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Preliminary Communication |

Microalbuminuria and Risk of Venous Thromboembolism FREE

Bakhtawar K. Mahmoodi, BSc; Ron T. Gansevoort, MD, PhD; Nic J. G. M. Veeger, MSc; Abigail G. Matthews, PhD; Gerjan Navis, MD, PhD; Hans L. Hillege, MD, PhD; Jan van der Meer, MD, PhD; for the Prevention of Renal and Vascular End-stage Disease (PREVEND) Study Group
[+] Author Affiliations

Author Affiliations: Division of Hemostasis, Thrombosis and Rheology, Department of Hematology (Messrs Mahmoodi and Veeger and Dr van der Meer), Department of Nephrology (Drs Gansevoort and Navis), and Trial Coordination Center, Department of Epidemiology (Mr Veeger and Dr Hillege), University Medical Center Groningen, Groningen, the Netherlands; and Laboratory of Statistical Genetics, Rockefeller University, New York, New York (Dr Matthews).
†Deceased.


JAMA. 2009;301(17):1790-1797. doi:10.1001/jama.2009.565.
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Published online

Context Microalbuminuria (albuminuria 30-300 mg per 24-hour urine collection) is a well-known risk marker for arterial thromboembolism. It is assumed that microalbuminuria reflects generalized endothelial dysfunction. Hence, microalbuminuria may also predispose for venous thromboembolism (VTE).

Objective To assess whether microalbuminuria is associated with VTE.

Design, Setting, and Participants Prevention of Renal and Vascular End-stage Disease (PREVEND) study, an ongoing community-based prospective cohort study initiated in 1997. All inhabitants of Groningen, the Netherlands, aged 28 through 75 years (n = 85 421) were sent a postal questionnaire and a vial to collect a first morning urine sample for measurement of urinary albumin concentration. Of those who responded (40 856), a cohort (8592 participants) including more participants with higher levels of urinary albumin concentration completed screening at an outpatient clinic. Screening data were collected on urinary albumin excretion (UAE) and risk factors for cardiovascular and renal disease.

Main Outcome Measure Symptomatic and objectively verified VTE (ie, deep vein thrombosis, pulmonary embolism, or both) between study initiation and June 1, 2007.

Results Of 8574 evaluable participants (mean [SD] age, 49 [13] years; 50% men), 129 experienced VTE during a mean (SD) follow-up period of 8.6 (1.8) years, corresponding to overall annual incidence of 0.14% (95% confidence interval [CI], 0.11%-0.19%). Annual incidences were 0.12%, 0.20%, 0.40%, and 0.56% in participants with UAE of less than 15 (n = 6013), 15-29 (n = 1283), 30-300 (n = 1144), and greater than 300 (n = 134) mg per 24-hour urine collection, respectively (P for trend <.001). When adjusted for age, cancer, use of oral contraceptives, and atherosclerosis risk factors, hazard ratios associated with UAE levels of 15-29, 30-300, and greater than 300 mg/24 h were 1.40 (95% CI, 0.86-2.35), 2.20 (95% CI, 1.44-3.36), and 2.82 (95% CI, 1.21-6.61), respectively, compared with participants with UAE of less than 15 mg/24 h (global P = .001). Adjusted hazard ratio for microalbuminuria vs normoalbuminuria (UAE <30 mg/24 h) was 2.00 (95% CI, 1.34-2.98; P < .001). Microalbuminuria-related number needed to harm was 388 per year.

Conclusion Microalbuminuria is independently associated with an increased risk for VTE.

Figures in this Article

The overall incidence of venous thromboembolism (VTE) in developed countries is about 0.15% per year, varying from less than 0.005% in individuals younger than 15 years to as high as 0.5% at 80 years.13 More than a century ago, Virchow postulated 3 main causes of thrombosis: stasis of the blood, changes in the vessel wall, and changes in the composition of the blood.4 Known risk factors for VTE fall in the first (stasis) and the third groups (blood composition).5 However, in as many as 50% of VTE cases, none of the known risk factors are present.1

Arterial thromboembolism has historically been viewed as a different pathophysiological entity with distinct risk factors. However, this dichotomy between VTE and arterial thromboembolism has recently been questioned since an increased risk of arterial thromboembolism and atherosclerosis had been reported in patients with prior VTE.6,7 Moreover, an increasing amount of data indicate that classic atherosclerosis risk factors (ie, hypertension, hyperlipidemia, diabetes, obesity, and smoking) may also predispose individuals to VTE.8 This emerging concept may indicate the involvement of vessel wall changes in the pathogenesis of VTE.9

Classic atherosclerosis risk factors are also strongly correlated with microalbuminuria (albuminuria of 30-300 mg/d), which is itself an established risk marker for arterial thromboembolism.10,11 Microalbuminuria is assumed to be a sensitive marker for generalized endothelial dysfunction that is, among others, associated with changes in the levels of several coagulation proteins.1219 The effect of coagulation disorders is more evident in the pathogenesis of VTE than in the pathogenesis of arterial thromboembolism. Hence, in theory, a link between microalbuminuria and VTE is likely; however, research addressing this issue has yet to be conducted. We performed a study to assess whether microalbuminuria is associated with VTE in a population-based cohort study.

Study Population and Design

This study was conducted on participants in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study. The PREVEND study was designed to investigate prospectively the natural course of albuminuria and its relation to renal and cardiovascular disease in a large cohort drawn from the general population. Details of the study protocol have been published elsewhere10,20 and can be found at http://www.prevend.org. In brief, during 1997-1998, all 85 421 inhabitants of the city of Groningen, the Netherlands, between the ages of 28 and 75 years old were sent a 1-page postal questionnaire regarding demographics, cardiovascular morbidity, use of medication, and pregnancy, and a vial to collect a first morning void urine sample. A total of 40 856 (47.8%) individuals responded (Figure 1). Since the link between cardiovascular or renal disease and microalbuminuria in individuals with insulin-dependent diabetes mellitus was well established, and pregnant females may present with temporary microalbuminuria, these individuals were excluded from the PREVEND study. After the additional exclusion of individuals who were unable or unwilling to participate in the study, a total of 6000 individuals with a urinary albumin concentration of 10 mg/L or greater and a random control sample of individuals with a urinary albumin concentration of less than 10 mg/L (n = 2592) completed the screening protocol and formed the baseline PREVEND cohort (n = 8592). These participants twice visited an outpatient department where demographic, anthropometric, and cardiovascular risk factors were assessed. For the current analysis, 18 participants were excluded because of missing data on 24-hour urinary albumin excretion (UAE), leaving a total of 8574 participants. The PREVEND study has been approved by the local medical ethics committee and is conducted in accordance with the guidelines of the Declaration of Helsinki. Written informed consent was obtained from all participants.

Place holder to copy figure label and caption
Figure 1. Participant Selection for the PREVEND Study Cohort
Graphic Jump Location

Urinary albumin concentration (UAC) was assessed in a first morning void urine sample and measured in milligrams per liter. The number of randomly selected participants was arbitrarily set at 3395 to obtain a total cohort size of approximately 10 000 accounting for a 15% nonparticipation rate.

Laboratory Measurements and Definitions

Fasting blood samples were obtained during the morning in all participants. Serum creatinine, total cholesterol, and plasma glucose were measured by dry chemistry (Eastman Kodak, Rochester, New York). High-density lipoprotein cholesterol was measured with a homogeneous method (direct HDL, Aeroset TM System, Abbott Laboratories, Abbott Park, Illinois). Triglycerides were measured enzymatically. High-sensitivity C-reactive protein was determined by nephelometry (BN II, Dade Behring, Marburg, Germany). Plasma antigen levels of tissue plasminogen activator and plasminogen activator inhibitor type-1 were measured using an ELISA kit from Technoclone Gmbh (Vienna, Austria). Participants collected two 24-hour urine samples, in which urinary albumin concentration was determined by nephelometry with a threshold of 2.3 mg/L and intra- and inter-assay coefficients of variation of less than 2.2% and less than 2.6%, respectively (Dade Behring Diagnostic, Marburg, Germany).

Hypertension was defined as systolic blood pressure of 140 mm Hg or greater or diastolic blood pressure of 90 mm Hg or greater, or the use of antihypertensive drugs. Diabetes was defined as a fasting glucose level of 126 mg/dL or greater (≥7.0 mmol/L), nonfasting plasma glucose level of 200 mg/dL or greater (≥11.1 mmol/L), or the use of oral antidiabetic drugs. Hypercholesterolemia was defined as a total serum cholesterol concentration of 250 mg/dL or greater (≥6.5 mmol/L), or in the case of a previous myocardial infarction (MI) or stroke a concentration of 193 mg/dL or greater (≥5.0 mmol/L), or the use of lipid-lowering drugs. The metabolic syndrome was defined according to the Adult Treatment Panel III of the National Cholesterol Education Program.21 Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Estimated glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease study equation, taking into account sex, age, race, and serum creatinine level.22 Low-density lipoprotein cholesterol was estimated using the Friedewald formula.23 The UAE was measured as the mean of two 24-hour urine collections and was classified according to clinical classes: low-normal (<15 mg/24-hour urine collection), high-normal (15-29 mg/24-hour urine collection), microalbuminuria (30-300 mg/24-hour urine collection), and macroalbuminuria (>300 mg/24-hour urine collection).10

Identification and Validation of Venous Thromboembolic Events

We used the regional anticoagulation clinic database to identify participants of the PREVEND study who developed VTE between January 1, 1997, and June 1, 2007. This clinic monitors the anticoagulant therapy of all patients in the city of Groningen and in a well-defined geographical area proximal to the city. For fatal VTE cases, we searched the national registry of death certificates (Central Bureau of Statistics, The Hague/Heerlen, the Netherlands) and, as an additional check of the anticoagulant clinic database, we searched the database of the national registry of hospital discharge diagnoses (Prismant, Utrecht, the Netherlands). Patients' medical records were reviewed for all participants of the PREVEND study who had VTE according to any of the aforementioned databases. The investigators (B.K.M. and N.J.G.M.V.) who collected these clinical data were blinded for the UAE status of these participants.

Only objectively verified symptomatic thromboembolic events were considered. Deep vein thrombosis was confirmed by compression ultrasound; and pulmonary embolism, by ventilation/perfusion lung scanning, spiral computed tomography, or at autopsy. VTE was considered provoked if it had occurred at or within 3 months after having acquired risk factors including major surgery, trauma, immobilization for more than 7 days, oral contraceptives, hormone therapy, pregnancy, malignant disease, or miscellaneous (ie, long-distance travel for longer than 4 hours, active infectious disease, paresis/paralysis of the leg, or heart failure). In the absence of these acquired risk factors, VTE was considered unprovoked.

Statistical Analysis

We assessed adjusted annual incidences of VTE for the enrichment of our cohort with participants with higher UAE, using survey probability weights.24 The observation time for each patient was defined as the period from the testing of albuminuria (1997-1998) until the first episode of VTE or a censoring event (withdrawal from the study, moving out of the city, death, or end of the study). The 95% confidence intervals (CIs) were computed by a Jackknife approach assuming a Poisson distribution, and the P value for the test of trend was calculated via the Mantel-Haenszel method.

To evaluate the effects of baseline characteristics on VTE-free survival, we used univariate and sex- and age-adjusted Cox proportional hazards models. A multivariate model was developed that considered known VTE risk factors (ie, age, malignancies, BMI, and use of oral contraceptives) as well as cardiovascular risk factors that yielded a P  <.15 from the univariate model. Results were expressed as hazard ratios (HRs) with 95% CIs and P values.

Continuous variables are presented as mean (SD) or as medians with the interquartile range (IQR) for skewed data. Categorical data are presented as counts and frequencies. For continuous data, differences were evaluated by Kruskal-Wallis test or 1-way analysis of variance, depending on the normality of the data. Categorical variables were compared with χ2 test of association. Statistical significance was considered as a 2-tailed P  <.05. All statistical analyses were performed using STATA software version 10.0 (StataCorp LP, College Station, Texas).

Study Population

Individuals who responded (40 856) were more often women (54.4% vs 45.4%) and older (mean age 51.9 vs 46.4 years) than those who did not (Figure 1). The randomly selected group of 2592 participants with urinary albumin concentration of less than 10 mg/L was representative of the 30 890 eligible responding individuals with urinary albumin concentration of less than 10 mg/L, as previously reported.25

The Table represents baseline clinical characteristics of the analyzed study cohort of 8574 participants stratified into subgroups of UAE. Of the overall cohort, 70% (6013), 15% (1283), 13% (1144), and 1.6% (134) of participants had UAE of less than 15, 15-29, 30-300, and greater than 300 mg per 24 hour urine collection, respectively. The prevalence of male sex, hypertension, hyperlipidemia, current smoking status, diabetes, metabolic syndrome, history of myocaridal infarction, stroke, malignancy, and use of oral contraceptives were all higher in participants with increased levels of UAE (P < .05). Similarly, age, BMI, total cholesterol, low-density lipoprotein cholesterol, triglycerides, C-reactive protein, tissue plasminogen activator, and plasminogen activator inhibitor-1 levels were positively associated with UAE (P < .001). High-density lipoprotein cholesterol levels were inversely associated with UAE (P < .001).

Urinary Albumin Excretion and Venous Thromboembolism

Overall, 129 participants developed at least 1 VTE during a mean (SD) observation period of 8.6 (1.8) years, corresponding to survey design–adjusted annual incidence of 0.14% (95% CI, 0.11%-0.19%), ranging from 0.12% (95% CI, 0.09%-0.17%) in participants with UAE of less than 15 mg/24 h to 0.56% (95% CI, 0.26%-1.47%) in participants with UAE of greater than 300 mg/24 h (Figure 2). These annual incidences were 0.40% (95% CI, 0.26%-0.65%) in microalbuminuric vs 0.12% (0.10%-0.17%) in normoalbuminuric participants (UAE <30 mg/24 hour urine collection). The drop-out rate due to study withdrawal and migration out of the city was 16% (1388) and was comparable between subgroups of UAE (P = .17). For these individuals, the available mean (SD) observation period was 6.5 (1.8) years.

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Figure 2. Adjusted Annual Incidences of Venous Thromboembolism in Relation to Urinary Albumin Excretion by Clinical Class
Graphic Jump Location

The annual incidences are adjusted for the enrichment of the cohort with participants with higher urinary albumin excretion using the survey probability weights.

The most commonly encountered first VTE was deep vein thrombosis (73, 57%), followed by pulmonary embolism (44, 34%), and combined deep vein thrombosis and pulmonary embolism (12, 9%). Types of VTE (pulmonary embolism vs deep vein thrombosis) did not differ among subgroups of UAE (P = .23). Of pulmonary embolism cases, 4 out of 56 (7%) were fatal. Of participants with VTE during follow-up, 24 (19%) had prior VTE and that rate was similar among different subgroups of UAE (P = .47). At onset of VTE, 63 participants (49%) were exposed to an acquired risk factor for VTE: 20 (32%) had a malignancy, 14 (22%) had surgery or trauma, 8 (13%) had a combined malignancy and surgery, 8 (13%) used oral contraceptives, 4 (6%) were immobilized, and 9 (14%) had other acquired risk factors.

Figure 3 shows the association of various variables at baseline with the unadjusted and sex- and age-adjusted risk of VTE. In the univariate analyses, multiple variables were associated with VTE. After adjustment for sex and age, only UAE, BMI, premenopausal use of oral contraceptives, and plasminogen activator inhibitor type-1 levels were significantly related to VTE. The multivariate Cox model included the following variables: UAE, established VTE risk factors (ie, age, malignancies, BMI, and use of oral contraceptives), hypertension, current smoking, history of myocardial infarction, eGFR, C-reactive protein,26 and plasminogen activator inhibitor-1. In this model, UAE of 15-29, 30-300 and greater than 300 mg per 24-hour urine collection had HRs of 1.40 (95% CI, 0.86-2.35; P = .14), 2.20 (95% CI, 1.44-3.36; P < .001) and 2.82 (95% CI, 1.21-6.61; P = .02), respectively, as compared with participants with UAE of less than 15 mg per 24 hour urine collection (global P = .001). When UAE was entered as a dichotomous variable, that is, microalbuminuria vs normoalbuminuria (<30 mg/24 hour urine collection) in the multivariate Cox model, microalbuminuria conferred an HR of 2.00 (95% CI, 1.34-2.98; P < .001). This adjusted HR conferred by microalbuminuria was 1.93 (95% CI, 1.24-3.03; P = .004) if participants with prior VTE were excluded from the analysis. Of the mentioned variables in the multivariate model, age and eGFR were entered as continuous variables. Since metabolic syndrome is a cluster of other cardiovascular risk factors21 and tissue plasminogen activator complexes with plasminogen activator inhibitor type-1, these 2 variables were not included in the multivariate model so as to minimize collinearity.

Place holder to copy figure label and caption
Figure 3. Univariate and Sex- and Age-Adjusted Proportional Hazards Analysis of Association With the First Venous Thromboembolism
Graphic Jump Location

eGFR indicates estimated glomerular filtration rate22; MI, myocardial infarction; UAE, urinary albumin excretion; VTE, venous thromboembolism. To convert values for cholesterol, HDL, and LDL to mmol/L, multiply by 0.0259; to convert values for triglycerides to mmol/L, multiply by 0.0113; to convert CRP to nmol/L multiply by 9.524; to convert PAI-1 to pmol/L, multiply by 19.231.
aSex- and age-adjusted hazard ratios (HRs) with corresponding 95% confidence intervals (95% CIs). Sex was adjusted for age only and age for sex only. Use of oral contraceptives was also adjusted for age only.
bBody mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), metabolic syndrome, cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides were classified according to the Adult Treatment Panel III of the National Cholesterol Education Program.21
cC-reactive protein (CRP) was classified according to the Centers for Disease Control and Prevention and the American Heart Association.26
dSince normal ranges of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) in the general population are unknown, we dichotomized these variables using their medians as cutoffs.

During 8 years of follow-up, 3% of microalbuminuric participants and 1% of normoalbuminuric participants developed VTE (Figure 4). As compared with participants with normoalbuminuria, the microalbuminuria-related number needed to harm was 388 per year.

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Figure 4. Cumulative Incidence of Venous Thromboembolism
Graphic Jump Location

Microalbuminuria denotes urinary albumin excretion of 30 to 300 mg/24 h; normoalbuminuria, urinary albumin excretion of less than 30 mg/24 h.

When we confined our analysis to participants with unprovoked VTE, UAE of 15-29, 30-300 and >300 mg per 24-hour urine collection conferred HRs (adjusted for age, malignancies, BMI, and use of oral contraceptives) of 1.07 (95%CI, 0.48-2.35), 3.03 (1.71-5.38), and 4.97 (1.87-13.18), respectively, as compared with participants with UAE of less than 15 mg per 24-hour urine collection (global P < .001). Hazard ratios were 1.74 (95% CI, 0.94-3.24), 1.50 (0.77-2.92), and 0.98 (0.13-7.22), respectively, for provoked VTE (global P = .31).

When UAE measured in 24-hour urine collection was substituted by urinary albumin concentration measured in a spot urine sample, the adjusted HR for microalbuminuria (ie, urinary albumin concentration 20-200 mg/L) was the same, that is, 1.95 (95% CI, 1.34-2.83; P < .001) as compared with normoalbuminuria (ie, urinary albumin concentration <20 mg/L). When the multivariate Cox model was also adjusted for the enrichment of the study cohort with participants with higher UAE, using survey probability weights,27 the corresponding HR for microalbuminuria measured in 24-hour urine collection was 2.33 (95% CI, 1.34-4.05; P = .003), as compared with normoalbuminuria.

As previously reported for UAE and arterial thromboembolism,11,28 we found a gradual relationship between UAE and VTE in the normal ranges of UAE (<30 mg/24 h): adjusted HRs of UAE 10-19 and 20-29 mg per 24-hour urine collection were 1.31 (95% CI, 0.81-2.11) and 1.86 (95% CI, 1.00-3.43), as compared with UAE of less than 10 mg per 24-hour urine collection. Finally, there was no interaction between UAE and eGFR (P = .67)

This study explored the relationship between microalbuminuria and VTE. A clear gradual relationship was found between levels of UAE and the incidence of VTE, even in the normal range of UAE. Besides UAE, multiple classic atherosclerosis risk factors were related to VTE in univariate analyses. However, after adjustment for sex and age, only UAE, BMI, premenopausal use of oral contraceptives, and plasminogen activator inhibitor type-1 levels were related to VTE. In a multivariate model, UAE remained an independent predictor of VTE. About half of the VTE cases were unprovoked. Moreover, higher levels of UAE were particularly associated with unprovoked VTE.

Several studies addressed the link between atherosclerosis risk factors and VTE.8,2933 Our results on atherosclerosis risk factors are consistent with a comparable community-based prospective cohort study33 in which only BMI and diabetes were related to VTE; after adjustment for age, sex, and race. In our study, diabetes was not related to VTE; however, our results could not be generalized to all diabetics since individuals with insulin-dependent diabetes were excluded.10,20 In a recent meta-analysis,8 obesity, hypertension, diabetes, and higher triglyceride levels were positively associated with VTE, whereas higher high-density cholesterol levels were inversely related to VTE, and smoking and total cholesterol were not significantly related to increased risk of VTE. However, there was a significant heterogeneity among studies evaluated in this meta-analysis.8 Moreover, most of the analyzed studies were not primarily conducted to assess the link between atherosclerosis risk factors and VTE, some were limited to only 1 sex, and the results from cohort studies were not adjusted for age. In our study, metabolic syndrome,21 a cluster of cardiovascular risk factors, was not related to elevated risk of VTE after sex and age adjustment. In several studies, metabolic syndrome was associated with an approximately 2-fold increased risk of VTE.34 However, this link might be due to the association between individual features of the metabolic syndrome and VTE.35

The value of microalbuminuria as an independent predictor of arterial thromboembolism has been demonstrated in individuals with diabetes as well as in those without.10,11,36,37 In our previous publication,10 microalbuminuria was related to an adjusted relative risk of 1.29 (95% CI, 1.04-1.60) and 1.58 (1.10-2.26) for MI and stroke, respectively, as compared with participants with normoalbuminuria. In the HOPE study,11 adjusted HRs for MI, stroke, or cerebrovascular death were 1.75 (95% CI, 1.49-2.05) and 1.42 (1.18-1.71) in the placebo and intervention group, respectively. In comparison, in the current analysis microalbuminuria conferred an adjusted HR of 2.00 (95% CI, 1.34-2.98) for VTE, as compared with normoalbuminuria. Moreover, nephrotic-range proteinuria is a well-known risk factor for VTE and predisposes at least as often to VTE as arterial thromboembolism.38 The high risk of VTE in individuals with nephrotic-range proteinuria is assumed to be secondary to loss of anticoagulant proteins. In individuals with microalbuminuria, this is unlikely to be a direct cause; more likely, the increased risk of VTE is secondary to endothelial injury and/or the related changes in the levels of procoagulant proteins.9,1219

The fact that microalbuminuria has a high prevalence in the general population (7.2%) suggests that on the population level, microalbuminuria may be an important risk factor for VTE.39 Moreover, in contrast to most of the established VTE risk factors, microalbuminuria could be treated by nonanticoagulant medication (eg, renin-angiotensin system inhibitors). Future studies are needed to evaluate the effect of these drugs on the risk of VTE.

Our study has some potential limitations that should be addressed. The incidence of VTE in our cohort may be underestimated as VTE cases were retrospectively identified. However, as compared with other prospective studies, the annual incidence of 0.14% is rather elevated given the very high incidence of VTE in individuals older than 75 years, whereas our cohort was confined to individuals aged 28 to 75 years. Furthermore, VTE was not adjudicated by an independent committee. Nevertheless, since only symptomatic and objectively verified events were considered, misclassification seems unlikely. Enrichment with participants with higher UAE is unlikely to have influenced our risk estimates (ie, HRs), as these estimates did not significantly change after accounting for the study design. Since we used predefined cut-off values for UAE, spectrum bias is unlikely despite the differences in sex and age between individuals who responded and those who did not. Due to lack of sufficient statistical power, as only 134 participants were known with malignant disease, malignancy was not associated with VTE after age and sex adjustment. Data on the use of oral contraceptives could not be generalized as participants younger than 28 years were not enrolled.

Despite these limitations, this is the first study assessing a link between microalbuminuria and VTE. Moreover, the PREVEND cohort is unique in its large population-based prospective setting in which UAE is assessed in two 24-hour urine samples, which is considered the criterion standard for measuring UAE. Although criterion standard is desirable for the proof of concept, in the clinical setting microalbuminuria is generally assessed in a spot urine sample. When we used the microalbuminuria definition for a spot urine sample (ie, urinary albumin concentration of 20-200 mg/L), results were the same.

In conclusion, microalbuminuria is an independent risk factor for VTE. The relative risk of VTE associated with microalbuminuria is comparable to previously reported risk of MI or stroke in individuals with microalbuminuria.

Corresponding Author: Bakhtawar K. Mahmoodi, BSc, Division of Hemostasis, Thrombosis and Rheology, Department of Hematology, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands (b.k.mahmoodi@int.umcg.nl).

Author Contributions: Mr Mahmoodi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Mahmoodi, Gansevoort, van der Meer.

Acquisition of data: Mahmoodi, Veeger.

Analysis and interpretation of data: Mahmoodi, Gansevoort, Veeger, Matthews, Navis, Hillege, van der Meer.

Drafting of the manuscript: Mahmoodi.

Critical revision of the manuscript for important intellectual content: Gansevoort, Veeger, Matthews, Navis, Hillege, van der Meer.

Statistical analysis: Mahmoodi, Matthews.

Study supervision: van der Meer.

Financial Disclosures: None reported.

Funding/Support: The PREVEND Study has been made possible by grants from the Dutch Kidney Foundation.

Role of the Sponsor: The Dutch Kidney Foundation was not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Additional Contributions: We thank Frits R. Rosendaal, MD, PhD, Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; and Martin H. Prins, MD, PhD, Department of Clinical Epidemiology and Medical Technology Assessment, Academic Hospital, Maastricht, the Netherlands, for clinical and statistical advice. Neither individual received compensation for the contributions.

Dr van der Meer recently died following a sudden illness. We thank Hanneke C. Kluin-Nelemans, MD, PhD, Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands, for providing help to guide the paper during revision after Dr van der Meer's death.

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PubMed   |  Link to Article
Kario K, Matsuo T, Kobayashi H,  et al.  Factor VII hyperactivity and endothelial cell damage are found in elderly hypertensives only when concomitant with microalbuminuria.  Arterioscler Thromb Vasc Biol. 1996;16(3):455-461
PubMed   |  Link to Article
Gruden G, Cavallo-Perin P, Bazzan M, Stella S, Vuolo A, Pagano G. PAI-1 and factor VII activity are higher in IDDM patients with microalbuminuria.  Diabetes. 1994;43(3):426-429
PubMed   |  Link to Article
Festa A, D'Agostino R, Howard G, Mykkänen L, Tracy RP, Haffner SM. Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: the Insulin Resistance Atherosclerosis Study.  Kidney Int. 2000;58(4):1703-1710
PubMed   |  Link to Article
Collier A, Rumley A, Rumley AG,  et al.  Free radical activity and hemostatic factors in NIDDM patients with and without microalbuminuria.  Diabetes. 1992;41(8):909-913
PubMed   |  Link to Article
Agewall S, Lindstedt G, Fagerberg B. Independent relationship between microalbuminuria and plasminogen activator inhibitor-1 activity (PAI-1) activity in clinically healthy 58-year-old men.  Atherosclerosis. 2001;157(1):197-202
PubMed   |  Link to Article
Agewall S, Fagerberg B, Attvall S,  et al; Risk Factor Intervention Study Group.  Microalbuminuria, insulin sensitivity and haemostatic factors in non-diabetic treated hypertensive men: Risk Factor Intervention Study Group.  J Intern Med. 1995;237(2):195-203
PubMed   |  Link to Article
Clausen P, Feldt-Rasmussen B, Jensen G, Jensen JS. Endothelial haemostatic factors are associated with progression of urinary albumin excretion in clinically healthy subjects: a 4-year prospective study.  Clin Sci (Lond). 1999;97(1):37-43
PubMed   |  Link to Article
Pinto-Sietsma SJ, Janssen WM, Hillege HL, Navis G, De Zeeuw D, De Jong PE. Urinary albumin excretion is associated with renal functional abnormalities in a nondiabetic population.  J Am Soc Nephrol. 2000;11(10):1882-1888
PubMed
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).  Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.  Circulation. 2002;106(25):3143-3421
PubMed
Levey AS, Bosch J, Lewis J, Greene T, Rogers N, Roth D.Modification of Diet in Renal Disease Study Group.  A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation.  Ann Intern Med. 1999;130(6):461-470
PubMed   |  Link to Article
Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.  Clin Chem. 1972;18(6):499-502
PubMed
 Survival Analysis and Epidemiological Tables Reference Manual Release 10. College Station, TX: Stata Press; 2007
Lambers Heerspink HJ, Brantsma AH, de Zeeuw D, Bakker SJ, de Jong PE, Gansevoort RT.PREVEND Study Group.  Albuminuria assessed from first-morning-void urine samples versus 24-hour urine collections as a predictor of cardiovascular morbidity and mortality.  Am J Epidemiol. 2008;168(8):897-905
PubMed   |  Link to Article
Pearson T, Mensah G, Alexander RW,  et al; Centers for Disease Control and Prevention; American Heart Association.  Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association.  Circulation. 2003;107(3):499-511
PubMed   |  Link to Article
 Survey Data Reference Manual Release 10. College Station, TX: Stata Press; 2007
Arnlöv J, Evans JC, Meigs JB,  et al.  Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study.  Circulation. 2005;112(7):969-975
PubMed   |  Link to Article
Deguchi H, Pecheniuk N, Elias D, Averell P, Griffin J. High-density lipoprotein deficiency and dyslipoproteinemia associated with venous thrombosis in men.  Circulation. 2005;112(6):893-899
PubMed   |  Link to Article
Goldhaber SZ, Grodstein F, Stampfer MJ,  et al.  A prospective study of risk factors for pulmonary embolism in women.  JAMA. 1997;277(8):642-645
PubMed   |  Link to Article
Hansson PO, Eriksson H, Welin L, Svardsudd K, Wilhelmsen L. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: “The Study of Men Born in 1913.”  Arch Intern Med. 1999;159(16):1886-1890
PubMed   |  Link to Article
Petrauskiene V, Falk M, Waernbaum I, Norberg M, Eriksson JW. The risk of venous thromboembolism is markedly elevated in patients with diabetes.  Diabetologia. 2005;48(5):1017-1021
PubMed   |  Link to Article
Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology.  Arch Intern Med. 2002;162(10):1182-1189
PubMed   |  Link to Article
Franchini M, Targher G, Montagnana M, Lippi  G. The metabolic syndrome and the risk of arterial and venous thrombosis.  Thromb Res. 2008;122(6):727-735
PubMed   |  Link to Article
Ray JG, Lonn E, Yi Q,  et al; HOPE-2 Investigators.  Venous thromboembolism in association with features of the metabolic syndrome.  QJM. 2007;100(11):679-684
PubMed   |  Link to Article
Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion: an independent predictor of ischemic heart disease.  Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997
PubMed   |  Link to Article
Yuyun MF, Khaw KT, Luben R,  et al.  Microalbuminuria and stroke in a British population: the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study.  J Intern Med. 2004;255(2):247-256
PubMed   |  Link to Article
Mahmoodi BK, ten Kate MK, Waanders F,  et al.  High absolute risks and predictors of venous and arterial thromboembolic events in patients with nephrotic syndrome: results from a large retrospective cohort study.  Circulation. 2008;117(2):224-230
PubMed   |  Link to Article
Rosendaal FR. Risk factors for venous thrombotic disease.  Thromb Haemost. 1999;82(2):610-619
PubMed

Figures

Place holder to copy figure label and caption
Figure 1. Participant Selection for the PREVEND Study Cohort
Graphic Jump Location

Urinary albumin concentration (UAC) was assessed in a first morning void urine sample and measured in milligrams per liter. The number of randomly selected participants was arbitrarily set at 3395 to obtain a total cohort size of approximately 10 000 accounting for a 15% nonparticipation rate.

Place holder to copy figure label and caption
Figure 2. Adjusted Annual Incidences of Venous Thromboembolism in Relation to Urinary Albumin Excretion by Clinical Class
Graphic Jump Location

The annual incidences are adjusted for the enrichment of the cohort with participants with higher urinary albumin excretion using the survey probability weights.

Place holder to copy figure label and caption
Figure 3. Univariate and Sex- and Age-Adjusted Proportional Hazards Analysis of Association With the First Venous Thromboembolism
Graphic Jump Location

eGFR indicates estimated glomerular filtration rate22; MI, myocardial infarction; UAE, urinary albumin excretion; VTE, venous thromboembolism. To convert values for cholesterol, HDL, and LDL to mmol/L, multiply by 0.0259; to convert values for triglycerides to mmol/L, multiply by 0.0113; to convert CRP to nmol/L multiply by 9.524; to convert PAI-1 to pmol/L, multiply by 19.231.
aSex- and age-adjusted hazard ratios (HRs) with corresponding 95% confidence intervals (95% CIs). Sex was adjusted for age only and age for sex only. Use of oral contraceptives was also adjusted for age only.
bBody mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), metabolic syndrome, cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides were classified according to the Adult Treatment Panel III of the National Cholesterol Education Program.21
cC-reactive protein (CRP) was classified according to the Centers for Disease Control and Prevention and the American Heart Association.26
dSince normal ranges of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) in the general population are unknown, we dichotomized these variables using their medians as cutoffs.

Place holder to copy figure label and caption
Figure 4. Cumulative Incidence of Venous Thromboembolism
Graphic Jump Location

Microalbuminuria denotes urinary albumin excretion of 30 to 300 mg/24 h; normoalbuminuria, urinary albumin excretion of less than 30 mg/24 h.

Tables

References

White RH. The epidemiology of venous thromboembolism.  Circulation. 2003;107(23):(suppl1)  I4-I8
PubMed   |  Link to Article
Nordström M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population.  J Intern Med. 1992;232(2):155-160
PubMed   |  Link to Article
Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrøm J. Incidence and mortality of venous thrombosis: a population-based study.  J Thromb Haemost. 2007;5(4):692-699
PubMed   |  Link to Article
Virchow R. Phlogose und thrombose im gefässystem. In: Gesammelte Abhandlungen zur Wissenschaftlichen Medicin. Frankfurt, Germany: Meidinger; 1856
Rosendaal FR. Venous thrombosis: a multicausal disease.  Lancet. 1999;353(9159):1167-1173
PubMed   |  Link to Article
Sørensen HT, Horvath-Puho E, Pedersen L, Baron JA, Prandoni P. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study.  Lancet. 2007;370(9601):1773-1779
PubMed   |  Link to Article
Prandoni P, Bilora F, Marchiori A,  et al.  An association between atherosclerosis and venous thrombosis.  N Engl J Med. 2003;348(15):1435-1441
PubMed   |  Link to Article
Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular risk factors and venous thromboembolism: a meta-analysis.  Circulation. 2008;117(1):93-102
PubMed   |  Link to Article
Migliacci R, Becattini C, Pesavento R,  et al.  Endothelial dysfunction in patients with spontaneous venous thromboembolism.  Haematologica. 2007;92(6):812-818
PubMed   |  Link to Article
Hillege HL, Janssen WM, Bak AA,  et al; PREVEND Study Group.  Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity.  J Intern Med. 2001;249(6):519-526
PubMed   |  Link to Article
Gerstein HC, Mann JF, Yi Q,  et al; HOPE Study Investigators.  Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals.  JAMA. 2001;286(4):421-426
PubMed   |  Link to Article
Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage: the Steno hypothesis.  Diabetologia. 1989;32(4):219-226
PubMed   |  Link to Article
Kario K, Matsuo T, Kobayashi H,  et al.  Factor VII hyperactivity and endothelial cell damage are found in elderly hypertensives only when concomitant with microalbuminuria.  Arterioscler Thromb Vasc Biol. 1996;16(3):455-461
PubMed   |  Link to Article
Gruden G, Cavallo-Perin P, Bazzan M, Stella S, Vuolo A, Pagano G. PAI-1 and factor VII activity are higher in IDDM patients with microalbuminuria.  Diabetes. 1994;43(3):426-429
PubMed   |  Link to Article
Festa A, D'Agostino R, Howard G, Mykkänen L, Tracy RP, Haffner SM. Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: the Insulin Resistance Atherosclerosis Study.  Kidney Int. 2000;58(4):1703-1710
PubMed   |  Link to Article
Collier A, Rumley A, Rumley AG,  et al.  Free radical activity and hemostatic factors in NIDDM patients with and without microalbuminuria.  Diabetes. 1992;41(8):909-913
PubMed   |  Link to Article
Agewall S, Lindstedt G, Fagerberg B. Independent relationship between microalbuminuria and plasminogen activator inhibitor-1 activity (PAI-1) activity in clinically healthy 58-year-old men.  Atherosclerosis. 2001;157(1):197-202
PubMed   |  Link to Article
Agewall S, Fagerberg B, Attvall S,  et al; Risk Factor Intervention Study Group.  Microalbuminuria, insulin sensitivity and haemostatic factors in non-diabetic treated hypertensive men: Risk Factor Intervention Study Group.  J Intern Med. 1995;237(2):195-203
PubMed   |  Link to Article
Clausen P, Feldt-Rasmussen B, Jensen G, Jensen JS. Endothelial haemostatic factors are associated with progression of urinary albumin excretion in clinically healthy subjects: a 4-year prospective study.  Clin Sci (Lond). 1999;97(1):37-43
PubMed   |  Link to Article
Pinto-Sietsma SJ, Janssen WM, Hillege HL, Navis G, De Zeeuw D, De Jong PE. Urinary albumin excretion is associated with renal functional abnormalities in a nondiabetic population.  J Am Soc Nephrol. 2000;11(10):1882-1888
PubMed
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).  Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.  Circulation. 2002;106(25):3143-3421
PubMed
Levey AS, Bosch J, Lewis J, Greene T, Rogers N, Roth D.Modification of Diet in Renal Disease Study Group.  A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation.  Ann Intern Med. 1999;130(6):461-470
PubMed   |  Link to Article
Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.  Clin Chem. 1972;18(6):499-502
PubMed
 Survival Analysis and Epidemiological Tables Reference Manual Release 10. College Station, TX: Stata Press; 2007
Lambers Heerspink HJ, Brantsma AH, de Zeeuw D, Bakker SJ, de Jong PE, Gansevoort RT.PREVEND Study Group.  Albuminuria assessed from first-morning-void urine samples versus 24-hour urine collections as a predictor of cardiovascular morbidity and mortality.  Am J Epidemiol. 2008;168(8):897-905
PubMed   |  Link to Article
Pearson T, Mensah G, Alexander RW,  et al; Centers for Disease Control and Prevention; American Heart Association.  Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association.  Circulation. 2003;107(3):499-511
PubMed   |  Link to Article
 Survey Data Reference Manual Release 10. College Station, TX: Stata Press; 2007
Arnlöv J, Evans JC, Meigs JB,  et al.  Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study.  Circulation. 2005;112(7):969-975
PubMed   |  Link to Article
Deguchi H, Pecheniuk N, Elias D, Averell P, Griffin J. High-density lipoprotein deficiency and dyslipoproteinemia associated with venous thrombosis in men.  Circulation. 2005;112(6):893-899
PubMed   |  Link to Article
Goldhaber SZ, Grodstein F, Stampfer MJ,  et al.  A prospective study of risk factors for pulmonary embolism in women.  JAMA. 1997;277(8):642-645
PubMed   |  Link to Article
Hansson PO, Eriksson H, Welin L, Svardsudd K, Wilhelmsen L. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: “The Study of Men Born in 1913.”  Arch Intern Med. 1999;159(16):1886-1890
PubMed   |  Link to Article
Petrauskiene V, Falk M, Waernbaum I, Norberg M, Eriksson JW. The risk of venous thromboembolism is markedly elevated in patients with diabetes.  Diabetologia. 2005;48(5):1017-1021
PubMed   |  Link to Article
Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology.  Arch Intern Med. 2002;162(10):1182-1189
PubMed   |  Link to Article
Franchini M, Targher G, Montagnana M, Lippi  G. The metabolic syndrome and the risk of arterial and venous thrombosis.  Thromb Res. 2008;122(6):727-735
PubMed   |  Link to Article
Ray JG, Lonn E, Yi Q,  et al; HOPE-2 Investigators.  Venous thromboembolism in association with features of the metabolic syndrome.  QJM. 2007;100(11):679-684
PubMed   |  Link to Article
Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion: an independent predictor of ischemic heart disease.  Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997
PubMed   |  Link to Article
Yuyun MF, Khaw KT, Luben R,  et al.  Microalbuminuria and stroke in a British population: the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study.  J Intern Med. 2004;255(2):247-256
PubMed   |  Link to Article
Mahmoodi BK, ten Kate MK, Waanders F,  et al.  High absolute risks and predictors of venous and arterial thromboembolic events in patients with nephrotic syndrome: results from a large retrospective cohort study.  Circulation. 2008;117(2):224-230
PubMed   |  Link to Article
Rosendaal FR. Risk factors for venous thrombotic disease.  Thromb Haemost. 1999;82(2):610-619
PubMed
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