Global Research Trends in Traditional Chinese Medicine for Diabetic Kidney Disease: A 20-Year Bibliometric Analysis

Abstract

Background and Purpose

The global burden of diabetic kidney disease (DKD) continues to escalate, establishing it as a predominant contributor to chronic kidney failure; nonetheless, effective therapeutic options remain limited. Emerging evidence indicates that traditional chinese medicine (TCM) may offer novel strategies for addressing this condition. However, the existing literature is characterized by considerable heterogeneity in both the specific TCM interventions employed (eg, single herbs, compound formulas, and phytochemical extracts) and the reported therapeutic outcomes across individual studies, and previous reviews have been constrained by a narrow focus on specific herbal preparations or single-outcome measures, lacking a systematic overview of the entire research landscape. Consequently, to obtain a holistic understanding of TCM research in DKD, this study applied bibliometric methods to systematically map the current status, research breadth, and evolving trends within this domain.

Patients and Methods

A bibliometric analysis was conducted on 1249 publications retrieved from the Web of Science Core Collection, spanning two decades (2004–2024). To ensure comprehensive coverage, the search strategy broadly defined TCM research to include single herbs, compound formulas, phytochemical constituents, network pharmacology approaches, clinical observational studies, and experimental mechanistic investigations. Data were analyzed using CiteSpace and VOSviewer to visualize publication trajectories, author/institutional collaborations, keyword clusters, and research hotspots. Focus areas included thematic shifts, methodological advancements, and clinical translation challenges.

Results

A systematic literature search yielded 1249 eligible publications. Over the two-decade study period, annual publication output demonstrated substantial growth, peaking in 2022. Geographically, primary research contributions originated from East Asian nations, particularly China, alongside the United States. Quantitative analyses identified the top 10 most productive authors, leading journals, and highly cited articles; additionally, 16 distinct citation clusters were delineated, and keyword evolution was tracked across seven thematic categories. Notably, 2022 witnessed marked increases in knowledge base expansion, collaborative intensity, and publication productivity. The field exhibits pronounced interdisciplinary characteristics, with network pharmacology emerging as a dominant paradigm in contemporary TCM research. Burst detection analysis further revealed that the integration of TCM and DKD research converges on two principal biological processes: inflammatory pathways and oxidative stress mechanisms.

Conclusion

This study represents the first systematic, quantitative, and visual documentation of the evolutionary trajectory of TCM applications in DKD treatment, revealing substantial acceleration in recent years. These findings underscore the pivotal importance of interdisciplinary collaboration and the imperative for strengthened global research partnerships. Leveraging technological advances in the big data era, network pharmacology provides a holistic, systems-based paradigm that offers innovative pathways for investigating TCM and its mechanisms of action. Three ethnomedicinal species—Astragalus mongholicus Bunge, Salvia miltiorrhiza Bunge, and Cornus officinalis Siebold & Zucc.—demonstrate potential as sources of bioactive compounds for DKD therapy, supported by extensive historical clinical application.

Graphical Abstract

Introduction

Over the past several decades, the global prevalence of diabetes has risen steadily, establishing it as one of the world’s foremost public health challenges.¹ Diabetic kidney disease (DKD), a severe microvascular complication, has experienced a parallel increase in its global incidence, with approximately 30–40% of type 2 diabetes patients eventually developing DKD.^2–4 As the disease evolves, proteinuria transitions from microalbuminuria to overt proteinuria, accompanied by progressive deterioration of renal function and elevated serum creatinine levels, ultimately culminating in nephrotic syndrome, which manifests as massive proteinuria, hypoalbuminemia, and peripheral edema.^2,5 In the absence of timely and effective intervention, up to 32.0% of DKD patients are reported to progress to end‑stage kidney disease within five years.⁶ These pathological alterations not only impair patients’ quality of life but also impose a mounting socioeconomic burden on healthcare systems. Consequently, DKD has emerged as a critical public health priority. DKD is a major contributor to kidney failure and end-stage renal disease (ESRD) and is linked to a markedly elevated risk of mortality among patients with diabetes.² Current approaches to DKD prevention and treatment emphasize comprehensive disease management, including intensive glycemic control,^7–9 optimization of metabolic status, lifestyle intervention,¹⁰ and appropriate management of disease-related complications.¹¹ Recent advances in DKD management have introduced several novel pharmacological agents, such as SGLT2 inhibitors, GLP-1 receptor agonists, endothelin receptor antagonists, and MRAs, which have demonstrated favorable kidney-protective effects by lowering albuminuria and preserving renal function.^12,13 These pharmacological therapies are commonly implemented alongside lifestyle measures, such as low-sodium, low-fat, and low-protein dietary patterns, smoking cessation, alcohol restriction, regular health monitoring, patient education, and risk-factor control, to slow disease progression. Among these agents, finerenone, a non-steroidal selective MRA, has shown significant clinical benefits in DKD by blocking mineralocorticoid receptor activation, thereby attenuating inflammation and fibrosis and ultimately preserving kidney function.¹⁴ Therefore, integrated management approaches and individualized treatment strategies remain crucial for improving clinical outcomes and enhancing the quality of life of patients with DKD.

Although substantial progress has been achieved in delaying the onset and progression of DKD through contemporary medical interventions, several challenges remain, including difficulties in early detection, rapid disease progression, complex pathogenic factors, limited therapeutic options, and considerable economic burden.^13,15 From the perspective of traditional Chinese medicine (TCM), DKD is generally associated with spleen–kidney deficiency, deficiency of qi and yin, and blood stasis syndrome. Guided by syndrome differentiation and individualized therapeutic principles, TCM has been extensively applied to relieve clinical manifestations and improve the quality of life of patients with DKD. With its holistic therapeutic concept and multi-component herbal formulations, TCM is considered to exert multi-target regulatory effects, reduce adverse drug reactions, and provide antioxidant and anti-inflammatory benefits, thereby contributing to the delay of disease progression.^16,17 Recent experimental and clinical evidence has further indicated that representative medicinal herbs, such as Huangqi and Danshen, exhibit renoprotective effects and may enhance renal function while alleviating renal fibrosis.¹⁸ In addition, the integration of TCM with conventional Western medicine has shown promising potential for optimizing DKD management and improving clinical outcomes. Ongoing basic and clinical investigations are expected to expand the application of TCM in DKD treatment and provide further evidence supporting its therapeutic value in this field.^14,19

Over the past two decades, the annual output of TCM-related publications on DKD has shown a marked upward trajectory, reflecting growing scholarly attention to this therapeutic avenue. The proliferation of research outputs, however, has rendered it increasingly difficult for individual researchers or clinicians to keep abreast of the full spectrum of developments, let alone to discern overarching patterns or shifting priorities within the literature. Systematic mapping of the existing knowledge base thus becomes indispensable, as it can reveal the structural organization of the field, highlight dominant research clusters, and uncover under-investigated areas that merit further exploration. Traditional review articles, while offering qualitative syntheses, are inherently constrained by their reliance on selective literature sampling and subjective interpretation, which may introduce bias and limit their capacity to capture the full landscape. Bibliometric approaches offer a complementary and more systematic alternative, enabling researchers to process large volumes of bibliographic data with objectivity and reproducibility. By quantifying publication trends, collaboration patterns, and citation dynamics, bibliometrics provides a bird’s-eye view of the field that is difficult to achieve through conventional narrative summaries alone.

Although several bibliometric studies have previously addressed the topic of DKD, the present study offers several distinctive contributions.^20–23 First, our analysis covers a longer and more up-to-date time span, encompassing publications from 2000 to 2024, thereby capturing the most recent developments in this rapidly evolving field. Second, beyond conventional publication and citation analyses, we incorporated citation burst detection to identify emerging research frontiers and hotspots with unprecedented growth momentum. Third, we integrated two complementary bibliometric tools—CiteSpace and VOSviewer—to leverage their respective strengths in network visualization and co-citation analysis, enabling a more robust and multidimensional depiction of the research landscape. These combined approaches allow us to not only depict the current state of the field but also project future directions, thereby providing a more holistic and forward-looking perspective than earlier investigations.

In this study, we employed bibliometric tools to analyze publications from the Web of Science Core Collection. Through multidimensional visual analyses, we mapped the research landscape of TCM in DKD, covering annual publication trends, collaborative patterns across countries and institutions, co-authorship networks, journal and reference co-citation relationships, and keyword evolution. Our bibliometric scope encompassed all categories of TCM-based DKD research. This included single herbs (eg, Huangqi, Danshen), compound formulas (eg, Shenqi Dihuang decoction), and bioactive phytochemicals derived from TCM (eg, astragaloside IV, tanshinone IIA). We also incorporated studies across multiple modalities—mechanistic investigations of molecular pathways (anti-inflammatory, antioxidant), preclinical animal experiments, clinical trials assessing efficacy and safety, and network or systems pharmacology approaches predicting multi-target interactions. This comprehensive coverage ensured that our analysis captured the full spectrum of TCM research in DKD, from fundamental mechanistic exploration to translational clinical applications. The aims of this study were to systematically evaluate the current research landscape, identify major thematic domains, and investigate emerging research trends. The findings are expected to provide a scientific reference for clinical drug development and evidence-based therapeutic strategies for DKD. Moreover, this work may offer useful insights for researchers, policymakers, and funding organizations involved in this field.

Methods and Materials

Data Source and Search Strategy

The WoSCC is widely regarded as one of the most authoritative databases for bibliometric studies due to its standardized indexing system and reliable literature classification. Accordingly, WoSCC was chosen as the data source for this study. On July 24, 2024, all publications related to TCM and diabetic nephropathy published between January 1, 2004, and July 24, 2024, were retrieved from the WoSCC database. The search strategy was constructed using the following terms: (((((((TS=(natural product*)) OR TS=(natural compound*)) OR TS=(traditional chinese medicine*)) OR TS=(TCM*)) OR TS=(Chinese herb*)) OR TS=(phytochemical*)) OR TS=(secondary metabolite*)) OR TS=(natural medicine*)) AND (((((((((((((((((TS=(Diabetic Nephropathies)) OR TS=(Nephropathies, Diabetic)) OR TS=(Nephropathy, Diabetic)) OR TS=(Diabetic Nephropathy)) OR TS=(Diabetic Kidney Disease)) OR TS=(Diabetic Kidney Diseases)) OR TS=(Kidney Disease, Diabetic)) OR TS=(Kidney Diseases, Diabetic)) OR TS=(Diabetic Glomerulosclerosis)) OR TS=(Glomerulosclerosis, Diabetic)) OR TS=(Intracapillary Glomerulosclerosis)) OR TS=(Nodular Glomerulosclerosis)) OR TS=(Glomerulosclerosis, Nodular)) OR TS=(Kimmelstiel-Wilson Syndrome)) OR TS=(Kimmelstiel Wilson Syndrome)) OR TS=(Syndrome, Kimmelstiel-Wilson)) OR TS=(Kimmelstiel-Wilson Disease)) OR TS=(Kimmelstiel Wilson Disease)). The literature selection process was conducted based on the following inclusion criteria: (1) publications focusing on TCM and diabetic nephropathy with accessible full-text information; (2) English-language articles and reviews; and (3) studies involving human subjects and experimental animals published between January 1, 2004, and July 24, 2024. The exclusion criteria included: (1) studies unrelated to TCM and diabetic nephropathy; and (2) document types such as conference abstracts, news items, editorials, and brief communications. All eligible records were exported in plain-text format for subsequent bibliometric analysis. The detailed search strategy and literature selection procedure are illustrated in Figure 1.

Figure 1.

Flowchart of literature search.

Bibliometric and Visualize Analysis

GraphPad Prism v8.0.2 was utilized for the analysis and visualization of annual publication output, national publication patterns, and publication proportions. Bibliometric analyses and knowledge-map visualization were carried out using CiteSpace (version 6.2.4R, 64-bit Advanced Edition) and VOSviewer (version 1.6.19). VOSviewer, developed by Waltman et al, is a widely applied bibliometric visualization software for constructing and analyzing large-scale scientific networks.^24,25 Based on distance-oriented mapping techniques, it clusters closely related items into distinct groups, with nodes sharing the same color indicating stronger relationships. The software also provides overlay visualization, in which node color and spatial distribution reflect temporal characteristics and network associations. In the present study, VOSviewer was applied to construct co-authorship networks for evaluating collaborations among authors and institutions, as well as keyword co-occurrence networks for identifying major research topics and their interrelationships. CiteSpace, developed by Chen, is a knowledge-mapping tool designed to identify research patterns and emerging trends through bibliometric analysis of scientific literature.²⁶ In this study, CiteSpace was mainly applied to conduct co-citation analyses of authors and references, generate journal dual-map visualizations, and identify highly cited references and keywords exhibiting strong citation bursts over defined time periods.

Base R (version 4.3.1) was employed to merge, validate, and cross-check raw data retrieved from the Web of Science database alongside outputs from the two aforementioned statistical software programs, thereby ensuring data consistency and accuracy throughout the analytical workflow.

Research Status of TCM Associated with Diabetic Kidney Disease

Annual Distribution of Publication

A total of 1249 publications related to TCM and DKD were retrieved from the WoSCC database between January 1, 2004, and July 23, 2024, including 867 original research articles and 382 review articles. These publications involved 86 countries and regions, 1653 institutions, and 5812 authors. Based on annual publication patterns, the evolution of this research field can be generally divided into four stages. As shown in Figure 2, research in this field has been continuously published since 2004, indicating sustained scholarly interest over the past two decades. According to the annual publication trend, the development of this research area can be broadly categorized into four stages. During the initial stage (2004–2010), research activity remained relatively modest, with fewer than 10 publications reported annually. In the second stage (2011–2018), publication output increased steadily from 17 to 64. This was followed by a period of rapid growth, reaching a peak of 186 publications in 2022. Thereafter, the number of publications showed a slight decline from 2023 onwards.

Figure 2.

Number of annual publications on TCM and DKD Distribution of countries/regions.

Distribution of Countries/Regions

A total of 86 countries and regions have participated in research on the application of TCM in DKD. The annual publication trends of the 10 most productive countries over the past decade are presented in Figure 3A. China, India, the United States, South Korea, and Iran were the primary contributors in this field. Of these, China produced 816 publications, accounting for 65.33% of the total output and markedly exceeding all other countries. India and the United States ranked second and third, contributing 109 (8.73%) and 104 (8.33%) publications, respectively.

Figure 3.

Countries and institutions analysis of the field of diabetes kidney disease. (A) Line graph of national publications. (B) Networks of country cooperation. Node size corresponds to publication output, with larger nodes indicating greater productivity. Link thickness reflects publication frequency, whereas color gradients represent publication contribution rates, with warmer colors (yellow–green) corresponding to higher levels of contribution.

According to Table 1, China occupied the leading position in total citations among the top 10 countries/regions, reaching 15,622 citations, which markedly surpassed the citation counts of the remaining contributors. However, its average citation per publication was 19.14, placing ninth among the top 10 countries and suggesting a relatively lower citation impact at the individual article level. India, the second most productive country, received 2392 citations and showed a comparable citation-per-publication value (21.94). By comparison, the United States exhibited the highest average citation rate (53.84), indicating a greater academic impact of its published studies.

Table 1.

The Top 10 Countries/Territories by Publication Volume

Rank	Country/Territory	Article Counts	Centrality	Percentage (%)	Citation	Citation per Publication
1	China	816	0.32	65.33	15,622	19.14
2	India	109	0.47	8.73	2392	21.94
3	The United States	104	0.24	8.33	5605	53.89
4	South Korea	44	0.05	3.52	890	20.23
5	Iran	35	0.15	2.80	999	28.54
6	Saudi Arabia	34	0.19	2.72	490	14.41
7	Egypt	24	0.15	1.92	935	38.96
8	Italy	24	0.14	1.92	759	31.63
9	Australia	24	0.02	1.92	857	35.71
10	Japan	23	0.02	1.84	829	36.04

The international collaboration network is illustrated in Figure 3B. Nodes encircled by purple rings represent countries with high centrality, reflecting their importance within the collaborative network. In CiteSpace, centrality is commonly used to evaluate the intermediary role of countries in a specific research domain. The progressive color transition of nodes from purple to yellow between 2004 and 2024 indicates the temporal evolution of collaborative relationships. Strong collaborative links were identified between China and India, the two most productive countries. China also maintained close collaborative ties with South Korea, Japan, and the United States, whereas India showed relatively stronger cooperation with Italy, the United Kingdom, and Egypt. In terms of publication output, citation counts, and network centrality (0.32), China held a leading position in this research field.

Contributions of Institutions

Research on TCM and DKD involved 1653 institutions worldwide. Of the 10 most productive institutions, nine were from China and one was from Egypt (Table 2). Beijing University of Chinese Medicine ranked first with 72 publications, accumulating 1091 citations and an average of 15.15 citations per article. The China Academy of Chinese Medical Sciences ranked second with 56 publications, 784 citations, and 14.00 citations per publication. Nanjing University of Chinese Medicine and Chengdu University of Traditional Chinese Medicine ranked third and fourth, contributing 47 and 44 publications and receiving 720 and 506 citations, respectively. The Chinese Academy of Medical Sciences showed the highest average citation performance, with 27.34 citations per publication.

Table 2.

The Top 10 Institutions by Publication Volume

Rank	Institution	Country	Number of Studies	Total Citations	Average Citation
1	Beijing University of Chinese Medicine	China	72	1091	15.15
2	China Academy of Chinese Medical Sciences	China	56	784	14.00
3	Nanjing University of Chinese Medicine	China	47	720	15.32
4	Chengdu University of Traditional Chinese Medicine	China	44	506	11.50
5	China-Japan Friendship Hospital	China	43	765	17.79
6	Guang’anmen Hospital	China	41	766	18.68
7	Shanghai University of Traditional Chinese Medicine	China	38	712	18.74
8	Chinese Academy of Medical Sciences - Peking Union Medical College	China	32	875	27.34
9	Guangzhou University of Chinese Medicine	China	30	339	11.30
10	Egyptian Knowledge Bank (EKB)	Egypt	22	431	19.59

The institutional collaboration network revealed extensive cooperation among research organizations, particularly among institutions within the same country (Figure 4). Nevertheless, interactions between domestic and international institutions remain comparatively limited. Enhanced cross-institutional and international collaboration may facilitate knowledge exchange, reduce academic fragmentation, and further advance research development in this field.

Figure 4.

Networks of institutional cooperation.

Distribution of Thematic

A journal dual-map overlay was used to further investigate the disciplinary distribution of publications (Figure 5). Journal labels represent the corresponding subject areas, while colored citation paths illustrate the relationships between citing journals (left) and cited journals (right). Four major citation trajectories were identified. The analysis revealed that journals in the molecular biology/genetics, health/nursing/medicine, and environmental/toxicology/nutrition categories were mainly cited by journals in the molecular biology/immunology discipline. Moreover, journals classified as molecular biology/genetics were frequently cited by journals in the psychology, education, and social science fields.

Figure 5.

Dual map of journals.

Distribution of Source Journals

As shown in Table 3, Frontiers in Pharmacology was the most productive journal in the field of TCM and DKD, contributing 88 publications (7.05%). It was followed by Journal of Ethnopharmacology with 82 publications (6.57%), Evidence-Based Complementary and Alternative Medicine with 48 publications (3.84%), Molecules with 44 publications (2.64%), and Biomedicine & Pharmacotherapy with 31 publications (2.48%). Among the 10 leading journals by publication output, Biomedicine & Pharmacotherapy possessed the highest impact factor (IF=6.9). In addition, 90% of these journals were distributed within the JCR Q1 or Q2 categories.

Table 3.

The Top 10 Journal with Most Publications in the Field of TCM and DKD

Rank	Journal	Article Counts	Percentage (1249)	IF	Quartile in Category
1	Frontiers in Pharmacology	88	7.05%	4.4	Q1
2	Journal of Ethnopharmacology	82	6.57%	4.8	Q1
3	Evidence-based Complementary and Alternative Medicine	48	3.84%	2.6	Q3
4	Molecules	33	2.64%	4.2	Q2
5	Biomedicine & Pharmacotherapy	31	2.48%	6.9	Q1
6	Phytomedicine	31	2.48%	6.7	Q1
7	Medicine	23	1.84%	1.3	Q2
8	PLOS One	22	1.76%	2.9	Q1
9	Journal of DiabetesResearch	17	1.36%	3.6	Q2
10	Heliyon	16	1.28%	3.4	Q1

Journal influence can also be evaluated through co-citation analysis (Figure 6). In the present study, Journal of Ethnopharmacology ranked first in co-citation frequency with 624 citations, followed by Kidney International (608 citations) and Diabetes (568 citations). Among the 10 most frequently co-cited journals, Kidney International had the highest impact factor (IF=14.8), followed by the Journal of the American Society of Nephrology (IF=10.3). In addition, nine of the ten most frequently co-cited journals were classified as JCR Q1 or Q2, underscoring their strong academic standing in this research field (Table 4).

Figure 6.

Co-citation network map of journals.

Table 4.

Co-Citation Table of Journals

Rank	Cited Journal	Co-Citation	IF (2023)	Quartile in Category	Rank
1	Journal of Ethnopharmacology	624	4.8	Q1	1
2	Kidney International	608	14.8	Q1	2
3	Diabetes	568	6.2	Q1	3
4	PLOS One	547	2.9	Q1	4
5	Journal of the American Society of Nephrology	546	10.3	Q1	5
6	Biomed Pharmacother	479	6.9	Q1	6
7	International Journal of Molecular Sciences	465	4.9	Q1	7
8	Evidence-based Complementary and Alternative Medicine	441	2.6	Q3	8
9	Frontiers in Pharmacology	432	4.6	Q1	9
10	Phytomedicine	418	6.7	Q1	10

Co-Authorship and Co-Cited Analysis of Authors

Table 5 lists the 10 most productive authors in the field of TCM and DKD research. Collectively, these authors contributed 137 publications, accounting for 10.97% of the total publications included in this analysis. Li Ping et al ranked first with 39 publications, followed by Zhao Tingting (15 publications), Zhang Haojun (12 publications), and Tong Xiaolin (11 publications). The collaboration network among these authors is visualized in Figure 7A using CiteSpace.

Table 5.

Author’s Publications and Co-Citation Table

Rank	Author	Count	Rank	Co-Cited Author	Citation
1	Li, ping	39	1	Zhang l	136
2	Zhao, tingting	15	2	Wang y	115
3	Zhang, haojun	12	3	Li y	107
4	Tong, xiaolin	11	4	Zhang y	91
5	Liu, peng	10	5	Forbes jm	87
6	Wang, qian	10	6	Liu y	83
7	Yan, meihua	10	7	Alicic rz	83
8	Yang, liping	10	8	Brownlee m	82
9	Zhang, lei	10	9	Chen y	82
10	Zhao, hailing	10	10	Navarro-gonzalez jf	80

Figure 7.

(A) Co-operation network of authors. (B) Co-citation network of authors.

In addition, an analysis of author co-citation patterns was conducted to identify influential scholars in this field. As shown in Figure 7B and Table 5, the 10 authors with the highest co-citation frequencies and citation counts were identified. Overall, 146 authors were cited more than 50 times, indicating substantial academic influence in this research area. The largest nodes in the co-citation network correspond to the most frequently co-cited authors, including Zhang L (136 citations), Wang Y (115 citations), and Li Y (107 citations).

References and Co-Cited References

Citation analysis is a widely applied bibliometric method for identifying influential publications, as citation frequency is commonly used to reflect the academic impact and significance of a study within a given research domain.²⁷ A reference co-citation network was constructed from the 1249 publications retrieved from the WoSCC database using a one-year time-slicing approach covering the period from 2004 to 2023. The network consisted of 918 nodes and 3174 connections (Figure 8A). Detailed information on the 10 most highly cited references is presented in Table 6. Among these references, the article entitled “Diabetic Kidney Disease: Challenges, Progress, and Possibilities”, published in the Clinical Journal of the American Society of Nephrology, ranked first with 44 co-citations. As the largest node within the co-citation network, this publication can be regarded as a pivotal reference, underscoring its substantial influence in the field. The authors reported that approximately 40% of individuals with diabetes develop DKD and that many patients die from cardiovascular events or infections before reaching ESRD. DKD progression is characterized by glomerular hyperfiltration, albuminuria, and a progressive decline in glomerular filtration rate, ultimately leading to ESRD. Although current therapeutic interventions have improved disease management, the residual risk of progression remains substantial. The authors further emphasized the need for novel biomarkers, optimized clinical trial strategies, and kidney-specific therapeutic targets, together with improved implementation of evidence-based clinical practices.²⁸ The second most frequently co-cited publication was “Clinical Efficacies, Underlying Mechanisms, and Molecular Targets of Chinese Medicines for Diabetic Nephropathy Treatment and Management”, published in Acta Pharmaceutica Sinica B, which received 38 citations.¹¹ The third-ranked reference was “IDF Diabetes Atlas: Global, Regional and Country-Level Diabetes Prevalence Estimates for 2021 and Projections for 2045”, published in Diabetes Research and Clinical Practice, with 37 citations.¹

Figure 8.

(A) Co-cited network of reference. (B) Clustering of co-cited reference. (C) Timeline view of the co-citation network. (D) Visualization of references with the strongest citation bursts.

Table 6.

The Top 10 Cited Articles

Rank	Title	Journal	First Author	Total Citations
1	Diabetic Kidney Disease Challenges, Progress, and Possibilities	Clinical journal of the American Society of Nephrology	Alicic RZ	44
2	Clinical efficacies, underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management	ACTA PHARMACEUTICA SINICA B	Tang GY	38
3	IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045	Diabetes Research and Clinical Practice	Sun H	37
4	Diabetic Nephropathy: Challenges in Pathogenesis, Diagnosis, and Treatment	Biomed Research International	Samsu N	36
5	Update on Diabetic Nephropathy: Core Curriculum 2018	American Journal of Kidney Disease	Umanath K	31
6	Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition	Diabetes Research and Clinical Practice	Saeedi P	29
7	The Efficacy and Mechanism of Chinese Herbal Medicine on Diabetic Kidney Disease	Journal of Diabetes Research	Lu ZZ	27
8	An updated overview of diabetic nephropathy: Diagnosis, prognosis, treatment goals and latest guidelines	Diabetes Obesity & Metabolism	Selby NM	27
9	IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045	Diabetes Research and Clinical Practice	Cho NH	26
10	Innate immunity in diabetic kidney disease	Nature Reviews Nepthrology	Tang SCW	23

To better illustrate hotspots and frontiers in research on DKD and TCM, we conducted co-citation reference clustering and temporal clustering analysis (Figure 8B and C). The results identified a total of 16 clusters, numbered from 0 to 15. Based on the progression of time, the early research hotspots included animal models (cluster 11), pyridoxamine (cluster 12), type 2 diabetes (cluster 13), exercise (cluster 14), macroangiopathy (cluster 15), and valsartan (cluster 16). The mid-term research hotspots comprised Smad2/3 (cluster 1), kidney (cluster 4), rehmanniae radix (cluster 5), and chronic kidney failure (cluster 10). Current hot topics and emerging trends in the field include diabetic kidney disease (cluster 0), network pharmacology (cluster 2), interleukin-6 (cluster 3), phytotherapy (cluster 5), EGCG (cluster 7), ferroptosis (cluster 8), and traditional chinese medicines (cluster 9).

Figure 8D illustrates the 50 references with the most prominent citation bursts. In this visualization, the blue line indicates the time span from 2004 to 2024, while the red bar represents the period during which a reference experienced a citation burst. Among all identified references, the review article entitled “Review of Herbal Traditional Chinese Medicine for the Treatment of Diabetic Nephropathy”, published in 2016, exhibited the most pronounced citation burst. The publication “Diabetic Kidney Disease: Challenges, Progress, and Possibilities”, published in the Clinical Journal of the American Society of Nephrology, exhibited the highest burst strength (12.21). Furthermore, 14 references are still undergoing citation bursts, reflecting continuing scholarly attention and suggesting that TCM-related interventions for DKD will remain an important research focus in the foreseeable future.

Keyword Analysis

We performed a co-occurrence analysis of keywords to rapidly understand the current status and trends in DKD and TCM. The top 5 keywords were diabetic nephropathy (409 times), oxidative stress (396 times), inflammation (223 times), expression (126 times), and traditional chinese medicine (123 times) (Table 7). To further explore and present the relationships among keywords, irrelevant keywords were removed and a network comprising 164 keywords appearing at least 26 times was constructed, resulting in five distinct clusters (Figure 9A). For instance, Cluster 1 (labeled in red) contains 51 keywords, including acid, aldose reductase, antioxidant activity, assay, complications, diabetes, extract, end product, identification, glucose, liver, lipid peroxidation, medicinal plants, metabolic syndrome, methylglyoxal, obesity, nephrotoxicity, pharmacology, polyphenols, rat models. Cluster 2 (green) contains 49 keywords, including inflammation, renal injury, rats, pathway, inhibition, fibrosis, apoptosis, activation, dysfunction, growth, mechanism, molecular docking, podocytes, protect, protein, NF-kappa B, SIRT1, stress, pathogenesis. Cluster 3 (blue) contains 41 keywords, including albuminuria, anti-inflammatory, association, blood pressure, diagnosis, efficacy, epidemiology, hypertension, management, mellitus, mortality, prevalence, progression, retinopathy, risk factor, safety, therapy. Cluster 4 (yellow) contains 36 keywords, including activated protein kinase, astragaloside IV, berberine, double-blind, down regulation, fatty liver disease, growth factor, gut microbiota, high glucose, mechanism, mesangial cells, natural products, NLRP3 inflammasome, renal fibrosis, TGF-beta. Cluster 5 (purple) contains 14 keywords, including advanced glycation end product, biomarkers, db/db mice, endothelial cells, NADPH oxidase, nitric oxide, range, receptor. Furthermore, CiteSpace was employed to generate a volcano map for visualizing the temporal evolution of research themes (Figure 9B and C). Among the 434 keywords showing citation bursts, the 50 terms with the highest burst strength were selected for subsequent analysis (Figure 9D). Keywords including “growth factor beta” (2004–2016), “TGF-beta” (2006–2020), and “endothelial dysfunction” (2004–2015) maintained burst activity for the longest periods, indicating sustained research interest over time. More recently, “pharmacology network” exhibited the highest burst strength (10.06), suggesting its growing prominence and highlighting a major focus of current investigations in this field.

Table 7.

High Frequency Keyword

Rank	Keyword	Counts	Rank	Keyword	Counts
1	Oxidative stress	396	11	Mechanisms	85
2	Diabetic nephropathy	294	12	Kidney-disease	80
3	Inflammation	223	13	Fibrosis	78
4	Gene expression	126	14	Diabetes mellitus	75
5	Traditional Chinese medicine	123	15	Glycation end-products	73
6	Diabetic kidney disease	115	16	Network pharmacology	72
7	Apoptosis	107	17	Insulin-resistance	68
8	NF-kappa-b	99	18	Inhibition	67
9	Activation	98	19	Signaling pathway	63
10	Injury	91	20	Renal fibrosis	62

Figure 9.

(A) Co-occurrence network of high-frequency keywords. (B) Cluster visualization of keywords. (C) Timeline view of keyword clusters. (D) Visualization of keywords with the strongest citation bursts.

Bibliometric Overview of Global Dynamics in TCM and DKD

Evolutionary Trends in TCM and DKD

Research collaboration and knowledge expansion in the field of TCM for DKD have shown a sustained upward trend over the past two decades. Exploratory studies can be traced back to 2004, whereas substantial progress emerged around 2006, marked by the publication of the first report describing the protective effects of an Astragalus mongholicus Bunge–Angelica sinensis (Oliv). Diels herbal combination against diabetic nephropathy progression in rats.²⁹

A pronounced increase in publication output was observed after 2022, indicating a pivotal stage in the development of this research field. Two factors may have contributed substantially to this growth. On the one hand, accumulating evidence regarding the effectiveness of TCM for DKD attracted increasing scholarly attention. On the other hand, the emergence and continuous refinement of network pharmacology databases and online analytical resources since 2019 facilitated mechanistic studies and accelerated research advancement. Notably, the number of newly contributing authors also increased substantially, with strong collaborative patterns observed among institutions and individual researchers. Co-citation analysis and keyword clustering further demonstrated the continuous expansion of this research field. In addition, favorable national policies, especially the “14th Five-Year Plan for the Development of Traditional Chinese Medicine” issued by the Chinese State Council, further accelerated research activity after 2022.

Country Contributions and Influence in TCM and DKD

As the birthplace of TCM, China occupies a dominant position in this field regarding publication output, institutional participation, author contributions, and funding support, accounting for 65.33% of the total publications, far exceeding India (8.73%) and the United States (8.33%).

This advantage may be attributed to several factors. First, China possesses a long history of TCM application and extensive clinical experience in DKD management. Second, continuous governmental support and funding, together with the contributions of major institutions such as Beijing University of Chinese Medicine, have promoted the development of TCM research. Third, the rising prevalence of diabetes and DKD in China has further stimulated research demand.

Despite the large volume of publications, the global citation impact of Chinese studies remains comparatively modest. Chinese publications averaged 19.14 citations per paper, placing it ninth among the top ten contributing countries. This observation highlights that research quantity does not necessarily guarantee international influence. In contrast, countries such as the United States, Italy, and Australia consistently outperformed Chinese studies in citation metrics. Several factors likely contribute to this gap, including research topic overlap, inconsistencies in methodological quality, and limited access to high‑impact international platforms. Addressing these issues—by fostering international collaboration, optimizing study designs, and incorporating advanced methodologies—represents a viable pathway for elevating the global profile of TCM‑related DKD research.

Author Contributions and Influence in TCM and DKD

The leading authors in the field of TCM and DKD have collaboratively published several influential studies. One representative study, entitled Intrarenal metabolomics reveals the association of local organic toxins with the progression of diabetic kidney disease, highlighted the application of metabolomics-based strategies to investigate DKD progression.³⁰ This platform integrated metabolite identification, pathway analysis, biomarker screening, and metabolic network regulation, emphasizing the importance of systems biology approaches in DKD research.

Subsequent studies integrated clinical sample analysis with experimental validation to systematically elucidate the mechanisms underlying TCM formulae in DKD treatment.^31–33 Additional in vivo and in vitro studies further clarified the signaling pathways responsible for herbal formula-mediated renoprotection.³⁴ These findings demonstrated that integrating clinical evidence with mechanistic studies is essential for identifying therapeutic targets and understanding the complex pharmacological actions of TCM prescriptions.

In addition, network pharmacology has become an important research direction. Relevant platforms integrate multidimensional information, including chemical properties, ADME characteristics, therapeutic targets, disease associations, and interaction networks. Such strategies provide valuable tools for linking TCM theory with modern drug discovery and systems pharmacology. Collectively, collaborations among leading scholars have substantially promoted the mechanistic and translational development of TCM-based DKD research.

Key Research Groups Contributions and Influence in TCM and DKD

Beyond mere productivity metrics, a closer examination of the research priorities among the leading groups reveals distinct yet complementary scientific orientations. The top-ranked group, led by Professor Li Ping at China-Japan Friendship Hospital, has systematically concentrated on network pharmacology and multi-omics integration, aiming to decode the “multi-component, multi-target” characteristics of traditional chinese medicine formulas at the systems biology level.³⁵ Concurrently, the China Academy of Chinese Medical Sciences, ranking second in institutional output, has directed its efforts toward the clinical validation and mechanistic exploration of classical herbal prescriptions. Specifically, Shenqi Huoxue Formula has been shown to attenuate renal tubular ferroptosis and epithelial-mesenchymal transition by modulating the HIF-1α/HIF-2α balance,³⁶ while Qihuang Yishen Formula appears to exert regulatory effects on the cGAS/STING signaling pathway.³⁷ Of note, contributions from India, predominantly originating from the All India Institute of Medical Sciences, encompass bioinformatics analyses and clinical trials,³⁸ which provide valuable evidence for distinguishing DKD from non-diabetic renal diseases. These divergent research paradigms—systems pharmacology, and mechanistic dissection—offer substantial opportunities for interdisciplinary synergy. However, the current collaboration network analysis suggests that such synergistic potential remains underexploited. We advocate for the establishment of international consortia that jointly design standardized research protocols, share biospecimens, and validate the efficacy of TCM interventions across diverse ethnic populations, thereby enhancing the global generalizability of research findings in this field.

Traditional Uses of Ethnomedical Plants in Diabetic Kidney Disease

Burst keyword analysis identified three representative medicinal plants frequently associated with DKD: Huangqi (the dried root of Astragalus mongholicus Bunge or Astragalus membranaceus Fisch. ex Bunge),¹⁸ Danshen (the dried root and rhizome of Salvia miltiorrhiza Bunge),³⁹ and Shanzhuyu (the dried ripe sarcocar of Cornus officinalis Siebold & Zucc).⁴⁰ Although systematic investigations of TCM in DKD have expanded mainly during the past two decades, the ethnomedical use of these herbs can be traced back to classical Chinese medical literature.

Among these herbs, Huangqi was first documented in Shennong Bencao Jing and has traditionally been used to replenish Qi deficiency. Modern pharmacological studies have demonstrated that Huangqi exhibits anti-inflammatory and anti-fibrotic activities through modulation of PI3K/Akt, AMPK, and related signaling pathways, making it one of the most intensively investigated herbs in DKD research. Danshen is traditionally prescribed to promote blood circulation and remove blood stasis. Since “blood stasis obstructing the collaterals” is considered a major pathological feature of DKD in TCM theory, Danshen-based therapies have shown strong ethnopharmacological relevance to DKD management. Shanhzuyu, another classical medicinal herb recorded in Shennong Bencao Jing, is traditionally used to nourish the liver and kidney. Recent studies have revealed that its iridoid glycosides, including morroniside and loganin, exert renoprotective effects by suppressing inflammation and regulating autophagy, thereby attracting increasing attention in DKD-related pharmacological research (Table 8). All botanical names cited in this article have been verified against the most recent revision available through the World Flora Online (www.worldfloraonline.org).

Table 8.

Traditional Applications and Modern Research of TCM in DKD

Category	Names	Source	Traditional Applications	Modern Research
Huangqi	Root	《Chinese Pharmacopoeia》	Supplementing Qi and consolidating the exterior; supplementing Qi to activate blood circulation	Regulates oxidative stress, inflammatory responses, fibrosis progression, immune homeostasis, and glucolipid metabolic disorders41
	Astragaloside IV	Compound	/	Modulates AMPK, PI3K/AKT, NF-κB, cAMP/PKA, and HIF-1α/HMOX1 signaling pathways; targets oxidative stress, inflammation, podocyte injury, and ferroptosis42–44
	Astragalus polysaccharides		/	Modulates the HMGB1/RAGE/TLR4 signaling cascade; attenuates renal inflammation and fibrosis45
	Shenqi Dihuang Decoction	《Zabing Xizhu》	Supplementing Qi and nourishing Yin; strengthening the spleen and tonifying the kidney	Regulates PI3K/AKT, AMPK/SIRT1/FOXO1, and Nrf2/HO-1 pathways; anti-oxidative stress, anti-inflammation, improvement of insulin resistance, and anti-renal fibrosis46
	Fangji Huangqi Decoction	《Bei Ji Qian Jin Yao Fang》	Supplementing Qi and consolidating the exterior; dispelling wind and eliminating dampness; promoting diuresis to reduce edema	Improves renal function; reduces SCr, BUN, U-mAlb, UACR, 24h-UP, and inflammatory cytokines including TNF-α, IL-8, and IL-1347
	Modified Fangji Huangqi Decoction
	Tangshenning	Empirical Formula	Supplementing Qi and consolidating the exterior; dispelling wind and eliminating dampness; promoting diuresis to reduce edema	Enhances Sestrin2/AMPK/PGC-1α pathway activity; restores mitochondrial function; inhibits ferroptosis in renal tubular epithelial cells48
Danshen	Root and rhizome	《Chinese Pharmacopoeia》	Activating blood and resolving stasis; unblocking collaterals and draining turbidity	Anti-inflammatory, anti-oxidative, and anti-fibrotic effects39,49
	Salvianolic acid B	Compound	/	Activates PPARγ and upregulates PTEN; inhibits the PI3K/AKT signaling pathway to alleviate renal fibrosis50
	Tanshinone IIA		/	Modulates the Txnip/NLRP3 inflammasome pathway; inhibits glomerular endothelial cell pyroptosis and alleviates oxidative stress51
	Erdan Decoction	《Compound》	Supplementing Qi and activating blood; resolving stasis and dissipating nodules	Improves renal function, regulates immunity, anti-inflammatory and anti-oxidative effects, and improves hemodynamics52
	Danshen-containing preparations	/	/	Reduces SCr, BUN, and UAER; lowers inflammatory cytokine levels including CRP, TNF-α, and IL-6; improves vascular endothelial function53
	Buxue Erdan Decoction	Empirical Formula		Improves renal function and immune function in patients with chronic renal insufficiency and DKD54
Shanzhuyu	Mature sarcocarp	《Chinese Pharmacopoeia》	Tonifying the kidney and consolidating Essence; nourishing Yin and replenishing marrow	Regulates glucolipid metabolism; alleviates inflammation and oxidative stress; protects podocyte function; modulates autophagy55
	Loganin	Compound	/	Inhibits fibronectin and IL-6 expression56
	Morroniside		/	Inhibits the AGE/RAGE signaling pathway; reduces blood glucose and proteinuria; alleviates oxidative stress57
	Cornuside		/	Reduces FBG, 24h-UP, BUN, SCr, and IL-12 levels; alleviates renal fibrosis and pathological injury58
	Liuwei Dihuang Pill	《Jin Gui Yao Lue》	Warming and replenishing kidney Yang; transforming Qi to promote diuresis	Improves renal function; regulates glucolipid metabolism; anti-inflammatory, anti-oxidative, anti-fibrotic, and diuretic effects59
	Liuwei Dihuang Pill	《Xiao’er Yao Zheng Zhi Jue》	Nourishing kidney Yin; replenishing Essence and marrow	Improves renal function and reduces proteinuria levels in DKD patients60–62
	Shenqi Dihuang Decoction	《Zabing Xizhu》	Supplementing Qi and nourishing Yin; strengthening the spleen and tonifying the kidney
	Zuogui Pill	《Jing Yue Quan Shu》	Nourishing kidney Yin; replenishing Essence and marrow

Astragalus membranaceus Fisch. Ex Bunge (Huangqi)

Huangqi is among the most commonly used Qi-tonifying herbs in clinical TCM practice. According to the Chinese Pharmacopoeia, it is mainly produced in Shanxi, Gansu, Heilongjiang, Inner Mongolia, and Shaanxi provinces of China.⁶³ Phytochemical investigations have demonstrated that Huangqi contains abundant polysaccharides, saponins, and flavonoids, particularly astragaloside IV, calycosin, formononetin, kaempferol, and quercetin. These active components have been reported to exert diverse biological functions, particularly in the regulation of oxidative stress, inflammatory responses, fibrotic progression, immune homeostasis, and glucose–lipid metabolic disorders.⁴¹

A recent text-mining analysis of clinical studies involving TCM interventions for DKD revealed that Huangqi ranked among the most frequently used herbal medicines.⁶⁴ This herb lowers blood glucose by modulating the AGE‑RAGE signaling pathways, and is commonly used clinically for type 2 diabetes mellitus.⁶⁵ According to TCM theory, DKD belongs to the categories of “Xiaoke”, “edema”, and “consumptive disease”, with “qi deficiency and blood stasis” regarded as the core pathogenesis. Huangqi is therefore traditionally used to replenish qi, promote diuresis, and improve circulation.

Several classical prescriptions containing Huangqi have long been applied in diabetic complications. Shenqi Dihuang Decoction, recorded in Zabing Xizhu, consists of Renshen, Huangqi, Dihuang, Shanyao, Fuling, Mudanpi, and Shanzhuyu. The formula nourishes qi and yin while strengthening spleen and kidney functions, and is currently applied in DKD management.⁴⁶ In addition, Beiji Qianjin Yaofang documented Huangqi-containing formulas for treating Xiaoke and its complications. In modern clinical practice, prescriptions such as Fangji Huangqi Decoction are frequently combined with conventional therapies for DKD. A 12-week clinical intervention with modified Fangji Huangqi Decoction resulted in significant improvements in renal function and proteinuria-related indicators, including serum creatinine, blood urea nitrogen, urinary microalbumin, urinary albumin-to-creatinine ratio, and 24-h urinary protein excretion, accompanied by reductions in inflammatory cytokines such as TNF-α, IL-8, and IL-13.⁴⁷ In addition, Tangshenning, a Huangqi-based herbal formula, has been reported to delay DKD progression by enhancing Sestrin2/AMPK/PGC-1α pathway activity, restoring mitochondrial function, and suppressing ferroptotic injury in tubular epithelial cells.⁴⁸

Mechanistic evidence indicates that astragaloside IV exerts broad renoprotective actions in DKD by targeting oxidative stress, inflammation, podocyte injury, and ferroptosis. These effects have been linked to the regulation of AMPK, PI3K/Akt, NF-κB, cAMP/PKA, and HIF-1α/HMOX1 signaling pathways.^42–44 In parallel, Huangqi polysaccharides have been reported to alleviate renal inflammation and fibrosis through modulation of the HMGB1/RAGE/TLR4 signaling cascade.⁴⁵ Overall, the available evidence highlights the multi-target and multi-pathway characteristics of Huangqi and supports its promising therapeutic potential in DKD.

Salvia miltiorrhiza Bunge (Danshen)

Traditionally, Danshen has been regarded as a top-grade herb with functions of promoting blood circulation and removing blood stasis. It is mainly distributed in Shaanxi, Sichuan, Anhui, Jiangsu, and Shandong provinces of China.⁶³ Its distinctive red roots led to the traditional saying that “one herb is equivalent to Siwu Decoction”, underscoring its importance in blood-nourishing and circulation-promoting therapies. Contemporary phytochemical and pharmacological studies have identified lipophilic tanshinones and hydrophilic phenolic acids as its principal active constituents, which contribute to its anti-inflammatory, antioxidative, and antifibrotic properties.^39,49

In DKD management, Danshen is among the most frequently prescribed herbs. Importantly, its glucose‑lowering activity has been reported to occur in a dose‑dependent manner.⁶⁶ TCM theory proposes that “blood stasis obstructing the collaterals” is a major pathological mechanism of DKD, and S Danshen improves microcirculation and vascular function through its blood-activating properties.⁵³ Clinical evidence highlights Danshen as an important agent in DKD management. In randomized controlled trial analyses, it ranked second only to Huangqi in terms of frequency of use within TCM prescriptions for DKD.⁶⁷ Subsequent meta-analyses indicated that Danshen-containing formulations significantly improved renal function and proteinuria-related parameters, as evidenced by reductions in serum creatinine, blood urea nitrogen, and urinary albumin excretion rate. These benefits were accompanied by decreased levels of inflammatory markers, including CRP, TNF-α, and IL-6, while maintaining a favorable safety profile.⁵³

In Bianzheng Lu, Erdan Decoction was recorded for Xiaoke syndrome characterized by excessive urination, polydipsia, and emaciation.⁵² Such traditional applications laid the foundation for subsequent pharmacological investigations. Modern clinical studies have reported that Danshen-centered prescriptions improve renal and immune function in patients with chronic renal insufficiency and DKD.⁵⁴

At the molecular level, salvianolic acid B alleviated renal fibrosis by activating PPARγ, upregulating PTEN, and suppressing PI3K/Akt signaling.⁵⁰ Tanshinone IIA was shown to inhibit pyroptosis in glomerular endothelial cells and reduce oxidative stress by regulating the Txnip/Nlrp3 inflammasome pathway.⁵¹ Although the early use of Danshen for DKD was largely empirical, accumulating evidence from experimental studies,¹⁸ omics analyses,⁶⁸ network pharmacology,⁶⁹ and systematic reviews⁷⁰ has progressively clarified its scientific basis. Nevertheless, additional high-quality randomized controlled trials are still required to validate its efficacy and long-term safety across different DKD stages.

Cornus officinalis Siebold & Zucc. (Shanzhuyu)

Shanzhuyu was classified as a commonly used herb for nourishing the liver and kidney. It is mainly distributed in Zhejiang, Henan, Anhui, Shaanxi, and Shanxi provinces, with Lin’an in Zhejiang and Xixia in Henan regarded as authentic producing regions.⁶³ Modern studies showed that Shanzhuyu contains iridoid glycosides including morroniside, loganin, and cornuside, as well as tannins and flavonoids, which exhibit hypoglycemic, anti-inflammatory, antioxidant, and autophagy-regulating activities.⁵⁵

According to TCM theory, DKD is closely associated with “liver-kidney Yin deficiency and blood stasis”. Therefore, Shanzhuyu is commonly prescribed to nourish the liver and kidney while preventing excessive loss of essence. Statistical analysis of 333 publications involving 478 prescriptions from 2010 to 2021 further confirmed that Shanzhuyu is a high-frequency medicinal herb in DKD formulas, often combined with yam, poria, alisma, and moutan bark in prescriptions such as Liuwei Dihuang Pill and Shenqi Dihuang Decoction.⁷¹

Although the Shennong Bencao Jing did not explicitly mention diabetes, it established the theoretical basis for later application in Xiaoke-related disorders.⁷² In Jingui Yaolue, Shenqi Pill containing Shanzhuyu was prescribed for Xiaoke accompanied by polyuria.⁵⁹ During the Song dynasty, Qian Yi modified this formula into Liuwei Dihuang Pill in Xiao’er Yaozheng Zhijue, which later became a representative prescription for nourishing kidney Yin and treating diabetic complications.⁷³ Contemporary clinical studies demonstrated that formulas containing Shanzhuyu, such as Liuwei Dihuang Pill,⁶⁰ Shenqi Dihuang Decoction,⁶¹ and Zuogui Pill,⁶² significantly improved renal function and reduced proteinuria in DKD patients.

Available evidence links the renoprotective effects of Shanzhuyu to regulation of metabolic disorders, inhibition of oxidative stress and inflammation, preservation of podocyte integrity, and modulation of autophagy.⁴⁰ Among its major bioactive constituents, loganin, morroniside, and cornuside have been demonstrated to ameliorate key DKD pathologies, including extracellular matrix accumulation, proinflammatory cytokine production, hyperglycemia, proteinuria, oxidative stress, and renal fibrosis. Specifically, morroniside attenuates proteinuria by lowering blood glucose through inhibition of the AGE-RAGE signaling pathway, whereas cornuside markedly reduces fasting blood glucose, thereby alleviating renal fibrosis and pathological injury.^56–58 Taken together, these studies offer mechanistic insights into the traditional use of Shanzhuyu and support its therapeutic potential in DKD management.

Thematic Insights and Emerging Research Frontiers in TCM and DKD

By systematically reviewing representative publications in this field, the present study summarized key findings and provided detailed bibliometric evidence in the Results section. The present study was designed to provide a concise overview for researchers regarding the knowledge architecture and evolutionary trajectory of research on TCM and DKD. In co-citation analyses, high-quality clinical trials, authoritative reviews, and established databases emerged as pivotal references because of their fundamental scientific value and influence on future research directions.

Burst-reference analyses identified three major thematic domains: (1) pathological mechanisms underlying DKD progression, (2) therapeutic applications of TCM in DKD management, and (3) the expanding role of network pharmacology databases. The emergence of the keyword “network pharmacology” reflects growing interest in applying systematic and integrative approaches to elucidate the complex therapeutic mechanisms of TCM. Citation burst analyses further demonstrated persistent scholarly attention toward DKD prevention and early intervention. Moreover, hotspot analyses indicated that inflammation and oxidative stress remained the dominant biological processes at the intersection of TCM and DKD research up to 2024.

Diabetic Kidney Disease

Compared with diabetic retinopathy and diabetic neuropathy, DKD has long remained a major research focus in nephrology and metabolic diseases because of its high mortality risk. Keyword co-occurrence and clustering analyses demonstrated that oxidative stress, inflammatory injury, podocyte dysfunction, and renal fibrosis constitute the principal research directions in this field. DKD is among the major causes of ESRD globally and is histopathologically characterized by thickening of the glomerular basement membrane, expansion of the mesangial matrix, loss of podocytes, and progressive tubulointerstitial fibrosis. From a clinical perspective, UACR, eGFR, and renal histopathology remain fundamental indicators for assessing disease progression and severity.²⁸

Recent studies have increasingly emphasized therapeutic strategies targeting oxidative stress, inflammatory, and fibrotic pathways. Persistent hyperglycemia promotes excessive ROS production and activates TGF-β1/Smad, NF-κB, and NLRP3 inflammasome signaling, thereby accelerating inflammatory cytokine release and extracellular matrix deposition, ultimately resulting in renal structural and functional impairment.⁷⁴ Among these pathways, Nrf2 and NF-κB are recognized as critical regulators of oxidative stress and chronic inflammation. Activation of Nrf2 enhances antioxidant enzyme expression, including HO-1 and NQO1, whereas inhibition of NF-κB signaling alleviates inflammatory injury and renal fibrosis. Consequently, the Nrf2/NF-κB axis has become an important therapeutic target for DKD management.⁷⁵ In addition, MAPK, PI3K/Akt, and AGE-RAGE pathways have also been implicated in glomerulosclerosis and podocyte injury during DKD progression.⁷⁶

In view of the complex pathogenesis of DKD, TCM has gained increasing attention because of its multi-component composition and multi-target therapeutic features. Growing evidence demonstrates that integrating TCM with conventional glucose-lowering therapies and renin–angiotensin system blockade can effectively decrease proteinuria, retard the decline of renal function, and improve oxidative stress as well as inflammatory responses.⁷⁷ Consistent with these findings, meta-analytic studies have demonstrated that Chinese patent medicines used alongside standard therapy provide greater improvements in 24h urinary protein, serum creatinine, and eGFR than conventional treatment alone.⁷⁸ Among frequently studied medicinal herbs, Huangqi has been extensively investigated for its renoprotective properties. Mechanistic studies have shown that astragaloside IV can attenuate renal fibrosis through regulation of the TGF-β1/Smad pathway,⁷⁹ and preserve podocyte function by modulating NF-κB pathway.⁸⁰ In addition, Renshen has demonstrated considerable therapeutic potential in DKD. Its major active constituents, including ginsenosides Rg1 and Rb1, exert anti-inflammatory, antioxidative, antifibrotic, anti-apoptotic, and anti-pyroptotic effects, thereby contributing to the attenuation of disease progression.⁸¹ Furthermore, Danshen and its bioactive constituents, including tanshinones and phenolic acids, can modulate oxidative stress, inflammation, autophagy, and fibrosis, contributing to renal protection in DKD.⁸² In formula-based studies, combinations of Huangqi and Danshen, the Liuwei Dihuang pill, and the Dang-Gui-Bu-Xue decoction have demonstrated favorable effects, including the reduction of proteinuria, alleviation of inflammation, and preservation of renal function.^54,62,83

Collectively, a growing body of evidence suggests that TCM and its bioactive components confer renoprotective effects in DKD by orchestrating the coordinated regulation of signaling pathways such as Nrf2, TGF-β/Smad, NF-κB/NLRP3, MAPK, and PI3K/Akt, thereby mitigating oxidative stress, inflammatory injury, and fibrosis during disease progression.⁸⁴

Network Pharmacology

Network pharmacology represents one of the most active and emerging research hotspots in this field. The concept was first proposed by Andrew L. Hopkins in 2008 and emphasizes understanding complex disease–drug interactions from the perspective of biological networks.⁸⁵ This paradigm aligns closely with the holistic philosophy and synergistic properties inherent in TCM formulas, thereby establishing a novel framework for advancing the modernization of TCM research.

Driven by advances in systems biology, multi-omics technologies, bioinformatics, and artificial intelligence, network pharmacology has progressively shifted from the conventional “single target” model toward integrated multi-component and multi-pathway regulation.⁸⁶ Such a transition enables researchers to investigate DKD pathogenesis from a systems perspective rather than focusing solely on isolated signaling pathways. Because DKD involves oxidative stress, inflammation, extracellular matrix deposition, glomerulosclerosis, and podocyte injury, single-target therapies often show limited efficacy, whereas TCM formulas exhibit advantages in systems-level intervention.

Since 2012, the application of network pharmacology in TCM research has expanded rapidly. Li et al established an integrated analytical framework combining oral bioavailability screening, target prediction, and network analysis, laying the foundation for mechanistic investigations of herbal formulas.⁸⁷ Subsequently, machine learning algorithms, bioinformatics analyses, and molecular docking approaches have been extensively applied to target identification and interaction network construction. Studies demonstrated that Huangqi, Danshen, and Huangqin, together with their active constituents, modulate the PI3K/Akt, NF-κB, TGF-β/Smad, AGE-RAGE, and MAPK pathways, thereby attenuating renal inflammation and fibrosis in DKD. Moreover, quercetin, resveratrol, astragaloside IV, and dehydromiltirone have shown antioxidant, anti-inflammatory, and glomerular protective effects.^88–92 Recent advances in databases and analytical platforms, including TCMSP, GeneCards, DisGeNET, OMIM, and SwissTargetPrediction, have further promoted DKD-related network pharmacology research.^93–96

In parallel, the integration of transcriptomics, proteomics, and metabolomics with network pharmacology has enhanced both the mechanistic depth and translational reliability of TCM studies.⁶⁸ This “computational prediction–experimental validation” strategy has substantially improved the scientific robustness of mechanistic studies in DKD.⁸⁹

Nevertheless, challenges remain, including incomplete databases, insufficient experimental validation, and inconsistent quality-control standards. Future studies should strengthen database integration, quality-marker research, and translational validation to facilitate precision-oriented DKD research.

Inflammation

Inflammation plays a central role in the initiation and progression of DKD and has emerged as a major focus in nephrology research. Burst keyword analysis further supports this trend. Increasing evidence indicates that DKD is not merely a metabolic disorder, but rather a chronic low-grade inflammatory disease characterized by progressive renal injury. Hyperglycemia stimulates mesangial cells, podocytes, and tubular epithelial cells to release pro-inflammatory mediators, including IL-1β, IL-6, TNF-α, and MCP-1, thereby promoting immune-cell recruitment and disruption of the renal microenvironment.⁹⁷ Persistent inflammation subsequently accelerates glomerulosclerosis and tubulointerstitial damage.

Current studies demonstrate that NF-κB, JAK/STAT, and NLRP3 inflammasome pathways are critically involved in inflammatory amplification during DKD progression. Sustained inflammatory activation promotes macrophage infiltration, extracellular matrix deposition, and tubular epithelial transdifferentiation, ultimately contributing to renal fibrosis.⁹⁸ Moreover, inflammatory biomarkers are closely associated with proteinuria, eGFR decline, and pathological injury severity, indicating that inflammatory networks participate throughout the entire course of.⁹⁹

TCM exhibits multi-target anti-inflammatory properties in DKD treatment. Salvianolic acid B and tanshinone IIA from Danshen suppress renal inflammation through regulation of the PI3K/Akt/NF-κB pathway.¹⁰⁰ Triptolide from Tripterygium wilfordii Hook. f. alleviates podocyte injury by inhibiting NLRP3 inflammasome activation.¹⁰¹ In addition, astragaloside IV from Huangqi attenuates podocyte injury through modulation of the Klotho and NF-κB/NLRP3 pathways.⁸⁰ Additionally, the Qiling Hushen Formula alleviated DKD through inhibition of the TLR4/NF-κB/NLRP3 inflammatory signaling cascade.¹⁰² Compared with single-target therapies, TCM demonstrates broader regulatory effects on immune imbalance and renal injury progression.

Recent clinical and experimental evidence further confirms that inflammation is involved throughout DKD progression. Biomarkers including TNF receptor 1/2, IL-18, and MCP-1 have shown predictive value for DKD progression risk.¹⁰³ Nevertheless, the interactions among inflammatory pathways remain incompletely understood, and the synergistic mechanisms of complex herbal formulas require further investigation. Future integration of multiomics technologies and precision medicine strategies may provide novel insights into inflammation-targeted DKD therapy.

Oxidative Stress

Oxidative stress has become another major research focus in DKD and remains highly represented in keyword clustering and cocitation analyses. Accumulating evidence suggests that oxidative imbalance is a key pathological driver of DKD progression.¹⁰⁴ Chronic hyperglycemia induces mitochondrial electron transport dysfunction, xanthine oxidase activation, and excessive protein kinase C activation, resulting in ROS accumulation and subsequent injury to glomerular endothelial cells, mesangial cells, and tubular epithelial cells.¹⁰⁵

ROS activates multiple downstream pathways, including PKC, MAPK, and AGEs/RAGE signaling, thereby enhancing AP-1 and NF-κB mediated inflammatory responses and forming a persistent oxidative-inflammatory feedback loop.¹⁰⁶ Meanwhile, Nrf2-dependent antioxidant defense systems, including HO-1, SOD, and NQO1, are suppressed in DKD, contributing to redox imbalance.⁷⁵ Mitochondrial dysfunction further aggravates ROS overproduction and metabolic abnormalities in glomerular cells.¹⁰⁷

Given the critical role of oxidative stress in DKD, increasing attention has been directed toward the multi-target antioxidant effects of TCM. Salviolone from Danshen reduces ROS and MDA levels while restoring SOD activity, thereby alleviating inflammation and renal injury.¹⁰⁸ Astragaloside IV preserves RNase P activity and protects tubular epithelial cells from oxidative damage by upregulating CPT1A-mediated succinylation of HSD17B10 at lysine 99.¹⁰⁹ Furthermore, it alleviates mitochondrial oxidative stress by activating the Nrf2-ARE/TFAM axis.¹¹⁰ In addition, total triterpenes from Shanzhuyu reduce oxidative burden by decreasing MDA levels and enhancing CAT and SOD activities.¹¹¹

Overall, oxidative stress interacts closely with inflammation, metabolic dysregulation, and cellular injury throughout DKD progression. TCM and natural bioactive compounds provide promising therapeutic strategies by targeting ROS production and antioxidant defense systems through multiple pathways. However, the precise molecular interactions and longterm clinical efficacy of herbal interventions still require further investigation.

Strengths and Limitations

This bibliometric study systematically reviews the research landscape of TCM interventions for DKD over the past two decades. In contrast to traditional narrative reviews, the present work integrates knowledge mapping, keyword co-occurrence analysis, cluster analysis, and co-citation network analysis to afford a more objective and quantitative depiction of the intellectual framework, evolutionary trajectories, and emerging frontiers in this domain. Our analyses of high-frequency keywords, influential authors, leading research institutions, and core journals further demonstrate that TCM-based DKD research is progressively transitioning from empirically oriented practice toward mechanism-driven and systems-level inquiry.

Of particular note, research foci in DKD have progressively shifted from an early emphasis on the renin–angiotensin–aldosterone system toward multiple interconnected axes, encompassing oxidative stress, inflammation, podocyte injury, and renal fibrosis. In parallel, TCM-related investigations are exhibiting increasingly profound integration of network pharmacology methodologies with mechanistic studies of formula actions, underscoring substantial cross-fertilization among systems biology, experimental pharmacology, and clinical translation. This interdisciplinary evolution epitomizes the ongoing consolidation of fundamental research, clinical practice, and methodological innovation. However, this transformation also gives rise to emerging challenges, including the imperative to validate network-predicted outcomes through rigorously designed clinical trials, to standardize quality control protocols for TCM compound formulas, and to decipher their complex mechanisms of action using multi-omics technologies. Moreover, the predominance of review articles among currently high-intensity burst publications suggests that original mechanistic investigations and high-quality clinical evidence remain priority areas in need of urgent reinforcement.

Notwithstanding these encouraging developments revealed by the present bibliometric analysis, several limitations and controversies in TCM-DKD research must be candidly acknowledged. First, the methodological quality of clinical trials evaluating TCM interventions for DKD varies considerably, with many studies constrained by small sample sizes, short follow-up durations, absence of rigorous blinding, and inconsistent outcome measures—factors that collectively limit the generalizability and robustness of the evidence base. Second, the pharmacological complexity of TCM compound formulas poses substantial obstacles to quality control, standardization, and reproducibility; these issues, though frequently understated in the literature, critically impede clinical translation. Third, concerns regarding potential herb–drug interactions, the nephrotoxic potential of certain botanical constituents, and the scarcity of long-term safety data remain inadequately addressed in existing studies. Fourth, persistent academic debate surrounds the compatibility between TCM’s holistic syndrome differentiation system and the reductionist paradigm of evidence-based medicine, which creates difficulties for integrating TCM into conventional clinical care pathways. By acknowledging these limitations alongside the documented therapeutic benefits, we aspire to present a more balanced and scientifically rigorous overview of the current state of the field.

Additionally, the present study has several methodological limitations of its own. First, data were primarily derived from the WoSCC, which may have excluded certain regional studies and non-English publications. Second, inconsistencies in author name and institutional affiliation records may introduce bias into collaboration network analyses. Finally, variations in keyword extraction strategies and parameter settings may affect the stability of the results.

Conclusions and Perspectives

This study presents a bibliometric analysis of TCM interventions for DKD, utilizing quantitative and visualization methods to investigate trends and emerging research hotspots beyond the coverage of conventional narrative reviews. Notably, research on TCM for DKD has formed a multidisciplinary frontier, with this phenomenon being particularly evident in journals of molecular biology, biology, and immunology, as discussed in our mapping analyses. Over the past two decades, these disciplines have evolved from small‑team collaborations into deep interdisciplinary partnerships, with a marked acceleration over the most recent five‑year period. Collaborations among well‑established scholars have produced a substantial number of influential publications, most of which milestone studies have emerged since 2022.

Regarding publication output, China ranks first globally among scholars, institutions, and funding bodies, yet falls short of the United States in average citations per paper and international collaboration networks. Several countries demonstrate strong industry‑academia collaboration patterns. Future research should prioritize the establishment of broad interdisciplinary partnerships to fully harness the therapeutic potential of TCM in DKD management.

Concerning journal impact, Frontiers in Pharmacology and the Journal of Ethnopharmacology occupy prominent positions in the academic community, as evidenced by their high citation rates and sustained influence. Although the medical and clinical research fields have accumulated a wealth of clinical investigation data, their citation rates remain relatively low. Hence, future investigations should prioritize more clinical trials, with particular emphasis on advancing randomized controlled trials (RCTs) to build a higher‑standard evidence‑based medicine framework.

Since 2022, network pharmacology has experienced explosive growth, driven by the continuous expansion of database resources. Confirmed as the latest research hotspot through co‑citation analysis, network pharmacology aligns well with the holistic principles of TCM. TCM formulas characterized by “multi‑component, multi‑target, multi‑pathway” mechanisms show significant promise in advancing evidence‑based research on neurodegenerative diseases. Moreover, mechanisms such as inflammatory responses and oxidative stress may contribute to elucidating the therapeutic efficacy of TCM in DKD treatment.

Regarding three specific medicinal plants—Huangqi, Danshen, and Shanzhuyu—their therapeutic value in DKD management is being actively explored, alongside their traditional clinical application experience. These historical research data provide potential avenues for investigating bioactive compounds derived from these plants in DKD management.

Overall, this study offers a valuable reference for future mechanistic research, clinical evaluation, and drug development in DKD.

Funding Statement

The current work was jointly supported by National Natural Science Foundation of China (Nos. 82460913 and 82460873), the Research Project of Jiangxi Provincial Department of Education (No. GJJ2200936).

Data Sharing Statement

The data used to support the findings are available from the corresponding author upon request.

Author Contributions

Song Xue: Conceptualization, Data curation, Writing-original draft. Yaru Wang: Formal analysis, Validation. Yiwei Huang: Formal analysis, Investigation, Writing-review & editing. Liyun Xu: Investigation, Methodology. Yuan Lu: Software, Writing-review & editing. Hui Ke: Conceptualization, Supervision, Writing-review & editing. All authors made substantial contributions to the conception, design, execution, or interpretation of the work; drafted or critically revised the work. All authors gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. All authors declare no competing interests. Data are available from the corresponding author upon reasonable request.

Disclosure

Song Xue reports Support for the work from the Research Project of Jiangxi Provincial Department of Education, The current work was jointly supported by National Natural Science Foundation of China, during the conduct of the study. The authors declare that there is no other conflict of interest.