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Relationship of asymmetric dimethylarginine to dialysis treatment and atherosclerotic disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase. Its concentration is elevated in patients with end-stage renal disease (ESRD), in part because it is excreated via the kidneys. In addition, ADMA is degraded by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyzes ADMA to L-citrulline and dimethylamine. Activity of DDAH is decreased by oxidized low density lipoprotein (LDL) or tumor necrosis factor-α (TNF-α) in vitro yielding increased levels of ADMA. Furthermore, plasma levels of ADMA are elevated in hyperhomocyst(e) inemia and in hypertensive patients on a high salt diet. Data from several experimental studies suggest that ADMA concentrations in a pathophysiologically high range (3 to 10 μmol/L) significantly inhibit vascular NO formation by NO synthase in the presence of L-arginine in isolated human blood vessels, cultured macrophages, and in cultured endothelial cells. It has been well demonstrated that ADMA accumulates in chronic renal failure. Although there is controversy concerning the absolute concentration of ADMA, all authors found a two-to sixfold increase in ADMA levels in patients in chronic renal failure as compared to controls. Different dialysis treatment strategies differentially affect ADMA levels. The presence of atherosclerosis is associated with higher ADMA levels in patients with normal renal function as well as in dialysis patients, but this phenomenon may be unrelated to renal handling of ADMA. Reduced NO elaboration secondary to accumulation of ADMA may be an important pathogenic factor for atherosclerosis in chronic renal failure and ADMA may be a new uremic toxin. Clinical studies on the effect of ADMA are needed to further elucidate its pathophysiological role in atherosclerosis and uremia. [ABSTRACT FROM AUTHOR]

Role of nitric oxide in the synthesis of guanidinosuccinic acid, at activator of the N-methyl-d-asparate receptor. Background We propose that reactive oxygn and arginiosuccinic acid (ASA) form guanidinosuccinic acid (GSA). An alternative to this hypothesis is the so-called guanidine cycle, which consists of a series of hydroxyurea derivatives that serve as intermediates in a pathway leading from urea to GSA. We compare the role of the guanidine cycle to that of nitric oxide (NO) in the synthesis of GSA. Methods The members of the guanidine cycle (hydroxyurea, hydroxylamine plus homoserine, L-canaline, and L-canavanine) were incubated with isolated rat hepatocytes. The known NO donors, NOR-2, NOC-7, and SIN-1, were incubated with ASA in vitro. Ornithine, arginine, or citrulline, which increase arginine, a precursor of NO, were incubated with isolated rat hepatocytes. GSA was determined by high-performance liquid chromatography. Results None of guanidine cycle members except for urea formed GSA. SIN-1, which generates superoxide and NO formed GSA, but other simple NO donors, did not. Both carboxy-PTIO, a scavenger, completely inhibited GSA synthesis by SIN-1. GSA formation by SIN-1 reached a maximum at 0.5 mmol/L and decreased at higher concentrations GSA synthesis, stimulated by urea in isolated hepatocytes, was inhibitd by orinithine, arginine, or citrullin with ammonia, but not by ornithine without ammonia, where arginine production is limited. Conclusion GSA is formed ASA and the hydroxyl radical. When arginine increased in hepatocytes, GSA synthesis decreased. These data suggest that increased NO, which results from high concentrations of arginine, or SIN-1, scavanges the hydroxyl radical. This may explain the decreased GSA synthesis in inborn errors of the urea cycle where ASA is decreased, and also the diminished GSA excretion in arginemia. [ABSTRACT FROM AUTHOR]

Erythrocyte transketolase activity and guanidino compounds in hemodialysis patients Background The toxic effects of guanidino compounds on enzymatic activity in uremic patients are known. Thus, we determined the hemodialysis (HD) impact on this toxicity. Methods The erythrocyte transketolase activity (ETAK), total guanidino compounds (TGCs), and guanidinosuccnic acid (GSA) levels in plasma were compared before, after 5 hours of HD, and at 12 and 24 hours from the end of HD. Thirty-seven HD patients (28 to 49 years old) with primary glomerulopathies participated in this study. Thirty healthy volunteers (HVs) served as controls. Results At the beginning of this study, ETKA was in uremics (1.94 ± 0.45) than in HVs (2.59 ± 0.26). The TGC and GSA plasma levels were higher (26.07 ± 5.34 and 4.5 ± 1.22) than in HVs (10.41 ± 1.42 and 0.76 ± 0.09, P < 0.001), respectively. After five hours of HD, the ETKA increased to 2.49 ± 2.02 ( P < 0.001). The plasma levels TGC decreasd to 12.56 ± 2.02 ( P < 0.001) and the GSA to 2.12 ± 0.68 ( P < 0.001). After 12 and 24 hours from the end of HD, the ETKA decreased to 2.25 ± 0.56 and 2.09 ± 0.49 ( P 0.001), respectively. The plasma levels for TGC and GSA both increased: TGC to 19.39 ± 3.67 and 25.68 ± 4.61 ( P < 0.001), respctively; GSA to 3.49 ± 1.11 and 4.53 ± 1.12 ( P < 0.001), respectively. Conclusion There was no significant correlation between ETKA and the plasma levels of the examined toxins. By removing the guanidino compounds, HD temporarily decreases the inhibition of EKTA, diminishing other metabolic disturbances connected with pentose phosphate cycle. [ABSTRACT FROM AUTHOR]

White adipose tissue secretes a large variety of compounds named adipokines amongst which, leptin exhibits pleiotropic metabolic actions. Leptin is an anorexigenic hormone, secreted in proportion of fat mass, with additional effects on the regulation of inflammation, cardiovascular system, immunity, hematopoiesis and bone metabolism. Chronic kidney disease (CKD) is characterized by an increase of plasma leptin concentration that may be explained by a lack of renal clearance. Hyperleptinemia plays a key role in the pathogenesis of complications associated with CKD such as cachexia, protein energy wasting, chronic inflammation, insulin resistance, cardiovascular damages and bone complications. Leptin is also involved in the progression of renal disease through its pro-fibrotic and pro-hypertensive actions. Most of the adverse effects of leptin have been documented both experimentally and clinically. Leptin may therefore be considered as an uremic toxin in CKD. The aim of this review is to summarize the pathophysiological and clinical role of leptin in in vitro studies, experimental models, as well as in patients suffering from CKD., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Chronic kidney disease (CKD) is associated with increased risks of cardiovascular morbidity and mortality. Cardiac remodeling including myocardial fibrosis and hypertrophy is frequently observed in CKD patients. In this study, we investigate the mechanism involved in cardiac hypertrophy associated with CKD using a rat model, by morphological and chemical component changes of the hypertrophic and non-hypertrophic hearts. Sprague-Dawley rats were 4/5 nephrectomized (Nx) at 11 weeks of age and assigned to no treatment and treatment with AST-120, which was reported to affect the cardiac damage, at 18 weeks of age. At 26 weeks of age, the rats were euthanized under anesthesia, and biochemical tests as well as analysis of cardiac condition were performed by histological and spectrophotometric methods. Cardiac hypertrophy and CKD were observed in 4/5 Nx rats even though vascular calcification and myocardial fibrosis were not detected. The increasing myocardial protein was confirmed in hypertrophic hearts by infrared spectroscopy. The absorption of amide I and other protein bands in hypertrophic hearts increased at the same position as in normal cardiac absorption. Infrared spectra also showed that lipid accumulation was also detected in hypertrophic heart. Conversely, the absorptions of protein were obviously reduced in the myocardium of non-hypertrophic heart with CKD compared to that of hypertrophic heart. The lipid associated absorption was also decreased in non-hypertrophic heart. Our results suggest that cardiac remodeling associated with relatively early-stage CKD may be suppressed by reducing increased myocardial protein and ameliorating cardiac lipid load., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Intensive hemodialysis (HD) may have significant benefits. Recently, the role of extended hemodiafiltration (HDF) has gained interest. The aim of this study was to evaluate the acute effects of extended HD and HDF on hemodynamic response and solute removal., Study Design: Randomized crossover trial., Settings & Participants: Stable patients with end-stage renal disease undergoing conventional HD., Intervention: 13 patients randomly completed a single study of 4-hour HD (HD4), 4-hour HDF (HDF4), 8-hour HD (HD8), and 8-hour HDF (HDF8), with a 2-week interval between study sessions. Between study sessions, patients received routine conventional HD treatments., Outcomes: Acute hemodynamic effects and uremic toxin clearance., Measurements: Blood pressure and heart rate, pulse wave analysis, cardiac output, and microvascular density by sublingual capillaroscopy, as well as relative blood volume and thermal variables, were measured. Clearance and removal of uremic toxins also were studied., Results: Long treatments showed more stability of peripheral systolic blood pressure (change during HD4, -21.7±15.6 mm Hg; during HDF4, -23.3±20.8 mm Hg; during HD8, -6.7±15.2 mm Hg [P=0.04 vs. HD4; P=0.08 vs. HDF4]; and during HDF8, -0.5±14.4 mm Hg [P=0.004 vs. HD4; P=0.008 vs. HDF4]). A similar observation was found for peripheral diastolic and central blood pressures. Cardiac output remained more stable in extended sessions (change during HD4, -1.4±1.5 L/min; during HDF4, -1.6±1.0 L/min; during HD8, -0.4±0.9 L/min [P=0.02 vs. HDF4]; and during HDF8, -0.5±0.8 L/min [P=0.06 vs. HD4; P=0.03 vs. HDF4), in line with the decreased relative blood volume slope in long dialysis. No differences in microvascular density were found. Energy transfer rates were comparable (HD4, 13.3±4.7 W; HDF4, 16.2±5.6 W; HD8, 14.2±6.0 W; and HDF8, 14.5±4.3 W). Small-molecule and phosphate removal were superior during long treatments. β2-Microglobulin and fibroblast growth factor 23 (FGF-23) reduction ratios were highest in HDF8., Limitations: Small sample size, only acute effects were studied., Conclusions: Treatment time, and not modality, was the determinant for the hemodynamic response. HDF significantly improved removal of middle molecules, with superior results in extended HDF., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Malnutrition is a common feature seen in chronic dialysis patients, and the survival rate of obese patients receiving such treatment is higher than that of lean patients. Irrespective of obesity or diabetes, dialysis patients commonly have insulin resistance, and the leading cause of death is cardiovascular (CV) disease. It has been reported that the concentration of p-cresol, a uremic toxin, is highly associated with CV events. As uremic toxin levels are high in dialysis patients, they may be involved in the pathogenesis of insulin resistance and CV disease in this population. However, little is known so far. Thus, we focused on this uremic toxin to examine its effects on adipocytes and their precursors. 3T3-L1 cells, a mouse preadipocyte cell line, were cultured until 90% confluency. The cells were then differentiated with 500 μM 3-isobutyl-methylxanthine, 250 nM dexamethasone, and 10 μg/mL insulin. Cell proliferation was evaluated by cell counting and bromodeoxyuridine (Brd-U) incorporation assay. Glucose uptake was estimated using radiolabeled 2-deoxyglucose. The range of concentrations of p-cresol used in the experiments was from 2 to 200 μM. The investigation of cell proliferation by cell counting revealed that, compared with control, 3T3-L1 cells treated with 100 and 200 μM p-cresol were significantly decreased in number at day 3 and day 7 of culture. The Brd-U incorporation assay also demonstrated similar inhibitory effects on cell proliferation, suggesting that p-cresol affected the normal cell cycle. Oil Red O staining at day 7 showed that the number of mature adipocytes was decreased by treatment with 200 μM p-cresol. Consistent with that finding, the number of apoptotic cells at day 7 was increased by treatment with 100 and 200 μM p-cresol. Peroxisome proliferator-activated receptor γ (PPARγ) mRNA expression increased time-dependently during the differentiation process of 3T3-L1 cells. p-Cresol dose-dependently decreased differentiation-induced mRNA expression of PPARγ. Uptake of 3H-labeled 2-deoxyglucose was markedly decreased by 200 μM p-cresol in the presence or in the absence of insulin, mainly because of the decreased number of mature adipocytes. High concentrations of p-cresol disturbed the cell cycle, induced apoptosis, inhibited the differentiation of preadipocytes into mature adipocytes, and decreased glucose uptake at baseline and after insulin stimulation. These findings indicate that accumulated p-cresol may induce reduction in adipose tissue, insulin resistance, and malnutrition, eventually leading to poor outcomes in chronic dialysis patients., (Copyright © 2014 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

The development of proteomic and metabolomic technologies holds the promise to significantly impact patient management by improving diagnosis, unraveling more appropriate therapeutic targets, and enabling more precise prognosis of disease development. Proteomics and metabolomics have been applied with the aim of improving dialysis, defining uremic toxins, and unraveling their origin. Ideally, these technologies should inform us which proteomic or metabolomic compounds are subject to significant alterations of concentration or structure as a result of failing kidney function, and thus can be considered as potential uremic toxins. After a few years of applying these technologies in the area of uremic toxicity studies we are now in a position where we can estimate how and what they can contribute to the field. In this review we critically examine the current literature on the application of proteomics and metabolomics in the context of dialysis and uremic toxins. We highlight the most promising findings, indicate where we see the current need, and which future developments consequently are to be expected, given the technological constraints that undoubtedly exist., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Uremic toxins such as indoxyl sulfate contribute to the pathogenesis of chronic kidney disease (CKD) by promoting glomerulosclerosis and interstitial fibrosis with loss of nephrons and vascular damage. AST-120, an orally administered intestinal sorbent, adsorbs indole, a precursor of indoxyl sulfate, thereby reducing serum and urinary concentrations of indoxyl sulfate. AST-120 has been available in Japan since 1991, and subsequently Korea (2005), and the Philippines (2010) as an agent to prolong the time to initiation of hemodialysis and for improvement of uremic symptoms in patients with CKD. A Medline search was performed to identify data supporting clinical experience with AST-120 for managing CKD. Prospective open-label and double-blind trials as well as retrospective analyses were included. In prospective trials and retrospective analyses, AST-120 has been shown to prolong the time to initiation of hemodialysis, and slow decline in glomerular filtration rate and the increase serum creatinine. In an initial randomized, double-blind, placebo-controlled trial in the United States, AST-120 was associated with a significant dose-dependent reduction in serum indoxyl sulfate levels and a decrease in uremia-related malaise. The Evaluating Prevention of Progression in CKD (EPPIC) trials, two double-blind, placebo-controlled trials undertaken in North America/Latin America and Europe, are evaluating the efficacy of AST-120 for preventing the progression of CKD. The results of the EPPIC trials will further define the role of AST-120 in this debilitating condition.

The methylation of carrier-free 74As-arsenite by liver cytosol of Flemish Giant rabbits is highly susceptible to additions of trace elements. In vitro supplementation of essential trace elements like zinc (Zn2+), vanadium (V5+), iron (Fe2+), copper (Cu2+) and selenate was shown to increase the methylation efficiency. Trivalent metal ions (e.g. Al3+, Cr3+ and Fe3+), Hg2+, Tl+ and SeO32- had a deleterious effect. The inhibitory effect of EDTA, oxime and many divalent cations (Ca2+, Mg2+, Sr2+, ...) suggest a co-factor role for a specific divalent metal ion, possibly Zn2+. Chelating agentsused in clinical treatment of acute and chronic inorganic arsenic poisoning lower the methylation capacity of cytosol by rendering the trivalent arsenic unavailable for the methyltransferase enzymes. S-adenosylhomocysteine and periodate-oxidized adenosine, inhibitors of s-adenosylmethionine dependent methylation pathways, inhibit the methylation of arsenite. Pyrogallol, a catechol-O-methyltransferase inhibitor, blocks the action of arsenite- and monomethylarsonic methyltransferase enzymes, suggesting a close structural relationship between the active sites of the different enzymes. Some uraemic toxins, namely oxalate, p-cresol, hypoxanthine, homocysteine and myo-inositol, inhibit arsenic methylation. [ABSTRACT FROM AUTHOR]

Beraprost sodium, a stable prostacyclin analog, was showed to improve survival rates in two different rat models, anti-glomerular basement membrane (GBM) glomerulonephritis (GN) and 5/6 nephrectomized (Nx) chronic kidney disease (CKD) rats. In the anti-GBM rat, beraprost sodium (0.2 and 0.6 mg/kg/day) improved survival rate (hazard ratio for beraprost sodium 0.6 mg/kg/day group, 0.10; 95% confidence interval, 0.01 to 0.68). Subsequently, in the 5/6 Nx CKD rat, beraprost sodium (0.6 mg/kg/day) improved survival rate (hazard ratio for beraprost sodium, 0.46; 95% confidence interval, 0.23 to 0.92), serum creatinine doubling time and the slope of the reciprocal of serum creatinine. In the anti-GBM GN rats, beraprost sodium suppressed the serum accumulation of representative uremic toxins such as indoxyl sulfate. Furthermore, beraprost sodium inhibited human aortic endothelial cell (HAEC) injury induced by indoxyl sulfate, indicating that beraprost sodium might have a protective effect against cardiovascular damage due to CKD. These results show that beraprost sodium can improve the survival rates in two rat models of anti-GBM GN and 5/6 Nx CKD rats by protecting endothelial cells and thereby ameliorating decreased renal function. Therefore, clinical studies are needed in patients with chronic kidney failure to determine whether beraprost sodium will become a useful medication in CKD., (© 2013 Elsevier B.V. All rights reserved.)

Accelerated cardiovascular disease is a frequent complication of CKD. Monocyte-mediated inflammation and adhesion of monocytes to vascular endothelium are key events in atherogenesis. An oral adsorbent, AST-120, retards renal function deterioration by lowering IS, which is known to accumulate in CKD patients. However, the effect of AST-120 on CKD-related monocyte activation is unknown. We aimed to determine whether AST-120 improves monocyte-mediated inflammation through IS reduction. Flow cytometric analysis showed that Mac-1 expression and ROS production were significantly higher in peripheral blood monocytes of subtotal Nx CKD mice than in sham-operated mice. AST-120 treatment significantly decreased Mac-1 expression and ROS production in CKD model mice. Furthermore, administration of IS induced monocyte-mediated inflammation and ROS generation. In vitro studies indicated that IS dose-dependently increased THP-1 monocytic cell adhesion to IL-1β-activated HUVECs under physiological flow conditions. IS also induced monocyte-mediated inflammation and ROS production in THP-1 cells. Phosphorylation of p38 MAPK and membrane translocation of NAD(P)H oxidase subunit p47phox in THP-1 cells were induced by IS. Both SB203580 (p38 MAPK inhibitor) and apocynin [NAD(P)H oxidase inhibitor] reduced THP-1 cell adhesion to HUVECs. Apocynin also inhibited IS-induced ROS production in THP-1 cells. IS induced monocyte-driven inflammation through NAD(P)H oxidase- and p38 MAPK-dependent pathways in monocytes. The main finding of this study was that AST-120 inhibited monocyte activation by reducing IS in vivo. This provides new insights on how AST-120 attenuates the progression of atherosclerosis in CKD.