Diurnal Variations of Blood Pressure and Microalbuminuria in Essential Hypertension

Transcription

1 A] H 1994;7:23-29 Diurnal Variations of Blood Pressure and Microalbuminuria in Essential Hypertension Stefano Bianchi, Roberto Bigazzi, Giorgio Balàari, Gianpaolo Sgherri, and Vito M. Campese The extensive use of ambulatory blood pressure monitoring (ABPM) has improved our knowledge of the circadian variability of arterial blood pressure. Typically, blood pressure tends to be the highest during the morning, to gradually decrease during the course of the day, and to reach the lowest levels at night. 1-8 The morning rise in blood pressure may contribute to the greater Received April 12, Accepted September 21, From the U.O. di Nefrologia, Spedali Riuniti, Livorno, Italy, and Division of Nephrology, University of Southern California (VMC), Los Angeles, California. This work was supported in part by grant R 01 HL47881 from the National Institutes of Health. Address correspondence and reprint requests to Stefano Bianchi, MD, U.O. Nephrology, Spedali Riuniti, Viale Alfieri, 36, Livorno, Italy Microalbuminuria has been shown in approximately 40% of patients with essential hypertension. Previous studies have failed to demonstrate any consistent relationship between microalbuminuria and levels of office blood pressure. Because average ambulatory blood pressure correlates with incidence of cardiovascular morbidity and mortality better than office blood pressure, we have studied whether levels of urinary albumin excretion correlate with average diurnal, nocturnal, or 24-h blood pressure better than with office blood pressure. Sixty-three patients with essential hypertension and 21 healthy volunteers were included in the study. Twenty-four hypertensive patients failed to show the normal nighttime fall in blood pressure of at least 10/5 mm Hg and were defined as "nondippers"; the remaining were defined as "dippers." Office blood pressure was not different between dippers and nondippers. However, nighttime systolic and diastolic blood pressures were significantly greater in nondippers than in dippers. The median urinary albumin excretion in nondippers (42 mg/24 h) was significantly greater (P <.001) than in dippers (17.5 mg/24 h), and in normal subjects (8.6 mg/24 h). A significant correlation was present between nighttime systolic and diastolic blood pressure and urinary albumin excretion (UAE) and between 24-h systolic blood pressure and UAE in all hypertensive patients; in addition, a significant correlation was present between 24-h diastolic and nighttime diastolic blood pressure and UAE in nondippers. The increased amount of UAE in nondipper hypertensive patients suggests the presence of greater renal damage than in dippers. Am J Hypertens 1994;7:23-29 KEY WORDS: Hypertension, microalbuminuria, ambulatory blood pressure monitoring. incidence of cardiovascular events during this time of the day. A significant number of hypertensive patients fail to manifest the normal nocturnal fall of blood pressure and they have been called "nondippers," 6,9-11 whereas those with a normal circadian rhythm are called "dippers." A large body of evidence has shown that average ambulatory blood pressure correlates with the incidence of cardiovascular complications, silent cerebrovascular disease, 21 and early glomerular injury 22 " 24 better than office blood pressure. A relationship seems also to exist between the absence of nocturnal fall in arterial blood pressure and the severity of cardiovascular target organ damage. 6,21 Whether the absence of a normal fall of blood pressure at night is also associated with greater risk of renal damage remains to be established by the American Journal of Hypertension, Ltd /94/$6.00

2 24 BIANCHI ET AL AJH-JANUARY 1994-VOL. 7, NO. 1 Microalbuminuria is present in approximately 40% of patients with essential hypertension 25 and is considered an initial sign of glomerular injury in normotensive and hypertensive diabetic patients, as well as in patients with essential hypertension In small numbers of patients with essential hypertension, some investigators have observed a significant correlation between office diastolic blood pressure and microalbuminuria. 29 ' 33 However, in a large number of patients, we failed to demonstrate a significant relationship between microalbuminuria and office systolic or diastolic blood pressure. 34 In this study we measured urinary albumin excretion (UAE) and average ambulatory blood pressure in a large number of patients with essential hypertension to determine whether nondippers excrete greater amounts of urinary albumin than dippers. PATIENTS AND METHODS These studies were approved by the Human Research Committee of the Spedali Riuniti of Livorno, Italy, and all subjects gave their informed consent. Sixty-three patients with essential hypertension and 21 healthy normotensive subjects were included in the study. A diagnosis of secondary hypertension was adequately excluded by the findings of normal routine blood chemistry, urinalysis, electrocardiogram, chest x-rays, and, when clinically indicated, by normal urinary metanephrines, plasma aldosterone, diethylenetriaminepentaacetic acid technetium scan, and renal angiogram. None of the hypertensive patients was receiving antihypertensive drugs at the time of the study. Twenty-eight patients had never received antihypertensive drugs before the study; in the remaining 35 patients, antihypertensive drugs were discontinued at least 4 weeks before the first collection of urines for UAE. We did not include in the study patients previously treated with angiotensin converting enzyme inhibitors, because these drugs can reduce UAE for longer than 4 weeks. 35 On the other hand, patients previously treated with calcium channel antagonists, ß-blockers, and diuretics were included in the study because, as previously shown by us, these drugs do not affect UAE in patients with essential hypertension. 36 Hypertensive patients were included in this study if their blood pressure was consistently more than 140/95 mm Hg in three subsequent clinic visits, and if their creatinine clearance was greater than 80 ml/ min/1.73 m 2. Exclusion criteria included a positive dip-stick test for proteinuria, nocturia, or other reasons for arising from bed during the night, body mass index (BMI) greater than 30, use of sedatives or stimulating agents, diabetes mellitus, postural hypotension, heart failure, coronary and cerebrovascular disease, central nervous system dysfunction or depression, and difficulty with sleep. Patients who fulfilled the inclusion criteria were instructed to collect 24-h urines on three different occasions, 1 week apart, to measure UAE and creatinine clearance. To ensure completeness of the 24-h urine collections, urinary creatinine was measured and only values greater than 20 mg/kg in men and greater than 15 mg/kg in women were considered consistent with good urine collections. Those urine samples that did not fulfill these criteria were discarded. Patients were defined as having microalbuminuria if the average of the three determinations was greater than 30 mg/24 h. After completion of the three urine collections, 24-h ambulatory blood pressure was measured by the Takeda A and D model TM-2420 (Osaka, Japan). The efficiency and reliability of this ABPM device have been validated extensively in previous trials. 37,38 The TM-2420 uses the first and the fifth Korotkoff sounds as systolic and diastolic pressure, respectively. Two microphones within the pneumatic cuff can differentiate between the Korotkoff sounds and extraneous noises. The TM-2420 was calibrated against a mercury sphygmomanometer before each recording. Left arm readings were taken with a standard size cuff beginning at 7 AM and ending after 24 h. Measurements were made every 20 min from 7 AM to 11 PM (daytime period) and every 30 min from 11 PM to 7 AM (nighttime period). The recorder automatically discarded artifactual readings and the computer analysis excluded diastolic blood pressure values lower than 40 mm Hg or systolic pressures greater than 240 mm Hg, or values with differential arterial pressure less than 20 mm Hg. ABPM was performed during a working day and all subjects were required to keep a diary of all daily activities, including whether, for any reason, they awakened at night. All subjects were instructed to be woken up at 7 AM by an alarm clock. From the 24-h blood pressure profile we calculated average 24-h systolic and diastolic blood pressures, and average daytime and nighttime systolic and diastolic values. Serum and urine creatinine were measured by autoanalyzer and microalbuminuria by immunoturbidimetry. 39,40 Body mass index was calculated as weight (kg) divided by the height (m) squared. Statistical Analysis The program S-Plus Software (Statistical Sciences, Inc., Seattle, WA) was used for the statistical analysis of the data. Because of the possibility of outliers, we used nonparametric and robust statistical techniques. One-way analysis of variance (ANOVA) using the Kruskal-Wallis rank sum test was performed to determine differences among controls versus dippers and nondippers. 41

3 AJH-JANUARY 1994-VOL. 7, NO. 1 MICROALBUMINURIA AND DIURNAL VARIATIONS OF BLOOD PRESSURE 25 Box plots were used to display the level of microalbuminuria by group (controls, dippers, and nondippers). The box plot display uses a box to represent the median (horizontal line within each box), the 25th percentile (lower edge of the box), and the 75th percentile (upper edge of the box). The length of the box represents the interquartile range (IQR). Whiskers (the dashed vertical lines extending below and above each box) are used to represent the minimum and the maximum observation. The minimum (maximum) is represented by the lower (upper) tip of the lower (upper) whisker, respectively. Outliers are considered to be present if there are observations smaller (larger) than the lower (upper) fence, (ie, 1.5 times the IQR below [above] the median). In that case, the lower (upper) tip of the lower (upper) whisker represents the lower (upper) fence. When large outliers are present on the box plot, it suggests that a logarithmic transformation of the data will resolve the outliers. We used the Spearman rank correlation technique to estimate correlations and robust regressions to estimate the relationship between various measures of blood pressure and μα. 42 RESULTS The clinical characteristics of all subjects included in the study are described in Table 1. We considered as dippers those patients in whom the difference between mean daytime systolic/diastolic blood pressure and mean nighttime blood pressure was 10/5 mm Hg or more. Based on this criterion, 39 patients were classified as dippers and 24 as nondippers. The median age of dippers was 50 years (range, 21 to 65), not significantly different from that of nondippers (51 years; range, 30 to 65) and of normotensive individuals (39 years; range, 25 to 73). Thirty-six hypertensive patients were men and 27 women; 10 normotensive subjects were men and 11 women. The BMI, heart rate, and creatinine clearance did not differ among hypertensive and normotensive subjects. Duration of hypertension and office systolic and diastolic blood pressure did not differ between dippers and nondippers. However, nighttime systolic and diastolic blood pressures were significantly (P <.05) greater in nondippers than in dippers. The median 24-h systolic (155 mm Hg; range, 121 to 181) and diastolic blood pressures (97 mm Hg; range, 80 to 114) in nondippers were greater than in dippers (145 and 89 mm Hg; range, 118 to 206 and 71 to 118, respectively), but the difference did not reach statistical significance (P <.1). Daytime systolic and diastolic blood pressures were not different between these two groups (Table 2). The median UAE in nondippers (42 mg/24 h) was greater (P <.001) than in dippers (17.5 mg/24 h) and normal subjects (8.6 mg/24 h) (Figure 1). Thirty-four (81%) nondippers had microalbuminuria as opposed to only 8 (19%) dippers. No significant correlation was present between UAE and office blood pressure. However, a significant correlation was present between UAE and 24 h diastolic blood pressure (r = 0.43, Ρ <.04) and nighttime diastolic (r = 0.45, Ρ <.04) in nondippers. In addition, there was a significant correlation between UAE and 24-h systolic blood pressure (r = 0.33; Ρ =.01), nighttime systolic blood pressure (r = 0.34; Ρ <.01), and nighttime diastolic blood pressure (r = 0.29; Ρ <.03) in all hypertensive patients (Table 3; Figure 2). DISCUSSION It is well established that hypertension increases the risk of cardiovascular morbidity and mortality. With the availability of continuous ABPMs, it has been established that cardiovascular morbidity correlates better with average 24-h blood pressure than with casual office blood pressure. The availability of ABPM has allowed a better estimation and understanding of the circadian patterns of both systolic and diastolic blood pressures. In most normotensive and hypertensive subjects, blood pressure decreases substantially during sleep and it rises TABLE 1. CLINICAL CHARACTERISTICS OF DIPPER, NONDIPPER HYPERTENSIVES, AND NORMAL SUBJECTS Dippers Nondippers Controls Number of subjects Age (yr) 50 (21-65) 51 (30-65) 39 (25-73) Duration of hypertension (mo) 18 (1-180) 24 (1-144) Body mass index 24.7 ( ) 24.2 ( ) 25.4 ( ) Office systolic blood pressure (mm Hg) 160 ( ) 170 ( ) 130 ( )* Office diastolic BP (mm Hg) 104 (97-121) 107 ( ) 81 (70-86)* Heart rate (beats/min) 75 (58-110) 72 (54μ89) 70 (55-92) Creatinine clearance (ml/min/1.73 m 2 ) 95 (82-130) 100 (80-120) 102 (87-139) The data are provided as median (min-max). Comparisons among groups were done by the Kruskal-Wallis rank sum test. *P <.05 compared with dippers and controls.

4 26 BIANCHI ET AL AJH-JANUARY 199^-VOL. 7, NO. 1 TABLE 2. AMBULATORY BLOOD PRESSURE RECORDINGS IN DIPPER, NONDIPPER HYPERTENSIVES, AND IN NORMAL SUBJECTS Dippers Nondippers Controls 24-h systolic BP (mm Hg) 145 ( ) 155 ( ) 116 (89-140)t 24-h diastolic BP (mm Hg) 89 (71 118) 97 (80-114) 75 (60-80)+ Daytime systolic BP (mm Hg) 152 ( ) 155 ( ) 120 (104^144)t Daytime diastolic BP (mm Hg) 93 (74H19) 99 (80-114) 77 (70-80)t Nighttime systolic BP (mm Hg) 129 (92-189) 157 ( )* 102 (81-131)+ Nighttime diastolic BP (mm Hg) 79 (62-114) 94 (77-111)* 62 (50-85)+ 24-h heart rate (beats/min) 75 (58-110) 71 (5^89) 64 (55-92) Daytime heart rate (beats/min) 81 (56-115) 75 (54-94) 74 (5^94) Nighttime heart rate (beats/min) 64 (51-91)t 68 (52-79)t 68 (52-79)}: The data are provided as median (min-max). Comparisons among groups were done by ANOVA and by the Kruskal-Wallis rank sum test. *P <.05 compared with dippers and controls; t Ρ <.01 compared with hypertensives; fp <.01 compared with daytime heart rate. again in the early morning. In some patients, however, blood pressure fails to fall during the night; those patients are defined as nondippers and the former as dippers. Several studies have shown that nondippers manifest greater evidence of organ damage than dippers. Verdecchia et al 10 classified patients as nondippers on the basis of a nighttime fall in blood pressure of less than 10%; in 55 nondippers they observed that left ventricular mass index (98.3 g/m 2 ) was significantly greater than in 82 dippers (83.5 g/m 2 ). A statistically significant inverse correlation was present between left ventricular mass index and percentage of nocturnal reduction in blood pressure zr 50- E I 25- < FIGURE 1. Urinary albumin excretion (UAE) in normal subjects and in hypertensive patients with a normal fall of blood pressure at night (dippers) and in those without a normal fall of blood pressure at night (nondippers). The KrusM-Wallis rank sum test was used to determine differences among groups. The differences between nondippers and dippers or between hypertensives and normotensives were significant (P <.001). Box plots are used to display the level of microalbuminuria by group. Using a log transformation renders the variances of the three groups more similar and the large values of microalbuminuria are no longer outliers. Shimada et al, 9 using magnetic resonance imaging techniques, found that the absence of a nocturnal fall in blood pressure was associated with silent cerebrovascular damage. The pathophysiology and significance of microalbuminuria in essential hypertension have not been established. Some have shown a significant correlation between levels of office blood pressure and urinary albumin excretion, 27,29,31 but other laboratories, including our own, 22,32,34 have failed to find a significant correlation between these two parameters. The current study indicates that average 24-h blood pressure and nighttime blood pressure correlate with 24-h UAE better than casual office blood pressure. Opsahl et al 23 observed a significant correlation between average 24-h systolic but not diastolic blood pressure and microalbuminuria in 42 untreated patients with essential hypertension. In this study, there was no mention of the relationship between average daytime and nighttime blood pressure and microalbuminuria. In 21 patients with borderline hypertension, Giaconi et al 22 showed a significant correlation only between daytime diastolic blood pressure and microalbuminuria. On the other hand, in 53 patients with essential hypertension, Cerasola et al 24 observed a significant correlation between average 24-h systolic and diastolic blood pressures and UAE, degree of retinopathy, and left ventricular mass index. In this study, we have not only confirmed that UAE correlates better with average 24-h blood pressure than with office blood pressure, but we have also shown that nondippers manifest a greater amount of UAE than dippers. Whether the greater amount of UAE in nondippers is the result of a lack of marked circadian blood pressure rhythm or of higher average 24-h blood pressure, or both, remains to be established. Pickering and James 43 have recently argued that, because daytime blood pressure is the re-

5 G D AJH-JANUARY 1994-VOL. 7, NO. 1 MICROALBUMINURIA AND DIURNAL VARIATIONS OF BLOOD PRESSURE 27 TABLE 3. CORRELATION COEFFICIENTS (r) AND P VALUES BETWEEN URINARY ALBUMIN EXCRETION (UAE) AND BLOOD PRESSURE (BP) IN DIPPER AND NONDIPPER HYPERTENSIVES Dippers Nondippers All Hypertensives UAE ν office systolic BP NS NS NS UAE ν office diastolic BP NS NS NS UAE ν 24-h systolic BP NS NS P =.01 (0.33) UAE ν 24-h diastolic BP NS P <.04 (0.43) NS UAE ν daytime systolic BP NS NS NS UAE ν daytime diastolic BP NS NS NS UAE ν nighttime systolic BP NS NS P <.01 (0.34) UAE ν nighttime diastolic BP NS P <.04 (0.45) P <.03 (0.29) Spearman's rank correlation technique was used to estimate the correlation and the robust regression to estimate the relationship between various measures of blood pressure and UAE. BP, blood pressure; NS, not significant; UAE, urinary albumin excretion. suit of a variety of physical, emotional, and nutritional influences, it would be more appropriate to consider the nighttime blood pressure as the baseline level. In doing so, the dippers would actually be "peakers" (ie, those whose blood pressure increases during the day), whereas the nondippers would be "nonpeakers" (ie, those patients whose blood pressure does not increase during the day). The significance of increased UAE in hypertension remains to be determined. Proteinuria and microalbuminuria are considered independent cardiovascular risk factors, 30,44^6 and significant predictors of progressive renal failure in normotensive and hypertensive diabetic patients, and in patients with virtually all forms of glomerulonephritis. 47,48 It remains to be determined whether microalbuminuria also represents an initial sign of renal damage and a prognostic indicator of progressive renal disease in patients with essential hypertension. In conclusion, these studies have shown that in patients with essential hypertension, a lack of Controls Dippers Non-Dippers G π π,- - ' ' '. ^ D ' S π FIGURE 2. The correlation between nighttime diastolic blood pressure and microalbuminuria in all subjects combined. The nonparametric estimate using Spearman rank correlation is 0.29, Ρ <.03. marked circadian variations of blood pressure is associated with greater amounts of UAE, a possible marker of renal damage. ACKNOWLEDGMENTS Computational assistance was provided by NIH NCRR GCRC MOI RR-43 Clinfo Project and by Dr. Madeline Bauer. The authors thank Antonella Antoni, RN, Silvia Niccolini, RN, and Dina Malvaldi, RN, for their invaluable assistance. REFERENCES 1. Pickering TG, Harshfield G A, Kleinert HD, et al: Blood pressure during normal daily activities, sleep, and exercise. JAMA 1982;247: Millar-Craig MW, Bishop CN, Raftery EB: Diurnal variation of blood pressure. Lancet 1979;i: Mancia G, Ferrari A, Gregorini L, et al: Blood pressure and heart rate variabilities in normotensive and hypertensive human beings. Circ Res 1983;53: National High Blood Pressure Education Program Coordinating Committee: National High Blood Pressure Education Program working group report on ambulatory blood pressure monitoring. Arch Intern Med 1990;150: White WB, Morganroth J: Usefulness of ambulatory monitoring of the blood pressure in assessing antihypertensive therapy. Am J Cardiol 1989;63: O'Brien E, Sheridan J, O'Mally K: Dippers and non dippers. Lancet 1988;ii: Khoury AF, Sunderajan P, Kaplan NM: The early morning rise in blood pressure is related mainly to ambulation. Am J Hypertens 1992;5: Elskjaer H, Pedersen EB: The relationship between casual and ambulatory blood pressure in essential hypertension: the influence of work, duration of hypertension and antihypertensive treatment. J Intern Med 1989;225: Shimada K, Kaxamoto A, Matsubayashi K, et al: Diurnal blood pressure variations and silent cerebrovascular damage in elderly patients with hypertension. J Hypertens 1992;10:

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7 AJH-JANUARY 1994-VOL. 7, NO. 1 MICROALBUMINURIA AND DIURNAL VARIATIONS OF BLOOD PRESSURE Heiberger RM, Becker RA: Design of an S function for robust regression using iteratively reweighted least squares. J Comp Graph Stat 1992;3: Pickering TG, James GD: Determinants and consequences of the diurnal rhythm of blood pressure. Am J Hypertens 1993;6(suppl):166S-169S. 44. Lewin A, Blaufox D, Castle H, et al: Apparent prevalence of curable hypertension in the hypertension detection and follow-up program. Arch Intern Med 1985; 145: Bulpitt CJ, Beevers DG, Butler A, et al: The survival of treated hypertensive patients and their causes of death: a report from the DHSS Hypertensive Care Computing Project (DHCCP). J Hypertens 1986;4: Kannel WB, Stampfer MJ, Castelli WP, et al: The prognostic significance of proteinuria: the Framingham Study. Am Heart J 1984;108: Neelakantappa K, Gallo GR, Baldwin DS: Proteinuria in IgA nephropathy. Kidney Int 1988;33: Maschio G, Oldrizzi L, Rugiu C, et al: Factors affecting progression of renal failure in patients on long term dietary protein restriction. Kidney Int 1983;32(suppl 22):S49-S52.