Original Article
Low-grade albuminuria and incidence of
cardiovascular disease and all-cause mortality in
nondiabetic and normotensive individuals
Fumitaka Tanaka a, Ryosuke Komi a, Shinji Makita a, Toshiyuki Onoda b, Kozo Tanno b,
Masaki Ohsawa b, Kazuyoshi Itai b, Kiyomi Sakata b, Shinichi Omama c, Yuki Yoshida c,
Kuniaki Ogasawara c, Yasuhiro Ishibashi d, Toru Kuribayashi e, Akira Okayama f,
Motoyuki Nakamura a, on behalf of Iwate-Kenco Study Group
See editorial comment on page 399
Background: Recent studies indicate that, in people with
diabetes or hypertension and in the general population,
low-grade albuminuria (LGA) below the microalbuminuria
threshold is a predictor for incidence of cardiovascular
disease (CVD) and mortality. However, it remains unclear
whether LGA predicts the risk of CVD incidence and death
in nondiabetic and normotensive individuals.
Methods: A total of 3599 individuals aged not less than
40 years from the general population who are free of CVD
in nondiabetic and normotensive individuals with preserved
glomerular filtration rate were followed for CVD incidence
and all-cause death. LGA was defined as urinary albumin
to creatinine ratio (UACR) less than 30 mg/g. It was
examined whether there is an association between LGA
and CVD incidence or all-cause death.
Results: During the average 5.9 years of follow-up, 61
individuals had first CVD events, and 85 individuals died.
The hazard ratios (HRs) for CVD incidence and all-cause
death after full adjustment by potential confounders
increased significantly in the top tertile of LGA (UACR
 9.6 mg/g for men,  12.0 mg/g for women) compared
with the first tertile [HR ¼ 2.79, 95% confidence interval
(CI), 1.41–5.52, HR ¼ 1.69, 95% CI, 1.00–2.84,
respectively]. Population-attributable fractions of the top
tertile of LGA for CVD incidence and all-cause death were
37.9 and 20.1%, respectively.
Conclusion: In apparently healthy individuals with optimal
blood pressure and no diabetes, LGA independently
predicts CVD incidence and all-cause death, particularly
with the large contribution to the excessive incidence of
CVD.
Keywords: cardiovascular disease, follow-up studies,
microalbuminuria, mortality, nondiabetic, nonhypertensive
Abbreviations: AMI, acute myocardial infarction; BNP,
B-type natriuretic peptide; CI, confidence interval; CVD,
cardiovascular disease; GFR, glomerular filtration rate; HR,
hazard ratio; hsCRP, high-sensitivity C-reactive protein;
LGA, low-grade albuminuria; PAF, population-attributable
fraction; SCD, sudden cardiac death; SD, standard
deviation; UACR, urinary albumin creatinine ratio
506 www.jhypertension.com
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
INTRODUCTION
M
icroalbuminuria (30–300 mg of albumin/24 h) is a
well known independent risk factor for cardio-
vascular disease (CVD) and mortality in people
with diabetes or hypertension and in the general popu-
lation [1–6]. In particular, diabetes and hypertension have
the close linkage with a greater prevalence of microalbu-
minuria [7,8], and microalbuminuria is well documented to
correlate with CVD outcomes in these individuals [1–4].
These evidences raise a question about whether the linkage
between albuminuria and CVD outcomes is attributable to
elevated blood pressure and glucose intolerance, or urinary
albumin excretion itself. This would be worth considering
to focus the target for intervention of albuminuria-related
risk.
The recent reports from meta-analysis documented that,
in individuals without hypertension or diabetes, increased
CVD risk is observed in individuals with low-grade albu-
minuria (LGA) lower than those currently employed to
define microalbuminuria [9–11]. Furthermore, there were
the LGA-related risk of CVD incidence and all-cause
mortality also in nondiabetic individuals without hyperten-
sion [12,13]. However, these studies included individuals
with prehypertension which was defined as SBP from 120
to 139 mmHg/diastolic blood pressure (DBP) from 80 to 89
mmHg. Therefore, even in individuals without hyperten-
sion, blood pressure may partially account for the associ-
ation between LGA and the risk of CVD events and death, as
prehypertension is an independent indicator of albuminu-
ria [14] and is a predictor for the risk of CVD and all-cause
mortality [15,16].
Journal of Hypertension 2016, 34:506–512
a
Department of Internal Medicine, bDepartment of Hygiene and Preventive Medicine,
c
Department of Neurosurgery, dDepartment of Neurology, Iwate Medical University,
e
Department of Health and Physical Education, Faculty of Education, Iwate University,
Morioka and fThe Research Institute of Strategy for Prevention, Tokyo, Japan
Correspondence to Fumitaka Tanaka, MD, 19–1 Uchimaru, Morioka, Iwate, Japan.
Tel: +81 19 651 5111; fax: +81 19 651 0401; e-mail: ftanaka@iwate-med.ac.jp
Received 27 August 2015 Revised 14 October 2015 Accepted 23 October 2015
J Hypertens 34:506–512 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights
reserved.
DOI:10.1097/HJH.0000000000000809
Volume 34  Number 3  March 2016

It remains unclear whether LGA predicts the risk of CVD
events and death in nondiabetic and normotensive indi-
viduals. This clarification could lead to identify the albu-
minuria-related risk which is independent of elevated
blood pressure in no diabetes. The aim of this study was
to investigate the association between LGA and the risk of
CVD incidence and all-cause death in a community-based
sample of nondiabetic and normotensive individuals with
preserved glomerular filtration rate (GFR).
METHODS
Study participants
The Iwate-KENCO study cohort is a population-based
prospective study in Japanese residents in three districts
(Ninohe, Kuji, and Miyako) of the northern Iwate prefec-
ture, northeast of Honsyu, Japan. Details of this cohort are
provided elsewhere [17]. Participants were recruited from a
government-regulated health checkup programme which
was conducted between April 2002 and January 2005. Of
this original cohort in the Ninohe and Kuji districts (n ¼ 15
927), 97% of study participants agreed to participate in this
cohort study. We excluded 12 328 participants for the
following reasons: the age less than 40 years (n ¼ 583),
missing data at baseline (n ¼ 840), a urinary albumin crea-
tinine ratio (UACR) at least 30 mg/g (micro- or macro-
albuminuria; n ¼ 3533), prevalent CVD (myocardial infarc-
tion, angina pectoris, or stroke; n ¼ 500), prevalent pre-
hypertension or hypertension (SBP  120 mmHg, DBP
 80 mmHg, or use of antihypertensive medications;
n ¼ 10 442), prevalent diabetes mellitus (n ¼ 1121), the
estimated GFR less than 60 ml/min per 1.73 m2 (n ¼ 2141)
or menstruating (n ¼ 156). Finally, 3599 participants (982
males and 2617 females) were included in the analysis.
Outcome
Patients with newly diagnosed stroke, acute myocardial
infarction (AMI)/sudden cardiac death (SCD), heart failure,
or all-cause death were registered until October 2009.
Registration was initially performed by attending physicians
at each hospital. To ensure complete capture of all regis-
trations, investigators consisting of physicians and trained
research nurses visited and reviewed medical charts and/or
discharge summaries at referral hospitals within the study
area. Dates of death and relocation from the study area
were annually or biannually confirmed by investigators
who reviewed population-registration sheets at each local
government office. People who were known to be alive at
the end of the follow-up and those who had moved away
from the study area were treated as censored cases. The
follow-up rate was 99%.
The end point of the study was a composite cardiovas-
cular outcome comprising stroke, AMI/SCD, and heart
failure; and all-cause death. Stroke was defined on the
basis of symptoms (sudden onset of a focal neurological
deficit of 24-h duration) and brain imaging including brain
computed tomography or magnetic resonance imaging,
and was identified by local stroke registry data [18]. Heart
failure was defined according to the Framingham criteria
[19] and was identified by investigators from medical
records at all general hospitals located within the study
Journal of Hypertension
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Low-grade albuminuria and outcomes
area. AMI was defined according to the MONICA (monitor-
ing of trends and determinants in CVD) criteria [20] and was
identified from hospital registration survey data. According
to the WHO criteria for sudden death, SCD was defined as
sudden unexpected death either within 1 h of symptom
onset (event witnessed), or within 24 h of having been
observed alive and symptom free (unwitnessed) [21]. SCD
was identified by reviewing death certificates filed at refer-
ral hospitals and/or public health centers in the study area,
and was determined by a committee consisting of cardiol-
ogists, neurologists, and epidemiologists. The study was
approved by our institutional ethics committee.
Measurement
BMI was calculated by dividing weight (in kilograms) by the
square of height (in meters). Participants completed a self-
report questionnaire to document their medical history
including current medications and lifestyle factors such
as smoking habits. Blood pressure was measured twice
using an automatic digital sphygmomanometer after 5 min
of rest in a sitting position, and the average of these two
values was used for analysis. The both fasting (n ¼ 1287)
and nonfasting (n ¼ 6644) blood samples were drawn from
an antecubital vein and collected into vacuum tubes con-
taining a serum separator gel. Tubes were stored immedi-
ately after sampling in an icebox and were transported to
the laboratory less than 8 h after collection. Plasma levels of
B-type natriuretic peptide (BNP) were measured by direct
radioimmunoassay using monoclonal antibodies specific
for human BNP (Shionoria RIA BNP kit; Shionogi & Co. Ltd.,
Osaka, Japan). Serum levels of high-sensitivity C-reactive
protein (hsCRP) were measured using the Behring
latex-enhanced CRP assay on a Behring nephelometer
BN-100. The eGFR was calculated using an equation
(ml/min per 1.73 m2) ¼ 194  serum creatinine1.094 
age0.278 ( 0.739 for women) from the Modification of
Diet in Renal Disease (MDRD) study [22]. Diabetes was
defined as a random blood glucose level not less than
200 mg/dl, a fasting blood glucose level at least 126 mg/
dl, a glycosylated hemoglobin (NGSP equivalent value) not
less than 6.5%, and/or current antidiabetic therapy. Dysli-
pidemia was defined as total cholesterol levels at least
240 mg/dl, high-density lipoprotein cholesterol levels less
than 40 mg/dl, and/or current lipid lowering therapy.
Smoking habits were defined as current smoking. At the
baseline examination, a single-void urine sample was col-
lected during the daytime and was used to measure UACR.
Urinary albumin was assessed quantitatively using an
immunonephelometric method (N antiserum albumin,
Dade Behring) and urinary creatinine was measured quan-
titatively on enzymatic colorimetric test [23]. The between-
assay coefficient of variation for urinary albumin and
creatinine was within 5% throughout the range of concen-
trations. The sensitivity limit for urinary albumin concen-
tration was 6 mg/l. Urinary albumin showing levels below
this limit were regarded as no LGA irrespective of their
urinary creatinine concentration.
Statistical analysis
Data are presented as mean  standard deviation (SD)
or percentage. Skewed variables were logarithmically
www.jhypertension.com 507
Tanaka et al.

TABLE 1. Baseline characteristics of study participants according to categories of low-grade albuminuria

Category of urinary albumin creatinine ratio
First tertile Second tertile Third tertile P value
Number 1467 939 1193
Range of urinary albumin creatinine ratio
Men 0.0 3.5–9.5 9.6–29.8
Women 0.0 4.1–11.9 12.0–29.8
Men (%) 24.9 31.1 27.2 0.004
Age (years) 56.8  9.6 55.9  10.2 60.5  9.9 < 0.001
BMI (kg/m2) 22.8  2.8 23.0  3.0 22.9  3.0 0.322
Systolic blood pressure (mmHg) 106.9  8.1 106.8  8.3 107.8  8.0 0.003
DBP (mmHg) 65.3  6.6 65.5  6.8 65.8  6.5 0.160
Current smoking (%) 13.2 17.0 12.4 0.005
Dyslipidemia (%) 19.6 19.1 17.0 0.222
BNP (pg/ml) 17.8  17.0 15.4  16.8 20.0  23.8 < 0.001
HsCRP (mg/l) 0.73  1.83 0.74  1.79 1.02  3.31 0.152

Data are presented as mean  SD or percentage. BMI, body mass index; BNP, B-type natriuretic peptide; HsCRP, high-sensitivity C-reactive protein.

transformed to improve normality prior to analysis. To
evaluate the relationship between each parameter and
the UACR, the participants were stratified according to
sex-specific tertiles of LGA (UACR < 30 mg/g). As the result,
all individuals categorized to the first tertile of UACR had
urinary albumin levels below the sensitivity limit (6 mg/l) in
both sexes (n ¼ 365 for male, 1102 for female). The ranges
of the second and the third tertiles of UACR were 3.5–9.5,
9.6–29.8 mg/g for males and 4.1–11.9, 12.0–29.8 mg/g for
females, respectively. Analysis of covariance and logistic
regression with adjustments for CVD risk factors were
conducted to compare means and proportions, respect-
ively, across the LGA tertiles. Comparison of continuous
variables at baseline was performed by one way analysis of
variance with the Scheffe’s post hoc test. Furthermore, the
Kruskal–Wallis analysis was used to compare BNP and
hsCRP levels among the LGA tertiles. x2 test was used for
comparison of categorical variables. The Kaplan–Meier
method with log-rank test was used to compare event-free
rates for CVD events and all-cause death in tertiles of UACR.
The multivariate regression analysis was adjusted as fol-
lows: model 1: age, sex; model 2: BMI, SBP, dyslipidemia
(yes or no), smoking habits (yes or no), log BNP and log
hsCRP in addition to model 1. Cox regression analysis was
used to calculate hazard ratios (HRs) and corresponding
95% confidence intervals (CIs) for the risk of CVD events
and all-cause death in tertiles of UACR. To express the
impact of LGA categories on outcomes in the participants,
we estimated the population-attributable fraction (PAF).
This index was estimated as Pe  (HR1)/HR, in which
Pe is the proportion of incident cases in the LGA category
and HR is the full multiple-adjusted HR. All of the data were
analyzed with SPSS statistical software, version 11.0; SPSS
Inc., Chicago, Illinois, USA). P less than 0.05, which was
considered to be statistically significant.
RESULTS
The present cohort consisted of approximately 70% females
and 30% elderly people who were older than 65 years of
age. The characteristics of the study participants according
to sex-specific tertiles of UACR are shown in Table 1. Age
and levels of SBP and BNP tended to be high in individuals
with the third tertile of LGA, in which, inversely, current
smokers were less frequent.
During the average 5.9  1.2 years of follow-up, 61
participants (1.7%) had the first CVD events which were
consisting of 51 events with stroke, seven events with AMI/
SCD, and three events with heart failure. During the follow-
up period, 85 individuals (2.4%) died from cardiac (17.6%)
and no-cardiac cause (82.4%). The cumulative incidence of
CVD and all-cause death were 0.7 and 1.5% in the first tertile
of LGA, 1.5 and 2.2% in the second tertile of LGA, and 3.0
and 3.5% in the third tertile of LGA, respectively. In Fig. 1,
the Kaplan–Meier curves showed that the differences of
cumulative incidence of CVD and all-cause death were
significant among the LGA tertiles (P < 0.001, Fig. 1).
Table 2 shows the relationship between the LGA
category and the risk of CVD events or all-cause death
after adjustment for potential confounding factors in the
Cox model. The HR for the incidence of CVD after full
adjustment by potential confounders including log BNP
and log hsCRP increased significantly in the third tertile of
LGA (HR ¼ 2.79, 95% CI,1.41–5.52) compared with the first
tertile. Similarly, the HR for all-cause death after full adjust-
ment by potential confounders increased significantly in the
third tertile of LGA (HR ¼ 1.69, 95% CI, 1.00–2.84) com-
pared with the first tertile (Table 2). From the PAF, we
estimated the positive fraction of incidence of CVD and all-
cause death attributable to exposure for each LGA category
at baseline (Fig. 2). As the results, 37.9% of CVD and 20.1%
of all-cause death were excessive incidence due to the third
tertile of LGA, whereas 11.2% of CVD incidence and 6.8% of
all-cause death were attributable to the second tertile
of LGA.
DISCUSSION
The present study was conducted in nondiabetic and
normotensive individuals with preserved GFR and no
cardiovascular history. Even in such apparently healthy
population, we found the positive relation between LGA

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Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

 Low-grade albuminuria and outcomes

Incident CVD All-cause death

100 100

98 98

Survival (%)

Survival (%)
96 96

94 94

P = 0.0001 P = 0.0078
92 92
0 2 4 6 8 0 2 4 6 8
Follow-up period in years Follow-up period in years
UACR
1sttertile
2nd tertile
3rd tertile
FIGURE 1 Cumulative incidence of cardiovascular disease and all-cause death according to tertiles of baseline urinary albumin creatinine ratio (UACR) levels.

TABLE 2. Hazard ratios for cardiovascular events and all-cause death according to tertiles of baseline UACR levels
Sex and age Multivariable-
No. of No. of No./1000 adjusted HR and adjusted HRa
Tertile of LGA participants events person years 95% CI P value and 95% CI P value
Cardiovascular disease
T1 1467 11 1.3 1.00 1.00
T2 939 14 2.4 1.82 0.82–4.01 0.138 1.95 0.88–4.31 0.098
T3 1193 36 5.0 2.86 1.45–5.65 0.002 2.79 1.41–5.52 0.003
All-cause death
T1 1467 22 2.6 1.00 1.00
T2 939 21 3.6 1.32 0.72–2.40 0.365 1.38 0.76–2.52 0.295
T3 1193 42 5.8 1.71 1.02–2.88 0.043 1.69 1.00–2.84 0.049

BNP, B-type natriuretic peptide; CI, confidence interval; HR, hazard ratio; hsCRP, high-sensitivity C-reactive protein; LGA, low-grade albuminuria; UACR, urinary albumin creatinine ratio.
a
Hazard ratio in a multivariate Cox proportional hazards model including age, sex, BMI, SBP, dyslipidemia (yes or no), smoking (yes or no), log hsCRP and log BNP.
Hazard ratios for incidence of CVD

3 3
Hazard ratios for all-cause death

2 37.9%* 2

11.2%*
20.1%*
6.8%*
1 1

0 0
18.0% 23.0% 59.0% 25.9% 24.7% 49.4%
T1 T2 T3 T1 T2 T3
Frequencies of the UACR tertile in event cases Frequencies of the UACR tertile in event cases
FIGURE 2 Multivariate-adjusted hazard ratios and population-attributable fractions for cardiovascular events and all-cause death according to tertiles of baseline urinary
albumin creatinine ratio (UACR) levels. Multivariate analyses are adjusted for age, sex, BMI, SBP, dyslipidemia (yes or no), smoking (yes or no), log hsCRP and log BNP. The
population-attributable fraction from exposure for each LGA category at baseline.

Journal of Hypertension www.jhypertension.com 509

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Tanaka et al.
and CVD events or all-cause mortality. In addition, this
relationship was independent of not only traditional risk
factors such as age and blood pressure, but circulating
levels of BNP and hsCRP as a predictive marker of CVD
events.
Although the association of CVD and mortality with
microalbuminuria is well documented, recent prospective
studies indicate that the association between urinary albu-
min and the risk of CVD or all-cause death is continuous
without threshold effects in diabetic individuals [24] and
general population [9–11]. In addition, this association was
documented both in individuals with and without hyper-
tension or diabetes in recent reports from meta-analysis
[25,26]. Furthermore, the prospective cohort studies that
excluded patients with hypertension and diabetes docu-
mented a similar continuous association between LGA and
CVD development [12] or all-cause mortality [13]. In the
Framingham heart study, nondiabetic nonhypertensive
participants with UACR levels not less than 3.9 mg/mg for
men or at least 7.5 mg/mg for women had a nearly three-
fold risk of CVD [12]. The Nord-Trøndelag health study
revealed a positive association between all-cause mortality
and UACR levels not less than 6.7 mg/mg [13]. However,
these data were from the participants including prehyper-
tensives who are likely to have more amount of urinary
albumin excretion and excess risk of CVD events and
mortality compared with normotensives [14–16]. The
present study demonstrated that even normotensive and
nondiabetic individuals had an LGA-related risk of devel-
oped CVD. This result suggests that the linkage between
albuminuria and CVD is not through elevated blood pres-
sure, which has been known to be closely associated with
urinary albumin excretion [27], in nondiabetic individuals.
Previous literatures have advocated a hypothesis that the
mechanism underlying association of microalbuminuria
with CVD events involves a hypercoagulative and hypofi-
brinolytic state [28], endothelial dysfunction [29], or chronic
inflammatory state [30]. This theory is based on previous
studies which have been conducted among populations
with different proportions of hypertension, diabetes, and
renal dysfunction, which are linked with a risk of CVD.
Cross-sectional studies for individuals with neither hyper-
tension nor diabetes have demonstrated that microalbumi-
nuria was associated with waist circumference [31], SBP
[31], serum CRP levels [32]. Our findings suggest that, in
normotensive individuals with no diabetes, the association
between albuminuria and a risk of CVD was unlikely to be
through blood pressure and inflammation, as this associ-
ation remained significant after adjustment for SBP and
hsCRP levels. In addition, subclinical cardiac dysfunction,
which has been shown to be correlated with presence of
microalbuminuria [33,34], also is unlikely to account for
albuminuria-related risk, as this risk was not almost atte-
nuated after adjustment for the plasma BNP levels. Further-
more, in participants without diabetes or hypertension
participated in the Cardiovascular Health Study, in contrast
to those with diabetes or hypertension, microalbuminuria
was associated not with subclinical vascular disease but
with prevalent clinical CVD [35]. Thus, Cao et al. advocated
a hypothesis that microalbuminuria leads to clinical
vascular disease through destabilization of existing
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atherosclerosis [35]. This report may explain the part of
mechanism of our findings about a LGA-related risk of CVD
in nondiabetic and normotensive individuals. In addition,
it is possible that measurable urinary albumin reflects
residual and unmeasured confounding effects such as
insulin resistance [36], habits of dietary intake of protein
[37], sodium [38] and potassium [38], and low birth weight
[39].
In the present study, LGA was related also to the
mortality risk. This result has a consistency with the
previous reports in general population [10,11,13]. All-cause
mortality could be attributed to death due to malignant
neoplasms, other than that are due to CVD. Albuminuria
has been reported to be associated with cancer incidence
and this association has been regarded to be from the
mechanism through a paraneoplastic phenomenon which
is different from generalized atherosclerosis [40]. The
Framingham and the Hoorn studies showed that albumi-
nuria had weaker association with all-cause death than CVD
events [12,41]. In the PREVEND study, the excess risk of
mortality from urinary albumin was more attributable to
death from CVD causes [9]. These reports were consistent
with the present finding that LGA had less association with
all-cause death.
The present study had several limitations. First, urinary
albumin was estimated from only single measurement. This
raises a possibility that individuals with albuminuria who
occasionally passed as physiological reaction were catego-
rized to the albuminuria group with a higher amount of
urinary albumin. However, this possibility could lead to an
underestimation of the true albuminuria-related risk and,
thus, would not weaken the relation with albuminuria and
outcomes. Second, urinary albumin showing levels below
6 mg/l as the sensitivity limit were regarded as no LGA
irrespective of their urine creatinine concentration. These
individuals were 40.8% (n ¼ 1467) of the whole, so all of
them were classified to the lowest tertile of LGA. Therefore,
the cutoff levels of UACR as CVD risk may be actually lower
than those defined in the present study ( 9.6 mg/g for
men,  12.0 mg/g for women). This might underestimate
the true albuminuria-related risk. Third, individuals with
bacteriuria could have evidence of albuminuria through the
mechanism that is different from those without bacteriuria,
and, however, were not excluded in the present study.
Therefore, this could possibly lead LGA to some misclassi-
fications. Fourth, the present study did not evaluate
whether the participants had insulin resistance as the main
pathophysiology of metabolic syndrome, which has been
known to be associated with presence of albuminuria [42]
and incidence of CVD [43]. Therefore, it is unclear whether
insulin resistance affected an LGA-related risk of developed
CVD and mortality. Fifth, the present study did not register
outpatients with no hospital admission even if they devel-
oped CVD events. This raises a possibility that CVD events
with no hospital admission, such as mild cases of heart
failure, have not been captured. Sixth, the present study did
not conduct an estimation of urinary albumin, CVD risk
factors and prescribed drugs during the follow-up. Finally,
in the present study conducted on Japanese population,
the cumulative incidence of stroke was higher than that of
AMI/SCD (5.5 vs. 1.4%). This agrees with reports from
Volume 34  Number 3  March 2016

previous Japanese epidemiological studies [16,43]. There-
fore, our results may not be simply extrapolated to
other populations.
Hypertension and diabetes are major causes of death
[44]. The economic burdens of diagnosed hypertension and
diabetes on the society are large and keep increasing in
recent years [45,46]. Therefore, the risk management for
patients who have not yet had high blood pressure or
glucose intolerance may be beneficial for prevention of
illness and reducing medical expenses. For the first time,
the present study, in nondiabetic and normotensive indi-
viduals, showed that very low levels of albuminuria had a
significant association with the risk of CVD or all-cause
death, and they largely contributed to the excessive inci-
dence of CVD, as shown as 38% of PAF in the top tertile of
LGA. Therefore, in nondiabetic individuals with optimal
blood pressure, LGA could be adopted as a marker of the
detection of cardiovascular and mortality risk and the
implementation of interventions. However, it remains
unclear what is the target of the intervention for lowering
LGA-related risk. In order to solve this question, further
prospective studies would be necessary.
In conclusion, in apparently healthy individuals with
optimal blood pressure and no diabetes, LGA independ-
ently predicts CVD incidence and all-cause death, particu-
larly with the large contribution to the excessive incidence
of CVD.
ACKNOWLEDGEMENTS
This research was supported in part by grants-in-aid from
the scientific research fund of the Ministry of Education,
Science, and Culture of Japan (26461082 and 26461083),
Tokyo, Japan.
Conflicts of interest
The authors have no conflicts of interest to declare.
REFERENCES
1. Deckert T, Yokoyama H, Mathiesen E, Ronn B, Jensen T, Feldt-
Rasmussen B, et al. Cohort study of predictive value of urinary albumin
excretion for atherosclerotic vascular disease in patients with insulin
dependent diabetes. BMJ 1996; 312:871–874.
2. Dinneen SF, Gerstein HC. The association of microalbuminuria and
mortality in noninsulin-dependent diabetes mellitus: a systematic over-
view of the literature. Arch Intern Med 1997; 157:1413–1418.
3. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, et al.
Albuminuria and risk of cardiovascular events, death, and heart failure
in diabetic and nondiabetic individuals. JAMA 2001; 286:421–426.
4. Bigazzi R, Bianchi S, Baldari D, Campese VM. Microalbuminuria
predicts cardiovascular events and renal insufficiency in patients with
essential hypertension. J Hypertens 1998; 16:1325–1333.
5. Muntner P, He J, Hamm L, Loria C, Whelton PK. Renal insufficiency and
subsequent death resulting from cardiovascular disease in the United
States. J Am Soc Nephrol 2002; 13:745–753.
6. Cao JJ, Biggs ML, Barzilay J, Konen J, Psaty BM, Kuller L, et al.
Cardiovascular and mortality risk prediction and stratification using
urinary albumin excretion in older adults ages 68-102: the Cardiovas-
cular Health Study. Atherosclerosis 2008; 197:806–813.
7. Mlacak B, Jaksić Z, Vuletić S. Albuminuria, cardiovascular morbidity
and mortality in diabetic and nondiabetic subjects in a rural general
practice. Fam Pract 1999; 16:580–585.
8. Mann JF, Yi QL, Gerstein HC. Albuminuria as a predictor of cardio-
vascular and renal outcomes in people with known atherosclerotic
cardiovascular disease. Kidney Int Suppl 2004; 92:S59–62.
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Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Low-grade albuminuria and outcomes
9. Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van
Veldhuisen DJ, et al. Urinary albumin excretion predicts cardiovascular
and noncardiovascular mortality in general population. Prevention of
Renal and Vascular End Stage Disease (PREVEND) Study Group.
Circulation 2002; 106:1777–1782.
10. Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der
Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, et al. .
Association of estimated glomerular filtration rate and albuminuria
with all-cause and cardiovascular mortality in general population
cohorts: a collaborative meta-analysis. Lancet 2010; 375:2073–2081.
11. Kovesdy CP, Lott EH, Lu JL, Malakauskas SM, Ma JZ, Molnar MZ, et al.
Outcomes associated with microalbuminuria: effect modification by
chronic kidney disease. J Am Coll Cardiol 2013; 61:1626–1633.
12. Arnlöv J, Evans JC, Meigs JB, Wang TJ, Fox CS, Levy D, et al. Low-grade
albuminuria and incidence of cardiovascular disease events in non-
hypertensive and nondiabetic individuals: the Framingham Heart
Study. Circulation 2005; 112:969–975.
13. Romundstad S, Holmen J, Kvenild K, Hallan H, Ellekjaer H. Micro-
albuminuria and all-cause mortality in 2,089 apparently healthy indi-
viduals: a 4.4-year follow-up study. The Nord-Trøndelag Health Study
(HUNT), Norway. Am J Kidney Dis 2003; 42:466–473.
14. Lee JE, Kim YG, Choi YH, Huh W, Kim DJ, Oh HY. Serum uric acid is
associated with microalbuminuria in prehypertension. Hypertension
2006; 47:962–967.
15. Vasan RS, Larson MG, Leip EP, Evans JC, O’Donnell CJ, Kannel WB,
et al. Impact of high-normal blood pressure on the risk of cardio-
vascular disease. N Engl J Med 2001; 345:1291–1297.
16. Ikeda A, Iso H, Yamagishi K, Inoue M, Tsugane S. Blood pressure and
the risk of stroke, cardiovascular disease, and all-cause mortality
among Japanese: the JPHC Study. Am J Hypertens 2009; 22:273–280.
17. Nakamura M, Onoda T, Itai K, Ohsawa M, Satou K, Sakai T, et al.
Association between serum C-reactive protein levels and microalbu-
minuria: a population-based cross-sectional study in northern Iwate,
Japan. Intern Med 2004; 43:919–925.
18. Omama S, Yoshida Y, Ogawa A, Onoda T, Okayama A. Differences in
circadian variation of cerebral infarction, intracerebral haemorrhage
and subarachnoid haemorrhage by situation at onset. J Neurol Neuro-
surg Psychiatry 2006; 77:1345–1349.
19. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history
of congestive heart failure: the Framingham Study. N Engl J Med 1971;
285:1441–1446.
20. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas
AM, Pajak A. Myocardial infarction and coronary deaths in the World
Health Organization MONICA Project. Registration procedures, event
rates, and case-fatality rates in 38 populations from 21 countries in four
continents. Circulation 1994; 90:583–612.
21. Chugh SS, Jui J, Gunson K, Stecker EC, John BT, Thompson B, et al.
Current burden of sudden cardiac death: multiple source surveillance
versus retrospective death certificate-based review in a large U.S.
community. J Am Coll Cardiol 2004; 44:1268–1275.
22. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al.,
Collaborators developing the Japanese equation for estimated GFR.
Revised equations for estimated GFR from serum creatinine in Japan.
Am J Kidney Dis 2009; 53:982–992.
23. Ohsawa M, Itai K, Tanno K, Onoda T, Ogawa A, Nakamura M, et al.
Cardiovascular risk factors in the Japanese northeastern rural popu-
lation. Int J Cardiol 2009; 137:226–235.
24. Ruggenenti P, Porrini E, Motterlini N, Perna A, Ilieva AP, Iliev IP, et al.,
BENEDICT Study Investigators. Measurable urinary albumin predicts
cardiovascular risk among normoalbuminuric patients with type 2
diabetes. J Am Soc Nephrol 2012; 23:1717–1724.
25. Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, Heerspink HJ,
et al., Chronic Kidney Disease Prognosis Consortium. Associations of
kidney disease measures with mortality and end-stage renal disease in
individuals with and without diabetes: a meta-analysis. Lancet 2012;
380:1662–1673.
26. Mahmoodi BK, Matsushita K, Woodward M, Blankestijn PJ, Cirillo M,
Ohkubo T, et al., Chronic Kidney Disease Prognosis Consortium.
Associations of kidney disease measures with mortality and end-stage
renal disease in individuals with and without hypertension: a meta-
analysis. Lancet 2012; 380:1649–1661.
27. Tanaka S, Takase H, Dohi Y, Kimura G. The prevalence and charac-
teristics of microalbuminuria in the general population: a cross-
sectional study. BMC Res Notes 2013; 6:256.
www.jhypertension.com 511
Tanaka et al.
28. Gruden G, Cavallo-Perin P, Bazzan M, Stella S, Vuolo A, Pagano G. PAI-
1 and factor VII activity are higher in IDDM patients with micro-
albuminuria. Diabetes 1994; 43:426–429.
29. Pedrinelli R, Giampietro O, Carmassi F, Melillo E, Dell’Omo G,
Catapano G, et al. Microalbuminuria and endothelial dysfunction in
essential hypertension. Lancet 1994; 344:14–18.
30. Yudkin JS, Stehouwer CDA, Emeis JJ, Coppack SW. Insulin resistance
syndrome and endothelial damage: role of adipose tissue derived
proinflammatory cytokines [Abstract]. Diabetologia 1997; 40:A305.
31. Chang Y, Yoo T, Ryu S, Huh BY, Cho BL, Sung E, et al. Abdominal
obesity, systolic blood pressure, and microalbuminuria in normoten-
sive and euglycemic Korean men. Int J Obes (Lond) 2006; 30:800–
804.
32. Barzilay JI, Peterson D, Cushman M, Heckbert SR, Cao JJ, Blaum C,
et al. The relationship of cardiovascular risk factors to micro-
albuminuria in older adults with or without diabetes mellitus or
hypertension: the cardiovascular health study. Am J Kidney Dis
2004; 44:25–34.
33. Katz DH, Selvaraj S, Aguilar FG, Martinez EE, Beussink L, Kim KY, et al.
Association of low-grade albuminuria with adverse cardiac mechanics:
findings from the hypertension genetic epidemiology network (Hyper
GEN) study. Circulation 2014; 129:42–50.
34. Jensen JS, Borch-Johnsen K, Feldt-Rasmussen B, Appleyard M,
Jensen G. Urinary albumin excretion and history of acute myocardial
infarction in a cross-sectional population study of 2,613 individuals.
J Cardiovasc Risk 1997; 4:121–125.
35. Cao JJ, Barzilay JI, Peterson D, Manolio TA, Psaty BM, Kuller L, et al.
The association of microalbuminuria with clinical cardiovascular dis-
ease and subclinical atherosclerosis in the elderly: the Cardiovascular
Health Study. Atherosclerosis 2006; 187:372–377.
36. Kim CH, Kim HK, Park JY, Park HS, Hong SK, Park SW, et al. Association
of microalbuminuria and atherosclerotic risk factors in nondiabetic
subjects in Korea. Diabetes Res Clin Pract 1998; 40:191–199.
Reviewers’ Summary Evaluations
Reviewer 2
Strengths of the study: The authors have performed an
elegant prospective study conducted in normotensive
and nondiabetic participants without prior cardiovascular
disease, and they found that even within normal levels of
urinary albumin to creatinine ratio (< 30 mg/g), those in the
highest tertile presented an increased incidence of
512 www.jhypertension.com
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
37. Lin J, Hu FB, Curhan GC. Associations of diet with albuminuria and
kidney function decline. Clin J Am Soc Nephrol 2010; 5:836–843.
38. Sharma S, McFann K, Chonchol M, de Boer IH, Kendrick J. Association
between dietary sodium and potassium intake with chronic kidney
disease in US adults: a cross-sectional study. Am J Nephrol 2013;
37:526–533.
39. Hoy WE, White AV, Tipiloura B, Singh G, Sharma SK, Bloomfield H,
et al. The multideterminant model of renal disease in a remote
Australian Aboriginal population in the context of early life risk factors:
lower birth weight, childhood poststreptococcal glomerulonephritis,
and current body mass index influence levels of albumi. Clin Nephrol
2015; 83:75–81.
40. Jørgensen L, Heuch I, Jenssen T, Jacobsen BK. Association of albu-
minuria and cancer incidence. J Am Soc Nephrol 2008; 19:992–998.
41. Jager A, Kostense PJ, Ruhé HG, Heine RJ, Nijpels G, Dekker JM, et al.
Microalbuminuria and peripheral arterial disease are independent
predictors of cardiovascular and all-cause mortality, especially among
hypertensive subjects: five-year follow-up of the Hoorn Study. Arte-
rioscler Thromb Vasc Biol 1999; 19:617–624.
42. Palaniappan L, Carnethon M, Fortmann SP. Association between
microalbuminuria and the metabolic syndrome: NHANES III. Am J
Hypertens 2003; 16:952–958.
43. Ninomiya T, Kubo M, Doi Y, Yonemoto K, Tanizaki Y, Rahman M, et al.
Impact of metabolic syndrome on the development of cardiovascular
disease in a general Japanese population: the Hisayama study. Stroke
2007; 38:2063–2069.
44. Ikeda N, Saito E, Kondo N, Inoue M, Ikeda S, Satoh T, et al. What has
made the population of Japan healthy? Lancet 2011; 378:1094–1105.
45. American Diabetes Association. Economic costs of diabetes in the U.S.
in 2012. Diabetes Care 2013; 36:1033–1046.
46. Arredondo A, Aviles R. Costs and epidemiological changes of chronic
diseases: implications and challenges for health systems. PLoS One
2015; 10:e0118611.
cardiovascular disease and mortality. It is very well known
that prehypertension is associated with higher cardiovas-
cular risk during follow-up. It would be interesting to asses
in future studies if this level of low-grade albuminuria can
explain at least a part of this increased risk.
Weaknesses: No data on changes in albuminuria and
other risk factors and the different therapeutic interventions
during the follow-up are provided.
Volume 34  Number 3  March 2016