Association Between Albumin:Creatinine Ratio and 24-Hour Ambulatory Blood Pressure in Essential Hypertension

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1 AJH 2001; 14: Association Between Albumin:Creatinine Ratio and 24-Hour Ambulatory Blood Pressure in Essential Hypertension Vladimir A. Boulatov, Aud Stenehjem, and Ingrid Os Microalbuminuria (MAU) is often found in essential hypertension (EH) and represents a sign of renal and cardiovascular damage. In the present study, we aimed to look at the association between ambulatory blood pressure (BP) and urinary albumin excretion (UAE). We studied 140 patients aged years referred for 24-h ambulatory blood pressure monitoring (ABPM) and, separately, 46 untreated subjects with newly diagnosed EH. Urinary albumin excretion was evaluated by determination of the albumin-to-creatinine ratio (ACR) in the first voided morning urine sample taken the same day as the ABPM was started. According to the ACR, patients were categorized as having normoalbuminuria (ACR 1.5 mg/mmol), borderline MAU (1.5 ACR 3.0 mg/mmol), and overt MAU (ACR 3.0 mg/mmol). Mean ACR was significantly higher in hypertensive than normotensive individuals ( mg/mmol and mg/mmol, respectively, P.012). Average Microalbuminuria (MAU) is usually referred to as an abnormal urinary albumin excretion (UAE) not detectable by the usual dipstick methods for urine protein. Because increased urinary excretion of albumin was first recognized in essential hypertension (EH) in 1974 by Parving et al, 1 a large number of studies concerning different aspects of increased UAE in diabetes mellitus as well as in EH has been performed. The prevalence of MAU varies greatly from one study to another ranging between 5% and 40%, dependent on the population characteristics, methods used, and threshold levels. 2 9 Most of the articles published, with some exceptions, 8 showed microalbuminuric hypertensive patients to have higher levels of blood pressure (BP) compared to normoalbuminuric subjects, 3 5,10 19 and hypertensive patients manifest higher levels of UAE than do normotensive individuals. 1,6 8,20 Several studies have shown a positive correlation between UAE and office BP levels in hypertensive 1,3,7,16,21 27 and normotensive individuals. 28,29 24-h, daytime and nighttime systolic BP and diastolic BP were lower in patients with normoalbuminuria than in the other two groups and did not differ among the two microalbuminuric groups. Univariate regression analysis showed a close relationship between ACR and ambulatory BP. Strong correlation between BP and ACR in the normoalbuminuric and borderline microalbuminuric range was also obtained in the group of 46 newly diagnosed hypertensive patients. In conclusion, the threshold level of ACR 3.0 mg/ mmol currently used to define microalbuminuria may be not applicable to EH. Instead, a threshold level of ACR 1. 5 mg/mmol may be more appropriate. Am J Hypertens 2001;14: American Journal of Hypertension, Ltd. Key Words: Microalbuminuria, essential hypertension, ambulatory blood pressure. However, a better relationship between the BP and UAE is observed when 24-h ambulatory blood pressure monitoring is used instead of office BP recordings. A positive correlation has been shown between 24-h, daytime, nighttime systolic BP (SBP) and diastolic BP (DBP) and UAE, 4,5,7,12,14,15,20,24,25,30 as well as altered circadian BP profile in microalbuminuric patients. 5,30 The interest in the significance of MAU in EH was probably stimulated by the recognition of a relationship between increased UAE and major cardiovascular risk factors. Nondiabetic hypertensive subjects with MAU are more likely to have dyslipidemia, 3,9,10,12,17,19,31,32 insulin resistance, 13,22,31,33 and increased serum uric acid levels. 3,9 Moreover, several studies have shown MAU to be a predictor of cardiovascular morbidity and mortality. 9,13,26 Patients with elevated UAE are more likely to exhibit increased left ventricular mass index and left ventricular hypertrophy, 11,18,34,35 thicker carotid arteries, 11,19,31,34 Received April 18, Accepted August 17, From the Department of Nephrology, Ulleval University Hospital, Oslo, Norway. Address correspondence and reprint request to Ingrid Os, Department of Nephrology, Ulleval University Hospital, N-0407 Oslo, Norway; ingrid.os@ulleval.no /01/$ by the American Journal of Hypertension, Ltd. PII S (00) Published by Elsevier Science Inc.

2 AJH April 2001 VOL. 14, NO. 4, PART 1 MICROALBUMINURIA AND ESSENTIAL HYPERTENSION 339 pronounced atherosclerosis, 22 and major electrocardiographic changes and retinal vascular changes. 3 However, in spite of an increased interest in the significance of MAU and EH, several aspects of hypertensive microalbuminuria still remain uncertain and await elicitation. The mechanisms underlying the observed predictive role of UAE with regard to cardiovascular morbidity are not clear. Furthermore, several methods can be used for the evaluation of UAE, and the threshold level of significant UAE remains debatable. In the present study, we aimed to look at the association between ambulatory BP and UAE using the albumin-tocreatinine ratio (ACR) in patients referred to 24-h blood pressure monitoring. Methods Subjects At the first stage of the research we studied 140 patients who were referred to the Department of Nephrology for 24-h ambulatory BP monitoring. All patients included in the study had SBP 140 mm Hg or DBP 90 mm Hg in the sitting position after 5 min of rest as measured by the general practitioner in duplicate or triplicate. Patients with serum creatinine level 130 mol/l, positive urine albumin dipstick, glucose, or culture were excluded from the study. Patients with type 2 (non-insulin dependent) diabetes mellitus (n 6) and subjects receiving antihypertensive therapy at the moment of the study, that is, insufficiently treated patients (n 34), were not excluded. For the second stage of the study, of these 140 patients we recruited 46 subjects with newly diagnosed EH who had never received antihypertensive medications. Patients with diabetes mellitus, severe hypertension (defined as daytime SBP 180 mm Hg or DBP 110 mm Hg) and MAU (albumin-to-creatinine ratio 3.0 mg/mmol) were excluded. Urinary Albumin Excretion Urinary albumin excretion was evaluated by determination of the ACR in the first voided morning urine sample taken the same day as the BP monitoring was started. In some patients, those who met the inclusion criteria for the second stage of the study (n 46), repeated measurements were taken (ie, ACR was measured also on the second day of the BP monitoring). The mean between the two measurements was used for calculation. According to the ACR, patients were categorized as having normoalbuminuria (ACR 1.5 mg/mmol), borderline MAU (1.5 ACR 3.0 mg/mmol), and overt MAU (ACR 3.0 mg/mmol). Albumin levels in the urine were measured by immunoturbidometry, 36 and urine creatinine on Integra Analyser (Roche, Basel, Switzerland). Ambulatory Blood Pressure Monitoring The 24-h ambulatory blood pressure monitoring (ABPM) was performed using an oscillometric-based device (model ; SpaceLabs Medical Inc.) and the Ambulatory Blood Pressure Report Management System delivered by SpaceLabs Medical Inc., Redmond, WA. Recording began between 7:00 and 11:00 AM. Blood pressure readings were taken every 20 min during the daytime period (between 6:00 AM and 10:00 PM) and every 30 min during the nighttime period (between 10:00 PM and 6:00 AM). Mean ABPM for each subject was calculated for 24 h and separately for daytime and nighttime periods, as well as for the first hour (1-hour BP). Daytime SBP 140 mm Hg or DBP 90 mm Hg were considered as hypertensive values. Statistical Analysis All statistical computations were carried out with SPSS/ PC software (SPSS Inc., version 9.0, Chicago, IL). Because of inequality of the variances and the size of the three groups, nonparametric Kruskal-Wallis test followed by the Dunn procedure was used to analyze data from patients grouped according to ACR. Mann-Whitney test was used to test differences between hypertensive and normotensive patients. A 2 test was used for group comparisons regarding prevalences. Urinary albumin excretion showed a skewed distribution, and logarithm of ACR was used for correlation and regression analyses. Linear relationships between log ACR and ABPM were examined by Pearson s correlation coefficient and linear regression analysis. A value of P.05 was considered significant. Results Characteristics of the Study Population Ambulatory blood pressure monitoring revealed that of the 140 patients, 99 were hypertensive and 41 were normotensive. Clinical characteristics and ABPM parameters of the entire population and separately of the hypertensive and normotensive individuals are presented in Table 1. Hypertensive patients were more likely to be men than their normotensive counterparts. However, there were no differences in mean age, serum creatinine level, or heart rate between the normotensive and hypertensive individuals. Of the 46 patients selected for the second stage of the study, 32 were men and 14 were women with the mean age of years. Mean daytime BP was / mm Hg. All individuals had ACR 3.0 mg/mmol (mean, mg/mmol). Borderline MAU was determined in 16 patients (34.8%). Thirty subjects (65.2%) had normal UAE. Albumin-to-Creatinine Ratio and the Prevalence of Microalbuminuria Mean ACR was significantly higher in hypertensive than normotensive individuals ( mg/mmol and mg/mmol, respectively, P.012). Thirtytwo of 41 normotensive individuals (78.0%) and 55 of 99

3 340 MICROALBUMINURIA AND ESSENTIAL HYPERTENSION AJH April 2001 VOL. 14, NO. 4, PART 1 Table 1. Clinical characteristics and ambulatory blood pressure measurements of the entire population study (n 140) hypertensive patients (55.6%) were normoalbuminuric. Borderline MAU with ACR between 1.5 and 3.0 mg/mmol was found in 7 normotensive and 32 hypertensive subjects (17.1% and 32.3%, respectively). The prevalence of overt MAU with ACR 3.0 mg/mmol was 4.9% in the group of patients with normal BP and 12.1% in patients with EH (Fig. 1). Total Hypertensive (n 99) Normotensive (n 41) P* Age NS Men/women 76/64 64/35 12/ Serum creatinine ( mol/l) NS Urine albumin (mg) Urine creatinine (mmol) NS Albumin:creatinine ratio (mg/mmol) h systolic blood pressure (mm Hg) h diastolic blood pressure (mm Hg) h pulse pressure (mm Hg) h heart rate (beats/min) NS Daytime systolic blood pressure (mm Hg) Daytime diastolic blood pressure (mm Hg) Daytime pulse pressure (mm Hg) Daytime heart rate (beats/min) NS Nighttime systolic blood pressure (mm Hg) Nighttime diastolic blood pressure (mm Hg) Nighttime pulse pressure (mm Hg) Nighttime heart rate (beats/min) NS NS not significant. Data are means SD. * P hypertensive versus normotensive. Twenty-Four-Hour Blood Pressure According to Albumin-to-Creatinine Ratio Table 2 shows demographic characteristics and ABPM parameters of the patients grouped by ACR. All three groups were similar in age, gender, and serum creatinine level. Average 24-h, daytime, and nighttime SBP and DBP were higher in patients with overt MAU than in those with normal albumin excretion rate and borderline MAU, but did not differ between the two microalbuminuric groups. Fig. 2 presents daytime SBP and DBP of the three groups of patients according to ACR. Heart rate for 24-h and separately for daytime and nighttime periods were similar in the three groups. No significant difference was observed in SBP and DBP decrease during the night (data not presented). Comparisons of the ambulatory BP values performed on the patients who fulfilled the inclusion criteria for the second stage of the study (n 46) showed similar results. Patients with borderline MAU showed higher FIG. 1. Prevalence of microalbuminuria measured as albumin/creatinine ratio (ACR) in hypertensive (daytime blood pressure 140/90 mm Hg) and normotensive (daytime blood pressure 140/90 mm Hg) individuals. Black bar, ACR 3.0 mg/mmol; grey bar, 1.5 ACR 3.0 mg/mmol; open bar, ACR 1.5 mg/mmol.

4 AJH April 2001 VOL. 14, NO. 4, PART 1 MICROALBUMINURIA AND ESSENTIAL HYPERTENSION 341 Table 2. Characteristics of the 140 patients grouped by the albumin:creatinine ratio Albumin:Creatinine Ratio (mg/mmol) <1.5 >1.5 and <3.0 >3.0 P* n/% 87/ / /10.0 Age NS Men/women 48/39 22/17 6/8 NS Serum creatinine ( mol/l) NS Urine albumin (mg) Urine creatinine (mmol) Albumin:creatinine ratio (mg/mmol) h systolic blood pressure (mm Hg) h diastolic blood pressure (mm Hg) h pulse pressure (mm Hg) h heart rate (beats/min) NS Daytime systolic blood pressure (mm Hg) Daytime diastolic blood pressure (mm Hg) Daytime pulse pressure (mm Hg) Daytime heart rate (beats/min) NS Nighttime systolic blood pressure (mm Hg) Nighttime diastolic blood pressure (mm Hg) Nighttime pulse pressure (mm Hg) Nighttime heart rate (beats/min) NS NS not significant. Data are means SD. * P shows the significance level of multiple comparison between the three groups. P.0005 v group 1; P.01 v group 1; P.005 v group 1; P.001 v group 1. levels of 24-h, daytime, and nighttime SBP and DBP than normoalbuminuric individuals (24-h SBP mm Hg v mm Hg, P.003; 24-h DBP mm Hg v mm Hg, P.005; daytime SBP mm Hg v mm Hg, P.007; daytime DBP mm Hg v mm Hg, P.02; nighttime SBP mm Hg v mm Hg, P.002; nighttime DBP mm Hg v mm Hg, P.001). Relationship Between Albumin/Creatinine Ratio and Blood Pressure Table 3 shows the univariate correlations between log ACR and ambulatory BP performed in the entire study population. It revealed significant positive relationship between log ACR and 24-h, daytime, and nighttime SBP and DBP (r to 0.415, P.0005, except for nighttime DBP). Correlation seems to be better for log FIG. 2. Daytime ambulatory blood pressure in patients grouped by albumin/creatinine ratio. HR average heart rate during daytime; ACR albumin/creatinine ratio.

5 342 MICROALBUMINURIA AND ESSENTIAL HYPERTENSION AJH April 2001 VOL. 14, NO. 4, PART 1 Table 3. Univariate correlation between the logarithm of albumin:creatinine ratio and 24-h ambulatory blood pressure in the entire study population (n 140) r P 24-h SBP h DBP Daytime SBP Daytime DBP Nighttime SBP Nighttime DBP SBP systolic blood pressure; DBP diastolic blood pressure. ACR and 24-h SBP (r 0.415, P.0005). There was no significant correlation between log ACR and heart rate. We also performed the correlation analysis between average ACR measured in two morning urine samples and ambulatory BP on newly diagnosed untreated hypertensive patients with normal UAE (Table 4). The ACR was significantly related to 24-h, daytime, and nighttime SBP and DBP (r to 0.585, P.0005). Discussion The gold standard method of determination of UAE involves collection of 24-h urine sample. However, it seems to be inconvenient for the patients and often unreliable due to inaccurate volume collection. Recently, more practical and easier methods have been proposed. One of these includes determination of the ACR in a single morning urine sample. In contrast to random spot urine sample, morning urine is less likely to be influenced by activity and posture. The measurement of ACR in the first voided morning urine sample was shown to be an accurate and sensitive alternative to measurement of the UAE in timed collections, when screening for MAU We have shown that ACR measured in a single morning urine sample correlated with 24-h, daytime, and nighttime SBP and DBP in hypertensive patients. Hypertensive patients Table 4. Univariate correlation between albumin: creatinine ratio and 24-h ambulatory blood pressure in newly diagnosed untreated hypertensive patients r P 24-h SBP h DBP Daytime SBP Daytime DBP Nighttime SBP Nighttime DBP Abbreviations as in Table 3. manifested higher values of ACR than normotensive individuals. Ambulatory BP was higher in the microalbuminuric patients than subjects with normal UAE. In the present study we showed that values of ambulatory blood pressure (24-h, daytime, and nighttime SBP and DBP) were lower in subjects with normal albumin excretion than in patients with borderline and overt microalbuminuria. On the other hand, BP did not differ between the two microalbuminuric groups. These results obtained on the entire study population (n 140) were confirmed on selected patients with newly diagnosed borderline to moderate hypertension. Thus, we suggest that the threshold levels of ACR 3.0 mg/mmol currently used to define MAU may not be applicable to hypertension. This lends support to the study by Palatini et al, 4 who suggested a new threshold level of UAE of 15 mg/24 h for defining MAU in hypertensives instead of the traditionally used level of UAE 30 mg/24 h. At least two mechanisms are currently discussed for the increased UAE in hypertensive patients. 40,41 First, there is a functional transmission of an elevated BP to the glomeruli and an increased permeability in the glomerular basement membrane. The existence of the functional component is supported by the observations that pharmacologic reduction of BP pressure leads to a decrease in UAE. 42,43 Second, there seem to be structural alterations that appear in long-standing disease. We showed a strong correlation between ACR and ambulatory BP on the population of 46 newly diagnosed hypertensive patients. These subjects had never been treated with antihypertensive drugs, thus eliminating any treatment-induced changes in UAE. Patients with diabetes mellitus, urologic and renal pathology were excluded for better estimation of the damage produced by hypertension. Thus, a close relationship between ABPM and ACR in the normoalbuminuric and borderline microalbuminuric range could mean that elevated UAE already exists in the early stages of essential hypertension, probably reflecting the functional alterations in renal hemodynamics. In conclusion, the present study confirms a higher prevalence of microalbuminuria in patients with essential hypertension and a close relationship between ambulatory BP and ACR. Moreover, we have shown that the threshold levels of ACR 3.0 mg/mmol currently used to define microalbuminuria may not be applicable to hypertension and deserve further investigation. Acknowledgment We thank Rita Hansen and Sigrun Elden for skillful technical support, and Marianne Bjorndahl and Christa Bruun for help in the data collection. Vladimir A. Boulatov is a student of I.M. Sechenov Moscow Medical Academy, faculty for training research workers and medical educators who took part in an exchange program between I.M. Sechenov Moscow Medical Academy and the University of Oslo.

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