Chronic kidney disease and venous thromboembolism:

epidemiology and mechanisms

Keattiyoat Wattanakita and Mary Cushmanb
a
Department of Medicine, University of Texas Purpose of review
Southwestern Medical Center, Dallas, Texas and
b
Departments of Medicine and Pathology, University of
An estimated 13% of Americans have kidney disease. We sought to describe the
Vermont, Burlington, Vermont, USA association of kidney disease with risk of venous thromboembolism and discuss
Correspondence to Mary Cushman, MD, MSc, possible mechanisms explaining this association.
University of Vermont, 208 South Park Drive, Recent findings
Colchester, VT 05446, USA
Tel: +1 802 656 8968; fax: +1 802 656 8965; All severities of kidney disease appear to increase the risk of venous thromboembolism.
e-mail: mary.cushman@uvm.edu In the general population the risk associated with mild to moderate kidney disease is
Current Opinion in Pulmonary Medicine 2009,
1.3–2-fold increased, and present even for microalbuminuria, although stage 1 chronic
15:408–412 kidney disease itself has not been studied. End-stage renal disease is also associated
with a 2.3-fold increased risk, compared to the general population. Although data are
limited, risk increases after kidney transplant and with nephrotic syndrome as well.
Summary
Rates of kidney disease are increasing rapidly in the population and kidney disease is a
risk factor for venous thromboembolism. An improved understanding of mechanisms
linking kidney disease with venous thromboembolism will allow further study of best
prevention efforts.

Keywords
blood coagulation, kidney disease, risk factor, venous thromboembolism

Curr Opin Pulm Med 15:408–412

ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
1070-5287

factor VIII/von Willebrand factor, and deficiencies of

Introduction antithrombin, protein C and protein S. Given the high
The epidemiology of deep venous thrombosis (DVT) prevalence of chronic kidney disease (CKD), especially
and pulmonary embolism, collectively referred as venous with aging, there is recent interest in evaluating the role
thromboembolism (VTE), has been studied in the gen- of CKD as a risk factor for VTE. This is not a surprise
eral population, although there are many areas needing given that CKD patients have underlying hemostatic
further work. The annual incidence of VTE is approxi- derangements predisposing to a hypercoagulable state.
mately 1 in 1000 adults, with a sharply higher risk in the This review summarizes the epidemiology of VTE in the
elderly [1,2]. Proposed nearly 150 years ago, Virchow was CKD population and focuses on potential mechanisms
the first to suggest that VTE occurs as a result of vascular leading to its development.
endothelial injury, alteration in blood flow, and a hyper-
coagulable state [3]. When these abnormalities co-occur,
the combination of endogenous and acquired risk factors Overview of chronic kidney disease
leads to a VTE episode. For example, when reduced In order to understand the association of CKD with VTE
blood flow occurs as in the case of immobility, pooling of risk it is first important to understand the epidemiology of
blood leads to activation of coagulation locally and sim- CKD and trends over time in its prevalence.
ultaneous consumption of blood coagulation inhibitors.
In other words, the pathogenesis of VTE is multifactorial, Chronic kidney disease is common in the general US
often requiring the presence of multiple risk factors to population, affecting 13% of adults 20 years and older
cause a clinical event. studied between 1999 and 2004 [4]. The rate of kidney
failure requiring dialysis, or end-stage renal disease
Established VTE risk factors include surgery, cancer, (ESRD), increased 43% over the 1990s [5], and is felt
hospitalization, immobilization, obesity, exogenous hor- largely due to increases in diabetes, hypertension and
mones, pregnancy and the puerperium and inherited obesity. Determination of CKD status is typically done
thrombophilia. The well known inherited thrombophilias using creatinine measurement, along with age, sex and
include factor V Leiden, prothrombin 20210A, elevated race, to calculate estimated glomerular filtration rate
1070-5287 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MCP.0b013e32832ee371

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 Kidney disease and venous thromboembolism Wattanakit and Cushman 409

Table 1 Definition and prevalence of chronic kidney disease ment with the expected rate in the US population. The
GFR Prevalence incidence was 149.9 events per 100 000 dialysis patients
Stage Description (ml/min/1.72 m2) in USa compared with an expected rate of 24.6 per 100 000
0 Normal GFR, no kidney damage 87% people in the US population. This led to an age-adjusted
1 Kidney damage with normal GFR 90b 1.8% incidence rate ratio of 2.34. Because this utilized admin-
2 Kidney damage with mildly 60–89 3.2%
decreased GFR
istrative data, errors in coding and sampling are possible.
3 Moderately decreased GFR 30–59 7.7%
4 Severely decreased GFR 15–29 0.3% Chronic kidney disease and venous thromboembolism
5 Kidney failure <15 (or dialysis) –
To date, the Longitudinal Investigation of Thromboem-
a
Data from NHANES 1999–2004 survey of adults aged 20 years and bolism Etiology (LITE) study is the only population-
older. Stage 5 not studied [3]. based study we are aware of that evaluated VTE risk in
b
Persistent microalbuminuria.
the nondialysis, nontransplant CKD population [13]. In
that study, 19 073 middle-aged and elderly adults were
(eGFR). A commonly used equation for this is the four- followed for an average of 12 years. Kidney disease was
variable modification of diet in renal disease equation: associated with increased risk of future VTE, with inci-
dence rates per 1000 person-years of 1.5, 1.9, and 4.5 for
eGFR ¼ 186
serum creatinine1:154
age0:203 normal kidney function, mildly decreased renal function,
and stage 3 or 4 CKD. The age, sex and race-adjusted

1:212 ðif blackÞ
0:742 ðif femaleÞ: relative risk of VTE with stage 3 or 4 kidney disease
was 2.1 [95% confidence interval (CI) 1.5–3.0]. In fact,
Table 1 shows the classification of the stages of increasing the risk began to rise when the eGFR was less than
severity of CKD. The eGFR can also be determined 75 ml/min/1.73 m2, which is above the threshold defining
in research settings using equations based on cystatin stage 3 or 4 CKD. The investigators also evaluated the
C measurement [6], and by newer creatinine-based association of cystatin C, a novel marker of renal function,
equations [7]. with risk of VTE. An independent association was not
observed. This may have been due to insufficient stat-
istical power, as cystatin C was measured in a smaller
Associations of stages of chronic kidney number of participants. The main limitation of this study
disease with risk of venous is that estimation of renal function was measured on
thromboembolism average 12 years before the index event. Thus, change
We review here the evidence for associations of CKD in renal function during the follow-up time would have
with risk of VTE. resulted in misclassification of the exposure status, and
underestimation of the true risk of VTE in people with
End-stage renal disease and venous thromboembolism CKD. Thus, it is likely that the true risk associated
Epidemiologic evidence on the VTE risk in the ESRD with stage 3 or 4 kidney disease is likely greater than
population is very limited. Initial postmortem examin- two-fold increased.
ations suggested that VTE is a rare event in ESRD [8–
11]. However, the series by Wiesholzer et al. [11] in 1999 In the LITE study mildly decreased kidney function
was the first to suggest that VTE in dialysis patients was was associated with a 1.3-fold increased risk of VTE, but
relatively common. In that study, pulmonary embolism this was not independent of cardiovascular risk factor
was observed in 1753 of 8051 (21.8%) postmortem exam- levels. In contrast, Mahmoodi and colleagues [14]
inations in nondialysis patients who were hospitalized. recently reported that microalbuminuria was indepen-
This compared to a prevalence of pulmonary embolism of dently associated with increased VTE risk in a com-
23 of 185 (12.5%) postmortem examinations in chronic munity cohort of 8574 men and women, associated with
dialysis patients who were hospitalized. Although signifi- a two-fold increased risk (95% CI 1.3–3.0). However, the
cantly less than the nondialysis group, the frequency investigators did not exclude participants with abnormal
among dialysis patients was higher than anticipated, eGFR from the analysis so the impact of stage 1 kidney
suggesting that the occurrence of VTE in dialysis patients disease itself was not addressed. Since microalbuminuria
was more common than previously believed. in the absence of kidney damage (stage 1 CKD) is very
common in the general population, if this finding can be
Other investigators have used larger databases to further confirmed by others, the proportion of VTE attributed to
investigate the risk of VTE in patients with ESRD. Tveit kidney disease in general would be high.
et al. [12] combined the US Renal Data System records
from 1996 and data from the National Center for Health Nephrotic syndrome and venous thromboembolism
Statistics to compare the incidence of pulmonary embo- Multiple small studies consistently suggested that nephro-
lism occurring within 1 year after initiating dialysis treat- tic syndrome is a risk factor for VTE [15,16,17,18,19]. Of

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 410 Disorders of the pulmonary circulation

these, the largest study was conducted using data from the fibrin. At the site of vascular injury, tissue factor is
US National Hospital Discharge Survey [19]. Of 925 000 exposed, which then binds and activates factor VII. This
patients discharged from hospitals between 1979 and 2005 results in activation of factor X and factor IX and con-
with nephrotic syndrome, 19 000 (2%) had VTE events version of prothrombin to thrombin. This cascade is
(0.5% with pulmonary embolism or renal vein thrombosis known as the extrinsic pathway.
and 1.5% with DVT). Among 898 253 000 patients dis-
charged without a diagnosis of nephrotic syndrome, Through the extrinsic pathway, a limited amount of
approximately 11 500 (1.3%) had VTE events. Compared thrombin is generated. At this initial stage, a fibrin clot
to patients without nephrotic syndrome, those with that is formed is susceptible to fibrinolysis. To maintain
nephrotic syndrome had a 39% increased risk of DVT coagulation, more thrombin is generated through a
and a 72% increased risk of pulmonary embolism. On the positive feedback loop. That is a small amount of throm-
contrary, renal vein thrombosis in the same study was rare bin generated initially activates platelets, factor V, factor
and not significantly different between nephrotic and VIII, and factor XI, leading to amplification of thrombin.
nonnephrotic patients.
Whereas procoagulant reactions are ongoing, termination
Renal transplantation and venous thromboembolism of the clotting cascade occurs simultaneously by acti-
To date, few studies have evaluated the risk of VTE in vation of endogenous anticoagulants, including antith-
patients with renal transplant. Using the US Renal Data rombin, the protein C and S pathway, and tissue factor
System database, consisting of 28 924 renal transplant pathway inhibitor. This phase is critical in modulating the
patients between 1996 and 2000, Abbott and colleagues extent of clot formation. If left unchecked, hemostatic
[20] reported that VTE was common in this population, response could lead to thrombosis and vascular damage.
with an incidence per 1000 persons of 2.9 episodes at 1 year
and 4.3 episodes at 2 years. In a multivariable adjusted Following hemostasis, the organized clot must be
model, those with eGFR less than 30 ml/min/1.37 m2 after removed. This is accomplished by conversion of plasmi-
transplant had a two-fold higher risk of VTE than those nogen to plasmin. Plasmin can cleave polymerized fibrin,
whose eGFR was higher [20]. In another study of 484 fibrinogen, and a variety of plasma proteins and clotting
renal transplant patients 9% developed a VTE at a median factors, thereby removing organized clots.
follow-up of 17 months [21]. Patients were screened for
VTE and 40% of cases were asymptomatic. This study Activation of procoagulation
also noted a high incidence of recurrent VTE after anti- To understand mechanisms that might explain an
coagulation was discontinued. Compared to age and sex- increased risk of VTE in CKD, several epidemiologic
matched controls with normal renal function who had a first studies have compared the levels of procoagulant markers
VTE, renal transplant patients who discontinued anti- in patients with and without kidney disease. In general,
coagulation therapy had a 10-fold higher risk of recurrent patients with ESRD and predialysis renal failure, nephro-
VTE, highlighting the importance of careful consideration tic syndrome, and even mild CKD have elevated levels
of treatment strategies in this population, and the need for of D-dimer, C-reactive protein (CRP), fibrinogen, factor
further study. VII, and factor VIII and von Willebrand factor [22,23,24].
It is presumed that the elevated levels are due to
increased synthesis out of proportion to urinary losses.
Mechanisms linking chronic kidney disease Lower levels of factors IX, XI, and XII demonstrated in
and venous thromboembolism ESRD and nephrotic syndrome were believed to be due
Although exact mechanisms are unclear, it is believed to increased urinary loss. The exact mechanisms on how
that CKD patients have underlying hemostatic derange- these changes in proteins mediate a VTE risk are unclear.
ments predisposing to VTE. Much of the work has To date, factors VII, VIII [25,26], IX [27], and XI [28],
focused on activation of procoagulant markers, decreased fibrinogen [29], and D-dimer [30] have been correlated
endogenous anticoagulants, enhanced platelet activation with VTE risk in the general population. Studies of
and aggregation, and decreased activity of the fibrinolytic procoagulant factors and VTE risk specific to the type
system. of renal disease are not available.

Overview of hemostasis Decreased endogenous anticoagulants

A review of normal hemostasis is essential in order to Antithrombin, protein C, and protein S are anticoagulant
understand the hemostatic derangement in the CKD proteins and inherited deficiency states increase VTE
population. Following vascular injury, a series of dynamic risk. The evidence that these endogenous anticoagulants
and interwoven steps occurs leading to hemostasis. play a role in increasing VTE risk in the CKD population
Central to hemostasis is the generation of thrombin, is inconclusive. Studies have consistently reported
which is critical in converting fibrinogen to insoluble lower levels of antithrombin in patients with nephrotic

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 Kidney disease and venous thromboembolism Wattanakit and Cushman 411

syndrome [31]. This is presumably due to increased activation and aggregation, and decreased fibrinolytic
urinary loss of antithrombin out of proportion to syn- activity. The pathogenesis likely differs depending on
thesis. Clinical correlation of antithrombin deficiency and the cause of the kidney disease (nephrotic syndrome,
VTE risk in nephrotic syndrome was demonstrated in nonnephrotic and ESRD). Environmental factors and
some studies [17,32], but not others [33]. On the con- comorbid condition are certain to play a modulating role,
trary, a few small studies showed that levels of protein C although few specific data are available. Future prospec-
and protein S were increased in patients with nephrotic tive studies should evaluate specific hemostatic abnorm-
syndrome compared to healthy adults, suggesting protec- alities and environmental risk factors across the spectrum
tion against VTE [34,35]. We are not aware of studies of CKD in relation to risk of VTE, and confirm an
relating levels of protein C or protein S to VTE risk in association of stage 1 CKD with risk of VTE. This would
CKD patients. allow study of application of risk stratification tools that
might be further studied in trials of preventive treatments
Enhanced platelet activation and aggregation in this special population.
Markers of platelet activation, such as circulating P-
selectin concentration, are increased in nephrotic syn-
drome patients [36,37]. With vascular injury, nearby
Acknowledgements
We acknowledge research collaborations with Drs Aaron Folsom and
intact endothelial cells secrete arachidonic acid. Arachi- Michael Shlipak in the study of VTE and hemostatic changes in
donic acid, normally bound to albumin, is converted to kidney disease.
thromboxane A2 by the enzyme cyclooxygenase-1 in
platelets. Patients with nephrotic syndrome usually have Funding: National Institutes of Health, National Heart, Lung and Blood
Institute: N01 HC 95166, HL59367, HL083926, N01-HC-85086.
hypoalbuminemia, resulting in increased availability of
thromboxane A2 [38,39]. Platelet aggregation then
ensues because thromboxane A2 is a potent platelet
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