Circulating levels of ICAM-1, VCAM-1, and MCP-1 are increased in haemodialysis patients: association with inflammation, dyslipidaemia, and vascular events
Aikaterini Papayianni,
Efstathios Alexopoulos,
Panagiotis Giamalis,
Lazaros Gionanlis,
Anna-Maria Belechri,
Paraschos Koukoudis and
Dimitrios Memmos
Department of Nephrology, Hippokration General Hospital, Thessaloniki, Greece
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Abstract
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Background. Increased levels of circulating adhesion molecules and chemokines have been reported in haemodialysis (HD) patients but the influence of the HD membranes on their secretion, as well as their pathophysiological implications, remains largely unknown.
Methods. Circulating levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) were measured by immunosorbent assay (ELISA) in 81 HD patients (45 male, mean age 57±13 years) and 35 normal subjects. All patients had been stabilized on renal replacement therapy for >3 months and were free of active infection. Thirty-three patients (40.7%) were routinely dialysed with modified cellulose membranes and 48 patients (59.3%) were dialysed with polysulfone membranes. Blood samples were taken directly from the arteriovenous fistula immediately before and at the end of a routine HD session.
Results. Pre-dialysis levels were significantly elevated in HD patients compared with controls (ICAM-1 515±177 vs 238±64 ng/ml, P<0.0001; VCAM-1 2107±648 vs 1012±115 ng/ml, P<0.0001; MCP-1 427±148 vs 125±42 pg/ml, P<0.0001). The HD session resulted in a significant increase in the levels of all three molecules measured (515±177 vs 679±187 ng/ml, P<0.0001; 2107±648 vs 2662±800 ng/ml, P<0.0001; 427±148 vs 567±153 pg/ml, P<0.0001, respectively). There was no difference in pre- or post-dialysis levels of the above molecules between patients routinely dialysed with either modified cellulose or polysulfone membranes. MCP-1 levels had a positive correlation with ICAM-1 levels (r=0.41, P<0.0005). VCAM-1 levels had a negative correlation with HDL levels (r=-0.30, P<0.01) and were significantly elevated in patients with HDL <35 mg/dl compared with patients with HDL
35 mg/dl (2300±606 vs 1890±633 ng/ml, P<0.005). Log-transformed exact C-reactive protein (CRP) values were significantly correlated with ICAM-1 and VCAM-1 levels (r=0.41, P<0.005 and r=0.43, P<0.005, respectively). In addition, compared with patients with normal CRP values, patients with elevated CRP had significantly increased levels of ICAM-1 (466±166 vs 580±172 ng/ml, P<0.005). Patients with cardiovascular, cerebrovascular, or peripheral vascular diseases had significantly increased serum CRP and ICAM-1 levels compared with patients with no evidence of vascular disease (19.2±12.9 vs 7.9±11.8 mg/l, P<0.001 and 608±189 vs 474±155 ng/ml, P<0.005 respectively).
Conclusions. Serum levels of ICAM-1, VCAM-1, and MCP-1 are increased in HD patients and probably result from either inadequate clearance or enhanced synthesis and release. HD session resulted in a significant increase of the above molecule levels but the exact mechanism(s) responsible for these alterations are yet to be fully elucidated. Increased levels of adhesion molecules are associated with inflammation, dyslipidaemia, and cardiovascular events. However, the potential link between these processes and its clinical significance warrants further investigation.
Keywords: adhesion molecules; atherosclerosis; cardiovascular disease; chemokines; haemodialysis
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Introduction
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During haemodialysis (HD) the leukocytes in the circulation are activated and a number of proinflammatory cytokines are secreted including interleukin-1ß, (IL-1ß) and tumor necrosis factor-
(TNF-
) [1]. Indeed, the magnitude of the activation of cellular elements of blood has been used as an index of biocompatibility and several groups have examined the effect of different dialysis membranes on cytokine production [2,3]. The above factors activate and up-regulate the expression of adhesion molecules which play a fundamental role in many pathophysiological processes. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are two members of the Ig-like supergene family of adhesion molecules (molecular weight 90110 kDa range) that are normally expressed by endothelial cells. Cytokine activation up-regulates dramatically their expression on the cell surface where they support the interaction of leukocytes and endothelial cells [4]. In addition to being expressed on the cell surface, soluble forms of adhesion molecules have been detected in circulating blood in recent years and have been shown to retain their functional ability [5]. Monocyte chemoattractant protein-1 (MCP-1) is a chemotactic cytokine (molecular weight 810 kDa) produced by endothelial cells after exposure to cytokines (IL-1ß, TNF-
) and oxidized lipoproteins. MCP-1 plays an important role in the migration and activation of monocytes and T cells and moreover, regulates the proliferation of vascular smooth muscle cells [6,7]. Recently emerging evidence suggests a role for these molecules in the pathogenesis of atherosclerotic cardiovascular disease [8,9], which is a significant cause of morbidity and mortality for HD patients.
Increased levels of soluble adhesion molecules and chemokines have been reported previously in patients with chronic renal failure, both on conservative treatment and on HD [1017], but the influence of HD membrane on their secretion as well as their pathological and clinical implications remain largely unknown. The aim of the present study was to investigate the serum levels of ICAM-1, VCAM-1, and MCP-1 in patients on chronic maintenance HD and their potential alterations during a routine HD session. In addition, an attempt was made to correlate their levels with the type of dialysis membranes and their probable association with some of the most common complications of uraemia such as inflammation, dyslipidaemia, and cardiovascular events.
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Subjects and methods
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Patients
Eighty-one adult patients (45 male) on chronic maintenance HD, who were clinically stable and free of active infection, participated in the study after giving their informed consent. All patients had been stabilized on renal replacement therapy for >3 months. Chronic renal failure was attributed to glomerulonephritis in 34 cases, tubulointerstitial nephritis in 26, polycystic kidney disease in seven, renovascular hypertension in three, and was undetermined in 11 cases. Patients with diabetes mellitus, liver disease, autoimmune diseases, or malignancies were excluded in order to avoid the possible effects of these comorbid conditions on cytokine production. None of the patients were receiving antibiotics, corticosteroids, or cytotoxic drugs at the time of the study. The mean age of the patients was 57±13 (range 2380) years and the mean time on HD 86±81 (range 4408) months. All patients were receiving conventional 4-h HD, three times weekly, with bicarbonate dialysate and low-molecular weight heparin as standard anticoagulation. Dialysis prescription was guided by a goal of achieving a value of
0.65 for the urea reduction ratio and a value of Kt/V
1.2. The above indices of adequacy of dialysis were calculated by the formula [(pre-dialysis urea)-(post-dialysis urea)/pre-dialysis urea] and by the second generation Daugirdas equation, respectively. Body mass index (BMI) was calculated by dividing the dry weight in kilograms by the square of the height in meters. Patients had fluid removal down to their dry weight. Serum molecule concentrations (C) at the end of treatment were corrected according to the formula Ccorrected/Cpost=Ppre/Ppost where P was the total protein concentration. The HD group consisted of 33 patients (40.7%) routinely dialysed with modified cellulose membranes (21 male, mean age 55±13 years, mean time on HD 103±98 months) and 48 patients (59.3%) routinely dialysed with polysulfone membranes (24 male, mean age 58±13 years, mean time on HD 73±65 months). Sixty-two patients (76%) with pre-dialysis blood pressure
160/90 were considered hypertensive and were receiving one or more antihypertensive drugs at the time of the study. Seventy patients (86.4%) were on recombinant human erythropoietin therapy and the mean dosage was 102±40 U/kg body weight/week. Twenty-five patients (30.9%) had clinical signs or previous history of vascular diseases. Of the 25 patients, 17 had a history of myocardial infarction, coronary artery bypass, or clinical signs of angina pectoris, three had suffered from stroke and five had peripheral vascular disease. Thirty-five healthy subjects from the hospital staff who were receiving no drugs at the time of the study provided blood samples for laboratory investigations and were used as a control group. These control subjects did not have any history of hypertension, diabetes mellitus, renal or vascular disease.
Laboratory methods
Blood samples from the HD patients were taken directly from the arteriovenous fistula immediately before the beginning and at the end of a 4-h routine HD session. Serum samples were separated from clotted blood by immediate centrifugation (1500 g for 10 min), aliquoted, and stored at -70 °C until assay. Serum levels of the circulating adhesion molecules ICAM-1 and VCAM-1 and the chemokine MCP-1 were measured by an enzyme-linked immunosorbent assay (ELISA) using commercially available standard kits (Quantikine human sICAM-1, sVCAM-1, and MCP-1, Research and Diagnostic Systems Europe Ltd, Abington, UK). Sera were diluted 1/30, 1/75, and 1/3 respectively, for the quantification of ICAM-1, VCAM-1, and MCP-1. The concentrations of these molecules were calculated by reference to standard curves performed with the corresponding recombinant molecule. All serum samples were tested in duplicate. The sensitivity of the ELISA system was 2 ng/ml, 2 ng/ml, and 5 pg/ml for ICAM-1, VCAM-1, and MCP-1, respectively. Haematocrit and biochemistries were determined by routine techniques using an automated analyser. Serum C-reactive protein (CRP) levels were measured by nephelometry. The detection limit was 3.75 mg/l and in the statistical evaluation all values <3.75 mg/l were treated as 3 mg/l.
Statistical analysis
Data are expressed as means±SD. Student's t test was used to compare molecule levels between patients and controls, as well as pre- and post-dialysis levels between patients treated with different dialysis membranes (unpaired data) and to compare pre- and post-dialysis levels (paired data). MannWhitney U test was used to compare molecule levels between different groups of patients. Correlations were tested by regression analysis. Not normally distributed variables were log-transformed before entering regression analysis. The calculations were performed using Statview v. 4.5 statistical software (Abacus Concept, Inc., Berkeley, CA, USA). A two-tailed P value <0.05 was considered to be statistically significant.
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Results
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Pre-dialysis levels of adhesion molecules and chemokines
Compared with the control subjects, patients on HD showed a significant increase in pre-dialysis serum concentrations of ICAM-1 (238±64 vs 515±177 ng/ml, P<0.0001), VCAM-1 (1012±115 vs 2107±648 ng/ml, P<0.0001), and MCP-1 (125±42 vs 427±148 pg/ml, P<0.0001) (Figure 1
). Pre-dialysis serum levels of ICAM-1, VCAM-1, and MCP-1 were 525±163 ng/ml, 2129±580 ng/ml, and 413±135 pg/ml, respectively, in patients treated with modified cellulose membranes and 508±187 ng/ml, 2093±696 ng/ml, and 437±158 pg/ml, respectively, in patients treated with polysulfone membranes (Table 1
). As pre-dialysis serum molecule levels were comparable in the two groups, these patients were grouped together for comparison of adhesion molecules and chemokine levels with clinical and biochemical parameters.

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Fig. 1. Serum levels (mean±SD) of ICAM-1 (ng/ml), VCAM-1 (ng/ml), and MCP-1 (pg/ml) in 35 normal subjects and 81 patients on chronic maintenance HD, before and at the end of a routine HD session.
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Table 1. Serum levels (mean±SD) of ICAM-1 (ng/ml), VCAM-1 (ng/ml), and MCP-1 (pg/ml) before and at the end of a routine HD session in 81 patients, 33 dialysed with modified cellulose membranes (MCM) and 48 dialysed with polysulfone membranes (PSM)
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Effect of HD session on adhesion molecules and chemokine levels
HD session resulted in a significant increase of ICAM-1 (515±177 vs 679±187, P<0.0001), VCAM-1 (2107±648 vs 2662±800 ng/ml, P<0.0001), and MCP-1 (427±148 vs 567±153 pg/ml, P<0.0001) levels (Figure 1
and Table 1
). Post-dialysis levels of ICAM-1, VCAM-1, and MCP-1 were comparable in patients treated with either modified cellulose or polysulfone membranes (672±167 vs 684±201 ng/ml, 2733±787 vs 2614±813 ng/ml, and 565±139 vs 569±164 pg/ml, respectively) (Table 1
). The differences between pre- and post-dialysis levels of ICAM-1, VCAM-1, and MCP-1 were statistically significant both in patients routinely haemodialysed with modified cellulose (525±163 vs 672±167 ng/ml P<0.0001, 2129±580 vs 2733±787 ng/ml P<0.002 and 413±135 vs 565±139 pg/ml P<0.0001, respectively) and polysulfone membranes (508±187 vs 684±201 ng/ml P<0.0001, 2093±696 vs 2614±813 ng/ml P<0.002 and 437±158 vs 569±164 pg/ml P<0.0001, respectively) (Table 1
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Adhesion molecules and inflammation, dyslipidaemia, and cardiovascular events
Mean haematocrit was 33±8% (range 2342%). Mean total protein and albumin concentration were 7.6±0.6 (range 5.78.7 g/dl, normal range 69.7 g/dl) and 4.5±0.4 g/dl (range 35.1 g/dl, normal range 3.85.1 g/dl), respectively. Mean cholesterol and triglyceride levels were 223±50 (range 100350 mg/dl, normal range 120220 mg/dl) and 188±112 mg/dl (range 63782 mg/dl, normal range 40150 mg/dl), respectively. Mean HDL and LDL levels were 35±10 (range 1465 mg/dl, normal range 3555 mg/dl) and 164±41 mg/dl (range 100277 mg/dl, normal range 125195 mg/dl). Forty-three patients had HDL below 35 mg/dl. Mean CRP was 11.4±13.2 mg/l (range <3.7561.4 mg/l, normal range 05 mg/l) and 35 patients had elevated CRP (>5 mg/l).
There was no correlation between pre-dialysis serum molecule levels and the duration of HD treatment, the haematocrit values, the presence or not of hypertension, and the treatment or not with erythropoietin. A positive correlation was observed between ICAM-1 and MCP-1 levels (r=0.41, P<0.0005) (Figure 2
) but not between VCAM-1 and MCP-1 or ICAM-1 and VCAM-1. VCAM-1 levels were negatively correlated with HDL levels (r=-0.30, P<0.01) (Figure 3
) and were significantly increased in patients with HDL <35 mg/dl compared with those with HDL
35 mg/dl (2300±606 vs 1890±633 ng/ml, P<0.005). ICAM-1 or MCP-1 levels did not differ significantly between patients with HDL
35 or <35 mg/dl (516±195 vs 514±156 ng/ml and 418±147 vs 438±151 pg/ml, respectively). No correlation was observed between serum levels of VCAM-1 or ICAM-1 and cholesterol, triglyceride, or LDL levels. Compared with patients with normal CRP values, patients with elevated CRP had significantly increased levels of ICAM-1 (466±166 vs 580±172 ng/ml, P<0.005) but not VCAM-1 (2006±624 vs 2241±663 ng/ml) or MCP-1 (417±159 vs 441±135 pg/ml). Moreover, log-transformed CRP correlated significantly with both ICAM-1 and VCAM-1 (r=0.27, P<0.01 and r=0.34, P<0.005, respectively), but not MCP-1. The correlations were even higher when only the 49 patients with an exact CRP value (
3.75 mg/l) were entered in the regression analysis (r=0.41, P<0.005 and r=0.43, P<0.005, respectively) (Figure 4
).

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Fig. 2. Correlation between pre-dialysis serum ICAM-1 and MCP-1 levels in 81 patients on chronic maintenance HD.
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Fig. 3. Correlation between pre-dialysis serum VCAM-1 and HDL levels n=81 patients on chronic maintenance HD.
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Fig. 4. Correlation between log-transformed exact CRP values and pre-dialysis serum ICAM-1 (upper panel) and VCAM-1 (lower panel) levels in 49 patients on chronic maintenance HD.
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Twenty-five patients had clinically evident vascular diseases and 56 had no history of vascular diseases. The clinical and biochemical characteristics of both groups as well as the risk factors for cardiovascular disease are shown in Table 2
. No significant difference was observed between the study groups in the prevalence of traditional and uraemia-related cardiovascular risk factors such as sex, age, BMI, HD duration, dialysis adequacy, hypertension, smoking, malnutrition, and dyslipidaemia. In contrast, CRP levels were significantly elevated in patients with established vascular disease compared with patients with no vascular events (19.2±12.9 vs 7.9±11.8 mg/l, P<0.001). Moreover, the latter group had significantly lower pre-dialysis serum ICAM-1 levels (474±155 vs 608±189 ng/ml, P<0.005) whereas VCAM-1 and MCP-1 levels did not differ significantly between the two groups (1998±610 vs 2157±664 ng/ml and 448±144 vs 418±151 pg/ml, respectively).
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Discussion
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The present study showed a significant increase in circulating levels of ICAM-1, VCAM-1, and MCP-1 in HD patients compared with control subjects and this is in accordance with previous reports [1017]. The possibility that the routinely used blood sampling directly from the arteriovenous fistula and the local endothelial cell injury might have influenced our results cannot be totally excluded. However, this seems rather unlikely as comparably elevated levels of the above molecules have been demonstrated using this blood sampling method in HD and pre-dialysis patients [12,14]. Alternatively, elevated serum levels of these molecules in HD patients may result from either inadequate clearance or enhanced synthesis and release. The linear correlation, which has been observed between serum creatinine and adhesion molecule levels, may suggest that the kidney plays an important role in their catabolism [12]. On the other hand, the comparable levels reported in HD, CAPD, and pre-dialysis patients probably indicates that HD itself does not affect significantly their elimination [10,12,14]. Also, our study showed that the type of dialysis membrane used does not influence circulating pre-dialysis levels of these molecules, suggesting that other factors may be responsible for the observed alterations. In accordance with the above speculation, chronic uraemia is known to be associated with elevated pro-inflammatory cytokine levels, which can up-regulate the expression and release of different adhesion molecules [3,4]. The levels of ICAM-1 and VCAM-1 in this study were comparable with those reported in previous studies [10,11,13,15,16]. In contrast, the MCP-1 levels were more than twice as high than in previous reports [1416]. This difference can be, at least partially, explained by differences in blood sampling and serum separation methods, in ELISA assays or in the dialysis membranes used. However, it is worth mentioning that a recent study reported significantly increased levels of MCP-1 in patients treated with erythropoietin and that the majority of our patients were on long-term erythropoietin treatment [16].
HD with both modified cellulose and polysulfone membranes resulted in a significant and comparable increase of these molecule levels after correcting for haemoconcentration. Reports on the effect of different dialysis membranes on adhesion molecule levels are limited and the results are often inconsistent. Moreover, in these studies no attempt was made to correlate adhesion molecule levels with clinical or biochemical parameters. Treatment using less biocompatible membranes, such as cuprophane, was reported to decrease [11,13] or to have no effect [12,17] on serum ICAM-1 levels, whereas serum VCAM-1 levels were reported to decrease during HD with cuprophane [11] or increase during HD with either cuprophane or synthetic membranes [13]. The serum levels of ICAM-1 and VCAM-1 reported in two of the previous studies were rather comparable with the levels found in our patient population [11,12] while in the others they were relatively lower [13,17]. The discrepant and often inconsistent results reported previously emphasize the need for larger studies to clarify the potential effect of different dialysers on the adhesion molecule levels.
The responsible mechanism(s) for the observed post-dialysis increase in the adhesion molecule levels are yet to be fully elucidated. With the large size of the soluble ICAM-1 and VCAM-1 (molecular weight 90110 kDa range) it is unlikely that these molecules could be effectively cleared intact through the membranes used [4]. On the other hand, losses into the dialysate and/or adherence to the membranes cannot be excluded. Nevertheless, this study demonstrated a significant increase of ICAM-1 and VCAM-1 at the end of HD session using either modified cellulose or polysulfone membranes, which may indicate that membrane adsorptive properties do not exert a major influence on the above molecule levels. Furthermore, as VCAM-1, in contrast to ICAM-1, is not found in leukocytes and hence would not be expected to be shed on leukocytemembrane interactions, it is tempting to postulate that increased levels of these molecules may be regarded as a marker of endothelial cell activation. However it must be emphasized that, apart from leukocytes and endothelial cells, various other cell types including fibroblasts and smooth muscle cells have been shown to be cellular sources for these molecules. It is obvious that the identification of the cells responsible for adhesion molecules release during HD will considerably aid the interpretation of the above results.
HD with both membranes resulted also in a significant increase in MCP-1 levels. There is only one report of intradialytic MCP-1 release using either cuprophane or synthetic membranes [14], but the exact mechanism, as well as the cellular source(s) of MCP-1, is yet to be investigated. Interestingly, a recent study demonstrated that exposure of peripheral blood monocytes to cuprophane membranes resulted in MCP-1 mRNA overexpression associated with a paradoxically reduced protein release [18]. In contrast, long-term HD with synthetic membranes was associated with down-regulation of MCP-1 gene expression and improvement of the ability of peripheral blood monocytes to secrete this cytokine [18], and this may partially explain the particularly increased MCP-1 levels in our patient population.
Over the last years, emerging evidence suggests an important role for endothelial cell adhesion molecules in the pathogenesis of atherosclerosis through their effect on leukocyte activation, cell migration, and smooth muscle cell proliferation [8]. Elevated levels of ICAM-1 have been reported in patients with coronary heart disease, and high circulating levels of this molecule have been shown to be a prognostic risk factor for future cardiovascular events in the general population [1922]. In addition, epidemiological data have suggested a significant association between increasing concentration of ICAM-1 and the risk of future myocardial infarction in apparently healthy men and women [23,24]. Also, elevated serum ICAM-1 levels were found to be an independent predictor of mortality in pre-dialysis patients with cardiovascular disease [25]. Finally, some studies suggested that circulating VCAM-1 levels may be used to determine the stage of atherosclerosis while a role for MCP-1 in atherogenesis has been also recently proposed [9,26,27]. The highly significant association between ICAM-1 and MCP-1 levels, which has not been reported previously, is intringuing. However, this finding does not indicate a causal relationship, as other factors such as chronic endothelial cell injury at the arteriovenous fistula level would account, at least in part, for the observed correlation. Additional studies are required to establish such a relationship and to identify the potential link between this chemokine and adhesion molecule secretion in HD patients.
Both systemic inflammation and low HDL levels have been regarded as cardiovascular risk factors. Our study demonstrated a negative correlation between serum VCAM-1 and HDL levels and a highly significant correlation between both ICAM-1 and VCAM-1 and CRP levels and this is the first report of such relationships in chronic HD patients. Moreover, compared with patients with normal CRP, patients with elevated CRP had significantly increased serum ICAM-1. The above findings are particularly important, as CRP is an accepted index of overall inflammatory activity and a surrogate of underling cytokine stimulus. Based on the above results, an association between inflammation, adhesion molecule release, dyslipidaemia and atherosclerosis could be postulated. Furthermore, it could be hypothesized that a chronic inflammatory process may, at least partially, promote atherosclerosis via a stimulatory effect on adhesion molecules. The latter idea is further strengthened by the significantly elevated serum CRP and ICAM-1 levels observed in HD patients with established vascular disease. However, VCAM-1 and MCP-1 levels were not found to differ significantly between the two groups. Although the reason(s) for the above is unclear, it seems that these molecules probably act at different stages of the development of vascular damage. Whether their serial measurements may be of value in identifying patients with infra-clinical vascular disease or at increased risk for cardiovascular disease, as well as their specific role in atherogenesis deserve further investigation.
In conclusion, serum levels of ICAM-1, VCAM-1, and MCP-1 are increased in HD patients and probably result from either inadequate clearance or enhanced synthesis and release. HD session resulted in a significant increase of the above molecules, which was independent of the HD membrane used but the mechanism(s) responsible for their release and their cellular sources remain to be fully identified. Increased levels of ICAM-1, VCAM-1, and MCP-1 are associated with inflammation, dyslipidaemia, and cardiovascular events. However, the potential link between these processes and its clinical significance requires additional studies.
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Acknowledgments
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Preliminary results from this study were presented at the XXXVIIth Congress of ERA-EDTA, September 2000, Nice, France and were published in abstract form.
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Notes
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Correspondence and offprint requests to: Aikaterini Papayianni, MD, Department of Nephrology, Hippokration General Hospital, 50 Papanastasiou Str., 54642 Thessaloniki, Greece. Email: aikpapag{at}otenet.gr 
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Received for publication: 27.11.00
Revision received 26.10.01.