Skip main navigation

In Vivo Shear Stress Determines Circulating Levels of Endothelial Microparticles in End-Stage Renal Disease

Originally published 2007;49:902–908


Shear stress is a major determinant of endothelial apoptosis, but its role in the in vivo release of shed membrane microparticles by endothelial cells remains unknown. Thus, we sought to evaluate the possible relationship between circulating endothelial microparticle levels and laminar shear stress in end-stage renal disease patients with high cardiovascular risk, whose levels of endothelial microparticles are elevated. In 34 hemodialyzed patients, we analyzed the relationships between brachial artery and aortic shear stress and circulating microparticles levels. Only endothelial microparticles were inversely correlated with laminar shear stress values (P<0.0001) or its components shear rate and whole blood viscosity, independent of age or arterial blood pressure. Changes in hematocrit resulting from hemodialysis-induced hemoconcentration or erythropoietin anemia improvement induced a significant increase in whole blood viscosity and shear stress and were associated with a significant decrease in endothelial microparticles with a significant and inverse correlation with changes in hematocrit/hemoglobin or laminar shear stress. These results demonstrate that, in end-stage renal disease patients, laminar shear stress is an important determinant of plasma levels of endothelial microparticles. Anemia as an important determinant of whole blood viscosity and shear stress, contributes to endothelial apoptosis, and could play an indirect role in the pathogenesis of accelerated arteriosclerosis in this high-risk population.

Microparticles (MPs) are submicron vesicles shed from plasma membranes after cell activation or apoptosis.1 MPs of different cellular origin are found in the plasma of healthy subjects, and their numbers increase in patients with cardiovascular diseases.2–6 Surprisingly, the mechanisms leading to the in vivo formation and release of MPs by endothelial cells remain obscure. Yet, apoptotic stimuli are extensively used in vitro to generate MPs from cultured cells.6 Shear stress (SS) is a major determinant of endothelial apoptosis, and physiological laminar fluid SS promotes endothelial cell survival and quiescence.7 Maintenance of a physiological laminar SS is crucial for normal vascular structure and function and exerts atheroprotective effects in vivo through the release of substances that promote anticoagulation, inhibit inflammation, and induce vasodilation.7–10 In association with anemia-related low whole blood viscosity (WBV), SS is reduced in patients with end-stage renal disease (ESRD),11 and this abnormality is associated with arterial outward remodelling, increased arterial stiffness, and reduced flow-mediated dilation.12 Increased SS because of partial anemia correction was associated with reduced arterial stiffness and improved flow-mediated dilation.12 Plasma levels of endothelial MPs in patients with ESRD predict the severity of these arterial and endothelial dysfunctions independent of other classical risk factors,5 but the eventual role of SS alterations on the in vivo formation and release of MPs by endothelial cells remains unknown. Thus, in the present study we sought to evaluate the relationship between circulating endothelial MPs levels and SS and its determinants in ESRD patients known to represent a high cardiovascular risk population, with high levels of circulating endothelial MPs,5 and to evaluate the effects of acute and chronic anemia correction-related SS changes on circulating platelets and endothelial MPs.


An expanded Methods section is available in an online supplement available at Thirty-four ESRD patients on hemodialysis (HD) for ≥3 months were included. Inclusion criteria were as follows: (1) no clinical cardiovascular complication, (2) absence of aortic valves stenosis, and (3) agreement to participate in the study, which was approved by our institutional review board and adhered to the principles of the Declaration of Helsinki. Patients were dialyzed for 4 to 6 hours 3 times weekly on high-flux hemodialyzers with a synthetic biocompatible membrane (Nephral 500 Hospal Merieux). Twenty ESRD patients received antihypertensive therapy, which was stopped 10 days before the study. Patients received sevelamer as a phosphate binder and, if necessary, were on erythropoietin (EPO) and intravenous iron therapy to maintain hemoglobin level ≥110g/L. Twenty-five matched healthy control subjects were included.

Arterial Hemodynamic Measurements

Experiments were carried out as reported previously.13–16

MP Isolation and Cytofluorometry Analysis

Circulating MPs isolated from venous citrated blood after 3 days off dialysis were analyzed by flow cytometry5,6,17–19 (Figure S1). Platelet- and endothelial-derived MPs were defined as CD41+CD31+ and CD41−CD31+ MPs, respectively. Endothelial MPs were also identified as CD144+ MPs.


Characteristics of Study Populations

Table S1 includes blood chemistry characteristics of ESRD patients. Abnormalities were those classically observed in ESRD, that is, lower hemoglobin, lower WBV, high parathormone, and serum phosphates. Blood lipids, serum albumin, and serum total or ionized calcium were in the reference range. C-reactive protein was slightly above the normal values (2 mg/L), but microinflammation was mild. All of the studied MPs were elevated in comparison with values in the control population (Table S1).

Hemorheologic Characteristics and Relationships With MPs

Brachial artery characteristics determined by direct measures are given in Table S2. ESRD patients were characterized by larger brachial artery diameter, lower mean flow velocity, and lower shear rate. Lower shear rate and lower WBV were responsible for decreased SS in ESRD patients, but the values were still within the typically observed range (5 to 20 dynes/cm2).

In univariate correlation analysis, endothelial CD144+ MPs were significantly correlated only with age (r=0.597; P<0.01), systolic blood pressure (BP; r=0.618; P<0.001), and mean SS (r=−0.770; P<0.0001). The correlation of CD144+ MPs with peak SS was also significant but weaker (r=−0.565; P<0.01). In multivariate analyses, circulating CD144+ MPs were strongly and inversely correlated with brachial artery SS or its 2 determinants, that is, shear rate, and WBV, that is, hematocrit (Figure 1), and positively correlated with age and systolic BP (Table 1). Shear rate and aortic SS, which was computerized from stroke volume, aortic diameter, and WBV, were lower in ESRD patients and were significantly correlated with directly measured parameters in brachial artery. Furthermore, circulating CD144+ MPs were strongly and inversely correlated with aortic SS (Figure 2). In univariate correlation analysis, endothelial CD41−CD31+ MPs only correlated with systolic BP (r=0.718; P<0.0001) and mean SS (r=−0.565; P<0.005). Multivariate analyses of variables associated with endothelial CD41−CD31+ MPs are shown in Table 1. An independent and significant positive correlation was observed between CD41−CD31+MPs and systolic BP. Circulating CD41−CD31+ MPs were strongly and inversely correlated with SS. In univariate and multivariate correlation analysis, circulating platelets MPs were associated with plasma fibrinogen (P=0.048) and no other parameter.

Figure 1. Correlations between brachial artery SS (expressed as dyne/cm2) and CD144+ MPs (A), CD41−CD31+ MPs (B), CD41+CD31+ MPs (C), and annexin V+ MPs (D).

TABLE 1. Multiple Correlation Report for CD144+ and CD41−CD31+ Endothelial MPs as a Dependent Variable in ESRD Patients

R2 = 0.687; P<0.0001 for the CD144+ model. R2 = 0.666; P<0.0001 for the CD41−CD31+ model.
    Age, y2.0510.049
    Systolic BP, mm Hg2.2430.0321
    Brachial artery SS, dynes/cm2−3.730<0.001
    Systolic BP, mm Hg4.0090.0004
    Brachial artery SS, dynes/cm2−3.4160.0019

Figure 2. Correlations between brachial artery and ascending aortic SS (A), between brachial artery and aortic shear rates (B), and between aortic SS and CD144+ MPs (C).

Effect of Increasing SS on Circulating MPs

The effects of acute systolic BP and rheology changes on circulating MPs were analyzed after HD ultrafiltration-induced hemoconcentration in 25 patients, including 14 patients with repeated brachial artery hemodynamics (Table 2). Hemodialysis induced a significant decrease in systolic BP (P<0.0001) and increased brachial artery SS (P<0.01) associated with increased WBV and hematocrit (P<0.0001) and increased shear rate (P<0.01). Changes in systolic BP were significantly and inversely correlated with changes in BA shear stress (r=−0.619; P=0.014). HD induced a significant decrease in CD41−CD31+ MPs with no effects on CD41+CD31+ MPs or annexin V+ MPs. In 14 patients with repeated measurement of SS, changes in CD41−CD31+MPs were positively correlated with changes in systolic BP (r=0.454; P<0.01) and negatively correlated with changes in SS (r=−0.643; P<0.01; Figure 3). When analyzed in shear stress components, the decrease in CD41−CD31+ MPs was inversely associated with changes in WBV (P=0.015) and with changes in shear rate (P=0.050).

TABLE 2. Effect of HD on Brachial Artery SS and CD41−CD31+ Endothelial and CD41+CD31+ Platelet MPs (n=25)

VariablesBefore HDAfter HDP
Values as means±SD.
Body weight, kg72.3±1469.6±13.60.0001
Systolic BP, mm Hg142±32125±280.0001
Whole blood viscosity, cPoise3.00±0.523.21±0.600.0001
Hemoglobin, g/L115±13128±9.50.0001
Hematocrit, %35±3.638.0±3.80.0001
CD41−CD31+ MPs, ev/μL1356±1066678±4730.0001
CD41+CD31+ MPs, ev/μL7702±118944780±10610NS
Annexin V+ MPs, ev/μL4661±92034934±12303NS
Brachial artery shear rate, s−1*31±1847±250.01
Brachial artery SS, dynes/cm2*8.9±6.115.6±10.10.01

Figure 3. Correlation between brachial artery shear rate and CD144+ microparticles (A) and between WBV and CD144+ MPs (B). Correlation between hematocrit and CD144+ MPs (C) and between hematocrit and CD41−CD31+ MPs (D).

In univariate analysis concerning all 25 of the patients, changes in CD41−CD31+ MPs were inversely correlated with increased hematocrit/WBV (r=−0.579; P<0.001) and positively correlated with changes in systolic BP (r=0.440; P<0.01). Because of significant inverse correlation between changes in systolic BP and brachial artery SS (P<0.01) in multivariate analysis, only changes in hematocrit/WBV were inversely correlated with changes in MPs (r=−0.513; P<0.01; Figure 4). Changes in CD41−CD31+MPs were not correlated with changes in blood chemistries.

Figure 4. Correlation between changes in CD41−CD31+ MPs and hemodialysis-induced hematocrit (A), hemodialysis-induced SS (B), or long-term hemoglobin changes (EPO dose adjustments; C).

Association between long-term hematocrit–hemoglobin–WBV changes and MPs was studied in 18 patients, including 10 patients with repeated BA hemodynamics, after treatments with EPO and/or intravenous iron. During this period (15±4 weeks) hemoglobin and WBV increased in all but 2 of the patients (in 2 iron-depleted patients, the hemoglobin decreased). Although CD41−CD31+ MPs significantly decreased, the CD41+CD31+ population did not change significantly. BA hemodynamics were repeated in 10 subjects. The shear rate was unaffected, and increased SS (P<0.05) was entirely associated with increased WBV (Table 3). A significant inverse relationship was observed between changes in circulating CD41−CD31+ endothelial MPs and changes in hemoglobin (Figure 4) or hematocrit and WBV (data not shown). No correlation was observed between the EPO dose and endothelial (r=0.067; P=0.819) or platelet MPS. BP, CD41+CD31+ MPs, and blood chemistries (data not shown) were unchanged.

TABLE 3. Effect of Long-Term Hemoglobin Changes on CD41−CD31+ Endothelial and CD41+CD31+ Platelet MPs (n=18) and on Brachial Artery SS (n=10)

Values are mean±SD. NS indicates not significant.
Systolic BP, mm Hg140±30142±25NS
Whole blood viscosity, cPoise2.92±0.203.16±0.23<0.01
Hemoglobin, g/L106±13113±9<0.01
Hematocrit, %32.7±3.835.6±3.8<0.01
Erythropoietin, units per wk5824±42906470±3624NS
Microparticles CD41−CD31+, ev/μL1730±1039835±657<0.01
Microparticles CD41+CD31+, ev/μL4110±25313085±1722NS
Brachial artery shear rate, s−132±1636±22NS
Brachial artery SS, dynes/cm27.5±4.212±6.4<0.05


The present study is the first to identify a robust relationship between in vivo measured shear stress level and circulating endothelial MPs, independent of age and BP. The inverse relationship between shear stress and MPs concerned more specifically endothelial MPs and was not observed with platelet MPs.

Several recent studies support the concept that plasma levels of endothelial MPs represent a surrogate marker of endothelial cell damage.1,2,6 Endothelium-derived MPs impair endothelial function in vitro,5,19 and recent studies in patients with ESRD or acute myocardial infarction have demonstrated a strong and independent association between circulating endothelial MPs with several indexes of arteriosclerosis and decreased flow-mediated arterial dilation.5 Maintenance of physiological laminar fluid SS is crucial for normal vascular function and structure.8,9 Laminar SS affects multiple endothelial functions, such as proliferation, apoptosis, migration, permeability, and remodelling, as well as gene expression.7,20 Hence, our results show an inverse correlation between circulating endothelial MPs and baseline SS values, suggesting that both enhanced productions of CD144+ and CD41−CD31+ endothelial MPs result from increased apoptosis of the endothelium, triggered by low laminar stress on the vessel wall. Moreover, previous results in ESRD populations showed that circulating levels of endothelial MPs are associated with alteration of mechanical properties of arteries and decreased endothelial flow-mediated dilation5 and that increased SS because of partial anemia correction was associated with reduced arterial stiffness and improved flow-mediated dilation.12 The major determinants of in vivo SS are blood viscosity, blood flow, and arterial diameter. Arterial enlargement with outward remodeling is well documented in ESRD patients.14,21 These changes are already observed in patients with mild-to-moderate chronic kidney disease in the absence of anemia.21 Hematocrit is a major determinant of blood viscosity, and modest decreases in hemoglobin concentration have been shown to impair flow-mediated dilatation in the human brachial artery of normal subjects.22 The present study indicates that the degree of anemia as a determinant of SS is independently and inversely associated with values of endothelial circulating MPs and the degree of endothelium injury.

Endothelial dysfunction is observed in patients with ESRD23–27 and is attributed to the presence of NOS inhibitors and accumulation of uremic toxins.27–29 In agreement with a previous study,12 the present results suggest that, other than the role of metabolic disorders, anemia, indirectly through its influence on SS, could play a role in the development of endothelial and arterial dysfunctions observed in ESRD patients. We analyzed the possibility that an increase in SS induced by increased WBV and increased hematocrit could be associated with decreased MP concentrations. We repeated the study following acute and long-term changes in SS obtained by HD ultrafiltration/hemoconcentration or long-term hemoglobin/hematocrit increase. Hemodialysis induced a significant decrease of endothelial-derived MPs associated with an increase in SS but also with decreased systolic BP, both factors associated with MPs levels. Because of a significant correlation between HD-induced changes in SS and BP, the separate effect of these changes on MP variation is difficult to analyze. In a multivariate model including the respective roles of systolic pressure and WBV changes on endothelial MPs, only changes in blood viscosity and or hematocrit were significantly associated with MP variations. Faure et al28 have shown recently that, in vitro, the uremic toxins p-cresol and indoxyl sulfate increase endothelial MP release from cultured endothelial cells, and the present study cannot rule out the possibility that the observed decreased MP after HD results from the removal of uremic toxins. Nevertheless, no association between changes in MPs and changes in HD-induced biochemistry, including urea removal rate and an index of dialysis adequacy (Kt/V), were observed. Hemodialysis induced a significant decrease in endothelial-derived MPs but has no effect on platelet-derived MPs. Our results differ from those of Daniel et al,30 who observed a significant increase of circulating platelet MPs during HD. The difference could be because of the high use of cellulosic membranes in this study, whereas only biocompatible synthetic membranes were used in our study.

Long-term anemia and hematocrit changes were associated with changes in SS because of variations in WBV but not because of changes in shear rate. Changes in hemoglobin/hematocrit and WBV were only associated with reciprocal variations in circulating endothelial, but not platelet, MPs. Conditions of the measurements before and after the long-term hematocrit changes were identical, that is, before HD and with similar blood chemistries and unchanged BP. The observed decrease in endothelial MPs could result from the protective effect of higher SS or from the effect of EPO used to correct anemia. Treatment with a long-acting EPO analogue enhances endothelial progenitor cell proliferation and differentiation in renal patients and confers vascular protection.31,32 The role of EPO cannot be excluded, but the concentrations used were not related to MP levels, and, in some patients, the anemia improvement was achieved only by intravenous iron.

Platelet MPs were also increased in ESRD patients, but their concentration was not associated with prevailing SS. Although SS in ESRD patients was lower than in control subjects, it was still within the usual range observed in large conduit arteries.8 Activation of platelets MPs is induced by high SS largely over the physiological range,33 which is not the situation observed in the present study.


This study has a limitation concerning aortic SS, which was not directly measured but computerized from the Hagen–Poiseuille equation. The limitation is principally because of uncertainty about the laminar flow regime and the flow unidirectional pattern in the proximal ascending aorta. We presented the results concerning aortic shear stress to illustrate that SS differences in ESRD patients are systemic and not only limited to the brachial artery, as well as to illustrate that the relationships between MPs and SS are present in local and systemic circulation. Nevertheless, because brachial artery SS was directly measured and not dependent on the Hagen–Poiseuille formula, this study focused mainly on brachial artery rheology. Another limitation concerns the measurement of the wall shear rate, which is underestimated in large arteries when assuming a parabolic velocity profile, although this is less pronounced for brachial arteries.15,16,34


Our study demonstrates for the first time the relation between in vivo circulating endothelial MPs and mechanic hemorheological parameters in hemodialyzed patients, depicting SS as a major determinant for endothelial cell injury and vesiculation. Because changes in SS appear to be related also to the low hematocrit value in our population, and because changes in hemoglobin–hematocrit–WBV are independently associated with changes in endothelial MPs, the present results suggest that anemia and resulting alterations in SS increased endothelial apoptosis and could indirectly contribute to the high prevalence of arterial diseases and cardiovascular events in an ESRD population. This might also explain the poor survival rate observed in ESRD patients with cardiovascular diseases and low hematocrit.35

We thank Dr Dieter Frei for his support.

Sources of Funding

This work was supported by an unrestricted grant from Ortho-Biotech Biopharmaceuticals EMEA, CKD Steering Committee Project N°124026, Groupe d’Étude de la Physiopathologie de l’Insuffisance Rénale; an educational grant of the Institut Recherches Servier; and the European Vascular Genomics Network (N°LSHM-CT-503254). N.A. was supported by Assistance Publique–Hôpitaux de Marseille.




Correspondence to Chantal M. Boulanger, INSERM Unit 689, 41 bd de la Chapelle, 75475 Paris Cedex 10, France. E-mail


  • 1 Huguel B, Martinez MC, Kunzelmann C, Freyssinet JM. Membranes microparticles: two sites of the coin. Physiology. 2005; 20: 22–27.CrossrefMedlineGoogle Scholar
  • 2 Boulanger CM, Amabile N, Tedgui A. Circulating microparticles: a potential prognostic marker for atherosclerotic vascular disease. Hypertension. 2006; 48: 1–7.LinkGoogle Scholar
  • 3 Diamant M, Tushuizen ME, Sturk A, Nieuwland R. Cellular microparticles: new players in the field of vascular disease? Eur J Clin Invest. 2004; 34: 392–401.CrossrefMedlineGoogle Scholar
  • 4 Werner N, Wassmann S, Ahlers P, Kosiol S, Nickening G. Circulating CD31+/annexin V+ apoptotic microparticles correlate with coronary endothelial function in patients with coronary artery disease. Arterioscler Thromb Vasc Biol. 2006; 26: 112–116.LinkGoogle Scholar
  • 5 Amabile N, Guérin AP, Leroyer A, Mallat Z, Nguyen C, Boddaert J, London GM, Tedgui A, Boulanger CM. Circulating endothelial microparticles are associated with vascular dysfunction in patients with end-stage renal failure. J Am Soc Nephrol. 2005; 16: 3381–3388.CrossrefMedlineGoogle Scholar
  • 6 Combes V, Simon AC, Grau GE, Arnoux D, Camoin L, Sabatier F, Mutin M, Sanmarco M, Sampol J, Dignat-George F. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J Clin Invest. 2004; 104: 93–102.Google Scholar
  • 7 Tricot O, Mallat Z, Heymes C, Belmin J, Leseche G, Tedgui A. Relation between endothelial cell apoptosis and blood flow direction in human atherosclerotic plaques. Circulation. 2000; 101: 2450–2453.CrossrefMedlineGoogle Scholar
  • 8 Cunningham KS, Gotlieb AI. The role of shear stress in the pathogenesis of atherosclerosis. Lab Investig. 2005; 85: 9–23.CrossrefMedlineGoogle Scholar
  • 9 Li YSJ, Haga JH, Chien S. Molecular basis of shear stress on vascular endothelial cells. J Biomechanics. 2005; 38: 1949–1971.CrossrefMedlineGoogle Scholar
  • 10 Yamawaki H, Pan S, Lee RT, Berk BC. Fluid shear stress inhibits vascular inflammation by decreasing thioredoxin-interacting protein in endothelial cells. J Clin Invest. 2005; 115: 733–738.CrossrefMedlineGoogle Scholar
  • 11 Samijo SK, Barkhuysen R, Willigers JM, Leunissen KM, Ledoux LA, Kitslaar PJ, Hoeks AP. Wall shear stress assessment in common carotid artery of end-stage renal failure patients. Nephron. 2002; 92: 557–563.CrossrefMedlineGoogle Scholar
  • 12 Verbeke FH, Agharazii M, Boutouyrie P, Pannier B, Guérin AP, London GM Local shear stress and brachial artery functions in end-stage renal disease. J Am Soc Nephrol. 2007; 18: 621–628.CrossrefMedlineGoogle Scholar
  • 13 Hoeks AP, Willekes C, Boutouyrie P, Brands PJ, Wimmigers JM, Renemans RS. Automated detection of local artery wall thickness based on M-line signal processing. Ultrasound Med Biol. 1997; 23: 1017–1023.CrossrefMedlineGoogle Scholar
  • 14 London GM, Guérin AP, Marchais SJ, Pannier B, Safar ME, Day M, Métivier F. Cardiac and arterial interactions in end-stage renal disease. Kidney Int. 1996; 50: 600–608.CrossrefMedlineGoogle Scholar
  • 15 Brands PJ, Hoeks AP, Hofstra L, Reneman RS. A noninvasive method to estimate wall shear rate using ultrasound. Ultrasound Med Biol. 1995; 21: 171–185.CrossrefMedlineGoogle Scholar
  • 16 Hoeks AP, Samijo SK, Brands PJ, Reneman RS. Noninvasive determination of shear-rate distribution across the arterial lumen. Hypertension. 1995; 26: 26–33.CrossrefMedlineGoogle Scholar
  • 17 Bernal-Mizrachi L, Jy W, Jimenez JJ, Pastor J, Mauro LM, Horstman LL, de Marchena E, Ahn YS. High levels of circulating endothelial microparticles in patients with acute coronary syndromes. Am Heart J. 2003; 145: 962–970.CrossrefMedlineGoogle Scholar
  • 18 VanWijk MJ, Nieuwland R, Boer K, van der Post JA, VanBavel E, Sturk A. Microparticle subpopulations are increased in preeclampsia: Possible involvement in vascular dysfunction? Am J Obstet Gynecol. 2002; 187: 450–456.CrossrefMedlineGoogle Scholar
  • 19 Brodsky SV, Zhang F, Nasjletti A, Goligorsky MS. Endothelium-derived microparticles impair endothelial function in vitro. Am J Physiol-Heart Circ Physiol. 2004; 286: 1910–1915.CrossrefMedlineGoogle Scholar
  • 20 Davis ME, Cai H, Drummond GR, Harrison DG. Shear stress regulates endothelial nitric oxide synthase expression through c-Src by divergent signaling pathways. Circ Res. 2001; 89: 1073–1080.CrossrefMedlineGoogle Scholar
  • 21 Briet M, Bozec E, Laurent S, Fassot C, London GM, Jacquot C, Froissart M, Houillier P, Boutouyrie P. Arterial stiffness and enlargement in mild-to-moderate chronic kidney disease. Kidney Int. 2006; 69: 350–357.CrossrefMedlineGoogle Scholar
  • 22 Giannattasio C, Piperno A, Failla M, Vergani A, Mancia G. Effects of hematocrit changes on flow-mediated and metabolic vasodilation in humans. Hypertension. 2002; 40: 74–77.LinkGoogle Scholar
  • 23 Joannides R, Bakkali EH, Le Roy F, Rivault O, Godin M, Moore N, Fillastre J-P, Thuillez C. Altered flow-dependent vasodilatation of conduit arteries in maintenance haemodialysis. Nephrol Dial Transplant. 1997; 12: 2623–2628.CrossrefMedlineGoogle Scholar
  • 24 Wever R, Boer P, Hijmering M, Stroes E, Verhaar M, Kastelein J, Versluis K, Lagerwferf F, van Rijn H, Koomans H, Rabelink T. Nitric oxide production is reduced in patients with chronic renal failure. Arterioscler Thromb Vasc Biol. 1999; 19: 1168–1172.CrossrefMedlineGoogle Scholar
  • 25 Van Guldener C, Janssen MJF, Lambert J, Steyn M, Donker AJN, Stehouwer CDA. Endothelium-dependent vasodilatation is impaired in peritoneal dialysis patients. Nephrol Dial Transplant. 1998; 13: 1782–1786.CrossrefMedlineGoogle Scholar
  • 26 Cross JM, Donald A, Vallance PJ, Deanfield JE, Woolfson RG, MacAllister RJ. Dialysis improves endothelial function in humans. Nephrol Dial Transplant. 2001; 16: 1823–1829.CrossrefMedlineGoogle Scholar
  • 27 Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992; 339: 572–575.CrossrefMedlineGoogle Scholar
  • 28 Faure V, Dou L, Sabatier F, Cerini C, Sampol J, Berland Y, Brunet P, Dignat-George F. Elevation of circulating endothelial microparticles in patients with chronic renal failure. J Thromb Haemost. 2006; 4: 566–573.CrossrefMedlineGoogle Scholar
  • 29 Zoccali C, Bode-Boger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L, Cataliotti A, Bellanuova I, Fermo I, Frolich J, Boger R. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet. 2001; 358: 2113–2117.CrossrefMedlineGoogle Scholar
  • 30 Daniel L, Fakhouri F, Joly D, Mouthon L, Nusbaum P, Grunfeld J-P, Schifferli J, Guillevin L, Lesavre P, Halbwachs-Mecarelli L. Increase of circulating neutrophil and platelet microparticles during acute vasculitis and hemodialysis. Kidney Int. 2006; 69: 1416–1423.CrossrefMedlineGoogle Scholar
  • 31 Beleslin-Cokic BB, Cokic VP, Yu X, Weksler BB, Schechter AN, Noguchi CT. Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood. 2004; 104: 2073–2080.CrossrefMedlineGoogle Scholar
  • 32 Bahlmann FH, DeGroot K, Duckert T, Niemczyk E, Bahlmann E, Boehm SM, Haller H, Fliser D. Endothelial progenitor cell proliferation and differentiation is regulated by erythropoietin. Kidney Int. 2003; 64: 1648–1652.CrossrefMedlineGoogle Scholar
  • 33 Nomura S, Tandon NN, Nakamura T, Cone J, Fukuhara S, Kambayashi J. High-shear-stress-induced activation of platelets and microparticles enhances expression of cell adhesion molecules in THP-1 and endothelial cells. Atherosclerosis. 2001; 158: 277–287.CrossrefMedlineGoogle Scholar
  • 34 Reneman RS, Arts T, Hoeks AP. Wall shear stress–an important determinant of endothelial cell fonction and structure–in the arterial system in vivo. Discrepancies with theory. J Vasc Res. 2006; 43: 251–269.CrossrefMedlineGoogle Scholar
  • 35 Ebben J, Xia H, Collins AJ. Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol. 1999; 10: 610–619.CrossrefMedlineGoogle Scholar


eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.