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High-Normal Serum Creatinine Concentration Is a Predictor of Cardiovascular Risk in Essential Hypertension
Giuseppe Schillaci, MD;
Gianpaolo Reboldi, MD, MSc, PhD;
Paolo Verdecchia, MD
Arch Intern Med. 2001;161:886-891.
ABSTRACT
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Background Determination of serum creatinine concentration is recommended in all
patients with hypertension as a marker of target organ damage. However, the
possibility that creatinine values within the reference range might contribute
to stratification of cardiovascular risk in essential hypertension has never
been tested.
Patients and Methods In the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale
Study, for up to 11 years (mean, 4 years) we followed up 1829 white patients
with hypertension (mean ± SD age, 51 ± 12 years; 53% men; office
blood pressure, 157/98 mm Hg) free of cardiovascular events and with normal
pretreatment creatinine levels (men, <136 µmol/L [<1.5 mg/dL];
women, <120 µmol/L [<1.4 mg/dL]) who also underwent 24-hour blood
pressure monitoring and electrocardiography before therapy.
Results During follow-up, there were 175 fatal or nonfatal major cardiovascular
morbid events (2.4 per 100 patient-years). Event rate increased progressively
from the first to the fourth sex-specific quartiles of creatinine distribution
(1.5, 2.3, 2.3, and 3.5 per 100 patient-years; P
= .003 by log-rank test). After adjustment (in a multivariate Cox model) for
age, sex, diabetes, cholesterol, smoking, left ventricular hypertrophy, and
24-hour pulse and mean blood pressures (P<.05
for all), creatinine concentration was an independent adverse predictor of
cardiovascular morbid events (P = .01). The observed
excess risk was 1.30 (95% confidence interval, 1.07-1.59) for a 20-µmol/L
(0.23-mg/dL) increase in creatinine concentration.
Conclusions A serum creatinine value within the reference range is a predictor of
cardiovascular morbidity in white patients with essential hypertension. Its
prognostic value persists after adjustment for several powerful confounders,
including average 24-hour blood pressure and left ventricular hypertrophy.
INTRODUCTION
THE KIDNEY is a main target of organ damage in hypertension, and long-term
exposure to elevations in blood pressure (BP), even within the normotensive
range, can induce early renal damage.1 Current
expert guidelines2-3 for the management
of hypertension recommend determination of the serum creatinine concentration
in all patients with hypertension as a marker of target organ damage. In the
Joint National Committee VI guidelines,2 a
frankly elevated creatinine concentration or the presence of proteinuria is
considered a sign of organ damage, and a creatinine level of 106 to 178 µmol/L
(1.2-2.0 mg/dL) is a major tool for risk stratification according to the World
Health Organization–International Society of Hypertension guidelines.3 Nevertheless, few data exist about the prognostic
value of normal or minimally elevated creatinine levels in hypertension. Despite
the fact that renal hemodynamic values become abnormal even in the early stages
of hypertension,4-5 the glomerular
filtration rate is usually not significantly reduced until late in the course
of the disease,6-7 and an elevated
serum creatinine level is therefore a late sign of renal damage in essential
hypertension. Although not an ideal marker for renal function,8
an increased serum creatinine level is strongly predictive of the subsequent
development of end-stage renal disease.9 Moreover,
frankly elevated serum creatinine values predict a poor prognosis in patients
with hypertension,10-13
and mild elevations in serum creatinine levels were associated with an increased
all-cause mortality rate in population-based samples of elderly patients14-15 and in patients with heart failure.16
Thus, to our knowledge, the prognostic significance of serum creatinine
levels in the upper-normal range has not been investigated to date in patients
with hypertension. In the present study, we investigated the relation between
serum creatinine concentration and subsequent risk for cardiovascular morbid
events in patients with essential hypertension and normal levels of serum
creatinine.
PATIENTS AND METHODS
The Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA)
Study is a prospective registry of complications and death in white adults
with essential hypertension. The study design and procedures have been reported
previously.17-19
Patients with hypertension were referred to 1 of 3 participating medical centers
(Perugia General Hospital, Città della Pieve Civic Hospital, and Castiglione
del Lago Civic Hospital) for baseline evaluation by a group of general practitioners
practicing in Umbria in central Italy. A total of 1829 patients with complete
follow-up data enrolled between January 1, 1988, and December 31, 1996, and
all were included in the present analysis. All study patients fulfilled the
following criteria: (1) office systolic BP of 140 mm Hg or higher, diastolic
BP of 90 mm Hg or higher, or both on 3 or more visits at 1-week intervals;
(2) no previous treatment for hypertension (70% of patients) or withdrawal
from antihypertensive drug therapy 4 weeks or more before the study (30% of
patients); (3) no clinical or laboratory evidence of heart failure, coronary
heart disease, previous stroke, valvular defects or secondary causes of hypertension,
or important concomitant disease; (4) 1 or more valid BP measurements per
hour during 24 hours; and (5) normal serum creatinine levels (men, <136
µmol/L [<1.5 mg/dL]; women, <120 µmol/L [<1.4 mg/dL]).
These cutoff points represent the 95th percentile of the distribution of serum
creatinine in a population of 3241 healthy white individuals from the Framingham
Heart Study.20 All patients gave informed consent
to participate in the study.
BASELINE MEASUREMENTS
Office BP was measured by physicians in the medical centers with a mercury
sphygmomanometer after patients sat for 10 minutes or longer. The average
of 3 or more measurements at 2 or more sessions was considered for the analysis.
Ambulatory BP was recorded with an oscillometric device (models 90202 and
90207; SpaceLabs, Redmond, Wash) that was set to take a reading every 15 minutes
throughout 24 hours. Normal daily activities were allowed and encouraged,
and patients were told to keep their nondominant arm still and relaxed to
the side during measurements. Reading, editing, and analysis of data were
performed as previously described.17-18
Serum creatinine concentration was measured in an autoanalyzer (Technicon,
Tarrytown, NY) by means of an automated technique measuring dialyzable Jaffe
chromogen,21 and the presence of proteinuria
was assessed by standard dipstick examination of an early-morning spot urine
sample. To maximize the diagnostic sensitivity of electrocardiography, left
ventricular hypertrophy was defined by a multifactorial criterion (S wave
in V3 + R wave in a VL  2.4 mV in men or 2.0 mV in women, typical left
ventricular strain, or Romhilt-Estes score 5) with significantly higher
sensitivity, accuracy, and prognostic value than several other more widely
used standard criteria.22-23
FOLLOW-UP PROCEDURES AND END POINT EVALUATION
All patients were followed up by their family physicians, in cooperation
with the outpatient clinic of the referring hospital, and treated with the
aim of reducing office BP to less than 140/90 mm Hg using standard lifestyle
and pharmacological measures. Most patients continue to be periodically referred
to our institutions for BP control and other diagnostic procedures. Diuretics, ß-adrenergic
blocking agents, angiotensin-converting enzyme inhibitors, calcium channel
blockers, and  1-blockers, alone or in various combinations,
were the most frequently prescribed antihypertensive drugs. Contacts with
family physicians and telephone interviews were periodically undertaken to
determine the incidence of major cardiovascular complications of hypertension.
For patients who developed cardiovascular morbid events, we reviewed in conference
hospital record forms and other available original source documents. Cardiovascular
events included new-onset coronary artery disease (myocardial infarction,
unstable angina with documentation of ischemic electrocardiographic changes,
sudden cardiac death, or coronary revascularization procedure), stroke, transient
cerebral ischemic attack, symptomatic aortoiliac occlusive disease verified
by angiography, and congestive heart failure that required hospitalization.
The international standard criteria used to diagnose cardiovascular events
in the PIUMA Study have been reported previously.17, 19
STATISTICAL ANALYSIS
Parametric data are reported as mean ± SD. Standard descriptive
and comparative analyses were undertaken. The rates of events are presented
as the number of events per 100 patient-years, based on the ratio of the number
of events observed to the total number of patient-years of exposure up to
the terminating event or censor. For patients without events, the date of
censor was that of the last contact with the patient. For patients who experienced
multiple events, survival analysis was restricted to the first event. For
patients who subsequently died, classification of the terminating event could
differ from that of the previous nonfatal event. Survival curves were estimated
using the Kaplan-Meier product-limit method24
and compared using the Mantel-Haenszel (logistic-rank) test.25
The effect of prognostic factors on survival was evaluated using the stepwise
Cox semiparametric regression model.26 The
assumption of linearity for the Cox model was tested through visual inspection,
and no violation of proportional hazards was found. We tested the variables
of age, sex, serum cholesterol level, serum creatinine level, proteinuria,
left ventricular hypertrophy on the electrocardiogram, smoking habits, body
mass index (calculated as weight in kilograms divided by the square of height
in meters), office and 24-hour mean BP and pulse pressures, diabetes, and
antihypertensive drug treatment at the follow-up contact. We also divided
patients by sex-specific quartiles of serum creatinine distribution. The partition
values were 83, 92, and 103 µmol/L (0.94, 1.04, and 1.17 mg/dL) in men
and 70, 76, and 84 µmol/L (0.79, 0.86, and 0.95 mg/dL) in women. A statistical
software package (SPSS release 8.0; SPSS Inc, Chicago, Ill) was used to perform
the analyses. Differences were considered statistically significant at P<.05.
RESULTS
Table 1 shows the main clinical
characteristics of the study population with and without cardiovascular events
during follow-up. Patients who will develop an event were older, had a longer
duration of hypertension, and were more frequently men and diabetic. In addition,
serum cholesterol and serum creatinine levels, prevalence of left ventricular
hypertrophy and proteinuria, and BP values (office and ambulatory) were higher
in patients who will vs will not develop a cardiovascular event. The prevalence
of smoking and body mass index did not differ between the groups.
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Table 1. Clinical Characteristics of 1829 Study Patients With and Without
Future Cardiovascular Events*
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During follow-up of 4.0 ± 2.0 years (range, 1.0-10.8 years),
there were 175 new cardiovascular morbid events (2.37 events per 100 patient-years)
at the cardiac (n = 84), cerebrovascular (n = 75), or peripheral vascular
(n = 16) level. Specifically, there were 33 patients with myocardial infarction,
8 with sudden cardiac death, 3 with cardiac death from other causes, 21 with
unstable angina, 6 with coronary revascularization procedures, 13 with heart
failure that required hospitalization, 56 with stroke, 19 with transient cerebral
ischemia, and 16 with new-onset aortoiliac occlusive disease. During follow-up,
we also registered 75 deaths from all causes (0.96 events per 100 patient-years),
of which 36 were from cardiovascular causes (3 fatal myocardial infarctions,
12 sudden cardiac deaths, 11 other cardiac deaths, and 10 fatal strokes).
The rate of total (fatal plus nonfatal) cardiovascular events was 1.47,
2.30, 2.27, and 3.52 per 100 patient-years in the first, second, third, and
fourth sex-specific quartiles of creatinine distribution, respectively (Figure 1). Event-free survival curves in
the 4 quartiles of creatinine distribution differed significantly (P<.003 by log-rank test) (Figure
2). The cumulative cardiovascular event rate for the highest quartile
was greater than 50% at 11 years compared with a cumulative rate of less than
20% for the lowest quartile. Event rate was intermediate in the second and
third quartiles.
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Figure 1. Progressive increase in cardiovascular
morbidity from the first to the fourth quartiles of serum creatinine distribution.
Partition values were 83, 92, and 103 µmol/L (0.94, 1.04, and 1.17 mg/dL)
in men and 70, 76, and 84 µmol/L (0.79, 0.86, and 0.95 mg/dL) in women.
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Figure 2. Cumulative cardiovascular event–free
survival by quartile of serum creatinine distribution. There were 1829 patients
at risk at 0 years, 1502 at 2 years, 953 at 4 years, 288 at 6 years, 72 at
8 years, and 25 at 10 years. Partition values were 83, 92, and 103 µmol/L
(0.94, 1.04, and 1.17 mg/dL) in men and 70, 76, and 84 µmol/L (0.79,
0.86, and 0.95 mg/dL) in women. P<.003 by log-rank
test.
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Results of multivariate survival analysis are shown in Table 2. The association between serum creatinine level and subsequent
cardiovascular morbidity was maintained after adjustment for the confounding
effects of age, sex, smoking, diabetes, cholesterol level, left ventricular
hypertrophy, proteinuria, office and 24-hour ambulatory BP values, treatment
status, body mass index, and family history of early-onset coronary heart
disease. The observed excess risk was 1.30 (95% confidence interval [CI],
1.07-1.59; P = .01) for each 20-µmol/L (0.23-mg/dL)
increase in creatinine concentration. The prognostic impact of creatinine
level remained significant also when multivariate analysis was restricted
to the subgroup of patients without proteinuria (n = 1605), in whom the excess
risk was 1.27 (95% CI, 1.02-1.59; P = .03) for each
20-µmol/L (0.23-mg/dL) increase in creatinine.
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Table 2. Independent Predictors of Cardiovascular Morbid Events (Cox
Model)*
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A significant risk gradient for adverse events was evident across the
quartiles of creatinine distribution. In a multivariate analysis, the excess
risk compared with the first quartile was significant for the fourth quartile
(creatinine level, 103 µmol/L [1.17 mg/dL] in men and 84
µmol/L [0.95 mg/dL] in women; relative risk, 1.61; 95% CI, 1.02-2.54; P = .047) and bordered significance for the third (relative
risk, 1.56; 95% CI, 0.95-2.55; P = .08) and second
(relative risk, 1.55; 95% CI, 0.95-2.51; P = .08)
quartiles.
The rate of all-cause deaths was 0.66, 0.76, 0.73, and 1.71 per 100
patient-years in the first, second, third, and fourth quartiles of serum creatinine
distribution, respectively (P = .01 by log-rank test).
However, in a multivariate Cox regression analysis, only age, diabetes, male
sex, and 24-hour pulse pressure were independent predictors af all-cause deaths
(P<.05 for all), and the prognostic impact of
serum creatinine concentration was no longer significant (P = .24).
COMMENT
Results of the present study show a strong relation between serum creatinine
level and subsequent cardiovascular morbidity in patients with initially untreated
and uncomplicated essential hypertension and normal baseline creatinine values.
The relation was statistically significant and persisted after correction
for the effect of several traditional risk factors, including age, sex, diabetes,
cigarette smoking, left ventricular hypertrophy, serum cholesterol level,
and office and 24-hour ambulatory BP values. For every 20-µmol/L (0.23-mg/dL)
increase in creatinine concentration, there was a 30% increase in the observed
age- and risk factor–adjusted risk of fatal or nonfatal cardiovascular
end points.
PREVIOUS STUDIES
Among participants in the Hypertension Detection and Follow-up Program,13 a frankly elevated serum creatinine level (>150 µmol/L
[>1.7 mg/dL]) was an uncommon finding, being present in 2.8% of the population,
but represented a strong independent risk factor for mortality. In that study,13 despite a gradual increase in the crude mortality
rate for baseline creatinine levels greater than 106 µmol/L (>1.2 mg/dL),
the independent prognostic value of mildly elevated serum creatinine values
was not assessed. In a case-control study27
of patients with treated hypertension, the all-cause mortality rate was lower
in those with normal (<124 µmol/L [<1.4 mg/dL] in men and <106
µmol/L [<1.2 mg/dL] in women) than elevated (>178 µmol/L [>2.0
mg/dL]) creatinine levels, but no significant difference was found compared
with patients with intermediate values. In a recent overview28
of the placebo-treated control groups of 8 antihypertensive intervention trials,
a reduction by 30 mL/min in glomerular filtration rate, as determined using
the Cockcroft formula,29 was associated with
a significant and independent 27% increase in cardiovascular deaths during
average follow-up of 5 years, but no data were reported on the prognostic
significance of glomerular filtration rate in patients who did not have overt
renal failure. In a different clinical setting, patients with asymptomatic
or symptomatic left ventricular dysfunction from the Studies of Left Ventricular
Dysfunction trials whose creatinine clearance was less than 1.00 mL/s (<60
mL/min) exhibited an increased risk for all-cause death, largely explained
by an increase in pump-failure death.16 Taken
together, available data could not provide a definite answer to the question
regarding the prognostic impact of serum creatinine level in most patients
with essential hypertension and normal or minimally elevated creatinine values.
PRESENT STUDY
To our knowledge, this is the first report of an association between
serum creatinine concentration and subsequent cardiovascular morbid events
in a large, untreated hypertensive population with normal creatinine values
and without cardiovascular disease at baseline evaluation. The association
was maintained after adjustment for several independent predictors of prognosis,
including concomitant risk factors (age, male sex, smoking, diabetes, and
serum cholesterol level), markers of target organ damage (left ventricular
hypertrophy and proteinuria), and 24-hour BP values.
All patients had baseline good-quality 24-hour BP tracings. Average
24-hour BP is a better predictor of cardiovascular prognosis than office BP
in patients with hypertension30; in the present
study, the prognostic value of creatinine concentration was maintained after
adjustment for mean BP and pulse pressure, which seems to be the strongest
predictor of adverse prognosis in hypertension.31
Also, besides serum creatinine level, another simple indicator of kidney damage
and a valuable prognostic marker in hypertension is proteinuria.11-12,32
In our study, however, the proportion of patients with dipstick-detectable
proteinuria was only 7%, and the independent prognostic value of creatinine
concentration was confirmed also when the analysis was restricted to patients
free of proteinuria. Thus, a high-normal creatinine level seemed to be a more
sensitive marker of kidney damage than proteinuria and a more valuable tool
for risk stratification in patients with uncomplicated hypertension. There
is also initial evidence that microalbuminuria can be associated with a greater
risk for cardiovascular complications in hypertension33;
determination of microalbuminuria was not available routinely in the PIUMA
Study.
Our study does not allow us to draw firm conclusions about the potential
mechanisms underlying the association between serum creatinine level and cardiovascular
risk. A likely explanation for our finding is that creatinine level, even
within the conventionally accepted reference range, might behave as a time-integrated
marker of long-term systemic exposure to elevated BP values and, therefore,
as a predictor of outcome also in nonrenal target organs. It is currently
recognized34 that deterioration of renal function
in patients with essential hypertension can be attributed to glomerular hypotension
and ischemia induced by damage to preglomerular arteries and arterioles and
to transmission of the elevated systemic pressure to the glomeruli, which
induces glomerular capillary hyperperfusion and hypertension and eventually
leads to glomerular structural injury. In this regard, higher BP values within
the reference range precede and explain part of the following decline in renal
function in middle-aged patients,1 and this
finding has been recently confirmed in young black men.35
Alternatively, creatinine level might be regarded as a marker not only of
renal function but also of subclinical renal artery atherosclerosis. Renal
artery stenosis is a common finding in patients with ischemic heart disease,
and its presence has been associated with more advanced coronary lesions.36 Despite the fact that patients with renovascular
hypertension and overt coronary and extracoronary atherosclerotic disease
were excluded from our study, the possibility that a subtle form of ischemic
renal disease, possibly associated with diffuse subclinical atherosclerotic
disease, might explain in part the high-normal creatinine values cannot be
ruled out with certainty in the absence of serial renal biopsies or angiograms
of the renal arteries.
STUDY LIMITATIONS
The large number of cardiovascular events in the present study allowed
adjustment for the confounding effects of several risk markers. However, the
number of fatal events was smaller, and this might have precluded the observation
of an independent association between creatinine concentration and the all-cause
mortality rate. Our findings have been obtained in initially untreated white
patients, so results might not be extended to different racial groups or to
patients receiving antihypertensive drug treatment at the time of the qualifying
serum creatinine determination. Finally, serum creatinine levels are affected
by a variety of conditions not associated with glomerular filtration rate,
including muscle mass, vigorous exercise, ingestion of cooked meat, and treatment
with some drugs.8 Creatinine clearance is a
more accurate measure of renal function than is serum creatinine level but
requires a 24-hour urine collection, which is impractical in large studies.
CLINICAL IMPLICATIONS
Our findings show a powerful and independent relation between baseline
serum creatinine concentration and cardiovascular risk in initially untreated
men and women with essential hypertension free of overt cardiovascular disease
and with creatinine values below commonly accepted upper limits of normal
(<136 µmol/L [<1.5 mg/dL] in men and <120 µmol/L [<1.4
mg/dL] in women).20 An increased risk for cardiovascular
events was detectable for creatinine values of 103 µmol/L or greater
(1.17 mg/dL) in men and 84 µmol/L or greater (0.95 mg/dL) in
women. These findings have important implications for clinical practice. The
Joint National Committee VI guidelines2 recommend
serum creatinine determination in all patients with hypertension, but only
a frankly elevated creatinine level and the presence of proteinuria are considered
relevant findings for the assessment of cardiovascular risk in a given hypertensive
patient, despite being relatively uncommon in uncomplicated hypertension.13 Our study adds to the current literature by showing
that a high-normal serum creatinine level in an untreated patient with hypertension
should be regarded not only as a risk factor for renal failure9
but as an important sign of target organ damage and as a simple and valuable
tool for cardiovascular risk stratification.
AUTHOR INFORMATION
Accepted for publication September 14, 2000.
This study was supported in part by grants from the Associazione Umbra
Cuore e Ipertensione, Perugia, Italy.
Corresponding author and reprints: Giuseppe Schillaci, MD, Unit of
Internal Medicine, Angiology, and Arteriosclerosis, Department of Clinical
and Experimental Medicine, University of Perugia Medical School via Brunamonti,
51, 06122 Perugia, Italy (e-mail: skill{at}unipg.it).
From the Unit of Internal Medicine, Angiology, and Arteriosclerosis,
the Departments of Clinical and Experimental Medicine (Dr Schillaci) and Internal
Medicine (Dr Reboldi), University of Perugia Medical School, and the Department
of Cardiology, "R. Silvestrini" Hospital (Dr Verdecchia), Perugia, Italy.
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