title: Renal risk-benefit determinants of recombinant human erythropoietin therapy in the remnant kidney rat model - hypertension, anaemia, inflammation and drug dose.
abstract: Clinical studies showed that high doses of recombinant human erythropoietin (rHuEPO) used to correct anaemia in chronic kidney disease (CKD) hyporesponsive patients may lead to deleterious effects. The aim of this study was to analyze the effects of rHuEPO in doses usually used to correct CKD-anaemia (100, 200 IU/kg body weight (BW) per week) and in higher doses used in the treatment of hyporesponsive patients (400, 600 IU/kg BW per week), focusing on renal damage, hypoxia, inflammation and fibrosis. Male Wistar rats with chronic renal failure (CRF) induced by 5/6 nephrectomy were treated with rHuEPO or with vehicle, over a 3-week period. Haematological, biochemical and renal function analyses were performed. Kidney and liver mRNA levels were evaluated by quantitative real-time polymerase chain reaction (qPCR) and protein expression by Western blot and immunohistochemistry. Kidney histopathological evaluations were also performed. The CRF group developed anaemia, hypertension and a high score of renal histopathologic lesions. Correction of anaemia was achieved with all rHuEPO doses, with improvement in hypertension, renal function and renal lesions. In addition, the higher rHuEPO doses also improved inflammation. Blood pressure was reduced in all rHuEPO-treated groups, compared to the CRF group, but increased in a dose-dependent manner. The current study showed that rHuEPO treatment corrected anaemia and improved urinary albumin excretion, particularly at lower doses. In addition, it is suggested that a short-term treatment with high doses, used to overcome an episode of hyporesponsiveness to rHuEPO therapy, can present benefits by reducing inflammation, without worsening of renal lesions; however, the pro-hypertensive effect should be considered, and carefully managed to avoid a negative cardiorenal impact.
authors.affiliation: Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ribeiro
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Centre for Neuroscience and Cell Biology - Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, Coimbra, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Garrido
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Centre for Neuroscience and Cell Biology - Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, Coimbra, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Fernandes
authors.affiliation: Centre for Studies in Education, Technologies and Health (CI&DETS), CITAB, Agrarian School of Viseu, Polytechnic Institute of Viseu, Viseu, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Vala
authors.affiliation: Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.
authors.forename: Petronila
authors.initials: P
authors.lastname: Rocha-Pereira
authors.affiliation: Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Elísio
authors.initials: E
authors.lastname: Costa
authors.affiliation: Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Belo
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Centre for Neuroscience and Cell Biology - Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, Coimbra, Portugal.
authors.forename: Flávio
authors.initials: F
authors.lastname: Reis
authors.affiliation: Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Alice
authors.initials: A
authors.lastname: Santos-Silva
mesh_terms: D000740:Anemia / Q000150:complications*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000150:complications*; D007249:Inflammation / Q000150:complications; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D012306:Risk; D018570:Risk Assessment
chemical_list: D011994:Recombinant Proteins; D004921:Erythropoietin
keywords: CKD; anaemia; high rHuEPO doses; hypertension; hyporesponsiveness; inflammation