Masked and White-Coat Hypertension in Chronic Kidney Disease: A Meta-analysis

Farhan Bangash* and Rajiv Agarwal*† *Department of Medicine, Indiana University School of Medicine and †Department of Medicine, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana

Background and objectives: Poor hypertension control observed in patients with chronic kidney disease (CKD) may in part be due to the suboptimal assessment of BP with clinic BP measurements alone. The goal of this meta-analysis was to estimate the prevalence and determinants of white-coat and masked hypertension in the adult CKD population. Design, setting, participants, & measurements: Articles reporting prevalence of masked and white-coat hypertension in patients with CKD were obtained from two major databases. We then performed a meta-analysis to derive pooled estimates of prevalence and determinants of these two conditions. Results: Among 980 patients with CKD identified in six studies, the overall prevalence of masked hypertension was 8.3% and of white-coat hypertension was 18.3%. More alarming, 40.4% of patients who had CKD and were thought to have normotension (or adequately treated hypertension) in fact had hypertension at home. Also 30.0% of patients who had CKD and were thought to have hypertension had normotension at home. The thresholds for classification of clinic and ambulatory BP as hypertensive strongly influenced the risk for diagnosis of masked hypertension in favor of white-coat hypertension. Conclusions: Because clinic BP measurements alone lead to substantial misclassification in BP, we estimate that the prevalence of poorly controlled hypertension is likely less than currently estimated. Out-of-office BP monitoring may improve the management of hypertension in patients with CKD. Standardized definitions for the diagnosis of masked and white-coat hypertension would facilitate research. Clin J Am Soc Nephrol 4: 656–664, 2009. doi: 10.2215/CJN.05391008

revalent in 80 to 90% of patients with chronic kidney ble to measure discrepancies between clinic-recorded BP and disease (CKD) (1), hypertension is widely known to ambulatory BP readings to define characteristics of hyperten- P accelerate progression of CKD and increase the risk for sion that are dependent on the location of BP measurement. A cardiovascular events (2). Despite the recommendations for widely known condition is white-coat hypertension, defined as stricter BP control in patients with CKD (Ͻ130/80 mmHg) elevated BP in the clinic but a normal ambulatory BP (6). compared with those with , only 27% Somewhat less recognized but potentially of great importance Ͻ achieve a BP goal of 140/90 mmHg, and even fewer (11%) is the discovery of patients with higher BP on ambulatory BP Ͻ reach goal BP of 130/85 mmHg (2). A major reason that monitoring (ABPM) compared with clinic BP; this condition is approximately 90% of patients with CKD are unable to achieve called masked hypertension, a term coined by Pickering et al. goal BP is because of volume overload as well as activation of (7). If the likelihood of white-coat hypertension is greater than numerous mechanisms as a direct result of underlying kidney the likelihood of masked hypertension, then the true preva- disease, which makes BP resistant to control with antihyper- lence of poorly controlled hypertension may be lower. tensive drugs (3); however, often ignored is the consideration Location-dependent hypertension (masked hypertension that hypertension may seem to be poorly controlled because of and white-coat hypertension) is not simply a statistical quirk suboptimal BP assessment. that may influence the estimates of true prevalence of poorly Automatic ambulatory BP measurement and self-measure- controlled hypertension. Location-dependent hypertension ments of BP allow not only a greater number of measurements informs the prognosis of patients with hypertension (8,9). In but also because BP are sampled in the patients’ natural envi- the general population, people with white-coat hypertension ronment make these measurements more valid. In fact, numer- ous studies have documented that self-measured or automatic have a more benign prognosis than individuals with true ambulatory BP is prognostically superior (4,5). It is now possi- hypertension, and people with masked hypertension have worse outcomes compared with people with true normoten- sion (10). In the CKD population, patients with masked Received October 20, 2008. Accepted December 7, 2008. hypertension are more likely to progress to ESRD and die (11). Thus, estimating the prevalence of masked hyperten- Published online ahead of print. Publication date available at www.cjasn.org. sion and white-coat hypertension is of epidemiologic as well Correspondence: Dr. Rajiv Agarwal, Department of Medicine, VAMC, 111N, 1481 West 10th Street, Indianapolis, IN 46202. Phone: 317-988-2241; Fax: 317-988- as of clinical importance. Accordingly, the goal of this sys- 2171; E-mail: [email protected] tematic review was to estimate the prevalence and determi-

Copyright © 2009 by the American Society of Nephrology ISSN: 1555-9041/403–0656 Clin J Am Soc Nephrol 4: 656–664, 2009 Location-Dependent Hypertension in CKD 657 nants of white-coat and masked hypertension in the adult CKD population.

Materials and Methods Search Strategy and Selection Criteria We searched the PubMed database with the terms “masked hyper- tension” and “kidney disease.” In addition, we searched using MeSH terms “kidney failure, chronic,” “masked hypertension,” and “white- coat hypertension.” Keywords used were “masked hypertension,” “re- verse white coat hypertension,” “renal disease,” and “chronic kidney disease.” We also searched the OVID/MEDLINE (1950 to present) database using the subject heading terms “kidney failure, chronic,” “hypertension,” and “prevalence.” Keywords used were “masked hy- pertension,” “chronic kidney disease,” and “white-coat hypertension.” We restricted our search to humans. To be included in our study, Figure 1. Inclusion and exclusion diagram for articles that fi- studies had to report the prevalence of masked hypertension or provide nally were selected for meta-analysis. enough information to calculate this, and methods of BP measurement needed to be clearly noted. In addition to this search, we manually reviewed references cited in our retrieved articles and review articles. The prevalence of masked hypertension from the individual Our medical librarian did an additional search to ensure completeness. studies ranged from 4.7 to 31.3%. The average weighted prev- Only one article obtained was not in English and judging by abstract alence from all studies was 8.3% (95% CI 6.6 to 10.0%; Figure 2). was not included because it was not relevant. Among patients who had normotension on the basis of clinic All data were abstracted with a standardized data collection form by BP, the prevalence of masked hypertension was 40.4% (95% CI both authors. From each article included, we abstracted the study design, year, number of included patients, age, gender, race, body mass 35.1 to 45.7%). There was substantial heterogeneity between 2 index, alcohol use, smoking status, diabetes status, hypertension treat- studies (I statistic 83.7%; Figure 3). The study of Uchida et al. ment status, , proteinuria, estimated GFR, prevalence of (13) was statistically influential in inflating the prevalence es- masked hypertension, white-coat hypertension, and normotension and timates, and omitting this study reduced the prevalence of sustained hypertension in patients with CKD only. masked hypertension among those who had normotension in clinic to 33.0% (95% CI 25.5 to 40.5%) and also reduced the Statistical Analysis between-study heterogeneity (I2 statistic 53.8%). Proportions of patients and the exact binomial confidence intervals The thresholds for classification of clinic and out-of-office (CI) were calculated. Using the inverse of the SE of these proportions, hypertension were heterogeneous (Table 2). Masked hyperten- we pooled the prevalence between studies with a fixed-effects model. sion was defined as clinic BP of Ͻ130 mmHg and ambulatory For the sake of comparison, random-effects models are also reported. BP Ն130 mmHg in two studies (17,18), clinic BP of Ͻ140 mmHg We used Forest plots to visualize the extent of variation between and home BP Ն130 mmHg in two studies (14,15), and clinic BP studies and the I2 statistic to quantify heterogeneity between studies. I2 of Ͻ140 mmHg and home BP Ն135 mmHg in two studies values that range from 0 to 100% describe the proportion of variation in (13,16). One study (16) measured home BP in triplicate, twice prevalence estimates that is due to between-study variation rather than sampling error (12). We obtained the group-specific and overall I2 as daily for 4 d, whereas others measured it over 2 wk to 1 mo but standard output of the metan program. All analyses were performed by only in the morning (13–15). The provenance of heterogeneity metan command of Stata 10.1 (Stata Corp., College Station, TX). The was explored by analyzing the studies by various definitions of impact of single studies on the overall pooled estimates was calculated masked hypertension used by the authors. If patients with CKD using metaninf program also in Stata 10.1. and with clinic BP Ͻ140 mmHg but Ն130 mmHg by out-of- office BP are considered to have masked hypertension, then Results such patients are more likely to be classified as having masked A total of 54 studies were obtained from our search, six of hypertension compared with patients with clinic BP Ͻ130 which were of adults with CKD and used for analysis (13–18). mmHg but Ն130 mmHg by out-of-office BP. The prevalence of The reasons for exclusion are shown in Figure 1. masked hypertension in studies that used the stricter definition The total number of patients with CKD from all studies was (clinic Ͻ130 mmHg, out of clinic Ն130 mmHg) was 5.3% (95% 930, and range of patients per study was 48 to 290 (Table 1). In CI 3.4 to 7.2%) compared with 19.8% (95% CI 16.1 to 23.6%) in four studies, all patients had CKD (14,15,17,18), whereas the studies that used the more liberal (clinic Ͻ140 mmHg, out of other two studies (13,16) defined the percentage of patients clinic Ն130 mmHg) definition (overall test of heterogeneity with CKD. In three studies (13–15), all patients were treated between subgroups 45.3; P Ͻ 0.001; Figure 2). Of note, there with antihypertensive drugs, in one study none of the patients was still a large amount of variability in the prevalence of were treated with antihypertensive drugs (16), and in two masked hypertension in studies that used the more liberal studies (17,18) mostly treated patients (approximately 90%) definition of masked hypertension. This may have been related were included in the study. Four of the studies used self BP to no exposure to antihypertensive drugs in the study of Matsui monitoring (13–16) and two studies (17,18) used 24-h BP mon- et al. (16), in contrast to between 90 to 100% prevalence of itoring as the reference standard. use in other studies. 5 lnclJunlo h mrcnSceyo Nephrology of Society American the of Journal Clinical 658

Table 1. Characteristics of studies to masked hypertensiona

Population Characteristics Clinic BP Out-of-Office BP GFR (ml/ Author Year BP Treatment Treated Diabetes Proteinuria min per Classification Status (%) Smokers (%) (g/d) 2 Systolic Diastolic Systolic Diastolic N Age Men BMI 1.73 m ) (%) (kg/m2) (%) (mmHg) (mmHg) (mmHg) (mmHg)

Andersen (18) 2005 ALL Tr & Untr 89.7 232 67 96.1 30.4 20.7 38.8 0.124 48.0 154.1 83.3 135.2 75.6 Normotensive Tr & Untr – 32 – – – – – – – – – – – Masked Tr & Untr – 11 – – – – – – – – – – – White-coat Tr & Untr – 57 – – – – – – – – – – – Sustained Tr & Untr – 132 – – – – – – – – – – – HTN Kuriyama (14) 2005 Normotensive Tr 100.0 22 57 – 23.5 22.0 60.0 0.900 – – – – – Masked Tr 100.0 11 63 – 22.5 36.0 51.0 – – – – – – White-coat Tr 100.0 7 60 – 23.3 28.0 52.0 – – – – – – Sustained Tr 100.0 17 61 – 24.1 23.0 48.0 2.600 – – – – – HTN Matsui (16) 2007 Normotensive Untr 0.0 16 – – – – – – – 130.0 76.0 122.0 72.0 Masked Untr 0.0 6 – – – – – – – 133.0 79.0 145.0 81.0 White-coat Untr 0.0 12 – – – – – – – 151.0 84.0 126.0 72.0 Sustained Untr 0.0 40 – – – – – – – 161.0 85.0 154.0 82.0 HTN Minutolo (17) 2007 Normotensive Tr & Untr 84.4 45 56.4 62.2 27.7 24.4 17.8 0.760 38.0 118.0 78.0 117.0 74.0 Masked Tr & Untr 94.1 17 70.3 64.7 25.9 17.6 29.4 0.860 35.2 123.0 69.0 139.0 75.0 White-coat Tr & Untr 96.7 92 68.3 54.3 29.5 16.3 31.5 0.540 38.7 146.0 82.0 120.0 71.0 Sustained Tr & Untr 94.9 136 67.5 61.0 28.5 24.3 41.9 1.340 34.4 158.0 83.0 147.0 80.0 HTN Kuriyama (15) 2007 ALL Tr 100.0 48 64 – – – 38.0 2.400 17.6 135.0 80.0 138.0 82.0 Normotensive Tr 100.0 13 – – – – – – – – – – –

Masked Tr 100.0 15 – – – – – – – – – – – 2009 656–664, 4: Nephrol Soc Am J Clin White-coat Tr 100.0 6 – – – – – – – – – – – Sustained Tr 100.0 14 – – – – – – – – – – – HTN Uchida (13) 2008 Normotensive Tr 100.0 44 – – – – – – – 126.0 75.0 125.0 77.0 Masked Tr 100.0 64 – – – – – – – 129.0 74.0 149.0 84.0 White-coat Tr 100.0 24 – – – – – – – 152.0 83.0 127.0 77.0 Sustained Tr 100.0 97 – – – – – – – 155.0 84.0 153.0 84.0 HTN

a BMI, body mass index; Clinic BP, BP taken in office eGFR, estimated GFR; HTN, hypertension; Out-of-Office BP, either self BP monitoring or 24-h BP monitoring; Tr, treated; Untr, untreated. Clin J Am Soc Nephrol 4: 656–664, 2009 Location-Dependent Hypertension in CKD 659

study yr Prevalence (95% CI) Weight Masked Total (%) (n) (n)

Method: clinic BP = out-of-office BP

Minutolo (17) 2007 0.06 (0.03, 0.09) 40.1 17 290

Andersen (18) 2005 0.05 (0.02, 0.07) 39.2 11 232

Fixed Subtotal (I-squared = 0.0%, p = 0.568) 0.05 (0.03, 0.07) 79.3

Random Subtotal 0.05 (0.03, 0.07)

clinic>out of office BP

Kuriyama -epo (15) 2007 0.31 (0.18, 0.44) 1.7 15 48

Matsui (16) 2007 0.08 (0.02, 0.14) 7.6 6 74

Uchida (13) 2008 0.28 (0.22, 0.34) 8.7 64 229

Kuriyama (14) 2005 0.19 (0.09, 0.30) 2.8 11 57

Fixed Subtotal (I-squared = 87.5%, p <0.001) 0.20 (0.16, 0.24) 20.7

Random Subtotal 0.21 (0.10, 0.33)

Heterogeneity between groups: p <0.001

Fixed Overall (I-squared = 92.8%, <0.001) 0.08 (0.07, 0.10) 100

Random Overall 0.15 (0.08, 0.22)

0 .1 .2 .3 .4 .5

Figure 2. Forest plot shows the prevalence of masked hypertension. When studies were divided on the basis of the criteria used for diagnosis of masked hypertension, it was found that studies that used a more strict criterion (clinic systolic BP Ͻ130 mmHg, ambulatory BP Ն130 mmHg) were less likely to find masked hypertension, compared with studies that used a more liberal criterion (clinic systolic BP Ͻ140 mmHg, home BP Ն130 to 135 mmHg).

The prevalence of white-coat hypertension from the individ- Given the information in the previous paragraph, it is likely ual studies ranged from 10.5 to 31.7%. The average weighted that definitions that are used to classify patients as having prevalence of white-coat hypertension from all studies was masked hypertension or normotension are likely to influence 18.3% (95% CI 15.9 to 20.7%; Figure 4). Among patients who the risk for being classified as having masked hypertension had hypertension on the basis of clinic BP, the prevalence of when patients have normal clinic BP compared with the risk for white-coat hypertension was 30.0% (95% CI 26.5 to 33.5%; being classified as having white-coat hypertension when they Figure 5). There was substantial heterogeneity between studies have elevated clinic BP. Figure 6 illustrates that the definitions (I2 statistic 74.3%). No one study was influential. that are used to classify patients as having hypertension or The provenance of heterogeneity was explored by analyzing normotension indeed can influence the risk for being classified the studies by various definitions of white-coat hypertension as having masked hypertension compared with white-coat hy- used by the authors. The prevalence of white-coat hypertension pertension. When the thresholds for classification of clinic and in studies that used the ambulatory BP–guided definition was ambulatory BP are equal, the risk for diagnosis of masked 28.3% (95% CI 24.4 to 32.1%) compared with 11.7% (95% CI 8.6 hypertension is less: Risk ratio 0.74 (95% CI 0.53 to 1.04). When to 14.9%) in studies that used the more strict definition (Figure the clinic BP can be higher and home BP lower, the risk for the 4). Of note, there was still a large amount of variability in the diagnosis of masked hypertension is greater: Risk ratio 1.36 prevalence of white-coat hypertension between studies using (95% CI 1.08 to 1.70), overall test for heterogeneity between the more liberal definition of white-coat hypertension (I2 sta- subgroups 21.2 (P Ͻ 0.001). tistic 69.8%). This may have been related to measurement meth- ods (e.g., Andersen et al. [18] measured BP in both arms in the Discussion clinic and used the higher of the two measurements as the clinic In patients with masked hypertension, early studies sug- BP, whereas Minutolo et al. [17] did not), true difference in gested greater prevalence of target organ damage (19). Subse- prevalence, or other factors. quently, it was discovered that in patients with essential hy- 660 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: 656–664, 2009

yduts ry ecnelaverP %59( )IC Weight Masked Normal Clinic (%) (n) BP (n)

Method: clinic BP = out-of-office BP Minutolo (17) 2007 0.27 (0.16, 0.39) 23.0 17 62 Andersen (18) 2005 0.26 (0.13, 0.39) 16.7 11 43 Fixed Subtotal (I-squared = 0.0%, p = 0.833) 0.27 (0.18, 0.35) 39.6 RandomSubtotal 0.27 (0.18, 0.35)

Clinic>out-of-office BP Kuriyama-epo (15) 2007 0.54 (0.35, 0.72) 8.3 15 28 Matsui (16) 2007 0.27 (0.09, 0.46) 8.2 6 22 Uchida (13) 2008 0.59 (0.50,(, 0.69) )33.0 64 108 Kuriyama (14) 5002 0.3333.0 (0.17,,71.0( 0.49))94.0 11.0 11 33 Random Subtotal (I-squared = 78.3%, p = 0.003) 0.49 (0.43, 0.56) 60.4 Fixed Subtotal 0.44 (0.28, 0.60)

Heterogeneity between groups: p<0.001 Fixed Overall (I-squared = 83.7%, p<0.001) 0.40 (0.35, 0.46) 100.00 Random Overall 0.38 (0.24, 0.52)

0 .1 .2 .3 .4 .5 .6 .7 .8

Figure 3. Forest plot shows the prevalence of masked hypertension among patients with normal BP in the clinic. When studies were divided on the basis of the criteria used for diagnosis of masked hypertension, it was found that studies that used a more strict criterion (clinic systolic BP Ͻ130 mmHg, ambulatory BP Ն130 mmHg) were less likely to find masked hypertension, compared with studies that used a more liberal criterion (clinic systolic BP Ͻ140 mmHg, home BP Ն130 to 135 mmHg).

Table 2. Technique of BP monitoringa

Clinic BP Out-of-Office BP Study Threshold of Threshold of Hypertension Technique Hypertension Method Technique

Andersen (18) 130/80 Two visits, sitting, triplicate, 130/80 ABPM Awake ambulatory (2005) both arms, higher of the recorded every 20 min two used, oscillometric Kuriyama (14) 140/90 “Each visit,” one 130/85 Home BP Several times during (2005) measurement, no method approximately 2 wk, stated within 30 min of waking Matsui (16) 140/90 Two visits, sitting, triplicate, 135/85 Home BP Triplicate, measured in (2007) oscillometric morning and evening for4d Minutolo (17) 130 Two visits, sitting, triplicate, 130 ABPM Daytime ambulatory, (2007) auscultated recorded every 15 min Kuriyama (15) 140/90 “Each visit,” one 130/85 Home BP Seated, 2 wk, average of (2007) measurement, no method several stated Uchida (13) 140 One visit, sitting, between 135 Home BP Single recording, three (2008) 9:00 and 11:00 a.m. consecutive days within1hofwaking

aABPM, ambulatory BP monitoring. Clin J Am Soc Nephrol 4: 656–664, 2009 Location-Dependent Hypertension in CKD 661

Prevalence (95% CI) Weight White-coat Total study yr (%) (n) (n)

Method: clinic BP = out-of-office BP Minutolo (17) 2007 0.32 (0.26, 0.37) 20.5 92 290

Andersen (18) 2005 0.25 (0.19, 0.30) 19.1 57 232 Fixed Subtotal (I-squared = 69.8%, p = 0.069) 0.28 (0.24, 0.32) 39.6 Random Subtotal 0.28 (0.21, 0.35)

clinic > out-of-office BP Kuriyama -epo (15) 2007 0.13 (0.03, 0.22) 6.7 6 48 Matsui (16) 2007 0.16 (0.08, 0.25) 8.3 12 74 Uchida (13) 2008 0.10 ((,0.07, 0.14 ) 37.3 24 229

0.12 (0.04, 0.21) 8.1 7 57 Fixed Subtotal (I-squared = 0.0%, p = 0.678) 0.12 (0.09, 0.15) 60.4

Random Subtotal 0.12 (0.09, 0.15)

Heterogeneity between groups: p <0.001 Fixed Overall (I-squared = 89.5%, p <0.001) 0.18 (0.16, 0.21) 100 Random Overall 0.18 (0.10, 0.26)

0 .1 .2 .3 .4 .5

Figure 4. Forest plot shows the prevalence of white-coat hypertension. When studies were divided on the basis of the criteria used for diagnosis of white-coat hypertension, it was found that studies that used a more strict criterion (clinic systolic BP Ն130 mmHg, ambulatory BP Ͻ130 mmHg) were more likely to find white-coat hypertension, compared with studies that used a more liberal criterion (clinic systolic BP Ն140 mmHg, home BP Ն130 to 135 mmHg). pertension, masked hypertension was also associated with poor clinic and ambulatory BP are equal, the risk for diagnosis of outcomes (20). A recent meta-analysis noted that cardiovascu- masked hypertension is less (risk ratio 0.74). When the clinic BP lar events and mortality both are elevated in patients with threshold is higher and home BP threshold is lower, the risk for masked hypertension detected by self-measured BP (8). In a the diagnosis of masked hypertension is greater (risk ratio 1.36). small and only study in patients with CKD, masked hyperten- These data also suggest that true prevalence of well-controlled sion increased the chances of ESRD compared with those with hypertension is greater in patients with CKD than what is truly normal BP, and those with white-coat hypertension had currently estimated from clinic BP measurements alone. As a lower risk for ESRD compared with patients with persistent direct example, in one study, adequate systolic BP control hypertension (11). (Ͻ130 mmHg) was seen only among 19% of patients with CKD In this meta-analysis, we found that in patients with CKD, with clinic BP but doubled to 38% when ABPM was performed the overall prevalence of masked hypertension was approxi- for the same patients (18). mately 8% and of white-coat hypertension was approximately There was a notable heterogeneity in prevalence of masked 18%. Perhaps more alarming, one third of patients who had hypertension between studies that is unlikely to be a result of CKD and were thought to have normotension (or adequately the variations in the technique of out-of-office BP measure- treated hypertension) in fact had hypertension at home. Also, ments whether they are performed by self-measured or auto- approximately one third of patients who had CKD and were matic ambulatory measurements (21). The heterogeneity may thought to have hypertension (or inadequately treated hyper- be better explained by the cutoffs used to define normal and tension) in fact did have normotension at home. Thus, clinic BP abnormal BP. In this context, hypertension in patients with measurement leads to substantial misclassification in BP. CKD poses a dilemma. Because clinic BP is targeted to Ͻ130/80 Another important finding of our study was that the defini- instead of Ͻ140/90 mmHg in those with essential hypertension tions that are used to classify patients as having hypertension and because hypertension is more difficult to control in those or normotension can influence the risk for being classified as with CKD, fewer patients with CKD are classified as having having masked hypertension compared with white-coat hyper- normotension. If the thresholds that are used to diagnose hy- tension. We found that when the thresholds for classification of pertension control in CKD are those recommended for essential 662 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: 656–664, 2009

study yr Prevalence (95% CI) Weight White-coat High Clinic (%) (n) BP (n)

Method: clinic BP = out-of-office BP Minutolo (17) 2007 0.40 (0.34, 0.47) 30.5 92 136

Andersen (18) (Std) 2005 0.30 (0.24, 0.37) 28.9 57 132

Fixed Subtotal (I-squared = 79.1%, p = 0.029) 0.35 (0.31, 0.40) 59.3

Random Subtotal 0.35 (0.25, 0.45)

clinic> out-of-office BP

Kuriyama (EPO) (15) 2007 0.30 (0.10, 0.50) 3.1 6 14

Matsui (16) 2007 0.23 (0.12, 0.35) 9.4 12 40

Uchida (13) 2008 0.20 (0.13, 0.27) 24.5 24 97

0.29 (0.11, 0.47) 3.7 7 17

Fixed Subtotal (I-squared = 0.0%, p = 0.661) 0.22 (0.17, 0.28) 40.7

Random Subtotal 0.22 (0.17, 0.28)

Heterogeneity between groups: p < 0.001

Fixed Overall (I-squared = 74.3%, p = 0.002) 0.30 (0.27, 0.34) 100

Random Overall 0.29 (0.21, 0.37)

0 .1 .2 .3 .4 .5 .6

Figure 5. Forest plot shows the risk ratio of masked hypertension (among clinic normotension) to white-coat hypertension (among clinic hypertension). The risk for white-coat hypertension was greater in studies that used a more strict criterion to diagnose masked hypertension (clinic systolic BP Ͻ130 mmHg, ambulatory BP Ն130 mmHg). The risk for masked hypertension was greater in studies that used a more liberal criterion to diagnose masked hypertension (clinic systolic BP Ͻ140 mmHg, home BP Ն130 to 135 mmHg).

hypertension, then the prevalence of well-controlled hyperten- clinic diastolic BP persistently between 90 and 104 mmHg (6). sion in clinic should increase, which may also inflate the prev- Among patients with hypertension in the clinic, we found a alence of masked hypertension. In fact, in a recently reported prevalence of 30.0% (95% CI 26.5 to 33.5%), which is at least as meta-analysis, the prevalence of masked hypertension in pa- high as seen in the population without CKD. tients with essential hypertension was found to be 16.8% (95% Some recommendations for more uniform reporting of CI 13.0 to 20.5%). When we used definitions to diagnose masked and white-coat hypertension can be formulated on the masked hypertension that are used in the general population, basis of this review. Hypertension treatment for patients with our results found a similar prevalence of masked hypertension CKD is guided by clinic-measured BP, and guidelines call for (19.8%; 95% CI 16.1 to 23.6%); however, using CKD-specific targeting this BP to Ͻ130/80 mmHg. Similar guidelines for thresholds lowered the prevalence of masked hypertension to ambulatory BP are not available; however, some information 5.3% (95% CI 3.4% to 7.2%). Thus, patients with CKD may have can be derived to target ambulatory BP from the international a prevalence that is similar to what has been reported in the collaboration of investigators that led to analysis of pooled data general population, but this depends largely on the definition. in normal individuals and patients with essential hypertension The meta-analysis of Verberk et al. (21) in the general popula- in several countries to calibrate the BP level using ABPM that is tion included studies that excluded patients with poorly con- associated with optimal, normal, or hypertensive clinic BP (22). trolled clinic hypertension, which may have inflated prevalence From these investigations, the threshold BP that would corre- estimates. Our data provide support for the notion that the true late with cardiovascular mortality rate similar to BP thresholds prevalence can be reliably estimated only by including patients of Ͻ130/80 mmHg would be 125/75 mmHg for 24-h recording, with CKD regardless of BP control. Excluding patients with 130/80 mmHg for daytime recording, and 110/65 mmHg for hypertension will inflate estimates of the prevalence of masked nighttime recording. Because the diagnoses of masked and hypertension. white-coat hypertension are made during the day, considering The prevalence of white-coat hypertension in the population a daytime threshold of Ն130/80 mmHg in patients who have without CKD was reported to be 21% among patients with CKD and are not on dialysis seems appropriate. Keeping in Clin J Am Soc Nephrol 4: 656–664, 2009 Location-Dependent Hypertension in CKD 663

study yr Risk Ratio (95% CI) Weight (%) Method: clinic BP = out-of-office BP Minutolo (17) 2007 0.68 (0.44, 1.05) 26.6 Andersen (18) 2005 0.85 (0.49, 1.48) 16.4 Fixed Subtotal (I2 = 0.0%, p = 0.537) 0.74 (0.53, 1.04) 43.0 Random Subtotal 0.74 (0.53, 1.04)

clinic>out-of-office BP Kuriyama-epo (15) 2007 1.79 (0.84, 3.79) 8.9 Matsui (16) 2007 1.18 (0.51, 2.75) 7.1 Uchida (13) 2008 2.99 (2.02, 4.42) 32.9 (14) 1.14 (0.52, 2.51) 8.1 Fixed Subtotal (I2 = 59.2%, p = 0.061) 2.14 (1.59, 2.89) 57.0 Random Subtotal 1.78 (1.05, 3.01)

Heterogeneity between groups: p <0.<0 001 Fixed Overall (I2= 82.7%, p <0.001) 1.36 (1.08, 1.70) 100 Random Overall 1.27 (0.72, 2.25)

2. 151 .4

Figure 6. Forest plot shows that the definitions that are used to classify patients as having hypertension or normotension indeed can influence the risk for being classified as having masked hypertension compared with white-coat hypertension. When the thresholds for classification of clinic and ambulatory BP are equal, the risk for diagnosis of masked hypertension is less: Risk ratio 0.74 (95% CI 0.53 to 1.04). When the clinic BP can be higher and home BP lower, the risk for the diagnosis of masked hypertension is greater: Risk ratio 1.36 (95% CI 1.08 to 1.70), overall test for heterogeneity between subgroups 21.2 (P Ͻ 0.001). mind these considerations, the exact methods of measurement treated and those with masked hypertension may not be of clinic and out-of-office BP should be specified by investiga- treated enough. Because a large number of patients may be left tors. In fact, simply taking “usual” BP recordings in the clinic untreated (masked hypertension) or treated too aggressively and comparing them with standardized measurements of BP (white-coat hypertension), a simple yet effective strategy and can dramatically alter the prevalence estimates of white-coat one supported by the American Heart Association is to monitor and masked hypertension (18). Investigators should report the home BP to assess BP control (23). Home BP monitoring can absolute BP and their SD and the differences in BP and the SD improve achievement of BP targets (24). Although home BP of the differences obtained in the office and out of office. This monitoring is an excellent tool to detect and manage hyperten- will allow better estimation of the magnitude of masked hy- sion, it cannot rule out masked hypertension or white-coat pertension effect and white-coat effect in patients with CKD. hypertension. Physical activity can have a powerful effect on What is unclear from these studies of patients with CKD is BP, especially in patients with CKD, who are more sedentary, whether masked hypertension is a chance finding or a repro- and those who are not treated with antihypertensive drugs (25). ducible phenomenon. Whether patients who have masked hy- Circadian rhythms can be identified only with ABPM. Thus, for pertension on one occasion will have the same diagnosis when research purposes, ABPM remains a reference standard. repeatedly studied should be evaluated in future studies. The causes that underlie masked hypertension remain obscure. The Acknowledgments samples that were used in this analysis were for the most part This study was supported by a grant from the Veterans Administra- clinically diagnosed patients who had hypertension and were tion Merit Review. receiving treatment. This sample would be biased in favor of diagnosing white-coat hypertension. For better defining the Disclosures prevalence of masked hypertension, representative samples of None. the population with CKD without regard to office-based BP status (and thus including office-based patients with normo- tension) should be studied in the future. More research is References needed to ascertain the clinical significance of masked hyper- 1. Sarafidis PA, Li S, Chen SC, Collins AJ, Brown WW, Klag tension and white-coat hypertension in patients with CKD. MJ, Bakris GL: Hypertension awareness, treatment, and The results of this study may have therapeutic implications, control in chronic kidney disease. Am J Med 121: 332–340, because patients with white-coat hypertension may be over- 2008 664 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: 656–664, 2009

2. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS: organ damage in patients with renal diseases: Effect of Prevalence of chronic kidney disease and decreased kidney intensive antihypertensive therapy in patients with dia- function in the adult US population: Third National Health betic nephropathy. Intern Med 44: 1239–1246, 2005 and Nutrition Examination Survey. Am J Kidney Dis 41: 15. Kuriyama S, Otsuka Y, Iida R, Matsumoto K, Hosoya T: 1–12, 2003 Morning at home predicts erythropoietin- 3. Campese VM, Mitra N, Sandee D: Hypertension in renal induced hypertension in patients with chronic renal dis- parenchymal disease: Why is it so resistant to treatment? eases. Clin Exp Nephrol 11: 66–70, 2007 Kidney Int 69: 967–973, 2006 16. Matsui Y, Eguchi K, Ishikawa J, Hoshide S, Shimada K, 4. Agarwal R: Ambulatory blood pressure and cardiovascu- Kario K: Subclinical arterial damage in untreated masked lar events in chronic kidney disease. Semin Nephrol 27: hypertensive subjects detected by home blood pressure 538–543, 2007 measurement. Am J Hypertens 20: 385–391, 2007 5. Hansen TW, Kikuya M, Thijs L, Bjorklund-Bodegard K, 17. Minutolo R, Borrelli S, Scigliano R, Bellizzi V, Chiodini P, Kuznetsova T, Ohkubo T, Richart T, Torp-Pedersen C, Cianciaruso B, Nappi F, Zamboli P, Conte G, De Nicola L: Lind L, Jeppesen J, Ibsen H, Imai Y, Staessen JA: Prognostic Prevalence and clinical correlates of white coat hyperten- superiority of daytime ambulatory over conventional sion in chronic kidney disease. Nephrol Dial Transplant 22: blood pressure in four populations: A meta-analysis of 2217–2223, 2007 7,030 individuals. J Hypertens 25: 1554–1564, 2007 18. Andersen MJ, Khawandi W, Agarwal R: Home blood pres- 6. Pickering TG, James GD, Boddie C, Harshfield GA, Blank sure monitoring in CKD. Am J Kidney Dis 45: 994–1001, S, Laragh JH: How common is white coat hypertension? 2005 JAMA 259: 225–228, 1988 19. Liu JE, Roman MJ, Pini R, Schwartz JE, Pickering TG, 7. Pickering TG, Davidson K, Gerin W, Schwartz JE: Masked Devereux RB: Cardiac and arterial target organ damage in hypertension. Hypertension 40: 795–796, 2002 adults with elevated ambulatory and normal office blood 8. Bobrie G, Chatellier G, Genes N, Clerson P, Vaur L, Vaisse pressure. Ann Intern Med 131: 564–572, 1999 B, Menard J, Mallion JM: Cardiovascular prognosis of 20. Fagard RH, Cornelissen VA: Incidence of cardiovascular “masked hypertension” detected by blood pressure self- events in white-coat, masked and sustained hypertension measurement in elderly treated hypertensive patients. versus true normotension: A meta-analysis. J Hypertens 25: JAMA 291: 1342–1349, 2004 2193–2198, 2007 9. Bobrie G, Clerson P, Menard J, Postel-Vinay N, Chatellier 21. Verberk WJ, Kessels AG, de Leeuw PW: Prevalence, G, Plouin PF: Masked hypertension: A systematic review. J Hypertens 26: 1715–1725, 2008 causes, and consequences of masked hypertension: A 10. Clement DL, De Buyzere ML, De Bacquer DA, de Leeuw meta-analysis. Am J Hypertens 21: 969–975, 2008 PW, Duprez DA, Fagard RH, Gheeraert PJ, Missault LH, 22. Kikuya M, Hansen TW, Thijs L, Bjorklund-Bodegard K, Braun JJ, Six RO, Van Der NP, O’Brien E: Prognostic value Kuznetsova T, Ohkubo T, Richart T, Torp-Pedersen C, of ambulatory blood-pressure recordings in patients with Lind L, Ibsen H, Imai Y, Staessen JA: Diagnostic thresholds treated hypertension. N Engl J Med 348: 2407–2415, 2003 for ambulatory blood pressure monitoring based on 10- 11. Agarwal R, Andersen MJ: Prognostic importance of clinic year cardiovascular risk. Circulation 115: 2145–2152, 2007 and home blood pressure recordings in patients with 23. Pickering TG, Miller NH, Ogedegbe G, Krakoff LR, Artin- chronic kidney disease. Kidney Int 69: 406–411, 2006 ian NT, Goff D: Call to action on use and reimbursement 12. Higgins JP, Thompson SG, Deeks JJ, Altman DG: Measur- for home blood pressure monitoring: A joint scientific ing inconsistency in meta-analyses. BMJ 327: 557–560, 2003 statement from the American Heart Association, American 13. Uchida H, Nakamura Y, Kaihara M, Norii H, Hanayama Y, Society of Hypertension, and Preventive Cardiovascular Makino H: The MUSCAT study: A Multicenter PROBE Nurses Association. Hypertension 52: 10–29, 2008 Study Comparing the Effects of Angiotensin II Type-1 24. Cappuccio FP, Kerry SM, Forbes L, Donald A: Blood pres- Receptor Blockers on Self-Monitored Home Blood Pressure sure control by home monitoring: Meta-analysis of ran- in Patients with Morning Hypertension—Study design and domised trials. BMJ 329: 145, 2004 background characteristics. Hypertens Res 31: 51–58, 2008 25. Agarwal R, Light RP: Physical activity and hemodynamic 14. Kuriyama S, Otsuka Y, Iida R, Matsumoto K, Tokudome G, reactivity in chronic kidney disease. Clin J Am Soc Nephrol Hosoya T: Morning blood pressure predicts hypertensive 3: 1660–1668, 2008