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NDT Advance Access originally published online on December 1, 2006
Nephrology Dialysis Transplantation 2007 22(3):911-916; doi:10.1093/ndt/gfl642
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Reverse white-coat effect as an independent risk for microalbuminuria in treated hypertensive patients

Toako Kato, Takeshi Horio, Mari Tomiyama, Kei Kamide, Satoko Nakamura, Fumiki Yoshihara, Hiroto Nakata, Hajime Nakahama and Yuhei Kawano

Division of Hypertension and Nephrology, Department of Medicine, National Cardiovascular Center, Suita, Japan

Correspondence and offprint requests to: Takeshi Horio, MD, Division of Hypertension and Nephrology, Department of Medicine, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan. Email: thorio{at}ri.ncvc.go.jp



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. The influence of the converse phenomenon of white-coat hypertension called ‘reverse white-coat hypertension’ or ‘masked hypertension’ on hypertensive target organ damage has not been fully elucidated. The present study assessed the hypothesis that this phenomenon may specifically associate with microalbuminuria, a marker of early renal damage, in treated hypertension.

Methods. A total of 267 treated essential hypertensive patients (133 men and 134 women; mean age, 66 years) without renal insufficiency or macroalbuminuria were enroled in this study. Patients were classified into three groups by the difference between office and day-time ambulatory systolic blood pressure (BP) levels; i.e. subjects with white-coat effect (W group: office – day-time systolic BP ≥20 mmHg, n = 48), with reverse white-coat effect (R group: office – day-time systolic BP < – 10 mmHg, n = 43) and without white-coat or reverse white-coat effect (N group: –10 mmHg ≤ office – day-time systolic BP <20 mmHg, n = 176). The urinary albumin (U-Alb) level was measured as the albumin to creatinine excretion ratio in the urine. Microalbuminuria was defined as U-Alb of ≥30 and <300 mg/g Cr.

Results. R group had a well-controlled office BP (130/77 mmHg), but their day-time BP (148/87 mmHg) was elevated compared with the other two groups. The levels of U-Alb excretion in N group, W group and R group were 12.3 (8.4, 25.6), 16.0 (10.5, 31.7) and 24.3 (10.2, 79.7) mg/g Cr [median (interquartile range)], respectively. Both U-Alb level and prevalence of microalbuminuria were significantly greater in R group than in N group. Multivariate analyses revealed that the presence of reverse white-coat effect, but not white-coat effect, was a significant predictor for microalbuminuria, independent of various clinical variables including ambulatory BP levels (odds ratio 2.63 vs N group, P = 0.02).

Conclusion. These findings suggest that the presence of reverse white-coat effect may be an independent risk for early renal damage in treated hypertensive patients.

Keywords: ambulatory blood pressure monitoring; hypertension; microalbuminuria



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Ambulatory blood pressure (BP) is an important determinant of target organ damage and a significant predictor for cardiovascular morbidity and mortality in hypertensive patients [1–6]. There is often a discrepancy between office and ambulatory BPs, and many studies have investigated the association between white-coat hypertension, a normal ambulatory but elevated office BP, and cardiovascular risk [7, 8]. On the other hand, the converse phenomenon of white-coat hypertension called ‘reverse white-coat hypertension’ or ‘masked hypertension’, i.e. a high ambulatory but normal (or well-controlled) office BP, has received little attention [9]. Whereas, some studies have revealed that the proportion of subjects with reverse white-coat effect evaluated by the difference between office and ambulatory BPs is 20–40% in the general population and hypertensives [10, 11]. In treated hypertensive patients with this phenomenon, particularly, the chance of active and sufficient antihypertensive treatment may be lost by an apparent well-controlled BP in the office. Recent studies suggested that an elevated ambulatory or home BP despite a well-controlled office BP, is associated with poor cardiovascular prognosis in treated hypertensive patients [12, 13]. However, the influence of reverse white-coat effect on target organ damage in treated hypertension has remained to be elucidated.

Microalbuminuria, which is one of the early end-organ changes observed in hypertensives, has been shown to be a significant risk for not only renal insufficiency but also cardiovascular events [14, 15]. Thus, the present study was aimed to investigate the association of reverse white-coat effect with microalbuminuria as a sensitive marker of target organ damage in treated hypertensive patients.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Subjects
From 314 consecutive patients with essential hypertension who were chronically treated and underwent a 24-h ambulatory BP monitoring at an outpatient clinic of our hospital between May 2000 and December 2003, 267 subjects [133 men and 134 women; age, 30–90 years (mean, 66 years)] in whom urinary albumin (U-Alb) data were simultaneously obtained were enroled in our retrospective study. Patients with secondary hypertension, stroke, ischaemic heart disease including myocardial infarction, congestive heart failure or insulin-treated diabetes mellitus were excluded from this study. Individuals with chronic glomerulonephritis, nephrotic syndrome, renal insufficiency (serum creatinine ≥1.5 mg/dl), or macroalbuminuria (described later) were also excluded. Diabetes mellitus was diagnosed according to the American Diabetes Association criteria, such as a fasting plasma glucose of ≥126 mg/dl and/or a plasma glucose level at 2 h after a 75 g oral glucose load of ≥200 mg/dl, or when medication was taken for treatment of hyperglycaemia. A diagnosis of hyperlipidaemia required a serum total cholesterol level of ≥220 mg/dl and/or a serum triglyceride level of ≥150 mg/dl or the use of lipid-lowering drugs.

All patients had taken antihypertensive drugs for at least 1 year (average, 12 years). A total of 185 (69%) were treated with Ca channel blockers, 86 (32%) with angiotensin II receptor blockers, 41 (15%) with angiotensin-converting enzyme inhibitors, 83 (31%) with ß-blockers, 51 (19%) with diuretics and 27 (10%) with other classes of agents. All subjects gave their informed consent to participate in the present study. All procedures of the present study were carried out in accordance with institutional and national ethical guidelines for human studies.

Measurement of BP
In each visit, office BP was measured twice by a physician in a hospital outpatient clinic with the patient in a sitting position after over 20 min of rest, using an appropriate-size arm cuff and mercury sphygmomanometer. The first and fifth Korotkoff sounds were used to identify systolic and diastolic values, respectively. Office BP was determined by averaging six measurements taken on three separate occasions during a 3-month period.

In the same study period, all subjects underwent 24-h ambulatory BP monitoring. BP was measured every 30 min during the day and night by the oscillometric method using an automatic monitoring device (TM-2421, A&D Co Ltd, Tokyo, Japan) [16]. The accuracy and performance of this device have been demonstrated previously [17]. The patients were instructed to carry on with their normal daily activities during measurements and note their activity and location in a diary. According to the diary, day-time and night-time were determined as the waking and sleeping periods of the patient, respectively, and mean values of 24-h, day-time and night-time BPs (systolic and diastolic) were calculated. Nocturnal BP dipping was determined as 100 x (day-time BP–night-time BP)/day-time BP.

In the present study, all subjects were classified into three groups by the difference between office and day-time ambulatory systolic BP levels according to some previous studies [10, 11, 18], with minor modifications; that is, subjects with overt white-coat effect (W group: office systolic BP – day-time systolic BP ≥20 mmHg), with overt reverse white-coat effect (R group: office systolic BP – day-time systolic BP <–10 mmHg) and with neither white-coat nor reverse white-coat effect (N group: –10 mmHg ≤ office systolic BP – day-time systolic BP <20 mmHg).

Biochemical measurement
Blood samples were obtained in the morning after an overnight fast. Fasting plasma glucose, haemoglobin A1c, total cholesterol, triglycerides and serum creatinine levels were determined by standard laboratory measurements. Creatinine clearance was calculated from the Cockcroft and Gault formula [19]. The U-Alb level was measured as the albumin to creatinine excretion ratio (mg/g Cr) in the urine. Mircoalbuminuria was defined as U-Alb of ≥30 and <300 mg/g Cr. Patients with macroalbuminuria (U-Alb ≥300 mg/g Cr) were excluded from the study.

Statistical analysis
Statistical analysis was performed using StatView Version 5.0 Software (Abacus Concepts Inc., Berkeley, CA, USA). Values are expressed as mean ± SE, except for U-Alb, and frequencies are expressed as percentages. Levels of U-Alb are given as median and interquartile range (25–75th percentiles). The significance of differences among the three groups (N group, W group and R group) was evaluated by an unpaired ANOVA with subsequent Scheffe's multiple comparison test. Due to skewed distribution, U-Alb levels were analysed by a non-parametric Kruskal–Wallis test. In addition, log-transformed U-Alb levels were used for comparison between groups or for correlation analysis. Simple correlations between log-transformed U-Alb and BP parameters were assessed using univariate linear regression analyses and Pearson's correlation coefficient. A multiple logistic regression analysis was used to identify independent determinants of microalbuminuria. A value of P < 0.05 was accepted as statistically significant.



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Clinical characteristics of the three subject groups classified according to the difference between office and day-time ambulatory systolic BP levels are summarized in Table 1. Forty-eight (18.0%) and 43 (16.1%) patients were identified as having overt white-coat effect (W group) and reverse white-coat effect (R group), respectively, and the other 176 (65.9%) patients belonged to N group. The proportion of men was higher and body mass index was greater in R group compared with W group. Duration of hypertension and period of medication were significantly shorter in R group than in W group. The prevalence of diabetes mellitus and hyperlipidaemia, the rate of current smokers, renal function and glucose and lipid parameters did not differ among the three groups. In addition, no intergroup differences were found in the use of any class of antihypertensive agent including angiotensin II receptor blocker and angiotensin-converting enzyme inhibitor and total number of classes of antihypertensive drugs.


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  		Table 1. Clinical characteristics of study subjects

 
Office systolic and diastolic BPs were significantly higher in W group and lower in R group compared with N group. Day-time, night-time and average 24-h ambulatory BPs were significantly elevated in R group than in the other two groups. There were no significant differences in ambulatory BPs between N group and W group, except that day-time systolic BP was somewhat lower in W group than in N group. The degree of nocturnal BP dipping, an index of circadian BP variation, did not differ among the three groups.

The U-Alb levels in N group, W group and R group were 12.3 (8.4, 25.6), 16.0 (10.5, 31.7) and 24.3 (10.2, 79.7) mg/g Cr, respectively, indicating that R group had a significantly higher level of U-Alb compared with N group (Figure 1A). The percentage of patients with microalbuminuria was also significantly higher in R group than in N group (Figure 1B). U-Alb level and prevalence of microalbuminuria in W group did not differ from those in N group.


Figure 1
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  		Fig. 1. U-Alb levels (A) and prevalence of microalbuminuria (B) in the three groups classified by the difference between office and day-time systolic BP levels. Values are given as median and interquartile range (25th–75th percentiles) (A) or percentage (B). Due to skewed distribution, U-Alb levels were analysed by a non-parametric Kruskal–Wallis test (P = 0.0095). Log-transformed U-Alb levels were used for comparison between groups.

 
To avoid the influence of diabetes mellitus or the specific effect of renin–angiotensin system (RAS) inhibitors (i.e. angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors) on U-Alb excretion, we re-examined the U-Alb level after excluding some subjects. Even after excluding patients with diabetes mellitus (n = 218), U-Alb level was significantly increased in R group than in N group [24.3 (10.5, 73.8) and 11.5 (7.6, 24.2) mg/g Cr, P = 0.0024]. Likewise, even after excluding patients receiving RAS inhibitors (n = 141), U-Alb level in R group was still higher compared with that in N group [36.5 (19.0, 101.3) and 12.1 (8.7, 26.2) mg/g Cr, P = 0.0004].

Simple correlations of office and ambulatory BPs with U-Alb levels were examined in all 267 subjects. Although office systolic or diastolic BP had no correlation with log-transformed U-Alb level (data not shown), log U-Alb was positively correlated with ambulatory systolic BP during day-time (r = 0.272, P < 0.0001), night-time (r = 0.230, P = 0.0001), and 24 h (r = 0.246, P < 0.0001). The difference between office and day-time systolic BP tended to correlate inversely with log U-Alb, but it was not statistically significant (r = –0.114, P = 0.0628).

To confirm whether the influence of reverse white-coat phenomenon on U-Alb excretion was independent of various clinical parameters including ambulatory BP levels, we investigated possible predictive factors using a multiple logistic regression analysis in all subjects. As shown in Table 2, the presence of reverse white-coat effect (i.e. R group) was found to be a significant predictor for microalbuminuria, independent of age, sex, hypertension duration, use of RAS inhibitor, complication of diabetes mellitus, renal function (creatinine clearance) and day-time average systolic and diastolic BP levels [odds ratio (OR) 2.627 vs N group, P = 0.0197]. The presence of white-coat effect (i.e. W group) was not an independent determinant of microalbuminuria (OR 1.163 vs N group, P = 0.7125). The significant predictive value of reverse white-coat effect remained even though average 24-h systolic and diastolic BPs, instead of day-time BPs, were adopted as independent predictors (data not shown).


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  		Table 2. Independent predictors for microalbuminuria by multiple logistic regression analysis

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
This study has demonstrated that the presence of reverse white-coat effect is one of the independent predictors for microalbuminuria in patients with treated essential hypertension. Our study provided the novel findings to prove the significant association of reverse white-coat phenomenon with U-Alb excretion in essential hypertension, because the relation between reverse white-coat hypertension (or masked hypertension) and early renal damage such as microalbuminuria in hypertensive subjects has not been elucidated.

In the present study, subjects with reverse white-coat effect (R group) had a well-controlled office BP (<130/80 mmHg) in spite of elevated ambulatory BP, suggesting that R group took on an aspect of masked hypertension. There have been a few studies reporting the possible association between masked hypertension and cardiac and carotid arterial structural changes. Liu et al. [20] originally found that left ventricular mass and carotid wall thickness in subjects with masked hypertension were significantly greater than those in true normotensive subjects and similar to those in patients with sustained hypertension. Another study also showed that left ventricular mass index and prevalence of left ventricular hypertrophy were increased in untreated subjects with masked hypertension and sustained hypertension than in those with true normotension [21]. Therefore, the present findings were broadly consistent with these previous observations concerning the association between masked hypertension and target organ damage. Recent prospective studies revealed that a high ambulatory or home BP is a powerful predictor for cardiovascular morbidity and mortality in the general population and treated hypertensive patients even when their office BP is normal or well controlled [12, 13, 22–24]. Taken together, it is likely that advanced target organ changes in patients with masked hypertension or reverse white-coat condition are linked to poor cardiovascular prognosis in such patients.

A higher level of ambulatory BP is a major determinant of target organ damage in hypertensive patients [1, 2]. In the present study, average levels of day-time, night-time and 24-h ambulatory BPs were the highest in R group. Whereas, since the association of reverse white-coat effect with microalbuminuria was still significant after adjusted for average day-time (or 24-h) BP levels, our results suggest that other factors than a higher ambulatory BP could contribute to target organ damage in reverse white-coat hypertension. A shorter period of antihypertensive medication might partially explain the advanced end-organ change in the present subjects with reverse white-coat effect. However, our study has not provided the specific mechanism by which reverse white-coat effect could promote renal damage in patients with treated hypertension. Further investigations are required to clarify how reverse white-coat or masked hypertension has a specific unfavourable effect on the hypertensive target organ.

There were some limitations in our study. Considering the intra-individual variability of U-Alb level, the evaluation of albuminuria using a single urine collection might underestimate the prevalence of microalbuminuria and weaken the relationship between U-Alb and patterns of BP variation. In addition, our subjects were divided into subgroups on the basis of office–day-time systolic BP difference obtained from one-time examination of ambulatory BP monitoring. A reverse white-coat phenomenon is usually identified as an office BP lower than day-time (or 24-h) ambulatory BP [10, 11]. In the present study, however, it was defined as office–day-time systolic BP of <–10 mmHg to detect only overt reverse white-coat effect from one-time monitoring of ambulatory BP.

All patients in the present study had received antihypertensive medication. As another limitation of this study, therefore, we must consider the possibility that different classes of antihypertensive drugs may have differently affected U-Alb excretion. RAS inhibitors, particularly, are known to have BP fall-independent protective effects against renal damage. However, the percentage of patients treated with angiotensin II receptor antagonists or angiotensin converting enzyme inhibitors did not differ among the three study groups. Our multivariate analysis also showed that the relation of reverse white-coat effect to microalbuminuria was independent of the use of RAS inhibitors. Nonetheless, since BP reduction per se, regardless of classes of antihypertensive drugs, decreases U-Alb excretion, the determination of U-Alb level under drug-free period might be more desirable to evaluate the basal renal damage.

In conclusion, the present study indicates that reverse white-coat effect is a significant predictor for microalbuminuria in patients with treated essential hypertension, independent of average ambulatory BP levels and various other clinical risk factors. Our findings suggest that the presence of this phenomenon may be an independent risk for early renal damage in treated hypertensive patients and ambulatory BP monitoring (or home BP measurement) seems to be necessary to unmask this latent risk that is not detectable by routine BP measuring in the office.



   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
This study was supported by the Grant for Cardiovascular Disease (11C-5) and the Health and Labor Sciences Research Grants (H14-kouka-021) from the Ministry of Health, Labor and Welfare of Japan and the Grant from Japan Cardiovascular Research Foundation. We thank Chikako Tokudome, Yoko Oikawa and Yoko Saito for their secretarial assistance.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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Received for publication: 30. 5.06
Accepted in revised form: 6.10.06


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