Keywords diabetic kidney disease - laws of syndromes and treatment - high-frequency Chinese
Herbs - real-world study - TCM - network pharmacology - molecular docking - diabetes
mellitus - action mechanism
Introduction
Diabetic kidney disease (DKD) is a chronic kidney disease caused by diabetes mellitus
(DM). The clinical characteristics of DKD are that the estimated glomerular filtration
rate (eGFR) is less than 60 ml min−1 ·1.73m2 )−1 or persistent albuminuria.[1 ] The incidence of DKD in diabetic patients worldwide is as high as 40%, which significantly
increases the mortality of diabetic patients.[2 ] As far as the clinical status is concerned, Western medicine treatment of DKD cannot
prevent the development process of the disease.[3 ] In recent years, it has been found that traditional Chinese medicine (TCM) plays
an increasingly obvious role in alleviating symptoms such as fatigue, edema, lumbar
soreness, reducing urinary protein content, protecting kidney function, and improving
prognosis in DKD patients and is gradually recognized and valued.[4 ] At present, it lacks high-level evidence-based medical research on the efficacy
of DKD, and its mechanism needs to be further clarified.
Randomized controlled trials, clinical observation analysis, and cohort study analysis
are the main methods of TCM clinical trials based on the current medical model, and
TCM clinical trials have their own relative perfect theoretical systems from ancient
times to the present. Therefore, the direct application of modern medical clinical
research methods in TCM clinical trials will inevitably lead to some problems. Real-world
study (RWS) is the process of collecting relevant information about patients in the
actual medical environment and analyzing the benefits and risks of herbs. The adaptability
of the two has changed to some extent. RWS evaluates the effects of herbs on large
numbers of users in a real medical environment. This study aims to combine real clinical
data with bio-information technology, study evidence and treatment strategies, analyze
the characteristics of Chinese medicine in treating DKD, clarify the action mechanism
of high-frequency Chinese herbs, and provide standard treatment guidelines for DKD.
Retrospective Study on Traditional Chinese Medicine Syndromes and Treatment Laws of
Diabetic Kidney Disease Based on Real-World Study
Retrospective Study on Traditional Chinese Medicine Syndromes and Treatment Laws of
Diabetic Kidney Disease Based on Real-World Study
Materials and Methods
Sources of Materials
The First Hospital Affiliated to the Henan University of Chinese Medicine provided
experimental data for this study. The electronic medical records of DKD patients who
had received treatment in the department of endocrinology from January 1, 2014 to
December 31, 2021 were read through the hospital information management system to
obtain the case data of patients with the first visit. The ethics committee of the
First Hospital Affiliated to Henan University of Chinese Medicine approved this experimental
study (ethical batch No: 022HL-080-01).
Diagnostic Criteria
Western medicine diagnostic criteria: cases with a history of DM were searched according
to the Chinese Guidelines for the Clinical Diagnosis and Treatment of Diabetic Nephropathy
[5 ] and the Chinese Guidelines for the Prevention and Treatment of Diabetic Nephropathy ,[6 ] and DKD could be diagnosed if one of the following conditions was met: (1) The urinary
albumin creatine rate (UACR) or urinary albumin excretion rate (UAER) was detected
three times within 3 to 6 months, and UACR ≥ 30 mg/g or UAER ≥ 30 mg/24 h occurred
at least twice. (2) The kidney biopsy was consistent with the pathological changes
of DKD, such as nodular glomerulosclerosis and diffuse glomerulosclerosis. (3) eGFR < 60
ml min−1 ·1.73m2 )−1 for more than 3 months. It can be considered as DKD with liver and kidney yin deficiency
and blood stasis syndrome if three of the following five items, together with item
6 from TCM diagnostic criteria are met: according to liver and kidney yin deficiency
and blood stasis syndrome in the Internal Medicine of Chinese Medicine (Zhong Yi Nei Ke Xue) ,[7 ] the Development and Application of TCM Syndrome Differentiation Guidelines for Diabetic
Nephropathy ,[8 ] and the 2011 Edition of TCM Prevention and Treatment Guidelines for Diabetic Nephropathy : (1) turbid urine and frequent and profuse urination; (2) fatigue, shortness of breath,
and laziness to speak; (3) dry throat and mouth, feverish palms, and soles; (4) insomnia
and dreaminess; (5) palpitation and restlessness; (6) dark or red thin tongue, or
tortuous sublingual veins, petechia and ecchymosis, and deep pulse.
Inclusion Criteria
Inclusion criteria were (1) cases conforming the above diagnostic criteria; (2) relatively
complete cases in the system data (such as definite and confirmed diseases); (3)mainly
Chinese medicine compounds and certain Western medicine prescriptions used; and (4)
the treatment outcome (such as recovery or death) clearly reflected in the case information.
Exclusion Criteria
Exclusion criteria were (1) pregnant, lactating, and menstruating women; (2) concomitant
with other serious organic diseases (such as cancer); (3) concomitant with other primary
or secondary renal disease and systemic disease; (4) various recent emergencies and
infections occurred during data acquisition; and (5) patients with mental disorders
and allergies.
Data Standardization and Database Establishment
The syndrome patterns of DKD are standardized by referring to the Guidelines for Combination of Diabetes and Nephropathy ,[9 ] such as classifying the “Qi Yin Kui Xu Zheng (qi and yin deficiency syndrome)” as
the “Qi Yin Liang Xu Zheng (deficiency syndrome of both qi and yin).” According to
the syndrome patterns of DKD included in the clinical data in Science of Syndrome Elements Syndrome Differentiation (Zheng Su Bian Zheng Xue) ,[10 ] the involved syndrome patterns are structurally divided according to “syndrome pattern = disease
location element + disease nature elements.” The names, efficacies, flavors, and meridian
tropism of Chinese herbs involved in the administration of herbs by patients were
standardized through the 2020 edition of the Pharmacopoeia of the People's Republic of China .[11 ] For example, the specifications of “Xueshen” and “Honggen” were “Danshen (Salviae
Miltiorrhizae Radix et Rhizoma)”, “Huaishan” was “Shanyao (Dioscoreae Rhizoma)”, “Erhua”
and “Shuanghua” were “Jinyinhua (Lonicerae Japonicae Flos)”, and “Jinbuchang” was
“Sanqi (Notoginseng Radix et Rhizoma)”. In the Excel 2016 software database, components
were input by individual independent retrieval and checked by two people and double
computers. The data processing software IBM SPSS Statistics 25 was used to perform
statistical analysis of the case contents and draw corresponding charts as required.[12 ]
Results
Distribution Analysis of Syndrome Patterns
According to the screening and processing of previous case data, a total of 1,201
patients with DKD were obtained, including 72 TCM syndrome patterns, with a total
frequency of 1,749 times. DKD includes deficiency syndrome and excess syndrome. Spleen
and kidney deficiency syndrome is the most common,[13 ] complicated with the most frequent phlegm-dampness, blood stasis, and turbid toxin,
see [Table 1 ].
Table 1
Distribution of the top seven TCM syndromes of DKD
Syndrome patterns
Frequency/times
Frequency/%
Syndrome of both spleen and kidney deficiency
403
23.04
Syndrome of blood stasis obstructing the collaterals
382
21.84
Syndrome of dampness accumulation and blood stasis
353
20.18
Syndrome of both qi and yin deficiency
235
13.43
Syndrome of turbid toxin and blood stasis
77
4.40
Syndrome of both yin and yang deficiency
39
2.22
Syndrome of Liver and kidney yin deficiency
19
1.08
Abbreviations: DKD, diabetic kidney disease; TCM, traditional Chinese medicine.
Analysis of Disease Nature Element and Disease Location Element
According to the analysis, nine disease nature elements were extracted, including
two deficiency syndrome elements (qi deficiency and yin deficiency) and seven excess
syndrome elements (blood stasis, dampness accumulation, turbid toxin, phlegm and blood
stasis, heat toxin, dampness turbidity, and qi stagnation), with a total frequency
of 1,643 times. The proportion of qi deficiency and yin deficiency in the deficiency
syndrome elements was relatively high; blood stasis was the most frequent evidence
of excess syndrome element, followed by dampness accumulation and turbid toxicity,
see [Table 2 ]. Six disease location elements were extracted, with a total frequency of 916 times.
The disease location element with the highest frequency was the kidney, followed by
the spleen, liver and lung, see [Table 3 ].
Table 2
Analysis of disease nature element of DKD
Disease nature element
Frequency/times
Frequency/%
Blood stasis
850
51.73
Dampness accumulation
354
21.54
Qi deficiency
261
15.88
Turbid toxin
77
4.69
Phlegm and blood stasis
41
2.49
Heat toxin
28
1.70
Yin deficiency
19
1.16
Damp turbidity
10
0.60
Qi stagnation
3
0.18
Abbreviation: DKD, diabetic kidney disease.
Table 3
Analysis of disease location elements of DKD
Disease location element
Frequency/times
Frequency/%
Kidney
435
47.48
Spleen
420
45.85
Liver
25
2.72
Lung
15
1.63
Stomach
12
1.31
Heart
9
0.98
Abbreviation: DKD, diabetic kidney disease.
Frequency Analysis of Herbs
Through the extraction and correction of experimental data, a total of 1,201 prescriptions
were included, involving 405 Chinese herbs. The cumulative frequency of the use of
Chinese herbs was 11,366 times. The top five high-frequency Chinese herbs were Baizhu
(Atractylodis Macrocephalae Rhizoma; 435 times), Fuling (Poria; 415 times), Huangqi
(Astragali Radix; 403 times), Chuanxiong (Chuanxiong Rhizoma; 278 times), and Danshen
(Salviae Miltiorrhizae Radix et Rhizoma; 265 times), see [Table 4 ].
Table 4
Top 15 Chinese herbs in the prescriptions for the treatment of DKD treatment
Chinese herb
Frequency/times
Frequency/%
Classifications
Efficacy
Baizhu (Atractylodis Macrocephalae Rhizoma)
435
3.83
Qi-tonifying herb
Invigorating the spleen and benefiting qi, drying dampness and promoting diuresis
Fuling (Poria)
415
3.65
Diuresis-promoting and dampness-diffusing herbs
Promoting diuresis and diffusing dampness, strengthening the spleen
Huangqi (Astragali Radix)
403
3.55
Qi-tonifying herb
Tonifying qi and promoting yang, benefiting defensive phase and consolidating the
exterior
Chuanxiong (Chuanxiong Rhizoma)
278
2.45
Blood-activating and pain-relieving herbs
Promoting blood and qi circulation, dispelling wind and relieving pain
Danshen (Salviae Miltiorrhizae Radix et Rhizoma)
265
2.33
Blood-activating and menstruation-regulating herbs
Promoting blood circulation and removing blood stasis, dredging meridians and relieving
pain
Gancao (Glycyrrhizae Radix et Rhizoma)
260
2.29
Qi-tonifying herb
Tonifying the spleen and qi, relieving spasm and pain
Chenpi (Citri Reticulatae Pericarpium)
256
2.25
Qi-regulating herb
Regulating qi and harmonizing the middle Jiao, dry dampness and resolving phlegm
Danggui (Angelicae Sinensis Radix)
240
2.11
Blood-nourishing herb
Tonifying blood and promoting blood circulation, regulating menstruation and relieving
pain, moistening intestine and promoting bowel movement
Dangshen (Codonopsis Radix)
192
1.69
Qi-tonifying herb
Tonifying the middle Jiao and benefiting qi, promoting body fluid generation and nourishing
blood
Zexie (Alismatis Rhizoma)
181
1.59
Diuresis-promoting and dampness-diffusing herbs
Promoting diuresis and diffusing
dampness, purging heat
Guizhi (Cinnamomi Ramulus)
167
1.47
Pungent-warming exterior-relieving herb
Promoting sweating and expelling pathogenic factors from the muscles, warming and
dredging meridians, promoting yang and transforming qi
Baishao (Paeoniae Alba Radix)
165
1.45
Blood-nourishing herb
Nourishing blood, regulating menstruation, astringing yin, relieving sweating, softening
liver and relieving pain
Yiyiren (Coicis Semen)
162
1.42
Diuresis-promoting and dampness-diffusing herbs
Promoting diuresis and diffusing dampness, strengthening the spleen and stopping diarrhea,
clearing heat and excreting pus
Abbreviation: DKD, diabetic kidney disease.
Analysis of Efficacy Categories and Meridian Tropism of the Properties and Flavors
of the Commonly Used Chinese Herbs
Through screening and analysis of the 30 commonly used Chinese herbs with a frequency
of ≥100 times, the cumulative frequency of use was 5,585 times. The efficacy categories
of Chinese herbs were mainly deficiency tonifying herbs (2,083 times, 40.44%), blood-activating,
and stasis-dispelling herbs (899 times, 17.45%); the herb properties were mainly warm
(9 times, 29.03%) and mild (7 times, 22.58%); the herbs of sweetness (16 times, 34.78%)
and bitterness (13 times, 28.26%) were the most common. As to meridian tropism, the
main meridian tropism was the spleen meridian (19 times, 19.00%) and lung meridian
(14 times, 14.00%), see [Figure 1 ].
Fig. 1 The properties, flavors, and meridian tropism of commonly used Chinese herbs (frequency
≥100 times).
Clustering of Commonly Used Chinese Herbs
Combined with the characteristics of the syndromes of DKD and clinical practice, the
top 30 high-frequency Chinese herbs include Baizhu (Atractylodis Macrocephalae Rhizoma),
Fuling (Poria), Huangqi (Astragali Radix), Chuanxiong (Chuanxiong Rhizoma), Danshen
(Salviae Miltiorrhizae Radix et Rhizoma), Gancao (Glycyrrhizae Radix et Rhizoma),
Chenpi (Citri Reticulatae Pericarpium), Danggui (Angelicae Sinensis Radix), Guizhi
(Cinnamomi Ramulus), Baishao (Paeoniae Alba Radix), Yiyiren (Coicis Semen), Chishao
(Paeoniae Rubra Radix) Qingbanxia (Pinelliae Rhizoma Praeparatum cum Alumine), Shanyao
(Dioscoreae Rhizoma), Chuanniuxi (Cyathulae Radix), Dilong (Pheretima), Huanglian
(Coptidis Rhizoma), Sharen (Amomi Fructus), Dahuang (Rhei Radix et Rhizoma), Jixuecao
(Centellae Herba), Zhishi (Aurantii Fructus Immaturus), Maidong (Ophiopogonis Radix),
Houpo (Magnoliae Officinalis Cortex), Taizishen (Pseudostellariae Radix), Shuizhi
(Hirudo), Honghua (Carthami Flos), Dangshen (Codonopsis Radix), Zexie (Alismatis Rhizoma),
Gegen (Puerariae Lobatae Radix), Shudihuang (Rehmanniae Radix Praeparata). According
to the average intergroup connection, the 30 commonly used Chinese herbs were reasonably
clustered into six categories, see [Figure 2 ] and [Table 5 ].
Fig. 2 Clustering analysis of the top 30 Chinese herbs in frequency.
Table 5
Clustering analysis results of top 30 high-frequency Chinese herbs
No.
Composition
Treatment method
C1
Baizhu (Atractylodis Macrocephalae Rhizoma), Fuling (Poria), Dangshen (Codonopsis
Radix), Zexie (Alismatis Rhizoma), Chenpi (Citri Reticulatae Pericarpium), Qingbanxia
(Pinelliae Rhizoma Praeparatum cum Alumine), Huanglian (Coptidis Rhizoma), Shuizhi
(Hirudo), Sharen (Amomi Fructus), Yiyiren (Coicis Semen), Gegen (Puerariae Lobatae
Radix)
Tonifying qi and strengthening spleen, promoting diuresis and diffusing dampness
C2
Dahuang (Rhei Radix et Rhizoma), Zhishi (Aurantii Fructus Immaturus) and Houpo (Magnoliae
Officinalis Cortex)
Promoting blood circulation and removing blood stasis, drying dampness and resolving
phlegm
C3
Dihuang (Rehmanniae Radix), Shanyao (Dioscoreae Rhizoma), Gancao (Glycyrrhizae Radix
et Rhizoma), Baishao (Paeoniae Alba Radix), Maidong (Ophiopogonis Radix)
Invigorating the spleen and kidney, nourishing yin and promoting body fluid production
C4
Danggui (Angelicae Sinensis Radix), Honghua (Carthami Flos), Chuanxiong (Chuanxiong
Rhizoma), Danshen (Salviae Miltiorrhizae Radix et Rhizoma)
Tonifying blood and promoting blood circulation, dredging the meridians and relieving
pain
C5
Chishao (Paeoniae Rubra Radix), Chuanniuxi (Cyathulae Radix), Guizhi (Cinnamomi Ramulus)
Activating blood circulation and dredging the meridians, dissipating blood stasis
and relieving pain
C6
Huangqi (Astragali Radix), Jixuecao (Centellae Herba), Taizishen (Pseudostellariae
Radix), Dilong (Pheretima)
Tonifying qi and promoting body fluid generation, promoting diuresis and dredging
the collaterals
Research on the Action Mechanism Based on Network Pharmacology
Research on the Action Mechanism Based on Network Pharmacology
Materials and Methods
Screening of Active Ingredients of High-Frequency Herbs and the Related Targets
The chemical composition of herbs (high-frequency herbs) with a frequency of ≥100
times was retrieved by using the TCM systems pharmacology database and analysis platform,
TCMSP (TCMSP, http://tcmspw.com/tcmsp.php ), and the effective components and the action targets of Chinese herbs were screened
under the conditions of oral bioavailability ≥30% and herblikeness (DL) ≥ 0.18. The
target gene names were standardized through the UniProt (https://sparql.uniprot.org ) online platform.
Target Screening of Diabetic Kidney Disease
The GeneGards database (http://www.genecards.org ), DisGeNET database (https://www.disgenet.org/ ), and online mendelian inheritance in man (OMIM, https://www.omim.org/ ) were searched with the keyword “diabetic kidney disease” to obtain the disease target
and finally get the collection of disease targets.
"Active Ingredients–Potential Targets" Network and Protein–Protein Interaction Network
Construction
The intersections of the targets of high-frequency Chinese herbs and the disease targets
of DKD were achieved by using the Venn online network platform (http://bioinfogp.cnb.csic.es/tools/venny/ ), and the intersection targets were the potential targets of high-frequency Chinese
herbs for the treatment of DKD. The potential targets and their corresponding active
ingredients were input into Cytoscape 3.7.2 software to construct the “active ingredient-potential
target” network graph, and the core chemical composition was screened by topological
analysis. The potential targets were imported into STRING database (http://cn.string-db.org ), protein–protein interaction (PPI) network was constructed, and key targets were
screened by topological analysis.
Analysis of Signal Pathway Enrichment in Kyoto Encyclopedia of Genes and Genomes
The intersection targets were input into the Metascape database (https://metascape.org ) for Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment
analysis.
Validation of Docking Between Key Active Ingredients and Key Target Protein Molecules
The key proteins in the top three of the number of nodes in the PPI network were molecularly
interfaced with the core components in the top five of the network degree of the “active
ingredient-potential target” by using AutoDock software.
Results
Prediction Results of the Active Ingredients and Action Targets of the High-Frequency
Herbs
Based on the screening of TCMSP, 58 active ingredients, including Baizhu (Atractylodis
Macrocephalae Rhizoma), Fuling (Poria), Huangqi (Astragali Radix), Chuanxiong (Chuanxiong
Rhizoma), and Danshen (Salviae Miltiorrhizae Radix et Rhizoma) and 164 herb action
targets were obtained.
Target Screening of Diabetic Kidney Disease
According to the databases of GeneGards, OMIM, and DisGeNET, etc., 2,253 DKD targets
were obtained, and a total of 1,434 targets were obtained after integration and deduplication.
“Active Ingredients—Potential Target” Network and Protein–Protein Interaction Network
Construction
Using the Venn online network platform, the intersections of high-frequency Chinese
medicine targets and DKD targets were selected, and 90 intersection targets were screened
out, which were potential targets of high-frequency Chinese herbs for the treatment
of DKD. The “active ingredient-potential target” network graph includes 222 nodes
(58 active ingredients and 164 target genes). Topological analysis indicated that
quercetin, luteolin, 7-O-methylisoxitol, hederagenin, and 4-methylene miltirone were
the five core chemical components of high-frequency Chinese herbs for the treatment
of DKD, as shown in [Fig. 3 ]. Ninety potential targets were input into the STRING database and the PPI network
was plotted, as shown in [Fig. 4 ]. The network topology analysis suggested that the top five target proteins were
protein kinase B1 (AKT1), interleukin-6 (IL-6), tumor necrosis factor (TNF), vascular
endothelial growth factor A (VEGFA), and tumor protein P53 (TP53).
Fig. 3 “Active ingredient-potential target” network.
Fig. 4 PPI network diagram.
Analysis of Kyoto Encyclopedia of Genes and Genomes Pathway Enrichment
The enrichment analysis of KEGG showed that the key targets were mainly enriched in
20 signaling pathways including tumor-associated pathways (pathways in cancer, proteoglycans
in cancer, and transcriptional misregulation in cancer), viral infection-associated
pathways (human cytomegalovirus infection, malaria, and epithelial cell signaling
in helicobacter pylori infection) and glucose metabolism-associated signaling pathways
(AGE-RAGE signaling pathway in diabetic complications, NK-kappa B signaling pathway,
diabetic cardiomyopathy, and viral myocarditis), as shown in [Fig. 5 ].
Fig. 5 Analysis of KEGG pathway enrichment.
Verification of Docking Between the Key Active Ingredients of High-Frequency Herbs
and Core Protein Molecules
It was found that luteolin, 4-methylene neoketone, and hederagenin had strong binding
to AKT1 with binding energies of −6.72 kJ/mol−1 , −7.2 kJ/mol−1 , and −8.13 kJ/mol−1 , respectively. The potential binding sites were mainly the amino acid residues of
TRP-99, LYS-39, GLU-40, GLU-91, LYS-8, TRP-11, GLU-95, HIS-13, as shown in [Fig. 6 ]. Through analysis, it was discovered that luteolin, 4-methylene neoketone, and hederagenin
all had multiple active groups, and their chemical structures were highly similar,
forming hydrogen bonds with amino acids with an average of 2.45, suggesting that the
hydrogen bond distance was short, and it also reflected that the three chemical components
could well match the active pocket of AKT1 core protein, see [Fig. 7 ].
Fig. 6 Binding energy thermogram of main components of high-frequency Chinese herbs with
AKT1, IL-6, and TNF (kcal/mol). Notes: The darker the color is, the lower the binding
energy is; number represents binding energy.
Fig. 7 Molecular docking diagram of "key active ingredient-core protein". (A ) AKT1-hederagenin, (B ) AKT1-4-methylenemiltirone, (C ) AKT1-luteolin,(D ) IL-6-7-O-methylisomucronulat, (E ) IL-6-hederagenin, (F ) IL-6-quercetin,(H ) TNF-luteolin, (I ) TNF-quercetin, and (J ) TNF-7-O-methylisomucronulat.
Discussion
There is no clear record of the name of DKD in TCM classics and the literature. Through
clinical symptom analysis, DKD can be classified into the categories of “Xiao Ke or
Xiao Dan” (consumptive thirst), “edema”, “kidney consumption”, and “urine turbidity”.[14 ] It is recorded in Formulas from Benevolent Sages Compiled during the Taiping Era (Tai Ping Sheng Hui
Fang) that “Three Xiaos (consumptions) are originated from kidney deficiency”. The kidney
stores essence and is the innate foundation of human beings. In ancient times, it
is generally believed that consumptive thirst is related to kidney deficiency and
blood stasis in collaterals.[15 ] The liver governs the free flow of qi. As early as given in Ling Shu:Wubian
( Spiritual Pivot:Five Changes) , it has the description of consumptive thirst caused by emotional disturbance, and
this is an early record of “consumption caused by emotions”. In the Treatise on the Three Consumption (San Xiao Lun) , it believes that the disease is caused by excessive five emotions and led by excessive
anger which will lead to endogenous internal fire and results in consumptive thirst.[16 ] As the saying goes in Jingui Zhenyan Lun(Discussion on the Important Ideas in the Golden Chamber of Huangdi's
Cannon of Internal Medicine) , the abdomen belongs to yin, and the yin within yin is kidney; the abdomen belongs
to yin, and the yang within yin is the liver. Both the liver and kidney are situated
in the lower Jiao, with one pertaining to yang and the other yin. The kidney governs
storage and the liver governs the free flow of qi. They work together to dominate
the generation of essence and blood so as to nourish the meridians of the whole body.
The spleen is the root of the acquired constitution among the five internal organs,
which governs qi and blood production and dominates transportation and transformation.[17 ] According to the characteristics of different stages of DKD, the great TCM master
Boshou Xue emphasized the importance of spleen-strengthening, kidney-nourishing, dampness-dissolving,
and turbidity-purging in the treatment of DKD.[18 ] Through real-world data analysis, it discovered that in DKD, spleen and kidney deficiency
syndrome, high-frequency syndrome patterns of syndrome of blood stasis obstructing
the collaterals, and the disease location elements mainly include the kidney, liver,
spleen, etc., while the commonly used herbs mainly pertain to the kidney meridian,
liver meridian, and spleen meridian. It can be seen that in the clinical syndrome
differentiation and treatment of DKD, the kidney should be taken as the root, liver
and spleen should be regulated, the kidney should be nourished and the liver should
be softened, so as to achieve kidney–spleen harmony and liver–kidney cotreatment.
Baizhu (Atractylodis Macrocephalae Rhizoma), Fuling (Poria), Huangqi (Astragali Radix),
Chuanxiong (Chuanxiong Rhizoma), and Danshen (Salviae Miltiorrhizae Radix et Rhizoma)
are the top five high-frequency Chinese herbs in clinical application. Huangqi Powder
can slow down the development of DKD by inhibiting the signaling pathways of phosphatidylinositol
3-kinase/protein kinase B (AKT)/mammalian target of rapamycin (mTOR).[19 ] Huangqi (Astragali Radix), Baizhu (Atractylodis Macrocephalae Rhizoma), and Fuling
(Poria) in the Supplemented Qiwei Baizhu Powder have the effects of supplementing
qi and nourishing yin and have good curative effects on the clinical treatment of
DKD.[20 ] It also shows that although there are many causes of DKD, they are generally summarized
as the imbalance between yin and yang, disorder of qi and blood, deficiency, and excess.
Huangqi (Astragali Radix), Fuling (Poria) plus Danshen (Salviae Miltiorrhizae Radix
et Rhizoma), and Chuanxiong (Chuanxiong Rhizoma) have the effects of removing dampness
and relieving swelling, and simultaneously promoting blood circulation and resolving
blood stasis, promoting qi circulation and relieving pain.[21 ] Qiqi Dihuang Pill was found to have a significant protective effect on DKD, which
may be related to the reduction of inflammatory response and oxidative stress damage
in the body.[22 ] To sum up, in the treatment of DKD, the Chinese herbs with the effects of supplementing
qi and nourishing yin, promoting blood circulation, and resolving blood stasis should
be well and skilfully used so that the herbs can directly reach the disease sites
to exert their curative effects.
The data analysis showed that DKD is mainly treated with warm and sweet herbs. The
most widely used herbs are deficiency-invigorating herbs, diuresis-promoting and dampness-diffusing
herbs, blood-activating and stasis-dispelling herbs, etc., which correspond to the
blood stasis, dampness accumulation, qi deficiency, etc., in the disease nature elements.
Through literature study combined with the Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes (2020 edition) , the Chinese Clinical Guidelines for the Prevention and Control of Type 2 Diabetes in the
Elderly (2022 edition) and cluster analysis results,[23 ]
[24 ]
[25 ] it was indicated that “promoting blood circulation and resolving blood stasis” and
“reducing mass and dredging the collaterals” were the therapeutic principles of DKD.
Through clinical studies, Dan Tang found that Chinese herbs with functions of promoting
blood circulation and resolving blood stasis, reducing mass, and dredging the collaterals
have remarkable effects on DKD.[26 ] To sum up, in the clinical treatment of DKD, we should pay attention to the overall
“harmony” in the compatibility of the herbs in the prescription.
The high-frequency Chinese herbs found in this study are Baizhu (Atractylodis Macrocephalae
Rhizoma), Fuling (Poria), Huangqi (Astragali Radix), Chuanxiong (Chuanxiong Rhizoma),
Danshen (Salviae Miltiorrhizae Radix et Rhizoma), etc., which have a high coincidence
with the Chinese medicine composition of Zhenhua Li's Yishen Tongluo Prescription.
Both of them reflect the principle of tonifying the kidney and dredging the collaterals.
Through clustering and implicit structure analysis, it showed that the Chinese herbs
with effects of tonifying the kidney and dredging the collaterals have good clinical
effects on DKD. Quercetin, luteolin, 7-O-methylisoxitol, hederagenin, and 4-methylene
neoketone were the key active ingredients of the above-mentioned herbs. Quercetin
is a flavanol compound widely existing in the plant world. It can promote the release
of inflammatory factors of IL-1, IL-8, etc., by regulating the renal NF-κB signaling
pathway and reduce inflammation and ease the development process of DKD; it can also
protect the damage caused by DKD by intervening TGF-β1 and Smad7 pathways by alleviating
oxidative stress response in the body[27 ]
[28 ]; Huangqi Guizhi Wuwu Decoction can reduce the complications of DKD.[29 ] Luteolin is a flavonoid in Danshen (Salviae Miltiorrhizae Radix et Rhizoma), which
can delay the development of DKD.[30 ] Yao et al found that the glomerular basement membrane hyperplasia and fat inflammation
of diabetic mice were well relieved after the use of hederagenin through three omics
studies.[31 ] AKT1, IL-6, TNF, VEGFA, and TP53 are important potential action targets of high-frequency
Chinese herbs of Baizhu (Atractylodis Macrocephalae Rhizoma), Fuling (Poria), Huangqi
(Astragali Radix), Chuanxiong (Chuanxiong Rhizoma), and Danshen (Salviae Miltiorrhizae
Radix et Rhizoma) in the treatment of DKD. It was found that Huangqi (Astragali Radix)
(quercetin and hederagenin) can regulate autophagy through negative regulation of
AKT1/mTOR signaling pathway in the development of DKD.[32 ] Bupi Yishen Huoxue Decoction can delay the development of DKD by reducing the levels
of IL-6 and TNF-α.[33 ]
Conclusion
Based on the real-world data, this paper makes a preliminary study on the syndrome
laws of DKD and the action mechanism of high-frequency Chinese herbs through retrospective
analysis, network pharmacology, molecular docking, etc. It has found that the differentiation
and treatment of DKD with TCM follows the principles of “taking kidney as the root,
considering both the liver and spleen, tonifying qi and nourishing yin, promoting
blood circulation and resolving blood stasis.” High-frequency Chinese herbs for the
treatment of DKD have multicomponent, multitarget, and multipath characteristics.
This can provide a basis for the clinical treatment of DKD. However, the proper integrative
treatment by Chinese medicine and Western medicine needs to be effectively discussed
in combination with the actual clinical situation.
