{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:47:41Z","timestamp":1785322061483,"version":"3.55.0"},"reference-count":34,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,11]],"date-time":"2026-01-11T00:00:00Z","timestamp":1768089600000},"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>Protein-bound uremic toxins (PBUT), particularly indoxyl sulphate (IS) and p-cresyl sulphate (pCS), are poorly removed by conventional haemodialysis because of their strong albumin binding. These toxins are associated with cardiovascular morbidity and mortality in haemodialysis patients. Displacer molecules such as ibuprofen enhance PBUT clearance by competing for albumin-binding sites, but the optimal dose and route of administration remain unclear. The aim of this study was to evaluate the effect of different ibuprofen doses, infusion durations, and routes of administration on the removal of IS and pCS during on-line hemodiafiltration (OL-HDF). In this prospective, single-centre, crossover study, 21 chronic haemodialysis patients receiving intradialytic analgesia underwent nine OL-HDF sessions. Ibuprofen was administered at two doses (400 or 800 mg) either in the arterial pre-filter line (infusion over 1 h, 2 h, or 3 h) or in the venous post-filter line (30 min). Reduction ratios (RR) of total IS and pCS were determined by LC-MS and corrected for haemoconcentration. Statistical analysis included repeated-measures ANOVA with post-hoc testing. Baseline RR for IS and pCS were 53.7 \u00b1 9.9% and 47.1 \u00b1 10.9%, respectively. The highest RR was achieved with 800 mg ibuprofen infused via the arterial line over 2 h (IS: 60.8 \u00b1 8.6%; pCS: 57.8 \u00b1 9.7%). All arterial-line 800 mg regimens and the 3-h 400 mg infusion significantly improved pCS clearance versus baseline; IS clearance improved significantly only with arterial-line 800 mg regimens and with the 400 mg 3-h infusion. Infusion rate (1\u20133 h) had no significant effect on RR within the same dose group. Pain scores decreased significantly after dialysis regardless of ibuprofen regimen. Arterial-line administration of ibuprofen enhances total IS and pCS removal during OL-HDF, with higher doses yielding greater clearance. Prolonged low-dose infusion appears similarly effective for pCS and may reduce systemic exposure, potentially lowering toxicity risk. These findings support the arterial line as the preferred route for displacer administration in clinical practice.<\/jats:p>","DOI":"10.3390\/toxins18010037","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T08:20:37Z","timestamp":1768206037000},"page":"37","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Optimization of Ibuprofen Route and Dosage to Enhance Protein-Bound Uremic Toxin Clearance During Hemodialysis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0411-207X","authenticated-orcid":false,"given":"V\u00edctor Joaqu\u00edn","family":"Escudero-Saiz","sequence":"first","affiliation":[{"name":"Nephrology and Renal Transplantation, Hospital Cl\u00ednic de Barcelona, 08036 Barcelona, Spain"},{"name":"Medicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2412-6911","authenticated-orcid":false,"given":"Elena","family":"Cuadrado-Pay\u00e1n","sequence":"additional","affiliation":[{"name":"Nephrology and Renal Transplantation, Hospital Cl\u00ednic de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Rodr\u00edguez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Genetics Department\u2014CDB, Hospital Cl\u00ednic de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3271-1371","authenticated-orcid":false,"given":"Gregori","family":"Casals","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Genetics Department\u2014CDB, Hospital Cl\u00ednic de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lida Mar\u00eda","family":"Rodas","sequence":"additional","affiliation":[{"name":"Nephrology and Renal Transplantation, Hospital Cl\u00ednic de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00e9stor","family":"Fontser\u00e9","sequence":"additional","affiliation":[{"name":"Nephrology and Renal Transplantation, Hospital Cl\u00ednic de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda del Carmen","family":"Salgado","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Genetics Department\u2014CDB, Hospital Cl\u00ednic de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0845-8107","authenticated-orcid":false,"given":"Carla","family":"Bastida","sequence":"additional","affiliation":[{"name":"Pharmacy Department, University of Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5667-0650","authenticated-orcid":false,"given":"Nayra","family":"Rico","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Genetics Department\u2014CDB, Hospital Cl\u00ednic de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4559-9083","authenticated-orcid":false,"given":"Jos\u00e9 Jes\u00fas","family":"Broseta","sequence":"additional","affiliation":[{"name":"Nephrology and Renal Transplantation, Hospital Cl\u00ednic de Barcelona, 08036 Barcelona, Spain"},{"name":"Medicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1673-0353","authenticated-orcid":false,"given":"Francisco","family":"Maduell","sequence":"additional","affiliation":[{"name":"Nephrology and Renal Transplantation, Hospital Cl\u00ednic de Barcelona, 08036 Barcelona, Spain"},{"name":"Medicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Ospina, D., Mas-Fontao, S., Gracia-Iguacel, C., Avello, A., de Rivera, M.G., 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_2","doi-asserted-by":"crossref","first-page":"100299","DOI":"10.1016\/j.impact.2021.100299","article-title":"Protein-bound uremic toxins (PBUTs) in chronic kidney disease (CKD) patients: Production pathway, challenges and recent advances in renal PBUTs clearance","volume":"21","author":"Daneshamouz","year":"2021","journal-title":"NanoImpact"},{"key":"ref_3","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_4","doi-asserted-by":"crossref","unstructured":"Vanholder, R., Pletinck, A., Schepers, E., and Glorieux, G. (2018). Biochemical and clinical impact of organic uremic retention solutes: A comprehensive update. Toxins, 10.","DOI":"10.3390\/toxins10010033"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"501391","DOI":"10.1016\/j.nefro.2025.501391","article-title":"Factores que influyen en la depuraci\u00f3n de toxinas ur\u00e9micas unidas a prote\u00ednas en hemodiafiltraci\u00f3n","volume":"45","author":"Casals","year":"2025","journal-title":"Nefrolog\u00eda"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1124\/dmd.112.045617","article-title":"Interaction between Two Sulfate-Conjugated Uremic Toxins, p-Cresyl Sulfate and Indoxyl Sulfate, during Binding with Human Serum Albumin","volume":"40","author":"Watanabe","year":"2012","journal-title":"Drug Metab. Dispos."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1159\/000495343","article-title":"Effect of ionic strength, pH and chemical displacers on the percentage protein binding of protein-bound uremic toxins","volume":"47","author":"Shi","year":"2019","journal-title":"Blood Purif."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1093\/ndt\/gfr453","article-title":"Serum free p-cresyl sulfate levels predict cardiovascular and all-cause mortality in elderly hemodialysis patients-A prospective cohort study","volume":"27","author":"Wu","year":"2012","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1038\/sj.ki.5000115","article-title":"Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients","volume":"69","author":"Bammens","year":"2006","journal-title":"Kidney Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1038\/ki.2008.31","article-title":"Free p-cresol is associated with cardiovascular disease in hemodialysis patients","volume":"73","author":"Meijers","year":"2008","journal-title":"Kidney Int."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Rodrigues, F.S.C., and Faria, M. (2023). Adsorption- and Displacement-Based Approaches for the Removal of Protein-Bound Uremic Toxins. Toxins, 15.","DOI":"10.3390\/toxins15020110"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Maheshwari, V., Tao, X., Thijssen, S., and Kotanko, P. (2021). Removal of protein-bound uremic toxins using binding competitors in hemodialysis: A narrative review. Toxins, 13.","DOI":"10.3390\/toxins13090622"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6589","DOI":"10.1021\/acsami.3c15291","article-title":"Ibuprofen-Immobilized Thin Films: A Novel Approach to Improve the Clearance of Protein-Bound Uremic Toxins","volume":"16","author":"Rodrigues","year":"2024","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"394","DOI":"10.2215\/CJN.05240418","article-title":"Removal of protein-bound uremic toxins during hemodialysis using a binding competitor","volume":"14","author":"Madero","year":"2019","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Escudero-Saiz, V.J., Cuadrado-Pay\u00e1n, E., Rodriguez-Garcia, M., Casals, G., Rodas, L.M., Fontser\u00e9, N., Salgado, M.d.C., Bastida, C., Rico, N., and Broseta, J.J. (2024). The Choice of Anti-Inflammatory Influences the Elimination of Protein-Bound Uremic Toxins. Toxins, 16.","DOI":"10.3390\/toxins16120545"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"sfaf195","DOI":"10.1093\/ckj\/sfaf195","article-title":"Loop diuretics in anuric hemodialysis patients for the clearance of protein-bound uremic toxins","volume":"18","author":"Cote","year":"2025","journal-title":"Clin. Kidney J."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Da Cunha, R.S., Santos, A.F., Barreto, F.C., and Stinghen, A.E.M. (2020). How do uremic toxins affect the endothelium?. Toxins, 12.","DOI":"10.3390\/toxins12060412"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1093\/ndt\/gfp592","article-title":"Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease","volume":"25","author":"Liabeuf","year":"2010","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.2215\/CJN.03980609","article-title":"Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients","volume":"4","author":"Barreto","year":"2009","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"sfad248","DOI":"10.1093\/ckj\/sfad248","article-title":"Study of the association between serum levels of kynurenine and cardiovascular outcomes and overall mortality in chronic kidney disease","volume":"17","author":"Larabi","year":"2024","journal-title":"Clin. Kidney J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1093\/ndt\/gfv038","article-title":"Protein-bound uraemic toxins, dicarbonyl stress and advanced glycation end products in conventional and extended haemodialysis and haemodiafiltration","volume":"30","author":"Cornelis","year":"2015","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1093\/ndt\/15.1.50","article-title":"Intradialytic removal of protein-bound uraemic toxins: Role of solute characteristics and of dialyser membrane","volume":"15","author":"Lesaffer","year":"2000","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kim, Y.G., Lee, S.H., Jung, S.W., Jung, G.T., Lim, H.J., Kim, K.P., Jo, Y.-I., Jin, K., and Moon, J.Y. (2022). The Medium Cut-Off Membrane Does Not Lower Protein-Bound Uremic Toxins. Toxins, 14.","DOI":"10.3390\/toxins14110779"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3278","DOI":"10.1093\/ndt\/gfs060","article-title":"Removal of water-soluble and protein-bound solutes with reversed mid-dilution versus post-dilution haemodiafiltration","volume":"27","author":"Eloot","year":"2012","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1111\/aor.12704","article-title":"Hemodiafiltration with Endogenous Reinfusion Improved Microinflammation and Endothelial Damage Compared with Online-Hemodiafiltration: A Hypothesis Generating Study","volume":"41","author":"Buendia","year":"2017","journal-title":"Artif. Organs"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1093\/ndt\/gfr691","article-title":"Selectively increasing the clearance of protein-bound uremic solutes","volume":"27","author":"Sirich","year":"2012","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/s41598-018-37195-1","article-title":"In silico comparison of protein-bound uremic toxin removal by hemodialysis, hemodiafiltration, membrane adsorption, and binding competition","volume":"9","author":"Maheshwari","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_28","first-page":"2","article-title":"Improved dialytic removal of protein-bound uraemic toxins with use of albumin binding competitors: An in vitro human whole blood study","volume":"6","author":"Tao","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.phymed.2018.12.018","article-title":"Improved dialysis removal of protein-bound uremic toxins by salvianolic acids","volume":"57","author":"Li","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1093\/ndt\/gfz079","article-title":"Improved dialytic removal of protein-bound uremic toxins by intravenous lipid emulsion in chronic kidney disease rats","volume":"34","author":"Shi","year":"2019","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1002\/j.1552-4604.1986.tb02931.x","article-title":"The Influence of Hemodialysis on the Pharmacokinetics of Ibuprofen and Its Major Metabolites","volume":"26","author":"Antal","year":"1986","journal-title":"J. Clin. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e0132589","DOI":"10.1371\/journal.pone.0132589","article-title":"Meta-analysis of the associations of p-cresyl sulfate (PCS) and indoxyl sulfate (IS) with cardiovascular events and all-cause mortality in patients with chronic renal failure","volume":"10","author":"Lin","year":"2015","journal-title":"PLoS ONE"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/S0140-6736(87)90266-2","article-title":"No change in corrected \u03b22-microglobulin concentration after cuprophane haemodialysis","volume":"329","author":"Wehle","year":"1987","journal-title":"Lancet"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Garc\u00eda, M., Mart\u00ednez, I., Aliart, I., de Medrano, J.I.S., Rico, N., Escudero-Saiz, V.J., Maduell, F., Morales-Ruiz, M., and Casals, G. (2025). Validation of an LC\u2013HRMS Method for Quantifying Indoxyl Sulfate and p-Cresyl Sulfate in Human Serum. Molecules, 30.","DOI":"10.3390\/molecules30040782"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/18\/1\/37\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T08:26:15Z","timestamp":1768206375000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/18\/1\/37"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,11]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["toxins18010037"],"URL":"https:\/\/doi.org\/10.3390\/toxins18010037","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,11]]}}}