{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:04:55Z","timestamp":1792037095180,"version":"4.4.0"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T00:00:00Z","timestamp":1646265600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017902","name":"Panion & BF Biotech Inc.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017902","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>We explored the long-term safety and efficacy of ferric citrate in hemodialysis patients in Taiwan, and further evaluated the iron repletion effect and change of iron parameters by different baseline groups.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>This was a 12-month, Phase IV, multicenter, open-label study. The initial dose of ferric citrate was administered by patients\u2019 clinical condition and further adjusted to maintain serum phosphorus at 3.5\u20135.5 mg\/dL. The primary endpoint was to assess the safety profiles of ferric citrate. The secondary endpoints were to evaluate the efficacy by the time-course changes and the number of subjects who achieved the target range of serum phosphorus.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>A total of 202 patients were enrolled. No apparent or unexpected safety concerns were observed. The most common treatment-emergent adverse events were gastrointestinal-related with discolored feces (41.6%). Serum phosphorus was well controlled, with a mean dose of 3.35\u00b11.49 g\/day, ranging from 1.5 to 6.0 g\/day. Iron parameters were significantly improved. The change from baseline of ferritin and TSAT were 227.17 ng\/mL and 7.53%, respectively (p-trend&lt;0.001), and the increase started to slow down after 3\u20136 months of treatment. In addition, the increase trend was found only in patients with lower baseline level of ferritin (\u2264500 ng\/mL) and TSAT (&lt;30%).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Ferric citrate is an effective phosphate binder with favorable safety profile in ESRD patients. The iron-repletion by ferric citrate is effective, and the increase is limited in patients with a higher baseline. In addition to controlling hyperphosphatemia, ferric citrate also shows additional benefits in the treatment of renal anemia.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Clinical trial registration<\/jats:title>\n<jats:p>ClinicalTrials.gov ID: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03256838\" xlink:type=\"simple\">NCT03256838<\/jats:ext-link>; 12\/04\/2017.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0264727","type":"journal-article","created":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T19:15:13Z","timestamp":1646334913000},"page":"e0264727","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Long-term safety and efficacy of ferric citrate in phosphate-lowering and iron-repletion effects among patients with on hemodialysis: A multicenter, open-label, Phase IV trial"],"prefix":"10.1371","volume":"17","author":[{"given":"Chien-Te","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-Chan","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Ju","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Wen","family":"Chiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyh-Gang","family":"Leu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Shiou","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Sen","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai-Szu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5718-4128","authenticated-orcid":true,"given":"Der-Cherng","family":"Tarng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,3,3]]},"reference":[{"issue":"3","key":"pone.0264727.ref001","first-page":"15","article-title":"Hyperparathyroidism of Renal Disease.","volume":"20","author":"NK Yuen","year":"2016","journal-title":"Perm J."},{"issue":"11","key":"pone.0264727.ref002","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1001\/jama.2011.308","article-title":"Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis","volume":"305","author":"SC Palmer","year":"2011","journal-title":"JAMA"},{"issue":"8","key":"pone.0264727.ref003","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.1097\/01.ASN.0000133041.27682.A2","article-title":"Mineral metabolism, mortality, and morbidity in maintenance hemodialysis","volume":"15","author":"GA Block","year":"2004","journal-title":"J Am Soc Nephrol"},{"issue":"12","key":"pone.0264727.ref004","doi-asserted-by":"crossref","first-page":"2961","DOI":"10.1093\/ndt\/gft244","article-title":"Phosphate control in end-stage renal disease: barriers and opportunities","volume":"28","author":"AA Waheed","year":"2013","journal-title":"Nephrol Dial Transplant"},{"issue":"10","key":"pone.0264727.ref005","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.3109\/0886022X.2012.718724","article-title":"The adequacy of phosphorus binder prescriptions among American hemodialysis patients","volume":"34","author":"AM Huml","year":"2012","journal-title":"Ren Fail"},{"issue":"6","key":"pone.0264727.ref006","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1097\/PAS.0000000000000385","article-title":"Peculiar histiocytic lesions with massive lanthanum deposition in dialysis patients treated with lanthanum carbonate","volume":"39","author":"J Haratake","year":"2015","journal-title":"Am J Surg Pathol"},{"issue":"8","key":"pone.0264727.ref007","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s40265-014-0224-6","article-title":"Next-generation phosphate binders: focus on iron-based binders","volume":"74","author":"D Nastou","year":"2014","journal-title":"Drugs"},{"issue":"4","key":"pone.0264727.ref008","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.amjcard.2018.04.062","article-title":"Usefulness of Oral Ferric Citrate in Patients With Iron-Deficiency Anemia and Chronic Kidney Disease With or Without Heart Failure","volume":"122","author":"PA McCullough","year":"2018","journal-title":"Am J Cardiol"},{"issue":"7","key":"pone.0264727.ref009","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1093\/ndt\/gfy318","article-title":"Effect of ferric citrate on serum phosphate and fibroblast growth factor 23 among patients with nondialysis-dependent chronic kidney disease: path analyses","volume":"34","author":"GA Block","year":"2019","journal-title":"Nephrol Dial Transplant"},{"issue":"6","key":"pone.0264727.ref010","doi-asserted-by":"crossref","first-page":"E154","DOI":"10.1002\/ajh.25088","article-title":"Hemoglobin response to ferric citrate in patients with nondialysis-dependent chronic kidney disease and iron deficiency anemia","volume":"93","author":"PE Pergola","year":"2018","journal-title":"Am J Hematol"},{"issue":"11","key":"pone.0264727.ref011","doi-asserted-by":"crossref","first-page":"e0188712","DOI":"10.1371\/journal.pone.0188712","article-title":"Safety and efficacy of ferric citrate in patients with nondialysis-dependent chronic kidney disease.","volume":"12","author":"GM Chertow","year":"2017","journal-title":"PLoS One."},{"issue":"4","key":"pone.0264727.ref012","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1007\/s10157-017-1510-x","article-title":"Effect of ferric citrate hydrate on FGF23 and PTH levels in patients with non-dialysis-dependent chronic kidney disease with normophosphatemia and iron deficiency","volume":"22","author":"A Iguchi","year":"2018","journal-title":"Clin Exp Nephrol"},{"issue":"6","key":"pone.0264727.ref013","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1681\/ASN.2016101053","article-title":"Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia","volume":"28","author":"S Fishbane","year":"2017","journal-title":"J Am Soc Nephrol"},{"issue":"1","key":"pone.0264727.ref014","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s12185-021-03123-9","article-title":"Efficacy and safety of ferric citrate hydrate compared with sodium ferrous citrate in Japanese patients with iron deficiency anemia: a randomized, double-blind, phase 3 non-inferiority study","volume":"114","author":"N Komatsu","year":"2021","journal-title":"Int J Hematol"},{"issue":"7","key":"pone.0264727.ref015","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1159\/000516012","article-title":"Ferric Citrate Dosing in Iron Deficiency Anemia in Nondialysis-Dependent Chronic Kidney Disease.","volume":"52","author":"PE Pergola","year":"2021","journal-title":"Am J Nephrol"},{"issue":"2","key":"pone.0264727.ref016","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1681\/ASN.2014020212","article-title":"Ferric citrate controls phosphorus and delivers iron in patients on dialysis","volume":"26","author":"JB Lewis","year":"2015","journal-title":"J Am Soc Nephrol"},{"issue":"3","key":"pone.0264727.ref017","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s40268-015-0103-y","article-title":"Ferric Citrate, an Iron-Based Phosphate Binder, Reduces Health Care Costs in Patients on Dialysis Based on Randomized Clinical Trial Data","volume":"15","author":"RA Rodby","year":"2015","journal-title":"Drugs R D."},{"key":"pone.0264727.ref018","article-title":"Long-term efficacy and safety of iron-based phosphate binders, ferric citrate hydrate and sucroferric oxyhydroxide, in hemodialysis patients","author":"T Yoshida","year":"2021","journal-title":"Int Urol Nephrol"},{"issue":"1","key":"pone.0264727.ref019","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/ki.2014.275","article-title":"Data from the Dialysis Outcomes and Practice Patterns Study validate an association between high intravenous iron doses and mortality","volume":"87","author":"GR Bailie","year":"2015","journal-title":"Kidney Int"},{"issue":"9674","key":"pone.0264727.ref020","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1016\/S0140-6736(09)60502-X","article-title":"Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials","volume":"373","author":"J Bohlius","year":"2009","journal-title":"Lancet"},{"issue":"2","key":"pone.0264727.ref021","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1093\/ckj\/sfv142","article-title":"Safety concerns about intravenous iron therapy in patients with chronic kidney disease","volume":"9","author":"L Del Vecchio","year":"2016","journal-title":"Clin Kidney J"},{"issue":"3","key":"pone.0264727.ref022","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1053\/j.ajkd.2017.09.026","article-title":"Update on Anemia in ESRD and Earlier Stages of CKD: Core Curriculum 2018","volume":"71","author":"S Fishbane","year":"2018","journal-title":"Am J Kidney Dis"},{"issue":"19","key":"pone.0264727.ref023","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1001\/jama.2015.15572","article-title":"Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products","volume":"314","author":"C Wang","year":"2015","journal-title":"JAMA"},{"issue":"10","key":"pone.0264727.ref024","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.2215\/CJN.02600315","article-title":"Understanding the Recent Increase in Ferritin Levels in United States Dialysis Patients: Potential Impact of Changes in Intravenous Iron and Erythropoiesis-Stimulating Agent Dosing","volume":"10","author":"A Karaboyas","year":"2015","journal-title":"Clinical journal of the American Society of Nephrology: CJASN"},{"issue":"1","key":"pone.0264727.ref025","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/kisup.2015.6","article-title":"Thresholds of iron markers for iron deficiency erythropoiesis-finding of the Japanese nationwide dialysis registry","volume":"5","author":"T Hamano","year":"2015","journal-title":"Kidney international supplements"},{"issue":"1","key":"pone.0264727.ref026","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s40620-014-0108-6","article-title":"Effect of oral ferric citrate on serum phosphorus in hemodialysis patients: multicenter, randomized, double-blind, placebo-controlled study","volume":"28","author":"CT Lee","year":"2015","journal-title":"Journal of nephrology"},{"issue":"4","key":"pone.0264727.ref027","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1053\/j.jrn.2014.03.006","article-title":"Long-term safety and efficacy of a novel iron-containing phosphate binder, JTT-751, in patients receiving hemodialysis","volume":"24","author":"K Yokoyama","year":"2014","journal-title":"Journal of renal nutrition: the official journal of the Council on Renal Nutrition of the National Kidney Foundation"},{"issue":"12","key":"pone.0264727.ref028","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1111\/nep.12332","article-title":"Anaemia management in patients with chronic kidney disease: Taiwan practice guidelines","volume":"19","author":"SC Hung","year":"2014","journal-title":"Nephrology (Carlton, Vic)"},{"issue":"4","key":"pone.0264727.ref029","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1056\/NEJMra1004967","article-title":"Iron overload in human disease","volume":"366","author":"RE Fleming","year":"2012","journal-title":"N Engl J Med"},{"issue":"7","key":"pone.0264727.ref030","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/nrneph.2011.70","article-title":"Chronic kidney disease: Association between ESA use and stroke in patients with CKD","volume":"7","author":"L. Szczech","year":"2011","journal-title":"Nat Rev Nephrol"},{"issue":"3","key":"pone.0264727.ref031","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/ki.2011.49","article-title":"Erythropoiesis-stimulating agents increase the risk of acute stroke in patients with chronic kidney disease","volume":"80","author":"SL Seliger","year":"2011","journal-title":"Kidney Int"},{"issue":"Pt 1","key":"pone.0264727.ref032","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1113\/jphysiol.2006.122689","article-title":"Erythropoietin treatment elevates haemoglobin concentration by increasing red cell volume and depressing plasma volume","volume":"578","author":"C Lundby","year":"2007","journal-title":"J Physiol"},{"issue":"5","key":"pone.0264727.ref033","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1055\/s-0030-1255448","article-title":"Thrombotic complications of erythropoiesis-stimulating agents","volume":"36","author":"G Lippi","year":"2010","journal-title":"Semin Thromb Hemost"},{"issue":"12","key":"pone.0264727.ref034","first-page":"CD010590","article-title":"Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis","author":"SC Palmer","year":"2014","journal-title":"Cochrane Database Syst Rev"},{"issue":"12","key":"pone.0264727.ref035","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1345\/aph.1L231","article-title":"Tumor progression associated with erythropoiesis-stimulating agents","volume":"42","author":"AM Newland","year":"2008","journal-title":"Ann Pharmacother"},{"issue":"20","key":"pone.0264727.ref036","doi-asserted-by":"crossref","first-page":"6373","DOI":"10.1158\/1078-0432.CCR-10-2577","article-title":"The role of erythropoietin and erythropoiesis-stimulating agents in tumor progression","volume":"17","author":"BD Hedley","year":"2011","journal-title":"Clin Cancer Res"},{"issue":"8","key":"pone.0264727.ref037","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1001\/jama.299.8.914","article-title":"Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia","volume":"299","author":"CL Bennett","year":"2008","journal-title":"JAMA"},{"issue":"2","key":"pone.0264727.ref038","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/ndt\/gft269","article-title":"Iron toxicity: relevance for dialysis patients","volume":"29","author":"S Fishbane","year":"2014","journal-title":"Nephrol Dial Transplant"},{"issue":"9","key":"pone.0264727.ref039","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1681\/ASN.2007101084","article-title":"Intravenous iron exacerbates oxidative DNA damage in peripheral blood lymphocytes in chronic hemodialysis patients","volume":"19","author":"KL Kuo","year":"2008","journal-title":"J Am Soc Nephrol"},{"issue":"8","key":"pone.0264727.ref040","first-page":"1330","article-title":"Iron-related parameters in dialysis patients treated with sucroferric oxyhydroxide","volume":"32","author":"AC Covic","year":"2017","journal-title":"Nephrol Dial Transplant"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0264727","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T19:15:42Z","timestamp":1646334942000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0264727"}},"subtitle":[],"editor":[{"given":"Pasqual","family":"Barretti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,3,3]]},"references-count":40,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3,3]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0264727","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,3]]}}}