Download Renal Resistive Index and Cardiovascular and

Renal Resistive Index and Cardiovascular and Renal
Outcomes in Essential Hypertension
Yohei Doi, Yoshio Iwashima, Fumiki Yoshihara, Kei Kamide, Shin-ichirou Hayashi, Yoshinori Kubota,
Satoko Nakamura, Takeshi Horio, Yuhei Kawano
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Abstract—Increased renal restive index (RI) measured using Doppler ultrasonography has been shown to correlate with the
degree of renal impairment in hypertensive patients. We investigated the prognostic role of RI in cardiovascular and
renal outcomes. A total of 426 essential hypertensive subjects (mean age, 63 years; 50% female) with no previous
cardiovascular disease were included in this study. Renal segmental arterial RI was measured by duplex Doppler
ultrasonography. During follow-up (mean, 3.1 years), 57 participants developed the primary composite end points
including cardiovascular and renal outcomes. In multivariate Cox regression analysis, RI was an independent predictor
of worse outcome in total subjects (hazard ratio, 1.71 for 1 SD increase), as well as in patients with estimated glomerular
filtration rate (eGFR) ⬍60 mL/min per 1.73 m2 (hazard ratio, 2.11 for 1 SD increase; P⬍0.01, respectively). When
divided into 4 groups based on the respective sex-specific median levels of RI in the eGFR ⱖ60 and eGFR ⬍60 mL/min
per 1.73 m2 groups, the group with eGFR ⬍60 and high RI (male ⱖ0.73, female ⱖ0.72) had a significantly poorer
event-free survival rate (␹2⫽126.4; P⬍0.01), and the adjusted hazard ratio by multivariate Cox regression analysis was
9.58 (95% CI, 3.26 –32.89; P⬍0.01). In conclusion, impairment of renal hemodynamics evaluated by increased RI is
associated with an increased risk of primary composite end points, and the combination of high RI and low eGFR
is a powerful predictor of these diseases in essential hypertension. In hypertensive patients with chronic kidney
disease, RI evaluation may complement predictors of cardiovascular and renal outcomes. (Hypertension. 2012;
60:770-777.)
Key Words: cardiovascular disease 䡲 renal hemodynamics 䡲 ultrasonography 䡲 hypertension 䡲 predictor
I
n the past few years, there has been growing attention to
markers of subclinical renal damage because they provide an
accurate prediction of global cardiovascular outcome.1 Renal
Doppler sonography permits noninvasive assessment of intrarenal hemodynamics in addition to evaluation of anatomic information. Intrarenal arterial waveforms recorded by Doppler
sonography have been widely used to evaluate renal dysfunction.2,3 Previous studies have explored the capacity of resistive
index (RI) calculated from blood flow velocity in vessels to
predict the progression of renal function in patients with hypertension,4 diabetes mellitus,5 or chronic nephropathy.6,7 In addition, histological studies demonstrated that RI not only reflects
changes in intrarenal perfusion and renovascular resistance but
was increased in several pathological conditions, such as renal
atherosclerosis8 and tubulointerstitial damage.9,10 In previous
studies, the prognostic value of RI was examined only in chronic
nephropathy,6 elderly,11 or heart failure patients12; however, the
results obtained were inconsistent. Thus, the status of RI as an
independent cardiovascular risk marker remains to be eluci-
dated. Estimated glomerular filtration rate (eGFR), which is a
measure of the kidneys’ ability to filter blood, has proven to be
a predictor of cardiovascular disease in the general population,13,14 as well as in hypertensive patients.15–17 Evaluation of
renal RI in addition to eGFR may help to assess not only renal
function but also intrarenal hemodynamics, as well as intrarenal
vascular resistance, and thus may provide clinically sensitive
prognostic information in patients with essential hypertension.
However, the additional predictive value of these abnormalities
has not been elucidated. Therefore, this study was undertaken to
identify the clinical significance of RI, in middle-aged and
elderly essential hypertensive subjects, to determine its impact
on cardiovascular and renal outcome. In addition, we further
examined whether assessment of RI adds to the prognostic
information provided by eGFR.
Methods
The study protocol was approved by the ethics committee of our
institution. All of the subjects enrolled in this study were Japanese
and gave informed consent to participate in this study.
Received April 8, 2012; first decision April 23, 2012; revision accepted July 3, 2012.
From the Divisions of Hypertension and Nephrology (Y.D., Y.I., F.Y., S.-i.H., S.N., Y.Ka.), and Laboratory Medicine (Y.Ku.), Department of
Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan; Department of Geriatric Medicine and Nephrology (K.K.), Osaka University
Graduate School of Medicine, Osaka, Japan; Third Department of General Medicine (T.H.), Kawasaki Hospital, Kawasaki Medical School, Kawasaki,
Japan.
Correspondence to Yoshio Iwashima, Division of Hypertension and Nephrology, Department of Medicine, National Cerebral and Cardiovascular
Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail [email protected]
© 2012 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.112.196717
770
Doi et al
Study Subjects
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This study enrolled 426 (213 female) essential hypertensive patients
in normal sinus rhythm who had good quality renal sonographic
recordings. The patients were consecutively recruited for this study
from among those attending the outpatient clinic. In our laboratory
(the National Cerebral and Cardiovascular Center), all of the hypertensive patients attended the renal sonographic laboratory, and renal
sonographic data were routinely collected. Exclusion criteria included ischemic heart disease, acute coronary syndrome, congestive
heart failure (New York Heart Association class II or greater),
valvular heart disease including moderate or severe aortic or mitral
regurgitation, old cerebral infarction, history of transient ischemic
attack, secondary hypertension, renal artery stenosis, heart rate ⬎100
bpm, low ejection fraction (⬍45%), or receiving hemodialysis or
erythropoietin therapy. Hypertension was defined as systolic blood
pressure (BP) of ⱖ140 mm Hg or diastolic BP of ⱖ90 mm Hg on
multiple measurements during ⱖ2 separate office visits or receiving
antihypertensive treatment. Diabetes mellitus was defined according
to the American Diabetes Association criteria.18 Smoking status was
determined by interview and defined as never smoker, former
smoker (smoked ⱖ100 cigarettes in his/her lifetime, but had not
smoked for ⬎1 year at the time of interview), and current smoker.
Baseline Clinical Characteristics
After fasting overnight, BP was measured with an appropriate arm
cuff and a mercury column sphygmomanometer on the left arm after
a resting period of ⱖ10 minutes in the sitting posture. After BP
measurement, venous blood sampling from all of the subjects was
performed. Height and body weight were measured, and body mass
index was calculated. The following parameters were also determined: total cholesterol, triglycerides, high-density lipoprotein cholesterol, fasting glucose, hemoglobin A1c, creatinine, and highsensitive C reactive protein. eGFR was calculated using the
Japanese coefficient-modified Chronic Kidney Disease Epidemiology Collaboration equation in milliliters per minute per 1.73
meters squared.19,20 Urinary albumin excretion was evaluated in
each patient by measuring the albumin:creatinine ratio (ACR) in
3 consecutive first morning samples. The mean of 3 urine
collections was taken as ACR for each patient (see the onlineonly Data Supplement).
Renal Ultrasonography and Doppler Studies
Ultrasonographic examinations were performed using duplex Doppler sonography; the ultrasonographic procedure that we adopted has
been described previously (see the online-only Data Supplement).21–23 Peak systolic velocity (PSV) and minimum end-diastolic
velocity (EDV) were determined using the angle correction menu of
the apparatus, and RI was defined as follows: (PSV⫺EDV)/PSV. All
of the velocities were determined for each segmental artery and
averaged to obtain the mean value for each patient. All of the
measurements were performed by 2 experienced physicians (K.K.
and Y.I.), who were blinded to the clinical data of the subjects. The
reproducibility of RI measurements by 2 investigators was assessed
in a subgroup of 20 patients, in whom measurements were performed
within 1 hour by both investigators in a blinded fashion. The
intraobserver and interobserver coefficients of variation for the
measurements were 2.7% and 3.2%.
Cardiovascular and Renal Outcomes
For survival analysis, observation began on the day of renal
ultrasonography with verified updates through September 2011. All
of the subjects were followed at the National Cerebral and Cardiovascular Center and treated by implementation of standard lifestyle
and pharmacological measures. All of the participants were periodically referred to our institution for BP control and other diagnostic
procedures. The primary end point of this study was first occurrence
of composite of cardiovascular and renal events including all-cause
death, myocardial infarction, stroke, congestive heart failure requiring hospitalization, aortic dissection, and end-stage renal failure
requiring regular hemodialysis (see the online-only Data Supple-
Renal Resistive Index in Hypertension
771
ment). All of the cardiovascular and renal events were determined by
an independent review panel of physicians who were unaware of the
renal ultrasonographic and clinical findings. For patients who experienced multiple nonfatal episodes of cardiovascular and renal
events, the analysis included only the first event.
Statistical Analysis
Summary statistics are presented as mean (⫾SD) for continuous
variables and percentages for categorical variables unless otherwise
specified. The subjects were divided into 2 groups according to
whether RI was below or above the median value for each sex, and
then the significance of any differences between groups was
evaluated using unpaired t test. Event-free survival analysis was
performed using the Kaplan-Meier method to plot the cumulative
incidence of primary composite end points according to median
value of RI for each sex, and the groups were compared by Mantel
log-rank test. Cox proportional hazard analysis was used to
examine the association between variables and the cumulative
incidence of primary composite end points in crude and multivariate models, after accounting for relevant variables using a P
value of ⬍0.05 as the selection criterion. These effects were
measured by the hazard ratio (HR) and 95% CI based on Cox
regression models.
The relationships between RI and various parameters were assessed using univariate linear regression analysis and Pearson
correlation coefficient. We next divided the participants into 2
groups by eGFR of 60 mL/min per 1.73 m2 and then stratified the
participants into 4 groups according to the respective sex-specific
median values of RI in participants with eGFR ⱖ60 or ⬍60.
One-way ANOVA with Scheffe multiple comparison posttest was
used to analyze data among the 4 groups. Event-free survival
analysis was performed using the Kaplan-Meier method to plot the
cumulative incidence of primary composite end points. The relative
risk of primary composite end points in Cox proportional hazard
analysis was assessed in crude and multivariate models, and the
cumulative incidence was calculated using the group with high eGFR
and low RI as a reference for each. All of the P values were 2 sided,
and those ⬍0.05 were considered statistically significant. All of the
calculations were performed using a standard statistical package
(SPSS, version 17.0; SPSS Inc, Chicago, IL).
Results
Baseline Characteristics and Cardiovascular and
Renal Outcomes
Baseline clinical characteristics of the study subjects are
listed in Table 1. Mean age was 63.1⫾13.5 years (range,
20 – 85 years); 50% were female, and body mass index was
24.7⫾4.3 kg/m2. Diabetes mellitus was present in 28.9% of
the subjects, and 43.2% were former or current smokers.
Among the 426 subjects, 57 (13.4%; 19 women) developed
the primary composite end points during a mean follow-up of
3.1⫾2.1 years. Specifically, there were 21 patients with
nonfatal congestive heart failure, 12 with stroke, 3 with
myocardial infarction, 4 with aortic dissection, 11 requiring
regular hemodialysis therapy, and 6 patients died. No patient
underwent kidney transplantation.
RI was significantly higher in patients who developed the
primary composite end points during the follow-up period
than in event-free subjects (0.77⫾0.10 versus 0.66⫾0.08;
P⬍0.01). Specifically, RI was significantly higher in both
patients who developed cardiovascular end points including
nonfatal congestive heart failure, stroke, myocardial infarction, aortic dissection, and death (0.76⫾0.10 versus
0.66⫾0.08), as well as end-stage renal failure patients requiring regular hemodialysis therapy (0.81⫾0.06 versus
772
Hypertension
Table 1.
September 2012
Baseline Clinical Characteristics of Study Subjects
Variables
Total
n
426
Male, %
RI Less Than Median
(Male ⬍0.65, Female ⬍0.68)
214
RI Median or More
(Male ⱖ0.65, Female ⱖ0.68)
212
50.0
50.0
50.0
Age, y
63.1⫾13.5
56.1⫾13.4
70.2⫾9.3†
Body mass index, kg/m2
24.7⫾4.3
24.9⫾4.4
24.6⫾4.1
Former or current smokers, %
Duration of hypertension, y
Diabetes mellitus, %
43.2
43.5
42.9
15.5⫾12.0
13.1⫾11.5
17.9⫾12.0†
28.9
20.6
37.3†
Downloaded from http://hyper.ahajournals.org/ by guest on June 14, 2017
Systolic blood pressure, mm Hg
141⫾17
140⫾18
142⫾17
Diastolic blood pressure, mm Hg
80⫾12
84⫾12
75⫾9
Heart rate, bpm
67⫾9
68⫾8
65⫾9†
Total cholesterol, mmol/L
5.07⫾1.01
4.97⫾1.01
5.18⫾0.99*
Triglycerides, mmol/L
1.53⫾1.08
1.55⫾1.07
1.50⫾1.09
HDL cholesterol, mmol/L
1.33⫾0.39
1.38⫾0.40
1.28⫾0.37†
Fasting glucose, mmol/L
6.01⫾1.81
5.91⫾1.90
6.12⫾1.72
Hemoglobin A1c, %
5.92⫾1.21
5.81⫾1.07
6.02⫾1.32
Serum creatinine, mmol/L
96.4⫾84.6
72.4⫾27.6
120.7⫾111.7
eGFR, ml/min per 1.73 m2
66.1⫾23.9
75.9⫾17.7
56.3⫾25.4†
ACR, mg/g creatinine, median (IQR)
14.8 (6.3–118.2)
9.3 (5.0–33.4)
25.6 (8.6–446.5)†
Hs-CRP, mg/L, median (IQR)
0.80 (0.40–1.68)
0.70 (0.35–1.50)
0.90 (0.40–1.80)
Right kidney, cm
10.3⫾1.0
10.4⫾0.9
10.2⫾1.1†
Left kidney, cm
10.3⫾1.0
10.5⫾1.0
10.1⫾1.1†
Renal RI
0.67⫾0.09
0.60⫾0.05
0.75⫾0.06†
71.8
63.4
80.2†
Antihypertensive medication, %
Calcium channel blocker
␤-blocker
25.9
21.1
30.7*
ACEI or ARB
58.1
52.1
64.2*
29.4
23.0
Diuretic
Primary composite end points, n
35.9†
57
8
49†
Cardiovascular events, n
46
7
39†
ESRF requiring hemodialysis, n
11
1
10†
Values are mean⫾SD or frequency (%). IQR is 25th to 75th percentile. RI indicates resistive index; HDL cholesterol, high-density
lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; ACR, albumin:creatinine ratio; Hs-CRP, high-sensitive C reactive
protein; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ESRF, end-stage renal failure; IQR,
interquartile range.
*P⬍0.05 vs RI less than median.
†P⬍0.01 vs RI less than median.
0.66⫾0.08; P⬍0.01, respectively). Because RI was significantly lower in male than in female participants (0.66⫾0.10
versus 0.69⫾0.08; P⬍0.01), different median values for men
and women were used to separate the high and low RI groups
(male, ⬍0.65; female, ⬍0.68). The group with high RI
showed significantly older age, longer duration of hypertension, lower heart rate, higher prevalence of diabetes mellitus,
higher total cholesterol, lower high-density lipoprotein cholesterol, lower eGFR, and higher ACR than that with low RI
(Table 1).
Relation of RI to Primary Composite End Points
Life table analysis of the primary composite end points
throughout the follow-up period in the 2 groups based on RI
is plotted in Figure 1. These curves illustrate the significantly
poorer event-free survival in the group with high RI. A
univariate Cox proportional-hazard model showed that RI
(HR, 1.81 for each 1 SD [ie, 0.10 for male and 0.08 for
female] increase [95% CI, 1.45–2.27]; P⬍0.01) was a significant predictor of the primary composite end points. Other
variables in this study that significantly predicted the primary
end points included age (HR, 2.01 for each 1 SD [ie, 13.5
years] increase [95% CI, 1.44 –2.87]; P⬍0.01), sex (HR, 2.25
for male [95% CI, 1.32–3.99]; P⬍0.01), systolic BP (HR,
1.36 for each 1 SD [ie, 17 mm Hg] increase [95% CI,
1.06 –1.71]; P⫽0.02), diabetes mellitus (HR, 2.50 for yes
[95% CI, 1.48 – 4.22]; P⬍0.01), high-density lipoprotein
cholesterol (HR, 0.60 for each 1 SD [ie, 0.39 for male and
0.37 mmol/L for female] increase [95% CI, 0.44 – 0.81];
P⬍0.01), eGFR (HR, 0.27 for each 1 SD [ie, 19.1 mL/min per
Cumulative event-free survival rate
Doi et al
RI < median
RI ≥ median
1.0
0.8
0.6
0.4
0
2
4
6
Time, years
Figure 1. Kaplan-Meier estimates of primary composite end
points in 2 groups with restive index (RI) less than and at or
more than the median value (log-rank ␹2⫽30.12; P⬍0.01).
Downloaded from http://hyper.ahajournals.org/ by guest on June 14, 2017
1.73 m2] increase [95% CI, 0.20 – 0.35]; P⬍0.01), ACR (HR,
1.68 for each 1 SD [ie, 893.0 for male and 954.7 mg/g of
creatinine for female] increase [95% CI, 1.49 –1.86];
P⬍0.01), and left kidney-size (HR, 0.59 for each 1 SD [ie, 1.0
cm for male and female] increase [95% CI, 0.49 – 0.73];
P⬍0.01). Log-transformed ACR, as well as left kidney size,
was significantly associated with RI (ACR: male, r⫽0.53,
female, r⫽0.45; kidney-size: male, r⫽⫺0.33, female:
r⫽⫺0.26) and eGFR (ACR: male, r⫽⫺0.65, female,
r⫽⫺0.60; kidney size: male, r⫽0.52, female, r⫽0.42;
P⬍0.01, respectively), and, thus, multivariate Cox regression
analysis in which ACR and kidney size were not included in
the same model was first performed. After adjusting for other
risk factors (age, sex, systolic BP, diabetes mellitus, highdensity lipoprotein cholesterol, and eGFR) in multivariate
Cox regression analysis, independence of RI (HR, 1.71 for
each 1 SD increase [95% CI, 1.19 –2.56]; P⬍0.01) as a
predictor of the primary composite end points was found. The
further addition of ACR, left kidney size, and antihypertensive medication to the model did not meaningfully influence
the results (HR, 1.72 for each 1 SD increase [95% CI,
1.18 –2.59]; P⬍0.01).
We next repeated our analysis for the 133 patients with
eGFR ⬍60 mL/min per 1.73 m2. In this analysis, 44 primary
composite end point events (33.1%, 14 female) occurred
during the follow-up period. A univariate Cox proportional
hazard model showed that RI was a significant predictor of
the primary composite end points (HR, 2.12 for 1 SD [ie, 0.10
for male and 0.09 for female] increase [95% CI, 1.57–2.89];
P⬍0.01). Other variables in this subgroup that significantly
predicted the primary composite end points included sex
(HR, 1.77 for male [95% CI, 1.10 –2.97]; P⬍0.05) and
eGFR (HR, 0.28 for 1 SD [ie, 16.64 mL/min per 1.73 m2]
increase [95% CI, 0.18 – 0.41]; P⬍0.01). The results of
multivariate Cox regression analysis including sex and
eGFR showed that RI (HR, 2.11 for 1 SD increase [95%
CI, 1.44 –3.16]; P⬍0.01) was an independent predictor of
the composite end points.
Renal Resistive Index in Hypertension
773
Joint Effect of RI and eGFR on Primary
Composite End Points
In both total subjects (male: r⫽⫺0.62, female: r⫽⫺0.55) and
the subgroup with eGFR ⬍60 mL/min per 1.73 m2 (male:
r⫽⫺0.39, female: r⫽⫺0.54), RI was significantly associated
with eGFR (P⬍0.01, respectively). To assess the combined
effects of eGFR and RI, therefore, we constructed survival
curves after dividing the subjects into 2 groups by eGFR of 60
mL/min per 1.73 m2 and then stratified the subjects into 4
groups according to the sex-specific median values of RI in
the group with eGFR ⱖ60 (RI, 0.62 for male and 0.67 for
female) and that with eGFR ⬍60 (RI, 0.73 for male and 0.72
for female). As a result, the subjects were divided into 4
groups as follows: eGFR ⱖ60 and low RI, eGFR ⱖ60 and
high RI, eGFR ⬍60 and low RI, and eGFR ⬍60 and high RI.
The baseline clinical and biochemical characteristics of the
study subjects are shown in Table 2. Compared with the
group with eGFR ⱖ60 and low RI, the group with eGFR ⬍60
and high RI showed an increased risk of cardiovascular
morbidity, such as significantly higher age, longer duration of
hypertension, higher prevalence of diabetes mellitus, lower
high-density lipoprotein cholesterol, and higher ACR. Life
table analyses of the primary composite end points throughout the follow-up period according to the 4 groups of eGFR
and RI are plotted in Figure 2. These curves illustrate the
significantly poorer event-free survival in the group with
eGFR ⬍60 and high RI. We next performed Cox regression
analysis to examine whether the influence of a low eGFR and
high RI on the primary composite end points was independent
of other risk factors (Table 3). The risk of the primary
composite end points was significantly higher in the group
with eGFR ⬍60 and high RI compared with that in the
group with eGFR ⱖ60 and low RI (HR, 19.8). In multivariate Cox regression analysis including age, sex, systolic
BP, diabetes mellitus, and high-density lipoprotein cholesterol, the combination of eGFR ⬍60 and high RI was an
independent predictor of the primary composite end points
(HR, 9.58). The relative risk in the eGFR ⬍60 and high RI
group remained highly significant even after including
ACR, left kidney size, and antihypertensive medication in
the model (HR, 5.64 [95% CI, 31.84 –20.16]; P⬍0.01).
Even when the group with eGFR ⬍60 and low RI was used
as a reference, the group with eGFR ⬍60 and high RI had
a significantly higher risk of the primary composite end
points in univariate Cox regression analysis (HR, 5.48
[95% CI, 2.74 –12.16]; P⬍0.01) and in a multivariate
model (HR, 4.78 [95% CI, 2.19 –11.65]; P⬍0.01).
In addition, the influence of the combination of renal RI
and eGFR on outcomes was also examined by dividing the
4 groups according to eGFR of 45 mL/min per 1.73 m2 and
the sex-specific median values of RI in the group with
eGFR ⱖ45 mL/min per 1.73 m2 (RI, 0.63 for male and
0.67 for female) and that with eGFR ⬍45 mL/min per 1.73
m2 (RI, 0.75 for male and 0.77 for female); that is, eGFR
ⱖ45 and low RI (n⫽172), eGFR ⱖ45 and high RI
(n⫽168), eGFR ⬍45 and low RI (n⫽43), and eGFR ⬍45
and high RI (n⫽43). The relative risks of the primary
composite end points in the eGFR ⱖ45 and low RI, eGFR
ⱖ45 and high RI, eGFR ⬍45 and low RI, and eGFR ⬍45
774
Hypertension
Table 2.
September 2012
Baseline Clinical Characteristics of Study Subjects
eGFR ⱖ60 mL/min per 1.73 m2
Variables
n
Low RI
High RI
Low RI
High RI
(Male ⬍0.62, Female ⬍0.67) (Male ⱖ0.62, Female ⱖ0.67) (Male ⬍0.73, Female ⬍0.72) (Male ⱖ0.73, Female ⱖ0.72)
148
Male, %
eGFR ⬍60 mL/min per 1.73 m2
145
45.3
67
46.2
66
59.7
59.1
Age, y
53.4⫾13.2§
67.8⫾9.1†
64.2⫾12.2†
73.4⫾9.8†§
Body mass index, kg/m2
24.8⫾4.7
25.2⫾3.8
24.6⫾4.1
23.7⫾4.1
Former or current smokers, %
43.2
34.5
Duration of hypertension, years
11.0⫾10.3§
16.8⫾12.4†
17.8⫾11.6†
20.8⫾11.9†
14.2§
32.4†
41.8†
40.9†
140⫾17
142⫾16
136⫾16
145⫾22‡
Diabetes mellitus, %
Systolic blood pressure, mm Hg
50.8
54.6
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Diastolic blood pressure, mm Hg
85⫾12§
77⫾10†
80⫾9†
Heart rate, bpm
68⫾9
64⫾8†§
69⫾8
73⫾11†§
66⫾11
Total cholesterol, mmol/L
4.98⫾0.94
5.27⫾0.94‡
4.81⫾1.27
5.12⫾0.92
Triglycerides, mmol/L
1.53⫾1.18
1.47⫾1.12
1.74⫾0.93
1.44⫾0.86
HDL cholesterol, mmol/L
1.44⫾0.43‡
1.30⫾0.31*
1.27⫾0.32*
1.24⫾0.44†
Fasting glucose, mmol/L
5.96⫾2.13
5.99⫾1.45
5.90⫾1.27
6.30⫾2.18
Hemoglobin A1c, %
5.76⫾1.08
5.94⫾1.20
6.04⫾1.22
6.07⫾1.44
Serum creatinine, mmol/L
62.4⫾14.0§
61.1⫾12.3§
143.7⫾94.3†
eGFR, mL/min per 1.73 m2
83.5⫾10.8§
76.2⫾7.2*§
41.3⫾14.7†
30.1⫾16.6†§
484.0 (97.5–1944.8)†§
ACR, mg/g creatinine, median (IQR)
Hs-CRP, mg/L, median (IQR)
8.8 (4.7–28.0)
9.8 (6.0–18.5)
16.5 (6.5–340.2)
0.65 (0.30–1.40)
0.80 (0.40–1.68)
0.90 (0.40–1.50)
202.4⫾133.6†§
1.10 (0.30–3.20)
Right kidney, cm
10.6⫾0.9§
10.5⫾0.9‡
10.1⫾1.0†
Left kidney, cm
10.7⫾1.0§
10.5⫾0.9
10.1⫾1.0†
9.6⫾1.1†‡
9.5⫾1.1†‡
Renal RI
0.59⫾0.05§
0.71⫾0.05†§
0.65⫾0.05†
0.81⫾0.05†§
Antihypertensive medication, %
Calcium channel blocker
59.2
75.9*
71.6
90.9†
␤-blocker
18.4
28.3
23.9
39.4*
ACEI or ARB
49.0
55.2
68.7
74.2†
Diuretic
15.7§
22.1
38.8†
66.7†§
Primary composite endpoints, n
5
8
9
35†§
Cardiovascular events, n
5
7
9
25†§
ESRF requiring hemodialysis, n
0
1
0
10†§
Values are mean⫾SD or frequency (%). IQR is 25th to 75th percentile. RI indicates resistive index; HDL cholesterol, high-density lipoprotein cholesterol; eGFR,
estimated glomerular filtration rate; ACR, albumin:creatinine ratio; Hs-CRP, high-sensitive C reactive protein; ACEI, angiotensin-converting enzyme inhibitor; ARB,
angiotensin II receptor blocker; ESRF, end-stage renal failure; IQR, interquartile range.
*P⬍0.05 vs eGFR ⱖ60/low RI.
†P⬍0.01 vs eGFR ⱖ60/low RI.
‡P⬍0.05 vs eGFR ⬍60/low RI.
§P⬍0.01 vs eGFR ⬍60/low RI.
and high RI groups were 1.0 (reference), 2.32 (95% CI,
0.86 –7.28), 8.88 (95% CI, 3.29 –27.92), and 28.03 (95%
CI, 11.77– 82.66) in univariate Cox regression analysis and
1.0 (reference), 1.29 (95% CI, 0.44 – 4.37), 4.97 (95% CI,
1.70 –16.60), and 11.45 (95% CI, 3.97–38.96) in multivariate Cox regression analysis, respectively. Even when the
group with eGFR ⬍45 and low RI was used as a reference,
the independent predictive value of eGFR ⬍45 and high RI
for primary composite end points was also confirmed in
univariate Cox regression analysis (HR, 3.16 [95% CI,
1.64 – 6.47]; P⬍0.01) and in a multivariate model (HR,
2.30 [95% CI, 1.10 –5.14]; P⫽0.02).
Discussion
The present study demonstrated that the relationship between
high RI and cardiovascular and renal outcomes is significant
and persisted after multivariate Cox regression analysis,
including traditional risk factors. Moreover, even in the
subgroup with eGFR ⬍60 mL/min per 1.73 m2, high RI was
a significant predictor of the primary composite end points.
The combination of high RI and low eGFR was a powerful
independent predictor of worse outcome.
Our results showed that a high RI is independently associated with cardiovascular and renal outcomes and suggest
that assessment of RI by ultrasonography, a simple method of
Doi et al
eGFR≥ 60/ Low RI
eGFR≥ 60/ High RI
Cumulative event-free survival rate
eGFR <60/ Low RI
eGFR <60/ High RI
1.0
0.8
0.6
0.4
0.2
0
0
2
4
6
Time, years
Downloaded from http://hyper.ahajournals.org/ by guest on June 14, 2017
Figure 2. Kaplan-Meier estimates of primary composite end
points in 4 groups stratified by both restive index (RI) and estimated glomerular filtration rate (eGFR) (log-rank ␹2⫽126.42;
P⬍0.01).
assessing intrarenal hemodynamics,2,3 is useful for predicting
the risk of these diseases in essential hypertension. Furthermore, even when analysis was restricted to the subgroup with
eGFR ⬍60 mL/min per 1.73 m2, which is defined as chronic
kidney disease,24 the independent role of RI in outcomes was
maintained. These findings were partially in agreement with
those from previous studies on high-risk patients with chronic
nephropathy,6 transplant renal allograft,22 or heart failure12
and extend the predictive role of renal hemodynamic abnormalities to essential hypertensive patients. These findings
corroborate the hypothesis that the impact of RI on cardiovascular and renal risk is marked and that identifying renal
hemodynamic abnormalities is useful for predicting cardiovascular and renal outcomes, especially in hypertensive
patients with chronic kidney disease. The precise mechanisms
by which the risk for these diseases becomes higher with
increasing RI are unclear; however, there are several hypothetical mechanisms. Previous histological studies have also
Table 3.
Renal Resistive Index in Hypertension
demonstrated that RI correlates not only with renal function25
but also with renal histopathologic findings, such as renal
atherosclerosis or tubulointerstitial damage.8–10 In renal allograft patients, RI of the transplanted kidney significantly
correlates with the age of the recipient but not with the age of
the kidney,26 suggesting that extrarenal factors, such as
stiffness of the prerenal vessels, for example, the aorta, have
a major effect on renal Doppler indices. Vascular resistance
and especially vascular compliance, which is the rate of
change of volume of a vessel as a function of pressure, are the
main predictors of renal RI.2 Other studies have investigated
the relationship between RI of transplanted kidneys and
parameters of cardiovascular disease and found a significant
correlation of renal RI with ankle-brachial BP index27 and
carotid-femoral pulse wave velocity,28 without any correlation with creatinine clearance of the graft. Other studies also
found that, in essential hypertension, RI was associated with
ambulatory arterial stiffness index29 or central pulse pressure
and aortic stiffness.30 Therefore, renal RI should be considered as a marker of systemic atherosclerotic vessel damage
rather than a specific marker of renal damage.
It is noteworthy that patients with both decreased eGFR
and increased RI had a significant burden of cardiovascular
risk factors and a higher risk of the primary composite end
points as compared with those with either isolated decreased
eGFR or increased RI. The Kidney Disease: Improving
Global Outcomes foundation has recently modified the classification of stage 3 chronic kidney disease by subdivision
into 2 stages at eGFR of 45 mL/min per 1.73 m2,31 and, thus,
we repeated analysis by categorizing our study group according to eGFR of 45 mL/min per 1.73 m2 and found increased
risk in those patients with eGFR ⬍45 mL/min per 1.73 m2
and high RI. These findings suggest that combined screening
for eGFR and intrarenal hemodynamics might improve their
combined predictive power, especially in hypertensive patients with chronic kidney disease. On the other hand, in the
group with eGFR ⱖ60 mL/min per 1.73 m2, the risk of
outcomes did not become higher with increasing RI. Therefore, once a patient is diagnosed with chronic kidney disease,
RI appears to be a useful marker to estimate their cardiovas-
Predictors of Primary End Points by Cox Regression Analysis
Variables, unit of increase
Crude, HR (95% CI)
P Value
Multivariate, HR (95% CI)*
P Value
eGFR and RI
eGFR ⱖ60/low RI
eGFR ⱖ60/high RI
775
1 (reference)
1.59 (0.53–5.25)
1 (reference)
0.41
1.09 (0.34–3.87)
0.89
eGFR ⬍60/low RI
3.61 (1.25–11.76)
0.02
eGFR ⬍60/high RI
19.78 (8.47–57.73)
⬍0.01
9.58 (3.26–32.89)
Age, 1 SD (ie, 13.5 y)
2.01 (1.44–2.87)
⬍0.01
1.23 (0.85–1.85)
0.28
Sex, male
2.25 (1.32–3.99)
⬍0.01
1.59 (0.89–2.93)
0.12
Systolic blood pressure, 1 SD (ie, 17 mm Hg)
1.36 (1.06–1.71)
0.02
1.29 (1.03–1.60)
0.03
Diabetes mellitus, yes
2.50 (1.48–4.22)
⬍0.01
1.72 (0.99–2.97)
0.052
HDL cholesterol, 1 SD (ie, 0.39 for male,
0.37 mmol/L for female)
0.60 (0.44–0.81)
⬍0.01
0.82 (0.61–1.09)
0.18
2.00 (0.62–7.01)
0.24
⬍0.01
HR indicates hazard ratio; eGFR, estimated glomerular filtration rate; RI, resistive index; HDL chol, high-density lipoprotein
cholesterol.
*Data were adjusted by age, sex, systolic blood pressure, diabetes mellitus, and HDL cholesterol.
776
Hypertension
September 2012
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cular or renal risk. A cluster of traditional cardiovascular risk
factors, such as older age, severity and duration of hypertension, and worse dyslipidemia, was observed in the subgroup
with lower eGFR and higher RI; however, the risk of primary
composite end points remained significantly worse even after
adjusting for these confounders. Although both eGFR and
increased RI reflect renal dysfunction, the pathophysiological
mechanisms leading to these abnormalities may be, at least in
part, different. It has been shown that a decrease in eGFR is
associated with oxidative stress, subclinical inflammation,
increased homocysteine, insulinemia, and coagulability.32
Increased RI could be considered a marker of systemic
atherosclerotic vessel damage, and compounded with reduced
eGFR it may significantly increase the cardiovascular and
renal risk.
To define subclinical renal damage, previous studies have
suggested measurement of albuminuria stage at all of the
glomerular filtration rate stages,31 and the combination of
eGFR and albuminuria has been reported to be a useful
predictor of cardiovascular disease.33–35 Albuminuria is subject to large within-individual variations, with reported coefficient of variation of 50%,36 and the conclusion as to whether
microalbuminuria is present should preferably be based on
repeated measurements. On the other hand, RI evaluation is
easier because the same probe is used for the heart, and it
causes little physical stress to patients. In the context of
long-standing hypertension, microalbuminuria and reduction
of kidney size might signal the development of nephrosclerosis, which is usually associated with reduced renal blood
flow and increased RI. Previous studies found an independent
association between RI and albuminuria,25,37 and, thus, evaluation of both eGFR and RI instead of albuminuria could be
another investigative option to identify essential hypertensive
subjects without clinical evidence of cardiovascular disease
who are predisposed to worse outcomes. However, further
investigation is required to examine these hypotheses.
Previous reports have shown that antihypertensive agents
affect RI.8,38,39 Because our study population included patients with treated essential hypertension at the start of the
study, our results suggest the importance of evaluating RI to
assess cardiovascular and renal outcomes, even in patients
receiving antihypertensive medication. These results could,
however, underestimate the involvement of BP or RI itself in
the development of abnormal renal hemodynamics and cardiovascular events. Other limitations were the relatively short
follow-up period and the lack of control over occasional
changes in the antihypertensive regimens over time. Even in
elderly subjects without renal insufficiency, normal RI can
exceed 0.70,3 and, thus, it remains unclear whether our results
apply to very elderly subjects.11 The relatively small number
of events recorded in the present study may have limited the
statistical power of our findings.
Perspectives
Our findings suggest that impaired renal hemodynamics
evaluated by increased RI on the baseline Doppler ultrasonography is associated with an increased risk of cardiovascular and renal outcomes and highlight that the combination
of high RI and low eGFR may be a powerful predictor of
worse outcome in essential hypertension. Especially in hypertensive patients with chronic kidney disease, RI evaluation
will complement screening for cardiovascular risk. A large,
prospective population-based study will be important to
confirm our preliminary observations.
Acknowledgments
We thank Yoko Saito and Erumu Hayase for their secretarial
assistance.
Disclosures
None.
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Novelty and Significance
What Is New?
●
Impaired renal hemodynamics evaluated by increased renal RI on
baseline Doppler ultrasonography is associated with an increased risk of
cardiovascular and renal outcomes and highlights that the combination
of high RI and low eGFR may be a powerful predictor of worse outcome
in essential hypertension.
What Is Relevant?
●
The impact of RI on cardiovascular and renal risk is marked, and
identifying renal hemodynamic abnormalities is useful for predicting
cardiovascular and renal outcomes, especially in hypertensive patients
with chronic kidney disease.
Summary
In hypertensive patients with chronic kidney disease, RI evaluation
may complement predictors of cardiovascular and renal outcomes.
Renal Resistive Index and Cardiovascular and Renal Outcomes in Essential Hypertension
Yohei Doi, Yoshio Iwashima, Fumiki Yoshihara, Kei Kamide, Shin-ichirou Hayashi, Yoshinori
Kubota, Satoko Nakamura, Takeshi Horio and Yuhei Kawano
Downloaded from http://hyper.ahajournals.org/ by guest on June 14, 2017
Hypertension. 2012;60:770-777; originally published online July 23, 2012;
doi: 10.1161/HYPERTENSIONAHA.112.196717
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2012 American Heart Association, Inc. All rights reserved.
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ONLINE SUPPLEMENT
Renal Resistive Index and Cardiovascular and Renal Outcomes in Essential
Hypertension
Yohei Doi, MD1, Yoshio Iwashima, MD, PhD1, Fumiki Yoshihara, MD, PhD1, Kei
Kamide, MD, PhD2, Shin-ichirou Hayashi, MD, PhD1, Yoshinori Kubota, ME3, Satoko
Nakamura, MD,PhD1, Takeshi Horio, MD, PhD4, Yuhei Kawano, MD, PhD, FAHA1
Divisions of Hypertension and Nephrology1, and Laboratory Medicine3, Department of
Medicine, National Cerebral and Cardiovascular Center
2
Department of Geriatric Medicine and Nephrology, Osaka University Graduate School
of Medicine
4
Third Department of General Medicine, Kawasaki Hospital, Kawasaki Medical School
Corresponding author:
Yoshio Iwashima, MD, PhD, Division of Hypertension and Nephrology, Department of
Medicine, National Cerebral and Cardiovascular Center, 5-7-1, Fujishirodai, Suita,
Osaka 565-8565, Japan
Phone: +81-6-6833-5012
FAX: +81-6-6872-7486
E-mail: [email protected]
Methods Supplement
Baseline clinical characteristics
Urine albumin concentration was measured by an immunoturbidimetric method. Urine
collection was repeated if the patient was menstruating, because this makes albumin
measurement unreliable.
Renal ultrasonography and Doppler studies
Ultrasonographic examinations were performed using duplex Doppler sonography with
a Sienna Sonoline ultrasound machine (Siemens, Erlangen, Germany) or Aplio MX
ultrasound machine (Toshiba, Tochigi, Japan) with 2.5-MHz pulsed Doppler frequency
and 3.5-MHz convex array transducer. The ultrasonographic procedure that we adopted
has been described previously.1-3 In brief, with the patient in the supine position, pulse
rate was calculated from beat-by-beat measurements of Doppler waveforms. The
maximum length of the kidneys was determined by B-mode measurements, and
intrarenal Doppler signals were obtained from three representative proximal segmental
arteries (the first vessels branching off the main renal artery). The Doppler angle chosen
was less than 50°, and special care was taken not to compress the kidney and not to
have the patient perform a Valsalva maneuver, because both can increase renal RI.
Cardiovascular and Renal Outcomes
The primary endpoint of this study was first occurrence of composite of cardiovascular
and renal events including all-cause death, myocardial infarction confirmed by
electrocardiographic changes, coronary angiography or myocardial scintigraphy
findings, stroke confirmed by clinical symptoms, computed tomography and magnetic
resonance angiography or cerebrovascular angiography findings, congestive heart
failure requiring hospitalization, aortic dissection, and end stage renal failure requiring
regular hemodialysis. Congestive heart failure was defined by the Framingham Heart
Study criteria,4 which require the simultaneous presence of at least two major criteria, or
one major criterion in conjunction with two minor criteria,5 and requiring treatment with
diuretics, vasodilators, or antihypertensive drugs. Aortic dissection was defined as any
nontraumatic dissection when a participant was admitted to hospital with a dissection
that required intervention, and diagnosis was based on confirmatory imaging or
intraoperative visualization.
1.
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2.
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3.
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advanced heart failure. Artif Organs. 2012;36:353-358.
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