Yao-Ping Lin

Intravenous ferric chloride hexahydrate supplementation induced endothelial dysfunction and increased cardiovascular risk among hemodialysis patients.

Background The association between intravenous (IV) iron administration and outcomes in hemodialysis (HD) patients is still debated. Therefore, this study was aimed to assess the relationship between the IV administration of ferric chloride hexahydrate (Atofen®) and cardiovascular (CV) outcome and the interaction between iron-induced oxidative stress and endothelial dysfunction in chronic HD patients. Methodology/Principal Findings A cohort of 1239 chronic HD patients was recruited. In a follow-up of 12 months, Kaplan-Meier survival curves showed that higher doses of IV Atofen associated with higher risks for CV events and deaths in HD patients. In multivariate Cox models, compared to no iron supplementation, IV Atofen administration was an independent predictor for CV events and overall mortality. However, the nature of the observational cohort study possibly bears selection bias. We further found that IV Atofen enhanced the superoxide production of mononuclear cells (MNCs), the levels of circulating soluble adhesion molecules, and the adhesion of MNCs to human aortic endothelial cells (HAECs). In vitro experiments showed that Atofen increased the expression of intracellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 in HAECs and aggravated the endothelial adhesiveness in a dose-dependent manner. These iron-induced changes were significantly attenuated by the co-treatment of HAECs with N-acetylcysteine and inhibitors of NADPH oxidase, nuclear factor κB, and activator protein-1. Conclusion A cumulative dose of IV Atofen >800 mg within 6 months was associated with an adverse CV outcome and a higher mortality among chronic HD patients. The detrimental effects of IV iron supplementation were partly due to the increased oxidative stress and induction of MNC adhesion to endothelial cells, a pivotal index of early atherogenesis.

Volume Status and Blood Pressure During Long-Term Hemodialysis: Role of Ventricular Stiffness

Abstract—The importance of volume status on blood pressure in hemodialysis patients has long been recognized. We hypothesized that the enhanced volume dependency of blood pressure is partly determined by ventricular stiffness at end systole. A total of 115 long-term hemodialysis patients were invited to receive a comprehensive, noninvasive cardiovascular examination. End-systolic elastance was determined by using a novel, noninvasive echo-Doppler technique. The positive ratios of the interdialytic systolic blood pressure change vs weight gain during the subsequent 25 hemodialysis sessions were averaged to obtain the volume sensitivity index (mm Hg/kg). The averaged interdialytic weight gain per fat-free mass was correlated significantly with averaged percent change in systolic blood pressure (r =0.45, P <0.001). The estimated end-systolic elastance at baseline was significantly correlated with subsequently observed volume sensitivity index (volume sensitivity index=[1.17×end-systolic elastance]+6.4; r =0.34, P =0.001). End-systolic elastance was also significantly correlated with various vascular function parameters, including effective arterial elastance (r =0.48, P <0.001), pulse wave velocity (r =0.30, P =0.001), carotid augmentation index (r =0.31, P <0.001), and aortic compliance (r =−0.49, P <0.001). The results suggest that end-systolic elastance, a direct measure of left ventricular mechanical properties at end systole, is coupled to arterial mechanical properties and predicts the extent of subsequent interdialytic systolic blood pressure rise relative to weight gain. Therefore, ventricular stiffness at end systole is a determinant of the enhanced volume sensitivity of blood pressure in hemodialysis patients.

Postdialysis blood pressure rise predicts long-term outcomes in chronic hemodialysis patients: a four-year prospective observational cohort study

BackgroundThe blood pressure (BP) of a proportion of chronic hemodialysis (HD) patients rises after HD. We investigated the influence of postdialysis BP rise on long-term outcomes.MethodsA total of 115 prevalent HD patients were enrolled. Because of the fluctuating nature of predialysis and postdialysis BP, systolic BP (SBP) and diastolic BP before and after HD were recorded from 25 consecutive HD sessions during a 2-month period. Patients were followed for 4 years or until death or withdrawal.ResultsKaplan-Meier estimates revealed that patients with average postdialysis SBP rise of more than 5 mmHg were at the highest risk of both cardiovascular and all-cause mortality as compared to those with an average postdialysis SBP change between -5 to 5 mmHg and those with an average postdialysis SBP drop of more than 5 mmHg. Furthermore, multivariate Cox regression analysis indicated that both postdialysis SBP rise of more than 5 mmHg (HR, 3.925 [95% CI, 1.410-10.846], p = 0.008) and high cardiothoracic (CT) ratio of more than 50% (HR, 7.560 [95% CI, 2.048-27.912], p = 0.002) independently predicted all-cause mortality. We also found that patients with an average postdialysis SBP rise were associated with subclinical volume overload, as evidenced by the significantly higher CT ratio (p = 0.008).ConclusionsA postdialysis SBP rise in HD patients independently predicted 4-year cardiovascular and all-cause mortality. Considering postdialysis SBP rise was associated with higher CT ratio, intensive evaluation of cardiac and volume status should be performed in patients with postdialysis SBP rise.

Erythropoiesis-stimulating agents in chronic kidney disease: what have we learned in 25 years?

Since the pioneering studies by Eschbach et al in 1987, erythropoiesis-stimulating agents (ESAs) have become the mainstay of anemia therapy in chronic kidney disease (CKD) patients. The introduction of ESAs 25 years ago markedly improved the lives of many patients with CKD, who until then had severe, often transfusion-dependent anemia. However, randomized controlled trials demonstrate an increased risk for cardiovascular events such as stroke, thrombosis, and death at nearly normal hemoglobin concentrations and higher ESA doses in CKD. By contrast, kidney transplant recipients may represent a unique population of CKD patients who may benefit from ESA therapy. This review discusses potential mechanisms involving the erythropoietic and nonerythropoietic effects of ESA treatment and ESA resistance. Further research aimed at elucidating the causal pathways is strongly recommended. Given current knowledge, however, clinical practice should avoid disproportionately high dosages of ESAs to achieve recommended hemoglobin targets, particularly in those with significant cardiovascular morbidity or ESA resistance. The key to CKD anemia management will be individualization of the potential benefits of reducing blood transfusions and anemia-related symptoms against the risks of harm.

Comparative proteomic analysis of rat aorta in a subtotal nephrectomy model

Although accelerated atherosclerosis and arteriosclerosis are the main causes of cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients, the molecular pathogenesis remains largely obscure. Our study of the aortic function in a typical CKD model of subtotal nephrectomy (SNX) rats demonstrated phenotypes that resemble CKD patients with aortic stiffness. The 2‐DE analysis of rat aortas followed by MS identified 29 up‐regulated and 53 down‐regulated proteins in SNX rats. Further Western blot and immunohistochemistry analyses validated the decreased HSP27 and increased milk fat globule epidermal growth factor‐8 (MFG‐E8) in SNX rats. Functional classification of differential protein profiles using KOGnitor revealed that the two major categories involved in aortic stiffness are posttranslational modification, protein turnover, chaperones (23%) and cytoskeleton (21%). Ingenuity Pathway Analysis highlighted cellular assembly and organization, and cardiovascular system development and function as the two most relevant pathways. Among the identified proteins, the clinical significance of the secreted protein MFG‐E8 was confirmed in 50 CKD patients, showing that increased serum MFG‐E8 level is positively related to aortic stiffness and renal function impairment. Drug interventions with an inhibitor of the angiotensin converting enzyme, enalapril, in SNX rats improved aortic stiffness and decreased MFG‐E8 depositions. Together, our studies provide a repertoire of potential biomarkers related to the aortic stiffness in CKD.

Aldosterone and Mortality in Hemodialysis Patients: Role of Volume Overload

Background Elevated aldosterone is associated with increased mortality in the general population. In patients on dialysis, however, the association is reversed. This paradox may be explained by volume overload, which is associated with lower aldosterone and higher mortality. Methods We evaluated the relationship between aldosterone and outcomes in a prospective cohort of 328 hemodialysis patients stratified by the presence or absence of volume overload (defined as extracellular water/total body water >48%, as measured with bioimpedance). Baseline plasma aldosterone was measured before dialysis and categorized as low (<140 pg/mL), middle (140 to 280 pg/mL) and high (>280 pg/mL). Results Overall, 36% (nu200a=u200a119) of the hemodialysis patients had evidence of volume overload. Baseline aldosterone was significantly lower in the presence of volume overload than in its absence. During a median follow-up of 54 months, 83 deaths and 70 cardiovascular events occurred. Cox multivariate analysis showed that by using the low aldosterone as the reference, high aldosterone was inversely associated with decreased hazard ratios for mortality (0.49; 95% confidence interval, 0.25–0.76) and first cardiovascular event (0.70; 95% confidence interval, 0.33−0.78) in the presence of volume overload. In contrast, high aldosterone was associated with an increased risk for mortality (1.97; 95% confidence interval, 1.69–3.75) and first cardiovascular event (2.01; 95% confidence interval, 1.28−4.15) in the absence of volume overload. Conclusions The inverse association of aldosterone with adverse outcomes in hemodialysis patients is due to the confounding effect of volume overload. These findings support treatment of hyperaldosteronemia in hemodialysis patients who have achieved strict volume control.

Early and late endophthalmitis following trabeculectomy in a Chinese population.

Purpose To investigate the rate of bleb-related endophthalmitis over 5 years in a Chinese population. Methods Retrospective chart review. Results Of 988 trabeculectomies performed over 5 years, one case (0.1%) developed early endophthalmitis caused by Morganella morganii, which was rarely reported in the literature. Six cases (0.6%) developed late-onset endophthalmitis. Mitomycin C significantly increased the risk of late-onset endophthalmitis (p=0.0002). Conclusions Physicians should weigh the benefits against the risks of mitomycin C application in performing trabeculectomies.

Plasma Protein Characteristics of Long-Term Hemodialysis Survivors

Hemodialysis (HD) patients are under recurrent circulatory stress, and hemodialysis has a high mortality rate. The characteristics of plasma proteomes in patients surviving long-term HD remain obscure, as well as the potential biomarkers in predicting prognoses. This study reports the proteome analyses of patient plasma from non-diabetic long-term HD (LHD, dialysis vintage 14.9±4.1 years, nu200a=u200a6) and the age/sex/uremic etiology-comparable short-term HD (SHD, dialysis vintage 5.3±2.9 years, nu200a=u200a6) using 2-DE and mass spectrometry. In addition, a 4-year longitudinal follow-up of 60 non-diabetic HD patients was subsequently conducted to analyze the baseline plasma proteins by ELISA in predicting prognosis. Compared to the SHD, the LHD survivors had increased plasma vitamin D binding proteins (DBP) and decreased clusterin, apolipoprotein A-IV, haptoglobin, hemopexin, complement factors B and H, and altered isoforms of α1-antitrypsin and fibrinogen gamma. During the 45.7±15 months for follow-up of the 60 HD patient cases, 16 patients died. Kaplan-Meier analysis demonstrated that HD patients with the lowest tertile of the baseline plasma DBP level have a significantly higher mortality rate. Multivariate Cox regression analysis further indicated that DBP is an independent predictor of mortality. In summary, the altered plasma proteins in LHD implicated accelerated atherosclerosis, defective antioxidative activity, increased inflammation/infection, and organ dysfunction. Furthermore, lower baseline plasma DBP in HD patients is related to mortality. The results suggest that the proteomic approach could help discover the potential biomarker in HD prognoses.

Decoy Receptor 3, a Novel Inflammatory Marker, and Mortality in Hemodialysis Patients

BACKGROUND AND OBJECTIVESnInflammation is closely associated with cardiovascular disease, the leading cause of mortality in patients with CKD. Serum decoy receptor 3 (DcR3) is a member of the TNF receptor superfamily. CKD patients have higher levels of DcR3 than the general population, but whether DcR3 predicts mortality in CKD patients on hemodialysis has not been explored.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnDcR3 levels were measured in 316 prevalent hemodialysis patients who were followed up from November 1, 2004, to June 30, 2009, for cardiovascular and all-cause mortality.nnnRESULTSnThe baseline DcR3 concentration showed a strong positive correlation with inflammatory markers including high-sensitivity C-reactive protein, IL-6, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). During a follow-up period of 54 months, 90 patients died (34 cardiovascular deaths). Kaplan-Meier survival analysis showed higher cardiovascular and all-cause mortality in patients with higher DcR3 levels. The hazard ratios (95% confidence intervals) of the highest versus lowest tertiles of DcR3 were 2.8 (1.1-7.3; P for trend=0.04) for cardiovascular mortality and 2.1 (1.1-3.7; P for trend=0.02) for all-cause mortality, respectively. Based on the minimal increase in the area under the receiver operating characteristic curve from 0.79 to 0.80, the addition of DcR3 to established risk factors including VCAM-1, albumin, and IL-6 does not improve the prediction of mortality.nnnCONCLUSIONSnHigher DcR3 levels strongly correlate with inflammation and independently predict cardiovascular and all-cause mortality in CKD patients on hemodialysis.

High Uric Acid Ameliorates Indoxyl Sulfate-Induced Endothelial Dysfunction and Is Associated with Lower Mortality among Hemodialysis Patients

High uric acid (UA) can act as a pro-oxidant in normal physiological conditions; however, emerging evidence is still debatable with regard to the association between high UA and poor outcomes among chronic hemodialysis (HD) patients. In the present study, 27,229 stable prevalent HD patients were enrolled and divided into four groups according to the quartiles of baseline UA concentration, and 5737 died during a median follow-up of 38 months. Multivariate Cox regression analysis showed that a UA level of <6.1 mg/dL was associated with a higher risk of all-cause mortality compared with a UA level of >8.1 mg/dL [HR, 1.20, 95% CI (1.10–1.31)] adjusting for baseline demographic and biochemical parameters. Moreover, a UA level of <6.1 mg/dL was associated with greater risks of cardiovascular mortality [HR, 1.26, 95% CI (1.13–1.41)] and stroke-related mortality [HR, 1.59, 95% CI (1.12–2.25)], respectively. In vitro experiments further showed an increase in oxidative stress and an inhibition nitric oxide synthesis by indoxyl sulfate (IS) in human aortic endothelial cells, which were significantly attenuated by UA in a dose-dependent manner. We concluded that higher UA in serum was associated with lower risk of all-cause and cardiovascular mortality among HD patients probably through its antioxidant property in ameliorating the IS-related vascular toxicity.