Evolution and global research trends of immunity in diabetic nephropathy: a bibliometric and visual analysis from 2004 to 2023

The Web of Science Core Collection (WoSCC) database (https://www.webofscience.com/wos/woscc/basic-search↗) has better accuracy in labeling literature types than any other database and is considered the best choice for literature analysis [33]. Therefore, we chose to conduct the retrieval in this database. On January 15, 2024, we searched the WOS database for all articles published between 2004 and December 31, 2023, related to the role of immunity in DN. The search strategy was as follows: ((((((TS = (immunity)) OR TS = (immunize)) OR TS = (immune)) OR TS = (immunization)) OR TS = (immunifaction))) OR TS = (immunothera*) 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).

All relevant publications were independently assessed by two authors and each disagreement was fully discussed with a third author. Literature selection for this study was based on the following inclusion criteria: (1) there were full-text publications related to the role of immunity in DN; (2) the manuscripts of the articles and reviews were written in English; and (3) the literature was published from January 1, 2004, to December 31, 2023. The exclusion criteria were as follows: (1) the topic was not related to the role of immunization in DN; and (2) the type of article was a conference abstract, news, briefing paper, etc. Plain text versions of the publications were exported for analysis. The following data were extracted from the included publications: title, institution, country, journal, year of publication, number of citations, keywords, references, etc.

GraphPad Prism v8.0.2 software was used to analyze trends and proportions of annual publications and national publications. In addition, CtieSpace (Premium version 6.2.4R (64-bit)) and VOSviewer (version 1.6.18) were used to analyze the extracted data and visualize the scientific knowledge graph. The VOSviewer v.1.6.17, created by Waltman et al. in 2009, is a free JAVA-based software for analyzing large amounts of literature data and displaying it as a map format [34]. In this study, VOSviewer software was used to create visual graphs and analyze the most prolific journals, author collaborations, and high frequency keywords. To visualize the results of research in a particular field by mapping the literature co-citation network, Professor Chaomei Chen created the CiteSpace (6.1.6R) software, which envisions the use of an experimental framework for studying new concepts and evaluating existing technologies [35]. This enables users to better understand areas of knowledge, research frontiers, and trends, and to predict their future research perspectives. This study used CiteSpace software to visualize country/institution collaborations, co-cited journals, co-cited authors, co-cited references, and keyword clustering.

This study was a bibliometric analysis of existing publications and did not require ethical approval.

According to the search strategy, the WoSCC database contained 1431 publications on the role of immunity in DN. First, we excluded 148 studies that were not between 2004 and 2023. Then, 27 studies including book chapters, errata, and editorial material were excluded. Ultimately, after excluding 10 studies that were not written in English, 1246 studies meeting the inclusion criteria were included in the bibliometric analysis, including 838 (84.96%) articles and 408 reviews (15.04%). The specific literature search process is shown in Fig. 1. The literature covered 81 countries and regions, 1751 institutions, and 6584 authors.

Since 2004, there has been a slow increase in the number of publications per year (Fig. 2A). We divided the growth process of publications into three stages (Fig. 2A). The number of publications grew slowly from 2004 to 2008, with fewer than 30 articles per year, suggesting that the field has not received much attention from researchers. The number of publications gradually increased from 2009 to 2013, indicating that the area has gradually entered the researchers' field of vision. After 2014, the number of publications in this field increased rapidly and peaked in 2023, which shows that the field has received widespread attention since 2014.

Research on the role of immunity in DN has been conducted in 81 countries and regions. Figure 2B and C showed the annual publication volume of the top 10 countries during the last two decades, and the top 5 countries in this field were the United States, China, Germany, Italy, and Iran. China accounts for 34.91% of the total number of papers published, far more than any other country (Table 1). Among the top ten countries/regions in terms of the number of published papers, papers from the United States were cited 18,161 times (Table 1), far exceeding all other countries/regions, and its citation/publication ratio (57.11) ranked 5th among all countries/regions, indicating that the quality of its published papers is generally high. China ranked first in the number of publications (435) while ranking second in the number of citations (10,756), and its citation/publication ratio (24.73) ranked at the back of the list, suggesting that the quality of its published papers is generally low.

The collaboration network among countries (Fig. 3A) showed that there was close cooperation between China with the highest production and the United States. The United States had close cooperation with Germany, Italy, and the United Kingdom, while China cooperated more closely with India, Japan, and Egypt. China had not only a large number of publications but also a high citation frequency, indicating that it was currently the leading country in the field. In recent years, countries such as the United States and Japan have seen a rapid increase in the number of publications, which may be related to China's cooperation.

1751 institutions systematically published papers on the role of immunity in DN. Among the top ten institutions in terms of number of publications, five were from the United States, two were from China, one was from Egypt, one was from Australia, and one was from Spain (Table 2, Fig. 3B). The University of California System published the most literature (25 papers, 1062 citations, 42.48 citations per paper). Egyptian Knowledge Bank (EKB) (24 papers, 296 citations, 12.33 citations per paper) ranked second and Harvard University (21 papers, 1411 citations, 67.19 citations per paper) ranked third. After further analysis, we found that domestic and foreign institutions prefer to cooperate with their domestic units, so we call for strengthening cooperation between domestic and foreign institutions and breaking down academic barriers.

Table 3 and Fig. 3C showed the top 10 most productive and most cited journals. The Frontiers in Immunology (30, 2.41%) was the journal with the most publications in this field, followed by Frontiers in Endocrinology (29, 2.33%), International Journal of Molecular Sciences (29, 2.33%) and Journal of the American Society of Nephrology (24 articles, 1.93%). Among the top ten most prolific journals, Nature Reviews Nephrology has the highest impact factor (IF) of 41.5. All these journals were classified as Q1 or Q2.

Journal impact is determined by its frequency of being co-cited, which indicates whether the journal has a significant impact on the scientific community [36]. According to Fig. 3D and Table 4, the journal with the highest number of co-citations is Kidney International (863 citations), followed by the Journal of the American Society of Nephrology (827 citations) and Diabetes (707). Among the top 10 most co-cited journals, Kidney International was cited 863 times and had the highest IF of 19.6. Of the co-cited journals, all were distributed in Q1 or Q2.

With a time slice of one year and a period ranging from 2000 to 2023, the co-cited references network had 960 nodes and 3,478 links (Fig. 4A). Among the top 10 most co-cited references (Table 5), the article titled " Innate immunity in diabetic kidney disease" in Nature Reviews Nephrology (IF = 41.5) ranked first as the most co-cited reference, and Escobar- Morreale, Hector F was the first author of the article [37]. Increasing evidence suggests that renal inflammation is an important factor in the pathogenesis and progression of DN and anti-inflammatory therapies may be nephroprotective in DN. In this context, immune cells that activate innate immunity and renal resident cells play a crucial role in triggering and maintaining inflammation. In this article [37], the authors also discussed the mechanisms by which innate immune pathways may contribute to DN and the therapeutic potential of targeting these pathways. For example, Toll-like receptors can induce aseptic tubulointerstitial inflammatory responses through the NF-kB signaling pathway. The NLRP3 inflammasome links the sensing of metabolic stress in diabetic kidneys to the activation of proinflammatory cascades through the induction of IL-1 β and IL-18. Thus, the author suggests that research targeting these innate immune pathways may lead to the development of novel therapies for DN [37].

We performed co-citation reference clustering and temporal clustering analysis (Fig. 4B and C). We found that hyperglycemia (cluster3), systems biology (cluster9), glycation (cluster10), and chemokines (cluster11) were the early research hotspots. Toll-like receptor (cluster2), immune complexes (cluster5), nuclear hormone receptor (cluster7), human immunodeficiency virus (cluster12), rage (cluster 13), complement system (cluster14), and triptolide (cluster15) were research hotspots in the mid-term. Ferroptosis (cluster0), cytokines (cluster1), b7-1 (cluster4), inflammasome (cluster6), p33-mapk (cluster8), and mesangial cells (cluster16) were the hot topics and trends in this field.

Using CiteSpace software, we derived the 50 most reliable citation bursts in the field of the role of immunity in DN. One of the most cited (12.77) references was titled " Toll-Like Receptor 4 Promotes Tubular Inflammation in Diabetic Nephropathy" published in the Journal of the American Society of Nephrology [38]. The first author of the article was Lin, Miao, which concluded that inflammation was a cause of tubulointerstitial lesions in DN. Toll-like receptors can regulate immune responses and inflammatory diseases, but their function in DN is unclear. In this study [38], the authors found that the expression of TLR4 was increased in the renal tubules of patients with DN and the intensity of its expression was directly related to interstitial macrophage infiltration and hemoglobin A1c levels and inversely associated with the estimated glomerular filtration rate. In vitro experiments demonstrated that hyperglycemia induces TLR4 expression through protein kinase C activation in a time- and dose-dependent manner, leading to up-regulated expression of IL-6 and chemokine (C–C motif) ligand 2 (CCL-2) in human proximal tubular epithelial cells through IκB/NF-κB activation. Overall, these studies indicated that TLR4-mediated pathways may promote tubulointerstitial inflammation in DN [38]. All 50 references were published from 2004 to 2023, suggesting that these papers were frequently cited during the last 20 years. Importantly, 27 of these papers are currently at peak citation (Fig. 6A), which implies that the study of the role of immunity in DN will continue to be of interest in the future.

Among the 786 strongest bursts of keywords in the field, we focused on the 50 keywords with the strongest bursts (Fig. 6B), including microalbuminuria, low density lipoprotein, renin angiotensin system, insulin resistance, macrophages, nod mice, toll-like receptors, systemic lupus erythematosus, dendritic cells, inflammatory cytokines, immune cell infiltration, etc. These keywords represent current research hotspots in the field and possible future research trends.

The number of papers published each year can visually reflect the development status and popularity of a particular field. Our study found that the literature on the role of immunity in DN has tended to increase annually over the past 20 years. It could be roughly categorized into three phases: 2004–2008 was a stagnant period with less than 30 articles per year; 2009–2013 was a slow-growth period with between 30 and 50 articles; and 2014–2023 was a rapid growth period, with a rapid increase in the number of papers per year in the field and reaching a peak in 2023, especially in the last three years when the number of papers per year has exceeded 120. This indicates that the field has attracted sustained academic attention and has become a new hotspot in current research on the DN. Therefore, we venture to speculate that the number of publications in this field will continue to increase.

The number of publications in a research field is an important indicator to assess the level of scientific research of a country, institution or author [41]. Our study found that 81 countries and regions have conducted research on the role of immunity in DN. The top 10 countries published a total of 1,165 publications, with the top 2 countries being China (435) and the United States (318). Obviously, the outstanding contribution of the United States in this field is due to its long-term scientific research foundation, a large number of excellent research talents, abundant research funding, and relatively free academic atmosphere [42]. Interestingly, China, as a developing country, has surpassed the United States to rank first in the number of publications in this field, despite its weak research foundation and late start. This may be related to our large population base, the strategy of rejuvenating the country through science and education, and the fact that we have the largest number of diabetics worldwide [43]. Generally, the total number of citations is a major measure of the quality and attractiveness of an article [44]. Although China ranked first in terms of the number of publications, the total number of citations in the literature was 10,756, and the average number of citations per publication was 24.73, which ranked 8th among the top ten countries in terms of the number of publications. This showed that the quality of the papers published in China was generally low. While the United States had the highest number of citations for publications at 18,161, far outstripping other countries. Notably, the number of papers published in England was 38, but the average number of citations per publication was as high as 92.32, ranking first. This reflected the higher quality of the papers published in England and the United States. Regarding country collaboration, we found close and extensive cooperation between China and the United States. The United States cooperated closely with countries such as Germany, Italy, and England, while China cooperated even more closely with countries such as India, Japan, and Egypt. From the analysis of institutions, among the top ten institutions in terms of the number of publications, five were from the United States and two were from China. Of which, the University of California System, which belongs to the United States, published the most publications (25 papers, 1,062 citations, 42.48 citations per paper). This also reflected the strong research strength of the United States. Shanghai Jiao Tong University from China ranked sixth (18 papers, 920 citations, 51.11 citations per paper), which may be related to Shanghai's location in China's Yangtze River Delta. This may be due to the fact that it is one of the most active regions for economic development, openness, and innovation in China [45]. After further analysis, we found that domestic and foreign institutions preferred to collaborate with organizations within their own countries, and we speculated that this phenomenon might be related to factors such as geographical and cultural differences, varying quality of research methods, and official barriers. If these challenges can be actively addressed, this will facilitate broader international cooperation and innovation, ultimately advancing the field and contributing to scientific progress globally.

Journal source distribution and journal co-citation analysis can provide researchers with valuable information that can help them quickly find the most appropriate target journal when searching the literature or submitting a study [46]. Among the top ten most prolific journals, Frontiers in Immunology (30 papers, 2.41%) and Frontiers in Endocrinology (29 papers, 2.33%) from the Frontiers publishing platform were ranked first and second, respectively. This indicated that the majority of articles in the field might be considered for publication on this publishing platform. In addition, our study found that Nature Reviews Nephrology was the journal with the highest impact factor of 41.5. The most co-cited journal was Kidney International (863 citations), followed by the Journal of the American Society of Nephrology (827 citations) and Diabetes (707 citations). Most of these journals were located in the Q1 region. This showed that studies on the role of immunity in DN were often able to be published in journals of high impact and scholarly value.

To reveal the research frontiers and trends in the field, we performed cluster analysis, co-occurrence analysis, and burst analysis of co-cited references and keywords. The most co-cited reference was entitled " Innate immunity in diabetic kidney disease". This article explored in detail the mechanisms by which innate immune pathways may contribute to DKD and the therapeutic potential of targeting these pathways. Timeline clustering analysis of the co-cited references showed that the latest hot topics in the field involved ferroptosis, cytokines, b7-1, and inflammasome. According to the co-occurrence of keywords, the hottest keywords were mainly inflammation and oxidative stress. Burst analysis of references showed the most cited reference was entitled " Toll-Like Receptor 4 Promotes Tubular Inflammation in Diabetic Nephropathy". The article emphasized the role of TLR4 in promoting tubular inflammation in DN. The 50 keywords with the strongest citation bursts in this field were mainly related to low density lipoprotein, renin angiotensin system, insulin resistance, macrophages, toll-like receptors, dendritic cells, inflammatory cytokines, immune cell infiltration, and so on. Overall, immune-related mechanisms are still the hotspots of DN research, and future research trends may involve the following three aspects: (1) the mechanism of immune-related inflammation involved in DN; (2) the role of ferroptosis in immunity and DN; and (3) the role of lipid metabolism in immunity and DN.

DN was thought to be the result of the interaction of hemodynamic and metabolic factors. Its pathogenesis involved many factors and pathways, among which immune cells and immune-related chronic inflammatory responses played an important role in the occurrence and development of DN [20]. Macrophages are key members of the mononuclear phagocyte system and part of innate immunity. High glucose and late glycosylation end products in the DN environment promote macrophage recruitment, migration, and activation, and activated macrophages release proinflammatory factors, leading to renal injury and fibrosis [47]. Dendritic cells (DCS) are the primary regulators of innate and adaptive immune responses. It can interact with B cells and T cells to manipulate humoral and cellular immune responses [48]. Studies have shown that high glucose can trigger DC maturation and induce a proinflammatory cytokine profile in human DCs, which subsequently mediates tubulointerstitial injury in DN [49, 50]. Besides that, there were many other inflammation-related cytokines aggregated in the renal tissues of patients in the development of DN [18–20], such as chemokines [51], cell adhesion factors [52], growth factors, inflammatory factors, nuclear factors, and so on. However, this mechanism remains controversial and deserves further investigation.

Ferroptosis, a novel mode of cell death induced by iron-dependent oxidative damage, is characterized by lipid peroxidation due to intracellular iron overload and accumulation of reactive oxygen species (ROS) [53]. Recent studies have shown that ferroptosis has been identified as one of the forms of cell death for several immune cells, affecting the immune response. There may be potential interactions between ferroptosis and the immune response in some cases [54]. Iron ions were reabsorbed by renal tubules after glomerular filtration, and renal tubular epithelial cells were extremely active sites for iron ions and ROS. Characteristic changes of ferroptosis, such as iron overload, lipid peroxidation, and mitochondrial alterations, were detected in human renal proximal tubular epithelial cells (HK-2) cultured in high glucose [55]. It was found that ferroptosis was closely associated with renal tubular cell death in diabetic conditions [56]. These findings have also been used to explain the action mechanisms of drugs which may be potentially valuable in the treatment of DN. For example, Ghanim et al.'s study found that dagliflozin was effective in reducing serum iron-regulatory protein levels and improving iron metabolism disorders in patients with type 2 diabetes mellitus [57]. Huang et al. observed that liraglutide alleviated glomerular extracellular matrix accumulation and renal injury in DN by enhancing Wnt/β-catenin signaling [58]. Therefore, an in-depth exploration of the mechanism of ferroptosis in immunity and DN could provide new therapeutic ideas and potential drug targets for DN patients.

Studies have shown that lipid metabolism could regulate the differentiation and function of immune cells [59]. T helper cells secreting IL-17 play a pathogenic role in a variety of inflammatory and autoimmune diseases, and its development requires endogenous fatty acid synthesis [60]. Different types of macrophages have different requirements for fatty acid synthesis and catabolism. Factors that promote M1 macrophages induce fatty acid synthesis, whereas anti-inflammatory signals that favor M2 macrophages drive fatty acid oxidation [61]. Conversely, immune cells are an important part of the lipid microenvironment, influencing local and systemic lipid metabolism [62]. Renal lipid homeostasis has received increasing attention in recent years [63]. Altered fatty acid and cholesterol metabolism were recognized as crucial pathways for renal lipid accumulation, inflammation, oxidative stress, and fibrosis [64]. Oxidized low-density lipoprotein (ox-LDL) may promote the development of DN by damaging renal endothelial, thylakoid, and tubular cells through lipid metabolic pathways, inflammatory damage, and hemodynamic factors [65]. In addition, abnormal renal lipid metabolism was found to be present in the kidneys of mice with DN and high glucose-induced renal podocytes [66]. Thus, podocyte lipid accumulation has been considered a potential therapeutic target for DN. Looking forward, understanding more regulatory details of lipid metabolism involved in immunity and DN will provide more valuable clues for the study and treatment of DN.

Although, we were able to gain a detailed view of the research evolution and global trends in the relationship between immunity and DN using visual analysis tools such as CiteSpace and VOSviewer. However, this study also has some limitations. First, we only retrieved the WoSCC database in this study, and there were many other noteworthy databases that have not yet been searched, such as the Scopus, PubMed, and Embase databases. However, considering that the WoSCC database is one of the most used and comprehensive global databases [67–71], it is sufficient to reflect the general trend in this research field. Second, we only analyzed studies published in English, which could lead to the fact that some non-English studies could be missed due to language limitations. Finally, considering the presence of near-synonyms, abbreviations, and full names, the keyword bursts may differ from the actual results. Therefore, the results need to be interpreted with caution.

The study was conducted without any business or financial relationships that could be interpreted as potential conflicts of interest.

This study did not involve animal or human experimentation. Therefore, ethical approval from an institutional review board was not required. Author Contributions.

All original contributions are included in the manuscript.