The epidemiology of deep vein thrombosis and pulmonary embolism (PE), collectively referred as venous thromboembolism (VTE), has been well investigated in the general population.1–3 The overall average VTE incidence rate in adults ranges from 0.7 to 1.9 events per 1000 persons-years.1,4 Risk factors for VTE include major surgery, trauma, cancer, obesity, diabetes, and hereditary predisposition.5
Patients with chronic kidney disease (CKD) share some of these predisposing risk factors and might be at increased risk for VTE. Autopsy series have suggested that VTE events are relatively common in patients with ESRD.6,7 Furthermore, epidemiologic studies have reported an increased risk for VTE in dialysis8 and in renal transplant patients.9 To our knowledge, CKD has not been evaluated as a risk factor for VTE in the general population. If an association were found, then this would increase understanding of VTE etiology and identify a subset of the population at high risk for possible prophylaxis. Using data from the Longitudinal Investigation of Thromboembolism Etiology (LITE), we therefore conducted a prospective study to investigate the association between CKD and VTE.
Among the 19,071 participants (mean age 59 yr), the mean estimated GFR (eGFR) was 90.4 ml/min per 1.73 m2 (SD 22.4 ml/min per 1.73 m2). There were 8312 (43.6%) participants with normal kidney function, 9472 (49.7%) with mildly decreased kidney function, and 1287 (6.8%) with stage 3/4 CKD. The mean eGFR among the participants with stage 3/4 CKD was 51.4 ml/min per 1.73 m2 (SD 8.5 ml/min per 1.73 m2). Compared with participants with normal kidney function (Table 1), those with CKD were more likely to be male, older, and white; to have diabetes and hypertension; and to have greater mean values of body mass index (BMI) and factor VIIIc. In contrast, participants with mildly decreased kidney function had a similar risk factor profile to those with normal kidney function.
During a mean follow-up time of 11.8 yr (224,275 person-years), 413 participants developed incident VTE (41% idiopathic and 59% secondary VTE). Participants with incident VTE had a greater mean baseline age, BMI, and factor VIIIc level and higher prevalence of diabetes and hypertension than those without incident VTE. The incidence rates of VTE per 1000 person-years were 1.5, 1.9, and 4.5 for normal kidney function, mildly decreased kidney function, and stage 3/4 CKD, respectively (Table 2). Compared with individuals with normal kidney function, the age-, gender-, race-, and study-adjusted relative risk (RR) for VTE was 1.28 (95% confidence interval [CI] 1.02 to 1.59) for those with mildly decreased kidney function and 2.09 (95% CI 1.47 to 2.96) for those with stage 3/4 CKD. After additional adjustment for risk factors associated with both CKD and VTE (model 2), patients with mildly decreased kidney function and those with stage 3/4 CKD still had an increased incidence of VTE, with multivariable adjusted RR of 1.29 (95% CI 1.02 to 1.62) and 1.71 (95% CI 1.18 to 2.49), respectively. Testing for effect modification showed no statistically significant interaction on the multiplicative scale between level of kidney function and gender, race, diabetes, hypertension, smoking, lipids, BMI, or factor VIIIc. As shown in Table 3, the incidence rates and RR for VTE with lower eGFR were similar for idiopathic and secondary VTE.
For further examination of the dose-response relation between renal function and VTE, a smoothed curve of predicted RR with adjustment for the full set of covariates was graphed against eGFR (Figure 1). The predicted RR for VTE increased below eGFR of 75 ml/min per 1.73 m2. Compared with individuals with eGFR of 90 ml/min per 1.73 m2, the predicted RR for VTE for those with eGFR of 75, 60, 45, 30, and 15 ml/min per 1.73 m2 were 1.14, 1.38, 1.68, 2.08, and 2.53, respectively. These results were largely supportive of the categorical analysis.
We also examined the incidence rate and RR for VTE with increasing level of serum creatinine. The incidence rates of VTE per 1000 person-years were 1.6, 1.9, 2.2, and 4.6 for serum creatinine levels <1.10, 1.10 to 1.29, 1.30 to 1.49, and ≥1.5 mg/dl, respectively. In the multivariable adjusted model, compared with the first category of serum creatinine, the second and third categories of serum creatinine had a similar VTE risk (RR 1.17 [95% CI 0.89 to 1.53] and RR 1.15 [95% CI 0.75 to 1.78], respectively), but the fourth category had almost double the VTE risk (RR 1.86; 95% CI 1.21 to 2.81).
During VTE case review, we recorded whether the patients with VTE developed renal failure or required dialysis within 90 d before the VTE. Of the 413 participants with incident VTE, 31 (7.5%) had medical chart documentation of renal failure or dialysis; 13 came from the 146 participants with normal kidney function at baseline (8.9%); nine came from the 215 participants with mildly decreased kidney function at baseline (4.2%); and nine came from the 52 participants with stage 3/4 CKD at baseline (17.3%). Thus, proportionately more participants with baseline stage 3/4 CKD had incident VTE events in the presence of renal failure.
Cystatin C was available for 4013 patients from the Cardiovascular Health Study (CHS). During 9.7 yr (39,079 person-years) of follow-up, 129 patients developed incident VTE (40% idiopathic). There was no association between cystatin C and VTE. The multivariable adjusted RR for VTE were 0.53 (95% CI 0.25 to 1.10), 0.85 (95% CI 0.44 to 1.63), 1.02 (95% CI 0.54 to 1.92), and 1.12 (95% CI 0.58 to 2.16) comparing the second (0.89 to 0.99 mg/L), third (1.00 to 1.10 mg/L), fourth (1.11 to 1.26 mg/L), and fifth (>1.27 mg/L) quintiles of cystatin C with the first (<0.89 mg/L) quintile, respectively (P = 0.18 for trend).
In this large community-based sample, mildly decreased kidney function and CKD, measured by eGFR, was a moderate, independent risk factor for VTE. Patients with CKD (eGFR between 15 and 59 m/min per 1.73 m2) had an almost two-fold increased risk for VTE compared with those with normal renal function (eGFR >90 ml/min per 1.73 m2). This risk is similar in magnitude to several other established VTE risk factors, such as bed rest, prolonged immobilization, and obesity.5 This study was not able to demonstrate an independent association between cystatin C and VTE in CHS, perhaps because insufficient statistical power.
This study is largely consistent with data from the dialysis and transplant population demonstrating a higher risk for VTE in dialysis patients compared with the general population. Using data from the US Renal Data System record in 1996 and the National Center for Health Statistics, Tveit et al.8 reported that the incidence of PE occurring within 1 yr after initiation of dialysis therapy was approximately 149.9 events per 100,000 dialysis-dependent patients compared with an expected rate of 24.6 per 100,000 people in the US population, with an age-adjusted incidence ratio of 2.34. Similarly, Abbott et al.9 reported that the incidence rate of VTE in a cohort of 28,924 Medicare renal transplant patients was 9.8 events per 1000 person-years; those with renal insufficiency (eGFR <30 ml/min per 1.73 m2) at 1 yr after renal transplantation had a two-fold higher risk for VTE compared with those with eGFR >30 ml/min per 1.73 m2. Our study seems to be the first to report an association between mildly decreased kidney function and stage 3/4 CKD and VTE in the general population. The incidence rates for the mildly decreased kidney function (1.9 events per 1000 person-years) and stage 3/4 CKD groups (4.5 events per 1000 person-years) were lower than that reported by Abbott et al., perhaps because our population had less severe CKD and fewer coexisting medical conditions than in renal transplant patients. Unique to this study is that our spline regression analysis demonstrated that the risk for VTE began to increase with eGFR as high as 75 ml/min per 1.73 m2 and gradually increased for lower levels of eGFR. Overall, our findings are consistent with the previous large studies in more severe CKD and provide supporting evidence of increased risk for VTE in relation to impaired kidney function in the general population.
This finding has potentially important clinical implications. The American College of Chest Physicians has recommended routine VTE prophylaxis for several groups of hospitalized patients. These include patients with congestive heart failure, severe lung disease, and cancer; patients who are on bed rest; and patients who undergo major general, urologic, and gynecologic surgery, hip surgery, and lower extremity arthroplasty.10,11 Conversely, patients with CKD—inpatients or outpatients—generally do not receive routine prophylaxis unless there are other known concomitant risk factors placing them in the high-risk group.10 The findings of our study call for an awareness of increased VTE risk in patients with CKD. Recognition of the increased risk in this population is important because clinical trials have demonstrated that VTE is preventable with prophylactic anticoagulation treatment12,13; however, further studies are needed to show at what level of eGFR prophylaxis might be cost-effective or safe, given the increased bleeding risk associated with anticoagulation. There are other considerations for safety of VTE diagnosis and treatment in CKD, such as the risk for contrast-induced nephropathy for contrast-based imaging and that low molecular weight heparin is not recommended in advanced kidney disease.
Mechanisms linking CKD and VTE are unknown. In our study, the strength of association was attenuated only modestly after adjustment for demographic factors, diabetes, BMI, and factor VIIIc, suggesting that these factors may only partly explain an increased risk for VTE in the CKD population. Patients with CKD, particularly those with the nephrotic syndrome, have elevated blood levels of fibrinogen and inflammatory markers; however, these factors were not VTE risk factors in LITE. Patients with CKD and nephrotic syndrome may also have endothelial cell dysfunction,14 enhanced platelet activation and aggregation,15 activation of the coagulation system,16,17 and decreased endogenous anticoagulants.17,18 Larger studies, with data on proteinuria, are needed to evaluate the hemostatic mechanisms mediating the association between CKD and VTE.
The strengths of our study were that it was a large, prospective, population-based study and that VTE was classified by standardized criteria. Our study was performed in a population generally without previous diagnosis of CKD, which should reduce diagnostic suspicion bias that might arise if VTE were sought more thoroughly in patients with diagnosed CKD than in patients without CKD; therefore, the findings seem to be valid and should be generalizable to the CKD population in the United States. We also acknowledge a series of limitations. First, there are potential sources of misclassification. Renal function estimated by the Modification of Diet in Renal Disease (MDRD) formula and serum creatinine is not as accurate as a direct measurement from iothalamate or creatinine clearance using a 24-h urine collection; however, direct measurement of GFR is not feasible in a large epidemiologic study. Estimation of renal function was based on only one measure of serum creatinine and may be subject to intraindividual variation. Furthermore, creatinine was measured on average 11.8 yr before incident VTE events. Change in kidney function during the interval would have resulted in misclassification of CKD status. In fact, our supplemental analysis showed that small numbers of patients who had VTE and whose baseline kidney function was normal (n = 13) or mildly decreased (n = 10) had renal failure or were on dialysis around the time of incident VTE. Nevertheless, these numbers were small and still proportionately fewer than for those who had CKD at baseline. Second, we pooled two large population-based studies because of similar protocols. Differences in exposure measurement could have affected results, but RR for CKD were elevated in the same direction in each study. Third, we unfortunately did not have information on proteinuria before VTE onset. It would be useful to explore whether proteinuria identifies a subset of patients who have CKD and are at risk for VTE and therefore deserve VTE prophylaxis. Fourth, VTE cases could have been missed if VTE events had not occurred in the hospital or been recognized by clinicians, but this is true of any epidemiologic study. We believe that such events were uncommon. In fact, LITE data suggest through 2001 that most VTE were treated in the hospital. We believe that many of these limitations would lead to bias toward the null hypothesis.
In conclusion, non-dialysis and non-renal transplant CKD patients are at increased risk for incident VTE events. An awareness of the increased risk in the CKD population is important to prevent morbidity and mortality related to VTE.
The LITE combined the established cohorts from the Atherosclerosis Risk in Communities (ARIC) Study and the CHS, involving six US communities. The ARIC Study enrolled 15,792 adults aged 45 to 64 yr at baseline, and the CHS enrolled 5888 adults aged ≥65 yr (5201 recruited between 1989 and 1990 and an additional 687 black patients between 1992 and 1993). Cardiovascular risk factors were collected at the baseline examination conducted from 1987 to 1989 in ARIC and from 1989 to 1990 or 1992 to 1993 (black cohort) in CHS. Informed consent was obtained from participants, with approval of methods by the institutional review boards at each study center.
Measurement of Baseline Risk Factors
Factor VIIIc was measured.19,20 BMI was calculated. Diabetes was defined as a fasting serum glucose level ≥7.0 mmol/L (126 mg/dl), nonfasting glucose level ≥11.1 mmol/L (200 mg/L), or current use of any diabetes medication. Hypertension was defined as seated diastolic BP ≥90 mmHg, systolic BP ≥140 mmHg, or use of antihypertensive medications within the past 2 wk.
Estimation of the Level of Kidney Function
Serum creatinine was measured by each study using the modified kinetic Jaffe method. Level of kidney function was defined by eGFR using the MDRD formula21: eGFR = 186.3 × (serum creatinine−1.154) × (age−0.203) × 1.212 (if black) × 0.742 (if female). Because serum creatinine values measured in different laboratories may vary, we indirectly calibrated ARIC and CHS serum creatinine values to results obtained at the Cleveland Clinic Laboratory (where serum creatinine was measured in the MDRD study) by using the Third National Health and Nutrition Examination Survey (NHANES III) data. Because both NHANES III and the studies were designed as population samples, it was assumed that the mean serum creatinine in the studies for a given age, race, and gender should be comparable to NHANES III. A linear regression of data showed that serum creatinine values were 0.24 higher in ARIC22 and 0.11 higher in CHS23 than among NHANES III participants. We therefore subtracted these values from measured serum creatinine levels before using the MDRD formula in this study. We assigned participants with an implausibly high eGFR to a value of 200 ml/min per 1.73 m2 (n = 21). Baseline eGFR was divided into the following categories on the basis of the National Kidney Foundation guidelines: eGFR >90 ml/min per 1.73 m2 for normal kidney function, eGFR between 60 and 89 ml/min per 1.73 m2 for mildly decreased kidney function, and eGFR between 15 and 59 ml/min per 1.73 m2 for stage 3/4 CKD.
Cystatin C (available only in CHS), a sensitive marker of renal function,24 was measured by means of a particle-enhanced immunonephelometric assay with a nephelometer (BNII; Dade Behring, Deerfield, IL).25 The assay has an intraindividual coefficient of variation of 7.7%.
VTE Identification and Classification
ARIC participants were contacted annually by telephone or through clinic visits, and CHS participants were contacted twice a year, alternating clinic visits and telephone calls. Hospitalizations were identified by participants or proxy reports in both ARIC and CHS, by surveillance of local hospital discharge lists in ARIC, and by a search of Health Care Financing Administration records in CHS. All records with possible VTE were identified and copied.
Deep vein thrombosis was classified independently by two physicians (A.R.F. and M.C.) and was defined on the basis of duplex ultrasound or venogram or, in rare cases, by impedance plethysmography, computed tomography, or autopsy. Definite PE required ventilation/perfusion scanning showing multiple segmental or subsegmental mismatched perfusion defects, or a positive pulmonary angiogram, computed tomography, or autopsy.26 Thrombosis events were further classified as idiopathic or secondary (occurring within 90 d of major trauma, surgery, hospitalization, or marked immobility or associated with active cancer or chemotherapy).
Of 21,680 participants, we excluded those who at baseline reported a history of VTE (n = 630) or cancer (n = 1629) or were taking warfarin (n = 128). In addition, we excluded 195 participants with missing data on creatinine and 27 participants with eGFR <15 ml/min per 1.73 m2, leaving a total of 19,071 participants for the final analyses. Length of follow-up was calculated as a time elapsed between the baseline examination and the VTE event; date of last known contact; death; or December 31, 2001.
We compared baseline risk factors of the participants according to the three categories of renal function using a χ2 test for categorical variables and ANOVA for continuous variables. Incidence rates per 1000 person-years were estimated for the three categories of kidney function by dividing the number of cases by the follow-up time. With normal kidney function as a reference group, proportional hazards regression was used to calculate RR and 95% CI for incident VTE, adjusting for age, gender, race (white, black), and study (ARIC, CHS). A subsequent model additionally adjusted for risk factors related to both CKD and VTE: Diabetes (yes, no), BMI (continuous variable), and factor VIIIc (continuous variable). To examine the dose-response relation between the risk for VTE and eGFR, we fitted a restricted cubic spline regression model to the data with three knots placed at eGFR values (ml/min per 1.73 m2) of 62 (fifth percentile), 90 (50th percentile), and 141 (95th percentile). We also repeated the same analyses using serum creatinine levels categorized as <1.10, 1.10 to 1.29, 1.30 to 1.49, and ≥1.5 mg/dl. Because eGFR during the follow-up period was not available, change in kidney function during the interval would have resulted in misclassification of CKD status. In a supplemental analysis, we therefore evaluated the number of patients who had baseline kidney function that was misclassified around the time of VTE incidence. We also calculated the associations of cystatin C (CHS only) in quintiles with VTE events. All statistical analyses were conducted using SAS 8.2 software (SAS Institute, Cary, NC).
Support was provided by the National Heart, Lung, and Blood Institute under grant R01 HL59367 (LITE) and contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 (ARIC) and N01-HC-85079 to N01-HC-85086, N01-HC-75150, and N01-HC-45133 (CHS).
Published online ahead of print. Publication date available at www.jasn.org.
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