Risk factors for thromboembolic events in renal failure

International Journal of Cardiology 101 (2005) 19 – 25 www.elsevier.com/locate/ijcard

Risk factors for thromboembolic events in renal failure

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John A. D’Elia a,b,c,*, Larry A. Weinrauch a,b,c,d,e, Ray E. Gleason c, Izabela Lipinska b,c,d, Boguslaw Lipinski b,c,d, Annette T. Lee f, Geoffrey H. Tofler b,c,d a Joslin Diabetes Center, Boston, MA 02215, USA Beth Israel Deaconess Medical Center, Boston, MA 02215, USA c Harvard Medical School, Boston, MA 02215, USA d Institute for the Prevention of Cardiovascular Disease, Boston, MA 02215, USA e Mount Auburn Hospital, Cambridge, MA 02238, USA f Laboratory for Biology and Human Genetics, North Shore University Hospital, Manhassett, NY, USA b

Received 2 July 2003; received in revised form 18 February 2004; accepted 1 March 2004 Available online 19 May 2004

Abstract Objectives: To determine whether prior thromboembolic events (TE) influence current measures of hemostasis, inflammation and oxidative stress in a population at high cardiovascular risk. Background: Renal failure patients demonstrate a remarkably elevated incidence of TE. Methods: Relationships between plasma test results and prior TE history were studied in 78 diabetic and 23 non-diabetic patients with renal failure. TE were defined as myocardial infarction, stroke or vascular surgery. Results: Markers for inflammation (interleukin (IL)-6, C reactive protein (CRP)), thrombosis (fibrinogen, low molecular weight (LMW) fibrinogen, factor VII, viscosity), fibrinolysis (fibrinolytic activity, plasminogen activator inhibitor (PAI)), endothelial/platelet activity (P-selectin, von Willebrand factor (vWf)) and oxidative stress (antibody to oxidized low-density lipoprotein (LDL), advanced glycated end products) were significantly different from a healthy control population. Dialysis patients with diabetes were twice as likely to have sustained a TE (58 vs. 30%, p=0.032). Those patients in the total group with levels above the median for IL-6 ( p=0.045), and CRP ( p<0.017) were more likely to have sustained a TE than those with levels below the median. Those diabetic patients with levels above the median for CRP were more likely to have a prior history of TE ( p<0.021). For non-diabetic patients, levels above the median of IL-6 were associated with a prior history of TE ( p=0.027). Multiple correlations for factors of inflammation, hemostasis and oxidative stress indicate that these mechanisms are not independent of one another. Conclusion: Prior TE was associated with markers of inflammation a relationship that may influence the interpretation of these tests which are strongly interrelated in patients at high cardiovascular risk. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Thromboembolic events; Renal failure; Hemostasis

1. Introduction The single most important risk factor for the future development of thromboembolic events (TE) is their prior occurrence. We present the relationship between the pres$

Parts of this manuscript have been presented at Federation of American Societies for Experimental Biology (American Federation for Medical Research), San Diego, CA April 15 – 18, 2000, the American Society of Nephrology, Toronto, Ontario, Canada October 14 – 16, 2000, and the American Society of Hypertension, San Francisco CA May 15 – 19, 2001 and New York, May 14 – 18, 2002. * Corresponding author. John Cook Renal Unit, Joslin Clinic, 1 Joslin Place, Boston, MA 02215, USA. Tel.: +1-617-732-2477; fax: +1-617-7322467. E-mail address: [email protected] (J.A. D’Elia). 0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2004.03.007

ence of prior thromboembolic events and markers of inflammation, hemostasis and oxidative stress in a group of renal failure patients, the majority of whom have diabetes mellitus.

2. Subjects and methods 2.1. Enrollment Chronic, stable hemodialysis patients (n=101) were enrolled in a cross-sectional study to determine the effect of prior TE on present laboratory indices of hemostasis, inflammation and oxidative stress used to assess cardiovascular risk.

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After passage of the protocol and informed consent by the appropriate Institutional Review Boards, stable patients in the participating hospital and free-standing dialysis units were requested to donate blood samples at baseline and at 2 years. History of myocardial infarction, cerebrovascular accident or intervention for coronary arterial, carotid arterial or peripheral vascular (including arteriovenous fistula/graft) occlusion was recorded in all patients. Requirement for, and class of antihypertensive drugs was recorded in a subset. Routine discarding of flow sheets in a participating dialysis unit led to loss of lipid information in 23 patients and blood pressure information in 36 patients. This initial report evaluates the relationships among procoagulant factors and prior thromboembolic events.

for significance using Pearson’s correlations. Differences between diabetic and non-diabetic group means and between history and no history of cardiovascular event group means and gender group means were tested for significance using unpaired t-tests. Healthy normal results were compared with those from hemodialysis patients using a onesample t-test [6]. Data are expressed as frequencies or means with standard deviation as a measure of dispersion. An alpha level of 0.05 was considered statistically significant. Analyses were done using SAS software, Version 7.0 (SAS Institute, Cary, NC).

2.2. Laboratory methods

One hundred and one patients (51 female) had a mean age of 56F15 years. The mean age of 78 diabetic patients was 55F14; 63F9 years for 50 type 2 and 41F9 years for 28 type 1 diabetic patients ( p<0.0001). The mean age of 23 non-diabetic patients was 60F18 years.

Fibrinogen levels were determined by measuring clotting times [1]. Low molecular weight (LMW) fibrinogen was measured utilizing EDTA plasma with the addition of thrombin, calcium, and magnesium [2]. Factor VII antigen was determined from citrated plasma by immunoassay (ELISA) using a commercially available kit (Asserchrom VII: Diagnostica STAGO, 5 Century Drive Parsippany, NJ 07054). Antigen levels of tissue plasminogen activator inhibitor (PAI-I) were determined from citrated plasma by immunoassay (ELISA) using kits (Biopool International, 6025 Nicolle St., Ventura, CA 93003). von Willebrand factor (vWf) was measured in EDTA plasma by an immunoassay (ELISA) as described by Penny et al. [3]. Fibrinolytic activity was quantified as citrated plasma in euglobulins (fibrin plate method) [4]. C reactive protein antigen (CRP) was determined by enzyme immunoassay using kits [UPI-Magiwell (United Biotech.) 110 Pioneer Way, Mountain View, CA]. Plasma viscosity was measured using a Brookfield digital viscometer (Cone/Plate Model DV-11). Levels of advanced glycated end products (AGEs) were measured in plasma by immunoassay (ELISA) using polyclonal antibodies to AGE-modified proteins (Picower Institute, Manhasset, NY) [5]. Antibodies to oxidized low-density lipoprotein (LDL) were measured by enzyme immunoassay [ELISA (ALPCO Diagnostic PO Box 451, Wingham NH 03087)]. Platelet (P)-selectin was determined by immunoassay (ELISA) using kits (Aymed Lab, 458 Carlton Court, San Francisco, CA 94080). Interleukin-6 (IL-6) was measured in EDTA plasma by immunoassay (ELISA) using kits (Quantikine HS, R&D Systems, Minneapolis, MN). Blood sampling was accomplished prior to a routine dialysis treatment. 2.3. Statistical methods Frequency data were tested for significance using Fishers exact test (two-tail) since many expected frequencies were five or less. Interrelationships among variables were tested

3. Results

3.1. Factors for inflammation, hemostasis and oxidative stress: comparison of healthy controls with study patients Normal levels (non-dialysis) were obtained from a healthy cohort of the Framingham offspring [7] study participants (Table 1). The 101 renal failure patients showed statistically significantly elevated mean levels of fibrinogen, LMW fibrinogen, factor VII, viscosity, P-selectin, vWf, CRP, IL-6, advanced glycated end products, and antibody to oxidized LDL with lower than normal levels of fibrinolytic activity and PAI-1, compared to healthy subjects (all p=0.01). The same pattern was noted in the subgroup of 78 diabetic patients. In the subgroup of 23 non-diabetic patients, mean levels of viscosity and oxidized LDL antibody were not different from healthy controls, but all other variables were elevated. Diabetic patients showed higher mean levels of fibrinogen ( p=0.022), LMW fibrinogen ( p=0.041), fibrinolytic activity ( p=0.002), and antibody to oxidized LDL ( p=0.009) than non-diabetic patients. Type 1 diabetic patients had a significantly lower mean CRP ( p=0.008) than type 2 diabetic patients, but did not differ significantly from the non-diabetic group. 3.2. Thromboembolic events: comparison of clinical and laboratory findings in diabetic vs. non-diabetic study patients Prior TE were noted in 52 of 101 patients. There was evidence for myocardial infarction in 10 patients, cerebrovascular accident in 9 and peripheral vascular surgery in 22. An additional 7 patients had experienced events in two systems, and 4 had previously sustained events in all three systems (Table 2). Peripheral vascular disease was more common in type 1 ( p<0.044), type 2 ( p<0.007), and total

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Table 1 Comparison of mean laboratory test results for hemodialysis patient groups Variable

Healthy control population

Total study Type 1 DM population*

Type 2 DM

Type 1 vs. All DM Type 2

Non-DM

DM vs. non-DM

Prothrombosis Fibrinogen Low molecular weight fibrinogen Factor VII Viscosity

276F30 mg/dl 48F10 mg/dl

400F11 100F5

386F20 (28)** 99F9

430F16 (50) ns*** 109F8 ns

413F12 (78) 105F6

355F18 (23) 0.022 80F10 0.041

93.4F0.9% 1.24F0.003 centipoise

114F2 1.27F0.01

115F3 1.27F0.02

115F3 1.28F0.01

ns ns

115F2 1.28F0.01

112F4 1.25F0.02

Fibrinolysis Fibrinolytic activity PAI

120.0F0.9 mm2 25.8F0.3 ng/ml

71F5 17F1

82F9 16F2

73F9 16F1

ns ns

76F7 16F1

53F4 20F2

Platelet endothelium P-selectin von Willebrand factor

<100 ng/ml 102F6%

196F12 183F6

236F24 192F11

187F16 186F8

ns ns

205F14 188F7

159F16 167F12

ns ns

7213F581 25.1F3.9 17.1F0.8

5001F830 25.6.F7.1 16.5F1.6

8770F931 29.7F6.5 17.1F1.2

7417F695 28.3F4.9 16.9F0.9

6520F993 18.4F4.6 18.0F1.8

ns ns ns

835F126

1083F284

887F192

960F160

441F107

Inflammation and oxidative stress C reactive protein <2000 ng/ml Interleukin-6 <5.6 pg/ml Advanced glycated <10 IU end-products Oxidized LDL antibody 275F25 mU/ml

0.008 ns ns ns

ns ns

0.002 ns

0.009

* All variables statistically significantly different from healthy control population. ** Number of patients in each group. *** p value, ns=not statistically significant.

( p=0.009) diabetic dialysis cohorts than the non-diabetic subgroup. The combined prevalence of myocardial infarction, cerebrovascular accident, and peripheral vascular surgery was significantly higher for diabetic than for nondiabetic patients (58.0 vs. 30%, p=0.032). The prevalence of myocardial infarction or cerebrovascular accident individually or in combination was similar in the non-diabetic and diabetic subgroups. Table 3 summarizes relationships between prior TE and laboratory test results above and below the median for our hemodialysis population. For all study patients, those most likely to have sustained prior thromboembolic events had the highest levels of IL-6 and CRP. When the group with a TE history was compared with the group without such history, there was no statistically significant difference with respect to age (58.4F15.2; 54.2F14.7), gender (27 females, 25 males; 24 females, 25 males), antiangiotensin drug use (21 yes, 16 no; 20 yes, 16 no), serum cholesterol (175 mg/ Table 2 Number of hemodialysis patients with prior history of unequivocal thromboembolic events at time of study enrollment by diabetic status (DM) Thromboembolic event

Total patients

Myocardial infarction 10 Cerebrovascular accident 9 Peripheral vascular surgery 22 Two out of three 7 All three 4 Total patients with events 52 (101)

NonDM

Total DM

Type 1 DM

Type 2 DM

1 9 2 7 3 6 2 4 0 22 9 13 1 6 1 5 2 2 0 2 7 (23) 45 (78) 14 (28) 31 (50)

dlF42; 155F60), triglycerides (166 mg/dlF101; 170F98), systolic blood pressure (153 mm HgF24; 145F25), diastolic blood pressure (80 mm HgF17; 78F13). When mean values were compared by t-test, CRP showed a statistically significant difference for patients with or without TE (TE positive 8365 ng/mlF5913; negative 5990F5565, p=0.041) as did PAI-1 (18.9 ng/mlF10.3; 14.7F8.5, p=0.029). No other factors included in Table 3 suggested statistical significance in distribution between patients with or without a history of TE. 3.3. Gender and age comparisons For the total study group, there was no evidence for gender protection from TE, i.e.; there were no statistically significant differences in thromboembolic events for males (25 events) when compared to females (27 events) in any study group. When patients were classified by age, it became apparent that males with or without prior TE were of similar age (56F13 vs. 55F15 years, p=0.9045) with similar CRP levels (7642F4600 vs. 6916F6024, p=0.6343). Females with prior TE had significantly higher CRP levels (9034F6935 vs. 5026F4986, p=0.0232) and averaged 8 years older than those without such events. Although there was a significant correlation between age and CRP in the total female group (r=0.245, p=0.014), the relationship between the presence or absence of prior TE and CRP was still evident in the youngest female type 1 diabetic patients (6986F1348 vs. 2562F822, p=0.013). Non diabetic females with a prior history of TE had higher

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Table 3 Relationship between laboratory test results and presence or absence of prior thromboembolic events (evidence for myocardial infarction, stroke or peripheral vascular surgery) for hemodialysis patient groups Variable Prothrombosis Fibrinogen >median Vmedian Low molecular weight fibrinogen >median Vmedian Factor VII >median Vmedian Viscosity >median Vmedian Profibrinolysis Fibrinolytic activity >median Vmedian Plasminogen activator inhibitor >median Vmedian Platelet endothelium P-selectin >median Vmedian von Willebrand factor >median Vmedian Inflammation and oxidative stress C-reactive protein >median Vmedian Interleukin-6 >median Vmedian Advanced glycated end products >median Vmedian Oxidized LDL antibody >median Vmedian

Total DM (meanFS.E.M.)

% Patients with prior TE

Non-DM

% Patients with prior TE

All patient

% Patients with prior TE

500F81 325F52

64 51

429F59 288F34

27 33

487F78 314F48

60 43

149F66 66F21

47 66

114F49 45F9

45 9

141F45 59F19

49 52

128F14 102F11

60 56

128F10 97F12

36 25

128F13 101F11

56 48

1.34F0.09 1.19F0.03

56 59

1.31F0.03 1.18F0.04

25 33

1.35F0.08 1.20F0.08

49 54

119F58 38F16

58 58

77F12 40F7

50 20

107F54 36F12

57 47

23F8 9F3

69 46

28F7 11F4

45 18

24F8 9F3

62 42

287F127 129F27

58 54

220F68 116F68

12 27

271F120 124F25

52 46

237F37 139F26

69 45

214F46 123F20

9 50

233F39 134F24

60 43

12493F4492 2342F1799

72* 44

10710F3058 2678F517

33 25

12100F4256 2421F1785

64** 39

48.3F5.6 5.6F2.2

63 50

31.5F26.3 6.5F2.7

55* 8

46.2F47 6.0F2.4

62* 40

24.4F4.9 10.6F4.2

51 62

25.4F2.7 12.3F6.7

30 31

24F4.7 10.2F4.7

42 60

1679F1672 281F93

46 62

735F621 170F32

18 42

1479F1545 255F106

44 52

* p=0.05. ** p=0.02.

levels of low molecular weight fibrinogen (154F78 vs. 62F32 mg/dl, p=0.023). Males with a prior history of TE had higher mean levels of von Willebrand factor (200F43% vs. 170F52%, p=0.030. Type 2 diabetic males with prior TE had significantly higher levels of factor VII (120F24% vs. 102F15%, p=0.040). 3.4. Lipids Lipid measurements were available for 78 patients (type 1 diabetic, n=20; type 2 diabetic, n=40; non-diabetic patients, n=18). Mean baseline cholesterol and triglyceride

levels were 175F52 and 168F99, respectively. Given these numbers, few patients were taking medications to further lower lipid concentrations. Females had higher cholesterol levels than males (188F57 vs. 160F42, p=0.014). There were no significant differences between mean serum cholesterol and triglycerides of study patients defined by TE history or diabetic status. Oxidized LDL cholesterol antibody levels were significantly higher in diabetic compared to non-diabetic patients ( p=0.008); however, the prevalence of TE was not significantly decreased in study patients with the highest oxidized LDL antibody levels (Table 3).

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3.5. Hypertension Blood pressure and antihypertensive medications were recorded at the beginning of a regular hemodialysis treatment (n=65). Mean systolic pressure for 24 type 1 diabetic patients was 150F21 mm Hg; for 27 type 2 diabetic patients was 149F26 mm Hg; and for 14 non-diabetic patients was 147F30 mm Hg ( p=ns). Target systolic blood pressure of 120 to 140 mm Hg was attained in 30% of patients with 60% above 140 mm Hg and 10% below 120 mm Hg. TE history was not associated with any significant difference in attained blood pressure level, use of anti-angiotensin drugs, or use of larger doses or greater numbers of antihypertensive medications at entry. Diabetic patients were more likely than non-diabetic patients to receive angiotensin converting enzyme inhibitors or receptor blockers (57% vs. 14%, p=0.015). For type 2 diabetic patients, there was a significant correlation between level of blood pressure and number of types of antihypertensive agents (r=0.580, p=0.002). 3.6. Prior thromboembolic events When the group of patients with prior TE was compared with the group with no such history, we found similar gender distribution (27/51 female vs. 25/50 male), age distribution (mean 58.4F15 vs. 54.2F15), systolic (153F24 vs. 145F25) and diastolic blood pressures (80F17 vs. 79F13), numbers of antihypertensive drugs, use of angiotensin active drugs, serum cholesterol (175F42 vs. 174F1) and triglyceride (166 vs. 101 vs. 170F98) measurements (all p=ns). In this study, mean CRP levels were significantly higher in patients who had a history of prior TE than those who did not (8365F5913 vs. 5990F5565, p=0.041). When measures of inflammation, hemostasis and oxidative stress were compared above and below the median, an excess of TE in the total study group was associated with IL-6 ( p=0.045), and CRP ( p=0.017). For the diabetic study group, an excess of TE was associated with CRP ( p=0.021). Study patients with levels of IL-6 or CRP below the median had the lowest percentage of prior TE ( p=0.045, p=0.017), respectively, (Table 3). When data from these two variables were combined, the group equal to or below the median level had a lower percentage of prior TE then either variable considered individually ( p=0.012). 3.7. Inter-test correlations Fig. 1 outlines the statistical relationship between the various blood levels measured in this study. For the entire study group, there was a positive correlation between CRP and IL-6 (r=0.475, p<0.001), fibrinogen (r=0.399, p<0.001), PAI-1 (r=0.225, p=0.021), von Willebrand factor (r=0.221, p=0.026), and age in years (r=0.245, p=0.014). Also, positive correlations were seen between IL-6 and fibrinogen (r=0.329, p<0.001), LMW fibrinogen (r=0.405,

Fig. 1. Correlation for tests of inflammation, hemostasis and oxidative stress in renal failure. IL-6, and CRP, were significantly correlated to each other and related to prior history of thromboembolic events. Other factors were correlated with one another, but did not have a significant relationship with prior thromboembolic events; — positive correlation ( p<0.05); - - negative correlation ( p<0.05); *p=0.056.

p<0.001) and PAI-1 (r=0.257, p=0.010). Additional positive correlations were found for viscosity with fibrinogen (r= 0.361, p<0.001) LMW fibrinogen (r=0.364, p<0.001), antibody to oxidized LDL (r=0.246, p=0.016), platelet selectin (r=0.227, p=0.028), and a negative correlation with advanced glycated end products (r= 0.230, p=0.021). Pselectin was also positively correlated with PAI-1 (r=0.302, p=0.003) and oxidized LDL antibody (r=0.309, p=0.003).

4. Discussion In order to assess the utility of any laboratory test for thromboembolic event risk, the presence or absence of prior atherosclerotic complications must be considered in the analysis [8]. In this study, markers of inflammation, but not hemostasis or oxidative stress were associated with a prior history of TE which had occurred in 58% of the diabetic patients and 29% of the non-diabetic group. 4.1. Inflammation and hemostasis The total study group demonstrated associations between TE and both CRP and IL-6. The diabetic group also demonstrated a relationship between thromboembolic events and CRP. The described statistical relationship among the tested blood variables is not surprising as each step in inflammation, oxidative stress and thrombosis is dependent upon the one before. Several prothrombotic factors were correlated with viscosity, but increased levels of viscosity were not associated with a prior TE. Correlation of CRP and IL-6 with markers for hemostasis is consistent with clinical reports of an increased risk of myocardial infarction following inflammatory reactions with prevention by aspirin therapy [9]. Of the 101 patients studied, only 22% had IL-6 or CRP levels within the upper limit for a healthy control group

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(<5.6 pg/ml, <2000 ng/ml, respectively). CRP is an active participant in all phases of atherogenesis. It is a marker for the intensity of the inflammatory reaction that initiates atherosclerosis as well as the formation and rupture of plaque. CRP potentiates the uptake of LDL cholesterol by macrophages. Macrophages infiltrate the vessel wall and are the foam cells in the lipid core of the atheromatous plaque. Both CRP and IL-6 stimulate hepatic production of fibrinogen that binds platelets and forms clots. IL-6 levels are increased during and after hemodialysis [10]. The CRP relationship to TE remained statistically significant when comparison of means or values above and below the median were used. Excess thrombosis in diabetic patients is partially related to increased fibrinogen and LMW fibrinogen. Crosslinking with advanced glycated end products renders fibrin resistant to lysis thus even in the presence of enhanced fibrinolytic potential, the diabetic hemodialysis patients remain at increased TE risk. 4.2. Lipids Once proteinuria has been terminated by renal failure, the hyperlipidemia of the nephrotic syndrome resolves over 6 to 12 months of dialysis. We have previously demonstrated a significant relationship between vasculopathic events and a derived LDL cholesterol >75 mg/dl in a hemodialysis population [11] whose mean cholesterol and triglyceride concentrations were very similar to the current study and within the normal range; these lipid levels did not discriminate TE history. Very few patients in that study population or in the present group were receiving medication to lower cholesterol. LDL cholesterol may be vasculopathic at concentrations below 100 mg/dl due to the increased oxidation potential of LDL observed in hemodialysis patients [12]. Oxidized LDL antibody was elevated in our hemodialysis patients, especially the diabetic subgroup. Since this antibody removes oxidized LDL from the circulation, the long-term incidence of cardiovascular mortality can be expected to be significantly lower when antibody levels are higher [13]. In our study patients, oxidized LDL antibody levels were similar in the presence or absence of prior TE. Glycated LDL as opposed to oxidized LDL may be resistant to oxidized LDL antibody. Angiotensin related cardiac injury may be attenuated by the use of HMG Co A reductase inhibition that lowers LDL cholesterol and CRP [14] with their associated endothelial effects [15]. In light of these findings, HMG Co A reductase inhibitors may be useful in patients with LDL concentrations >75 mg/dl who have a prior TE history.

knowledge, this observation has not previously been reported. Both diabetic and non-diabetic females had significantly higher mean cholesterol concentrations than their male counterparts, but oxidized LDL antibody levels were not different. 4.4. Hypertension We observed that 62% of hemodialysis patients had a pre-dialysis systolic blood pressure greater than 140 mm Hg. The risk of hypotension during dialysis leads nephrologists to order lower doses of antihypertensive medications pre-dialysis which results in acceptance of higher blood pressures at the outset of each treatment. Hypertension is associated with increased concentrations of fibrinogen [16]. Since reduction of plasma fibrinogen and LDL cholesterol may occur with use of angiotensin suppressor agents [15,17], these medications should be considered for hypertensive patients with a prior history of TE. Medications used in our study included angiotensin active drugs (converting enzyme inhibitors, receptor blockers), calcium channel blockers, beta blockers, clonidine and other vasodilators. The most frequently used group were those that were angiotensin active: type 1 diabetic patients (55%), type 2 diabetic patients (43%), non-diabetic patients (18%).

5. Conclusion Using the data from this study, we determined that while markers of inflammation, hemostasis, and oxidative stress were each abnormal in renal failure patients, they were not equally effective in identifying patients with prior TE. The present study demonstrates that concentrations of CRP and IL-6 reflect the prevalence of prior atherosclerotic events. It is well known that one cardiovascular incident increases the statistical likelihood of another. Studies advancing the proposition that a blood test adds predictive value to the clinical setting should be required to identify the prior history upon which that marker was evaluated.

Acknowledgements The authors thank Jo-Anne Pratt RN and Kathryn Tierney RN, MEd for their assistance with this study. This work was supported in part by Amgen (Thousand Oaks, CA), Bayer Laboratories, and the Pat Covelli Foundation.

4.3. Gender A higher concentration of IL-6 identified both females and males with prior TE. Higher concentrations of CRP identified females, but not males, with TE history. To our

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