Nephrology Division, Federal University of São Paulo, São Paulo, Brazil.
Wake Forest Institute for Regenerative Medicine, Winston Salem, North Carolina.
Am J Physiol Renal Physiol. 2020 Apr 1;318(4):F861-F869. doi: 10.1152/ajprenal.00433.2019. Epub 2020 Jan 31.
Serum soluble Fas (sFas) levels are associated with erythropoietin (Epo) hyporesponsiveness in patients with chronic kidney disease (CKD). Whether sFas could predict the need for erythropoiesis-stimulating agent (ESA) usage and its influence in erythropoiesis remain unclear. We evaluated the relation between sFas and ESA therapy in patients with CKD with anemia and its effect on erythropoiesis in vitro. First, we performed a retrospective cohort study with 77 anemic patients with nondialysis CKD. We performed in vitro experiments to investigate whether sFas could interfere with the behavior of hematopoietic stem cells (HSCs). HSCs were isolated from umbilical cord blood and incubated with recombinant sFas protein in a dose-dependent manner. Serum sFas positively correlated with Epo levels ( = 0.30, = 0.001) but negatively with hemoglobin ( = -0.55, < 0.001) and glomerular filtration rate ( = -0.58, < 0.001) in patients with CKD at baseline. Elevated sFas serum levels (4,316 ± 897 vs. 2,776 ± 749, < 0.001) with lower estimated glomerular filtration rate (26.2 ± 10.1 vs. 33.5 ± 14.3, = 0.01) and reduced hemoglobin concentration (11.1 ± 0.9 vs. 12.5 ± 1.2, < 0.001) were identified in patients who required ESA therapy compared with patients with non-ESA. Afterward, we detected that the sFas level was slight correlated with a necessity of ESA therapy in patients with nondialysis CKD and anemia. In vitro assays demonstrated that the erythroid progenitor cell frequency negatively correlated with sFas concentration ( = -0.72, < 0.001). There was decreased erythroid colony formation in vitro when CD34 HSCs were incubated with a higher concentration of sFas protein (1.56 ± 0.29, 4.33 ± 0.53, < 0.001). Our findings suggest that sFas is a potential predictor for ESA therapy in patients with nondialysis CKD and that elevated sFas could affect erythropoiesis in vitro.
血清可溶性 Fas（sFas）水平与慢性肾脏病（CKD）患者的促红细胞生成素（Epo）反应低下有关。sFas 是否可以预测促红细胞生成素刺激剂（ESA）的使用需求及其对红细胞生成的影响尚不清楚。我们评估了贫血非透析 CKD 患者中 sFas 与 ESA 治疗之间的关系及其对体外红细胞生成的影响。首先，我们进行了一项回顾性队列研究，纳入了 77 例非透析 CKD 伴贫血的患者。我们进行了体外实验，以研究 sFas 是否可以干扰造血干细胞（HSCs）的行为。从脐带血中分离出 HSCs，并以剂量依赖性方式与重组 sFas 蛋白孵育。在基线时，CKD 患者的血清 sFas 与 Epo 水平呈正相关（ = 0.30， = 0.001），与血红蛋白（ = -0.55， < 0.001）和肾小球滤过率（ = -0.58， < 0.001）呈负相关。与非 ESA 治疗的患者相比，需要 ESA 治疗的患者的血清 sFas 水平升高（4,316 ± 897 比 2,776 ± 749， < 0.001），估算的肾小球滤过率降低（26.2 ± 10.1 比 33.5 ± 14.3， = 0.01），血红蛋白浓度降低（11.1 ± 0.9 比 12.5 ± 1.2， < 0.001）。随后，我们发现血清 sFas 水平与非透析 CKD 伴贫血患者 ESA 治疗的必要性轻度相关。体外检测表明，红系祖细胞频率与 sFas 浓度呈负相关（ = -0.72， < 0.001）。当用更高浓度的 sFas 蛋白孵育 CD34 HSCs 时，体外红细胞集落形成减少（1.56 ± 0.29，4.33 ± 0.53， < 0.001）。我们的研究结果表明，sFas 是预测非透析 CKD 患者 ESA 治疗的一个潜在指标，升高的 sFas 可能会影响体外红细胞生成。
