Nephrology Dialysis Transplantation

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Nephrol Dial Transplant (2001) 16: 1442-1447
© 2001 European Renal Association-European Dialysis and Transplant Association

Endothelial dysfunction marker von Willebrand factor antigen in haemodialysis patients: associations with pre-dialysis blood pressure and the acute phase response

Jacek Borawski, Beata Naumnik, Krystyna Pawlak and Michal Mysliwiec

Department of Nephrology and Internal Medicine, Medical Academy, Bialystok, Poland

	Abstract

Top Abstract Introduction Subjects and methods Results Discussion References

 
Background. Increased plasma soluble von Willebrand factor antigen (vWF : Ag) level, a marker of vascular endothelial cell dysfunction, is a strong predictor of atherosclerotic cardiovascular disease (CVD) in the general population. We studied cross-sectional associations between vWF : Ag level, prevalence of CVD, and related factors including pre-dialysis arterial blood pressure (BP) and some markers of inflammation in maintenance haemodialysis (HD) patients.

Methods and results. Plasma vWF : Ag level measured by an enzyme-linked immunosorbent assay (ELISA) was higher in 110 HD patients than in 20 controls. On bivariate regression analysis, vWF : Ag level was directly associated with the presence of CVD, age, fibrinogen and the use of enoxaparin (vs unfractionated heparin) during HD procedures, and inversely with albumin and pre-dialysis BP. The patients with prevalent CVD were older, had higher vWF : Ag, white blood cell and platelet counts, fibrinogen and triglycerides, lower albumin levels, and were less frequently on combination antihypertensive therapy. Multivariable analyses identified low pre-dialysis BP, hypoalbuminaemia and hyperfibrinogenaemia (in descending order of significance) as independent predictors of high vWF : Ag level. There were no associations between vWF : Ag levels and gender, ABO blood type, smoking, body mass index, renal failure cause, duration of HD therapy, K_t/V, normalized protein catabolic rate, dialysate buffers, dialysers, viral hepatitis, erythropoietin treatment, specific antihypertensive drugs, haemoglobin, white blood cell and platelet counts, liver enzymes, phosphorous, total cholesterol, and triglycerides.

Conclusion. Elevated plasma levels of endothelial dysfunction marker vWF : Ag in maintenance HD patients are associated with established cardiovascular mortality risk factors such as low pre-dialysis blood pressure and the activated acute phase response.

Keywords: acute phase response; blood pressure; cardiovascular disease; endothelium; haemodialysis; von Willebrand factor

	Introduction

Top Abstract Introduction Subjects and methods Results Discussion References

 
Vascular endothelial cell dysfunction is pathogenically related to the development of atherosclerosis and cardiovascular disease (CVD). von Willebrand factor (vWF), a procoagulant glycoprotein derived from endothelial cells and platelets, is involved in platelet adhesion and aggregation at sites of vascular injury, and serves as a carrier for coagulation factor VIII [1]. Raised levels of plasma soluble vWF antigen (vWF:Ag) is an established index of endothelial cell activation and/or dysfunction in patients with atherosclerotic CVD, as well as in those at increased risk of CVD [1]. Recently, large epidemiological studies [2–6] have proved that high vWF : Ag concentration is an independent predictor of CVD-related ischaemic events in the general population.

CVD remains the main cause of morbidity and mortality in maintenance haemodialysis (HD) patients [7]. It has been documented that markers of the activated acute phase reaction, such as increased C-reactive protein [8–10], fibrinogen [10–12], lipoprotein(a) [10,11] and low albumin concentrations [10,13,14] are all direct and independent predictors of CVD in long-term HD patients. These findings proved that the association between inflammation and atherosclerosis is particularly strong in this population. The detrimental role of endothelial dysfunction in renal failure patients was recently shown by the direct association between soluble intercellular adhesion molecule-1 and increased mortality when on dialysis [15].

The soluble vWF : Ag level has been repeatedly found to be increased in maintenance HD patients [16–21]. However, studies addressing links between vWF as an endothelial dysfunction marker, atherosclerosis, and particularly CVD in HD patients, are scarce and incomplete [19–22]. These studies did show that increased vWF : Ag levels are associated with alterations of the microcirculation characterized by decreased post-ischaemic vasodilation [19], and with activated intravascular blood coagulation [20]. However, vWF:Ag was not found to be predictive of prior HD fistula thrombosis or the presence of peripheral vascular disease [21]. On the other hand, enhanced ristocetin-induced platelet aggregation in whole blood, being a measure of plasma vWF : Ag concentration [18], was found to be indicative of the exacerbation of anaemia due to subclinical inflammation in chronic HD patients [22].

The aim of this cross-sectional study was to evaluate associations between soluble vWF : Ag level as an index of endothelial injury, and the prevalence of CVD, pre-dialysis arterial blood pressure (BP), and some markers of the activated acute phase response in maintenance HD patients.

	Subjects and methods

Top Abstract Introduction Subjects and methods Results Discussion References

 
Patients
One-hundred-and-ten Caucasian, non-diabetic, chronic HD patients were enrolled in a cross-sectional study (Table 1). Patients who presented clinical evidence of any inflammatory or infectious disease within the preceding month were excluded. HD was performed for 3.5–5 h three times weekly using the double-needle technique and native arteriovenous fistulas. Unfractionated heparin (UFH) (Heparin, Biochemie, Kundl, Austria; mean dose of 4760±1425 IU/HD session) or low-molecular-weight heparin enoxaparin (Clexane, Bellon Rhóne-Poulenc Rorer, Montrouge, France; median dose of 40 mg/HD (20–60 mg/HD session) were used as anticoagulants during HD procedures. The patients were treated with subcutaneous recombinant erythropoietin (rHuEpo) (Eprex, Cilag AG Int., Zug, Switzerland), at a median dose of 86.0 IU/kg/week (13.2–190.5 IU/kg/week) for a median period of 38 weeks (4–102 weeks), supplements of folic acid, vitamins and iron, and calcium-containing phosphate binders. They were also taking antihypertensive drugs, including angiotensin I converting enzyme inhibitors (n=44, 40%), calcium channel antagonists (n=65, 59.1%) and ß-receptor blockers (n=17, 15.4%), as well as mononitrites (n=32, 29.1%).

View this table: [in this window] [in a new window]   Table 1. Demographic and clinical characteristics of 110 haemodialysis patients

 
The K_t/V and normalized protein catabolic rate were calculated using a single-compartment model. Smoking habit was defined as regular tobacco use within the previous 3 years. Systolic and diastolic arterial BP was calculated as a mean of 10 consecutive pre-dialysis readings preceding the study point. Mean arterial BP was calculated as mean BP=diastolic BP+((systolic BP–diastolic BP)/3). CVD was defined as a present or prior pectoral angina, or myocardial infarction proven by a history, elevated cardiac enzymes or ECG, ischaemic cerebrovascular accident proven by a history and/or CT, or peripheral vascular disease (at least one non-pulsatile peripheral artery or vascular thrill, except for arteriovenous fistula).

Twenty age- and sex-matched healthy volunteers served as controls for determination of plasma vWF antigen. Approval by the institutional review board for human studies was obtained, and all patients and controls gave their informed consent.

Methods
Fasting blood was obtained from the arterial outlet of the fistula before heparinization or initiation of the mid-week morning HD session. Cell-free plasma for vWF : Ag determination was prepared from citrated blood by a conventional method, and it was stored in aliquots at -40°C until assayed. Complete blood counts were performed on a K-1000 automated haematology analyser (Sysmex, Kobe, Japan). Blood chemistries were determined on a Cobas Mira autoanalyser (Roche, Basel, Switzerland) using routine colorimetric enzymatic methods for blood urea nitrogen, alanine aminotransferase, alkaline phosphatase, total cholesterol, triglycerides and phosphorus. Serum albumin was measured by the bromocresol green method. Plasma fibrinogen was determined with the clotting method of Clauss. Serum anti-hepatitis C virus antibodies and hepatitis B virus surface antigen were measured with third generation, enzyme-linked immunosorbent assays (ELISA) using an AxSYM analyser and kits purchased from Abbott Laboratories (Abbott Park, IL, USA).

Plasma vWF : Ag level was measured by ELISA using an Asserachrom vWF kit (Diagnostica Stago, Asniéres sur Seine, France) and expressed as a percentage of normal value. The assays were performed in duplicates on a 400 SFC photometer (SLT-Labinstruments, Grödig/Salzburg, Austria), and were calibrated using the standards provided and reference samples. For calculation of the results, a computer and a curve-fitting program were used. Intra- and inter-assay coefficients of variations were <10%.

Statistical analysis
Shapiro-Wilk's W-test of normality was used for data distribution analysis. The normally distributed data were presented as mean±1 SD and the non-Gaussian data as median (range). The skewed data were log-transformed in order to normalize their distribution prior to statistical analysis. Bivariate associations between variables of interest were analysed by Pearson's linear or logistic regression analysis. For inter-group comparisons, the Student's t-test for independent samples, ² or Fisher's exact test, and one-way analysis of variance with post hoc comparisons performed by Scheffe's procedure were used when appropriate. Backward stepwise multiple linear regression analysis was employed to evaluate any association between plasma vWF : Ag level as the outcome variable and multiple independent variables. The independent variables were selected on the basis of being correlated with vWF : Ag using a P cut-off value <0.150. P values<0.05 were considered statistically significant. Analyses were performed using Statistica 5.1 (StatSoft Inc., Tulsa, OK, USA).

	Results

Top Abstract Introduction Subjects and methods Results Discussion References

 
Bivariate and independent predictors of soluble vWF : Ag
A soluble vWF : Ag concentration of 136.0% (60.5–288.5%) in HD patients was significantly higher than in the controls (98.3% (47.4–177.0%), P<0.0001).

On logistic regression analysis, an increased vWF:Ag level was directly associated with the presence of CVD (²=4.97, P=0.026) and the use of enoxaparin (vs UFH) (²=12.69, P=0.004). There was no correlation between vWF : Ag and the dose of either heparin.

On linear regression analysis, vWF:Ag correlated positively with age (r=0.236, P=0.013) and fibrinogen (r=0.335, P=0.0003) (Figure 1A), and inversely with albumin (r=–0.273, P=0.004) (Figure 1B), pre-dialysis systolic BP (r=-0.473, P<0.0001), diastolic BP (r=-0.408, P<0.0001) and mean arterial BP (r=-0.464, P<0.0001) (Figure 1C). There was no association between vWF:Ag level and the antihypertensive treatment or the use of any of the particular antihypertensive drugs (data not shown). Correlations at a P value of<0.150 were found between vWF: Ag and phosphorous (r=0.171, P=0.075), white blood cell count (r=0.143, P=0.136) and triglycerides (r=0.138, P=0.148). There were no associations between vWF:Ag levels and gender, ABO blood type, smoking, body mass index, renal failure cause, duration of dialysis, K_t/V, normalized protein catabolic rate, dialysate buffers, dialysers, viral hepatitis seropositivity, rHuEpo treatment, haemoglobin (9.32±1.85 mg/dl), platelet count, alanine aminotransferase (21 IU/l (4–256 IU/l)), alkaline phosphatase (80 IU/l (15–2023 IU/l)), and total cholesterol (165 mg/dl (95–275 mg/dl)) (data not shown).

View larger version (26K): [in this window] [in a new window]   Fig. 1. Relationship between soluble von Willebrand factor antigen and fibrinogen (A), albumin (B) and pre-dialysis mean arterial blood pressure (C) in 110 haemodialysis patients. vWF:Ag, fibrinogen and albumin were log-transformed to adjust for their non-normal distribution.

 
The multivariable analysis (Table 2) showed that both low pre-dialysis mean BP and serum albumin independently predicted high vWF : Ag level, with mean BP being the stronger predictor. When mean BP was excluded from the regression analysis, albumin became the only predictor of vWF : Ag level. If albumin was excluded, mean BP remained the strongest independent negative predictor of vWF : Ag, followed by increased fibrinogen level. The analyses yielded the same results when pre-dialysis systolic BP or diastolic BP, which were multicollinear with mean BP (r=0.898 and r=0.955, respectively), were used instead of mean BP.

View this table: [in this window] [in a new window]   Table 2. Variables predicting soluble von Willebrand factor antigen level in 110 haemodialysis patients in the backward stepwise multiple regression analysis

 

Categorization by CVD status
Forty-one (37.3%) of the HD patients studied had CVD. All of them had evidence of ischaemic heart disease, 12 (29.3%) had peripheral vascular disease, and two (4.9%) had a history of ischaemic stroke.

Soluble vWF : Ag level was found to be higher in the patients with CVD compared with those without (Table 3). The former subjects were older, had higher white blood cell and platelet counts, fibrinogen, triglycerides, and lower albumin levels than the latter ones. Soluble vWF : Ag level did not correlate with the platelet count in either of these groups. There were no inter-group differences in pre-dialysis BP or the frequencies of using any of the particular antihypertensive drugs, except for vasoactive mononitrites, which were used exclusively in the CVD patients. The percentage of patients on antihypertensive therapy who required one drug to control their BP was significantly higher in the CVD group, whereas those without CVD were on combination therapy more frequently. None of the other parameters studied differed between these groups.

View this table: [in this window] [in a new window]   Table 3. Comparison of haemodialysis patients categorized by cardiovascular disease status

 

	Discussion

Top Abstract Introduction Subjects and methods Results Discussion References

 
This study shows that increased levels of plasma-soluble vWF : Ag are closely associated with low pre-dialysis BP and a persistent inflammatory response in maintenance HD patients. This finding reflects a highly noxious clustering of the CVD risk factors in this population. Elevated soluble vWF : Ag level, a marker of endothelial dysfunction and/or activation, was independently associated with the acute phase reaction markers previously identified as independent predictors of CVD in long-term HD patients, namely low albumin [10,13,14] and increased fibrinogen levels [10–12.] Moreover, our results are in accordance with the European Concerted Action on Thrombosis and Disabilities (ECAT) Angina Pectoris Study [4] and the Atherosclerosis Risk in Communities (ARIC) study [5] which also revealed positive correlations between vWF : Ag and fibrinogen in the general population.

Low pre-dialysis BP was unexpectedly found to be the strongest independent predictor of the increased vWF : Ag level in our maintenance HD patients. The association between vWF : Ag and pre-dialysis BP has been studied for the first time in these patients, and the strong, inverse relationship was in contrast to the positive one revealed in both healthy subjects and patients with prevalent CVD without renal disease [23]. Low pre-dialysis BP was more significantly associated with increased soluble vWF : Ag than were inflammatory markers such as hypoalbuminaemia and increased fibrinogen levels.

Hypertension is an established risk factor for the development of atherosclerosis and its cardiovascular complications in long-term HD patients [24]. At the same time, however, low pre-dialysis BP was predictive of the enhanced CVD mortality in this high-risk population [14,25–27], with the exception of cerebrovascular deaths [27]. It is plausible that the development of cardiovascular complications results in heart dysfunction that is followed by an ominous fall in BP. In confirmation of this link, the pre-dialysis patients with atherosclerotic plaques in the carotid arteries have been reported to have a significantly lower diastolic BP than those without [28], while increased carotid arterial stiffness and decreased diastolic BP were found to be independent predictors of all-cause and cardiovascular mortality in HD patients [26]. Recently, the Haemodialysis Study (HEMO) [29] showed that pre-dialysis diastolic BP was inversely associated with the prevalence of coronary heart disease, whereas systolic BP was not related to any form of CVD in maintenance HD patients.

Inflammation in chronic HD patients is multifactorial and commonly connected with malnutrition [30]. Hypoalbuminaemia, a hallmark of both these comorbid states [13,14], was the second strongest independent predictor of raised vWF : Ag level in our patients. When albumin was excluded from the multivariable analysis, it was replaced by increased fibrinogen, characteristic of the activated acute phase response. Thus, it is plausible that albumin and fibrinogen are probable interchangeable markers for the process of chronic low-grade inflammation underlying the increase of soluble vWF : Ag level in our otherwise clinically stable HD patients. Multivariable analysis shows that those inflammatory markers have a stronger influence on vWF : Ag level than the presence of CVD itself.

Soluble vWF : Ag concentration did not relate to any of the studied causes of subclinical inflammation in long-term HD patients, such as bioincompatibility of the dialyser membranes, underlying renal disease or chronic viral hepatitis. Regarding alternative causes of this comorbid state, possible roles of some infectious agents [31], the use of not ultrapure dialysate [32], and reduced nitric oxide production by endothelial cells [33,34] should be considered in the development of endothelial injury, atherosclerosis and CVD.

Our HD patients with prevalent CVD, when compared with those without, were older and presented with higher vWF : Ag, white blood cell and platelet counts, fibrinogen, triglycerides, and lower albumin concentration. Among the components of that highly atherogenic profile, both low albumin levels and increasing age were reported to be related to the increased intima-media thickness and the presence of atherosclerotic plaque in the carotid and femoral arteries of HD patients [35]. In this study, we found low albumin to be a strong independent predictor of increased vWF : Ag, and confirmed the positive relationship between age and this endothelial injury marker [17,19]. Based on these associations, it is conceivable that an increased vWF : Ag level also reflects the greater severity of atherosclerosis underlying CVD in HD patients. On the other hand, we failed to find any differences in the pre-dialysis BP between the patients with CVD vs those without, which, if present, could explain the inverse relationship between vWF : Ag and BP levels. The lack of these differences could be due to the more aggressive, combined antihypertensive treatment in our patients without CVD. It could also be confounded by complex effects of rHuEpo and different dialysate buffers on BP in HD patients, as well as by the fact that ischaemic heart disease was defined on the clinical basis, which is less sensitive than coronary angiography for diagnosis of atherosclerotic CVD.

Based on the strong inverse relationship of high soluble vWF : Ag level with the mortality-predictive low pre-dialysis BP, its increased concentration in the patients with prevalent CVD, and the consistent associations between vWF : Ag and some inflammation-related CVD risk factors, we suggest that increased plasma levels of the endothelial dysfunction marker vWF : Ag can identify those HD patients at a particularly increased risk of atherosclerotic CVD-related death. However, a prospective study is required to confirm this hypothesis.

The association between the use of enoxaparin instead of UFH for blood anticoagulation during HD procedures and increased vWF : Ag levels was lost in the multivariable analysis when we adjusted for the CVD-related variables. However, the aspect of possibly different effects of those heparins on the vascular endothelium in maintenance HD patients deserves prospective evaluation. Regarding variables reported to influence soluble vWF : Ag level, we did not find this endothelial marker to be directly associated with either rHuEpo treatment, which could activate the endothelial cells to secrete vWF [36], or a number of circulating platelets that could release their vWF pool on activation [1]. We can not confirm the positive association between vWF : Ag and time on HD [16]. In contrast to the general population, vWF : Ag in chronic HD patients was not related to either smoking or hypercholesterolaemia [1], and was not lower in the subjects with blood type O [2,3].

In conclusion, increased levels of plasma-soluble vWF : Ag, a marker of endothelial dysfunction, are associated with low pre-dialysis BP and some markers of the activated acute phase response in maintenance HD patients. Prospective evaluation is needed to establish whether vWF : Ag could predict an increased cardiovascular mortality in this population, as well as to define further the relationships between inflammation, endothelial dysfunction and atherosclerosis in long-term HD patients.

	Acknowledgments

 
The work was supported by grant No. 4P05B 014 15 from the National Research Committee (Komitet Bada Naukowych) Poland. It also won one of the 2000 ERA-EDTA Congress Grants and was presented in oral form during the XXXVII European Renal Association–European Dialysis and Transplant Association Congress first combined Congress with European Kidney Research Association, Nice, France, September 17–20, 2000.

	Notes

 
Correspondence and offprint requests to: Dr Jacek Borawski, Department of Nephrology and Internal Medicine, Medical Academy, 14 Zurawia Street, PL 15-540 Bialystok, Poland.

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Received for publication: 3.10.00
Revision received 31. 1.01.
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				J. Borawski and M. Mysiwiec Effects of Recombinant Erythropoietin Therapy on Circulating Endothelial Markers in Hemodialysis Patients Clinical and Applied Thrombosis/Hemostasis, January 1, 2002; 8(1): 77 - 84. [Abstract] [PDF]

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