Sang Koo Lee

Prevalence of Coronary Artery Disease Using Thallium-201 Single Photon Emission Computed Tomography among Patients Newly Undergoing Chronic Peritoneal Dialysis and Its Association with Mortality

Background: Previous data about the prevalence of coronary artery disease in dialysis patients were mainly based on history or electrocardiogram. Methods: We evaluated the prevalence of coronary artery disease using routine thallium-201 single photon emission computed tomography (SPECT) in 227 patients at the start of chronic peritoneal dialysis between January 1996 and October 2003. We also analyzed its association with mortality. Results: Fifty-one patients (22.5%) were positive on thallium SPECT. There were significant differences in age, underlying diabetic nephropathy, and C-reactive protein (CRP), serum albumin, total cholesterol, and prealbumin levels among patients positive and negative on thallium SPECT. Multivariate logistic regression analysis showed that age (≧60 years), underlying diabetic nephropathy, and CRP (≧0.5 mg/dl) were independent predictors of positive thallium SPECT, with the patients positive for all three factors having a probability for positive thallium SPECT of 43%, whereas patients negative for all three factors had a probability of only 4%. Ninety patients died, and 137 survived during the median follow-up period of 34 (range 3–99) months. Kaplan-Meier survival analysis revealed that age, underlying diabetic nephropathy, serum albumin, prealbumin, and CRP levels, positive thallium SPECT, and smoking affected survival. Survival was not different according to gender, presence of hypertension, body mass index, total cholesterol, or lipoprotein(a). Cox regression analysis showed that only underlying diabetic nephropathy and age (≧60 years) were independent predictors of mortality. Conclusions: We found that 22.5% of the patients who started chronic peritoneal dialysis had a positive thallium SPECT. Age, underlying diabetic nephropathy, and CRP were independent predictors of a positive thallium SPECT. Underlying diabetic nephropathy and age, but not positive thallium SPECT, were independent predictors of mortality.

Comparison of the MDRD Study and CKD-EPI Equations for the Estimation of the Glomerular Filtration Rate in the Korean General Population: The Fifth Korea National Health and Nutrition Examination Survey (KNHANES V-1), 2010

Background: We compared the accuracy of the Modification of Diet in Renal Disease (MDRD) study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in Korean patients and evaluated the difference in CKD prevalence determined using the two equations in the Korean general population. Methods: The accuracy of the two equations was evaluated in 607 patients who underwent a chromium-51-ethylenediaminetetraacetic acid GFR measurement. Additionally, we compared the difference in CKD prevalence determined by the two equations among 5,822 participants in the fifth Korea National Health and Nutrition Examination Survey, 2010. Results: Among the 607 subjects, the median bias of the CKD-EPI equation was significantly lower than that of the MDRD study equation (0.9 vs. 2.2, p=0.020). The accuracy of the two equations was not significantly different in patients with mGFR <60 mL/min/1.73m2; however, the accuracy of the CKD-EPI equation was significantly higher than that of the MDRD study equation in patients with GFR ≥60 mL/min/1.73m2. The prevalences of the CKD stages 1, 2 and 3 in the Korean general population were 47.56, 49.23, and 3.07%, respectively, for the MDRD study equation; and were 68.48, 28.89, and 2.49%, respectively, for the CKD-EPI equation. Conclusions: These data suggest that the CKD-EPI equation might be more useful in clinical practice than the MDRD study equation in Koreans.

EFFECTS OF HORMONAL REPLACEMENT THERAPY ON OXIDATIVE STRESS AND TOTAL ANTIOXIDANT CAPACITY IN POSTMENOPAUSAL HEMODIALYSIS PATIENTS

Background: Oxidative stress is known to be implicated in the pathogenesis of atherosclerotic cardiovascular disease. Many studies have demonstrated that hormone replacement therapy (HRT) has beneficial effects on oxidation injury in postmenopausal women with normal renal function. In this study, we examined the effects of HRT on plasma malondialdehyde (MDA) level and total antioxidant capacity (TAC) in postmenopausal hemodialysis women. Methods: We randomly assigned 70 postmenopausal women on maintenance hemodialysis into either a HRT group or a control group. Oral conjugated estrogen (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) was given daily for 12 weeks in HRT group. Plasma MDA, TAC, albumin, uric acid and C-reactive protein (CRP) were measured before, 4 and 12 weeks after the start of medication in the HRT group. In the control group, the same parameters were measured without HRT. Results: There was no difference in baseline values between the two groups. In the control group (n = 32), all these parameters showed no change at 4 and 12 weeks. HRT decreased MDA from 1.32 (0.55–1.88) µM to 1.08 (0.44–1.50) µM (p<0.001) at 4 weeks and to 1.11 (0.50–1.37) µM (p<0.001) at 12 weeks (n = 33). TAC was not changed at 4 weeks, however, it decreased from 1.59 (1.27–2.00) mM to 1.45 (1.08–1.65) mM (p<0.05) at 12 weeks. The albumin, uric acid and CRP levels were not changed significantly after HRT. Conclusions: These results suggest that HRT has a favorable effect on oxidative stress in postmenopausal women with ESRD as in the general population.BACKGROUND Oxidative stress is known to be implicated in the pathogenesis of atherosclerotic cardiovascular disease. Many studies have demonstrated that hormone replacement therapy (HRT) has beneficial effects on oxidation injury in postmenopausal women with normal renal function. In this study, we examined the effects of HRT on plasma malondialdehyde (MDA) level and total antioxidant capacity (TAC) in postmenopausal hemodialysis women. METHODS We randomly assigned 70 postmenopausal women on maintenance hemodialysis into either a HRT group or a control group. Oral conjugated estrogen (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) was given daily for 12 weeks in HRT group. Plasma MDA, TAC, albumin, uric acid and C-reactive protein (CRP) were measured before, 4 and 12 weeks after the start of medication in the HRT group. In the control group, the same parameters were measured without HRT. RESULTS There was no difference in baseline values between the two groups. In the control group (n = 32), all these parameters showed no change at 4 and 12 weeks. HRT decreased MDA from 1.32 (0.55-1.88) microM to 1.08 (0.44-1.50) microM (p < 0.001) at 4 weeks and to 1.11 (0.50-1.37) microM (p < 0.001) at 12 weeks (n = 33). TAC was not changed at 4 weeks, however, it decreased from 1.59 (1.27-2.00) mM to 1.45 (1.08-1.65) mM (p < 0.05) at 12 weeks. The albumin, uric acid and CRP levels were not changed significantly after HRT. CONCLUSIONS These results suggest that HRT has a favorable effect on oxidative stress in postmenopausal women with ESRD as in the general population.

Activation of spleen tyrosine kinase is required for TNF-α-induced endothelin-1 upregulation in human aortic endothelial cells.

Endothelin‐1 (ET‐1) promotes atherosclerosis. We tested whether spleen tyrosine kinase (Syk) mediates tumor necrosis factor‐α (TNF‐α)‐induced ET‐1 upregulation in human aortic endothelial cells (HAECs) and sought to identify the signal pathways involved. TNF‐α‐induced reactive oxygen species (ROS) activated Syk and phosphatidylinositol 3‐kinase (PI3K), which was required for the activation of AP‐1 and subsequent ET‐1 gene transcription. ROS mediated c‐Jun NH2‐terminal kinase (JNK) is also required for AP‐1 activation, but Syk and PI3K regulated AP‐1 activation independently of JNK. Through regulation of ET‐1 production, Syk could be implicated in atherosclerosis.

Spleen tyrosine kinase mediates high glucose-induced transforming growth factor-β1 up-regulation in proximal tubular epithelial cells

The role of spleen tyrosine kinase (Syk) in high glucose-induced intracellular signal transduction has yet to be elucidated. We investigated whether Syk is implicated in high glucose-induced transforming growth factor-β1 (TGF-β1) up-regulation in cultured human proximal tubular epithelial cells (HK-2 cell). High glucose increased TGF-β1 gene expression through Syk, extracellular signal-regulated kinase (ERK), AP-1 and NF-κB. High glucose-induced AP-1 DNA binding activity was decreased by Syk inhibitors and U0126 (an ERK inhibitor). Syk inhibitors suppressed high glucose-induced ERK activation, whereas U0126 had no effect on Syk activation. High glucose-induced NF-κB DNA binding activity was also decreased by Syk inhibitors. High glucose increased nuclear translocation of p65 without serine phosphorylation of IκBα and without degradation of IκBα, but with an increase in tyrosine phosphorylation of IκBα that may account for the activation of NF-κB. Both Syk inhibitors and Syk-siRNA attenuated high glucose-induced IκBα tyrosine phosphorylation and p65 nuclear translocation. Depletion of p21-activated kinase 2 (Pak2) by transfection of Pak2-siRNA abolished high glucose-induced Syk activation. In summary, high glucose-induced TGF-β1 gene transcription occurred through Pak2, Syk and subsequent ERK/AP-1 and NF-κB pathways. This suggests that Syk might be implicated in the diabetic kidney disease.

STAT1-Independent Down-Regulation of Interferon-Gamma-Induced Class II Transactivator and HLA-DR Expression by Transforming Growth Factor Beta-1 in Human Glomerular Endothelial Cells

Background: The competition between STAT1 and Smad3 for a limiting amount of the nuclear protein p300, a transcriptional coactivator, was suggested to be a mechanism for the antagonism between interferon-γ (IFN-γ) and transforming growth factor-β1 (TGF-β1). We investigated the effect of TGF-β1 on IFN-γ-induced HLA-DR production in cultured human glomerular endothelial cells (HGECs), and the involvement of p300 in this process. Methods: Cell surface expression of HLA-DR and mRNA levels of HLA-DR and class II transactivator (CIITA), the master regulator of HLA-DR gene transcription, were measured by cellular ELISA and Northern blot, respectively. The levels of STAT1 and Smad3 protein were analyzed by Western blot. Nuclear binding activity of STAT1 was assessed by electrophoretic mobility shift assay. Results: IFN-γ increased the cell surface expression of HLA-DR along with increases in the mRNA levels of CIITA and HLA-DR, while these stimulatory effects of IFN-γ were down-regulated by TGF-β1. IFN-γ increased phosphorylation of STAT1 and this activation was not inhibited by TGF-β1. IFN-γ increased binding of p-STAT1 to p300, while TGF-β1 increased binding of Smad3 to p300. TGF-β1-induced Smad3 binding to p300 was inhibited by IFN-γ, whereas IFN-γ-induced p-STAT1 binding to p300 was not inhibited by TGF-β1. IFN-γ increased DNA binding activity of STAT1. Inhibition of interaction between STAT1 and p300 by addition of anti-p300 antibody to nuclear extract down-regulated DNA binding activity of STAT1. In contrast, TGF-β1 did not inhibit IFN-γ-induced STAT1 binding to DNA. Conclusions: TGF-β1 down-regulated IFN-γ-induced CIITA and HLA-DR expression in HGECs. Though there was an antagonism between IFN-γ and TGF-β1, the competition for p300 between p-STAT1 and Smad3 was not the mechanism for it.