Elevated Pulse Pressure Is Associated With Low Renal Function in Elderly Patients With

Isolated Systolic Hypertension

Jacobien C. Verhave, Pierre Fesler, Guilhem du Cailar, Jean Ribstein, Michel E. Safar and
Albert Mimran

Hypertension. 2005;45:586-591; originally published online February 28, 2005;

doi: 10.1161/01.HYP.0000158843.60830.cf
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2005 American Heart Association, Inc. All rights reserved.
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 Elevated Pulse Pressure Is Associated With Low Renal
Function in Elderly Patients With Isolated
Systolic Hypertension
Jacobien C. Verhave, Pierre Fesler, Guilhem du Cailar, Jean Ribstein, Michel E. Safar, Albert Mimran

AbstractIn the past decade, pulse pressure has emerged as a strong predictor of cardiovascular morbidity and mortality.
During aging, elevation of pulse pressure is a consequence of stiffening of the arterial wall. The relationship between
pulse pressure and the renal aging process was studied in a cohort of 212 patients with never-treated isolated systolic
hypertension. Glomerular filtration rate and effective renal plasma flow were measured using constant infusion of
technetium 99m (99mTc)-DTPA and 131I-ortho-iodohippurate, respectively, and timed urine collections. The relationship
between pulse pressure and renal function was studied using a linear regression model in the total population and in 40
to 49, 50 to 59, and 60 years and older age categories. In the whole population, there was an inverse relationship between
pulse pressure and glomerular filtration rate; however, this relation did not persist after adjustment for age. In fact, the
inverse relationship between pulse pressure and glomerular filtration rate was only present in patients 60 years of age
or older. This relationship in elderly patients remained after adjustment for age, gender, MAP, and cardiovascular risk
factors (P0.006). It is suggested that pulse pressure, a marker of arterial stiffening, may have a detrimental influence
on the age-related decline in glomerular filtration rate, after 60 years of age in patients with never-treated isolated
systolic hypertension. (Hypertension. 2005;45:586-591.)
Key Words: age glomerular filtration rate hypertension pulse

I n the past decade, pulse pressure (PP), defined as the

difference between systolic and diastolic blood pressure
(DBP), emerged as a strong predictor of cardiovascular and
cerebrovascular mortality.1,2 In the Framingham study of
1924 individuals 50 to 79 years of age, higher PP increased
the risk of coronary heart disease.3 A high PP was also a
predictor of all-cause, cardiovascular, and, especially, coro-
nary mortality in 19 083 men (40 to 69 years of age) with
relatively low cardiovascular risk.4 Interestingly, it was re-
ported that although PP predicts coronary heart disease in
subjects older than 60 years, DBP was the strongest predictor
in subjects younger than 50 years.5
The increase in PP is considered in subjects older than 40
years of age as a consequence of stiffening of the arterial
system, as shown by its correlation with aortic pulse wave
velocity.6,7 The relationship between PP and age is J-shaped,
being negative in subjects aged younger than 40 years and
becomes positive after age 40, thus suggesting a different
signification of PP in younger versus older subjects.8 In
subjects with preserved ejection fraction aged younger than
40, PP may be related to hyperdynamic cardiovascular
condition,9 whereas after age 60, the contribution of arterial
stiffening is probably crucial. In fact, after 60 years of age, PP
increases because of a decrease in DBP and the continuous
increase in systolic blood pressure (SBP).10 Evidence is
presently accumulating that renal function impairment is an
independent contributor of cardiovascular risk.1113 In the
Multiple Risk Factor Intervention Trial (MRFIT) population,
a high risk of end-stage renal disease was found in patients
with isolated systolic hypertension (ISH), who are those with
a normal DBP and an elevated PP.14
The relationship between arterial stiffening and renal
function is unclear and the possibility that modification of
vascular compliance could participate or eventually enhance
the age-related decline in glomerular filtration rate (GFR)
deserves investigation. Longitudinal studies conducted in
elderly subjects with ISH suggest that in patients with
increased PP but nearly normal mean arterial pressure
(MAP), the increase in PP may be preferentially be transmit-
ted to the glomerulus and thus favor arteriolosclerosis and
reduced renal function.15 This hypothesis, which has never
been tested, requires human investigations, which may be
obtained in cross-sectional studies and using adequate and
reliable measurements of renal hemodynamics and function.
In the present study, the relationship between precisely
measured intrarenal hemodynamics and PP was assessed in
never-treated patients with ISH.

Received November 19, 2004; first decision December 27, 2004; revision accepted January 27, 2005.
From the Department of Internal Medicine (J.C.V., P.F., G.d.C., J.R., A.M.), CHU Montpellier, France; Diagnosis Center (M.E.S.), Hotel-Dieu
Hospital, Paris, France.
Correspondence to A. Mimran, Department of Internal Medicine, Hopital Lapeyronie, 34295 Montpellier Cedex 5, France. E-mail
amimran@wanadoo.fr
2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org DOI: 10.1161/01.HYP.0000158843.60830.cf

586
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 Verhave et al
Materials and Methods
Study Population
The study population consisted of 212 patients with ISH selected
from a cohort of 658 patients with never-treated essential hyperten-
sion aged 40 years or older. ISH was defined as a SBP of
140 mm Hg and a DBP of 90 mm Hg.16 Patients were recruited
from the outpatient clinic of the department of internal medicine,
where patients came directly or were referred by general practitio-
ners for detection or investigation of their cardiovascular risk profile.
Patients came to the ward with 2 consecutive 24-hour urine collec-
tions for the determination of urinary sodium (as an index of sodium
intake), urinary urea (as an index of protein intake), and urinary
albumin excretion (radioimmunoassay; Beckman Coulter Company,
Immunotech). Body mass index (BMI) was calculated as weight (kg)
divided by square of height (m2). Microalbuminuria was defined as
a urinary albumin excretion of 20 to 199 g/min. Patients with
clinical evidence of atherosclerosis (stroke, coronary and peripheral
artery disease), heart failure, renal failure (serum creatinine
130 mol/L), clinical proteinuria (dipstick-positive), diabetes mel-
litus (fasting glucose level 7.0 mmol/L), a history of alcohol abuse
(5 drinks per day), and secondary hypertension were excluded. All
subjects gave informed consent and the local medical ethics com-
mittee approved the study.
Blood Pressure Measurement
After 10 minutes of rest, blood pressure was automatically measured
every 3 minutes in the supine position (Model 8800; Colin).17
Reported blood pressure values are the mean of at least 10 successive
measurements. PP was calculated as the difference between SBP and
DBP. MAP was calculated as DBP plus one-third (SBPDBP). In
addition, blood samples for the measurement of serum creatinine
(enzymatic method; Randox, Mauguio), glucose, lipids, and plasma
renin activity (RIA using the CEA Sorin kit) were obtained.
Measurements of Renal Function
GFR and effective renal plasma flow (ERPF) were estimated by
urinary clearances of technetium-labeled diethylene triaminopenta-
acetic acid (99mTc-DTPA) and 131I-ortho iodohippurate, respectively.
The constant infusion technique with timed urine collections was
used as previously described.18 Renal hemodynamic values were
expressed as mL/min per 1.73 m2. Filtration fraction was calculated
as GFR/ERPF. The reproducibility of measurements of renal hemo-
dynamics was obtained in 20 subjects; the variation coefficient of
GFR and ERPF was 6.4% and 6.3%, respectively.
Statistical Analysis
Data are presented as meanstandard deviation (SD) or median and
interquartile range when variables were not normally distributed.
The population was stratified by age into 3 groups: 40 to 49, 50 to 59,
and 60 years and older, and characteristics of age groups were
compared by Student t test or 2 test. In the total population of 212
patients, the relationship between PP and renal function was studied
by a linear regression model with, respectively, GFR, ERPF, and
filtration fraction as dependent variables and PP as an independent
variable. The linear regression model of PP and renal function was
also constructed after stratification for the 3 age categories. In the
multivariate analysis, MAP, age, gender, smoking, BMI, total
cholesterol, and fasting glucose were also entered in the model. In a
secondary analysis, urinary sodium and urea excretion and albumin-
uria were added to the multivariate model to substantiate their
influence on the relationship between PP and renal function. To
obtain optimal distribution of residuals, urinary albumin excretion
was log-transformed.
Each age category was divided into tertiles of PP, and a compar-
ison between renal function parameters was assessed by analysis of
variance or covariance with Bonferroni post hoc test. Covariates
were MAP, age, gender, smoking, BMI, total cholesterol, and fasting
glucose.
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Pulse Pressure and Renal Function 587
All probability values are 2-sided and P0.05 was considered
statistically significant (SPSS, Chicago version 11.5).
Results
Characteristics of the Population
The present cohort of 212 patients consisted of 33% men and
mean age was 52 years (range, 40 to 99). Obesity (BMI 30
kg/m2) was present in 20% of patients. The characteristics of
every age category are presented in Table 1. SBP was higher
and DBP lower, and as a consequence PP was higher in the
older group. MAP and heart rate were not different between
age groups. Lower mean values of GFR and ERPF were
found in the elderly as compared with the other age groups,
and no difference in filtration fraction was detected. Urinary
sodium, urea, and albumin excretion were not different over
the age categories; however, microalbuminuria was present in
12.5% of the patients in the elderly group versus 5% in
patients 40 to 49 years of age (P0.05).
Relationship Between PP and
Renal Hemodynamics
When the whole population was considered, GFR and ERPF
(dependent variables, indexed to 1.73 m2 of body surface
area) were inversely correlated with PP; however, this rela-
tionship did not persist after adjustment for age. When
analysis was performed within each age group, the negative
relationship between PP and GFR and ERPF was only found
in the older (60 years and older) age group (model r20.17;
beta coefficient 0.690 mL/min per 1.73 m2/mm Hg of PP;
P0.001 for GFR; and model r20.12; beta coefficient
2.51 mL/min per 1.73 m2/mm Hg of PP; P0.007 for
ERPF). In patients aged 60 or older, the inverse correlation
between PP and GFR remained after adjustment for MAP,
heart rate, age, gender, smoking, BMI, total cholesterol, and
fasting glucose (model r20.49; beta coefficient 0.727
mL/min per 1.73m2/mm Hg of PP; P0.006). When ERPF
instead of GFR was introduced as the dependent variable, the
relationship with PP was consistently weaker (model
r20.45; beta coefficient 1.913 mL/min per 1.73m2 mm Hg
of PP; P0.096). Of interest, in the older age group, the
inverse relationship between PP and GFR was maintained
when urinary sodium, urea, and albumin excretions were
entered into the model. When GFR and ERPF were expressed
as mL/min, all relationships between GFR or ERPF and PP
were maintained after inclusion of body weight and height
instead of BMI into the model. No relationship between PP
and filtration fraction was detected.
In patients 60 years of age or older, PP was inversely
correlated with measured creatinine clearance; however, this
relationship was not independent of age. No univariate
relationship between PP and other estimates of renal function
using the Modification of Diet in Renal Disease (MDRD)19 or
the Cockcroft-Gault formula20 was detected.
Tertiles of PP and Renal Function Within Each
Age Category
Renal hemodynamics according to tertiles of PP within each
age group are shown in Table 2 and Figure 1. As compared
with the lowest tertile, GFR and ERPF were significantly
588 Hypertension April 2005

TABLE 1. Characteristics of Patients With Isolated Systolic Hypertension

According to Age Categories
Age Categories, y

Parameters 40 49 50 59 60
Number 64 85 63
Male, % 32.8 40.0 25.4
Age, y 45.12.7 54.02.9 67.17.5
Body mass index, kg/m2 26.45.0 26.34.0 26.54.5
SBP, mm Hg 1498 1519 15612*
DBP, mm Hg 853 855 835*
MAP, mm Hg 1064 1075 1076
Pulse pressure, mm Hg 648 669 7311*
Heart rate, beats/min 709 6712 668
Glucose, mmol/L 4.70.6 4.90.7 4.70.7
Total cholesterol, mmol/L 6.01.3 6.11.1 6.21.0
HDL cholesterol, mmol/L 1.50.5 1.50.5 1.50.5
Triglycerides, mmol/L 1.0 (0.71.6) 1.1 (0.81.7) 1.0 (0.71.6)
Smoking, % 31.3 20.5 14.5*
GFR, mL/min/1.73 m2 106.817.3 98.417.8* 83.918.1*
ERPF, mL/min/1.73 m2 46684 43082* 36980*
Filtration fraction, % 23.22.9 23.13.4 22.93.1
Urinary sodium excretion, mmol/24 h 13971 14362 13462
Urinary urea excretion, mmol/24 h 396161 391140 338140
Urinary albumin excretion, g/min 5.7 (3.98.4) 6.7 (4.412.7) 7.2 (4.113.7)
Values are meanSD or mean (interquartile range).
* P0.05 vs age category 40 49.
P0.05 vs age category 50 59.

lower in the second and third tertiles of PP only in the 60 and
older age group. No difference in filtration fraction across
tertiles of PP in each age category was detected.
In patients 60 years and older only, the mean value of GFR
in the highest tertile of PP was still significantly lower than
the lowest tertile after correction for MAP, age, gender,
smoking, BMI, total cholesterol, and fasting glucose
(P0.008). Also, adjustment for serum high-density lipopro-
tein cholesterol and triglycerides instead of total cholesterol
did not change the relationship between PP and GFR. The

TABLE 2. Renal Hemodynamics According to Tertiles of Pulse Pressure in Each Age Group
Age Categories, y 40 49 (n64) 50 59 (n85)

Tertile of Pulse Pressure I II III I II III

Pulse Pressure (mm Hg)* 56 (5259) 62 (59 65) 73 (65103) 58 (53 61) 64 (61 68) 76 (68 91)
Gender (male), % 47.6 31.8 19.0 57.1 41.4 21.4
Age, y 44.52.9 45.22.6 45.52.6 53.62.9 53.82.5 54.53.2
Body mass index, kg/m2 25.84.8 25.03.1 28.66.1 27.44.4 25.53.1 26.14.4
MAP, mm Hg 1052 1063 1085 1053 1054 1096
GFR, mL/min/1.73 m2 108.415.2 104.013.4 108.122.5 94.515.3 97.720.6 103.116.5
ERPF, mL/min/1.73 m2 47766 47176 451107 41969 42791 44484
Filtration fraction, % 22.93.1 22.43.0 24.22.4 22.62.4 23.24.3 23.53.1
Plasma renin activity, 0.82 (0.401.21) 1.00 (0.631.56) 0.65 (0.212.21) 0.70 (0.421.10) 0.41 (0.250.96) 0.52 (0.241.18)
ng/mL/h*
Urinary sodium, mmol/24 h 14387 14458 12969 15366 13753 13967
Urinary urea, mmol/24 h 387160 400129 400201 449123 365140 356141
Urinary albumin, g/min 5.5 (3.77.7) 5.1 (3.07.2) 7.1 (5.314.1) 6.7 (4.514.1) 7.0 (4.610.6) 6.5 (4.310.9)
Values are meanSD.
* Mean and range.
Mean and interquartile range.
P0.05 vs first tertile of pulse pressure.
P0.05 vs second tertile of pulse pressure.

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 Verhave et al Pulse Pressure and Renal Function 589

difference in ERPF over tertiles of PP did not persist after known cardiovascular risk factors. The influence of PP was
correction for all confounders when urinary sodium, urea, or still present after additional adjustment for natriuresis and
albumin excretions were entered into the regression model. urinary urea excretion (ie, taken as indicators of dietary
Our observation of a lower GFR in the oldest age group with sodium and protein intake), 2 important factors known to
the highest PP was confirmed when GFR was not corrected influence GFR. Such a finding was not obtained in subjects
for body surface area (mL/min) or corrected for height (GFR aged 40 to 49 and 50 to 59 years. These results suggest that
mL/min per meter) (an expression of GFR known to mini- PP, an accepted marker of arterial stiffening in elderly
mize the influence of obesity21,22). patients,6 may have a detrimental effect on renal hemody-
No significant effect of PP on renal function estimated by namics and function. Of crucial importance, GFR was pres-
creatinine clearance, the MDRD, or the Cockcroft-Gault ently measured using a widely accepted tracer and timed
formula was detected. urine collections.
Although plasma renin activity progressively decreased The fact that in the oldest age category the negative
with increasing age, despite no difference in natriuresis, no influence of PP on GFR was confirmed after adjustment for
between-tertile difference in mean values of plasma renin age suggests that an increasing PP may accelerate the aging
activity were found within each age group. process of GFR and renal plasma flow. Although it was
demonstrated that a high level of blood pressure accelerates
Albuminuria and PP the age-associated decline in GFR measured as creatinine
As shown in Table 2, urinary albumin excretion was not clearance23 or the Tc-DTPA technique,18 the present obser-
significantly influenced by PP in the 40 to 49 and 50 to 59 age vation persisted after adjustment for MAP.
groups. In patients older than 60, there was a trend for an In 1290 untreated subjects with normal or high blood
increase in albuminuria with increasing PP; however, albu- pressure, it was reported that only in the lowest tertile of
minuria expressed as albumin-to-creatinine ratio was higher calculated renal function calculated by the Cockcroft-Gault
(P0.05) in the highest tertile of PP compared with the formula was there a negative association between pulse wave
lowest tertile (2.1 versus 0.8 mg/mmol). Univariate analyses velocity (a parameter highly correlated with PP7) and renal
of the determinants of log-transformed UAE showed positive function independently of age, gender, MAP, and classical
correlations with SBP and PP; no relationship was observed risk factors. Nevertheless, the relationship between pulse
with MAP, DBP, or renal function parameters. In a multivar- wave velocity and renal function was stronger in subjects
iate model, UAE remained positively correlated only with PP younger than 55 years of age than in older people.24 In the
and SBP. Nevertheless, this correlation disappeared after Gubbio population of nondiabetic subjects aged 45 to 64
introduction of cardiovascular risk factors. years, PP was not associated with GFR as measured by
creatinine clearance.25 In 4736 subjects with ISH and older
Discussion than 65 years of age included in the Systolic Hypertension in
In the present study conducted in 212 patients with never- the Elderly Program (SHEP), it was observed that SBP, and
treated isolated systolic hypertension, it was observed that to a lower extent, PP, and MAP were significant predictors of
only in the group of subjects aged 60 or older was PP a decline in kidney function corresponding to an increase in
inversely related to GFR, independently of age, MAP, and serum creatinine of 0.4 mg/dL within 5 years of follow-
up.15 Although the present results were obtained in a cross-
TABLE 2. Continued sectional study and using a precise measurement of GFR,
they are in agreement with the SHEP longitudinal study.
60 (n63)
In patients older than 60 years of age, the lower GFR found
I II III in the highest tertile of PP was associated with a proportion-
62 (55 66) 72 (66 77) 86 (77101) ally lower ERPF; as a consequence, no modification in
19.0 28.6 28.6 filtration fraction was found. These results are suggestive of
63.93.7 70.210.2 67.26.0 a renal blood flow-dependent influence of PP on GFR,
25.54.2 26.33.9 27.75.2 probably resulting from an increase in preglomerular resis-
1044 1057 1125
tance. The primary cause in favor of such a proposition could
be the existence of structural changes (hypertrophy or remod-
95.118.2 79.918.3 76.912.4
eling) within intrarenal vessels in elderly subjects. However,
41364 35482 34277 the possibility of functional vascular changes in addition to
23.02.8 22.73.3 23.03.3 stiffening of intrarenal vessels remains. When perfusion
0.38 (0.120.52) 0.30 (0.130.54) 0.32 (0.160.91) pressure increases, autoregulation of renal blood flow is
mediated by an increase in afferent arteriolar tone to maintain
12852 14262 13276 a constant glomerular hydrostatic pressure and subsequently a
345117 367127 299173 constant GFR. In fact, myogenic tone of the afferent arteriole,
5.1 (3.28.0) 8.3 (4.313.7) 9.5 (4.619.7) which modulates most of the autoregulatory process, is
affected by pressure pulsatility.26 Consequently, when PP
increases out of proportion to MAP, as seen in isolated
systolic hypertension, renal blood flow would decrease and
result in a decline in GFR. In experimental studies conducted
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590 Hypertension April 2005
Adjusted values of GFR (A), ERPF (B), and filtration fraction (C)
according to tertiles of pulse pressure in each age category.
*P0.05.
in the remnant kidney model, in the presence of reduced
afferent arteriolar resistance, the increase in PP rather than
MAP is more selectively transmitted to the glomerulus and
thus favors glomerulosclerosic changes.27
It is of interest that in the present study, the decrease in
GFR and ERPF associated with increasing PP was present
only in subjects older than 60 years. Among suggested
mechanisms operative in elderly patients are the presence of
an impairment in the production of endogenous substances
with vasodilator capacity such as nitric oxide through accel-
erated degradation by anion superoxides28 or the presence of
an increased concentration of an endogenous inhibitor of
nitric oxide such as asymmetrical dimethylarginine.29 Circu-
lating concentration of asymmetrical dimethylarginine was
shown to be higher in elderly subjects, to correlate with a
decreased ERPF, and finally to act as a potent vasoconstrictor
when infused in healthy subjects.30 In addition, it has been
shown that nitric oxide-mediated dilatation declines with
aging, becoming particularly apparent during the sixth de-
cade, at the time when PP tends to increase markedly.31 In
experimental studies using isolated microperfused rabbit
renal vessels, it was demonstrated that nitric oxide exerts its
vasodilator effect preferentially on the afferent arteriole.32
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It was recently reported that low (but within the normal
range) GFR, as determined by the MDRD formula, was
associated with reduced vasodilator response to acetylcholine
in the forearm circulation in patients with uncomplicated
never-treated essential hypertension.33 Nevertheless, there is
no unequivocal evidence that endothelial dysfunction of the
forearm circulation is paralleled by a similar alteration of the
renal circulation. Of interest, a blunted response of renal
blood flow to L-arginine (the substrate for nitric oxide
generation) infusion was observed in essential
hypertension.34,35
In the present study, albuminuria was elevated in the
highest tertile of PP only in patient older than 60 years of age;
in contrast, no modification of albuminuria with increasing
PP was observed in younger patients. Although the observed
increase in albuminuria may result from the increase in
systolic pressure (the main mechanism of albuminuria) in
normotensive and hypertensive subjects,18 the hypothesis that
increased albuminuria may be a marker of intrarenal lesions
and subsequent accelerated decline in GFR deserves further
longitudinal studies.
The present observation that the higher the PP, the lower
the GFR only in patients with ISH and older than 60 years of
age is of interest. As recently mentioned by Mitchell,36
evaluation of the relationship between aortic stiffness and
GFR requires direct assessment of GFR rather than estimates
of renal function by serum creatinine-based formulas. Along
this line, no relationship between PP and GFR was observed
when estimates of renal function by creatinine clearance or
MDRD or Cockcroft-Gault formula were used.
Perspectives
PP is a predictor of cardiovascular morbidity and mortality. In
aging subjects, PP increases, partly because of stiffening of
the arterial vessel wall. In the present cross-sectional study
conducted in 212 patients with isolated systolic hypertension,
increasing PP was related to lower GFR only in subjects 60
years of age or older when compared with younger groups of
patients. This suggests that the age-related decline in GFR
may be accelerated in the presence of elevated PP. Whether
the lower GFR value with respect to age may predict further
accelerated renal function decline remains to be documented.
Study of the effect of long-term control of PP would be of
great interest.
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