{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:08:31Z","timestamp":1785802111544,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T00:00:00Z","timestamp":1700697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Patients undergoing hemodialysis often require zinc supplementation owing to hypozincemia, which may reduce serum copper concentrations. However, hypoxia-inducible factor\u2013prolyl hydroxylase inhibitors (HIF-PHIs), which are used to treat renal anemia, have been reported to increase serum copper. Therefore, this study investigates the effectiveness of a combination of HIF-PHIs and zinc for the stabilization of serum copper and zinc concentrations during zinc supplementation for patients undergoing hemodialysis with renal anemia and hypozincemia. The serum zinc and copper concentrations were retrospectively compared over an 8-month period in 20 patients being administered roxadustat (an HIF-PHI) and 20 controls. The changes in concentrations were tracked in participants taking roxadustat who initiated or increased zinc supplementation. The serum zinc concentrations of the participants were significantly higher (p &lt; 0.001) during zinc supplementation, regardless of roxadustat administration. Post-roxadustat, the serum copper concentrations were significantly higher than those pre-roxadustat or in non-roxadustat-treated participants, irrespective of zinc supplementation (p &lt; 0.005). Even post-roxadustat, the serum copper concentrations were significantly lower, with no increase during zinc supplementation (p &lt; 0.040). When zinc supplementation was initiated or increased in participants taking roxadustat, copper and zinc concentrations were normalized. Thus, combining zinc supplementation with roxadustat prevents both an excessive increase in serum copper and a decrease in serum zinc.<\/jats:p>","DOI":"10.3390\/nu15234887","type":"journal-article","created":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T03:45:56Z","timestamp":1700711156000},"page":"4887","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Co-Administration of Roxadustat and Zinc Stabilizes Both Serum Copper and Zinc Concentrations in Patients Undergoing Hemodialysis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6392-8349","authenticated-orcid":false,"given":"Akira","family":"Takahashi","sequence":"first","affiliation":[{"name":"Dialysis Center, Tesseikai Neurosurgical Hospital, 28-1 Nakanohonmachi, Shijonawate 575-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/nep.13835","article-title":"APSN HIF-PHI Recommendation Committee. Recommendations by the Asian Pacific Society of Nephrology (APSN) on the appropriate use of HIF-PH inhibitors","volume":"26","author":"Yap","year":"2021","journal-title":"Nephrology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1159\/000525735","article-title":"Four cases of serum copper excess in patients with renal anemia receiving a hypoxia-inducible factor-prolyl hydroxylase inhibitor: A possible safety concern","volume":"12","author":"Nakamura","year":"2022","journal-title":"Case Rep. Nephrol. Dial."},{"key":"ref_3","unstructured":"(2023, January 12). Post-Marketing Surveillance of EVRENZO\u00ae Tablets (Roxadustat) in Patients with Renal Anemia. ClinicalTrials.gov Identifier: NCT04408820. [Internet]. Available online: https:\/\/amn.astellas.jp\/content\/dam\/jp\/amn\/jp\/ja\/di\/doc\/Pdfs\/DocNo202110238_y.pdf?redirect=false."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1289\/ehp.94102958","article-title":"Gastrointestinal upsets associated with ingestion of copper-contaminated water","volume":"102","author":"Knobeloch","year":"1994","journal-title":"Environ. Health Perspect."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.jtemb.2005.01.003","article-title":"Prevalence of zinc deficiency and immune response in short-term hemodialysis","volume":"18","author":"Ozkan","year":"2005","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Wang, L.-J., Wang, M.-Q., Hu, R., Yang, Y., Huang, Y.-S., Xian, S.-X., and Lu, L. (2017). Effect of zinc supplementation on maintenance hemodialysis patients: A systematic review and meta-analysis of 15 randomized controlled trials. Biomed. Res. Int., 2017.","DOI":"10.1155\/2017\/1024769"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1093\/ajcn\/34.9.1670","article-title":"The effect of dietary zinc on intestinal copper absorption","volume":"34","author":"Fischer","year":"1981","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.3389\/fphys.2019.01584","article-title":"Zinc inhibits HIF-prolyl hydroxylase inhibitor-aggravated VSMC calcification induced by high phosphate","volume":"10","author":"Nagy","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.mehy.2007.04.051","article-title":"Alzheimer\u2019s disease as copper deficiency","volume":"70","author":"Klevay","year":"2008","journal-title":"Med. Hypotheses"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.3233\/JAD-150611","article-title":"Association Between Serum Ceruloplasmin Specific Activity and Risk of Alzheimer\u2019s Disease","volume":"50","author":"Siotto","year":"2016","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_11","unstructured":"Royer, A., and Sharman, T. (2023, January 12). Copper Toxicity [Updated 27 March 2023], StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK557456\/."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"809","DOI":"10.3233\/JAD-131247","article-title":"Meta-analysis of serum non-ceruloplasmin copper in Alzheimer\u2019s disease","volume":"38","author":"Squitti","year":"2014","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1053\/j.jrn.2022.02.007","article-title":"Role of zinc and copper in erythropoiesis in patients on hemodialysis","volume":"32","author":"Takahashi","year":"2022","journal-title":"J. Ren. Nutr."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Nishime, K., Kondo, M., Saito, K., Miyawaki, H., and Nakagawa, T. (2020). Zinc Burden Evokes Copper Deficiency in the Hypoalbuminemic Hemodialysis Patients. Nutrients, 12.","DOI":"10.3390\/nu12020577"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10655","DOI":"10.1021\/bi700798b","article-title":"Zinc lowers amyloid-beta toxicity by selectively precipitating aggregation intermediates","volume":"46","author":"Garai","year":"2007","journal-title":"Biochemistry"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9490","DOI":"10.1073\/pnas.0913114107","article-title":"Zinc ions promote Alzheimer Abeta aggregation via population shift of polymorphic states","volume":"107","author":"Miller","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4772","DOI":"10.1038\/s41598-018-23122-x","article-title":"Zinc ion rapidly induces toxic, off-pathway amyloid-\u03b2 oligomers distinct from amyloid-\u03b2 derived diffusible ligands in Alzheimer\u2019s disease","volume":"8","author":"Lee","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_18","first-page":"329","article-title":"Circadian characteristics of serum calcium, magnesium and eight trace elements and of their metallo-moieties in urine of healthy middle-aged men","volume":"159","author":"Kanabrocki","year":"2008","journal-title":"Clin. Ter."},{"key":"ref_19","unstructured":"Shibata, S., and Kitamura, M. (1964). Modern diagnostic testing system. Routine Clinical Biochemical Quantitative Methods, Nakayama Shoten Co, Ltd.. (In Japanese)."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kodama, H., Tanaka, M., Naito, Y., Katayama, K., and Moriyama, M. (2020). Japan\u2019s practical guidelines for zinc deficiency with a particular focus on taste disorders, inflammatory bowel disease, and liver cirrhosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082941"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s41100-017-0114-y","article-title":"2015 Japanese Society for Dialysis Therapy: Guidelines for renal anemia in chronic kidney disease","volume":"3","author":"Yamamoto","year":"2017","journal-title":"Ren. Replace. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/s41422-019-0260-6","article-title":"Transferrin plays a central role in coagulation balance by interacting with clotting factors","volume":"30","author":"Tang","year":"2020","journal-title":"Cell Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1161\/CIRCRESAHA.119.316453","article-title":"Iron-Deficiency and Estrogen Are Associated With Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability","volume":"127","author":"Tang","year":"2020","journal-title":"Circ. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1007\/s11255-012-0211-3","article-title":"Clinical factors associated with serum copper levels and potential effect of sevelamer in hemodialysis patients","volume":"45","author":"Ikee","year":"2013","journal-title":"Int. Urol. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"30","DOI":"10.5414\/CNP73030","article-title":"Metal ion and vitamin adsorption profiles of phosphate binder ion-exchange resins","volume":"73","author":"Takagi","year":"2010","journal-title":"Clin. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1042\/bj1990289","article-title":"Metal-dependent properties of metallothionein. Replacement in vitro of zinc in zinc-thionein with copper","volume":"199","author":"Suzuki","year":"1981","journal-title":"Biochem. J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Nakatani, S., Mori, K., Shoji, T., and Emoto, M. (2021). Association of Zinc Deficiency with Development of CVD Events in Patients with CKD. Nutrients, 13.","DOI":"10.3390\/nu13051680"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1172\/JCI38499","article-title":"HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice","volume":"119","author":"Mastrogiannaki","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1053\/j.gastro.2011.03.007","article-title":"Hypoxia-inducible factor-2\u03b1 mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice","volume":"140","author":"Taylor","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1242\/jcs.043216","article-title":"Copper transport into the secretory pathway is regulated by oxygen in macrophages","volume":"122","author":"White","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1016\/j.febslet.2012.05.058","article-title":"Basal expression of copper transporter 1 in intestinal epithelial cells is regulated by hypoxia-inducible factor 2\u03b1","volume":"586","author":"Pourvali","year":"2012","journal-title":"FEBS Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"C1298","DOI":"10.1152\/ajpcell.00023.2011","article-title":"Transcriptional regulation of the Menkes copper ATPase (Atp7a) gene by hypoxia-inducible factor (HIF2{alpha}) in intestinal epithelial cells","volume":"300","author":"Xie","year":"2011","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/s12011-011-9103-0","article-title":"The correlation of serum trace elements and heavy metals with carotid artery atherosclerosis in maintenance hemodialysis patients","volume":"144","author":"Ari","year":"2011","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"907","DOI":"10.2215\/CJN.11451017","article-title":"Concentrations of trace elements and clinical outcomes in hemodialysis patients: A prospective cohort study","volume":"13","author":"Tonelli","year":"2018","journal-title":"CJASN"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1080\/17474086.2022.2142113","article-title":"Copper deficiency, a rare but correctable cause of pancytopenia: A review of literature","volume":"15","author":"Tahir","year":"2022","journal-title":"Expert Rev. Hematol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.4065\/81.10.1371","article-title":"Copper Deficiency Myelopathy (Human Swayback)","volume":"81","author":"Kumar","year":"2006","journal-title":"Mayo Clin. Proc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1152\/physrev.00035.2014","article-title":"The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism","volume":"95","author":"Kambe","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ejphar.2018.07.019","article-title":"The effect of zinc supplementation on plasma C-reactive protein concentrations: A systematic review and meta-analysis of randomized controlled trials","volume":"834","author":"Mousavi","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1111\/jcmm.12239","article-title":"Zinc is essential for the transcription function of Nrf2 in human renal tubule cells in vitro and mouse kidney in vivo under the diabetic condition","volume":"18","author":"Li","year":"2014","journal-title":"J. Cell. Mol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"283","DOI":"10.4162\/nrp.2008.2.4.283","article-title":"Glycemic control of type 2 diabetic patients after short-term zinc supplementation","volume":"2","author":"Oh","year":"2008","journal-title":"Nutr. Res. Pract."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.3945\/ajcn.112.045575","article-title":"Dietary patterns and risk of dementia in an elderly Japanese population: The Hisayama Study","volume":"97","author":"Ozawa","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Canevelli, M., Lucchini, F., Quarata, F., Bruno, G., and Cesari, M. (2016). Nutrition and Dementia: Evidence for Preventive Approaches?. Nutrients, 8.","DOI":"10.3390\/nu8030144"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"171","DOI":"10.3233\/JAD-121474","article-title":"Longitudinal analysis of serum copper and ceruloplasmin in Alzheimer\u2019s disease","volume":"34","author":"Rembach","year":"2013","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"446","DOI":"10.3389\/fnagi.2017.00446","article-title":"Role of Copper in the Onset of Alzheimer\u2019s Disease Compared to Other Metals","volume":"9","author":"Bagheri","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1093\/aje\/kwac040","article-title":"The Associations of Dietary Copper with Cognitive Outcomes","volume":"191","author":"Wei","year":"2022","journal-title":"Am. J. Epidemiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"S74","DOI":"10.1016\/j.neurobiolaging.2014.03.033","article-title":"Dietary and lifestyle guidelines for the prevention of Alzheimer\u2019s disease","volume":"35","author":"Barnard","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3783","DOI":"10.3390\/nu7053783","article-title":"Oral zinc supplementation reduces the erythropoietin responsiveness index in patients on hemodialysis","volume":"7","author":"Kobayashi","year":"2015","journal-title":"Nutrients"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3109\/0886022X.2014.959412","article-title":"Effect of zinc supplementation on bone formation in hemodialysis patients with normal or low turnover bone","volume":"37","author":"Shiota","year":"2015","journal-title":"Ren. Fail."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.kint.2016.05.020","article-title":"Hypoxia-inducible factor-1 plays a role in phosphate-induced vascular smooth muscle cell calcification","volume":"90","author":"Mokas","year":"2016","journal-title":"Kidney Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1681\/ASN.2017050492","article-title":"Zinc inhibits phosphate-induced vascular calcification through TNFAIP3-mediated suppression of NF-\u03baB","volume":"29","author":"Voelkl","year":"2018","journal-title":"J. Am. Soc. Nephrol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/23\/4887\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:27:57Z","timestamp":1760131677000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/23\/4887"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,23]]},"references-count":50,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["nu15234887"],"URL":"https:\/\/doi.org\/10.3390\/nu15234887","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,23]]}}}