Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
PLoS One. 2012;7(9):e41339. doi: 10.1371/journal.pone.0041339. Epub 2012 Sep 5.
Combined heart and renal failure is associated with high cardiovascular morbidity and mortality. Anti-oxidant and anti-inflammatory, non-hematopoietic effects of erythropoietin (EPO) treatment have been proposed. Monocytes may act as biosensors of the systemic environment. We hypothesized that monocyte transcriptomes of patients with cardiorenal syndrome (CRS) reflect the pathophysiology of the CRS and respond to short-term EPO treatment at a recommended dose for treatment of renal anemia.
Patients with CRS and anemia (n = 18) included in the EPOCARES trial were matched to healthy controls (n = 12). Patients were randomized to receive 50 IU/kg/week EPO or not. RNA from CD14(+)-monocytes was subjected to genome wide expression analysis (Illumina) at baseline and 18 days (3 EPO injections) after enrolment. Transcriptomes from patients were compared to healthy controls and effect of EPO treatment was evaluated within patients.
In CRS patients, expression of 471 genes, including inflammation and oxidative stress related genes was different from healthy controls. Cluster analysis did not separate patients from healthy controls. The 6 patients with the highest hsCRP levels had more differentially expressed genes than the 6 patients with the lowest hsCRP levels. Analysis of the variation in log(2) ratios of all individual 18 patients indicated that 4 of the 18 patients were different from the controls, whereas the other 14 were quite similar. After short-term EPO treatment, every patient clustered to his or her own baseline transcriptome. Two week EPO administration only marginally affected expression profiles on average, however, individual gene responses were variable.
In stable, treated CRS patients with mild anemia, monocyte transcriptomes were modestly altered, and indicated imprints of inflammation and oxidative stress. EPO treatment with a fixed dose has hematopoietic effects, had no appreciable beneficial actions on monocyte transcription profiles, however, could also not be associated with undesirable transcriptional responses.
心脏和肾脏同时衰竭与较高的心血管发病率和死亡率相关。促红细胞生成素(EPO)的抗氧化和抗炎、非造血作用已被提出。单核细胞可能作为全身环境的生物传感器。我们假设,心肾综合征(CRS)患者的单核细胞转录组反映了 CRS 的病理生理学,并对推荐剂量的 EPO 短期治疗做出反应,以治疗肾性贫血。
纳入 EPOCARES 试验的 CRS 伴贫血患者(n=18)与健康对照者(n=12)相匹配。患者随机接受 50IU/kg/周 EPO 或不接受。在基线和入组后 18 天(3 次 EPO 注射)时,用 CD14(+)单核细胞的 RNA 进行全基因组表达分析(Illumina)。将患者的转录组与健康对照者进行比较,并在患者内部评估 EPO 治疗的效果。
在 CRS 患者中,包括炎症和氧化应激相关基因在内的 471 个基因的表达与健康对照者不同。聚类分析未能将患者与健康对照者分开。hsCRP 水平最高的 6 例患者比 hsCRP 水平最低的 6 例患者有更多差异表达的基因。对所有 18 例患者个体 log2 比值变化的分析表明,18 例患者中有 4 例与对照组不同,而其余 14 例则非常相似。短期 EPO 治疗后,每位患者均聚类到自身的基线转录组。平均而言,两周 EPO 给药仅轻微影响表达谱,但个体基因的反应是可变的。
在稳定、经治疗的 CRS 患者中,轻度贫血时单核细胞转录组发生适度改变,并提示炎症和氧化应激的痕迹。用固定剂量的 EPO 治疗具有造血作用,但对单核细胞转录谱没有明显的有益作用,然而,也不能与不良的转录反应相关联。