Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
Oncology Lifecycle Management Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
Pharmacology. 2021;106(1-2):45-52. doi: 10.1159/000506995. Epub 2020 Aug 21.
Although erythropoiesis-stimulating agents (ESAs) exert renoprotective effects in renal disease models, it has not been revealed whether the prolonged duration of action of ESAs contributes to their renoprotective effects.
We examined whether the prolonged duration of ESAs' action contributes to their renoprotective effects by comparing a divided administration of a short-acting ESA, epoetin beta (EPO), or a single administration of a long-acting ESA, epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.), to a single administration of EPO in chronic glomerulonephritis (GN) rats.
Chronic GN was induced by intravenous injection of anti-Thy 1.1 antibody (0.6 mg/kg) into uninephrectomized rats (day 0). Chronic GN rats were intravenously injected once with vehicle (disease control; DC), EPO 5,000 IU/kg (single EPO), or C.E.R.A. 25 μg/kg (single C.E.R.A.) on day 1; or 3 times during the first week with EPO 1,667 IU/kg from day 1 (divided EPO; total 5,000 IU/kg). Hemoglobin (Hb) level and urinary total protein (U-TP) level which are the indexes of hematopoiesis and renoprotective effects, respectively, were measured several times over 8 weeks.
Divided EPO and single C.E.R.A. increased Hb levels more greatly than did single EPO. In all chronic GN rats, elevated U-TP levels decreased transiently 2 weeks after chronic GN induction and then flared again. Single EPO significantly suppressed this exacerbation of U-TP levels compared to DC. Divided EPO and single C.E.R.A. each significantly suppressed the exacerbation of U-TP levels compared to single EPO.
Prolonged duration of ESAs' action contributed significantly to their renoprotective effects.
尽管促红细胞生成素刺激剂（ESAs）在肾病模型中具有肾保护作用，但ESAs 的作用持续时间是否与其肾保护作用有关尚不清楚。
通过比较短效 ESA 促红素β（EPO）的分剂量给药或长效 ESA 聚乙二醇化促红素β（连续促红细胞生成素受体激活剂；C.E.R.A.）与单次给予 EPO 在慢性肾小球肾炎（GN）大鼠中的作用，来评估 ESA 的作用持续时间是否与其肾保护作用有关。
通过静脉注射抗 Thy 1.1 抗体（0.6mg/kg）到单侧肾切除大鼠（第 0 天）来诱导慢性 GN。在第 1 天，慢性 GN 大鼠分别静脉注射一次载体（疾病对照组；DC）、EPO5000IU/kg（单次 EPO）或 C.E.R.A.25μg/kg（单次 C.E.R.A.）；或在第 1 天开始的第 1 周内每天分 3 次给予 EPO1667IU/kg（分剂量 EPO；总量 5000IU/kg）。分别在 8 周内多次测量血红蛋白（Hb）水平和尿总蛋白（U-TP）水平，这分别是造血和肾保护作用的指标。
分剂量 EPO 和单次 C.E.R.A.比单次 EPO 更能显著提高 Hb 水平。在所有慢性 GN 大鼠中，升高的 U-TP 水平在慢性 GN 诱导后 2 周短暂下降，然后再次加剧。与 DC 相比，单次 EPO 显著抑制了 U-TP 水平的这种加剧。与单次 EPO 相比，分剂量 EPO 和单次 C.E.R.A.均显著抑制了 U-TP 水平的加剧。
ESAs 的作用持续时间与其肾保护作用显著相关。
