Prevalence and risk factors for cardiovascular disease among chronic kidney disease patients: results from the Chinese cohort study of chronic kidney disease (C-STRIDE)
Yuan et al. BMC Nephrology
Prevalence and risk factors for cardiovascular disease among chronic kidney disease patients: results from the Chinese cohort study of chronic kidney disease (C-STRIDE)
Jun Yuan 0
Xin-Rong Zou 0
Si-Ping Han 0
Hong Cheng 0
Xiao-Qin Wang 0
on behalf of the C-STRIDE study group
0 Renal Division, Department of Medicine, Hubei Provincial Hospital of Traditional Chinese Medicine, The Affiliated Hospital of Hubei University of Chinese Medicine , Wuhan 430061 , China
Background: Although a high incidence of cardiovascular disease (CVD) is observed among chronic kidney disease (CKD) patients in developed countries, limited information is available about CVD prevalence and risk factors in the Chinese CKD population. The Chinese Cohort of Chronic Kidney Disease (C-STRIDE) was established to investigate the prevalence and risk factors of CVD among Chinese CKD patients. Methods: Participants with stage 1-4 CKD (18-74 years of age) were recruited at 39 clinical centers located in 28 cities from 22 provinces of China. At entry, the socio-demographic status, medical history, anthropometric measurements and lifestyle behaviors were documented, and blood and urine samples were collected. Estimated glomerular filtration rate (eGFR) was calculated by the CKD-EPI creatinine equation. CVD diagnosis was based on patient self-report and review of medical records by trained staff. A multivariable logistic regression model was used to estimate the association between risk factors and CVD. Results: Three thousand four hundred fifty-nine Chinese patients with pre-stage 5 CKD were enrolled, and 3168 finished all required examinations and were included in the study. In total, 40.8% of the cohort was female, with a mean age of 48.21 ± 13.70 years. The prevalence of CVD was 9.8%, and in 69.1% of the CVD cases cerebrovascular disease was observed. Multivariable analysis showed that increasing age, lower eGFR, presence of hypertension, abdominal aorta calcification and diabetes were associated with comorbid CVD among CKD patients. The odds ratios and 95% confidence intervals for these risk factors were 3.78 (2.55-5.59) for age 45-64 years and 6.07 (3.89-9. 47) for age ≥65 years compared with age <45 years; 2.07 (1.28-3.34) for CKD stage 3a, 1.66 (1.00-2.62) for stage 3b, and 2.74 (1.72-4.36) for stage 4 compared with stages 1 and 2; 2.57 (1.50-4.41) for hypertension, 1.82 (1.23-2.70) for abdominal aorta calcification, and 1.70 (1.30-2.23) for diabetes, respectively. Conclusions: We reported the CVD prevalence among a CKD patient cohort and found age, hypertension, diabetes, abdominal aorta calcification and lower eGFR were independently associated with higher CVD prevalence. Prospective follow-up and longitudinal evaluations of CVD risk among CKD patients are warranted.
Cardiovascular Disease; Cerebrovascular Disease; Chronic Kidney Disease; Cohort Study; C-STRIDE; Epidemiology; Hypertension; Risk Factors
The prevalence of chronic kidney disease (CKD) has
increased dramatically in economically developed
countries as well as in developing countries. It is
estimated that CKD has affected more than 100
million Chinese . Many studies have showed a high
incidence of cardiovascular disease (CVD) among CKD
patients. The prevalence of CVD in CKD was 26.8%,
33.4%, 47.2%, and 39.1%, in CKD-ROUTE (Japan), CRIC
(US), CRISIS (UK) and MERENA (Spain), respectively
[2–5]. The mortality rate of end-stage renal disease
(ESRD) was above 20% per year despite the use of
dialysis, and more than half of the death was related
to CVD . Lower estimated glomerular filtration
rate (eGFR) has been recognized as a strong and
independent risk factor for CVD . Other predictive
factors contributing to higher prevalence of CVD in
CKD, including hypertension, diabetes mellitus (DM),
dyslipidemia, anemia (hemoglobin < 110 g/L), and
albuminuria, have also been investigated substantively
in epidemiological studies [2–5]. Thus, early detection
and treatment of these risk factors is a key strategy in
the prevention of CVD in CKD. However, little is
known about the prevalence and risk factors for CVD
among the Chinese population with established CKD
whose genetic and economic heterogeneities are
different from those in developed countries.
Therefore, we have established the Chinese cohort
study of chronic kidney disease (C-STRIDE), the first
national prospective CKD cohort of Chinese population. It
was designed to explore risk factors for CKD progression
and adverse consequences, especially CVD events. The
purpose of the current study is to examine the baseline
characteristics of this cohort and to identify risk factors
for CVD in CKD patients.
The design and methods of the C-STRIDE study were
published in details previously . The study is an
ongoing multicenter prospective project involving 39
clinical centers located at 28 cities in 22 provinces of China
(Fig. 1). The enrollment was carried out between
November 2011 and March 2016. Altogether, 3459 Chinese
patients with pre-stage 5 CKD were enrolled, and 3168
of them finished all required examinations and are
included in the study.
The Renal Institute of Peking University organized the
C-STRIDE study and established a steering committee
consisting of nephrologists, epidemiologists and
statisticians to provide training course for the research staff
who performed the clinical procedures. A manual of
operation procedure (MOP) was drawn up to ensure all
aspects of the study were carried out in a standard and
CKD stages were determined by the KDIGO
classification . eGFR was determined with the CKD-EPI
creatinine equation using serum creatinine (SCr) measured
by the Roche enzymatic method . For GN patients,
the eGFR should be ≥15 ml/min/1.73 m2. For DN
patients, the defining eligibility is 15 ml/min/1.73 m2 ≤
eGFR < 60 ml/min/1.73 m2 or eGFR ≥ 60 ml/min/
1.73 m2 with “nephrotic range” proteinuria, defined as
24-h urinary protein ≥3.5 g or urinary albumin
creatinine ratio (UACR) ≥2 000 mg/g. For non-GN and
nonDN patients, 15 ml/min/1.73 m2 ≤ eGFR < 60 ml/min/
1.73 m2 was the cutoff for enrollment.
Clinical information and biological specimens for each
patient were collected at entry. Their socio-demographic
status (age, gender, income, region, education), etiology
of kidney disease, health history (hypertension, diabetes,
and cardiovascular disease), lifestyle (smoking, exercise)
and body mass index (BMI) were documented.
Anthropometric measurements (weight, height, waist
circumference, hip circumference, resting blood pressure,
heart rate) were recorded. Electrocardiogram, abdominal
aorta calcification (AAC) and 24-h urine protein were
determined with standardized procedures at all centers.
Biochemical parameters including SCr, calcium,
phosphorus, hemoglobin (Hb), fasting glucose, hemoglobin
A1C (HbA1c), triglyceride (TG), total cholesterol (TC),
high density lipoprotein cholesterol (HDL-C), low density
lipoprotein cholesterol (LDL-C), intact parathyroid
hormone (iPTH) and high-sensitivity C-reactive protein
(hs-CRP) were measured in a central laboratory to avoid
testing variations among laboratories.
Definition of hypertension, diabetes, and cardiovascular
Hypertension at entry was defined as either systolic
blood pressure >140 mmHg, or diastolic blood pressure
>90 mmHg (confirmed by at least three elevated
readings taken at least 1 week apart), or use of
antihypertensive medications, or any self-reported history of
hypertension. In addition, 24-hour ambulatory blood
pressure was measured for every participant. Diabetes
mellitus was defined as either a fasting glucose
≧7.0 mmol/L, or HbA1c ≧ 6.5%, or use of insulin or oral
anti-diabetic medications, or any self-reported history of
diabetes. CVD was defined as a history of myocardial
infarction, hospitalization for congestive heart failure,
serious cardiac arrhythmia incidents (resuscitated
cardiac arrest, ventricular fibrillation, sustained ventricular
tachycardia, paroxysmal ventricular tachycardia, atrial
fibrillation or flutter, severe bradycardia or heart block),
peripheral arterial disease (PAD), or cerebrovascular
events (cerebral infarction, transient ischemic attack,
cerebral hemorrhage or subarachnoid hemorrhage).
Reporting of CVD was based on both the patients’
selfFig. 1 The distribution of the 39 clinical sites of the C-STRIDE Study and population size of each province in China in 2013. a The distribution of
the clinical sites in China. The hollow triangles represent for the clinical sites in China. b The population size of each province in China in 2013
report and review of their medical records by trained
staff on the same date of the baseline interview.
The statistical analysis for C-STRIDE has been
previously described . Baseline values are presented as
mean ± standard deviation (SD) or medians and
interquartile ranges for continuous variables, and as numbers
and percentages for categorical data. Baseline
characteristics were compared between groups using analysis of
variance (ANOVA), or chi-square tests, as appropriate. If
the distribution of the continuous variable did not satisfy
normal distribution, the Kruskal-Wallis rank sum test
was used. The cardiovascular risk factors were analyzed
with covariates with multivariable logistic regression
models. The crude and multivariable adjusted odds
ratios (aOR) with 95% confidence interval (CI) are
presented. Covariates included in the multivariable logistic
regression models were gender, age (18–44 (as reference)
vs 45–64 vs 65–74), smoking history (yes or no),
exercises more than 3.5 h per week (yes or no), hypertension
(yes or no), SBP > 130 mmHg (yes or no), diabetes (yes
or no), BMI≧24.0 kg/m2 (yes or no), CKD stages (stage
1–2 (as reference) vs 3a vs 3b vs 4), Hb < 11 g/dl (yes or
no), serum calcium <8.4 mg/dl (yes or no), serum
phosphorus > 4.5 mg/dl (yes or no), iPTH > 65 pg/ml (yes or
no), LDL-C > 120 mg/dl (yes or no), HDL-C < 35 mg/dl
(yes or no), TG > 150 mg/dl (yes or no), AAC (yes or
All P values are two-sided, and P < 0.05 was
considered statistically significant. Analyses were conducted
with SAS software (version 9.4).
Baseline demographic and clinical characteristics
Anticipated and actual target distributions of CKD
etiology and renal function are shown in Additional file 1:
Table S1. The actual percentage of participants with
glomerulonephritis (GN) was 60.6%, two times higher
than the targeted 30%. The percentages of diabetic
nephropathy (DN) and other causes were 13.9% and 25.6%,
much lower than the anticipated 30% and 40%,
respectively. Other causes include hypertensive renal damage,
chronic pyelonephritis, hyperuricemic nephropathy,
tubulointerstitial lesion and obstructive nephropathy.
The proportions of participants with eGFR (ml/min/
1.73 m2) < 45 and ≥45 were 53.5% and 46.5%, consistent
with the target of 40–60%. The proportions of
participants in CKD stage 1 and 2, stage 3a, stage 3b and stage
4 were 30.8%, 15.7%, 24.3%, and 29.3%, respectively.
The baseline demographic characteristics of the cohort
are shown in Table 1. The final enrolled cohort had a
mean age of 48.21 ± 13.7 years with 40.8% of women.
Totally, 56.0% of the enrollments completed a high
school education, and 36.1% had annual income ≦RMB
30,000 Yuan. The 2015 per capita disposable income of
urban residents in China is RMB 31,195 Yuan “(http://
tml)”. The cohort is regionally diverse with 916 (28.9%)
subjects from south of Yellow River and 2252 (71.1%)
patients from the north. Mean BMI was 24.47 kg/m ,
with 53.4% of all participants having a BMI ≧24 kg/m .
38.2% of the cohort participants were current smokers,
and almost half of the participants exercised less than
3.5 h per week. Table 1 indicated that the CKD
participants with CVD were more likely to be older, male, from
the north, current smokers, and higher BMI than those
without CVD (P < 0.005).
Baseline CVD prevalence in different stages of CKD
The baseline CVD prevalence in different stage of CKD is
shown in Table 2. The overall CVD prevalence of the
cohort was 9.8%, in which the percentages of MI, CHF,
cerebrovascular disease and PAD were 20.6%,9.0%,69.1% and
16.1%, respectively. The prevalence of cerebrovascular
Table 1 Baseline demographic characteristics of participants of C-STRIDE Study (Nov 2011–Mar 2016)
≤ 30 000 yuan
> 30 000 yuan
BMI category (kg/m2)
eGFR (ml/min/1.73 m2)
Junior high school degree or below
High school degree or above
(n = 3168)
(n = 311)
(n = 2857)
Continuous variables are presented as mean ± SD. Categorical data are presented as numbers (n) of patients and percentages. BMI body mass index
events was significantly higher than that of other
cardiovascular events. The participants with advanced CKD
were more likely to have CVD. The prevalence of MI
increased with declining eGFR, with percentage of 0.6, 1.8,
2.9, 2.9%, respectively (P for trend = 0.001). The same
pattern was observed with cerebrovascular disease (P for
trend < 0.001) and PAD (P for trend = 0.001). The
proportions of MI, cerebrovascular disease and PAD were
significant higher in CKD stages 3b and 4 (eGFR < 45 ml/min/
1.73 m2) (P < 0.001). The proportion of CHF presented a
gradual increment with CKD progression, but no
significant difference was observed through eGFR groups (P for
trend = 0.14).
Traditional CVD risk factors
Table 3 shows the baseline characteristics of the
traditional risk factors for CVD. Comparisons between
patients with and without CVD are presented. The
participants with CVD were more likely to have
hypertension and diabetes (P < 0.001). SBP, blood glucose and
HbA1C were significantly higher in CKD participants
with CVD than without CVD (P < 0.001). The TC,
LDLC and HDL-C were also different with and without CVD
(P < 0.05). However, no significant difference was
observed in DBP (P = 0.83) or TG (P = 0.72).
Lower lipid levels were observed in the CVD-CKD
population compared to the non-CVD CKD population
(P < 0.001). The CVD population likely attracts more
attention for hyperlipidemia and receives prescription
medications for lowering lipid levels, whereas the
nonCVD population is less likely to receive treatment. This
is confirmed by our finding that the proportion of statin
treatment was 37.9% in the CVD patients versus 17.0%
in the non-CVD patients.
Non-traditional CVD risk factors
Table 4 shows the baseline characteristics of
nontraditional risk factors for CVD. The participants with
CVD had higher SCr than those without CVD (P < 0.001).
iPTH and abdominal aorta calcification were significantly
different with and without CVD as well (P < 0.001).
Significant difference was also found in hemoglobin and
HsCRP (P < 0.05). There were no significant differences in
UTP/24 h, serum calcium and phosphorus.
Table 3 Baseline characteristics of traditional risk factors characteristics for CVD in C-STRIDE Study (Nov 2011–Mar 2016)
Blood glucose (mg/dl)
Continuous variables are presented as mean ± SD. Categorical data are presented as numbers (n) of patients and percentages. SBP systolic blood pressure, DBP
diastolic blood pressure, G-Hb glycosylated hemoglobin, TC total cholesterol, LDL-C low density lipoprotein cholesterol, HDL-C high density lipoprotein cholesterol,
Table 4 Baseline characteristics of non-traditional risk factors characteristics for CVD in C-STRIDE Study (Nov 2011–Mar 2016)
Continuous variables are presented as mean ± SD, or median with interquartile ranges. Categorical data are presented as numbers (n) of patients. SCr serum
creatinine, AAC abdominal aorta calcification, hs-CRP high-sensitivity C-reactive protein
eGFR (ml/min/1.73 m2)
Urine protein/24 h (g)
Serum calcium (mg/dl)
Serum phosphorus (mg/dl)
Total iPTH (pg/mL)
(n = 3168)
Overall CVD risk factors
The results of multiple logistic regression analysis of the
traditional and non-traditional risk factors for CVD
prevalence at enrollment are shown in Table 5. ORs
were adjusted mutually for all potential risk factors listed
in the table. In multivariable analysis, the variables
significantly associated with the presence of CVD were age,
hypertension, diabetes mellitus, CKD stage, and AAC.
The risk factors of CVD with higher ORs were older age
(OR: 3.78; 95% CI: 2.55–5.59) (P < 0.001) in age 45–64
years, (OR: 6.07; 95% CI: 3.89–9.47) (P < 0.001) in age
65–74 years), followed by lower eGFR (OR: 2.07;95%
CI:1.28–3.34) in CKD stage 3a (P = 0.003), (OR: 1.66;
95% CI: 1.00–2.62) in CKD stage 3b (P = 0.032), (OR:
2.73; 95% CI: 1.72–4.36) in CKD stage 4 (P < 0.001)),
hypertension (OR: 2.57; 95% CI:1.50–4.41) (P < 0.001),
AAC (OR: 1.82; 95% CI: 1.23–2.70) (P = 0.003) and
diabetes (OR: 1.70; 95%CI:1.30–2.23) (P < 0.001).
C-STRIDE is a prospective observational multicenter
study of the risk factors for CVD in stage 1–4 CKD.
Here we investigated the prevalence and risk factors of
CVD in CKD populations. We report that the overall
prevalence of CVD among 3168 participants was 9.8% at
enrollment. The percentage of different CVD subtypes
among the subset of patients with CVD was MI 20.6%,
CHF 9.0%, cerebrovascular disease 69.1%, and PAD
10.1%, respectively. Our results also show that age,
diabetes, hypertension, abdominal aorta calcification and
stage 3 & 4 CKD are significantly associated with the
prevalence of CVD.
C-STRIDE was designed to establish a Chinese cohort
similar to the CRIC study , and to examine risk
factors for CKD progression and CVD development in
CKD patients with an eGFR between 15–90 ml/min/
1.73 m2. C-STRIDE’s cohort consists of Chinese living in
China, while CRIC is a mix of 45% White, 46% Black,
(n = 311)
(n = 2857)
and 5% Hispanic participants living in the US. There are
many differences between Chinese and Western
populations, such as ethnicity, calorie intake, and body size
. These differences are apparent between the
CSTRIDE and CRIC cohorts, which also show differences
in age, causes of CKD, prevalence of hypertension,
diabetes and CVD, BMI, and eGFR. Any of these
differences could affect the progression and treatment of
CKD. As shown in Table 6, the C-STRIDE participants
were younger with a lower average BMI, and with a
lower prevalence of diabetes, hypertension and CVD.
The C-STRIDE baseline indicated that age is an
independent and graded risk factor for CVD events in 45–74
year old patients. China is a rapidly aging society in
which more than one quarter of Chinese will be older
than 65 years by 2050 . The C-STRIDE study will
help clarify the dimension of risks for ESRD and CVD
among aging individuals with CKD. As summarized in
Tables 3, 4 and 5, the C-STRIDE cohort exhibits
numerous risk factors for CVD and several differences with the
CRIC cohort. The baseline prevalence of CVD was
33.4% in CRIC, more than three times the 9.8%
prevalence reported in C-STRIDE. The blood glucose control
in diabetic participants was also better in C-STRIDE
(mean A1C 6.0%) versus CRIC (mean A1C 7.7%).
Finally, the mean BMI in C-STRIDE was 24.47 kg/m2,
considerably lower than that in CRIC (32.1 kg/m2). A
comparison of baseline characteristics between multiple
CKD cohort studies is shown in Table 6 [2–5].
The overall CVD prevalence of 9.8% in CKD patients
is much lower than reported in developed countries
including Japan, but much higher than the overall
percentage of 1.4% in the general Chinese population . The
significantly lower prevalence of baseline CVD observed
in our study compared to similar cohorts might be
attributable to the higher average eGFR, lower prevalence
of diabetes and hypertension, and/or the younger age of
subjects. These variables have been confirmed to be
Tobacco use (yes/no)
Exercises < 3.5 h/week (yes/no)
HDL-C <35 mg/dl
LDL-C >120 mg/dl
TG >150 mg/dl
Ca <8.4 mg/dl
IPTH >65 pg/mL
Table 5 Risk factors for the prevalence of CVD in C-STRIDE Study (Nov 2011 - Mar 2016)
Note: aAll variables listed in the table were included in the multivariate adjusted analysis. OR odds ratio, CI confidence interval, LDL-C low density lipoprotein
cholesterol, HDL-C high density lipoprotein cholesterol, TG triglycerides, BMI body mass index, P serum phosphorus, Ca serum calcium, iPTH intact parathyroid
hormone, AAC abdominal aorta calcification, Hb hemoglobin
independent risk factors for CVD among CKD patients
[15–19]. Deserving additional attention is the
prominence of cerebrovascular disease among C-STRIDE
participants exhibiting CVD. This is similar to the findings
of the ROUTE study (Japan) , but different from the
MERENA (Spain)  and CRIC (USA)  studies, in
which heart disease and PAD constituted the majority of
CVD events. There are two possible explanations for the
high incidence of cerebrovascular disease. First, the
CSTRIDE study excluded CKD patients with NYHA Class
III or IV heart failure. Second, it appears that the
Chinese general population may have a higher CVA
prevalence than is observed in other countries. In a
Chinese cohort study of ischemic cardiovascular disease,
45 cases (5.4%) of ischemic stroke and 24 cases (2.9%) of
coronary heart disease were reported in 840 middle age
men followed for 20 years . The Japan Public Health
Center-based prospective Study revealed 1,565 strokes
(2.7%) among 57,017 subjects in a Japanese
populationbased cohort .
Based on the results of previous similar cohorts
including the US CRIC  and the Japan CKD-JAC 
studies, we had anticipated that the distribution of CKD
etiology in C-STRIDE would be 30% glomerulonephritis
(GN) and 30% diabetic nephropathy (DN) . However,
the actual distribution of CKD etiology was GN 60.6%
(twice as high as the targeted 30%), DN 13.9% (less than
half of the targeted 30%) and other causes 25.6%. This is
consistent with the data from the Chinese Renal Data
System, a national registry system for patients
undergoing dialysis, which revealed that in China glomerular
disease was the most common cause of ESRD (57.4%),
OR (95% CI)a
Table 6 Comparison of baseline characteristics of CKD cohort studies
Inclusion range of eGFR (ml/min/1.73 m2)
Male gender (%)
Actual eGFR (ml/min/1.73 m2)
CVD prevalence (%)
eGFR estimated glomerular filtration rate, BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, Hb hemoglobin, HDL-C high density
lipoprotein cholesterol, LDL-C low density lipoprotein cholesterol, Ca calcium, P, phosphorus, iPTH intact parathyroid hormone, CVD cardiovascular disease, g/gCr
gram per gram creatinine
followed by DN (16.4%), hypertension (10.5%), and cystic
kidney disease (3.5%) . Together, these data indicate
that the etiological constituents of CKD in China are
different from those reported in developed countries,
where the leading cause of ESRD is DN [2–5].
Nevertheless, China has the highest overall number of diabetic
patients in the world, rising rapidly from 92.4 million in
2007 to 113.9 million diabetic patients in 2013 .
Therefore, diabetes complications such as DN will likely
become the main cause of ESRD in the coming decades.
Proteinuria is considered a risk factor for CVD and
mortality in patients with CKD. Microalbuminuria, or
even normal-range albuminuria, constitutes a risk for
CVD [27–32]. For instance, the AASK study of African
Americans, which investigated the cardiovascular and
renal outcomes of 59,508 participants with stage 1–3
CKD, indicated a significantly increased risk of CVD
with higher urinary albumin excretion, despite relatively
low levels of baseline proteinuria . Likewise, in a
population-based cohort study in Taiwan, elevated
albuminuria was a key predictor of progression to CKD or
ESRD as well as indicating a higher risk of CVD and
mortality . The amount of urinary protein in the
CSTRIDE patients (0.94 g/24 h) was higher compared
with the CRIC cohort (0.17 g/24 h). In the Chinese
cohort, urine protein was not significantly associated with
CVD in CKD (P = 0.526) (Table 4). This is different from
the results found in Japan  and US , where
increased proteinuria was associated with a higher CVD
It is generally thought that albuminuria always
precedes loss of renal function in diabetic kidney disease
. However, an increasing number of studies have cast
doubt on this classic paradigm. In a large number of
recent studies, 20–39% of patients with diabetes and
reduced eGFR had normal albuminuria [34–37]. In some
clinical trials [38, 39], improvement in proteinuria did
not translate into increased GFR or reduced end points
such as the need for dialysis or death. Therefore, the role
of proteinuria in representing renal function and in
predicting adverse outcomes of CKD warrants further
research. At baseline of our study, proteinuria was not
associated with CVD. Long-term follow-up will provide
more information to help answer this question.
Over the past two decades the leading causes of
mortality and morbidity have shifted from infectious diseases
to non-communicable disease such as vascular disease,
renal disease and DM. These disorders have become
major public health problems in developed and
developing countries alike, imposing heavy economic burdens
[40, 41]. The relationship between DM and CVD has
been demonstrated in a series of studies [2–5, 42]. One
recent study reported that the prevalence of DM among
a representative sample of Chinese adults was 11.6%,
and the prevalence of pre-diabetes was 50.1% . These
statistics illustrate the importance of DM as a public
health problem in China and suggest that DM will
become the leading future cause of ESRD in China .
Indeed, DN now accounts for 46.2% and 43.2% of ESRD
cases in economically advanced regions such as Hong
Kong and Taiwan . Unfortunately, despite recent
improvements in glycemic and blood pressure control as
well as proteinuria reduction, DN remains the leading
cause of ESRD in developed countries . Therefore,
there is an urgent need for development of novel
therapeutic approaches that offer effective nephroprotection
and that block key pathogenic pathways leading to
diabetic kidney disease.
Hypertension is a main cause of secondary CKD in
China . Numerous studies have demonstrated
hypertension as an important risk factor for CVD and all
causes of mortality [24, 46, 47]. With the 24-h
ambulatory blood pressure (ABP) monitoring, the baseline of
C-STRIDE showed higher SBP and similar DBP in those
with CVD. ABP was recently demonstrated to be more
important than office blood pressure for predicting CVD
and mortality . Morning surge in blood pressure was
shown to be a predictor of stroke in elderly
hypertensives . In the CKD-JAC study, where ABP was
measured at different times to distinguish the impacts of
night and morning blood pressure, a higher morning
ABP surge was associated with CVD risk independently
. In short, nearly all studies support the importance
of effective BP management in CKD as a public health
Internationally, a BMI of 25.0–29.9 kg/m2 is
considered overweight and a BMI ≥30 kg/m2 is considered
obese. Based on the BMI data of the Chinese population,
the Working Group on Obesity of the International Life
Science Institute China Office recommended a BMI of
24 kg/m2 as the cut-off value for overweight and 28 kg/m2
as the cut-off value for obesity for Chinese . The
CSTRIDE cohort and the ROUTE cohort (Japan) 
had similar BMI, both lower than that in Western
studies [3–5]. Although some reports have suggested
higher BMI as an independent risk factor for advanced
CKD and CVD , the link between BMI and CVD is
not clear cut. Our study does not support a correlation
between higher BMI and CVD. Several studies have shown
that higher BMI was actually associated with favorable
outcomes. For instance, a BMI greater than 30 kg/m2 was
associated with lower mortality among 920 patients with
advanced CKD in a Swedish study . In the
Atherosclerosis Risk in Communities (ARIC) cohort, a higher
body size was also associated with better overall survival
in stage 3 CKD .
Our results demonstrate declining GFR as a major risk
factor for CVD prevalence in the C-STRIDE cohort. To
better examine the function of eGFR, we employed the
staging of 3a and 3b instead of a single stage 3. Although
a cohort study of Taiwan found no difference between
3a and 3b in predicting CVD incidence , we
observed significant differences in the occurrence of MI,
cerebrovascular disease and PAD between stages 3a and
3b. A multitude of studies have clearly demonstrated
that overt renal dysfunction is independently and
significantly associated with an increased risk of CVD events
and mortality [53–55]. A study from Japan indicated that
even after adjustment for other risk factors, the presence
of CKD conferred a higher risk of cardiovascular death
with a hazard ratio of 1.20 . A negative graded
correlation between eGFR and risk of cardiovascular death
was observed. The Framingham Heart Study suggested
the same association . The KORA Study
demonstrated that CKD was strongly associated with an
increased risk of incident MI and CVD mortality,
independent from common cardiovascular risk factors in
men and women . The MATISS Study suggested
that in an elderly general population with low risk of
CVD and low incidence of reduced renal function, even
a modest eGFR reduction was related to all-cause
mortality and CVD incidence .
The overall prevalence of AAC in the C-STRIDE study
baseline was 32.9%, with statistically higher percentages
in stages 3b and 4. Multiple regression analysis indicated
that AAC increases the risk for CVD in CKD. Another
Chinese study  reported an AAC incidence of 54% in
the CKD patients, and also showed a strong association
between the incidence of AAC and cardiovascular risks.
Specifically, AAC was positively correlated with left
atrial anteroposterior diameter (LAD), pulmonary
arterial systolic pressure (PASP) and carotid artery
intimamedia thickness (IMT), and negatively correlated with
ejection fraction (EF) and shortening fraction (SF) .
A cohort study performed on adult Japanese patients
with pre-dialysis CKD demonstrated 82% subjects had
AAC, and identified AAC as independent predictors for
de novo cardiovascular events in CKD stages 4 and 5
. A US study  evaluated the association of AAC
and CVD in 1974 randomly selected subjects (45 to
84 years old) with complete AAC and coronary artery
calcification (CAC) data from computerized
tomographic scans. It was found that AAC and CAC
predicted hard coronary heart disease and hard CVD events
independent of one another. Only AAC was
independently related to CVD mortality, and AAC showed a
stronger association with total mortality than CAC.
It is worth noting some limitations of our study. First,
we had a less-than-anticipated diabetes recruitment,
which could cause a potential bias. The strict criteria for
DN screening may in part account for the lower diabetes
diagnosis in our cohort. The defining eligibility of DN
was eGFR 15–59 ml/min/1.73 m2, or eGFR ≥ 60 ml/min/
1.73 m2 with “nephrotic range” proteinuria, which was
defined as 24-h urinary protein ≥3.5 g or urinary
albumin creatinine ratio (UACR) ≥2 000 mg/g . As a
result, early stage DN was not adequately screened for.
Nevertheless, this design would ensure sufficient power
to observe adverse consequences in the DN-subgroup
population, which will provide valuable information on
diabetes as a cause of CKD in China. Second, we used
self-report and review of medical records to define CVD
in this study. This may have missed a small group of
participants with undiagnosed CVD, and therefore the
results of CVD-related morbidity may not be
allinclusive. Third, abdominal aorta calcification was
determined by radiograph, which is less sensitive in detecting
atherosclerotic lesions than newer modalities such as
computerized tomography . Therefore, early stage
vascular calcification may have been under reported.
Computerized tomography was not available in this
research due to the high costs. However, color Doppler
ultrasound has been used in the C-STRIDE cohort to
evaluate carotid artery calcification. This will improve
diagnostic sensitivity of cardiovascular calcification by
integration of radiographic and ultrasound techniques
In summary, the C-STRIDE baseline analysis has
demonstrated that participants with progressive CKD have a
higher prevalence of CVD at entry than the general
Chinese population. Age, diabetes, hypertension,
abdominal aorta calcification and stage 3 & 4 CKD are
significantly associated with the prevalence of CVD. In the
next phase of the study, all subjects will be sampled
annually for at least 5 years. This Long-term follow-up of
participants will provide critical insight into the
epidemiology of CVD in CKD, reveal the impact of individual
risk factors on adverse outcomes, and serve as a
foundation for future interventional investigations.
Additional file 1: Table S1. Anticipated and actual target distributions
of CKD etiology and renal function, C-STRIDE study (Nov 2011- Mar 2016).
(DOC 33 kb)
AAC: Abdominal aorta calcification; ABP: Ambulatory blood pressure;
ANOVA: Analysis of variance; aOR: Adjusted odds ratios; ARIC: Atherosclerosis
risk in communities; BMI: Body mass index; CAC: Coronary artery calcification;
CI: Confidence interval; CKD: Chronic kidney disease; CRIC: Chronic renal
insufficiency cohort; C-STRIDE: Chinese Cohort Study of Chronic Kidney
Disease; CVD: Cardiovascular disease; DBP: Diastolic blood pressure;
DM: Diabetes mellitus; DN: Diabetic nephropathy; EF: Ejection fraction;
eGFR: Estimated glomerular filtration rate; ESRD: End-stage renal disease;
GN: Glomerulonephritis; Hb: Hemoglobin; HbA1c: Hemoglobin A1C;
HDLC: High density lipoprotein cholesterol; hs-CRP: High-sensitivity C-reactive
protein; IMT: Intima-media thickness; iPTH: Intact parathyroid hormone;
KDIGO: Kidney Disease Improving Global Outcomes; LAD: Left atrial
anteroposterior diameter; LDL-C: Low density lipoprotein cholesterol;
MI: Myocardial infarction; MOP: Manual of operation procedure; NYHA: New
York Heart Association; PAD: Peripheral arterial disease; PASP: Pulmonary
arterial systolic pressure; ROUTE: Research and outcome in treatment and
epidemiology; SAS: Statistical analysis system; SBP: Systolic blood pressure;
SCr: Serum creatinine; SD: Standard deviation; SF: Shortening fraction;
TC: Total cholesterol; TG: Triglyceride; UACR: Urinary albumin creatinine ratio;
UACR: Urinary albumin creatinine ratio
The authors thank every member of C-STRIDE Group for close and seamless
cooperation. The detailed information on the members of the C-STRIDE Group
can be found in the published literature . We thank Drs. Yuan Clare Zhang
and Parker B. Antin for critical reading of the manuscript and constructive
The study was supported by National Key Technology R&D Program of the
Ministry of Science and Technology (Project 2011BAI10B01) and Beijing Science
and Technology Committee (Project D131100004713007, “Establishment of
early diagnosis pathway and model for evaluating progression of chronic
kidney disease”). We declare that the funding bodies didn’t take part in the
design of the study and collection, analysis, and interpretation of data and in
writing the manuscript.
Availability of data and material
The datasets during the current study are available from the corresponding
author on reasonable request.
Study concept and design: XQW, JY; Acquisition of data: SPH, LW, XRZ;
Analysis and interpretation of data: JWW, LXZ; Drafting of the manuscript: JY,
HC, XQW; Critical revision of the manuscript for important content: JWW,
LXZ, MHZ; Statistical analysis: JWW, LXZ; Person in charge of study: XQW. All
authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
This study was approved by the ethics committee of Peking University First
Hospital. The institutional review boards of each participating hospitals
approved the study protocol and the study was conducted in accordance
with the ethical principles of the Declaration of Helsinki. The written
informed consents were obtained from all study participants.
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