Resistance to Recombinant Human Erythropoietin Therapy in a Rat Model of Chronic Kidney Disease Associated Anemia

International Journal of Molecular Sciences

Patrໜia Garrido³  Sandra Ribeiro⁴  João Fernandes³  Helena Vala¹  Petronila Rocha-Pereira²  Elsa Bronze-da-Rocha⁴  Luís Belo⁴  Elísio Costa⁴  Alice Santos-Silva⁴  Flávio Reis³ 

[1] Center for Studies in Education, and Health Technologies, CI&DETS, CITAB, Agrarian School of Viseu, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal;Research Centre in Health Sciences, University of Beira Interior, 6201-001 Covilhã, Portugal;Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;UCIBIO@REQUIMTE, Faculty of Pharmacy, Department of Biological Sciences, Laboratory of Biochemistry, University of Porto, 4050-313 Porto, Portugal;

关键词: chronic kidney disease;    anemia;    resistance to rHuEPO therapy;    erythropoiesis;    iron metabolism;    kidney hypoxia;    inflammation and fibrosis;    remnant kidney rat model;   

DOI  :  10.3390/ijms17010028

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.