The intellectual base and global trends in contrast-induced acute kidney injury: a bibliometric analysis

Abstract Contrast-induced acute kidney injury (CI-AKI) has become the third leading cause of hospital-acquired kidney injury. A comprehensive analysis of the current state of research in the field of CI-AKI will help to reveal trends and hot topics in the field. To date, there are no published bibliometric analyses related to CI-AKI studies. Here, we analyze the relevant literature since the emergence of the concept and provide valuable insights. The literature was collected from the Web of Science Core Collection. The data were analyzed visually using CiteSpace and VOSviewer software. We collected a total of 4775 papers, with the United States and Guangdong Acad Med Sci as the major publishing powers in terms of country/region and institution. J AM COLL CARDIOL was the journal with the most published and cocited articles. Cluster analysis showed that clinical trials are the current research hotspot. The areas of risk assessment, prevention strategies, risk factors, and vascular lesions have been popular in recent years. Research on the mechanism of injury in CI-AKI will be the focus of future research, which will be crucial to reduce the clinical incidence of CI-AKI. In summary, this study provides a comprehensive analysis of the development process in the field of CI-AKI and discusses future research directions based on the analysis of objective data from many studies on CI-AKI.


Introduction
In recent years, with the continuous development of imaging CT technology and intracavitary cardiovascular and peripheral vascular interventional techniques, the application of contrast medium (CM) has become increasingly frequent, and contrast-induced acute kidney injury (CI-AKI) has become a research hotspot in the fields of nephrology, radiology, cardiovascular and peripheral vasculature [1][2][3][4]. The definition of CI-AKI given by the Kidney Disease: Improving Global Outcomes (KDIGO) organization is a rise in serum creatinine (SCr) of !0.5 mg/dL (!44 lmol/L) or a 25% increase from baseline, assessed at 48 h after a radiological procedure [5,6]. CI-AKI occurs in up to 30% of patients receiving iodine contrast and is often considered to be the third leading cause of hospital-acquired kidney injury [7,8]. The causal relationship between contrast and AKI has not been strictly established, but rather the AKI is called contrast-associated acute kidney injury (CA-AKI). In particular, the prevalence in high-risk patients with advanced age, diabetes, chronic kidney disease (CKD), and hypertensive disease is 40%, of whom $11% develop end-stage renal disease [5,[9][10][11]. In addition, acute kidney injury often leads to multiorgan damage, but the exact mechanism of injury has not been clarified [12]. The pathophysiological mechanisms of CI-AKI are not fully understood. Three main mechanisms of CI-AKI are known, including direct tubular toxic effects, intrarenal vasoconstriction, and excessive generation of reactive oxygen species (ROS) [13].
The key pathophysiological mechanisms underlying the development of CI-AKI are direct cytotoxic effects and hemodynamic alterations leading to renal hypoperfusion [14,15]. Oxidative stress and hypoxia-mediated direct cytotoxic effects mainly damage renal tubular epithelial and endothelial cells [16,17]. The hemodynamic changes are the result of vasoconstriction and indirect damage to the peritubular vascular endothelium via reactive oxygen species [18,19]. CI-AKI has become an important medical complication that endangers human health, but restricting the use of CM in high-risk groups has become a barrier to clinical diagnosis and treatment.
Currently, most of the research on CI-AKI is focused on clinical trials and molecular mechanisms. Review articles account for a significant proportion of articles but are more focused on a limited number of aspects, such as meta-analyses exploring risk factors, practice guidelines, and traditional reviews [20][21][22]. These articles suffer from a lack of integration and limited reproducibility. Bibliometrics is an effective method for describing trends in research fields and is widely used in medical research [23,24]. CiteSpace and VOSviewer are software programs that facilitate visual analysis of new trends in scientific development, helping researchers quickly identify existing scientific progress and discover and track research hotspots [25,26]. The purpose of this study was to qualitatively and quantitatively analyze the significant, reliable, and comprehensive information in the CI-AKI field over the last 40 years since the emergence of reports on this topic. We hope to gain a deeper understanding of current hot spots and to generate intense discussion of potential research directions.

Data source and search strategy
The literature used in this paper is drawn from the core collection database of the WoS website (WoSCC), as this is considered one of the most systematic, authoritative, and comprehensive databases and is widely used in bibliometric and visual analyses [27,28]. All data were independently searched and downloaded by the two authors on 25 August 2022, after which no raw data were downloaded from the database. The effect of daily updates to the database on the articles was ignored. The search strategy was as follows: (TS ¼ (Contrastinduced acute kidney injury) OR TS ¼ (Contrast-associated acute kidney injury) OR TS ¼ (Contrast-induced nephropathy)) AND LA ¼ (English). The selection criteria were as follows: (i) language: English; (ii) document type: all types; (iii) time span: up to 25 August 2022; (iv) document format: plain text; and (v) record content: full record with cited references. A total of 4775 documents were retrieved.

Data analysis and visualization
CiteSpace 6.1 R3 and VOSviewer 1.6.18 were used to build a visual bibliometric analysis based on collaborative networks, co-word analysis, and cocitation analysis. The information used includes authors' names, institutions, nationalities, journals, keywords, references, etc., and these important scientific terms are visualized by constructing a co-occurrence network.

Article volume characteristics
We retrieved a total of 4775 articles from the WoSCC database. It has been 38 years since the concept of CI-AKI was first introduced in 1984, and the number of articles has shown a yearly growth and stabilization trend. Among them, the highest number of articles was published in 2020, with 376 articles, accounting for 7.874% (Figure 1(A)). These results suggest that CI-AKI research is attractive, and more prospective studies are still needed in the field of CI-AKI in the future.
From a global perspective, a total of 83 countries/regions published articles in this field. Among them, USA has the highest number of publications with 1362 articles, while PEOPLES R CHINA (839), ITALY (426), and TURKEY (325) are also countries with high publication volume in this field (Figure 1(B)).

Fund support
Funding support in this area is shown in Figure 1(E), with the National Natural Science Foundation of China (231) providing the highest amount of financial support, followed by the United States Department of Health Human Services (179), National Institutes of Health (163), National Institute of Diabetes Digestive Kidney Diseases (56), Science and Technology Planning Project of Guangdong Province (43), and National Heart Lung Blood Institute (42). This indicates that the United States and China are the largest sources of financial support in this field.

Visual analysis of countries/regions and institutions
On 25 August 2022, we retrieved a total of 4775 articles through WoS, and after importing them into CiteSpace 6.1.R3 software, 3570 articles were extracted for analysis after data deduplication and cleaning. There were five types of articles: reviews, proceedings, editorial material, and letters. The 3570 articles were all in English, from 673 research institutions in 83 countries/regions, and published in 854 journals (an article could be counted multiple times because multiple countries/regions, institutions, and authors are involved). The screening process is shown in Figure 2.

Countries/regions
Through CiteSpace analysis, the ten countries with the highest number of papers had a total article output of   Burst detection was used to detect sudden changes in topics, literature, authors, and journal citation information and may be the result of a breakthrough in the field. The USA was the country with the highest intensity and longest duration of citation bursts (15.22), followed by Germany (13.77), Canada (12.02), and Italy (7.52); Egypt, India, Pakistan, and Saudi Arabia were the countries with new citation bursts in the last three years (Supplementary Figure 1(A)). It is worth noting that China, the country publishing the second most articles, did not experience any citation burst. Centrality, also known as mediator centrality, is a measure whose higher values represent a more active and close role a node plays in cooperative relationships with other nodes. Individuals with high centrality are marked as purple circles in the graph. The United States had the highest centrality (0.56), followed by Germany (0.18), the United Kingdom (0.16), and Italy (0.15), indicating that they each play an important role as a bridge in the network of national cooperation in this field.
According to VoSviewer's analysis (Supplementary Figure 1(B)), the country/region with the highest number of citations was the United States (49,621), followed by Italy (13,620), Germany (10,791) and the United Kingdom (10,370). In addition, the connecting lines between nodes represent the cooperation between countries/regions, and the thickness of the connecting lines represents the intensity of cooperation. We found that many countries/regions cooperated extensively with each other, the most obvious cooperation being between China and the United States. The total link strength was significantly higher in the U.S. than in other countries, indicating that it works more closely with other countries.

Institutions
According to the analysis of CiteSpace data (Figure 3 According to the analysis of VoSviewer data (Supplementary Figure 1(D)), Univ Michigan (7342), Columbia Univ (7338), and Mayo Clin (6610) had the most total citations. Columbia Univ had the highest total link strength, followed by William Beaumont Hosp, Univ Michigan, and Univ Pittsburgh, indicating that U.S. institutions are more focused on communication and collaboration.

Visual analysis of journals and cocited journals
VoSviewer shows a total of 4775 articles related to the field of CI-AKI published in 854 journals. The top 10 journals with the most published articles and the 10 most cocited journals are listed in Table 2. Among these journals ( Figure 4  and ANGIOLOGY (141, IF ¼ 3.299). Of these, seven of the top ten journals were in JCR Q2 and above. Among the cocited journals (Figure 4  top ten journals were in JCR Q1. This indicates the high quality and impact of journals related to the CI-AKI field. The dual-map overlay of journals is a new way to display information about the distribution, citation trajectories, and drift of gravity of papers across disciplines. In Figure 5, the left side is the citing journal, the right side is the cited journal, and the curve is the citation linkage, which shows the complete citation relationship. In the dual-map overlay of journals, the more articles a journal publishes, the longer the vertical axis of the ellipse; the more authors it has, the longer the horizontal axis of the ellipse. Two of the main reference paths (in green) indicate that articles published in molecular/biology/genetics and health/nursing/medicine journals are frequently cited by medicine/medical/clinical journals.

Visual analysis of authors and cocited authors
CiteSpace showed that a total of 17,357 authors were involved in the publication of these articles ( Figure 6(A), Table 3). Liu Y was an author on the most articles (147), followed by Chen J (111), Tan N (94), and Chen S (81). We also note the total number of citations of the authors, as it reflects the recognition of their results in the field. Mehran R (8257) was the author with the most total citations, publishing 77 articles; Blankenship Jc published only nine articles but ranked second in total citations, while authors with the highest number of publications, such as Liu Y (1258 citations), did not have significant total citations. In addition, Mehran R ranked first in total link strength, indicating that he collaborated closely with other researchers.
VoSviewer showed that the total number of cocited authors was 39,940 ( Figure 6(B), Table 3). Cocited author analysis refers to two articles by two authors being cited by a third article. The higher the number of cocitations, the closer the researcher's academic interests and the greater the research density. Sixty-two authors had more than 200 cocitations in this study, and the most frequently cocited author was Mccullough Pa (2316), followed by Mehran R (1773), Marenzi G (1495), and Briguori C (1052).

Visual analysis of articles and cocited references
Citation analysis was performed on the retrieved literature (Supplementary Figure 2(A)), and VoSviewer showed 203 articles with total citations above 100, and the 10 articles with the highest total citations are shown in Table 4. Nine of the articles were in the review or guideline recommendation category, and one was a clinical study. The article titled 'KDIGO clinical practice guidelines for acute kidney injury' had the highest total citations, but the link strength was low, indicating a weak linkage to other articles in the CI-AKI field.
When two articles are cited by a third article at the same time, it is called a literature cocitation relationship. References are often considered the knowledge base of a specific field, and the more frequently a paper is cited, the more significant it is in a particular field. Based on the number of cocitations, we selected the  top ten references, each of which was cited at least 120 times in the CI-AKI field (Table 5). Of the top 10 cocited articles, five were from the United States and three were from Italy; seven were clinical trials and three were reviews. The most cocited clinical study, entitled 'Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial' (170), was published by Merten et al. [38] in the Journal of the American Medical Association. They concluded that hydration with sodium bicarbonate before contrast injection was more effective in preventing contrastinduced renal failure than hydration with sodium chloride. A review entitled 'Contrast-Associated Acute Kidney Injury' (126), published in The New England Journal of Medicine, provides more detailed information on the pathophysiology, diagnostic criteria, and risk stratification and prevention of CI-AKI [44]. An article published in the journal Annals of Internal Medicine entitled 'Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy' had the greatest centrality (0.19), indicating a significant impact on other researchers [47]. A citation burst in the cocited literature is a sudden increase in guideline articles over a certain period of time. The 13 most intense bursts of literature were obtained through CiteSpace (Supplementary Figure  2(B)), with the selection criterion of a minimum duration of 6 years. The most bursty reference was Merten's article, which also had the highest number of cocitations. In addition, an article entitled 'Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis' [48] was published in the Annals of Internal Medicine journal and is currently a popular article with a burst from 2016 to 2022.
To reveal research trends and hotspots over time, we drew a timeline view of the cocited literature (Figure 7(B)).
It was clear that cluster #0 was made up of by far the most popular cocited literature; cluster #2 contained the most literature with higher-level bursts; cluster #3 lasted the longest; and clusters #8 and #9 were unlinked to the other clusters, being relatively isolated.

Visual analysis of keywords
Keywords usually reflect the topic and research content of the article. By analyzing the co-occurrence of keywords, we can quickly understand the research focus and research direction in the field of CI-AKI. We used CiteSpace and VOSviewer to construct a keyword cooccurrence network (Figure 8(A,B)). A total of 827 keywords were extracted, among which 150 keywords appeared 30 times or more. Table 7 shows the top 20 keywords. The most frequent keyword was  'contrast-induced nephropathy' (n ¼ 1151), while the keywords with the highest centrality (0.04) were 'computed tomography', 'high-risk patient', 'radiocontrast', 'abdominal aortic aneurysm', 'blood flow', 'high osmolality', 'diabetic nephropathy', and 'fractional flow reserve'. Excluding the conceptual terms related to CI-AKI and some meaningless words, 'percutaneous coronary intervention', 'acute renal failure', 'angiography', 'chronic kidney disease', 'acetylcysteine coronary angiography', 'sodium bicarbonate', 'serum creatinine', and other key words appeared more frequently. This suggests that most of the research on CI-AKI has focused on clinical trials related to risk factors for its onset, high-risk groups, and clinical presentation.
A total of 73 keywords were analyzed among the citation bursts with a duration of 5 years (Supplementary Figure 3). The keyword with the highest burst was 'randomized controlled trial' (37.77). The citations with the longest burst durations were 'nephrotoxicity' and 'clinical trial' (24). The keywords with the longest citation burst durations were 'elevation myocardial infarction', 'multivessel disease', and 'high risk', representing the current hot research topics.

CI-AKI global research quality
This paper is the first to use a bibliometric approach to provide a detailed and comprehensive visual analysis of existing articles in the field of CI-AKI research to provide guidance for future research. Based on our selection criteria, 4775 CI-AKI-related articles were obtained from the WoSCC database, spanning the years 1984-2022. Using CiteSpace software to deduplicate and clean the data, a total of 3570 articles were extracted from 673 research institutions in 83 countries/regions, published in a total of 854 journals. Five types of literature are included: articles, reviews, proceedings, editorial material, and letters. During this nearly 40-year period, the number of publications has been increasing and remains high, indicating rapid growth and continued research interest in the field of CI-AKI. We found that the number of articles exceeded 100 in 2006, 200 in 2010, and 300 in 2014. The sharp rise in the number of articles during this period may be related to the publication of various guides [49][50][51][52][53][54][55][56]. These guideline recommendations and expert consensuses provide guidance for clinical trials and establish diagnostic criteria for CI-AKI that can be used in animal studies.
Analysis of country/regional and institutional distribution helps to facilitate teamwork and global collaboration in a given field. The United States is the clear leader in CI-AKI, with the highest volume of publications, the highest intermediary centrality, and the highest intensity of citation bursts. This may be due to important contributions from research institutions, such as Mayo Clin, Univ Michigan, and Univ Pittsburgh. It is worth noting that the author with the highest total citations, Mehran R, and the most frequently cocited author, Mccullough Pa, are both from the United States. In contrast, China, the second largest country in terms of paper output, has the top two institutions and the top three authors in terms of publication volume. Unfortunately, the centrality of China and the global citations of its articles are low, and there has been no citation explosion. This suggests that China should focus on the quality and global impact of its articles.
The analysis of journals and cocited journals can help researchers to choose the right journal to submit their manuscripts. Among the top ten journals in terms These data indicate that journals related to CI-AKI research have a high impact and are favored. In fact, of the top ten journals in terms of number of articles published in the field of CI-AKI research, only one is in the field of nephrology, and the others are in the cardiovascular and peripheral vascular fields. This suggests that CI-AKIrelated research is more likely to be favored by specialists in the field of circulatory systems.

Current status of CI-AKI research
The main feature of CI-AKI is a decrease in renal function within a few days after intravascular administration of iodine contrast. The definition and diagnostic criteria of CI-AKI have evolved over time. Early on, CI-AKI was referred to as contrast-induced nephropathy (CIN), defined as acute impairment of renal function following exposure to CM, for which other etiologies have been ruled out [57]. Serial measurement of serum creatinine is considered the most practical and sensitive method, and an elevation of 1.0 mg/dL compared to baseline is an accepted diagnostic criterion [58]. In 2012, the KDIGO organization continued the name of CIN with the diagnostic criteria of renal impairment (elevation of serum creatinine above 25% or 44 lmol/L) within 3 days after intravascular contrast injection in the absence of other etiologies [5]. In 2018, ESUR recommended replacing 'CIN' with 'postcontrast acute kidney injury' (PC-AKI) and retaining the term 'CI-AKI' to describe the causal relationship between CM and deteriorating renal function [59]. The latest diagnostic criteria for CI-AKI are an increase in serum creatinine !0.3 mg/dL or !1.5-1.9 times the baseline level within 48-72 h after administration of CM. This guideline is also followed by the French Nephrology societies (SFNDT) and the French Radiological Society (SFR) [60]. Given the clinical value of CI-AKI, guidelines from the clinical departments of nephrology, cardiovascular medicine, and peripheral vasculature are even more important. Notably, a consensus from the American College of Radiology and the National Kidney Foundation pointed out the difference between CA-AKI and CI-AKI [61]. Due to the historical confusion between CA-AKI and CI-AKI, many articles do not make the distinction [62]. CA-AKI is defined as any AKI that occurs within 48 h of the administration of contrast media [63]. It is clear that CI-AKI should be a subset of CA-AKI, as CI-AKI implies a causal relationship between contrast injection and AKI. In clinical practice, however, this correlation vs. causation is not well distinguished, leading to a possible exaggeration of the harm caused by contrast media [61]. It may be that this potential causal relationship can only be established if well-matched controls are included in a study. There is a paucity of this type of article.
The incidence of CI-AKI is related to the contrast agent, the patient's own condition, and the type of procedure. The influence of the contrast agent itself on the incidence of CI-AKI is mainly reflected in cocited literature cluster #9. Lautin et al. [64] found that hypotonic CM reduced CI-AKI to varying degrees compared to hyperosmotic CM. In contrast, hypotonic CM is more toxic than isotonic CM and more likely to cause endothelial dysfunction and disorders of the prothrombin and fibrinolytic systems in ex vivo experiments in rats [65]. In the cocited literature, cluster #4 mainly shows the relevance of underlying diseases for the occurrence of CI-AKI. For example, CKD, diabetes mellitus, congestive heart failure, hypotension, peripheral vascular disease, anemia, and age are all high-risk factors for CI-AKI [31,66,67].
Interestingly, the risk of developing CI-AKI appears to differ by route of administration. In some retrospective studies, CI-AKI caused by intravenous and intra-arterial iodixanol injections was not significantly different and was no more common than after unenhanced CT scans [68][69][70]. However, in a prospective study of patients with suspected coronary artery disease, intravenous contrast for coronary CT imaging produced a lower rate of CI-AKI than arterial contrast for conventional coronary angiography [71]. The intravenous route of administration reduces the concentration of contrast agent delivered to the kidney and avoids microcirculatory embolism from the aorta to the kidney compared to intra-arterial injection [44,72]. For example, patients with ST-segment elevation infarction who undergo PCI are at higher risk of CI-AKI [73]. Wang et al. found that the same dose of contrast agent injected through the renal artery was more significant than that injected through the femoral artery or ear vein in a rabbit CI-AKI model [74]. Cocited literature clusters #0 and #2 are mainly concerned with clinical prevention strategies for CI-AKI. Currently, prophylactic hydration remains an important strategy to protect renal function from intravascular iodine CM, and sodium bicarbonate, saline, N-acetylcysteine, and ascorbic acid are commonly used clinical hydration agents [38][39][40]42,43]. In addition, statins may also prevent the development of CI-AKI [75][76][77]. Interestingly, in cluster #8, it was noted that vasodilator therapy with dobutamine inhibited the occurrence of CI-AKI [78].
The pathophysiological mechanisms of CI-AKI are not fully understood, but direct and indirect cytotoxic effects and hemodynamic alterations remain the main mechanisms of injury [44]. In keyword clusters #0 and #4, the keywords 'oxidative stress' and 'nitric oxide' were associated with pathophysiological mechanisms, while 'cystatin c' and 'gelatinase-associated lipocalin' were relevant markers of injury. Direct toxic effects of CM on renal tubular epithelial cells lead to cell death and dysfunction [22,79]. Indirect effects are mainly related to ischemic-hypoxic injury due to vasodilatory changes mediated by vasoactive substances, such as endothelin, reactive oxygen species, nitric oxide, and prostaglandins [80][81][82][83]. The outer renal medulla has a relatively low partial pressure of oxygen, which when combined with enhanced metabolic demands makes the medulla particularly susceptible to the hemodynamic effects of CM [83][84][85]. In addition, we found that the pathological changes in the peritubular capillaries precede those in the renal tubules in the early stage of CI-AKI, and the related molecular mechanisms are being investigated.

Limitations
In this study, we used CiteSpace and VOSviewer software for visual analysis of the WoSS database and may have missed papers published in other databases. Since the search strategy we created was designed to obtain the most comprehensive data possible, the topics of the included articles may not be highly relevant to CI-AKI. In addition, both software programs cannot obtain information on all authors of articles, cannot distinguish the order of authors, cannot combine different formats of the same author name, and may not evaluate the roles played by researchers in the field with sufficient precision.

Future vision of CI-AKI
Currently, most of the research on CI-AKI is done in clinical trials, while animal models also play an important role in the study of the molecular mechanisms of CI-AKI. Clinical trials play an important role in investigating risk factors, prevention strategies, and treatment options for CI-AKI and should be a hot spot for future research. We believe that research on CI-AKI should adopt a multicentric, multi-institutional model, increase the sample sizes, do longer patient follow-up, and collect the most comprehensive clinical data and laboratory and imaging data possible. In addition, there is a paucity of basic research on clinical specimens. Multiomics analysis of human specimens or single-cell sequencing should be performed in compliance with ethical requirements, which is expected to yield more information on the mechanism of injury.

Conclusion
Based on a visual grid analysis built with CiteSpace and VOSviewer software, we discuss trends emerging from collaborative networks, key clustering, citation bursts, and time-line relationships. Through bibliometric analysis, we find that the main areas of knowledge in the field of CI-AKI research are risk factors for CI-AKI, prevention and treatment strategies, evaluation of the effects of CM, and potential mechanisms of injury. From the keywords and cocited literature, clinical trials are still a popular direction for CI-AKI research today. The progress of research in the field of CI-AKI is explored through a visual analysis of the literature using a bibliometric approach. This method can help researchers visualize the current state of research and future trends. Compared to traditional reviews, bibliometrics has its own unique value but also suffers from a lack of research depth. We are grateful to the development team of CiteSpace and VOSviewer software and hope that they will further optimize the software features to achieve a more accurate and in-depth visual analysis of the research field.

Disclosure statement
No potential conflict of interest was reported by the author(s).