Value of Morning Home Blood Pressure as a Predictor of Decline in Renal Function in Patients with Chronic Kidney Disease

Home blood pressure (HBP) measurement has numerous advantages over control of BP based on clinic BP in the management of hypertension [1, 2]. HBP has more predictive power than clinic BP in target-organ damage and cardiovascular disease in the general population or treated hypertensive patients [3, 4]. In patients with chronic kidney disease (CKD), BP control has an important role in preventing the decline in renal function and the progression to end-stage renal disease [5, 6]. HBP measurement may be of value for strict BP control, however the significance of HBP on the progression of CKD has not been fully investigated. Previously limited studies have demonstrated that HBP is a better predictor of the progression of CKD than clinic BP [7,8,9]. However, there are few studies concerning the differences of the predictive power of HBP at different times for the decline in renal function. Therefore, we analyzed the difference of the predictive power among morning BP, evening BP and clinic BP for the decline in renal function in the patients with stage 3–5 CKD.The study subjects included 137 patients who met the eligibility criteria among who were treated at our department between December 2003 and November 2007. The inclusion criteria were as follows: they had to be willing to perform HBP measurements at regular and continuous intervals for at least 2 years or more, they had been treated since for at least 3 months ago at our clinic, they provided a 24-hour urine collection specimen, and estimated glomerular filtration rate (eGFR) was <60 ml/min/1.73 m2. We excluded those receiving dialysis therapy, or whose HBP data were judged inaccurate or inadequate. Baseline clinical characteristics are shown in table 1.Clinic BP was measured by a nurse using a mercury sphygmomanometer in a sitting position after at least 2 min of rest between 9 a.m. and 3 p.m. The value of a single measurement was recorded. HBP was measured according to the guidelines for HBP measurement of the Japanese Society of Hypertension [10]. HBP was measured using a semiautomatic arm device in a sitting position after at least 1 min of rest. The nurses checked that the patients knew how to use the devices accurately and checked the validity of the devices. HBP was measured in the morning, within 1 h after waking, and in the evening, just before going to bed. The value of a single measurement was recorded each time. The patients recorded HBP for a period of 7 consecutive days until the day before their semiannual visit to the clinic. The morning and evening BP values for each patient were calculated as the mean values of 7 daily measurements, respectively.We collected 24-hour urine sample within the 7-day period of HBP measurement and measured urinary protein, creatinine, sodium excretion. The dietary sodium intake was estimated from the 24-hour urinary sodium excretion. Urinary urea excretion was measured and the dietary protein intake was estimated by Maroni’s equation [11]. In addition, hemoglobin, serum creatinine measured by enzymatic method, LDL cholesterol, and HDL cholesterol were collected.We treated the patients according to the current guidelines for BP control. We set up a target BP of <130/80 mm Hg both at home and in the clinic. The mean follow-up period was 32 ± 5 months with a range of 24–36 months (24 months: 37 patients, 30 months: 20 patients, 36 months: 80 patients). After the baseline examination, the patients visited the clinic every 2–3 months and the above clinical data were obtained every 6 months. The mean values of each variable were obtained for each patient. eGFR was calculated by the MDRD study equation modified with the Japanese coefficient (0.741 × MDRD) [12]. The annual change in eGFR during the follow-up period was defined by the following formula: (final eGFR – initial eGFR)/(follow-up months) × 12 (ml/min/1.73 m2/year). We examined the correlation between the change in eGFR and BP data. We also examined independent variables affecting the change in eGFR by multivariate regression analysis.During the follow-up period, we changed the treatment in several patients to improve BP control. The doses or numbers of antihypertensive drugs were increased in 73 patients. They were decreased or changed to another drug in the same class in 14 patients. They were unchanged or continued not to be administered in 50 patients. In 73 patients who received increased doses or classes of antihypertensive drugs, the increased numbers of drugs or classes of drugs were seen as follows: 1, 38 patients; 2, 23 patients; 3 or more, 12 patients; angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 51 patients; calcium channel blocker, 26 patients; α-blocker 25 patients, and furosemide, 16 patients. In 23 patients, erythropoietin was given during 6 months or more of the follow-up period. In 21 patients, erythropoietin was administered prior to baseline and was given continuously during the follow-up period.Informed consent to use the clinical data in this study was obtained from all the patients.The data were expressed as means ± SD. A p value <0.05 was considered to indicate a statistically significant difference. The changes in BP profile were analyzed by Wilcoxon signed rank test. The changes in eGFR in patients with a systolic BP (SBP) ≥130 mm Hg and those with a SBP <130 mm Hg were compared by the Mann-Whitney test. Correlations between the change in eGFR and the above clinical variables were analyzed by Pearson’s correlation coefficient. Finally, stepwise multivariate regression analysis was performed with the change in eGFR as a dependent variable.Table 1 shows the baseline characteristics of the patients and table 2 shows the profile of BP. Both morning SBP and diastolic BP (DBP) significantly decreased after 6 months from baseline. Morning SBP and DBP in 36 months were 6.8 ± 15.3 and 5.0 ± 9.6 mm Hg lower compared with baseline. There was a significant decrease in evening SBP from 12 months and in evening DBP from 24 months. Evening SBP and DBP at 36 months were 3.6 ± 14.4 and 3.1 ± 9.0 mm Hg lower compared with baseline. Clinic SBP was significantly lower from baseline only at 12 and 36 months. Clinic DBP was significantly lower from baseline only at 12 months.Table 3 shows the numbers of patients who achieved the recommended BP values (mean morning or clinic BP values of <130/80 mm Hg during the follow-up in each patient). Although a total of 56.9% of the patients (n = 78) achieved a mean clinic BP of <130/80 mm Hg, only 25.5% of the patients (n = 35) achieved a mean morning BP of <130/80 mm Hg.The annual change in eGFR in all patients was –2.15 ± 2.33 (3.73 to –9.35) ml/min/1.73 m2/year. The annual change in creatinine clearance in all patients was –3.43 ± 4.65 (13.17 to –15.83) ml/min/1.73 m2/year. Table 4 shows the correlation between the change in eGFR and several clinical variables. Mean values in each variable indicate the mean values of the data obtained every 6 months including the baseline data during the follow-up. There were significant correlations between the change in eGFR and both morning and evening SBP (table 4). The correlation coefficient with mean morning SBP was the highest among all BP values. The correlation between change in eGFR and mean clinic SBP was weakly significant. On the other hand, there was no significant correlation between the change in eGFR and morning DBP, evening DBP or clinic DBP (fig. 1).We compared the change in eGFR in patients with a mean SBP ≥130 mm Hg and those with a mean SBP <130 mm Hg (fig. 2).The change in eGFR in patients with a mean morning SBP ≥130 mm Hg was significantly greater than that in patients with a mean morning SBP <130 mm Hg (p < 0.001). On the other hand, there was no significant difference between the change in eGFR in patients with a mean evening SBP ≥130 mm Hg and that in patients with a mean evening SBP <130 mm Hg (p = 0.09). There was also no significant difference between the change in eGFR in patients with a mean clinic SBP ≥130 mm Hg and that in patients with a mean clinic SBP <130 mm Hg (p = 0.08).Stepwise multivariate regression analysis using the factors listed in table 5 showed that mean morning SBP and mean urinary protein excretion were significant independent variables associated with the change in eGFR.Both final morning SBP and DBP significantly decreased from baseline (137.0 ± 14.9 → 131.1 ± 12.1 mm Hg, 78.9 ± 10.2 → 75.1 ± 9.5 mm Hg, both p < 0.001) in all patients. Both final evening SBP and DBP also significantly decreased from baseline (131.4 ± 15.3 → 127.5 ± 12.8 mm Hg, 74.0 ± 10.1 → 71.7 ± 9.9 mm Hg, both p < 0.001). Final clinic SBP significantly decreased from baseline (132.0 ± 18.2 → 126.4 ± 16.7 mm Hg, p < 0.01), however clinic DBP did not significantly change (69.3 ± 10.6 → 70.1 ± 13.7 mm Hg, n.s.). The decrease in urinary protein excretion (UP) was borderline significant (1.39 ± 1.60 → 1.20 ± 1.50 g/day, p = 0.06). Final hemoglobin levels significantly decreased from baseline (12.1 ± 2.1 → 11.7 ± 1.8 g/dl, p < 0.001). There were no significant changes in LDL cholesterol, HDL cholesterol, estimated sodium intake, and estimated protein intake during the follow-up.The change in morning SBP during the follow-up period was defined by ‘final morning SBP – baseline morning SBP’ and the change in UP was defined by ‘final UP – baseline UP’ in each patient. There was a significant correlation between the change in morning SBP and the change in UP (r = 0.478, p < 0.001).In this study, we identified that mean morning SBP during the follow-up period is the best predictor of decline in renal function among SBP measured at different times in CKD patients. Even both initial and final morning SBP also significantly correlated with the change in eGFR and they had stronger correlations than evening SBP or clinic SBP, however they lost significance in multivariate analysis.In CKD patients, as previous studies have shown, it is difficult to achieve and maintain a target BP value of <130/80 mm Hg [13, 14]. This study also showed similar results. In addition, many CKD patients were still classified into the group with masked hypertension (HBP value of ≥130/80 mm Hg and a clinic BP value of <130/80 mm Hg) [15, 16]. Therefore, it is clear that HBP measurement is necessary and essential for strict BP control in CKD patients.Previously, studies concerning the association between HBP and the progression of CKD were very limited [7,8,9]. Although the current guidelines recommend that the target BP is <130/80 mm Hg [17, 18], the HBP control was insufficient and the average SBP during follow-up in the previous studies were greater than those in this study (138/83 mm Hg in the study by Rave et al. [7], 138/82 mm Hg in the study by Suzuki et al. [8]). In the study by Agarwal and Andersen [9], although HBP during follow-up was not available, initial HBP was 147/78 mm Hg. On the other hand, mean morning BP in this study was 133/76 mm Hg. These results indicate that even under the more strict BP control of nearly 130/80 mm Hg, HBP may have an influence on the decline in renal function.There was only one study concerning the differences of the predictive power of HBP at different times for the decline in renal function [8]. In that study, the correlation coefficient between morning SBP and the decline in GFR was the highest in all BP values and multivariate analysis also showed the significant correlations, which agrees with our results.The mechanisms by which morning BP has a strong association with the decline in renal function are not clearly defined. Although only 24-hour ambulatory BP monitoring can detect the nocturnal BP profile, we suggest that high BP in the morning may reflect a diminished nocturnal BP decrease. Morning hypertension means either sustained hypertension during sleep or early morning BP surge, or both. Several previous studies have shown that the prevalence of sustained hypertension was higher than that of morning surge in treated hypertensive patients [19,20,21]. Non-dipping is observed in more than 50% of CKD patients. As GFR decreases, non-dipping increases [22, 23]. In addition, several studies have demonstrated an association between diminished nocturnal BP decrease and faster decline in renal function [24,25,26]. Therefore, it is also possible that morning hypertension assessed by HBP measurement may be associated with renal damage in CKD.In contrast, the association between evening BP and decline in GFR was weaker. Previous studies have shown inconsistent results regarding whether evening BP was lower than morning BP assessed by HBP measurement in the general population or treated hypertensive patients [27, 28]. Evening BP may be influenced by several factors such as diet, alcohol intake, or bathing [29]. In addition, BP variability was greater in the evening compared with the morning [27]. Therefore, it is possible that hypertension may be masked by various physiological factors in the evening and evening BP may be a less reliable predictor of renal damage than morning BP.A similar predictive power of pretreatment morning BP has been shown in the other study [30]. Although the numerous antihypertensive drugs are long-acting in recent years, the response to drugs differs in each patient. A morning BP just before the administration of the antihypertensive drug reflects the effect of the trough level of treatment. In addition to less reliability of BP data after the administration of the antihypertensive drug, various factors associated with daily activities have an influence on BP on the rest of the day. Our study also obtained BP data before the administration of the antihypertensive drug in the morning. From our results and the previous studies, morning trough BP is considered to provide the most reliable information of BP control regardless of the different measurement procedures. It is reasonable to adopt morning trough BP for the evaluation of antihypertensive treatment in some previous studies [31, 32].In this study, we assessed the renal function by eGFR by the MDRD study equation modified by the Japanese coefficient. For Japanese patients, GFR estimation by the original MDRD study equation is less accurate and modification with a coefficient is needed to improve the accuracy of GFR estimation. At present, the Japanese Society of Nephrology recommends 0.741 as the Japanese coefficient and that this equation should be used only in the range of GFR <60 ml/min/1.73 m2[12]. Because creatinine clearance overestimates true GFR in patients with impaired renal function and fluctuates largely due to physiological factors such as dietary intake, we did not use creatinine clearance as a marker to evaluate renal function.There were several reasons for difficulty of lowering morning BP in this study, including insufficient salt restriction, or insufficient use of antihypertensive agents or diuretics. These factors may influence excess of fluid volume and nocturnal hypertension.To clarify the favorable effects on CKD progression of lowering morning BP, an interventional study is needed. In addition, the renoprotective effects of restoring the nocturnal dip in BP would also be clarified. There are some approaches to lowering morning BP. Salt restriction restores dipping status in patients with salt-sensitive hypertension [33]. The shift of the administration of antihypertensive drugs to before sleeping may reduce nocturnal BP in CKD patients [34]. The CKD patients have increased sympathetic nervous system activity [35]. The administration of antihypertensive drugs which attenuate sympathetic nervous system activity may reduce morning BP effectively [36, 37].Although morning SBP and proteinuria were independent predictors of GFR decline in this study, there was a significant correlation between the change in morning SBP and that in proteinuria during the course. BP control itself reduces proteinuria. Conversely, it is possible that insufficient BP control aggravates proteinuria, resulting in further worsening of GFR decline in some cases. It is difficult to separate perfectly the influence of BP from that of proteinuria on GFR decline despite a multivariate analysis in this study. However, the important finding is that only morning SBP remained to be a significant determinant of GFR decline among several parameters of BP. Although many studies have shown that both hypertension and proteinuria are risk factors for GFR decline, those interact on GFR decline each other and the weight of those differs with the population studied [6].There are several limitations to the study. First, the number of subjects was relatively small and the observational periods are still short. Only those patients who continued HBP measurement regularly were included in this study. Second, the devices used in HBP measurement are not uniform. However, we checked the devices and obtained a total of 49 BP values (7 days × 7 times at an interval of 6 months) during 36 months in each patient. We suggest that differences in devices have little influence on the results and that the overall mean values obtained from these data do actually reflect the patients’ HBP. Third, we could not exclude the influence of antihypertensive therapy on changes in GFR. The antihypertensive drugs were increased in a total of 53% of patients during the follow-up. The decrease in BP itself may decrease GFR. However, it is impossible to judge the hemodynamic effects of antihypertensive therapy or diet on GFR during the follow-up in this study. We suggest that the influence of the change in GFR due to antihypertensive therapy on the results was small compared with that due to disease progression.In conclusion, morning BP predicted the decline in renal function better than evening BP or clinic BP in the advanced CKD patients. Further studies are needed to gain greater insight into the favorable effects of lowering morning BP on CKD progression.The authors are indebted to Prof. J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of the manuscript.