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Received: 30 October 2017    Revised: 8 February 2018    Accepted: 13 February 2018

DOI: 10.1111/jch.13255

ORIG INAL PAPER

Proteinuria and risk of stroke in patients with hypertension:

The Kailuan cohort study

Anxin Wang PhD1,2,3,4,5,6 | Liye Dai MD1 | Zhaoping Su MD1,2,3,4 | Shuohua Chen MD7 | 

Junjuan Li MD8 | Shouling Wu MD7 | Yongjun Wang MD1,2,3,4  | 
Yilong Wang MD, PhD1,2,3,4

1
Department of Neurology, Beijing Tiantan
Hospital, Capital Medical University, Beijing, Proteinuria is associated with stroke, but the effects of changes in proteinuria on
China stroke risk are not well understood in the hypertensive population. This study exam-
2
China National Clinical Research Center for ined whether proteinuria changes across 2-­year assessments were associated with
Neurological Diseases, Beijing, China
3 incident stroke in individuals with hypertension. We used visit data from 24 300 par-
Center of Stroke, Beijing Institute for Brain
Disorders, Beijing, China ticipants with hypertension of the Kailuan study who were stroke free at baseline.
4
Beijing Key Laboratory of Translational Based on the baseline and 2-­year dipstick screening results, participants were classi-
Medicine for Cerebrovascular Disease,
Beijing, China
fied as having no, remittent, incident, or persistent proteinuria. The relationship be-
5
Beijing Municipal Key Laboratory of Clinical tween proteinuria and stroke was analyzed using Cox proportional-­hazards models
Epidemiology, Beijing, China after adjusting for potential variables. During a median of 6.89-­year follow-­up, we
6
Department of Epidemiology and Health
identified 1197 people with stroke. Compared to those with no proteinuria, stroke
Statistics, School of Public Health, Capital
Medical University, Beijing, China risk was significantly increased in participants with incident (hazard ratio [HR] 1.41,
7
Department of Cardiology, Kailuan 95% CI, 1.05-­1.77) and persistent proteinuria (HR 1.49, 95% CI, 1.25-­1.89) after ad-
Hospital, North China University of Science
and Technology, Tangshan, China
justment for other factors, which was consistent in ischemic stroke and intracerebral
8
Department of Nephrology, Kailuan hemorrhage. No interaction was found between changes of proteinuria and diabetes
Hospital, North China University of Science mellitus in the hypertensive population. Changes in proteinuria exposure, particularly
and Technology, Tangshan, China
persistent proteinuria, play a role in reflecting the risk of stroke in patients with
Correspondence hypertension.
Yilong Wang, MD, PhD, Department of
Neurology, Beijing Tiantan Hospital, Capital
Medical University, Beijing, China.
Email: yilong528@gmail.com

1 |  I NTRO D U C TI O N
Studies demonstrated that a decreased level of kidney function is an in-
dependent risk factor for all-­cause mortality as well as adverse cardio-
vascular disease outcomes including myocardial infarction, stroke, and
progression of heart failure.1-4 As an important marker of chronic kid-
ney disease (CKD), proteinuria was proved to be associated with inci-
dent stroke during the last few decades.5 Data suggested that baseline
proteinuria confers a 50%-­92% greater risk of future stroke. Previous 6
study demonstrated that the prevalence of proteinuria was higher in
the hypertensive group than in the normotensive group (hypertensive
group, 33.9%; normotensive, 10%).7 Furthermore, data from the China
National Stroke Screening Survey (CNSSS) showed that hypertension
ranked in first place among factors contributing to stroke in China.8
The association between proteinuria and stroke, in particular, should
be noted in the hypertensive population who are at high risk for the
development of stroke. More important, proteinuria often changes dy-
namically, showing regression or progression.9 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.
The value of multiple dipstick measurements for changes in proteinuria
and its relation with stroke outcomes has rarely been investigated.

Anxin Wang and Liye Dai contributed equally to the manuscript.

J Clin Hypertens. 2018;1–10. ©2018 Wiley Periodicals, Inc. |  1

wileyonlinelibrary.com/journal/jch  
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2       WANG et al.
Therefore, we conducted this study to assess the relationship
between proteinuria change and stroke incidence in participants
with hypertension.
2 |  M E TH O DS
2.1 | Study population
The design, method, rationale, and examination details of the Kailuan
10-13
cohort study have been published previously. In brief, the Kailuan
study is a population-­based prospective cohort study. Between June
2006 and October 2007, a total of 101 510 individuals aged 18-­98
were recruited to participate in the study and were followed up until
present by means of biennial face-­to-­face examinations and annual
comprehensive surveillance of medical records and death certificates.
All participants recruited underwent routine history and physical ex-
amination, anthropometry, and laboratory assessment.
Out of the whole cohort at the first examination, 42 698 hy-
pertensive participants without previous stroke and with complete
dipstick assessment of proteinuria participated in the second exam-
ination of the Kailuan study in the year 2008-­2009. Hypertension
was defined as systolic blood pressure (SBP) at least 140 mm Hg or
diastolic blood pressure (DBP) at least 90 mm Hg or history of hy-
pertension and/or use of antihypertensive agents. After exclusion
for new finding of stroke during the period 2006-­2007 to 2008-­
2009 or missing proteinuria data, 24 300 participants remained
eligible for the present analysis. A flowchart of the present cohort
study is shown in Figure 1. All participants provided informed con-
sent. The study was performed according to the guidelines of the
Helsinki Declaration and was approved by the Ethics Committee of
the Kailuan Hospital and the Beijing Tiantan Hospital.
2.2 | Measurements of proteinuria
At the baseline examination, a dipstick urine analysis was performed.
The urine dipstick is a widely used tool in clinical screening for
proteinuria on the basis of easy accessibility and low cost.14 Dipstick
positive proteinuria, seen as a sign of chronic kidney disease (CKD),
has emerged as a powerful and independent predictor of cardiovas-
cular disease.6 In this study, proteinuria was screened by dipstick
strictly following the direction of the kit. A freshly obtained urine
sample was first visually examined for 1 minute by a trained physi-
cian (H12-­MA, DIRUI N-­600).15 Using a color scale, the results of
the urine strip test were semiquantified as absent, trace, 1+, 2+, or
3+. Proteinuria positive was defined as trace or more with dipstick
analysis either at baseline or at the follow-­up visit.
We defined 4 proteinuria groups according to changes in protein-
uria from baseline to the follow-­up visit. Based on the baseline and
2-­year dipstick screening results, participants were classified as having
no, remittent, incident, or persistent proteinuria. “No proteinuria” was
defined as proteinuria absent both at the baseline visit and at the fol-
low-­up visit. “Remittent proteinuria” was defined as proteinuria present
at the baseline but absent at the follow-­up visit. “Incident proteinuria”
was defined as proteinuria absent at the baseline visit but occurring at
the follow-­up visit. “Persistent proteinuria” was defined as proteinuria
present at the baseline visit and also at the follow-­up visit. Reduction in
proteinuria was defined as baseline minus 2-­year proteinuria.
2.3 | Potential covariates
The variables involved in this research including age, gender, current
smoker, current alcohol, physical activity, body mass index, diabetes
mellitus, dyslipidemia, total cholesterol, triglycerides, low-­density li-
poprotein, high-­density lipoprotein, systolic blood pressure, diastolic
blood pressure, fasting blood glucose, and estimated glomerular fil-
tration rate (eGFR). All these variables were mentioned and described
in previous studies. Data on smoking, drinking, physical activity, and
other demographic variables including sex and age were collected
using questionnaires. SBP and DBP were measured twice in the seated
position using a mercury sphygmomanometer. The average of the 2
readings was used for the analyses. The change of blood pressure
was calculated by diastolic in 2008-diastolic in 2006. We included this
F I G U R E   1   Flowchart of the study
WANG et al.
variable to decrease the influence of progression by blood pressure.
Weight and height were measured during the interview and body mass
index (BMI) was calculated as weight (kg)/height (m) ². Blood pressure
was measured with a standard mercury sphygmomanometer by a phy-
sician or trained nurses. Blood samples were collected from the an-
tecubital vein after an overnight fast. All blood samples were tested
using a Hitachi 747 auto-­analyzer (Hitachi, Tokyo, Japan) at the central
laboratory of the Kailuan General Hospital for serum total cholesterol,
low-­density lipoprotein cholesterol (LDL-­C), high-­density lipoprotein
cholesterol (HDL-­C), fasting blood glucose (FBG), and other factors.
Previous history of disease, including hypertension, diabetes mellitus,
and hyperlipidemia, was collected by self-­report. The use of medicine
such as antihypertensives within the past 2 weeks before the baseline
interview was also self-­reported.
2.4 | Follow-­up and stroke assessment
We considered the 2008 survey as the starting point and December
31, 2015 as the endpoint of the follow-­up in the present prospec-
tive study. Follow-­up evaluations included biennial measurements of
laboratory parameters and the occurrence of adverse events.
The outcome was the first occurrence of stroke, either the first
nonfatal stroke event or stroke death without a preceding nonfatal
event. A nonfatal stroke is defined as the sudden onset of a focal
neurological deficit with a vascular mechanism lasting > 24 hours,
including hemorrhagic stroke, ischemic stroke, and subarachnoid
hemorrhage. Stroke is diagnosed according to the World Health
Organization criteria combined with a brain computed tomography
(CT) or magnetic resonance (MR) for confirmation16 and classified
into 3 types: cerebral infarction, cerebral hemorrhage, and sub-
arachnoid hemorrhage. Subarachnoid hemorrhage was usually based
on aneurysm or vascular malformation instead of chronic stroke
risk factors. Considering the small sample size (n = 31) and differ-
ent mechanism, we did not include the subarachnoid hemorrhage
group in the subgroup analysis. The diagnostic criteria were consis-
tent across all participating hospitals and all stroke outcomes were
validated by the Data Safety Monitoring Board and the Arbitration
Committee for Clinical Outcomes. The outcome information was
further confirmed by checking discharge summaries and the medical
records from medical insurance. For analysis of stroke-­specific data,
patients who ended up with unrelated causes were considered as
censored.
2.5 | Statistical analyses
Continuous variables were described as means ± standard deviation (SD)
and were compared using ANOVA or Kruskal-­Wallis test. Categorical var-
iables were described as counts (percentages) and were compared using
the chi-­square test or the Fisher exact test. Incidence rates of stroke were
calculated per 1000 person-­years of follow-­up. Participants contributed
person-­time of follow-­up from the date of return of the 2-­year survey
questionnaire to either the date of stroke onset, death, or end of follow-
­up. Cox proportional-­hazards regression was used to calculate the hazard
|
      3
ratio and 95% confidence interval (CI) for stroke outcomes by changes in
proteinuria, using participants with no proteinuria as the reference group.
Variables with a P value < .2 and the well-­established predictors were se-
lected as adjustment covariates into the multivariable analyses.
We fitted 3 multivariable Cox proportional hazards models.
Model 1 was adjusted for age and sex. Model 2 was further adjusted
for current smoker, current alcohol user, physical activity, and body
mass index. Model 3 was adjusted for variables in model 2 plus di-
abetes mellitus, dyslipidemia, total cholesterol, high-­density lipo-
protein, systolic blood pressure, change of blood pressure, fasting
blood glucose, and eGFR. We used these models with a sandwich
covariance matrix as a random effect to account for the potential
confounding effect of the 11 different hospitals in the study. In the
analysis of stroke risk for per-­degree decrease of proteinuria, base-
line proteinuria was adjusted in addition to the three models.
To test the robustness of our findings, we conducted model 3 in
participants excluding individuals with eGFR < 30 mL/min/1.73 m² in
2008 as sensitive analysis. Furthermore, we tested interactions between
changes in proteinuria with diabetes mellitus and sex for the risk of stroke.
3 | R E S U LT S
A total of 24 300 participants with available data of proteinuria
(men, 82.35%) were analyzed in our study. The mean age of the re-
maining population was 55.04 ± 10.88 years. We divided the par-
ticipants into 4 categories according to changes in proteinuria from
2006 to 2008. The baseline characteristics in both 2006 and 2008
of the 4 categories of participants are shown in Table 1. For changes
in proteinuria, 77.4% had no proteinuria, whereas 7.14% had remit-
tent proteinuria, 10.60% had incident proteinuria, and 4.81% had
persistent proteinuria. Differences in age, sex, BMI, physical activ-
ity, cholesterol concentration, eGFR, blood pressure, concomitant
morbidities (diabetes or dyslipidemia), and medicine treatment were
found between proteinuria change groups (P < .05) in both 2006 and
2008. No significant differences in participants who smoke or taking
antilipidemic agents were observed between groups. Characteristics
of participants included and excluded are showed in Table S1.
During a median follow-­u p of 6.89 (6.56, 7.19) years, we
identified 1197 subjects with incident strokes. The incident
stroke rate was 6.32 events per 1000 person-­y ears for subjects
with no proteinuria, 8.76 for remittent proteinuria, 10.96 for in-
cident proteinuria, and 13.87 for persistent proteinuria. We ad-
ditionally analyzed the association between stroke and different
proteinuria level. The result is shown in Table 2. The relationship
between stroke and proteinuria is not consistent from 2006 to
2008. Table 3 shows the adjusted HRs of incident stroke and
subtypes associated with changes in proteinuria exposure.
Compared with subjects without proteinuria, HRs for stroke
were 1.63 (95% CI, 1.38-­1 .92) for incident proteinuria, and 2.04
(95% CI, 1.65-­2 .53) for persistent proteinuria (Model 1), attenu-
ated but still significant after fully adjustment. The same trends
were found in the association between changes in proteinuria
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4       WANG et al.

TA B L E   1   Characteristics in 2006 and 2008 according to the change in proteinuria from 2006 to 2008 in participants with hypertension

Change of proteinuria

Variable Total No proteinuria Remittent proteinuria Incident proteinuria Persistent proteinuria P value

No. of participants 24 300 20 665 593 2430 612

Age, years 55.03 ± 10.88 54.89 ± 10.86 55.78 ± 11.10 55.80 ± 10.91 55.97 ± 11.06 <.0001
Sex, male, n (%) 20 010 (82.35) 16 295 (81.90) 491 (82.80) 2084 (85.76) 510 (83.33) <.0001
Baseline information in 2006
Current smoker, 8686 (35.74) 7503 (36.31) 226 (38.11) 784 (32.26) 173 (28.27) <.0001
n (%)
Current alcohol, 9602 (39.51) 8370 (40.50) 228 (38.45) 818 (33.66) 186 (30.39) <.0001
n (%)
Active physical 5024 (20.67) 4401 (21.30) 166 (27.99) 373 (15.35) 84 (13.73) <.0001
activity, n (%)
Antihypertension 6360 (26.17) 5431 (26.28) 193 (32.55) 564 (23.21) 172 (28.10) <.0001
agents, n (%)
Antidiabetes 891 (3.67) 683 (3.31) 38 (6.41) 118 (4.86) 52 (8.50) <.0001
mellitus agents,
n (%)
Antilipidemic 366 (1.51) 296 (1.43) 10 (1.69) 44 (1.81) 16 (2.61) .0582
agents, n (%)
Diabetes mellitus, 3151 (12.97) 2365 (11.44) 152 (25.63) 433 (17.82) 201 (32.84) <.0001
n (%)
Dyslipidemia, 10 444 (42.98) 8710 (42.15) 313 (52.78) 1096 (45.10) 325 (53.10) <.0001
n (%)
Body mass index, 26.13 ± 3.47 26.06 ± 3.44 26.60 ± 3.54 26.41 ± 3.48 27.05 ± 4.02 <.0001
kg/m2
Systolic blood 147.50 ± 17.54 146.80 ± 17.15 152.79 ± 21.19 150.42 ± 18.33 154.41 ± 19.63 <.0001
pressure, mm
Hg
Diastolic blood 92.40 ± 10.43 92.08 ± 10.17 95.00 ± 12.39 93.62 ± 11.23 95.60 ± 12.38 <.0001
pressure, mm
Hg
Fasting blood 5.68 ± 1.83 5.60 ± 1.68 6.43 ± 2.53 5.93 ± 2.25 6.79 ± 2.98 <.0001
glucose, mmol/L
Total cholesterol, 5.16 ± 1.10 5.16 ± 1.07 5.32 ± 1.19 5.07 ± 1.21 5.24 ± 1.36 .0001
mmol/L
Triglycerides, 1.84 ± 1.48 1.80 ± 1.44 2.05 ± 1.58 2.00 ± 1.59 2.42 ± 1.92 <.0001
mmol/L,
Low-­density 2.43 ± 0.99 2.45 ± 0.94 2.57 ± 1.08 2.33 ± 1.23 2.29 ± 1.23 <.0001
lipoprotein,
mmol/L
High-­density 1.54 ± 0.41 1.54 ± 0.41 1.54 ± 0.46 1.58 ± 0.44 1.57 ± 0.42 <.0001
lipoprotein,
mmol/L
Estimated 79.75 (25.42) 80.23 (23.16) 80.01 (22.44) 77.57 (40.45) 72.13 (22.16) <.0001
glomerular
filtration rate,
mL/min/1.73 m²
2008-­2009 follow-­up
Current smoker, 8726 (35.91) 7410 (35.86) 209 (35.24) 890 (36.63) 217 (35.46) .8653
n (%)
Current alcohol, 9109 (37.49) 7827 (37.88) 209 (35.24) 872 (35.88) 201 (32.84) .0123
n (%)

(Continues)
WANG et al. |
      5

TA B L E   1   (Continued)

Change of proteinuria

Variable Total No proteinuria Remittent proteinuria Incident proteinuria Persistent proteinuria P value

Active physical 5513 (22.69) 4869 (23.56) 135 (22.77) 396 (16.30) 113 (18.46) <.0001
activity, n (%)
Antihypertension 4855 (19.98) 3988 (19.30) 159 (26.81) 523 (21.52) 185 (30.23) <.0001
agents, n (%)
Antidiabetes 1192 (4.91) 880 (4.26) 61 (10.29) 169 (6.95) 82 (13.40) <.0001
mellitus agents,
n (%)
Antilipidemic 366 (1.51) 296 (1.43) 10 (1.69) 44 (1.81) 16 (2.61) .0582
agents, n (%)
Diabetes mellitus, 1812 (7.46) 1351 (6.54) 83 (14.00) 257 (10.58) 121 (19.77) <.0001
n (%)
Dyslipidemia, 2493 (10.26) 2117 (10.24) 70 (11.80) 221 (9.09) 85 (13.89) .0031
n (%)
Body mass index, 25.87 ± 3.45 25.83 ± 3.43 26.19 ± 3.44 25.95 ± 3.52 26.56 ± 3.91 <.0001
kg/m2
Systolic blood 144.52 ± 20.09 143.59 ± 19.58 148.35 ± 20.94 149.13 ± 22.32 154.06 (21.44) <.0001
pressure, mm
Hg
Diastolic blood 90.70 ± 11.87 90.31 ± 11.61 91.43 ± 12.32 92.83 ± 13.09 94.62 ± 13.31 <.0001
pressure, mm
Hg
Fasting blood 5.95 ± 2.05 5.85 ± 1.90 6.41 ± 2.20 6.37 ± 2.73 7.15 ± 2.96 <.0001
glucose, mmol/L
Total cholesterol, 5.17 ± 1.56 5.16 ± 1.56 5.30 ± 1.22 5.23 ± 1.73 5.42 ± 1.29 <.0001
mmol/L
Triglycerides, 1.79 ± 1.97 1.75 ± 1.92 2.04 ± 1.85 1.88 ± 2.10 2.38 ± 2.84 <.0001
mmol/L,
Low-­density 2.71 ± 1.36 2.70 ± 1.40 2.83 ± 0.98 2.79 ± 1.73 2.80 ± 0.96 <.0001
lipoprotein,
mmol/L
High-­density 1.52 ± 0.62 1.51 ± 0.49 1.64 ± 1.77 1.51 ± 0.95 1.49 ± 0.48 .0004
lipoprotein,
mmol/L
Estimated 82.01 ± 21.53 82.90 ± 21.26 82.14 ± 22.89 76.43 ± 21.45 73.96 ± 24.32 <.0001
glomerular
filtration rate,
mL/min/1.73 m²
All-­t ype stroke, 1197 (4.93) 920 (4.45) 42 (7.08) 183 (7.53) 52 (8.50) <.0001
n (%)
Ischemic stroke 1003 (4.13) 779 (3.77) 36 (6.07) 143 (5.88) 45 (7.35) <.0001
Intracerebral 203 (0.84) 151 (0.73) 6 (1.01) 38 (1.56) 8 (1.31) .0002
hemorrhage
Subarachnoid 31 (0.13) 23 (0.11) 0 (0.00) 7 (0.29) 1 (0.16) .1040
hemorrhage

and stroke subtypes (ischemic stroke and hemorrhagic stroke).
Notably, each degree of proteinuria decline was associated with
a significant 12% reduction of stroke risk (HR 0.88, 95% CI, 0.82-­
0.93), independent from age, sex, and other potential risk fac-
tors. Findings were consistent for stroke subtypes, with a 11%
decrease (HR 0.89, 95% CI, 0.83-­0 .96) for ischemic stroke and
a 19% decrease (HR 0.81, 95% CI, 0.70-­0 .94) for intracerebral
hemorrhage. Sensitivity analysis yielded the same pattern of re-
sults in this entire test.
Figure 2 shows 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 par-
ticipants in the other groups during the 6.89-­year follow-­up period for
total stroke events (log-­rank test, P < .01) (Figure 2A), ischemic stroke
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6       WANG et al.

TA B L E   2   Stroke incidence rate and hazard ratios for stroke risk by proteinuria in participants with hypertension in 2006 and 2008

Proteinuria Stroke Ischemic stroke Intracerebral hemorrhage

2006-­2007 follow-­up − Ref Ref Ref

a
Trace 1.26 (1.04-­1.54) 1.25 (1.01-­1.54) 1.57 (1.01-­2.43)
+ 1.01 (0.73-­1.39) 1.08 (0.77-­1.51) 0.63 (0.23-­1.71)
++ 1.25 (0.84-­1.86) 1.36 (0.90-­2.05) 0.96 (0.30-­3.03)
+++ 2.51 (1.71-­3.70) 2.19 (1.40-­3.43) 4.01 (1.86-­8.63)
2008-­2009 follow-­up − Ref Ref Ref
Tracea 1.57 (1.18-­2.09) 1.72 (1.27-­2.31) 1.29 (0.60-­2.78)
+ 1.48 (1.25-­1.76) 1.37 (1.13-­1.66) 1.71 (1.15-­2.54)
++ 1.15 (0.84-­1.58) 1.13 (0.80-­1.59) 1.58 (0.82-­3.04)
+++ 1.57 (1.05-­2.36) 1.49 (0.95-­2.34) 1.77 (0.71-­4.39)
a
Adjusted for age, gender, current smoker, current alcohol user, physical activity, body mass index, diabetes mellitus, dyslipidemia, total cholesterol,
high-­density lipoprotein, systolic blood pressure, fasting blood glucose, and eGFR.

TA B L E   3   Stroke incidence rate and hazard ratios for stroke risk by changes in proteinuria in participants with hypertension

Changes in proteinuria

Per degree
No proteinuria Remittent proteinuria Incident proteinuria Persistent proteinuria decreasea

All-­t ype stroke

Incidence rate, per 6.32 8.76 10.96 13.87
1000 person-­years
Model 1 Reference 1.37 (1.11-­1.69) 1.63 (1.38-­1.92) 2.04 (1.65-­2.53) 0.82 (0.79-­0.90)
Model 2 Reference 1.36 (1.10-­1.68) 1.60 (1.35-­1.89) 1.99 (1.61-­2.47) 0.85 (0.79-­0.90)
Model 3 Reference 1.20 (0.87-­1.64) 1.41 (1.05-­1.77) 1.49 (1.25-­1.89) 0.88 (0.82-­0.93)
Sensitive analysisb Reference 1.21 (0.88-­1.69) 1.40 (1.04-­1.80) 1.51 (1.27-­1.88) 0.92 (0.86-­0.95)
Ischemic stroke
Incidence rate, per 5.29 7.53 8.93 11.39
1000 person-­years
Model 1 Reference 1.40 (1.12-­1.76) 1.60 (1.34-­1.92) 2.02 (1.60-­2.56) 0.86 (0.80-­0.92)
Model 2 Reference 1.39 (1.11-­1.74) 1.57 (1.31-­1.89) 1.97 (1.55-­2.49) 0.86 (0.80-­0.93)
Model 3 Reference 1.19 (0.84-­1.67) 1.36 (1.12-­1.65) 1.41 (1.03-­1.94) 0.89 (0.83-­0.96)
Sensitive analysisb Reference 1.20 (0.85-­1.69) 1.37 (1.13-­1.67) 1.42 (1.03-­1.96) 0.95 (0.88-­0.97)
Intracerebral hemorrhage
Incidence rate, per 1.04 1.33 1.83 2.64
1000 person-­years
Model 1 Reference 1.29 (0.76-­2.19) 1.65 (1.11-­2.46) 2.38 (1.46-­3.87) 0.80 (0.69-­0.92)
Model 2 Reference 1.29 (0.76-­2.18) 1.65 (1.11-­2.47) 2.40 (1.47-­3.91) 0.79 (0.68-­0.92)
Model 3 Reference 1.15 (0.50-­2.61) 1.99 (1.35-­2.93) 2.49 (1.71-­3.10) 0.81 (0.70-­0.94)
b
Sensitive analysis Reference 1.15 (0.50-­2.62) 2.04 (1.38-­3.00) 2.34 (1.61-­2.93) 0.87 (0.75-­1.01)

Model 1: adjusted for age and gender.

Model 2: adjusted for age, gender, current smoker, current alcohol user, physical activity, and body mass index.
Model 3: adjusted for variables in model 2 plus diabetes mellitus, dyslipidemia, total cholesterol, high-­density lipoprotein, systolic blood pressure,
fasting blood glucose, and eGFR.
a
Adjusted for proteinuria at baseline survey in addition to model 1, 2 and 3, respectively.
b
Adjusted for model 3 and further excluded individuals with an estimated glomerular filtration rate < 30 mL/min per 1.73 m2 in 2008.
WANG et al. |
      7

F I G U R E   2   Kaplan-­Meier curve of (A)

all-­t ype stroke incidence rate; (B) ischemic
stroke incidence rate; (C) intracerebral
hemorrhage incidence rate by changes
in proteinuria in participants with
hypertension
 |
8       WANG et al.
(log-­rank test, P < .01) (Figure 2B), and hemorrhagic stroke (log-­rank
test, P < .01) (Figure 2C).
No interactions of proteinuria with diabetes mellitus (P = .14) or
sex (P = .25) were found.
4 |  D I S CU S S I O N
In our study, the presence of proteinuria as detected by urine dip-
stick screening independently predicted an increased risk for incident
stroke during median 6.89 years of follow-­up. We observed significant
associations of changes in proteinuria and the incidence of stroke and
subtypes in the Chinese hypertensive population. This relationship
persisted independently of other known major risk factors, including
diabetes mellitus, dyslipidemia, and obesity. No interactions of protein-
uria with sex contribute to this relationship. Compared with changes
in proteinuria, proteinuria levels in different years are not consistent.
This result indicated that compared with single measurement, changes
in proteinuria might be a more stable risk factor for stroke.
Proteinuria has acted as a risk multiplier of cardiovascular risk
and mortality across all stages of kidney disease.17 Assessing pro-
teinuria using the simple urine dipstick test could be a convenient
way to reflect an individual’s systematic vasculature permeability
18
and susceptibility to target organ damage. Previous studies have
reported that baseline proteinuria was associated with a higher
6,19
stroke risk, with the risk greatest for ischemic stroke. A recent
study from the China Stroke Primary Prevention Trial also found
that baseline proteinuria as measured by dipstick was an indepen-
dent risk factor for first incident stroke and ischemic stroke.20 A
meta-­analysis of cohort studies or randomized controlled trials also
21
concluded that increasing albuminuria increased the risk of stroke.
Findings from the current study extend those from previous stud-
ies. 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. As proteinuria often changes dynamically, showing
regression or progression,9 changes in proteinuria are more likely
to reflect the risk of stroke, compared with proteinuria collected
at a single time point in the hypertensive population. Previous
study showed a 10% proteinuria reduction corresponded to 29%
reduction of stroke in people with hypertension and/or diabetes.22
Current result showed that each degree of proteinuria decline was
associated with a significant 12% reduction of future stroke risk.
This reinforces the concept that stroke risk is reduced when pro-
teinuria is diminished, independent of other traditional cardiovas-
cular risk factors.
Our study investigated this association by distinguishing between
ischemic and hemorrhagic stroke, as the patterns of results were con-
sistent with total stroke. The effect size of changes in proteinuria for
risks of stroke subtypes including ischemic stroke and hemorrhagic
stroke was similar. In accordance with this result, previous studies
also showed albuminuria was significant association with both stroke
types.23
Chronic kidney disease was highly prevalent among patients with
type 2 diabetes mellitus.24 According to previous studies, proteinuria
was believed to be associated with diabetes mellitus. 41% increased
risks for persistent proteinuria development over 20 years were
found among 1304 participants with diabetes in the DCCT/EDIC
study.25 Elevated insulin levels are associated with increased vascular
inflammation and, hence, the connection with proteinuria.26 It is im-
portant to emphasize that this result showed there was no evidence
of effect modification by diabetes mellitus. Changes in proteinuria
are associated with stroke in the hypertensive population ignoring
diabetes status. As corroboration, results from other studies also
demonstrated that any degree of proteinuria is a risk factor for car-
diovascular events in individuals with or without diabetes mellitus.27
Screening for proteinuria to identify people at high risk of stroke is
essential in the hypertensive population regardless of the diabetes
status.
The mechanism linking proteinuria to stroke risk remains ob-
scure. The Steno hypothesis suggested that proteinuria not only
reflects localized renal damage but also is an independent marker
of systemic vascular endothelial dysfunction or microvascular dis-
ease.28 Proteinuria is associated with several inflammatory and
thrombogenic factors, which play important roles in the devel-
opment of atherosclerosis and stroke.21 Otherwise, proteinuria
is associated with a high prevalence of traditional cardiovascular
risk factors, such as hypertension and diabetes. Proteinuria may be
a sign of shared risk factors for vascular disease and not a direct
cause of new strokes. Urine protein change over time can be an
indicator for the severity of those stroke risk factors. In the hyper-
tensive population, proteinuria and hypertension have reciprocal
effects.7 Increased proteinuria in hypertensive patients is consid-
ered an early manifestation of generalized vascular impairment,
which is regarded to be an important marker of the risk of renal
and cardiovascular events.29 According to these findings, we should
pay more attention to proteinuria, especially in the hypertensive
population. Hypertension and proteinuria are both clinical mani-
festation of renal disease, both also playing important roles in car-
diovascular and cerebrovascular events. Whether proteinuria is a
therapeutic target for stroke warrants clinical attention and further
investigations.
Strengths of our study were the ability to consider dynamic as-
pects of proteinuria using the biennial assessment of proteinuria to
estimate the risk of stroke, the prospective design, use of a large
cohort, and long follow-­up period. Our results should be interpreted
in the context of some limitations. First, awareness of the limita-
tions of the dipstick test is necessary. The dipstick method could
overlook proteinuria.14 A timed 24 hours urine collection or albu-
min:creatinine ratio might be more precise in measuring proteinuria,
although dipstick has a cost advantage.30 Second, we have adjusted
confounding variables when evaluating the proteinuria recorded in
different years, but there were still some factors we failed to take
into consideration. Last, unlike a randomized clinical trial, protein-
uria could be associated with substantial morbidity and mortality in
the population we excluded, which might be especially vulnerable
WANG et al.
to bias due to attrition. Additionally, proteinuria may be a sign of
shared risk factors for vascular disease and chronic kidney disease.
The association between proteinuria and stroke may contributed by
multiple effect. Specific diseases such as chronic glomerulonephritis
cannot be simply ruled out. Urine protein change over time can be
an indicator for the severity of those stroke risk factors. Because
observational study is unable to determine causality in its findings,
whether changes in proteinuria are a risk factor or treatment target
needs more exploration.
5 | CO N C LU S I O N S
In conclusion, we emphasized that changes in proteinuria, particu-
larly persistent proteinuria, were significantly associated with inci-
dent stroke in participants with hypertension. Our study provides
valuable information to public health and medical professionals by
examining a dynamic relationship between changes in proteinuria
and incident stroke in the hypertensive population.
C O N FL I C T O F I N T E R E S T
None of the authors have competing financial interests to declare.
ORCID
Yongjun Wang  http://orcid.org/0000-0002-7189-2523
Yilong Wang  http://orcid.org/0000-0003-2725-2788
REFERENCES
1. Li H, Meng Q, Sun X, Salter A, Briggs NE, Hiller JE. Prevalence,
awareness, treatment, and control of hypertension in rural
China: results from Shandong Province. J Hypertens. 2010;28:
432‐438.
2. Dries DL, Exner DV, Domanski MJ, Greenberg B, Stevenson LW.
The prognostic implications of renal insufficiency in asymptomatic
and symptomatic patients with left ventricular systolic dysfunction.
J Am Coll Cardiol. 2000;35:681‐689.
3. Best PJ, Lennon R, Ting HH, et al. The impact of renal insufficiency
on clinical outcomes in patients undergoing percutaneous coronary
interventions. J Am Coll Cardiol. 2002;39:1113‐1119.
4. Manjunath G, Tighiouart H, Ibrahim H, et al. Level of kidney func-
tion as a risk factor for atherosclerotic cardiovascular outcomes in
the community. J Am Coll Cardiol. 2003;41:47‐55.
5. Ovbiagele B. Microalbuminuria: risk factor and potential therapeu-
tic target for stroke? J Neurol Sci. 2008;271:21‐28.
6. Lee M, Saver JL, Chang KH, Liao HW, Chang SC, Ovbiagele B.
Impact of microalbuminuria on incident stroke: a meta-­analysis.
Stroke. 2010;41:2625‐2631.
7. Tenekecioglu E, Yilmaz M, Yontar OC, et al. Microalbuminuria in un-
treated prehypertension and hypertension without diabetes. Int J
Clin Exp Med. 2014;7:3420‐3429.
8. Guan T, Ma J, Li M, et al. Rapid transitions in the epidemiology of
stroke and its risk factors in China from 2002 to 2013. Neurology.
2017;89:53‐61.
|
      9
9. Brantsma AH, Bakker SJ, de Zeeuw D, de Jong PE, Gansevoort
RTGroup PS. Extended prognostic value of urinary albumin excretion
for cardiovascular events. J Am Soc Nephrol. 2008;19:1785‐1791.
10. Zhang Q, Zhou Y, Gao X, et al. Ideal cardiovascular health metrics
and the risks of ischemic and intracerebral hemorrhagic stroke.
Stroke. 2013;44:2451‐2456.
11. Wang A, Chen S, Wang C, et al. Resting heart rate and risk of cardio-
vascular diseases and all-­cause death: the Kailuan study. PLoS ONE.
2014;9:e110985.
12. Peng M, Wu S, Jiang X, Jin C, Zhang W, Kailuan Cardiovascular
Survey G. Long-­term alcohol consumption is an independent risk
factor of hypertension development in northern China: evidence
from Kailuan study. J Hypertens. 2013;31:2342‐2347.
13. Liu X, Cui L, Wang A, et al. Cumulative exposure to ideal cardio-
vascular health and incident diabetes in a Chinese population: the
Kailuan study. J Am Heart Assoc. 2016;5:e004132.
14. White SL, Yu R, Craig JC, Polkinghorne KR, Atkins RC, Chadban SJ.
Diagnostic accuracy of urine dipsticks for detection of albuminuria
in the general community. Am J Kidney Dis. 2011;58:19‐28.
15. Li Z, Wang A, Cai J, et al. Impact of proteinuria and glomerular filtra-
tion rate on risk of ischaemic and intracerebral hemorrhagic stroke:
a result from the Kailuan study. Eur J Neurol. 2015;22:355‐360.
16. 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.
17. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic
kidney disease and cardiovascular risk: epidemiology, mechanisms,
and prevention. Lancet. 2013;382:339‐352.
18. Eckardt KU, Coresh J, Devuyst O, et al. Evolving importance of
kidney disease: from subspecialty to global health burden. Lancet.
2013;382:158‐169.
19. Zhang C, Wang X, He M, et al. Proteinuria is an independent risk
factor for first incident stroke in adults under treatment for hyper-
tension in China. J Am Heart Assoc. 2015;4:e002639.
20. Zhang Y, Zhang T, Zhang C, et al. Identification of reciprocal cau-
sality between non-­alcoholic fatty liver disease and metabolic syn-
drome by a simplified Bayesian network in a Chinese population.
BMJ Open. 2015;5:e008204.
21. 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.
22. Savarese G, Dei Cas A, Rosano G, et al. Reduction of albumin urinary
excretion is associated with reduced cardiovascular events in hyper-
tensive and/or diabetic patients. A meta-­regression analysis of 32 ran-
domized trials. Int J Cardiol. 2014;172:403‐410.
23. Mahmoodi BK, Yatsuya H, Matsushita K, et al. Association of kidney dis-
ease measures with ischemic versus hemorrhagic strokes: pooled analyses
of 4 prospective community-­based cohorts. Stroke. 2014;45:1925‐1931.
24. Low SK, Sum CF, Yeoh LY, et al. Prevalence of chronic kidney disease
in adults with type 2 diabetes mellitus. Ann Acad Med Singapore.
2015;44:164‐171.
25. Boger CA, Chen MH, Tin A, et al. CUBN is a gene locus for albumin-
uria. J Am Soc Nephrol. 2011;22:555‐570.
26. Bakris GL, Molitch M. Microalbuminuria as a risk predictor in diabe-
tes: the continuing saga. Diabetes Care. 2014;37:867‐875.
27. Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardio-
vascular events, death, and heart failure in diabetic and nondiabetic
individuals. JAMA. 2001;286:421‐426.
28. 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.
29. Leoncini G, Sacchi G, Viazzi F, et al. Microalbuminuria identifies
overall cardiovascular risk in essential hypertension: an artificial
neural network-­based approach. J Hypertens. 2002;20:1315‐1321.
 |
10       WANG et al.

3 0. Levin A, Stevens PE. Summary of KDIGO 2012 CKD Guideline: be-

hind the scenes, need for guidance, and a framework for moving How to cite this article: Wang A, Dai L, Su Z, et al.
forward. Kidney Int. 2014;85:49‐61. Proteinuria and risk of stroke in patients with hypertension:
The Kailuan cohort study. J Clin Hypertens. 2018;00:1–10.

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