Background

Diabetes mellitus (DM) is a severe global health problem and contributes to increased health care costs. It is estimated that more than 450 million people are affected by this disease, and this number will reach 700 million people by 2045 [1]. Diabetic kidney disease (DKD) is one of the most important complications of DM, and chronic kidney disease occurs in more than 20–40% of DM patients [2]. Thus, overall comprehension of the mechanism and treatment of DKD is essential for nephrologists, especially young researchers.

Recent reviews have helped researchers understand the mechanism, diagnosis, and treatment of DKD, as summarized in Table S1. These studies highlight the vital roles of immunity and inflammation [3,4,5], oxidative stress (OS) [6,7,8], haemodynamic and metabolic shifts [9], epigenetic factors [10] and tubule function [11] in the pathogenesis and prognosis of DKD. However, these content-based reviews have 3 limitations. First, the review contents are deep but narrow, which makes it difficult for readers to understand the overall research status of the subject. Second, the articles referenced in the reviews were manually selected. The large workload leads to limited numbers. However, subjective judgement may lead to the loss of information. Authors may miss important research. Even if an article is cited, its importance and influence may be neglected. Third, readers cannot learn the evolution of the subject or evolution of popular topics and thus cannot develop a deeper comprehension of the subject.

Clinical and experimental studies on DKD have developed rapidly. In total, there were 23,968 items in the Web of Science Core Collection on the subject of DKD from 1999 to September 28th, 2020. In a sense, the citation time (CT) represents the influence and significance of the article. Bibliometric analysis is a method utilized in many fields to illustrate the landscape of subjects [12, 13]. Based on CT, bibliometric analysis objectively includes articles of subject on subject in the analysis and reflects the evolution of a subject, trends of popular topics and collaborative relationships among researchers and countries [14,15,16]. To determine the influential research, the distribution of disparate topics and the evolution of research trends, we performed a bibliometric analysis of the top 100 most cited articles in clinical and experimental studies of DKD.

Materials and methods

Data collection and filtration

To acquire literature data representing high-quality research, we retrieved publications on the subject of DKD from the Web of Science Core Collection using the search strategy: TOPIC: (DKD OR (diabetic NEAR/0 nephropathy) OR (diabetic NEAR/0 kidney)). Research results were ranked by CT, which was based on the absolute number of citations for each article through September 28th, 2020. Articles involving the following research objects were defined as publications on the subject of DKD and were manually selected: DKD populations; diabetes populations with proteinuria or kidney disease; tissue, blood, or urine from DKD and diabetes patients with proteinuria or kidney disease; diabetic animals with kidney injury; and renal cell models simulating diabetes injury. Only full-length original articles were included in this study while other types of articles, such as guidelines, reviews, and meta-analyses, were excluded. Finally, only the top 100 most cited full-length original articles written in English on the subject of DKD were included in this study.

Data analysis and visualization

Elements including the article title, author, address, abstract, keyword, journal, publication year and CT were included in the analysis. The article number was equal to the article rank among the 100 articles. The relevant countries were analysed according to the corresponding authors. If the corresponding authors came from the same country, the article was defined as a single-country publication; otherwise, it was defined as a multi-country publication. Subcategories and topics were manually summarized and counted. The average citation time (ACT) of each article was equal to the CT divided by the number of years the article was cited, and the number of years the article was cited was equal to 2020 plus 1 minus the number of the published year. In addition, the number of citations per article per year was equal to the sum of ACTs of all articles published in the same year divided by the number of articles. The author’s influence score was represented by the sum of the ACT, and one article was scored on only the publication year.

Bibliometric analysis was performed using the Bibliometric R Package [17]. Journal analysis was performed using the module of most relevant sources. Country analysis was performed using the module of the corresponding author’s country. The frequencies of key words included in the word cloud were determined using the module of most frequent words with abstract parameters.

Figures were made by Microsoft PowerPoint, ggplot2 R Package, and ggwordcloud R Package. The process of data preparation and analysis is shown in Fig. 1.

Fig. 1
figure 1

Strategy for data preparation and analysis. We retrieved publications on the subject of DKD from the Web of Science Core Collection and ranked the top 100 most cited articles. After subcategory and topic identification, we performed analyses of the journals, countries, author contributions, distributions and topic evolution

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Results

Basic information of the top 100 most cited articles

As shown in Table 1, the top 100 most cited articles were published in 26 journals, and 55% of the articles were published in the following 4 journals: Journal of the American Society of Nephrology (21%), Diabetes (16%), Kidney International (10%), and The New England Journal of Medicine (8%).

Table 1 List of the relevant scientific journals
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The 100 articles were published from 1999 to 2017 and were cumulatively cited 38,855 times. The publication time spans are shown in Fig. 2. There were 20 articles published from 1999 to 2002, 38 articles published from 2003 to 2007, 31 articles published from 2008 to 2012 and 11 articles published from 2013 to 2017. In 2003, 13 articles were published, which made 2013 the year with the most publications.

Fig. 2
figure 2

Timespans of the top 100 most cited articles. The blue bars represent the number of publications for each year, and the yellow line represents the number of citations per article per year. The distributions of articles and citation in disparate years are shown in the figure

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Finally, we analysed the authors, and their affiliations, of the top 100 most cited articles. The authors shown in Figure S1 were the top 10 most relevant authors ranked by the author’s influence score. The dot size represents the score of authors, and the dot colour reflects the number of works published by the author. In Table 2, we found that scientists from the USA contributed the most publications.

Table 2 List of the relevant countries analysed according to the corresponding author
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Identification of the subcategories of the top 100 articles

We divided the articles into 4 subcategories according to the research type and content. The most abundant article subcategory was ‘Experimental studies (EG)’, which explained the phenotypic changes and mechanisms in experimental DKD and comprised 65 articles (49.62% of all citations). The second most abundant subcategory was ‘Clinical studies (CS)’, which focused on the clinical biomarkers and treatment strategies for DKD, and in this subcategory, 26 articles contributed to 41.55% of the total citations. Moreover, 7 articles with 2603 total citations were determined to belong to the subcategory ‘Epidemiological studies (ES)’, and 2 articles specifically describing the pathological and pathophysiological characteristics of DKD belonged to the subcategory ‘Pathological and pathophysiological studies (PP)’. In Table 3, we list the article number and percentage of total citations for each subcategory.

Table 3 Subcategories of the top 100 most cited articles
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To learn more about the contents of the 100 articles, we analysed the key words. Figure 3 shows the highly frequent words related to the top 100 most cited articles on DKD. To further determine the hotspots in DKD research, we analysed articles in the subcategories ‘EG’ and ‘CS’ by their topic. In Table 4, we list the top 100 most cited articles and their topics.

Fig. 3
figure 3

Word cloud of the top 100 most cited articles. Key words were extracted from the abstracts of the top 100 most cited articles to illustrate a word cloud

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Table 4 List of the top 100 most cited articles
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Distributions of the top 100 most cited articles in regard to different subcategories, topics and periods

In Fig. 4, we show the distribution of the top 100 most cited articles. We divided the year of publication into 4 periods. The distributions of the 100 articles are shown in Fig. 4a. Most ‘CS’ articles were published from 2003 to 2007 (Fig. 4b), while most ‘MG’ articles were published from 2008 to 2012 (Fig. 4c).

Fig. 4
figure 4

Distributions of the subcategories, topics and time periods. The distributions of the 100 articles are shown in the figure (a). The distributions of clinical studies (b) and experimental studies (c) in different time periods are shown as pie charts. The distributions of topics in clinical (d) and experimental studies (e) are showed as Nightingale rose charts

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Intriguingly, we revealed popular research fields via topic analysis. We found that the renin-angiotensin-aldosterone system (RAAS) was the most popular topic. Clinical trials on the application of RAAS blockade in DKD (article number 1, 2, 3, 7, 9, 10, 15, 27, 41, 52, 62, 64, 75, and 86, a total of 11,852 citations, 30.50% of the total citations) included 6 of the top 10 most cited articles, which contributed to 26.52% of the total citations. Correspondingly, 6 articles (article number 25, 39, 71, 84, 92, and 95, a total of 1579 citations, 4.06% of the total citations) explained the mechanism of RAAS in DKD. In addition, RAAS blockade-based combination treatment was also popular among researchers, as it was associated with 6 articles that were cited 1756 times (4.52% of the total citations). RAAS blockade combined with vitamin D analogues (article number 17, 97) and mineralocorticoid antagonism (article number 35, 80, 93) were recommended for renal function protection, but RAAS combined with the endothelin antagonist avosentan (article number 50) was considered to induce fluid overload. Taken together, these data indicated the crucial role of RAAS blockade in therapeutic strategies for DKD.

The next most important topic was how the OS participates in DKD, which was associated with 17 articles published from 2000 to 2013 (article number 5, 18, 22, 24, 45, 55, 63, 67, 70, 72, 73, 81, 85, 88, 89, 91, and 100, a total of 5080 citations, 13.07% of the total citations). In experimental DKD, the increase in reactive oxygen species (ROS) (article number 5) and NAD(P)H oxidase levels (article number 22, 63, 67, and 91), activation of PKC (article number 24 and 81), decrease in eNOS (article number 55, 85, and 100) and mitochondrial dysfunction (article number 70, 72, and 89) promote OS injury, while Nrf2 (article number 45, 73, and 88) protects the kidney from OS in DKD as an antioxidant factor. However, a phase 3 clinical study (article number 18) found that the Nrf2 activator bardoxolone methyl did not ameliorate the loss of renal function. Instead, bardoxolone methyl led to a higher cardiovascular risk.

The accumulation of advanced glycation end products (AGEs) is also a classic pathogenic mechanism in DKD. Among the top 100 most cited articles, 7 articles (article number 19, 21, 30, 38, 44, 51, and 60, a total of 2322 citations) focused on AGEs and the receptor for AGEs (RAGE), which constituted 5.98% of the total citations. Although they slowed the progression of experimental DKD, agents targeting AGEs/RAGE were not easily translated into the clinic. In a randomized clinical trial, pimagedine, an inhibitor of AGE formation, did not ameliorate nephropathy in patients with type 1 diabetic mellitus (T1DM) (article number 44).

In addition to therapies developed based on classic mechanisms, researchers have highlighted new drugs developed based on new mechanisms in recent years. The sodium-glucose cotransporter 2 (SGLT-2) inhibitor empagliflozin and glucagon-like peptide 1 (GLP-1) agonist liraglutide are two rising stars in DKD treatment. There were 2 articles on empagliflozin among the top 100 most cited articles, one clinical trial (article number 36, 324 citations) published in 2013 and one experimental study (article number 96, 219 citations) published in 2014. Moreover, the clinical trial of liraglutide published in 2017 (article number 32, 337 citations) was the latest among the 100 articles. These new drugs represent new trends in DKD research.

Some experimental studies uncovered the crucial mechanisms of DKD, but the clinical translations of these studies were not included in the top 100 most cited articles. Fifteen articles elucidated the important roles of podocyte dysfunction (article number 33, 37, 54, 59, 77, and 87, a total of 1637 citations), immune cells and inflammation (article number 31, 43, 53, 68, 79, and 90, a total of 1616 citations), and vascular endothelial growth factor (VEGF) (article number 23, 28, 74, totally cited 943 times) in DKD, and 4 articles that were cited 1858 times demonstrated that transforming growth factor (TGF)-β (article number 6), fibroblasts (article number 12), and connective tissue growth factor (CTGF) (article number 40, 42) contribute to renal fibrosis in DKD. A new mechanism drawing the attention of researchers was the role of microRNAs (miRs) in DKD, which was discussed in 8 articles published from 2007 to 2013 (article number 13, 20, 34, 48, 57, 78, 83, and 99, a total of 2503 citations). Furthermore, metabolomics and transcriptomics analyses deepened researchers’ understanding of DKD. Targeting metabolic alterations (article number 29, 56, 65, and 82, a total of 1085 citations) and novel transcription factors (TFs) (article number 49, 61, 69, and 94, a total of 998 citations) had therapeutic effects in experimental DKD.

The articles above revealed the mechanism of and treatment strategies for DKD. In the remaining clinical studies, one article (article number 8, 571 citations) emphasized the importance of blood pressure (BP) control in DKD, and 2 articles discussed microalbuminuria (article number 14, 66, a total of 744 citations) in T1DM. Figure 4d and e show the distributions of topics in ‘CS’ and ‘MG’ articles respectively. Furthermore, in Table 5, we separately list the information and results of clinical studies in regard to their critical roles in clinical guidance.

Table 5 List of the clinical studies among the top 100 most cited articles
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Regarding other article types, 9 articles subcategorized as ‘ES’ and ‘PP’ helped researchers understand DKD from disparate aspects. Seven articles (article number 4, 16, 26, 46, 58, 76, and 99, a total of 2603 citations) were based on the epidemiological aspects of DKD, and 2 articles (article number 11, 47, a total of 828 citations) defined the pathological characteristics and classifications of DKD. Four of the 9 articles (article number 4, 26, 47, and 58) were specifically on nephropathy in T1DM.

Evolution of topics in clinical and experimental studies of DKD

To elucidate the trends in DKD research, we analysed the distributions of topics of ‘CS’ and ‘MG’ articles in different periods and illustrated their evolution, as shown in Figure S2. Interestingly, we found that RAAS and OS are continuous hotspots of DKD research, again emphasizing the significance of the two research fields. Although attention has been given in the past, the number of studies on AGEs and RAGE has declined in recent years, which may be due to the frustration of clinical translation. Articles on miRs were predominately concentrated from 2008 to 2012, indicating the trendy miR-related study outbreak and attraction of numerous researchers in those years. In addition, some topics have appeared in recent years, including SGLT-2 and GLP-1, which have become new hotspots and have led to novel breakthroughs in DKD studies.

Discussion

In this study, we ranked the top 100 most cited articles on DKD according to the total number of citations in the Web of Science Core Collection. In addition, we analysed the journals, timespans, authors, countries and topics of the 100 articles. This bibliometric analysis helps readers quickly understand the influential studies in DKD research, which topics attract other researchers, and the evolution of the research trend, thus guiding researchers to find interesting research directions and may help facilitate international collaborations. Popular clinical studies guide readers in clinical practice to provide more benefits for patients. Important experimental studies provide laboratory evidence for clinical trials and deepen the comprehension of the development and progression of DKD. Although some studies have not yet been clinically translated, they may direct future research and provide potential biomarkers and therapeutic targets as the subject develops in the future.

Bibliometric analysis is an effective method that is utilized in diverse areas of study [12,13,14,15,16, 18,19,20]. A bibliometric analysis performed in 2019 [19] showed that 3 of the top 10 most cited articles in nephrology were on the subject of RAAS blockade usage in DKD. A former bibliometric analysis of DKD [20] highlighted the authors and co-citation networks but not the subcategories or contents. In this study, we further performed a bibliometric analysis of the top 100 most cited articles to elucidate what has been done and what needs to be completed in DKD research. In addition, there were some limitations in this study. We performed this study based on data from the Web of Science Core Collection, which means that some high-quality articles that were published earlier or were not in English were potentially excluded from this study. Another limitation is that the drawback of the bibliometric citation analysis method may contain bias, as recent articles have less time to be cited. Thus, we also listed the number of citations for each article per year, which helps to highlight the influence of recent studies [21] in addition to the total number of citations. On the other hand, we discussed the recent advances in traditional topics and more findings in the latest hotspots.

The most relevant field and a persistent interest in DKD research is RAAS, which was associated with most articles and citations. In the latest Kidney Disease: Improving Global Outcomes guidelines [1], angiotensin-converting enzyme inhibitors (ACEis) and angiotensin-II receptor blockers (ARBs) are recommended for use in DKD patients. In addition to ACEis and ARBs, there are other types of RAAS blockades, including direct renin inhibitors and ectoenzyme neutral endopeptidase inhibitors. In 2008, a randomized study showed that the combination of losartan and aliskiren, a direct renin inhibitor, significantly reduced the mean urine albumin-to-creatinine ratio (UACR) compared with that achieved with losartan combined with placebo in T2DM patients (article number 3, 751 citations). In 2018, the intention-to-treat analysis of UK HARP-III [22] showed that sacubitril, an ectoenzyme neutral endopeptidase inhibitor, combined with valsartan had a similar renal benefit and additional heart function protection when compared to that achieved with irbesartan in patients with an estimated glomerular filtration rate of 60 to 20 mL/min/1.73 m2. The intention-to-treat analysis of PARADIGM-HF [23] showed that sacubitril combined with valsartan took advantage of delaying renal function decline and protecting heart function when compared with enalapril in patients with diabetes. Novel RAAS inhibitors have promising prospects in the treatment of DKD owing to their advantages.

Notably, article number 71 (239 citations) highlights the expression of angiotensin-converting enzyme 2 (ACE2) in DKD. However, the expression of ACE2 in DKD is controversial [24, 25]. One recent study [26] found that the mRNA level of ACE2 was increased in the proximal tubular epithelial cells of DKD patients. In addition, some studies [27, 28] have shown that RAAS inhibitors upregulate the expression of ACE2. ACE2 is the receptor for SARS-CoV-2 [29,30,31], which is responsible for the COVID-19 outbreak, giving rise to the following two questions: will renal injury be increased in COVID-19 patients with diabetes and will ACEi/ARB treatment have an impact on the renal outcome of COVID-19 patients with diabetes? COVID-19 patients with T2DM have higher acute kidney injury prevalence rates than individuals without diabetes [32], which may be explained by ACE2-mediated viral cytopathic effects [26, 33]. Some studies [34, 35] implied that RAAS inhibitors increased the risk of acute kidney injury, suggesting more concern about renal outcomes in patients with severe COVID-19 with diabetes who are treated with ACEis/ARBs. More studies are needed to further elucidate the roles of ACE2 and ACEi/ARB-induced ACE2 in DKD.

Strategies for protecting renal function are a permanent topic of DKD. Although RAAS blockade benefits a substantial population of patients, there are still some questions regarding DKD treatment. Unfortunately, the development of novel drugs based on new mechanisms in DKD treatment has been uneven. Fortunately, two novel types of drugs, SGLT-2 inhibitors and GLP-1 receptor agonists, may represent the future of DKD treatment methods. CREDENCE [36] and the following analysis of CREDENCE [37, 38] revealed that canagliflozin reduces the risk of renal failure and cardiovascular events and decreases anaemia-associated outcomes in T2DM patients with kidney disease. DAPA-CKD [39] showed that dapagliflozin, another SGLT-2 inhibitor, reduces kidney and cardiovascular events in chronic kidney disease patients with and without T2DM. Intriguingly, the latest publication among the top 100 most cited articles is a clinical trial of another new drug, liraglutide, a GLP-1 receptor agonists (article number 32), which has been proven to reduce the occurrence of persistent macroalbuminuria. Encouragingly, the two novel types of agents showed more advantages for kidney function protection than dipeptidyl peptidase-4 inhibitor or sulfonylureas [40] and were recommended by the Kidney Disease: Improving Global Outcomes guidelines guidelines [1] and consensus report by American Diabetes Association and the European Association for the study of diabetes [41, 42] in T2DM patients with chronic kidney disease. To develop more novel targets of DKD treatment, further comprehension of the mechanisms of DKD is indispensable.

Technological innovation promotes scientific development. High-throughput technology and multiomics studies help researchers further understand the pathogenesis and prognosis of DKD (article number 65, 69). The application of single-cell and single-nucleus transcriptomics [43,44,45] identifies novel types of cells, describes cell-to-cell crosstalk, discovers further mechanisms and provides new insight into renal diseases. Further understanding the disease will help researchers find potential biomarkers and novel therapeutic strategies in the future.

Moreover, artificial intelligence is widely applied in the analysis of clinical indicators, digital imaging data, and digital pathological data in renal diseases [46, 47] and improves the diagnosis and prognostication of DKD [48,49,50]. High-performance models built by artificial intelligence may contribute to more effective and accurate interventions in the clinical practice of DKD.

Conclusion

In conclusion, this article focused on the top 100 most cited articles on the subject of DKD. By reviewing the popular studies over several decades, researchers can better understand the evolution of DKD research. The important roles of ACEis and ARBs were once again emphasized in this study, and the prospects of SGLT-2 inhibitors and GLP-1 receptor activators are promising. Influential studies deepen the understanding of DKD and provide evidence for novel biomarkers and potential therapeutic strategies. This study helps readers quickly understand the important studies on DKD research, the distribution of popular topics and the evolution of the subject, thus providing a guide for research direction, international collaboration and clinical practice to better server patients.