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Background
End-stage renal disease (ESRD), a final-stage kidney disease, is an important health issue worldwide. Increasing ESRD populations have become a substantial burden on global healthcare expenditures [1]. In addition, the rapid decline in renal function, defined as the glomerular filtration rate (GFR), is associated with an increased risk of cardiovascular and all-cause mortality [2]. According to KDIGO 2012 guidelines, the progression from chronic kidney disease (CKD) to ESRD is characterized by grade 5 CKD requiring renal replacement therapy such as kidney transplantation or hemodialysis. The United States Renal Data System (USRDS) Annual Data Report of 2014 indicated that Mexico (466.5 per million population), Taiwan (449.7 per million population), and the United States (358.7 per million population) are with the highest incidence rate of ESRD in 2012. Besides, Taiwan (2902.1 per million population), Japan (2365.2 per million population), and the United States (1975.5 per million population) are with the highest ESRD prevalence in 2012. In particular in Taiwan, a CKD epidemic area, around 60,000 ~ 70,000 ESRD patients receive dialysis each year, and consume 5.89% of the National Health Insurance budget [3].
The impairment of the renal endocrine role in ESRD patients can lead to anemia [4], and the incidence of secondary anemia increases as the GFR declines. In a healthy condition, renal secretion of erythropoietin (EPO) plays a crucial role in red blood cell (RBC) proliferation and differentiation, and insufficient EPO production in ESRD patients leads to both decreasing RBC production and a 30% ~ 70% shorter RBC lifespan [5]. In 2013, Lin et al. reported a significant decrease in the hemoglobin (Hb) level in CKD patients compared to non-CKD samples in both elderly (?60 years old) and non-elderly (>60 years old) subjects using a large Taiwanese cohort (n?=?3352). As anemia may lead to a significant increase of cardiovascular disease risk and faster renal function decline, managing anemia is therefore crucial for the quality of life of ESRD patients. As a good management of anemia will improve the clinical outcomes of ESRD patients, erythropoiesis-stimulating agents (ESAs) are therefore widely used in ESRD-associated anemia. However, some ESRD patients show poor responsibility to EPO treatment. The resistance to EPO was reported to be associated with adverse prognoses and poorer clinical outcomes [6, 7]. Patients with ESRD...