{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T19:03:46Z","timestamp":1775675026151,"version":"3.50.1"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T00:00:00Z","timestamp":1554336000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T00:00:00Z","timestamp":1554336000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Pharmacosmos","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Intravenous (IV) iron is frequently used to treat iron deficiency\/anemia in patients who are unable to tolerate oral iron or the oral iron is not sufficient toreplete iron\u00a0requirements. However, safety concerns regarding the potential increase in oxidative stress and other adverse effects persist and it remains unclear whether all iron preparations are equivalent. Indeed, the comparative risk of adverse events with IV iron preparations has not been extensively assessed.<\/jats:p><jats:p>We hypothesize that IV iron leads to changes in oxidative stress, endothelial function, and potential renal damage depending on the iron formulation (related to the generation of \u201cfree\u201d or catalytic labile iron) and this may result in more tubular and glomerular injury manifested as increased proteinuria and raised neutrophil gelatinase\u2013associated lipocalin (NGAL) levels in patients with chronic kidney disease (CKD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>IRON-CKD is a prospective, open-label, explorative, randomized, single-center study designed to compare the safety and efficacy of three parenteral iron preparations: low-molecular-weight iron dextran\u2013Cosmofer, iron sucrose\u2013Venofer, and iron isomaltoside\u2013Monofer. The study includes 40 adults who have established CKD stages 3\u20135 and serum ferritin (SF) of less than 200 \u03bcg\/L or transferrin saturation (TS) of less than 20% (or both); they were randomly assigned in a 1:1:1:1 ratio to 200\u2009mg iron dextran, 200\u2009mg iron sucrose, 200\u2009mg iron isomaltoside, or 1000\u2009mg iron isomaltoside. After randomization, participants undergo baseline assessments and then an iron infusion. Each participant is followed up at 2\u2009h, day 1, week 1, and months 1 and 3. At each follow-up visit, patients undergo clinical review, measurement of pulse wave velocity (PWV), blood tests for renal function, and collection of serum\/plasma samples for oxidative stress and inflammatory markers.<\/jats:p><jats:p>The primary outcomes are measures of oxidative stress, inflammatory markers, and markers of acute renal injury in comparison with baseline measures\u00a0of each iron preparation and between each of the iron preparations. Secondary objectives include effects on hematinic profiles and hemoglobin concentrations, changes in arterial stiffness, incidence of significant side effects, and change in patients\u2019 quality of life.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Between October 2015 and April 2018, 521 individuals were identified as potential participants; 216 were contacted, 56 expressed an interest, 49 attended a screening visit, and 40 were confirmed to meet the eligibility criteria and were randomly assigned. The mean age was 58.3 (standard error of the mean 4.4) years, and 23 (58%) were male. All patients were white and English-speaking. The mean SF was 66.6 \u03bcg\/L, TS was 21.2%, and hemoglobin was 121.6\u2009g\/L at randomization for the whole group. The mean estimated glomerular filtration rate was 27.8\u2009mL\/min, the urinary protein\/creatinine ratio was 104.3\u2009mg\/mmol, and CRP was 6.65\u2009mg\/L.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>IRON-CKD will provide important information on the short-term effects of three preparations of IV iron in CKD patients with biochemical functional or absolute iron deficiency on measures of oxidative stress, inflammation, endothelial function, and renal injury.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration<\/jats:title><jats:p>European Clinical Trials Database (EudraCT) number<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.clinicaltrialsregister.eu\/ctr-search\/search?query=2010-020452-64\" ext-link-type=\"uri\">2010-020452-64<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s13063-019-3291-x","type":"journal-article","created":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T13:03:59Z","timestamp":1554383039000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Protocol and baseline data for a prospective open-label explorative randomized single-center comparative study to determine the effects of various intravenous iron preparations on markers of oxidative stress and kidney injury in chronic kidney disease (IRON-CKD)"],"prefix":"10.1186","volume":"20","author":[{"given":"Ahmed","family":"Ziedan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0996-9622","authenticated-orcid":false,"given":"Sunil","family":"Bhandari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,4,4]]},"reference":[{"key":"3291_CR1","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1159\/000151720","volume":"110","author":"HJ Cox","year":"2008","unstructured":"Cox HJ, Bhandari S, Rigby AS, Kilpatrick ES. Mortality at low and high estimated GFR values. A U- shaped curve. Nephron Clin Pract. 2008;110:67\u201372.","journal-title":"Nephron Clin Pract"},{"key":"3291_CR2","doi-asserted-by":"publisher","first-page":"S 112","DOI":"10.1053\/ajkd.1998.v32.pm9820470","volume":"32","author":"MJ Sarnak","year":"1998","unstructured":"Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998;32:S 112\u20139.","journal-title":"Am J Kidney Dis"},{"issue":"6","key":"3291_CR3","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1016\/S0272-6386(97)90087-1","volume":"30","author":"S Bhandari","year":"1997","unstructured":"Bhandari S, Norfolk D, Brownjohn A, Turney J. Evaluation of red blood cell ferritin and reticulocyte measurements in monitoring response to intravenous iron therapy. Am J Kidney Dis. 1997;30(6):814\u201321.","journal-title":"Am J Kidney Dis"},{"key":"3291_CR4","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1681\/ASN.V113530","volume":"11","author":"A Besarab","year":"2000","unstructured":"Besarab A, Amin N, Ashan M, Vogel SE, Zazuwa, Frinak S, et al. Optimisation of epoetin therapy with intravenous iron supplementation in haemodialysis patients. J Am Soc Nephrol. 2000;11:530\u20138.","journal-title":"J Am Soc Nephrol"},{"key":"3291_CR5","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1111\/j.1365-2753.2007.00932.x","volume":"14","author":"S Bhandari","year":"2008","unstructured":"Bhandari S, Naudeer S. Improving efficiency and value in Health Care. Intravenous iron management for anaemia associated with chronic kidney disease. Linking treatment to an outpatient clinic, optimising service provision and patient choice. J Eval Clin Pract. 2008;14:996\u20131001.","journal-title":"J Eval Clin Pract"},{"key":"3291_CR6","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1681\/ASN.2006050500","volume":"18","author":"SV Shah","year":"2007","unstructured":"Shah SV, Baliga R, Fonseca VA, Rajapurkar M. Oxidants in chronic kidney disease. J Am Soc Nephrol. 2007;18:16\u201328.","journal-title":"J Am Soc Nephrol"},{"key":"3291_CR7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0076-6879(90)86093-B","volume":"186","author":"B Halliwell","year":"1990","unstructured":"Halliwell B, Gutteridge JMC. Role of free radicals and catalytic metal ions in human disease: an overview. Meth Enzymol. 1990;186:1\u201385.","journal-title":"Meth Enzymol"},{"key":"3291_CR8","first-page":"57","volume":"18","author":"MM Rajapurkar","year":"2007","unstructured":"Rajapurkar MM, Baliga R, Shah SV. Treatment of patients with glomerulonephritis with an oral iron chelator [abstract]. J Am Soc Nephrol. 2007;18:57\u201358A.","journal-title":"J Am Soc Nephrol"},{"key":"3291_CR9","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1056\/NEJMoa021672","volume":"348","author":"J-L Lin","year":"2003","unstructured":"Lin J-L, Lin-Tan D-T, Hsu K-H, Yu C-C. Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N Engl J Med. 2003;348:277\u201386.","journal-title":"N Engl J Med"},{"key":"3291_CR10","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1002\/ajh.20056","volume":"76","author":"SB Silverstein","year":"2004","unstructured":"Silverstein SB, Rodgers GM. Parenteral iron preparations. Am J Haematol. 2004;76:74\u20138.","journal-title":"Am J Haematol"},{"key":"3291_CR11","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1053\/ajkd.2002.33917","volume":"40","author":"RA Zager","year":"2002","unstructured":"Zager RA, Johnson AC, Hanson SY, Wasse H. Parenteral iron formulations: a comparative toxicological analysis and mechanisms of cell injury. Am J Kid Dis. 2002;40:90\u2013103.","journal-title":"Am J Kid Dis"},{"key":"3291_CR12","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1111\/j.1523-1755.2004.00716.x","volume":"66","author":"RA Zager","year":"2004","unstructured":"Zager RA, Johnson AC, Hanson SY. Parenteral iron nephrotoxicity, potential mechanisms and consequences. Kidney Int. 2004;66:144\u201356.","journal-title":"Kidney Int"},{"key":"3291_CR13","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1016\/j.ejpb.2011.03.016","volume":"78","author":"MR Jahn","year":"2011","unstructured":"Jahn MR, Andreasen HB, F\u00fctterer S, Nawroth T, Sch\u00fcnemann V, Kolb U, et al. A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer), a new intravenous iron preparation and its clinical implications. Eur J Pharm Biopharm. 2011;78:480\u201391.","journal-title":"Eur J Pharm Biopharm"},{"key":"3291_CR14","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1038\/sj.ki.5002165","volume":"71","author":"K Mori","year":"2007","unstructured":"Mori K, Nakao K. Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage. Kidney Int. 2007;71:967\u201370.","journal-title":"Kidney Int"},{"key":"3291_CR15","doi-asserted-by":"crossref","first-page":"10425","DOI":"10.1016\/S0021-9258(18)82217-7","volume":"268","author":"L Kjeldsen","year":"1993","unstructured":"Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem. 1993;268:10425\u201332.","journal-title":"J Biol Chem"},{"key":"3291_CR16","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1016\/S0140-6736(05)74811-X","volume":"65","author":"J Mishra","year":"2005","unstructured":"Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, et al. NGAL as a biomarker of acute renal injury after cardiac surgery. Lancet. 2005;65:1231\u20138.","journal-title":"Lancet"},{"key":"3291_CR17","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1093\/ndt\/gfl408","volume":"22","author":"H Bachorzewska-Gajewska","year":"2007","unstructured":"Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, Malyszko JS, Dobrzyckin S. Neutrophil gelatinase-associated lipocalin (NGAL) correlations with cystatin C, serum creatinine and eGFR in patients with normal serum creatinine undergoing coronary angiography. Nephrol Dial Transplant. 2007;22:295\u20136.","journal-title":"Nephrol Dial Transplant"},{"key":"3291_CR18","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1159\/000078452","volume":"24","author":"J Mishra","year":"2004","unstructured":"Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P. Neutrophil gelatinase-associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol. 2004;24:307\u201315.","journal-title":"Am J Nephrol"},{"key":"3291_CR19","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1186\/s12882-017-0688-1","volume":"18","author":"A Mikhail","year":"2017","unstructured":"Mikhail A, Brown C, Williams JA, Mathrani V, Shrivastava R, Evans J, et al. Renal association clinical practice guideline on Anaemia of Chronic Kidney Disease. BMC Nephrol. 2017;18:345.","journal-title":"BMC Nephrol"},{"key":"3291_CR20","first-page":"5","volume":"25","author":"B Gandek","year":"2004","unstructured":"Gandek B, Sinclair SJ, Kosinski M, Ware JE. Psychometric Evaluation of the SF 36\u00ae Health Survey in Medicare Managed Care. Health Care Financ Rev. 2004;25:5\u201325.","journal-title":"Health Care Financ Rev"},{"key":"3291_CR21","first-page":"738","volume":"63","author":"M Broncel","year":"2006","unstructured":"Broncel M, Koter-Michalak M, Chojnowska-Jezierska J. The effect of statins on lipids peroxidation and activities of antioxidants enzymes in patients with dyslipidemia. Przeglad Lekarski. 2006;63:738\u201342 Retrieved from http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/17479860 .","journal-title":"Przeglad Lekarski"}],"updated-by":[{"DOI":"10.1186\/s13063-020-04238-w","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T00:00:00Z","timestamp":1584403200000}}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-019-3291-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13063-019-3291-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-019-3291-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T07:21:59Z","timestamp":1663226519000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-019-3291-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,4]]},"references-count":21,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["3291"],"URL":"https:\/\/doi.org\/10.1186\/s13063-019-3291-x","relation":{"correction":[{"id-type":"doi","id":"10.1186\/s13063-020-04238-w","asserted-by":"object"}]},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,4]]},"assertion":[{"value":"21 August 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 March 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 April 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 March 2020","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"After publication of our article [1], the database of IRON-CKD has undergone vigorous inspection \ufffd\ufffd\ufffd the authors have therefore re-examined database.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 information"}},{"value":"The study was given a favorable opinion from the Northern Regional Ethics Service (NRES) Committee Yorkshire and the Humber - Leeds East, UK (approval reference number 10\/H1306\/40). Study participants have all details explained to them in writing and in person before giving informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Neither this article nor substantial parts of it are under consideration for publication elsewhere or have been published or made available elsewhere in a manner that could be construed as a prior or duplicate publication of the same content.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"AZ declares that he has no competing interests. SB has received honorarium for lectures, attended expert opinion committees, and received educational funds to attend the European Society of Dialysis and Transplantation\u00a0(EDTA annual scienctic meeting 2016\u00a0and 2017) from Pharmacosmos and Vifor Pharma.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Publisher\u2019s Note"}}],"article-number":"194"}}