COVID-19 Vaccine in Renal Transplant Recipients: A Bibliometric-Based Analysis of Trends


                  Background
                  The global community has been affected by COVID-19, which emerged in December 2019. Since then, many studies have been conducted on kidney transplant recipients (KTRs) and COVID-19. This study aimed to perform a bibliometric and visual analysis of the published relationship between KTRs and COVID-19.
               
                  Objective
                  To discuss the current status, hot spots, and development trend of research on KTRs vaccination with the COVID-19 vaccine and to provide a reference for researchers in related fields.
               
                  Methods
                  Visual analysis of countries/regions, institutions, authors, references cited, and keywords for 2020 to 2023 via Microsoft Office Excel 2019 and CiteSpace (6.1.R6) based on the Web of Science core database.
               
                  Results
                  A total of 366 publications were included after screening, with a rapid increase in the global literature studying the COVID-19 vaccine of KTRs. The US has the highest number of publications, indicating that it is the leading country in this field of research. Charite University of Medicine Berlin and Schrezenmeier E are the most published institutions and authors, respectively. “Antibody Response After a Third Dose of the messenger RNA-1273 SARS-CoV-2 Vaccine in Kidney Transplant Recipients With Minimal Serologic Response to 2 Doses” is the most central co-cited reference; The keywords “kidney transplant recipient,” “covid 19 vaccine,” and “mortality” have become hot topics of research. The keywords “humoral response” and "bnt162b2" are the latest research frontiers for detecting bursts.
               
                  Conclusions
                  This paper analyzed the current status and trends of vaccination studies in KTRs through bibliometric analysis. Several studies support the vaccination of KTRs with the COVID-19 vaccine. However, the evidence for improving vaccine efficacy by adjustment of immunosuppression is still limited, and future studies on vaccination will remain a hot topic in this field.
               

SARS-CoV-2 has put an unprecedented strain on the world's health care systems and economies.More than 760 million confirmed cases of COVID-19 had been reported to the World Health Organization as of March 12, 2023, with 6.8 million deaths [2].Notably, the prevalence of severe COVID-19 is substantially higher in patients with specific immune weaknesses, such as oncology patients with autoimmune illnesses, patients getting immunosuppressive medicines following organ transplantation, or patients taking anticancer drugs [3].Even though multiple studies have been completed and several vaccines have been approved to prevent SARS-CoV-2, these specific patient populations were not included in the trials, leaving the efficacy and safety of vaccination in immunocompromised individuals in doubt.
Kidney transplant recipients (KTRs) are particularly susceptible to severe cases of COVID-19, and they experience higher morbidity and mortality rates than the general population [4].COVID-19 vaccine remains an essential method for preventing KTR infection.Evidence shows that uremia may reduce vaccine-induced immunity in end-stage chronic kidney disease and KTRs [5].Toxin retention, environmental dysregulation, metabolic problems, and the normal immune response to vaccination can be compromised by all forms of dialysis, resulting in inflammation and immune cell malfunction [6].Immunosuppressive medicines may impair vaccine efficacy in KTRs, with more than half failing to produce an immunologic response even after 4 doses of the anti-COVID-19 vaccine [7].As a result of the patients' absence of antibody responses, they are at an extremely high risk of contracting SARS-CoV-2 and severe COVID-19 disorders [8].
Bibliometrics is an effective quantitative analysis method that can be used not only to evaluate the quality and quantity of published papers but also to investigate the focus and trends of research, the distribution of authors and institutions, and the influence of publications, journals, and countries on papers [9].This study examines research articles from 2020 to 2023 through a visual analysis of bibliometrics to inform COVID-19 vaccine studies in KTRs and provide an extensive overview of the most recent developments in the COVID-19 vaccine of KTRs.

MATERIALS AND METHODS Data Sources and Search Strategies
The Web of Science (WOS) Core Collection is the most well-known and prominent scientific literature collection, the database of choice for bibliometric analysis.The WOS core set database was used to gather all data in this paper.The following are the search strategies: #1 TS = (COVID-19) OR TS = (SARS-CoV-2), #2 TS = (vacc*), #3 = (#2 AND #1), #4 TS = (Kidney Transplant*) OR TS = (Renal Transplant*), #5=(#4 AND #3).To prevent potential bias owing to daily changes, the search period was set from January 2020 to January 2023, the type was all types, and the search data were collected within 1 day.There were 555 publications found in total.After changing the language to English and removing other document types such as meeting abstracts, editorial material, letters, corrections, and early access, 366 publications were exported as complete records with cited references, 299 for articles and 67 for reviews, respectively, as a sample for subsequent econometric analysis.The flow chart of the literature selection is shown in Fig 1.

Research Methodologies and Data Analysis
All 366 papers were analyzed using Microsoft Office Excel 2019 and CiteSpace (6.1.R6), and the tables were created using Excel 2019.Document visualization and analysis can be performed using CiteSpace (a web application based on Java) [10].CiteSpace was used in this work to generate visual knowledge maps of the distribution of countries/ regions, institutions, authors, references, and keywords.CiteSpace's parameters are as follows: time slice (2020-2023), number of years per slice (1), term source (all selections), node type (1 at a time), selection criteria (first 50 objects), and pruning (content includes pathfinding, pruning of slice network, and pruning of merge network); all other parameters are left at their default values.

RESULTS AND ANALYSIS National/Regional and Institutional Cooperation
A collaboration network between a country or region, an institution, or an author can be classified into macro, meso, or micro collaboration networks.Graphic knowledge graphs can assist academics in identifying significant research teams and possible collaborators, allowing them to create collaborative ties [11].In a visual knowledge graph, each circle represents a country or institution.The size of the circles reflects how many publications are produced by the country/institution, and the lines represent a collaboration between countries and institutions.As the line widens, the closer the collaboration becomes.According to CiteSpace's research of country collaboration networks, 366 publications were published from 60 distinct countries/regions and 139 institutions.As shown in Table 1, the country with the most publications (81, 15.37%) is the United States, followed by Germany (43, 8.15%) and France (34, 6.45%).As measured by the number of publications, the United States is significantly ahead of other countries, showing that it is the leading country in COVID-19 vaccine research for KTRs.
Nodes having an intermediary centrality >0.1 are considered crucial sites in CiteSpace [12].CiteSpace finds and ranks publications according to their mediated centrality.The purple circles indicate node-mediated centrality values of >0.1, showing that publications (or authors, nations, and organizations) are frequently important hubs connecting 2 domains, called CiteSpace turning points [13].The visual knowledge map demonstrates that the United Kingdom has the highest intermediary centrality (Fig 2 ) and is closely tied to other countries, showing that the United Kingdom is a powerful country in the field.China lags behind other countries in terms of academic impact and attention to research outcomes in this study area and hence needs to increase research quality, reliability, and innovation.
Collaboration among research institutes can facilitate academic exchanges among academics and advance field research.According to a cooccurrence analysis of research institutions, Charite University of Medicine Berlin had the most published articles (Table 2), whereas Stanford University had the highest intermediate centrality (Table 3).Stanford University   According to Table 4, Schrezenmeier E has the most publications, followed by Budde K and Halleck F. Eckardt K has the most citations (43,446)   others, primarily dedicated to the study of immune mechanisms in renal transplant patients after vaccination.They all collaborate closely, and in the context of the New Coronary Pneumonia pandemic, these representative writers have a high academic reputation for their significant contributions to mechanisms theorized, the study of clinical cases, and national or regional outbreak control.

References Co-cited
An analysis of co-citations is a method for tracking references that are cited in the same document at the same time.It is feasible to reveal the study field's knowledge structure and transitions by evaluating clusters and transitions in cocitation networks [14].Table 5 displays the 10 most cited documents from the 432 co-cited documents obtained, with "Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients" [15] being the most referenced (131).
Figure 5 shows the co-citation network for renal transplantation and COVID-19 vaccine studies.Two nodes are readily visible in the network, shown by purple circles.The centrality of "Two Doses of Inactivated Influenza Vaccine   Research Hotspots Keyword cooccurrence.A paper's keywords represent its essence and core.Pairs of words or noun phrases co-occurring in a collection are used to determine if topics are related within the discipline the collection represents [27].The value of the clustering module Q is a network modularity indicator, and the network clustering structure resulting from Q >.3 is noteworthy [12].It is determined whether the network is homogeneous by evaluating its contour.A cluster with S values >0.5 is considered reasonable if the contour value S is close to 1, whereas clustering findings >0.7 are considered very dependable [12].
By analyzing keyword cooccurrences in network mapping, clusters can be constructed to summarize research hotspots and obtain basic knowledge.CiteSpace's K-means clustering analysis of keywords found 12 clusters with network module value Q = 0.8174 and profile value S = 0.9461, indicating viable clusters and excellent consistency among cluster members in this publication.Figure 7  Keyword emergence.CiteSpace offers burst detection, which pulls emerging words from subject terms in the literature, displaying the research frontiers and trends in a particular field [28].By using keyword co-occurrence networks, we were able to identify the 20 keywords that were cited most frequently in renal transplantation and COVID-19 trials.According to Fig 8, the blue line represents the timeline, with the red portion representing burst detection, indicating the burst duration, beginning, and ending dates.A citation explosion means new hotspots and growing academic trends, identifying potential hot issues in kidney transplantation and COVID-19 vaccine research and predicting new research frontiers [13].
In 2020, the SARS-CoV-2 pandemic started in the world, and "coronavirus" became the keyword of emergence this year, then anti-neo-coronavirus drugs became the hot research, "interferon alpha," "tocilizumab" is the star drug of anti-coronavirus, and

COVID-19 VACCINE IN RENAL TRANSPLANT RECIPIENTS
"cyclosporine A" can be used as an adjuvant treatment of COVID 19 virus infection.Clinical and immunologic response studies in this field will be handled gradually beginning in 2021, emphasizing key phrases such as "graft rejection," "CD4 (+) T cell," and "humoral response."Recently, Bnt162b2, an mRNA vaccine created by Pfizer in conjunction with BioN-Tech, became the buzzword for the emergence of the first vaccine to get emergency approval during the pandemic.Bnt162b2 is a nucleoside-modified mRNA expressa mutant pinch protein of SARS-CoV-2 encapsulated in lipid nanoparticles injected intramuscularly [29].

DISCUSSION Research Developments in Renal Transplantation and COVID-19 Vaccine
By evaluating the data by country/region, we discovered that the United States, Germany, and France have the most published articles on this topic.This finding was associated with an outbreak that began in Wuhan, China.Still, the Chinese government took concrete preventive measures.The sample size of studies assessing the efficacy of the COVID-19 vaccine in transplant recipients was limited, resulting in fewer publications than in Western countries.European and American countries have sophisticated economies, advanced medical technology, and robust data management and academic systems, all of which contribute to a higher output of relevant research papers in these regions.
The Charite University of Medicine Berlin ranks first for the number of research articles published (16), where researchers discovered in a prospective, multicenter observational study that the quantity and classification of immunosuppressive agents, as well as the type of vaccine, were primary factors of seroconversion failure in patients undergoing dialysis and transplantation [30].Stanford University has the highest level of intermediary centrality (0.53).Stanford University, one of the world's top research universities, is powerful and has collaborated closely with several other institutions.Figures 2 and 3 show that the linkages and collaboration among various countries and institutions are reasonably strong, which enables the solution to the SARS-CoV-2 epidemic and the challenges it brings through global forces.
The examination of core authors aids in the research of publication dispersion.According to a review of the relevant literature, Schrezenmeier is the most frequently appearing author on this topic.He created 5 distinct multivariate serologic response prediction models to predict KTR responses to a third or fourth dose of the SARS-CoV-2 vaccine to diminish inter-individual variation in serologic response in KTRs raised by repeated COVID-19 immunization [20].
Nine of the top 10 citations focused on COVID-19 0 s clinical features and course, demonstrating that researchers in this field are increasingly focused on the actual clinical situation of patients.Furthermore, we retrieved 1 article with a mediated centrality >0.1."Antibody Response After a Third Dose of the mRNA-1273 SARS-CoV-2 Vaccine in Kidney Transplant Recipients With Minimal Serologic Response to 2 Doses" [21] was published in the Journal of the American Medical Association in 2021 and discovered that 49% of KTRs who had not developed an immune response after the first 2 doses of the mRNA-1273 vaccine did so after the third dose.This outcome is consistent with prior studies on the COVID-19 vaccine in recipients of solid organ transplants.

Research Hotspots for Kidney Transplantation and COVID-19 Vaccine
Research sweet spots in a given subject can be gleaned from the high-frequency keywords that appear in keyword cooccurrences.Keyword cluster analysis is the grouping of keywords closely related to 1 another and can reflect current research hotspots in a given topic.Based on the software analysis results, 12 keyword clusters can be identified, indicating the present research hotspots for kidney transplantation and the COVID-19 vaccine.We can divide these 12 clusters into the following categories: #2, #3, #6, and #10 are classified as the effect of COVID-19 infection on KTRs and the danger of death.Categories #1, #4, #8, #9, #5, and #12 are grouped as immune responsiveness of renal transplant patients after vaccination with different COVID-19 vaccines.In contrast, the current clinical effectiveness and safety investigations of the COVID-19 vaccine in renal transplant patients are grouped as #0, #7, and #11, and these clusters are analyzed in detail next.
Those infected with COVID-19 are more likely to have thrombotic problems, which may increase mortality and morbidity.These consequences can potentially result from systemic hyperinflammation caused by COVID-19, which promotes endothelial activation and tissue damage [34].However, the exact mechanisms leading to these complications remain unknown.But some researchers have discovered that a possible explanation for COVID-19 patients' elevated platelet adhesion is serum amyloid A (SAA), so lowering levels of SAA by reducing inflammatory or inhibitive SAA's binding activity to platelets may be an effective way to eliminate complications associated with COVID-19 that lead to thrombosis [35].
Immunoreactivity of KTRs after COVID-19 vaccine (#1, #4, #8, #9, #5 #12).SARS-CoV-2 is a single-stranded RNA encapsulated virus with a 40-to 60-nm diameter and an enormous genome among RNA viruses [36,37].Membranes, nucleocapsid proteins, envelope proteins, and spiking proteins are all encoded by SARS-CoV-2 RNA [38].SARS-CoV-2 infection is dependent on its particular receptor, ACE2 [39].It has been proposed that human recombinant soluble ACE2 can considerably inhibit the early phases of SARS-CoV-2 infection [40].It has also been shown that the protease TMPRSS2 plays a role in the stimulation of ACE2 binding to coronaviruses, indicating that it may be a potential target for antiviral medication, and protease inhibitors may prevent SARS-CoV-2 entry [41].In immunocompromised patients, COVID-19 immunization experiments in transplant recipients revealed a low prevalence of SARS-CoV-2 spike-in antibody development [35].The potential for the mRNA vaccine for stinger protein to stimulate other immune responses, as the production of antibodies to HLA, which may promote the development of acute cellular or humoral rejection when antibodies are directed to donor HLA, has not been thoroughly evaluated [42].In a study conducted in the United States, 741 solid organ transplant recipients were assessed for their response to 2 doses of the mRNA vaccine for SARS-CoV-2; patients developed acute rejection [43].This shows that our mRNA SARS-CoV-2 immunization could result in homozygous sensitization.
Many dysfunctions associated with the uremic condition can be corrected after kidney transplantation, but immunosuppressive medication can hamper humoral and cellular responses.KTRs are at high risk of infection because of patients' lower immunity to the virus from immunosuppression, and vaccination is required to limit COVID-19 transmission and death [34].Mycophenolate esters are immunosuppressive medications that inhibit the proliferation of activated B and T cells [44].Some studies have found that MMF-treated kidney transplant recipients have lower immune responses to the vaccination [45,46].In one study, patients who took MMF had considerably lower antibody levels than those who did not take MMF or lowered their dosage [33].However, it is unclear whether this is a unique effect of MMF or the result of enhanced normal immunosuppression caused by MMF.
Clinical study of COVID-19 vaccine in renal transplant patients (#0, #7, and #11).The prolonged use of immunosuppression after transplantation is crucial to the function of the transplanted kidney in patients with KTRs; however, immunosuppression that lasted for an extended period enhanced the likelihood that KTRs would develop a severe illness following infection with SARS-CoV-2 [47].Vaccination against the spiking protein is critical for adaptive immunity against SARS-CoV-2.Two mRNA vaccines, BNT162b2 (Pfizer) and mRNA-1273 (Modena), as well as 1 adenovirus vector vaccine, Ad26.COV2.S, and 1 viral protein vaccine, Nuvaxavid, have been licensed in the United States.
Slizie n et al [48] conducted a long-term controlled trial in 300 KTRs and 143 control patients to evaluate the safety of evaluating the COVID-19 mRNA vaccine in KTRs and examined local and systemic reactivity and adverse events using a standardized questionnaire.Within 7 days of vaccination, 84.7% (first dose) and 65.3% (second dose) of KTRs had local reactions, 67.1% and 60.1% of control patients had local reactions, and there were no significant adverse effects.This evidence implies that KTRs are tolerated better than mRNA vaccinations.Furthermore, research by Demir [49] found that, although the COVID-19 vaccine did not prevent death in all KTRs, it did reduce hospitalization rates and length of stay in most patients.The American Association of Transplantation recommends vaccination at least 2 weeks before transplantation and no later than 1 to 6 months after transplantation [50].

Renal Transplantation Research Frontiers and COVID-19 Vaccine
We hypothesize that humoral response and bnt162b2 are this subject's most recent research frontiers, based on keywords and emergent word maps in the literature.The humoral immune response has been studied in Renal Transplant Recipients in response to the COVID-19 vaccine.Whether the bnt162b2 vaccination induces B-cell and plasma-cell responses in KTRs is unknown.Rincon-Arevalo et al [30] studied antibody, plasma cell, and memory B-cell responses in healthy people, dialysis patients, and renal transplant patients before and after vaccination with the COVID-19 mRNA BNT162b2 vaccine.They discovered that dialysis and KTRs had weak antibody and B-cell responses to the vaccine, implying that they did not obtain effective immunologic protection against SARS-CoV-2 infection.IgA antibodies serve as the initial line of defense against SARS-CoV-2 infection.Lower serum IgA antibody concentrations following mRNA vaccination have been linked to an increased risk of infection [51].Nevertheless, research on IgA immune responses in RTR recipients is limited.
Several new SARS-CoV-2 variants have recently emerged due to recombination between 2 separate parental lineages or sublineages within the same lineage, prompting speculation about the possibility of enhanced viral infectivity and immune evasion.As a recombinant form of BA.2.10 and BA.2.75, XBB is of great interest to various countries because of the potential for escaping infectious and immune systems.In a study that compared the ability of this recombinant protein to evade vaccine-induced antibody neutralization with the ability of an ancestral spectrum (B.1) and another cocirculating variant (B.1.1.529BA.5), the researchers found that BA.5 and XBB had significantly higher immune evasion than the ancestral strain in individuals who had previously been vaccinated with BNT162b2, which suggests that this particular vaccine achieves only partial novel variant cross-neutralization [52].

CONCLUSIONS
The ability of posttransplant renal patients to receive the COVID-19 vaccine is still being considered.It is recommended by both the European Society of Organ Transplantation and the American Society of Transplantation to vaccinate the solid organ transplantation population because the potential benefits outweigh the risks.Unfortunately, there needs to be more information regarding the new COVID-19 vaccine's immunogenicity and safety in this population.Vaccination is challenging for kidney transplant candidates and patients because most do not respond to immunizations and boosters.An immune response cannot be developed in almost half of KTRs, mainly when antimetabolites are used.This increases their chances of getting SARS-CoV-2 and severe COVID-19.This study uses Cite-Space software to analyze research directions and hotspots in KTRs and vaccination from WOS database sources.It summarizes the scientific progress and clinical research of vaccination against KTRs during the epidemic, which can show readers the hotspots and trends of research development in this field in a relatively intuitive and concrete manner.We hope other researchers will use our findings to uncover new study areas and questions that may help countries, groups, and individuals suffering from COVID-19.

LIMITATIONS
This study found objective and dependable results using the WOS database.Because the database is continuously updated and the search is confined to English research, there may be changes between the results and the actual findings.More research can be undertaken using Medline, Scopus, or Google Scholar databases to obtain more specific results.It is also possible that the number of publications included and the search results may differ because of changes in the database.Some discrepancies may result from excluding books, chapters, and letters as well as examining only English articles.Comprehensive epidemiologic and statistical studies of diseases will gain increased attention.On the other hand, immune response studies and the creation of effective vaccines for KTRs after the COVID-19 vaccine remain the primary research priorities.A more multidisciplinary approach is required for the optimal COVID-19 solution.

Fig 1 .
Fig 1.The flow chart for the search and selection strategy of the study.

Fig 2 .
Fig 2. Country cooperation network map.The nodes in the map represent countries or territories.The lines between the nodes means cooperation relationships.The different colors of the nodes represent the different years.The larger the node area, the larger the number of publications.The purple ring represents centrality, and nodes with high centrality are considered pivotal points in the literature.

Figure 4
Figure 4 depicts the collaboration network between the various writers as analyzed by CiteSpace software.A total of 182 writers contributed to the publication of research papers on renal transplantation and the COVID-19 vaccine.There is an author for each node; this connection indicates collaboration between the authors; the color of the connection indicates first cooperation and indicators of author cooperation include the thickness of the connection.Because of the large number of citation authors, the core author group was formed using Price's law and the formula m 0.749 (nmax 1/2), where m represents the minimum number of articles published by core authors in the research field, and nmax means the maximum number of articles published by core authors in the field.The nmax is 11 entered into the algorithm to obtain m as 3.31, which may be used to calculate the core author as 3.According to Table4, Schrezenmeier E has the most publications, followed by Budde K and Halleck F. Eckardt K has the most citations(43,446)  and a much higher H-index (94) than the other writers.The 182 core authors forming the author co-occurrence map (Fig 4) show that the core authors formed a research team among themselves, represented by Choi M, Schrezenmeier H, and Osmanodja B, among

Fig 3 .
Figure 4 depicts the collaboration network between the various writers as analyzed by CiteSpace software.A total of 182 writers contributed to the publication of research papers on renal transplantation and the COVID-19 vaccine.There is an author for each node; this connection indicates collaboration between the authors; the color of the connection indicates first cooperation and indicators of author cooperation include the thickness of the connection.Because of the large number of citation authors, the core author group was formed using Price's law and the formula m 0.749 (nmax 1/2), where m represents the minimum number of articles published by core authors in the research field, and nmax means the maximum number of articles published by core authors in the field.The nmax is 11 entered into the algorithm to obtain m as 3.31, which may be used to calculate the core author as 3.According to Table4, Schrezenmeier E has the most publications, followed by Budde K and Halleck F. Eckardt K has the most citations(43,446)  and a much higher H-index (94) than the other writers.The 182 core authors forming the author co-occurrence map (Fig 4) show that the core authors formed a research team among themselves, represented by Choi M, Schrezenmeier H, and Osmanodja B, among

Fig 4 .
Fig 4. Collaborative cooccurrence diagram of authors.The nodes represent authors, and the lines between the nodes represent collaborative relationships.The different colors of the nodes represent the different years.The larger the node area, the greater the number of publications.

Fig 5 .
Fig 5. Co-citation network diagram of references.The nodes represent cited references, and the lines between the nodes represent the co-citation relationships.The different colors of the nodes represent the different years.The larger the node area, the greater the number of co-citations.The purple ring represents centrality, and nodes with high centrality are considered pivotal points in the publications.

Fig 6 .
Fig 6.Keyword cooccurrence network diagram.The nodes represent keywords, and the lines between the nodes represent the cooccurrence relationships.The different colors of the nodes represent the different years.The larger the node area, the higher the frequency.The purple ring represents centrality, and high centrality nodes are considered pivotal points in the publications.

Fig 8 .
Fig 8. Keyword emergence map.Top 20 keywords with the strongest citation bursts.The red bars mean that the keywords were cited frequently, and the green bars show that the keywords were cited infrequently.

Table 1 .
Top 5 Countries in Terms of the Number of Articles Published

Table 2 .
Top 5 Institutions With the Highest Number of Publications

Table 3 .
Top 5Institutions with the Highest Centrality

Table 4 .
Top 10 Authors With the Most Published Articles

Table 6 .
The 10 Most Frequently Occurring Keywords Fig 7. Clusters analysis of keyboard network.