Qiong Liu 1 Min Zheng1 Xin Wang 4 Qijing Wu1 Enchao Zhou1 Jihong Chen1
Lingdong Xv1 and Weiming He 1
1Division of Nephrology Affiliated Hospital of Nanjing University of Chinese MedicineJiangsu Province Hospital of Chinese Medicine Nanjing 210029 China2School of Artificial Intelligence and Information Technology Nanjing University of Chinese Medicine Nanjing 210029 China3Division of Gerontology +e +ird Affiliated Hospital of Nanjing University of Chinese Medicine Nanjing 210000 China4Division of Nephrology Suzhou Hospital of Integrated Medicine Suzhou 215200 China
Correspondence should be addressed to Wei Sun goalkeenhotmailcom and Weiming He mousehwm163com
Received 9 August 2019 Revised 13 November 2019 Accepted 4 December 2019 Published 25 January 2020
Academic Editor Hajime Nakae
Copyright copy 2020 Ping Xia et alis is an open access article distributed under the Creative CommonsAttribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
Background Traditional Chinese medicine (TCM) has long been used to treat chronic kidney disease (CKD) in Asia Its ef-fectiveness and safety for CKD treatment have been confirmed in documented studies However the prescription rule of formulaefor Chinese medicinal herbs is complicated and remains uncharacterized us we used data mining technology to evaluate thetreatment principle and coprescription pattern of these formulae in CKD TCM treatment Methods Data on patients with CKDwere obtained from the outpatient system of a TCM hospital We established a Chinese herb knowledge base based on the ChinesePharmacopoeia and the Chinese Materia Medica en following extraction of prescription information we deweighted andstandardized each prescribed herb according to the knowledge base to establish a database of CKD treatment formulae Weanalyzed the frequency with which individual herbs were prescribed as well as their properties tastes meridian tropisms andcategories en we evaluated coprescription patterns and assessed medication rules by performing association rule learningcluster analysis and complex network analysis Results We retrospectively analyzed 299 prescriptions of 166 patients with CKDreceiving TCM treatment e most frequently prescribed core herbs for CKD treatment were Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis Herb (Baihuasheshecao) Root of Snow of June (Baimagu) Radix Astragali (Huangqi) Poria (Fulin) RhizomaAtractylodis Macrocephalae (Baizhu) Radix Pseudostellariae (Taizishen) and Fructus Corni (Shanzhuyu)e TCMproperties ofthe herbs were mainly being warm mild and cold e tastes of the herbs were mainly sweet followed by bitter e mainmeridian tropisms were Spleen Meridian of Foot-Taiyin Liver Meridian of Foot-Jueyi Lung Meridian of Hand-Taiyin StomachMeridian of Foot-Yangming and Kidney Meridian of Foot-Shaoyin e top three categories were deficiency-tonifying heat-clearing and dampness-draining diuretic Conclusion Using an integrated analysis method we confirmed that the primary TCMpathogeneses of kidney disease were deficiency and dampness-heat e primary treatment principles were tonifying deficiencyand eliminating dampness-heat
1 Introduction
Chronic kidney disease (CKD) is a worldwide public healthproblem and its prevalence is more than 10 It eventuallyprogresses to end-stage renal disease in 20ndash30 of casesresulting in tremendous social and economic burdens [1 2]According to the Global Burden of Disease Study CKD was
the 19th leading cause of years of life lost in 1990 and rose to16th place in 2016 and is expected to further rise to 5th placeby 2040 [3] How to slow or stop the progression of CKD is amajor challenge for nephrologists Unfortunately earlydetection and effective treatment remain difficult to date InChina the prevalence of CKD is 108 [4] Many Chinesepatients with CKD benefit from traditional Chinese
HindawiEvidence-Based Complementary and Alternative MedicineVolume 2020 Article ID 9719872 14 pageshttpsdoiorg10115520209719872
medicine (TCM) [5] which is perceived as a cost-effectivealternative medicine TCM originated in ancient China andhas continued to evolve for over 2500 years Notably it haslong been used to treat kidney disease [6] e effectivenessand safety of TCMhave progressed considerably over severaldecades especially in the case of some herbs and herbalcompounds prescribed for CKD treatment [7ndash10]
Syndrome differentiation and treatment are the core ofTCM in clinical practice ere are three basic principles forcuring disease with Chinese medicinal herbs eliminating thecause of illness dispelling pathogenic factors and restoringcoordination of the internal organs so that excess and deficientyin or yang can be corrected Most TCM prescriptions consistof more than two herbs According to the TCM theory severalherbs prescribed together are superior to a single herb fordisease treatment because the full extent of their advantages isrealized and their disadvantages are inhibited Differenttherapeutic effects may result from prescribing different herbsand herb combinations the toxicity of other coprescribedherbs may also be decreased In clinical practice it is necessaryto be flexible in modifying the formulae for Chinese medicinalherbs according to the condition of the illness and the status ofthe patient under the guidance of TCM compatibility prin-ciples e specific prescription reflects both the patientrsquoscharacteristics and the physicianrsquos experience Only when theprinciples are unified flexibly can the prescription be con-gruent with the syndromes to be treated en the expectedefficacy will be achieved us it is necessary to follow theprinciple but not adhere to the initially established formulaCollection and analysis of formulae are one of the essentialmethods for learning and passing on knowledge of TCMHowever flexible intervention is extremely complicated inclinical practice which causes considerable difficulties forclinical research It also limits TCM from further developingand becoming more widespread Many researchers and ne-phrologists are concerned about how to utilize TCM herbformulae safely and effectively in kidney disease Much at-tention has been paid to exploring the core herbs used in TCMfundamental therapy principles and prescription methodserefore interpretation of herbal formulae is expected to helpidentify the most effective herbs and improve the treatment ofkidney disease It should also contribute to the development ofnovel drugs for CKD treatment
Machine learning has been used to analyze the pre-scription patterns of Chinese medicine from clinical dataand to discover potential associations between Chinesemedicinal herbs and disease [11] At present data mining inthe field of TCM covers a wide range of conditions pre-scriptions cases and diagnostics Frequency statistics as-sociation rule learning cluster analysis and complexnetwork analysis are commonly used techniques [12ndash14]Scholars have surveyed clinical data from the NationalHealth Insurance Database and used frequency analysis andassociation rule learning to explore TCM treatment forinsomnia and depression ey showed the prescriptionpatterns of Chinese herbs for patients with sleep disorderandmajor depressive disorder [12] Another study was basedon hierarchical clustering of herbal effects and determinedstandard prescription rules combined with the theory of qi
and blood to explore the consistency of TCM theory andherbs [13] We previously designed a prescription recom-mendation algorithm based on the complex networkmethod to explore the core herbs for lung cancer treatment[14] It is important to note complex factors of TCM whichdo not meet the requirements of data mining clinical di-agnosis and treatment information various data structuresand high information dimensions erefore it is necessaryto determine a method that includes data cleansing and datamining
In this study we proposed an integrated analysis methodto extract and mine TCM medical records We collectedclinical cases in which patients were given herbal pre-scriptions by one of our hospitalrsquos TCM specialists ProfessorLijuan Gong en we analyzed prescriptions for CKDtreatment using association rule learning cluster analysisand complex networks to explore conventional TCM pre-scriptions the law of medication and potential core pre-scriptions We aimed to identify the main treatmentprinciple and herb prescriptions of TCM specialists for CKDtreatment using modern data computer technology
2 Materials and Methods
21 Data Source We retrospectively analyzed a patientsample from the Jiangsu Province Hospital of ChineseMedicine and determined the prevalence of prescribedChinese medicinal herbs in patients with CKD from 2011 to2016 CKD diagnosis was based on the National KidneyFoundation Kidney Disease Outcome Quality Initiative 2002guidelines and was defined as abnormalities in kidneystructure or function present for gt3 months or glomerularfiltration rate lt60mlmin173m2 Exclusion criteria were(1) acute kidney injury diagnosis (2) receiving renal re-placement therapy (3) incomplete prescription compositionor dosage and (4) not receiving herb formula treatment Intotal 299 prescriptions in 166 patients were enrolled in thisstudy e study procedures were approved by the ResearchEthics Committee of the Affiliated Hospital of NanjingUniversity of Chinese Medicine and performed in strictconformity with our institutional guidelines e detailedworkflow diagram is summarized in Figure 1
22 Data Processing
221 Data Collection We screened all the clinical infor-mation from the clinical cases of outpatients Patient in-formation was collected including age sex home addressdiagnosis and TCM diagnosis Herbal prescriptions at eachpatientrsquos first visit and subsequent follow-up visits wererecorded
222 Data Process e data processing methods mainlyincluded establishing the TCM knowledge base normalizingthe prescriptionrsquos content structure separating the com-pound medicine into individual herbs standardizing TCMterminology and correcting for manual error
2 Evidence-Based Complementary and Alternative Medicine
In brief we first established a Chinese medicinal herbknowledge base according to the Chinese Pharmacopoeiaand the Chinese Materia Medica [15 16] First we identifiedthe herbs in the prescriptions and unified them according tocontent structure based on the knowledge base Second weeliminated duplicate herbs and applied standardized ter-minology for the expression of the herbs en we extractedinformation on prescriptions and herbs All these data weretransferred to Microsoft Excel 2016 to establish a TCMnephrology database e information collection processwas confirmed by two researchers
23 Statistical Analysis All the data were processed byR-Studio Version 353 First we used the Apriori algorithmto analyze the association rules of the herbs Second hier-archical clustering was used to classify high-frequency herbsFinally complex network analysis was used to confirm thecore herbs prescribed for CKD treatment
231 Apriori Algorithm eApriori algorithm is a frequentitemset algorithm for mining association rules We used it toillustrate the specific rules of TCM in CKD treatment In ourdata each herb was treated as a variable A fixed combi-nation can be understood as a herb pair in TCM theory eformulae were as follows
support(X⟶ Y) σ(XcupY)
N
confidence(X⟶ Y) σ(XcupY)
σ(X)
lift(X⟶ Y) confidence(X⟶ Y)
σ(Y)
(1)
where X⟶ Y is an association rule X (left-hand side[LHS]) and Y (right-hand side [RHS]) represent the set ofherb items σ(X) is the frequency of itemset X XcupY is theunion of itemset X and Y σ(XcupY) is the frequency with
Text type
Word Text
Structurized type
Excel Database
Text structurenormalize
Contentstructure
normalization
Completion ofprescription
Removingduplicate herbs
Association rule Hierarchical clustering Complex network
The coprescription pattern and treatment principle and in CKD
Herbstandardization
Chinesepharmacopoeia
Chinese materiamedica
Figure 1 Data mining flowchart e integrated data mining method included data processing frequency statistics association rulescluster analysis and complex network analysis
Evidence-Based Complementary and Alternative Medicine 3
which itemset X and itemset Y appear together support(X⟶ Y) is the frequency with which X and Y appear togetherand confidence(X⟶ Y) is the probability that itemset Yappears in the presence of X e lift is the ratio of theprobability of itemset Y appearing in the presence of X to thefrequency of Y Support and confidence are often used toeliminate meaningless combinations lift is the validity of therules
232 Hierarchical Clustering Algorithm In the hierarchicalclustering algorithm each herb was regarded as a clusterand N clusters were combined to form a new class based on asimilarity measure between objects e Euclidean metricwas used to calculate the similarity between herbs theformula of which is
d(x y)
1113944n
k1xk minus yk( 1113857
2
11139741113972
(2)
Herbs used more than 30 times were extracted for wordclustering
233 Complex Network Analysis We used complex networkanalysis to confirm the core herb in each prescriptionComplex network analysis is used to analyze complex inter-action laws in complex systems in the real world based on anetwork model of nodes and edges e complexities ofdiseases and human life systems are gradually being recog-nized such that medical research from a network perspectivehas become an important topic in current medical researchWe regarded the constituent herbs for CKD treatment asnodes and connections between two herbs as edges us wecould rationalize all medical record data into a network of drugnodes and edges using Liquorice (a complex network analysistool) and the multiscale backbone algorithm
Node degree and confidence level are the keys to mea-suring the association between drugs Node degree is thenumber of edges connected to a node and the confidence levelrepresents the reliability of the data e multiscale backboneis a statistical model established by identifying significantedges the parts of the network that are retained are those inwhich the nodes are strongly associated We set the screeningcriteria as a node degree of 36 and a confidence level of 095
3 Results
31 CKD Patient Characteristics We analyzed 299 pre-scriptions of 166 patients with CKD Of the patients 66(397) were male and 100 (603) were female with a maleto female ratio of 1 151 Age ranged from 4 to 82 (mean4892plusmn 1769) years On the kidney disease spectrum mostpatients had glomerular disease hypertensive kidney dis-ease or diabetic kidney disease
32 Herb Frequency and Analysis We analyzed herb fre-quency in all prescriptions because formulae for Chinesemedicinal herbs usually consider two or more herbs Among
the 299 prescriptions 202 Chinese medicinal herbs appeared4123 times as shown in Table 1 e most frequently pre-scribed herb was Rhizoma Dioscoreae (Shanyao) whichappeared 231 times (frequency 773) e following mostfrequently prescribed herbs in descending order wereSpreadingHedyotis Herb (Baihuasheshecao) Root of Snow ofJune (Baimagu) Radix Astragali (Huangqi) Poria (Fulin)Rhizoma Atractylodis Macrocephalae (Baizhu) Radix Pseu-dostellariae (Taizishen) Fructus Corni (Shanzhuyu) RadixRehmanniae (Shengdihuang) Fructus Lycii (Gouqizi) FlosCarthami (Honghua) Common Sage Herb (Lizhicao) Per-icarpium Citri Reticulate (Chenpi) Cortex Phellodendri(Huangbai) Semen Coicis (Yiyiren) Rhizoma Imperatae(Baimaogen) and Rhizoma Anemarrhenae (Zhimu) esetop 17 most frequently prescribed herbs appeared more than78 times (frequency more than 25) ese results dem-onstrate that these were preferred herbs in CKD
33 Properties Tastes and Meridian Tropisms of HerbsWe analyzed the properties and tastes of the herbs AsFigure 2(a) shows the TCM properties were mainly beingwarm mild and cold We adopted five tastes for analysispungent sweet sour bitter and salty e herbs mainlytasted sweet followed by bitter (Figure 2(b)) Sweet taste hasnourishing harmonizing and moistening functions Bittertaste has the functions of clearing away dampness andpurging ese data indicate that nourishing and purgingwere the principal functions of TCM in CKD treatmentMeridian tropism refers to medicinal herbs that often andselectively produce therapeutic effects on specific parts of thehuman body e theory of meridian tropism plays a vitalrole in the clinical selection of Chinese medicinal herbs efrequency of a herbrsquos meridian tropism can be determined byclassification using a tree diagram Spleen Meridian of Foot-Taiyin Liver Meridian of Foot-Jueyi Lung Meridian ofHand-Taiyin Stomach Meridian of Foot-Yangming and
Table 1 Herbs appearing over 40 times in prescriptions
Herb Number FrequencyRhizoma Dioscoreae (Shanyao) 231 0773Spreading Hedyotis Herb(Baihuasheshecao) 196 0656
Root of Snow of June (Baimagu) 175 0585Radix Astragali (Huangqi) 174 0582Poria (Fulin) 166 0555Rhizoma Atractylodis Macrocephalae(Baizhu) 162 0542
4 Evidence-Based Complementary and Alternative Medicine
Kidney Meridian of Foot-Shaoyin Our results showed thattherapeutic effects were predominant for the kidney spleenliver and lung and reflected that TCM is holistic
34 Action Category of Herbs Chinese medicinal herbs havespecific efficacy and can be classified into different specificaction categories Table 2 details the categories and thefrequency with which herbs were classified into these cat-egories e top ten categories for CKD treatment weredeficiency-tonifying herbs heat-clearing herbs dampness-draining diuretic herbs hemostatic herbs astringent herbsqi-regulating herbs blood-activating and stasis-resolvingherbs cough-suppressing and panting-calming herbs ex-terior-releasing herbs and digestant herbs
35 Prescription Patterns of Chinese Medicinal HerbsCompatibility of Chinese medicinal herbs refers to thecombination of two or more herbs with a purpose based onclinical requirements and medicinal properties and actions
0
400
800
1200
1600Cold
Warm
MildCool
Hot
Properties of herbs
(a)
0500
10001500200025003000
Sweet
Bitter
Pungent
Sour
WeakAstringent
Salty
Flavors of herbs
(b)
Meridian tropism of herbs
SpleenLiverLung
StomachKidneyHeart
Large intestineBladderSmall intestine
GallbladderPericardiumTri-jiao
(c)
Figure 2 Property taste and meridian tropism of herbs (a) Herb properties All herbs in each prescription were analyzed using a radarchart divided into five categories (b) Herb taste Tastes were divided into six categories using a radar chart (c) Meridian tropism of herbsWe created a tree diagram of the meridian tropism of all herbs Different meridian tropisms are indicated by different colors as shown at thebottom of the diagram All images were analyzed using Microsoft Excel 2016
Table 2 Frequency of herb categories
Herb category Frequency Rate ()Deficiency-tonifying herbs 1233 2991Heat-clearing herbs 1027 2491Dampness-draining diuretic herbs 410 994Hemostatic herbs 198 48Astringent herbs 170 412Qi-regulating herbs 169 41Blood-activating and stasis-resolving herbs 162 393Cough-suppressing and panting-calmingherbs 151 366
Evidence-Based Complementary and Alternative Medicine 5
It is the primary clinical method of medicinal applicationand the basis of herbal formulae composition Here we useddata mining to assess the standard prescription patterns ofthe formulae for CKD treatment
351 Herb Pair Analysis In clinical practice paired usage ofChinese medicinal herbs is essential therapeutically andcomprises the herb prescription method us we analyzedherb pairs
First we used the Apriori algorithm to analyze the as-sociation rules of the herbs in all prescriptions We focusedon two parameters support and confidence level Supportwas set as ge30 and confidence level as ge85 [11] and a totalof 30 herb pairs and suitable association rules were obtainede detailed association rules are shown in Table 3 and thecorrelation rules are shown in Figure 3 As shown in Table 3Astragali Radix (Huangqi)gtRhizoma Dioscoreae (Sha-nyao) had the highest degree of support at 5151 Rhi-zoma Atractylodis Macrocephalae (Baizhu) Fructus Corni(Shanzhuyu)gtRhizoma Dioscoreae (Shanyao) had thehighest confidence level at 9588 and Poria (Fulin) RadixAstragali (Huangqi)gtRhizoma Atractylodis Macro-cephalae (Baizhu) had the highest degree of lift at 168
A grouping matrix diagram displaying the general dis-tribution of association rules grouped into categories withsimilar rules is shown in Figure 4 is diagram allows us tonot only extract the general rule but also more deeply searchfor and extract important rules with commonality among theassociation rulesX-axis is the LHS andY-axis is the RHSecirclersquos color depth indicates the degree of lift such that thedarker the color the higher the degree of lift e size of thecircle indicates the degree of support such that the larger thecircle the higher the degree of support We found three coreherbs of paired prescriptions Astragali Radix (Huangqi)Rhizoma Dioscoreae (Shanyao) and Rhizoma AtractylodisMacrocephalae (Baizhu) ese herbs were usually combinedwith other herbs such as Astragali Radix (Huangqi) pairedwith Fructus Corni (Shanzhuyu) Rhizoma Dioscoreae(Shanyao) paired with Spreading Hedyotis Herb (Baihua-sheshecao) and Rhizoma Atractylodis Macrocephalae(Baizhu) paired with Poria (Fulin) to strengthen the spleentonify the kidney and eliminate dampness-heat respectively
In Figure 3 association rules were determined with agraphics-based visualization technique using a vertex torepresent herbs and relationships e strength of the re-lationship is expressed in the color depth or the size of thevertex e graph includes Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis Herb (Baihuasheshecao) Root of Snowof June (Baimagu) Radix Astragali (Huangqi) Poria (Fulin)Rhizoma Atractylodis Macrocephalae (Baizhu) RadixPseudostellariae (Taizishen) and Fructus Corni (Shanz-huyu) Among these eight herbs Radix Astragali (Huangqi)and Rhizoma Atractylodis Macrocephalae (Baizhu) are atthe center of the association rule graph
352 Novel Prescriptions Analysis Cluster analysis aggre-gates herbs into categories based on data attributes eclustering algorithm is an unsupervised learning algorithm
that can directly extract valuable information from the inputdata objects without input of any prior knowledge It iswidely used for data mining in TCM and mainly used fordetermining the compatibility law between drugs to identifythe combination rule of different TCM therapeutic methodse advantage of this method is that it allows for discovery ofpotential new prescriptions for CKD treatment Here weanalyzed 32 core herbs that were prescribed more than 30times using hierarchical clustering According to classicTCM theory five categories were considered suitable in thisstudy Figure 5 shows the herbs belonging to each cluster
353 Core Prescription Analysis Chinese medicinal herbsare usually applied as a combination of core herbs and otherherbs To further analyze the role of various herbs and theircombinations in CKD treatment we used the complexnetwork method and found that the core herbs in CKDtreatment were Rhizoma Dioscoreae (Shanyao) SpreadingHedyotis Herb (Baihuasheshecao) Root of Snow of June(Baimagu) Radix Astragali (Huangqi) Poria (Fulin) Rhi-zoma Atractylodis Macrocephalae (Baizhu) Radix Pseu-dostellariae (Taizishen) and Fructus Corni (Shanzhuyu)(Figure 6)ese eight herbs were also found to be frequentlyprescribed for CKD treatment and appeared in the associ-ation rule graph ese results indicate that these Chinesemedicinal herbs may have not only an effect on CKDtreatment but also a united one
4 Discussion
is study determined effective herbal prescriptions forCKD treatment by proposing a comprehensive methodbased on clinical cases integration of association rulescluster analysis and complex network analysis
We analyzed herb frequency and the properties and ac-tions of herbs and assessed the compatibility rules betweendrugs Our data showed that the most frequently prescribedherbs were Rhizoma Dioscoreae (Shanyao) SpreadingHedyotis Herb (Baihuasheshecao) Root of Snow of June(Baimagu) Radix Astragali (Huangqi) Poria (Fulin) Rhi-zoma Atractylodis Macrocephalae (Baizhu) Radix Pseudos-tellariae (Taizishen) Fructus Corni (Shanzhuyu) RadixRehmanniae (Shengdihuang) and Fructus Lycii (Gouqizi)e properties of these herbs were mainly being warm mildand colde tastes of the herbs were mainly sweet and bittere herbs were generally distributed to spleen lung liver andkidney channels and most were deficiency-tonifying herbsheat-clearing herbs and dampness-draining diuretic herbse most frequently used combinations of herbs obtainedusing association rules were Radix Astragali (Huangqi) andRhizoma Dioscoreae (Shanyao) ere were three core herbsof paired prescriptions Rhizoma Atractylodis Macrocephalae(Baizhu) Radix Astragali (Huangqi) and Rhizoma Dio-scoreae (Shanyao) Cluster analysis was used to divide theherbs into five clusters Herbs in cluster 1 mainly targeted thespleen and lung herbs in cluster 2 were prescribed to nourishthe liver-kidney and to clear heat-dampness and herbs incluster 3 were prescribed for clearing heat cooling blood and
6 Evidence-Based Complementary and Alternative Medicine
Table 3 Association rules of herbs for CKD treatment
Evidence-Based Complementary and Alternative Medicine 7
clearing dampness Cluster 4 herbs were prescribed forregulating qi flow eliminating phlegm activating blood andpurging turbidity Herbs in cluster 5 were not frequently usedWe used the complex networkmethod to analyze interactionsbetween herbs and found that the core herbs were RhizomaDioscoreae (Shanyao) Spreading Hedyotis Herb (Baihua-sheshecao) Root of Snow of June (Baimagu) Radix Astragali(Huangqi) Poria (Fulin) Rhizoma Atractylodis Macro-cephalae (Baizhu) Radix Pseudostellariae (Taizishen) andFructus Corni (Shanzhuyu)
e properties and actions of Chinese medicinal herbsare the essential bases for the analysis and clinical use ofherbs ey are summarized in medical practice and basedon the theories of yin and yang zang-fu meridian tropismsand TCM therapeutic principles [17] Chinese medicinal
herb theory is usually summarized as four properties and fivetastes meridian tropism and so on In this study the herbalproperties for CKD treatment were mainly sweet and warmwhich have a replenishing effect e next most frequentlyprescribed herbs had bitter and cold properties whichgenerally have a clearing action us tonifying deficiencywas the most important CKD treatment followed byclearing and disinhibiting is finding reflects the conceptthat TCM replenishes missing substances and rids the bodyof excess substances to regulate the balance of the bodyMeridian tropism is a theory that helps in understanding theorientation of drug action In this study the herbs weregenerally prescribed to target the spleen liver lung stom-ach and kidney meridian (ie the zang-fu requiringtreatment) In one studyrsquos retrospective analysis the basic
Figure 3 Association rule combination matrix e association rule combination matrix was analyzed using R-studio 353 Sizeindicatesconfidence (0855ndash0959) and color indicates lift (1106ndash1667)
8 Evidence-Based Complementary and Alternative Medicine
syndromes of kidney disease were identified as spleen andkidney deficiency lung and kidney qi deficiency and liverand kidney yin deficiency [18] Our research further indi-cates the important role of the kidney spleen stomach liverand lung in nephropathy Similarly the efficacious herbswere mainly deficiency-tonifying herbs heat-clearing herbsand dampness-draining diuretic herbs us these were themain TCM treatments for CKD Conversely the therapeuticprinciple could be used to determine the pathogenesis of thedisease at is the pathogenic factors could be divided intoheat and dampness and deficiency may be mainly caused bythe kidney spleen lung and liver
We identified commonly used herbs and their combina-tions (Tables 1 and 3)emain herbs for CKD treatment wereRhizoma Dioscoreae (Shanyao) Radix Astragali (Huangqi)Poria (Fulin) Rhizoma Atractylodis Macrocephalae (Baizhu)Radix Pseudostellariae (Taizishen) and Fructus Corni(Shanzhuyu) these all have the function of replenishing
Specifically Rhizoma Dioscoreae (Shanyao) targets the spleenlung and kidney Radix Astragali (Huangqi) and RadixPseudostellariae (Taizishen) can supplement the lung andspleen Macrocephalae (Baizhu) and Poria (Fulin) are pre-scribed to invigorate the spleen and Fructus Corni (Shanz-huyu) can nourish the liver and kidney ese six drugs indifferent combinations comprised the 11 most frequentcombinations Among them the most frequent combinationsincluded Rhizoma Dioscoreae (Shanyao) Rhizoma Dioscor-eae (Shanyao) can treat all deficiency syndromes according toTCM theory and is important for tonifying deficiency usherb combinations showed that the tonifying-deficiency cat-egory was the most important for CKD treatment In TCMnephrology kidney deficiency is the basis of kidney diseaseand tonifying kidney treatment should be vital [19] Howeverour research showed that the methods of supplementing thelung and spleen and nourishing the liver and kidney weremore frequently used in CKD Tonifying the spleen lung or
Grouped matrix for 30 Rules Size support Color li
1 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Por
ia (F
ulin
) +1
item
s
3 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Rhi
zom
aAt
ract
ylod
is M
acro
ceph
alae
(Bai
zhu)
+2
item
s
6 ru
les
Por
ia (F
ulin
) Ra
dix
Astr
agal
i (H
uang
qi)
+2 it
ems
6 ru
les
Rhi
zom
a Atr
acty
lodi
s Mac
roce
phal
ae (B
aizh
u)
Fruc
tus C
orni
(Sha
nzhu
yu)
+2 it
ems
14 ru
les
Rad
ix P
seud
oste
llaria
e (Ta
izish
en)
Spre
adin
g H
edyo
tis H
erb(
Baih
uash
eshe
cao)
+5
item
s
Rhizoma Dioscoreae (Shanyao)
Radix Astragali (Huangqi)
Rhizoma Atractylodis Macrocephalae (Baizhu)
Item
s in
LHS
grou
p
RHS
Figure 4 Association rule diagram Association rule learning was performed using R-studio 353 X-axis is the antecedent (or calledlefthandside LHS) and Y-axis is the consequent (or called right-hand side RHS) Size indicates support and color indicates lift
Evidence-Based Complementary and Alternative Medicine 9
liver is well known to achieve the purpose of nourishing thekidney but herbs that tonify the kidney were not frequentlyprescribed in this researchis indicates that amultiple-organdisorder underlies the TCM pathogenesis of CKD When and
how to nourish the kidney directly or indirectly requiresfurther study In TCM practice tonifying-deficiency herbs areoften used in combination with heat-clearing and dampness-draining diuretic herbs Table 3 shows that two or more herbs
Poria (Fulin)
Radix Astragali (Huangqi)Rhizoma Atractylodis
Macrocephalae (Baizhu)
Fructus Corni (Shanzhuyu)
Radix Pseudostellariae (Taizishen)
Fructus Lycii (Gouqizi)
Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis
Herb (Baihuasheshecao)Root of Snow of June (Baimagu)
Rhizoma Imperatae (Baimaogen)
Radix Cirsii Japonici (Daji)
Herba Cirsii (Xiaoji)
Radix Rehmanniae (Shengdihuang)
Common Sage Herb (Lizhicao)
Rhizoma Smilacis Glabrae (Tufulin)
Cortex Phellodendri (Huangbai)
Rhizoma Anemarrhenae (Zhimu)
Pericarpium Citri Reticulatae (Chenpi)
Rhizoma Pinelliae (Banxia)
Semen Coicis (Yiyiren)
Flos Carthami (Honghua)
Radix et Rhizoma Rhei (Dahuang)
Herba Taxilli (Sangjisheng)
Cortex Eucommiae (Duzhong)
Corn Stigma (Yumixu)
Radix Codonopsis (Dangshen)
Radix Salviae Miltiorrhizae (Danshen)
Medicated Leaven (Shenqu)
Radix Saposhnikoviae (Fangfeng)
Radix Ophiopogonis (Maidong)
Herba Taraxaci (Pugongying)
Radix Glycyrrhizae (Gancao)
Cluster dendrogram
Height
Figure 5 Cluster analysis tree diagram e cluster analysis tree diagram was created using R-studio 353 e 32 most frequentlyprescribed herbs were analyzed Each category is represented by a different color
10 Evidence-Based Complementary and Alternative Medicine
were usually combined with Spreading Hedyotis Herb (Bai-huasheshecao) or Root of Snow of June (Baimagu) whichwerethe two most frequently used heat-clearing herbs anddampness-removing diuretic herbs Tonifying treatment wasalso indicated to be more important than heat-clearing ordampness-draining treatment How to balance tonifyingtreatment and clearing-diuresis treatment under specificconditions needs to be investigated further
e pathogenesis of kidney disease is complex and oftenmanifests as multiple syndrome combinationse formulaedetermined by clustering were for composite syndromesHerbs in cluster 1 were for tonifying the lung strengtheningthe spleen and removing dampness and were prescribed totreat spleen-lung qi deficiency and dampness Herbs incluster 2 were for nourishing the liver and kidney andclearing heat or dampness and were prescribed to treat liver-kidney yin deficiency and dampness or heat ose in cluster3 were for nourishing yin clearing heat and cooling bloodese herbs can be found in Zhi Bai Di Huang Wan and are
prescribed to treat fire excess from yin deficiency and blood-heat syndromeose in cluster 4 were for regulating qi floweliminating phlegm activating blood and purging turbidityey were prescribed to treat phlegm-damp blood stasisand turbidity syndromesese four clusters of prescriptionsfor different syndrome types can provide useful ideas forCKD treatment e herbs in cluster 5 had multiple func-tions such as tonifying the kidney releasing the exteriorand promoting digestion It may be used auxiliarily to targetcomplications and requires further study
Complex network analysis revealed eight core herbs forCKD Rhizoma Dioscoreae (Shanyao) Spreading HedyotisHerb (Baihuasheshecao) Root of Snow of June (Baimagu)Radix Astragali (Huangqi) Poria (Fulin) Rhizoma Atrac-tylodis Macrocephalae (Baizhu) Radix Pseudostellariae(Taizishen) and Fructus Corni (Shanzhuyu) Interestinglythese herbs are included in clusters 1 and 2 ey were alsoidentified as high-frequency herbs for CKD treatment so webelieved that such a prescription could be used as a basis for
Spreading Hedyotis
Herb
Fructus Corni
Rhizoma Dioscoreae
Root of Snow of
June
Poria Radix Astragali
Radix Pseudostellariae
Rhizoma Atractylodis
Macrocephalae
124
154
105
100
154
134
99
129
100
115
98
86
95 98
141
119
115
127
87
146
139
136
131
115
112
102
97
97
89
Figure 6 Core prescription network e core prescription network was created using Liquorice e weight represents the frequency withwhich two herbs appeared together
Evidence-Based Complementary and Alternative Medicine 11
further research Modern pharmacology has also shown thatthese herbs can improve kidney injury through anti-in-flammatory and antioxidant activity (Table 4) [20ndash29]
Our data mining approach has several advantages Firstthere was no requirement for the data structure is is verypractical for data mining of Chinese medicine prescriptionsbecause the data structure of most Chinese medicines is notuniform Second we combined a variety of data miningmethods to perform comprehensive analysis and to ensurethat the conclusion was reliable Finally we focused on themain treatment methods and uses of herbs which is anefficient way to learn TCM treatment Our research also hassome limitations We collected only prescription informa-tion but not diagnostic information so our conclusionscannot be completely confirmed We also examined onlyeffective treatment cases not invalid treatment cases sowhether a gap exists between these two case types remainsunclearus it is also unclear whether the core prescriptionshould be corrected Finally the safety and efficacy of thecore prescriptions were not evaluated and should be in-vestigated in a future study
In summary we adopted a practical approach based onformulae prescribed in clinical practice To our knowledgethis is the first study on CKD treatment with TCM whichcombines frequency analysis association rule learning andcomplex network analysis Using this approach we deter-mined the frequency and combination patterns of CKDtreatment and discovered possibilities for new CKD
treatment prescriptions We also summarized herbal CKDtreatment finding that CKD syndromes are extremelycomplicated and various CKD treatmentmethods exist suchas those for cooling blood and eliminating phlegm How-ever we found that the treatment methods were mainly fortonifying deficiency and clearing heat or dampness
5 Conclusions
Our study found that kidney spleen lung or liver deficiencyand dampness-heat were the primary TCM pathogenesisus the primary treatment principle was tonifying defi-ciency and eliminating dampness and heat Furthermoreour study verified that the integrated analysis method canhelp to explore the TCM treatment strategy is analysis ofherbal TCM prescriptions potentially contributes to thedevelopment of novel drugs for CKD
Data Availability
e data used to support the findings of this study are in-cluded within the article
Conflicts of Interest
e authors declare that there are no conflicts of interestregarding the publication of this article
Table 4 Possible mechanisms of the core Chinese medical herbs for CKD treatment
Increases catalase (CAT) superoxide dismutase(SOD) and glutathione peroxidase (GSH-px)
activities in the kidneys of diabetic rats as well asenhancing renal peroxisome proliferator-activatedreceptor-c (PPARc) expression in diabetic rats [28]
Radix Pseudostellariae (Taizishen) Polysaccharide
Decreases serum triglyceride total cholesterol low-density-lipoprotein cholesterin urea nitrogen andcreatinine increase serum high-density-lipoproteincholesterol and reduce renal histopathology change
[29]
12 Evidence-Based Complementary and Alternative Medicine
Authorsrsquo Contributions
Ping Xia and Kun Gao contributed equally to this studyWeiming He and Kun Gao designed the research Ping XiaMing Shi Wei Li Jing Zhao Jin Yan Qiong Liu Min ZhengXin Wang and Qijing Wu collected and processed the dataPing Xia and Jiadong Xie analyzed the data Wei Sun JihongChen Enchao Zhou and Lingdong Xv participated in in-tellectual discussions Ping Xia and Kun Gao wrote thepaper All authors approved the final edited version of themanuscript
Acknowledgments
is study was financially supported by the PostgraduateResearch amp Practice Innovation Program of Jiangsu Prov-ince (KYCX19_1189 to Ping Xia) and the National NaturalScience Foundation of China (81673912 and 81873259 toKun Gao 81804219 to Jiadong Xie and 81774269 toWeiming He) e authors gratefully acknowledge the as-sistance of Dr Buhui Liu their colleague in the AffiliatedHospital of Nanjing University of Chinese Medicine
References
[1] A Levin M Tonelli J Bonventre et al ldquoGlobal kidney health2017 and beyond a roadmap for closing gaps in care researchand policyrdquo +e Lancet vol 390 no 10105 pp 1888ndash19172017
[2] A C Webster E V Nagler R L Morton and P MassonldquoChronic kidney diseaserdquo +e Lancet vol 389 no 10075pp 1238ndash1252 2017
[3] K J Foreman N Marquez A Dolgert et al ldquoForecasting lifeexpectancy years of life lost and all-cause and cause-specificmortality for 250 causes of death reference and alternativescenarios for 2016ndash40 for 195 countries and territoriesrdquo +eLancet vol 392 no 10159 pp 2052ndash2090 2017
[4] L Zhang F Wang L Wang et al ldquoPrevalence of chronickidney disease in China a cross-sectional surveyrdquo+e Lancetvol 379 no 9818 pp 815ndash822 2012
[5] X Li and HWang ldquoChinese herbal medicine in the treatmentof chronic kidney diseaserdquo Advances in Chronic KidneyDisease vol 12 no 3 pp 276ndash281 2005
[6] Q Zhang L Zhu and W Lerberghe ldquoe importance oftraditional Chinese medicine services in health care provisionin Chinardquo Universitas Forum vol 2 no 2 pp 1ndash8 2011
[7] Y J Wang L Q He W Sun et al ldquoOptimized project oftraditional Chinese medicine in treating chronic kidneydisease stage 3 a multicenter double-blinded randomizedcontrolled trialrdquo Journal of Ethnopharmacology vol 139no 3 pp 757ndash764 2012
[8] Y Chen Y Deng Z Ni et al ldquoEfficacy and safety of tradi-tional Chinese medicine (Shenqi particle) for patients withidiopathic membranous nephropathy a multicenter ran-domized controlled clinical trialrdquo American Journal of KidneyDiseases vol 62 no 6 pp 1068ndash1076 2013
[9] L Zhang P Li C Y Xing et al ldquoEfficacy and safety of Abel-moschus manihot for primary glomerular disease a prospectivemulticenter randomized controlled clinical trialrdquo AmericanJournal of Kidney Diseases vol 64 no 1 pp 57ndash65 2014
[10] W Li W He P Xia et al ldquoTotal extracts of abelmoschusmanihot L Attenuates adriamycin-induced renal tubule
injury via suppression of ROS-ERK12-mediated NLRP3inflammasome activationrdquo Frontiers in Pharmacology vol 10p 567 2019
[11] X Zhang X Zhou R Zhang et al ldquoReal-world clinical datamining on TCM clinical diagnosis and treatment a surveyrdquo inProceedings of the IEEE International Conference on E-HealthNetworking IEEE Beijing China October 2012
[12] L Chen C Y Lee K H Huang Y H Kuan and M ChenldquoPrescription patterns of Chinese herbal products for patientswith sleep disorder and major depressive disorder in TaiwanrdquoJournal of Ethnopharmacology vol 171 pp 307ndash316 2015
[13] J Cao ldquoe Common prescription patterns based on thehierarchical clustering of herb-pairs efficaciesrdquo Evidence-Based Complementary and Alternative Medicine vol 2016Article ID 6373270 7 pages 2016
[14] C J Hu J He J D Xie et al ldquoResearch on TCM treatment oflung cancer based on complex networks methodrdquo Journal ofMedical Informatics vol 39 no 11 pp 63ndash68 2018 inChinese
[15] National Pharmacopoeia Commission Pharmacopoeia of thePeoplersquos Republic of China China Medical Science andTechnology Press Bejing China 2010 in Chinese
[16] Chinese Materia Medica Commission of National Adminis-tration of Traditional Chinese Medicine Chinese MateriaMedica Shanghai Science and Technology Press ShanghaiChina 1999 in Chinese
[17] J Pang J Fu M Yang et al ldquoCorrelation between the dif-ferent therapeutic properties of Chinese medicinal herbs anddelayed luminescencerdquo Luminescence vol 31 no 2pp 323ndash327 2016
[18] X M Chen Z H Ni Y N Liu et al ldquoGuidelines for thediagnosis and treatment of chronic renal failure with inte-grated traditional Chinese and Western medicinerdquo HebeiTraditional ChineseMedicine vol 38 no 2 pp 313ndash317 2016in Chinese
[19] Y Q Zou and E C Zhou ldquoSummary of differentiation andtreatment of traditional Chinese medicine nephropathyrdquoJiangsu Journal of Traditional Chinese Medicine vol 50 no 1pp 1ndash5 2018 in Chinese
[20] Y Qiao L Xu X Tao et al ldquoProtective effects of dioscinagainst fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress fibrosis lipid metabolism and in-flammationrdquo Toxicology Letters vol 284 pp 37ndash45 2018
[21] J Su Y Wei M Liu et al ldquoAnti-hyperuricemic and neph-roprotective effects of Rhizoma Dioscoreae septemlobae ex-tracts and its main component dioscin via regulation ofmOAT1 mURAT1 and mOCT2 in hypertensive micerdquo Ar-chives of Pharmacal Research vol 37 no 10 pp 1336ndash13442014
[22] J H Ye M H Liu X L Zhang et al ldquoChemical profiles andprotective effect of Hedyotis diffusa Willd in lipopolysac-charide-induced renal inflammation micerdquo InternationalJournal of Molecular Sciences vol 16 no 11 pp 27252ndash272692015
[23] X B Sun and N N Yu ldquoRoot of Snow of June for treatingkidney diseasesrdquo Chinese Medicine Guide vol 19 no 10pp 127-128 2013 in Chinese
[24] W Zhang Z X Lin C Xu C Leung and L S ChanldquoAstragalus (a traditional Chinese medicine) for treatingchronic kidney diseaserdquo Cochrane Database of SystematicReviews vol 10 2014
[25] S Ren H Zhang Y Mu et al ldquoPharmacological effects ofAstragaloside IV a literature reviewrdquo Journal of TraditionalChinese Medicine vol 33 no 3 pp 413ndash416 2013
Evidence-Based Complementary and Alternative Medicine 13
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
medicine (TCM) [5] which is perceived as a cost-effectivealternative medicine TCM originated in ancient China andhas continued to evolve for over 2500 years Notably it haslong been used to treat kidney disease [6] e effectivenessand safety of TCMhave progressed considerably over severaldecades especially in the case of some herbs and herbalcompounds prescribed for CKD treatment [7ndash10]
Syndrome differentiation and treatment are the core ofTCM in clinical practice ere are three basic principles forcuring disease with Chinese medicinal herbs eliminating thecause of illness dispelling pathogenic factors and restoringcoordination of the internal organs so that excess and deficientyin or yang can be corrected Most TCM prescriptions consistof more than two herbs According to the TCM theory severalherbs prescribed together are superior to a single herb fordisease treatment because the full extent of their advantages isrealized and their disadvantages are inhibited Differenttherapeutic effects may result from prescribing different herbsand herb combinations the toxicity of other coprescribedherbs may also be decreased In clinical practice it is necessaryto be flexible in modifying the formulae for Chinese medicinalherbs according to the condition of the illness and the status ofthe patient under the guidance of TCM compatibility prin-ciples e specific prescription reflects both the patientrsquoscharacteristics and the physicianrsquos experience Only when theprinciples are unified flexibly can the prescription be con-gruent with the syndromes to be treated en the expectedefficacy will be achieved us it is necessary to follow theprinciple but not adhere to the initially established formulaCollection and analysis of formulae are one of the essentialmethods for learning and passing on knowledge of TCMHowever flexible intervention is extremely complicated inclinical practice which causes considerable difficulties forclinical research It also limits TCM from further developingand becoming more widespread Many researchers and ne-phrologists are concerned about how to utilize TCM herbformulae safely and effectively in kidney disease Much at-tention has been paid to exploring the core herbs used in TCMfundamental therapy principles and prescription methodserefore interpretation of herbal formulae is expected to helpidentify the most effective herbs and improve the treatment ofkidney disease It should also contribute to the development ofnovel drugs for CKD treatment
Machine learning has been used to analyze the pre-scription patterns of Chinese medicine from clinical dataand to discover potential associations between Chinesemedicinal herbs and disease [11] At present data mining inthe field of TCM covers a wide range of conditions pre-scriptions cases and diagnostics Frequency statistics as-sociation rule learning cluster analysis and complexnetwork analysis are commonly used techniques [12ndash14]Scholars have surveyed clinical data from the NationalHealth Insurance Database and used frequency analysis andassociation rule learning to explore TCM treatment forinsomnia and depression ey showed the prescriptionpatterns of Chinese herbs for patients with sleep disorderandmajor depressive disorder [12] Another study was basedon hierarchical clustering of herbal effects and determinedstandard prescription rules combined with the theory of qi
and blood to explore the consistency of TCM theory andherbs [13] We previously designed a prescription recom-mendation algorithm based on the complex networkmethod to explore the core herbs for lung cancer treatment[14] It is important to note complex factors of TCM whichdo not meet the requirements of data mining clinical di-agnosis and treatment information various data structuresand high information dimensions erefore it is necessaryto determine a method that includes data cleansing and datamining
In this study we proposed an integrated analysis methodto extract and mine TCM medical records We collectedclinical cases in which patients were given herbal pre-scriptions by one of our hospitalrsquos TCM specialists ProfessorLijuan Gong en we analyzed prescriptions for CKDtreatment using association rule learning cluster analysisand complex networks to explore conventional TCM pre-scriptions the law of medication and potential core pre-scriptions We aimed to identify the main treatmentprinciple and herb prescriptions of TCM specialists for CKDtreatment using modern data computer technology
2 Materials and Methods
21 Data Source We retrospectively analyzed a patientsample from the Jiangsu Province Hospital of ChineseMedicine and determined the prevalence of prescribedChinese medicinal herbs in patients with CKD from 2011 to2016 CKD diagnosis was based on the National KidneyFoundation Kidney Disease Outcome Quality Initiative 2002guidelines and was defined as abnormalities in kidneystructure or function present for gt3 months or glomerularfiltration rate lt60mlmin173m2 Exclusion criteria were(1) acute kidney injury diagnosis (2) receiving renal re-placement therapy (3) incomplete prescription compositionor dosage and (4) not receiving herb formula treatment Intotal 299 prescriptions in 166 patients were enrolled in thisstudy e study procedures were approved by the ResearchEthics Committee of the Affiliated Hospital of NanjingUniversity of Chinese Medicine and performed in strictconformity with our institutional guidelines e detailedworkflow diagram is summarized in Figure 1
22 Data Processing
221 Data Collection We screened all the clinical infor-mation from the clinical cases of outpatients Patient in-formation was collected including age sex home addressdiagnosis and TCM diagnosis Herbal prescriptions at eachpatientrsquos first visit and subsequent follow-up visits wererecorded
222 Data Process e data processing methods mainlyincluded establishing the TCM knowledge base normalizingthe prescriptionrsquos content structure separating the com-pound medicine into individual herbs standardizing TCMterminology and correcting for manual error
2 Evidence-Based Complementary and Alternative Medicine
In brief we first established a Chinese medicinal herbknowledge base according to the Chinese Pharmacopoeiaand the Chinese Materia Medica [15 16] First we identifiedthe herbs in the prescriptions and unified them according tocontent structure based on the knowledge base Second weeliminated duplicate herbs and applied standardized ter-minology for the expression of the herbs en we extractedinformation on prescriptions and herbs All these data weretransferred to Microsoft Excel 2016 to establish a TCMnephrology database e information collection processwas confirmed by two researchers
23 Statistical Analysis All the data were processed byR-Studio Version 353 First we used the Apriori algorithmto analyze the association rules of the herbs Second hier-archical clustering was used to classify high-frequency herbsFinally complex network analysis was used to confirm thecore herbs prescribed for CKD treatment
231 Apriori Algorithm eApriori algorithm is a frequentitemset algorithm for mining association rules We used it toillustrate the specific rules of TCM in CKD treatment In ourdata each herb was treated as a variable A fixed combi-nation can be understood as a herb pair in TCM theory eformulae were as follows
support(X⟶ Y) σ(XcupY)
N
confidence(X⟶ Y) σ(XcupY)
σ(X)
lift(X⟶ Y) confidence(X⟶ Y)
σ(Y)
(1)
where X⟶ Y is an association rule X (left-hand side[LHS]) and Y (right-hand side [RHS]) represent the set ofherb items σ(X) is the frequency of itemset X XcupY is theunion of itemset X and Y σ(XcupY) is the frequency with
Text type
Word Text
Structurized type
Excel Database
Text structurenormalize
Contentstructure
normalization
Completion ofprescription
Removingduplicate herbs
Association rule Hierarchical clustering Complex network
The coprescription pattern and treatment principle and in CKD
Herbstandardization
Chinesepharmacopoeia
Chinese materiamedica
Figure 1 Data mining flowchart e integrated data mining method included data processing frequency statistics association rulescluster analysis and complex network analysis
Evidence-Based Complementary and Alternative Medicine 3
which itemset X and itemset Y appear together support(X⟶ Y) is the frequency with which X and Y appear togetherand confidence(X⟶ Y) is the probability that itemset Yappears in the presence of X e lift is the ratio of theprobability of itemset Y appearing in the presence of X to thefrequency of Y Support and confidence are often used toeliminate meaningless combinations lift is the validity of therules
232 Hierarchical Clustering Algorithm In the hierarchicalclustering algorithm each herb was regarded as a clusterand N clusters were combined to form a new class based on asimilarity measure between objects e Euclidean metricwas used to calculate the similarity between herbs theformula of which is
d(x y)
1113944n
k1xk minus yk( 1113857
2
11139741113972
(2)
Herbs used more than 30 times were extracted for wordclustering
233 Complex Network Analysis We used complex networkanalysis to confirm the core herb in each prescriptionComplex network analysis is used to analyze complex inter-action laws in complex systems in the real world based on anetwork model of nodes and edges e complexities ofdiseases and human life systems are gradually being recog-nized such that medical research from a network perspectivehas become an important topic in current medical researchWe regarded the constituent herbs for CKD treatment asnodes and connections between two herbs as edges us wecould rationalize all medical record data into a network of drugnodes and edges using Liquorice (a complex network analysistool) and the multiscale backbone algorithm
Node degree and confidence level are the keys to mea-suring the association between drugs Node degree is thenumber of edges connected to a node and the confidence levelrepresents the reliability of the data e multiscale backboneis a statistical model established by identifying significantedges the parts of the network that are retained are those inwhich the nodes are strongly associated We set the screeningcriteria as a node degree of 36 and a confidence level of 095
3 Results
31 CKD Patient Characteristics We analyzed 299 pre-scriptions of 166 patients with CKD Of the patients 66(397) were male and 100 (603) were female with a maleto female ratio of 1 151 Age ranged from 4 to 82 (mean4892plusmn 1769) years On the kidney disease spectrum mostpatients had glomerular disease hypertensive kidney dis-ease or diabetic kidney disease
32 Herb Frequency and Analysis We analyzed herb fre-quency in all prescriptions because formulae for Chinesemedicinal herbs usually consider two or more herbs Among
the 299 prescriptions 202 Chinese medicinal herbs appeared4123 times as shown in Table 1 e most frequently pre-scribed herb was Rhizoma Dioscoreae (Shanyao) whichappeared 231 times (frequency 773) e following mostfrequently prescribed herbs in descending order wereSpreadingHedyotis Herb (Baihuasheshecao) Root of Snow ofJune (Baimagu) Radix Astragali (Huangqi) Poria (Fulin)Rhizoma Atractylodis Macrocephalae (Baizhu) Radix Pseu-dostellariae (Taizishen) Fructus Corni (Shanzhuyu) RadixRehmanniae (Shengdihuang) Fructus Lycii (Gouqizi) FlosCarthami (Honghua) Common Sage Herb (Lizhicao) Per-icarpium Citri Reticulate (Chenpi) Cortex Phellodendri(Huangbai) Semen Coicis (Yiyiren) Rhizoma Imperatae(Baimaogen) and Rhizoma Anemarrhenae (Zhimu) esetop 17 most frequently prescribed herbs appeared more than78 times (frequency more than 25) ese results dem-onstrate that these were preferred herbs in CKD
33 Properties Tastes and Meridian Tropisms of HerbsWe analyzed the properties and tastes of the herbs AsFigure 2(a) shows the TCM properties were mainly beingwarm mild and cold We adopted five tastes for analysispungent sweet sour bitter and salty e herbs mainlytasted sweet followed by bitter (Figure 2(b)) Sweet taste hasnourishing harmonizing and moistening functions Bittertaste has the functions of clearing away dampness andpurging ese data indicate that nourishing and purgingwere the principal functions of TCM in CKD treatmentMeridian tropism refers to medicinal herbs that often andselectively produce therapeutic effects on specific parts of thehuman body e theory of meridian tropism plays a vitalrole in the clinical selection of Chinese medicinal herbs efrequency of a herbrsquos meridian tropism can be determined byclassification using a tree diagram Spleen Meridian of Foot-Taiyin Liver Meridian of Foot-Jueyi Lung Meridian ofHand-Taiyin Stomach Meridian of Foot-Yangming and
Table 1 Herbs appearing over 40 times in prescriptions
Herb Number FrequencyRhizoma Dioscoreae (Shanyao) 231 0773Spreading Hedyotis Herb(Baihuasheshecao) 196 0656
Root of Snow of June (Baimagu) 175 0585Radix Astragali (Huangqi) 174 0582Poria (Fulin) 166 0555Rhizoma Atractylodis Macrocephalae(Baizhu) 162 0542
4 Evidence-Based Complementary and Alternative Medicine
Kidney Meridian of Foot-Shaoyin Our results showed thattherapeutic effects were predominant for the kidney spleenliver and lung and reflected that TCM is holistic
34 Action Category of Herbs Chinese medicinal herbs havespecific efficacy and can be classified into different specificaction categories Table 2 details the categories and thefrequency with which herbs were classified into these cat-egories e top ten categories for CKD treatment weredeficiency-tonifying herbs heat-clearing herbs dampness-draining diuretic herbs hemostatic herbs astringent herbsqi-regulating herbs blood-activating and stasis-resolvingherbs cough-suppressing and panting-calming herbs ex-terior-releasing herbs and digestant herbs
35 Prescription Patterns of Chinese Medicinal HerbsCompatibility of Chinese medicinal herbs refers to thecombination of two or more herbs with a purpose based onclinical requirements and medicinal properties and actions
0
400
800
1200
1600Cold
Warm
MildCool
Hot
Properties of herbs
(a)
0500
10001500200025003000
Sweet
Bitter
Pungent
Sour
WeakAstringent
Salty
Flavors of herbs
(b)
Meridian tropism of herbs
SpleenLiverLung
StomachKidneyHeart
Large intestineBladderSmall intestine
GallbladderPericardiumTri-jiao
(c)
Figure 2 Property taste and meridian tropism of herbs (a) Herb properties All herbs in each prescription were analyzed using a radarchart divided into five categories (b) Herb taste Tastes were divided into six categories using a radar chart (c) Meridian tropism of herbsWe created a tree diagram of the meridian tropism of all herbs Different meridian tropisms are indicated by different colors as shown at thebottom of the diagram All images were analyzed using Microsoft Excel 2016
Table 2 Frequency of herb categories
Herb category Frequency Rate ()Deficiency-tonifying herbs 1233 2991Heat-clearing herbs 1027 2491Dampness-draining diuretic herbs 410 994Hemostatic herbs 198 48Astringent herbs 170 412Qi-regulating herbs 169 41Blood-activating and stasis-resolving herbs 162 393Cough-suppressing and panting-calmingherbs 151 366
Evidence-Based Complementary and Alternative Medicine 5
It is the primary clinical method of medicinal applicationand the basis of herbal formulae composition Here we useddata mining to assess the standard prescription patterns ofthe formulae for CKD treatment
351 Herb Pair Analysis In clinical practice paired usage ofChinese medicinal herbs is essential therapeutically andcomprises the herb prescription method us we analyzedherb pairs
First we used the Apriori algorithm to analyze the as-sociation rules of the herbs in all prescriptions We focusedon two parameters support and confidence level Supportwas set as ge30 and confidence level as ge85 [11] and a totalof 30 herb pairs and suitable association rules were obtainede detailed association rules are shown in Table 3 and thecorrelation rules are shown in Figure 3 As shown in Table 3Astragali Radix (Huangqi)gtRhizoma Dioscoreae (Sha-nyao) had the highest degree of support at 5151 Rhi-zoma Atractylodis Macrocephalae (Baizhu) Fructus Corni(Shanzhuyu)gtRhizoma Dioscoreae (Shanyao) had thehighest confidence level at 9588 and Poria (Fulin) RadixAstragali (Huangqi)gtRhizoma Atractylodis Macro-cephalae (Baizhu) had the highest degree of lift at 168
A grouping matrix diagram displaying the general dis-tribution of association rules grouped into categories withsimilar rules is shown in Figure 4 is diagram allows us tonot only extract the general rule but also more deeply searchfor and extract important rules with commonality among theassociation rulesX-axis is the LHS andY-axis is the RHSecirclersquos color depth indicates the degree of lift such that thedarker the color the higher the degree of lift e size of thecircle indicates the degree of support such that the larger thecircle the higher the degree of support We found three coreherbs of paired prescriptions Astragali Radix (Huangqi)Rhizoma Dioscoreae (Shanyao) and Rhizoma AtractylodisMacrocephalae (Baizhu) ese herbs were usually combinedwith other herbs such as Astragali Radix (Huangqi) pairedwith Fructus Corni (Shanzhuyu) Rhizoma Dioscoreae(Shanyao) paired with Spreading Hedyotis Herb (Baihua-sheshecao) and Rhizoma Atractylodis Macrocephalae(Baizhu) paired with Poria (Fulin) to strengthen the spleentonify the kidney and eliminate dampness-heat respectively
In Figure 3 association rules were determined with agraphics-based visualization technique using a vertex torepresent herbs and relationships e strength of the re-lationship is expressed in the color depth or the size of thevertex e graph includes Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis Herb (Baihuasheshecao) Root of Snowof June (Baimagu) Radix Astragali (Huangqi) Poria (Fulin)Rhizoma Atractylodis Macrocephalae (Baizhu) RadixPseudostellariae (Taizishen) and Fructus Corni (Shanz-huyu) Among these eight herbs Radix Astragali (Huangqi)and Rhizoma Atractylodis Macrocephalae (Baizhu) are atthe center of the association rule graph
352 Novel Prescriptions Analysis Cluster analysis aggre-gates herbs into categories based on data attributes eclustering algorithm is an unsupervised learning algorithm
that can directly extract valuable information from the inputdata objects without input of any prior knowledge It iswidely used for data mining in TCM and mainly used fordetermining the compatibility law between drugs to identifythe combination rule of different TCM therapeutic methodse advantage of this method is that it allows for discovery ofpotential new prescriptions for CKD treatment Here weanalyzed 32 core herbs that were prescribed more than 30times using hierarchical clustering According to classicTCM theory five categories were considered suitable in thisstudy Figure 5 shows the herbs belonging to each cluster
353 Core Prescription Analysis Chinese medicinal herbsare usually applied as a combination of core herbs and otherherbs To further analyze the role of various herbs and theircombinations in CKD treatment we used the complexnetwork method and found that the core herbs in CKDtreatment were Rhizoma Dioscoreae (Shanyao) SpreadingHedyotis Herb (Baihuasheshecao) Root of Snow of June(Baimagu) Radix Astragali (Huangqi) Poria (Fulin) Rhi-zoma Atractylodis Macrocephalae (Baizhu) Radix Pseu-dostellariae (Taizishen) and Fructus Corni (Shanzhuyu)(Figure 6)ese eight herbs were also found to be frequentlyprescribed for CKD treatment and appeared in the associ-ation rule graph ese results indicate that these Chinesemedicinal herbs may have not only an effect on CKDtreatment but also a united one
4 Discussion
is study determined effective herbal prescriptions forCKD treatment by proposing a comprehensive methodbased on clinical cases integration of association rulescluster analysis and complex network analysis
We analyzed herb frequency and the properties and ac-tions of herbs and assessed the compatibility rules betweendrugs Our data showed that the most frequently prescribedherbs were Rhizoma Dioscoreae (Shanyao) SpreadingHedyotis Herb (Baihuasheshecao) Root of Snow of June(Baimagu) Radix Astragali (Huangqi) Poria (Fulin) Rhi-zoma Atractylodis Macrocephalae (Baizhu) Radix Pseudos-tellariae (Taizishen) Fructus Corni (Shanzhuyu) RadixRehmanniae (Shengdihuang) and Fructus Lycii (Gouqizi)e properties of these herbs were mainly being warm mildand colde tastes of the herbs were mainly sweet and bittere herbs were generally distributed to spleen lung liver andkidney channels and most were deficiency-tonifying herbsheat-clearing herbs and dampness-draining diuretic herbse most frequently used combinations of herbs obtainedusing association rules were Radix Astragali (Huangqi) andRhizoma Dioscoreae (Shanyao) ere were three core herbsof paired prescriptions Rhizoma Atractylodis Macrocephalae(Baizhu) Radix Astragali (Huangqi) and Rhizoma Dio-scoreae (Shanyao) Cluster analysis was used to divide theherbs into five clusters Herbs in cluster 1 mainly targeted thespleen and lung herbs in cluster 2 were prescribed to nourishthe liver-kidney and to clear heat-dampness and herbs incluster 3 were prescribed for clearing heat cooling blood and
6 Evidence-Based Complementary and Alternative Medicine
Table 3 Association rules of herbs for CKD treatment
Evidence-Based Complementary and Alternative Medicine 7
clearing dampness Cluster 4 herbs were prescribed forregulating qi flow eliminating phlegm activating blood andpurging turbidity Herbs in cluster 5 were not frequently usedWe used the complex networkmethod to analyze interactionsbetween herbs and found that the core herbs were RhizomaDioscoreae (Shanyao) Spreading Hedyotis Herb (Baihua-sheshecao) Root of Snow of June (Baimagu) Radix Astragali(Huangqi) Poria (Fulin) Rhizoma Atractylodis Macro-cephalae (Baizhu) Radix Pseudostellariae (Taizishen) andFructus Corni (Shanzhuyu)
e properties and actions of Chinese medicinal herbsare the essential bases for the analysis and clinical use ofherbs ey are summarized in medical practice and basedon the theories of yin and yang zang-fu meridian tropismsand TCM therapeutic principles [17] Chinese medicinal
herb theory is usually summarized as four properties and fivetastes meridian tropism and so on In this study the herbalproperties for CKD treatment were mainly sweet and warmwhich have a replenishing effect e next most frequentlyprescribed herbs had bitter and cold properties whichgenerally have a clearing action us tonifying deficiencywas the most important CKD treatment followed byclearing and disinhibiting is finding reflects the conceptthat TCM replenishes missing substances and rids the bodyof excess substances to regulate the balance of the bodyMeridian tropism is a theory that helps in understanding theorientation of drug action In this study the herbs weregenerally prescribed to target the spleen liver lung stom-ach and kidney meridian (ie the zang-fu requiringtreatment) In one studyrsquos retrospective analysis the basic
Figure 3 Association rule combination matrix e association rule combination matrix was analyzed using R-studio 353 Sizeindicatesconfidence (0855ndash0959) and color indicates lift (1106ndash1667)
8 Evidence-Based Complementary and Alternative Medicine
syndromes of kidney disease were identified as spleen andkidney deficiency lung and kidney qi deficiency and liverand kidney yin deficiency [18] Our research further indi-cates the important role of the kidney spleen stomach liverand lung in nephropathy Similarly the efficacious herbswere mainly deficiency-tonifying herbs heat-clearing herbsand dampness-draining diuretic herbs us these were themain TCM treatments for CKD Conversely the therapeuticprinciple could be used to determine the pathogenesis of thedisease at is the pathogenic factors could be divided intoheat and dampness and deficiency may be mainly caused bythe kidney spleen lung and liver
We identified commonly used herbs and their combina-tions (Tables 1 and 3)emain herbs for CKD treatment wereRhizoma Dioscoreae (Shanyao) Radix Astragali (Huangqi)Poria (Fulin) Rhizoma Atractylodis Macrocephalae (Baizhu)Radix Pseudostellariae (Taizishen) and Fructus Corni(Shanzhuyu) these all have the function of replenishing
Specifically Rhizoma Dioscoreae (Shanyao) targets the spleenlung and kidney Radix Astragali (Huangqi) and RadixPseudostellariae (Taizishen) can supplement the lung andspleen Macrocephalae (Baizhu) and Poria (Fulin) are pre-scribed to invigorate the spleen and Fructus Corni (Shanz-huyu) can nourish the liver and kidney ese six drugs indifferent combinations comprised the 11 most frequentcombinations Among them the most frequent combinationsincluded Rhizoma Dioscoreae (Shanyao) Rhizoma Dioscor-eae (Shanyao) can treat all deficiency syndromes according toTCM theory and is important for tonifying deficiency usherb combinations showed that the tonifying-deficiency cat-egory was the most important for CKD treatment In TCMnephrology kidney deficiency is the basis of kidney diseaseand tonifying kidney treatment should be vital [19] Howeverour research showed that the methods of supplementing thelung and spleen and nourishing the liver and kidney weremore frequently used in CKD Tonifying the spleen lung or
Grouped matrix for 30 Rules Size support Color li
1 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Por
ia (F
ulin
) +1
item
s
3 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Rhi
zom
aAt
ract
ylod
is M
acro
ceph
alae
(Bai
zhu)
+2
item
s
6 ru
les
Por
ia (F
ulin
) Ra
dix
Astr
agal
i (H
uang
qi)
+2 it
ems
6 ru
les
Rhi
zom
a Atr
acty
lodi
s Mac
roce
phal
ae (B
aizh
u)
Fruc
tus C
orni
(Sha
nzhu
yu)
+2 it
ems
14 ru
les
Rad
ix P
seud
oste
llaria
e (Ta
izish
en)
Spre
adin
g H
edyo
tis H
erb(
Baih
uash
eshe
cao)
+5
item
s
Rhizoma Dioscoreae (Shanyao)
Radix Astragali (Huangqi)
Rhizoma Atractylodis Macrocephalae (Baizhu)
Item
s in
LHS
grou
p
RHS
Figure 4 Association rule diagram Association rule learning was performed using R-studio 353 X-axis is the antecedent (or calledlefthandside LHS) and Y-axis is the consequent (or called right-hand side RHS) Size indicates support and color indicates lift
Evidence-Based Complementary and Alternative Medicine 9
liver is well known to achieve the purpose of nourishing thekidney but herbs that tonify the kidney were not frequentlyprescribed in this researchis indicates that amultiple-organdisorder underlies the TCM pathogenesis of CKD When and
how to nourish the kidney directly or indirectly requiresfurther study In TCM practice tonifying-deficiency herbs areoften used in combination with heat-clearing and dampness-draining diuretic herbs Table 3 shows that two or more herbs
Poria (Fulin)
Radix Astragali (Huangqi)Rhizoma Atractylodis
Macrocephalae (Baizhu)
Fructus Corni (Shanzhuyu)
Radix Pseudostellariae (Taizishen)
Fructus Lycii (Gouqizi)
Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis
Herb (Baihuasheshecao)Root of Snow of June (Baimagu)
Rhizoma Imperatae (Baimaogen)
Radix Cirsii Japonici (Daji)
Herba Cirsii (Xiaoji)
Radix Rehmanniae (Shengdihuang)
Common Sage Herb (Lizhicao)
Rhizoma Smilacis Glabrae (Tufulin)
Cortex Phellodendri (Huangbai)
Rhizoma Anemarrhenae (Zhimu)
Pericarpium Citri Reticulatae (Chenpi)
Rhizoma Pinelliae (Banxia)
Semen Coicis (Yiyiren)
Flos Carthami (Honghua)
Radix et Rhizoma Rhei (Dahuang)
Herba Taxilli (Sangjisheng)
Cortex Eucommiae (Duzhong)
Corn Stigma (Yumixu)
Radix Codonopsis (Dangshen)
Radix Salviae Miltiorrhizae (Danshen)
Medicated Leaven (Shenqu)
Radix Saposhnikoviae (Fangfeng)
Radix Ophiopogonis (Maidong)
Herba Taraxaci (Pugongying)
Radix Glycyrrhizae (Gancao)
Cluster dendrogram
Height
Figure 5 Cluster analysis tree diagram e cluster analysis tree diagram was created using R-studio 353 e 32 most frequentlyprescribed herbs were analyzed Each category is represented by a different color
10 Evidence-Based Complementary and Alternative Medicine
were usually combined with Spreading Hedyotis Herb (Bai-huasheshecao) or Root of Snow of June (Baimagu) whichwerethe two most frequently used heat-clearing herbs anddampness-removing diuretic herbs Tonifying treatment wasalso indicated to be more important than heat-clearing ordampness-draining treatment How to balance tonifyingtreatment and clearing-diuresis treatment under specificconditions needs to be investigated further
e pathogenesis of kidney disease is complex and oftenmanifests as multiple syndrome combinationse formulaedetermined by clustering were for composite syndromesHerbs in cluster 1 were for tonifying the lung strengtheningthe spleen and removing dampness and were prescribed totreat spleen-lung qi deficiency and dampness Herbs incluster 2 were for nourishing the liver and kidney andclearing heat or dampness and were prescribed to treat liver-kidney yin deficiency and dampness or heat ose in cluster3 were for nourishing yin clearing heat and cooling bloodese herbs can be found in Zhi Bai Di Huang Wan and are
prescribed to treat fire excess from yin deficiency and blood-heat syndromeose in cluster 4 were for regulating qi floweliminating phlegm activating blood and purging turbidityey were prescribed to treat phlegm-damp blood stasisand turbidity syndromesese four clusters of prescriptionsfor different syndrome types can provide useful ideas forCKD treatment e herbs in cluster 5 had multiple func-tions such as tonifying the kidney releasing the exteriorand promoting digestion It may be used auxiliarily to targetcomplications and requires further study
Complex network analysis revealed eight core herbs forCKD Rhizoma Dioscoreae (Shanyao) Spreading HedyotisHerb (Baihuasheshecao) Root of Snow of June (Baimagu)Radix Astragali (Huangqi) Poria (Fulin) Rhizoma Atrac-tylodis Macrocephalae (Baizhu) Radix Pseudostellariae(Taizishen) and Fructus Corni (Shanzhuyu) Interestinglythese herbs are included in clusters 1 and 2 ey were alsoidentified as high-frequency herbs for CKD treatment so webelieved that such a prescription could be used as a basis for
Spreading Hedyotis
Herb
Fructus Corni
Rhizoma Dioscoreae
Root of Snow of
June
Poria Radix Astragali
Radix Pseudostellariae
Rhizoma Atractylodis
Macrocephalae
124
154
105
100
154
134
99
129
100
115
98
86
95 98
141
119
115
127
87
146
139
136
131
115
112
102
97
97
89
Figure 6 Core prescription network e core prescription network was created using Liquorice e weight represents the frequency withwhich two herbs appeared together
Evidence-Based Complementary and Alternative Medicine 11
further research Modern pharmacology has also shown thatthese herbs can improve kidney injury through anti-in-flammatory and antioxidant activity (Table 4) [20ndash29]
Our data mining approach has several advantages Firstthere was no requirement for the data structure is is verypractical for data mining of Chinese medicine prescriptionsbecause the data structure of most Chinese medicines is notuniform Second we combined a variety of data miningmethods to perform comprehensive analysis and to ensurethat the conclusion was reliable Finally we focused on themain treatment methods and uses of herbs which is anefficient way to learn TCM treatment Our research also hassome limitations We collected only prescription informa-tion but not diagnostic information so our conclusionscannot be completely confirmed We also examined onlyeffective treatment cases not invalid treatment cases sowhether a gap exists between these two case types remainsunclearus it is also unclear whether the core prescriptionshould be corrected Finally the safety and efficacy of thecore prescriptions were not evaluated and should be in-vestigated in a future study
In summary we adopted a practical approach based onformulae prescribed in clinical practice To our knowledgethis is the first study on CKD treatment with TCM whichcombines frequency analysis association rule learning andcomplex network analysis Using this approach we deter-mined the frequency and combination patterns of CKDtreatment and discovered possibilities for new CKD
treatment prescriptions We also summarized herbal CKDtreatment finding that CKD syndromes are extremelycomplicated and various CKD treatmentmethods exist suchas those for cooling blood and eliminating phlegm How-ever we found that the treatment methods were mainly fortonifying deficiency and clearing heat or dampness
5 Conclusions
Our study found that kidney spleen lung or liver deficiencyand dampness-heat were the primary TCM pathogenesisus the primary treatment principle was tonifying defi-ciency and eliminating dampness and heat Furthermoreour study verified that the integrated analysis method canhelp to explore the TCM treatment strategy is analysis ofherbal TCM prescriptions potentially contributes to thedevelopment of novel drugs for CKD
Data Availability
e data used to support the findings of this study are in-cluded within the article
Conflicts of Interest
e authors declare that there are no conflicts of interestregarding the publication of this article
Table 4 Possible mechanisms of the core Chinese medical herbs for CKD treatment
Increases catalase (CAT) superoxide dismutase(SOD) and glutathione peroxidase (GSH-px)
activities in the kidneys of diabetic rats as well asenhancing renal peroxisome proliferator-activatedreceptor-c (PPARc) expression in diabetic rats [28]
Radix Pseudostellariae (Taizishen) Polysaccharide
Decreases serum triglyceride total cholesterol low-density-lipoprotein cholesterin urea nitrogen andcreatinine increase serum high-density-lipoproteincholesterol and reduce renal histopathology change
[29]
12 Evidence-Based Complementary and Alternative Medicine
Authorsrsquo Contributions
Ping Xia and Kun Gao contributed equally to this studyWeiming He and Kun Gao designed the research Ping XiaMing Shi Wei Li Jing Zhao Jin Yan Qiong Liu Min ZhengXin Wang and Qijing Wu collected and processed the dataPing Xia and Jiadong Xie analyzed the data Wei Sun JihongChen Enchao Zhou and Lingdong Xv participated in in-tellectual discussions Ping Xia and Kun Gao wrote thepaper All authors approved the final edited version of themanuscript
Acknowledgments
is study was financially supported by the PostgraduateResearch amp Practice Innovation Program of Jiangsu Prov-ince (KYCX19_1189 to Ping Xia) and the National NaturalScience Foundation of China (81673912 and 81873259 toKun Gao 81804219 to Jiadong Xie and 81774269 toWeiming He) e authors gratefully acknowledge the as-sistance of Dr Buhui Liu their colleague in the AffiliatedHospital of Nanjing University of Chinese Medicine
References
[1] A Levin M Tonelli J Bonventre et al ldquoGlobal kidney health2017 and beyond a roadmap for closing gaps in care researchand policyrdquo +e Lancet vol 390 no 10105 pp 1888ndash19172017
[2] A C Webster E V Nagler R L Morton and P MassonldquoChronic kidney diseaserdquo +e Lancet vol 389 no 10075pp 1238ndash1252 2017
[3] K J Foreman N Marquez A Dolgert et al ldquoForecasting lifeexpectancy years of life lost and all-cause and cause-specificmortality for 250 causes of death reference and alternativescenarios for 2016ndash40 for 195 countries and territoriesrdquo +eLancet vol 392 no 10159 pp 2052ndash2090 2017
[4] L Zhang F Wang L Wang et al ldquoPrevalence of chronickidney disease in China a cross-sectional surveyrdquo+e Lancetvol 379 no 9818 pp 815ndash822 2012
[5] X Li and HWang ldquoChinese herbal medicine in the treatmentof chronic kidney diseaserdquo Advances in Chronic KidneyDisease vol 12 no 3 pp 276ndash281 2005
[6] Q Zhang L Zhu and W Lerberghe ldquoe importance oftraditional Chinese medicine services in health care provisionin Chinardquo Universitas Forum vol 2 no 2 pp 1ndash8 2011
[7] Y J Wang L Q He W Sun et al ldquoOptimized project oftraditional Chinese medicine in treating chronic kidneydisease stage 3 a multicenter double-blinded randomizedcontrolled trialrdquo Journal of Ethnopharmacology vol 139no 3 pp 757ndash764 2012
[8] Y Chen Y Deng Z Ni et al ldquoEfficacy and safety of tradi-tional Chinese medicine (Shenqi particle) for patients withidiopathic membranous nephropathy a multicenter ran-domized controlled clinical trialrdquo American Journal of KidneyDiseases vol 62 no 6 pp 1068ndash1076 2013
[9] L Zhang P Li C Y Xing et al ldquoEfficacy and safety of Abel-moschus manihot for primary glomerular disease a prospectivemulticenter randomized controlled clinical trialrdquo AmericanJournal of Kidney Diseases vol 64 no 1 pp 57ndash65 2014
[10] W Li W He P Xia et al ldquoTotal extracts of abelmoschusmanihot L Attenuates adriamycin-induced renal tubule
injury via suppression of ROS-ERK12-mediated NLRP3inflammasome activationrdquo Frontiers in Pharmacology vol 10p 567 2019
[11] X Zhang X Zhou R Zhang et al ldquoReal-world clinical datamining on TCM clinical diagnosis and treatment a surveyrdquo inProceedings of the IEEE International Conference on E-HealthNetworking IEEE Beijing China October 2012
[12] L Chen C Y Lee K H Huang Y H Kuan and M ChenldquoPrescription patterns of Chinese herbal products for patientswith sleep disorder and major depressive disorder in TaiwanrdquoJournal of Ethnopharmacology vol 171 pp 307ndash316 2015
[13] J Cao ldquoe Common prescription patterns based on thehierarchical clustering of herb-pairs efficaciesrdquo Evidence-Based Complementary and Alternative Medicine vol 2016Article ID 6373270 7 pages 2016
[14] C J Hu J He J D Xie et al ldquoResearch on TCM treatment oflung cancer based on complex networks methodrdquo Journal ofMedical Informatics vol 39 no 11 pp 63ndash68 2018 inChinese
[15] National Pharmacopoeia Commission Pharmacopoeia of thePeoplersquos Republic of China China Medical Science andTechnology Press Bejing China 2010 in Chinese
[16] Chinese Materia Medica Commission of National Adminis-tration of Traditional Chinese Medicine Chinese MateriaMedica Shanghai Science and Technology Press ShanghaiChina 1999 in Chinese
[17] J Pang J Fu M Yang et al ldquoCorrelation between the dif-ferent therapeutic properties of Chinese medicinal herbs anddelayed luminescencerdquo Luminescence vol 31 no 2pp 323ndash327 2016
[18] X M Chen Z H Ni Y N Liu et al ldquoGuidelines for thediagnosis and treatment of chronic renal failure with inte-grated traditional Chinese and Western medicinerdquo HebeiTraditional ChineseMedicine vol 38 no 2 pp 313ndash317 2016in Chinese
[19] Y Q Zou and E C Zhou ldquoSummary of differentiation andtreatment of traditional Chinese medicine nephropathyrdquoJiangsu Journal of Traditional Chinese Medicine vol 50 no 1pp 1ndash5 2018 in Chinese
[20] Y Qiao L Xu X Tao et al ldquoProtective effects of dioscinagainst fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress fibrosis lipid metabolism and in-flammationrdquo Toxicology Letters vol 284 pp 37ndash45 2018
[21] J Su Y Wei M Liu et al ldquoAnti-hyperuricemic and neph-roprotective effects of Rhizoma Dioscoreae septemlobae ex-tracts and its main component dioscin via regulation ofmOAT1 mURAT1 and mOCT2 in hypertensive micerdquo Ar-chives of Pharmacal Research vol 37 no 10 pp 1336ndash13442014
[22] J H Ye M H Liu X L Zhang et al ldquoChemical profiles andprotective effect of Hedyotis diffusa Willd in lipopolysac-charide-induced renal inflammation micerdquo InternationalJournal of Molecular Sciences vol 16 no 11 pp 27252ndash272692015
[23] X B Sun and N N Yu ldquoRoot of Snow of June for treatingkidney diseasesrdquo Chinese Medicine Guide vol 19 no 10pp 127-128 2013 in Chinese
[24] W Zhang Z X Lin C Xu C Leung and L S ChanldquoAstragalus (a traditional Chinese medicine) for treatingchronic kidney diseaserdquo Cochrane Database of SystematicReviews vol 10 2014
[25] S Ren H Zhang Y Mu et al ldquoPharmacological effects ofAstragaloside IV a literature reviewrdquo Journal of TraditionalChinese Medicine vol 33 no 3 pp 413ndash416 2013
Evidence-Based Complementary and Alternative Medicine 13
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
In brief we first established a Chinese medicinal herbknowledge base according to the Chinese Pharmacopoeiaand the Chinese Materia Medica [15 16] First we identifiedthe herbs in the prescriptions and unified them according tocontent structure based on the knowledge base Second weeliminated duplicate herbs and applied standardized ter-minology for the expression of the herbs en we extractedinformation on prescriptions and herbs All these data weretransferred to Microsoft Excel 2016 to establish a TCMnephrology database e information collection processwas confirmed by two researchers
23 Statistical Analysis All the data were processed byR-Studio Version 353 First we used the Apriori algorithmto analyze the association rules of the herbs Second hier-archical clustering was used to classify high-frequency herbsFinally complex network analysis was used to confirm thecore herbs prescribed for CKD treatment
231 Apriori Algorithm eApriori algorithm is a frequentitemset algorithm for mining association rules We used it toillustrate the specific rules of TCM in CKD treatment In ourdata each herb was treated as a variable A fixed combi-nation can be understood as a herb pair in TCM theory eformulae were as follows
support(X⟶ Y) σ(XcupY)
N
confidence(X⟶ Y) σ(XcupY)
σ(X)
lift(X⟶ Y) confidence(X⟶ Y)
σ(Y)
(1)
where X⟶ Y is an association rule X (left-hand side[LHS]) and Y (right-hand side [RHS]) represent the set ofherb items σ(X) is the frequency of itemset X XcupY is theunion of itemset X and Y σ(XcupY) is the frequency with
Text type
Word Text
Structurized type
Excel Database
Text structurenormalize
Contentstructure
normalization
Completion ofprescription
Removingduplicate herbs
Association rule Hierarchical clustering Complex network
The coprescription pattern and treatment principle and in CKD
Herbstandardization
Chinesepharmacopoeia
Chinese materiamedica
Figure 1 Data mining flowchart e integrated data mining method included data processing frequency statistics association rulescluster analysis and complex network analysis
Evidence-Based Complementary and Alternative Medicine 3
which itemset X and itemset Y appear together support(X⟶ Y) is the frequency with which X and Y appear togetherand confidence(X⟶ Y) is the probability that itemset Yappears in the presence of X e lift is the ratio of theprobability of itemset Y appearing in the presence of X to thefrequency of Y Support and confidence are often used toeliminate meaningless combinations lift is the validity of therules
232 Hierarchical Clustering Algorithm In the hierarchicalclustering algorithm each herb was regarded as a clusterand N clusters were combined to form a new class based on asimilarity measure between objects e Euclidean metricwas used to calculate the similarity between herbs theformula of which is
d(x y)
1113944n
k1xk minus yk( 1113857
2
11139741113972
(2)
Herbs used more than 30 times were extracted for wordclustering
233 Complex Network Analysis We used complex networkanalysis to confirm the core herb in each prescriptionComplex network analysis is used to analyze complex inter-action laws in complex systems in the real world based on anetwork model of nodes and edges e complexities ofdiseases and human life systems are gradually being recog-nized such that medical research from a network perspectivehas become an important topic in current medical researchWe regarded the constituent herbs for CKD treatment asnodes and connections between two herbs as edges us wecould rationalize all medical record data into a network of drugnodes and edges using Liquorice (a complex network analysistool) and the multiscale backbone algorithm
Node degree and confidence level are the keys to mea-suring the association between drugs Node degree is thenumber of edges connected to a node and the confidence levelrepresents the reliability of the data e multiscale backboneis a statistical model established by identifying significantedges the parts of the network that are retained are those inwhich the nodes are strongly associated We set the screeningcriteria as a node degree of 36 and a confidence level of 095
3 Results
31 CKD Patient Characteristics We analyzed 299 pre-scriptions of 166 patients with CKD Of the patients 66(397) were male and 100 (603) were female with a maleto female ratio of 1 151 Age ranged from 4 to 82 (mean4892plusmn 1769) years On the kidney disease spectrum mostpatients had glomerular disease hypertensive kidney dis-ease or diabetic kidney disease
32 Herb Frequency and Analysis We analyzed herb fre-quency in all prescriptions because formulae for Chinesemedicinal herbs usually consider two or more herbs Among
the 299 prescriptions 202 Chinese medicinal herbs appeared4123 times as shown in Table 1 e most frequently pre-scribed herb was Rhizoma Dioscoreae (Shanyao) whichappeared 231 times (frequency 773) e following mostfrequently prescribed herbs in descending order wereSpreadingHedyotis Herb (Baihuasheshecao) Root of Snow ofJune (Baimagu) Radix Astragali (Huangqi) Poria (Fulin)Rhizoma Atractylodis Macrocephalae (Baizhu) Radix Pseu-dostellariae (Taizishen) Fructus Corni (Shanzhuyu) RadixRehmanniae (Shengdihuang) Fructus Lycii (Gouqizi) FlosCarthami (Honghua) Common Sage Herb (Lizhicao) Per-icarpium Citri Reticulate (Chenpi) Cortex Phellodendri(Huangbai) Semen Coicis (Yiyiren) Rhizoma Imperatae(Baimaogen) and Rhizoma Anemarrhenae (Zhimu) esetop 17 most frequently prescribed herbs appeared more than78 times (frequency more than 25) ese results dem-onstrate that these were preferred herbs in CKD
33 Properties Tastes and Meridian Tropisms of HerbsWe analyzed the properties and tastes of the herbs AsFigure 2(a) shows the TCM properties were mainly beingwarm mild and cold We adopted five tastes for analysispungent sweet sour bitter and salty e herbs mainlytasted sweet followed by bitter (Figure 2(b)) Sweet taste hasnourishing harmonizing and moistening functions Bittertaste has the functions of clearing away dampness andpurging ese data indicate that nourishing and purgingwere the principal functions of TCM in CKD treatmentMeridian tropism refers to medicinal herbs that often andselectively produce therapeutic effects on specific parts of thehuman body e theory of meridian tropism plays a vitalrole in the clinical selection of Chinese medicinal herbs efrequency of a herbrsquos meridian tropism can be determined byclassification using a tree diagram Spleen Meridian of Foot-Taiyin Liver Meridian of Foot-Jueyi Lung Meridian ofHand-Taiyin Stomach Meridian of Foot-Yangming and
Table 1 Herbs appearing over 40 times in prescriptions
Herb Number FrequencyRhizoma Dioscoreae (Shanyao) 231 0773Spreading Hedyotis Herb(Baihuasheshecao) 196 0656
Root of Snow of June (Baimagu) 175 0585Radix Astragali (Huangqi) 174 0582Poria (Fulin) 166 0555Rhizoma Atractylodis Macrocephalae(Baizhu) 162 0542
4 Evidence-Based Complementary and Alternative Medicine
Kidney Meridian of Foot-Shaoyin Our results showed thattherapeutic effects were predominant for the kidney spleenliver and lung and reflected that TCM is holistic
34 Action Category of Herbs Chinese medicinal herbs havespecific efficacy and can be classified into different specificaction categories Table 2 details the categories and thefrequency with which herbs were classified into these cat-egories e top ten categories for CKD treatment weredeficiency-tonifying herbs heat-clearing herbs dampness-draining diuretic herbs hemostatic herbs astringent herbsqi-regulating herbs blood-activating and stasis-resolvingherbs cough-suppressing and panting-calming herbs ex-terior-releasing herbs and digestant herbs
35 Prescription Patterns of Chinese Medicinal HerbsCompatibility of Chinese medicinal herbs refers to thecombination of two or more herbs with a purpose based onclinical requirements and medicinal properties and actions
0
400
800
1200
1600Cold
Warm
MildCool
Hot
Properties of herbs
(a)
0500
10001500200025003000
Sweet
Bitter
Pungent
Sour
WeakAstringent
Salty
Flavors of herbs
(b)
Meridian tropism of herbs
SpleenLiverLung
StomachKidneyHeart
Large intestineBladderSmall intestine
GallbladderPericardiumTri-jiao
(c)
Figure 2 Property taste and meridian tropism of herbs (a) Herb properties All herbs in each prescription were analyzed using a radarchart divided into five categories (b) Herb taste Tastes were divided into six categories using a radar chart (c) Meridian tropism of herbsWe created a tree diagram of the meridian tropism of all herbs Different meridian tropisms are indicated by different colors as shown at thebottom of the diagram All images were analyzed using Microsoft Excel 2016
Table 2 Frequency of herb categories
Herb category Frequency Rate ()Deficiency-tonifying herbs 1233 2991Heat-clearing herbs 1027 2491Dampness-draining diuretic herbs 410 994Hemostatic herbs 198 48Astringent herbs 170 412Qi-regulating herbs 169 41Blood-activating and stasis-resolving herbs 162 393Cough-suppressing and panting-calmingherbs 151 366
Evidence-Based Complementary and Alternative Medicine 5
It is the primary clinical method of medicinal applicationand the basis of herbal formulae composition Here we useddata mining to assess the standard prescription patterns ofthe formulae for CKD treatment
351 Herb Pair Analysis In clinical practice paired usage ofChinese medicinal herbs is essential therapeutically andcomprises the herb prescription method us we analyzedherb pairs
First we used the Apriori algorithm to analyze the as-sociation rules of the herbs in all prescriptions We focusedon two parameters support and confidence level Supportwas set as ge30 and confidence level as ge85 [11] and a totalof 30 herb pairs and suitable association rules were obtainede detailed association rules are shown in Table 3 and thecorrelation rules are shown in Figure 3 As shown in Table 3Astragali Radix (Huangqi)gtRhizoma Dioscoreae (Sha-nyao) had the highest degree of support at 5151 Rhi-zoma Atractylodis Macrocephalae (Baizhu) Fructus Corni(Shanzhuyu)gtRhizoma Dioscoreae (Shanyao) had thehighest confidence level at 9588 and Poria (Fulin) RadixAstragali (Huangqi)gtRhizoma Atractylodis Macro-cephalae (Baizhu) had the highest degree of lift at 168
A grouping matrix diagram displaying the general dis-tribution of association rules grouped into categories withsimilar rules is shown in Figure 4 is diagram allows us tonot only extract the general rule but also more deeply searchfor and extract important rules with commonality among theassociation rulesX-axis is the LHS andY-axis is the RHSecirclersquos color depth indicates the degree of lift such that thedarker the color the higher the degree of lift e size of thecircle indicates the degree of support such that the larger thecircle the higher the degree of support We found three coreherbs of paired prescriptions Astragali Radix (Huangqi)Rhizoma Dioscoreae (Shanyao) and Rhizoma AtractylodisMacrocephalae (Baizhu) ese herbs were usually combinedwith other herbs such as Astragali Radix (Huangqi) pairedwith Fructus Corni (Shanzhuyu) Rhizoma Dioscoreae(Shanyao) paired with Spreading Hedyotis Herb (Baihua-sheshecao) and Rhizoma Atractylodis Macrocephalae(Baizhu) paired with Poria (Fulin) to strengthen the spleentonify the kidney and eliminate dampness-heat respectively
In Figure 3 association rules were determined with agraphics-based visualization technique using a vertex torepresent herbs and relationships e strength of the re-lationship is expressed in the color depth or the size of thevertex e graph includes Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis Herb (Baihuasheshecao) Root of Snowof June (Baimagu) Radix Astragali (Huangqi) Poria (Fulin)Rhizoma Atractylodis Macrocephalae (Baizhu) RadixPseudostellariae (Taizishen) and Fructus Corni (Shanz-huyu) Among these eight herbs Radix Astragali (Huangqi)and Rhizoma Atractylodis Macrocephalae (Baizhu) are atthe center of the association rule graph
352 Novel Prescriptions Analysis Cluster analysis aggre-gates herbs into categories based on data attributes eclustering algorithm is an unsupervised learning algorithm
that can directly extract valuable information from the inputdata objects without input of any prior knowledge It iswidely used for data mining in TCM and mainly used fordetermining the compatibility law between drugs to identifythe combination rule of different TCM therapeutic methodse advantage of this method is that it allows for discovery ofpotential new prescriptions for CKD treatment Here weanalyzed 32 core herbs that were prescribed more than 30times using hierarchical clustering According to classicTCM theory five categories were considered suitable in thisstudy Figure 5 shows the herbs belonging to each cluster
353 Core Prescription Analysis Chinese medicinal herbsare usually applied as a combination of core herbs and otherherbs To further analyze the role of various herbs and theircombinations in CKD treatment we used the complexnetwork method and found that the core herbs in CKDtreatment were Rhizoma Dioscoreae (Shanyao) SpreadingHedyotis Herb (Baihuasheshecao) Root of Snow of June(Baimagu) Radix Astragali (Huangqi) Poria (Fulin) Rhi-zoma Atractylodis Macrocephalae (Baizhu) Radix Pseu-dostellariae (Taizishen) and Fructus Corni (Shanzhuyu)(Figure 6)ese eight herbs were also found to be frequentlyprescribed for CKD treatment and appeared in the associ-ation rule graph ese results indicate that these Chinesemedicinal herbs may have not only an effect on CKDtreatment but also a united one
4 Discussion
is study determined effective herbal prescriptions forCKD treatment by proposing a comprehensive methodbased on clinical cases integration of association rulescluster analysis and complex network analysis
We analyzed herb frequency and the properties and ac-tions of herbs and assessed the compatibility rules betweendrugs Our data showed that the most frequently prescribedherbs were Rhizoma Dioscoreae (Shanyao) SpreadingHedyotis Herb (Baihuasheshecao) Root of Snow of June(Baimagu) Radix Astragali (Huangqi) Poria (Fulin) Rhi-zoma Atractylodis Macrocephalae (Baizhu) Radix Pseudos-tellariae (Taizishen) Fructus Corni (Shanzhuyu) RadixRehmanniae (Shengdihuang) and Fructus Lycii (Gouqizi)e properties of these herbs were mainly being warm mildand colde tastes of the herbs were mainly sweet and bittere herbs were generally distributed to spleen lung liver andkidney channels and most were deficiency-tonifying herbsheat-clearing herbs and dampness-draining diuretic herbse most frequently used combinations of herbs obtainedusing association rules were Radix Astragali (Huangqi) andRhizoma Dioscoreae (Shanyao) ere were three core herbsof paired prescriptions Rhizoma Atractylodis Macrocephalae(Baizhu) Radix Astragali (Huangqi) and Rhizoma Dio-scoreae (Shanyao) Cluster analysis was used to divide theherbs into five clusters Herbs in cluster 1 mainly targeted thespleen and lung herbs in cluster 2 were prescribed to nourishthe liver-kidney and to clear heat-dampness and herbs incluster 3 were prescribed for clearing heat cooling blood and
6 Evidence-Based Complementary and Alternative Medicine
Table 3 Association rules of herbs for CKD treatment
Evidence-Based Complementary and Alternative Medicine 7
clearing dampness Cluster 4 herbs were prescribed forregulating qi flow eliminating phlegm activating blood andpurging turbidity Herbs in cluster 5 were not frequently usedWe used the complex networkmethod to analyze interactionsbetween herbs and found that the core herbs were RhizomaDioscoreae (Shanyao) Spreading Hedyotis Herb (Baihua-sheshecao) Root of Snow of June (Baimagu) Radix Astragali(Huangqi) Poria (Fulin) Rhizoma Atractylodis Macro-cephalae (Baizhu) Radix Pseudostellariae (Taizishen) andFructus Corni (Shanzhuyu)
e properties and actions of Chinese medicinal herbsare the essential bases for the analysis and clinical use ofherbs ey are summarized in medical practice and basedon the theories of yin and yang zang-fu meridian tropismsand TCM therapeutic principles [17] Chinese medicinal
herb theory is usually summarized as four properties and fivetastes meridian tropism and so on In this study the herbalproperties for CKD treatment were mainly sweet and warmwhich have a replenishing effect e next most frequentlyprescribed herbs had bitter and cold properties whichgenerally have a clearing action us tonifying deficiencywas the most important CKD treatment followed byclearing and disinhibiting is finding reflects the conceptthat TCM replenishes missing substances and rids the bodyof excess substances to regulate the balance of the bodyMeridian tropism is a theory that helps in understanding theorientation of drug action In this study the herbs weregenerally prescribed to target the spleen liver lung stom-ach and kidney meridian (ie the zang-fu requiringtreatment) In one studyrsquos retrospective analysis the basic
Figure 3 Association rule combination matrix e association rule combination matrix was analyzed using R-studio 353 Sizeindicatesconfidence (0855ndash0959) and color indicates lift (1106ndash1667)
8 Evidence-Based Complementary and Alternative Medicine
syndromes of kidney disease were identified as spleen andkidney deficiency lung and kidney qi deficiency and liverand kidney yin deficiency [18] Our research further indi-cates the important role of the kidney spleen stomach liverand lung in nephropathy Similarly the efficacious herbswere mainly deficiency-tonifying herbs heat-clearing herbsand dampness-draining diuretic herbs us these were themain TCM treatments for CKD Conversely the therapeuticprinciple could be used to determine the pathogenesis of thedisease at is the pathogenic factors could be divided intoheat and dampness and deficiency may be mainly caused bythe kidney spleen lung and liver
We identified commonly used herbs and their combina-tions (Tables 1 and 3)emain herbs for CKD treatment wereRhizoma Dioscoreae (Shanyao) Radix Astragali (Huangqi)Poria (Fulin) Rhizoma Atractylodis Macrocephalae (Baizhu)Radix Pseudostellariae (Taizishen) and Fructus Corni(Shanzhuyu) these all have the function of replenishing
Specifically Rhizoma Dioscoreae (Shanyao) targets the spleenlung and kidney Radix Astragali (Huangqi) and RadixPseudostellariae (Taizishen) can supplement the lung andspleen Macrocephalae (Baizhu) and Poria (Fulin) are pre-scribed to invigorate the spleen and Fructus Corni (Shanz-huyu) can nourish the liver and kidney ese six drugs indifferent combinations comprised the 11 most frequentcombinations Among them the most frequent combinationsincluded Rhizoma Dioscoreae (Shanyao) Rhizoma Dioscor-eae (Shanyao) can treat all deficiency syndromes according toTCM theory and is important for tonifying deficiency usherb combinations showed that the tonifying-deficiency cat-egory was the most important for CKD treatment In TCMnephrology kidney deficiency is the basis of kidney diseaseand tonifying kidney treatment should be vital [19] Howeverour research showed that the methods of supplementing thelung and spleen and nourishing the liver and kidney weremore frequently used in CKD Tonifying the spleen lung or
Grouped matrix for 30 Rules Size support Color li
1 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Por
ia (F
ulin
) +1
item
s
3 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Rhi
zom
aAt
ract
ylod
is M
acro
ceph
alae
(Bai
zhu)
+2
item
s
6 ru
les
Por
ia (F
ulin
) Ra
dix
Astr
agal
i (H
uang
qi)
+2 it
ems
6 ru
les
Rhi
zom
a Atr
acty
lodi
s Mac
roce
phal
ae (B
aizh
u)
Fruc
tus C
orni
(Sha
nzhu
yu)
+2 it
ems
14 ru
les
Rad
ix P
seud
oste
llaria
e (Ta
izish
en)
Spre
adin
g H
edyo
tis H
erb(
Baih
uash
eshe
cao)
+5
item
s
Rhizoma Dioscoreae (Shanyao)
Radix Astragali (Huangqi)
Rhizoma Atractylodis Macrocephalae (Baizhu)
Item
s in
LHS
grou
p
RHS
Figure 4 Association rule diagram Association rule learning was performed using R-studio 353 X-axis is the antecedent (or calledlefthandside LHS) and Y-axis is the consequent (or called right-hand side RHS) Size indicates support and color indicates lift
Evidence-Based Complementary and Alternative Medicine 9
liver is well known to achieve the purpose of nourishing thekidney but herbs that tonify the kidney were not frequentlyprescribed in this researchis indicates that amultiple-organdisorder underlies the TCM pathogenesis of CKD When and
how to nourish the kidney directly or indirectly requiresfurther study In TCM practice tonifying-deficiency herbs areoften used in combination with heat-clearing and dampness-draining diuretic herbs Table 3 shows that two or more herbs
Poria (Fulin)
Radix Astragali (Huangqi)Rhizoma Atractylodis
Macrocephalae (Baizhu)
Fructus Corni (Shanzhuyu)
Radix Pseudostellariae (Taizishen)
Fructus Lycii (Gouqizi)
Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis
Herb (Baihuasheshecao)Root of Snow of June (Baimagu)
Rhizoma Imperatae (Baimaogen)
Radix Cirsii Japonici (Daji)
Herba Cirsii (Xiaoji)
Radix Rehmanniae (Shengdihuang)
Common Sage Herb (Lizhicao)
Rhizoma Smilacis Glabrae (Tufulin)
Cortex Phellodendri (Huangbai)
Rhizoma Anemarrhenae (Zhimu)
Pericarpium Citri Reticulatae (Chenpi)
Rhizoma Pinelliae (Banxia)
Semen Coicis (Yiyiren)
Flos Carthami (Honghua)
Radix et Rhizoma Rhei (Dahuang)
Herba Taxilli (Sangjisheng)
Cortex Eucommiae (Duzhong)
Corn Stigma (Yumixu)
Radix Codonopsis (Dangshen)
Radix Salviae Miltiorrhizae (Danshen)
Medicated Leaven (Shenqu)
Radix Saposhnikoviae (Fangfeng)
Radix Ophiopogonis (Maidong)
Herba Taraxaci (Pugongying)
Radix Glycyrrhizae (Gancao)
Cluster dendrogram
Height
Figure 5 Cluster analysis tree diagram e cluster analysis tree diagram was created using R-studio 353 e 32 most frequentlyprescribed herbs were analyzed Each category is represented by a different color
10 Evidence-Based Complementary and Alternative Medicine
were usually combined with Spreading Hedyotis Herb (Bai-huasheshecao) or Root of Snow of June (Baimagu) whichwerethe two most frequently used heat-clearing herbs anddampness-removing diuretic herbs Tonifying treatment wasalso indicated to be more important than heat-clearing ordampness-draining treatment How to balance tonifyingtreatment and clearing-diuresis treatment under specificconditions needs to be investigated further
e pathogenesis of kidney disease is complex and oftenmanifests as multiple syndrome combinationse formulaedetermined by clustering were for composite syndromesHerbs in cluster 1 were for tonifying the lung strengtheningthe spleen and removing dampness and were prescribed totreat spleen-lung qi deficiency and dampness Herbs incluster 2 were for nourishing the liver and kidney andclearing heat or dampness and were prescribed to treat liver-kidney yin deficiency and dampness or heat ose in cluster3 were for nourishing yin clearing heat and cooling bloodese herbs can be found in Zhi Bai Di Huang Wan and are
prescribed to treat fire excess from yin deficiency and blood-heat syndromeose in cluster 4 were for regulating qi floweliminating phlegm activating blood and purging turbidityey were prescribed to treat phlegm-damp blood stasisand turbidity syndromesese four clusters of prescriptionsfor different syndrome types can provide useful ideas forCKD treatment e herbs in cluster 5 had multiple func-tions such as tonifying the kidney releasing the exteriorand promoting digestion It may be used auxiliarily to targetcomplications and requires further study
Complex network analysis revealed eight core herbs forCKD Rhizoma Dioscoreae (Shanyao) Spreading HedyotisHerb (Baihuasheshecao) Root of Snow of June (Baimagu)Radix Astragali (Huangqi) Poria (Fulin) Rhizoma Atrac-tylodis Macrocephalae (Baizhu) Radix Pseudostellariae(Taizishen) and Fructus Corni (Shanzhuyu) Interestinglythese herbs are included in clusters 1 and 2 ey were alsoidentified as high-frequency herbs for CKD treatment so webelieved that such a prescription could be used as a basis for
Spreading Hedyotis
Herb
Fructus Corni
Rhizoma Dioscoreae
Root of Snow of
June
Poria Radix Astragali
Radix Pseudostellariae
Rhizoma Atractylodis
Macrocephalae
124
154
105
100
154
134
99
129
100
115
98
86
95 98
141
119
115
127
87
146
139
136
131
115
112
102
97
97
89
Figure 6 Core prescription network e core prescription network was created using Liquorice e weight represents the frequency withwhich two herbs appeared together
Evidence-Based Complementary and Alternative Medicine 11
further research Modern pharmacology has also shown thatthese herbs can improve kidney injury through anti-in-flammatory and antioxidant activity (Table 4) [20ndash29]
Our data mining approach has several advantages Firstthere was no requirement for the data structure is is verypractical for data mining of Chinese medicine prescriptionsbecause the data structure of most Chinese medicines is notuniform Second we combined a variety of data miningmethods to perform comprehensive analysis and to ensurethat the conclusion was reliable Finally we focused on themain treatment methods and uses of herbs which is anefficient way to learn TCM treatment Our research also hassome limitations We collected only prescription informa-tion but not diagnostic information so our conclusionscannot be completely confirmed We also examined onlyeffective treatment cases not invalid treatment cases sowhether a gap exists between these two case types remainsunclearus it is also unclear whether the core prescriptionshould be corrected Finally the safety and efficacy of thecore prescriptions were not evaluated and should be in-vestigated in a future study
In summary we adopted a practical approach based onformulae prescribed in clinical practice To our knowledgethis is the first study on CKD treatment with TCM whichcombines frequency analysis association rule learning andcomplex network analysis Using this approach we deter-mined the frequency and combination patterns of CKDtreatment and discovered possibilities for new CKD
treatment prescriptions We also summarized herbal CKDtreatment finding that CKD syndromes are extremelycomplicated and various CKD treatmentmethods exist suchas those for cooling blood and eliminating phlegm How-ever we found that the treatment methods were mainly fortonifying deficiency and clearing heat or dampness
5 Conclusions
Our study found that kidney spleen lung or liver deficiencyand dampness-heat were the primary TCM pathogenesisus the primary treatment principle was tonifying defi-ciency and eliminating dampness and heat Furthermoreour study verified that the integrated analysis method canhelp to explore the TCM treatment strategy is analysis ofherbal TCM prescriptions potentially contributes to thedevelopment of novel drugs for CKD
Data Availability
e data used to support the findings of this study are in-cluded within the article
Conflicts of Interest
e authors declare that there are no conflicts of interestregarding the publication of this article
Table 4 Possible mechanisms of the core Chinese medical herbs for CKD treatment
Increases catalase (CAT) superoxide dismutase(SOD) and glutathione peroxidase (GSH-px)
activities in the kidneys of diabetic rats as well asenhancing renal peroxisome proliferator-activatedreceptor-c (PPARc) expression in diabetic rats [28]
Radix Pseudostellariae (Taizishen) Polysaccharide
Decreases serum triglyceride total cholesterol low-density-lipoprotein cholesterin urea nitrogen andcreatinine increase serum high-density-lipoproteincholesterol and reduce renal histopathology change
[29]
12 Evidence-Based Complementary and Alternative Medicine
Authorsrsquo Contributions
Ping Xia and Kun Gao contributed equally to this studyWeiming He and Kun Gao designed the research Ping XiaMing Shi Wei Li Jing Zhao Jin Yan Qiong Liu Min ZhengXin Wang and Qijing Wu collected and processed the dataPing Xia and Jiadong Xie analyzed the data Wei Sun JihongChen Enchao Zhou and Lingdong Xv participated in in-tellectual discussions Ping Xia and Kun Gao wrote thepaper All authors approved the final edited version of themanuscript
Acknowledgments
is study was financially supported by the PostgraduateResearch amp Practice Innovation Program of Jiangsu Prov-ince (KYCX19_1189 to Ping Xia) and the National NaturalScience Foundation of China (81673912 and 81873259 toKun Gao 81804219 to Jiadong Xie and 81774269 toWeiming He) e authors gratefully acknowledge the as-sistance of Dr Buhui Liu their colleague in the AffiliatedHospital of Nanjing University of Chinese Medicine
References
[1] A Levin M Tonelli J Bonventre et al ldquoGlobal kidney health2017 and beyond a roadmap for closing gaps in care researchand policyrdquo +e Lancet vol 390 no 10105 pp 1888ndash19172017
[2] A C Webster E V Nagler R L Morton and P MassonldquoChronic kidney diseaserdquo +e Lancet vol 389 no 10075pp 1238ndash1252 2017
[3] K J Foreman N Marquez A Dolgert et al ldquoForecasting lifeexpectancy years of life lost and all-cause and cause-specificmortality for 250 causes of death reference and alternativescenarios for 2016ndash40 for 195 countries and territoriesrdquo +eLancet vol 392 no 10159 pp 2052ndash2090 2017
[4] L Zhang F Wang L Wang et al ldquoPrevalence of chronickidney disease in China a cross-sectional surveyrdquo+e Lancetvol 379 no 9818 pp 815ndash822 2012
[5] X Li and HWang ldquoChinese herbal medicine in the treatmentof chronic kidney diseaserdquo Advances in Chronic KidneyDisease vol 12 no 3 pp 276ndash281 2005
[6] Q Zhang L Zhu and W Lerberghe ldquoe importance oftraditional Chinese medicine services in health care provisionin Chinardquo Universitas Forum vol 2 no 2 pp 1ndash8 2011
[7] Y J Wang L Q He W Sun et al ldquoOptimized project oftraditional Chinese medicine in treating chronic kidneydisease stage 3 a multicenter double-blinded randomizedcontrolled trialrdquo Journal of Ethnopharmacology vol 139no 3 pp 757ndash764 2012
[8] Y Chen Y Deng Z Ni et al ldquoEfficacy and safety of tradi-tional Chinese medicine (Shenqi particle) for patients withidiopathic membranous nephropathy a multicenter ran-domized controlled clinical trialrdquo American Journal of KidneyDiseases vol 62 no 6 pp 1068ndash1076 2013
[9] L Zhang P Li C Y Xing et al ldquoEfficacy and safety of Abel-moschus manihot for primary glomerular disease a prospectivemulticenter randomized controlled clinical trialrdquo AmericanJournal of Kidney Diseases vol 64 no 1 pp 57ndash65 2014
[10] W Li W He P Xia et al ldquoTotal extracts of abelmoschusmanihot L Attenuates adriamycin-induced renal tubule
injury via suppression of ROS-ERK12-mediated NLRP3inflammasome activationrdquo Frontiers in Pharmacology vol 10p 567 2019
[11] X Zhang X Zhou R Zhang et al ldquoReal-world clinical datamining on TCM clinical diagnosis and treatment a surveyrdquo inProceedings of the IEEE International Conference on E-HealthNetworking IEEE Beijing China October 2012
[12] L Chen C Y Lee K H Huang Y H Kuan and M ChenldquoPrescription patterns of Chinese herbal products for patientswith sleep disorder and major depressive disorder in TaiwanrdquoJournal of Ethnopharmacology vol 171 pp 307ndash316 2015
[13] J Cao ldquoe Common prescription patterns based on thehierarchical clustering of herb-pairs efficaciesrdquo Evidence-Based Complementary and Alternative Medicine vol 2016Article ID 6373270 7 pages 2016
[14] C J Hu J He J D Xie et al ldquoResearch on TCM treatment oflung cancer based on complex networks methodrdquo Journal ofMedical Informatics vol 39 no 11 pp 63ndash68 2018 inChinese
[15] National Pharmacopoeia Commission Pharmacopoeia of thePeoplersquos Republic of China China Medical Science andTechnology Press Bejing China 2010 in Chinese
[16] Chinese Materia Medica Commission of National Adminis-tration of Traditional Chinese Medicine Chinese MateriaMedica Shanghai Science and Technology Press ShanghaiChina 1999 in Chinese
[17] J Pang J Fu M Yang et al ldquoCorrelation between the dif-ferent therapeutic properties of Chinese medicinal herbs anddelayed luminescencerdquo Luminescence vol 31 no 2pp 323ndash327 2016
[18] X M Chen Z H Ni Y N Liu et al ldquoGuidelines for thediagnosis and treatment of chronic renal failure with inte-grated traditional Chinese and Western medicinerdquo HebeiTraditional ChineseMedicine vol 38 no 2 pp 313ndash317 2016in Chinese
[19] Y Q Zou and E C Zhou ldquoSummary of differentiation andtreatment of traditional Chinese medicine nephropathyrdquoJiangsu Journal of Traditional Chinese Medicine vol 50 no 1pp 1ndash5 2018 in Chinese
[20] Y Qiao L Xu X Tao et al ldquoProtective effects of dioscinagainst fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress fibrosis lipid metabolism and in-flammationrdquo Toxicology Letters vol 284 pp 37ndash45 2018
[21] J Su Y Wei M Liu et al ldquoAnti-hyperuricemic and neph-roprotective effects of Rhizoma Dioscoreae septemlobae ex-tracts and its main component dioscin via regulation ofmOAT1 mURAT1 and mOCT2 in hypertensive micerdquo Ar-chives of Pharmacal Research vol 37 no 10 pp 1336ndash13442014
[22] J H Ye M H Liu X L Zhang et al ldquoChemical profiles andprotective effect of Hedyotis diffusa Willd in lipopolysac-charide-induced renal inflammation micerdquo InternationalJournal of Molecular Sciences vol 16 no 11 pp 27252ndash272692015
[23] X B Sun and N N Yu ldquoRoot of Snow of June for treatingkidney diseasesrdquo Chinese Medicine Guide vol 19 no 10pp 127-128 2013 in Chinese
[24] W Zhang Z X Lin C Xu C Leung and L S ChanldquoAstragalus (a traditional Chinese medicine) for treatingchronic kidney diseaserdquo Cochrane Database of SystematicReviews vol 10 2014
[25] S Ren H Zhang Y Mu et al ldquoPharmacological effects ofAstragaloside IV a literature reviewrdquo Journal of TraditionalChinese Medicine vol 33 no 3 pp 413ndash416 2013
Evidence-Based Complementary and Alternative Medicine 13
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
which itemset X and itemset Y appear together support(X⟶ Y) is the frequency with which X and Y appear togetherand confidence(X⟶ Y) is the probability that itemset Yappears in the presence of X e lift is the ratio of theprobability of itemset Y appearing in the presence of X to thefrequency of Y Support and confidence are often used toeliminate meaningless combinations lift is the validity of therules
232 Hierarchical Clustering Algorithm In the hierarchicalclustering algorithm each herb was regarded as a clusterand N clusters were combined to form a new class based on asimilarity measure between objects e Euclidean metricwas used to calculate the similarity between herbs theformula of which is
d(x y)
1113944n
k1xk minus yk( 1113857
2
11139741113972
(2)
Herbs used more than 30 times were extracted for wordclustering
233 Complex Network Analysis We used complex networkanalysis to confirm the core herb in each prescriptionComplex network analysis is used to analyze complex inter-action laws in complex systems in the real world based on anetwork model of nodes and edges e complexities ofdiseases and human life systems are gradually being recog-nized such that medical research from a network perspectivehas become an important topic in current medical researchWe regarded the constituent herbs for CKD treatment asnodes and connections between two herbs as edges us wecould rationalize all medical record data into a network of drugnodes and edges using Liquorice (a complex network analysistool) and the multiscale backbone algorithm
Node degree and confidence level are the keys to mea-suring the association between drugs Node degree is thenumber of edges connected to a node and the confidence levelrepresents the reliability of the data e multiscale backboneis a statistical model established by identifying significantedges the parts of the network that are retained are those inwhich the nodes are strongly associated We set the screeningcriteria as a node degree of 36 and a confidence level of 095
3 Results
31 CKD Patient Characteristics We analyzed 299 pre-scriptions of 166 patients with CKD Of the patients 66(397) were male and 100 (603) were female with a maleto female ratio of 1 151 Age ranged from 4 to 82 (mean4892plusmn 1769) years On the kidney disease spectrum mostpatients had glomerular disease hypertensive kidney dis-ease or diabetic kidney disease
32 Herb Frequency and Analysis We analyzed herb fre-quency in all prescriptions because formulae for Chinesemedicinal herbs usually consider two or more herbs Among
the 299 prescriptions 202 Chinese medicinal herbs appeared4123 times as shown in Table 1 e most frequently pre-scribed herb was Rhizoma Dioscoreae (Shanyao) whichappeared 231 times (frequency 773) e following mostfrequently prescribed herbs in descending order wereSpreadingHedyotis Herb (Baihuasheshecao) Root of Snow ofJune (Baimagu) Radix Astragali (Huangqi) Poria (Fulin)Rhizoma Atractylodis Macrocephalae (Baizhu) Radix Pseu-dostellariae (Taizishen) Fructus Corni (Shanzhuyu) RadixRehmanniae (Shengdihuang) Fructus Lycii (Gouqizi) FlosCarthami (Honghua) Common Sage Herb (Lizhicao) Per-icarpium Citri Reticulate (Chenpi) Cortex Phellodendri(Huangbai) Semen Coicis (Yiyiren) Rhizoma Imperatae(Baimaogen) and Rhizoma Anemarrhenae (Zhimu) esetop 17 most frequently prescribed herbs appeared more than78 times (frequency more than 25) ese results dem-onstrate that these were preferred herbs in CKD
33 Properties Tastes and Meridian Tropisms of HerbsWe analyzed the properties and tastes of the herbs AsFigure 2(a) shows the TCM properties were mainly beingwarm mild and cold We adopted five tastes for analysispungent sweet sour bitter and salty e herbs mainlytasted sweet followed by bitter (Figure 2(b)) Sweet taste hasnourishing harmonizing and moistening functions Bittertaste has the functions of clearing away dampness andpurging ese data indicate that nourishing and purgingwere the principal functions of TCM in CKD treatmentMeridian tropism refers to medicinal herbs that often andselectively produce therapeutic effects on specific parts of thehuman body e theory of meridian tropism plays a vitalrole in the clinical selection of Chinese medicinal herbs efrequency of a herbrsquos meridian tropism can be determined byclassification using a tree diagram Spleen Meridian of Foot-Taiyin Liver Meridian of Foot-Jueyi Lung Meridian ofHand-Taiyin Stomach Meridian of Foot-Yangming and
Table 1 Herbs appearing over 40 times in prescriptions
Herb Number FrequencyRhizoma Dioscoreae (Shanyao) 231 0773Spreading Hedyotis Herb(Baihuasheshecao) 196 0656
Root of Snow of June (Baimagu) 175 0585Radix Astragali (Huangqi) 174 0582Poria (Fulin) 166 0555Rhizoma Atractylodis Macrocephalae(Baizhu) 162 0542
4 Evidence-Based Complementary and Alternative Medicine
Kidney Meridian of Foot-Shaoyin Our results showed thattherapeutic effects were predominant for the kidney spleenliver and lung and reflected that TCM is holistic
34 Action Category of Herbs Chinese medicinal herbs havespecific efficacy and can be classified into different specificaction categories Table 2 details the categories and thefrequency with which herbs were classified into these cat-egories e top ten categories for CKD treatment weredeficiency-tonifying herbs heat-clearing herbs dampness-draining diuretic herbs hemostatic herbs astringent herbsqi-regulating herbs blood-activating and stasis-resolvingherbs cough-suppressing and panting-calming herbs ex-terior-releasing herbs and digestant herbs
35 Prescription Patterns of Chinese Medicinal HerbsCompatibility of Chinese medicinal herbs refers to thecombination of two or more herbs with a purpose based onclinical requirements and medicinal properties and actions
0
400
800
1200
1600Cold
Warm
MildCool
Hot
Properties of herbs
(a)
0500
10001500200025003000
Sweet
Bitter
Pungent
Sour
WeakAstringent
Salty
Flavors of herbs
(b)
Meridian tropism of herbs
SpleenLiverLung
StomachKidneyHeart
Large intestineBladderSmall intestine
GallbladderPericardiumTri-jiao
(c)
Figure 2 Property taste and meridian tropism of herbs (a) Herb properties All herbs in each prescription were analyzed using a radarchart divided into five categories (b) Herb taste Tastes were divided into six categories using a radar chart (c) Meridian tropism of herbsWe created a tree diagram of the meridian tropism of all herbs Different meridian tropisms are indicated by different colors as shown at thebottom of the diagram All images were analyzed using Microsoft Excel 2016
Table 2 Frequency of herb categories
Herb category Frequency Rate ()Deficiency-tonifying herbs 1233 2991Heat-clearing herbs 1027 2491Dampness-draining diuretic herbs 410 994Hemostatic herbs 198 48Astringent herbs 170 412Qi-regulating herbs 169 41Blood-activating and stasis-resolving herbs 162 393Cough-suppressing and panting-calmingherbs 151 366
Evidence-Based Complementary and Alternative Medicine 5
It is the primary clinical method of medicinal applicationand the basis of herbal formulae composition Here we useddata mining to assess the standard prescription patterns ofthe formulae for CKD treatment
351 Herb Pair Analysis In clinical practice paired usage ofChinese medicinal herbs is essential therapeutically andcomprises the herb prescription method us we analyzedherb pairs
First we used the Apriori algorithm to analyze the as-sociation rules of the herbs in all prescriptions We focusedon two parameters support and confidence level Supportwas set as ge30 and confidence level as ge85 [11] and a totalof 30 herb pairs and suitable association rules were obtainede detailed association rules are shown in Table 3 and thecorrelation rules are shown in Figure 3 As shown in Table 3Astragali Radix (Huangqi)gtRhizoma Dioscoreae (Sha-nyao) had the highest degree of support at 5151 Rhi-zoma Atractylodis Macrocephalae (Baizhu) Fructus Corni(Shanzhuyu)gtRhizoma Dioscoreae (Shanyao) had thehighest confidence level at 9588 and Poria (Fulin) RadixAstragali (Huangqi)gtRhizoma Atractylodis Macro-cephalae (Baizhu) had the highest degree of lift at 168
A grouping matrix diagram displaying the general dis-tribution of association rules grouped into categories withsimilar rules is shown in Figure 4 is diagram allows us tonot only extract the general rule but also more deeply searchfor and extract important rules with commonality among theassociation rulesX-axis is the LHS andY-axis is the RHSecirclersquos color depth indicates the degree of lift such that thedarker the color the higher the degree of lift e size of thecircle indicates the degree of support such that the larger thecircle the higher the degree of support We found three coreherbs of paired prescriptions Astragali Radix (Huangqi)Rhizoma Dioscoreae (Shanyao) and Rhizoma AtractylodisMacrocephalae (Baizhu) ese herbs were usually combinedwith other herbs such as Astragali Radix (Huangqi) pairedwith Fructus Corni (Shanzhuyu) Rhizoma Dioscoreae(Shanyao) paired with Spreading Hedyotis Herb (Baihua-sheshecao) and Rhizoma Atractylodis Macrocephalae(Baizhu) paired with Poria (Fulin) to strengthen the spleentonify the kidney and eliminate dampness-heat respectively
In Figure 3 association rules were determined with agraphics-based visualization technique using a vertex torepresent herbs and relationships e strength of the re-lationship is expressed in the color depth or the size of thevertex e graph includes Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis Herb (Baihuasheshecao) Root of Snowof June (Baimagu) Radix Astragali (Huangqi) Poria (Fulin)Rhizoma Atractylodis Macrocephalae (Baizhu) RadixPseudostellariae (Taizishen) and Fructus Corni (Shanz-huyu) Among these eight herbs Radix Astragali (Huangqi)and Rhizoma Atractylodis Macrocephalae (Baizhu) are atthe center of the association rule graph
352 Novel Prescriptions Analysis Cluster analysis aggre-gates herbs into categories based on data attributes eclustering algorithm is an unsupervised learning algorithm
that can directly extract valuable information from the inputdata objects without input of any prior knowledge It iswidely used for data mining in TCM and mainly used fordetermining the compatibility law between drugs to identifythe combination rule of different TCM therapeutic methodse advantage of this method is that it allows for discovery ofpotential new prescriptions for CKD treatment Here weanalyzed 32 core herbs that were prescribed more than 30times using hierarchical clustering According to classicTCM theory five categories were considered suitable in thisstudy Figure 5 shows the herbs belonging to each cluster
353 Core Prescription Analysis Chinese medicinal herbsare usually applied as a combination of core herbs and otherherbs To further analyze the role of various herbs and theircombinations in CKD treatment we used the complexnetwork method and found that the core herbs in CKDtreatment were Rhizoma Dioscoreae (Shanyao) SpreadingHedyotis Herb (Baihuasheshecao) Root of Snow of June(Baimagu) Radix Astragali (Huangqi) Poria (Fulin) Rhi-zoma Atractylodis Macrocephalae (Baizhu) Radix Pseu-dostellariae (Taizishen) and Fructus Corni (Shanzhuyu)(Figure 6)ese eight herbs were also found to be frequentlyprescribed for CKD treatment and appeared in the associ-ation rule graph ese results indicate that these Chinesemedicinal herbs may have not only an effect on CKDtreatment but also a united one
4 Discussion
is study determined effective herbal prescriptions forCKD treatment by proposing a comprehensive methodbased on clinical cases integration of association rulescluster analysis and complex network analysis
We analyzed herb frequency and the properties and ac-tions of herbs and assessed the compatibility rules betweendrugs Our data showed that the most frequently prescribedherbs were Rhizoma Dioscoreae (Shanyao) SpreadingHedyotis Herb (Baihuasheshecao) Root of Snow of June(Baimagu) Radix Astragali (Huangqi) Poria (Fulin) Rhi-zoma Atractylodis Macrocephalae (Baizhu) Radix Pseudos-tellariae (Taizishen) Fructus Corni (Shanzhuyu) RadixRehmanniae (Shengdihuang) and Fructus Lycii (Gouqizi)e properties of these herbs were mainly being warm mildand colde tastes of the herbs were mainly sweet and bittere herbs were generally distributed to spleen lung liver andkidney channels and most were deficiency-tonifying herbsheat-clearing herbs and dampness-draining diuretic herbse most frequently used combinations of herbs obtainedusing association rules were Radix Astragali (Huangqi) andRhizoma Dioscoreae (Shanyao) ere were three core herbsof paired prescriptions Rhizoma Atractylodis Macrocephalae(Baizhu) Radix Astragali (Huangqi) and Rhizoma Dio-scoreae (Shanyao) Cluster analysis was used to divide theherbs into five clusters Herbs in cluster 1 mainly targeted thespleen and lung herbs in cluster 2 were prescribed to nourishthe liver-kidney and to clear heat-dampness and herbs incluster 3 were prescribed for clearing heat cooling blood and
6 Evidence-Based Complementary and Alternative Medicine
Table 3 Association rules of herbs for CKD treatment
Evidence-Based Complementary and Alternative Medicine 7
clearing dampness Cluster 4 herbs were prescribed forregulating qi flow eliminating phlegm activating blood andpurging turbidity Herbs in cluster 5 were not frequently usedWe used the complex networkmethod to analyze interactionsbetween herbs and found that the core herbs were RhizomaDioscoreae (Shanyao) Spreading Hedyotis Herb (Baihua-sheshecao) Root of Snow of June (Baimagu) Radix Astragali(Huangqi) Poria (Fulin) Rhizoma Atractylodis Macro-cephalae (Baizhu) Radix Pseudostellariae (Taizishen) andFructus Corni (Shanzhuyu)
e properties and actions of Chinese medicinal herbsare the essential bases for the analysis and clinical use ofherbs ey are summarized in medical practice and basedon the theories of yin and yang zang-fu meridian tropismsand TCM therapeutic principles [17] Chinese medicinal
herb theory is usually summarized as four properties and fivetastes meridian tropism and so on In this study the herbalproperties for CKD treatment were mainly sweet and warmwhich have a replenishing effect e next most frequentlyprescribed herbs had bitter and cold properties whichgenerally have a clearing action us tonifying deficiencywas the most important CKD treatment followed byclearing and disinhibiting is finding reflects the conceptthat TCM replenishes missing substances and rids the bodyof excess substances to regulate the balance of the bodyMeridian tropism is a theory that helps in understanding theorientation of drug action In this study the herbs weregenerally prescribed to target the spleen liver lung stom-ach and kidney meridian (ie the zang-fu requiringtreatment) In one studyrsquos retrospective analysis the basic
Figure 3 Association rule combination matrix e association rule combination matrix was analyzed using R-studio 353 Sizeindicatesconfidence (0855ndash0959) and color indicates lift (1106ndash1667)
8 Evidence-Based Complementary and Alternative Medicine
syndromes of kidney disease were identified as spleen andkidney deficiency lung and kidney qi deficiency and liverand kidney yin deficiency [18] Our research further indi-cates the important role of the kidney spleen stomach liverand lung in nephropathy Similarly the efficacious herbswere mainly deficiency-tonifying herbs heat-clearing herbsand dampness-draining diuretic herbs us these were themain TCM treatments for CKD Conversely the therapeuticprinciple could be used to determine the pathogenesis of thedisease at is the pathogenic factors could be divided intoheat and dampness and deficiency may be mainly caused bythe kidney spleen lung and liver
We identified commonly used herbs and their combina-tions (Tables 1 and 3)emain herbs for CKD treatment wereRhizoma Dioscoreae (Shanyao) Radix Astragali (Huangqi)Poria (Fulin) Rhizoma Atractylodis Macrocephalae (Baizhu)Radix Pseudostellariae (Taizishen) and Fructus Corni(Shanzhuyu) these all have the function of replenishing
Specifically Rhizoma Dioscoreae (Shanyao) targets the spleenlung and kidney Radix Astragali (Huangqi) and RadixPseudostellariae (Taizishen) can supplement the lung andspleen Macrocephalae (Baizhu) and Poria (Fulin) are pre-scribed to invigorate the spleen and Fructus Corni (Shanz-huyu) can nourish the liver and kidney ese six drugs indifferent combinations comprised the 11 most frequentcombinations Among them the most frequent combinationsincluded Rhizoma Dioscoreae (Shanyao) Rhizoma Dioscor-eae (Shanyao) can treat all deficiency syndromes according toTCM theory and is important for tonifying deficiency usherb combinations showed that the tonifying-deficiency cat-egory was the most important for CKD treatment In TCMnephrology kidney deficiency is the basis of kidney diseaseand tonifying kidney treatment should be vital [19] Howeverour research showed that the methods of supplementing thelung and spleen and nourishing the liver and kidney weremore frequently used in CKD Tonifying the spleen lung or
Grouped matrix for 30 Rules Size support Color li
1 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Por
ia (F
ulin
) +1
item
s
3 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Rhi
zom
aAt
ract
ylod
is M
acro
ceph
alae
(Bai
zhu)
+2
item
s
6 ru
les
Por
ia (F
ulin
) Ra
dix
Astr
agal
i (H
uang
qi)
+2 it
ems
6 ru
les
Rhi
zom
a Atr
acty
lodi
s Mac
roce
phal
ae (B
aizh
u)
Fruc
tus C
orni
(Sha
nzhu
yu)
+2 it
ems
14 ru
les
Rad
ix P
seud
oste
llaria
e (Ta
izish
en)
Spre
adin
g H
edyo
tis H
erb(
Baih
uash
eshe
cao)
+5
item
s
Rhizoma Dioscoreae (Shanyao)
Radix Astragali (Huangqi)
Rhizoma Atractylodis Macrocephalae (Baizhu)
Item
s in
LHS
grou
p
RHS
Figure 4 Association rule diagram Association rule learning was performed using R-studio 353 X-axis is the antecedent (or calledlefthandside LHS) and Y-axis is the consequent (or called right-hand side RHS) Size indicates support and color indicates lift
Evidence-Based Complementary and Alternative Medicine 9
liver is well known to achieve the purpose of nourishing thekidney but herbs that tonify the kidney were not frequentlyprescribed in this researchis indicates that amultiple-organdisorder underlies the TCM pathogenesis of CKD When and
how to nourish the kidney directly or indirectly requiresfurther study In TCM practice tonifying-deficiency herbs areoften used in combination with heat-clearing and dampness-draining diuretic herbs Table 3 shows that two or more herbs
Poria (Fulin)
Radix Astragali (Huangqi)Rhizoma Atractylodis
Macrocephalae (Baizhu)
Fructus Corni (Shanzhuyu)
Radix Pseudostellariae (Taizishen)
Fructus Lycii (Gouqizi)
Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis
Herb (Baihuasheshecao)Root of Snow of June (Baimagu)
Rhizoma Imperatae (Baimaogen)
Radix Cirsii Japonici (Daji)
Herba Cirsii (Xiaoji)
Radix Rehmanniae (Shengdihuang)
Common Sage Herb (Lizhicao)
Rhizoma Smilacis Glabrae (Tufulin)
Cortex Phellodendri (Huangbai)
Rhizoma Anemarrhenae (Zhimu)
Pericarpium Citri Reticulatae (Chenpi)
Rhizoma Pinelliae (Banxia)
Semen Coicis (Yiyiren)
Flos Carthami (Honghua)
Radix et Rhizoma Rhei (Dahuang)
Herba Taxilli (Sangjisheng)
Cortex Eucommiae (Duzhong)
Corn Stigma (Yumixu)
Radix Codonopsis (Dangshen)
Radix Salviae Miltiorrhizae (Danshen)
Medicated Leaven (Shenqu)
Radix Saposhnikoviae (Fangfeng)
Radix Ophiopogonis (Maidong)
Herba Taraxaci (Pugongying)
Radix Glycyrrhizae (Gancao)
Cluster dendrogram
Height
Figure 5 Cluster analysis tree diagram e cluster analysis tree diagram was created using R-studio 353 e 32 most frequentlyprescribed herbs were analyzed Each category is represented by a different color
10 Evidence-Based Complementary and Alternative Medicine
were usually combined with Spreading Hedyotis Herb (Bai-huasheshecao) or Root of Snow of June (Baimagu) whichwerethe two most frequently used heat-clearing herbs anddampness-removing diuretic herbs Tonifying treatment wasalso indicated to be more important than heat-clearing ordampness-draining treatment How to balance tonifyingtreatment and clearing-diuresis treatment under specificconditions needs to be investigated further
e pathogenesis of kidney disease is complex and oftenmanifests as multiple syndrome combinationse formulaedetermined by clustering were for composite syndromesHerbs in cluster 1 were for tonifying the lung strengtheningthe spleen and removing dampness and were prescribed totreat spleen-lung qi deficiency and dampness Herbs incluster 2 were for nourishing the liver and kidney andclearing heat or dampness and were prescribed to treat liver-kidney yin deficiency and dampness or heat ose in cluster3 were for nourishing yin clearing heat and cooling bloodese herbs can be found in Zhi Bai Di Huang Wan and are
prescribed to treat fire excess from yin deficiency and blood-heat syndromeose in cluster 4 were for regulating qi floweliminating phlegm activating blood and purging turbidityey were prescribed to treat phlegm-damp blood stasisand turbidity syndromesese four clusters of prescriptionsfor different syndrome types can provide useful ideas forCKD treatment e herbs in cluster 5 had multiple func-tions such as tonifying the kidney releasing the exteriorand promoting digestion It may be used auxiliarily to targetcomplications and requires further study
Complex network analysis revealed eight core herbs forCKD Rhizoma Dioscoreae (Shanyao) Spreading HedyotisHerb (Baihuasheshecao) Root of Snow of June (Baimagu)Radix Astragali (Huangqi) Poria (Fulin) Rhizoma Atrac-tylodis Macrocephalae (Baizhu) Radix Pseudostellariae(Taizishen) and Fructus Corni (Shanzhuyu) Interestinglythese herbs are included in clusters 1 and 2 ey were alsoidentified as high-frequency herbs for CKD treatment so webelieved that such a prescription could be used as a basis for
Spreading Hedyotis
Herb
Fructus Corni
Rhizoma Dioscoreae
Root of Snow of
June
Poria Radix Astragali
Radix Pseudostellariae
Rhizoma Atractylodis
Macrocephalae
124
154
105
100
154
134
99
129
100
115
98
86
95 98
141
119
115
127
87
146
139
136
131
115
112
102
97
97
89
Figure 6 Core prescription network e core prescription network was created using Liquorice e weight represents the frequency withwhich two herbs appeared together
Evidence-Based Complementary and Alternative Medicine 11
further research Modern pharmacology has also shown thatthese herbs can improve kidney injury through anti-in-flammatory and antioxidant activity (Table 4) [20ndash29]
Our data mining approach has several advantages Firstthere was no requirement for the data structure is is verypractical for data mining of Chinese medicine prescriptionsbecause the data structure of most Chinese medicines is notuniform Second we combined a variety of data miningmethods to perform comprehensive analysis and to ensurethat the conclusion was reliable Finally we focused on themain treatment methods and uses of herbs which is anefficient way to learn TCM treatment Our research also hassome limitations We collected only prescription informa-tion but not diagnostic information so our conclusionscannot be completely confirmed We also examined onlyeffective treatment cases not invalid treatment cases sowhether a gap exists between these two case types remainsunclearus it is also unclear whether the core prescriptionshould be corrected Finally the safety and efficacy of thecore prescriptions were not evaluated and should be in-vestigated in a future study
In summary we adopted a practical approach based onformulae prescribed in clinical practice To our knowledgethis is the first study on CKD treatment with TCM whichcombines frequency analysis association rule learning andcomplex network analysis Using this approach we deter-mined the frequency and combination patterns of CKDtreatment and discovered possibilities for new CKD
treatment prescriptions We also summarized herbal CKDtreatment finding that CKD syndromes are extremelycomplicated and various CKD treatmentmethods exist suchas those for cooling blood and eliminating phlegm How-ever we found that the treatment methods were mainly fortonifying deficiency and clearing heat or dampness
5 Conclusions
Our study found that kidney spleen lung or liver deficiencyand dampness-heat were the primary TCM pathogenesisus the primary treatment principle was tonifying defi-ciency and eliminating dampness and heat Furthermoreour study verified that the integrated analysis method canhelp to explore the TCM treatment strategy is analysis ofherbal TCM prescriptions potentially contributes to thedevelopment of novel drugs for CKD
Data Availability
e data used to support the findings of this study are in-cluded within the article
Conflicts of Interest
e authors declare that there are no conflicts of interestregarding the publication of this article
Table 4 Possible mechanisms of the core Chinese medical herbs for CKD treatment
Increases catalase (CAT) superoxide dismutase(SOD) and glutathione peroxidase (GSH-px)
activities in the kidneys of diabetic rats as well asenhancing renal peroxisome proliferator-activatedreceptor-c (PPARc) expression in diabetic rats [28]
Radix Pseudostellariae (Taizishen) Polysaccharide
Decreases serum triglyceride total cholesterol low-density-lipoprotein cholesterin urea nitrogen andcreatinine increase serum high-density-lipoproteincholesterol and reduce renal histopathology change
[29]
12 Evidence-Based Complementary and Alternative Medicine
Authorsrsquo Contributions
Ping Xia and Kun Gao contributed equally to this studyWeiming He and Kun Gao designed the research Ping XiaMing Shi Wei Li Jing Zhao Jin Yan Qiong Liu Min ZhengXin Wang and Qijing Wu collected and processed the dataPing Xia and Jiadong Xie analyzed the data Wei Sun JihongChen Enchao Zhou and Lingdong Xv participated in in-tellectual discussions Ping Xia and Kun Gao wrote thepaper All authors approved the final edited version of themanuscript
Acknowledgments
is study was financially supported by the PostgraduateResearch amp Practice Innovation Program of Jiangsu Prov-ince (KYCX19_1189 to Ping Xia) and the National NaturalScience Foundation of China (81673912 and 81873259 toKun Gao 81804219 to Jiadong Xie and 81774269 toWeiming He) e authors gratefully acknowledge the as-sistance of Dr Buhui Liu their colleague in the AffiliatedHospital of Nanjing University of Chinese Medicine
References
[1] A Levin M Tonelli J Bonventre et al ldquoGlobal kidney health2017 and beyond a roadmap for closing gaps in care researchand policyrdquo +e Lancet vol 390 no 10105 pp 1888ndash19172017
[2] A C Webster E V Nagler R L Morton and P MassonldquoChronic kidney diseaserdquo +e Lancet vol 389 no 10075pp 1238ndash1252 2017
[3] K J Foreman N Marquez A Dolgert et al ldquoForecasting lifeexpectancy years of life lost and all-cause and cause-specificmortality for 250 causes of death reference and alternativescenarios for 2016ndash40 for 195 countries and territoriesrdquo +eLancet vol 392 no 10159 pp 2052ndash2090 2017
[4] L Zhang F Wang L Wang et al ldquoPrevalence of chronickidney disease in China a cross-sectional surveyrdquo+e Lancetvol 379 no 9818 pp 815ndash822 2012
[5] X Li and HWang ldquoChinese herbal medicine in the treatmentof chronic kidney diseaserdquo Advances in Chronic KidneyDisease vol 12 no 3 pp 276ndash281 2005
[6] Q Zhang L Zhu and W Lerberghe ldquoe importance oftraditional Chinese medicine services in health care provisionin Chinardquo Universitas Forum vol 2 no 2 pp 1ndash8 2011
[7] Y J Wang L Q He W Sun et al ldquoOptimized project oftraditional Chinese medicine in treating chronic kidneydisease stage 3 a multicenter double-blinded randomizedcontrolled trialrdquo Journal of Ethnopharmacology vol 139no 3 pp 757ndash764 2012
[8] Y Chen Y Deng Z Ni et al ldquoEfficacy and safety of tradi-tional Chinese medicine (Shenqi particle) for patients withidiopathic membranous nephropathy a multicenter ran-domized controlled clinical trialrdquo American Journal of KidneyDiseases vol 62 no 6 pp 1068ndash1076 2013
[9] L Zhang P Li C Y Xing et al ldquoEfficacy and safety of Abel-moschus manihot for primary glomerular disease a prospectivemulticenter randomized controlled clinical trialrdquo AmericanJournal of Kidney Diseases vol 64 no 1 pp 57ndash65 2014
[10] W Li W He P Xia et al ldquoTotal extracts of abelmoschusmanihot L Attenuates adriamycin-induced renal tubule
injury via suppression of ROS-ERK12-mediated NLRP3inflammasome activationrdquo Frontiers in Pharmacology vol 10p 567 2019
[11] X Zhang X Zhou R Zhang et al ldquoReal-world clinical datamining on TCM clinical diagnosis and treatment a surveyrdquo inProceedings of the IEEE International Conference on E-HealthNetworking IEEE Beijing China October 2012
[12] L Chen C Y Lee K H Huang Y H Kuan and M ChenldquoPrescription patterns of Chinese herbal products for patientswith sleep disorder and major depressive disorder in TaiwanrdquoJournal of Ethnopharmacology vol 171 pp 307ndash316 2015
[13] J Cao ldquoe Common prescription patterns based on thehierarchical clustering of herb-pairs efficaciesrdquo Evidence-Based Complementary and Alternative Medicine vol 2016Article ID 6373270 7 pages 2016
[14] C J Hu J He J D Xie et al ldquoResearch on TCM treatment oflung cancer based on complex networks methodrdquo Journal ofMedical Informatics vol 39 no 11 pp 63ndash68 2018 inChinese
[15] National Pharmacopoeia Commission Pharmacopoeia of thePeoplersquos Republic of China China Medical Science andTechnology Press Bejing China 2010 in Chinese
[16] Chinese Materia Medica Commission of National Adminis-tration of Traditional Chinese Medicine Chinese MateriaMedica Shanghai Science and Technology Press ShanghaiChina 1999 in Chinese
[17] J Pang J Fu M Yang et al ldquoCorrelation between the dif-ferent therapeutic properties of Chinese medicinal herbs anddelayed luminescencerdquo Luminescence vol 31 no 2pp 323ndash327 2016
[18] X M Chen Z H Ni Y N Liu et al ldquoGuidelines for thediagnosis and treatment of chronic renal failure with inte-grated traditional Chinese and Western medicinerdquo HebeiTraditional ChineseMedicine vol 38 no 2 pp 313ndash317 2016in Chinese
[19] Y Q Zou and E C Zhou ldquoSummary of differentiation andtreatment of traditional Chinese medicine nephropathyrdquoJiangsu Journal of Traditional Chinese Medicine vol 50 no 1pp 1ndash5 2018 in Chinese
[20] Y Qiao L Xu X Tao et al ldquoProtective effects of dioscinagainst fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress fibrosis lipid metabolism and in-flammationrdquo Toxicology Letters vol 284 pp 37ndash45 2018
[21] J Su Y Wei M Liu et al ldquoAnti-hyperuricemic and neph-roprotective effects of Rhizoma Dioscoreae septemlobae ex-tracts and its main component dioscin via regulation ofmOAT1 mURAT1 and mOCT2 in hypertensive micerdquo Ar-chives of Pharmacal Research vol 37 no 10 pp 1336ndash13442014
[22] J H Ye M H Liu X L Zhang et al ldquoChemical profiles andprotective effect of Hedyotis diffusa Willd in lipopolysac-charide-induced renal inflammation micerdquo InternationalJournal of Molecular Sciences vol 16 no 11 pp 27252ndash272692015
[23] X B Sun and N N Yu ldquoRoot of Snow of June for treatingkidney diseasesrdquo Chinese Medicine Guide vol 19 no 10pp 127-128 2013 in Chinese
[24] W Zhang Z X Lin C Xu C Leung and L S ChanldquoAstragalus (a traditional Chinese medicine) for treatingchronic kidney diseaserdquo Cochrane Database of SystematicReviews vol 10 2014
[25] S Ren H Zhang Y Mu et al ldquoPharmacological effects ofAstragaloside IV a literature reviewrdquo Journal of TraditionalChinese Medicine vol 33 no 3 pp 413ndash416 2013
Evidence-Based Complementary and Alternative Medicine 13
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
Kidney Meridian of Foot-Shaoyin Our results showed thattherapeutic effects were predominant for the kidney spleenliver and lung and reflected that TCM is holistic
34 Action Category of Herbs Chinese medicinal herbs havespecific efficacy and can be classified into different specificaction categories Table 2 details the categories and thefrequency with which herbs were classified into these cat-egories e top ten categories for CKD treatment weredeficiency-tonifying herbs heat-clearing herbs dampness-draining diuretic herbs hemostatic herbs astringent herbsqi-regulating herbs blood-activating and stasis-resolvingherbs cough-suppressing and panting-calming herbs ex-terior-releasing herbs and digestant herbs
35 Prescription Patterns of Chinese Medicinal HerbsCompatibility of Chinese medicinal herbs refers to thecombination of two or more herbs with a purpose based onclinical requirements and medicinal properties and actions
0
400
800
1200
1600Cold
Warm
MildCool
Hot
Properties of herbs
(a)
0500
10001500200025003000
Sweet
Bitter
Pungent
Sour
WeakAstringent
Salty
Flavors of herbs
(b)
Meridian tropism of herbs
SpleenLiverLung
StomachKidneyHeart
Large intestineBladderSmall intestine
GallbladderPericardiumTri-jiao
(c)
Figure 2 Property taste and meridian tropism of herbs (a) Herb properties All herbs in each prescription were analyzed using a radarchart divided into five categories (b) Herb taste Tastes were divided into six categories using a radar chart (c) Meridian tropism of herbsWe created a tree diagram of the meridian tropism of all herbs Different meridian tropisms are indicated by different colors as shown at thebottom of the diagram All images were analyzed using Microsoft Excel 2016
Table 2 Frequency of herb categories
Herb category Frequency Rate ()Deficiency-tonifying herbs 1233 2991Heat-clearing herbs 1027 2491Dampness-draining diuretic herbs 410 994Hemostatic herbs 198 48Astringent herbs 170 412Qi-regulating herbs 169 41Blood-activating and stasis-resolving herbs 162 393Cough-suppressing and panting-calmingherbs 151 366
Evidence-Based Complementary and Alternative Medicine 5
It is the primary clinical method of medicinal applicationand the basis of herbal formulae composition Here we useddata mining to assess the standard prescription patterns ofthe formulae for CKD treatment
351 Herb Pair Analysis In clinical practice paired usage ofChinese medicinal herbs is essential therapeutically andcomprises the herb prescription method us we analyzedherb pairs
First we used the Apriori algorithm to analyze the as-sociation rules of the herbs in all prescriptions We focusedon two parameters support and confidence level Supportwas set as ge30 and confidence level as ge85 [11] and a totalof 30 herb pairs and suitable association rules were obtainede detailed association rules are shown in Table 3 and thecorrelation rules are shown in Figure 3 As shown in Table 3Astragali Radix (Huangqi)gtRhizoma Dioscoreae (Sha-nyao) had the highest degree of support at 5151 Rhi-zoma Atractylodis Macrocephalae (Baizhu) Fructus Corni(Shanzhuyu)gtRhizoma Dioscoreae (Shanyao) had thehighest confidence level at 9588 and Poria (Fulin) RadixAstragali (Huangqi)gtRhizoma Atractylodis Macro-cephalae (Baizhu) had the highest degree of lift at 168
A grouping matrix diagram displaying the general dis-tribution of association rules grouped into categories withsimilar rules is shown in Figure 4 is diagram allows us tonot only extract the general rule but also more deeply searchfor and extract important rules with commonality among theassociation rulesX-axis is the LHS andY-axis is the RHSecirclersquos color depth indicates the degree of lift such that thedarker the color the higher the degree of lift e size of thecircle indicates the degree of support such that the larger thecircle the higher the degree of support We found three coreherbs of paired prescriptions Astragali Radix (Huangqi)Rhizoma Dioscoreae (Shanyao) and Rhizoma AtractylodisMacrocephalae (Baizhu) ese herbs were usually combinedwith other herbs such as Astragali Radix (Huangqi) pairedwith Fructus Corni (Shanzhuyu) Rhizoma Dioscoreae(Shanyao) paired with Spreading Hedyotis Herb (Baihua-sheshecao) and Rhizoma Atractylodis Macrocephalae(Baizhu) paired with Poria (Fulin) to strengthen the spleentonify the kidney and eliminate dampness-heat respectively
In Figure 3 association rules were determined with agraphics-based visualization technique using a vertex torepresent herbs and relationships e strength of the re-lationship is expressed in the color depth or the size of thevertex e graph includes Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis Herb (Baihuasheshecao) Root of Snowof June (Baimagu) Radix Astragali (Huangqi) Poria (Fulin)Rhizoma Atractylodis Macrocephalae (Baizhu) RadixPseudostellariae (Taizishen) and Fructus Corni (Shanz-huyu) Among these eight herbs Radix Astragali (Huangqi)and Rhizoma Atractylodis Macrocephalae (Baizhu) are atthe center of the association rule graph
352 Novel Prescriptions Analysis Cluster analysis aggre-gates herbs into categories based on data attributes eclustering algorithm is an unsupervised learning algorithm
that can directly extract valuable information from the inputdata objects without input of any prior knowledge It iswidely used for data mining in TCM and mainly used fordetermining the compatibility law between drugs to identifythe combination rule of different TCM therapeutic methodse advantage of this method is that it allows for discovery ofpotential new prescriptions for CKD treatment Here weanalyzed 32 core herbs that were prescribed more than 30times using hierarchical clustering According to classicTCM theory five categories were considered suitable in thisstudy Figure 5 shows the herbs belonging to each cluster
353 Core Prescription Analysis Chinese medicinal herbsare usually applied as a combination of core herbs and otherherbs To further analyze the role of various herbs and theircombinations in CKD treatment we used the complexnetwork method and found that the core herbs in CKDtreatment were Rhizoma Dioscoreae (Shanyao) SpreadingHedyotis Herb (Baihuasheshecao) Root of Snow of June(Baimagu) Radix Astragali (Huangqi) Poria (Fulin) Rhi-zoma Atractylodis Macrocephalae (Baizhu) Radix Pseu-dostellariae (Taizishen) and Fructus Corni (Shanzhuyu)(Figure 6)ese eight herbs were also found to be frequentlyprescribed for CKD treatment and appeared in the associ-ation rule graph ese results indicate that these Chinesemedicinal herbs may have not only an effect on CKDtreatment but also a united one
4 Discussion
is study determined effective herbal prescriptions forCKD treatment by proposing a comprehensive methodbased on clinical cases integration of association rulescluster analysis and complex network analysis
We analyzed herb frequency and the properties and ac-tions of herbs and assessed the compatibility rules betweendrugs Our data showed that the most frequently prescribedherbs were Rhizoma Dioscoreae (Shanyao) SpreadingHedyotis Herb (Baihuasheshecao) Root of Snow of June(Baimagu) Radix Astragali (Huangqi) Poria (Fulin) Rhi-zoma Atractylodis Macrocephalae (Baizhu) Radix Pseudos-tellariae (Taizishen) Fructus Corni (Shanzhuyu) RadixRehmanniae (Shengdihuang) and Fructus Lycii (Gouqizi)e properties of these herbs were mainly being warm mildand colde tastes of the herbs were mainly sweet and bittere herbs were generally distributed to spleen lung liver andkidney channels and most were deficiency-tonifying herbsheat-clearing herbs and dampness-draining diuretic herbse most frequently used combinations of herbs obtainedusing association rules were Radix Astragali (Huangqi) andRhizoma Dioscoreae (Shanyao) ere were three core herbsof paired prescriptions Rhizoma Atractylodis Macrocephalae(Baizhu) Radix Astragali (Huangqi) and Rhizoma Dio-scoreae (Shanyao) Cluster analysis was used to divide theherbs into five clusters Herbs in cluster 1 mainly targeted thespleen and lung herbs in cluster 2 were prescribed to nourishthe liver-kidney and to clear heat-dampness and herbs incluster 3 were prescribed for clearing heat cooling blood and
6 Evidence-Based Complementary and Alternative Medicine
Table 3 Association rules of herbs for CKD treatment
Evidence-Based Complementary and Alternative Medicine 7
clearing dampness Cluster 4 herbs were prescribed forregulating qi flow eliminating phlegm activating blood andpurging turbidity Herbs in cluster 5 were not frequently usedWe used the complex networkmethod to analyze interactionsbetween herbs and found that the core herbs were RhizomaDioscoreae (Shanyao) Spreading Hedyotis Herb (Baihua-sheshecao) Root of Snow of June (Baimagu) Radix Astragali(Huangqi) Poria (Fulin) Rhizoma Atractylodis Macro-cephalae (Baizhu) Radix Pseudostellariae (Taizishen) andFructus Corni (Shanzhuyu)
e properties and actions of Chinese medicinal herbsare the essential bases for the analysis and clinical use ofherbs ey are summarized in medical practice and basedon the theories of yin and yang zang-fu meridian tropismsand TCM therapeutic principles [17] Chinese medicinal
herb theory is usually summarized as four properties and fivetastes meridian tropism and so on In this study the herbalproperties for CKD treatment were mainly sweet and warmwhich have a replenishing effect e next most frequentlyprescribed herbs had bitter and cold properties whichgenerally have a clearing action us tonifying deficiencywas the most important CKD treatment followed byclearing and disinhibiting is finding reflects the conceptthat TCM replenishes missing substances and rids the bodyof excess substances to regulate the balance of the bodyMeridian tropism is a theory that helps in understanding theorientation of drug action In this study the herbs weregenerally prescribed to target the spleen liver lung stom-ach and kidney meridian (ie the zang-fu requiringtreatment) In one studyrsquos retrospective analysis the basic
Figure 3 Association rule combination matrix e association rule combination matrix was analyzed using R-studio 353 Sizeindicatesconfidence (0855ndash0959) and color indicates lift (1106ndash1667)
8 Evidence-Based Complementary and Alternative Medicine
syndromes of kidney disease were identified as spleen andkidney deficiency lung and kidney qi deficiency and liverand kidney yin deficiency [18] Our research further indi-cates the important role of the kidney spleen stomach liverand lung in nephropathy Similarly the efficacious herbswere mainly deficiency-tonifying herbs heat-clearing herbsand dampness-draining diuretic herbs us these were themain TCM treatments for CKD Conversely the therapeuticprinciple could be used to determine the pathogenesis of thedisease at is the pathogenic factors could be divided intoheat and dampness and deficiency may be mainly caused bythe kidney spleen lung and liver
We identified commonly used herbs and their combina-tions (Tables 1 and 3)emain herbs for CKD treatment wereRhizoma Dioscoreae (Shanyao) Radix Astragali (Huangqi)Poria (Fulin) Rhizoma Atractylodis Macrocephalae (Baizhu)Radix Pseudostellariae (Taizishen) and Fructus Corni(Shanzhuyu) these all have the function of replenishing
Specifically Rhizoma Dioscoreae (Shanyao) targets the spleenlung and kidney Radix Astragali (Huangqi) and RadixPseudostellariae (Taizishen) can supplement the lung andspleen Macrocephalae (Baizhu) and Poria (Fulin) are pre-scribed to invigorate the spleen and Fructus Corni (Shanz-huyu) can nourish the liver and kidney ese six drugs indifferent combinations comprised the 11 most frequentcombinations Among them the most frequent combinationsincluded Rhizoma Dioscoreae (Shanyao) Rhizoma Dioscor-eae (Shanyao) can treat all deficiency syndromes according toTCM theory and is important for tonifying deficiency usherb combinations showed that the tonifying-deficiency cat-egory was the most important for CKD treatment In TCMnephrology kidney deficiency is the basis of kidney diseaseand tonifying kidney treatment should be vital [19] Howeverour research showed that the methods of supplementing thelung and spleen and nourishing the liver and kidney weremore frequently used in CKD Tonifying the spleen lung or
Grouped matrix for 30 Rules Size support Color li
1 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Por
ia (F
ulin
) +1
item
s
3 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Rhi
zom
aAt
ract
ylod
is M
acro
ceph
alae
(Bai
zhu)
+2
item
s
6 ru
les
Por
ia (F
ulin
) Ra
dix
Astr
agal
i (H
uang
qi)
+2 it
ems
6 ru
les
Rhi
zom
a Atr
acty
lodi
s Mac
roce
phal
ae (B
aizh
u)
Fruc
tus C
orni
(Sha
nzhu
yu)
+2 it
ems
14 ru
les
Rad
ix P
seud
oste
llaria
e (Ta
izish
en)
Spre
adin
g H
edyo
tis H
erb(
Baih
uash
eshe
cao)
+5
item
s
Rhizoma Dioscoreae (Shanyao)
Radix Astragali (Huangqi)
Rhizoma Atractylodis Macrocephalae (Baizhu)
Item
s in
LHS
grou
p
RHS
Figure 4 Association rule diagram Association rule learning was performed using R-studio 353 X-axis is the antecedent (or calledlefthandside LHS) and Y-axis is the consequent (or called right-hand side RHS) Size indicates support and color indicates lift
Evidence-Based Complementary and Alternative Medicine 9
liver is well known to achieve the purpose of nourishing thekidney but herbs that tonify the kidney were not frequentlyprescribed in this researchis indicates that amultiple-organdisorder underlies the TCM pathogenesis of CKD When and
how to nourish the kidney directly or indirectly requiresfurther study In TCM practice tonifying-deficiency herbs areoften used in combination with heat-clearing and dampness-draining diuretic herbs Table 3 shows that two or more herbs
Poria (Fulin)
Radix Astragali (Huangqi)Rhizoma Atractylodis
Macrocephalae (Baizhu)
Fructus Corni (Shanzhuyu)
Radix Pseudostellariae (Taizishen)
Fructus Lycii (Gouqizi)
Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis
Herb (Baihuasheshecao)Root of Snow of June (Baimagu)
Rhizoma Imperatae (Baimaogen)
Radix Cirsii Japonici (Daji)
Herba Cirsii (Xiaoji)
Radix Rehmanniae (Shengdihuang)
Common Sage Herb (Lizhicao)
Rhizoma Smilacis Glabrae (Tufulin)
Cortex Phellodendri (Huangbai)
Rhizoma Anemarrhenae (Zhimu)
Pericarpium Citri Reticulatae (Chenpi)
Rhizoma Pinelliae (Banxia)
Semen Coicis (Yiyiren)
Flos Carthami (Honghua)
Radix et Rhizoma Rhei (Dahuang)
Herba Taxilli (Sangjisheng)
Cortex Eucommiae (Duzhong)
Corn Stigma (Yumixu)
Radix Codonopsis (Dangshen)
Radix Salviae Miltiorrhizae (Danshen)
Medicated Leaven (Shenqu)
Radix Saposhnikoviae (Fangfeng)
Radix Ophiopogonis (Maidong)
Herba Taraxaci (Pugongying)
Radix Glycyrrhizae (Gancao)
Cluster dendrogram
Height
Figure 5 Cluster analysis tree diagram e cluster analysis tree diagram was created using R-studio 353 e 32 most frequentlyprescribed herbs were analyzed Each category is represented by a different color
10 Evidence-Based Complementary and Alternative Medicine
were usually combined with Spreading Hedyotis Herb (Bai-huasheshecao) or Root of Snow of June (Baimagu) whichwerethe two most frequently used heat-clearing herbs anddampness-removing diuretic herbs Tonifying treatment wasalso indicated to be more important than heat-clearing ordampness-draining treatment How to balance tonifyingtreatment and clearing-diuresis treatment under specificconditions needs to be investigated further
e pathogenesis of kidney disease is complex and oftenmanifests as multiple syndrome combinationse formulaedetermined by clustering were for composite syndromesHerbs in cluster 1 were for tonifying the lung strengtheningthe spleen and removing dampness and were prescribed totreat spleen-lung qi deficiency and dampness Herbs incluster 2 were for nourishing the liver and kidney andclearing heat or dampness and were prescribed to treat liver-kidney yin deficiency and dampness or heat ose in cluster3 were for nourishing yin clearing heat and cooling bloodese herbs can be found in Zhi Bai Di Huang Wan and are
prescribed to treat fire excess from yin deficiency and blood-heat syndromeose in cluster 4 were for regulating qi floweliminating phlegm activating blood and purging turbidityey were prescribed to treat phlegm-damp blood stasisand turbidity syndromesese four clusters of prescriptionsfor different syndrome types can provide useful ideas forCKD treatment e herbs in cluster 5 had multiple func-tions such as tonifying the kidney releasing the exteriorand promoting digestion It may be used auxiliarily to targetcomplications and requires further study
Complex network analysis revealed eight core herbs forCKD Rhizoma Dioscoreae (Shanyao) Spreading HedyotisHerb (Baihuasheshecao) Root of Snow of June (Baimagu)Radix Astragali (Huangqi) Poria (Fulin) Rhizoma Atrac-tylodis Macrocephalae (Baizhu) Radix Pseudostellariae(Taizishen) and Fructus Corni (Shanzhuyu) Interestinglythese herbs are included in clusters 1 and 2 ey were alsoidentified as high-frequency herbs for CKD treatment so webelieved that such a prescription could be used as a basis for
Spreading Hedyotis
Herb
Fructus Corni
Rhizoma Dioscoreae
Root of Snow of
June
Poria Radix Astragali
Radix Pseudostellariae
Rhizoma Atractylodis
Macrocephalae
124
154
105
100
154
134
99
129
100
115
98
86
95 98
141
119
115
127
87
146
139
136
131
115
112
102
97
97
89
Figure 6 Core prescription network e core prescription network was created using Liquorice e weight represents the frequency withwhich two herbs appeared together
Evidence-Based Complementary and Alternative Medicine 11
further research Modern pharmacology has also shown thatthese herbs can improve kidney injury through anti-in-flammatory and antioxidant activity (Table 4) [20ndash29]
Our data mining approach has several advantages Firstthere was no requirement for the data structure is is verypractical for data mining of Chinese medicine prescriptionsbecause the data structure of most Chinese medicines is notuniform Second we combined a variety of data miningmethods to perform comprehensive analysis and to ensurethat the conclusion was reliable Finally we focused on themain treatment methods and uses of herbs which is anefficient way to learn TCM treatment Our research also hassome limitations We collected only prescription informa-tion but not diagnostic information so our conclusionscannot be completely confirmed We also examined onlyeffective treatment cases not invalid treatment cases sowhether a gap exists between these two case types remainsunclearus it is also unclear whether the core prescriptionshould be corrected Finally the safety and efficacy of thecore prescriptions were not evaluated and should be in-vestigated in a future study
In summary we adopted a practical approach based onformulae prescribed in clinical practice To our knowledgethis is the first study on CKD treatment with TCM whichcombines frequency analysis association rule learning andcomplex network analysis Using this approach we deter-mined the frequency and combination patterns of CKDtreatment and discovered possibilities for new CKD
treatment prescriptions We also summarized herbal CKDtreatment finding that CKD syndromes are extremelycomplicated and various CKD treatmentmethods exist suchas those for cooling blood and eliminating phlegm How-ever we found that the treatment methods were mainly fortonifying deficiency and clearing heat or dampness
5 Conclusions
Our study found that kidney spleen lung or liver deficiencyand dampness-heat were the primary TCM pathogenesisus the primary treatment principle was tonifying defi-ciency and eliminating dampness and heat Furthermoreour study verified that the integrated analysis method canhelp to explore the TCM treatment strategy is analysis ofherbal TCM prescriptions potentially contributes to thedevelopment of novel drugs for CKD
Data Availability
e data used to support the findings of this study are in-cluded within the article
Conflicts of Interest
e authors declare that there are no conflicts of interestregarding the publication of this article
Table 4 Possible mechanisms of the core Chinese medical herbs for CKD treatment
Increases catalase (CAT) superoxide dismutase(SOD) and glutathione peroxidase (GSH-px)
activities in the kidneys of diabetic rats as well asenhancing renal peroxisome proliferator-activatedreceptor-c (PPARc) expression in diabetic rats [28]
Radix Pseudostellariae (Taizishen) Polysaccharide
Decreases serum triglyceride total cholesterol low-density-lipoprotein cholesterin urea nitrogen andcreatinine increase serum high-density-lipoproteincholesterol and reduce renal histopathology change
[29]
12 Evidence-Based Complementary and Alternative Medicine
Authorsrsquo Contributions
Ping Xia and Kun Gao contributed equally to this studyWeiming He and Kun Gao designed the research Ping XiaMing Shi Wei Li Jing Zhao Jin Yan Qiong Liu Min ZhengXin Wang and Qijing Wu collected and processed the dataPing Xia and Jiadong Xie analyzed the data Wei Sun JihongChen Enchao Zhou and Lingdong Xv participated in in-tellectual discussions Ping Xia and Kun Gao wrote thepaper All authors approved the final edited version of themanuscript
Acknowledgments
is study was financially supported by the PostgraduateResearch amp Practice Innovation Program of Jiangsu Prov-ince (KYCX19_1189 to Ping Xia) and the National NaturalScience Foundation of China (81673912 and 81873259 toKun Gao 81804219 to Jiadong Xie and 81774269 toWeiming He) e authors gratefully acknowledge the as-sistance of Dr Buhui Liu their colleague in the AffiliatedHospital of Nanjing University of Chinese Medicine
References
[1] A Levin M Tonelli J Bonventre et al ldquoGlobal kidney health2017 and beyond a roadmap for closing gaps in care researchand policyrdquo +e Lancet vol 390 no 10105 pp 1888ndash19172017
[2] A C Webster E V Nagler R L Morton and P MassonldquoChronic kidney diseaserdquo +e Lancet vol 389 no 10075pp 1238ndash1252 2017
[3] K J Foreman N Marquez A Dolgert et al ldquoForecasting lifeexpectancy years of life lost and all-cause and cause-specificmortality for 250 causes of death reference and alternativescenarios for 2016ndash40 for 195 countries and territoriesrdquo +eLancet vol 392 no 10159 pp 2052ndash2090 2017
[4] L Zhang F Wang L Wang et al ldquoPrevalence of chronickidney disease in China a cross-sectional surveyrdquo+e Lancetvol 379 no 9818 pp 815ndash822 2012
[5] X Li and HWang ldquoChinese herbal medicine in the treatmentof chronic kidney diseaserdquo Advances in Chronic KidneyDisease vol 12 no 3 pp 276ndash281 2005
[6] Q Zhang L Zhu and W Lerberghe ldquoe importance oftraditional Chinese medicine services in health care provisionin Chinardquo Universitas Forum vol 2 no 2 pp 1ndash8 2011
[7] Y J Wang L Q He W Sun et al ldquoOptimized project oftraditional Chinese medicine in treating chronic kidneydisease stage 3 a multicenter double-blinded randomizedcontrolled trialrdquo Journal of Ethnopharmacology vol 139no 3 pp 757ndash764 2012
[8] Y Chen Y Deng Z Ni et al ldquoEfficacy and safety of tradi-tional Chinese medicine (Shenqi particle) for patients withidiopathic membranous nephropathy a multicenter ran-domized controlled clinical trialrdquo American Journal of KidneyDiseases vol 62 no 6 pp 1068ndash1076 2013
[9] L Zhang P Li C Y Xing et al ldquoEfficacy and safety of Abel-moschus manihot for primary glomerular disease a prospectivemulticenter randomized controlled clinical trialrdquo AmericanJournal of Kidney Diseases vol 64 no 1 pp 57ndash65 2014
[10] W Li W He P Xia et al ldquoTotal extracts of abelmoschusmanihot L Attenuates adriamycin-induced renal tubule
injury via suppression of ROS-ERK12-mediated NLRP3inflammasome activationrdquo Frontiers in Pharmacology vol 10p 567 2019
[11] X Zhang X Zhou R Zhang et al ldquoReal-world clinical datamining on TCM clinical diagnosis and treatment a surveyrdquo inProceedings of the IEEE International Conference on E-HealthNetworking IEEE Beijing China October 2012
[12] L Chen C Y Lee K H Huang Y H Kuan and M ChenldquoPrescription patterns of Chinese herbal products for patientswith sleep disorder and major depressive disorder in TaiwanrdquoJournal of Ethnopharmacology vol 171 pp 307ndash316 2015
[13] J Cao ldquoe Common prescription patterns based on thehierarchical clustering of herb-pairs efficaciesrdquo Evidence-Based Complementary and Alternative Medicine vol 2016Article ID 6373270 7 pages 2016
[14] C J Hu J He J D Xie et al ldquoResearch on TCM treatment oflung cancer based on complex networks methodrdquo Journal ofMedical Informatics vol 39 no 11 pp 63ndash68 2018 inChinese
[15] National Pharmacopoeia Commission Pharmacopoeia of thePeoplersquos Republic of China China Medical Science andTechnology Press Bejing China 2010 in Chinese
[16] Chinese Materia Medica Commission of National Adminis-tration of Traditional Chinese Medicine Chinese MateriaMedica Shanghai Science and Technology Press ShanghaiChina 1999 in Chinese
[17] J Pang J Fu M Yang et al ldquoCorrelation between the dif-ferent therapeutic properties of Chinese medicinal herbs anddelayed luminescencerdquo Luminescence vol 31 no 2pp 323ndash327 2016
[18] X M Chen Z H Ni Y N Liu et al ldquoGuidelines for thediagnosis and treatment of chronic renal failure with inte-grated traditional Chinese and Western medicinerdquo HebeiTraditional ChineseMedicine vol 38 no 2 pp 313ndash317 2016in Chinese
[19] Y Q Zou and E C Zhou ldquoSummary of differentiation andtreatment of traditional Chinese medicine nephropathyrdquoJiangsu Journal of Traditional Chinese Medicine vol 50 no 1pp 1ndash5 2018 in Chinese
[20] Y Qiao L Xu X Tao et al ldquoProtective effects of dioscinagainst fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress fibrosis lipid metabolism and in-flammationrdquo Toxicology Letters vol 284 pp 37ndash45 2018
[21] J Su Y Wei M Liu et al ldquoAnti-hyperuricemic and neph-roprotective effects of Rhizoma Dioscoreae septemlobae ex-tracts and its main component dioscin via regulation ofmOAT1 mURAT1 and mOCT2 in hypertensive micerdquo Ar-chives of Pharmacal Research vol 37 no 10 pp 1336ndash13442014
[22] J H Ye M H Liu X L Zhang et al ldquoChemical profiles andprotective effect of Hedyotis diffusa Willd in lipopolysac-charide-induced renal inflammation micerdquo InternationalJournal of Molecular Sciences vol 16 no 11 pp 27252ndash272692015
[23] X B Sun and N N Yu ldquoRoot of Snow of June for treatingkidney diseasesrdquo Chinese Medicine Guide vol 19 no 10pp 127-128 2013 in Chinese
[24] W Zhang Z X Lin C Xu C Leung and L S ChanldquoAstragalus (a traditional Chinese medicine) for treatingchronic kidney diseaserdquo Cochrane Database of SystematicReviews vol 10 2014
[25] S Ren H Zhang Y Mu et al ldquoPharmacological effects ofAstragaloside IV a literature reviewrdquo Journal of TraditionalChinese Medicine vol 33 no 3 pp 413ndash416 2013
Evidence-Based Complementary and Alternative Medicine 13
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
It is the primary clinical method of medicinal applicationand the basis of herbal formulae composition Here we useddata mining to assess the standard prescription patterns ofthe formulae for CKD treatment
351 Herb Pair Analysis In clinical practice paired usage ofChinese medicinal herbs is essential therapeutically andcomprises the herb prescription method us we analyzedherb pairs
First we used the Apriori algorithm to analyze the as-sociation rules of the herbs in all prescriptions We focusedon two parameters support and confidence level Supportwas set as ge30 and confidence level as ge85 [11] and a totalof 30 herb pairs and suitable association rules were obtainede detailed association rules are shown in Table 3 and thecorrelation rules are shown in Figure 3 As shown in Table 3Astragali Radix (Huangqi)gtRhizoma Dioscoreae (Sha-nyao) had the highest degree of support at 5151 Rhi-zoma Atractylodis Macrocephalae (Baizhu) Fructus Corni(Shanzhuyu)gtRhizoma Dioscoreae (Shanyao) had thehighest confidence level at 9588 and Poria (Fulin) RadixAstragali (Huangqi)gtRhizoma Atractylodis Macro-cephalae (Baizhu) had the highest degree of lift at 168
A grouping matrix diagram displaying the general dis-tribution of association rules grouped into categories withsimilar rules is shown in Figure 4 is diagram allows us tonot only extract the general rule but also more deeply searchfor and extract important rules with commonality among theassociation rulesX-axis is the LHS andY-axis is the RHSecirclersquos color depth indicates the degree of lift such that thedarker the color the higher the degree of lift e size of thecircle indicates the degree of support such that the larger thecircle the higher the degree of support We found three coreherbs of paired prescriptions Astragali Radix (Huangqi)Rhizoma Dioscoreae (Shanyao) and Rhizoma AtractylodisMacrocephalae (Baizhu) ese herbs were usually combinedwith other herbs such as Astragali Radix (Huangqi) pairedwith Fructus Corni (Shanzhuyu) Rhizoma Dioscoreae(Shanyao) paired with Spreading Hedyotis Herb (Baihua-sheshecao) and Rhizoma Atractylodis Macrocephalae(Baizhu) paired with Poria (Fulin) to strengthen the spleentonify the kidney and eliminate dampness-heat respectively
In Figure 3 association rules were determined with agraphics-based visualization technique using a vertex torepresent herbs and relationships e strength of the re-lationship is expressed in the color depth or the size of thevertex e graph includes Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis Herb (Baihuasheshecao) Root of Snowof June (Baimagu) Radix Astragali (Huangqi) Poria (Fulin)Rhizoma Atractylodis Macrocephalae (Baizhu) RadixPseudostellariae (Taizishen) and Fructus Corni (Shanz-huyu) Among these eight herbs Radix Astragali (Huangqi)and Rhizoma Atractylodis Macrocephalae (Baizhu) are atthe center of the association rule graph
352 Novel Prescriptions Analysis Cluster analysis aggre-gates herbs into categories based on data attributes eclustering algorithm is an unsupervised learning algorithm
that can directly extract valuable information from the inputdata objects without input of any prior knowledge It iswidely used for data mining in TCM and mainly used fordetermining the compatibility law between drugs to identifythe combination rule of different TCM therapeutic methodse advantage of this method is that it allows for discovery ofpotential new prescriptions for CKD treatment Here weanalyzed 32 core herbs that were prescribed more than 30times using hierarchical clustering According to classicTCM theory five categories were considered suitable in thisstudy Figure 5 shows the herbs belonging to each cluster
353 Core Prescription Analysis Chinese medicinal herbsare usually applied as a combination of core herbs and otherherbs To further analyze the role of various herbs and theircombinations in CKD treatment we used the complexnetwork method and found that the core herbs in CKDtreatment were Rhizoma Dioscoreae (Shanyao) SpreadingHedyotis Herb (Baihuasheshecao) Root of Snow of June(Baimagu) Radix Astragali (Huangqi) Poria (Fulin) Rhi-zoma Atractylodis Macrocephalae (Baizhu) Radix Pseu-dostellariae (Taizishen) and Fructus Corni (Shanzhuyu)(Figure 6)ese eight herbs were also found to be frequentlyprescribed for CKD treatment and appeared in the associ-ation rule graph ese results indicate that these Chinesemedicinal herbs may have not only an effect on CKDtreatment but also a united one
4 Discussion
is study determined effective herbal prescriptions forCKD treatment by proposing a comprehensive methodbased on clinical cases integration of association rulescluster analysis and complex network analysis
We analyzed herb frequency and the properties and ac-tions of herbs and assessed the compatibility rules betweendrugs Our data showed that the most frequently prescribedherbs were Rhizoma Dioscoreae (Shanyao) SpreadingHedyotis Herb (Baihuasheshecao) Root of Snow of June(Baimagu) Radix Astragali (Huangqi) Poria (Fulin) Rhi-zoma Atractylodis Macrocephalae (Baizhu) Radix Pseudos-tellariae (Taizishen) Fructus Corni (Shanzhuyu) RadixRehmanniae (Shengdihuang) and Fructus Lycii (Gouqizi)e properties of these herbs were mainly being warm mildand colde tastes of the herbs were mainly sweet and bittere herbs were generally distributed to spleen lung liver andkidney channels and most were deficiency-tonifying herbsheat-clearing herbs and dampness-draining diuretic herbse most frequently used combinations of herbs obtainedusing association rules were Radix Astragali (Huangqi) andRhizoma Dioscoreae (Shanyao) ere were three core herbsof paired prescriptions Rhizoma Atractylodis Macrocephalae(Baizhu) Radix Astragali (Huangqi) and Rhizoma Dio-scoreae (Shanyao) Cluster analysis was used to divide theherbs into five clusters Herbs in cluster 1 mainly targeted thespleen and lung herbs in cluster 2 were prescribed to nourishthe liver-kidney and to clear heat-dampness and herbs incluster 3 were prescribed for clearing heat cooling blood and
6 Evidence-Based Complementary and Alternative Medicine
Table 3 Association rules of herbs for CKD treatment
Evidence-Based Complementary and Alternative Medicine 7
clearing dampness Cluster 4 herbs were prescribed forregulating qi flow eliminating phlegm activating blood andpurging turbidity Herbs in cluster 5 were not frequently usedWe used the complex networkmethod to analyze interactionsbetween herbs and found that the core herbs were RhizomaDioscoreae (Shanyao) Spreading Hedyotis Herb (Baihua-sheshecao) Root of Snow of June (Baimagu) Radix Astragali(Huangqi) Poria (Fulin) Rhizoma Atractylodis Macro-cephalae (Baizhu) Radix Pseudostellariae (Taizishen) andFructus Corni (Shanzhuyu)
e properties and actions of Chinese medicinal herbsare the essential bases for the analysis and clinical use ofherbs ey are summarized in medical practice and basedon the theories of yin and yang zang-fu meridian tropismsand TCM therapeutic principles [17] Chinese medicinal
herb theory is usually summarized as four properties and fivetastes meridian tropism and so on In this study the herbalproperties for CKD treatment were mainly sweet and warmwhich have a replenishing effect e next most frequentlyprescribed herbs had bitter and cold properties whichgenerally have a clearing action us tonifying deficiencywas the most important CKD treatment followed byclearing and disinhibiting is finding reflects the conceptthat TCM replenishes missing substances and rids the bodyof excess substances to regulate the balance of the bodyMeridian tropism is a theory that helps in understanding theorientation of drug action In this study the herbs weregenerally prescribed to target the spleen liver lung stom-ach and kidney meridian (ie the zang-fu requiringtreatment) In one studyrsquos retrospective analysis the basic
Figure 3 Association rule combination matrix e association rule combination matrix was analyzed using R-studio 353 Sizeindicatesconfidence (0855ndash0959) and color indicates lift (1106ndash1667)
8 Evidence-Based Complementary and Alternative Medicine
syndromes of kidney disease were identified as spleen andkidney deficiency lung and kidney qi deficiency and liverand kidney yin deficiency [18] Our research further indi-cates the important role of the kidney spleen stomach liverand lung in nephropathy Similarly the efficacious herbswere mainly deficiency-tonifying herbs heat-clearing herbsand dampness-draining diuretic herbs us these were themain TCM treatments for CKD Conversely the therapeuticprinciple could be used to determine the pathogenesis of thedisease at is the pathogenic factors could be divided intoheat and dampness and deficiency may be mainly caused bythe kidney spleen lung and liver
We identified commonly used herbs and their combina-tions (Tables 1 and 3)emain herbs for CKD treatment wereRhizoma Dioscoreae (Shanyao) Radix Astragali (Huangqi)Poria (Fulin) Rhizoma Atractylodis Macrocephalae (Baizhu)Radix Pseudostellariae (Taizishen) and Fructus Corni(Shanzhuyu) these all have the function of replenishing
Specifically Rhizoma Dioscoreae (Shanyao) targets the spleenlung and kidney Radix Astragali (Huangqi) and RadixPseudostellariae (Taizishen) can supplement the lung andspleen Macrocephalae (Baizhu) and Poria (Fulin) are pre-scribed to invigorate the spleen and Fructus Corni (Shanz-huyu) can nourish the liver and kidney ese six drugs indifferent combinations comprised the 11 most frequentcombinations Among them the most frequent combinationsincluded Rhizoma Dioscoreae (Shanyao) Rhizoma Dioscor-eae (Shanyao) can treat all deficiency syndromes according toTCM theory and is important for tonifying deficiency usherb combinations showed that the tonifying-deficiency cat-egory was the most important for CKD treatment In TCMnephrology kidney deficiency is the basis of kidney diseaseand tonifying kidney treatment should be vital [19] Howeverour research showed that the methods of supplementing thelung and spleen and nourishing the liver and kidney weremore frequently used in CKD Tonifying the spleen lung or
Grouped matrix for 30 Rules Size support Color li
1 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Por
ia (F
ulin
) +1
item
s
3 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Rhi
zom
aAt
ract
ylod
is M
acro
ceph
alae
(Bai
zhu)
+2
item
s
6 ru
les
Por
ia (F
ulin
) Ra
dix
Astr
agal
i (H
uang
qi)
+2 it
ems
6 ru
les
Rhi
zom
a Atr
acty
lodi
s Mac
roce
phal
ae (B
aizh
u)
Fruc
tus C
orni
(Sha
nzhu
yu)
+2 it
ems
14 ru
les
Rad
ix P
seud
oste
llaria
e (Ta
izish
en)
Spre
adin
g H
edyo
tis H
erb(
Baih
uash
eshe
cao)
+5
item
s
Rhizoma Dioscoreae (Shanyao)
Radix Astragali (Huangqi)
Rhizoma Atractylodis Macrocephalae (Baizhu)
Item
s in
LHS
grou
p
RHS
Figure 4 Association rule diagram Association rule learning was performed using R-studio 353 X-axis is the antecedent (or calledlefthandside LHS) and Y-axis is the consequent (or called right-hand side RHS) Size indicates support and color indicates lift
Evidence-Based Complementary and Alternative Medicine 9
liver is well known to achieve the purpose of nourishing thekidney but herbs that tonify the kidney were not frequentlyprescribed in this researchis indicates that amultiple-organdisorder underlies the TCM pathogenesis of CKD When and
how to nourish the kidney directly or indirectly requiresfurther study In TCM practice tonifying-deficiency herbs areoften used in combination with heat-clearing and dampness-draining diuretic herbs Table 3 shows that two or more herbs
Poria (Fulin)
Radix Astragali (Huangqi)Rhizoma Atractylodis
Macrocephalae (Baizhu)
Fructus Corni (Shanzhuyu)
Radix Pseudostellariae (Taizishen)
Fructus Lycii (Gouqizi)
Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis
Herb (Baihuasheshecao)Root of Snow of June (Baimagu)
Rhizoma Imperatae (Baimaogen)
Radix Cirsii Japonici (Daji)
Herba Cirsii (Xiaoji)
Radix Rehmanniae (Shengdihuang)
Common Sage Herb (Lizhicao)
Rhizoma Smilacis Glabrae (Tufulin)
Cortex Phellodendri (Huangbai)
Rhizoma Anemarrhenae (Zhimu)
Pericarpium Citri Reticulatae (Chenpi)
Rhizoma Pinelliae (Banxia)
Semen Coicis (Yiyiren)
Flos Carthami (Honghua)
Radix et Rhizoma Rhei (Dahuang)
Herba Taxilli (Sangjisheng)
Cortex Eucommiae (Duzhong)
Corn Stigma (Yumixu)
Radix Codonopsis (Dangshen)
Radix Salviae Miltiorrhizae (Danshen)
Medicated Leaven (Shenqu)
Radix Saposhnikoviae (Fangfeng)
Radix Ophiopogonis (Maidong)
Herba Taraxaci (Pugongying)
Radix Glycyrrhizae (Gancao)
Cluster dendrogram
Height
Figure 5 Cluster analysis tree diagram e cluster analysis tree diagram was created using R-studio 353 e 32 most frequentlyprescribed herbs were analyzed Each category is represented by a different color
10 Evidence-Based Complementary and Alternative Medicine
were usually combined with Spreading Hedyotis Herb (Bai-huasheshecao) or Root of Snow of June (Baimagu) whichwerethe two most frequently used heat-clearing herbs anddampness-removing diuretic herbs Tonifying treatment wasalso indicated to be more important than heat-clearing ordampness-draining treatment How to balance tonifyingtreatment and clearing-diuresis treatment under specificconditions needs to be investigated further
e pathogenesis of kidney disease is complex and oftenmanifests as multiple syndrome combinationse formulaedetermined by clustering were for composite syndromesHerbs in cluster 1 were for tonifying the lung strengtheningthe spleen and removing dampness and were prescribed totreat spleen-lung qi deficiency and dampness Herbs incluster 2 were for nourishing the liver and kidney andclearing heat or dampness and were prescribed to treat liver-kidney yin deficiency and dampness or heat ose in cluster3 were for nourishing yin clearing heat and cooling bloodese herbs can be found in Zhi Bai Di Huang Wan and are
prescribed to treat fire excess from yin deficiency and blood-heat syndromeose in cluster 4 were for regulating qi floweliminating phlegm activating blood and purging turbidityey were prescribed to treat phlegm-damp blood stasisand turbidity syndromesese four clusters of prescriptionsfor different syndrome types can provide useful ideas forCKD treatment e herbs in cluster 5 had multiple func-tions such as tonifying the kidney releasing the exteriorand promoting digestion It may be used auxiliarily to targetcomplications and requires further study
Complex network analysis revealed eight core herbs forCKD Rhizoma Dioscoreae (Shanyao) Spreading HedyotisHerb (Baihuasheshecao) Root of Snow of June (Baimagu)Radix Astragali (Huangqi) Poria (Fulin) Rhizoma Atrac-tylodis Macrocephalae (Baizhu) Radix Pseudostellariae(Taizishen) and Fructus Corni (Shanzhuyu) Interestinglythese herbs are included in clusters 1 and 2 ey were alsoidentified as high-frequency herbs for CKD treatment so webelieved that such a prescription could be used as a basis for
Spreading Hedyotis
Herb
Fructus Corni
Rhizoma Dioscoreae
Root of Snow of
June
Poria Radix Astragali
Radix Pseudostellariae
Rhizoma Atractylodis
Macrocephalae
124
154
105
100
154
134
99
129
100
115
98
86
95 98
141
119
115
127
87
146
139
136
131
115
112
102
97
97
89
Figure 6 Core prescription network e core prescription network was created using Liquorice e weight represents the frequency withwhich two herbs appeared together
Evidence-Based Complementary and Alternative Medicine 11
further research Modern pharmacology has also shown thatthese herbs can improve kidney injury through anti-in-flammatory and antioxidant activity (Table 4) [20ndash29]
Our data mining approach has several advantages Firstthere was no requirement for the data structure is is verypractical for data mining of Chinese medicine prescriptionsbecause the data structure of most Chinese medicines is notuniform Second we combined a variety of data miningmethods to perform comprehensive analysis and to ensurethat the conclusion was reliable Finally we focused on themain treatment methods and uses of herbs which is anefficient way to learn TCM treatment Our research also hassome limitations We collected only prescription informa-tion but not diagnostic information so our conclusionscannot be completely confirmed We also examined onlyeffective treatment cases not invalid treatment cases sowhether a gap exists between these two case types remainsunclearus it is also unclear whether the core prescriptionshould be corrected Finally the safety and efficacy of thecore prescriptions were not evaluated and should be in-vestigated in a future study
In summary we adopted a practical approach based onformulae prescribed in clinical practice To our knowledgethis is the first study on CKD treatment with TCM whichcombines frequency analysis association rule learning andcomplex network analysis Using this approach we deter-mined the frequency and combination patterns of CKDtreatment and discovered possibilities for new CKD
treatment prescriptions We also summarized herbal CKDtreatment finding that CKD syndromes are extremelycomplicated and various CKD treatmentmethods exist suchas those for cooling blood and eliminating phlegm How-ever we found that the treatment methods were mainly fortonifying deficiency and clearing heat or dampness
5 Conclusions
Our study found that kidney spleen lung or liver deficiencyand dampness-heat were the primary TCM pathogenesisus the primary treatment principle was tonifying defi-ciency and eliminating dampness and heat Furthermoreour study verified that the integrated analysis method canhelp to explore the TCM treatment strategy is analysis ofherbal TCM prescriptions potentially contributes to thedevelopment of novel drugs for CKD
Data Availability
e data used to support the findings of this study are in-cluded within the article
Conflicts of Interest
e authors declare that there are no conflicts of interestregarding the publication of this article
Table 4 Possible mechanisms of the core Chinese medical herbs for CKD treatment
Increases catalase (CAT) superoxide dismutase(SOD) and glutathione peroxidase (GSH-px)
activities in the kidneys of diabetic rats as well asenhancing renal peroxisome proliferator-activatedreceptor-c (PPARc) expression in diabetic rats [28]
Radix Pseudostellariae (Taizishen) Polysaccharide
Decreases serum triglyceride total cholesterol low-density-lipoprotein cholesterin urea nitrogen andcreatinine increase serum high-density-lipoproteincholesterol and reduce renal histopathology change
[29]
12 Evidence-Based Complementary and Alternative Medicine
Authorsrsquo Contributions
Ping Xia and Kun Gao contributed equally to this studyWeiming He and Kun Gao designed the research Ping XiaMing Shi Wei Li Jing Zhao Jin Yan Qiong Liu Min ZhengXin Wang and Qijing Wu collected and processed the dataPing Xia and Jiadong Xie analyzed the data Wei Sun JihongChen Enchao Zhou and Lingdong Xv participated in in-tellectual discussions Ping Xia and Kun Gao wrote thepaper All authors approved the final edited version of themanuscript
Acknowledgments
is study was financially supported by the PostgraduateResearch amp Practice Innovation Program of Jiangsu Prov-ince (KYCX19_1189 to Ping Xia) and the National NaturalScience Foundation of China (81673912 and 81873259 toKun Gao 81804219 to Jiadong Xie and 81774269 toWeiming He) e authors gratefully acknowledge the as-sistance of Dr Buhui Liu their colleague in the AffiliatedHospital of Nanjing University of Chinese Medicine
References
[1] A Levin M Tonelli J Bonventre et al ldquoGlobal kidney health2017 and beyond a roadmap for closing gaps in care researchand policyrdquo +e Lancet vol 390 no 10105 pp 1888ndash19172017
[2] A C Webster E V Nagler R L Morton and P MassonldquoChronic kidney diseaserdquo +e Lancet vol 389 no 10075pp 1238ndash1252 2017
[3] K J Foreman N Marquez A Dolgert et al ldquoForecasting lifeexpectancy years of life lost and all-cause and cause-specificmortality for 250 causes of death reference and alternativescenarios for 2016ndash40 for 195 countries and territoriesrdquo +eLancet vol 392 no 10159 pp 2052ndash2090 2017
[4] L Zhang F Wang L Wang et al ldquoPrevalence of chronickidney disease in China a cross-sectional surveyrdquo+e Lancetvol 379 no 9818 pp 815ndash822 2012
[5] X Li and HWang ldquoChinese herbal medicine in the treatmentof chronic kidney diseaserdquo Advances in Chronic KidneyDisease vol 12 no 3 pp 276ndash281 2005
[6] Q Zhang L Zhu and W Lerberghe ldquoe importance oftraditional Chinese medicine services in health care provisionin Chinardquo Universitas Forum vol 2 no 2 pp 1ndash8 2011
[7] Y J Wang L Q He W Sun et al ldquoOptimized project oftraditional Chinese medicine in treating chronic kidneydisease stage 3 a multicenter double-blinded randomizedcontrolled trialrdquo Journal of Ethnopharmacology vol 139no 3 pp 757ndash764 2012
[8] Y Chen Y Deng Z Ni et al ldquoEfficacy and safety of tradi-tional Chinese medicine (Shenqi particle) for patients withidiopathic membranous nephropathy a multicenter ran-domized controlled clinical trialrdquo American Journal of KidneyDiseases vol 62 no 6 pp 1068ndash1076 2013
[9] L Zhang P Li C Y Xing et al ldquoEfficacy and safety of Abel-moschus manihot for primary glomerular disease a prospectivemulticenter randomized controlled clinical trialrdquo AmericanJournal of Kidney Diseases vol 64 no 1 pp 57ndash65 2014
[10] W Li W He P Xia et al ldquoTotal extracts of abelmoschusmanihot L Attenuates adriamycin-induced renal tubule
injury via suppression of ROS-ERK12-mediated NLRP3inflammasome activationrdquo Frontiers in Pharmacology vol 10p 567 2019
[11] X Zhang X Zhou R Zhang et al ldquoReal-world clinical datamining on TCM clinical diagnosis and treatment a surveyrdquo inProceedings of the IEEE International Conference on E-HealthNetworking IEEE Beijing China October 2012
[12] L Chen C Y Lee K H Huang Y H Kuan and M ChenldquoPrescription patterns of Chinese herbal products for patientswith sleep disorder and major depressive disorder in TaiwanrdquoJournal of Ethnopharmacology vol 171 pp 307ndash316 2015
[13] J Cao ldquoe Common prescription patterns based on thehierarchical clustering of herb-pairs efficaciesrdquo Evidence-Based Complementary and Alternative Medicine vol 2016Article ID 6373270 7 pages 2016
[14] C J Hu J He J D Xie et al ldquoResearch on TCM treatment oflung cancer based on complex networks methodrdquo Journal ofMedical Informatics vol 39 no 11 pp 63ndash68 2018 inChinese
[15] National Pharmacopoeia Commission Pharmacopoeia of thePeoplersquos Republic of China China Medical Science andTechnology Press Bejing China 2010 in Chinese
[16] Chinese Materia Medica Commission of National Adminis-tration of Traditional Chinese Medicine Chinese MateriaMedica Shanghai Science and Technology Press ShanghaiChina 1999 in Chinese
[17] J Pang J Fu M Yang et al ldquoCorrelation between the dif-ferent therapeutic properties of Chinese medicinal herbs anddelayed luminescencerdquo Luminescence vol 31 no 2pp 323ndash327 2016
[18] X M Chen Z H Ni Y N Liu et al ldquoGuidelines for thediagnosis and treatment of chronic renal failure with inte-grated traditional Chinese and Western medicinerdquo HebeiTraditional ChineseMedicine vol 38 no 2 pp 313ndash317 2016in Chinese
[19] Y Q Zou and E C Zhou ldquoSummary of differentiation andtreatment of traditional Chinese medicine nephropathyrdquoJiangsu Journal of Traditional Chinese Medicine vol 50 no 1pp 1ndash5 2018 in Chinese
[20] Y Qiao L Xu X Tao et al ldquoProtective effects of dioscinagainst fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress fibrosis lipid metabolism and in-flammationrdquo Toxicology Letters vol 284 pp 37ndash45 2018
[21] J Su Y Wei M Liu et al ldquoAnti-hyperuricemic and neph-roprotective effects of Rhizoma Dioscoreae septemlobae ex-tracts and its main component dioscin via regulation ofmOAT1 mURAT1 and mOCT2 in hypertensive micerdquo Ar-chives of Pharmacal Research vol 37 no 10 pp 1336ndash13442014
[22] J H Ye M H Liu X L Zhang et al ldquoChemical profiles andprotective effect of Hedyotis diffusa Willd in lipopolysac-charide-induced renal inflammation micerdquo InternationalJournal of Molecular Sciences vol 16 no 11 pp 27252ndash272692015
[23] X B Sun and N N Yu ldquoRoot of Snow of June for treatingkidney diseasesrdquo Chinese Medicine Guide vol 19 no 10pp 127-128 2013 in Chinese
[24] W Zhang Z X Lin C Xu C Leung and L S ChanldquoAstragalus (a traditional Chinese medicine) for treatingchronic kidney diseaserdquo Cochrane Database of SystematicReviews vol 10 2014
[25] S Ren H Zhang Y Mu et al ldquoPharmacological effects ofAstragaloside IV a literature reviewrdquo Journal of TraditionalChinese Medicine vol 33 no 3 pp 413ndash416 2013
Evidence-Based Complementary and Alternative Medicine 13
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
Table 3 Association rules of herbs for CKD treatment
Evidence-Based Complementary and Alternative Medicine 7
clearing dampness Cluster 4 herbs were prescribed forregulating qi flow eliminating phlegm activating blood andpurging turbidity Herbs in cluster 5 were not frequently usedWe used the complex networkmethod to analyze interactionsbetween herbs and found that the core herbs were RhizomaDioscoreae (Shanyao) Spreading Hedyotis Herb (Baihua-sheshecao) Root of Snow of June (Baimagu) Radix Astragali(Huangqi) Poria (Fulin) Rhizoma Atractylodis Macro-cephalae (Baizhu) Radix Pseudostellariae (Taizishen) andFructus Corni (Shanzhuyu)
e properties and actions of Chinese medicinal herbsare the essential bases for the analysis and clinical use ofherbs ey are summarized in medical practice and basedon the theories of yin and yang zang-fu meridian tropismsand TCM therapeutic principles [17] Chinese medicinal
herb theory is usually summarized as four properties and fivetastes meridian tropism and so on In this study the herbalproperties for CKD treatment were mainly sweet and warmwhich have a replenishing effect e next most frequentlyprescribed herbs had bitter and cold properties whichgenerally have a clearing action us tonifying deficiencywas the most important CKD treatment followed byclearing and disinhibiting is finding reflects the conceptthat TCM replenishes missing substances and rids the bodyof excess substances to regulate the balance of the bodyMeridian tropism is a theory that helps in understanding theorientation of drug action In this study the herbs weregenerally prescribed to target the spleen liver lung stom-ach and kidney meridian (ie the zang-fu requiringtreatment) In one studyrsquos retrospective analysis the basic
Figure 3 Association rule combination matrix e association rule combination matrix was analyzed using R-studio 353 Sizeindicatesconfidence (0855ndash0959) and color indicates lift (1106ndash1667)
8 Evidence-Based Complementary and Alternative Medicine
syndromes of kidney disease were identified as spleen andkidney deficiency lung and kidney qi deficiency and liverand kidney yin deficiency [18] Our research further indi-cates the important role of the kidney spleen stomach liverand lung in nephropathy Similarly the efficacious herbswere mainly deficiency-tonifying herbs heat-clearing herbsand dampness-draining diuretic herbs us these were themain TCM treatments for CKD Conversely the therapeuticprinciple could be used to determine the pathogenesis of thedisease at is the pathogenic factors could be divided intoheat and dampness and deficiency may be mainly caused bythe kidney spleen lung and liver
We identified commonly used herbs and their combina-tions (Tables 1 and 3)emain herbs for CKD treatment wereRhizoma Dioscoreae (Shanyao) Radix Astragali (Huangqi)Poria (Fulin) Rhizoma Atractylodis Macrocephalae (Baizhu)Radix Pseudostellariae (Taizishen) and Fructus Corni(Shanzhuyu) these all have the function of replenishing
Specifically Rhizoma Dioscoreae (Shanyao) targets the spleenlung and kidney Radix Astragali (Huangqi) and RadixPseudostellariae (Taizishen) can supplement the lung andspleen Macrocephalae (Baizhu) and Poria (Fulin) are pre-scribed to invigorate the spleen and Fructus Corni (Shanz-huyu) can nourish the liver and kidney ese six drugs indifferent combinations comprised the 11 most frequentcombinations Among them the most frequent combinationsincluded Rhizoma Dioscoreae (Shanyao) Rhizoma Dioscor-eae (Shanyao) can treat all deficiency syndromes according toTCM theory and is important for tonifying deficiency usherb combinations showed that the tonifying-deficiency cat-egory was the most important for CKD treatment In TCMnephrology kidney deficiency is the basis of kidney diseaseand tonifying kidney treatment should be vital [19] Howeverour research showed that the methods of supplementing thelung and spleen and nourishing the liver and kidney weremore frequently used in CKD Tonifying the spleen lung or
Grouped matrix for 30 Rules Size support Color li
1 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Por
ia (F
ulin
) +1
item
s
3 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Rhi
zom
aAt
ract
ylod
is M
acro
ceph
alae
(Bai
zhu)
+2
item
s
6 ru
les
Por
ia (F
ulin
) Ra
dix
Astr
agal
i (H
uang
qi)
+2 it
ems
6 ru
les
Rhi
zom
a Atr
acty
lodi
s Mac
roce
phal
ae (B
aizh
u)
Fruc
tus C
orni
(Sha
nzhu
yu)
+2 it
ems
14 ru
les
Rad
ix P
seud
oste
llaria
e (Ta
izish
en)
Spre
adin
g H
edyo
tis H
erb(
Baih
uash
eshe
cao)
+5
item
s
Rhizoma Dioscoreae (Shanyao)
Radix Astragali (Huangqi)
Rhizoma Atractylodis Macrocephalae (Baizhu)
Item
s in
LHS
grou
p
RHS
Figure 4 Association rule diagram Association rule learning was performed using R-studio 353 X-axis is the antecedent (or calledlefthandside LHS) and Y-axis is the consequent (or called right-hand side RHS) Size indicates support and color indicates lift
Evidence-Based Complementary and Alternative Medicine 9
liver is well known to achieve the purpose of nourishing thekidney but herbs that tonify the kidney were not frequentlyprescribed in this researchis indicates that amultiple-organdisorder underlies the TCM pathogenesis of CKD When and
how to nourish the kidney directly or indirectly requiresfurther study In TCM practice tonifying-deficiency herbs areoften used in combination with heat-clearing and dampness-draining diuretic herbs Table 3 shows that two or more herbs
Poria (Fulin)
Radix Astragali (Huangqi)Rhizoma Atractylodis
Macrocephalae (Baizhu)
Fructus Corni (Shanzhuyu)
Radix Pseudostellariae (Taizishen)
Fructus Lycii (Gouqizi)
Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis
Herb (Baihuasheshecao)Root of Snow of June (Baimagu)
Rhizoma Imperatae (Baimaogen)
Radix Cirsii Japonici (Daji)
Herba Cirsii (Xiaoji)
Radix Rehmanniae (Shengdihuang)
Common Sage Herb (Lizhicao)
Rhizoma Smilacis Glabrae (Tufulin)
Cortex Phellodendri (Huangbai)
Rhizoma Anemarrhenae (Zhimu)
Pericarpium Citri Reticulatae (Chenpi)
Rhizoma Pinelliae (Banxia)
Semen Coicis (Yiyiren)
Flos Carthami (Honghua)
Radix et Rhizoma Rhei (Dahuang)
Herba Taxilli (Sangjisheng)
Cortex Eucommiae (Duzhong)
Corn Stigma (Yumixu)
Radix Codonopsis (Dangshen)
Radix Salviae Miltiorrhizae (Danshen)
Medicated Leaven (Shenqu)
Radix Saposhnikoviae (Fangfeng)
Radix Ophiopogonis (Maidong)
Herba Taraxaci (Pugongying)
Radix Glycyrrhizae (Gancao)
Cluster dendrogram
Height
Figure 5 Cluster analysis tree diagram e cluster analysis tree diagram was created using R-studio 353 e 32 most frequentlyprescribed herbs were analyzed Each category is represented by a different color
10 Evidence-Based Complementary and Alternative Medicine
were usually combined with Spreading Hedyotis Herb (Bai-huasheshecao) or Root of Snow of June (Baimagu) whichwerethe two most frequently used heat-clearing herbs anddampness-removing diuretic herbs Tonifying treatment wasalso indicated to be more important than heat-clearing ordampness-draining treatment How to balance tonifyingtreatment and clearing-diuresis treatment under specificconditions needs to be investigated further
e pathogenesis of kidney disease is complex and oftenmanifests as multiple syndrome combinationse formulaedetermined by clustering were for composite syndromesHerbs in cluster 1 were for tonifying the lung strengtheningthe spleen and removing dampness and were prescribed totreat spleen-lung qi deficiency and dampness Herbs incluster 2 were for nourishing the liver and kidney andclearing heat or dampness and were prescribed to treat liver-kidney yin deficiency and dampness or heat ose in cluster3 were for nourishing yin clearing heat and cooling bloodese herbs can be found in Zhi Bai Di Huang Wan and are
prescribed to treat fire excess from yin deficiency and blood-heat syndromeose in cluster 4 were for regulating qi floweliminating phlegm activating blood and purging turbidityey were prescribed to treat phlegm-damp blood stasisand turbidity syndromesese four clusters of prescriptionsfor different syndrome types can provide useful ideas forCKD treatment e herbs in cluster 5 had multiple func-tions such as tonifying the kidney releasing the exteriorand promoting digestion It may be used auxiliarily to targetcomplications and requires further study
Complex network analysis revealed eight core herbs forCKD Rhizoma Dioscoreae (Shanyao) Spreading HedyotisHerb (Baihuasheshecao) Root of Snow of June (Baimagu)Radix Astragali (Huangqi) Poria (Fulin) Rhizoma Atrac-tylodis Macrocephalae (Baizhu) Radix Pseudostellariae(Taizishen) and Fructus Corni (Shanzhuyu) Interestinglythese herbs are included in clusters 1 and 2 ey were alsoidentified as high-frequency herbs for CKD treatment so webelieved that such a prescription could be used as a basis for
Spreading Hedyotis
Herb
Fructus Corni
Rhizoma Dioscoreae
Root of Snow of
June
Poria Radix Astragali
Radix Pseudostellariae
Rhizoma Atractylodis
Macrocephalae
124
154
105
100
154
134
99
129
100
115
98
86
95 98
141
119
115
127
87
146
139
136
131
115
112
102
97
97
89
Figure 6 Core prescription network e core prescription network was created using Liquorice e weight represents the frequency withwhich two herbs appeared together
Evidence-Based Complementary and Alternative Medicine 11
further research Modern pharmacology has also shown thatthese herbs can improve kidney injury through anti-in-flammatory and antioxidant activity (Table 4) [20ndash29]
Our data mining approach has several advantages Firstthere was no requirement for the data structure is is verypractical for data mining of Chinese medicine prescriptionsbecause the data structure of most Chinese medicines is notuniform Second we combined a variety of data miningmethods to perform comprehensive analysis and to ensurethat the conclusion was reliable Finally we focused on themain treatment methods and uses of herbs which is anefficient way to learn TCM treatment Our research also hassome limitations We collected only prescription informa-tion but not diagnostic information so our conclusionscannot be completely confirmed We also examined onlyeffective treatment cases not invalid treatment cases sowhether a gap exists between these two case types remainsunclearus it is also unclear whether the core prescriptionshould be corrected Finally the safety and efficacy of thecore prescriptions were not evaluated and should be in-vestigated in a future study
In summary we adopted a practical approach based onformulae prescribed in clinical practice To our knowledgethis is the first study on CKD treatment with TCM whichcombines frequency analysis association rule learning andcomplex network analysis Using this approach we deter-mined the frequency and combination patterns of CKDtreatment and discovered possibilities for new CKD
treatment prescriptions We also summarized herbal CKDtreatment finding that CKD syndromes are extremelycomplicated and various CKD treatmentmethods exist suchas those for cooling blood and eliminating phlegm How-ever we found that the treatment methods were mainly fortonifying deficiency and clearing heat or dampness
5 Conclusions
Our study found that kidney spleen lung or liver deficiencyand dampness-heat were the primary TCM pathogenesisus the primary treatment principle was tonifying defi-ciency and eliminating dampness and heat Furthermoreour study verified that the integrated analysis method canhelp to explore the TCM treatment strategy is analysis ofherbal TCM prescriptions potentially contributes to thedevelopment of novel drugs for CKD
Data Availability
e data used to support the findings of this study are in-cluded within the article
Conflicts of Interest
e authors declare that there are no conflicts of interestregarding the publication of this article
Table 4 Possible mechanisms of the core Chinese medical herbs for CKD treatment
Increases catalase (CAT) superoxide dismutase(SOD) and glutathione peroxidase (GSH-px)
activities in the kidneys of diabetic rats as well asenhancing renal peroxisome proliferator-activatedreceptor-c (PPARc) expression in diabetic rats [28]
Radix Pseudostellariae (Taizishen) Polysaccharide
Decreases serum triglyceride total cholesterol low-density-lipoprotein cholesterin urea nitrogen andcreatinine increase serum high-density-lipoproteincholesterol and reduce renal histopathology change
[29]
12 Evidence-Based Complementary and Alternative Medicine
Authorsrsquo Contributions
Ping Xia and Kun Gao contributed equally to this studyWeiming He and Kun Gao designed the research Ping XiaMing Shi Wei Li Jing Zhao Jin Yan Qiong Liu Min ZhengXin Wang and Qijing Wu collected and processed the dataPing Xia and Jiadong Xie analyzed the data Wei Sun JihongChen Enchao Zhou and Lingdong Xv participated in in-tellectual discussions Ping Xia and Kun Gao wrote thepaper All authors approved the final edited version of themanuscript
Acknowledgments
is study was financially supported by the PostgraduateResearch amp Practice Innovation Program of Jiangsu Prov-ince (KYCX19_1189 to Ping Xia) and the National NaturalScience Foundation of China (81673912 and 81873259 toKun Gao 81804219 to Jiadong Xie and 81774269 toWeiming He) e authors gratefully acknowledge the as-sistance of Dr Buhui Liu their colleague in the AffiliatedHospital of Nanjing University of Chinese Medicine
References
[1] A Levin M Tonelli J Bonventre et al ldquoGlobal kidney health2017 and beyond a roadmap for closing gaps in care researchand policyrdquo +e Lancet vol 390 no 10105 pp 1888ndash19172017
[2] A C Webster E V Nagler R L Morton and P MassonldquoChronic kidney diseaserdquo +e Lancet vol 389 no 10075pp 1238ndash1252 2017
[3] K J Foreman N Marquez A Dolgert et al ldquoForecasting lifeexpectancy years of life lost and all-cause and cause-specificmortality for 250 causes of death reference and alternativescenarios for 2016ndash40 for 195 countries and territoriesrdquo +eLancet vol 392 no 10159 pp 2052ndash2090 2017
[4] L Zhang F Wang L Wang et al ldquoPrevalence of chronickidney disease in China a cross-sectional surveyrdquo+e Lancetvol 379 no 9818 pp 815ndash822 2012
[5] X Li and HWang ldquoChinese herbal medicine in the treatmentof chronic kidney diseaserdquo Advances in Chronic KidneyDisease vol 12 no 3 pp 276ndash281 2005
[6] Q Zhang L Zhu and W Lerberghe ldquoe importance oftraditional Chinese medicine services in health care provisionin Chinardquo Universitas Forum vol 2 no 2 pp 1ndash8 2011
[7] Y J Wang L Q He W Sun et al ldquoOptimized project oftraditional Chinese medicine in treating chronic kidneydisease stage 3 a multicenter double-blinded randomizedcontrolled trialrdquo Journal of Ethnopharmacology vol 139no 3 pp 757ndash764 2012
[8] Y Chen Y Deng Z Ni et al ldquoEfficacy and safety of tradi-tional Chinese medicine (Shenqi particle) for patients withidiopathic membranous nephropathy a multicenter ran-domized controlled clinical trialrdquo American Journal of KidneyDiseases vol 62 no 6 pp 1068ndash1076 2013
[9] L Zhang P Li C Y Xing et al ldquoEfficacy and safety of Abel-moschus manihot for primary glomerular disease a prospectivemulticenter randomized controlled clinical trialrdquo AmericanJournal of Kidney Diseases vol 64 no 1 pp 57ndash65 2014
[10] W Li W He P Xia et al ldquoTotal extracts of abelmoschusmanihot L Attenuates adriamycin-induced renal tubule
injury via suppression of ROS-ERK12-mediated NLRP3inflammasome activationrdquo Frontiers in Pharmacology vol 10p 567 2019
[11] X Zhang X Zhou R Zhang et al ldquoReal-world clinical datamining on TCM clinical diagnosis and treatment a surveyrdquo inProceedings of the IEEE International Conference on E-HealthNetworking IEEE Beijing China October 2012
[12] L Chen C Y Lee K H Huang Y H Kuan and M ChenldquoPrescription patterns of Chinese herbal products for patientswith sleep disorder and major depressive disorder in TaiwanrdquoJournal of Ethnopharmacology vol 171 pp 307ndash316 2015
[13] J Cao ldquoe Common prescription patterns based on thehierarchical clustering of herb-pairs efficaciesrdquo Evidence-Based Complementary and Alternative Medicine vol 2016Article ID 6373270 7 pages 2016
[14] C J Hu J He J D Xie et al ldquoResearch on TCM treatment oflung cancer based on complex networks methodrdquo Journal ofMedical Informatics vol 39 no 11 pp 63ndash68 2018 inChinese
[15] National Pharmacopoeia Commission Pharmacopoeia of thePeoplersquos Republic of China China Medical Science andTechnology Press Bejing China 2010 in Chinese
[16] Chinese Materia Medica Commission of National Adminis-tration of Traditional Chinese Medicine Chinese MateriaMedica Shanghai Science and Technology Press ShanghaiChina 1999 in Chinese
[17] J Pang J Fu M Yang et al ldquoCorrelation between the dif-ferent therapeutic properties of Chinese medicinal herbs anddelayed luminescencerdquo Luminescence vol 31 no 2pp 323ndash327 2016
[18] X M Chen Z H Ni Y N Liu et al ldquoGuidelines for thediagnosis and treatment of chronic renal failure with inte-grated traditional Chinese and Western medicinerdquo HebeiTraditional ChineseMedicine vol 38 no 2 pp 313ndash317 2016in Chinese
[19] Y Q Zou and E C Zhou ldquoSummary of differentiation andtreatment of traditional Chinese medicine nephropathyrdquoJiangsu Journal of Traditional Chinese Medicine vol 50 no 1pp 1ndash5 2018 in Chinese
[20] Y Qiao L Xu X Tao et al ldquoProtective effects of dioscinagainst fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress fibrosis lipid metabolism and in-flammationrdquo Toxicology Letters vol 284 pp 37ndash45 2018
[21] J Su Y Wei M Liu et al ldquoAnti-hyperuricemic and neph-roprotective effects of Rhizoma Dioscoreae septemlobae ex-tracts and its main component dioscin via regulation ofmOAT1 mURAT1 and mOCT2 in hypertensive micerdquo Ar-chives of Pharmacal Research vol 37 no 10 pp 1336ndash13442014
[22] J H Ye M H Liu X L Zhang et al ldquoChemical profiles andprotective effect of Hedyotis diffusa Willd in lipopolysac-charide-induced renal inflammation micerdquo InternationalJournal of Molecular Sciences vol 16 no 11 pp 27252ndash272692015
[23] X B Sun and N N Yu ldquoRoot of Snow of June for treatingkidney diseasesrdquo Chinese Medicine Guide vol 19 no 10pp 127-128 2013 in Chinese
[24] W Zhang Z X Lin C Xu C Leung and L S ChanldquoAstragalus (a traditional Chinese medicine) for treatingchronic kidney diseaserdquo Cochrane Database of SystematicReviews vol 10 2014
[25] S Ren H Zhang Y Mu et al ldquoPharmacological effects ofAstragaloside IV a literature reviewrdquo Journal of TraditionalChinese Medicine vol 33 no 3 pp 413ndash416 2013
Evidence-Based Complementary and Alternative Medicine 13
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
clearing dampness Cluster 4 herbs were prescribed forregulating qi flow eliminating phlegm activating blood andpurging turbidity Herbs in cluster 5 were not frequently usedWe used the complex networkmethod to analyze interactionsbetween herbs and found that the core herbs were RhizomaDioscoreae (Shanyao) Spreading Hedyotis Herb (Baihua-sheshecao) Root of Snow of June (Baimagu) Radix Astragali(Huangqi) Poria (Fulin) Rhizoma Atractylodis Macro-cephalae (Baizhu) Radix Pseudostellariae (Taizishen) andFructus Corni (Shanzhuyu)
e properties and actions of Chinese medicinal herbsare the essential bases for the analysis and clinical use ofherbs ey are summarized in medical practice and basedon the theories of yin and yang zang-fu meridian tropismsand TCM therapeutic principles [17] Chinese medicinal
herb theory is usually summarized as four properties and fivetastes meridian tropism and so on In this study the herbalproperties for CKD treatment were mainly sweet and warmwhich have a replenishing effect e next most frequentlyprescribed herbs had bitter and cold properties whichgenerally have a clearing action us tonifying deficiencywas the most important CKD treatment followed byclearing and disinhibiting is finding reflects the conceptthat TCM replenishes missing substances and rids the bodyof excess substances to regulate the balance of the bodyMeridian tropism is a theory that helps in understanding theorientation of drug action In this study the herbs weregenerally prescribed to target the spleen liver lung stom-ach and kidney meridian (ie the zang-fu requiringtreatment) In one studyrsquos retrospective analysis the basic
Figure 3 Association rule combination matrix e association rule combination matrix was analyzed using R-studio 353 Sizeindicatesconfidence (0855ndash0959) and color indicates lift (1106ndash1667)
8 Evidence-Based Complementary and Alternative Medicine
syndromes of kidney disease were identified as spleen andkidney deficiency lung and kidney qi deficiency and liverand kidney yin deficiency [18] Our research further indi-cates the important role of the kidney spleen stomach liverand lung in nephropathy Similarly the efficacious herbswere mainly deficiency-tonifying herbs heat-clearing herbsand dampness-draining diuretic herbs us these were themain TCM treatments for CKD Conversely the therapeuticprinciple could be used to determine the pathogenesis of thedisease at is the pathogenic factors could be divided intoheat and dampness and deficiency may be mainly caused bythe kidney spleen lung and liver
We identified commonly used herbs and their combina-tions (Tables 1 and 3)emain herbs for CKD treatment wereRhizoma Dioscoreae (Shanyao) Radix Astragali (Huangqi)Poria (Fulin) Rhizoma Atractylodis Macrocephalae (Baizhu)Radix Pseudostellariae (Taizishen) and Fructus Corni(Shanzhuyu) these all have the function of replenishing
Specifically Rhizoma Dioscoreae (Shanyao) targets the spleenlung and kidney Radix Astragali (Huangqi) and RadixPseudostellariae (Taizishen) can supplement the lung andspleen Macrocephalae (Baizhu) and Poria (Fulin) are pre-scribed to invigorate the spleen and Fructus Corni (Shanz-huyu) can nourish the liver and kidney ese six drugs indifferent combinations comprised the 11 most frequentcombinations Among them the most frequent combinationsincluded Rhizoma Dioscoreae (Shanyao) Rhizoma Dioscor-eae (Shanyao) can treat all deficiency syndromes according toTCM theory and is important for tonifying deficiency usherb combinations showed that the tonifying-deficiency cat-egory was the most important for CKD treatment In TCMnephrology kidney deficiency is the basis of kidney diseaseand tonifying kidney treatment should be vital [19] Howeverour research showed that the methods of supplementing thelung and spleen and nourishing the liver and kidney weremore frequently used in CKD Tonifying the spleen lung or
Grouped matrix for 30 Rules Size support Color li
1 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Por
ia (F
ulin
) +1
item
s
3 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Rhi
zom
aAt
ract
ylod
is M
acro
ceph
alae
(Bai
zhu)
+2
item
s
6 ru
les
Por
ia (F
ulin
) Ra
dix
Astr
agal
i (H
uang
qi)
+2 it
ems
6 ru
les
Rhi
zom
a Atr
acty
lodi
s Mac
roce
phal
ae (B
aizh
u)
Fruc
tus C
orni
(Sha
nzhu
yu)
+2 it
ems
14 ru
les
Rad
ix P
seud
oste
llaria
e (Ta
izish
en)
Spre
adin
g H
edyo
tis H
erb(
Baih
uash
eshe
cao)
+5
item
s
Rhizoma Dioscoreae (Shanyao)
Radix Astragali (Huangqi)
Rhizoma Atractylodis Macrocephalae (Baizhu)
Item
s in
LHS
grou
p
RHS
Figure 4 Association rule diagram Association rule learning was performed using R-studio 353 X-axis is the antecedent (or calledlefthandside LHS) and Y-axis is the consequent (or called right-hand side RHS) Size indicates support and color indicates lift
Evidence-Based Complementary and Alternative Medicine 9
liver is well known to achieve the purpose of nourishing thekidney but herbs that tonify the kidney were not frequentlyprescribed in this researchis indicates that amultiple-organdisorder underlies the TCM pathogenesis of CKD When and
how to nourish the kidney directly or indirectly requiresfurther study In TCM practice tonifying-deficiency herbs areoften used in combination with heat-clearing and dampness-draining diuretic herbs Table 3 shows that two or more herbs
Poria (Fulin)
Radix Astragali (Huangqi)Rhizoma Atractylodis
Macrocephalae (Baizhu)
Fructus Corni (Shanzhuyu)
Radix Pseudostellariae (Taizishen)
Fructus Lycii (Gouqizi)
Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis
Herb (Baihuasheshecao)Root of Snow of June (Baimagu)
Rhizoma Imperatae (Baimaogen)
Radix Cirsii Japonici (Daji)
Herba Cirsii (Xiaoji)
Radix Rehmanniae (Shengdihuang)
Common Sage Herb (Lizhicao)
Rhizoma Smilacis Glabrae (Tufulin)
Cortex Phellodendri (Huangbai)
Rhizoma Anemarrhenae (Zhimu)
Pericarpium Citri Reticulatae (Chenpi)
Rhizoma Pinelliae (Banxia)
Semen Coicis (Yiyiren)
Flos Carthami (Honghua)
Radix et Rhizoma Rhei (Dahuang)
Herba Taxilli (Sangjisheng)
Cortex Eucommiae (Duzhong)
Corn Stigma (Yumixu)
Radix Codonopsis (Dangshen)
Radix Salviae Miltiorrhizae (Danshen)
Medicated Leaven (Shenqu)
Radix Saposhnikoviae (Fangfeng)
Radix Ophiopogonis (Maidong)
Herba Taraxaci (Pugongying)
Radix Glycyrrhizae (Gancao)
Cluster dendrogram
Height
Figure 5 Cluster analysis tree diagram e cluster analysis tree diagram was created using R-studio 353 e 32 most frequentlyprescribed herbs were analyzed Each category is represented by a different color
10 Evidence-Based Complementary and Alternative Medicine
were usually combined with Spreading Hedyotis Herb (Bai-huasheshecao) or Root of Snow of June (Baimagu) whichwerethe two most frequently used heat-clearing herbs anddampness-removing diuretic herbs Tonifying treatment wasalso indicated to be more important than heat-clearing ordampness-draining treatment How to balance tonifyingtreatment and clearing-diuresis treatment under specificconditions needs to be investigated further
e pathogenesis of kidney disease is complex and oftenmanifests as multiple syndrome combinationse formulaedetermined by clustering were for composite syndromesHerbs in cluster 1 were for tonifying the lung strengtheningthe spleen and removing dampness and were prescribed totreat spleen-lung qi deficiency and dampness Herbs incluster 2 were for nourishing the liver and kidney andclearing heat or dampness and were prescribed to treat liver-kidney yin deficiency and dampness or heat ose in cluster3 were for nourishing yin clearing heat and cooling bloodese herbs can be found in Zhi Bai Di Huang Wan and are
prescribed to treat fire excess from yin deficiency and blood-heat syndromeose in cluster 4 were for regulating qi floweliminating phlegm activating blood and purging turbidityey were prescribed to treat phlegm-damp blood stasisand turbidity syndromesese four clusters of prescriptionsfor different syndrome types can provide useful ideas forCKD treatment e herbs in cluster 5 had multiple func-tions such as tonifying the kidney releasing the exteriorand promoting digestion It may be used auxiliarily to targetcomplications and requires further study
Complex network analysis revealed eight core herbs forCKD Rhizoma Dioscoreae (Shanyao) Spreading HedyotisHerb (Baihuasheshecao) Root of Snow of June (Baimagu)Radix Astragali (Huangqi) Poria (Fulin) Rhizoma Atrac-tylodis Macrocephalae (Baizhu) Radix Pseudostellariae(Taizishen) and Fructus Corni (Shanzhuyu) Interestinglythese herbs are included in clusters 1 and 2 ey were alsoidentified as high-frequency herbs for CKD treatment so webelieved that such a prescription could be used as a basis for
Spreading Hedyotis
Herb
Fructus Corni
Rhizoma Dioscoreae
Root of Snow of
June
Poria Radix Astragali
Radix Pseudostellariae
Rhizoma Atractylodis
Macrocephalae
124
154
105
100
154
134
99
129
100
115
98
86
95 98
141
119
115
127
87
146
139
136
131
115
112
102
97
97
89
Figure 6 Core prescription network e core prescription network was created using Liquorice e weight represents the frequency withwhich two herbs appeared together
Evidence-Based Complementary and Alternative Medicine 11
further research Modern pharmacology has also shown thatthese herbs can improve kidney injury through anti-in-flammatory and antioxidant activity (Table 4) [20ndash29]
Our data mining approach has several advantages Firstthere was no requirement for the data structure is is verypractical for data mining of Chinese medicine prescriptionsbecause the data structure of most Chinese medicines is notuniform Second we combined a variety of data miningmethods to perform comprehensive analysis and to ensurethat the conclusion was reliable Finally we focused on themain treatment methods and uses of herbs which is anefficient way to learn TCM treatment Our research also hassome limitations We collected only prescription informa-tion but not diagnostic information so our conclusionscannot be completely confirmed We also examined onlyeffective treatment cases not invalid treatment cases sowhether a gap exists between these two case types remainsunclearus it is also unclear whether the core prescriptionshould be corrected Finally the safety and efficacy of thecore prescriptions were not evaluated and should be in-vestigated in a future study
In summary we adopted a practical approach based onformulae prescribed in clinical practice To our knowledgethis is the first study on CKD treatment with TCM whichcombines frequency analysis association rule learning andcomplex network analysis Using this approach we deter-mined the frequency and combination patterns of CKDtreatment and discovered possibilities for new CKD
treatment prescriptions We also summarized herbal CKDtreatment finding that CKD syndromes are extremelycomplicated and various CKD treatmentmethods exist suchas those for cooling blood and eliminating phlegm How-ever we found that the treatment methods were mainly fortonifying deficiency and clearing heat or dampness
5 Conclusions
Our study found that kidney spleen lung or liver deficiencyand dampness-heat were the primary TCM pathogenesisus the primary treatment principle was tonifying defi-ciency and eliminating dampness and heat Furthermoreour study verified that the integrated analysis method canhelp to explore the TCM treatment strategy is analysis ofherbal TCM prescriptions potentially contributes to thedevelopment of novel drugs for CKD
Data Availability
e data used to support the findings of this study are in-cluded within the article
Conflicts of Interest
e authors declare that there are no conflicts of interestregarding the publication of this article
Table 4 Possible mechanisms of the core Chinese medical herbs for CKD treatment
Increases catalase (CAT) superoxide dismutase(SOD) and glutathione peroxidase (GSH-px)
activities in the kidneys of diabetic rats as well asenhancing renal peroxisome proliferator-activatedreceptor-c (PPARc) expression in diabetic rats [28]
Radix Pseudostellariae (Taizishen) Polysaccharide
Decreases serum triglyceride total cholesterol low-density-lipoprotein cholesterin urea nitrogen andcreatinine increase serum high-density-lipoproteincholesterol and reduce renal histopathology change
[29]
12 Evidence-Based Complementary and Alternative Medicine
Authorsrsquo Contributions
Ping Xia and Kun Gao contributed equally to this studyWeiming He and Kun Gao designed the research Ping XiaMing Shi Wei Li Jing Zhao Jin Yan Qiong Liu Min ZhengXin Wang and Qijing Wu collected and processed the dataPing Xia and Jiadong Xie analyzed the data Wei Sun JihongChen Enchao Zhou and Lingdong Xv participated in in-tellectual discussions Ping Xia and Kun Gao wrote thepaper All authors approved the final edited version of themanuscript
Acknowledgments
is study was financially supported by the PostgraduateResearch amp Practice Innovation Program of Jiangsu Prov-ince (KYCX19_1189 to Ping Xia) and the National NaturalScience Foundation of China (81673912 and 81873259 toKun Gao 81804219 to Jiadong Xie and 81774269 toWeiming He) e authors gratefully acknowledge the as-sistance of Dr Buhui Liu their colleague in the AffiliatedHospital of Nanjing University of Chinese Medicine
References
[1] A Levin M Tonelli J Bonventre et al ldquoGlobal kidney health2017 and beyond a roadmap for closing gaps in care researchand policyrdquo +e Lancet vol 390 no 10105 pp 1888ndash19172017
[2] A C Webster E V Nagler R L Morton and P MassonldquoChronic kidney diseaserdquo +e Lancet vol 389 no 10075pp 1238ndash1252 2017
[3] K J Foreman N Marquez A Dolgert et al ldquoForecasting lifeexpectancy years of life lost and all-cause and cause-specificmortality for 250 causes of death reference and alternativescenarios for 2016ndash40 for 195 countries and territoriesrdquo +eLancet vol 392 no 10159 pp 2052ndash2090 2017
[4] L Zhang F Wang L Wang et al ldquoPrevalence of chronickidney disease in China a cross-sectional surveyrdquo+e Lancetvol 379 no 9818 pp 815ndash822 2012
[5] X Li and HWang ldquoChinese herbal medicine in the treatmentof chronic kidney diseaserdquo Advances in Chronic KidneyDisease vol 12 no 3 pp 276ndash281 2005
[6] Q Zhang L Zhu and W Lerberghe ldquoe importance oftraditional Chinese medicine services in health care provisionin Chinardquo Universitas Forum vol 2 no 2 pp 1ndash8 2011
[7] Y J Wang L Q He W Sun et al ldquoOptimized project oftraditional Chinese medicine in treating chronic kidneydisease stage 3 a multicenter double-blinded randomizedcontrolled trialrdquo Journal of Ethnopharmacology vol 139no 3 pp 757ndash764 2012
[8] Y Chen Y Deng Z Ni et al ldquoEfficacy and safety of tradi-tional Chinese medicine (Shenqi particle) for patients withidiopathic membranous nephropathy a multicenter ran-domized controlled clinical trialrdquo American Journal of KidneyDiseases vol 62 no 6 pp 1068ndash1076 2013
[9] L Zhang P Li C Y Xing et al ldquoEfficacy and safety of Abel-moschus manihot for primary glomerular disease a prospectivemulticenter randomized controlled clinical trialrdquo AmericanJournal of Kidney Diseases vol 64 no 1 pp 57ndash65 2014
[10] W Li W He P Xia et al ldquoTotal extracts of abelmoschusmanihot L Attenuates adriamycin-induced renal tubule
injury via suppression of ROS-ERK12-mediated NLRP3inflammasome activationrdquo Frontiers in Pharmacology vol 10p 567 2019
[11] X Zhang X Zhou R Zhang et al ldquoReal-world clinical datamining on TCM clinical diagnosis and treatment a surveyrdquo inProceedings of the IEEE International Conference on E-HealthNetworking IEEE Beijing China October 2012
[12] L Chen C Y Lee K H Huang Y H Kuan and M ChenldquoPrescription patterns of Chinese herbal products for patientswith sleep disorder and major depressive disorder in TaiwanrdquoJournal of Ethnopharmacology vol 171 pp 307ndash316 2015
[13] J Cao ldquoe Common prescription patterns based on thehierarchical clustering of herb-pairs efficaciesrdquo Evidence-Based Complementary and Alternative Medicine vol 2016Article ID 6373270 7 pages 2016
[14] C J Hu J He J D Xie et al ldquoResearch on TCM treatment oflung cancer based on complex networks methodrdquo Journal ofMedical Informatics vol 39 no 11 pp 63ndash68 2018 inChinese
[15] National Pharmacopoeia Commission Pharmacopoeia of thePeoplersquos Republic of China China Medical Science andTechnology Press Bejing China 2010 in Chinese
[16] Chinese Materia Medica Commission of National Adminis-tration of Traditional Chinese Medicine Chinese MateriaMedica Shanghai Science and Technology Press ShanghaiChina 1999 in Chinese
[17] J Pang J Fu M Yang et al ldquoCorrelation between the dif-ferent therapeutic properties of Chinese medicinal herbs anddelayed luminescencerdquo Luminescence vol 31 no 2pp 323ndash327 2016
[18] X M Chen Z H Ni Y N Liu et al ldquoGuidelines for thediagnosis and treatment of chronic renal failure with inte-grated traditional Chinese and Western medicinerdquo HebeiTraditional ChineseMedicine vol 38 no 2 pp 313ndash317 2016in Chinese
[19] Y Q Zou and E C Zhou ldquoSummary of differentiation andtreatment of traditional Chinese medicine nephropathyrdquoJiangsu Journal of Traditional Chinese Medicine vol 50 no 1pp 1ndash5 2018 in Chinese
[20] Y Qiao L Xu X Tao et al ldquoProtective effects of dioscinagainst fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress fibrosis lipid metabolism and in-flammationrdquo Toxicology Letters vol 284 pp 37ndash45 2018
[21] J Su Y Wei M Liu et al ldquoAnti-hyperuricemic and neph-roprotective effects of Rhizoma Dioscoreae septemlobae ex-tracts and its main component dioscin via regulation ofmOAT1 mURAT1 and mOCT2 in hypertensive micerdquo Ar-chives of Pharmacal Research vol 37 no 10 pp 1336ndash13442014
[22] J H Ye M H Liu X L Zhang et al ldquoChemical profiles andprotective effect of Hedyotis diffusa Willd in lipopolysac-charide-induced renal inflammation micerdquo InternationalJournal of Molecular Sciences vol 16 no 11 pp 27252ndash272692015
[23] X B Sun and N N Yu ldquoRoot of Snow of June for treatingkidney diseasesrdquo Chinese Medicine Guide vol 19 no 10pp 127-128 2013 in Chinese
[24] W Zhang Z X Lin C Xu C Leung and L S ChanldquoAstragalus (a traditional Chinese medicine) for treatingchronic kidney diseaserdquo Cochrane Database of SystematicReviews vol 10 2014
[25] S Ren H Zhang Y Mu et al ldquoPharmacological effects ofAstragaloside IV a literature reviewrdquo Journal of TraditionalChinese Medicine vol 33 no 3 pp 413ndash416 2013
Evidence-Based Complementary and Alternative Medicine 13
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
syndromes of kidney disease were identified as spleen andkidney deficiency lung and kidney qi deficiency and liverand kidney yin deficiency [18] Our research further indi-cates the important role of the kidney spleen stomach liverand lung in nephropathy Similarly the efficacious herbswere mainly deficiency-tonifying herbs heat-clearing herbsand dampness-draining diuretic herbs us these were themain TCM treatments for CKD Conversely the therapeuticprinciple could be used to determine the pathogenesis of thedisease at is the pathogenic factors could be divided intoheat and dampness and deficiency may be mainly caused bythe kidney spleen lung and liver
We identified commonly used herbs and their combina-tions (Tables 1 and 3)emain herbs for CKD treatment wereRhizoma Dioscoreae (Shanyao) Radix Astragali (Huangqi)Poria (Fulin) Rhizoma Atractylodis Macrocephalae (Baizhu)Radix Pseudostellariae (Taizishen) and Fructus Corni(Shanzhuyu) these all have the function of replenishing
Specifically Rhizoma Dioscoreae (Shanyao) targets the spleenlung and kidney Radix Astragali (Huangqi) and RadixPseudostellariae (Taizishen) can supplement the lung andspleen Macrocephalae (Baizhu) and Poria (Fulin) are pre-scribed to invigorate the spleen and Fructus Corni (Shanz-huyu) can nourish the liver and kidney ese six drugs indifferent combinations comprised the 11 most frequentcombinations Among them the most frequent combinationsincluded Rhizoma Dioscoreae (Shanyao) Rhizoma Dioscor-eae (Shanyao) can treat all deficiency syndromes according toTCM theory and is important for tonifying deficiency usherb combinations showed that the tonifying-deficiency cat-egory was the most important for CKD treatment In TCMnephrology kidney deficiency is the basis of kidney diseaseand tonifying kidney treatment should be vital [19] Howeverour research showed that the methods of supplementing thelung and spleen and nourishing the liver and kidney weremore frequently used in CKD Tonifying the spleen lung or
Grouped matrix for 30 Rules Size support Color li
1 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Por
ia (F
ulin
) +1
item
s
3 ru
les
Rhi
zom
a Dio
scor
eae (
Shan
yao)
Rhi
zom
aAt
ract
ylod
is M
acro
ceph
alae
(Bai
zhu)
+2
item
s
6 ru
les
Por
ia (F
ulin
) Ra
dix
Astr
agal
i (H
uang
qi)
+2 it
ems
6 ru
les
Rhi
zom
a Atr
acty
lodi
s Mac
roce
phal
ae (B
aizh
u)
Fruc
tus C
orni
(Sha
nzhu
yu)
+2 it
ems
14 ru
les
Rad
ix P
seud
oste
llaria
e (Ta
izish
en)
Spre
adin
g H
edyo
tis H
erb(
Baih
uash
eshe
cao)
+5
item
s
Rhizoma Dioscoreae (Shanyao)
Radix Astragali (Huangqi)
Rhizoma Atractylodis Macrocephalae (Baizhu)
Item
s in
LHS
grou
p
RHS
Figure 4 Association rule diagram Association rule learning was performed using R-studio 353 X-axis is the antecedent (or calledlefthandside LHS) and Y-axis is the consequent (or called right-hand side RHS) Size indicates support and color indicates lift
Evidence-Based Complementary and Alternative Medicine 9
liver is well known to achieve the purpose of nourishing thekidney but herbs that tonify the kidney were not frequentlyprescribed in this researchis indicates that amultiple-organdisorder underlies the TCM pathogenesis of CKD When and
how to nourish the kidney directly or indirectly requiresfurther study In TCM practice tonifying-deficiency herbs areoften used in combination with heat-clearing and dampness-draining diuretic herbs Table 3 shows that two or more herbs
Poria (Fulin)
Radix Astragali (Huangqi)Rhizoma Atractylodis
Macrocephalae (Baizhu)
Fructus Corni (Shanzhuyu)
Radix Pseudostellariae (Taizishen)
Fructus Lycii (Gouqizi)
Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis
Herb (Baihuasheshecao)Root of Snow of June (Baimagu)
Rhizoma Imperatae (Baimaogen)
Radix Cirsii Japonici (Daji)
Herba Cirsii (Xiaoji)
Radix Rehmanniae (Shengdihuang)
Common Sage Herb (Lizhicao)
Rhizoma Smilacis Glabrae (Tufulin)
Cortex Phellodendri (Huangbai)
Rhizoma Anemarrhenae (Zhimu)
Pericarpium Citri Reticulatae (Chenpi)
Rhizoma Pinelliae (Banxia)
Semen Coicis (Yiyiren)
Flos Carthami (Honghua)
Radix et Rhizoma Rhei (Dahuang)
Herba Taxilli (Sangjisheng)
Cortex Eucommiae (Duzhong)
Corn Stigma (Yumixu)
Radix Codonopsis (Dangshen)
Radix Salviae Miltiorrhizae (Danshen)
Medicated Leaven (Shenqu)
Radix Saposhnikoviae (Fangfeng)
Radix Ophiopogonis (Maidong)
Herba Taraxaci (Pugongying)
Radix Glycyrrhizae (Gancao)
Cluster dendrogram
Height
Figure 5 Cluster analysis tree diagram e cluster analysis tree diagram was created using R-studio 353 e 32 most frequentlyprescribed herbs were analyzed Each category is represented by a different color
10 Evidence-Based Complementary and Alternative Medicine
were usually combined with Spreading Hedyotis Herb (Bai-huasheshecao) or Root of Snow of June (Baimagu) whichwerethe two most frequently used heat-clearing herbs anddampness-removing diuretic herbs Tonifying treatment wasalso indicated to be more important than heat-clearing ordampness-draining treatment How to balance tonifyingtreatment and clearing-diuresis treatment under specificconditions needs to be investigated further
e pathogenesis of kidney disease is complex and oftenmanifests as multiple syndrome combinationse formulaedetermined by clustering were for composite syndromesHerbs in cluster 1 were for tonifying the lung strengtheningthe spleen and removing dampness and were prescribed totreat spleen-lung qi deficiency and dampness Herbs incluster 2 were for nourishing the liver and kidney andclearing heat or dampness and were prescribed to treat liver-kidney yin deficiency and dampness or heat ose in cluster3 were for nourishing yin clearing heat and cooling bloodese herbs can be found in Zhi Bai Di Huang Wan and are
prescribed to treat fire excess from yin deficiency and blood-heat syndromeose in cluster 4 were for regulating qi floweliminating phlegm activating blood and purging turbidityey were prescribed to treat phlegm-damp blood stasisand turbidity syndromesese four clusters of prescriptionsfor different syndrome types can provide useful ideas forCKD treatment e herbs in cluster 5 had multiple func-tions such as tonifying the kidney releasing the exteriorand promoting digestion It may be used auxiliarily to targetcomplications and requires further study
Complex network analysis revealed eight core herbs forCKD Rhizoma Dioscoreae (Shanyao) Spreading HedyotisHerb (Baihuasheshecao) Root of Snow of June (Baimagu)Radix Astragali (Huangqi) Poria (Fulin) Rhizoma Atrac-tylodis Macrocephalae (Baizhu) Radix Pseudostellariae(Taizishen) and Fructus Corni (Shanzhuyu) Interestinglythese herbs are included in clusters 1 and 2 ey were alsoidentified as high-frequency herbs for CKD treatment so webelieved that such a prescription could be used as a basis for
Spreading Hedyotis
Herb
Fructus Corni
Rhizoma Dioscoreae
Root of Snow of
June
Poria Radix Astragali
Radix Pseudostellariae
Rhizoma Atractylodis
Macrocephalae
124
154
105
100
154
134
99
129
100
115
98
86
95 98
141
119
115
127
87
146
139
136
131
115
112
102
97
97
89
Figure 6 Core prescription network e core prescription network was created using Liquorice e weight represents the frequency withwhich two herbs appeared together
Evidence-Based Complementary and Alternative Medicine 11
further research Modern pharmacology has also shown thatthese herbs can improve kidney injury through anti-in-flammatory and antioxidant activity (Table 4) [20ndash29]
Our data mining approach has several advantages Firstthere was no requirement for the data structure is is verypractical for data mining of Chinese medicine prescriptionsbecause the data structure of most Chinese medicines is notuniform Second we combined a variety of data miningmethods to perform comprehensive analysis and to ensurethat the conclusion was reliable Finally we focused on themain treatment methods and uses of herbs which is anefficient way to learn TCM treatment Our research also hassome limitations We collected only prescription informa-tion but not diagnostic information so our conclusionscannot be completely confirmed We also examined onlyeffective treatment cases not invalid treatment cases sowhether a gap exists between these two case types remainsunclearus it is also unclear whether the core prescriptionshould be corrected Finally the safety and efficacy of thecore prescriptions were not evaluated and should be in-vestigated in a future study
In summary we adopted a practical approach based onformulae prescribed in clinical practice To our knowledgethis is the first study on CKD treatment with TCM whichcombines frequency analysis association rule learning andcomplex network analysis Using this approach we deter-mined the frequency and combination patterns of CKDtreatment and discovered possibilities for new CKD
treatment prescriptions We also summarized herbal CKDtreatment finding that CKD syndromes are extremelycomplicated and various CKD treatmentmethods exist suchas those for cooling blood and eliminating phlegm How-ever we found that the treatment methods were mainly fortonifying deficiency and clearing heat or dampness
5 Conclusions
Our study found that kidney spleen lung or liver deficiencyand dampness-heat were the primary TCM pathogenesisus the primary treatment principle was tonifying defi-ciency and eliminating dampness and heat Furthermoreour study verified that the integrated analysis method canhelp to explore the TCM treatment strategy is analysis ofherbal TCM prescriptions potentially contributes to thedevelopment of novel drugs for CKD
Data Availability
e data used to support the findings of this study are in-cluded within the article
Conflicts of Interest
e authors declare that there are no conflicts of interestregarding the publication of this article
Table 4 Possible mechanisms of the core Chinese medical herbs for CKD treatment
Increases catalase (CAT) superoxide dismutase(SOD) and glutathione peroxidase (GSH-px)
activities in the kidneys of diabetic rats as well asenhancing renal peroxisome proliferator-activatedreceptor-c (PPARc) expression in diabetic rats [28]
Radix Pseudostellariae (Taizishen) Polysaccharide
Decreases serum triglyceride total cholesterol low-density-lipoprotein cholesterin urea nitrogen andcreatinine increase serum high-density-lipoproteincholesterol and reduce renal histopathology change
[29]
12 Evidence-Based Complementary and Alternative Medicine
Authorsrsquo Contributions
Ping Xia and Kun Gao contributed equally to this studyWeiming He and Kun Gao designed the research Ping XiaMing Shi Wei Li Jing Zhao Jin Yan Qiong Liu Min ZhengXin Wang and Qijing Wu collected and processed the dataPing Xia and Jiadong Xie analyzed the data Wei Sun JihongChen Enchao Zhou and Lingdong Xv participated in in-tellectual discussions Ping Xia and Kun Gao wrote thepaper All authors approved the final edited version of themanuscript
Acknowledgments
is study was financially supported by the PostgraduateResearch amp Practice Innovation Program of Jiangsu Prov-ince (KYCX19_1189 to Ping Xia) and the National NaturalScience Foundation of China (81673912 and 81873259 toKun Gao 81804219 to Jiadong Xie and 81774269 toWeiming He) e authors gratefully acknowledge the as-sistance of Dr Buhui Liu their colleague in the AffiliatedHospital of Nanjing University of Chinese Medicine
References
[1] A Levin M Tonelli J Bonventre et al ldquoGlobal kidney health2017 and beyond a roadmap for closing gaps in care researchand policyrdquo +e Lancet vol 390 no 10105 pp 1888ndash19172017
[2] A C Webster E V Nagler R L Morton and P MassonldquoChronic kidney diseaserdquo +e Lancet vol 389 no 10075pp 1238ndash1252 2017
[3] K J Foreman N Marquez A Dolgert et al ldquoForecasting lifeexpectancy years of life lost and all-cause and cause-specificmortality for 250 causes of death reference and alternativescenarios for 2016ndash40 for 195 countries and territoriesrdquo +eLancet vol 392 no 10159 pp 2052ndash2090 2017
[4] L Zhang F Wang L Wang et al ldquoPrevalence of chronickidney disease in China a cross-sectional surveyrdquo+e Lancetvol 379 no 9818 pp 815ndash822 2012
[5] X Li and HWang ldquoChinese herbal medicine in the treatmentof chronic kidney diseaserdquo Advances in Chronic KidneyDisease vol 12 no 3 pp 276ndash281 2005
[6] Q Zhang L Zhu and W Lerberghe ldquoe importance oftraditional Chinese medicine services in health care provisionin Chinardquo Universitas Forum vol 2 no 2 pp 1ndash8 2011
[7] Y J Wang L Q He W Sun et al ldquoOptimized project oftraditional Chinese medicine in treating chronic kidneydisease stage 3 a multicenter double-blinded randomizedcontrolled trialrdquo Journal of Ethnopharmacology vol 139no 3 pp 757ndash764 2012
[8] Y Chen Y Deng Z Ni et al ldquoEfficacy and safety of tradi-tional Chinese medicine (Shenqi particle) for patients withidiopathic membranous nephropathy a multicenter ran-domized controlled clinical trialrdquo American Journal of KidneyDiseases vol 62 no 6 pp 1068ndash1076 2013
[9] L Zhang P Li C Y Xing et al ldquoEfficacy and safety of Abel-moschus manihot for primary glomerular disease a prospectivemulticenter randomized controlled clinical trialrdquo AmericanJournal of Kidney Diseases vol 64 no 1 pp 57ndash65 2014
[10] W Li W He P Xia et al ldquoTotal extracts of abelmoschusmanihot L Attenuates adriamycin-induced renal tubule
injury via suppression of ROS-ERK12-mediated NLRP3inflammasome activationrdquo Frontiers in Pharmacology vol 10p 567 2019
[11] X Zhang X Zhou R Zhang et al ldquoReal-world clinical datamining on TCM clinical diagnosis and treatment a surveyrdquo inProceedings of the IEEE International Conference on E-HealthNetworking IEEE Beijing China October 2012
[12] L Chen C Y Lee K H Huang Y H Kuan and M ChenldquoPrescription patterns of Chinese herbal products for patientswith sleep disorder and major depressive disorder in TaiwanrdquoJournal of Ethnopharmacology vol 171 pp 307ndash316 2015
[13] J Cao ldquoe Common prescription patterns based on thehierarchical clustering of herb-pairs efficaciesrdquo Evidence-Based Complementary and Alternative Medicine vol 2016Article ID 6373270 7 pages 2016
[14] C J Hu J He J D Xie et al ldquoResearch on TCM treatment oflung cancer based on complex networks methodrdquo Journal ofMedical Informatics vol 39 no 11 pp 63ndash68 2018 inChinese
[15] National Pharmacopoeia Commission Pharmacopoeia of thePeoplersquos Republic of China China Medical Science andTechnology Press Bejing China 2010 in Chinese
[16] Chinese Materia Medica Commission of National Adminis-tration of Traditional Chinese Medicine Chinese MateriaMedica Shanghai Science and Technology Press ShanghaiChina 1999 in Chinese
[17] J Pang J Fu M Yang et al ldquoCorrelation between the dif-ferent therapeutic properties of Chinese medicinal herbs anddelayed luminescencerdquo Luminescence vol 31 no 2pp 323ndash327 2016
[18] X M Chen Z H Ni Y N Liu et al ldquoGuidelines for thediagnosis and treatment of chronic renal failure with inte-grated traditional Chinese and Western medicinerdquo HebeiTraditional ChineseMedicine vol 38 no 2 pp 313ndash317 2016in Chinese
[19] Y Q Zou and E C Zhou ldquoSummary of differentiation andtreatment of traditional Chinese medicine nephropathyrdquoJiangsu Journal of Traditional Chinese Medicine vol 50 no 1pp 1ndash5 2018 in Chinese
[20] Y Qiao L Xu X Tao et al ldquoProtective effects of dioscinagainst fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress fibrosis lipid metabolism and in-flammationrdquo Toxicology Letters vol 284 pp 37ndash45 2018
[21] J Su Y Wei M Liu et al ldquoAnti-hyperuricemic and neph-roprotective effects of Rhizoma Dioscoreae septemlobae ex-tracts and its main component dioscin via regulation ofmOAT1 mURAT1 and mOCT2 in hypertensive micerdquo Ar-chives of Pharmacal Research vol 37 no 10 pp 1336ndash13442014
[22] J H Ye M H Liu X L Zhang et al ldquoChemical profiles andprotective effect of Hedyotis diffusa Willd in lipopolysac-charide-induced renal inflammation micerdquo InternationalJournal of Molecular Sciences vol 16 no 11 pp 27252ndash272692015
[23] X B Sun and N N Yu ldquoRoot of Snow of June for treatingkidney diseasesrdquo Chinese Medicine Guide vol 19 no 10pp 127-128 2013 in Chinese
[24] W Zhang Z X Lin C Xu C Leung and L S ChanldquoAstragalus (a traditional Chinese medicine) for treatingchronic kidney diseaserdquo Cochrane Database of SystematicReviews vol 10 2014
[25] S Ren H Zhang Y Mu et al ldquoPharmacological effects ofAstragaloside IV a literature reviewrdquo Journal of TraditionalChinese Medicine vol 33 no 3 pp 413ndash416 2013
Evidence-Based Complementary and Alternative Medicine 13
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
liver is well known to achieve the purpose of nourishing thekidney but herbs that tonify the kidney were not frequentlyprescribed in this researchis indicates that amultiple-organdisorder underlies the TCM pathogenesis of CKD When and
how to nourish the kidney directly or indirectly requiresfurther study In TCM practice tonifying-deficiency herbs areoften used in combination with heat-clearing and dampness-draining diuretic herbs Table 3 shows that two or more herbs
Poria (Fulin)
Radix Astragali (Huangqi)Rhizoma Atractylodis
Macrocephalae (Baizhu)
Fructus Corni (Shanzhuyu)
Radix Pseudostellariae (Taizishen)
Fructus Lycii (Gouqizi)
Rhizoma Dioscoreae (Shanyao)Spreading Hedyotis
Herb (Baihuasheshecao)Root of Snow of June (Baimagu)
Rhizoma Imperatae (Baimaogen)
Radix Cirsii Japonici (Daji)
Herba Cirsii (Xiaoji)
Radix Rehmanniae (Shengdihuang)
Common Sage Herb (Lizhicao)
Rhizoma Smilacis Glabrae (Tufulin)
Cortex Phellodendri (Huangbai)
Rhizoma Anemarrhenae (Zhimu)
Pericarpium Citri Reticulatae (Chenpi)
Rhizoma Pinelliae (Banxia)
Semen Coicis (Yiyiren)
Flos Carthami (Honghua)
Radix et Rhizoma Rhei (Dahuang)
Herba Taxilli (Sangjisheng)
Cortex Eucommiae (Duzhong)
Corn Stigma (Yumixu)
Radix Codonopsis (Dangshen)
Radix Salviae Miltiorrhizae (Danshen)
Medicated Leaven (Shenqu)
Radix Saposhnikoviae (Fangfeng)
Radix Ophiopogonis (Maidong)
Herba Taraxaci (Pugongying)
Radix Glycyrrhizae (Gancao)
Cluster dendrogram
Height
Figure 5 Cluster analysis tree diagram e cluster analysis tree diagram was created using R-studio 353 e 32 most frequentlyprescribed herbs were analyzed Each category is represented by a different color
10 Evidence-Based Complementary and Alternative Medicine
were usually combined with Spreading Hedyotis Herb (Bai-huasheshecao) or Root of Snow of June (Baimagu) whichwerethe two most frequently used heat-clearing herbs anddampness-removing diuretic herbs Tonifying treatment wasalso indicated to be more important than heat-clearing ordampness-draining treatment How to balance tonifyingtreatment and clearing-diuresis treatment under specificconditions needs to be investigated further
e pathogenesis of kidney disease is complex and oftenmanifests as multiple syndrome combinationse formulaedetermined by clustering were for composite syndromesHerbs in cluster 1 were for tonifying the lung strengtheningthe spleen and removing dampness and were prescribed totreat spleen-lung qi deficiency and dampness Herbs incluster 2 were for nourishing the liver and kidney andclearing heat or dampness and were prescribed to treat liver-kidney yin deficiency and dampness or heat ose in cluster3 were for nourishing yin clearing heat and cooling bloodese herbs can be found in Zhi Bai Di Huang Wan and are
prescribed to treat fire excess from yin deficiency and blood-heat syndromeose in cluster 4 were for regulating qi floweliminating phlegm activating blood and purging turbidityey were prescribed to treat phlegm-damp blood stasisand turbidity syndromesese four clusters of prescriptionsfor different syndrome types can provide useful ideas forCKD treatment e herbs in cluster 5 had multiple func-tions such as tonifying the kidney releasing the exteriorand promoting digestion It may be used auxiliarily to targetcomplications and requires further study
Complex network analysis revealed eight core herbs forCKD Rhizoma Dioscoreae (Shanyao) Spreading HedyotisHerb (Baihuasheshecao) Root of Snow of June (Baimagu)Radix Astragali (Huangqi) Poria (Fulin) Rhizoma Atrac-tylodis Macrocephalae (Baizhu) Radix Pseudostellariae(Taizishen) and Fructus Corni (Shanzhuyu) Interestinglythese herbs are included in clusters 1 and 2 ey were alsoidentified as high-frequency herbs for CKD treatment so webelieved that such a prescription could be used as a basis for
Spreading Hedyotis
Herb
Fructus Corni
Rhizoma Dioscoreae
Root of Snow of
June
Poria Radix Astragali
Radix Pseudostellariae
Rhizoma Atractylodis
Macrocephalae
124
154
105
100
154
134
99
129
100
115
98
86
95 98
141
119
115
127
87
146
139
136
131
115
112
102
97
97
89
Figure 6 Core prescription network e core prescription network was created using Liquorice e weight represents the frequency withwhich two herbs appeared together
Evidence-Based Complementary and Alternative Medicine 11
further research Modern pharmacology has also shown thatthese herbs can improve kidney injury through anti-in-flammatory and antioxidant activity (Table 4) [20ndash29]
Our data mining approach has several advantages Firstthere was no requirement for the data structure is is verypractical for data mining of Chinese medicine prescriptionsbecause the data structure of most Chinese medicines is notuniform Second we combined a variety of data miningmethods to perform comprehensive analysis and to ensurethat the conclusion was reliable Finally we focused on themain treatment methods and uses of herbs which is anefficient way to learn TCM treatment Our research also hassome limitations We collected only prescription informa-tion but not diagnostic information so our conclusionscannot be completely confirmed We also examined onlyeffective treatment cases not invalid treatment cases sowhether a gap exists between these two case types remainsunclearus it is also unclear whether the core prescriptionshould be corrected Finally the safety and efficacy of thecore prescriptions were not evaluated and should be in-vestigated in a future study
In summary we adopted a practical approach based onformulae prescribed in clinical practice To our knowledgethis is the first study on CKD treatment with TCM whichcombines frequency analysis association rule learning andcomplex network analysis Using this approach we deter-mined the frequency and combination patterns of CKDtreatment and discovered possibilities for new CKD
treatment prescriptions We also summarized herbal CKDtreatment finding that CKD syndromes are extremelycomplicated and various CKD treatmentmethods exist suchas those for cooling blood and eliminating phlegm How-ever we found that the treatment methods were mainly fortonifying deficiency and clearing heat or dampness
5 Conclusions
Our study found that kidney spleen lung or liver deficiencyand dampness-heat were the primary TCM pathogenesisus the primary treatment principle was tonifying defi-ciency and eliminating dampness and heat Furthermoreour study verified that the integrated analysis method canhelp to explore the TCM treatment strategy is analysis ofherbal TCM prescriptions potentially contributes to thedevelopment of novel drugs for CKD
Data Availability
e data used to support the findings of this study are in-cluded within the article
Conflicts of Interest
e authors declare that there are no conflicts of interestregarding the publication of this article
Table 4 Possible mechanisms of the core Chinese medical herbs for CKD treatment
Increases catalase (CAT) superoxide dismutase(SOD) and glutathione peroxidase (GSH-px)
activities in the kidneys of diabetic rats as well asenhancing renal peroxisome proliferator-activatedreceptor-c (PPARc) expression in diabetic rats [28]
Radix Pseudostellariae (Taizishen) Polysaccharide
Decreases serum triglyceride total cholesterol low-density-lipoprotein cholesterin urea nitrogen andcreatinine increase serum high-density-lipoproteincholesterol and reduce renal histopathology change
[29]
12 Evidence-Based Complementary and Alternative Medicine
Authorsrsquo Contributions
Ping Xia and Kun Gao contributed equally to this studyWeiming He and Kun Gao designed the research Ping XiaMing Shi Wei Li Jing Zhao Jin Yan Qiong Liu Min ZhengXin Wang and Qijing Wu collected and processed the dataPing Xia and Jiadong Xie analyzed the data Wei Sun JihongChen Enchao Zhou and Lingdong Xv participated in in-tellectual discussions Ping Xia and Kun Gao wrote thepaper All authors approved the final edited version of themanuscript
Acknowledgments
is study was financially supported by the PostgraduateResearch amp Practice Innovation Program of Jiangsu Prov-ince (KYCX19_1189 to Ping Xia) and the National NaturalScience Foundation of China (81673912 and 81873259 toKun Gao 81804219 to Jiadong Xie and 81774269 toWeiming He) e authors gratefully acknowledge the as-sistance of Dr Buhui Liu their colleague in the AffiliatedHospital of Nanjing University of Chinese Medicine
References
[1] A Levin M Tonelli J Bonventre et al ldquoGlobal kidney health2017 and beyond a roadmap for closing gaps in care researchand policyrdquo +e Lancet vol 390 no 10105 pp 1888ndash19172017
[2] A C Webster E V Nagler R L Morton and P MassonldquoChronic kidney diseaserdquo +e Lancet vol 389 no 10075pp 1238ndash1252 2017
[3] K J Foreman N Marquez A Dolgert et al ldquoForecasting lifeexpectancy years of life lost and all-cause and cause-specificmortality for 250 causes of death reference and alternativescenarios for 2016ndash40 for 195 countries and territoriesrdquo +eLancet vol 392 no 10159 pp 2052ndash2090 2017
[4] L Zhang F Wang L Wang et al ldquoPrevalence of chronickidney disease in China a cross-sectional surveyrdquo+e Lancetvol 379 no 9818 pp 815ndash822 2012
[5] X Li and HWang ldquoChinese herbal medicine in the treatmentof chronic kidney diseaserdquo Advances in Chronic KidneyDisease vol 12 no 3 pp 276ndash281 2005
[6] Q Zhang L Zhu and W Lerberghe ldquoe importance oftraditional Chinese medicine services in health care provisionin Chinardquo Universitas Forum vol 2 no 2 pp 1ndash8 2011
[7] Y J Wang L Q He W Sun et al ldquoOptimized project oftraditional Chinese medicine in treating chronic kidneydisease stage 3 a multicenter double-blinded randomizedcontrolled trialrdquo Journal of Ethnopharmacology vol 139no 3 pp 757ndash764 2012
[8] Y Chen Y Deng Z Ni et al ldquoEfficacy and safety of tradi-tional Chinese medicine (Shenqi particle) for patients withidiopathic membranous nephropathy a multicenter ran-domized controlled clinical trialrdquo American Journal of KidneyDiseases vol 62 no 6 pp 1068ndash1076 2013
[9] L Zhang P Li C Y Xing et al ldquoEfficacy and safety of Abel-moschus manihot for primary glomerular disease a prospectivemulticenter randomized controlled clinical trialrdquo AmericanJournal of Kidney Diseases vol 64 no 1 pp 57ndash65 2014
[10] W Li W He P Xia et al ldquoTotal extracts of abelmoschusmanihot L Attenuates adriamycin-induced renal tubule
injury via suppression of ROS-ERK12-mediated NLRP3inflammasome activationrdquo Frontiers in Pharmacology vol 10p 567 2019
[11] X Zhang X Zhou R Zhang et al ldquoReal-world clinical datamining on TCM clinical diagnosis and treatment a surveyrdquo inProceedings of the IEEE International Conference on E-HealthNetworking IEEE Beijing China October 2012
[12] L Chen C Y Lee K H Huang Y H Kuan and M ChenldquoPrescription patterns of Chinese herbal products for patientswith sleep disorder and major depressive disorder in TaiwanrdquoJournal of Ethnopharmacology vol 171 pp 307ndash316 2015
[13] J Cao ldquoe Common prescription patterns based on thehierarchical clustering of herb-pairs efficaciesrdquo Evidence-Based Complementary and Alternative Medicine vol 2016Article ID 6373270 7 pages 2016
[14] C J Hu J He J D Xie et al ldquoResearch on TCM treatment oflung cancer based on complex networks methodrdquo Journal ofMedical Informatics vol 39 no 11 pp 63ndash68 2018 inChinese
[15] National Pharmacopoeia Commission Pharmacopoeia of thePeoplersquos Republic of China China Medical Science andTechnology Press Bejing China 2010 in Chinese
[16] Chinese Materia Medica Commission of National Adminis-tration of Traditional Chinese Medicine Chinese MateriaMedica Shanghai Science and Technology Press ShanghaiChina 1999 in Chinese
[17] J Pang J Fu M Yang et al ldquoCorrelation between the dif-ferent therapeutic properties of Chinese medicinal herbs anddelayed luminescencerdquo Luminescence vol 31 no 2pp 323ndash327 2016
[18] X M Chen Z H Ni Y N Liu et al ldquoGuidelines for thediagnosis and treatment of chronic renal failure with inte-grated traditional Chinese and Western medicinerdquo HebeiTraditional ChineseMedicine vol 38 no 2 pp 313ndash317 2016in Chinese
[19] Y Q Zou and E C Zhou ldquoSummary of differentiation andtreatment of traditional Chinese medicine nephropathyrdquoJiangsu Journal of Traditional Chinese Medicine vol 50 no 1pp 1ndash5 2018 in Chinese
[20] Y Qiao L Xu X Tao et al ldquoProtective effects of dioscinagainst fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress fibrosis lipid metabolism and in-flammationrdquo Toxicology Letters vol 284 pp 37ndash45 2018
[21] J Su Y Wei M Liu et al ldquoAnti-hyperuricemic and neph-roprotective effects of Rhizoma Dioscoreae septemlobae ex-tracts and its main component dioscin via regulation ofmOAT1 mURAT1 and mOCT2 in hypertensive micerdquo Ar-chives of Pharmacal Research vol 37 no 10 pp 1336ndash13442014
[22] J H Ye M H Liu X L Zhang et al ldquoChemical profiles andprotective effect of Hedyotis diffusa Willd in lipopolysac-charide-induced renal inflammation micerdquo InternationalJournal of Molecular Sciences vol 16 no 11 pp 27252ndash272692015
[23] X B Sun and N N Yu ldquoRoot of Snow of June for treatingkidney diseasesrdquo Chinese Medicine Guide vol 19 no 10pp 127-128 2013 in Chinese
[24] W Zhang Z X Lin C Xu C Leung and L S ChanldquoAstragalus (a traditional Chinese medicine) for treatingchronic kidney diseaserdquo Cochrane Database of SystematicReviews vol 10 2014
[25] S Ren H Zhang Y Mu et al ldquoPharmacological effects ofAstragaloside IV a literature reviewrdquo Journal of TraditionalChinese Medicine vol 33 no 3 pp 413ndash416 2013
Evidence-Based Complementary and Alternative Medicine 13
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
were usually combined with Spreading Hedyotis Herb (Bai-huasheshecao) or Root of Snow of June (Baimagu) whichwerethe two most frequently used heat-clearing herbs anddampness-removing diuretic herbs Tonifying treatment wasalso indicated to be more important than heat-clearing ordampness-draining treatment How to balance tonifyingtreatment and clearing-diuresis treatment under specificconditions needs to be investigated further
e pathogenesis of kidney disease is complex and oftenmanifests as multiple syndrome combinationse formulaedetermined by clustering were for composite syndromesHerbs in cluster 1 were for tonifying the lung strengtheningthe spleen and removing dampness and were prescribed totreat spleen-lung qi deficiency and dampness Herbs incluster 2 were for nourishing the liver and kidney andclearing heat or dampness and were prescribed to treat liver-kidney yin deficiency and dampness or heat ose in cluster3 were for nourishing yin clearing heat and cooling bloodese herbs can be found in Zhi Bai Di Huang Wan and are
prescribed to treat fire excess from yin deficiency and blood-heat syndromeose in cluster 4 were for regulating qi floweliminating phlegm activating blood and purging turbidityey were prescribed to treat phlegm-damp blood stasisand turbidity syndromesese four clusters of prescriptionsfor different syndrome types can provide useful ideas forCKD treatment e herbs in cluster 5 had multiple func-tions such as tonifying the kidney releasing the exteriorand promoting digestion It may be used auxiliarily to targetcomplications and requires further study
Complex network analysis revealed eight core herbs forCKD Rhizoma Dioscoreae (Shanyao) Spreading HedyotisHerb (Baihuasheshecao) Root of Snow of June (Baimagu)Radix Astragali (Huangqi) Poria (Fulin) Rhizoma Atrac-tylodis Macrocephalae (Baizhu) Radix Pseudostellariae(Taizishen) and Fructus Corni (Shanzhuyu) Interestinglythese herbs are included in clusters 1 and 2 ey were alsoidentified as high-frequency herbs for CKD treatment so webelieved that such a prescription could be used as a basis for
Spreading Hedyotis
Herb
Fructus Corni
Rhizoma Dioscoreae
Root of Snow of
June
Poria Radix Astragali
Radix Pseudostellariae
Rhizoma Atractylodis
Macrocephalae
124
154
105
100
154
134
99
129
100
115
98
86
95 98
141
119
115
127
87
146
139
136
131
115
112
102
97
97
89
Figure 6 Core prescription network e core prescription network was created using Liquorice e weight represents the frequency withwhich two herbs appeared together
Evidence-Based Complementary and Alternative Medicine 11
further research Modern pharmacology has also shown thatthese herbs can improve kidney injury through anti-in-flammatory and antioxidant activity (Table 4) [20ndash29]
Our data mining approach has several advantages Firstthere was no requirement for the data structure is is verypractical for data mining of Chinese medicine prescriptionsbecause the data structure of most Chinese medicines is notuniform Second we combined a variety of data miningmethods to perform comprehensive analysis and to ensurethat the conclusion was reliable Finally we focused on themain treatment methods and uses of herbs which is anefficient way to learn TCM treatment Our research also hassome limitations We collected only prescription informa-tion but not diagnostic information so our conclusionscannot be completely confirmed We also examined onlyeffective treatment cases not invalid treatment cases sowhether a gap exists between these two case types remainsunclearus it is also unclear whether the core prescriptionshould be corrected Finally the safety and efficacy of thecore prescriptions were not evaluated and should be in-vestigated in a future study
In summary we adopted a practical approach based onformulae prescribed in clinical practice To our knowledgethis is the first study on CKD treatment with TCM whichcombines frequency analysis association rule learning andcomplex network analysis Using this approach we deter-mined the frequency and combination patterns of CKDtreatment and discovered possibilities for new CKD
treatment prescriptions We also summarized herbal CKDtreatment finding that CKD syndromes are extremelycomplicated and various CKD treatmentmethods exist suchas those for cooling blood and eliminating phlegm How-ever we found that the treatment methods were mainly fortonifying deficiency and clearing heat or dampness
5 Conclusions
Our study found that kidney spleen lung or liver deficiencyand dampness-heat were the primary TCM pathogenesisus the primary treatment principle was tonifying defi-ciency and eliminating dampness and heat Furthermoreour study verified that the integrated analysis method canhelp to explore the TCM treatment strategy is analysis ofherbal TCM prescriptions potentially contributes to thedevelopment of novel drugs for CKD
Data Availability
e data used to support the findings of this study are in-cluded within the article
Conflicts of Interest
e authors declare that there are no conflicts of interestregarding the publication of this article
Table 4 Possible mechanisms of the core Chinese medical herbs for CKD treatment
Increases catalase (CAT) superoxide dismutase(SOD) and glutathione peroxidase (GSH-px)
activities in the kidneys of diabetic rats as well asenhancing renal peroxisome proliferator-activatedreceptor-c (PPARc) expression in diabetic rats [28]
Radix Pseudostellariae (Taizishen) Polysaccharide
Decreases serum triglyceride total cholesterol low-density-lipoprotein cholesterin urea nitrogen andcreatinine increase serum high-density-lipoproteincholesterol and reduce renal histopathology change
[29]
12 Evidence-Based Complementary and Alternative Medicine
Authorsrsquo Contributions
Ping Xia and Kun Gao contributed equally to this studyWeiming He and Kun Gao designed the research Ping XiaMing Shi Wei Li Jing Zhao Jin Yan Qiong Liu Min ZhengXin Wang and Qijing Wu collected and processed the dataPing Xia and Jiadong Xie analyzed the data Wei Sun JihongChen Enchao Zhou and Lingdong Xv participated in in-tellectual discussions Ping Xia and Kun Gao wrote thepaper All authors approved the final edited version of themanuscript
Acknowledgments
is study was financially supported by the PostgraduateResearch amp Practice Innovation Program of Jiangsu Prov-ince (KYCX19_1189 to Ping Xia) and the National NaturalScience Foundation of China (81673912 and 81873259 toKun Gao 81804219 to Jiadong Xie and 81774269 toWeiming He) e authors gratefully acknowledge the as-sistance of Dr Buhui Liu their colleague in the AffiliatedHospital of Nanjing University of Chinese Medicine
References
[1] A Levin M Tonelli J Bonventre et al ldquoGlobal kidney health2017 and beyond a roadmap for closing gaps in care researchand policyrdquo +e Lancet vol 390 no 10105 pp 1888ndash19172017
[2] A C Webster E V Nagler R L Morton and P MassonldquoChronic kidney diseaserdquo +e Lancet vol 389 no 10075pp 1238ndash1252 2017
[3] K J Foreman N Marquez A Dolgert et al ldquoForecasting lifeexpectancy years of life lost and all-cause and cause-specificmortality for 250 causes of death reference and alternativescenarios for 2016ndash40 for 195 countries and territoriesrdquo +eLancet vol 392 no 10159 pp 2052ndash2090 2017
[4] L Zhang F Wang L Wang et al ldquoPrevalence of chronickidney disease in China a cross-sectional surveyrdquo+e Lancetvol 379 no 9818 pp 815ndash822 2012
[5] X Li and HWang ldquoChinese herbal medicine in the treatmentof chronic kidney diseaserdquo Advances in Chronic KidneyDisease vol 12 no 3 pp 276ndash281 2005
[6] Q Zhang L Zhu and W Lerberghe ldquoe importance oftraditional Chinese medicine services in health care provisionin Chinardquo Universitas Forum vol 2 no 2 pp 1ndash8 2011
[7] Y J Wang L Q He W Sun et al ldquoOptimized project oftraditional Chinese medicine in treating chronic kidneydisease stage 3 a multicenter double-blinded randomizedcontrolled trialrdquo Journal of Ethnopharmacology vol 139no 3 pp 757ndash764 2012
[8] Y Chen Y Deng Z Ni et al ldquoEfficacy and safety of tradi-tional Chinese medicine (Shenqi particle) for patients withidiopathic membranous nephropathy a multicenter ran-domized controlled clinical trialrdquo American Journal of KidneyDiseases vol 62 no 6 pp 1068ndash1076 2013
[9] L Zhang P Li C Y Xing et al ldquoEfficacy and safety of Abel-moschus manihot for primary glomerular disease a prospectivemulticenter randomized controlled clinical trialrdquo AmericanJournal of Kidney Diseases vol 64 no 1 pp 57ndash65 2014
[10] W Li W He P Xia et al ldquoTotal extracts of abelmoschusmanihot L Attenuates adriamycin-induced renal tubule
injury via suppression of ROS-ERK12-mediated NLRP3inflammasome activationrdquo Frontiers in Pharmacology vol 10p 567 2019
[11] X Zhang X Zhou R Zhang et al ldquoReal-world clinical datamining on TCM clinical diagnosis and treatment a surveyrdquo inProceedings of the IEEE International Conference on E-HealthNetworking IEEE Beijing China October 2012
[12] L Chen C Y Lee K H Huang Y H Kuan and M ChenldquoPrescription patterns of Chinese herbal products for patientswith sleep disorder and major depressive disorder in TaiwanrdquoJournal of Ethnopharmacology vol 171 pp 307ndash316 2015
[13] J Cao ldquoe Common prescription patterns based on thehierarchical clustering of herb-pairs efficaciesrdquo Evidence-Based Complementary and Alternative Medicine vol 2016Article ID 6373270 7 pages 2016
[14] C J Hu J He J D Xie et al ldquoResearch on TCM treatment oflung cancer based on complex networks methodrdquo Journal ofMedical Informatics vol 39 no 11 pp 63ndash68 2018 inChinese
[15] National Pharmacopoeia Commission Pharmacopoeia of thePeoplersquos Republic of China China Medical Science andTechnology Press Bejing China 2010 in Chinese
[16] Chinese Materia Medica Commission of National Adminis-tration of Traditional Chinese Medicine Chinese MateriaMedica Shanghai Science and Technology Press ShanghaiChina 1999 in Chinese
[17] J Pang J Fu M Yang et al ldquoCorrelation between the dif-ferent therapeutic properties of Chinese medicinal herbs anddelayed luminescencerdquo Luminescence vol 31 no 2pp 323ndash327 2016
[18] X M Chen Z H Ni Y N Liu et al ldquoGuidelines for thediagnosis and treatment of chronic renal failure with inte-grated traditional Chinese and Western medicinerdquo HebeiTraditional ChineseMedicine vol 38 no 2 pp 313ndash317 2016in Chinese
[19] Y Q Zou and E C Zhou ldquoSummary of differentiation andtreatment of traditional Chinese medicine nephropathyrdquoJiangsu Journal of Traditional Chinese Medicine vol 50 no 1pp 1ndash5 2018 in Chinese
[20] Y Qiao L Xu X Tao et al ldquoProtective effects of dioscinagainst fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress fibrosis lipid metabolism and in-flammationrdquo Toxicology Letters vol 284 pp 37ndash45 2018
[21] J Su Y Wei M Liu et al ldquoAnti-hyperuricemic and neph-roprotective effects of Rhizoma Dioscoreae septemlobae ex-tracts and its main component dioscin via regulation ofmOAT1 mURAT1 and mOCT2 in hypertensive micerdquo Ar-chives of Pharmacal Research vol 37 no 10 pp 1336ndash13442014
[22] J H Ye M H Liu X L Zhang et al ldquoChemical profiles andprotective effect of Hedyotis diffusa Willd in lipopolysac-charide-induced renal inflammation micerdquo InternationalJournal of Molecular Sciences vol 16 no 11 pp 27252ndash272692015
[23] X B Sun and N N Yu ldquoRoot of Snow of June for treatingkidney diseasesrdquo Chinese Medicine Guide vol 19 no 10pp 127-128 2013 in Chinese
[24] W Zhang Z X Lin C Xu C Leung and L S ChanldquoAstragalus (a traditional Chinese medicine) for treatingchronic kidney diseaserdquo Cochrane Database of SystematicReviews vol 10 2014
[25] S Ren H Zhang Y Mu et al ldquoPharmacological effects ofAstragaloside IV a literature reviewrdquo Journal of TraditionalChinese Medicine vol 33 no 3 pp 413ndash416 2013
Evidence-Based Complementary and Alternative Medicine 13
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
further research Modern pharmacology has also shown thatthese herbs can improve kidney injury through anti-in-flammatory and antioxidant activity (Table 4) [20ndash29]
Our data mining approach has several advantages Firstthere was no requirement for the data structure is is verypractical for data mining of Chinese medicine prescriptionsbecause the data structure of most Chinese medicines is notuniform Second we combined a variety of data miningmethods to perform comprehensive analysis and to ensurethat the conclusion was reliable Finally we focused on themain treatment methods and uses of herbs which is anefficient way to learn TCM treatment Our research also hassome limitations We collected only prescription informa-tion but not diagnostic information so our conclusionscannot be completely confirmed We also examined onlyeffective treatment cases not invalid treatment cases sowhether a gap exists between these two case types remainsunclearus it is also unclear whether the core prescriptionshould be corrected Finally the safety and efficacy of thecore prescriptions were not evaluated and should be in-vestigated in a future study
In summary we adopted a practical approach based onformulae prescribed in clinical practice To our knowledgethis is the first study on CKD treatment with TCM whichcombines frequency analysis association rule learning andcomplex network analysis Using this approach we deter-mined the frequency and combination patterns of CKDtreatment and discovered possibilities for new CKD
treatment prescriptions We also summarized herbal CKDtreatment finding that CKD syndromes are extremelycomplicated and various CKD treatmentmethods exist suchas those for cooling blood and eliminating phlegm How-ever we found that the treatment methods were mainly fortonifying deficiency and clearing heat or dampness
5 Conclusions
Our study found that kidney spleen lung or liver deficiencyand dampness-heat were the primary TCM pathogenesisus the primary treatment principle was tonifying defi-ciency and eliminating dampness and heat Furthermoreour study verified that the integrated analysis method canhelp to explore the TCM treatment strategy is analysis ofherbal TCM prescriptions potentially contributes to thedevelopment of novel drugs for CKD
Data Availability
e data used to support the findings of this study are in-cluded within the article
Conflicts of Interest
e authors declare that there are no conflicts of interestregarding the publication of this article
Table 4 Possible mechanisms of the core Chinese medical herbs for CKD treatment
Increases catalase (CAT) superoxide dismutase(SOD) and glutathione peroxidase (GSH-px)
activities in the kidneys of diabetic rats as well asenhancing renal peroxisome proliferator-activatedreceptor-c (PPARc) expression in diabetic rats [28]
Radix Pseudostellariae (Taizishen) Polysaccharide
Decreases serum triglyceride total cholesterol low-density-lipoprotein cholesterin urea nitrogen andcreatinine increase serum high-density-lipoproteincholesterol and reduce renal histopathology change
[29]
12 Evidence-Based Complementary and Alternative Medicine
Authorsrsquo Contributions
Ping Xia and Kun Gao contributed equally to this studyWeiming He and Kun Gao designed the research Ping XiaMing Shi Wei Li Jing Zhao Jin Yan Qiong Liu Min ZhengXin Wang and Qijing Wu collected and processed the dataPing Xia and Jiadong Xie analyzed the data Wei Sun JihongChen Enchao Zhou and Lingdong Xv participated in in-tellectual discussions Ping Xia and Kun Gao wrote thepaper All authors approved the final edited version of themanuscript
Acknowledgments
is study was financially supported by the PostgraduateResearch amp Practice Innovation Program of Jiangsu Prov-ince (KYCX19_1189 to Ping Xia) and the National NaturalScience Foundation of China (81673912 and 81873259 toKun Gao 81804219 to Jiadong Xie and 81774269 toWeiming He) e authors gratefully acknowledge the as-sistance of Dr Buhui Liu their colleague in the AffiliatedHospital of Nanjing University of Chinese Medicine
References
[1] A Levin M Tonelli J Bonventre et al ldquoGlobal kidney health2017 and beyond a roadmap for closing gaps in care researchand policyrdquo +e Lancet vol 390 no 10105 pp 1888ndash19172017
[2] A C Webster E V Nagler R L Morton and P MassonldquoChronic kidney diseaserdquo +e Lancet vol 389 no 10075pp 1238ndash1252 2017
[3] K J Foreman N Marquez A Dolgert et al ldquoForecasting lifeexpectancy years of life lost and all-cause and cause-specificmortality for 250 causes of death reference and alternativescenarios for 2016ndash40 for 195 countries and territoriesrdquo +eLancet vol 392 no 10159 pp 2052ndash2090 2017
[4] L Zhang F Wang L Wang et al ldquoPrevalence of chronickidney disease in China a cross-sectional surveyrdquo+e Lancetvol 379 no 9818 pp 815ndash822 2012
[5] X Li and HWang ldquoChinese herbal medicine in the treatmentof chronic kidney diseaserdquo Advances in Chronic KidneyDisease vol 12 no 3 pp 276ndash281 2005
[6] Q Zhang L Zhu and W Lerberghe ldquoe importance oftraditional Chinese medicine services in health care provisionin Chinardquo Universitas Forum vol 2 no 2 pp 1ndash8 2011
[7] Y J Wang L Q He W Sun et al ldquoOptimized project oftraditional Chinese medicine in treating chronic kidneydisease stage 3 a multicenter double-blinded randomizedcontrolled trialrdquo Journal of Ethnopharmacology vol 139no 3 pp 757ndash764 2012
[8] Y Chen Y Deng Z Ni et al ldquoEfficacy and safety of tradi-tional Chinese medicine (Shenqi particle) for patients withidiopathic membranous nephropathy a multicenter ran-domized controlled clinical trialrdquo American Journal of KidneyDiseases vol 62 no 6 pp 1068ndash1076 2013
[9] L Zhang P Li C Y Xing et al ldquoEfficacy and safety of Abel-moschus manihot for primary glomerular disease a prospectivemulticenter randomized controlled clinical trialrdquo AmericanJournal of Kidney Diseases vol 64 no 1 pp 57ndash65 2014
[10] W Li W He P Xia et al ldquoTotal extracts of abelmoschusmanihot L Attenuates adriamycin-induced renal tubule
injury via suppression of ROS-ERK12-mediated NLRP3inflammasome activationrdquo Frontiers in Pharmacology vol 10p 567 2019
[11] X Zhang X Zhou R Zhang et al ldquoReal-world clinical datamining on TCM clinical diagnosis and treatment a surveyrdquo inProceedings of the IEEE International Conference on E-HealthNetworking IEEE Beijing China October 2012
[12] L Chen C Y Lee K H Huang Y H Kuan and M ChenldquoPrescription patterns of Chinese herbal products for patientswith sleep disorder and major depressive disorder in TaiwanrdquoJournal of Ethnopharmacology vol 171 pp 307ndash316 2015
[13] J Cao ldquoe Common prescription patterns based on thehierarchical clustering of herb-pairs efficaciesrdquo Evidence-Based Complementary and Alternative Medicine vol 2016Article ID 6373270 7 pages 2016
[14] C J Hu J He J D Xie et al ldquoResearch on TCM treatment oflung cancer based on complex networks methodrdquo Journal ofMedical Informatics vol 39 no 11 pp 63ndash68 2018 inChinese
[15] National Pharmacopoeia Commission Pharmacopoeia of thePeoplersquos Republic of China China Medical Science andTechnology Press Bejing China 2010 in Chinese
[16] Chinese Materia Medica Commission of National Adminis-tration of Traditional Chinese Medicine Chinese MateriaMedica Shanghai Science and Technology Press ShanghaiChina 1999 in Chinese
[17] J Pang J Fu M Yang et al ldquoCorrelation between the dif-ferent therapeutic properties of Chinese medicinal herbs anddelayed luminescencerdquo Luminescence vol 31 no 2pp 323ndash327 2016
[18] X M Chen Z H Ni Y N Liu et al ldquoGuidelines for thediagnosis and treatment of chronic renal failure with inte-grated traditional Chinese and Western medicinerdquo HebeiTraditional ChineseMedicine vol 38 no 2 pp 313ndash317 2016in Chinese
[19] Y Q Zou and E C Zhou ldquoSummary of differentiation andtreatment of traditional Chinese medicine nephropathyrdquoJiangsu Journal of Traditional Chinese Medicine vol 50 no 1pp 1ndash5 2018 in Chinese
[20] Y Qiao L Xu X Tao et al ldquoProtective effects of dioscinagainst fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress fibrosis lipid metabolism and in-flammationrdquo Toxicology Letters vol 284 pp 37ndash45 2018
[21] J Su Y Wei M Liu et al ldquoAnti-hyperuricemic and neph-roprotective effects of Rhizoma Dioscoreae septemlobae ex-tracts and its main component dioscin via regulation ofmOAT1 mURAT1 and mOCT2 in hypertensive micerdquo Ar-chives of Pharmacal Research vol 37 no 10 pp 1336ndash13442014
[22] J H Ye M H Liu X L Zhang et al ldquoChemical profiles andprotective effect of Hedyotis diffusa Willd in lipopolysac-charide-induced renal inflammation micerdquo InternationalJournal of Molecular Sciences vol 16 no 11 pp 27252ndash272692015
[23] X B Sun and N N Yu ldquoRoot of Snow of June for treatingkidney diseasesrdquo Chinese Medicine Guide vol 19 no 10pp 127-128 2013 in Chinese
[24] W Zhang Z X Lin C Xu C Leung and L S ChanldquoAstragalus (a traditional Chinese medicine) for treatingchronic kidney diseaserdquo Cochrane Database of SystematicReviews vol 10 2014
[25] S Ren H Zhang Y Mu et al ldquoPharmacological effects ofAstragaloside IV a literature reviewrdquo Journal of TraditionalChinese Medicine vol 33 no 3 pp 413ndash416 2013
Evidence-Based Complementary and Alternative Medicine 13
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
Authorsrsquo Contributions
Ping Xia and Kun Gao contributed equally to this studyWeiming He and Kun Gao designed the research Ping XiaMing Shi Wei Li Jing Zhao Jin Yan Qiong Liu Min ZhengXin Wang and Qijing Wu collected and processed the dataPing Xia and Jiadong Xie analyzed the data Wei Sun JihongChen Enchao Zhou and Lingdong Xv participated in in-tellectual discussions Ping Xia and Kun Gao wrote thepaper All authors approved the final edited version of themanuscript
Acknowledgments
is study was financially supported by the PostgraduateResearch amp Practice Innovation Program of Jiangsu Prov-ince (KYCX19_1189 to Ping Xia) and the National NaturalScience Foundation of China (81673912 and 81873259 toKun Gao 81804219 to Jiadong Xie and 81774269 toWeiming He) e authors gratefully acknowledge the as-sistance of Dr Buhui Liu their colleague in the AffiliatedHospital of Nanjing University of Chinese Medicine
References
[1] A Levin M Tonelli J Bonventre et al ldquoGlobal kidney health2017 and beyond a roadmap for closing gaps in care researchand policyrdquo +e Lancet vol 390 no 10105 pp 1888ndash19172017
[2] A C Webster E V Nagler R L Morton and P MassonldquoChronic kidney diseaserdquo +e Lancet vol 389 no 10075pp 1238ndash1252 2017
[3] K J Foreman N Marquez A Dolgert et al ldquoForecasting lifeexpectancy years of life lost and all-cause and cause-specificmortality for 250 causes of death reference and alternativescenarios for 2016ndash40 for 195 countries and territoriesrdquo +eLancet vol 392 no 10159 pp 2052ndash2090 2017
[4] L Zhang F Wang L Wang et al ldquoPrevalence of chronickidney disease in China a cross-sectional surveyrdquo+e Lancetvol 379 no 9818 pp 815ndash822 2012
[5] X Li and HWang ldquoChinese herbal medicine in the treatmentof chronic kidney diseaserdquo Advances in Chronic KidneyDisease vol 12 no 3 pp 276ndash281 2005
[6] Q Zhang L Zhu and W Lerberghe ldquoe importance oftraditional Chinese medicine services in health care provisionin Chinardquo Universitas Forum vol 2 no 2 pp 1ndash8 2011
[7] Y J Wang L Q He W Sun et al ldquoOptimized project oftraditional Chinese medicine in treating chronic kidneydisease stage 3 a multicenter double-blinded randomizedcontrolled trialrdquo Journal of Ethnopharmacology vol 139no 3 pp 757ndash764 2012
[8] Y Chen Y Deng Z Ni et al ldquoEfficacy and safety of tradi-tional Chinese medicine (Shenqi particle) for patients withidiopathic membranous nephropathy a multicenter ran-domized controlled clinical trialrdquo American Journal of KidneyDiseases vol 62 no 6 pp 1068ndash1076 2013
[9] L Zhang P Li C Y Xing et al ldquoEfficacy and safety of Abel-moschus manihot for primary glomerular disease a prospectivemulticenter randomized controlled clinical trialrdquo AmericanJournal of Kidney Diseases vol 64 no 1 pp 57ndash65 2014
[10] W Li W He P Xia et al ldquoTotal extracts of abelmoschusmanihot L Attenuates adriamycin-induced renal tubule
injury via suppression of ROS-ERK12-mediated NLRP3inflammasome activationrdquo Frontiers in Pharmacology vol 10p 567 2019
[11] X Zhang X Zhou R Zhang et al ldquoReal-world clinical datamining on TCM clinical diagnosis and treatment a surveyrdquo inProceedings of the IEEE International Conference on E-HealthNetworking IEEE Beijing China October 2012
[12] L Chen C Y Lee K H Huang Y H Kuan and M ChenldquoPrescription patterns of Chinese herbal products for patientswith sleep disorder and major depressive disorder in TaiwanrdquoJournal of Ethnopharmacology vol 171 pp 307ndash316 2015
[13] J Cao ldquoe Common prescription patterns based on thehierarchical clustering of herb-pairs efficaciesrdquo Evidence-Based Complementary and Alternative Medicine vol 2016Article ID 6373270 7 pages 2016
[14] C J Hu J He J D Xie et al ldquoResearch on TCM treatment oflung cancer based on complex networks methodrdquo Journal ofMedical Informatics vol 39 no 11 pp 63ndash68 2018 inChinese
[15] National Pharmacopoeia Commission Pharmacopoeia of thePeoplersquos Republic of China China Medical Science andTechnology Press Bejing China 2010 in Chinese
[16] Chinese Materia Medica Commission of National Adminis-tration of Traditional Chinese Medicine Chinese MateriaMedica Shanghai Science and Technology Press ShanghaiChina 1999 in Chinese
[17] J Pang J Fu M Yang et al ldquoCorrelation between the dif-ferent therapeutic properties of Chinese medicinal herbs anddelayed luminescencerdquo Luminescence vol 31 no 2pp 323ndash327 2016
[18] X M Chen Z H Ni Y N Liu et al ldquoGuidelines for thediagnosis and treatment of chronic renal failure with inte-grated traditional Chinese and Western medicinerdquo HebeiTraditional ChineseMedicine vol 38 no 2 pp 313ndash317 2016in Chinese
[19] Y Q Zou and E C Zhou ldquoSummary of differentiation andtreatment of traditional Chinese medicine nephropathyrdquoJiangsu Journal of Traditional Chinese Medicine vol 50 no 1pp 1ndash5 2018 in Chinese
[20] Y Qiao L Xu X Tao et al ldquoProtective effects of dioscinagainst fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress fibrosis lipid metabolism and in-flammationrdquo Toxicology Letters vol 284 pp 37ndash45 2018
[21] J Su Y Wei M Liu et al ldquoAnti-hyperuricemic and neph-roprotective effects of Rhizoma Dioscoreae septemlobae ex-tracts and its main component dioscin via regulation ofmOAT1 mURAT1 and mOCT2 in hypertensive micerdquo Ar-chives of Pharmacal Research vol 37 no 10 pp 1336ndash13442014
[22] J H Ye M H Liu X L Zhang et al ldquoChemical profiles andprotective effect of Hedyotis diffusa Willd in lipopolysac-charide-induced renal inflammation micerdquo InternationalJournal of Molecular Sciences vol 16 no 11 pp 27252ndash272692015
[23] X B Sun and N N Yu ldquoRoot of Snow of June for treatingkidney diseasesrdquo Chinese Medicine Guide vol 19 no 10pp 127-128 2013 in Chinese
[24] W Zhang Z X Lin C Xu C Leung and L S ChanldquoAstragalus (a traditional Chinese medicine) for treatingchronic kidney diseaserdquo Cochrane Database of SystematicReviews vol 10 2014
[25] S Ren H Zhang Y Mu et al ldquoPharmacological effects ofAstragaloside IV a literature reviewrdquo Journal of TraditionalChinese Medicine vol 33 no 3 pp 413ndash416 2013
Evidence-Based Complementary and Alternative Medicine 13
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
[26] X K Zheng Y Yu J Zhou et al ldquoEffects of chemical sep-aration components and their compatibility on nephroticsyndrome in ratsrdquo Chinese Journal of New Drugs and ClinicalPharmacology vol 27 no 4 pp 467ndash474 2016 in Chinese
[27] D Lee S Lee S H Shim et al ldquoProtective effect of lanostanetriterpenoids from the sclerotia of Poria cocos wolf againstcisplatin-induced apoptosis in LLC-PK1 cellsrdquo Bioorganicand Medicinal Chemistry Letters vol 27 no 13 pp 2881ndash2885 2017
[28] D Gao Q Li Z Gao and L Wang ldquoAntidiabetic effects ofCorni Fructus extract in streptozotocin-induced diabeticratsrdquo Yonsei Medical Journal vol 53 no 4 pp 691ndash700 2012
[29] X M Yao X C Duan J Wu et al ldquoEffect of Radix pseu-dostellariae polysaccharide on blood glucose lipid meta-bolism and renal pathology in experimental diabetic ratrdquoAnhui Medicine vol 18 no 1 pp 23ndash26 2014 in Chinese
14 Evidence-Based Complementary and Alternative Medicine
