{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T20:02:24Z","timestamp":1774987344737,"version":"3.50.1"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"crossref","award":["ANR-IA-COH-2012\/3731"],"award-info":[{"award-number":["ANR-IA-COH-2012\/3731"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"crossref"}]},{"name":"GlaxoSmithKline"},{"DOI":"10.13039\/501100014089","name":"Boehringer Ingelheim France","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100014089","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015699","name":"Fresenius Medical Care","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100015699","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Vifor France"},{"name":"Sanofi-Genzyme"},{"name":"Baxter and Merck Sharp & Dohme-Chibret"},{"name":"Amgen"},{"name":"Lilly France"},{"DOI":"10.13039\/501100007132","name":"Otsuka Pharmaceutical","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007132","id-type":"DOI","asserted-by":"crossref"}]},{"name":"AstraZeneca"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Furosemide appears to contribute to the accumulation of protein-bound uremic toxins (PBUTs) and to induce adverse drug reactions. We investigated the extent to which the association between the furosemide dose and serum PBUT concentrations mediates the relationship between the furosemide dose and the symptom burden in patients with chronic kidney disease (CKD). This cross-sectional analysis included patients with CKD stages 2 to 5 from the CKD-REIN cohort and with data on the baseline serum concentrations of the free fractions of indoxyl sulphate (IS), kynurenine (KYN), p-cresyl sulphate (PCS), and indole-3-acetic acid (IAA), as measured by liquid chromatography\u2013tandem mass spectrometry. The symptom burden was also assessed with a modified (8-item) symptom subscale from the Kidney Disease Quality of Life-36 (e.g., muscle soreness, cramps, itchy skin, dry skin, dizziness, appetite, numbness, and nausea). We used beta regressions to model the association between the furosemide dose and the symptom burden and used structural equation models to quantify the mediating effect of PBUT on this association. Among the 2053 included patients (males: 66%, median age: 68; mean estimated glomerular filtration rate: 35 mL\/min\/1.73 m2), those prescribed high-dose furosemide (&gt;120 mg\/day) had higher symptom burden than those not prescribed furosemide (i.e., a 5.67-point lower symptom score, 95%CI 1.41\u20139.93). The sum of PBUTs explained 3.78% (95%CI 0.10\u201318.01%) of this association. Similar results were observed for IS, KYN, and IAA, considered separately, but not for PCS, whose estimated mediation effect was nearly null. Although high-dose furosemide was associated with a greater symptom burden in patients with CKD, mediation by PBUT accumulation appeared to be minimal.<\/jats:p>","DOI":"10.3390\/toxins17110541","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T17:32:01Z","timestamp":1762191121000},"page":"541","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Furosemide and the Symptom Burden: The Potential Mediating Role of Uremic Toxins in Patients with CKD"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7910-698X","authenticated-orcid":false,"given":"Margaux","family":"Costes-Albrespic","sequence":"first","affiliation":[{"name":"Centre for Research in Epidemiology and Population Health (CESP), INSERM UMRS 1018, Paris-Saclay University, Versailles Saint-Quentin University, F-94807 Villejuif, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5384-9006","authenticated-orcid":false,"given":"Sophie","family":"Liabeuf","sequence":"additional","affiliation":[{"name":"Pharmaco-Epidemiology Unit, Department of Clinical Pharmacology, Amiens-Picardie University Medical Centre, F-80054 Amiens, France"},{"name":"MP3CV Laboratory, Jules Verne University of Picardie, F-80054 Amiens, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9015-5342","authenticated-orcid":false,"given":"Islam-Amine","family":"Larabi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, CARNOT Personalized Medicine Platform, Raymond Poincar\u00e9 Hospital, Assistance Publique\u2013H\u00f4pitaux de Paris, F-92380 Garches, France"},{"name":"\u00c9quipe MOODS, Centre for Research in Epidemiology and Population Health (CESP), French National Institute of Health and Medical Research (Inserm) Unit 1018, Paris-Saclay University, Versailles Saint-Quentin University, F-92380 Garches, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0214-5567","authenticated-orcid":false,"given":"Sol\u00e8ne M.","family":"Laville","sequence":"additional","affiliation":[{"name":"Pharmaco-Epidemiology Unit, Department of Clinical Pharmacology, Amiens-Picardie University Medical Centre, F-80054 Amiens, France"},{"name":"MP3CV Laboratory, Jules Verne University of Picardie, F-80054 Amiens, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B\u00e9n\u00e9dicte","family":"Stengel","sequence":"additional","affiliation":[{"name":"Centre for Research in Epidemiology and Population Health (CESP), INSERM UMRS 1018, Paris-Saclay University, Versailles Saint-Quentin University, F-94807 Villejuif, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdou Y.","family":"Omorou","sequence":"additional","affiliation":[{"name":"UMR 1319 INSPIIRE, French National Institute of Health and Medical Research (Inserm), Universit\u00e9 de Lorraine, F-54500 Vandoeuvre-L\u00e8s-Nancy, France"},{"name":"Clinical Investigation Center in Clinical Epidemiology, French National Institute of Health and Medical Research (Inserm), University Hospital of Nancy (CHRU Nancy), Universit\u00e9 de Lorraine, F-54500 Vandoeuvre-L\u00e8s-Nancy, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luc","family":"Frimat","sequence":"additional","affiliation":[{"name":"UMR 1319 INSPIIRE, French National Institute of Health and Medical Research (Inserm), Universit\u00e9 de Lorraine, F-54500 Vandoeuvre-L\u00e8s-Nancy, France"},{"name":"Nephrology Department, University Regional Hospital of Nancy, F-54500 Vandoeuvre-L\u00e8s-Nancy, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5344-9475","authenticated-orcid":false,"given":"Jean-Claude","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, CARNOT Personalized Medicine Platform, Raymond Poincar\u00e9 Hospital, Assistance Publique\u2013H\u00f4pitaux de Paris, F-92380 Garches, France"},{"name":"\u00c9quipe MOODS, Centre for Research in Epidemiology and Population Health (CESP), French National Institute of Health and Medical Research (Inserm) Unit 1018, Paris-Saclay University, Versailles Saint-Quentin University, F-92380 Garches, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziad A.","family":"Massy","sequence":"additional","affiliation":[{"name":"Centre for Research in Epidemiology and Population Health (CESP), INSERM UMRS 1018, Paris-Saclay University, Versailles Saint-Quentin University, F-94807 Villejuif, France"},{"name":"AURA (Association pour l\u2019Utilisation du Rein Artificiel), F-75010 Paris, France"},{"name":"Nephrology Department, Ambroise Par\u00e9 University Hospital, Assistance Publique\u2013H\u00f4pitaux de Paris, F-92100 Boulogne-Billancourt, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0438-6487","authenticated-orcid":false,"given":"Natalia","family":"Alencar de Pinho","sequence":"additional","affiliation":[{"name":"Centre for Research in Epidemiology and Population Health (CESP), INSERM UMRS 1018, Paris-Saclay University, Versailles Saint-Quentin University, F-94807 Villejuif, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"the CKD-REIN Study 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