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Renal risk‐benefit determinants of recombinant human erythropoietin therapy in the remnant kidney rat model – hypertension, anaemia, inflammation and drug dose
Author(s) -
Ribeiro Sandra,
Garrido Patrícia,
Fernandes João,
Vala Helena,
RochaPereira Petronila,
Costa Elísio,
Belo Luís,
Reis Flávio,
SantosSilva Alice
Publication year - 2016
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12541
Subject(s) - medicine , erythropoietin , kidney disease , renal function , kidney , nephrectomy , inflammation , endocrinology , anemia , fibrosis , gastroenterology , urology
Summary 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.