Skip to main content
  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

  • Home
  • About this Journal
    • General Statistics
    • Editorial Board
    • Top Reasons to Publish in JAHA
    • Open Access Information
    • → Article Publication Charges
    • → Payment Options for Institutions and Funders
    • → Copyright and License
    • → Open Access Policy
    • → Open Access Terms and Conditions for Reuse of JAHA Content
    • Indexing
    • Advertising and Article Reprints
    • Frequently Asked Questions (FAQs)
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • AHA Guidelines and Statements
    • Basic Science for Clinicians
    • Contemporary Reviews
    • JAHA Conference Reads
  • Resources
    • Instructions for Authors
    • → Article Types
    • → General Preparation Instructions
    • → Research Guidelines
    • → How to Submit a Manuscript
    • Journal Policies
    • AHA Journals RSS Feeds
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
  • Facebook
  • Twitter

  • My alerts
  • Sign In
  • Join

  • Advanced search

Header Publisher Menu

  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

JAHA
Journal of the American Heart Association

  • My alerts
  • Sign In
  • Join

  • Facebook
  • Twitter
  • Home
  • About this Journal
    • General Statistics
    • Editorial Board
    • Top Reasons to Publish in JAHA
    • Open Access Information
    • → Article Publication Charges
    • → Payment Options for Institutions and Funders
    • → Copyright and License
    • → Open Access Policy
    • → Open Access Terms and Conditions for Reuse of JAHA Content
    • Indexing
    • Advertising and Article Reprints
    • Frequently Asked Questions (FAQs)
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • AHA Guidelines and Statements
    • Basic Science for Clinicians
    • Contemporary Reviews
    • JAHA Conference Reads
  • Resources
    • Instructions for Authors
    • → Article Types
    • → General Preparation Instructions
    • → Research Guidelines
    • → How to Submit a Manuscript
    • Journal Policies
    • AHA Journals RSS Feeds
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
Original Research

Two‐Year Changes in Proteinuria and the Risk of Stroke in the Chinese Population: A Prospective Cohort Study

Anxin Wang, Xiaoxue Liu, Zhaoping Su, Shuohua Chen, Nan Zhang, Shouling Wu, Yongjun Wang, Yilong Wang
Download PDF
https://doi.org/10.1161/JAHA.117.006271
Journal of the American Heart Association. 2017;6:e006271
Originally published June 30, 2017
Anxin Wang
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaDepartment of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, ChinaBeijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, ChinaChina National Clinical Research Center for Neurological Diseases, Beijing, ChinaCenter of Stroke, Beijing Institute for Brain Disorders, Beijing, ChinaBeijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiaoxue Liu
Department of Cardiology, Tangshan People's Hospital, North China University of Science and Technology, Tangshan, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zhaoping Su
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaChina National Clinical Research Center for Neurological Diseases, Beijing, ChinaCenter of Stroke, Beijing Institute for Brain Disorders, Beijing, ChinaBeijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shuohua Chen
Department of Cardiology, Kailuan Hospital, North China University of Science and Technology, Tangshan, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nan Zhang
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaChina National Clinical Research Center for Neurological Diseases, Beijing, ChinaCenter of Stroke, Beijing Institute for Brain Disorders, Beijing, ChinaBeijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shouling Wu
Department of Cardiology, Kailuan Hospital, North China University of Science and Technology, Tangshan, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yongjun Wang
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaChina National Clinical Research Center for Neurological Diseases, Beijing, ChinaCenter of Stroke, Beijing Institute for Brain Disorders, Beijing, ChinaBeijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yilong Wang
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaChina National Clinical Research Center for Neurological Diseases, Beijing, ChinaCenter of Stroke, Beijing Institute for Brain Disorders, Beijing, ChinaBeijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Tables
  • Info & Metrics
  • eLetters

Jump to

  • Article
    • Abstract
    • Introduction
    • Methods
    • Results
    • Discussion
    • Conclusions
    • Sources of Funding
    • Disclosures
    • References
  • Figures & Tables
  • Info & Metrics
  • eLetters
Loading

Abstract

Background Whether changes in proteinuria are associated with incident stroke in the general population is unclear. This study aimed to investigate the association between changes in proteinuria and incident stroke and its subtypes.

Methods and Results The current study included 60 940 Chinese participants (mean age, 50.69 years) who were free of stroke at the time of surveys (2006–2007 and 2008–2009). Participants were divided into 4 categories according to 2‐year changes in proteinuria: no proteinuria, remittent proteinuria, incident proteinuria, and persistent proteinuria. Cox proportional hazards models were used to calculate hazard ratios and their 95% CIs for stroke. After a median follow‐up period of 6.92 years, 1769 individuals developed stroke. After adjustment for confounding factors, incident proteinuria and persistent proteinuria were associated with increased risk of stroke (hazard ratio, 1.46 [95% CI, 1.26–1.68] and hazard ratio, 1.71 [95% CI, 1.42–2.06], respectively) compared with no proteinuria, which were higher than proteinuria detected at one single point (hazard ratio, 1.25; 95% CI, 1.09–1.43). The effect size for risk of stroke subtypes including ischemic stroke and hemorrhagic stroke was similar.

Conclusions Changes in proteinuria exposure, particularly persistent proteinuria, are more likely to reflect the risk of stroke, compared with proteinuria collected at a single time point in the general population.

  • change in proteinuria
  • cohort study
  • hemorrhage
  • ischemic stroke
  • proteinuria

Clinical Perspective

What Is New?

  • Changes in proteinuria are more likely to reflect the risk of stroke, compared with proteinuria collected at a single time point in the general population.

  • Participants with persistent proteinuria had the highest risk of developing stroke.

  • The effect size of changes in proteinuria for risks of stroke subtypes including ischemic stroke and hemorrhagic stroke was similar.

What Are the Clinical Implications?

  • Change in proteinuria is a practical and effective risk factor for incident stroke in a community population in China.

  • Clinicians and public health practitioners should be aware that early detection and control of proteinuria may decrease the risk of stroke.

Introduction

Proteinuria is a major indicator of chronic kidney disease (CKD).1 In 2012, a national survey reported that the prevalence of CKD was 10.8%, with ≈119.5 million adults 18 years or older diagnosed with CKD in China.2 CKD and cardiovascular disease are major public health problems worldwide and often share the same pathophysiological mechanisms, including high blood pressure (BP), smoking, high cholesterol levels, and diabetes mellitus.3 Furthermore, individuals with CKD have worse functional outcomes and an increased risk of cardiovascular disease and all‐cause mortality, as well as progression to kidney failure.4, 5, 6, 7

Several prospective studies have suggested that the presence of protein in urine is directly associated with stroke.8, 9, 10, 11, 12, 13, 14 The VALUE (Valsartan Antihypertensive Long‐Term Use Evaluation) trial9 and a Japanese trial8 showed that proteinuria at baseline was a strong risk factor for stroke or cardiovascular events. The CRIC (Chronic Renal Insufficiency Cohort) study suggested that proteinuria and albuminuria are better predictors of stroke risk than estimated glomerular filtration rate in patients with CKD.12 The China Stroke Primary Prevention Trial, which was conducted in 19 599 adults, also showed that baseline proteinuria measured by dipstick was an independent risk factor for first incident stroke and ischemic stroke.10 However, an inherent limitation of previous studies is the reliance on a single time point by which to assess kidney damage and events using baseline proteinuria. This damage may have occurred several decades before the event and is thus likely to yield biased estimates of an association. Moreover, there has been no consideration of how proteinuria varies within individuals over time and the subsequent effect that this would have on changes in proteinuria (none, remittent, incident, and persistent) and the future risk of stroke. Therefore, the current study aimed to examine the prospective association between 2‐year changes in proteinuria and incident stroke and subtypes in the Chinese population during a median of 6.92 years of follow‐up.

Methods

Study Population

The Kailuan study15 was a prospective cohort study that was conducted in the community of Kailuan in Tangshan. Tangshan is an industrial and modern city that is located in the central section of the circulating Bohai Sea Gulf region of China. From June 2006 to October 2007, a total of 101 510 participants (81 110 men and 20 400 women, aged 18–98 years) were recruited to participate in the Kailuan study. We excluded 26 149 participants who did not finish the 2008–2009 follow‐up, 2047 participants with previous stroke before the 2008–2009 survey, and 12 374 participants without complete dipstick proteinuria data. Therefore, 60 940 participants who were free of stroke were included in the final analysis. We considered the 2008–2009 survey as the starting point and December 31, 2015, as the end point of the follow‐up (Figure 1). The follow‐up evaluations included biennial measurement of laboratory parameters and recording of adverse events. The study was approved by the ethics committees of Kailuan General Hospital, following the guidelines outlined by the Helsinki Declaration. All participants agreed to take part in the study and provided written informed consent.

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Study flowchart.

Measurements of Proteinuria

At the baseline visit, dipstick urinalysis was performed on a fresh urine sample by physicians and visually read 1 minute after the dipstick test.16 The urine test strip results were based on a color scale that quantified proteinuria as absent, trace, 1+, 2+, or 3+ proteinuria. Proteinuria was defined as trace or more protein at baseline or dipstick urinalysis at a follow‐up visit. We also conducted sensitivity analyses in which proteinuria was defined as 1+ or more.

We defined 4 types of proteinuria according to changes in proteinuria from the baseline examination to the follow‐up collection period. No proteinuria was defined as an absence of proteinuria during the baseline collection period and the follow‐up collection period. Remittent proteinuria was defined as proteinuria that was present during the baseline collection period, but was not present at the follow‐up collection period. Incident proteinuria was defined as proteinuria that was not present at baseline, but was present at the follow‐up collection period. Persistent proteinuria was defined as proteinuria that was present during the baseline collection period and at the follow‐up collection period.

Assessment of Potential Covariates

The demographic and clinical characteristics, including age, sex, alcohol use, personal monthly income, education, and history of disease were collected via questionnaires. Family per‐member monthly income was categorized as < ¥600(US$ 77), from ¥600(US$ 77) to ¥799(US$ 102), or at least ¥800(US$ 103). Educational attainment was categorized as illiteracy or primary, middle school, and high school or above. Physical activity was classified as ≥4 times per week and ≥20 minutes at a time, <80 minutes per week, or none. Smoking status and drinking status were classified as never, former, or current according to self‐reported information.

Weight and height was measured and body mass index was calculated as weight (kg)/height (m)2. Systolic BP and diastolic BP were measured 3 times with the participants in the seated position using a mercury sphygmomanometer, and the average of 3 readings was used in the analyses. Blood samples were collected from the antecubital vein after an overnight fast. All blood samples were tested using a Hitachi 747 auto‐analyzer. Baseline estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.17 Hypertension was defined as any self‐reported hypertension or use of antihypertensive drug, or BP ≥140/90 mm Hg. Dyslipidemia was defined as any self‐reported history or use of lipid‐lowering drugs, or serum triglyceride ≥1.69 mmol/L, low‐density lipoprotein cholesterol ≥3.62 mmol/L, or high‐density lipoprotein cholesterol ≤1.04 mmol/L. Diabetes mellitus was defined as any self‐reported diabetes mellitus or use of glucose‐lowering drugs, or fasting blood glucose ≥7 mmol/L.

Follow‐Up and Stroke Assessment

The primary outcome was the first occurrence of stroke, either the first nonfatal stroke event, or stroke death without a preceding nonfatal event. Participants were followed up by face‐to‐face interviews at every 2‐year routine medical examination until December 31, 2015, or until the event of interest or death. For the participants without face‐to‐face follow‐ups, outcome information was directly obtained by checking death certificates from provincial vital statistics offices, discharge summaries, and medical records. The outcome information was further confirmed by brain computed tomography or magnetic resonance imaging in medical records according to World Health Organization criteria18 and classified into 3 types: cerebral infarction, cerebral hemorrhage, and subarachnoid hemorrhage. The follow‐up examinations were performed by trained physicians who were blinded to the baseline data. Considering the small sample size (n=44), we did not include the subarachnoid hemorrhage group in the subgroup analysis.

Statistical Analyses

Continuous variables are described as mean±SD and were compared by t test, Wilcoxon test, ANOVA, or the Kruskal–Wallis test. Categorical variables are described as percentages and were compared using chi‐square test. Univariate survival analysis was performed by the Kaplan–Meier method and log‐rank test. Person‐years were calculated from the date of when the 2008–2009 interview was conducted to the date when first stroke was detected, the date of death, or the date of participating in the last interview in this analysis, whichever came first.

Cox proportional hazards regression was used to estimate the risk of stroke by calculating hazard ratios (HRs) and 95% CIs. We fitted 3 multivariable Cox proportional hazards models. Model 1 was adjusted for age and sex in 2008. Model 2 was further adjusted for education level, drinking, smoking, physical activity, and body mass index in 2008. Model 3 was further adjusted for a history of hypertension, diabetes mellitus, or dyslipidemia; total cholesterol; triglycerides; low‐density lipoprotein; high‐density lipoprotein; systolic BP; diastolic BP; fasting blood glucose; and estimated glomerular filtration rate in 2008. To test the robustness of our findings, we conducted model 3 in participants excluding individuals with an estimated glomerular filtration rate <30 mL/min per 1.73 m2 in 2008. Because 11 hospitals participated in the study, the hospital was treated as clusters in the Cox model and the sandwich estimators were used to account for the correlations and calculate the SE in the study. The proportional hazards assumption was tested by scaled Schoenfeld residuals; no appreciable violations were noted. All interactions were analyzed by multivariable Cox proportional hazards modeling.

In 12 374 participants with incomplete proteinuria data, 11 640 participants had 1 proteinuria data in 2006 or 2008. Considering that many individuals with incomplete proteinuria data both in 2006 and 2008 were excluded, which could have influenced the results. Therefore, we conducted 3 sensitivity analyses in participants with 1 or 2 measurements of proteinuria. First, all missing data of proteinuria in 2006 or 2008 were considered as no proteinuria. Second, all missing data of proteinuria in 2006 or 2008 were considered as presence of proteinuria. Finally, all missing data of proteinuria were considered as the same results as the other time measurements.

To compare the prediction ability for stroke risk between changes in proteinuria and baseline proteinuria, the area under receiver operating characteristic curve was used to give a quantitative assessment of the predictive ability.

Statistical analyses were performed using SAS 9.4 (SAS Institute; Cary, NC). All statistical tests were 2‐sided and the significance level was set at 0.05.

Results

A total of 60 940 participants with available data of proteinuria (men, 77.60%) were analyzed in our study. The mean age of the remaining population was 50.69±12.08 years. We divided the participants into 4 categories according to changes in proteinuria from 2006 to 2008. The baseline characteristics in 2006 and 2008 of the 4 categories of participants are shown in Table 1. Compared with participants with no proteinuria, participants in the other groups had a higher proportion of men, lower educational levels, lower incomes, and a higher prevalence of hypertension, diabetes mellitus, oer dyslipidemia (all P<0.0001). Considering the clinical importance of remittent proteinuria, we also tested the differences of risk factors between the remittent proteinuria group and the persistent proteinuria group. In brief, participants in the remittent proteinuria group were younger and more educated, had more active physical activity, and had a lower prevalence of hypertension, diabetes mellitus, and dyslipidemia (Table 1).

View this table:
  • View inline
  • View popup
Table 1. Characteristics of Participants According to Changes in Proteinuria From 2006 to 2008

After a mean follow‐up period of 6.92 years, a total of 1769 stroke events were recorded, including 1492 participants with ischemic stroke, 283 with hemorrhagic stroke, and 44 with subarachnoid hemorrhage stroke. The incidence per 1000 person‐years of total stroke ranged from 3.66 in the no proteinuria group to 11.23 in the persistent proteinuria group. Table 2 shows the adjusted HRs of incident stroke and subtypes associated with changes in proteinuria exposure. After adjustment for covariates, participants in the incident proteinuria and persistent proteinuria groups had 46% and 71% higher risks of developing stroke compared with participants in the no proteinuria group. The HRs were 1.46 (95% CI, 1.26–1.68) and 1.71 (95% CI, 1.42–2.06), respectively (all P<0.05). The same trends were found in the association between changes in proteinuria and stroke subtypes (ischemic stroke and hemorrhagic stroke). Sensitivity analysis yielded the same pattern of results (Tables 2, 3 through 4).

View this table:
  • View inline
  • View popup
Table 2. Association Between Changes in Proteinuria From 2006 to 2008 and Incident Stroke
View this table:
  • View inline
  • View popup
Table 3. The Association Between Changes in Proteinuria From 2006 to 2008 and Incident Strokea
View this table:
  • View inline
  • View popup
Table 4. Sensitivity Analysis in Participants With 1 or 2 Proteinuria Measurements

Figure 2A through 2C show the Kaplan–Meier cumulative risk for stroke and subtypes within groups defined by changes in proteinuria. Participants in the persistent proteinuria group experienced a higher risk than participants in the other groups during the 6.92‐year follow‐up period for total stroke events (log‐rank test, P<0.0001) (Figure 2A), ischemic stroke (log‐rank test, P<0.0001) (Figure 2B), and hemorrhagic stroke (log‐rank test, P<0.0001) (Figure 2C).

Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

Kaplan–Meier curve of (A) all‐type stroke incidence rate, (B) ischemic stroke incidence rate, and (C) hemorrhagic stroke incidence rate by changes in proteinuria.

The associations between changes in proteinuria from 2006 to 2008 and incident stroke stratified by age and sex are shown in Table 5. After adjustment for potential confounders, the HRs for incident stroke for participants with persistent proteinuria were 3.03 (95% CI, 1.79–5.13) for women and 1.47 (95% CI, 1.19–1.82) for men, and 1.73 (95% CI, 1.32–2.28) for those younger than 60 years and 1.50 (1.13–1.98) for those 60 years and older compared with participants with no proteinuria. We also tested the interactions between changes in proteinuria and age or sex in relation to stroke and subtypes. There were significant interactions between changes in proteinuria and sex in relation to total stroke and ischemic stroke (P<0.05). No interaction was found between changes in proteinuria and age (P>0.05), which may have been attributable to the small sample size.

View this table:
  • View inline
  • View popup
Table 5. The Association Between Changes in Proteinuria From 2006 to 2008 and Incident Stroke Stratified by Age and Sex

Table 6 shows the adjusted HRs of incident stroke and subtypes associated with baseline proteinuria exposure. In the fully adjusted model, participants with proteinuria at baseline had a 25% higher risk of developing stroke compared with participants with no proteinuria (HR, 1.25; 95% CI, 1.09–1.43). Similar patterns were found in ischemic stroke and hemorrhagic stroke.

View this table:
  • View inline
  • View popup
Table 6. Association Between Baseline Proteinuria in 2006 and Incident Stroke

The area under receiver operating characteristic curve values of changes in proteinuria and baseline proteinuria for risk of stroke were 0.56 (95% CI, 0.55–0.57) and 0.53 (95% CI, 0.52–0.54), respectively. These results showed that the changes of proteinuria were better than spot proteinuria in predicting the risk assessment of stroke.

Table 7 shows the comparison of demographic and other characteristics in 2006 of participants (n=60 940) and nonparticipants (n=12 374). In general, we found that nonparticipants were younger; were predominantly male; were less educated; had lower monthly incomes; had a lower proportion of current smokers, current alcohol use, and active physical activity; had a higher prevalence of hypertension and dyslipidemia; and had a slightly lower prevalence of diabetes mellitus.

View this table:
  • View inline
  • View popup
Table 7. Comparison of Demographic and Other Characteristics in 2006 of Participants and Nonparticipants

Discussion

In our study, the presence of proteinuria as detected by urine dipstick screening independently predicted an increased risk for incident stroke during 6.92 years of follow‐up. Moreover, we observed significant associations of changes in proteinuria and the incidence of stroke and subtypes in the Chinese population. This relationship persisted independently of other known major risk factors, including diabetes mellitus, hypertension, dyslipidemia, and obesity. Findings from the current study extend those from previous studies.10, 11, 12, 13, 14, 16 Our study shows that the presence of proteinuria is associated with a substantially higher risk of incident stroke compared with an absence of proteinuria when measured either at baseline or at follow‐up visits.

Stroke accounts for 5 million deaths worldwide each year and is a leading cause of serious disability.19 The stroke burden in China has increased during the past 30 years, and remains particularly high in rural areas. The recent NESS‐China study, which was conducted in 155 urban and rural centers in 31 provinces in China, showed that the incidence of stroke was 345.1 per 100 000 person‐years.20 Therefore, the growing disease burden of stroke indicates that prevention is a necessary strategy, which, in turn, highlights the need for awareness regarding risk factors and warning signs.21 Growing evidence has suggested an association between the presence of protein in the urine (proteinuria or albuminuria) and the risk of stroke.10, 11, 12, 13, 14, 22, 23 The Honolulu Heart Program showed that proteinuria that was detected at urine dipstick screening independently predicted an increased risk for incident stroke over 27 years of follow‐up.22 A recent study from the China Stroke Primary Prevention Trial also found that baseline proteinuria as measured by dipstick was an independent risk factor for first incident stroke and ischemic stroke.10 A meta‐analysis of cohort studies or randomized controlled trials concluded that increasing albuminuria increased the risk of stroke.23

In accordance with the above‐mentioned studies,10, 11, 12, 13, 14, 22, 23 we found a significant association between baseline proteinuria and the risk of stroke. Patients with baseline proteinuria showed a 25% higher risk of reaching an end point in the follow‐up. However, previous studies generally considered baseline proteinuria (a single point in time) as a risk predictor. The potential effect of a change in proteinuria over time was not well characterized in these studies. In the current study, 2‐year changes of proteinuria were considered to be associated with the risk of stroke. We also found that the risk factors including education level, active physical activity, hypertension, diabetes mellitus, and dyslipidemia were associated with remittent proteinuria. In terms of clinical significance, we could change the proteinuria status by controlling these risk factors, and, in turn, reduce the risk of stroke.

The current study is unique in that measurement of changes in proteinuria included 4 types (no, remittent, incident, and persistent proteinuria). Each of these types of proteinuria appeared to confer different risks of stroke, and the association between persistent proteinuria and incident stroke was the most significant. Patients with persistent proteinuria exposure showed a 71% higher risk of having stroke, which was higher than baseline proteinuria exposure. Moreover, the association between changes in proteinuria and the risk of stroke remained significant, even after excluding individuals with an estimated glomerular filtration rate of ≤30 mL/min per 1.73 m2 from the analysis. Furthermore, our study investigated this association by distinguishing between ischemic and hemorrhagic stroke, as the patterns of results were consistent with total stroke. Interestingly, in subgroup analysis, the associations between changes in proteinuria and incident total stroke and ischemic stroke were more significant in women than in men. The reason for this finding is unclear. Further studies are required to investigate the effect of sex on the associations between changes in proteinuria and incident stroke. However, these associations showed no significance difference in subgroups stratified by age. Our findings taken together with previous studies suggest that not only is baseline proteinuria important, but a longitudinal change in proteinuria predicts a high risk that is compatible or beyond the baseline value. Therefore, monitoring longitudinal patterns of changes in proteinuria in clinical practice is important.

The pathophysiological mechanisms that mediate the link between proteinuria and stroke are unknown and require further investigation. There are several potential explanations for why the presence of proteinuria may be a risk factor for incident stroke. First, reduced kidney function as assessed by the presence of proteinuria is associated with inflammation, thromboembolism, endothelial dysfunction, and arterial stiffness/calcification, among other factors, all of which may contribute to the risk of stroke.24, 25, 26 Second, participants with persistent proteinuria tend to have a higher prevalence of traditional risk factors for cardiovascular disease compared with participants without proteinuria. These risk factors include older age; a higher prevalence of hypertension, diabetes mellitus, and dyslipidemia; increased systolic and diastolic BP; higher fasting blood glucose levels; higher body mass index; and inactive physical activity. Third, proteinuria has been proposed to be associated with an increase in the albumin and fibrinogen transcapillary escape rate, which reflects widespread vascular damage.27

Strengths and Limitations

Our study has several strengths. This is the first prospective study to address the association between changes in proteinuria and the incidence of stroke in the general population. Furthermore, we distinguished between ischemic and hemorrhagic stroke. However, there are some inherent limitations. First, medications that modify urinary protein excretion (use of angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers) were not included in the models as a potential disease‐modifying therapy. Angiotensin‐converting enzyme inhibitor and angiotensin receptor blocker agents decrease albuminuria in individuals with diabetes mellitus and hypertension28 and decrease cardiovascular events in these patients.29 Second, because all of the participants were recruited from Tangshan City, the cohort is not nationally representative. Therefore, our findings pertaining to changes in proteinuria and stroke are not generalizable to other parts of China. Third, the incomplete measurements of proteinuria are a weakness of the study. Our study may ultimately underestimate the effect of changes of proteinuria on the incidence of stroke. However, we conducted 3 sensitivity analyses in patients including 1 or 2 measurements of proteinuria and the results were similar with the primary analysis.

Conclusions

Our findings suggest that changes in proteinuria, particularly persistent proteinuria, compared with spot urinary protein collected at a single time point, is a more practical and effective risk factor for incident stroke in a community population in China. Clinicians and public health practitioners should be aware that early detection and control of proteinuria may decrease the risk of stroke.

Sources of Funding

This study was supported by grants from the Ministry of Science and Technology of the People's Republic of China (No. 2011BAI08B02, 2008ZX09312‐008), the National Natural Science Foundation of China (No. 81322019), Beijing Municipal Science and Technology Commission (No. D151100002015001), and Beijing Biobank of Cerebral Vascular Disease (No. D131100005313003).

Disclosures

None.

References

  1. ↵
    Eckardt KU, Berns JS, Rocco MV, Kasiske BL. Definition and classification of CKD: the debate should be about patient prognosis—a position statement from KDOQI and KDIGO. Am J Kidney Dis. 2009;53:915–920.
    OpenUrlCrossRefPubMed
  2. ↵
    Zhang L, Wang F, Wang L, Wang W, Liu B, Liu J, Chen M, He Q, Liao Y, Yu X, Chen N, Zhang JE, Hu Z, Liu F, Hong D, Ma L, Liu H, Zhou X, Chen J, Pan L, Chen W, Wang W, Li X, Wang H. Prevalence of chronic kidney disease in china: a cross‐sectional survey. Lancet. 2012;379:815–822.
    OpenUrlCrossRefPubMed
  3. ↵
    Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Magid D, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, Nichol G, Paynter NP, Schreiner PJ, Sorlie PD, Stein J, Turan TN, Virani SS, Wong ND, Woo D, Turner MB; American Heart Association Statistics C, Stroke Statistics S . Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127:e6–e245.
    OpenUrlFREE Full Text
  4. ↵
    Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, McCullough PA, Kasiske BL, Kelepouris E, Klag MJ, Parfrey P, Pfeffer M, Raij L, Spinosa DJ, Wilson PW; American Heart Association Councils on Kidney in Cardiovascular Disease HBPRCC, Epidemiology, Prevention . Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108:2154–2169.
    OpenUrlFREE Full Text
  5. ↵
    Levey AS, Atkins R, Coresh J, Cohen EP, Collins AJ, Eckardt KU, Nahas ME, Jaber BL, Jadoul M, Levin A, Powe NR, Rossert J, Wheeler DC, Lameire N, Eknoyan G. Chronic kidney disease as a global public health problem: approaches and initiatives—a position statement from Kidney Disease Improving Global Outcomes. Kidney Int. 2007;72:247–259.
    OpenUrlCrossRefPubMed
  6. ↵
    Culleton BF, Larson MG, Parfrey PS, Kannel WB, Levy D. Proteinuria as a risk factor for cardiovascular disease and mortality in older people: a prospective study. Am J Med. 2000;109:1–8.
    OpenUrlPubMed
  7. ↵
    Kannel WB, Stampfer MJ, Castelli WP, Verter J. The prognostic significance of proteinuria: the Framingham Study. Am Heart J. 1984;108:1347–1352.
    OpenUrlCrossRefPubMed
  8. ↵
    Hayashi K, Saruta T, Goto Y, Ishii M; Group JS . Impact of renal function on cardiovascular events in elderly hypertensive patients treated with efonidipine. Hypertens Res. 2010;33:1211–1220.
    OpenUrlCrossRefPubMed
  9. ↵
    Ruilope LM, Zanchetti A, Julius S, McInnes GT, Segura J, Stolt P, Hua TA, Weber MA, Jamerson K; Investigators V . Prediction of cardiovascular outcome by estimated glomerular filtration rate and estimated creatinine clearance in the high‐risk hypertension population of the VALUE trial. J Hypertens. 2007;25:1473–1479.
    OpenUrlCrossRefPubMed
  10. ↵
    Zhang Y, Zhang T, Zhang C, Tang F, Zhong N, Li H, Song X, Lin H, Liu Y, Xue F. Identification of reciprocal causality between non‐alcoholic fatty liver disease and metabolic syndrome by a simplified Bayesian network in a Chinese population. BMJ Open. 2015;5:e008204.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    Guerrero‐Romero F, Rodriguez‐Moran M. Proteinuria is an independent risk factor for ischemic stroke in non‐insulin‐dependent diabetes mellitus. Stroke. 1999;30:1787–1791.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Sandsmark DK, Messe SR, Zhang X, Roy J, Nessel L, Lee Hamm L, He J, Horwitz EJ, Jaar BG, Kallem RR, Kusek JW, Mohler ER III., Porter A, Seliger SL, Sozio SM, Townsend RR, Feldman HI, Kasner SE; Investigators CS . Proteinuria, but not eGFR, predicts stroke risk in chronic kidney disease: chronic renal insufficiency cohort study. Stroke. 2015;46:2075–2080.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Ninomiya T, Perkovic V, Verdon C, Barzi F, Cass A, Gallagher M, Jardine M, Anderson C, Chalmers J, Craig JC, Huxley R. Proteinuria and stroke: a meta‐analysis of cohort studies. Am J Kidney Dis. 2009;53:417–425.
    OpenUrlCrossRefPubMed
  14. ↵
    Slowik A, Turaj W, Iskra T, Strojny J, Szczudlik A. Microalbuminuria in nondiabetic patients with acute ischemic stroke: prevalence, clinical correlates, and prognostic significance. Cerebrovasc Dis. 2002;14:15–21.
    OpenUrlCrossRefPubMed
  15. ↵
    Wu S, Huang Z, Yang X, Zhou Y, Wang A, Chen L, Zhao H, Ruan C, Wu Y, Xin A, Li K, Jin C, Cai J. Prevalence of ideal cardiovascular health and its relationship with the 4‐year cardiovascular events in a northern Chinese industrial city. Circ Cardiovasc Qual Outcomes. 2012;5:487–493.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Li Z, Wang A, Cai J, Gao X, Zhou Y, Luo Y, Wu S, Zhao X. Impact of proteinuria and glomerular filtration rate on risk of ischaemic and intracerebral hemorrhagic stroke: a result from the Kailuan study. Eur J Neurol. 2015;22:355–360.
    OpenUrlCrossRefPubMed
  17. ↵
    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF III., Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; Ckd EPI . A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–612.
    OpenUrlCrossRefPubMed
  18. ↵
    Stroke—1989. Recommendations on stroke prevention, diagnosis, and therapy. Report of the WHO Task Force on Stroke and other Cerebrovascular Disorders. Stroke. 1989;20:1407–1431.
    OpenUrlFREE Full Text
  19. ↵
    Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker‐Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez‐Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O'Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez‐Ruiz F, Perico N, Phillips D, Pierce K, Pope CA III., Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De Leon FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui‐Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095–2128.
    OpenUrlCrossRefPubMed
  20. ↵
    Wang W, Jiang B, Sun H, Ru X, Sun D, Wang L, Wang L, Jiang Y, Li Y, Wang Y, Chen Z, Wu S, Zhang Y, Wang D, Wang Y, Feigin VL; Investigators NE‐C . Prevalence, incidence and mortality of stroke in China: results from a nationwide population‐based survey of 480,687 adults. Circulation. 2017;135:759–771.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Straus SE, Majumdar SR, McAlister FA. New evidence for stroke prevention: scientific review. JAMA. 2002;288:1388–1395.
    OpenUrlCrossRefPubMed
  22. ↵
    Madison JR, Spies C, Schatz IJ, Masaki K, Chen R, Yano K, Curb JD. Proteinuria and risk for stroke and coronary heart disease during 27 years of follow‐up: the Honolulu Heart Program. Arch Intern Med. 2006;166:884–889.
    OpenUrlCrossRefPubMed
  23. ↵
    Masson P, Webster AC, Hong M, Turner R, Lindley RI, Craig JC. Chronic kidney disease and the risk of stroke: a systematic review and meta‐analysis. Nephrol Dial Transplant. 2015;30:1162–1169.
    OpenUrlCrossRefPubMed
  24. ↵
    Raggi P, Boulay A, Chasan‐Taber S, Amin N, Dillon M, Burke SK, Chertow GM. Cardiac calcification in adult hemodialysis patients. A link between end‐stage renal disease and cardiovascular disease? J Am Coll Cardiol. 2002;39:695–701.
    OpenUrlFREE Full Text
  25. ↵
    London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Arterial media calcification in end‐stage renal disease: impact on all‐cause and cardiovascular mortality. Nephrol Dial Transplant. 2003;18:1731–1740.
    OpenUrlCrossRefPubMed
  26. ↵
    Shlipak MG, Fried LF, Crump C, Bleyer AJ, Manolio TA, Tracy RP, Furberg CD, Psaty BM. Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation. 2003;107:87–92.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    Deckert T, Feldt‐Rasmussen B, Borch‐Johnsen K, Jensen T, Kofoed‐Enevoldsen A. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia. 1989;32:219–226.
    OpenUrlCrossRefPubMed
  28. ↵
    Galle J. Reduction of proteinuria with angiotensin receptor blockers. Nat Clin Pract Cardiovasc Med. 2008;5(suppl 1):S36–S43.
    OpenUrlCrossRefPubMed
  29. ↵
    Levey AS, Coresh J. Chronic kidney disease. Lancet. 2012;379:165–180.
    OpenUrlCrossRefPubMed
View Abstract
Back to top
Previous ArticleNext Article

This Issue

Journal of the American Heart Association
July 2017, Volume 6, Issue 7
  • Table of Contents
Previous ArticleNext Article

Jump to

  • Article
    • Abstract
    • Introduction
    • Methods
    • Results
    • Discussion
    • Conclusions
    • Sources of Funding
    • Disclosures
    • References
  • Figures & Tables
  • Info & Metrics
  • eLetters

Article Tools

  • Print
  • Citation Tools
    Two‐Year Changes in Proteinuria and the Risk of Stroke in the Chinese Population: A Prospective Cohort Study
    Anxin Wang, Xiaoxue Liu, Zhaoping Su, Shuohua Chen, Nan Zhang, Shouling Wu, Yongjun Wang and Yilong Wang
    Journal of the American Heart Association. 2017;6:e006271, originally published June 30, 2017
    https://doi.org/10.1161/JAHA.117.006271

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
  •  Download Powerpoint
  • Article Alerts
    Log in to Email Alerts with your email address.
  • Save to my folders
  • Request Permissions

Share this Article

  • Email

    Thank you for your interest in spreading the word on Journal of the American Heart Association.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    Two‐Year Changes in Proteinuria and the Risk of Stroke in the Chinese Population: A Prospective Cohort Study
    (Your Name) has sent you a message from Journal of the American Heart Association
    (Your Name) thought you would like to see the Journal of the American Heart Association web site.
  • Share on Social Media
    Two‐Year Changes in Proteinuria and the Risk of Stroke in the Chinese Population: A Prospective Cohort Study
    Anxin Wang, Xiaoxue Liu, Zhaoping Su, Shuohua Chen, Nan Zhang, Shouling Wu, Yongjun Wang and Yilong Wang
    Journal of the American Heart Association. 2017;6:e006271, originally published June 30, 2017
    https://doi.org/10.1161/JAHA.117.006271
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...

Subjects

  • Epidemiology, Lifestyle, and Prevention
    • Primary Prevention
    • Risk Factors
    • Epidemiology
  • Stroke
    • Cerebrovascular Disease/Stroke

Journal of the American Heart Association

  • About JAHA
  • Instructions for Authors
  • AHA CME
  • Statements and Guidelines
  • Email Alerts
  • Open Access Information
  • AHA Journals RSS
  • AHA Newsroom

Editorial Office Address:
200 5th Avenue
Suite 1020
Waltham, MA 02451 
email: jaha@journalaha.org

Information for:
  • Advertisers
  • International Users
American Heart Association Learn and Live
National Center
7272 Greenville Ave.
Dallas, TX 75231

Customer Service

  • 1-800-AHA-USA-1
  • 1-800-242-8721
  • Local Info
  • Contact Us

About Us

Our mission is to build healthier lives, free of cardiovascular diseases and stroke. That single purpose drives all we do. The need for our work is beyond question. Find Out More about the American Heart Association

  • Careers
  • SHOP
  • Latest Heart and Stroke News
  • AHA/ASA Media Newsroom

Our Sites

  • American Heart Association
  • American Stroke Association
  • For Professionals
  • More Sites

Take Action

  • Advocate
  • Donate
  • Planned Giving
  • Volunteer
  • You're the Cure

Online Communities

  • AFib Support
  • Empowered to Serve
  • Garden Community
  • Patient Support Network
  • Professional Online Network

Follow Us:

  • Follow Circulation on Twitter
  • Visit Circulation on Facebook
  • Follow Circulation on Google Plus
  • Follow Circulation on Instagram
  • Follow Circulation on Pinterest
  • Follow Circulation on YouTube
  • Rss Feeds
  • Privacy Policy
  • Copyright
  • Ethics Policy
  • Conflict of Interest Policy
  • Linking Policy
  • Diversity
  • Careers

©2018 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. The American Heart Association is a qualified 501(c)(3) tax-exempt organization.
*Red Dress™ DHHS, Go Red™ AHA; National Wear Red Day ® is a registered trademark.

  • PUTTING PATIENTS FIRST National Health Council Standards of Excellence Certification Program
  • BBB Accredited Charity
  • Comodo Secured