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1.  Association of Serum Uric Acid Concentration with Diabetic Retinopathy and Albuminuria in Taiwanese Patients with Type 2 Diabetes Mellitus 
Patients with type 2 diabetes mellitus (DM) may experience chronic microvascular complications such as diabetic retinopathy (DR) and diabetic nephropathy (DN) during their lifetime. In clinical studies, serum uric acid concentration has been found to be associated with DR and DN. The goal of this study was to evaluate the relationship between the increases in serum uric acid level and the severity of DR and albuminuria in Taiwanese patients with type 2 DM. We recorded serum uric acid concentration, the severity of DR, and the severity of albuminuria by calculating urinary albumin-to-creatinine ratio (UACR) in 385 patients with type 2 DM. In multivariate logistic regression analysis, a high uric acid concentration was a risk factor for albuminuria (odds ratio (OR), 1.227; 95% confidence interval (CI) = 1.015–1.482; p = 0.034) and DR (OR, 1.264; 95% CI = 1.084–1.473; p = 0.003). We also demonstrated that there was a higher concentration of serum uric acid in the patients with more severe albuminuria and DR. In conclusion, an increased serum uric acid level was significantly correlated with the severity of albuminuria and DR in Taiwanese patients with type 2 DM.
PMCID: PMC5000646  PMID: 27490538
diabetes mellitus; diabetic retinopathy; uric acid; albuminuria; diabetic nephropathy
2.  Association of Brachial-Ankle Pulse Wave Velocity and Cardiomegaly With Aortic Arch Calcification in Patients on Hemodialysis 
Medicine  2016;95(19):e3643.
Aortic arch calcification (AoAC) is associated with cardiovascular and all-cause mortality in end-stage renal disease population. AoAC can be simply estimated with an AoAC score using plain chest radiography. The objective of this study is to evaluate the association of AoAC with brachial-ankle pulse wave velocity (baPWV) and cardiomegaly in patients who have undergoing hemodialysis (HD).
We retrospectively determined AoAC and cardiothoracic ratio (CTR) by chest x-ray in 220 HD patients who underwent the measurement of baPWV. The values of baPWV were measured by an ankle-brachial index-form device. Multiple stepwise logistic regression analysis was used to identify the factors associated with AoAC score >4.
Compared patients with AoAC score ≦4, patients with AoAC score >4 had older age, higher prevalence of diabetes and cerebrovascular disease, lower diastolic blood pressure, higher baPWV, higher CTR, higher prevalence of CTR ≧50%, lower total cholesterol, and lower creatinine level. After the multivariate stepwise logistic analysis, old age, cerebrovascular disease, high baPWV (per 100 cm/s, odds ratio [OR] 1.065, 95% confidence interval [CI] 1.003–1.129, P = 0.038), CTR (per 1%, OR 1.116, 95% CI 1.046–1.191, P = 0.001), and low total cholesterol level were independently associated with AoAC score >4.
Our study demonstrated AoAC severity was associated with high baPWV and high CTR in patients with HD. Therefore, we suggest that evaluating AoAC on plain chest radiography may be a simple and inexpensive method for detecting arterial stiffness in HD patients.
PMCID: PMC4902526  PMID: 27175684
3.  Variability in Estimated Glomerular Filtration Rate by Area under the Curve Predicts Renal Outcomes in Chronic Kidney Disease 
The Scientific World Journal  2014;2014:802037.
Greater variability in renal function is associated with mortality in patients with chronic kidney disease (CKD). However, few studies have demonstrated the predictive value of renal function variability in relation to renal outcomes. This study investigates the predictive ability of different methods of determining estimated glomerular filtration rate (eGFR) variability for progression to renal replacement therapy (RRT) in CKD patients. This was a prospective observational study, which enrolled 1,862 CKD patients. The renal end point was defined as commencement of RRT. The variability in eGFR was measured by the area under the eGFR curve (AUC)%. A significant improvement in model prediction was based on the −2 log likelihood ratio statistic. During a median 28.7-month follow-up, there were 564 (30.3%) patients receiving RRT. In an adjusted Cox model, a smaller initial eGFR AUC%_12M (P < 0.001), a smaller peak eGFR AUC%_12M (P < 0.001), and a larger negative eGFR slope_12M (P < 0.001) were associated with a higher risk of renal end point. Two calculated formulas: initial eGFR AUC%_12M and eGFR slope_12M were the best predictors. Our results demonstrate that the greater eGFR variability by AUC% is associated with the higher risk of progression to RRT.
PMCID: PMC4226187  PMID: 25401155
4.  Stepwise Increases in Left Ventricular Mass Index and Decreases in Left Ventricular Ejection Fraction Correspond with the Stages of Chronic Kidney Disease in Diabetes Patients 
Experimental Diabetes Research  2011;2012:789325.
Aims. Patients with diabetic nephropathy are reported to have a high prevalence of left ventricular structural and functional abnormalities. This study was designed to assess the determinants of left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF) in diabetic patients at various stages of chronic kidney disease (CKD). Methods. This cross-sectional study enrolled 285 diabetic patients with CKD stages 3 to 5 from our outpatient department of internal medicine. Clinical and echocardiographic parameters were compared and analyzed. Results. We found a significant stepwise increase in LVMI (P < 0.001), LVH (P < 0.001), and LVEF <55% (P = 0.013) and a stepwise decrease in LVEF (P = 0.038) corresponding to advance in CKD stages. Conclusions. Our findings suggest that increases in LVMI and decreases in LVEF coincide with advances in CKD stages in patients with diabetes.
PMCID: PMC3155789  PMID: 21860616
5.  Association of Ankle-Brachial Index and Aortic Arch Calcification with Overall and Cardiovascular Mortality in Hemodialysis 
Scientific Reports  2016;6:33164.
Peripheral artery occlusive disease and vascular calcification are highly prevalent in hemodialysis (HD) patients, however the association of the combination of ankle-brachial index (ABI) and aortic arch calcification (AoAC) with clinical outcomes in patients undergoing HD is unknown. In this study, we investigated whether the combination of ABI and AoAC is independently associated with overall and cardiovascular mortality in HD patients. The median follow-up period was 5.7 years. Calcification of the aortic arch was assessed by chest X-ray. Forty-seven patients died including 24 due to cardiovascular causes during the follow-up period. The study patients were stratified into four groups according to an ABI < 0.95 or ≥0.95 and an AoAC score of >4 or ≤4 according to receiver operating characteristic curve. Those with an ABI < 0.95 and AoAC > 4 (vs. ABI ≥ 0.95 and AoAC score ≤ 4) were associated with overall (hazard ratio [HR], 4.913; 95% confidence interval [CI], 1.932 to 12.497; p = 0.001) and cardiovascular (HR, 3.531; 95% CI, 1.070 to 11.652; p = 0.038) mortality in multivariable analysis. The combination of a low ABI and increased AoAC was associated with increased overall and cardiovascular mortality in patients undergoing HD.
PMCID: PMC5016837  PMID: 27608939
6.  Systolic time intervals derived from electrocardiographic gated intra-renal artery Doppler waveform associated with left ventricular systolic function 
Scientific Reports  2016;6:29293.
The aims of this study were to investigate the correlation between renal and cardiac STIs, including pre-ejection period (PEP), ejection time (ET), and PEP/ET, and to assess the diagnostic values of renal STIs in predicting left ventricular ejection fraction (LVEF) <50%. The cross sectional observation study enrolled 230 participants. The renal STIs, including renal PEP (rPEP), renal ET (rET), and rPEP/rET, were measured from electrocardiographic gated renal Doppler ultrasound and cardiac PEP, ET, and PEP/ET were measured from echocardiography. Renal STIs were correlated with cardiac STIs (all P < 0.001). Multivariate analyses showed that rPEP/rET was independently associated with LVEF (unstandardized coefficient β = −0.116, P = 0.046) and LVEF <50% (odds ratio = 2.145, per 0.11 increase; P = 0.017). The areas under the curve for rPEP, 1/rET, and rPEP/rET in predicting LVEF <50% were 0.773, 0.764, and 0.821, respectively. The sensitivity and specificity of rPEP/rET > 0.46 in prediction of LVEF <50% were 76.7% and 78.1%, respectively. Our study demonstrated that the novel parameters of renal STIs were significantly associated with cardiac STIs. However, the clinical application of renal STIs needs to be investigated in future studies.
PMCID: PMC4995511  PMID: 27553182
7.  Bone Metastasis from Renal Cell Carcinoma 
About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastasis that are often osteolytic and cause substantial morbidity, such as pain, pathologic fracture, spinal cord compression and hypercalcemia. The presence of bone metastasis in RCC is also associated with poor prognosis. Bone-targeted treatment using bisphosphonate and denosumab can reduce skeletal complications in RCC, but does not cure the disease or improve survival. Elucidating the molecular mechanisms of tumor-induced changes in the bone microenvironment is needed to develop effective treatment. The “vicious cycle” hypothesis has been used to describe how tumor cells interact with the bone microenvironment to drive bone destruction and tumor growth. Tumor cells secrete factors like parathyroid hormone-related peptide, transforming growth factor-β and vascular endothelial growth factor, which stimulate osteoblasts and increase the production of the receptor activator of nuclear factor κB ligand (RANKL). In turn, the overexpression of RANKL leads to increased osteoclast formation, activation and survival, thereby enhancing bone resorption. This review presents a general survey on bone metastasis in RCC by natural history, interaction among the immune system, bone and tumor, molecular mechanisms, bone turnover markers, therapies and healthcare burden.
PMCID: PMC4926516  PMID: 27338367
renal cell carcinoma; bone metastasis; molecular mechanisms; bone turnover markers; therapies
8.  The Role of Galectin-3 in the Kidneys 
Galectin-3 is a 32- to 35-kDa member of the galectin family of b-galactoside-binding lectins, which is characterized by a carbohydrate recognition domain. Through its carbohydrate-binding function, it regulates cell growth, differentiation, and inflammation. It also plays a complex, context-dependent role in the kidneys. During development, it promotes nephrogenesis and is strongly expressed in the ureteric bud and its derivatives. An increase in the concentration of galectin-3 has been reported to be associated with fibrosis of the kidneys. Elevated levels of plasma galectin-3 are also associated with increased risks of rapid renal function decline, incident chronic kidney disease, and progressive renal impairment, and also with cardiovascular end points, infection, and all-cause mortality in patients with renal function impairment. This review discusses a general survey on galectin-3 expressions in nephrogenesis, kidney injury animal models, clinical renal diseases, renal transplantation and the potential role of galectin-3 for treatment in kidney disease.
PMCID: PMC4849021  PMID: 27089335
galectin-3; kidney; clinical renal disease; nephrogenesis
9.  Estimated Glomerular Filtration Rate and Systolic Time Intervals in Risk Stratification for Increased Left Ventricular Mass Index and Left Ventricular Hypertrophy 
Medicine  2016;95(10):e2917.
Either decreased renal function or increased systolic time interval is associated with cardiac hypertrophy and poor cardiac outcome. The aim of this study was to evaluate combination of renal function and brachial systolic time intervals were associated with increased left ventricular mass index (LVMI) and left ventricular hypertrophy (LVH).
In total of 990 patients were consecutively included in this study from January 2011 to December 2012. All study participants were further classified into 4 groups by the values of estimated glomerular filtration rate (eGFR) and ratio of brachial preejection period (bPEP) to brachial ejection time (bET). The classification of 4 groups were eGFR ≥ 45 mL/min/1.73 m2 and bPEP/bET < 0.38 (group 1), eGFR ≥ 45 ml/min/1.73 m2 and bPEP/bET ≥ 0.38 (group 2), eGFR < 45 mL/min/1.73 m2 and bPEP/bET < 0.38 (group 3), and eGFR < 45 mL/min/1.73 m2 and bPEP/bET ≥ 0.38 (group 4), respectively. Patients in groups 1 and 4 had the lowest and highest LVMI among 4 groups, respectively (P < 0.001). In multivariable analyses, increased LVMI and LVH were significantly associated with patients in groups 2, 3 and 4 (vs group 1) (P ≤ 0.019).
Our study demonstrated that joined parameter of renal function and systolic time intervals, in terms of eGFR and bPEP/bET, might be an alternative method in risk stratification for increased LVMI and LVH.
PMCID: PMC4998869  PMID: 26962788
10.  Platelet to Lymphocyte Percentage Ratio Is Associated With Brachial–Ankle Pulse Wave Velocity in Hemodialysis 
Medicine  2016;95(6):e2727.
Increased arterial stiffness in patients receiving hemodialysis (HD) is highly prevalent and is associated with cardiovascular morbidity and mortality. In HD, inflammation is one of the major causes of increased arterial stiffness. Activation of platelets and decreased lymphocyte percentage (LYMPH%) may exhibit inflammation. The aim of this study is to examine the relationship between platelet to LYMPH% ratio and arterial stiffness in HD patients.
A total of 220 patients receiving HD were enrolled in this study. The brachial–ankle pulse wave velocity (baPWV) was measured using an ankle–brachial index form device. Multivariate linear regression analysis was performed to investigate the relations of the platelet to LYMPH% ratio and baPWV.
The value of the platelet to LYMPH% ratio was 59.2 ± 33.3 (109 cells/L/%). After multivariate stepwise analysis, diabetes (β: 163.973, P = 0.02), high systolic blood pressure (per 1 mm Hg, β: 9.010, P < 0.001), high platelet to LYMPH% ratio (per 109 cells/L/%, β: 3.334, P < 0.01), and low albumin (per 0.1 mg/dL, β: −55.912, P < 0.001) were independently associated with an increased baPWV. Furthermore, high white blood cells (per 109 cells/L, β: 3.941, P < 0.001), high neutrophil percentage (per 1%, β: 1.144, P < 0.001), and high CRP (per 1 mg/L, β: 9.161, P = 0.03) were independently associated with an increased platelet to LYMPH% ratio.
An increased platelet to LYMPH% ratio is associated with an increased baPWV in HD patients. An easy and inexpensive laboratory measure of platelet to LYMPH% ratio may provide an important information regarding arterial stiffness in patients with HD.
PMCID: PMC4753908  PMID: 26871812
11.  Heart Rate Variability Change Before and After Hemodialysis is Associated with Overall and Cardiovascular Mortality in Hemodialysis 
Scientific Reports  2016;6:20597.
Low heart rate variability (HRV) has been recognized to correlate with adverse cardiovascular (CV) outcomes in hemodialysis (HD) patients. It has been reported that HRV might be improved after HD, but whether the improved HRV after HD predicts a better CV prognosis remains to be determined. This study examined the ability of the change in HRV before and after HD in predicting overall and CV mortality in HD patients. This study enrolled 182 patients under maintenance HD. HRV was examined to assess changes before and after HD. The change in HRV (ΔHRV) was defined as post-HD HRV minus pre-HD HRV. During a median follow-up period of 35.2 months, 29 deaths (15.9%) were recorded. Multivariate analysis showed that decreased ΔLF% was associated with increased overall (hazard ratios [HR], 0.978; 95% confidence interval [CI], 0.961–0.996; p = 0.019) and CV mortality (HR, 0.941; 95% CI, 0.914–0.970; p < 0.001), respectively. Moreover, adding ΔLF% to a clinical model provided an additional benefit in the prediction of overall (p = 0.002) and CV mortality (p < 0.001). HRV change before and after HD (ΔHRV) is an useful clinical marker, and it is stronger than HRV before HD in predicting overall and CV mortality.
PMCID: PMC4745005  PMID: 26854202
12.  Association of the Ratio of Early Mitral Inflow Velocity to the Global Diastolic Strain Rate with a Rapid Renal Function Decline in Atrial Fibrillation 
PLoS ONE  2016;11(1):e0147446.
The ratio of early mitral inflow velocity (E) to the global diastolic strain rate (E’sr) has been correlated with left ventricular filling pressure and predicts adverse cardiac outcomes in atrial fibrillation (AF). The relationship between the E/E’sr ratio and renal outcomes in AF has not been evaluated. This study examined the ability of the E/E’sr ratio in predicting progression to the renal endpoint, which is defined as a ≥ 25% decline in the estimated glomerular filtration rate in patients with AF. Comprehensive echocardiography was performed on 149 patients with persistent AF, and E’sr was assessed from three standard apical views using the index beat method. During a median follow-up period of 2.3 years, 63 patients (42.3%) were reaching the renal endpoint. Multivariate analysis showed that an increased E/E’sr ratio (per 10 cm) (hazard ratio, 1.230; 95% confidence interval, 1.088 to 1.391; p = 0.001) was associated with an increased renal endpoint. In a direct comparison, the E/E’sr ratio outperformed the ratio of E to early diastolic mitral annular velocity (E’) in predicting progression to the renal endpoint in both univariate and multivariate models (p ≤ 0.039). Moreover, adding the E/E’sr ratio to a clinical model and echocardiographic parameters provided an additional benefit in the prediction of progression to the renal endpoint (p = 0.006). The E/E’sr ratio is a useful parameter and is stronger than the E/E’ ratio in predicting the progression to the renal endpoint, and it may offer an additional prognostic benefit over conventional clinical and echocardiographic parameters in patients with AF.
PMCID: PMC4731152  PMID: 26820304
13.  Association of Far-Infrared Radiation Therapy and Ankle-Brachial Index of Patients on Hemodialysis with Peripheral Artery Occlusive Disease 
Background and Aim: The ankle-brachial index (ABI) is recognized to be a good marker for atherosclerosis, and is useful in the diagnosis of peripheral artery occlusive disease (PAOD) which is prevalent among patients on hemodialysis (HD).
Methods: This randomized trial aimed to evaluate the effect of far-infrared radiation (FIR) therapy on ABI in HD patients with PAOD. PAOD was defined as patients with ABI < 0.95. One hundred and eight HD patients were enrolled, including 50 in the control group and 58 in the FIR group. A WS TY101 FIR emitter was applied for 40 minutes during each HD session, three times per week for six months. The ABI was measured before and after the FIR therapy.
Results: Regardless of FIR therapy, the bilateral ABI decreased (in the FIR group, left: 0.88±0.22 to 0.85±0.24, p = 0.188; right: 0.92±0.20 to 0.90±0.23, p = 0.372; in control group, left: 0.91±0.23 to 0.88±0.21, p = 0144; right: 0.93±0.17 to 0.89±0.21, p = 0.082). Multivariate logistic analysis of the FIR group revealed that high uric acid (odds ratio [OR]: 2.335; 95% confidence interval [CI]: 1.117-4.882; p=0.024) and aspirin use (OR: 16.463; 95% CI: 1.787-151.638; p=0.013) were independently associated with increased bilateral ABI after FIR therapy.
Conclusions: This study demonstrates that ABI is not increased after FIR therapy in HD patients with PAOD. However, in the FIR group, patients with higher uric acid level or those who used aspirin have increased bilateral ABI after FIR therapy.
PMCID: PMC5165691  PMID: 27994503
ankle-brachial index; peripheral artery occlusive disease; far-infrared therapy; hemodialysis.
14.  Link between Peripheral Artery Disease and Heart Rate Variability in Hemodialysis Patients 
PLoS ONE  2015;10(8):e0120459.
Peripheral artery disease (PAD) and low heart rate variability (HRV) are highly prevalent in hemodialysis patients, and both are associated with increased cardiovascular morbidity and mortality. This study aims to examine the suggested relationship between PAD and HRV, and the relationship of parameters before and after hemodialysis. This study enrolled 161 maintenance hemodialysis patients. PAD was defined as ABI < 0.9 in either leg. HRV was performed to assess changes before and after hemodialysis. The change in HRV (△HRV) was defined as post-hemodialysis HRV minus pre-hemodialysis HRV. Patients’ clinical parameters were collected from the dialysis records. All HRV parameters except high frequency (HF) % were lower in patients with PAD than patients without PAD, though not achieving significant level. In patients without PAD, HF (P = 0.013), low frequency (LF) % (P = 0.028) and LF/HF (P = 0.034) were significantly elevated after hemodialysis, whereas no significant HRV parameters change was noted in patients with PAD. Serum intact parathyroid hormone was independently associated with △HF (β = -0.970, P = 0.032) and △LF% (β = -12.609, P = 0.049). Uric acid level (β = -0.154, P = 0.027) was negatively associated with △LF/HF in patients without PAD. Our results demonstrated that some of the HRV parameters were significantly increased after hemodialysis in patients without PAD, but not in patients with PAD, reflecting a state of impaired sympatho-vagal equilibrium. Severity of secondary hyperparathyroidism and hyperuricemia contributed to lesser HRV parameters increase after hemodialysis in patients without PAD.
PMCID: PMC4523171  PMID: 26237669
15.  Abnormally Low or High Ankle-Brachial Index Is Associated with Proliferative Diabetic Retinopathy in Type 2 Diabetic Mellitus Patients 
PLoS ONE  2015;10(7):e0134718.
Although some studies have reported that low ankle-brachial index (ABI) is associated with diabetic retinopathy (DR) in diabetic patients, it remains controversial as to which stage of DR. The aim of this study is to assess whether peripheral artery disease (PAD), indicated by abnormally low or high ABI, is associated with different stages of DR in patients with type 2 diabetes mellitus (DM), and further evaluate the risk factors. A total of 2001 (858 men and 1143 women) patients with type 2 DM who underwent ABI measurement in an outpatient clinic were enrolled. PAD was defined as ABI < 0.9 or ≧ 1.3 in either leg. DR was classified as non-DR, nonproliferative DR and proliferative DR stages. The clinical data were analyzed and the risk factors for abnormal ABI were determined by multivariate logistic regression analysis. The prevalence of ABI < 0.9 or ≧ 1.3 was 3.0%. Multivariate forward logistic regression analysis identified proliferative DR (vs. non-DR) was associated with abnormal ABI (odds ratio, 1.718; 95% confidence interval, 1.152 to 2.562; p = 0.008), but nonproliferative DR was not. Furthermore, the presence of coronary artery disease, cerebrovascular disease, declining renal function and patients without diuretics use were associated with abnormal ABI in patients with proliferative DR. Our study in patients of type 2 DM demonstrated that PAD was associated with proliferative DR. We emphasize the recommendation of performing the ABI test in this population at risk.
PMCID: PMC4521755  PMID: 26230390
16.  Body Mass Index, Mortality, and Gender Difference in Advanced Chronic Kidney Disease 
PLoS ONE  2015;10(5):e0126668.
Background and Aim
A higher body mass index (BMI) appears to be reversely associated with mortality in dialysis patients. Moreover, although women have better survival in chronic kidney disease (CKD), this survival advantage is cancelled in dialysis. The association between BMI and mortality and the gender difference remain controversial in advanced CKD.
This study enrolled 3,320 patients (1,938 men and 1,382 women) from southern Taiwan who had CKD stages 3–5 with a BMI of 15.0–35.0 kg/m2.
During a median 2.9-year follow-up, there were 328 (16.9%) all-cause mortality and 319 (16.5%) cardiovascular (CV) events and death in male patients, 213 (15.4%) all-cause mortality and 224 (16.2%) CV events and death in female patients. Compared with the reference BMI of 27.6–30.0 kg/m2 in an adjusted Cox model, lower-BMI groups in men, BMI 15.0–20.0 kg/m2 and 20.1–22.5 kg/m2, were associated with higher risks of all-cause mortality: hazard ratios (HRs) 3.19 (95% confidence interval [CI], 1.97–5.18) and 2.01 (95% CI, 1.29–3.14), respectively. Higher-BMI group in men, BMI 30.1–35.0 kg/m2, was associated with a higher risk of all-cause mortality: HR 1.72 (95% CI, 1.02–2.96). Likewise, lower- and higher-BMI groups in men were associated with a higher risk of CV events and death. In women, these associations between BMI and poor outcomes were not observed.
In advanced CKD, there was a reverse J-shaped association between BMI and all-cause mortality, and a U-shaped association between BMI and CV outcomes in men. Neutral associations between BMI and poor outcomes were detected in women. Gender could modify the effect of BMI on mortality in patients with CKD.
PMCID: PMC4420254  PMID: 25942584
17.  Significant Correlation between Brachial Pulse Pressure Index and Renal Resistive Index  
Acta Cardiologica Sinica  2015;31(2):98-105.
The renal resistive index (RI) is calculated as (peak systolic velocity - minimum diastolic velocity)/peak systolic velocity, and has been significantly associated with renal function. Pulse pressure index (PPI) is derived from a formula similar to renal RI, i.e. (systolic blood pressure - diastolic blood pressure)/systolic blood pressure. The purpose of this study was to investigate whether brachial PPI had a significant correlation with renal RI and could be used in identifying patients with impaired renal function.
We consecutively enrolled 255 patients referred for echocardiographic examination. The renal RI was measured from Doppler ultrasonography and blood pressure was measured from an ABI-form device.
Patients with brachial PPI ≥ 0.428 (mean value of brachial PPI) had a lower estimated glomerular filtration rate (eGFR) than those with brachial PPI < 0.428 (p < 0.001). After the multivariate analysis was completed, brachial PPI had a significant correlation with renal RI (unstandardized coefficient β = 0.53, p < 0.001). The areas under the curve for brachial PPI and renal RI in prediction of eGFR < 45 mL/min/1.73 m2 were 0.682 and 0.893 (both p < 0.001), respectively.
Brachial PPI was significantly correlated with renal RI. Patients with higher brachial PPI had a more reduced renal function. Hence, brachial PPI may be able to quickly reflect the intrarenal vascular hemodynamics, and may serve as an important tool for screening and follow-up for patients with abnormal renovascular resistance.
PMCID: PMC4804874  PMID: 27122855
Chronic kidney disease; Pulse pressure index; Resistive index
18.  Fluid Overload, Pulse Wave Velocity, and Ratio of Brachial Pre-Ejection Period to Ejection Time in Diabetic and Non-Diabetic Chronic Kidney Disease 
PLoS ONE  2014;9(11):e111000.
Fluid overload is one of the characteristics in chronic kidney disease (CKD). Changes in extracellular fluid volume are associated with progression of diabetic nephropathy. Not only diabetes but also fluid overload is associated with cardiovascular risk factors The aim of the study was to assess the interaction between fluid overload, diabetes, and cardiovascular risk factors, including arterial stiffness and left ventricular function in 480 patients with stages 4–5 CKD. Fluid status was determined by bioimpedance spectroscopy method, Body Composition Monitor. Brachial-ankle pulse wave velocity (baPWV), as a good parameter of arterial stiffness, and brachial pre-ejection period (bPEP)/brachial ejection time (bET), correlated with impaired left ventricular function were measured by ankle-brachial index (ABI)-form device. Of all patients, 207 (43.9%) were diabetic and 240 (50%) had fluid overload. For non-diabetic CKD, fluid overload was associated with being female (β = –2.87, P = 0.003), heart disease (β = 2.69, P = 0.04), high baPWV (β = 0.27, P = 0.04), low hemoglobin (β = –1.10, P<0.001), and low serum albumin (β = –5.21, P<0.001) in multivariate analysis. For diabetic CKD, fluid overload was associated with diuretics use (β = 3.69, P = 0.003), high mean arterial pressure (β = 0.14, P = 0.01), low bPEP/ET (β = –0.19, P = 0.03), low hemoglobin (β = –1.55, P = 0.001), and low serum albumin (β = –9.46, P<0.001). In conclusion, baPWV is associated with fluid overload in non-diabetic CKD and bPEP/bET is associated with fluid overload in diabetic CKD. Early and accurate assessment of these associated cardiovascular risk factors may improve the effects of entire care in late CKD.
PMCID: PMC4227653  PMID: 25386836
19.  P Wave Dispersion and Maximum P Wave Duration Are Associated with Renal Outcomes in Chronic Kidney Disease 
PLoS ONE  2014;9(7):e101962.
P wave parameters measured by 12-lead electrocardiogram (ECG) are commonly used as a noninvasive tool to evaluate left atrial enlargement. This study was designed to assess whether P wave parameters were associated with renal outcomes in chronic kidney disease (CKD) patients. This longitudinal study enrolled 439 patients with CKD stages 3–5. Renal end points were defined as the commencement of dialysis or death. Change in renal function was measured using the estimated glomerular filtration rate (eGFR) slope. We measured two ECG P wave parameters corrected for heart rate, i.e., corrected P wave dispersion and corrected maximum P wave duration. The values of P wave dispersion and maximum P wave duration were 88.8±21.7 ms and 153.3±21.7 ms, respectively. During the follow-up period (mean, 25.2 months), 95 patients (21.6%) started hemodialysis and 30 deaths (6.8%) were recorded. Multivariate Cox regression analysis identified that increased P wave dispersion [hazard ratio (HR), 1.020; 95% confidence interval (CI), 1.009–1.032; P<0.001] and maximum P wave duration (HR, 1.013; 95% CI, 1.003–1.024; P = 0.012) were associated with progression to renal end points. Furthermore, increased P wave dispersion (unstandardized coefficient β = –0.016; P = 0.037) and maximum P wave duration (unstandardized coefficient β = –0.014; P = 0.040) were negatively associated with the eGFR slope. We demonstrated that increased P wave dispersion and maximum P wave duration were associated with progression to the renal end points of dialysis or death and faster renal function decline in CKD patients. Screening CKD patients on the basis of P wave dispersion and maximum P wave duration may help identify patients at high risk for worse renal outcomes.
PMCID: PMC4090207  PMID: 25006682
20.  Association of Relatives of Hemodialysis Patients with Metabolic Syndrome, Albuminuria and Framingham Risk Score 
PLoS ONE  2014;9(5):e96362.
Background and Aim
Metabolic syndrome (MetS), albuminuria, and the Framingham Risk Score (FRS) are significant predictors for cardiovascular disease (CVD). However, the relationship and clinical significance of these CVD predictors in individuals with a family history of end-stage renal disease (ESRD) are unclear. We investigated the association of relatives of hemodialysis (HD) patients with MetS, albuminuria, and the FRS.
One hundred and sixty-six relatives of HD patients and 374 age- and sex- matched community controls were enrolled. MetS was defined using the Adult Treatment Panel III for Asians. Albuminuria was defined as urine albumin-to-creatinine ratio ≥30 mg/g. CVD risk was evaluated by the FRS.
A significantly higher prevalence of MetS (19.9% vs. 12.5%, P = 0.026), albuminuria (12.7% vs. 5.1%, P = 0.002) and high FRS risk ≥10% of 10-year risk (15.7% vs. 8.5%, P = 0.013) was found in relatives of HD patients compared to their counterpart controls. In multivariate analysis, being relatives of HD patients (vs. controls) was an independent determinant for MetS (odds ratio [OR], 1.785; 95% confidence interval [CI], 1.045 to 3.050), albuminuria (OR, 2.891; 95% CI, 1.431 to 5.841), and high FRS risk (OR, 1.863; 95% CI, 1.015 to 3.418). Higher low-density lipoprotein cholesterol (OR, 1.034; 95% CI, 1.017 to 1.052) and betel nut chewing (OR, 13.994; 95% CI, 3.384 to 57.871) were independent determinants for having a high FRS risk in relatives of HD patients.
Being relatives of HD patients was independently associated with MetS, albuminuria and high FRS risk, suggesting family members of ESRD patients may have higher CVD risks through the interactions of renal risk factors. Proactive surveillance of these CVD predictors and preventive strategies should be targeted to this high-risk population.
PMCID: PMC4012957  PMID: 24804770
21.  Association of Bilateral Brachial-Ankle Pulse Wave Velocity Difference with Peripheral Vascular Disease and Left Ventricular Mass Index 
PLoS ONE  2014;9(2):e88331.
Unequal arterial stiffness had been associated with cardiovascular risks. We investigated whether an association existed between unequal arterial stiffness indicated by bilateral brachial-ankle pulse wave velocity (baPWV) difference and ankle-brachial index (ABI), baPWV, echocardiographic parameters and interarm and interankle systolic blood pressure (BP) differences. A total of 1111 patients referred for echocardiographic examination were included in this study. The BPs, ABI and baPWV were measured simultaneously by an ABI-form device. The ΔbaPWV was defined as absolute value of difference between bilateral baPWV. We performed three multivariate analyses for determining the factors associated with a ΔbaPWV ≧ 185 cm/s (90 percentile of ΔbaPWV) (model 1: significant variables in univariate analysis and ABI <0.9 and baPWV; model 2: significant variables in univariate analysis and left ventricular mass index [LVMI]; model 3: significant variables in univariate analysis and interankle systolic BP difference ≧ 15 mmHg). The ABI <0.9 and high baPWV (both P<0.001) in model 1, high LVMI (P = 0.021) in model 2 and an interankle systolic BP difference ≧ 15 mmHg (P = 0.026) in model 3 were associated with a ΔbaPWV ≧ 185 cm/s, but the interarm systolic BP difference ≧ 10 mmHg was not (P = NS). Our study demonstrated ABI <0.9, high baPWV, high LVMI and an interankle systolic BP difference ≧ 15 mmHg were associated with unequal arterial stiffness.
PMCID: PMC3923774  PMID: 24551090
22.  Discrepancy between Serological and Virological Analysis of Viral Hepatitis in Hemodialysis Patients 
Background and Aim: Viral hepatitis is a health threat for hemodialysis (HD) patients and it may be transmitted during treatment. Some patients categorized to have viral hepatitis were found to be non-viremic. To clarify the discrepancy between the serological tests in HD patients, we conducted the study.
Methods: A total of 1681 HD patients was included. Blood samples were analyzed for hepatitis B surface antigen (HBsAg) and anti-hepatitis C antibody (anti-HCV). Detection of hepatitis B virus (HBV) DNA and hepatitis C virus (HCV) RNA were performed in either HBsAg (+) or anti-HCV (+) samples. HBV DNA/HCV RNA was also measured in a subset of HBsAg (-) and anti-HCV (-) patients. Liver function tests were analyzed and compared with the serological and virological tests.
Results: The serological tests showed that 230 patients (13.7%) were HBsAg (+) and 290 (17.3%) were anti-HCV (+). We were unable to detect HBV DNA in 97 of 230 (42.2%) HBsAg (+) patients, and HCV RNA could not be found in 76 of 290 (26.2%) anti-HCV (+) patients. In 167 HBsAg (-) patients, only one showed a trace amount of HBV DNA. None of 151 anti-HCV (-) patients showed detectable HCV RNA. The prevalence rate of viral hepatitis remains high in Taiwanese HD patients: 13.7% for HBV and 17.3% for HCV. However, virological analysis showed 42.2% non-viremic rate for HBsAg and 26.2% non-viremic rate for anti-HCV.
Conclusions: The findings might challenge the presently suggested principles of bed and machine dedication and the diagnosis of viral hepatitis in HD patients.
PMCID: PMC3970094  PMID: 24688305
hepatitis B virus; hepatitis C virus; hemodialysis; viremia.
23.  Is Fluid Overload More Important than Diabetes in Renal Progression in Late Chronic Kidney Disease? 
PLoS ONE  2013;8(12):e82566.
Fluid overload is one of the major presentations in patients with late stage chronic kidney disease (CKD). Diabetes is the leading cause of renal failure, and progression of diabetic nephropathy has been associated with changes in extracellular fluid volume. The aim of the study was to assess the association of fluid overload and diabetes in commencing dialysis and rapid renal function decline (the slope of estimated glomerular filtration rate (eGFR) less than -3 ml/min per 1.73 m2/y) in 472 patients with stages 4-5 CKD. Fluid status was determined by bioimpedance spectroscopy method, Body Composition Monitor. The study population was further classified into four groups according to the median of relative hydration status (△HS =fluid overload/extracellular water) and the presence or absence of diabetes. The median level of relative hydration status was 7%. Among all patients, 207(43.9 %) were diabetic. 71 (15.0%) subjects had commencing dialysis, and 187 (39.6%) subjects presented rapid renal function decline during a median 17.3-month follow-up. Patients with fluid overload had a significantly increased risk for commencing dialysis and renal function decline independent of the presence or absence of diabetes. No significantly increased risk for renal progression was found between diabetes and non-diabetes in late CKD without fluid overload. In conclusion, fluid overload has a higher predictive value of an elevated risk for renal progression than diabetes in late CKD.
PMCID: PMC3857275  PMID: 24349311
24.  Association of Metabolic Syndrome and Albuminuria with Cardiovascular Risk in Occupational Drivers 
Background and Aim
Metabolic syndrome (MetS) and albuminuria increase cardiovascular risk. However, in occupational drivers, the clinical significance of albuminuria and its association with MetS remain unclear. We investigated the prevalence of MetS, albuminuria and cardiovascular risk, and its associated risk factors in occupational drivers;
441 occupational drivers and 432 age- and sex-stratified matched counterpart controls were enrolled. MetS was defined using Adult Treatment Panel III for Asians. Albuminuria was defined as urine albumin-to-creatinine ratio ≥ 30 mg/g. Cardiovascular disease risk was evaluated by Framingham Risk Score (FRS);
A significantly higher prevalence of MetS (43.1% vs. 25.5%, p < 0.001), albuminuria (12.0% vs. 5.6%, p = 0.001) and high FRS risk ≥ 10% of 10-year risk (46.9% vs. 35.2%, p < 0.001) was found in occupational drivers compared with their counterpart controls. Multiple logistic regression analysis showed that old age, a history of diabetes, gout and betel nut chewing, less exercise and albuminuria (odds ratio [OR], 2.75; p = 0.01) were risk factors for MetS, while a history of renal disease, diabetes and hypertension, and MetS (OR, 2.28; p = 0.01) were risk factors for albuminuria in occupational drivers;
Our study demonstrated that MetS and albuminuria were public health problems in occupational drivers. An education program for promoting healthy lifestyle and a regular occupational health visit for early detection and interventions should be established.
PMCID: PMC3856047  PMID: 24201129
occupational driver; metabolic syndrome; albuminuria; Framingham Risk Score
25.  Framingham Risk Score with Cardiovascular Events in Chronic Kidney Disease 
PLoS ONE  2013;8(3):e60008.
The Framingham Risk Score (FRS) was developed to predict coronary heart disease in various populations, and it tended to under-estimate the risk in chronic kidney disease (CKD) patients. Our objectives were to determine whether FRS was associated with cardiovascular events, and to evaluate the role of new risk markers and echocardiographic parameters when they were added to a FRS model. This study enrolled 439 CKD patients. The FRS is used to identify individuals categorically as “low” (<10% of 10-year risk), “intermediate” (10–20% risk) or “high” risk (≧ 20% risk). A significant improvement in model prediction was based on the −2 log likelihood ratio statistic and c-statistic. “High” risk (v.s. “low” risk) predicts cardiovascular events either without (hazard ratios [HR] 2.090, 95% confidence interval [CI] 1.144 to 3.818) or with adjustment for clinical, biochemical and echocardiographic parameters (HR 1.924, 95% CI 1.008 to 3.673). Besides, the addition of albumin, hemoglobin, estimated glomerular filtration rate, proteinuria, left atrial diameter >4.7 cm, left ventricular hypertrophy or left ventricular ejection fraction<50% to the FRS model significantly improves the predictive values for cardiovascular events. In CKD patients, “high” risk categorized by FRS predicts cardiovascular events. Novel biomarkers and echocardiographic parameters provide additional predictive values for cardiovascular events. Future study is needed to assess whether risk assessment enhanced by using these biomarkers and echocardiographic parameters might contribute to more effective prediction and better care for patients.
PMCID: PMC3603980  PMID: 23527293

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