(Stroke. 1997;28:557-563.)
© 1997 American Heart Association, Inc.
Articles |
Serum Creatinine Concentration and Risk of Cardiovascular Disease
A Possible Marker for Increased Risk of Stroke
From the Department of Primary Care and Population Sciences, Royal Free Hospital School of Medicine, London, UK.
Correspondence to Dr S. Goya Wannamethee, Department of Primary Care and Population Sciences, Royal Free Hospital School of Medicine, Rowland Hill St, London, NW3 2PF, UK.
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Abstract |
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Background and Purpose Elevated serum creatinine has been associated with increased mortality in hypertensive persons, the elderly, and patients with myocardial infarction or stroke in whom cardiovascular disease is the major cause of death. We have examined the relationship between serum creatinine concentration and the risk of major ischemic heart disease and stroke events and all-cause mortality in a general population of middle-aged men.
Methods We present a prospective study of middle-aged men (aged 40 to 59 years) drawn from 24 British towns who have been followed up for an average of 14.75 years. Data on serum creatinine were available for 7690 men in whom there were 287 major stroke events, 967 major ischemic heart disease events, and 1259 deaths from all causes during follow-up.
Results The median serum creatinine concentration was
98 µmol/L (95% range, 76 to 129 µmol/L). Stroke risk was
significantly increased at levels above 116 µmol/L (90th
percentile) even after adjustment for a wide range of cardiovascular
risk factors (relative risk [RR], 1.6; 95% CI, 1.1 to 2.1;
116 µmol/L versus the rest). Risk of a major ischemic
heart disease event was significantly increased at or above 130
µmol/L (97.5 percentile), but this was attenuated after adjustment
(RR, 1.2; 95% CI, 0.8 to 1.7; 130 µmol/L versus the rest).
There was a weak but significant positive association between diastolic
blood pressure and creatinine concentration. However, elevated
creatinine concentration (116 µmol/L) was associated with a
significant increase in stroke in both normotensive and hypertensive
men. All-cause mortality and overall cardiovascular mortality were
significantly increased only above the 97.5 percentile, and no
significant association was seen with cancer or other noncardiovascular
mortality.
Conclusions A high serum creatinine concentration within the normal range is a marker for increased risk of cerebrovascular disease in both normotensive and hypertensive subjects. These findings support the evidence indicating that subtle impairment of renal function is a factor for increased risk of stroke and suggest mechanisms in the pathogenesis of stroke that warrant further investigation.
Key Words: cardiovascular disorders • creatinine • mortality • risk factors
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A number of studies indicate that elevated serum creatinine may be an independent predictor of all-cause and of cardiovascular disease mortality.1 2 3 4 These studies have focused on specific groups, such as hypertensive individuals,1 the elderly,2 patients with recent stroke,3 and survivors of myocardial infarction,4 in all of whom cerebrovascular and coronary heart disease are the major causes of death. In the Hypertension Detection and Follow-up Program study, the 8-year mortality risk increased progressively with increasing concentration of creatinine from low levels. In multivariate analysis, there was a more than twofold increased risk of death (mainly from cardiovascular disease) in subjects with serum creatinine at or above the 97th percentile relative to those with creatinine below this level.1 It has been suggested that serum creatinine acts as a marker for generalized vascular disease. The role of hypertension in determining the serum creatinine level in individuals has been examined in all of these studies but with no firm conclusion as to the primacy of blood pressure in determining the fatal outcome. Furthermore, few studies have addressed specific cardiovascular disease end points in detail, and the prognostic importance of serum creatinine in the incidence of major cerebrovascular or coronary heart disease events in the general population is uncertain. We have therefore examined the relationship between serum creatinine and the subsequent risk of major IHD and stroke (fatal and nonfatal) and all-cause mortality in a prospective population-based study of middle-aged British men. We have focused in particular on the role played by blood pressure and other potential confounders and on possible interactions with blood pressure status.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The British Regional Heart Study is a large prospective study of cardiovascular disease comprising 7735 men aged 40 to 59 years selected from the age-sex registers of one group general practice in each of 24 towns in England, Wales, and Scotland (78% response rate). The criteria for selecting the town, the general practice, and the subjects, as well as the methods of data collection, have been reported.5 The practices selected in each town had a social class distribution representative of men in that town, and the overall social class distribution of the cohort closely resembled that of middle-aged men in Great Britain. In 1978 through 1980, research nurses administered to each man a standard questionnaire that included questions on smoking habits, alcohol intake, physical activity, and medical history. Several physical measurements were made, including height and weight, and blood samples (nonfasting) were taken throughout the day between 8:30 AM and 6:30 PM. Blood samples for biochemical and hematological measurements were drawn into five separate evacuated Vacutainer tubes using a Velcro tourniquet on the upper arm. Serum separation tubes were allowed to stand for 30 minutes and spun for 10 minutes. All biochemical samples were stored vertically at 4°C and dispatched overnight to the Wolfson Research Laboratories, Queen Elizabeth Hospital, Birmingham, UK, where estimations were completed by noon on the following day. Thirteen biochemical measurements including serum creatinine were made using an autoanalyzer (model SMA 12/60) and standard Technicon methods. Serum creatinine was not estimated in 45 men.
Classification methods for smoking status, alcohol consumption, social
class (longest held occupation), and physical activity have been
reported.5 6 7 The men were classified according to their
current smoking status into six groups: those who had never smoked
cigarettes, ex-cigarette smokers, and four groups of current smokers (1
to 19, 20, 21 to 39, and 40 cigarettes per day). Those who had only
ever smoked a pipe and/or cigars were grouped as never smoked.
Ex-cigarette smokers who currently smoked a pipe or cigars were grouped
as ex-smokers. The men were classified into five groups based on weekly
alcohol intake: none, occasional, light, moderate, and
heavy.6 Heavy drinking is defined as drinking more than 6
units (1 UK unit=8 to 10 g alcohol) daily or on most days in the
week. A physical activity score was derived for each man on the basis
of frequency and type of activity, and the men were grouped into six
broad categories on the basis of their total score.7
Obesity was defined as BMI 28 kg/m2, the top fifth of the
distribution.
Blood Pressure
The London School of Hygiene sphygmomanometer (a random zero
device) was used to measure blood pressure twice in succession with the
subject seated and with the arm supported on a cushion. The mean of the
two readings was used in the analysis, and all blood pressure readings
were adjusted for observer variation within each town.8
The men were also asked whether they were receiving regular
antihypertensive treatment. Men with adjusted SBP 160 mm Hg or
adjusted DBP 90 mm Hg or subjects taking regular
antihypertensive treatment were regarded as hypertensive.
Preexisting IHD, Stroke, and Diabetes
The men were asked whether a doctor had ever told them that they
had angina or myocardial infarction (heart attack, coronary
thrombosis), stroke, and a number of other disorders. The WHO (Rose)
chest pain questionnaire9 was administered to all men at
the initial examination, and a three-orthogonal lead ECG was recorded
at rest.
Previous Stroke
Evidence of a previous stroke was determined by the subject's
recall of such a diagnosis being made by a doctor. There were 52 such
men in the study.
Ischemic Heart Disease
The men were separated into three groups according to the
evidence of IHD at screening: (1) no evidence of IHD on WHO chest pain
questionnaire or ECG and no recall of a doctor diagnosis of IHD
(n=5757); (2) men with evidence suggesting IHD short of a definite
myocardial infarction, including those with ECG evidence of possible or
definite myocardial ischemia or possible myocardial infarction
(asymptomatic), those with angina or a possible myocardial infarction
on WHO (Rose) chest pain questionnaire, or with recall of a doctor
diagnosis of angina (symptomatic) (n=1508); and (3) men with a previous
definite myocardial infarction on ECG or who recalled a doctor
diagnosis of a myocardial infarction ("heart attack")
(n=425).
The classification of men with preexisting IHD consists of groups 2 and 3 combined.
Diabetes
Diabetes mellitus prevalence was based on recall of a doctor
diagnosis of the condition (n=121).
Left Ventricular Hypertrophy
The diagnosis of LVH was based on R wave amplitude, ST-T
abnormalities, and abnormal QRS vector orientation. A scoring system
was used,10 with 6 points representing definite
hypertrophy and 4 to 5 points representing possible or probable
hypertrophy. Definite LVH equates with Minnesota code 3-1, and possible
or probable equates with code 3-3. Men with LVH included both definite
and possible (4 to 6 points).
Follow-up
All men were followed up for all-cause mortality and for
cardiovascular morbidity.11 All cardiovascular events
occurring in the period through December 1993 are included in the
study, for an average follow-up of 14.75 years (range, 13.5 to 16.0
years), and follow-up has been achieved for 99% of the cohort.
Information on death was collected through the established
"tagging" procedures provided by the National Health Service
registers in Southport (England and Wales) and Edinburgh (Scotland).
Nonfatal stroke events were those that produced a neurological deficit
that was present for more than 24 hours. Evidence regarding such
episodes was obtained by reports from general practitioners, by
semiannual reviews of the patients' notes through to the end of the
study period, and from personal questionnaires to surviving subjects at
the 5th year and 12th year after initial examination. Fatal stroke
episodes were those coded on the death certificate as ICD 430 to 438.
All death certificates in which it appeared that coding to stroke was
not appropriate, or in which stroke was not the attributed code when it
might have been, were explored by correspondence with the certifying
doctor and the hospital concerned. No information on the type of stroke
was available.
A nonfatal myocardial infarction was diagnosed according to WHO criteria, which included any report of myocardial infarction accompanied by at least two of the following: a history of severe chest pain, ECG evidence of myocardial infarction, and cardiac enzyme changes associated with myocardial infarction. Fatal events were defined as death from IHD (ICD, 9th revision, codes 410 to 414) as the underlying code.
Statistical Methods
The Cox proportional hazards model was used to assess the
independent contributions of serum creatinine to the risk of stroke and
coronary heart disease and to obtain the RRs adjusted for age and the
other risk factors.12 Age, DBP, and BMI were fitted as
continuous variables. Smoking (six levels), physical activity (six
levels), diabetes (yes/no), preexisting stroke (yes/no), use of
antihypertensive treatment (yes/no), and preexisting IHD on
questionnaire/ECG (three levels) were fitted as categorical variables.
Direct standardization was used to obtain age-adjusted rates per 1000
person-years using the study population as the standard.
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Results |
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Data on serum creatinine were available for 7690 men. The median was 98 µmol/L (95% range, 76 to 129 µmol/L). Only 27 men had levels above 150 µmol/L (1.7 mg), a level generally regarded as hypercreatinemia.
Serum Creatinine and Risk of Stroke Events
During the mean follow-up period of 14.8 years in the 7690 men
with data on serum creatinine, there were 287 major stroke cases (73
fatal and 214 nonfatal). The men were initially divided into
approximate equal fifths of the ranked distribution of serum creatinine
concentration of <88 (n=1583), 88 to 94 (n=1446), 95 to 100 (n=1627),
101 to 108 (n=1512), and 109 µmol/L (n=1522). Because of the
particular interest in those with high serum creatinine1
and to separate those above the normal range, we have further separated
those in the top fifth into three groups at percentile points
representing approximately 80%, 90%, and 97.5% of the total
distribution (109 to 115 µmol/L, n=720; 116 to 129
µmol/L, n=622; and 130 µmol/L, n=180). Thus, seven groups
are used in Fig 1
to show the age-adjusted stroke rate
per 1000 person-years. In men with levels <116 µmol/L (1st
through 9th decile), there was little difference in age-adjusted stroke
rates (range, 2.2 to 2.9 cases per 1000 person-years). Stroke risk was
significantly increased at levels of 116 to 129 µmol/L (3.7 per
1000 person-years) and rose sharply to 7.5 per 1000 person-years in the
top 2.5% of the population. The age-adjusted RRs and 95% CIs in men
with levels 116-129 and 130 µmol/L compared with all those
with levels <116 µmol/L were 1.5 (1.1 to 2.1) and 3.0 (1.9 to
4.7), respectively. In subsequent analyses, we have focused on the risk
of stroke in all men with levels 116 µmol/L (upper decile of
the serum creatinine distribution) relative to the rest of the
distribution.
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Serum Creatinine and Risk of Major IHD Events
During the follow-up period, there were 967 cases of major IHD
events. Fig 2 shows the age-adjusted rate per 1000
person-years for the seven groups. Risk of major IHD events increased
slightly at the 90th percentile (116 µmol/L) and was only
significantly increased in the top 2.5% of the men (130
µmol/L). The age-adjusted RRs and 95% CIs in men with levels 116-129
and 130 µmol/L relative to those with levels <116
µmol/L were 1.1 (0.9 to 1.3) and 1.5 (1.1 to 2.1), respectively.
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Serum Creatinine and Cardiovascular Risk Factors
Table 1 shows the levels of established risk
factors for cardiovascular disease in men in the top decile and in the
rest of the men. Men with elevated creatinine were significantly older
and heavier, were more likely to have hypertension (SBP 160, DBP
90 mm Hg, or taking antihypertensive treatment), had higher
prevalence of preexisting IHD (in particular, definite myocardial
infarction), and had a higher prevalence of previous stroke. They had
somewhat higher prevalence of LVH and diabetes, slightly higher mean
blood glucose levels, and lower levels of physical activity, but these
differences were not significant. They showed significantly lower rates
of current smoking but higher rates of ex-smoking status. No
association was seen with heavy drinking or social class.
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Blood Pressure and Serum Creatinine
Men receiving antihypertensive treatment (n=375) showed
significantly higher mean levels of serum creatinine than men not being
treated (106.7 versus 97.5 µmol/L). The relationship between SBP
and DBP and creatinine was examined separately in men with and without
antihypertensive treatment (Table 2). In men not being
treated, a significant positive association was seen with DBP and with
SBP (P<.0001), which was attenuated on adjustment for age
and BMI, although the relationship with DBP remained significant
(P=.004). In men with treatment, no significant association
was seen between DBP or SBP and creatinine, although men with DBP
110 mm Hg had somewhat higher mean creatinine than those with
blood pressure levels <110 mm Hg.
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Adjustment for Confounders
Stroke
We have examined the relationship between serum creatinine and
major stroke events, adjusting in succession for potential risk factors
for stroke that have been shown to be associated with creatinine. Age
adjustment alone produced an RR of stroke in the 10th decile
(116 µmol/L) relative to the 1st through 9th deciles combined
RR of 1.8 (95% CI, 1.3 to 2.4). Additional adjustment for BMI,
smoking, DBP, preexisting IHD, and use of antihypertensive drugs, as
well as diabetes and physical activity, reduced the risk slightly (RR,
1.6; 95% CI, 1.1 to 2.1), and further adjustment for LVH made no
difference. Exclusion of the small number of men with previous stroke
(n=52) did not alter the findings.
Ischemic Heart Disease
The significantly increased age-adjusted risk seen for IHD
in the top 2.5% (130 µmol) was attenuated after adjustment
for the potential confounders and was no longer statistically
significant (RR, 1.2; 95% CI, 0.8 to 1.7).
Age, Preexisting IHD, and Risk of Stroke
The relationship between elevated creatinine (top decile) and risk
of stroke was seen within all age groups (<50, 50 to 54, and 55 to 59
years), although it was more marked in the older age groups. The fully
adjusted RRs (95% CI) (top decile versus the rest) were 1.3 (0.6 to
2.7), 1.9 (1.1 to 3.3), and 1.6 (1.0 to 2.5) for the three age groups,
respectively. The increased risk of stroke in the upper decile of the
creatinine distribution was more marked in men with preexisting IHD.
The fully adjusted RRs (95% CI) were 1.2 (0.7 to 2.0) and 2.0 (1.3 to
2.9) in men with (n=1933, 110 cases) and without (n=5757, 177 cases)
preexisting IHD, respectively, but a test for interaction was not
significant (P=.2).
Creatinine, Hypertension, and Risk of Stroke
Because of the strong association between hypertension and stroke
and the association seen between blood pressure and serum creatinine,
and to assess the specific effects of elevated creatinine in
hypertensive persons, we have examined the relationship between
creatinine and stroke separately in normotensive and hypertensive
subjects (DBP 90 mm Hg or SBP 160 mm Hg or
antihypertensive treatment). Elevated creatinine (116 µmol/L)
was present in 8.6% of normotensives and in 13.8% of hypertensives
(test for difference, P<.001). In both normotensive and
hypertensive subjects, elevated creatinine was associated with a
significant increase in risk of stroke even after adjustment for the
potential confounders, including DBP and LVH. In normotensive subjects,
the RR was 1.7 (95% CI, 1.0 to 2.9; P=.04); in
hypertensives, those with creatinine levels 116 µmol/L showed
an RR of 1.5 (95% CI, 1.1 to 2.5; P=.03) compared with
hypertensives with levels <116 µmol/L.
Table 3 shows the combined effect of hypertension and
elevated creatinine on risk of stroke with use of normotensive subjects
with creatinine levels <116 µmol/L as the reference group after
full adjustment. In hypertensive men with creatinine levels <116
µmol/L, risk of stroke was increased 2.6-fold, and this increased to
over fourfold in men with elevated creatinine. Exclusion of men taking
antihypertensive treatment did not make a major difference to the
increased risk seen in hypertensive subjects with elevated creatinine
(Table 3).
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Antihypertensive Treatment
In the 375 men receiving antihypertensive treatment, in whom there
were 42 stroke cases, the age-adjusted stroke rate was significantly
higher than in hypertensive men not taking treatment and in
normotensive men (7.6 per 1000 person-years versus 4.0 and 1.7 per 1000
person-years, respectively). Elevated creatinine (116 µmol/L)
was present in 29% (n=109) of these 375 men and was associated with a
higher rate of stroke compared with men receiving antihypertensive
treatment with levels <116 µmol/L (age-adjusted rate 9.6 per
1000 person-years versus 6.7 per 1000 person-years; RR, 1.4; 95% CI,
0.8 to 2.6), although the difference was not statistically significant,
possibly because of small numbers. Adjustment for potential confounders
made little difference to the increased risk seen (RR, 1.5; 95% CI,
0.8 to 2.9).
Other Renal Function
Blood urea was significantly correlated with serum creatinine
(r=.4), and we therefore examined the relationship between
blood urea and risk of stroke. An association similar to but slightly
weaker than that observed with creatinine was seen, with risk of stroke
significantly increased in the top decile of the ranked distribution of
blood urea even after adjustment for potential confounders (fully
adjusted RR, 1.5; 95% CI, 1.1 to 2.1). However, the positive
association seen between the top decile of serum creatinine and risk of
stroke persisted after adjustment for blood urea (RR, 1.5; 95% CI, 1.1
to 2.0). The positive association with blood urea was slightly
attenuated and of marginal significance (P=.06) after
adjustment for serum creatinine (RR, 1.4; 95% CI, 1.0 to 1.9).
Serum Creatinine and All-Cause Mortality
The relationship between elevated serum creatinine and all-cause
mortality were examined initially in the seven original creatinine
groups shown in Figs 1
and 2. There was little difference in all-cause,
cardiovascular, and noncardiovascular mortality in men in the five
groups with levels <116 µmol/L (1st through 9th decile), and
these men have been combined so that the three groups presented in
Table 4 represent the 1st through 9th deciles and the
90th and 97.5th percentiles of the ranked distribution. For all causes
and for cardiovascular disease, age-adjusted mortality increased
slightly at the 90th percentile and was significantly raised in the top
2.5% of the men (130 µmol/L) (Table 4). No association was
seen with cancer mortality. Other noncardiovascular mortality was
highest in the top 2.5%, but the increase was not significant. The
increased risks for total and cardiovascular mortality in the top 2.5%
(130 µmol/L) remained significant even after adjustment for
the potential confounders.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In this study of middle-aged men, elevated serum creatinine concentration (
116 µmol/L) was associated with a significantly
increased risk of all major stroke events after adjustment for a number
of confounding factors, including SBP and antihypertensive treatment.
The increased risk was seen in the top decile of the distribution in
which the majority of values would be considered to be within the
normal range. There was little association between serum creatinine and
risk of major IHD events after adjustment. The risk of all-cause
mortality was increased only in the upper 2.5% of the distribution
(130 µmol/L). Deaths from cancer and other noncardiovascular
mortality were not associated with the creatinine concentration.
Previous Studies
Our findings are similar to those of the Hypertension Detection
and Follow-up Program, in which a significantly increased risk of
all-cause, cardiovascular, cerebrovascular, and noncardiovascular
mortality was observed in the top 3% of the creatinine distribution;
no association was seen with cancer mortality.1 The
authors suggested that the "elevated creatinine represents the
influence of generalized vascular disease in the kidney." This was
also suggested in a prospective study in New Zealand, which found serum
creatinine to be a strong and independent predictor of survival after
stroke in the elderly.3 However, in a Danish study of 223
elderly subjects without diabetes or recent stroke, serum creatinine
was also an independent predictor of mortality, suggesting that serum
creatinine predicts survival in elderly people irrespective of the
presence or absence of stroke.2 In a study of survivors of
myocardial infarction, serum creatinine was independently associated
with all-cause and coronary heart disease mortality.4 No
significant association was found between serum creatinine and the
severity of coronary heart disease or peripheral vascular disease,
suggesting that a higher creatinine level was not simply a
manifestation of generalized atherosclerosis. Given the weak
association between creatinine and risk of IHD in the present study,
generalized vascular disease is unlikely to explain the association
between elevated creatinine and stroke. Furthermore, in the present
study the increased risk of stroke was of greater magnitude in men with
no evidence of preexisting IHD at screening than in those with
preexisting IHD.
The increased risk was seen even after adjustment for doctor diagnosis of diabetes at screening. It is unlikely that subclinical diabetes or glucose intolerance could account for the increased risk, since serum creatinine was only weakly related to blood glucose levels, and hyperglycemia without a doctor diagnosis of diabetes is not an independent risk factor for stroke in our study (S.G.W. and I.J.P., unpublished data, 1996).
Blood Pressure and Creatinine
Hypertension is clearly an important potential confounder in the
association between creatinine and risk of stroke. An association
between blood pressure and serum creatinine has been observed both in
hypertensive persons and the general population. In the Multiple Risk
Factor Intervention Trial cohort of 5524 men with mild to moderate
hypertension (baseline DBP 90 mm Hg), no relationship was seen
between blood pressure at baseline and serum creatinine levels, but
those with higher blood pressures showed the greatest increase in serum
creatinine over a 6-year follow-up. Treatment resulting in reduction of
DBP was associated with an improvement in renal
function.13 The suggestion that current blood pressure may
indicate the long-term likelihood of increasing levels of creatinine is
supported by a study of 1399 middle-aged subjects from a
community-based cohort.14 In this study, a graded and
significant association was found between serum creatinine levels and
blood pressures taken 12 to 15 years previously but not with current
blood pressures. In a study of 897 subjects followed up for 9
years,15 subjects with essential hypertension had a
significantly greater rate of decline in renal function compared with
normotensive subjects. These observations suggest that blood pressure
elevations below the usual levels at which definite hypertension is
diagnosed may induce early renal damage.
In the present study, a weak but significant association was seen between DBP but not SBP and serum creatinine after adjustment for age and BMI. However, the relationship between serum creatinine and risk of stroke appeared to be independent of current blood pressure. Although blood pressure was measured on a single occasion, it is unlikely that the increased risk associated with elevated creatinine reflected higher average blood pressures, since blood pressure at screening examination is almost invariably higher than usual. In addition, the increased risk was seen in both normotensive and hypertensive subjects, and there was no evidence of an interaction between current blood pressure and serum creatinine.
Aside from confounding due to hypertension and vascular disease, an alternative explanation for the association between "high normal" creatinine and risk of stroke merits consideration. It is possible that in the upper decile of the creatinine distribution there are individuals who are susceptible to hypertension-associated renal impairment at relatively low blood pressure levels and that such individuals are also more susceptible to the cerebrovascular effects of raised blood pressure. This possibility is supported by the observation that at similar blood pressure levels, black Americans are at greater risk of both renal disease and stroke than white Americans.16
Clinical Implications
These findings have implications for further research and clinical
practice. In particular, they add to the growing evidence that subtle
impairment of renal function is a potent marker of increased risk of
cardiovascular disease.17 18 Serum creatinine in
particular would appear to be a sensitive indicator of the long-term
effects of raised blood pressure, not only on the kidney but on end
organs. In the present study, about 14% of the hypertensive subjects
had serum creatinine levels 116 µmol/L, the level at which a
significantly increased risk of stroke was observed. Clearly, a single
serum creatinine measurement provides an insensitive marker of early
renal impairment, and it is likely that repeated measurements and the
use of additional indices of renal function, such as reciprocal
creatinine slopes,13 urinary albumin excretion
rate,17 and estimation of glomerular filtration rate, will
be of value in identifying hypertensive persons at particularly high
risk of cardiovascular disease.
Conclusion
In this study of middle-aged British men followed up for almost 15
years, a baseline serum creatinine level in the upper decile of the
distribution (116 µmol/L) was associated with a significantly
increased risk of major stroke events in both normotensive and
hypertensive individuals. No independent association was seen with
major IHD events. An elevated serum creatinine concentration may be a
marker for subtle renal damage consequent to raised blood pressure and
may constitute an additional risk factor for cerebrovascular disease.
Alternatively, some individuals may have increased susceptibility to
hypertension-associated renal impairment and to the cerebrovascular
effects of raised blood pressure. Whatever the mechanism, subtle renal
impairment of renal function appears to be a marker of increased risk
of cerebrovascular disease in both normotensive and hypertensive
subjects.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The British Regional Heart Study is a British Heart Foundation Research Group and receives support from The Stroke Association and the Department of Health. Dr Wannamethee is a British Heart Foundation Research Fellow.
Received November 4, 1996; revision received December 10, 1996; accepted December 10, 1996.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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1. Shulman NB, Ford CE, Hall WD, Blaufox MD, Simon D, Langford HG, Schneider KA. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function: results from the Hypertension Detection and Follow-up Program. Hypertension. 1989;13(suppl I):I-80-I-93.
2. Damsgaard EM, Froland A, Jorgensen OD, Mogensen CE. Microalbuminuria as predictor of increased mortality in elderly people. BMJ. 1990;300:297-300.
3. Friedman PJ. Serum creatinine: an independent predictor of survival after stroke. J Intern Med. 1991;229:175-179. [Medline] [Order article via Infotrieve]
4. Matts JP, Karnegis JN, Campos CT, Fitch LL, Johnson JW, Buchwald H, and Posch Group. Serum creatinine as an independent predictor of coronary heart disease mortality in normotensive survivors of myocardial infarction. J Fam Pract. 1993;36:497-503. [Medline] [Order article via Infotrieve]
5. Shaper AG, Pocock SJ, Walker M, Cohen NM, Wale CJ, Thomson AG. British Regional Heart Study: cardiovascular risk factors in middle-aged men in 24 towns. Br Med J. 1981;283:179-186.
6. Shaper AG, Wannamethee G, Walker M. Alcohol and mortality in British men: explaining the U-shaped curve. Lancet. 1988;2:1266-1273.
7.
Shaper AG, Wannamethee G. Physical activity and
ischemic heart disease in middle-aged British men.
Br Heart J. 1991;66:384-394.
8. Bruce NG, Shaper AG, Walker M, Wannamethee G. Observer bias in blood pressure studies. J Hypertens. 1988;6:375-380. [Medline] [Order article via Infotrieve]
9.
Cook DG, Shaper AG, MacFarlane PW. Using the
WHO (Rose) angina questionnaire in cardiovascular epidemiological
studies. Int J Epidemiol. 1989;18:607-613.
10.
MacFarlane PW, Melville DI, Horton MR, Bailey
JJ. Comparative evaluation of the IBM (12-lead) and the Royal
Infirmary (orthogonal 3-lead) ECG computer programs.
Circulation. 1981;63:354-359.
11. Walker M, Shaper AG. Follow-up of subjects in prospective studies in general practice. J R Coll Gen Pract. 1984;34:365-370. [Medline] [Order article via Infotrieve]
12. Cox DR. Regression models and life tables. J R Stat Soc B. 1972;34:187-220.
13.
Walker G, Neaton J, Cutler JA, Neuwirth R, Cohen
JD. Renal function change in hypertensive members of the
Multiple Risk Factor Intervention Trial: racial and treatment
effects. JAMA. 1992;268:3085-3091.
14.
Perneger TV, Nieto FJ, Whelton PK, Klag MJ, Comstock
GW, Szklo M. A prospective study of blood pressure and serum
creatinine: results from the `Clue' and the ARIC study.
JAMA. 1993;269:488-493.
15.
Rosansky SJ, Hoover DR, Kig L, Gibson J. The
association of blood pressure levels and change in renal function in
hypertensive and non-hypertensive subjects. Arch Intern
Med. 1990;150:2073-2076.
16. Neaton J, Wentworth D, Sherwin R, Kittner S, Kuller L, Stamler J. Comparison of 10-year coronary and cerebrovascular disease mortality rates by hypertensive status for black and non-black men screened in the Multiple Risk Factor Intervention Trial (MRFIT). Circulation. 1989;80(suppl II):II-300. Abstract.
17. Rambausek M, Fliser D, Ritz E. Albuminuria of hypertensive patients. Clin Nephrol. 1992;38(suppl 1):S40-S45.
18. Yudkin JS, Forrest RD, Jackson CA. Microalbuminuria as a predictor of vascular disease in non-diabetic subjects. Lancet. 1988;2:530-533.[Medline] [Order article via Infotrieve]
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|
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|
|
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|
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|
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|
|
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|
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|
|
|
|
 |
|
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|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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