{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:03:11Z","timestamp":1789066991584,"version":"build-2803163510"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Uremic toxins accumulate as kidney disease progresses, contributing to diverse systemic disorders. Despite numerous studies, no comprehensive mapping has been performed. In this study, keywords related to uremic toxins were quantitatively analyzed using bibliometric methods to clarify research trends, key molecules, and unresolved challenges. Literature and molecular data on uremic toxins and chronic kidney disease were retrieved from the Web of Science and the European Uremic Toxin Work Group (EUTox) databases. Network, citation burst, and keyword frequency analyses were performed using KeyWords Plus. In total, 3302 articles were identified, showing an increasing trend. Citation burst analysis revealed a growing interest in gut microbiota-related topics (burst strength = 15.21), whereas keyword frequency analysis indicated that indoxyl sulfate (566 articles) and p-cresyl sulfate (537 articles) were the most studied toxins. Toxins such as trimethylamine-N-oxide have gained attention over the past 5 years. Analysis of the EUTox database identified 24 protein-bound uremic toxins; among the 94 toxins with unreported clinical toxicity, 15 molecules, including osteocalcin and quinolinic acid, were investigated in &lt;5 studies. These findings suggest that the gut microbiota and related uremic toxins are current research focuses; however, further investigation of underreported uremic toxins is required to define their clinical significance.<\/jats:p>","DOI":"10.3390\/toxins17110537","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T03:33:07Z","timestamp":1761881587000},"page":"537","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Comprehensive Bibliometric Analysis of Uremic Toxin Research"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3125-640X","authenticated-orcid":false,"given":"Marsuki","family":"Hardjo","sequence":"first","affiliation":[{"name":"Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Wakamatsu","sequence":"additional","affiliation":[{"name":"Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoko","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8279-2966","authenticated-orcid":false,"given":"Suguru","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1016\/j.kint.2019.07.012","article-title":"A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases","volume":"96","author":"Jager","year":"2019","journal-title":"Kidney Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1016\/S0140-6736(18)31694-5","article-title":"Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: Reference and alternative scenarios for 2016-40 for 195 countries and territories","volume":"392","author":"Foreman","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.1681\/ASN.2005101085","article-title":"Chronic kidney disease and mortality risk: A systematic review","volume":"17","author":"Tonelli","year":"2006","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1053\/j.jrn.2004.08.002","article-title":"Physical activity patterns in chronic hemodialysis patients: Comparison of dialysis and nondialysis days","volume":"15","author":"Majchrzak","year":"2005","journal-title":"J. Ren. Nutr."},{"key":"ref_5","first-page":"8876559","article-title":"Kidney Disease-Specific Quality of Life among Patients on Hemodialysis","volume":"2021","author":"Kamble","year":"2021","journal-title":"Int. J. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1016\/j.kint.2020.02.026","article-title":"Accumulation of protein-bound uremic toxins: The kidney remains the leading culprit in the gut-liver-kidney axis","volume":"97","author":"Burtey","year":"2020","journal-title":"Kidney Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1159\/000369817","article-title":"Uremic toxins and their effects on multiple organ systems","volume":"128","year":"2014","journal-title":"Nephron Clin. Pract."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Ospina, D., Mas-Fontao, S., Gracia-Iguacel, C., Avello, A., Gonz\u00e1lez de Rivera, M., Mujika-Marticorena, M., and Gonzalez-Parra, E. (2024). Displacing the Burden: A Review of Protein-Bound Uremic Toxin Clearance Strategies in Chronic Kidney Disease. J. Clin. Med., 13.","DOI":"10.3390\/jcm13051428"},{"key":"ref_9","first-page":"1514","article-title":"A history of uraemic toxicity and of the European Uraemic Toxin Work Group (EUTox)","volume":"14","author":"Vanholder","year":"2021","journal-title":"Clin. Kidney J."},{"key":"ref_10","first-page":"S9","article-title":"Uremic toxins","volume":"13","year":"1978","journal-title":"Kidney Int. Suppl."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1046\/j.1523-1755.2003.00924.x","article-title":"Review on uremic toxins: Classification, concentration, and interindividual variability","volume":"63","author":"Vanholder","year":"2003","journal-title":"Kidney Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1681\/ASN.2011121175","article-title":"Normal and pathologic concentrations of uremic toxins","volume":"23","author":"Duranton","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Cozzolino, M., Magagnoli, L., and Ciceri, P. (2025). From Physicochemical Classification to Multidimensional Insights: A Comprehensive Review of Uremic Toxin Research. Toxins, 17.","DOI":"10.3390\/toxins17060295"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.2215\/CJN.02660221","article-title":"Classification of Uremic Toxins and Their Role in Kidney Failure","volume":"16","author":"Rosner","year":"2021","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1159\/000528040","article-title":"Proposal for a New Classification of Solutes of Interest in Uremia and Hemodialysis","volume":"52","author":"Kashani","year":"2023","journal-title":"Blood Purif."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"100955","DOI":"10.1016\/j.xkme.2024.100955","article-title":"Metabolomics to Identify Unclassified Uremic Toxins: A Comprehensive Literature Review","volume":"7","author":"Vanholder","year":"2025","journal-title":"Kidney Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wakamatsu, T., Yamamoto, S., Ito, T., Sato, Y., Matsuo, K., Takahashi, Y., Kaneko, Y., Goto, S., Kazama, J.J., and Gejyo, F. (2018). Indoxyl Sulfate Promotes Macrophage IL-1\u03b2 Production by Activating Aryl Hydrocarbon Receptor\/NF-\u03ba\/MAPK Cascades, but the NLRP3 inflammasome Was Not Activated. Toxins, 10.","DOI":"10.3390\/toxins10030124"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Karbowska, M., Pawlak, K., Sieklucka, B., Domaniewski, T., Lebkowska, U., Zawadzki, R., and Pawlak, D. (2024). Dose-dependent exposure to indoxyl sulfate alters AHR signaling, sirtuins gene expression, oxidative DNA damage, and bone mineral status in rats. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-53164-3"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Yamamoto, S., Kazama, J.J., Omori, K., Matsuo, K., Takahashi, Y., Kawamura, K., Matsuto, T., Watanabe, H., Maruyama, T., and Narita, I. (2015). Continuous Reduction of Protein-Bound Uraemic Toxins with Improved Oxidative Stress by Using the Oral Charcoal Adsorbent AST-120 in Haemodialysis Patients. Sci. Rep., 5.","DOI":"10.1038\/srep14381"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Liu, W.C., Tomino, Y., and Lu, K.C. (2018). Impacts of Indoxyl Sulfate and p-Cresol Sulfate on Chronic Kidney Disease and Mitigating Effects of AST-120. Toxins, 10.","DOI":"10.3390\/toxins10090367"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Di Paola, R., De, A., Izhar, R., Abate, M., Zappavigna, S., Capasso, A., Perna, A.F., La Russa, A., Capasso, G., and Caraglia, M. (2023). Possible Effects of Uremic Toxins p-Cresol, Indoxyl Sulfate, p-Cresyl Sulfate on the Development and Progression of Colon Cancer in Patients with Chronic Renal Failure. Genes, 14.","DOI":"10.3390\/genes14061257"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1007\/s40620-022-01283-3","article-title":"High-volume hemodiafiltration decreases the pre-dialysis concentrations of indoxyl sulfate and p-cresyl sulfate compared to hemodialysis: A post-hoc analysis from the HDFit randomized controlled trial","volume":"35","author":"Lima","year":"2022","journal-title":"J. Nephrol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1681\/ASN.2013080905","article-title":"The gut microbiome, kidney disease, and targeted interventions","volume":"25","author":"Ramezani","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/ki.2012.345","article-title":"Chronic kidney disease alters intestinal microbial flora","volume":"83","author":"Vaziri","year":"2013","journal-title":"Kidney Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1159\/000360010","article-title":"Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD","volume":"39","author":"Wong","year":"2014","journal-title":"Am. J. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/s41581-018-0018-2","article-title":"The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease","volume":"14","author":"Yang","year":"2018","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1161\/CIRCRESAHA.116.305360","article-title":"Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease","volume":"116","author":"Tang","year":"2015","journal-title":"Circ. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1056\/NEJMoa1109400","article-title":"Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk","volume":"368","author":"Tang","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1111\/apm.13038","article-title":"Gut microbiota in atherosclerosis: Focus on trimethylamine N-oxide","volume":"128","author":"Zhu","year":"2020","journal-title":"APMIS"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.trsl.2020.08.007","article-title":"TMAO: How gut microbiota contributes to heart failure","volume":"228","author":"Zhang","year":"2021","journal-title":"Transl. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Chen, S.Y., Rong, X.Y., Sun, X.Y., Zou, Y.R., Zhao, C., and Wang, H.J. (2022). A Novel Trimethylamine Oxide-Induced Model Implicates Gut Microbiota-Related Mechanisms in Frailty. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.803082"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Pelletier, C.C., Croyal, M., Ene, L., Aguesse, A., Billon-Crossouard, S., Krempf, M., Lemoine, S., Guebre-Egziabher, F., Juillard, L., and Soulage, C.O. (2019). Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate. Toxins, 11.","DOI":"10.3390\/toxins11110635"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kalantar-Zadeh, K., Joshi, S., Schlueter, R., Cooke, J., Brown-Tortorici, A., Donnelly, M., Schulman, S., Lau, W.L., Rhee, C.M., and Streja, E. (2020). Plant-Dominant Low-Protein Diet for Conservative Management of Chronic Kidney Disease. Nutrients, 12.","DOI":"10.20944\/preprints202005.0516.v1"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1053\/j.jrn.2017.06.010","article-title":"Probiotic Supplementation in Chronic Kidney Disease: A Double-blind, Randomized, Placebo-controlled Trial","volume":"28","author":"Borges","year":"2018","journal-title":"J. Ren. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1053\/j.jrn.2018.08.008","article-title":"Prebiotic, Probiotic, and Synbiotic Supplementation in Chronic Kidney Disease: A Systematic Review and Meta-analysis","volume":"29","author":"McFarlane","year":"2019","journal-title":"J. Ren. Nutr."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Moser, S.C., and van der Eerden, B.C.J. (2018). Osteocalcin-A Versatile Bone-Derived Hormone. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00794"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1007\/s00774-005-0668-6","article-title":"Vascular calcification in chronic kidney disease","volume":"24","author":"Jono","year":"2006","journal-title":"J. Bone Miner. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1111\/j.1742-4658.2012.08485.x","article-title":"Quinolinic acid, the inescapable neurotoxin","volume":"279","author":"Guillemin","year":"2012","journal-title":"FEBS J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e180229","DOI":"10.1172\/jci.insight.180229","article-title":"Quinolinic acid potentially links kidney injury to brain toxicity","volume":"10","author":"Saliba","year":"2025","journal-title":"JCI Insight"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejor.2015.04.002","article-title":"A review of theory and practice in scientometrics","volume":"246","author":"Mingers","year":"2015","journal-title":"Eur. J. Oper. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s11192-009-0146-3","article-title":"Software survey: VOSviewer, a computer program for bibliometric mapping","volume":"84","author":"Waltman","year":"2010","journal-title":"Scientometrics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5303","DOI":"10.1073\/pnas.0307513100","article-title":"Searching for intellectual turning points: Progressive knowledge domain visualization","volume":"101","author":"Chen","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.joi.2017.08.007","article-title":"bibliometrix: An R-tool for comprehensive science mapping analysis","volume":"11","author":"Aria","year":"2017","journal-title":"J. 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