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Prevalence of High Blood Pressure and Elevated Serum Creatinine Level in the United States
Findings From the Third National Health and Nutrition Examination Survey (1988-1994)
Josef Coresh, MD, PhD;
G. Laura Wei, MHS;
Geraldine McQuillan, PhD;
Fredrick L Brancati, MD, MHS;
Andrew S. Levey, MD;
Camille Jones, MD, MPH;
Michael J. Klag, MD, MPH
Arch Intern Med. 2001;161:1207-1216.
ABSTRACT
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Background The prevalence and incidence of end-stage renal disease in the United
States are increasing, but milder renal disease is much more common and may
often go undiagnosed and undertreated.
Methods A cross-sectional study of a representative sample of the US population
was conducted using 16 589 adult participants aged 17 years and older
in the Third National Health and Nutrition Examination Survey (NHANES III)
conducted from 1988 to 1994. An elevated serum creatinine level was defined
as 141 µmol/L or higher ( 1.6 mg/dL) for men and 124 µmol/L
or higher (1.4 mg/dL) for women (>99th percentile for healthy young adults)
and was the main outcome measure.
Results Higher systolic and diastolic blood pressures, presence of hypertension,
antihypertensive medication use, older age, and diabetes mellitus were all
associated with higher serum creatinine levels. An estimated 3.0% (5.6 million)
of the civilian, noninstitutionalized US population had elevated serum creatinine
levels, 70% of whom were hypertensive. Among hypertensive individuals with
an elevated serum creatinine level, 75% received treatment. However, only
11% of all individuals with hypertension had their blood pressure reduced
to lower than 130/85 mm Hg (the Sixth Report of the Joint National Committee
on Detection, Evaluation, and Treatment of High Blood Pressure recommendation
for hypertensive individuals with renal disease); 27% had a blood pressure
lower than 140/90 mm Hg. Treated hypertensive individuals with an elevated
creatinine level had a mean blood pressure of 147/77 mm Hg, 48% of whom were
prescribed one antihypertensive medication.
Conclusion Elevated serum creatinine level, an indicator of chronic renal disease,
is common and strongly related to inadequate treatment of high blood pressure.
INTRODUCTION
ADEQUATE BLOOD pressure control is widely recognized as an essential
factor in slowing the progression of chronic renal disease and preventing
its main sequelae, end-stage renal disease (ESRD) and cardiovascular disease.1-7
As a result, antihypertensive blood pressure treatment goals are lower for
individuals with both hypertension and chronic renal disease (<130/85 mm
Hg for individuals with <1 g/d of proteinuria and <125/75 mm Hg for
individuals with >1 g/d of proteinuria) than for hypertensive individuals
without target organ damage (<140/90 mm Hg).6
At the same time, individuals with chronic renal disease are usually asymptomatic
and often go undiagnosed. Thus, hypertension may be undertreated among patients
with chronic renal disease. Data on the adequacy of blood pressure treatment
in this group are critical for preventive efforts to stem the epidemic of
ESRD8 and cardiovascular disease in chronic
renal disease.9
The Third National Health and Nutrition Examination Survey (NHANES III)
data offer the first opportunity to study the prevalence and number of people
with chronic renal disease (detected by an elevated serum creatinine level)
in a nationally representative sample. An initial analysis from NHANES III
showed that the prevalence of elevated serum creatinine level was higher among
non-Hispanic blacks than non-Hispanic whites and higher among older than younger
individuals.10 The present analysis was undertaken
to measure the prevalence of elevated serum creatinine level across different
categories of blood pressure and antihypertensive medication use. In addition,
we examined the number and type of antihypertensive medications used and the
achieved blood pressure among individuals with elevated serum creatinine levels
who were prescribed medicine for hypertension. We hypothesize that many individuals
with both elevated serum creatinine levels and hypertension are inadequately
treated.
SUBJECTS AND METHODS
We estimated the burden of hypertension-related chronic renal disease
using 16 589 participants aged 17 years and older in NHANES III. This
survey, conducted from 1988 to 1994 by the National Center for Health Statistics
(Hyattsville, Md) of the Centers for Disease Control and Prevention (Atlanta,
Ga), provides cross-sectional, nationally representative data on the health
and nutritional status of the civilian, noninstitutionalized US population.11-12 Non-Hispanic blacks and Mexican Americans
as well as the elderly and children were deliberately oversampled in this
survey. This oversampling makes it possible to obtain reliable estimates of
the distribution of creatinine in the 2 largest minority groups of the civilian,
noninstitutionalized US population as well as in a broad range of age groups.
Standardized questionnaires were administered in the home, followed by a detailed
physical examination at a mobile examination center.
MEASUREMENTS
Blood pressure measurements were obtained 3 times during the home interview
and another 3 times during the examination. Each measurement was made using
a mercury sphygmomanometer, with the participant seated. The arithmetic mean
was then calculated using all available systolic and diastolic readings. In
this analysis, individuals with a systolic blood pressure lower than 140 mm
Hg and diastolic blood pressure lower than 90 mm Hg who were not receiving
antihypertensive treatment were defined as normotensive. Individuals were
classified as hypertensive if they had a mean blood pressure of 140 mm Hg
or higher (systolic) or 90 mm Hg or higher (diastolic) or reported current
use of medication for hypertension.13 Among
the hypertensive participants, we further categorized individuals by treatment
status. Individuals were considered not treated if they had hypertension at
the time of the survey and did not report taking antihypertensive medication,
regardless of whether these individuals had been previously diagnosed as hypertensive.
We also analyzed the medications prescribed and classified them as angiotensin-converting
enzyme inhibitors, calcium channel blockers, ß-blockers,  -blockers
or -agonists, or diuretics.
Serum was collected at the mobile examination center and creatinine
measurements were performed at the White Sands Research Center laboratory,
Almogordo, NM, by the modified kinetic Jaffe reaction14
using a Hitachi 737 analyzer (Boehringer Mannheim Corporation, Indianapolis,
Ind) and were reported using conventional units (1 mg/dL = 88.4 µmol/L).
The coefficient of variation for creatinine determination ranged from 0.2%
to 1.4% during the 6 years of the NHANES III study. Data on physiologic variation
in creatinine level were obtained in a sample of 1921 participants who had
a second creatinine measurement. The assay had very stable quality-control
measures for the duration of the study. A review of the College of American
Pathologists Survey data indicates that the laboratory mean value for serum
creatinine levels during 1992-1994 was within acceptable limits but higher
than the mean value of all laboratories surveyed.
Blood pressure was categorized according to the Sixth Joint National
Committee Report on Detection, Evaluation, and Treatment of High Blood Pressure
(JNC-VI).6 Persons were categorized into 6
groups based on the higher of their systolic or diastolic blood pressure measurement:
(1) optimal blood pressure (<120 mm Hg systolic and <80 mm Hg diastolic);
(2) normal blood pressure (120-130 mm Hg systolic and 80-85 mm Hg diastolic);
(3) high-normal blood pressure (130-139 mm Hg systolic or 85-89 mm Hg diastolic);
(4) stage 1 hypertension (140-159 mm Hg systolic or 90-99 mm Hg diastolic);
(5) stage 2 hypertension (160-179 mm Hg systolic or 100-109 mm Hg diastolic);
and (6) stage 3 hypertension (180 mm Hg systolic or 110 mm Hg diastolic).
The primary outcome measure in this analysis was elevated serum creatinine
level (defined as a sex-specific cutoff point of 141 µmol/L [1.6
mg/dL] for men and 124 µmol/L [1.4 mg/dL] for women). These
cutoffs, which are higher than the reported reference range for serum creatinine
level using this assay, were used to provide greater specificity when defining
chronic renal disease based on a single serum creatinine measurement. These
criteria correspond to the 99.4th and 99.8th percentiles for men and women
aged 20 to 39 years without diabetes or hypertension in this study. In this
young healthy group, the mean (SD) creatinine level was 101 (13) µmol/L
(1.14 [0.15] mg/dL) for men and 80 (15) µmol/L (0.91 [0.17] mg/dL) for
women (29% and 35% lower than the cutoffs for elevated serum creatinine level).
Because serum creatinine level is inversely proportional to glomerular filtration
rate, young individuals with elevated serum creatinine levels are likely to
have lost approximately a third of their renal function while older persons
with elevated creatinine levels will have lost even more function because
muscle mass and creatinine production decreases with age. Analyses were repeated
using alternative cutoff points and yielded similar results.
Diabetes was defined by participants' medical history as well as their
blood glucose value. The primary analysis stratified individuals based on
a history of diagnosed diabetes mellitus because this information was available
for nearly all individuals and could be used by physicians for risk stratification.
Ancillary analyses examined the impact of using the American Diabetes Association
(ADA) criteria15 for diabetes mellitus in the
subset of individuals who fasted at least 8 hours.
STATISTICAL ANALYSIS
The complex survey design of NHANES III incorporated differential probabilities
of selection. To derive national estimates, sampling weights were used to
adjust for noncoverage and nonresponse. All prevalence estimates were weighted
to represent the civilian, noninstitutionalized US population and to account
for oversampling and nonresponse to the household interview and physical examination.12 All data analyses were conducted using STATA svy
commands (Stata Corporation, College Station, Tex; 1999) for analyzing complex
survey design data with 49 strata and 98 primary sampling units. A total of
16 589 participants (82.7%) of 20 050 examined had both blood pressure
and serum creatinine data available for this analysis. The rate of missing
data was higher among older than younger individuals (individuals missing
data were 4 years older), higher among men than among with women (17.9% vs
16.7%), and lower among Mexican Americans and other ethnicities (14%) than
among non-Hispanic whites (19%) and non-Hispanic blacks (18%). These differences
were primarily owing to missing phlebotomy data. To minimize bias, the combined
mobile examination center and home examination weights were divided by the
proportion of participants missing creatinine data in each of the design age,
sex, and race ethnicity strata. This corrected differences caused by missing
data across sampling strata but assumed that data are missing randomly within
strata.
RESULTS
Table 1 gives the number
of survey participants by demographic group, diabetes mellitus, and blood
pressure category as well as estimates of the proportion of individuals, mean
serum creatinine levels, and prevalence of elevated creatinine levels for
the civilian, noninstitutionalized US population. Overall, from 1988 to 1994,
the prevalence of elevated serum creatinine level was 3.0%, corresponding
to 5.6 million adults (803 survey participants). Older age and diabetes mellitus
were very strongly associated with a higher prevalence of elevated creatinine
level. Non-Hispanic blacks had a higher prevalence and Mexican Americans had
a lower prevalence of elevated creatinine level than non-Hispanic whites.
Higher categories of blood pressure, hypertension status, and use of antihypertensive
medications were associated with higher mean serum creatinine level and a
higher prevalence of elevated serum creatinine level. Elevated serum creatinine
level was 8 times more common in hypertensive (9.1%) than normotensive (1.1%)
individuals and 8 times more common in people already using medication for
high blood pressure compared with people not using such medication (13.0%
vs 1.6%).
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Table 1. Mean Serum Creatinine Level and Prevalence of Elevated Serum
Creatinine Level* by Demographics, Diabetes, and Blood Pressure: NHANES III,
1988-1994
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Figure 1 shows that the prevalence
of elevated serum creatinine level was markedly higher in individuals treated
for hypertension compared with untreated individuals at every category of
blood pressure. Among untreated individuals, prevalence of elevated serum
creatinine level increased monotonically with higher blood pressure categories
from 0.8 % to 13.6%. Among treated individuals, the association of prevalence
of elevated serum creatinine level with blood pressure was J-shaped. Prevalence
was lower in individuals with normal blood pressure (6.3%) compared with individuals
with optimal blood pressure (9.8%) or higher levels of blood pressure. The
higher prevalence of elevated creatinine level among treated hypertensive
individuals with an optimal blood pressure cannot be estimated reliably given
the relatively small size of this group (189 participants; 95% confidence
interval [CI], 3%-16%). In persons with high-normal blood pressure, the prevalence
was 13.6%, followed by a steady increase from 13.3% to 22.5% in hypertension
stages 1 to 3. The ratio of prevalence rates of treated to untreated individuals
declined with increasing blood pressure category from 12.2 for optimal blood
pressure category to 1.7 for stage 3 hypertension; hence, the relative difference
in prevalence between the untreated and treated groups narrowed at categories
of higher blood pressure.
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Figure 1. Prevalence of elevated serum creatinine
level by the Sixth Report of the Joint National Committee on Detection, Evaluation,
and Treatment of High Blood Pressure blood pressure category and self-reported
treatment with antihypertensive medications. Error bars indicate SEs.
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Figure 2 shows that the distribution
of individuals with elevated serum creatinine levels across blood pressure
categories is markedly different from the association of prevalence rates
with blood pressure categories shown in Figure
1. The prevalence of elevated serum creatinine level was greatest
in persons with stage 3 hypertension. In contrast, the largest number of the
individuals with an elevated serum creatinine level was in the stage 1 hypertension
category (Figure 2), the most common
form of hypertension (56% of all hypertensive individuals). More individuals
with an elevated serum creatinine level were treated than not treated for
blood pressure categories of high-normal and above. The largest number of
cases within a specific category was in treated persons with blood pressure
in the stage 1 hypertension category (n = 1.1 million treated and 0.5 million
untreated or 29% of all individuals with an elevated serum creatinine level).
Among the hypertensive individuals with elevated serum creatinine levels,
75% were treated, of whom only 36% had a blood pressure lower than 140/90
mm Hg (the JNC-VI recommendation for hypertensive individuals without target
organ damage) and only 14% had their blood pressure reduced to lower than
130/85 mm Hg (the JNC-VI recommendation for hypertensive individuals with
renal disease).6, 16 Overall, only
11% of all hypertensive individuals with an elevated serum creatinine level
had their blood pressure reduced to lower than 130/85 mm Hg and 27% had a
blood pressure lower than 140/90 mm Hg. Using lower or higher cutoff values
to define elevated serum creatinine level influenced the prevalence of elevated
creatinine level (11.7% of men had a creatinine level of 124 µmol/L
[1.4 mg/dL] and 9.3% of women had a creatinine level of 106 µmol/L
[1.2 mg/dL]) but not the shape of the association with blood pressure
category.
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Figure 2. Estimated number of individuals
with elevated serum creatinine by the Sixth Report of the Joint National Committee
on Detection, Evaluation, and Treatment of High Blood Pressure blood pressure
category and self-reported treatment with antihypertensive medications. Error
bars indicate SEs.
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Table 2 also gives the prevalence
and number of cases of elevated serum creatinine level in the major ethnic
subgroups as well as among older individuals. The number of individuals in
subgroup analyses was smaller, which resulted in decreased precision as indicated
by the higher standard errors. The prevalence rate of elevated serum creatinine
level among treated hypertensive individuals was greatest in non-Hispanic
blacks (19.3%), followed by non-Hispanic whites (11.9%) and Mexican Americans
(8.1%). Among individuals older than 60 years, the prevalence of elevated
creatinine level was higher among treated (18.0%) than untreated (6.9%) individuals.
Seventy-seven percent of all individuals with elevated creatinine were at
least 60 years old.
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Table 2. Prevalence (Percentage) and Estimated Number (in Thousands)
of Individuals With Elevated Serum Creatinine Level* by Race, Age, Blood Pressure,
and Antihypertensive Medication Use: NHANES III, 1988-1994
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Individuals using antihypertensive medication for controlling blood
pressure consistent with stage 1 hypertension made up the greatest proportion
of cases in each group. The prevalence and estimated number of individuals
in the US population with elevated serum creatinine levels stratified by self-reported
diabetes status are given in Table 3.
Diabetes was diagnosed in 1.1 million (19%) of the 5.6 million individuals
with an elevated serum creatinine level. The prevalence of elevated serum
creatinine level was higher at higher blood pressure categories in both individuals
with diabetes mellitus and individuals without diabetes mellitus, which is
similar to the total population. Individuals with diabetes mellitus treated
for high blood pressure (18.4%) had a higher prevalence of elevated serum
creatinine level than treated individuals without diabetes mellitus (12.0%).
Untreated individuals with diabetes mellitus (7.8%) had a higher prevalence
of elevated serum creatinine level than untreated individuals without diabetes
mellitus (1.4%). The associations with blood pressure categories were similar
to those in the total population. The inclusion of undiagnosed individuals
with both diabetes mellitus and fasting hyperglycemia (2.7% of the population17) increased the prevalence of diabetes mellitus and
slightly decreased the prevalence of elevated serum creatinine level among
individuals with diabetes mellitus, but it altered very little the prevalence
among the much larger number of individuals without diabetes mellitus.
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Table 3. Prevalence (Percentage) of Elevated Serum Creatinine* and
Estimated Number (in Thousands) of Individuals by Diabetes, Blood Pressure,
and Antihypertensive Medication Use: NHANES III, 1988-1994
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Hypertensive individuals were more likely to be non-Hispanic black and
older and have diabetes mellitus than the rest of the general population.
With the use of logistic regression analysis (after adjustment for age, race,
sex, diabetes, and a history of stroke, congestive heart failure, and cardiovascular
disease) the prevalence of elevated serum creatinine level was still directly
associated with higher blood pressure category, with the highest risk seen
at stage 3 hypertension (Table 4; P = .001). Repeating the analysis by estimating an adjusted
odds ratio for each of the blood pressure categories by hypertension treatment
group compared with individuals with optimal blood pressure without treatment
(last 2 columns of Table 4) yielded
wider CIs and some attenuation of the association. However, the prevalence
of elevated serum creatinine level remained associated with both elevated
blood pressure and blood pressure treatment.
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Table 4. Adjusted Odds Ratio of Having an Elevated Serum Creatinine
Level Associated With Blood Pressure Category and Antihypertensive Medication
Use: NHANES III, 1988-1994*
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Table 5 gives the number
of antihypertensive medications used to treat hypertensive individuals by
the presence of elevated serum creatinine level and achieved mean blood pressure
(this analysis is unweighted owing to small numbers in some data cells). Hypertensive
individuals with an elevated serum creatinine level were more likely to be
treated than hypertensive individuals with a lower serum creatinine level
(75% vs 49%; P<.001). When treated, persons with
an elevated serum creatinine level were prescribed a higher mean number of
medications (1.7 vs 1.4; P = .001) and, consequently,
were more likely to be prescribed every type of antihypertensive medication.
In a logistic regression model among individuals with hypertension (which
adjusted for the number of medications prescribed, age, sex, race, and diabetes)
the presence of elevated creatinine level was positively associated with the
prescription of diuretics (odds ratio, 1.7; 95% CI, 1.4-2.2), negatively associated
with prescription of ß-blockers (odds ratio, 0.7; 95% CI, 0.5-0.9), and
not associated with prescription of angiotensin-converting enzyme inhibitors
(odds ratio, 0.8; 95% CI, 0.6-1.0) or other agents.
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Table 5. Unweighted Analysis of Treatment With Antihypertensive Medication
and Achieved Blood Pressure by Presence of Elevated Serum Creatinine Level
Among Hypertensive Individuals: NHANES III, 1988-1994*
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Regardless of the number of medications they received, individuals with
an elevated serum creatinine level had a slightly higher mean systolic blood
pressure than individuals with a lower serum creatinine level (significant
before but not after adjustment for age). In contrast, their mean diastolic
blood pressure was slightly, although often not significantly, lower with
48% of individuals prescribed only 1 medication. Individuals prescribed 2
medications had a lower mean blood pressure than individuals prescribed 1
medication, despite the tendency to prescribe more medications to individuals
with more severe underlying hypertension.
The analyses were repeated using different definitions of antihypertensive
medication treatment and different cutoffs for elevated serum creatinine level
to examine the consistency of our results. The proportion of individuals with
an elevated serum creatinine level who were taking antihypertensive medications
for any indication was 66%, somewhat higher than the percentage of these individuals
reporting medical treatment for hypertension (52%). However, the pattern of
the association between elevated serum creatinine level and blood pressure
category as well as medication use was similar.
A sample of 1921 NHANES III participants had a second creatinine measurement
at a mean (SD) of 17.5 (8.0) days after the initial examination. The second
creatinine measurement showed good agreement with the initial creatinine measurement.
The mean (SD) percent difference between the 2 measurements was 0.2% (9.7%).
The percent difference was independent of the time difference between the
visits and the absolute creatinine level. This amount of measurement error
was added to the observed creatinine data in a computer simulation to estimate
its possible impact on prevalence estimates. The prevalence of elevated serum
creatinine level increased by a factor of 1.19 in women and 1.25 in men, suggesting
that the effect of measurement error and short-term physiologic variation
on our estimates of the prevalence of elevated serum creatinine level was
moderate.
COMMENT
Our results show that approximately 5.6 million individuals in the civilian,
noninstitutionalized US population have elevated serum creatinine levels,
25 times the number of prevalent ESRD cases, and 108 times the number of incident
ESRD cases in 1991 (the midpoint of NHANES III). Elevated serum creatinine
level is rare among young and middle-aged individuals with optimal blood pressure
(<1% prevalence) and becomes increasingly more common among individuals
in higher blood pressure categories as well as among individuals using antihypertensive
medications. Most (75%) hypertensive persons with elevated serum creatinine
levels in the US population are treated with antihypertensive medications,
but most are treated suboptimally. These cross-sectional data are consistent
with the hypothesis that poorly controlled hypertension is responsible for
much of the high-burden chronic kidney disease, but the data can only demonstrate
a strong association, not temporal sequence or causation. The largest number
of individuals with an elevated serum creatinine level have blood pressure
in the stage 1 hypertension category. Only half of the treated hypertensive
individuals with an elevated serum creatinine level are receiving more than
1 antihypertensive medication, and only 36% of them meet the blood pressure
guidelines for individuals without target organ damage (<140/90 mm Hg,
also the target blood pressure for all hypertensive individuals since 198816, 18), while only 14% of treated hypertensive
individuals meet the blood pressure guidelines proposed in 199119
for persons with renal disease (<130/85 mm Hg). Given that effective antihypertensive
treatment can slow the progression of renal disease, this finding implies
that improved management of hypertension might have a major impact on stemming
the epidemic of ESRD and cardiovascular disease in chronic renal disease.
Individuals with chronic renal disease have an increased risk of developing
ESRD or death.20-23
End-stage renal disease is a major public health problem in the United States.
Data from the US Renal Data System shows a prevalence of 304 083 treated
ESRD cases (110/100 000) and an incidence of 79 102 cases (28.7/100 000
person years) in 1997.8 Mortality among patients
treated by dialysis is approximately 23% per year, with cardiovascular disease
being the major cause of death. Annual treatment costs for patients treated
with dialysis exceeded $15 billion in 1997.
High blood pressure is an important independent predictor of the development
and progression of chronic renal disease as well as morbidity and mortality
in patients with chronic renal disease.2, 24-25
Prospective studies have shown the relationship between blood pressure and
incidence of renal disease to be positive and continuous throughout the entire
spectrum of blood pressure categories.2, 24, 26
As a result, the JNC-VI guidelines suggest lower target blood pressure goals
for individuals with renal disease (<130/85 mm Hg for individuals without
proteinuria and <125/75 mm Hg for individuals with proteinuria).6 Experience from recent clinical trials (Hypertension
Optimal Treatment [HOT], Antihypertensive and Lipid Lowering to Prevent Heart
Attack [ALLHAT], United Kingdom Prospective Diabetes Study [UKPDS], and Controlled
Onset Verapamil Investigation of Cardiovascular Endpoints [CONVINCE]) has
shown that low blood pressure goals can be achieved with high rates of success.27 More than 90% of the patients in the HOT trial achieved
the diastolic blood pressure goal of 90 mm Hg or lower. The 470 HOT trial
participants with a serum creatinine level of 132.6 µmol/L (1.5 mg/dL)
or higher required more antihypertensive medications than patients with a
lower serum creatinine level (2.8 vs 2.4 medication escalation steps) but
achieved their blood pressure target just as often (71% vs 70%).28
Participants in the African-American Study of Kidney Disease and Hypertension
(AASK) had a glomerular filtration rate of 70 mL/min per 1.73 m2
or lower at baseline and were randomized to a mean arterial pressure lower
than 92 mm Hg or 102 to 107 mm Hg. At entry, 66% had a mean arterial pressure
higher than 107 mm Hg. After 4 months on the assigned treatment, this was
reduced to 27% of the participants assigned to the blood pressure goal of
102 to 107 mm Hg and 11% of the participants assigned to the goal of lower
than 92 mm Hg. These marked improvements in blood pressure control were achieved
in a relatively uniform manner across education and income subgroups.29
The prevalence of elevated serum creatinine level was much higher among
individuals treated for hypertension compared with untreated hypertensive
individuals across all categories of blood pressure. These cross-sectional
data should not be used to argue that antihypertensive treatment does not
slow the progression of renal disease. First, despite similar current blood
pressure levels in treated and untreated individuals, treated individuals
are likely to have a longer duration of high blood pressure as well as a greater
past severity of hypertension, both of which are risk factors for nephrosclerosis.30 Second, antihypertensive medications may decrease
glomerular filtration rate by decreasing systemic and glomerular capillary
pressure and thus increasing serum creatinine levels. Angiotensin-converting
enzyme inhibitors, for example, often increase serum creatinine levels by
up to 20% at the initiation of therapy with greater increases seen among patients
with bilateral renal vascular disease31 and
smaller increases in unselected patients with chronic renal disease.32-34 Third, and most importantly,
a wealth of clinical trial data supports the benefit of effective antihypertensive
therapy in slowing the progression of renal disease.
Blacks have a disproportionately higher incidence of ESRD than whites
overall, especially ESRD due to hypertension.35-38
Our data show that although there are more whites (4.2 million) than blacks
(1.1 million) with elevated serum creatinine levels, blacks have a greater
prevalence of elevated serum creatinine level than whites (5.3% vs 2.9%).
The number of cases with an elevated serum creatinine level in each group
can be compared with the number of incident ESRD cases in 1991 based on the
US Renal Data System.39 This ratio is 1.3 ESRD
cases per 100 individuals with an elevated serum creatinine level for blacks
compared with 0.8 ESRD cases per 100 individuals with an elevated serum creatinine
level for whites. These data suggest that blacks are at an approximately 1.7
times higher risk of an elevated serum creatinine level progressing into ESRD
compared with whites (the ratio is higher if a definition of elevated serum
creatinine level with higher cutoffs for blacks than whites is used). This
observation also raises the question of whether competing causes of death
differ between blacks and whites among patients with elevated serum creatinine
levels.
Most individuals with elevated serum creatinine levels are in older
age groups. While the prevalence of elevated serum creatinine level is associated
with higher blood pressure in this group, 6.1% of older individuals without
hypertension have an elevated serum creatinine level. This represents 18%
of all individuals with elevated serum creatinine levels and emphasizes the
need for interventions other than blood pressure control to slow the progression
of renal disease. It also emphasizes the limitation of screening for renal
disease only among individuals with hypertension.
Use of a single cutoff to define an elevated serum creatinine level
may have limited accuracy in light of age and ethnic differences in serum
creatinine levels. Younger individuals, especially among men and blacks, have
slightly higher serum creatinine levels owing to greater muscle mass. Adjusting
for muscle mass was not possible because of limited availability of data in
NHANES III. Although there is no gold standard to measure the actual specificity
of our definition, it is possible to obtain a lower-limit estimate of specificity
by assuming that none of the individuals with optimal blood pressure without
antihypertensive treatment have renal disease. Only 0.8% of these individuals
have elevated serum creatinine levels, indicating an approximate specificity
of at least 99.2%. The specificity is likely to vary by race and age because
the definition was sex specific, but not race or age specific. The percentages
of untreated individuals with an optimal blood pressure who did not have elevated
serum creatinine levels were 99.1%, 98.8%, and 99.8% among non-Hispanic whites,
non-Hispanic blacks, and Mexican Americans, respectively, and 99.7%, 99.4%,
and 93.7% among patients aged 17 to 39, 40 to 59, and over 60 years, respectively.
Different definitions of elevated serum creatinine level would yield somewhat
different estimates of the number of individuals with an elevated serum creatinine
level in the population. However, the pattern of the association with blood
pressure category and antihypertensive treatment was largely unaffected.
Although a stringent criterion for elevated serum creatinine level was
used overall, a single measurement of serum creatinine level has limitations
in measuring true renal function. First, although serum creatinine level varies
inversely with the level of glomerular filtration rate, it is also affected
by factors other than glomerular filtration rate. In addition to age, sex,
and race, dietary intake of protein (in particular cooked meat) is an independent
determinant of creatinine production. Second, increased tubular secretion
of creatinine causes the rise in serum creatinine level to lag behind the
decline in glomerular filtration rate. Third, numerous studies have shown
that a reduced glomerular filtration rate is not a sensitive indicator of
chronic renal disease. Glomerular adaptations such as increased glomerular
capillary pressure and hypertrophy can increase single nephron glomerular
filtration rate, thereby maintaining a normal glomerular filtration rate despite
a reduction in nephron number.40 Misclassification
is especially likely in the elderly because of the simultaneous age-related
decline in glomerular filtration rate and muscle mass, leading to only minimal
elevation in serum creatinine level despite reduced renal function. Therefore,
misclassification of older individuals is especially likely.
Equations exist to estimate creatinine clearance41
and glomerular filtration rate42 based on serum
creatinine level, but their application requires a number of assumptions,
which are avoided by use of an empirically observed prevalence of elevated
serum creatinine level. Despite the above limitations, studies have shown
that serum creatinine level has a high specificity but low sensitivity for
detecting chronic renal disease43 (thus indicating
the high probability of correctly identifying the presence of disease), but
many cases of chronic renal disease will be missed by applying this and any
other diagnostic criterion based on serum creatinine level alone. Our results,
therefore, should be considered an underestimate of the number of individuals
with impaired renal function, especially among the elderly.
CONCLUSIONS
The burden of chronic renal disease extends far beyond ESRD. There are
25 cases of elevated serum creatinine level for every prevalent ESRD case
and 108 cases of elevated serum creatinine level for every incident ESRD case.
Our results show that chronic renal disease is strongly associated with inadequate
blood pressure control. Most individuals with chronic renal disease are hypertensive
and receive medications for controlling blood pressure. However, most of these
patients seem to be undertreated. The largest number of individuals with an
elevated serum creatinine level had stage 1 blood pressure (140-159 mm Hg
systolic or 90-99 mm Hg diastolic). These national estimates suggest that
there is a great potential for decreasing renal disease incidence and cardiovascular
mortality by optimizing blood pressure treatment in this high-risk population.
AUTHOR INFORMATION
Accepted for publication January 1, 2001.
This study was supported by grant R29-DK48362 (Dr Coresh) from the National
Institutes of Health, Bethesda, Md, and was partially supported by grants
5M01RR00722 (Dr Coresh) and RR00035 from the National Center for Research
Resources, Bethesda.
This work was started by G. Laura Wei as a Master of Health Science
student advised by Josef Coresh, MD, PhD, at the School of Hygiene and Public
Health, John Hopkins University, Baltimore, Md.
Corresponding author: Josef Coresh, MD, PhD, 2024 E Monument St,
Suite 2-600, Baltimore, MD 21205 (e-mail: coresh{at}jhu.edu).
From the Departments of Epidemiology (Drs Coresh and Brancati and Ms
Wei), Biostatistics (Dr Coresh), and Health Policy & Management (Dr Klag),
School of Hygiene and Public Health, and the Department of Medicine, School
of Medicine (Drs Coresh, Brancati, and Klag), Johns Hopkins University, Baltimore,
Md; the Welch Center for Prevention, Epidemiology, and Clinical Research,
Johns Hopkins University, Johns Hopkins Medical Institutions, Baltimore (Drs
Coresh, Brancati, and Klag); the Division of Health Examination Statistics,
National Center for Health Statistics, Centers for Disease Control and Prevention,
Hyattsville, Md (Dr McQuillan); the Department of Medicine, Tufts University
School of Medicine, Division of Nephrology, New England Medical Center Hospital,
Boston, Mass (Dr Levey); and the National Institutes of Health, National Institute
of Diabetes and Digestive and Kidney Diseases, Bethesda, Md (Dr Jones).
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