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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2015 Dec 30

PMID 26712750

Citations 6

Authors

Patricia Garrido

Sandra Ribeiro

Joao Fernandes

Helena Vala

Petronila Rocha-Pereira

Elsa Bronze-da-Rocha

Luis Belo

Elisio Costa

Alice Santos-Silva

Flavio Reis

Affiliations

Soon will be listed here.

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.

Citing Articles

Alkaloid fraction of flowers has low cytotoxicity and increases iron absorption through Erythropoietin-Matriptase-2-Hepcidin pathway in iron deficiency Hepatocarcinoma cell model.

Suselo Y, Indarto D, Wasita B, Hartono H Saudi J Biol Sci. 2022; 30(1):103508.

PMID: 36471797 PMC: 9718993. DOI: 10.1016/j.sjbs.2022.103508.

A Chinese herbal decoction, Jian-Pi-Yi-Shen, regulates the expressions of erythropoietin and pro-inflammatory cytokines in cultured cells.

Chen J, Gong A, Liu X, Li Z, Qi A, Dong T BMC Complement Altern Med. 2018; 18(1):119.

PMID: 29615029 PMC: 5883303. DOI: 10.1186/s12906-018-2146-4.

Alternative Erythropoietin Receptors in the Nervous System.

Ostrowski D, Heinrich R J Clin Med. 2018; 7(2).

PMID: 29393890 PMC: 5852440. DOI: 10.3390/jcm7020024.

Delivery of human erythropoietin gene with an adeno-associated virus vector through parotid glands to treat renal anaemia in a swine model.

Ma C, Fan Z, Gao Z, Wang S, Shan Z Gene Ther. 2017; 24(11):692-698.

PMID: 28753201 DOI: 10.1038/gt.2017.70.

Change in iron metabolism in rats after renal ischemia/reperfusion injury.

Xie G, Zhu L, Zhang Y, Zhang Q, Yu Q PLoS One. 2017; 12(4):e0175945.

PMID: 28426710 PMC: 5398610. DOI: 10.1371/journal.pone.0175945.

References

Kilpatrick R, Critchlow C, Fishbane S, Besarab A, Stehman-Breen C, Krishnan M . Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients. Clin J Am Soc Nephrol. 2008; 3(4):1077-83. PMC: 2440273. DOI: 10.2215/CJN.04601007. View

Strauch M, Gretz N . Animal models to induce renal failure: a historical survey. Contrib Nephrol. 1988; 60:1-8. DOI: 10.1159/000414783. View

Morrison A . Experimentally induced chronic renal insufficiency in the rat. Lab Invest. 1962; 11:321-32. View

Vaziri N . Anemia and anemia correction: surrogate markers or causes of morbidity in chronic kidney disease?. Nat Clin Pract Nephrol. 2008; 4(8):436-45. DOI: 10.1038/ncpneph0847. View

Risdon R, Sloper J, DE WARDENER H . Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet. 1968; 2(7564):363-6. DOI: 10.1016/s0140-6736(68)90589-8. View

Macdougall I . Antibody-mediated pure red cell aplasia (PRCA): epidemiology, immunogenicity and risks. Nephrol Dial Transplant. 2005; 20 Suppl 4:iv9-15. DOI: 10.1093/ndt/gfh1087. View

Haase V . Hypoxia-inducible factors in the kidney. Am J Physiol Renal Physiol. 2006; 291(2):F271-81. PMC: 4232221. DOI: 10.1152/ajprenal.00071.2006. View

Eddy A . Progression in chronic kidney disease. Adv Chronic Kidney Dis. 2005; 12(4):353-65. DOI: 10.1053/j.ackd.2005.07.011. View

Nankivell B, Boadle R, Harris D . Iron accumulation in human chronic renal disease. Am J Kidney Dis. 1992; 20(6):580-4. DOI: 10.1016/s0272-6386(12)70222-6. View

10.

Artunc F, Risler T . Serum erythropoietin concentrations and responses to anaemia in patients with or without chronic kidney disease. Nephrol Dial Transplant. 2007; 22(10):2900-8. DOI: 10.1093/ndt/gfm316. View

11.

Tanno T, Porayette P, Sripichai O, Noh S, Byrnes C, Bhupatiraju A . Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood. 2009; 114(1):181-6. PMC: 2710947. DOI: 10.1182/blood-2008-12-195503. View

12.

Acs G, Zhang P, McGrath C, Acs P, McBroom J, Mohyeldin A . Hypoxia-inducible erythropoietin signaling in squamous dysplasia and squamous cell carcinoma of the uterine cervix and its potential role in cervical carcinogenesis and tumor progression. Am J Pathol. 2003; 162(6):1789-806. PMC: 1868129. DOI: 10.1016/S0002-9440(10)64314-3. View

13.

Lombardero M, Kovacs K, Scheithauer B . Erythropoietin: a hormone with multiple functions. Pathobiology. 2011; 78(1):41-53. DOI: 10.1159/000322975. View

14.

Zhang A . Control of systemic iron homeostasis by the hemojuvelin-hepcidin axis. Adv Nutr. 2011; 1(1):38-45. PMC: 3042782. DOI: 10.3945/an.110.1009. View

15.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

16.

Palmer S, Navaneethan S, Craig J, Johnson D, Tonelli M, Garg A . Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med. 2010; 153(1):23-33. DOI: 10.7326/0003-4819-153-1-201007060-00252. View

17.

Preza G, Pinon R, Ganz T, Nemeth E . Cellular catabolism of the iron-regulatory peptide hormone hepcidin. PLoS One. 2013; 8(3):e58934. PMC: 3594189. DOI: 10.1371/journal.pone.0058934. View

18.

Donderski R, Szczepanek J, Domagalski K, Tretyn A, Korenkiewicz J, Marszalek A . Analysis of relative expression level of VEGF ( vascular endothelial growth factor ), HIF-1α ( hypoxia inducible factor 1α ) and CTGF ( connective tissue growth factor ) genes in chronic glomerulonephritis (CGN) patients. Kidney Blood Press Res. 2014; 38(1):83-91. DOI: 10.1159/000355754. View

19.

Fisher J . Erythropoietin: physiology and pharmacology update. Exp Biol Med (Maywood). 2003; 228(1):1-14. DOI: 10.1177/153537020322800101. View

20.

Weiss G . Iron metabolism in the anemia of chronic disease. Biochim Biophys Acta. 2008; 1790(7):682-93. DOI: 10.1016/j.bbagen.2008.08.006. View