Statin therapy may improve responsiveness to erythropoietin-stimulating agents in patients with end-stage renal disease. Although statins increase hepatic iron uptake and storage capacity in cholestatic rats, the underlying mechanisms are unclear. Therefore, we examined the effects of a statin (simvastatin) on the expression of hepcidin, erythropoietin receptor (EPOR) and erythropoietin (EPO) in cultured HepG2 cells. HepG2 cells (6-6.5 × 10(5) cells) were seeded in 6-cm dishes and incubated overnight. The cells were then treated with 0, 0.5, 1, 3, 5, or 10 μM simvastatin, and the mRNA expression of hepcidin, EPOR, and EPO was determined. Data were collected from three independent experiments. The cDNA extracted from the cells was used as a template for real-time polymerase chain reaction, and each sample was tested in duplicate. Significant differences (P < 0.05) among groups were determined using one-way analysis of variance with Fisher's least significant difference post hoc test. Data were adjusted using Bonferroni's method. The relative mRNA expression of hepcidin in HepG2 cells treated with 0.5, 1, 3, 5, and 10 μM simvastatin, relative to the control group, was 0.7273, 0.3303, 0.2418, 0.4131, and 0.4064, respectively. The relative mRNA expression of EPOR was 0.5196, 0.2319, 0.2398, 0.4253, and 0.1245, respectively, while that of EPO was 0.9751, 0.4712, 0.4613, 0.4875, and 0.1654. There was a reverse dose-dependent effect of simvastatin. These results suggest that statins increase erythropoiesis by targeting hepcidin and iron regulatory pathways, independent of erythropoietin.
BackgroundLeft ventricular (LV) dyssynchrony is associated with increased risk of all-cause mortality in patients with end-stage renal disease. Our aim was to determine the associations of LV dynamic dyssynchrony with peritoneal solute clearance in continuous ambulatory peritoneal dialysis (CAPD) patients. Our primary objective was to determine the association between dynamic LV dyssynchrony and CAPD clearance at 2 years. Secondary objectives were to identify the factors influencing dynamic dyssynchrony, and to examine the association between dialysis adequacy and echocardiography-assessed LV outcomes.MethodsFifty CAPD patients and 13 healthy volunteers underwent three-dimensional (3D) dobutamine stress echocardiography (DSE). The main endpoint was systolic dyssynchrony index (SDI). Secondary endpoints, including NT-proBNP, troponin I, Kt/V, and biochemical parameters, were measured before stress echocardiography, and Kt/V was measured again 2 years later. All values are expressed as medians and interquartile ranges (IQR).ResultsNT-proBNP (3872 [808–11779] vs. 4.99 [4.99–36.83] pg/mL, P < 0.001), and log NT-proBNP (3.587 [2.896–4.071] vs. 0.698 [0.698–1.540], P < 0.001) levels were significantly higher in the CAPD group than in the control group. Real-time 3D DSE showed that the systolic dyssynchrony index was significantly different between the two groups at the peak dobutamine stage (1.11% [0.76–1.64%] vs. 0.66% [0.50–1.02%], P = 0.004), but not at resting (1.30% [0.89–1.74%] vs. 1.22 % [0.72–1.68%], P = 0.358).The subgroup of patients in the CAPD group with greater improvements in dialysis adequacy had lower baseline dynamic SDI and more favorable echocardiographic findings at 2 years. Dialysis adequacy decreased significantly at 2 year in patients with higher, but not in those with lower dynamic SDI at baseline. In multivariate linear regression analysis, log NT-proBNP and SDI at the peak dobutamine dose were significantly associated with Kt/V and weekly creatinine clearance at 2 years, while log NT-proBNP was significant associated with SDI at the peak dobutamine stage. Female CAPD patients group had more pronounced dynamic LV dyssynchrony compared with male patients.ConclusionsDynamic systolic dyssynchrony was strongly associated with future dialysis adequacy in CAPD patients. Log NT-proBNP was the important predictor of dynamic dyssynchrony. Our study confirmed the concept that cardiac dysfunction has an impact on dialysis adequacy.
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