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ABSTRACT: Chronic kidney disease (CKD) is a devastating illness characterized by accumulation of uremic retention solutes in the body. The objective of this study was to develop and validate a simple, rapid, and robust UPLC-MS-MS method for simultaneous determination, in serum, of seven organic acid uremic retention toxins, namely uric acid (UA), hippuric acid (HA), indoxylsulfate (IS), p-cresylglucuronide (pCG), p-cresylsulfate (pCS), indole-3-acetic acid (IAA), and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF). Isotopically labeled internal standards (d(5)-HA; 1,3-(15)N(2)-UA, and d(5)-IAA) were used to correct for variations in sample preparation and system performance. Separation on a C18 column was followed by negative electrospray ionization and tandem mass spectrometric detection. Accuracy was below the 15 % threshold. Within-day precision varied from 0.60 to 4.54 % and between-day precision was below 13.33 % for all compounds. The applicability of the method was evaluated by analyzing 78 serum samples originating both from healthy controls and from patients at different stages of CKD. These results were compared with those obtained by use of conventional HPLC-PDA-FLD methods. A good correlation was obtained between both methods for all compounds.
Analytical and Bioanalytical Chemistry 01/2013; · 3.78 Impact Factor
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ABSTRACT: Purpose: Poor cardiovascular outcomes in chronic kidney disease (CKD) patients have prompted nephrologists to look for biomarkers that may improve risk stratification in this population. The objective of this study was to evaluate plasma myoglobin (Mb) levels according to the CKD stage and to determine whether they are associated with overall, cardiovascular (CV) mortality, CV events, and renal outcomes. Methods: Plasma Mb levels were determined in 140 CKD patients at different stage (mean ± SD age: 67 ± 12; males: 61%) who were prospectively monitored for overall and CV mortality, CV events and CKD progression. Twenty-seven healthy subjects served as controls.Results: Plasma Mb levels were higher in CKD patients than in controls and progressively increased as the glomerular filtration rate fell. Hemoglobin levels, CKD stage, the aortic calcification score and brain natriuretic peptide levels were associated with plasma Mb concentrations. In a multivariate analysis, only CKD stage was associated with Mb levels. During follow up (mean duration: 968 ± 374 days), 44 patients died and 63 had a cardiovascular event. In a crude analysis, plasma Mb >73.8 µg/l predicted overall and cardiovascular mortality and the occurrence of cardiovascular events (p = 0.01, 0.05 and 0.01, respectively). However, this association was lost after adjustment for other prognostic factors for mortality. Plasma Mb was not a significant predictor of the progression of CKD either.Conclusions: Plasma Mb levels were significantly higher in predialysis or dialyzed CKD patients than in healthy controls. However, we could not identify a relevant clinical outcome associated with this elevation. Larger studies are needed to confirm the present results.
The International journal of artificial organs 09/2012; · 1.86 Impact Factor
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ABSTRACT: Since beta-2 microglobulin (B2M) is a surrogate marker for middle molecular weight uremic toxins and the major protein component in dialysis-related amyloidosis, it has been frequently studied in dialysis patients. It is not known, however, whether B2M has an impact in patients with chronic kidney disease (CKD) not yet on dialysis. Here we studied the relationship of plasma B2M levels to clinical and cardiovascular outcomes in 142 patients (mean age of 67 years) at different stages of CKD. B2M levels increased with CKD stage and thus were highest in hemodialysis patients. Baseline B2M levels were associated with vascular calcification but not with arterial stiffness or bone density. During a mean follow-up of 969 days, 44 patients died and 49 suffered a cardiovascular event. Higher B2M levels were independently associated with overall and cardiovascular mortality and cardiovascular events in the whole cohort and with cardiovascular events in the predialysis cohort. Moreover, B2M appeared to be a better predictor than well-established factors associated with outcomes in this population, such as estimated glomerular filtration rate ((eGFR), only for predialysis patients), inflammation biomarkers, and other factors included in a propensity score. Thus, we confirm the strong relationship between B2M levels and eGFR and confirm the power of B2M to predict overall and cardiovascular mortality and cardiovascular events in patients at different stages of CKD.Kidney International advance online publication, 15 August 2012; doi:10.1038/ki.2012.301.
Kidney International 08/2012; · 6.61 Impact Factor
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ABSTRACT: The evolution of extracorporeal treatment of end-stage renal failure has enforced focus on the purity of dialysis fluid. A major challenge of high-flux haemodialysis (HD) and haemodiafiltration relates to the necessity for ultrapure dialysis fluid and for sterile non-pyrogenic substitution fluid. The present review focuses especially on the possible microbial contamination including, next to intact micro-organisms, a variety of microbial derivatives. It is pointed out that there are conditions (e.g. contamination by non-culturable micro-organisms or bacterial derivatives other than lipopolysaccharides) where the detection of biologically relevant contaminants can be missed when applying the recommended standard detection methods such as bacterial culture and limulus amoebocyte lysate test. Possible approaches for action upon positive sampling results, exceeding the levels recommended in the latest ISO 11663:2009, are described in detail and illustrated with flow charts. The issue of purity of dialysis fluids is highly relevant, since the chronic exposure of HD patients to low levels of cytokine-inducing microbial components can significantly contribute to the micro-inflammatory status of these patients.
Nephrology Dialysis Transplantation 07/2012; · 3.40 Impact Factor
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ABSTRACT: Uremic solute concentration increases as Glomerular Filtration Rate (GFR) declines. Weak associations were demonstrated between estimated GFR (eGFR) and the concentrations of several small water-soluble and protein-bound uremic solutes (MW<500Da). Since also middle molecular weight proteins have been associated with mortality and cardiovascular damage in Chronic Kidney Disease (CKD), we investigated the association between several eGFR formulae and the concentration of Low Molecular Weight Proteins (LMWP) (MW>500Da).
In 95 CKD-patients (CKD-stage 2-5 not on dialysis), associations between different eGFR-formulae (creatinine, CystatinC-based or both) and the natural logarithm of the concentration of several LMWP's were analyzed: i.e. parathyroid hormone (PTH), Cystatin C (CystC), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), leptin, retinol binding protein (RbP), immunoglobin light chains kappa and lambda (Ig-κ and Ig-λ), beta-2-microglobulin (β(2)M), myoglobin and fibroblast growth factor-23 (FGF-23)).
The regression coefficients (R(2)) between eGFR, based on the CKD-EPI-Crea-CystC-formula as reference, and the examined LMWP's could be divided into three groups. Most of the LMWP's associated weakly (R(2) <0.2) (FGF-23, leptin, IL-6, TNF-α, Ig-κ, Ig-λ) or intermediately (R(2) 0.2-0.7) (RbP, myoglobin, PTH). Only β(2)M and CystC showed a strong association (R(2) >0.7). Almost identical R(2)-values were found per LMWP for all eGFR-formulae, with exception of CystC and β(2)M which showed weaker associations with creatinine-based than with CystC-based eGFR.
The association between eGFR and the concentration of several LMWP's is inconsistent, with in general low R(2)-values. Thus, the use of eGFR to evaluate kidney function does not reflect the concentration of several LMWP's with proven toxic impact in CKD.
PLoS ONE 01/2012; 7(8):e44201. · 4.09 Impact Factor
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ABSTRACT: Although protein-bound uremic retention solutes are recognized as 1 of the 3 main categories of uremic retention solutes, they only recently have been submitted to thorough analysis. In vitro and ex vivo data link both p-cresyl sulfate and indoxyl sulfate, two of the main compounds of this solute group, to negative impact on the cardiovascular system and progression of kidney failure. Recent in vivo observational data also relate concentration of these compounds to survival outcome, inflammation, and vascular disease in different, even moderate, stages of chronic kidney disease. Removal by different dialysis strategies, even high-flux hemodialysis, is difficult, and only by applying convection, some improvement of removal has been obtained. The other strategy with the potential to decrease concentration is by influencing intestinal generation and/or absorption. The sorbent Kremezin (AST-120) has been shown in controlled studies to decrease protein-bound solute concentration. In pilot controlled studies, AST-120 has been shown to be superior on outcome parameters to placebo. Results from large randomized trials are awaited, before these data can be considered as solid enough to warrant the recommendation to use these compounds for overall therapeutic purposes.
Journal of Renal Nutrition 01/2012; 22(1):90-4. · 1.57 Impact Factor
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ABSTRACT: The uraemic retention solutes p-cresylsulphate (pCS) and p-cresylglucuronide (pCG), two conjugates of p-cresol, were never determined simultaneously. In the present paper, a high-performance liquid chromatography (HPLC) method was developed and used to quantify both compounds in parallel in an in vivo observational study and their in vitro effect was evaluated by flow cytometry.
pCS and pCG were determined in serum. For the validation specificity, linearity, recovery, precision and the quantification limit were evaluated. In vivo, concentrations of both compounds were determined in 15 controls and 77 haemodialysis patients, as well as protein binding in the dialysed group and the reduction ratios during haemodiafiltration. In addition, the in vitro effect of the solutes on leucocyte free radical production at measured concentrations was assessed.
A fast and accurate HPLC method was developed to simultaneously quantify pCS and pCG. Both conjugates are retained in uraemia with a substantially higher total serum pCS in comparison to pCG (31.4 ± 15.8 versus 7.3 ± 6.5 mg/L) but also a substantial difference in protein binding (92.4 ± 3.0 versus 8.3 ± 4.4%) and in reduction ratio during post-dilution haemodiafiltration (37.4 ± 7.1 versus 78.6 ± 6.4%). pCG per se has no effect on leucocyte oxidative burst activity, whereas in combination with pCS, a synergistic activating effect was observed.
Serum concentrations of pCS and pCG are elevated in uraemia. Both conjugates show a different protein binding, resulting in a different dialytic behaviour. Biologically, both conjugates are synergistic in activating leucocytes.
Nephrology Dialysis Transplantation 12/2011; 27(6):2388-96. · 3.40 Impact Factor
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ABSTRACT: This publication comments on the recently published findings of a study by Eloot et al. (cJASN, 6: 1266-1273, 2011) that evaluated the correlation between several formulae for calculating estimated GFR (eGFR) and different low molecular weight uremic toxins; eGFRs were based on serum creatinine (SCrea), cystatin C (Cys C), or a combination of both. Unexpectedly, the correlations for the different solutes were highly inconsistent, irrespective of the eGFR formula. On the other hand, the different eGFR formulae gave consistent results per solute. Correlation coefficients for some solutes were low (hippuric acid, p-cresylsulfate, indole acetic acid, uric acid, asymmetric dimethylarginine) to nonsignificant (carboxy-methyl-propyl-furanpropionic acid). These data point to the fact that eGFR is a deceiving predictor of uremic solute concentration and their biological action; this inconsistency is very likely the result of the impact of other factors affecting concentration, such as tubular secretion, generation by intestinal flora and metabolism.
Seminars in Dialysis 12/2011; 25(1):9-14. · 2.27 Impact Factor
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ABSTRACT: Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA).
In vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-α was studied followed by an evaluation of nuclear factor (NF)-κB activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo.
Monocytes incubated with SDMA showed increased IL-6 and TNF-α expression and a rise in active NF-κB. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 ± 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL-6, TNF-α, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-α at a high significance for SDMA (P < 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 ± 0.05) directly followed that of C-reactive protein (AUC: 0.82 ± 0.04) and albumin (AUC: 0.72 ± 0.05; for all, P < 0.0001) and preceded that of ADMA (P = 0.002).
The present study shows that SDMA is involved in the inflammatory process of CKD, activating NF-κB and resulting in enhanced expression of IL-6 and TNF-α, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages.
Clinical Journal of the American Society of Nephrology 08/2011; 6(10):2374-83. · 5.23 Impact Factor
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Sunny Eloot,
Eva Schepers,
Daniela V Barreto,
Fellype C Barreto,
Sophie Liabeuf,
Wim Van Biesen,
Francis Verbeke, Griet Glorieux,
Gabriel Choukroun,
Ziad Massy,
Raymond Vanholder
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ABSTRACT: The degree of chronic kidney disease (CKD) is currently expressed in terms of GFR, which can be determined directly or estimated according to different formulas on the basis of serum creatinine and/or cystatin C measurements (estimated GFR [eGFR]). The purpose of this study was to investigate whether eGFR values are representative for uremic toxin concentrations in patients with different degrees of CKD.
Associations between eGFR based on serum cystatin C and different uremic solutes (mol wt range 113 to 240 D; determined by colorimetry, HPLC, or ELISA) were evaluated in 95 CKD patients not on dialysis (CKD stage 2 to 5). The same analysis was also applied for six other eGFR formulas.
There was a substantial disparity in fits among solutes. In linear regression, explained variance of eGFR was extremely low for most solutes, with eGFR > 0.4 only for creatinine. The other eGFR formulations gave comparably disappointing results with regard to their association to uremic solutes. Relative similarity in R(2) values per solute for the different eGFR values and the strong disparity in values between solutes suggest that the differences in R(2) are mainly due to discrepancies in solute handling apart from GFR.
eGFR is poorly associated with concentrations of all studied uremic toxins in patients with different degrees of CKD, correlates differently with each individual solute, and can thus not be considered representative for evaluating the accumulation of solutes in the course of CKD.
Clinical Journal of the American Society of Nephrology 06/2011; 6(6):1266-73. · 5.23 Impact Factor
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Nephrology Dialysis Transplantation 03/2011; 26(5):1464-7. · 3.40 Impact Factor
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Mehmet Koc,
Ahmet Toprak,
Hakki Arikan,
Zekaver Odabasi,
Yesim Elbir,
Aysin Tulunay,
Ebru Asicioglu,
Emel Eksioglu-Demiralp, Griet Glorieux,
Raymond Vanholder,
Emel Akoglu
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ABSTRACT: Inflammation is one of the main contributors to atherosclerosis in haemodialysis (HD) patients. Activation of Toll-like receptors (TLRs) leads to inflammatory response. In this study, we aimed to evaluate the expression of TLRs on monocytes and relate their expression with inflammation in chronic kidney disease (CKD) and HD patients.
Thirty-four age- and gender-matched controls and stage 3-4 CKD patients and thirty-two HD patients were included in each study group. The effect of HD on the expression of Toll-like receptor-2 (TLR-2) and Toll-like receptor-4 (TLR-4) on CD14( +) monocytes was determined at the beginning (baseline), during (120 min) and following (300 min and 24 h) HD and compared with control and stage 3-4 CKD groups. The HD procedure was performed by using low-flux polysulphone dialysers. In addition, serum IL-6 levels were evaluated in both groups at baseline and after a HD session.
The percentage of CD14( +) monocytes expressing TLR-2 were similar in all of the study groups, whereas the percentage of CD14( +) monocytes expressing TLR-4 were significantly lower in both stage 3-4 CKD and HD patients at baseline than in controls. The mean fluorescence intensities (MFI) of TLR-2 were significantly lower in controls than in stage 3-4 CKD and HD patients at baseline. The MFI of TLR-4 was similar in all of the groups. The percentage of CD14( +) monocytes expressing TLR-2 did not change during and after HD. The MFI of TLR-2 decreased at 120 min of HD compared with baseline (1837 ± 672 vs 1650 ± 578, P < 0.05), and recovered back to baseline values at 300 min and at 24 h post-HD. MFI of TLR-4 increased at 24 h compared with baseline (941 ± 294 vs 1087 ± 441, P < 0.05). Serum IL-6 levels correlated with MFI of TLR-2 and TLR-4 in stage 3-4 CKD patients and in HD patients at baseline and after HD in univariate analysis. Stepwise multiple regression analysis revealed that MFI of TLR-2 was an independent determinant of serum IL-6 concentrations in stage 3-4 CKD and in HD patients at baseline, at 300 min and at 24 h post-HD. Conclusions. Our study demonstrates that TLR-2 is associated with the inflammatory response of non-dialysed and dialysed CKD patients.
Nephrology Dialysis Transplantation 03/2011; 26(3):955-63. · 3.40 Impact Factor
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ABSTRACT: Innovative modifications have been introduced in several types of dialyser membranes to improve adequacy and permselectivity. Which aspects of removal are modified and how this relates to different diffusive or convective strategies has, however, been insufficiently investigated.
In a prospective cross-over study, 14 chronic kidney disease (Stage 5D) patients were dialysed with a second-generation high-flux dialyser (Polynephron) in comparison to a first-generation type (DIAPES-HF800). Both dialysers were assessed in haemodialysis, in online pre-dilution and in post-dilution haemodiafiltration. Reduction ratio (RR, %) of small water-soluble compounds (urea and uric acid), low-molecular weight proteins (LMWPs) (β(2)-microglobulin, cystatin C, myoglobin and retinol-binding protein) and protein-bound solutes (hippuric acid, indole acetic acid, indoxylsulphate and p-cresylsulphate) was assessed, together with albumin losses into the dialysate.
Comparing the two types of membranes, the second-generation dialyser demonstrated a higher RR for LMWPs, whilst at the same time exhibiting lower albumin losses but only during post-dilution haemodiafiltration. No differences in RR were detected for both the small water-soluble and the protein-bound compounds. Comparing dialysis strategies, convection removed the same amount of solute or more as compared to diffusion.
The second-generation membrane resulted in a higher removal of LMWPs compared to the first-generation membrane, but for the other solutes, differences were less prominent. Convection was superior in removal of a broad range of uraemic retention solutes especially with the first-generation membrane.
Nephrology Dialysis Transplantation 02/2011; 26(8):2624-30. · 3.40 Impact Factor
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ABSTRACT: Chronic kidney disease (CKD) is characterized by the progressive retention of a myriad of compounds, several of which play a role in cardiovascular damage, a major cause of mortality in CKD. Over the past years, especially protein-bound compounds (e.g. indoxylsulfate and p-cresylsulfate) and/or middle molecules (e.g. AGEs, cytokines and dinucleoside polyphosphates) have been identified as some of the main toxins involved in vascular lesions affecting endothelial cell, leukocyte, platelet and/or vascular smooth muscle cell function in CKD. Many of these solutes, however, are difficult to remove by standard dialysis strategies. The removal of protein-bound solutes remains limited because only the free fraction of the solute is available for, mostly diffusive, removal, while removal of the larger middle molecules (mostly larger peptidic compounds) can be obtained by increasing dialyzer pore size and by applying convective strategies. In addition, new therapeutic strategies pursuing specific removal (e.g. by adsorption) and/ or pharmacological neutralization of the molecular impact of the responsible compounds are explored, aiming at an improved outcome in CKD patients.
Contributions to nephrology 01/2011; 168:117-28. · 1.49 Impact Factor
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Eva Schepers, Griet Glorieux,
Laetitia Dou,
Claire Cerini,
Nathalie Gayrard,
Loïc Louvet,
Charlotte Maugard,
Pierre Preus,
Maria Rodriguez-Ortiz,
Angel Argiles,
Philippe Brunet,
Gerald Cohen,
Joachim Jankowski,
Vera Jankowski,
Ziad Massy,
Mariano Rodriguez,
Raymond Vanholder
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ABSTRACT: Chronic kidney disease is considered a major cause of cardiovascular risk and non-traditional risk factors remain largely unknown. The in vitro toxicity of 10 guanidino compounds (GCs) was evaluated via a standardized approach on different cell systems of relevance in cardiovascular disease. The parameters evaluated were production of reactive oxygen species, expression of surface molecules, cell proliferation, cytotoxicity and calcification. Several GCs had a stimulatory effect on monocytes and granulocytes (SDMA, creatine and guanidinobutyric acid (GBA)). Some GCs (guandine (G), guanidinosuccinic acid (GSA) and SDMA) inhibited endothelial cell proliferation or reduced calcification in osteoblast-like human VSMC (ADMA, GSA and SDMA). Stimulation of osteoclastogenesis could be demonstrated for ADMA, G, guanidinoacetic acid and GBA in a RAW264.7 cell line. No compounds were cytotoxic to AoSMC or endothelial cells, nor influenced their viability. GCs, especially SDMA, likely contribute to cardiovascular complications in uremia, mainly those related to microinflammation and leukocyte activation.
Blood Purification 11/2010; 30(4):277-87. · 2.10 Impact Factor
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ABSTRACT: Although protein-bound uremic compounds have been related to outcome in observational studies, few current dialysis strategies provide more removal of those compounds than standard hemodialysis. We evaluated the evolution of protein-bound uremic solutes after a switch from high-flux hemodialysis to postdilution hemodiafiltration (n = 13). We compared predialysis solute concentration at 4, 5, and 9 weeks versus baseline for several protein-bound compounds and water-soluble solutes, as well as for beta(2)-microglobulin. After 9 weeks of postdilution hemodiafiltration, a significant decrease versus baseline could be detected for total concentration of protein-bound solutes: p-cresylsulfate (3.98 +/- 1.51-3.17 +/- 1.77 mg/dL, -20%, P < 0.01) and 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid (0.72 +/- 0.52-0.64 +/- 0.46 mg/dL, -11%, P < 0.01). For the other protein-bound solutes, hippuric acid, indoleacetic acid, and indoxylsulfate, no change in total concentration could be detected. The concentration of the middle molecule, beta(2)-microglobulin, decreased as well after 9 weeks of postdilution hemodiafiltration (24.7 +/- 9.3-18.1 +/- 6.7 mg/L, -27%, P < 0.01). For water-soluble compounds, no significant change of concentration was found. Postdilution hemodiafiltration in comparison to high-flux hemodialysis provided significant reduction of predialysis concentration of protein-bound compounds, especially those with the highest protein binding, and of beta(2)-microglobulin, by -11 to -27% in 9 weeks.
Artificial Organs 07/2010; 34(7):580-5. · 2.00 Impact Factor
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ABSTRACT: Dinucleoside polyphosphates (Np(n)N) have pathophysiologic roles in cardiovascular disease and are newly detected uraemic retention solutes. They were retrieved in human plasma, tissues and cells. Although their impact on several cell systems involved in vascular damage (endothelium, smooth muscle cells and thrombocytes) has been evaluated, their effect on different types of leucocytes has never been studied.
This study evaluates, for the first time, the impact of Np(n)N on monocyte, granulocyte and lymphocyte oxidative burst activity at baseline and after stimulation with N-formyl-methionine-leucine-phenylalanine (fMLP) and phorbol 12-myristate 13-acetate (PMA) in whole blood. Diadenosine triphosphate (Ap(3)A) to diadenosine hexaphosphate (Ap(6)A) were tested to investigate the effect of the number of phosphate groups on reactive oxygen species (ROS) production. The effect of the type of nucleoside was evaluated by comparing adenosine guanosine tetraphosphate, diguanosine tetraphosphate, uridine adenosine tetraphosphate (Up(4)A) and diadenosine tetraphosphate (Ap(4)A).
This study demonstrated that lymphocytes are especially susceptible to intracellular diadenosine polyphosphates. Depending on the phosphate chain length, different effects were observed. At baseline and with fMLP, Ap(4)A, Ap(5)A and Ap(6)A enhanced lymphocyted-free radical production. In addition, Ap(3)A, Ap(4)A and Ap(5)A increased PMA-stimulated ROS production in lymphocytes. Monocytes and granulocytes parallel the lymphocyte response albeit with an inhibition of Ap(6)A on granulocytes. Considering Np(n)N with four phosphate groups, Up(4)A showed the most important stimulatory effects on monocytes and Ap(4)A on lymphocytes.
Np(n)N mainly have a leucocyte-activating impact, most significant for Ap(4)A, considering phosphate chain length, and for Up(4)A, considering the type of nucleosides. These results suggest that the pro-inflammatory effects of Np(n)N can contribute to the development of atherosclerosis, probably in the early stages of chronic kidney disease, but their chemical composition affects their activity.
Nephrology Dialysis Transplantation 02/2010; 25(8):2636-44. · 3.40 Impact Factor
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ABSTRACT: Part of the uremic retention solutes are generated in the intestine, but this option is rarely discussed in the literature. In this publication, we describe consecutively the role of the intestine in generating uremic retention solutes, the pathophysiological importance of the generated solutes and therapeutic options that are inspired by this knowledge. Apart from its role as a route via which uremic toxins or their precursors enter the body, the intestine also acts as an active player by presenting more precursors for fermentation due to disturbances in assimilation caused by uremia, followed by alterations in further processing related to changes in the composition of the fermenting flora. Many of the toxins generated or introduced into the body via the intestine (advanced glycation end products, indoles, phenols) play an active role in vascular damage. Intestinal therapeutic interventions that could help decrease solute concentration are restriction of dietary intake, however at the expense of increasing the risk of malnutrition, rerouting of intestinal metabolism by administration of prebiotics or probiotics and/ or the administration of active sorbents such as AST-120 (Kremezin).
Blood Purification 01/2010; 29(2):130-6. · 2.10 Impact Factor
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ABSTRACT: A major complication of chronic kidney disease (CKD) is concomitant cardiovascular damage. Although patients suffering from
CKD are frequently affected by a number of other conditions and/or comorbidities that enhance the cardiovascular risk, such
as hypertension, insulin resistance, fluid overload, anemia, diabetes mellitus, and dyslipidaemia, the weight of these factors
perse is insufficient to explain the entire uremic cardiovascular problem; therefore, it has been suggested that factors specific
to CKD, such as the uremic milieu, must play a central role. In this chapter, we review current knowledge on uremic toxins
with a potential cardiovascular impact, emphasizing their specific effects on the major cell types involved in this process,
such as leukocytes, endothelial cells, vascular smooth muscle cells, and platelets.
KeywordsChronic kidney disease-Uremic toxins-Cardiovascular impact
12/2009: pages 219-234;
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ABSTRACT: Uraemic toxins are considered to be emerging mortality risk factors in chronic kidney disease (CKD) patients. p-Cresol (a prototype protein-bound uraemic retention solute) has been shown to exert toxic effects in vitro. Recently, it has been demonstrated that p-cresol is present in plasma as its sulphate conjugate, p-cresylsulphate. The present study evaluated the distribution of free and total p-cresylsulphate and sought to determine whether these parameters were associated with vascular calcification, arterial stiffness and mortality risk in a cohort of CKD patients.
One hundred and thirty-nine patients (mean +/- SD age: 67 +/- 12; males: 60%) at different stages of CKD (8% at Stage 2, 26.5% at Stage 3, 26.5% at Stage 4, 7% at Stage 5 and 32% at Stage 5D) were enrolled in this study.
Baseline total and free p-cresylsulphate presented an inverse relationship with renal function and were significantly associated with vascular calcification. During the study period (mean follow-up period: 779 +/- 185 days), 38 patients died [including 22 from cardiovascular (CV) causes]. In crude survival analyses, free (but not total) p-cresylsulphate was shown to be a predictor of overall and CV death. Higher free p-cresylsulphate levels (>0.051 mg/100 mL; median) were associated with mortality independently of well-known predictors of survival such as age, vascular calcification, anaemia and inflammation.
Serum levels of free and total p-cresylsulphate (the main in vivo circulating metabolites of p-cresol) were elevated in later CKD stages. However, only free p-cresylsulphate seems to be a predictor of survival in CKD.
Nephrology Dialysis Transplantation 11/2009; 25(4):1183-91. · 3.40 Impact Factor
