title: Resistance to Recombinant Human Erythropoietin Therapy in a Rat Model of Chronic Kidney Disease Associated Anemia.
abstract: This study aimed to elucidate the mechanisms explaining the persistence of anemia and resistance to recombinant human erythropoietin (rHuEPO) therapy in a rat model of chronic kidney disease (CKD)-associated anemia with formation of anti-rHuEPO antibodies. The remnant kidney rat model of CKD induced by 5/6 nephrectomy was used to test a long-term (nine weeks) high dose of rHuEPO (200 UI/kg bw/week) treatment. Hematological and biochemical parameters were evaluated as well as serum and tissue (kidney, liver and/or duodenum) protein and/or gene expression of mediators of erythropoiesis, iron metabolism and tissue hypoxia, inflammation, and fibrosis. Long-term treatment with a high rHuEPO dose is associated with development of resistance to therapy as a result of antibodies formation. In this condition, serum EPO levels are not deficient and iron availability is recovered by increased duodenal absorption. However, erythropoiesis is not stimulated, and the resistance to endogenous EPO effect and to rHuEPO therapy results from the development of a hypoxic, inflammatory and fibrotic milieu in the kidney tissue. This study provides new insights that could be important to ameliorate the current therapeutic strategies used to treat patients with CKD-associated anemia, in particular those that become resistant to rHuEPO therapy.
authors.affiliation: Laboratory of Pharmacology &amp; Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal. apatricia.garrido@gmail.com.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Garrido
authors.affiliation: UCIBIO@REQUIMTE, Faculty of Pharmacy, Department of Biological Sciences, Laboratory of Biochemistry, University of Porto, 4050-313 Porto, Portugal. sandra.ribeiro870@gmail.com.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ribeiro
authors.affiliation: Laboratory of Pharmacology &amp; Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal. fernandesjcg@gmail.com.|UCIBIO@REQUIMTE, Faculty of Pharmacy, Department of Biological Sciences, Laboratory of Biochemistry, University of Porto, 4050-313 Porto, Portugal. fernandesjcg@gmail.com.
authors.forename: João
authors.initials: J
authors.lastname: Fernandes
authors.affiliation: Center for Studies in Education, and Health Technologies, CI&amp;DETS, CITAB, Agrarian School of Viseu, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal. hvala@esav.ipv.pt.
authors.forename: Helena
authors.initials: H
authors.lastname: Vala
authors.affiliation: Research Centre in Health Sciences, University of Beira Interior, 6201-001 Covilhã, Portugal. petronila@live.com.pt.
authors.forename: Petronila
authors.initials: P
authors.lastname: Rocha-Pereira
authors.affiliation: UCIBIO@REQUIMTE, Faculty of Pharmacy, Department of Biological Sciences, Laboratory of Biochemistry, University of Porto, 4050-313 Porto, Portugal. elsa.rocha@ff.up.pt.
authors.forename: Elsa
authors.initials: E
authors.lastname: Bronze-da-Rocha
authors.affiliation: UCIBIO@REQUIMTE, Faculty of Pharmacy, Department of Biological Sciences, Laboratory of Biochemistry, University of Porto, 4050-313 Porto, Portugal. luisbelo@ff.up.pt.
authors.forename: Luís
authors.initials: L
authors.lastname: Belo
authors.affiliation: UCIBIO@REQUIMTE, Faculty of Pharmacy, Department of Biological Sciences, Laboratory of Biochemistry, University of Porto, 4050-313 Porto, Portugal. emcosta@ff.up.pt.
authors.forename: Elísio
authors.initials: E
authors.lastname: Costa
authors.affiliation: UCIBIO@REQUIMTE, Faculty of Pharmacy, Department of Biological Sciences, Laboratory of Biochemistry, University of Porto, 4050-313 Porto, Portugal. assilva@ff.up.pt.
authors.forename: Alice
authors.initials: A
authors.lastname: Santos-Silva
authors.affiliation: Laboratory of Pharmacology &amp; Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal. freis@fmed.uc.pt.|Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Consortium, University of Coimbra, 3000-548 Coimbra, Portugal. freis@fmed.uc.pt.
authors.forename: Flávio
authors.initials: F
authors.lastname: Reis
mesh_terms: D000740:Anemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology; D004351:Drug Resistance; D004386:Duodenum / Q000378:metabolism; D004921:Erythropoietin / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007501:Iron / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications*
chemical_list: D000906:Antibodies; D011994:Recombinant Proteins; D004921:Erythropoietin; D007501:Iron
keywords: anemia; chronic kidney disease; erythropoiesis; inflammation and fibrosis; iron metabolism; kidney hypoxia; remnant kidney rat model; resistance to rHuEPO therapy