CiteSpace-based Knowledge Graph Analysis of the Current Status and Trends of Chinese Medicine Research in Idiopathic Membranous Nephropathy

Fu-ru Hu, Fa-rong Zhang

1Shandong University of Traditional Chinese Medicine, Jinan, China, 250000.

2Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China, 250000.

Abstract: Objective: To analyze the current status and development trend of Chinese medicine research in the field of idiopathic membranous nephropathy since 2000.Methods: The literature related to Chinese medicine for idiopathic membranous nephropathy published in China Knowledge Network (CNKI) since 2000 was searched,and CiteSpacewas applied to visualize the publication time, authors, and keywords of the literature and to draw a visual knowledge graph.Results: 372 relevant literatures were included.Author analysis showed that there were 343 authors included, and the authors with the highest number of publications published 13 articles, and the core authors accounted for 10.2% of the total number; keyword analysis showed that 15 clusters were formed after burst analysis, and 10 emergent words were formed after keyword emergence analysis.Conclusion: Chinese medicine recognizes and intervenes in idiopathic membranous nephropathy in terms of evidence type, treatment method, common prescriptions and single herbs, auxiliary examination, treatment modality, and clinical research.The development trend lies in the combination of macroscopic and microscopic, the synergy between Chinese and Western, multidisciplinary collision diagnosis and treatment, as well as the use of Chinese medicine to intervene in the disease process at an early stage, and the integration of a worldwide standardized diagnosis and treatment guideline of Chinese medicine for idiopathic membranous nephropathy.

Keywords: idiopathic membranous nephropathy; traditional chinese medicine; CiteSpace; status and trends

Introduction

Idiopathic membranous nephropathy [1] (IMN) has an unknown pathogenesis and accounts for about 70%-80% of membranous nephropathy (MN) [2],often presenting clinically with massive proteinuria and pathologically with thickening of the glomerular basement membrane.Previously, the prevalence was higher in middle-aged and elderly men [3-4], but in recent years, IMN has gradually shown a trend toward lower age.The disease progresses slowly and spontaneously resolves in a small proportion of patients, but IMN is the most common cause of nephrotic syndrome in adults [5-6], and about 75%of IMN patients clinically present with nephrotic syndrome, and about 33.3% eventually progress to endstage renal disease [7-8].The overall incidence of IMN in China is increasing [2,3,9], and the current Western clinical treatment regimen mostly uses hormones combined with immunosuppressive therapy.Patients with long-term application may experience side effects such as increased chance of infection, immune tolerance, and hypercoagulability, with variable efficacy [10], and the effectiveness of applying this treatment regimen is questionable from the perspective of evidence-based medicine [11].Chinese medicine has been shown to be effective in the treatment of IMN, either alone in reducing clinical symptoms,modulating the immune function of patients, or in combination with immunosuppressive drugs and hormones to help enhance efficacy and reduce side effects [12].Knowledge graph [13] can show the development process and structure of a knowledge domain with diagrams and spectra, linking individual knowledge and complex knowledge networks to show a specific graph, visualizing the relationship between individual knowledge, and providing help for digital extension of the knowledge domain [14].In this study,we used CiteSpaceV5.7.R5 software [15-16] to draw the knowledge graph based on the relevant literature from Chinese National Knowledge Infrastructure(CNKI) after visual analysis and processing, which can accurately and systematically show the current status,hot spots and trends of research on IMN of Chinese medicine treatment.

1 Information and Methods

1.1 Data sources

Chinese National Knowledge Infrastructure (CNKI)was used as the data source to search the relevant literature about Chinese medicine for idiopathic membranous nephropathy, and the literature search formula: ("Chinese medicine" + "traditional Chinese medicine" + "Chinese herbal medicine " + "proprietary Chinese medicine" + "prescription" + "Chinese formula" + "animal medicine " + "mineral medicine"+ "phytotherapy" + "plant medicine" + "extracts " +"Chinese and Western medicine" + "Chinese medicine"+ "herbal medicine" + "sutra ") and ("idiopathic membranous nephropathy" + "primary membranous nephropathy" + "IMN" + " PMN").Advanced search was applied, and the search criteria were set as"precise".

1.2 Research method

The documents exported from CNKI in Refworks format were imported into JAVA platform-based CiteSpace5.7.R5.The parameters were set as Time Slicing (January 2000-July 2021), Time Slice (Years Per Slice) as 1, and the threshold ( Top N per Slice)is the default value.The node types were selected as: author, keyword.The former uses Pruning sliced networks, and the keywords use Pathfinder, Pruning sliced networks, and Pruning the merged network.After repeated debugging and comparison, the clustering analysis method finally adopts the Latent Semantic Idexing (LSI) in order to obtain scientific and reasonable clustering results [15].

2 Results

The search period was from January 2000 to July 2021, and 384 documents were initially obtained after screening out news, conference announcements and de-duplication by using CiteSpacesoftware, and 372 documents were included after manual browsing of literature content screening.

2.1 Age distribution of publications

The statistical analysis of the included literature on TCM for idiopathic membranous nephropathy is plotted in Figure 1, which shows that the basic trend is divided into three phases.The starting stage: from 2000 to 2006, the volume of published literature was low,with an average annual volume of 1.14 articles; the growth stage: from 2007 to 2014, the volume of articles began to grow steadily, with an average annual volume of 8.5 articles; the development stage: from 2015 to July 2021, the volume of 296 articles, accounting for 79.57%, reached the peak of research in recent years in 2019, due to the inclusion of literature The time limit until July 31, 2021, the number of articles published in the seven months of 2021 has been as high as 31, and the total number of articles published this year is still on the rise compared to previous years, as reasonably deduced by the authors.

Figure 1 distribution chart of annual publications of Chinese medicine for the treatment of idiopathic membranous nephropathy

2.2 Author cooperation network analysis

The generated author analysis graph is shown in Figure 2, which has 343 nodes and 605 lines.The number of nodes represents the number of authors, the size of nodes is positively correlated with the number of occurrences, and the thickness of connecting lines is positively correlated with the closeness of the connection and cooperation between individual authors[16].In summary, 372 relevant papers were included,containing a total of 343 authors, and according to Price Law [17], the minimum number of core authors'publications N ≈ 0.749 × Nmax1 /2 [18].The author with the highest number of publications is Deng Yueyi,with 13 publications, Nmax (the highest number of publications by distinguished authors) = 13, which can be calculated as N = 2.7.According to the statistics,there are 35 core authors, accounting for 10.2% of the total number, and there are fewer core authors and no core author group has been formed.

Figure 2 Author co-occurrence analysis of TCM for idiopathic membranous nephropathy

2.3 Research theme analysis

As the core vocabulary extracted from a paper,keywords are the condensation of the main information of the article and ref lect the theme of the literature [19],and the keyword visualization knowledge map is drawn to ref lect the evolutionary lineage, development history,important milestones and turning points of the research field, the development status of this field, research hotspots, cooperation of research subjects and future trends of research.

2.3.1 Keyword co-occurrence analysis

The high-frequency keywords in the co-occurrence graph network reflect the research hotspots in the f ield to a certain extent.The number of co-occurrence of keywords, which is the number of occurrences,is represented in the figure by the size of concentric circles [19], and the more occurrences of keywords, the larger the circles.In order to standardize the statistical results, this study included "TCM treatment," "TCM therapy," "TCM ""Chinese medicine"" were combined into "Chinese medicine treatment", and "combined Chinese and Western medicine therapy" "combined Chinese and Western medicine "were grouped into"combined Chinese and Western medicine Treatment".As shown in Figure 3, there were 362 nodes and 645 lines after the analysis, and the keyword with the highest frequency and centrality was "idiopathic membranous nephropathy", with a centrality of 0.8.The centrality [20] represents the importance of the node in the text, and the greater the centrality of the node, the closer the relationship between the node and the surrounding nodes.Nodes with high centrality in the graph play a pivotal role in the graph, which is shown as a purple outer ring, and nodes with centrality≥ 0.1 are called central nodes.The central node as shown in Table 1 includes " immunosuppressive agents, traditional Chinese medicine (TCM), nephrotic syndrome, membranous nephropathy, TCM syndrome type, hormones, invigorating blood circulation and removing stasis, review, clinical observation,integrated traditional Chinese and Western medicine treatment, TCM compound, Huangqi (Astragali Radix) Chonglou(Paridis Rhizoma) Kidney Formula,primary membranous nephropathy, tacrolimus, 24-hour urinary protein quantification, renal pathology,cyclophosphamide, rituximab " (ranked from highest to lowest centrality), The keywords listed in Table 2 with more than 15 times frequency include " idiopathic membranous nephropathy, membranous nephropathy,integration of traditional Chinese and Western medicine, nephrotic syndrome, Chinese medicine treatment, clinical research, Chinese medicine type, and Chinese medicine syndrome " (ranked from highest to lowest by frequency).

Table 2 Top 14 frequency of key words in Chinese medicine for idiopathic membranous nephropathy

Figure 3 Keyword co-occurrence analysis of Chinese medicine for idiopathic membranous nephropathy

2.3.2 Keyword clustering analysis and construction of basic knowledge structure

A keyword cluster analysis graph is formed by applying a Latent Semantic Idexing (SLI) for cluster analysis [21].CiteSpace software categorizes a large number of keywords according to their homogeneity,and the keywords in the clusters are closely related to each other, reflecting the basic knowledge structure within the research f ield [22].The larger the clustering number, the fewer keywords are included in the clusters.It can clearly show the research hotspots in the f ield.According to the note of Chaomei Chen [15]who is the developer of this software, Modularity Q and the Weighted Mean Sil- houette S can be used toreflect the clustering effect.0 ≤ Q value ≤ 1, Q value＞ 0.3 when the clusters possess significant structure,reasonable clusters usually have S value ＞ 0.5, credible and efficient As shown in Figure 4, a total of 15 clusters with CiteSpaceauto-naming labels were generated,and Q value = 0.8821 indicates that this figure has significant structure, and S value = 0.9776 indicates that the consistency among the members of the clusters is high and the clustering results are convincing.Among them, the main current research directions can be seen:#0 and #2 and #11 are the research of membranous nephropathy at the level of holistic view of TCM and experimental molecular biology, respectively; #1 is the clinical syndrome of the main manifestations of idiopathic membranous nephropathy; #3 is the main therapeutic drug; #4 and #12 are the TCM syndrome type and related symptoms; #5 and 7 and #13 are the key evaluation indicators; #6 is the main treatment method in TCM therapy; #8 is the representative drug in modern medical therapy.

Figure 4 Cluster analysis of Chinese medicine for idiopathic membranous nephropathy

Figure 5 Keyword emergence diagram of Chinese medicine for idiopathic membranous nephropathy

2.3.3 Keyword Citation Burst

Conversion to the keyword citation burst on the basis of Figure 4 is shown in Figure 5 for tuning parameters γ= 0.5, minimumduration = 1, burst key words refer to those that appear very frequently or citations in a short period of time, which can indicate that the research in this area has suddenly increased, and the generation of a map can clearly exhibit the change trend of research hotspots in this f ield [23-24].Burst detection algorithms can identify research frontiers, timely detect emerging trends and emergent functions, and are suitable for identifying emerging research frontiers concepts [25].A total of 10 hot key words were generated from the Citation Burst, " begin " indicates the beginning years," end " indicates the end years, " integrated traditional Chinese and Western medicine treatment " f irst appeared in 2000, focusing on " Yiqi and invigorating blood and promoting water " between 2010 and 2013 to reflect the treatment method, at the same time,research on the pathological mechanism changes of" Qi and water "; A brief focus on " renal pathology "from 2017 to 2018; Focusing on " data mining " and "medication rule " from 2019 to now, focusing on the clinical symptom of " edema " from 2020 to now, heat has continued to this day, indicating that they are newly emerging research hot spots in nearly three years and may continue to be research hot spots in the future.

3 Discussion

A review of the literature in the field of TCM treatment of IMN is methodologically backward and is affected by some subjective factors, and this study employs knowledge mapping, a new scientific metrology and information visualization method, to comprehensively and objectively analyze the current state of research and the trend of development in this field.

3.1 Current Situation Analysis

For the key words co-occurrence and clustering results analysis, TCM awareness and intervention IMN started from the following aspects:

3.1.1 Syndrome type recognition and treatment

Idiopathic membranous nephropathy does not have an exclusive TCM disease name, but can be assigned to the categories of TCM " cloudy urine, " "edema, " " kidney water." clinical onset often starts with proteinuria as the main symptom throughout,accompanied by intermittent edema.The Kidney Disease: Improving Global Outcomes (KDIGO)guidelines recommend [26]: when risk stratification is intermediate or high risk, treatment with hormones combined with immunosuppressive agents or biological agents is often used.The patient's confirmatory pattern also changed with the implementation of the treatment protocol [27].Clustering results showed that the TCM Patterns of this disease were more characterized by Qi Yin two deficiency syndrome, Qi deficiency blood stasis syndrome, and blood stasis syndrome, and the governing method focused on invigorating blood circulation and eliminating stasis, Yiqi Wenyang, Yiqi invigorating blood and eliminating water, and clearing heat and eliminating dampness, among others.At present, there are many doctrines in TCM, which are in the stage of academic fight.Doctrine such as " Yin Fire doctrine ", " Qi blood and water ".

3.1.2 The main prescription and single herb Chinese medicines

Self mimicking formulae such as Fuzheng Qufeng formula, Shenqi Dihuang Decoction, Yishen Tongluo formula, Qilou Gushen formula, Qidi Gushen formula, and Zishen decoction, reflect the clinical treatment of IMN based on invigorating spleen and replenishing kidney, taking into account the therapeutic characteristics of Qufeng, clearing heat, eliminating dampness, and activating blood to invigorate collaterals;Meridians such as Buyang Huanwu Decoction, Wandai decoction, Shenqi Dihuang chamber, huagai san,Danggui Buxue Decoction, Jiawei Shengjiang San,Jiawei Yanghe Decoction; Commonly used Chinese patent medicines are represented by Sanqi oral liquid,Qidi gushen piece, Jianpi zhiswel granules; Studies on the application of single herb Chinese medicines such as Shanzhuyu (Cornifructus), Chonglou(Paridis Rhizoma), Chuanniuxi (Cyathulae Radix), Danshen(Salviae Miltiorrhizae Radix Et Rhizoma), Renshen(Ginseng Radix Et Rhizoma), Xianlingpi (Epimedii Folium), Baihuashesheccao(Bungarusparvus).

3.1.3 Treatment modality

Traditional Chinese medicine (TCM) is based on decoction as the main way, which is dispensed with Yu recruit acupoint application, Huolong moxibustion, and so on.

3.1.4 Ancillary tests

24-hour urine protein quantification, coagulation,anti-PLA2R antibodies, Anti-THSD7A antibodies,renal function, serum albumin, T-cell subsets, renal pathology after renal needle biopsy were the main test items, mostly laboratory related test items.In addition to the gold standard of " renal pathology ", the " anti-PLA2R antibodies, Anti-THSD7A antibodies " may not only be used as a reference to diagnose this disease, but also reflect the disease changes and prognosis.

3.1.5 Clinical studies

Most of them are based on clinical trials and animal experiments, and clinical trials are mainly based on the combination of traditional Chinese and Western Medicine, which is often combined with hormone and immunosuppressive therapy to evaluate the clinical effects by auxiliary examination and TCM syndrome scores; Animal studies a variety of experimental Mn animal models, such as rabbits, rats, and mice, in which the intervention of cationized bovine serum albumin is often used, and experimental observations,such as Liang Jing [28], considered that the c-bsa16 mg / kg dose group of animal model had the most typical renal pathology and clinical symptoms and most closely matched human idiopathic membranous nephropathy.And Tomas et al [29-30] constructed an animal IMN model similar to human idiopathic membranous nephropathy by utilizing human Anti-THSD7A antibody as well as Rabbit anti human and mouse thsd7a antibodies, respectively.Studies on TCM compound formulas have delved into the molecular level, such as the complex Kidney Decoction, kunxian capsule, Qingkai Ling Injection, Yishen Tongluo formula, Sanjiao Qushi formula, and Wenyang Lishui formula, and studies on the constituents of single herbs such as those on Danshen polyphenolic acid salts [31];At the same time, the assisted platform of traditional Chinese medicine transmission and retrospective analysis were used to evaluate the rules of research drug use and to make relevant scales using the Delphi method.

3.2 developmental trends

Combined with keywords clustering time zone diagram,keywords prominence map and related literature analysis, we found that the field of TCM treating IMN exhibited the following trends:

3.2.1macro and micro

The understanding of the disease in modern medicine is gradually from clinical symptoms and pathological morphology to the molecular level.In the diagnosis and treatment of this disease, it is important to combine the local renal pathology with the whole analysis, from initially carrying out a sniff question and cutting the patient, to peeking in the tube and seeing each other, to diagnose the patient according to the clinical symptoms,and then to analyze the renal pathology, so as to guide the clinical.As well as the use of renal pathology to confirm the diagnosis of this disease showing the disease, it has gradually become possible in clinical practice to use diagnostic biomarkers anti-PLA2R antibodies, Anti-THSD7A antibodies instead of renal biopsy, and valid evaluation criteria other than urine protein, serum creatinine have also been established in judging the condition, clinical efficacy, and prognosis.In terms of disease research, the included efficacy criteria range from TCM syndrome scores at the macro level to molecules at the micro level.The field of traditional Chinese medicine (TCM) is investigating idiopathic membranous nephropathy with multitarget and comprehensive aspects in molecular biology,proteomics, pharmacology.

3.2.2 Traditional Chinese and Western synergism

Keywords highlight in 2000 to 2004 the hot spot mutant word is " integrated traditional Chinese and Western medicine treatment ", most of the existing clinical trials are conducted in combination of traditional Chinese medicine and Western medicine, and traditional Chinese medicine (TCM) can not only interfere with the disease progression in advance, but also play an important role in alleviating the side effects of Western medicine and improving immunity.

3.2.3 Multidisciplinary cross diagnosis and treatment

The research in this field now involves the computerassisted system of TCM expert system, TCM syndrome differentiation and treatment model, TCM computer diagnosis and treatment system and other techniques to standardize the diagnosis and treatment system, and the research level includes network pharmacology,molecular docking technology, according to the current development trend in the field, future research will conform to the trend and closely follow the scientific development, Major technology platforms such as systems biology technologies such as genomics are applied to study and establish multi omics profiles for the treatment of idiopathic membranous nephropathy;Promote the communication between research institutions and hospitals corresponding departments and colleges in engineering technology, merge big data machine learning, artificial intelligence, neural networks, knowledge mapping research and so on in the field.And idiopathic membranous nephropathy has the highest incidence among whites, followed by Asians [32].Only after sufficient clinical and animal experimental data have been collated using statistical methods to induce the world-wide expert consensus of TCM from a genetic level, can we guarantee a higher and wider path for TCM to achieve globalization sooner.

3.2.4 Early intervention

The KDIGO group considers not using immunosuppressive agents first when patients with idiopathic membranous nephropathy are at low risk and only administering supportive care to wait and watch.However, it also takes a longer time to treat glomerular injury because idiopathic membranous nephropathy as a progressive disease and serum pla2r AB often appears before clinical manifestations such as proteinuria appear by 8 months [33] and the clinical symptoms only disappear after the antibodies disappear.It is important to intervene early in the disease according to the guidelines, if the constantly leaking proteinuria also causes reverse damage to the kidney aggravating podocyte damage, leading to renal fibrosis, etc., then the patient can be adjusted to the overall condition,relieve local symptoms, improve mental status,delay the course of the disease, To improve the TCM syndrome score , reduce the 24-hour urine protein level, improve renal function urea nitrogen and blood creatinine, plasma albumin and lipid levels, shorten the disease course, macroscopic regulation combined with microscopic syndrome differentiation has a significant efficacy, is inexpensive, and long-term use of side effects is low, but also alleviates the side effects of hormones and immunosuppressants and reduces the incidence of adverse effects.

4 inadequacy and Outlook

In this study, knowledge graph analysis was performed from the related literature of China knowledge net reception, and the results were relatively reliable.Although this study has selected as many key words as possible to make the search more comprehensive, it is still possible that it failed to cover all papers under the research topic in this field, but did not affect the reliability of the conclusions drawn from the articles.Knowledge map is an intuitively effective way to exhibit knowledge.In this study, by visualizing the knowledge, an objective and quantitative analysis of the literature in the field of TCM treatment IMN for nearly 21 years on the CNKI database, explores the research hot spots and the frontiers in this field, and finds out some limitations among them.There is a lack of data on the long-term outcomes and multicenter and large sample clinical controlled trial studies of TCM for the treatment of idiopathic membranous nephropathy in the clinic, and a uniform guideline for diagnosis and treatment of TCM has not been formed in the clinic, and in the future, a large number of applications should be made to summarize the systems of computer science technology, systems biology and syndrome differentiation of TCM for the treatment of idiopathic membranous nephropathy, Using statistical techniques to integrate worldwide guidelines for the standardized diagnosis and treatment of Chinese medicine at the genetic level after competing with hundreds of doctors to provide a solid foundation for Chinese medicine to benefit patients with idiopathic membranous nephropathy in various countries worldwide.