TY - JOUR
T1 - Resistance to recombinant human erythropoietin therapy in a rat model of chronic kidney disease associated anemia
AU - Garrido, Patrícia
AU - Ribeiro, Sandra
AU - Fernandes, João
AU - Vala, Helena
AU - Rocha-Pereira, Petronila
AU - Bronze-da-Rocha, Elsa
AU - Belo, Luís
AU - Costa, Elísio
AU - Santos-Silva, Alice
AU - Reis, Flávio
N1 - Publisher Copyright:
© 2015 by the authors; licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2015/12/25
Y1 - 2015/12/25
N2 - 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.
AB - 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.
KW - Anemia
KW - Chronic kidney disease
KW - Erythropoiesis
KW - Inflammation and fibrosis
KW - Iron metabolism
KW - Kidney hypoxia
KW - Remnant kidney rat model
KW - Resistance to rHuEPO therapy
UR - http://www.scopus.com/inward/record.url?scp=84951811485&partnerID=8YFLogxK
U2 - 10.3390/ijms17010028
DO - 10.3390/ijms17010028
M3 - Article
C2 - 26712750
AN - SCOPUS:84951811485
SN - 1661-6596
VL - 17
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 1
M1 - 28
ER -