 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of beta-2-microglobulin for hypertensive nephropathy

Figure 11 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the SBPfor hypertensive nephropathy

strictly monitored and properly reported in future clinicaltrialsThird all tests produced positive results althoughmosttests were conducted with small samples We tried our best toavoid language bias and positional prejudice but cannot ruleout potential publication bias

Overall our results suggest that breviscapine injection iseffective and safe for the treatment of hypertensive nephropa-thy and this work has reference value for clinicians Morelarge-scale multicenter rigorously designed randomized

controlled trials are needed to provide accurate data tofurther validate the effectiveness and safety of breviscapineinjection

6 Conclusions

Evidence from this systematic review shows that breviscap-ine injection in combination with antihypertensive drugscan improve clinical efficacy and creatinine clearance rate

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

Evidence-Based Complementary and Alternative Medicine 11

Figure 6 Subgroup analysis of different doses of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone interms of Scr for hypertensive nephropathy

the efficacy of published studies might be overestimatedConsequently the possibility of publication bias could not beruled out

3410 Adverse Effects Nine of the included trials [29ndash36 38]described adverse effects in detail while the others did notmention adverse eventsOnly one showedmild facial flushingduring intravenous dripping of breviscapine [30] and afterthe speed of transfusion was slowed down the symptom gotremitted Two cases [38] showed redness of limb skin in theexperimental group There were two cases [31 32] of headinflation during the use of antihypertensive drugsTherewerethree cases [33 34] of head swelling and dizziness duringinfusion during the use of breviscapine injection Twenty-onecases showed dry cough due to the use of ACEI in six trials[29 31ndash33 35 36] None of the adverse events were seriousThese symptoms are self-limited and did not affect treatment

4 Discussion

Thismeta-analysis included 14 studies with 1170 total partici-pants comparing breviscapine injection plus antihypertensivedrugs versus antihypertensive drugs alone for hypertensivenephropathy Meanwhile the results demonstrated that theexpression levels of SCr and BUN were significantly lowerin patients treated with breviscapine injection in comparisonwith control subjects and the improvement of creatinineclearance was higher in patients treated with breviscapinein comparison with control subjects suggesting that thedrug serves as a protective role in the renal system ofpatients with hypertensive nephropathy Microalbuminuriais regarded as the earliest clinical sign of hypertensivenephropathy It is defined as a urinary albumin excretionrate ranging from 30 to 300mgday and the definitivemeasurement is based on a timed urine collection during

12 Evidence-Based Complementary and Alternative Medicine

Figure 7 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the 24 hUTP for hypertensive nephropathy

a 24-h period The present meta-analysis indicated thatbreviscapine injection can reduce 24-hour urinary proteinand the urinary beta-2-microglobulin a reduction in uri-nary protein may contribute towards the renal protectiveeffect of breviscapine injection in patients with hyperten-sive nephropathy Our analysis revealed that experimentalgroups showed better overall clinical efficacy than controlgroups

Erigeron breviscapus is a kind of traditional Chinesemedicine It was first recorded in the book of ldquoYunnan Mate-ria Medicardquo According to Chinese medicine theory erigeronbreviscapus is cold-natured sweet bitter and pungent intaste with the function of clearing heat relieving toxic-ity eliminating wind and dampness activating blood andremoving stasis expediting channel and activating meridianrelieving inflammation and alleviating pain The monomercomponent of Chinese herbal medicine (CHM) also knownas the natural pure compound drug has recently attractedmuch attention The natural extract artemisinin and itsderivatives are good examples of monomer components ofCHM that can treat diseases through various activities andcan be a good starting point to uncover the mechanism oftraditional Chinese medicine

Hypertensive renal injury is major target-organ damagedue to sustained high BP Long-term hypertension cancause renal sclerosis and gradually progress to chronic renalfailure Positive control of hypertension is the key to pre-venting hypertensive renal damage According to Chinesemedicine theory hypertensive renal injury is strongly relatedto fluid phlegm and dampness retention syndrome andliver-yang hyperactivity syndrome which are caused bydeficiency syndrome Chinese medicines which are usedto treat fluid phlegm and dampness retention syndromedeficiency syndrome and liver-yang hyperactivity syndromerespectively have certain advantages with regard to treatinghypertensive renal injury [45] Clinical research indicatesthat Chinese herbal medicine might control increased SBPinhibit the glomerular and tubular hyperplasia caused byhigh BP and significantly reduce urinary albumin and beta-2-microglobulin by increasing the activity of renal rennin andthe level of Ang II [46 47]

5 Limitations

Several limiting factors in this study should be consideredFirst the quality of the included randomized controlled trials

Evidence-Based Complementary and Alternative Medicine 13

Figure 8 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of theBUN for hypertensive nephropathy

Figure 9 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Ccrfor hypertensive nephropathy

was low All included trials showed high or undefined risk ofbias due to design reporting and methodology There wereno definitive randomized double-blind placebo-controlledtrials included in this meta-analysis No trials reporteddetailed randomization methods or allocation concealmentNo trial was double-blinded and unfortunately none ofRCT (randomized controlled trial) has a placebo in thetrial Therefore the reported strength of evidence should

be reevaluated and more rigorously designed placebo-controlled trials are warranted to give high-level evidencein future studies [48] Second five trials did not reportadverse reactions Therefore conclusions about safety can-not be made with confidence Furthermore certain activeingredients are chemically unstable which limits large-scalesynthesis These pressing issues should be resolved in futureresearch The safety of breviscapine injection needs to be

14 Evidence-Based Complementary and Alternative Medicine

Figure 10 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of beta-2-microglobulin for hypertensive nephropathy

Figure 11 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the SBPfor hypertensive nephropathy

strictly monitored and properly reported in future clinicaltrialsThird all tests produced positive results althoughmosttests were conducted with small samples We tried our best toavoid language bias and positional prejudice but cannot ruleout potential publication bias

Overall our results suggest that breviscapine injection iseffective and safe for the treatment of hypertensive nephropa-thy and this work has reference value for clinicians Morelarge-scale multicenter rigorously designed randomized

controlled trials are needed to provide accurate data tofurther validate the effectiveness and safety of breviscapineinjection

6 Conclusions

Evidence from this systematic review shows that breviscap-ine injection in combination with antihypertensive drugscan improve clinical efficacy and creatinine clearance rate

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

12 Evidence-Based Complementary and Alternative Medicine

Figure 7 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the 24 hUTP for hypertensive nephropathy

a 24-h period The present meta-analysis indicated thatbreviscapine injection can reduce 24-hour urinary proteinand the urinary beta-2-microglobulin a reduction in uri-nary protein may contribute towards the renal protectiveeffect of breviscapine injection in patients with hyperten-sive nephropathy Our analysis revealed that experimentalgroups showed better overall clinical efficacy than controlgroups

Erigeron breviscapus is a kind of traditional Chinesemedicine It was first recorded in the book of ldquoYunnan Mate-ria Medicardquo According to Chinese medicine theory erigeronbreviscapus is cold-natured sweet bitter and pungent intaste with the function of clearing heat relieving toxic-ity eliminating wind and dampness activating blood andremoving stasis expediting channel and activating meridianrelieving inflammation and alleviating pain The monomercomponent of Chinese herbal medicine (CHM) also knownas the natural pure compound drug has recently attractedmuch attention The natural extract artemisinin and itsderivatives are good examples of monomer components ofCHM that can treat diseases through various activities andcan be a good starting point to uncover the mechanism oftraditional Chinese medicine

Hypertensive renal injury is major target-organ damagedue to sustained high BP Long-term hypertension cancause renal sclerosis and gradually progress to chronic renalfailure Positive control of hypertension is the key to pre-venting hypertensive renal damage According to Chinesemedicine theory hypertensive renal injury is strongly relatedto fluid phlegm and dampness retention syndrome andliver-yang hyperactivity syndrome which are caused bydeficiency syndrome Chinese medicines which are usedto treat fluid phlegm and dampness retention syndromedeficiency syndrome and liver-yang hyperactivity syndromerespectively have certain advantages with regard to treatinghypertensive renal injury [45] Clinical research indicatesthat Chinese herbal medicine might control increased SBPinhibit the glomerular and tubular hyperplasia caused byhigh BP and significantly reduce urinary albumin and beta-2-microglobulin by increasing the activity of renal rennin andthe level of Ang II [46 47]

5 Limitations

Several limiting factors in this study should be consideredFirst the quality of the included randomized controlled trials

Evidence-Based Complementary and Alternative Medicine 13

Figure 8 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of theBUN for hypertensive nephropathy

Figure 9 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Ccrfor hypertensive nephropathy

was low All included trials showed high or undefined risk ofbias due to design reporting and methodology There wereno definitive randomized double-blind placebo-controlledtrials included in this meta-analysis No trials reporteddetailed randomization methods or allocation concealmentNo trial was double-blinded and unfortunately none ofRCT (randomized controlled trial) has a placebo in thetrial Therefore the reported strength of evidence should

be reevaluated and more rigorously designed placebo-controlled trials are warranted to give high-level evidencein future studies [48] Second five trials did not reportadverse reactions Therefore conclusions about safety can-not be made with confidence Furthermore certain activeingredients are chemically unstable which limits large-scalesynthesis These pressing issues should be resolved in futureresearch The safety of breviscapine injection needs to be

14 Evidence-Based Complementary and Alternative Medicine

Figure 10 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of beta-2-microglobulin for hypertensive nephropathy

Figure 11 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the SBPfor hypertensive nephropathy

strictly monitored and properly reported in future clinicaltrialsThird all tests produced positive results althoughmosttests were conducted with small samples We tried our best toavoid language bias and positional prejudice but cannot ruleout potential publication bias

Overall our results suggest that breviscapine injection iseffective and safe for the treatment of hypertensive nephropa-thy and this work has reference value for clinicians Morelarge-scale multicenter rigorously designed randomized

controlled trials are needed to provide accurate data tofurther validate the effectiveness and safety of breviscapineinjection

6 Conclusions

Evidence from this systematic review shows that breviscap-ine injection in combination with antihypertensive drugscan improve clinical efficacy and creatinine clearance rate

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

Evidence-Based Complementary and Alternative Medicine 13

Figure 8 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of theBUN for hypertensive nephropathy

Figure 9 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the Ccrfor hypertensive nephropathy

was low All included trials showed high or undefined risk ofbias due to design reporting and methodology There wereno definitive randomized double-blind placebo-controlledtrials included in this meta-analysis No trials reporteddetailed randomization methods or allocation concealmentNo trial was double-blinded and unfortunately none ofRCT (randomized controlled trial) has a placebo in thetrial Therefore the reported strength of evidence should

be reevaluated and more rigorously designed placebo-controlled trials are warranted to give high-level evidencein future studies [48] Second five trials did not reportadverse reactions Therefore conclusions about safety can-not be made with confidence Furthermore certain activeingredients are chemically unstable which limits large-scalesynthesis These pressing issues should be resolved in futureresearch The safety of breviscapine injection needs to be

14 Evidence-Based Complementary and Alternative Medicine

Figure 10 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of beta-2-microglobulin for hypertensive nephropathy

Figure 11 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the SBPfor hypertensive nephropathy

strictly monitored and properly reported in future clinicaltrialsThird all tests produced positive results althoughmosttests were conducted with small samples We tried our best toavoid language bias and positional prejudice but cannot ruleout potential publication bias

Overall our results suggest that breviscapine injection iseffective and safe for the treatment of hypertensive nephropa-thy and this work has reference value for clinicians Morelarge-scale multicenter rigorously designed randomized

controlled trials are needed to provide accurate data tofurther validate the effectiveness and safety of breviscapineinjection

6 Conclusions

Evidence from this systematic review shows that breviscap-ine injection in combination with antihypertensive drugscan improve clinical efficacy and creatinine clearance rate

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

14 Evidence-Based Complementary and Alternative Medicine

Figure 10 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of beta-2-microglobulin for hypertensive nephropathy

Figure 11 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of the SBPfor hypertensive nephropathy

strictly monitored and properly reported in future clinicaltrialsThird all tests produced positive results althoughmosttests were conducted with small samples We tried our best toavoid language bias and positional prejudice but cannot ruleout potential publication bias

Overall our results suggest that breviscapine injection iseffective and safe for the treatment of hypertensive nephropa-thy and this work has reference value for clinicians Morelarge-scale multicenter rigorously designed randomized

controlled trials are needed to provide accurate data tofurther validate the effectiveness and safety of breviscapineinjection

6 Conclusions

Evidence from this systematic review shows that breviscap-ine injection in combination with antihypertensive drugscan improve clinical efficacy and creatinine clearance rate

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

Evidence-Based Complementary and Alternative Medicine 15

Figure 12 Meta-analysis results of breviscapine injection plus antihypertensive drugs versus antihypertensive drugs alone in terms of clinicalefficacy for hypertensive nephropathy

and reduce serum creatinine blood urea nitrogen 24-hour urinary protein and beta-2-microglobulin in hyper-tensive nephropathy patients There is no evidence thatbreviscapine injection in combination with antihyperten-sive drugs can improve SBP in hypertensive nephropathypatients

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work is supported by Social Development Key Pro-grams of Science and Technology Commission Foundationof Jiangsu Province (grant BE2015730) and the first level ofldquo333rdquo Project of Jiangsu Province (grant BRA2016503)

Supplementary Materials

Supplementary Tables S1 and S2 search strategy Supple-mentary Figure S1 Eggerrsquos test to evaluate publication bias

of Scr Supplementary Figure S2 meta-analysis results ofbreviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the Scr for hyper-tensive nephropathy Supplementary Figure S3 sensitivityanalysis for Scr Supplementary Figure S4 sensitivity analysisfor 24-hour urinary total protein Supplementary Figure S5Eggerrsquos test to evaluate publication bias of 24-hour urinarytotal protein Supplementary Figure S6 meta-analysis resultsof breviscapine injection plus antihypertensive drugs versusantihypertensive drugs alone in terms of the 24 h UTP forhypertensive nephropathy Supplementary Figure S7 sensi-tivity analysis for BUN Supplementary Figure S8 Eggerrsquostest to evaluate publication bias of BUN SupplementaryFigure S9 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of the BUN for hypertensive nephropathySupplementary Figure S10 meta-analysis results of brevis-capine injection plus antihypertensive drugs versus antihy-pertensive drugs alone in terms of the Ccr for hyperten-sive nephropathy Supplementary Figure S11 meta-analysisresults of breviscapine injection plus antihypertensive drugsversus antihypertensive drugs alone in terms of the beta-2-microglobulin for hypertensive nephropathy SupplementaryFigure S12 meta-analysis results of breviscapine injection

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

16 Evidence-Based Complementary and Alternative Medicine

plus antihypertensive drugs versus antihypertensive drugsalone in terms of the systolic blood pressure for hypertensivenephropathy Supplementary Figure S13 sensitivity analysisfor clinical efficacy Supplementary Figure S14 Eggerrsquos test toevaluate publication bias of clinical efficacy SupplementaryFigure S15 meta-analysis results of breviscapine injectionplus antihypertensive drugs versus antihypertensive drugsalone in terms of clinical efficacy for hypertensive nephropa-thy (Supplementary Materials)

References

[1] S Lewington R Clarke N Qizilbash R Peto and R CollinsldquoAge-specific relevance of usual blood pressure to vascularmortality a meta-analysis of individual data for one millionadults in 61 prospective studiesrdquoe Lancet vol 360 no 9349pp 1903ndash1913 2002

[2] M H Forouzanfar P Liu G A Roth et al ldquoGlobal Burden ofhypertension and systolic blood pressure of at least 110 to 115mm Hgrdquo Jama vol 317 no 2 pp 165ndash182 1990

[3] J A Joles and H A Koomans ldquoCauses and Consequences ofIncreased Sympathetic Activity in RenalDiseaserdquoHypertensionvol 43 no 4 pp 699ndash706 2004

[4] O Grisk and R Rettig ldquoInteractions between the sympatheticnervous system and the kidneys in arterial hypertensionrdquoCardiovascular Research vol 61 no 2 pp 238ndash246 2004

[5] M Safar P Chamiot-Clerc G Dagher and J F RenaudldquoPulse pressure endothelium function and arterial stiffness inspontaneously hypertensive ratsrdquo Hypertension vol 38 no 6pp 1416ndash1421 2001

[6] B I Freedman P J Hicks M A Bostrom et al ldquoPoly-morphisms in the non-muscle myosin heavy chain 9 gene(MYH9) are strongly associated with end-stage renal diseasehistorically attributed to hypertension in African AmericansrdquoKidney International vol 75 no 7 pp 736ndash745 2009

[7] ALLHAT Officers and Coordinators for the ALLHAT Col-laborative Research Group ldquoMajor outcomes in high-riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic TheAntihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)rdquo Jama vol 288 no 23 pp 2981ndash2997 2002

[8] USRD ldquo2017 USRDS annual data report executive summaryrdquoAmerican Journal of Kidney Diseases vol 71 no 3 pp S1ndashS82018

[9] BWilliams GManciaW Spiering et al ldquoESCESH guidelinesfor the management of arterial hypertension the task forcefor the management of arterial hypertension of the europeansociety of cardiology and the european society of hypertensionthe task force for the management of arterial hypertension ofthe european society of cardiology and the european society ofhypertensionrdquo Journal of Hypertension vol 36 no 10 pp 1953ndash2041 2018

[10] F C Fervenza S C Textor D Zand and D Rosenthal ldquoNeph-rosclerosisrdquo httpedmedicinemedscapecom [Updated Dec29 2017]

[11] Fresenius Medical Care 2016 Annual Report ESRD patientsin 2016 A global perspective (FMC 2016) Available fromhttpswwwfreseniusmedicalcarecom

[12] A S Levey L A Stevens CH Schmid et al ldquoA new equation toestimate glomerular filtration raterdquoAnnals of Internal Medicinevol 150 no 9 pp 604ndash612 2009

[13] P K Whelton R M Carey W S Aronow et al ldquoACCAHAAAPAABCACPMAGSAPhAASHASPCNMAPCNAguide-line for the prevention detection evaluation and man-agement of high blood pressure in adults executive summarya report of the american college of cardiologyamerican heartassociation task force on clinical practice guidelinesrdquoHyperten-sion vol 71 no 6 pp 1269ndash1324 2018

[14] J Lv P EhteshamiM J Sarnak et al ldquoEffects of intensive bloodpressure lowering on the progression of chronic kidney diseasea systematic review and meta-analysisrdquo Canadian MedicalAssociation Journal vol 185 no 11 pp 949ndash957 2013

[15] J J Sim J Shi C P Kovesdy K Kalantar-Zadeh and S JJacobsen ldquoImpact of achieved blood pressures onmortality riskand end-stage renal disease among a large diverse hypertensionpopulationrdquo Journal of the American College of Cardiology vol64 no 6 pp 588ndash597 2014

[16] G L Bakris P A Sarafidis M R Weir et al ldquoRenal outcomeswith different fixed-dose combination therapies in patientswithhypertension at high risk for cardiovascular events (ACCOM-PLISH) a prespecified secondary analysis of a randomisedcontrolled trialrdquo e Lancet vol 375 no 9721 pp 1173ndash11812010

[17] R W Zhang Y L Zhang J S Wang et al ldquoIsolation andidentification of flavonoids from shortscape fleabane (Erigeronbreviscapus)rdquo Zhong Cao Yao vol 8 no 19 pp 199ndash201 1988

[18] J GaoG ChenHHe et al ldquoTherapeutic effects of breviscapinein cardiovascular diseases a reviewrdquo Frontiers in Pharmacologyvol 8 p 289 2017

[19] C Wang Y Li S Gao et al ldquoBreviscapine injection improvesthe therapeutic effect of western medicine on angina pectorispatientsrdquo PLoS ONE vol 10 no 6 p e0129969 2015

[20] M Wang W-B Zhang J-H Zhu G-S Fu and B-Q ZhouldquoBreviscapine ameliorates cardiac dysfunction and regulates themyocardial Ca2+-cycling proteins in streptozotocin-induceddiabetic ratsrdquo Acta Diabetologica vol 47 Suppl 1 no 1 ppS209ndashS218 2010

[21] J-H Jia K-P Chen S-X Chen K-Z Liu T-L Fan and Y-CChen ldquoBreviscapine a traditional Chinese medicine alleviatesmyocardial ischaemia reperfusion injury in diabetic ratsrdquo ActaCardiologica vol 63 no 6 pp 757ndash762 2008

[22] M Wang C Xie R-L Cai X-H Li X-Z Luo and Y QildquoStudies on antioxidant activities of breviscapine in the cell-freesystemrdquo American Journal of Chinese Medicine vol 36 no 6pp 1199ndash1207 2008

[23] L Jiang Q Xia X Dong et al ldquoNeuroprotective effect ofbreviscapine on traumatic brain injury in rats associated withthe inhibition of GSK3beta signaling pathwayrdquo Brain Researchvol 1660 pp 1ndash9 2017

[24] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[25] M Wang W B Zhang J L Song Y Luan and C Y JinldquoEffect of breviscapine on recovery of viable myocardium andleft ventricular remodeling in chronic total occlusion patientsafter revascularization rationale and design for a randomizedcontrolled trialrdquo Medical Science Monitor vol 24 pp 4602ndash4609 2018

Evidence-Based Complementary and Alternative Medicine 17

[26] M He Z-M Xue J Li and B-Q Zhou ldquoBreviscapine inhibitshigh glucose-induced proliferation and migration of culturedvascular smooth muscle cells of rats via suppressing the ERK12MAPK signaling pathwayrdquo Acta Pharmacologica Sinica vol 33no 5 pp 606ndash614 2012

[27] X Liu L Yao D Sun et al ldquoEffect of breviscapine injectionon clinical parameters in diabetic nephropathy Ameta-analysisof randomized controlled trialsrdquo Experimental anderapeuticMedicine vol 12 no 3 pp 1383ndash1397 2016

[28] X P Yang and Q F Li ldquoClinical study of breviscapine inthe treatment of acute cerebral infarctionrdquo Chinese Journal ofPractical Nervous Diseases vol 10 no 2 pp 11ndash13 2007

[29] Y Zhang J S Wang and L M Zhang ldquoEffect of breviscapinecombined with lisinopril on urinary microalbumin in patientswith hypertensionrdquo Hunan Journal of Traditional ChineseMedicine vol 20 no 6 pp 12-13 2004

[30] LWei and J Tan ldquoClinical observation onBreviscapine in treat-ing hypertension patients complicated with micro-albuminuriaof renal impairmentrdquo Chinese Journal of Integrative Medicinevol 11 no 1 pp 31ndash33 2005

[31] W Ren and HWWu ldquoTherapeutic effect of breviscapine com-bined with western medicine on hypertensive nephropathyrdquoModern Chinese Medicine vol 26 no 4 pp 35-36 2006

[32] X L Zheng ldquoTherapeutic effect of breviscapine combinedwith western medicine on hypertensive nephropathyrdquo PracticalChinese Medicine Journal vol 22 no 3 pp 144-145 2006

[33] Y J Chen L H Lin X T Huang and H Xiao ldquoTherapeuticeffect of breviscapine combined with benazepril on hyperten-sive nephropathyrdquo International Medicine and Health Reportvol 14 no 22 pp 69ndash71 2008

[34] P Ye ldquoClinical analysis of breviscapine in the treatment ofhypertensive nephropathyrdquo Chinese Contemporary Medicinevol 16 no 9 pp 64-65 2009

[35] B L He and L J Gen ldquoTherapeutic effect of breviscapinecombined with captopril on early renal damage in patients withhypertensionrdquo Chinese Journal of Misdiagnostics vol 10 no 10pp 2329-2330 2010

[36] W L Wang and L D Lan ldquoTherapeutic effect of breviscapinecombined with lisinopril on hypertensive nephropathyrdquo in Pro-ceedings of the Zhejiang Medical Association Clinical PharmacyAcademic Annual Conference 2012

[37] F Liu ldquoClinical study of breviscapine combined with benazeprilin the treatment of hypertensive renal damagerdquoChinese Journalof Practical Medicine vol 39 no 1 pp 84-85 2012

[38] J F Li and T B Song ldquoThe effects of Simiao Maqian decoctionin the treatment of gouty arthritisrdquo Guangming Journal ofChinese Medicine vol 28 no 6 pp 1161-1162 2013

[39] Z Ye ldquoClinical study of breviscapine injection in the treatmentof hypertensive nephropathyrdquo Journal of Guangxi University ofTraditional Chinese Medicine vol 16 no 2 pp 45-46 2013

[40] S Q Qiao ldquoClinical study of breviscapine injection in thetreatment of hypertensive nephropathyrdquoTCMClinical Researchvol 7 no 20 pp 13ndash15 2015

[41] Q Zhao and G Dong ldquoEffect of breviscapine on serum fibrosisindex and arterial elasticity index in patients with hypertensivenephropathyrdquo Chinese Journal of Biochemical Medicine vol 36no 1 pp 151ndash153 2016

[42] Review Manager (RevMan) [Computer program] Version 53The Nordic Cochrane Centre The Cochrane CollaborationCopenhagen Denmark 2014

[43] J P T Higgins and S GThompson ldquoQuantifying heterogeneityin ameta-analysisrdquo Statistics inMedicine vol 21 no 11 pp 1539ndash1558 2002

[44] H H Ma ldquoClinical effect of breviscapine injection in patientswith hypertensive nephropathyrdquoMedical Equipment vol 31 no1 pp 133-134 2018

[45] X Xiong X Yang Y Liu Y Zhang P Wang and J WangldquoChinese herbal formulas for treating hypertension in tra-ditional Chinese medicine perspective of modern sciencerdquoHypertension Research vol 36 no 7 pp 570ndash579 2013

[46] X Xiong X Yang L Duan et al ldquoTraditional chinesemedicinesuppresses left ventricular hypertrophy by targeting extracellu-lar signal-regulated kinases signaling pathway in spontaneouslyhypertensive ratsrdquo Scientific Reports vol 7 no 1 p 42965 2017

[47] H-C Shih T-H Lee S-C Chen C-Y Li and T ShibuyaldquoAnti-hypertension effects of traditional Chinese medicine Ju-Ling-Tang on renal hypertensive ratsrdquo American Journal ofChinese Medicine vol 33 no 6 pp 913ndash921 2005

[48] X Xiong ldquoIntegrating traditional chinese medicine into west-ern cardiovascular medicine an evidence-based approachrdquoNature Reviews Cardiology vol 12 no 6 Article ID 374 2015

Stem Cells International

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Disease Markers

Hindawiwwwhindawicom Volume 2018

BioMed Research International

OncologyJournal of

Hindawiwwwhindawicom Volume 2013

Hindawiwwwhindawicom Volume 2018

Oxidative Medicine and Cellular Longevity

Hindawiwwwhindawicom Volume 2018

PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

Journal of

ObesityJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Computational and Mathematical Methods in Medicine

Hindawiwwwhindawicom Volume 2018

Behavioural Neurology

OphthalmologyJournal of

Hindawiwwwhindawicom Volume 2018

Diabetes ResearchJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Research and TreatmentAIDS

Hindawiwwwhindawicom Volume 2018

Gastroenterology Research and Practice

Hindawiwwwhindawicom Volume 2018

Parkinsonrsquos Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom

Stem Cells International

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Disease Markers

Hindawiwwwhindawicom Volume 2018

BioMed Research International

OncologyJournal of

Hindawiwwwhindawicom Volume 2013

Hindawiwwwhindawicom Volume 2018

Oxidative Medicine and Cellular Longevity

Hindawiwwwhindawicom Volume 2018

PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

Journal of

ObesityJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Computational and Mathematical Methods in Medicine

Hindawiwwwhindawicom Volume 2018

Behavioural Neurology

OphthalmologyJournal of

Hindawiwwwhindawicom Volume 2018

Diabetes ResearchJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Research and TreatmentAIDS

Hindawiwwwhindawicom Volume 2018

Gastroenterology Research and Practice

Hindawiwwwhindawicom Volume 2018

Parkinsonrsquos Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom