
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12635-7
10.1016/j.heliyon.2024.e36604
e36604
Review Article
Immune-inflammatory process in nephrolithiasis: A bibliometric analysis (2000–2023)
Wang Yunhan 1
Dong Caitao 1
Jiang Qinhong
Liao Wenbiao liaowenbiao@whu.edu.cn
⁎⁎
Yang Sixing sxyang@whu.edu.cn
⁎
Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China
⁎ Corresponding author. sxyang@whu.edu.cn
⁎⁎ Corresponding author. liaowenbiao@whu.edu.cn
1 Yunhan Wang and Caitao Dong contributed equally to this work and should be considered co-first authors.

20 8 2024
30 8 2024
20 8 2024
10 16 e3660420 1 2024
18 8 2024
19 8 2024
© 2024 The Authors. Published by Elsevier Ltd.
2024

https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
The research on the mechanism of nephrolithiasis formation is of great importance due to the fact that the high incidence and recurrence rate of nephrolithiasis bring considerable economic burdens to patients and society. As an important component in the nephrolithiasis formation process, the immune-inflammatory process has been gradually valued by researchers in recent years. In this study, articles related to the immune-inflammatory process of nephrolithiasis published since 2000 were retrieved based on the Web of Science (WoS) database. Eventually, a total of 370 articles were selected for subsequent analyses. Besides, VOSviewer, CiteSpace, and Bibliometrix were employed to quantitatively analyze and visualize the data. The number of articles related to the immune-inflammatory process of nephrolithiasis has increased rapidly in the last five years. From the country level, most articles were contributed by China (n = 140) and the United States (n = 99) contributed the most documents. From the institution level, University of Florida (n = 36) and Nagoya City University (n = 21) had the most articles. From the journal level, Journal of Urology and Urolithiasis published the most articles in this field. Keywords mainly included inflammation, oxidative stress, calcium oxalate, osteopontin, and hyperoxaluria, which represented the research directions in this field. The most productive author was Khan SR (n = 33), whose articles obtained the highest number of citations (2086 times). These efforts may help researchers understand the current progress and status of research on the immune-inflammatory process of nephrolithiasis and identify future research hotspots and directions.

Keywords

Nephrolithiasis
Inflammation
Immune
Bibliometric analysis
==== Body
pmc1 Introduction

As a common urological disease, nephrolithiasis is increasingly prevalent worldwide [1]. The high incidence and recurrence rate of nephrolithiasis in China contribute to high treatment costs [2], posing a considerable economic burden to patients and society. Therefore, there is an urgent demand for clarifying the pathophysiological mechanism of nephrolithiasis. It has been demonstrated that the formation of nephrolithiasis is related to oxidative stress, immune-inflammation, and osteoblast-like events [[3], [4], [5], [6], [7]]. The proteomic analysis of kidney tissue, urine, and stone matrix in patients with nephrolithiasis reveals numerous proteins associated with the immune-inflammatory process [[8], [9], [10], [11]]. Besides, the high-calcium urine environment has been found to promote the transformation of renal tubular epithelial-osteoblast cells and the deposition of calcium crystals, thus leading to nephrolithiasis formation through the regulation of the ROS/NF-κB/MMP-9 axis [12]. Additionally, the infiltration and polarization of macrophages in the development of nephrolithiasis have been confirmed in recent studies [7,13,14]. Researchers have also found that up-regulating the Nrf2/HO-1 pathway can inhibit oxidative stress damage and promote macrophage polarization, thereby alleviating the inflammatory response and reducing crystal deposition [[15], [16], [17], [18]]. Recent research has focused more attention on the immune-inflammatory process of nephrolithiasis, which is worthy of further investigation. However, the focus of most existing studies is placed on the injuries to renal tubular epithelial cells, epithelial-osteoblast transformation, redox-dependent signaling pathways, and polarization and phagocytic activity of macrophages [[19], [20], [21]]. In addition, accumulating articles for publication have posed many obstacles for researchers, especially novice researchers, to completely comprehend, assess, and pinpoint the most important and pertinent data. Further, it is difficult to clarify the most recent research foci and trends in this field due to the intricate interplay between oxidative stress and immune-inflammation signaling pathways. Therefore, identifying the key triggering factors in the immune-inflammation cascade reaction is crucial for investigating the precise pathogenesis of nephrolithiasis and exploring novel therapeutic targets. Hence, it is required to establish new examination and analysis approaches in this field.

In this study, a bibliometric analysis was performed to investigate the role of the immune-inflammatory process in nephrolithiasis, and visual maps were utilized to illustrate relevant data and information. This analysis may realize the quantitative evaluation of the impact of researchers, research institutions, countries and regions, and journals in the field [[22], [23], [24]]. In addition, the co-citation analysis, co-authorship analysis, and keyword co-occurrence analysis were adopted in this study. Overall, this study elucidated a review of the current research and scientific achievements, identified potential research hotspots and directions, proposed current research trends, and summarized the past and future research processes.

2 Materials and methods

2.1 Data collection and cleaning

In this study, the documents related to the immune-inflammatory process of nephrolithiasis were retrieved based on the Web of Science Core Collection (WoSCC) Science Citation Index Expanded (SCI-Expanded) on October 11, 2023. To ensure that all relevant documents that met the requirements can be included, the search formula was defined as (TS = (cytokine* or inflamma* or immun* or macrophage) AND TS = (urolithiasis or nephrolithiasis or ureterolithiasis or (kidney NEAR/0 stone) or (urinary NEAR/0 calculi) or (urinary NEAR/0 stone) or (kidney NEAR/0 calculi)) AND (LA = English)). All articles and reviews published from January 1, 2000 to October 11, 2023 were selected. Eventually, a total of 1489 documents were collected. To make the collected documents as relevant as possible to the research topic and make the data more accurate and meaningful, we manually screened the searched documents. We focus on the immune-inflammatory process of the pathogenesis of nephrolithiasis. Some documents only provide a simple overview of the immune-inflammatory process in nephrolithiasis, without further experimentation and discussion. Some other documents mainly describe the systemic inflammatory response or the immune-inflammatory process of extrarenal systems in nephrolithiasis patients, without discussing the immune-inflammatory process of nephrolithiasis occurring in the kidneys. According to the screening process shown in Fig. 1, 370 documents that met the criteria were finally obtained, and relevant data were downloaded on the same day to avoid bias.Fig. 1 Flowchart for including and excluding documents study on the immune-inflammatory process of nephrolithiasis from January 1, 2000 to October 11, 2023.

Fig. 1

2.2 Bibliometric analysis

R (version 4.3.1) is a language and environment specifically designed for the computation and visualization of statistical data [25,26]. Open source R tool Bibliometrix analyzes scientific literature in a comprehensive way, integrating with other statistical and graphical packages [27]. In this study, the "bibliometrix" package was applied to the collection and processing of the data and the contribution analysis of authors and keywords. Data were collected, processed, and visualized simultaneously using VOSviewer [28] and CiteSpace [29]. VOSviewer can be employed to generate a collaborative network of authors, journals, institutions, and nations/regions. The number of documents and citations can be considered common bibliometric indicators to gauge the output and impact of published documents. It should be mentioned that the citation analysis makes use of the total number of times an article appears in the WOS database that another article has cited it. In this study, the number of times an article appeared in the documents from the screening was used in the co-citation analysis. To depict the relationship between citing and cited journals, a dual-map overlay of journals with respect to category was generated using CiteSpace. Additionally, CiteSpace could identify the 25 references that had the largest bursts of citations, which suggested that these documents had received much attention at a particular time. Moreover, a cluster analysis of co-cited references was also carried out. Fig. 1 was created using Figdraw. The content was created using Microsoft Excel/Word for Mac (version 16.84).

3 Result

3.1 The documents' annual publication trend

As shown in Fig. 2, there was a modest annual publication volume between 2000 and 2017 despite a sluggish increasing trend in the number of articles about the immune-inflammatory process of nephrolithiasis. The number of documents on the immune-inflammatory process of nephrolithiasis has expanded rapidly since 2018. This suggested that researchers had begun to value the immune-inflammatory mechanism in nephrolithiasis from that year. Since the records only lasted until October 2023, it can be predicted that the number of documents this year may continue to rise. Nevertheless, the low level of published studies each year serves as a reminder that there is still a dearth of knowledge regarding the immune-inflammatory mechanism underlying nephrolithiasis.Fig. 2 Annual global publication count of documents on the immune-inflammatory process of nephrolithiasis from 2000 to 2023.

Fig. 2

3.2 Contributions of countries and regions

England, Northern Ireland, Wales, and Scotland were all designated as the United Kingdom for statistical convenience. Taiwan (China) and the People's Republic of China were both referred to as the People's Republic of China. Most of the documents on the immune-inflammatory process in nephrolithiasis originated from Asia, North America, and Europe. Fig. 3A displays a global map illustrating the extent of collaboration between countries and regions, with the size of nodes denoting the number of articles. The line's thickness indicated the extent of collaboration between countries and regions and the strength of the relationship. The United States (n = 42) had the closest cooperation with various countries, followed by China (n = 21). Based on the number of articles, ten countries were ranked (Table 1). In terms of total citations, the United States led the field (99 documents, 3922 times), though it had a lower proportion of documents (26.76 %). Although China was the country with the largest proportion of documents (37.84 %), it ranked second in terms of total citations (140 documents, 1732 times). Of note, the Netherlands (92.33) ranked first in the average citations per document (i.e., citations/n). This demonstrated that even though there were relatively fewer published documents from this country, these studies were quite valuable. Fig. 3B shows the graphical analysis of international collaboration between countries and regions on the time dimension. Japan and the United States began international cooperative research on this subject sooner than China.Fig. 3 Countries and regions contribution graph for nephrolithiasis studies on the immune-inflammatory process. A. Global map showing the degree of cooperation among countries and regions. B. The visualization network of international cooperation, where the nodes represent the quantity of published documents, and the color denotes the average year that a nation engages in active cooperation with other nations.

Fig. 3

Table 1 The top ten countries and regions with the largest number of documents publications.

Table 1Rank	Country	Documents (n)	Percentage (n/370)	Total link strength	Citations	Average citations per document	
1	China	140	37.84 %	21	1732	12.37	
2	United States	99	26.76 %	42	3922	39.62	
3	Japan	39	10.54 %	11	1385	35.51	
4	India	21	5.68 %	7	167	7.95	
5	Thailand	21	5.68 %	2	562	26.76	
6	Germany	14	3.78 %	11	497	35.50	
7	Turkey	13	3.51 %	0	380	29.23	
8	Italy	10	2.70 %	5	285	28.50	
9	Netherlands	9	2.43 %	7	831	92.33	
10	United Kingdom	8	2.16 %	11	88	11.00	

3.3 Analysis of institutions

A total of 443 different institutions have made contributions to the body of knowledge regarding the immune-inflammatory process of nephrolithiasis. In Table 2, the top 10 institutions are ranked by the number of documents they have published. The universities that supplied the most documents included University of Florida (36 documents, 9.73 %), Nagoya City University (21 documents, 5.68 %), Mahidol University (17 documents, 4.59 %), Huazhong University of Science and Technology (17 documents, 4.59 %), and Guangxi Medical University (13 documents, 3.51 %). The University of Florida took a leading position in both the number of citations (2212 times) and average citations per document (61.44), followed by Nagoya City University (855 times, 40.71). This indicated that these universities preserved high productivity levels while maintaining the caliber of their research (Fig. 4A). Moreover a visual examination was also performed on the level of cooperation of these institutions (Fig. 4B). The number of publications is represented by nodes, and cooperative links are shown by lines. Indiana University School of Medicine exhibited the highest total link strength (TLS = 27), a sign of close collaboration with other academic institutions. Of note, there was a tendency for cooperation among institutions, and those with close cooperation were clustered and identified by color in the figure (Fig. 4B).Table 2 The top 10 institutions with the highest number of publications and total link strength.

Table 2Rank	Institution	Country	Documents (n)	Percentage (n/370)	Citations	Citations/n	Institution	Total link strength	
1	University of Florida	United States	36	9.73 %	2212	61.44	Indiana University School of Medicine	27	
2	Nagoya City University	Japan	21	5.68 %	855	40.71	Huazhong University of Science and Technology	24	
3	Mahidol University	Thailand	17	4.59 %	411	24.18	Guangzhou Medical University	21	
4	Huazhong University of Science and Technology	China	17	4.59 %	263	15.47	The University of Chicago	19	
5	Guangxi Medical University	China	13	3.51 %	209	16.08	University of Florida	19	
6	Wuhan University	China	10	2.70 %	51	5.10	Kunming Medical University	17	
7	Indiana University School of Medicine	United State	9	2.43 %	284	31.56	Indiana University School of Medicine	14	
8	Tyumen State Medical Academy	Russia	9	2.43 %	155	17.22	Klinikum der Universität München	14	
9	Guangzhou Medical University	China	8	2.16 %	111	13.88	Mayo clinic	14	
10	Anhui Medical University	China	8	2.16 %	102	12.75	New York University	14	

Fig. 4 Institutional contribution graph for nephrolithiasis studies on the immune-inflammatory process. A. Density plot of the number of documents. The brighter area indicates a larger number of documents. B. Visual network for inter institution cooperation. Nodes represent the number of documents and the color of the line and node indicated the cluster to which it belonged.

Fig. 4

3.4 Analysis of journals

A total of 160 academic journals have published documents related to the immune-inflammatory process in nephrolithiasis since 2000. The number of publications determines the journals' ranking (Table 3). The journals with the largest number of documents included Urological Research (n = 19), Journal of Urology (n = 19), and Urolithiasis (n = 19). It should be mentioned that Urolithiasis was formerly published as Urological Research, indicating the significance of this field in Urolithiasis. Frontiers in Immunology (n = 14) and American Journal of Physiology-Renal Physiology (n = 11) ranked fourth and fifth, respectively, in terms of documents (Table 3). Kidney International had the greatest impact factor (IF = 19.6 in 2022) among these 10 journals. Journal of Urology (1096 times) exhibited the largest number of citations. Journal of the American Society of Nephrology (96.86), Kidney International (59.71), and Journal of Urology (57.68) were the top three journals with the highest number of average citations per document (Table 3). Additionally, a co-citation analysis was also conducted on these included journals (Fig. 5A). Kidney International received the largest number of co-citations (1196 times), followed by Journal of Urology (944 times) and Journal of the American Society of Nephrology (759 times). Researchers exploring the immune-inflammatory mechanism of nephrolithiasis may find these three journals to be of greatest assistance.Table 3 The top 10 journals with the highest number of documents and co-citations.

Table 3Rank	Journals	Documents (n/370)	Citations	Citations/n	2022 IF	2022 JCR	Co-cited journals	Co-citations	2022 IF	2022 JCR	
1	Journal of Urology	19 (5.14 %)	1096	57.68	6.6	Q1	Kidney International	1196	19.6	Q1	
2	Urolithiasis	19 (5.14 %)	159	8.37	3.1	Q2	Journal of Urology	944	6.6	Q1	
3	Urological Research	19 (5.14 %)	773	40.68	3.1	Q2	Journal of the American Society of Nephrology	759	13.6	Q1	
4	Frontiers in Immunology	14 (3.78 %)	202	14.43	7.3	Q1	Urological Research	725	3.1	Q2	
5	American Journal of Physiology-Renal Physiology	11 (2.97 %)	300	27.27	4.2	Q1	American Journal of Physiology-Renal Physiology	419	4.2	Q1	
6	Oxidative Medicine and Cellular Longevity	10 (2.70 %)	178	17.80	7.31 (2021)	Q2 (2021)	Journal of Biological Chemistry	338	4.8	Q2	
7	BJU International	7 (1.89 %)	215	30.71	4.5	Q1	Urolithiasis	310	3.1	Q2	
8	Journal of the American Society of Nephrology	7 (1.89 %)	678	96.86	13.6	Q1	Journal of Clinical Investigation	285	15.9	Q1	
9	Kidney International	7 (1.89 %)	418	59.71	19.6	Q1	Nephrology Dialysis Transplantation	268	6.1	Q1	
10	PLoS One	7 (1.89 %)	172	24.57	3.7	Q2	American Journal of Kidney Diseases	255	13.2	Q1	

Fig. 5 Journal contribution graph for nephrolithiasis studies on the immune-inflammatory process. A. Visualization of journal network based on co-citation. Nodes represent the number of co-citations and the color of the line and node indicated the cluster to which it belonged. B. The dual-map overlay of journals on the research of immune-inflammatory process in nephrolithiasis. The colored path indicates the citation relationship, with the citing journals on the left and the cited journals on the right.

Fig. 5

Moreover, the data were analyzed using a dual-map overlay of journals concerning categories (Fig. 5B). This analytical technique may provide a deeper understanding of the reciprocal influence of the data sources and knowledge conclusions. In the dual map, there are four paths that connect the left and right portions. The left portion shows the citing journals, and these documents are primarily published in journals dealing with medicine, medical, and clinical trials. The right portion shows the documents that have been cited, showing that the majority of the frequently cited documents have been published in journals related to nursing, medicine, and health. With the assistance of this dual-map, which offered a thorough overview of the relationships between journals on the immune-inflammatory process of nephrolithiasis, researchers could find possible areas of cooperation and additional study prospects.

3.5 Analysis of authors

Based on the citation counts, the authors who studied the immune-inflammatory process in nephrolithiasis were also ranked (Table 4). Khan SR had the highest number of citations (2086 times), with Yasui T (933 times), Okada A (886 times), Kohri K (864 times), and Tozawa K (804 times) following in that order. Khan SR submitted 33 documents and was also the most productive author, followed by Yasui T (n = 22), Okada A (n = 20), Kohri K (n = 19), and Tozawa K (n = 17). In addition, a co-citation analysis was conducted on these authors (Fig. 6A). The most co-citations were attributed to Khan (827 times), Umekawa T (181 times), Taguchi K (162 times), Okada A (157 times), and Evan AP (155 times). A high number of co-citations suggests that the author is deeply involved in research on the immune-inflammatory process of nephrolithiasis. It also indicates that the author's work is widely recognized by most researchers in this field. H-index can be used to measure scholars' influence in this field. Khan SR, Thongboonkerd V, and Kohri K had the highest H-index, indicating they may have a higher academic output and impact (Table 4). Hence, it is possible to clarify the guidance and direction of relevant research by looking at the study of notable academics with the highest productivity or citations. Furthermore, a network related to author collaboration analyses was plotted in this study, which included 120 authors, with at least 3 published documents for each (Fig. 6B). The collaboration among authors can be roughly categorized into 9 clusters, indicating a clear tendency for cooperation among authors.Table 4 Top 10 authors with the highest number of citations and co-citations.

Table 4Rank	Author	Documents (n)	Citations	H-index	Co-cited author	Co-citations	
1	Khan SR	33	2086	55	Khan SR	827	
2	Yasui T	22	933	34	Umekawa T	181	
3	Okada A	20	886	36	Taguchi K	162	
4	Kohri K	19	864	47	Okada A	157	
5	Tozawa K	17	804	31	Evan AP	155	
6	Hamamoto S	16	600	26	Mulay Shrikant R	150	
7	Taguchi K	14	414	21	Lieske JC	118	
8	Thongboonkerd V	16	408	48	de Water R	114	
9	Deng Yaoliang	12	193	18	Thamilselvan S	95	
10	Guo Zhiyong	10	162	15	Coe FL	81	

Fig. 6 Author contribution graph for nephrolithiasis studies on the immune-inflammatory process. A. Visualization graph of author network based on co-citations. Nodes represent the times of co-citations and the color of the line and node indicated the cluster to which it belonged. B. Visual network for inter author cooperation. Nodes represent the number of documents and the color of the line and node indicated the cluster to which it belonged.

Fig. 6

3.6 Analysis of citation and co-citation

The collected documents were sorted by the number of citations, as shown in Table 5. The Multiple Functions and Mechanisms of Osteopontin (278 times) was the document with the largest number of citations, followed by Reactive Oxygen Species as the Molecular Modulators of Calcium Oxalate Nephrolithiasis Formation: Evidence from Clinical and Experimental Investigations (233 times) and Osteopontin is a critical inhibitor of calcium oxalate crystal formation and retention in renal tubules (228 times).Table 5 The top 10 most cited documents on the immune-inflammatory process of nephrolithiasis.

Table 5Rank	Title	First author	Journal	Year	Citations	DOI	Main conclusion	
1	The multiple functions and mechanisms of osteopontin	Icer MA	CLIN BIOCHEM	2018	278	https://doi.org/10.1016/j.clinbiochem.2018.07.003	OPN can regulate interleukin-10 (IL-10), interleukin-12 (IL-12), interleukin-3 (IL-3), and interferon-γ (IFN-γ), integrin α VB3, nuclear factor kappa B (NF-kB), regulates the secretion levels of macrophages and T cells, regulates the function of osteoclasts, and affects CD44 receptors.	
2	Reactive Oxygen Species as the Molecular Modulators of Calcium Oxalate Kidney Stone Formation: Evidence from Clinical and Experimental Investigations	Khan SR	J UROLOGY	2013	233	https://doi.org/10.1016/j.juro.2012.05.078	They hypothesized that localized OS induced inflammation resulting from interstitial CaP deposition in the renal papillae promotes fibrosis and collagen formation. Collagen mineralization promotes CaP propagation and RP growth. Antioxidants and anti-inflammatory therapy may impede RP growth and inhibit stone recurrence.	
3	Osteopontin is a critical inhibitor of calcium oxalate crystal formation and retention in renal tubules	Wesson JA	J AM SOC NEPHROL	2003	228	https://doi.org/10.1097/01.ASN.0000040593.93815.9D	Animal experiments have shown that osteopontin (OPN) can inhibit the formation and retention of calcium oxalate (CaOx) crystals. This supports the role of OPN in renal protection.	
4	Modulators of urinary stone formation	Khan SR	FRONT BIOSCI-LANDMRK	2004	211	https://doi.org/10.2741/1347	The effects of various regulators on calcium oxalate crystallization have been studied, including glycoproteins and glycosaminoglycans, Nephrocalcin, Tamm-Horsfall protein, osteopontin, urinary prothrombin fragment 1, bikunin, chondroitin sulfate, heparan sulfate and hyaluronic acid. It was found that there is a close relationship between inflammation and kidney stones.	
5	Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy	Preitner F	P NATL ACAD SCI USA	2009	184	https://doi.org/10.1073/pnas.0904411106	Glut9 plays a major role in urate homeostasis by its dual role in urate handling in the kidney and uptake in the liver.	
6	Uromodulin: from physiology to rare and complex kidney disorders	Devuyst O	NAT REV NEPHROL	2017	169	https://doi.org/10.1038/nrneph.2017.101	Through the study of the role of uromodulin in biochemistry, physiology, genetics, and pathology, it has been found that the UMOD gene encoding uromodulin is related to a series of rare and common kidney diseases, such as autosomal dominant tubulointerstitial kidney disease (ADTKD) and kidney stones.	
7	Calcium Oxalate Crystal Adherence to Hyaluronan-, Osteopontin-, and CD44-Expressing Injured/Regenerating Tubular Epithelial Cells in Rat Kidneys	Asselman M	J AM SOC NEPHROL	2003	169	https://doi.org/10.1097/01.ASN.0000099380.18995.F7	Calcium oxalate crystals in urine can adhere to damaged/regenerated renal tubular epithelial cells. These cells express hyaluronan (HA), osteopontin (OPN), and CD441, which seem to play a role in crystal retention in the kidneys.	
8	Hyperoxaluria-induced oxidative stress and antioxidants for renal protection	Khan SR	UROL RES	2005	155	https://doi.org/10.1007/s00240-005-0492-4	Hyperoxaluria can lead to the production of reactive oxygen species (ROS), causing oxidative stress, damage, and inflammation. Antioxidants and free radical scavengers can reduce the damage caused by Ox/CaOx crystals.	
9	Preventive effects of green tea on renal stone formation and the role of oxidative stress in nephrolithiasis	Itoh Y	J UROLOGY	2005	127	https://doi.org/10.1097/01.ju.0000141311.51003.87	Green tea has potential effects in preventing the formation of kidney stones, and its mechanism of action is related to anti-oxidative stress.	
10	Crystal nephropathies: mechanisms of crystal-induced kidney injury	Mulay SR	NAT REV NEPHROL	2017	111	https://doi.org/10.1038/nrneph.2017.10	The authors proposed a classification of crystal nephropathy based on the deposition location of the crystals in the renal vasculature (Type 1), renal unit (Type 2), or excretory urinary tract (Type 3). Further exploration of the molecular mechanisms of crystal-induced renal injury and renal remodeling may help develop innovative treatments for these diseases.	

There were 11,589 references cited in these 370 documents. A co-citation analysis of these references revealed that the most frequently co-cited reference was Reactive Oxygen Species as the Molecular Modulators of Calcium Oxalate Nephrolithiasis Formation: Evidence from Clinical and Experimental Investigations (66 times), followed by Reactive oxygen species, inflammation and calcium oxalate nephrolithiasis (55 times) and Crystal-induced inflammation of the kidneys: results from human studies, animal models, and tissue-culture studies (54 times), all three of which were submitted by Khan SR (Table 6).Table 6 The top 10 documents with the highest number of co-citations related to the immune-inflammatory process of nephrolithiasis.

Table 6Rank	Title	First author	Journal	Year	Citations	DOI	
1	Reactive Oxygen Species as the Molecular Modulators of Calcium Oxalate Kidney Stone Formation: Evidence from Clinical and Experimental Investigations	Khan SR	J UROLOGY	2013	66	https://doi.org/10.1016/j.juro.2012.05.078	
2	Reactive oxygen species, inflammation and calcium oxalate nephrolithiasis	Khan SR	TRANSL ANDROL UROL	2014	55	https://doi.org/10.3978/j.issn.2223-4683.2014.06.04	
3	Crystal-induced inflammation of the kidneys: results from human studies, animal models, and tissue-culture studies	Khan SR	CLIN EXP NEPHROL	2004	54	https://doi.org/10.1007/s10157-004-0292-0	
4	Kidney stones	Khan SR	NAT REV DIS PRIMERS	2016	53	https://doi.org/10.1038/nrdp.2016.8	
5	Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion	Mulay SR	J CLIN INVEST	2013	52	https://doi.org/10.1172/jci63679	
6	Renal macrophage migration and crystal phagocytosis via inflammatory-related gene expression during kidney stone formation and elimination in mice: Detection by association analysis of stone-related gene expression and microstructural observation	Okada A	J BONE MINER RES	2010	51	https://doi.org/10.1002/jbmr.158	
7	Oxalate ions and calcium oxalate crystals stimulate MCP-1 expression by renal epithelial cells	Umekawa T	KIDEY INT	2002	46	https://doi.org/10.1046/j.1523-1755.2002.00106.x	
8	Randall's plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle	Evan AP	J CLIN INVEST	2003	43	https://doi.org/10.1172/jci200317038	
9	Calcium oxalate nephrolithiasis: Effect of renal crystal deposition on the cellular composition of the renal interstitium	de Water R	AM J KIDNEY DIS	1999	42	https://doi.org/10.1016/s0272-6386(99)70231-3	
10	Successful formation of calcium oxalate crystal deposition in mouse kidney by intraabdominal glyoxylate injection	Okada A	UROL RES	2007	40	https://doi.org/10.1007/s00240-007-0082-8	

Using CiteSpace, 25 references with the strongest citation bursts from 2000 to 2023 were obtained, indicating a surge in citations for these documents during a certain period (Fig. 7A). The highest burst strength was observed in Khan SR's Reactive Oxygen Species as the Molecular Modulators of Calcium Oxalate Nephrolithiasis Formation: Evidence from Clinical and Experimental Investigations (strength = 11.67), followed by Khan SR's Reactive oxygen species, inflammation and calcium oxalate nephrolithiasis (strength = 10.73) and Mulay SR's Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion (strength = 10.64). Such clusters as “crystal-induced kidney injury/pyroptosis/inflammation”, “renal epithelial cell”, and “calcium stone formation” were found in the cluster visualization analysis of references with the aid of Citespace (Fig. 7B).Fig. 7 Reference contribution graph for nephrolithiasis studies on the immune-inflammatory process. A. Twenty-five references with the strongest citation bursts. B. Cluster network diagram of co-cited references for the study of immune-inflammatory process in nephrolithiasis, with darker colors indicating earlier time.

Fig. 7

3.7 Analysis of keywords

The hotspots of immune-inflammatory research in nephrolithiasis were tracked by analyzing the keywords. The keyword visualization analysis was performed with the aid of VOSviewer (Fig. 8A), and it can be intuitively found that the lighter nodes and lines indicated that these keywords represented the recent research direction of scholars. Besides, the trend topics were analyzed by bibliometrix. After some common words were filtered out, inflammation (106), oxidative stress (94), calcium oxalate (82), and osteopontin (73) appeared most frequently (Table 7). The words with the longest time span included inhibitor (2007–2022), identification (2003–2018), monohydrate (2006–2021), Tamm-Horsfall protein (2003–2017), and angiotensin-ii (2005–2019) (Fig. 8B).Fig. 8 Keyword contribution graph for nephrolithiasis studies on the immune-inflammatory process. A. Keyword co-occurrence analysis network, where nodes represent the frequency of keyword occurrences, and colors represent the average year of keyword occurrence. B. Theme word trend chart, with node size representing frequency and lines representing time span.

Fig. 8

Table 7 The top 20 keywords with the highest number of co-occurrences on the immune-inflammatory process of nephrolithiasis.

Table 7Rank	Keyword	Co-occurrences	Total link strength	
1	nephrolithiasis	158	1093	
2	inflammation	106	713	
3	oxidative stress	94	667	
4	expression	84	639	
5	calcium oxalate	82	658	
6	urolithiasis	82	535	
7	osteopontin	73	593	
8	kidney	64	464	
9	hyperoxaluria	55	431	
10	disease	46	320	
11	injury	45	330	
12	kidney stone	44	278	
13	oxalate	43	343	
14	cells	40	248	
15	epithelial-cells	40	352	
16	kidney-stones	35	218	
17	apoptosis	33	239	
18	stone formation	32	245	
19	kidney stones	28	217	
20	renal epithelial-cells	26	223	

4 Discussion

Nephrolithiasis is a prevalent disease affecting the urinary system with a high incidence and recurrence rate. Relevant studies on nephrolithiasis have been performed for almost a century. However, the formation process of nephrolithiasis has not been fully clarified. The goal of these studies is to identify the critical nodes that are pivotal in nephrolithiasis formation. However, it is evident that different circumstances and dimensions may contribute to the development of nephrolithiasis. The inflammation accompanied by nephrolithiasis can be an upstream pathogenic factor, or it can be a complication of nephrolithiasis as a downstream event. To comprehend the state of research in this field, identify potential research hotspots, and explore future paths for nephrolithiasis research, a bibliometric analysis of the immune-inflammatory process on nephrolithiasis was performed in this study.

The overall number of documents related to the immune-inflammatory process of nephrolithiasis from 2000 to 2023 is relatively small, with no more than 16 documents published each year before 2017. There is a lack of breakthrough discoveries in the involvement of the immune-inflammatory process in the development mechanism of nephrolithiasis. With a deeper understanding of the etiology of nephrolithiasis, researchers gradually begin to explore this field. The amount of publications has grown dramatically since 2018 when compared to previous years, continuing the trend of steady development to the present day. This suggests that during the next few years, research in this field may enter a golden period.

The United States came second in terms of the total number of documents published after accounting for the contributions of other countries and regions. However, it possessed the highest TLS and the greatest number of citations. This suggested the documents published by the United States may have higher quality. Besides, the United States collaborated most closely with other countries and regions and took a dominant position from the perspective of research quality. This contributed to the research cooperation on the immune-inflammatory mechanism of nephrolithiasis in various countries and regions. Nevertheless, China had the greatest quantity of documents, the average citations per document was only 12.37. At present, the policymakers in China also recognize the problem and are formulating a series of policies to raise the caliber of scholarly publications.

United States' University of Florida came in first place among the top ten most productive universities. From the perspective of journal contributions, Journal of Urology, Urolithiasis, Urological Research, Journal of the American Society of Nephrology and Kidney International may be the central journals within the domain of the immune-inflammatory process in nephrolithiasis. Certain institutions and journals have taken a leading role in terms of academic contributions and impacts. This could provide valuable references for researchers when choosing partners and journals to publish their research results. Keeping track of authors who rank high can not only aid in analyzing the current research status and trends but also facilitate the reflection and contemplation of past research findings in the field of the immune-inflammatory process in nephrolithiasis.

The analysis of references and keywords provided us with past and current research trends and hotspots. Among them, the part that oxidative stress and immune-inflammation play in the development of calcium oxalate stone formation was summarized in Khan SR's Reactive Oxygen Species as the Molecular Modulators of Calcium Oxalate Nephrolithiasis Formation: Evidence from Clinical and Experimental Investigations published in 2013 [30]. Antioxidants and anti-inflammatory therapies may hinder Randall's plaques growth and inhibit stone recurrence. Meanwhile, it is speculated that local OS induced by calcium phosphate (CaP) deposition in renal papillary interstitium induces inflammation and promotes fibrosis and collagen formation. Besides, collagen mineralization promotes CaP proliferation and RP growth. After excluding conventional keywords in the keyword analysis, inflammation, oxidative stress, calcium oxalate (CaOx), osteopontin (OPN), and hyperoxaluria appeared most frequently. OPN is a mineralization regulator/inhibitor, which first inhibits crystals and attracts monocytes/macrophages to eliminate crystals after stone formation [31,32], Further, OPN acts as a protective mediator to inhibit nephrolithiasis. However, if the conditions promoting crystal formation persist, continuous crystal formation will cause local inflammatory damage. Macrophages are essential to this procedure. Monocytes differentiate into M1 macrophages and M2 macrophages, respectively, which can induce inflammation, phagocytize crystals, and exert anti-adhesion effects [33,34]. Moreover, the overexpression of the Sirtuin 1 protein encourages macrophage polarization towards the M2 phenotype, which can reduce CaOx crystal deposition [16]. The formation process of stones is affected by many crystallization regulators/inhibitors. These regulators/inhibitors are regulated by reactive oxygen species (ROS), thus affecting the nucleation, growth, aggregation, and retention of crystals. Almost all molecules considered as crystallization inhibitors/regulators are related to the inflammatory process [30], and they are produced through redox-dependent signaling pathways. However, it is necessary to identify whether these macromolecules directly contribute tothe development of CaOx stones as upstream factors or whether they are by-products of the stone formation process. To support the causal relationship of immune responses and inflammation participation in the pathophysiological development of CaOx stones, relevant mechanistic investigations need to be carried out from a more thorough prospective.

As keywords closely related to the etiology of calcium oxalate stones, calcium oxalate and hyperoxaluria have been proposed by scholars for the long term, and they may be related to the damage of renal tubular epithelial cells (RTECs). The development of CaOx nephrolithiasis is significantly influenced by the RTEC-crystal reaction [35]. Reactive oxygen species are produced when the RTEC-crystal reaction-mediated inflammation causes renal cell inflammatory damage and increases NADPH oxidase expression [30,31,36]. Reactive oxygen species have the ability to activate caspase-1, recruit the ASC protein, and activate the NLRP3 inflammasome. This can lead to the release and maturation of inflammatory proteins like IL-18 and interleukin (IL)-1β [37]. Meanwhile, excessive ROS generation triggers the NF-κB signaling cascade, which induce inflammation and leading to RTEC degeneration, injury, and shedding, as well as the exposure of the basement membrane. This enables the environment in the renal tubular lumen to contribute to the aggregation of crystals, eventually resulting in the creation of CaOx nephrolithiasis [38,39]. The aforementioned process involves a multitude of cytokines and inflammatory substances that set off an inflammatory cascade reaction. This reaction promotes the aggregation, nucleation and growth of crystals, finally culminating in the formation of intrarenal crystals and stones. Overall, the activation of NF-κB and NLRP3/ASC/caspase 1/IL-1β is an important pathway for oxalate-related adverse inflammatory responses, and it is expected to become an anti-inflammatory treatment aim for the treatment and prevention of nephrolithiasis. It has been demonstrated that anti-IL-1β therapies can treat acute gout attacks and may even raise glomerular filtration rates in gout-affected patients with severe chronic kidney disease [40,41]. Therefore, the production and recurrence of stones may be reduced by inhibiting the NLRP3 upstream, reducing the release of inflammatory factors, and alleviating the inflammatory damage mediated by RTEC-crystal reactions. Additionally, it is also crucial to identify the right timing for anti-inflammatory treatment. Can one or more biomarkers be identified in urine to indicate the immune-inflammatory process of nephrolithiasis in the future? This may contribute to applying anti-inflammatory therapies to patients based on the developmental stage of stones, thus preventing nephrolithiasis or inhibiting their further growth. A recent study on the spatially anchored transcriptomic atlas of human renal papilla reveals that two matrix metalloproteinase molecules, namely MMP7 and MMP9, are identified as urinary biomarkers involved in nephrolithiasis and mineral deposition [42]. Future research is needed to identify other urinary markers and their utility in the treatment of patients with nephrolithiasis.

In conclusion, a bibliometric analysis was conducted on the documents related to the immune-inflammatory process of nephrolithiasis since 2000. Recent global publication trends indicate a growing acknowledgment among researchers regarding the significance of the immune-inflammatory mechanism in nephrolithiasis. Nonetheless, there is a pressing requirement for more innovative studies to pave new research pathways in this field. China has published the most documents in the field of the immune-inflammatory process in nephrolithiasis. In contrast, the United States is a major player in this field of study. Meanwhile, the journal contributions, article citation and co-citation contributions, and keyword contributions in this field were also elucidated based on this study. These results can give researchers insight into the current research state and potential hotspots, which may aid in the evaluation of the trends and advancements in this subject. However, there are still some limitations to consider. Firstly, manual and subjective filtering procedures might impede the reproducibility of these results by other researchers. Secondly, because of their lower citation frequencies, recent studies may have an understated impact on bibliometric analysis.

Funding

The 10.13039/100014717 National Natural Science Foundation of China supported this research (No. 82070723 ; No. 82270797 ).

Data availability statement

Data included in article/supp. material/referenced in article.

CRediT authorship contribution statement

Yunhan Wang: Writing – original draft, Software, Conceptualization. Caitao Dong: Data curation. Qinhong Jiang: Data curation. Wenbiao Liao: Writing – review & editing, Visualization. Sixing Yang: Writing – review & editing, Visualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A Supplementary data

The following is the supplementary data to this article:Multimedia component 1

Multimedia component 1

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2024.e36604.
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