Original Report: Patient-Oriented, Translational Research

American Journal of

Nephrology Am J Nephrol 2015;41:409–417 Received: January 29, 2015

Accepted: May 15, 2015
DOI: 10.1159/000433450
Published online: June 30, 2015

Kidney Measures with Diabetes and Hypertension

on Cardiovascular Disease: The Atherosclerosis
Risk in Communities Study
Nadine Alexander a Kunihiro Matsushita a Yingying Sang a Shoshana Ballew a
       

Bakhtawar K. Mahmoodi c Brad C. Astor b Josef Coresh a 

     

a
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md., b Departments of
   

Medicine and Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wis.,
USA; c Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen,
 

The Netherlands

Key Words
Chronic kidney disease · Diabetes · Hypertension ·
Cardiovascular disease
Abstract
Background: Whether the association of chronic kidney dis-
ease (CKD) with cardiovascular risk differs based on diabetes
mellitus (DM) and hypertension (HTN) status remains unan-
swered. Methods: We investigated 11,050 participants from
the Atherosclerosis Risk in Communities Study (fourth ex-
amination (1996–1998)) with follow-up for cardiovascular
outcomes (coronary disease, heart failure and stroke)
through 2009. Using the Cox regression models, we quanti-
fied cardiovascular risk associated with estimated glomeru-
lar filtration rate (eGFR) and urinary albumin-to-creatinine
ratio (ACR) in individuals with and without DM and/or HTN
and assessed their interactions. Results: Individuals with
DM and HTN generally had higher cardiovascular risk rela-
tive to those without at all the levels of eGFR and ACR. Car-
diovascular risk increased with lower eGFR and higher ACR
regardless of DM and HTN status (e.g. adjusted hazards ra-
tio  (HR) for eGFR 30–44 vs. 90–104 ml/min/1.73 m2, 2.32
(95%  CI, 1.66–3.26) in non-diabetics vs. 1.83 (1.25–2.67) in
diabetics and 2.45 (2.20–5.01) in non-hypertensives vs. 1.51
(1.27–1.81) in hypertensives and corresponding adjusted
HR  for ACR 30–299 vs. <10 mg/g, 1.70 (1.45–2.00) vs. 1.34
(1.10–1.64) and 1.42 (1.10–1.85) vs. 1.57 (1.36–1.81), respec-
tively). Only the ACR-DM interaction reached significance,
with a shallower relative risk gradient among diabetics than
among non-diabetics (p = 0.02). Analysis of individual car-
diovascular outcomes showed similar results. Conclusion:
Although individuals with DM and HTN generally had higher
cardiovascular risk relative to those without these complica-
tions, both low eGFR and high ACR were associated with car-
diovascular diseases regardless of the presence or absence
of DM and HTN. These findings reinforce the importance of
CKD in cardiovascular outcomes. © 2015 S. Karger AG, Basel
Introduction
Diabetes mellitus (DM) and hypertension (HTN) are
leading risk factors for chronic kidney disease (CKD) [1–
7]. DM accounts for 40% of incident end-stage renal dis-
ease cases, while approximately 30% of end-stage renal
disease cases are due to HTN [8]. The contributions of
The research was conducted at the Johns Hopkins Bloomberg School
of Public Health.

© 2015 S. Karger AG, Basel Dr. Kunihiro Matsushita

0250–8095/15/0415–0409$39.50/0 The Johns Hopkins Bloomberg School of Public Health
Department of Epidemiology, 2024 E. Monument Street
E-Mail karger@karger.com
Baltimore, MD 21287 (USA)
www.karger.com/ajn
E-Mail kmatsus5 @ jhmi.edu
DM and HTN to kidney disease have led to recommenda-
tions for CKD screening among individuals with these
conditions [9–13].
DM and HTN are also important risk factors for car-
diovascular diseases (CVDs) [2–7, 14]. The risk of CVD
among adults with DM is 2–4 times higher than in those
without [2]. Similarly, each 20 mm Hg of higher systolic
blood pressure is associated with a doubling of CVD risk
[15]. CVD is also one of the most important complica-
tions of CKD [16–19]. Thus, there is a complicated asso-
ciation between DM, HTN, CKD and CVD. However,
very few studies have formally evaluated the interaction
of CKD with DM and HTN on CVD outcomes.
The CKD Prognosis Consortium has reported that the
association of kidney disease measures (estimated glo-
merular filtration rate (eGFR) and albuminuria) with car-
diovascular mortality is largely similar among those with
and without DM and/or HTN [14, 20]. However, mortal-
ity can be affected by healthcare system factors (e.g. avail-
ability and accessibility of care). Thus, from an etiological
point of view, it is also important to investigate the inter-
actions for incident CVD including non-fatal cases. Fur-
thermore, since the contribution of risk factors to indi-
vidual CVDs (e.g. coronary heart disease (CHD), stroke
and heart failure) can vary [21], an evaluation of each
CVD subtype would be an added contribution to the ex-
isting body of knowledge.
Methods
Design and Participants
The Atherosclerosis Risk in Communities (ARIC) study is an
ongoing prospective cohort study of 15,792 individuals aged 45–64
years from 4 US communities (Forsyth County, N.C.; Jackson,
Miss.; Minneapolis, Minn. and Washington County, Md., USA)
between 1987 and 1989 [15, 18, 19]. At the initial and 3 short-term
follow-up examinations, which occurred approximately 3 years
apart, trained personnel collected demographic, social, medical and
physical data. Baseline characteristics of this study were taken from
the fourth examination (1996–1998) which was attended by a total
of 11,656 participants [22]. Of these, we excluded individuals with
missing values of key exposures (eGFR and albuminuria; n = 215),
key potential effect modifiers (DM and HTN; n = 92) and covariates
(n = 299), leaving a final study sample of 11,050 participants.
Kidney Disease Measures
GFR was estimated from serum creatinine, age, gender and race
(blacks vs. non-blacks) using the CKD Epidemiology Collabora-
tion (CKD-EPI) equation [23]. Serum creatinine was measured
using a modified kinetic Jaffé [22] and was calibrated to standard-
ized serum creatinine by adding 0.18 mg/dl and then reducing
that value by 5% [18, 24]. As recommended in clinical guidelines,
urinary albumin-to-creatinine ratio (ACR) was used as a measure
410 Am J Nephrol 2015;41:409–417
DOI: 10.1159/000433450
of albuminuria [19, 25]. Urinary albumin and urinary creati-
nine  were measured by nephelometry and the Jaffé method, re-
spectively.
Potential Effect Modifiers
DM was defined as self-reported physician diagnosis, use of
glucose lowering medications, a fasting blood glucose level ≥126
mg/dl or non-fasting blood glucose level ≥200 mg/dl [25]. HTN was
defined by a systolic blood pressure ≥140 mm Hg and a diastolic
blood pressure ≥90 mm Hg or the use of antihypertensive medica-
tions. Blood pressure was determined as the average of 2 seated
measurements from a random-zero sphygmomanometer [25].
Covariates
Age, gender and race were self-reported. Height and weight
were measured while the participants wore light clothing and no
shoes [25]; body mass index (BMI) was calculated as body weight
(in kilograms) over height (in meters) squared. Total cholesterol
levels were determined using enzymatic methods. Smoking status
was categorized as current vs. ex-/non-smokers. History of CVD
included a history of CHD, stroke or heart failure. A history of
CHD was determined by a self-report of myocardial infarction or
a coronary revascularization procedure, an adjudicated electrocar-
diogram evaluation of myocardial infarction at the initial visit or
any adjudicated incident CHD event between the initial and fourth
visits. History of stroke was similarly determined by self-report at
the first examination or adjudicated cases before the fourth ex-
amination [25]. Prevalent heart failure was determined through
self-reported use of heart failure medications or manifested heart
failure as defined by the Gothenburg criteria at the initial examina-
tion and hospitalization for heart failure before the fourth exami-
nation [25].
Outcome Definition
The primary outcome of interest was composite CVD, including
a diagnosis of incident CHD, stroke or heart failure. Each individu-
al CVD was separately analyzed as a secondary outcome. Informa-
tion about the outcome was initially obtained using annual tele-
phone calls, hospital records and obituaries [25]. CHD and stroke
were then adjudicated by certified experts [26]. Incident CHD in this
study was defined as a definite or probable myocardial infarction,
definite CHD death or a revascularization procedure [25]. Incident
stroke included definite and possible stroke [27]. Incident heart fail-
ure was defined as heart failure hospitalization or death due to heart
failure coded as 428 or I50 according to the ICD-9 or ICD-10, re-
spectively, on medical records or death certificates [25].
Statistical Analysis
Baseline characteristics were compared among groups using
DM and HTN status. Continuous and categorical variables were
compared between the subgroups using the analysis of variance
and the Chi-square tests, respectively. We defined follow-up time
as the period from baseline (fourth examination) to the first out-
come or loss to follow-up. Individuals who were free of the out-
comes by December 31, 2009, were administratively censored.
The Cox proportional hazards models were used to quantify the
association of each kidney measure with the outcomes of interest in
each subgroup by DM and HTN status. All analyses were adjusted
for age, gender, race, BMI, total cholesterol level, smoking status,
history of CVD, systolic blood pressure (when diabetics and non-
Alexander/Matsushita/Sang/Ballew/
Mahmoodi/Astor/Coresh
Table 1. Baseline characteristics of study participants according to HTN and DM status

Characteristic No DM and HTN DM only HTN only DM and HTN

(n = 5,189) (n = 628) (n = 4,022) (n = 1,211)

Age, years 62.0±5.6 62.3±5.5 63.7±5.6 63.8±5.6

Male 44.6 56.0 42.0 43.3
Black 12.9 22.4 27.7 41.3
BMI, kg/m2 27.3±4.8 30.4±5.7 29.3±5.8 32.4±5.9
Current smoker 16.1 15.1 14.3 11.7
Systolic blood pressure, mm Hg 117.2±11.9 120.5±10.8 138.5±19.1 139.4±19.8
Diastolic blood pressure, mm Hg 68.2±8.6 66.7±8.9 75.0±10.9 72.3±11.2
Fasting blood glucose, mmol/l 5.4±0.5 9.5±3.7 5.6±0.5 9.4±3.5
Total cholesterol, mmol/l 5.2±0.9 5.0±1.0 5.2±0.9 5.2±1.1
Prevalent CHD 5.2 11.8 9.8 16.6
Prevalent stroke 0.9 2.2 3.4 4.2
Prevalent heart failure 2.0 6.0 7.2 14.1
eGFR, ml/min/1.73 m2 85.3±13.2 87.1±15.0 82.7±16.5 82.8±20.6
ACR, mg/g 3.2 (1.6–5.7) 3.7 (1.3–10.0) 4.3 (2.0–9.5) 8.0 (2.4–40.1)
CVD events 833 219 1,128 578
Incidence rate of CVD, per 1,000 person-years 14.6 37.6 28.0 56.4

Values are mean ± SD, median (IQR), or percentage unless otherwise specified.

diabetics were compared) or DM (when those with HTN and those
without were compared) and eGFR or ACR, as appropriate. eGFR
and log-transformed ACR [14, 20] were first modeled as continu-
ous variables with linear splines (knots at each 15 ml/min/1.73 m2
from 30 to 105 for eGFR and knots at 10, 30 and 300 mg/g for ACR).
To evaluate interaction, models with and without product terms
between kidney measures and potential effect modifiers were con-
structed. Using the models with the product terms, we estimated the
hazard ratios (HRs) for eGFR and ACR with the reference of 95 ml/
min/1.73 m2 eGFR and 5 mg/g ACR within each subgroup. From
these models, ‘point-wise interaction’ was evaluated as the ratio of
these HRs between subgroups at each point of eGFR (1  ml/min/
1.73 m2 increment) and ACR (8% increment). ‘Overall interaction’
was tested based on a likelihood ratio test comparing the models
with and without the product terms. To account for the main effect
of DM and HTN on cardiovascular risk, estimates in subgroups
were compared using a single reference of eGFR and ACR in refer-
ence groups (those without DM and/or HTN). We also assessed
interaction for combined categories of eGFR (≥105, 90–104, 75–89,
60–74, 45–59, 30–44, 15–29 and <15 ml/min/1.73  m2) and ACR
(<10, 10–29, 30–299 and ≥300 mg/g) [14, 20].
A p value of <0.05 (2-tailed) was considered statistically sig-
nificant. All statistical analyses were performed using Stata 12
(StataCorp, College Station, Tex., USA).
Results
Participant Characteristics
A total of 5,189 (47.0%) participants had neither DM
nor HTN, 628 (5.7%) had only DM, 4,022 (36.4%) had
only HTN and 1,211 (11.0%) had both DM and HTN.
Participants with DM and/or HTN were more likely to be
older, black, obese and have a history of CVD as com-
pared to those without either (table 1). The participants
with both conditions had the highest level of systolic
blood pressure, mean fasting blood glucose and preva-
lence of CVD. The percentage of current smokers was
highest among participants without HTN and DM, and
levels of total cholesterol were not substantially different
across the 4 groups. During a median follow-up time of
11.7 years, there were 2,758 cases of composite CVD
(1,672 cases of CHD, 558 cases of stroke and 1,375 cases
of heart failure). The incidence rate of CVD was highest
in participants who have both DM and HTN followed by
those with only DM, those with only HTN and those
without either of these conditions (table 1).
Kidney Measures, DM and CVD
With a single reference at 95 ml/min/1.73 m2 eGFR
among those without DM, individuals with DM had a
higher risk of CVD relative to those without at all levels
of eGFR (fig. 1a). To more clearly illustrate potential dif-
ferences in the contribution of kidney measures to CVD
risk (potential effect modification) by the presence or ab-
sence of DM, we subsequently depicted adjusted HR ac-
cording to kidney measures with separate references for
those with and without DM (fig. 1b). The HR of CVD ac-
cording to low eGFR was generally similar among par-
ticipants with and without DM at the eGFR range of 45–

CKD-DM/HTN Interaction on CVD Am J Nephrol 2015;41:409–417 411

DOI: 10.1159/000433450
 Color version available online
16 No diabetes 16
Diabetes
8 8

Adjusted HR
Adjusted HR

4 4

2 2
1.5 1.5
1 1

0.5 0.5
15 30 45 60 75 90 105 120 15 30 45 60 75 90 105 120
a eGFR (ml/min/1.73 m2) b eGFR (ml/min/1.73 m2)

16 16

8 8

Adjusted HR
Adjusted HR

4 4

2 2
1.5 1.5
1
1
0.5
0.5
2.5 5 10 30 300 1,000 2.5 5 10 30 300 1,000
c ACR (mg/g) d ACR (mg/g)

Fig. 1. HRs for CVD risk according to eGFR and ACR in individu-
als with and without DM. a, b eGFR and CVD risk. c, d ACR and
CVD risk. One reference point is used in a and c (eGFR 95 ml/
min/1.73 m2 and ACR 5 mg/g in the no DM group). These panels
show the main effect of DM on CVD risk. Two reference points
are used in b and d (eGFR 95 ml/min/1.73 m2 and ACR 5 mg/g
among both groups). Adjustments were made for age, sex, race,
BMI, smoking status, total cholesterol, systolic blood pressure, his-
tory of CVD and log-ACR of eGFR splines, as appropriate.

90 ml/min/1.73 m2 but was higher among participants
without DM as compared to those with at an eGFR <45
ml/min/1.73 m2, although there was no significant point-
wise or overall (p = 0.49) interaction.
Overall, a similar pattern (higher relative risk accord-
ing to low eGFR among those without DM compared to
those with DM at eGFR <45 ml/min/1.73 m2) was ob-
served for CHD, heart failure and stroke (see online sup-
pl. fig. 1; for all online suppl. material, see www.karger.
com/doi/10.1159/000433450). Although overall interac-
tion did not reach statistical significance in any of the
CVD outcomes (p > 0.17), significant point-wise interac-
tion was observed at a limited range of eGFR for CHD
(32–39 ml/min/1.73 m2) and stroke (17–39 ml/min/
1.73 m2), indicating a higher contribution of low eGFR
to increased relative risk among those without DM com-
pared to those with DM.
Individuals with DM had a higher risk of CVD com-
pared to those without DM at all levels of ACR (fig. 1c).
With a reference of 5 mg/g ACR for both groups, CVD
risk increased at ACR 10–30 mg/g among those without
DM but only at ACR >30 mg/g among those with DM,
resulting in a significant overall (p = 0.02) and point-wise
interaction at ACR 14–110 mg/g. A less steep risk gradi-
ent according to higher ACR among the diabetic group
was similarly observed for CHD and heart failure (p for
overall interaction <0.05 for both outcomes), whereas the
risk gradient was almost superimposed for stroke among
those with and without DM (p for overall interaction =
0.9; online suppl. fig. 2).
Table 2 presents HRs for CVD risk for 32 categories of
eGFR and ACR for participants with and without DM.
Although there were a few quantitative differences, CVD
risk generally increased with lower eGFR and higher ACR
in both groups.
Kidney Measures, HTN and CVD
While observing the main effect of HTN on CVD risk,
it was found that higher HRs were generally observed
across the entire range of eGFR, except at 30–45 ml/

412 Am J Nephrol 2015;41:409–417 Alexander/Matsushita/Sang/Ballew/

DOI: 10.1159/000433450 Mahmoodi/Astor/Coresh
Table 2. HR of CVD according to combined categories of eGFR and ACR stratified by DM status

DM status
eGFR, ACR, mg/g
ml/min/
1.73 m2 no yes
<10 10–29 30–299 ≥300 overall <10 10–29 30–299 ≥300 overall

≥105 1.08 1.11 2.15 3.93 1.11 1.08 1.06 1.33 6.01 1.13
(0.83–1.41) (0.55–2.23) (1.25–3.69) (0.55–28.06) (0.88–1.40) (0.75–1.56) (0.59–1.92) (0.80–2.23) (2.91–12.40) (0.86–1.47)
90–104 reference 0.99 1.97 2.94 reference reference 1.30 0.96* 2.33 reference
(0.76–1.30) (1.42–2.72) (1.31–6.60) (0.92–1.83) (0.66–1.41) (1.46–3.71)
75–89 1.01 1.42 2.13 2.27 1.06 0.78 1.04 1.24* 2.74 0.88
(0.89–1.15) (1.14–1.77) (1.59–2.86) (1.17–4.42) (0.95–1.19) (0.61–1.00) (0.72–1.50) (0.87–1.76) (1.51–4.96) (0.73–1.07)
60–74 1.27 1.50 1.41 2.45 1.25 1.05 1.55 0.88 1.71 1.01
(1.10–1.47) (1.14–1.98) (0.97–2.03) (1.21–4.96) (1.09–1.42) (0.79–1.38) (1.03–2.32) (0.54–1.44) (0.99–2.94) (0.82–1.25)
45–59 1.32 2.24 2.91 2.82 1.50 1.21 2.02 2.06 2.69 1.41
(1.05–1.66) (1.48–3.39) (2.07–4.09) (1.05–7.58) (1.25–1.81) (0.79–1.84) (1.28–3.18) (1.31–3.24) (1.57–4.61) (1.10–1.82)
30–44 2.19 3.48 4.57 6.01 2.48 0.89 1.64 1.80 5.28 1.57
(1.36–3.52) (1.30–9.33) (2.43–8.58) (2.67–13.48) (1.78–3.47) (0.36–2.18) (0.52–5.16) (0.88–3.69) (3.16–8.82) (1.09–2.28)
15–29 1.35 N/A N/A 5.79 1.89 2.27 N/A 1.35 5.18 2.03
(0.19–9.62) (2.16–15.51) (0.78–4.60) (0.56–9.18) (0.19–9.72) (2.63–10.22) (1.12–3.68)
<15 N/A N/A 4.60 4.64 1.99 N/A N/A 1.97 4.36 1.79
(0.64–32.95) (1.72–12.51) (0.81–4.88) (0.27–14.12) (1.91–9.95) (0.83–3.85)
Overall reference 1.23 1.79 2.38 reference 1.35 1.21* 2.54
(1.08–1.41) (1.53–2.10) (1.73–3.27) (1.12–1.64) (0.99–1.47) (2.02–3.20)

N/A = No events or unreliable estimates. Bold indicates p < 0.05 relative to the reference category within each group by DM status. * Indicates p < 0.05
for interaction with DM status for the corresponding category.

min/1.73 m2, in patients with HTN compared to those
without (fig.  2a). We also observed a decline in HRs at
eGFR <30 ml/min/1.73 m2 among those without HTN but
the sample size was small in this category (4 CVD cases
out of 5 participants). When separate references were set
at an eGFR of 95 ml/min/1.73 m2 among participants with
and without HTN, the risk gradient was largely similar in
both the groups (fig. 2b). However, HRs according to low
eGFR among those with HTN appeared to be higher at
eGFR 60–75 ml/min/1.73 m2 (resulting in significant
point-wise interaction at a limited eGFR range) but slight-
ly lower around an eGFR of 30–45 ml/min/1.73 m2 as
compared to those without HTN. The overall interaction
was not statistically significant (p = 0.24).
Largely similar patterns were observed for CHD (on-
line suppl. fig. 3A) and heart failure (online suppl. fig. 3B),
although HRs for heart failure according to low eGFR
were higher among those without HTN than among
those at a broader eGFR range (reaching significance at
eGFR 36–39 ml/min/1.73 m2 but not overall (p = 0.28)).
We did not observe increased risk of stroke according to
low eGFR among those without HTN (online suppl.
fig.  3C), although there were a small number of stroke
cases in this population (6 cases out of 216 non-hyperten-
sives with eGFR <60 ml/min/1.73 m2).
Higher cardiovascular risk was observed among par-
ticipants with HTN than among those without at all ACR
ranges (fig. 2c). With a separate reference for each group,
an increasing risk gradient was observed with increasing
ACR among those with and without HTN, without sig-
nificant point-wise or overall (p = 0.84) interaction
(fig. 2d).
We observed largely similar results for CHD (online
suppl. fig. 4A) and heart failure (online suppl. fig. 4B; p
for overall interaction >0.25), with a steeper risk gradient
for heart failure. The risk of stroke conferred by high ACR
was higher among participants with HTN at an ACR of
10–300 mg/g, with a significant point-wise interaction at
14–70 mg/g ACR. Nevertheless, the overall interaction
was not significant (p = 0.17).

CKD-DM/HTN Interaction on CVD Am J Nephrol 2015;41:409–417 413

DOI: 10.1159/000433450
 Color version available online
16 No hypertensive 16
Hypertensive
Adjusted HR 8 8

Adjusted HR
4 4

2
2
1.5 1.5
1
1
0.5
0.5
15 30 45 60 75 90 105 120 15 30 45 60 75 90 105 120
a eGFR (ml/min/1.73 m2) b eGFR (ml/min/1.73 m2)

16 16

8 8

Adjusted HR
Adjusted HR

4 4

2 2
1.5 1.5
1 1

0.5 0.5
2.5 5 10 30 300 1,000 2.5 5 10 30 300 1,000
c ACR (mg/g) d ACR (mg/g)

Fig. 2. HRs for CVD risk according to eGFR and ACR in indi-
viduals with and without HTN. a, b eGFR and CVD risk. c, d ACR
and CVD risk. One reference point is used in panels a and c (eGFR
95 ml/min/1.73 m2 and ACR 5 mg/g in the no HTN group). These
panels show the main effect of HTN on CVD risk. Two reference
points are used in b and d (eGFR 95 ml/min/1.73 m2 and ACR
5  mg/g among both groups). Adjustments were made for age,
sex, race, BMI, smoking status, total cholesterol, DM, history of
CVD and log-ACR of eGFR splines, as appropriate.

Table 3 lists the HRs for CVD risk in 32 categories of >ACR 30 mg/g, resulting in significant point-wise inter-
eGFR and ACR among participants with and without action at an ACR of 24–41 mg/g compared to those with-
HTN. CVD risk generally increased with lower eGFR and out either.
higher ACR regardless of HTN status, without a substan-
tial difference in adjusted HR between corresponding cat-
egories for those with and without HTN. Discussion

Kidney Measures, Combination of DM and HTN, and
CVD
When we analyzed 4 groups according to DM and
HTN status separately, the CVD risk conferred by low
eGFR increased to around eGFR 60–75 ml/min/1.73 m2
in every group (online suppl. fig. 5), although the signif-
icance varied due to differences in sample size and events.
Similarly, the CVD risk conferred by high ACR was
largely consistent across the 4 groups and increased con-
siderably even within the normal range (<30 mg/g), ex-
cept among those with both DM and HTN. For this
group, CVD risk according to high ACR increased to
As anticipated, the risk of CVD was higher in individu-
als with DM or HTN regardless of the level of eGFR and
ACR. When we assessed the contribution of the kidney
measures to CVD risk, adjusted cardiovascular risk gener-
ally increased with lower eGFR and higher ACR, regard-
less of the presence or absence of DM and HTN. Of note,
these kidney measures were independently associated
with CVD risk even among those without both DM and
HTN. Our findings are largely consistent with the recent
meta-analyses from the CKD-PC in reinforcing the im-
portance of the kidney measures in health outcomes re-
gardless of DM and HTN status [14, 20]. We have, how-

414 Am J Nephrol 2015;41:409–417 Alexander/Matsushita/Sang/Ballew/

DOI: 10.1159/000433450 Mahmoodi/Astor/Coresh
Table 3. HR of CVD according to combined categories of eGFR and ACR stratified by HTN status

HTN status

eGFR, ACR, mg/g

ml/min/
1.73 m2 no yes
<10 10–29 30–299 ≥300 overall <10 10–29 30–299 ≥300 Overall

≥105 1.19 1.65 2.81 18.83 1.29 1.05 1.04 1.60 5.96 1.09
(0.85–1.65) (0.73–3.70) (1.32–5.97) (2.63–135.11) (0.97–1.73) (0.79–1.38) (0.61–1.79) (1.05–2.45) (2.92–12.16) (0.87–1.35)
90–104 reference 1.13 1.40 5.68 reference reference 1.13 1.49 2.56 reference
(0.79–1.61) (0.87–2.27) (2.11–15.29) (0.86–1.47) (1.11–1.99) (1.66–3.96)
75–89 0.93 1.08 1.99 1.26 0.94 0.98 1.44 1.64 3.06 1.05
(0.79–1.09) (0.78–1.49) (1.34–2.97) (0.31–5.09) (0.82–1.09) (0.83–1.15) (1.14–1.83) (1.25–2.1) (1.91–4.90) (0.92–1.20)
60–74 1.10 1.21 0.77 2.06 1.05 1.27 1.65 1.30 2.22 1.22
(0.90–1.33) (0.77–1.91) (0.34–1.72) (0.51–8.30) (0.88–1.26) (1.07–1.51) (1.26–2.16) (0.93–1.79) (1.42–3.49) (1.06–1.40)
45–59 1.10 3.35 1.77 2.58 1.24 1.31 1.99 2.74 2.87 1.48
(0.77–1.57) (1.71–6.53) (0.73–4.29) (0.36–18.47) (0.92–1.68) (1.01–1.67) (1.40–2.83) (2.04–3.69) (1.77–4.65) (1.24–1.76)
30–44 2.54 N/A 3.78 6.66 2.32 1.47 2.65 2.94 6.44 1.97
(1.05–6.17) (0.53–26.97) (1.65–26.83) (1.15–4.70) (0.91–2.38) (1.25–5.64) (1.79–4.82) (4.11–10.10) (1.50–2.58)
15–29 3.98 N/A N/A 4.03 2.64 0.91 N/A 1.22 5.72 1.84
(0.99–16.02) (0.56–28.86) (0.84–8.30) (0.13–6.49) (0.17–8.70) (3.19–10.23) (1.06–3.18)
<15 N/A N/A N/A 2.07 0.58 N/A N/A 6.22 6.31 2.69
(0.29–14.81) (0.08–4.14) (1.54–25.12) (3.23–12.33) (1.45–5.01)
Overall reference 1.20 1.54 2.42 reference 1.31 1.51 2.64
(0.99–1.47) (1.19–2.00) (1.41–4.16) (1.15–1.49) (1.32–1.74) (2.17–3.22)

N/A = No events or unreliable estimates. Bold indicates p < 0.05 relative to the reference category within each group by HTN status.

ever, expanded the research on the interaction of kidney
measures with DM and HTN by including non-fatal out-
comes and looking at each CVD outcome separately.
In our study, the only significant overall interaction on
CVD was observed for ACR and DM. The CVD risk gra-
dient according to ACR was significantly shallower in
those with DM than in those without, and this pattern was
consistent for CHD and heart failure, but not for stroke.
The potential mechanisms for this interaction were not
entirely clear. One possible explanation is the benefit of
the treatment provided to people with DM. For example,
angiotensin-converting enzyme inhibitors and angioten-
sin II receptor blockers (ARBs) are recommended as the
first-line medication options for patients with DM and
HTN [28] because of their high effectiveness at reducing
CVD risk in this population [29–31]. These medications
are known to reduce albuminuria, and the reduction of
albuminuria after the initiation of ARB was a strong pre-
dictor of lower CVD risk among those with DM [32]. The
shallowest CVD risk gradient according to high ACR was
observed among those with both DM and HTN (online
suppl. fig. 5B), and those with DM were more likely to
take these medications compared to those without (28.9
vs. 11.3%). One caveat to this explanation is in the fact
that the prescription of angiotensin-converting enzyme
inhibitors and ARB for persons with DM at ACR <30
mg/g is not common unless HTN coexists [33]. There-
fore, further studies are required to confirm the ACR-DM
interaction on CVD risk.
Our results emphasize the value of eGFR and albumin-
uria as predictors of CVD in those with and without DM
and HTN. The findings for those with DM and/or HTN
support screening for CKD in this high-risk population,
as recommended in clinical guidelines [10]. The findings
for those without either DM or HTN are particularly im-
portant since this population has been understudied in
this context [14, 20]. Although the question of screening
these individuals requires further assessment [9], our re-
sults suggest that CKD be regarded as an important risk
factor for CVD.

CKD-DM/HTN Interaction on CVD Am J Nephrol 2015;41:409–417 415

DOI: 10.1159/000433450
 This study has several limitations. First, the number of
persons with only DM or both DM and HTN was small,
limiting our ability to further analyze the 4 groups ac-
cording to DM and HTN status. Second, reflecting the
distribution in the general population [34], the number
of persons at eGFR categories 4 and 5 were small, result-
ing in unreliable estimates at this range in some stratified
models. Third, a single measurement of eGFR and ACR
was obtained, potentially leading to some degree of mis-
classification. Fourth, we used the CKD-EPI creatinine
equation for calculation of eGFR [23, 35], and thus con-
firmation of our findings with other kidney filtration
markers such as cystatin C would be needed [36]. Fifth,
the study participants were aged 52–75 years and were
either white or black; these results may not be generaliz-
able to individuals out of this age range and other racial/
ethnic groups. Sixth, as with any observational study,
there is a possibility of residual confounding. Finally, in-
cident heart failure was defined using the ICD code of
hospitalization records and death certificates, which may
underestimate the incidence of heart failure [37].
Despite some quantitative interactions, the associa-
tions of eGFR and ACR with CVD were generally consis-
tent among subgroups according to DM and HTN status,
with significantly increased risk beyond the current
thresholds of these kidney measures for CKD definition
and staging in every group. These kidney measures con-
tributed to increased CVD risk even among those without
either DM or HTN. These findings emphasize the impor-
tance of kidney diseases in the development of cardiovas-
cular outcomes, and thus the presence of CKD should
warrant clinical attention regardless of DM and HTN
status.
Acknowledgments
The ARIC Study is carried out as a collaborative study sup-
ported by National Heart, Lung, and Blood Institute contracts
(HHSN268201100005C, HHSN268201100006C, HHSN2682011
00007C, HHSN268201100008C, HHSN268201100009C, HHSN
268201100010C, HHSN268201100011C and HHSN268201100
012C). The authors thank the staff and participants of the ARIC
study for their important contributions.
Disclosure Statement
None of the authors have any conflict of interest to report.

References
1 Levey AS, Coresh J: Chronic kidney disease.
Lancet 2012;379:165–180.
2 Fox CS, Coady S, Sorlie PD, Levy D, Meigs JB,
D’Agostino RB Sr, Wilson PW, Savage PJ:
Trends in cardiovascular complications of di-
abetes. JAMA 2004;292:2495–2499.
3 Fox CS, Coady S, Sorlie PD, D’Agostino RB
Sr, Pencina MJ, Vasan RS, Meigs JB, Levy D,
Savage PJ: Increasing cardiovascular disease
burden due to diabetes mellitus: the framing-
ham heart study. Circulation 2007;115:1544–
1550.
4 Emerging Risk Factors Collaboration; Sesha-
sai SR, Kaptoge S, Thompson A, Di Angelan-
tonio E, Gao P, Sarwar N, Whincup PH, Mu-
kamal KJ, Gillum RF, Holme I, Njølstad I,
Fletcher A, Nilsson P, Lewington S, Collins R,
Gudnason V, Thompson SG, Sattar N, Selvin
E, Hu FB, Danesh J: Diabetes mellitus, fasting
glucose, and risk of cause-specific death. N
Engl J Med 2011;364:829–841.
5 Sowers JR, Epstein M, Frohlich ED: Diabetes,
hypertension, and cardiovascular disease: an
update. Hypertension 2001;37:1053–1059.
6 Vasan RS, Larson MG, Leip EP, Evans JC,
O’Donnell CJ, Kannel WB, Levy D: Impact of
high-normal blood pressure on the risk of
cardiovascular disease. N Engl J Med 2001;
345:1291–1297.
7 Wilson PW, D’Agostino RB, Levy D, Be-
langer AM, Silbershatz H, Kannel WB: Pre-
diction of coronary heart disease using risk
factor categories. Circulation 1998; 97: 1837–
1847.
8 US Renal Data System: USRDS 2011 Annual
Data Report: Atlas of Chronic Kidney Disease
and End-Stage Renal Disease in the United
States. Bethesda, MD, National Institutes of
Health, National Institute of Diabetes and Di-
gestive and Kidney Diseases, 2011.
9 Hallan SI, Stevens P: Screening for chronic
kidney disease: which strategy? J Nephrol
2010;23:147–155.
10 Crowe E, Halpin D, Stevens P; Guidelines De-
velopment Group: Early identification and
management of chronic kidney disease: sum-
mary of NICE guidance. BMJ 2008;337:a1530.
11 Mancia G, De Backer G, Dominiczak A,
Cifkova R, Fagard R, Germano G, Grassi G,
Heagerty AM, Kjeldsen SE, Laurent S, Nar-
kiewicz K, Ruilope L, Rynkiewicz A, Schmie-
der RE, Boudier HA, Zanchetti A; ESH-ESC
Task Force on the Management of Arterial
Hypertension: 2007 ESH-ESC practice guide-
lines for the management of arterial hyper-
tension: ESH-ESC task force on the manage-
ment of arterial hypertension. J Hypertens
2007;25:1751–1762.
12 Chobanian AV, Bakris GL, Black HR, Cush-
man WC, Green LA, Izzo JL Jr, Jones DW,
Materson BJ, Oparil S, Wright JT Jr, Roccella
EJ: The seventh report of the joint national
committee on prevention, detection, evalua-
tion, and treatment of high blood pressure:
the JNC 7 report. JAMA 2003;289:2560–2572.
13 Abramson JL, Jurkovitz CT, Vaccarino V,
Weintraub WS, McClellan W: Chronic kid-
ney disease, anemia, and incident stroke in a
middle-aged, community-based population:
the ARIC study. Kidney Int 2003;64:610–615.
14 Fox CS, Matsushita K, Woodward M, Bilo HJ,
Chalmers J, Heerspink HJ, Lee BJ, Perkins
RM, Rossing P, Sairenchi T, Tonelli M, Vas-
salotti JA, Yamagishi K, Coresh J, de Jong PE,
Wen CP, Nelson RG; Chronic Kidney Disease
Prognosis Consortium: Associations of kid-
ney disease measures with mortality and end-
stage renal disease in individuals with and
without diabetes: a meta-analysis. Lancet
2012;380:1662–1673.
15 Lewington S, Clarke R, Qizilbash N, Peto R,
Collins R; Prospective Studies Collaboration:
Age-specific relevance of usual blood pres-
sure to vascular mortality: a meta-analysis of
individual data for one million adults in 61
prospective studies. Lancet 2002; 360: 1903–
1913.

416 Am J Nephrol 2015;41:409–417 Alexander/Matsushita/Sang/Ballew/

DOI: 10.1159/000433450 Mahmoodi/Astor/Coresh
16 Matsushita K, Selvin E, Bash LD, Franceschi-
ni N, Astor BC, Coresh J: Change in estimated
GFR associates with coronary heart disease
and mortality. J Am Soc Nephrol 2009; 20:
2617–2624.
17 Sarnak MJ, Levey AS, Schoolwerth AC,
Coresh J, Culleton B, Hamm LL, McCullough
PA, Kasiske BL, Kelepouris E, Klag MJ, Par-
frey P, Pfeffer M, Raij L, Spinosa DJ, Wilson
PW: Kidney disease as a risk factor for devel-
opment of cardiovascular disease: a statement
from the American heart association councils
on kidney in cardiovascular disease, high
blood pressure research, clinical cardiology,
and epidemiology and prevention. Circula-
tion 2003;108:2154–2169.
18 Kottgen A, Russell SD, Loehr LR, Crainiceanu
CM, Rosamond WD, Chang PP, Chambless
LE, Coresh J: Reduced kidney function as a
risk factor for incident heart failure: the ath-
erosclerosis risk in communities (ARIC)
study. J Am Soc Nephrol 2007;18:1307–1315.
19 National Kidney Foundation: K/DOQI clini-
cal practice guidelines for chronic kidney dis-
ease: evaluation, classification, and stratifica-
tion. Am J Kidney Dis 2002;39(2 suppl 1):S1–
S266.
20 Mahmoodi BK, Matsushita K, Woodward M,
Blankestijn PJ, Cirillo M, Ohkubo T, Rossing
P,  Sarnak MJ, Stengel B, Yamagishi K, Ya-
mashita K, Zhang L, Coresh J, de Jong PE, Astor
BC: 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.
21 Roger VL, Go AS, Lloyd-Jones DM, Benjamin
EJ, Berry JD, Borden WB, Bravata DM, Dai S,
Ford ES, Fox CS, Fullerton HJ, Gillespie C,
Hailpern SM, Heit JA, Howard VJ, Kissela
BM, Kittner SJ, Lackland DT, Lichtman JH,
Lisabeth LD, Makuc DM, Marcus GM, Marel-
li A, Matchar DB, Moy CS, Mozaffarian D,
Mussolino ME, Nichol G, Paynter NP, Soli-
man EZ, Sorlie PD, Sotoodehnia N, Turan
TN, Virani SS, Wong ND, Woo D, Turner
MB; American Heart Association Statistics
Committee and Stroke Statistics Subcommit-
tee: Heart disease and stroke statistics – 2012
update: a report from the American heart as-
sociation. Circulation 2012;125:e2–e220.
CKD-DM/HTN Interaction on CVD
22 Astor BC, Shafi T, Hoogeveen RC, Matsushi-
ta K, Ballantyne CM, Inker LA, Coresh J: Nov-
el markers of kidney function as predictors of
ESRD, cardiovascular disease, and mortality
in the general population. Am J Kidney Dis 30
2012;59:653–662.
23 Matsushita K, Mahmoodi BK, Woodward M,
Emberson JR, Jafar TH, Jee SH, Polkinghorne
KR, Shankar A, Smith DH, Tonelli M, War-
nock DG, Wen CP, Coresh J, Gansevoort RT,
Hemmelgarn BR, Levey AS; Chronic Kidney 31
Disease Prognosis Consortium: Comparison
of risk prediction using the CKD-EPI equa-
tion and the MDRD study equation for esti-
mated glomerular filtration rate. JAMA 2012;
307:1941–1951.
24 Levey AS, Coresh J, Greene T, Marsh J, Ste- 32
vens LA, Kusek JW, Van Lente F; Chronic
Kidney Disease Epidemiology Collaboration:
Expressing the modification of diet in renal
disease study equation for estimating glomer-
ular filtration rate with standardized serum
creatinine values. Clin Chem 2007; 53: 766– 33
772.
25 Astor BC, Coresh J, Heiss G, Pettitt D, Sarnak
MJ: Kidney function and anemia as risk fac-
tors for coronary heart disease and mortali- 34
ty:  the atherosclerosis risk in communities
(ARIC) study. Am Heart J 2006;151:492–500.
26 Rasmussen ML, Folsom AR, Catellier DJ, Tsai
MY, Garg U, Eckfeldt JH: A prospective study 35
of coronary heart disease and the hemochro-
matosis gene (HFE) C282Y mutation: the ath-
erosclerosis risk in communities (ARIC)
study. Atherosclerosis 2001;154:739–746.
27 Suri MF, Yamagishi K, Aleksic N, Hannan PJ,
Folsom AR: Novel hemostatic factor levels
and risk of ischemic stroke: the atherosclero- 36
sis risk in communities (ARIC) study. Cere-
brovasc Dis 2010;29:497–502.
28 Arauz-Pacheco C, Parrott MA, Raskin P;
American Diabetes Association: Hyperten-
sion management in adults with diabetes. Di-
abetes Care 2004;27(suppl 1):S65–S67.
29 Lindholm LH, Ibsen H, Dahlöf B, Devereux 37
RB, Beevers G, de Faire U, Fyhrquist F, Julius
S, Kjeldsen SE, Kristiansson K, Lederballe-
Pedersen O, Nieminen MS, Omvik P, Oparil S,
Wedel H, Aurup P, Edelman J, Snapinn S; LIFE
Study Group: Cardiovascular morbidity and
Am J Nephrol 2015;41:409–417
DOI: 10.1159/000433450
mortality in patients with diabetes in the losar-
tan intervention for endpoint reduction in hy-
pertension study (LIFE): a randomised trial
against atenolol. Lancet 2002;359:1004–1010.
Heart Outcomes Prevention Evaluation Study
Investigators: Effects of ramipril on cardiovas-
cular and microvascular outcomes in people
with diabetes mellitus: results of the HOPE
study and MICRO-HOPE substudy. Lancet
2000;355:253–259.
Tatti P, Pahor M, Byington RP, Di Mauro P,
Guarisco R, Strollo G, Strollo F: Outcome re-
sults of the fosinopril versus amlodipine car-
diovascular events randomized trial (FACET)
in patients with hypertension and NIDDM.
Diabetes Care 1998;21:597–603.
de Zeeuw D, Remuzzi G, Parving HH, Keane
WF, Zhang Z, Shahinfar S, Snapinn S, Cooper
ME, Mitch WE, Brenner BM: Albuminuria, a
therapeutic target for cardiovascular protec-
tion in type 2 diabetic patients with nephrop-
athy. Circulation 2004;110:921–927.
KDOQI: KDOQI clinical practice guidelines
and clinical practice recommendations for di-
abetes and chronic kidney disease. Am J Kid-
ney Dis 2007;49(2 suppl 2):S12–S154.
Coresh J, Selvin E, Stevens LA, Manzi J, Kusek
JW, Eggers P, Van Lente F, Levey AS: Preva-
lence of chronic kidney disease in the United
States. JAMA 2007;298:2038–2047.
Levey AS, Stevens LA, Schmid CH, Zhang YL,
Castro AF 3rd, Feldman HI, Kusek JW, Egg-
ers P, Van Lente F, Greene T, Coresh J; CKD-
EPI (Chronic Kidney Disease Epidemiology
Collaboration): A new equation to estimate
glomerular filtration rate. Ann Intern Med
2009;150:604–612.
Shlipak MG, Matsushita K, Ärnlöv J, Inker
LA, Katz R, Polkinghorne KR, Rothenbacher
D, Sarnak MJ, Astor BC, Coresh J, Levey AS,
Gansevoort RT; CKD Prognosis Consortium:
Cystatin C versus creatinine in determining
risk based on kidney function. N Engl J Med
2013;369:932–943.
Matsushita K, Blecker S, Pazin-Filho A, Ber-
toni A, Chang PP, Coresh J, Selvin E: The as-
sociation of hemoglobin a1c with incident
heart failure among people without diabetes:
the atherosclerosis risk in communities study.
Diabetes 2010;59:2020–2026.
417