Objective-Tumor necrosis factor (TNF)-␣-induced endothelial injury, which is associated with atherosclerosis, is mediated by intracellular reactive oxygen species. Iron is essential for the amplification of oxidative stress. We tested whether TNF-␣ accelerated iron accumulation in vascular endothelium, favoring synthesis of hydroxyl radical. Methods and Results-Diverse iron transporters, including iron import proteins (transferrin receptor [TfR] and divalent metal transporter 1 [DMT1]) and an iron export protein (ferroportin 1 [FP1]) coexist in human umbilical endothelial cells (HUVECs). TNF-␣ caused upregulation of TfR and DMT1 and downregulation of FP1, which were demonstrated in mRNA as well as protein levels. These changes in iron transporters were accompanied by accumulation of iron that was both transferrin-dependent and transferrin-independent. Modifications of these mRNAs were regulated posttranscriptionally, and were coordinated with activation of binding activity of iron regulatory protein 1 to the iron responsive element on transporter mRNAs. Using a salicylate trap method, we observed that only simultaneous exposure of endothelial cells to iron and TNF-␣ accelerated hydroxyl radical production. Conclusions-TNF-␣ could cause intracellular iron sequestration, which may participate importantly in the pathophysiology of atherosclerosis and cardiovascular disease. Key Words: cytokines Ⅲ endothelium Ⅲ free radicals Ⅲ inflammation Ⅲ iron A therosclerosis now is generally recognized as a chronic inflammatory condition, and inflammatory cytokines such as tumor necrosis factor (TNF)-␣ have been associated with the development of atherosclerotic lesions and consequent cardiovascular events. 1,2 Dysfunction and loss of vascular endothelial cells, which provide a nonthrombogenic surface and a permeability barrier, occur early in atherosclerosis. 3 Several lines of evidence has suggested that TNF-␣-induced cell injury is mediated through its ability to promote intracellular reactive oxygen species (ROS) formation. 4,5 Among these species, superoxide anion (O 2 Ϫ ) and hydrogen peroxide (H 2 O 2 ) are not very reactive, and usually are neutralized by an elaborate antioxidant defense system. However, transition metal-catalyzed Haber-Weiss reaction can transform O 2 Ϫ and H 2 O 2 to hydroxyl radical, which are extremely powerful oxidizing species. 6,7 Iron is an essential element required for biochemical reactions subserving a wide variety of functions in cells and organisms. 8 However, free iron, possibly the most important transition metal in biologic systems, can act as an electron donor. 6,9 Excessive intracellular accumulation of iron therefore could amplify the damaging effect of oxidative stress in inflammatory conditions, leading to cell injury.The recent identification of iron transport proteins has rapidly expanded our knowledge of molecular aspects of iron processing, especially in the reticuloendothelial system and small intestine. 10,11 Such proteins include transferrin receptor (TfR), divalent metal tr...

Background/Aims: Mortality in end-stage renal disease patients with dialysis remains high. A high percentage of dialysis patients display signs of chronic microinflammation. To clarify whether microinflammation is involved in the high incidence of poor prognosis in dialysis patients, we investigated the association of inflammatory markers with mortality in a prospective observational cohort study. Methods: 120 patients undergoing hemodialysis were enrolled. Baseline cross-sectional analysis of the relationship between inflammatory markers [interleukin-6 (IL-6), tumor necrosis factor-α and high-sensitivity C-reactive protein] and other factors, along with a survival analysis for death, were performed. All subjects were divided into 2 groups according to the median value of IL-6. Results: The mortality rate was significantly higher in the high (20.0%) compared with the low IL-6 group (3.3%, p = 0.0046). Receiver-operating characteristic curves indicated high mortality to be closely associated with a high IL-6 level rather than tumor necrosis factor-α. In stepwise multiple regression analyses, age, phosphorus and high-sensitivity C-reactive protein were independent predictors of IL-6 (R² = 0.466, p < 0.0001). Conclusions: These data clearly show that plasma IL-6 is a powerful predictor of all-cause mortality in dialysis patients.

Background: Pleuroperitoneal leak is an uncommon but significant complication of peritoneal dialysis. Although the exact pathogenesis of pleuroperitoneal communication remains unclear, the pressure gradient between the thorax and abdominal cavity has been thought to play a major role. Case presentation: A 48-year-old man with diabetes mellitus and hypertension who had been treated with continuous ambulatory peritoneal dialysis (1.5 L dwells four times a day) for 3 months was admitted because of massive right-sided pleural effusion. He underwent video-assisted thoracoscopic surgery for blebs on the diaphragm. Six weeks after diaphragmatic repair, he resumed peritoneal dialysis (1.5 L dwells four times a day) with once-a-week hemodialysis. Thereafter, pleural effusion was not significant on a chest radiogram. Six months after surgery, his dwell volume increased from 1500 to 2000 ml, and significant right-sided pleural effusion also developed. Conclusion: Pleuroperitoneal leak caused by blebs can recur even after surgical treatment, and reducing the dwell volume may be effective for patients with pleuroperitoneal communication.

We tested the effect of three different dialysate calcium concentrations on calcium-phosphorus metabolism during the use of sevelamer hydrochloride. After a calcium-containing phosphate binder was switched to sevelamer, the serum calcium, phosphorus, and intact parathyroid hormone levels and the markers of bone turnover were measured in the patients whose dialysate calcium concentrations were 2.5, 2.75, and 3.0 mEq/L. As a result, in the 2.75-mEq/L group, the serum calcium concentrations decreased and the intact parathyroid hormone level increased significantly. In the 2.5-mEq/L group, transient hypocalcemia occurred and the levels of both bone-alkaline phosphatase and osteocalcin increased. In the 3.0-mEq/L group, the serum calcium concentrations did not change significantly and only bone-alkaline phosphatase increased. If a calcium-containing phosphate binder is completely switched to sevelamer, dialysis using a dialysate calcium concentration below 3.0 mEq/L may result in hypocalcemia and acceleration of bone turnover.

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