INTRODUCTION
Blood pressure (BP) is a predictor of cardiovascular and cerebrovascular diseases. Furthermore, high BP in chronic kidney disease (CKD) patients is a strong predictor of end-stage renal disease (ESRD) or death [
1-
4]. Korean data for a recent 15-year period (from 1985 to 2009) showed that hypertension is a major cause of ESRD, and the prevalence of hypertension would be increased by CKD itself [
5]. Although the gold standard for diagnosis of high BP is still office BP, it has been suggested that out-of-office BP measurements could provide more information, especially given the “white coat effect,” masked hypertension, or the dipping pattern. Out-of-office BP measurement methods include ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM) [
6]. However, ABPM tends to be inconvenient from a practical viewpoint, whereas HBPM is relatively easy to check and is reproducible [
7-
9]. Although several studies have suggested the usefulness of HBPM, few have recommended specific time points for HBPM measurements; some studies suggested that BP measurements should be performed more than twice during the day, on several consecutive days, and during the morning and night, but these studies did not provide specific time points for measurements [
10-
12]. The Japanese Society of Hypertension provided more detailed suggestions—they recommend that BP should be measured within 1 hour after waking up and just before going to bed, but no specific time points for BP measurement were provided [
13]. We considered that a specific time point for BP measurement, which is representative of the 24-hour mean BP, would be clinically useful for self-management of hypertension. This study was performed to determine a specific time point for measurement of systolic blood pressure (SBP) that is well correlated with the 24-hour mean SBP (mSBP) using a cross-sectional multicenter study involving hypertensive CKD patients in Korea (APrODiTe study) [
14].
RESULTS
A total of 1,317 patients from 21 centers were enrolled in this study (
Table 2). Their average age was 56.6 ± 11.9 years, and 62.9% were males. Most patients (48.6%) were CKD stage 3, and the cause of CKD in almost 40% of the patients was hypertension. The office mSBP was 137 ± 19.9 mmHg, and the 24-hour mSBP was 131 ± 16.4 mmHg.
Fig. 1 shows the differences between 24-hour mSBP and the SBPs at each time point for 24 hours. Using the paired
t test (
t value) inversely for the differences and correlations (
r value) with the 24-hour mSBP, 7:00 AM, 2:00 PM, and 9:30 PM were chosen according to the order of decreasing difference from 24-hour mSBP. Thus, 7:00 AM, 2:00 PM, and 9:30 PM were considered significant time points at which the SBP was most closely correlated with the 24-hour mSBP (
Table 1). The largest difference was 20.299 at 3:30 AM.
The linear correlation between the SBPs at three specific time points, the office mSBP, and the 24-hour mSBP based on the Passing-Bablok regression is shown in
Fig. 2. In this figure, the SBPs at 7:00 AM and 9:30 PM (
Fig. 2A and
2C) showed the best correlations with the 24-hour mSBP, compared with measurement at 2:00 PM and the office SBP (
Fig. 2B and
2D). The same regression method showed that the highest proportion of patients with SBP measurements within 30% of the 24-hour mSBP (proportion 30, P
30) were obtained at 7:00 AM and 9:30 PM (P
30 = 95.6%, P
30 = 95.3%, respectively). At 2:00 PM, 92.1% of the patients were included within P
30 (
Fig. 2).
Using the Passing-Bablok equation, we calculated the SBPs at the three time points as values that corresponded with the 24-hour mSBP of 135 mmHg (
Table 3). Measurements at 7:00 AM and 9:30 PM were much closer to 135 mmHg (136.74 and 138.78 mmHg, respectively). The office mSBP exhibited the greatest difference from 135 mmHg (142.61 mmHg). Using these calculated SBPs at the three time points and the 24-hour mSBP of 135 mmHg, the patients were classified into uncontrolled hypertensive groups, and the agreement among groups was analyzed (
Fig. 3). The uncontrolled hypertensive group based on values at 7:00 AM and 9:30 PM showed the best agreement with the group at ≥ 135 mmHg compared with the other groups (7:00 AM, 70.8%; 9:30 PM, 68.1%;
p < 0.001).
We evaluated the usefulness of the calculated SBP values at the three time points and the office measurement for diagnosis of uncontrolled hypertension with a ROC curve (
Fig. 4). The ROC curve showed that 7:00 AM and 9:30 PM had markedly larger area under the curve (AUC) values (AUC = 0.843,
p < 0.001; AUC = 0.831,
p < 0.001, respectively). The AUC values at 7:00 AM and 9:30 PM were significantly greater than those at 2:00 PM and the office measurement.
We performed subgroup analyses to test whether these time points for BP measurement were clinically meaningful. In CKD stage 2 patients, the SBPs at 7:30 AM, 3:00 PM, and 10:00 PM had smaller differences than those at previous time points; however, in the correlation or P
30 analyses, new time points showed similar or lower values compared with the three previously selected time points (7:00 AM, 2:00 PM, and 9:30 PM) (
Table 4). In CKD stage 4 patients, the SBP measurements at 6:30 PM and 3:00 PM were closer to the 24-hour mSBP, but the SBP at 7:00 AM showed a better correlation with the 24-hour mSBP than the SBP at 6:30 PM, and more patients were included in P
30 at 2:00 PM than at 3:00 PM.
The patients were classified as dippers if they had a ratio of < 0.9 and non-dippers if they had a ratio of ≥ 0.9. The dipper patients showed the same results as all patients, but in the non-dipper patients SBPs at 4:30 AM, 4:30 PM, and 11:00 PM had lower differences than at the three previous specific time points. However, based on the correlation and P30 analysis, the values at 7:00 AM, 2:00 PM, and 9:30 PM were found to be superior to the new time points (data not shown).
We also analyzed the subgroups by daytime and nighttime. The standard time points for classification into day and night were 8:00 AM and 10:00 PM, respectively, so the findings were different from the previous results. In daytime, the SBPs at 9:00 AM and 1:30 PM correlated with daytime mSBP, and at nighttime, the SBP at 4:30 AM correlated with nighttime mSBP (data not shown).
In other subgroups, such as diabetes/non-diabetes, left ventricular hypertrophy (LVH)/non-LVH, proteinuria/non-proteinuria, and gender groups, results similar to those for all patients were obtained using identical analysis methods. In these groups, predominantly the SBPs at 7:00 AM and 9:30 PM were highly correlated with the 24-hour mSBP (data not shown).
DISCUSSION
We examined the time points at which the measured SBP showed the closest correlation with the 24-hour mSBP in the hope that SBP measurements at those time points could replace the 24-hour mSBP in CKD patients. Out-of-office BP (ABPM, HBPM) provides different information about the patient’s BP condition, and so cannot be considered to be equivalent or alternative methods [
6]. HBPM is reproducible and more convenient than ABPM, but few studies have examined the detailed guidelines for the specific time points for self-BP measurement, especially in CKD patients [
9,
21,
22]. Here, we examined whether there may be a specific time of the day for measuring BP that is representative of the mean BP over the entire day and attempted to identify a specific time point for such BP measurement. The present study is among the first to suggest specific time points for out-of-office BP measurement in CKD patients.
We used several statistical methods to verify these specific time points for BP measurement. The results of several analyses consistently showed that measurements at three specific time points; i.e., 7:00 AM, 2:00 PM, and 9:30 PM, were closely correlated with the 24-hour mSBP. Therefore, we considered that these could be used as specific time points in the morning, afternoon, and night, respectively. Among them, the SBPs at 7:00 AM and 9:30 PM were more closely correlated with the 24-hour mSBP than that at 2:00 PM or office mSBP. These findings also indicated that the office mSBP is inferior to SBPs at our selected time points. The weaker correlation of the 2:00 PM value may be due to variations in BP [
23]. The BP at 2:00 PM can be affected by multiple factors, such as stress, diet, physical condition, smoking, and caffeine intake, although the difference between BP at 2:00 PM and the 24-hour mSBP was minimal. In addition, office mSBP may be influenced by the white coat effect.
In subgroup analysis, we obtained slightly different results in patients with CKD stage 2 and CKD stage 4, as well as the non-dippers. In the CKD stage 4 and non-dipper groups, these differences may be explained by the variability in SBP according to progression of renal disease. Patients with advanced stage CKD have a tendency toward variable BP and the dipper phenomenon [
24]. The different agreement between the uncontrolled hypertensive groups with CKD stage 4 could be explained in the same way. However, the different time points in these subgroups were mostly included within approximately the same time ranges, such as 7:00 AM, 2:00 PM, and 9:30 PM. In addition, the ROC curve supported these results in all of the subgroups. In the non-dipper and day/nighttime groups, we obtained findings that differed from the previous results. In the non-dipper group, the 4:30 AM, 4:30 PM, and 11:00 PM time points differed less from the 24-hour mSBP, but regression analyses showed that the correlations of the three previous time points with the 24-hour mSBP were higher than the newly presented time points. Therefore, 7:00 AM, 2:00 PM, and 9:30 PM were considered not to be inferior to the new time points in terms of correlation with the 24-hour mSBP. In the day/nighttime groups, 9:00 AM and 1:30 PM in the daytime group and 4:30 AM in the nighttime group were correlated with the daytime and nighttime mSBP. These results may have been influenced by the different time ranges in the daytime and nighttime designations of 8:00 AM and 10:00 PM. In addition, it is possible that several factors, such as physical activity and diet, influenced the daytime results. According to these results, we recommend that patients check their BP at 4:30 AM for the nighttime BP, but this time point is inconvenient for clinical use. Therefore, we suggest time points that are more convenient and clinically useful: checking BP at 7:00 AM, 2:00 PM, and 9:30 PM for whole-day monitoring would better ensure patient compliance.
The strength of the present study is that it suggested specific time points for out-of-office BP measurement, and involved CKD patients. Most studies of out-of-office BP schedules have been performed in populations with normal renal function [
9,
10,
25,
26]. A previous study on HBPM in CKD patients showed that out-of-office BP was better than office BP for diagnosis of hypertension; however, it did not specify the timing of the BP measurements [
27]. By using the SBP values at these specific time points, we could expect to monitor the BP status of patients more effectively, because the SBPs at the three time points were better correlated to the 24-hour mSBP than SBPs at other time points. We suggest the use of these time points for general monitoring of patient BP status rather than a diagnostic or prognostic method. For prognosis, nighttime BP measurement or ABPM should also be performed.
This study had several limitations. We checked ABPM only once, so between-visit variation in SBP could not be evaluated. Some studies restricted the times for BP measurement considering diet, sleep, and medication, while we did not because the purpose of this study was to determine more clinically convenient time points for BP measurement to increase patient compliance. We excluded DBP from these analyses to avoid correlations of a large number of time points for each SBP and DBP with the 24-hour mean BP. To verify the effects of these time points in monitoring and prognosis, future studies should consider several factors that influence BP and should include both SBP and DBP.
In conclusion, we found that 7:00 AM and 9:30 PM were specific time points that were highly correlated with the 24-hour mSBP for out-of-office SBP measurement in CKD patients. According to several analytical methods, these time points showed consistent correlations with 24-hour mSBP overall. Although further studies are needed to verify the practical usefulness and prognostic value of these results, this study represents a valuable starting point in the effort to establish more specific time points for SBP measurement.