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

Patrícia Garrido,Sandra Ribeiro,Helena Vala,Elísio Costa,Luís Belo,Petronila Rocha-Pereira,Elsa Bronze-Da-Rocha,Flávio Reis,Alice Santos-Silva,João Fernandes

doi:10.3390/ijms17010028

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.

Highlights

Chronic kidney disease (CKD) is a debilitating disease affecting about 7% of people over the age of 30, which translates to more than 70 million people in developed countries worldwide [1]
The aim of this study is to clarify the mechanisms underlying this hyporesponse to endogenous EPO, as well as the impact of the long-term treatment of anemia with high doses of Recombinant human erythropoietin (rHuEPO) associated with antibody mediated erythroid hypoplasia, in a rat model of CKD induced by 5/6 nephrectomy previously characterized by us [29], focusing on iron metabolism, kidney hypoxia, inflammation and fibrosis
The CRF rats treated with 200 IU rHuEPO exhibited values similar to those found for CRF animals, excepting a significantly lower (p < 0.05) KW/Body weight (BW)

Summary

Introduction

Chronic kidney disease (CKD) is a debilitating disease affecting about 7% of people over the age of 30, which translates to more than 70 million people in developed countries worldwide [1]. There is a marked variability in the sensitivity to rHuEPO, with up to 10-fold changeability in dose requirements to achieve correction of the anemia, and 5%–10% of CKD patients show weak responses [18]; this hyporesponsiveness (or resistance) to rHuEPO therapy is associated with higher morbidity and mortality in ESRD patients [19,20]. RHuEPO is weakly immunogenic, it may induce the production of immunoglobulin (Ig) G antibodies against the recombinant molecules and the residual endogenous EPO [25,26,27] This adverse effect might become more common with the introduction of biosimilar products, but the mechanisms underlying this form of resistance and the impact on the typical features of this anemia remains to be elucidated

Objectives

Results

Discussion

Conclusion