Visual Abstract
Keywords: ambulatory blood pressure monitoring, nocturnal systolic hypertension, chronic kidney disease, end-stage renal disease, cardiovascular events, hypertension
Abstract
Background and objectives
Nocturnal hypertension is associated with adverse outcomes in patients with CKD. However, the individual association of entities of nocturnal hypertension according to achievement of systolic and/or diastolic BP goals with kidney failure and cardiovascular outcomes of CKD is not clear.
Design, setting, participants, & measurements
Our study analyzed data from participants in the Chinese Cohort Study of Chronic Kidney Disease. Nocturnal hypertension was categorized into three entities: isolated nocturnal diastolic hypertension with diastolic BP ≥70 mm Hg and systolic BP <120 mm Hg, isolated nocturnal systolic hypertension with systolic BP ≥120 mm Hg and diastolic BP <70 mm Hg, and nocturnal systolic-diastolic hypertension with both systolic BP ≥120 mm Hg and diastolic BP ≥70 mm Hg. Associations of nocturnal hypertension entities with kidney failure and cardiovascular outcomes were evaluated by Cox regression.
Results
In total, 2024 patients with CKD stages 1–4 were included in our analysis (mean age, 49±14 years; 57% men; eGFR=51±29 ml/min per 1.73 m2; proteinuria: 0.9 [0.4–2.1] g/d). Among them, 1484 (73%) patients had nocturnal hypertension, with the proportions of 26%, 8%, and 66% for isolated nocturnal diastolic hypertension, isolated nocturnal systolic hypertension, and nocturnal systolic-diastolic hypertension, respectively. Three hundred twenty kidney events and 148 cardiovascular events were recorded during median follow-up intervals of 4.8 and 5.0 years for kidney and cardiovascular events, respectively. After adjustment, isolated nocturnal systolic hypertension was associated with a higher risk for cardiovascular events (hazard ratio, 3.17; 95% confidence interval, 1.61 to 6.23). Nocturnal systolic-diastolic hypertension showed a higher risk for both kidney failure (hazard ratio, 1.71; 95% confidence interval, 1.17 to 2.49) and cardiovascular outcomes (hazard ratio, 2.19; 95% confidence interval, 1.24 to 3.86). No association was observed between isolated nocturnal diastolic hypertension with either kidney failure or cardiovascular events.
Conclusions
Nocturnal systolic hypertension, either alone or in combination with diastolic hypertension, is associated with higher risks for adverse outcomes in patients with CKD.
Introduction
Hypertension is an important modifiable risk factor for progression of CKD and development of cardiovascular disease among patients with CKD (1). Substantial evidence has shown that ambulatory BP monitoring (ABPM) performs better in evaluation of hypertension than conventional clinical BP measurement, which helps to improve risk stratification and achievement of BP goals in patients with CKD (2–4).
One reason for the superiority of ABPM is its ability to capture nighttime BP values. There is frequently a blunting or loss of normal physiologic drop of BP during nighttime in patients with CKD (5). Several studies have addressed the association of nocturnal hypertension with target organ damage and adverse outcomes in patients with CKD, indicating the importance of nocturnal BP control for daily practice (6–8). According to achievement of nocturnal BP target(s), four entities exist (9): nocturnal normotension, isolated nocturnal diastolic hypertension, isolated nocturnal systolic hypertension, and nocturnal systolic-diastolic hypertension. Whether these entities of nocturnal hypertension had different associations with kidney and cardiovascular risks in patients with CKD was not known. The purpose of this study was to evaluate the individual prognostic value of nocturnal hypertension entity in a large, prospective cohort of Chinese patients with CKD not on dialysis.
Materials and Methods
Participants
This was a multicenter, prospective cohort study of patients with CKD stages 1–4 from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE). The design and methods of C-STRIDE have been described in detail elsewhere (10). In brief, C-STRIDE was designed to explore risk factors associated with CKD progression, kidney failure, and other adverse consequences (especially cardiovascular events). From November 2011 to December 2016, a total of 3700 eligible participants from 39 clinical centers in 22 provinces of China were enrolled in C-STRIDE. All of these clinical centers are nephrology departments from different hospitals. The inclusion and exclusion criteria of the cohort are listed in Supplemental Table 1. Among enrolled patients, 2114 had undergone ABPM; 90 were excluded because of invalid ABPM data. Finally, 2024 patients were included in this analysis with comparable baseline characteristics to those excluded (Supplemental Table 2). The study protocol was approved by the Ethics Committee of Peking University First Hospital and was in compliance with the tenets of the Declaration of Helsinki. All participants provided written informed consent prior to enrollment in the study.
Blood Pressure Measurement
Twenty-four–hour ABPM was performed via calibrated devices in each clinic center, with BP readings set at 15-minute intervals from 7:00 am to 10:00 pm and 30-minute intervals from 10:00 pm to 7:00 am. Twenty-four–hour BP, daytime BP, and nighttime BP were defined as the mean values of BP readings during a 24-hour cycle, daytime, and nighttime, respectively. Valid measurement was regarded as successful documentation of at least 70% of BP readings taken during a 24-hour period with at least nine readings during nighttime. ABPM measurements were taken from the nondominant arm with an appropriate cuff size. Nocturnal normotension was defined as nighttime systolic BP <120 mm Hg and diastolic BP <70 mm Hg (9). Nocturnal hypertension was defined as nighttime systolic BP ≥120 mm Hg and/or diastolic BP ≥70 mm Hg, which was further categorized into three entities: isolated nocturnal diastolic hypertension with diastolic BP ≥70 mm Hg and systolic BP <120 mm Hg, isolated nocturnal systolic hypertension with systolic BP ≥120 mm Hg and diastolic BP <70 mm Hg, and nocturnal systolic-diastolic hypertension with both systolic BP ≥120 mm Hg and diastolic BP ≥70 mm Hg. Isolated nocturnal hypertension was defined as nocturnal hypertension with daytime BP <135/85 mm Hg, and day-night sustained hypertension was defined as nocturnal hypertension with daytime BP ≥135/85 mm Hg.
Study Outcomes
The principle clinical outcomes were prespecified at the beginning of the establishment of the cohort. Kidney failure was defined as dialysis initiation and/or transplantation (11). Cardiovascular outcomes included a composite of acute myocardial infarction, unstable angina, hospitalization for congestive heart failure, cerebrovascular events (intraparenchymal hemorrhage, subarachnoid hemorrhage, cerebral infarction, etc.), and peripheral vascular diseases, whichever occurred first, as proposed by consensus statements and adopted by previous studies (6,12,13). Patients were followed up at 3-month intervals either by phone calls or routine clinical visits at each clinical center. After any end point event occurred, directors of the specific clinical center were requested to fill out the registration form for new-onset event and submit relevant clinical data to the Renal Institute of Peking University. The events with any suspicion were further evaluated by an independent committee to make final adjudgment. Follow-up was terminated at the occurrence of death or a predefined end date (December 31, 2017) in this analysis.
Covariate Definition
Smoking was defined as currently smoking or had ever smoked. Diabetes was defined as the fasting plasma glucose ≥7.0 mmol/L or a self-reported history of diabetes. Cardiovascular disease history was defined as the past occurrence of a myocardial infarction, admission into a hospital for congestive heart failure, or severe cardiac arrhythmia incidents (resuscitated cardiac arrest, ventricular fibrillation, sustained ventricular tachycardia, paroxysmal ventricular tachycardia, atrial fibrillation or flutter, severe bradycardia, or heart block). Dyslipidemia was defined by the presence of at least one of the following: serum total cholesterol level ≥200 mg/dl, triglycerides ≥150 mg/dl, LDL cholesterol ≥130 mg/dl, and HDL cholesterol <40 mg/dl or current use of lipid-lowering drugs. Anemia was defined as hemoglobin levels <100 g/L. Body mass index (BMI) was calculated by the following formula: BMI = weight (kilograms)/height2 (meters2). The GFR was estimated by the Chronic Kidney Disease Epidemiology Collaboration equation (14).
Statistical Analyses
Continuous variables with normal distribution are presented as the means ± SD, while non-normal distribution parameters are expressed as medians and interquartile ranges (IQRs). Categorical variables are expressed as frequency and proportions. One-way ANOVA, the Kruskal–Wallis test and the chi-squared test are used to compare variables among nocturnal hypertension entities where it is appreciated.
The incidence rates of kidney failure and cardiovascular events were calculated as number of events per 1000 patients-years. Survival curves were calculated by Kaplan–Meier methods. Log-rank test was used to compare the event rates among each group.
A multivariable Cox proportional hazards regression model was used to investigate the association between nocturnal hypertension entities and outcomes. Nocturnal normotension was regarded as the reference group. The model was adjusted for age (continuous), sex (man versus woman), BMI (continuous), smoker (yes versus no), previous history of cardiovascular disease (yes versus no), diabetes (yes versus no), renin-angiotensin system inhibitor treatment (yes versus no), dyslipidemia (yes versus no), albumin (continuous), anemia (yes versus no), urinary protein (continuous), 24-hour urine sodium (continuous), and eGFR (continuous). Additional adjustment with inclusion of other antihypertensive and hypoglycemic treatment was done. Hazards ratios (HRs) and 95% confidence intervals (95% CIs) are shown to express the results of regression model. Before conducting the multivariable regression analysis, the missing data for each covariate were filled with mean/median values for continuous variables and a separate category for categorical variables. Log minus log plots were used to assess the proportional hazards assumption. Sensitivity analyses were performed using multiple imputations to handle missing data. The regression method was used to impute missing values in a normally distributed continuous variable, predictive mean matching method was used in a skewed distributed continuous variable, and logistic regression was used in a categorical variable with binary or ordinal responses. Each imputed dataset was analyzed separately, and then pooled results were obtained. The associations between components of the cardiovascular diseases with nocturnal hypertension entities were performed. Additionally, we included an interaction term between CKD stages and status of nocturnal hypertension in the multivariable adjusted model to test if CKD stage could modify the association between nocturnal hypertension and the studied outcomes. Stratified analyses in patients with eGFR<60 ml/min per 1.73 m2 were performed.
Data were analyzed using SPSS software (version 22.0, IBM, Armonk, NY) and SAS System version 9.4 (SAS Institute, Cary, NC). A two-sided P<0.05 was considered statistically significant.
Results
Baseline Characteristics of the Study Participants
A total of 2024 patients with CKD were enrolled in this study. The mean age was 49±14 years, and 1164 were men (58%). Notably, 37% of patients were smokers, while 25% of patients exhibited diabetes, and 10% had a history of cardiovascular disease. The mean eGFR was 51±29 ml/min per 1.73 m2.
A total of 1484 (73%) patients had nocturnal hypertension (Supplemental Table 3). Among those with nocturnal hypertension, the proportions of patients with isolated nocturnal diastolic hypertension, isolated nocturnal systolic hypertension, and nocturnal systolic-diastolic hypertension were 26%, 8%, and 66%, respectively. Compared with isolated nocturnal diastolic hypertension, patients with isolated nocturnal systolic hypertension and nocturnal systolic-diastolic hypertension were older, had higher prevalence of diabetes and diabetic kidney disease, and had lower levels of hemoglobulin and eGFR. Compared with isolated nocturnal diastolic hypertension, patients with isolated nocturnal systolic hypertension had higher levels of both systolic BP and pulse pressure (PP) values and lower levels of diastolic BP values; meanwhile, patients with nocturnal systolic-diastolic hypertension had higher systolic BP, diastolic BP, mean arterial pressure (MAP), and PP values. In addition, patients with nocturnal systolic-diastolic hypertension had higher levels of systolic BP, diastolic BP, and MAP and lower levels of PP compared with those with isolated nocturnal systolic hypertension (Table 1).
Table 1.
Baseline characteristics of patients in the Chinese Cohort Study of Chronic Kidney Disease who underwent ambulatory BP monitoring
| Variable | Nocturnal Normotension, n=540 | Nocturnal Hypertension | ||
|---|---|---|---|---|
| Isolated Nocturnal Diastolic Hypertension, n=390 | Isolated Nocturnal Systolic Hypertension, n=120 | Nocturnal Systolic-Diastolic Hypertension, n=974 | ||
| Age, yr | 47±15 | 46±12 | 62±12 | 50±13 |
| Men, N (%) | 265 (49%) | 215 (55%) | 64 (53%) | 620 (64%) |
| BMI, kg/m2 | 23.9±3.6 | 24.2±3.6 | 24.4±2.9 | 25.3±4.1 |
| Smoker, N (%) | 141 (27%) | 138 (36%) | 45 (38%) | 413 (43%) |
| Diabetes, N (%) | 71 (16%) | 34 (11%) | 52 (49%) | 269 (31%) |
| History of cardiovascular disease, N (%) | 34 (6%) | 29 (8%) | 24 (20%) | 115 (12%) |
| CKD stages, N (%) | ||||
| 1 | 125 (23) | 68 (17) | 8 (7) | 71 (7) |
| 2 | 122 (23) | 79 (20) | 13 (11) | 133 (14) |
| 3 | 190 (35) | 148 (38) | 55 (46) | 424 (44) |
| 4 | 103 (19) | 95 (24) | 44 (38) | 346 (36) |
| eGFR, ml/min per 1.73 m2 | 62±32 | 55±30 | 42±25 | 44±26 |
| Proteinuria, g/d | 0.7 (0.2, 1.3) | 0.6 (0.3, 1.4) | 0.8 (0.3, 2.0) | 1.3 (0.5, 2.7) |
| 24-h urine sodium, mmol/d | 146±81 | 149±76 | 146±66 | 153±81 |
| Serum albumin, g/dl | 4.0±0.7 | 3.9±0.6 | 3.9±0.7 | 3.8±0.8 |
| Hemoglobin, g/dl | 12.9±2.0 | 13.0±2.1 | 11.8±2.4 | 12.5±2.4 |
| Triglyceride, mg/dl | 144 (104, 199) | 151 (100, 205) | 147 (116, 219) | 166 (114, 233) |
| Total cholesterol, mg/dl | 180 (151, 217) | 178 (151, 213) | 184 (152, 223) | 181 (149, 219) |
| HDL cholesterol, mg/dl | 43 (37, 53) | 42 (36, 52) | 42 (33, 49) | 41 (34, 50) |
| LDL cholesterol, mg/dl | 102 (82, 122) | 101 (78, 120) | 99 (83, 124) | 99 (82, 130) |
| Creatinine, mg/dl | 1.3 (0.9, 1.9) | 1.5 (1.0, 2.1) | 1.6 (1.3, 2.5) | 1.9 (1.3, 2.6) |
| Causes of kidney disease, N (%) | ||||
| GN | 378 (72) | 282 (73) | 38 (32) | 496 (52) |
| Diabetic kidney disease | 23 (4) | 14 (4) | 38 (32) | 177 (18) |
| Others/unknown | 126 (24) | 92 (24) | 43 (36) | 288 (30) |
| BP | ||||
| Clinic systolic BP, mm Hg | 120±15 | 124±12 | 135±13 | 136±18 |
| Clinic diastolic BP, mm Hg | 75±9 | 81±8 | 76±9 | 84±11 |
| 24-h systolic BP, mm Hg | 113±9 | 119±8 | 134±10 | 140±15 |
| 24-h diastolic BP, mm Hg | 69±6 | 79±6 | 70±6 | 86±9 |
| 24-h mean arterial pressure, mm Hg | 84±7 | 92±6 | 91±6 | 104±10 |
| 24-h pulse pressure, mm Hg | 44±7 | 40±6 | 64±9 | 54±12 |
| Daytime systolic BP, mm Hg | 117±10 | 121±9 | 135±11 | 141±15 |
| Daytime diastolic BP, mm Hg | 71±7 | 80±7 | 71±7 | 87±10 |
| Daytime mean arterial pressure, mm Hg | 86±7 | 94±7 | 92±7 | 105±10 |
| Daytime pulse pressure, mm Hg | 45±8 | 41±7 | 64±10 | 54±12 |
| Nocturnal systolic BP, mm Hg | 105±8 | 113±5 | 130±9 | 138±15 |
| Nocturnal diastolic BP, mm Hg | 62±5 | 75±4 | 65±4 | 84±9 |
| Nocturnal mean arterial pressure, mm Hg | 77±5 | 88±4 | 86±5 | 102±10 |
| Nocturnal pulse pressure, mm Hg | 43±7 | 38±6 | 65±9 | 54±13 |
| Nondipper, N (%) | 297 (55%) | 275 (71%) | 103 (86%) | 842 (86%) |
| Renin-angiotensin system inhibitor, N (%) | 326 (60%) | 224 (57%) | 63 (53%) | 540 (55%) |
Missing data: smoker, 36; diabetes, 285; history of cardiovascular disease, 11; 24-hour urine sodium, 152; triglyceride, 374; total cholesterol, 373; HDL cholesterol, 416; LDL cholesterol, 416; clinic systolic BP, 310; clinic diastolic BP, 307; body mass index (BMI), 194; serum albumin, 298; hemoglobin, 118; and causes of kidney disease, 29.
Incidence of Kidney Failure and Cardiovascular Events
Median duration of follow-up was 4.8 years (IQR, 3.8–5.5 years) and 5.0 years (IQR, 4.2–5.6 years) for kidney failure and cardiovascular events, respectively. During the period, 320 kidney failure events (event incidence: 35.57/1000 person-years) and 148 cardiovascular events (event incidence: 15.51/1000 person-years) were recorded. As shown in Figure 1, incidence rates of patients with nocturnal hypertension were higher than those of patients with nocturnal normotension with respect to kidney failure events and cardiovascular events (both P<0.001).
Figure 1.
Incidence of kidney failure and cardiovascular events in participants with nocturnal normotension and nocturnal hypertension. P was P value for log rank. (A) Kidney failure. (B) Cardiovascular events.
Association of Nocturnal Hypertension with Kidney Failure and Cardiovascular Events
Nocturnal hypertension (versus nocturnal normotension) was associated with a greater risk for kidney failure (HR, 1.56; 95% CI, 1.08 to 2.26) and cardiovascular events (HR, 2.19; 95% CI, 1.27 to 3.78) after adjustments (Table 2). Compared with nocturnal normotension, isolated nocturnal hypertension had higher risk for cardiovascular events (HR, 2.05; 95% CI, 1.14 to 3.71), whereas day-night sustained hypertension had higher risk for both kidney failure (HR, 1.80; 95% CI, 1.23 to 2.63) and cardiovascular events (HR, 2.29; 95% CI, 1.30 to 4.04) (Table 3).
Table 2.
Association of nocturnal hypertension with kidney failure and cardiovascular events
| Event | No. of Events (%) | Events per 1000 person-yr | Unadjusted Model Hazard Ratio (95% Confidence Interval) | Adjusted Model Hazard Ratio (95% Confidence Interval) |
|---|---|---|---|---|
| Kidney failure | ||||
| Nocturnal normotension, n=540 | 34 (6) | 13 | 1.00 (Reference) | 1.00 (Reference) |
| Nocturnal hypertension, n=1484 | 286 (19) | 45 | 3.35 (2.35 to 4.79) | 1.56 (1.08 to 2.26) |
| Cardiovascular events | ||||
| Nocturnal normotension, n=540 | 15 (3) | 6 | 1.00 (Reference) | 1.00 (Reference) |
| Nocturnal hypertension, n=1484 | 133 (9) | 19 | 3.38 (1.98 to 5.76) | 2.19 (1.27 to 3.78) |
Adjusted for age, sex, smoker, body mass index, diabetes mellitus, history of cardiovascular disease, renin-angiotensin system inhibitor, dyslipidemia, albumin, anemia, 24-hour urine protein, 24-hour urine sodium, and eGFR.
Table 3.
Association of nocturnal hypertension stratified by achievement of daytime BP target with kidney failure and cardiovascular events
| Event | No. of Events (%) | Events per 1000 person-yr | Unadjusted Model Hazard Ratio (95% Confidence Interval) | Adjusted Model Hazard Ratio (95% Confidence Interval) |
|---|---|---|---|---|
| Kidney failure | ||||
| Nocturnal normotension, n=540 | 34 (6) | 13 | 1.00 (Reference) | 1.00 (Reference) |
| Isolated nocturnal hypertension, n=600 | 75 (13) | 27 | 2.07 (1.38 to 3.10) | 1.23 (0.82 to 1.86) |
| Day-night sustained hypertension, n=884 | 211 (24) | 58 | 4.31 (3.00 to 6.19) | 1.80 (1.23 to 2.63) |
| Cardiovascular events | ||||
| Nocturnal normotension, n=540 | 15 (3) | 6 | 1.00 (Reference) | 1.00 (Reference) |
| Isolated nocturnal hypertension, n=600 | 44 (7) | 15 | 2.71 (1.51 to 4.87) | 2.05 (1.14 to 3.71) |
| Day-night sustained hypertension, n=884 | 89 (10) | 22 | 3.85 (2.23 to 6.65) | 2.29 (1.30 to 4.04) |
Adjusted for age, sex, smoker, body mass index, diabetes mellitus, history of cardiovascular disease, renin-angiotensin system inhibitor, dyslipidemia, albumin, anemia, 24-hour urine protein, 24-hour urine sodium, and eGFR.
Further analysis showed that nocturnal systolic-diastolic hypertension had higher risks for both kidney failure (HR, 1.71; 95% CI, 1.17 to 2.49) and cardiovascular events (HR, 2.19; 95% CI, 1.24 to 3.86) compared with nocturnal normotension after fully adjustment. Within the groups of patients with nocturnal hypertension achieving only systolic or diastolic target level, those achieving only the nighttime systolic BP target did not have a greater risk of the kidney failure (HR, 1.29; 95% CI, 0.82 to 2.38) and cardiovascular outcomes (HR, 1.63; 95% CI, 0.82 to 3.26) after adjustment; conversely, patients only achieving the diastolic target had an adjusted higher risk for cardiovascular events (HR, 3.17; 95% CI, 1.61 to 6.23) without higher risk for kidney failure (HR, 1.29; 95% CI, 0.69 to 2.38) (Figure 2). The result was consistent after further adjustment for antihypertensive and hypoglycemic treatment (Supplemental Table 4). Sensitivity analysis using multiple imputations to handle missing data also showed consistent results (Supplemental Table 5). The P value for the interaction between CKD stages and status of nocturnal hypertension was not statistically significant (>0.05). Also, similar results were found in participants with eGFR<60 ml/min per 1.73 m2 (Supplemental Table 6). The association between the components of the composite cardiovascular outcomes and nocturnal hypertension entities is shown in Supplemental Table 7.
Figure 2.
Risks of kidney failure and cardiovascular events in participants with different nocturnal hypertension entities. (A) Kidney failure. (B) Cardiovascular events. Adjusted for age, sex, smoker, body mass index, diabetes mellitus, history of cardiovascular disease, renin-angiotensin system blocker, dyslipidemia, albumin, anemia, 24-hour urine protein, 24-hour urine sodium, and eGFR. 95% CI, 95% confidence interval; DBP, diastolic BP; HR, hazard ratio; ref, reference; SBP, systolic BP.
Discussion
In this study, we investigated the associations of nocturnal hypertension entities with kidney and cardiovascular outcomes in a large prospective cohort of Chinese patients with CKD not on dialysis. Nocturnal hypertension was associated with a higher risk for kidney failure and cardiovascular events. Patients with isolated nocturnal systolic hypertension had a higher risk for cardiovascular events, whereas those with nocturnal systolic-diastolic hypertension showed a higher risk for both kidney and cardiovascular outcomes. These results suggest an important role of nocturnal systolic hypertension in the risk for adverse outcomes in patients with CKD.
In patients with CKD, increased salt excretions and overactivation of sympathetic system and renin-angiotensin system during nighttime, as well as sleeping disturbance, are quite common (15,16). These factors, either alone or in combination, decrease the normal declination of nighttime BP. Therefore, it is common to find a high prevalence of nocturnal hypertension in the CKD population, which is also the case in our cohort. Furthermore, nighttime hypertension has been found to be more closely associated with target organ damage and prognosis of patients with CKD (17,18). For instance, the association between masked hypertension and lower eGFR was found to be more pronounced in patients with elevated nighttime BP in the Chronic Renal Insufficiency Cohort study (19). Minutolo et al. (6) found that patients with CKD achieving the nighttime BP target did not have a greater risk of the kidney failure and cardiovascular events; conversely, patients achieving exclusively the daytime BP target had a greater risk of the cardiovascular end point. In another study from China, nocturnal hypertension was associated with a higher risk for both kidney failure and cardiovascular events compared with nocturnal normotension (7). In this study, patients with nocturnal hypertension showed 1.5- and two-fold higher risks for kidney failure and cardiovascular events. These results strongly supported the importance of nocturnal hypertension for prognosis of patients with CKD.
Hypertension could be diagnosed on the basis of elevated systolic BP, elevated diastolic BP, or both as isolated systolic hypertension, isolated diastolic hypertension, and systolic/diastolic hypertension. Difference of the prognostic significance of BP entities has been observed in general populations. For instance, isolated systolic hypertension and systolic/diastolic hypertension were associated with higher risk for cardiovascular mortality compared with normotension, whereas isolated diastolic hypertension was not in Ohasama study (20). In a recent analysis of US adults, no significant association was found between isolated diastolic hypertension and higher risk for cardiovascular outcomes (21). Therefore, we further analyzed the prognostic significance of different entities of nocturnal hypertension according to elevation of either systolic BP or diastolic BP. Interestingly, those not achieving the nighttime systolic BP target, either alone or in combination with uncontrolled nocturnal diastolic BP, showed a greater risk for adverse prognosis in this study. Conversely, those with only nocturnal diastolic BP over target did not show higher risks for both kidney and cardiovascular outcomes. These results suggested that nocturnal systolic BP over target might play a more important role in the pathogenesis of adverse prognosis than diastolic BP over target in patients with CKD, which needs to be verified by further observational and interventional studies.
Previous studies have reported adverse prognosis with higher nocturnal diastolic BP values. Katafuchi et al. (22) found that higher nighttime diastolic BP (quartile 4: 80–112 mm Hg) was associated with higher risks for composite kidney outcomes, whereas nighttime diastolic BP values over 70 and 75 mm Hg were associated with higher risk for cardiovascular events and kidney death, respectively (6). These results seemed contradictory to our finding. However, this analysis was not an examination of whether elevated nocturnal diastolic BP is harmful per se; rather, it evaluated the prognostic implications of a specific nocturnal hypertension phenotype.
Some findings of this study merit further discussions. Patients with isolated nocturnal systolic hypertension had a higher risk for cardiovascular events than patients with nocturnal systolic-diastolic hypertension in this analysis, although the absolute values of systolic and diastolic BP were lower in the former group than in the latter group. This might be explained by the relationship between PP and cardiovascular disease. Wide PP was regarded as an independent risk factor associated with greater risk of cardiovascular and all-cause mortality in the general population (23). PP values in patients with isolated nocturnal systolic hypertension were higher than those of patients with nocturnal systolic-diastolic hypertension in this study. In addition, patients with nocturnal systolic-diastolic hypertension showed a higher risk for kidney failure, whereas isolated nocturnal systolic hypertension did not. Analysis showed that patients with isolated nocturnal systolic hypertension had lower MAP compared with patients with nocturnal systolic-diastolic hypertension. Whether kidney vasculature is more prone to increased MAP needs to be studied further.
Chronotherapy has been proposed to treat nocturnal hypertension in recent years, of which controversy still remains. In a three-period, crossover trial, former participants of the African American Study of Kidney Disease did not show significant differences in nocturnal BP value when taking medication at bedtime compared with morning dosing of antihypertensive medications (24). However, the Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events study reported that subjects taking at least one antihypertensive drug at bedtime achieved better nighttime BP control with significantly lower risk of total cardiovascular events than those ingesting all medications upon awakening (25). Similar results were observed in patients with CKD with bedtime dosing in reduction in risk for cardiovascular events (26). More randomized controlled trials are needed to determine whether achieving nighttime BP goals is causally associated with good outcomes.
This study has some limitations. First, ABPM was not mandatory for patients’ enrollment into the C-STRIDE cohort. Therefore, those excluded patients who did not receive ABPM may introduce some unmeasured bias, although they had comparable baseline characteristics with those included in this analysis. In addition, ABPM was just performed once at enrollment. The reproducibility of nocturnal hypertension and its entity was not evaluated during follow-up. Second, doubling of serum creatinine and/or 50% decline in eGFR, as established surrogate kidney end points, were not included in this study. Because patients with CKD stages 1 and 2 were less likely to progress to initiation of dialysis or transplantation in this follow-up time frame, lack of this information might weaken the power for kidney failure evaluation. Third, although our multivariable analyses included careful adjustment for covariates, we cannot exclude the possibility of residual confounding from other unrecorded covariates that were not ascertained. For instance, nocturnal BP was also influenced by sleep length and status (27–29), data on which were lacking and unavailable for adjustment in this analysis. Finally, our cohort consisted of only Chinese patients with CKD, who may have different clinical features compared with other CKD cohorts from Western countries, such as CKD causes, comorbidity prevalence, and environmental as well as treatment factors. Hence, the results may not be directly extrapolated to other CKD populations.
Nocturnal systolic hypertension, either alone or in combination with diastolic hypertension, is associated with higher risks for adverse outcomes in patients with CKD. Treatment strategies that preferentially have nocturnal systolic BP under control may help to improve prognosis of CKD.
Disclosures
L. Zhang reports employment with Peking University. M. Zhao reports consultancy agreements with Roche; receiving honoraria from the Asian-Pacific Society of Nephrology, the Chinese Medical Association, the Chinese Society of Nephrology, and International Society of Nephrology; and serving as an executive member of Asian-Pacific Society of Nephrology, Vice President of the Chinese Society of Internal Medicine, and Vice President of the Chinese Society of Nephrology. All remaining authors have nothing to disclose.
Funding
This study was supported by National Health and Family Planning Commission of the People’s Republic of China Research Special Fund for Public Welfare Industry of Health grant 201002010; the National Key Technology R&D Program of the Ministry of Science and Technology grants 2011BAI10B01 and 2016YFC1305400; National Natural Science Foundation of China grants 91846101, 81771938, and 81301296; Beijing Nova Programme Interdisciplinary Cooperation project Z191100001119008; the University of Michigan Health System-Peking University Health Science Center Joint Institute for Translational and Clinical Research grants BMU20160466, BMU2018JI012, and BMU2019JI005; and Peking University grants BMU2018MX020 and PKU2017LCX05.
Supplementary Material
Acknowledgments
The authors express gratitude to every participant and member of the C‐STRIDE group for their collaboration.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
Contributor Information
Collaborators: The Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE) Collaborators, Ming-Hui Zhao, Luxia Zhang, Xiaoqin Wang, Jun Yuan, Qiaoling Zhou, Qiongjing Yuan, Menghua Chen, Xiaoling Zhou, Shuxia Fu, Shaomei Li, Yan Zha, Rongsai Huang, Zhangsuo Liu, JunJun Zhang, Li Wang, Lei Pu, Jian Liu, Suhua Li, Zuying Xiong, Wei Liang, Jinghong Zhao, Jiao Mu, Xiyan Lian, Yunjuan Liao, Hua Gan, Rong Wang, Zhimei Lv, Yunhua Liao, Ling Pan, Xiaoping Yang, Zhifeng Lin, Zongwu Tong, Yun Zhu, Qiang He, Fuquan Wu, Rong Li, Kai Rong, Caili Wang, Yanhui Zhang, Yue Wang, Wen Tang, Hua Wu, Ban Zhao, Rongshan Li, Lihua Wang, Detian Li, Feng Du, Yonggui Wu, Wei Zhang, Shan Lin, Pengcheng Xu, Hongli Lin, Zhao Hu, Fei Pei, Haisong Zhang, Yan Gao, Luying Sun, Xia Li, Wenke Wang, Fengling Lv, Deguang Wang, Xuerong Wang, Dongmei Xu, Lijun Tang, Yingchun Ma, Tingting Wang, Ping Fu, Tingli Wang, Changying Xing, Chengning Zhang, Xudong Xu, Haidong He, Xiaohui Liao, Shuqin Xie, Guicai Hu, and Lan Huang
Supplemental Material
This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.14420920/-/DCSupplemental.
Supplemental Table 1. The inclusion and exclusion criteria of the C-STRIDE study.
Supplemental Table 2. Comparison of baseline characteristics between included and excluded participants in this study.
Supplemental Table 3. Baseline characteristics of the participants stratified by nighttime BP control status.
Supplemental Table 4. Association of nocturnal hypertension entities with kidney failure and cardiovascular events after additional adjustment with antihypertensive and hypoglycemic treatment.
Supplemental Table 5. Association of nocturnal hypertension entities with kidney failure and cardiovascular events using multiple imputation to fill missing data of covariate.
Supplemental Table 6. Association of nocturnal hypertension entities with kidney failure and cardiovascular events in patients with eGFR<60 ml/min per 1.73 m2 (n=1405).
Supplemental Table 7. Association of nocturnal hypertension entities with components of the cardiovascular events.
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