{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:03:02Z","timestamp":1790103782105,"version":"4.0.1"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T00:00:00Z","timestamp":1645488000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>To elucidate the role of mTOR inhibitors on iron, hepcidin and erythropoietin-mediated regulation of hemopoiesis in stable renal transplant recipients (RTR).<\/jats:p><\/jats:sec><jats:sec><jats:title>Background<\/jats:title><jats:p>Impaired hemopoiesis is common following renal transplantation managed using mTOR inhibitors. The mechanisms responsible are uncertain but include direct effects on iron, hepcidin or erythropoietin-mediated hemopoiesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a single center prospective case-control study of 26 adult RTR with stable allograft function. RTR received stable mTOR dosing (cases, 11\/26 [42%]) or stable tacrolimus dosing (controls, 15\/26 [58%]). Baseline demographics, full blood count, renal function, iron studies, hepcidin-25, Interleukin-6 (IL-6) and erythropoietin (EPO) levels were determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>There were no differences in age, gender or allograft function. Mean daily sirolimus dose for cases was 1.72 mg, with mean trough level of 8.46 ng\/mL. Mean daily tacrolimus dose for controls was 4.3 mg, with mean trough level of 5.8 ng\/mL. There were no differences in mean hemoglobin (143 vs. 147 g\/L; <jats:italic>p<\/jats:italic> = 0.59), MCV (88 vs. 90 fL; <jats:italic>p<\/jats:italic> = 0.35), serum ferritin (150 vs. 85.7 \u03bcg\/L; <jats:italic>p<\/jats:italic> = 0.06), transferrin saturation (26 vs. 23.3%; <jats:italic>p<\/jats:italic> = 0.46), IL-6 (11 vs. 7.02 pg\/ml; <jats:italic>p<\/jats:italic> = 0.14) or hepcidin-25 (3.62 vs. 3.26 nM; <jats:italic>p<\/jats:italic> = 0.76) between the groups. EPO levels were significantly higher in the group receiving mTOR therapy (16.8 vs. 8.49 IU\/L; <jats:italic>p<\/jats:italic> = 0.028). On logistic regression analysis EPO level was the only variable that had a significant impact providing an odds ratio of 0.84 (95%CI 0.66\u20130.98). The area under the receiver operator characteristic curve (ROC) for the analysis was 0.77 (95%CI 0.54\u20130.94) with <jats:italic>p<\/jats:italic> = 0.04.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Higher levels of EPO in the absence of deranged iron biochemistry or hepcidin-25 levels suggest that EPO resistance rather than impaired iron metabolism may contribute to the impaired hemopoiesis previously demonstrated in RTR on mTOR therapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2022.722058","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T05:09:12Z","timestamp":1645506552000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["mTOR Inhibitors Induce Erythropoietin Resistance in Renal Transplant Recipients"],"prefix":"10.3389","volume":"9","author":[{"given":"Reece","family":"Jefferies","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harish","family":"Puttagunta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anoushka","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Irish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramyasuda","family":"Swaminathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John K.","family":"Olynyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1034\/j.1600-6143.2003.00133.x","article-title":"Prevalence and management of anemia in renal transplant recipients: a European survey","volume":"3","author":"Vanrenterghem","year":"2003","journal-title":"Am J Transplant"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3559","DOI":"10.1093\/ndt\/gfl457","article-title":"A prospective study of anaemia and long-term outcomes in kidney transplant recipients","volume":"21","author":"Winkelmayer","year":"2006","journal-title":"Nephrol Dial Transplant"},{"key":"B3","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1034\/j.1600-6143.2002.20506.x","article-title":"Late post-transplant anemia in adult renal transplant recipients. An under-recognized problem?","volume":"2","author":"Yorgin","year":"2002","journal-title":"Am J Transplant"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2001","DOI":"10.1111\/j.1600-6143.2004.00612.x","article-title":"Comparative effects of sirolimus and mycophenolate mofetil on erythropoiesis in kidney transplant patients","volume":"4","author":"Augustine","year":"2004","journal-title":"Am J Transplant"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2004","DOI":"10.1093\/ndt\/gfp778","article-title":"Cyclosporine, tacrolimus and sirolimus retain their distinct toxicity profiles despite low doses in the Symphony study","volume":"25","author":"Ekberg","year":"2010","journal-title":"Nephrol Dial Transplant"},{"key":"B6","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1093\/ndt\/16.1.18","article-title":"Sirolimus: a new promising immunosuppressive drug. Towards a rationale for its use in renal transplantation","volume":"16","author":"Morelon","year":"2001","journal-title":"Nephrol Dial Transplant"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1097\/01.tp.0000179106.07382.6a","article-title":"Anemia after late introduction of sirolimus may correlate with biochemical evidence of a chronic inflammatory state","volume":"80","author":"Thaunat","year":"2005","journal-title":"Transplantation"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2090","DOI":"10.1126\/science.1104742","article-title":"Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization","volume":"306","author":"Nemeth","year":"2004","journal-title":"Science"},{"key":"B9","doi-asserted-by":"publisher","first-page":"8780","DOI":"10.1073\/pnas.151179498","article-title":"Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice","volume":"98","author":"Nicolas","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"B10","doi-asserted-by":"publisher","first-page":"4596","DOI":"10.1073\/pnas.072632499","article-title":"Severe iron deficiency anemia in transgenic mice expressing liver hepcidin","volume":"99","author":"Nicolas","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"B11","doi-asserted-by":"publisher","first-page":"18975","DOI":"10.1074\/jbc.R115.650150","article-title":"Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation","volume":"290","author":"Schmidt","year":"2015","journal-title":"J Biol Chem"},{"key":"B12","doi-asserted-by":"publisher","first-page":"3204","DOI":"10.1182\/blood-2006-06-027631","article-title":"Interleukin-6 induces hepcidin expression through STAT3","volume":"108","author":"Wrighting","year":"2006","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1097\/01.tp.0000235545.49391.1b","article-title":"Sirolimus interferes with iron homeostasis in renal transplant recipients","volume":"82","author":"Maiorano","year":"2006","journal-title":"Transplantation"},{"key":"B14","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1097\/TP.0b013e3181814a96","article-title":"Reduction in erythropoietin resistance after conversion from sirolimus to enteric coated mycophenolate sodium","volume":"86","author":"Augustine","year":"2008","journal-title":"Transplantation"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1093\/ndt\/gfp674","article-title":"Anaemia, microcytosis and sirolimus\u2014is iron the missing link?","volume":"25","author":"Sofroniadou","year":"2010","journal-title":"Nephrol Dial Transplant"},{"key":"B16","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1007\/s40264-019-00810-9","article-title":"Sirolimus and mTOR inhibitors: a review of side effects and specific management in solid organ transplantation","volume":"42","author":"Nguyen","year":"2019","journal-title":"Drug Safety"},{"key":"B17","doi-asserted-by":"publisher","first-page":"604","DOI":"10.7326\/0003-4819-150-9-200905050-00006","article-title":"A new equation to estimate glomerular filtration rate","volume":"150","author":"Levey","year":"2009","journal-title":"Ann Intern Med"},{"key":"B18","volume-title":"Quantikine","year":"2015"},{"key":"B19","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1111\/nep.12815","article-title":"Association between serum hepcidin-25 and primary resistance to erythropoiesis-stimulating agents in chronic kidney disease: a secondary analysis of the HERO trial","volume":"22","author":"Gummer","year":"2017","journal-title":"Nephrology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/s40560-018-0328-2","article-title":"Hepcidin predicts response to IV iron therapy in patients admitted to the intensive care unit: a nested cohort study","volume":"6","author":"Litton","year":"2018","journal-title":"J Intens Care"},{"key":"B21","doi-asserted-by":"publisher","first-page":"19400","DOI":"10.1038\/s41598-019-55009-w","article-title":"Identification of The Canidae iron regulatory hormone hepcidin","volume":"9","author":"Mead","year":"2019","journal-title":"Sci Rep"},{"key":"B22","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1093\/ndt\/gfr318","article-title":"mTOR inhibition and erythropoiesis: microcytosis or anaemia?","volume":"27","author":"Diekmann","year":"2012","journal-title":"Nephrol Dial Transplant"},{"key":"B23","doi-asserted-by":"publisher","first-page":"6802","DOI":"10.3390\/ijms22136802","article-title":"New insights into red blood cell microcytosis upon mtor inhibitor administration","volume":"22","author":"Jakubowska","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B24","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.transproceed.2015.12.054","article-title":"Anemia and immunosuppressive regimen in renal transplanted patients: single-center retrospective study","volume":"48","author":"Carta","year":"2016","journal-title":"Transplant Proc"},{"key":"B25","doi-asserted-by":"publisher","first-page":"505","DOI":"10.3324\/haematol.2009.013136","article-title":"Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin","volume":"95","author":"Ashby","year":"2010","journal-title":"Haematologica"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1007\/s00421-011-2097-7","article-title":"Early effects of erythropoietin on serum hepcidin and serum iron bioavailability in healthy volunteers","volume":"112","author":"Lain\u00e9","year":"2012","journal-title":"Eur J Appl Physiol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"5727","DOI":"10.1182\/blood-2007-08-106195","article-title":"Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C\/EBPalpha","volume":"111","author":"Pinto","year":"2008","journal-title":"Blood"},{"key":"B28","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1111\/ejh.12122","article-title":"Serum hepcidin levels and muscle iron proteins in humans injected with low- or high-dose erythropoietin","volume":"91","author":"Robach","year":"2013","journal-title":"Eur J Haematol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.transproceed.2012.02.040","article-title":"Iron metabolism, hepcidin, and anemia in orthotopic heart transplantation recipients treated with mammalian target of rapamycin","volume":"45","author":"Przybylowski","year":"2013","journal-title":"Transplant Proc"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1097\/01.tp.0000260424.75005.c1","article-title":"Late introduction of sirolimus induces anemia in renal transplant recipients","volume":"83","author":"Thaunat","year":"2007","journal-title":"Transplantation"},{"key":"B31","doi-asserted-by":"publisher","first-page":"3915","DOI":"10.1002\/jmv.26654","article-title":"Defining IL-6 levels in healthy individuals: a meta-analysis","volume":"93","author":"Said","year":"2020","journal-title":"J Med Virol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"3436","DOI":"10.1182\/blood-2002-07-2332","article-title":"Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation","volume":"101","author":"Bouscary","year":"2003","journal-title":"Blood"},{"key":"B33","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/358070a0","article-title":"Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase","volume":"358","author":"Calvin","year":"1992","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1016\/0092-8674(92)90643-Q","article-title":"Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases","volume":"69","author":"Chung","year":"1992","journal-title":"Cell"},{"key":"B35","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/370071a0","article-title":"PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase","volume":"370","author":"Jongkyeong","year":"1994","journal-title":"Nature"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.722058\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T05:09:16Z","timestamp":1645506556000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.722058\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,22]]},"references-count":35,"alternative-id":["10.3389\/fmed.2022.722058"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2022.722058","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,22]]},"article-number":"722058"}}