Accepted Manuscript

Acute kidney injury and risk of deep vein thrombosis and

pulmonary embolism in Taiwan: A nationwide retrospective
cohort study

Tsung-Hang Kuo, Hsin-Yung Li, Sheng-Hsiang Lin

PII: S0049-3848(17)30004-X
DOI: doi: 10.1016/j.thromres.2017.01.004
Reference: TR 6557
To appear in: Thrombosis Research
Received date: 1 June 2016
Revised date: 4 December 2016
Accepted date: 5 January 2017

Please cite this article as: Tsung-Hang Kuo, Hsin-Yung Li, Sheng-Hsiang Lin , Acute
kidney injury and risk of deep vein thrombosis and pulmonary embolism in Taiwan:
A nationwide retrospective cohort study. The address for the corresponding author was
captured as affiliation for all authors. Please check if appropriate. Tr(2017), doi: 10.1016/
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 ACCEPTED MANUSCRIPT

Acute kidney injury and risk of deep vein thrombosis and pulmonary

embolism in Taiwan: A nationwide retrospective cohort study

Tsung-Hang Kuo a,b, Hsin-Yung Li a, Sheng-Hsiang Lin a,c,d,*

a
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University,

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Tainan, Taiwan;
b
Department of emergency, National Cheng Kung University Hospital, Tainan,

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Taiwan;

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c
Biostatistics Consulting Center, National Cheng Kung University Hospital, Tainan,
Taiwan
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d
Department of Public Health, College of Medicine, National Cheng-Kung University,
Tainan, Taiwan
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*Corresponding author at: Institute of Clinical Medicine, College of Medicine,

National Cheng Kung University, 138, Shengli Road, Tainan, Taiwan. Tel:
+886-6-2353535 ext 5962; fax: +886 6 2758781.
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E-mail address: [email protected]. (S.-H. Lin).

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ABSTRACT

Introduction: Chronic kidney disease (CKD) increases risk for deep vein thrombosis

(DVT) and pulmonary embolism (PE). However, few studies have investigated the

relationship between acute kidney injury (AKI) and risk of DVT and PE. Therefore,

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we conducted a nationwide longitudinal cohort study to determine whether patients

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with AKI are associated with increased risk of developing DVT and PE.

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Methods: We included more than 30 years-old inpatients (n=4734) receiving the

diagnosis of AKI from 2000-2006 and their age-and sex-matched non-AKI inpatients
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using medical service in the same year (n=47340). Diagnosis of DVT and PE was
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recorded within 5-year after the AKI event or index use of medical service. The
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hazard ratios were analyzed using Cox regression model and adjustments were made
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for demographic factors, selected comorbidities and treatments. A time-dependent

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covariate survival analysis was performed for variations of some comorbidities,

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treatments and hospitalization. Competing risk regression (CRR) model was also used
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to adjust the risk for death. Propensity score matching was used to minimize potential

selection bias. We also performed sensitivity analysis to examine the effect of other

possible residual confounding factors.

Results: After adjusting for demographic characteristics, selected comorbidities and

treatment, AKI remained a predisposing factor with a 1.44-fold (95% CI, 1.04-2.01)
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and 1.49-fold (95% CI, 1.12-1.97) increase in patients who were at a risk for

developing DVT within 3 and 5 years. AKI also remained a significant predisposing

factor with a 2.66-fold (95% CI, 1.49–3.20) increase in patients who were at a risk for

developing PE within 3 years. However, there were no significant results for PE within

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5 years. The hazard ratios of time-dependent covariate survival analysis and CRR

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model showed the similar results.

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Conclusions: Risk of DVT and PE is higher in patients with AKI than in the general

population
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Keywords: acute kidney injury, cohort study, national health Insurance, venous
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thromboembolism, deep vein thrombosis, pulmonary embolism

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Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; DVT, deep
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vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism; NHI,

national health insurance; NHIRD, the national health insurance research database;
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ICD-9-CM, international classification of diseases, 9th revision, clinical modification;

EC, enrollee category; CRR, Competing risk regression; ESRD, end stage renal

disease; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; OR, odds

ratio; CI, confidence interval.

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1. Introduction

Up to 10% of patients admitted to hospitals are affected by acute kidney injury

(AKI), which has a significantly increased mortality risk [1-4]. The incidence of AKI

is increasing, and the mortality rate remains unacceptably high [5, 6]. In multiple

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cohort studies, AKI has been demonstrated to be an independent risk factor for

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mortality [7]. Although early hazards of AKI have been demonstrated, the long-term

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consequences of AKI in survivors remain to be understood.

Venous thromboembolism (VTE) is a growing public health concern worldwide

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[8]. In the majority of cases, VTE manifests as deep vein thrombosis (DVT), which is
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characterized by the formation of blood clots in the deep veins. Thrombi

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predominantly occur in the legs and are associated with a short-term mortality rate of
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5%–10% [9-13]. Blood clots that travel to the lung result in pulmonary embolism
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(PE), a serious condition that leads to the blockage of the major pulmonary artery. PE
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is potentially life threatening, with a mortality rate of approximately 40% [13].

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The pathogenesis of venous thrombosis is multifactorial, and the presence of

multiple risk factors is often required to cause a clinical event [14]. However, few

studies have investigated the association between DVT and renal function [15-19]. In

a large longitudinal community-based study, mildly decreased kidney function and

CKD were found to be moderate independent risks for VTE [20]. It was also found
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that patients with CKD and ESRD were more likely to develop PE than people with

normal kidney function [21]. However, the associations among AKI, DVT, and PE

have not been well established. Neither AKI nor ESRD, which were independent risk

factors for VTE in critically ill patients, was found in a cohort study, but the study

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was conducted at one center in a small patient sample and only focused on critical

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patients. In addition, the follow-up time of the study was too short [22]. Therefore, we

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conducted a nationwide retrospective study to investigate whether AKI had similar

long-term effects as CKD on the risks for DVT and PE.

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2. Patients and methods

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2.1. Setting
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We retrospectively enrolled patients who suffered from AKI within a defined

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period as the AKI study cohort (AKI group) in this longitudinal observational study.
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As a comparison cohort (non-AKI group), we enrolled people from the same

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population who did not suffer from AKI. Both groups were followed up to assess

outcomes, including DVT and PE.

2.2 Database

The National Health Insurance (NHI) of Taiwan, initiated in March 1995, is a

universal health insurance plan that covers >99% of the nation’s population
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(approximately 23.74 million people). The National Health Insurance Research

Database (NHIRD) of Taiwan is derived from the payment system of the NHI

administration, which is managed by the National Health Research Institute. The data

used in this study were obtained from the Longitudinal Health Insurance Database

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2000, which includes 1 million insured people who were randomly selected from the

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entire population that is covered by NHI. This database covered NHI data from 1996

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to 2011. Statistically, as reported by NHIRD, there were no significant differences in

age, sex, or healthcare costs between the sample group and all enrollees. International
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Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) has been
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adopted for the study. Previous studies have described ICD-9-CM diagnoses in

NHIRD as highly accurate and valid [23-25]. The patients’ privacy was protected by
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encrypting all personal identification numbers before releasing the data files to the
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public for research purposes.

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2.3. Study Sample

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This retrospective cohort study comprised a study (AKI group) and comparison

groups (non-AKI group). Diagnosis codes were assigned by ICD-9-CM. Patients who

received a diagnosis of AKI (ICD-9-CM Code 584.9) between January 2000 and

December 2006 were defined as the AKI group. In Taiwan, patients were given a

diagnosis of AKI when they had a reduction in kidney function (an absolute increase
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in serum creatinine of 0.3 mg/dL or more within 48 hours or a percentage increase in

serum creatinine of 50% or more) according to Acute Kidney Injury Network Criteria

[26]. During the enrollment of patients with AKI, we excluded patients who were

aged ≤ 30 years to focus on a population at a higher risk and to assess the risk of

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developing DVT following a diagnosis of AKI. Individuals with a history of DVT

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(ICD-9-CM code 453.8) and PE (ICD-9-CM code 415.19) before enrollment were

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also excluded from the study. Finally, 4856 patients with diagnosed AKI were

included in this cohort study. AKI patients (n=4856) included 4734 inpatients and 122
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outpatients. For proper comparison, we deleted the outpatients and used the inpatients
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as our study sample for AKI group. Each individual was followed for 5 years.
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The comparison group was selected from the remaining inpatients in the database.
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First, we excluded patients aged ≤ 30 years, along with those having pre-existing
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DVT and PE before enrollment. Following this, we selected subjects from the
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remaining inpatients by frequency matching to ensure an equal distribution of

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variables between the groups. We selected patients with respect to the following strata:

sex, age (two categories, aged 30–59 and 60 years), and the year when they started

receiving medical service at a ratio of 1:10 for each patient with AKI.

2.4 Matching

To ensure comparability in terms of sex and age between the groups, we used
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frequency matching for age and sex using medical service in the same year. Besides,

because AKI and non-AKI patients tend to have different baseline characteristics and

clinical comorbidities, we also used propensity score matching to match the

differences between two groups. For each patient, an estimated propensity score was

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calculated using logistic regression to estimate the differences in baseline

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characteristics and comorbidities between two groups. The covariates in the

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propensity score model included age, sex, geographic region, urbanization, enrollee

category, income, hypertension, hyperlipidemia, diabetes mellitus, ischemic heart

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disease, atrial fibrillation, congestive heart failure, chronic obstructive pulmonary
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disease, CKD, cirrhosis, malignancy, cerebral vascular disease, fracture of lower limb,
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sepsis, hydronephrosis, pregnancy, obesity, central line insertion, treatment with

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plaster casts and anitcoagulants including heparin, warfarin and Clexane.

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2.5. Potential Confounders

Using the enrollee category (EC) as a proxy measure of socioeconomic status, we

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classified people into four subgroups: EC 1 (e.g., full-time or regularly paid personnel

in public schools and governmental agencies as well as civil servants), EC 2

(employees of privately owned enterprises), EC 3 (other employees or paid personnel,

members of farmers’ or fishermen’s associations, and self-employed people), and EC

4 (members of low-income families, substitute service draftees, and veterans). The EC

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1 subgroup was the most expensive with respect to payroll-related costs of health

insurance, followed by EC 2, EC 3, and EC 4 (least expensive), on an average.

Moreover, to evaluate the association between urbanization level and DVT, we

classified townships into three categories urban, suburban, and rural areas on the basis

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of the following five indices: population density, percentages of agricultural workers

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among residents, number of physicians per 100,000 people, percentages of residents

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with college or higher education, and percentage of residents aged ≥65 years. In

general, residents in urban and suburban areas enjoy a higher socioeconomic status.
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For all enrollees in both groups, we identified potential confounding risk factors for
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DVT and PE, such as hypertension (ICD-9-CM Codes 401-405), hyperlipidemia

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(ICD-9-CM Codes 272.0, 272.1, 272,2 and 272.4), diabetes mellitus (ICD-9-CM
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Code 250), ischemic heart disease (ICD-9-CM Codes 410-414), atrial

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fibrillation(ICD-9-CM Code 427.31), congestive heart failure (ICD-9-CM Code 428),

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chronic obstructive pulmonary disease (ICD-9-CM Code 496), CKD (ICD-9-CM

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Code 585), cirrhosis (ICD-9-CM Code 507), malignancy (ICD-9-CM Codes 140-208),

cerebral vascular disease (ICD-9-CM Codes 430-438), fracture of lower limb

(ICD-9-CM Codes 820-829), sepsis (ICD-9-CM Codes 995.91), hydronephrosis

(ICD-9-CM Codes 591), pregnancy (ICD-9-CM Codes 650-659), obesity (ICD-9-CM

Codes 278.00), central line insertion, treatment with plaster casts, and anitcoagulants
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including heparin, warfarin and Clexane.

2.6. Main Outcome Measures

The endpoints of this study were defined as DVT (ICD-9-CM code 453.8) and PE

(ICD-9-CM code 415.19). DVT and PE were defined on the basis of one patient

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record or at least two NHI ambulatory claim records.

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2.7. Statistical Analysis

The baseline sociodemographic and clinical characteristics of the AKI and

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non-AKI groups were compared using the chi-square test. We further calculated both
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the crude and adjusted hazard ratio (HR) with 95% confidence interval (95% CI) of

DVT and PE after AKI during the 3- and 5-year follow-up periods using the Cox
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regression analysis, and adjustments were made for age, sex, geographic locations,
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enrollee categories, income, urbanization level, selected comorbidities and treatment.

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A time-dependent covariate survival analysis was performed for variations of

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hospitalization, atrial fibrillation, sepsis, hydronephrosis, central line insertion,

treatment with plaster casts, and anitcoagulants during the follow-up period. A

competing risk regression (CRR) model was also used to adjust the risk for death

because death may be a competing risk for DVT and PE (R package “cmprsk”). To

compare the relative risk of DVT and PE between two groups, propensity score
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matching was used to minimize potential selection bias introduced. We used the SAS

9.3 statistical software package (SAS Institute, Cary, NC) to conduct all statistical

analyses except the CRR model.

2.8 Validation

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We validated the ICD-9-CM codes for the identification of first diagnosis with AKI

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by analyzing the medical records (charts) of 423 patients in National Cheng Kung

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University Hospital, a 2000-bed teaching hospital in Taiwan. We randomly selected
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50 patients who had AKI ICD-9-CM codes 584.9 from the inpatient and outpatient
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claims database between January 2013 and December 2015 in National Cheng Kung

University Hospital. The contents of this database were similar to those of the
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NHIRD. Clinical diagnosis of AKI was determined according to the Acute Kidney
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Injury Network criteria[26]. Positive predictive values of AKI were estimated. The
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results showed a positive predictive value of 100% (95% CI, 95.4-100%) for AKI.
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2.9 Sensitivity Analysis

To examine the effect of other possible residual confounding factors on the results

observed, we used sensitivity analyses or “obsSens” according to the R package. In

this analysis, we added another hypothetical unmeasured confounding factor with a

risk effect that was similar to that of our disease. Then, we evaluated how this added
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factor confounded our observation of differences in the prevalence of DVT and PE in

the AKI and non-AKI groups.

3. Results

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Among 4734 people (including beneficiaries) who were aged ≥30 years and who

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used health services attributable to AKI from January 2000 to December 2006, 2912

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patients (60.05%) were males (Table 1). We randomly selected 47340 patients as

subjects in the non-AKI group using the abovementioned matching criteria. The
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majority of patients with AKI were aged >60 years. The prevalence of hypertension,
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diabetes, and ischemic heart diseases was significantly higher in the AKI group than
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in the non-AKI group.

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Table 2 summarizes the data of 46 (0.97%) and 63 (1.33%) patients with AKI who
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were also diagnosed as having DVT in the 3- and 5-year follow-up periods. In the
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non-AKI group, 255 (0.54%) and 369 (0.78%) individuals without antecedent AKI
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had developed DVT at the 3- and 5-year follow-ups, respectively. After adjusting for

age, geographic location, urbanization level, EC, select comorbidities and treatment,

AKI remained a predisposing factor with a 1.44-fold (95% CI, 1.04-2.01) and

1.49-fold (95% CI, 1.12-1.97) increase in patients who were at a risk for developing

DVT within 3 and 5 years. After time-dependent survival covariate analysis, an

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increased risk for DVT within 3 years and 5 years were still observed in AKI group

(HR=1.56, 95% CI, 1.11-2.17 and HR=1.53, 95% CI, 1.15-2.03). Furthermore, if

death was considered as a competing risk factor, analysis of the CRR model also

revealed the similar results (HR=1.44, 95% CI, 1.00-2.08 and HR=1.49, 95% CI,

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1.10-2.00).

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Table 3 also shows that AKI remained a significant predisposing factor with a

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2.66-fold (95% CI, 1.50–4.76) increase in patients who were at a risk for developing

PE within 3 years. After time-dependent covariate survival analysis, an increased risk

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for PE within 3 years was still observed in AKI group (HR=2.30, 95% CI, 1.28-4.15).
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Analysis of the CRR model still demonstrate a significant difference when death was
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considered to be a competing risk factor for PE within 3 years. The table 3 shows no
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significant results for PE within 5 years.

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Tables 4, 5, S1, and S2 show the analysis results with respect to age. The final
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analysis included all patients who were classified into two age groups: group 1 (aged
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30–59 years) and group 2 (aged ≥60 years). Table 4 and table 5 show that the risk of

DVT and PE did not increase with age. Table 6 shows the effect of the number of

admission (i.e., admission frequency) on developing DVT and PE. An increased

number of admission for AKI was associated with an increased risk for PE, but was

not associated with an increased risk for DVT.

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To investigate the effect of other potential residual confounding factors on the

observed results, we also used sensitivity analysis to estimate trends in the AKI group

HR for DVT and PE using a multivariable-adjusted Cox regression model with the

addition of a residual confounding factor (Figures S1–S4). For example, when all

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patients non-AKI had the add-on residual confounder (prevalence of the unmeasured

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confounder is 1.0) and none of the patients in the AKI group had this residual

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confounder (prevalence of the unmeasured confounder is 0.0), the effect of AKI

would be a risk for DVT (HR =1.44, the top line in Figure S1). Figure S1 shows that
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in most situations, a higher risk for DVT occurrence was observed in patients with
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AKI than in patients without AKI, even if an unmeasured confounder existed.

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Table S3 presents the demographic characteristics, clinical comorbidities and

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treatment for two groups in propensity score-matched model. Table S4 and table S5
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also show AKI remained a predisposing factor in patients who were at a risk for
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developing DVT and PE within 3 years and 5 years (HR=1.65, 95% CI, 1.11-2.45 and
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HR=1.71, 95% CI, 1.21-2.40 for DVT within 3 years and 5 years, HR=2.41, 95% CI,

1.15-5.04 and HR=2.35, 95% CI, 1.18-4.68 for PE within 3 years and 5 years).

Table S6 and S7 show that crude and adjusted HRs of DVT and PE among the

cohort of sampled patients during 3-month follow-up period. It also shows AKI

remained a predisposing factor in patients who were at a risk for developing DVT and
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PE within 3 months (HR=2.75, 95% CI, 1.52-4.95 and HR=10.8, 95% CI, 3.87-30.3).

Table S8 and S9 also show the similar results in propensity score-matched model

(HR=1.89, 95% CI, 0.96-3.70 and HR=2.96, 95% CI, 1.05-8.36).

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4. Discussion

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To the best of our knowledge, this is the first cohort study to have used nationwide,

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population-based, epidemiological data to determine whether AKI is an independent

risk factor for DVT and PE. In this study, we demonstrated that the risks for DVT and
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PE were higher in the AKI group than in the non-AKI group. Our results showed that
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AKI was independently associated with increased incidences of DVT and PE.
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The results of the study have not completely understood the mechanism by
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which AKI may influence the incidence of VTE, although the etiology is believed to
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be multifactorial. The increased risk for VTE with AKI may be due to endothelial
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involvement and vascular injury [27] and the related changes found in procoagulant
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proteins, such as increased levels of fibrinogen, factor VII, factor VIII, von

Willebrand factor, and plasminogen activator inhibitor-1 or increased levels of

D-dimers [28-30]. On the other hand, an increased procoagulant state in patients with

CKD, such as prothrombin fragment 1 + 2, thrombin-antithrombin complex and

plasmin-antiplasmin complex, was also confirmed by functional coagulation assays.

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[28, 31, 32]. Recent epidemiological and mechanistic studies suggest that AKI and

CKD are closely interconnected [33], so some of CKD’s physiologic changes are

expected to affect AKI patients.

In our study, we can find the risks for DVT and PE in a 3-month follow-up were

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higher than those in a 3-year follow-up period and the risks in 3-year follow-up period

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were higher than those in a 5-year follow-up period. The severity of AKI or of the

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underlying condition leading to AKI may explain the 3-10 fold increased risk of

developing VTE in the 3 months following admission. The risk of VTE decrease with
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time after treatment. This finding also indicated that good healthcare for AKI may
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reduce the incidences of VTE. On the other hand, previous studies have demonstrated
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that the incidence of DVT was higher than that of PE, and the incidence rates of VTE
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exponentially increased with age [10, 12].

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The long-term prognosis after AKI varies depending on the cause and clinical
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setting, but it may also be partially explained by the underlying pre-AKI and
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post-AKI renal functions rather than the AKI episode alone [34]. However, an

increasing number of epidemiological studies with both adequate statistical power and

length of follow-up [35-39] have revealed that survivors of AKI exhibited a

persistently increased risk for progressive CKD, proteinuria, and an excess risk for

cardiovascular mortality [39]. This finding complements the results in laboratory

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animals that demonstrate that renal injury produced a senescence-associated

profibrotic secretory phenotype and a subsequent inflammatory milieu, which

promoted gradual accumulation of renal fibrosis, vascular rarefaction, and CKD

[40-42]. Therefore, the greater the number of episodes of AKI, the more likely it is

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that a patient will experience even more episodes of AKI and the greater the risk for

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CKD. Our study revealed that the higher the number of admissions for AKI, the

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higher the risk for PE. However, it is unclear whether other reasons for admission

affect the risk for PE.

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The strength of our study is that we enrolled large numbers of patients with AKI
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and non-AKI from a nationwide database in Taiwan. The retrospective cohort design
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and large sample size provided considerable statistical power for detecting the
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increased risks for DVT and PE after AKI. Additionally, in our study, we adjusted for
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adequate VTE risk factors, including comorbid clinical illnesses, treatments and
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hospitalization by the time-dependent covariate survival analysis and used the CRR
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model to adjust the risk for death.

Our study had several limitations. First, the diagnoses of AKI, DVT, PE and

comorbidities relied on administrative claims data, which could have been

misclassified. However, the Bureau of NHI regularly reviews the charts and assesses

the accuracy of claims files. Incorrect coding of diseases will result in no

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reimbursement. Previous database studies have demonstrated that the quality of the

NHIRD data is acceptable. [43-45]. Second, we used inpatients of AKI and non-AKI

as the study subjects because only a very small proportion of AKI patients was

outpatients. Thus, the variation in the risk of VTE for AKI outpatients could not be

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determined. Third, NHIRD does not provide detailed information on potentially

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confounding factors such as smoking, body mass index (BMI) and physical activity

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[46]. We adjusted for obesity into the analysis instead of BMI. However, not all

over-weight patients would have a diagnosis of obesity in NHIRD. Therefore, we

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could not completely exclude interference of the risk factors. We used sensitivity
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analyses to examine the effect of other possible residual confounding factors [47].
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In conclusion, the results from our nationwide population-based cohort study that
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examined approximately 5000 inpatients with AKI revealed that inpatients with AKI
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had an approximate 1.44-fold increased risk for developing DVT and a 2.66-fold
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increased risk for developing PE compared with those without AKI within 3 years.
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The risk is particular strong within 3 months after AKI and decrease with time. These

findings highlight the importance of early treatment for AKI. Whether anticoagulant

prophylaxis within 3 months after AKI for preventing occurrence of VTE is needed

further study. In addition, the mechanism underlying the association and a potential

link to VTE warrants further exploration.

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Funding

This study was supported by the research grant from the National Cheng Kung

University Hospital (NCKUH-10505033).

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Conflict of interest statement

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No conflicts of interest to declare

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Acknowledgements
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We are grateful to Mr. Wei-Ming Wang for providing the statistical consulting

services from the Biostatistics Consulting Center, National Cheng Kung University
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Hospital.
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Table 1. Demographic information and comorbidities for the cohort of sampled patients during
2000-2006
Patients with AKI Comparison group
(N=4734) (N=47340)
Variables N (%) N (%) P value
Sex
Male 2843 (60.05) 28430 (60.05) 1.0000
Age, years

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30-59 1177 (24.86) 11770 (24.86) 1.0000
60 3557 (75.14) 35570 (75.14)
Geographic region 0.0351

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North 1939 (40.96) 19580 (41.36)

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Central 1147 (24.23) 12162 (25.69)
South 1431 (30.23) 13619 (28.77)
East and offshore 217 (4.58) 1979 (4.18)
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Urbanization levela 0.0007
1 (most urbanization) 1212 (25.60) 12899 (27.25)
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2 1237 (26.13) 11267 (23.80)

3 (least urbanization) 2285 (48.27) 23174 (48.95)
Enrollee categoryb <0.0001
1 539 (11.39) 5179 (10.94)
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2 1218 (25.73) 13418 (28.34)

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3 2226 (47.02) 22278 (47.06)

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4 751 (15.86) 6465 (13.66)

Monthly income <0.0001
NT  $15,840 2080 (43.94) 17745 (37.48)
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NT $15,841-25,000 2215 (46.79) 23014 (48.61)

NT  $25,001 439 (9.27) 681 (13.90)
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Comorbidities
Hypertension 2987 (63.10) 23390 (49.41) <0.0001
Hyperlipidemia 744 (15.72) 8092 (17.09) 0.0161
Diabetes 1730 (36.54) 12136 (25.64) <0.0001
Ischemic heart disease 1540 (32.53) 11705 (24.73) <0.0001
Atrial fibrillation 316 (6.68) 1911 (4.04) <0.0001
Cognitive heart failure 1167 (24.65) 3820 (8.07) <0.0001
COPD 798 (16.86) 4766 (10.07) <0.0001
Chronic kidney disease 1159 (24.48) 2168 (4.58) <0.0001
Cirrhosis 1032 (21.80) 852 (1.80) <0.0001
 ACCEPTED MANUSCRIPT

Malignancy 1107 (23.38) 7114 (15.03) <0.0001

Cerebral vascular disease 1389 (29.34) 10313 (21.78) <0.0001
Fracture of lower limb 258 (5.45) 3189 (6.74) 0.0007
Sepsis 1436 (30.33) 2468 (5.21) <0.0001
Hydronephrosis 266 (5.62) 1280 (2.70) <0.0001
Pregnancy 4 (0.08) 718 (1.52) <0.0001
Obesity 16 (0.34) 202 (0.43) 0.3674
Treatment

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Central line insertion 2703 (57.10) 6274 (13.25) <0.0001
Treatment with plaster 156 (3.30) 2816 (5.95) <0.0001
casts

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Anitcoagulants 1308 (27.63) 5885 (12.43) <0.0001

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AKI=Acute kidney injury; COPD= Chronic obstructive pulmonary disease
a
There is one missing value in the geographic region.
b
There are twenty three missing values in the enrollee category.
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Table 2. Crude, adjusted and time-dependent HRs of deep vein thrombosis among the
cohort of sampled patients during the follow-up years
Total Male Female
Comparis Patient Comparis Patient Comparis Patient
on with on with on with
group AKI group AKI group AKI
N=47340 N=4734 N=28430 N=2843 N=18910 N=1891
N (%) N (%) N (%) N (%) N (%) N (%)

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3-year period
Yes 255 46 134 20 121 26

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(0.54) (0.97) (0.47) (0.70) (0.64) (1.37)
b
Crude HR 1 1.80 1 1.49 1 2.14b

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(95% CI) (1.31-2.4 (0.93-2.3 (1.40-3.2
6) 8) 7)
a
Adjusted HR 1 1.44 1 1.22 1 1.69a
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(95% CI) (1.04-2.0 (0.75-2.0 (1.07-2.6
1) 0) 5)
a a
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Time-depend 1 1.56 1 1.38 1 1.72

ent HR (1.11-2.1 (0.84-2.2 (1.09-2.7
7) 7) 2)
a a
CRR model 1 1.44 1 1.22 1 1.80
D

(95% CI) (1.00-2.0 (0.71-2.0 (1.08-2.9

E

8) 9) 9)
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5-year period
Yes 369 63 195 33 (1.16) 174 30 (1.59)
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(0.78) (1.33) (0.69) (0.92)

c b
Crude HR 1 1.70 1 1.69 1 1.72b
(95% CI) (1.30-2.2 (1.17-2.0 (1.16-2.5
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2) 6) 3)
a a
Adjusted HR 1 1.49 1 1.49 1 1.47
(95% CI) (1.12-1.9 (1.01-2.1 (0.98-2.2
7) 9) 2)
a a
Time-depend 1 1.53 1 1.67 1 1.38
ent HR (1.15-2.0 (1.14-2.4 (0.91-2.0
3) 7) 8)
a
CRR model 1 1.49 1 1.49 1 1.47
(95% CI) (1.10-2.0 (0.99-2.2 (0.95-2.2
0) 4) 9)
27
 ACCEPTED MANUSCRIPT

AKI=acute kidney injury; HR= hazard ratio; CI= confidence interval; CRR= fine and
gray competing-risk regression
a
P<0.05; bP<0.001; cP<0.0001

Table 3. Crude, adjusted and time-dependent HRs of pulmonary embolism among the
cohort of sampled patients during the follow-up years
Total Male Female

PT
Comparis Patient Comparis Patient Comparis Patient
on with on with on with
group AKI group AKI group AKI

RI
N=47340 N=4734 N=28430 N=2843 N=18910 N=1891

SC
N (%) N (%) N (%) N (%) N (%) N (%)
3-year period
Yes 60 (0.13) 16 31 (0.11) 10 29 6
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(0.34) (0.35) (0.15) (0.32)
b b
Crude HR 1 2.67 1 3.22 1 2.07
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(95% CI) (1.54-4.6 (1.58-6.5 (0.86-4.9

3) 8) 8)
b a
Adjusted HR 1 2.66 1 2.94 1 2.33
(95% CI) (1.50-4.7 (1.38-6.2 (0.94-5.7
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6) 7) 5)
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a a
Time-depend 1 2.30 1 2.93 1 1.81
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ent HR (1.28-4.1 (1.36-6.3 (0.72-4.6

5) 4) 0)
a b
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CRR model 1 2.67 1 2.94 1 2.33

(95% CI) (1.48-4.7 (1.41-6.1 (0.87-6.1
9) 5) 9)
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5-year period
Yes 113 18 59 (0.21) 11 (0.39) 54 (0.29) 7 (0.37)
(0.24) (0.38)
Crude HR 1 1.59 1 1.86 1 1.30
(95% CI) (0.97-2.6 (0.98-3.5 (0.59-2.8
2) 5) 5)
Adjusted HR 1 1.62 1 1.78 1 1.40
(95% CI) (0.97-2.7 (0.91-3.5 (0.63-3.1
2) 1) 5)
Time-depend 1 1.33 1 1.71 1 0.99
28
 ACCEPTED MANUSCRIPT

ent HR (0.80-2.2 (0.88-3.3 (0.44-2.2

3) 5) 3)
CRR model 1 1.62 1 1.78 1 1.40
(95% CI) (0.96-2.7 (0.92-3.4 (0.59-3.3
3) 5) 3)
AKI=acute kidney injury; HR= hazard ratio; CI= confidence interval; CRR= fine and
gray competing-risk regression
a
P<0.05; bP<0.001

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Table 4. Crude, adjusted and time-dependent HRs of deep vein thrombosis among the

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cohort of sampled patients during the 5-year follow-up under stratification by sex and

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age group
Total Male Female
Compari Patient Compari Patient Compari Patient
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son with son with son with
group AKI group AKI group AKI
Age, years N=47340 N=4734 N=28430 N=2843 N=18910 N=1891
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N (%) N (%) N (%) N (%) N (%) N (%)

30-59
Yes 36 (0.31) 12 29 (0.36) 8 7 (0.19) 4 (1.11)
D

(1.02) (0.98)
E

b
Crude HR 1 3.33 1 2.76a 1 5.71a
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(95%CI) (1.73-6. (1.26-6. (1.67-19

39) 03) .5)
Adjusted HR 1 2.54a 1 2.18 1 3.08
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(95% CI) (1.23-5. (0.92-5. (0.75-12

28) 21) .7)
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a
Time-depen 1 2.34 1 2.19 1 2.57
dent HR (1.11-4.9 (0.92-5. (0.44-14
2) 24) .9)
CRR model 1 2.54a 1 2.18 1 3.08
(95% CI) (1.20-5. (0.89-5. (0.60-16
42) 37) .0)
60
Yes 333 (0.94) 51 166 (0.82) 25 167 (1.09) 26
(1.43) (1.23) (1.70)
Crude HR 1 1.52a 1 1.50 1 1.55a

29
 ACCEPTED MANUSCRIPT

(95% CI) (1.14-2. (0.98-2. (1.02-2.

05) 28) 34)
Adjusted HR 1 1.46a 1 2.18 1 1.50
(95% CI) (1.07-1. (0.92-5. (0.98-2.
99) 21) 32)
a a
Time-depen 1 1.47 1 1.56 1 1.39
dent HR (1.08-2. (1.00-2. (0.90-2.
01) 43) 15)
1.46a

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CRR model 1 1 1.42 1 1.50
(95% CI) (1.05-2. (0.89-2. (0.95-2.
03) 27) 39)

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AKI=acute kidney injury; HR= hazard ratio; CI= confidence interval; CRR= fine and

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gray competing-risk regression
a
P<0.05; bP<0.001 NU
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E D
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 ACCEPTED MANUSCRIPT

Table 5. Crude, adjusted and time-dependent HRs of pulmonary embolism among the
cohort of sampled patients during the 5-year follow-up under stratification by sex and
age group
Total Male Female
Compari Patient Compari Patient Compari Patient
son with son with son with
group AKI group AKI group AKI
Age, years N=47340 N=4734 N=28430 N=2843 N=18910 N=1891

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N (%) N (%) N (%) N (%) N (%) N (%)
30-59
Yes 15 (0.13) 6 (0.51) 11 (0.13) 5 (0.61) 4 (0.11) 1 (0.28)

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a a
Crude HR 1 4.00 1 4.54 1 2.50

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(95%CI) (1.55-10 (1.58-13 (0.28-22
.3) .1) .4)
a
Adjusted HR 1 2.88 1 3.06 1 2.82
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(95% CI) (1.03-8. (0.97-9. (0.30-26
06) 68) .8)
a a
Time-depen 1 3.21 1 4.09 1 1.73
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dent HR (1.15-8. (1.32-12 (0.16-19

96) .7) .1)
CRR model 1 2.88 1 3.06 1 2.82
D

(95% CI) (0.94-8. (0.85-11. (0.29-27

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82) 0) .7)
60
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Yes 98 (0.28) 12 48 (0.24) 6 (0.30) 50 (0.33) 6 (0.39)

(0.34)
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Crude HR 1 1.22 1 1.25 1 1.20

(95% CI) (0.37-2. (0.53-2. (0.51-2.
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23) 92) 79)

Adjusted HR 1 1.40 1 1.37 1 1.45
(95% CI) (0.76-2. (0.57-3. (0.61-3.
60) 31) 44)
Time-depen 1 1.06 1 1.16 1 0.99
dent HR (0.57-1. (0.48-2. (0.41-2.
97) 79) 37)
CRR model 1 1.40 1 1.37 1 1.45
(95% CI) (0.75-2. (0.60-3. (0.57-3.
60) 15) 64)

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AKI=acute kidney injury; HR= hazard ratio; CI= confidence interval; CRR= fine and
gray competing-risk regression
a
P<0.05

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Table 6. Risk of deep vein thrombosis and pulmonary embolism in AKI patients by
numbers of admission comparing with non-AKI patients
Patient with AKI
N=4734
Admission=1 Admission>1
N=3803 N=931
Deep vein thrombosis 48 (1.26) 15 (1.61)
Crude HR (95%CI) 1 1.28 (0.72-2.29)

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Adjusted HR (95% CI) 1 1.22 (0.68-2.17)
Time-dependent HR 1 1.52 (0.83-2.77)

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CRR model (95% CI) 1 1.21 (0.68-2.17)

SC
Pulmonary embolism 10 (0.26) 8 (0.86)
a
Crude HR (95% CI) 1 3.27 (1.29-8.29)
Adjusted HR (95% CI) 1 3.57a (1.39-9.17)
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Time-dependent HR 1 4.60a (1.76-12.0)
CRR model (95% CI) 1 3.54a (1.43-8.76)
MA

AKI=acute kidney injury; HR= hazard ratio; CI= confidence interval; CRR= fine and
gray competing-risk regression
a
P<0.05
E D
PT
CE
AC

33
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Highlights

 This is the first cohort study to use population-based data to determine

whether AKI is an independent risk factor for DVT and PE.
 The risks for DVT and PE were higher in the AKI group than in the non-AKI
group.
 The findings emphasize the requirement for a multidisciplinary approach in
managing potential risk factors for VTE in patients with AKI.

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