Download Blood pressure variability as an adverse prognostic risk factor in end

Nephrol Dial Transplant (1999) 14: 1976–1981
Nephrology
Dialysis
Transplantation
Original Article
Blood pressure variability as an adverse prognostic risk factor in
end-stage renal disease
Masahiko Tozawa1, Kunitoshi Iseki2, Shinichiro Yoshi3 and Koshiro Fukiyama1
1Third Department of Internal Medicine, and 2Dialysis Unit, University of The Ryukyus, 3Okinawa Dai-ichi Hospital,
Okinawa, Japan
Abstract
Background. Prospective and case-control studies
show that blood-pressure variability is an independent
risk factor for severe organ damage and cardiovascular
events in hypertensives. We prospectively studied the
association between systolic blood pressure variability
and cardiovascular mortality and mortality from all
causes in end-stage renal disease patients.
Methods and results. The subjects were 144 patients
(86 men, 58 women; mean age±SD, 52±13 years)
who underwent dialysis in the same dialysis centre and
were examined for blood-pressure variability. The
study period was 38 months beginning in January
1995, during which six cardiovascular and seven noncardiovascular fatalities occurred. Coefficient of variation in systolic blood pressure in 1994, as an indicator
of systolic blood pressure variability, ranged from 7.8
to 14.6%. Cumulative incidence of death from all
causes was related to coefficient of variation in systolic
blood pressure. The difference between the maximum
and minimum systolic blood pressure (DSBP) in
1994 ranged from 44 to 146 mmHg (mean±SD,
78±13 mmHg) and correlated significantly with
coefficient of variation in systolic blood pressure (r=
0.65, P<0.0001). Cox regression analysis was used to
identify the independent predictors for mortality. The
hazard ratio for death from all causes increased 1.63
times per 1% increase in coefficient of variation in
systolic blood pressure (hazard ratio; 95% confidence
interval: 1.63; 1.05–2.53) and 1.03 times per 1 mmHg
increase in DSBP (1.08; 1.03–1.14).
Conclusion. These results suggest that systolic blood
pressure variability may be a significant prognostic
factor in end-stage renal disease.
Key words: blood pressure; haemodialysis; kidney; risk
factor; variability
Correspondence and offprint requests to: Masahiko Tozawa MD,
Third Department of Internal Medicine, University of The Ryukyus,
207 Uehara, Nishihara-cho, Okinawa 903–0215, Japan.
Introduction
The 1-year mortality rate for patients on dialysis in
Okinawa, Japan between 1971 and 1990 was 11.6%,
which was higher than that for the general population
(0.45%). Cardiovascular and cerebrovascular diseases
accounted for 45.1% of dialysis patient deaths [1].
Recent work suggest that blood pressure variability is
a risk factor for cardiovascular complications in essential hypertension [2], and hypertension in the elderly
[3] and a risk factor for complications in pregnant
women [4]. The relation between blood pressure variability and prognosis of dialysis patients, however, has
not been clarified. This study prospectively examines
the association between systolic blood pressure variability and fatal events in patients with end-stage renal
disease ( ESRD).
Subjects and methods
Subjects
At the start of 1995, 144 patients who were undergoing
regular dialysis three times per week in a single dialysis unit
of Okinawa, Japan were selected. The subjects were 86 men
(60%) and 58 women (40%) with a mean age of 52±13 years
(range 22–83). This dialysis unit is one of those included in
the Okinawa Dialysis Study (OKIDS) [1]. Some patients
received dialysis in the morning and others received it in the
evening; however, each patient always underwent dialysis in
the same manner at the same time (morning or evening).
The patients underwent dialysis three times a week in 4-h
sessions. Haemodialysis was performed with a cellulose membrane (surface area 1.0–2.0 m2) and a dialysate containing
140 mEq/l sodium, 100 mg/dl glucose, 30 mEq/l bicarbonate,
and 8 mEq/l acetate. During the follow-up period, the
regimen was changed when a patient suffered from heart
failure, pulmonary oedema or insufficient dialysis. The
number of these cases were small and were usually associated
with the end of life. The coefficient of variation in systolic
blood pressure was calculated from complete patient records
of 1994 (January to December) and all patients selected had
been introduced to chronic haemodialysis therapy by the end
of 1993.
Some patients were given antihypertensive medicines. The
© 1999 European Renal Association–European Dialysis and Transplant Association
BP Variability and prognosis of ESRD
time of their administration varied from patient to patient
and several types of drug were used over the study period in
different patients; however, the patients were encouraged to
take their medicine at a set recommended time every day.
Patients in this cross-sectional study were evaluated from
1 January 1995 to 28 February 1998 (38 months). We
reviewed all medical records and registered the cases in the
OKIDS. Baseline demographic data other than blood pressure were obtained in January 1994.
Systolic blood pressure variability
Immediately before each routine haemodialysis session, blood
pressure was taken in the right or left arm with the patient
assuming the supine position 5 min prior to measurement.
These reading were performed by trained nurses or paramedical staff using a standard mercury sphygmomanometer. We
previously verified the correlation between a single BP measurement and the 1-month average BP in the dialysis unit;
the coefficient of correlation was 0.81 for one-point SBP and
1-month average SBP and 0.72 for 1-point DBP and 1month average DBP [5]. We used the coefficient of variation
(CV: standard deviation/mean×100%) in systolic blood pressure as an indicator of systolic blood pressure variability.
Coefficients of variation in SBP measured before the dialysis
session were analysed from complete 1994 records which
included 156 records per person. The difference between the
maximum and minimum systolic blood pressure in 1994
(DSBP) was calculated in each patient and also used as an
index of systolic-blood-pressure variability.
Risk factors for vascular disease
Diabetes mellitus defined in one of our previous reports [6 ].
Total cholesterol and other biochemical data were determined
in January 1994.
Stroke events
Newly developed cerebrovascular disease was diagnosed by
both clinical symptoms and brain CT scan. Brain CT scan
was performed in all patients who were at risk for stroke.
Causes of death
Cause of death was confirmed from medical records.
Classification of cause of death in dialysis patients was
defined previously [7]. In this paper, we modified this classification as shown in Table 1.
Statistical analysis
Descriptive statistics are reported as frequency and percent
for categorical data and as mean and SD or range for
continuous data. Percentages were compared by x2 test.
Student’s t-test was used to compare continuous variables.
Cumulative incidence curves were compared with the logrank test. Cox regression analysis was used to evaluate the
significance of risk factors for mortality due to cardiovascular
events and to all causes. Significant risk factors for the model
were chosen from a set of variables that included a coefficient
of variation in systolic blood pressure, gender, age, smoking,
diabetes, duration of haemodialysis, antihypertensive medication, systolic blood pressure, diastolic blood pressure, body
weight gain between dialysis sessions, total cholesterol, serum
1977
Table 1. Causes of death in 13 patients during the follow-up
period (1 January, 1995 to 28 February, 1998)
Cardiovascular
Stroke
Cerebral haemorrhage
Cerebral infarction
Myocardial infarction
Congestive heart failure
Sudden death
Withdrawal from dialysis
Infection
Other
Total
Smaller SBPCV
range 7.8–10.1
n=72
Larger SBPCV
range 10.2–14.6
n=72
1
0
0
0
0
1
0
1
3
1
0
0
3
1
2
1
2
10
SBPCV: coefficient of variation in systolic blood pressure.
albumin, and serum creatinine. Hazard ratio and 95% confidence interval are reported. Statistical test results having a
probability of <0.05 were considered statistically significant.
Results
The mean duration of follow-up was 35.2±8.1 months.
Mean duration of haemodialysis was 87.5±60.0
months. Twenty-five (17%) patients were diabetic.
Forty-five patients (32%) had a history of smoking
(current or past) and 36 patients (26%) had a history
of moderate to excessive alcohol consumption (current
or past). Mean systolic and diastolic pressures
were 144±15 mmHg and 77±7 mmHg respectively.
Mean cholesterol concentration was 174±41 mg/dl.
Mean albumin and creatinine concentrations were
3.8±0.3 g/dl and 14.1±2.9 mg/dl respectively. The
coefficient of variation in systolic blood pressure, the
mean was 10.2±1.5%, median was 10.1%, and range
was 7.8–14.6%. The demographic data for patients in
each half of the coefficient of variation in systolic
blood pressure range are shown in Table 2. We subdivided the study population into two equal subgroups
on either side of the median coefficient of variation in
systolic blood pressure value. The demographic data
of the two groups were compared univariately ( Table
2) and non-parametrically ( Figure 1).
No significant differences in the prevalence of antihypertensive medication and erythropoietin therapy were
found between the groups ( Table 2). In addition, there
was no difference between the two groups with respect
to the types of antihypertensive medication used
( Table 3).
Systolic blood pressure variability and clinical outcomes
Three (2%) of the 144 patients underwent renal transplantation during the follow-up period. By Cox
hazards model, the hazard ratio can be analysed even
when subjects are withdrawn for various reasons
during the course of the study [8]. Therefore, we
1978
M. Tozawa et al.
Table 2. Demographic and clinical characteristics of patients divided into two groups based on the coefficient of variation in systolic
blood pressure
Smaller SBPCV
9.0% (7.8–10.1%)a
n=72
Age (years)
Female (%)
Duration of dialysis (months)
Causes of renal failure (%)
Chronic glomerulonephritis
Diabetes mellitus
Polycystic kidney disease
Systemic lupus erythematosus
Nephrosclerosis
Miscellaneous
Smoker (%)
Alcohol consumer (%)
Antihypertensive medication (%)
Erythropoietin therapy (%)
Body mass index (kg/m2)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
DBW (kg)
Total cholesterol (mg/dl )
Albumin (g/dl )
Creatinine (mg/dl )
49±12b
32
93±61
81
10
0
3
3
3
39
26
67
71
22±3
146±12
78±6
2.1±0.7
172±44
3.8±0.2
14.6±2.8
Larger SBPCV
11.1% (10.2–14.6%)a
n=72
P
55±13
49
82±59
0.013
0.061
0.291
62
25
3
0
4
6
25
26
63
78
22±4
142±17
75±8
2.0±0.7
177±38
3.7±0.3
13.4±2.7
0.016
0.028
0.476
0.476
0.999
0.677
0.082
–
0.727
0.445
0.827
0.101
0.023
0.198
0.524
0.106
0.001
aValues are median (range).
bMean±SD.
SBPCV: coefficient of variation in systolic blood pressure.
DBW: body-weight gain between dialysis sessions.
The coefficient of variation in systolic blood pressure was calculated from 156 records per person in 1994.
Fig 1. Cumulative incidence of cardiovascular death ( left panel ) and death from all causes (right panel ) during the follow-up period for
patients in the two SBPCV groups: lower half of the range and upper half of the range. The follow-up period was from 1 January 1995 to
28 February 1998.
included the patients’ data when analysing the hazard
ratio. Of the 144 patients, 13 (9%) died during the
follow-up period. Causes of mortality in these patients
are shown in Table 1 (6 cardiovascular and 7 noncardiovascular deaths occurred ). None of the patients
suffered from myocardial infarction during the followup period. Patients in the group with the greater
coefficient of variation in systolic blood pressure were
more likely to develop a cardiovascular fatal event (5
of 72, 7%) than patients in the first half of the range
(1 of 72, 1%; P=0.211). Cox regression analysis failed
to show that coefficient of variation in systolic blood
pressure is a significant independent predictor for
cardiovascular mortality (adjusted hazard ratio; 95%
confidence interval: 1.78; 0.94–3.37), but revealed that
it is an independent predictor for mortality from all
causes (1.63; 1.05–2.53) ( Table 4).
DSBP ranged from 44 to 146 mmHg (mean±SD,
78±13 mmHg) and correlated significantly with
coefficient of variation in systolic blood pressure (see
Figure 2). One outlier in DSBP was identified statistically by Grubbs–Smirnov test. We excluded the patient’s
data when analysing the hazard ratio of DSBP. Cox
regression analysis failed to show that DSBP is a
BP Variability and prognosis of ESRD
1979
Table 3. Types of antihypertensive medications used by the patients
Calcium-channel blockers
Beta blockers
ACE inhibitors
Centrally acting drugs
Alpha blockers
Smaller SBPCV range 7.8–10.1%
n=72
Larger SBPCV range 10.2–14.6%
n=72
P
38(53)a
22 (31)
6 (8)
3 (4)
2 (3)
35 (49)
22 (31)
10 (14)
1 (1)
0 (0)
0.738
—
0.426
0.612
0.476
aNumbers of patients (percentage) are shown.
SBPCV: coefficient of variation in systolic blood pressure.
Table 4. Cox regression analysis of cardiovascular mortality and mortality from all causes
Parameter
Cardiovascular mortality
SBPCV (%)
D SBP (mmHg)
Mortality from all causes
SBPCV (%)
D SBP (mmHg)
Crude hazard ratio
(95% CI )
Adjusted hazard ratioa
(95% CI )
1.93 (1.16–3.21)
1.10 (1.04–1.16)
1.78 (0.94–3.37)
1.75 (0.82–3.73)
1.70 (1.20–2.41)
1.07 (1.03–1.11)
1.63 (1.05–2.53)
1.08 (1.03–1.14)
aAdjustments were made for age, gender, duration of dialysis, diabetes, smoking habit, antihypertensive medication, systolic blood pressure,
diastolic blood pressure, body weight gain between dialysis sessions, total cholesterol, serum albumin, and serum creatinine.
CI, confidence interval; SBPCV, coefficient of variation in systolic blood pressure, DSBP, the difference between the maximum and minimum
systolic blood pressure in 1994.
diabetes, smoking, blood pressure, and cholesterol,
which were risk factors for cardiovascular disease, and
albumin, which has been shown to be a risk factor for
death in patients with ESRD [9–12]. Other clinical
factors such as duration of haemodialysis and antihypertensive medication used were also not significant.
The cumulative incidence of cardiovascular death in
the patients with the higher range of coefficient of
variation in systolic blood pressure was greater than
that for patients with the lower range, but the difference
was not significant (P=0.092, see Figure 1, left panel ).
The cumulative incidence of death from all causes for
patients in the larger coefficient of variation in systolic
blood pressure group was significantly higher than that
for patients in the smaller coefficient of variation in
systolic blood pressure group (P=0.039, see Figure 1,
right panel ).
Fig 2. Correlation between the difference between minimum and
maximum systolic blood pressure in 1994 (DSBP) and the coefficient
of variation in systolic blood pressure (SBPCV ).
significant independent predictor for cardiovascular
mortality (adjusted hazard ratio; 95% confidence interval: 1.75; 0.82–3.73), but revealed that it is an independent predictor for mortality from all causes (1.08;
1.03–1.14) ( Table 4).
These results correspond to the hazard ratio for
death from all causes, which increased 1.63 per 1%
increase in coefficient of variation in systolic blood
pressure and 1.08 per 1 mmHg increase in DSBP.
No significant results were obtained for age, gender,
Discussion
This study extends previous analyses in case-control
studies of hypertensives [2,3] and pregnant women [4]
and shows prospectively that there is a relation between
systolic blood pressure variability and mortality in
patients with ESRD.
A large number of papers [13–18] have described
seasonal variation of blood pressure. Therefore we
calculated the coefficient of variation in SBP from the
complete year records of SBP in this study. We analysed coefficient of variation in systolic blood pressure
but not coefficient of variation in diastolic blood
1980
pressure because SBP correlates better than DBP does
with epidemiological end-points [19,20].
The incidence of acute myocardial infarction in
dialysis patients in Okinawa, Japan was 1.1 per 1000
cases/year between April 1988 and March 1991 [21];
in other words, the rate was only 0.5 per 141 persons
over 3 years. No myocardial infarction occurred in our
study patients during the follow-up period, which was
compatible with the statistics in Okinawa, Japan.
Our method of BP sampling was different from those
used in previous studies. Frattola et al. [2] and Ayala
et al. [4] took hour-to-hour circadian blood pressure,
Hata et al. [3] used month-to-month measurements
for a year, and we took three measurements per week
for a year. Although the BP sampling methods differed,
all these reports showed a positive association between
BP variability and adverse events.
Determination of coefficient of variation in systolic
blood pressure calculated from complete records of a
full year of sessions may not be realistic for general
use. Therefore, we introduced DSBP as an index of the
variability of SBP and as an alternative to coefficient
of variation in systolic blood pressure. Although the
adjusted hazard ratio of DSBP is lower than that of
coefficient of variation in systolic blood pressure for
mortality from all causes, the hazard ratio is significant
( Table 4). This suggests that DSBP is a feasible,
acceptable variable for predicting prognosis in endstage renal disease.
Relative hypotension [22] and low diastolic blood
pressure [23] are risk factors for mortality in dialysis
patients. In our univariate and non-parametric analyses, patients whose coefficient of variation in systolic
blood pressure was in the range above the median had
lower DBP and a worse prognosis than those in the
range below the median. Cox regression analysis with
an adjustment for multiple factors, however, showed
that DBP was not a significant risk factor. In previous
studies with a short-term follow-up period, the effect
of blood pressure on mortality was not found to be
significant [9,24] which is agreement with our findings.
Although the pathogenesis is not clearly understood,
increased risk of cardiovascular disease is associated
with recombinant human erythropoietin therapy for
renal anaemia in chronic dialysis patients. This has
been demonstrated in both retrospective [25] and prospective studies [26 ]. In our study, the percentage of
patients using erythropoietin was not significantly
different between the two groups.
The mechanisms by which blood pressure variability
increases the risk of mortality remains uncertain. One
possible mechanism is that a change in the volume
gain between dialysis sessions may affect blood pressure
variability because the blood pressure of dialysis
patients is largely volume dependent [27] and controlled by adequate dialysis [28]. In this study, bodyweight gain between dialysis sessions was taken into
account during statistical analysis. This factor, however, was not different between the two groups and
was not an independent risk factor for mortality by
Cox analysis. Disorders of the autonomic nervous
M. Tozawa et al.
system may also be a possible factor in this situation
because sympathetic overactivity is a common finding
in end-stage renal disease and it correlates with the
increase in both vascular resistance and systemic blood
pressure [29]. Afferent signals from the kidney may be
the mechanism for this overactivity [29]. However, all
144 patients in this study had end-stage renal disease.
If a disorder of the autonomic nervous system was
involved, the degree of disorder suffered by the patients
should be different between the two coefficient of
variation in systolic blood pressure groups, and this
was not the case. Finally, sodium sensitivity also may
be a mechanism that contributes to this relation
because sodium sensitivity is an independent risk factor
for cardiovascular events in essential hypertension [30]
and the daily variability of sodium intake may influence
the variability of blood pressure.
Limitations of the present study include the relatively
short duration of follow-up (38 months), the small
patient numbers and the late stage in the entire course
of dialysis treatment (average 80 months). An analysis
of subsets such as elderly patients or patients in the
early stages of dialysis could not be performed. All the
patients survived while on haemodialysis through all
of 1994 and, therefore, these patients may have a better
prognosis than other ESRD patients.
In summary, the present study suggests that patients
with increased systolic blood pressure variability are
more likely to develop fatal events. Further study is
needed to establish methods of risk reduction.
Acknowledgements. We acknowledge the secretarial assistance of Ms
Chiho Iseki and the cooperation of other secretarial and nursing
staff in Okinawa Dai-ich Hospital.
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Received for publication: 5.11.98
Accepted in revised form: 23.4.99