Microalbuminuria is a predictor of cardiovascular

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1 AJH 2000;13: Spot Urinary Albumin Creatinine Ratio Predicts Left Ventricular Hypertrophy in Young Hypertensive African-American Men Wendy S. Post, Roger S. Blumenthal, James L. Weiss, David M. Levine, David R. Thiemann, Gary Gerstenblith, and Martha N. Hill Hypertensive patients with target organ damage are at increased cardiovascular risk, and should be treated most aggressively. The association between urinary albumin excretion and left ventricular hypertrophy (LVH) in prior studies is inconsistent, and has not been described using a single, random spot urine specimen. Therefore, we evaluated the association between the urinary albumin creatinine ratio (ACR) and left ventricular (LV) mass and also tested the hypothesis that a simple random, singlevoid urine ACR would identify high risk young, hypertensive, African-American men. We measured echocardiographic LV mass and a random spot urinary ACR in 109 untreated, hypertensive, young, inner city, African-American men. The mean age was 41 6 years and the mean blood pressure (BP) was / mm Hg. Microalbuminuria (ACR 30 to 300 mg/g) was Microalbuminuria is a predictor of cardiovascular events in hypertension. 1 3 Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC) VI 4 advocates more aggressive treatment of hypertension in patients with target organ damage such as left ventricular hypertrophy present in 22% of subjects. The ACR is higher in the men with LVH than in the men without LVH (P <.05). Increased ACR is a predictor of increased LV mass index (P <.003) using multiple linear regression. An ACR >30 mg/g has a sensitivity of 33% and a specificity of 82% for the diagnosis of echocardiographic LVH. In conclusion, elevated random spot ACR is a marker of increased LV mass, independent of BP, in young urban African-American men with hypertension, and may help to determine the aggressiveness of antihypertensive therapy in this high-risk group. Am J Hypertens 2000;13: American Journal of Hypertension, Ltd. KEY WORDS: Hypertrophy, hypertension, proteinuria, epidemiology, echocardiography. (LVH) and proteinuria. The recommended evaluation of the hypertensive patient includes a 12-lead electrocardiogram and routine urinalysis. However, measurement of microalbuminuria and echocardiography are considered optional. Urinary albumin excretion typically is assessed with a 24-h urine collection. However, this method is bur- Received August 17, Accepted March 16, From the Divisions of Cardiology (WSP, RSB, JLW, DRT, GG) and Internal Medicine (DML), Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Center for Nursing Research (MNH), The Johns Hopkins University School of Nursing, Baltimore, Maryland. This study was supported by grants from NIH-NINR grant #RO1 NR04119, Johns Hopkins GCRC NIH-NCRR grant #5M01RR00052, and Merck & Co. Address correspondence and reprint requests to Wendy S. Post, MD, MS, Carnegie 568, Cardiology Division, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21287; wpost@ jhmi.edu 2000 by the American Journal of Hypertension, Ltd /00/$20.00 Published by Elsevier Science, Inc. PII S (00)01181-X

2 AJH NOVEMBER 2000 VOL. 13, NO. 11 ALBUMIN CREATININE RATIO PREDICTS LVH 1169 densome for patients and not reliable if an incomplete collection is obtained. Random spot, single-voided, urine specimens for measurement of the albumin creatinine ratio (ACR) correlate well with 24-h urine collections 5,6 and are inexpensive, simple, and easy to obtain. The association between urinary albumin excretion and LVH in previous studies is inconsistent, 7 10 and has not been described using a single, random spot urine specimen. African-Americans are at particularly high risk for hypertension-related renal failure and LVH. Therefore, we evaluated the association between the urinary ACR and left ventricular (LV) mass and also tested the hypothesis that a simple random, single-void urine ACR would identify high risk young, hypertensive, African-American men, a rarely studied group. METHODS Subjects Subjects were ambulatory outpatients in a randomized single-center trial evaluating the effectiveness of a comprehensive program to improve blood pressure (BP) control in young, inner-city African-American men. Inclusion criteria for the trial are African-American men, aged 18 and 54 years, with hypertension, residing in inner city Baltimore. Hypertension was defined as having a systolic BP 140 mm Hg or diastolic BP 90 mm Hg, on 2 separate days, or as having been diagnosed with hypertension and being treated with an antihypertensive medication. Men receiving renal dialysis were excluded. Subjects were recruited from the Emergency Department, advertising, and word of mouth. Data for this analysis were obtained from the baseline visit, before randomization in the clinical trial. Three hundred nine men completed the baseline examination for the clinical trial. For the current analysis subjects who met any of the following criteria were serially excluded: 1) did not leave urine specimen (n 28), 2) did not complete echocardiogram (n 7), 3) technically limited echocardiogram (n 22), 4) diabetes (n 21), 5) current use of antihypertensive medication (n 110), 6) serum creatinine 1.6 mg/dl (n 8), and 7) ACR 300 mg/g (n 4). These men were excluded as diabetes and antihypertensive medication can affect urinary albumin excretion, and subjects with significant renal insufficiency or gross proteinuria may have primary renal disease rather than essential hypertension. Therefore, there were 109 men included in this analysis. Clinical Variables Blood pressure was measured three times in the sitting position by random zero sphygmomanometry at the randomization visit, after 5 min of rest, and the mean of the last two measurements were used for systolic and diastolic BP. Diabetes mellitus was defined as a random serum glucose 200 mg/dl, or use of oral hypoglycemic agents or insulin. Antihypertensive medication use was evaluated by self-report. Height and weight were measured, and body mass index (BMI) was calculated (weight/height 2 ) as a measure of obesity. A random spot, afternoon, single-void urine specimen was collected, as albumin in daytime, but not first void, urinary specimens, most closely relates to 24-h collections. 5 Urine albumin was measured using an immunonephelometric assay 11 (Boehring Nephelometer II, Deerfield, IL). Urine creatinine was measured (Kodak 700XR Chemistry Analyzer, Rochester, NY) and the ACR was calculated (expressed as milligrams of albumin per gram of creatinine). Microalbuminuria was defined as ACR 30 to 300 mg/g, and macroalbuminuria (overt proteinuria) as ACR 300 mg/g. Routine 12-lead electrocardiograms (ECG) were performed. Electrocardiographic LVH was defined according to the Cornell voltage criteria. The amplitude of the voltages of RaVL and SV 3 were measured by the Marquette computer system (Marquette Electronics, Milwaukee, WI) and a sum 2.8 mv was used as the definition of ECG LVH (Cornell). 12 Transthoracic echocardiography was performed by a trained sonographer using an HP Sonos 100 machine (Hewlett Packard, Palo Alto, CA). LV mass was calculated offline by a cardiologist (WSP). The two-dimensional 5/6 area length method was used, because of its potential for greater accuracy and reproducibility than M-mode methods. 13,14 LV mass was indexed to height (meters) raised to the 2.7 power to adjust for body size. 15 Echocardiographic LVH was defined as LV mass/height g/m 2.7. This study was approved by the Johns Hopkins Joint Committee on Clinical Investigation. All subjects signed informed consent. Statistical Analysis Statistical analyses were performed using SPSS software, Chicago, IL. Descriptive data are presented as mean standard deviation. Continuous variables were compared using Student t test. The ACR was log transformed for the parametric analyses as the distribution was positively skewed. A multivariable linear regression model was used to analyze the association between ACR and LV mass index, adjusting for other known predictors of LV mass and albuminuria. A two-sided P value.05 was considered statistically significant. RESULTS The mean age was 41 6 years, mean BP / mm Hg, and the prevalence of echocardiographic LVH was 27.5%. Microalbuminuria was present in 22% of subjects. Clinical characteristics of the study subjects stratified by the presence or absence of echocardiographic LVH are presented in Table 1.

3 1170 POST ET AL AJH NOVEMBER 2000 VOL. 13, NO. 11 TABLE 1. CLINICAL CHARACTERISTICS ACCORDING TO ECHOCARDIOGRAPHIC LVH STATUS Characteristics No LVH LVM g n 79 (72%) LVH LVM g n 30 (28%) Age (y) Systolic blood pressure (mm Hg) * Diastolic blood pressure (mm Hg) Body mass index (kg/m 2 ) Serum creatinine (mg/dl) * Albumin creatinine ratio (mg/g) LVH left ventricular hypertrophy; LVM left ventricular mass. *P.001; P.05; P.05 using natural log transformation. Systolic and diastolic BP, serum creatinine and urinary ACR are higher in the men with LVH than the men without LVH. There is no difference in age or BMI between the two groups. There is a significant correlation between echocardiographic LV mass and urinary ACR (r 0.27, P.005). Increased ACR is an independent predictor of increased LV mass index (P.003) using multiple linear regression to control for clinical variables potentially related to LV mass or ACR in a cross-sectional analysis of the baseline data (Table 2). Systolic BP and serum creatinine are also significant independent predictors of LV mass. The standardized coefficients suggest that the urinary ACR has a similar predictive value as systolic BP. The correlation between echocardiographic LV mass and urinary ACR is lower in the men currently receiving antihypertensive therapy, r 0.16, P.03. (These men have been excluded from all the other analyses.) Compared to Cornell voltage electrocardiographic criteria for LVH, 11 an ACR 30 mg/g has a similar sensitivity (ECG 35%; ACR 33%), but a lower specificity (ECG 99%, ACR 82%) for the diagnosis of echocardiographic LVH (Table 3). As the threshold for ACR increases, there is a progressive decrease in the sensitivity and an increase in specificity for the diagnosis of TABLE 2. MULTIPLE LINEAR REGRESSION Variables Beta SD Standardized Beta Systolic BP ln urinary ACR Serum creatinine Diastolic BP BP blood pressure; ln natural log; ACR albumin-creatinine ratio. Dependent variable, echocardiographic LV mass index (r , n 109). P LVH. When an ACR 30 mg/g is added to the presence of ECG LVH criteria, the sensitivity increases from 35% for ECG LVH alone to 59% when the two tests are combined; however, the specificity decreases from 99% to 82%. This results in the combined tests having a slightly greater negative predictive value (84%) compared with ECG LVH alone (80%), but a lower positive predictive value (ECG 91%; ACR ECG 55%). DISCUSSION We found that a simple, inexpensive, single-void urine ACR is a predictor of increased echocardiographic LV mass in young, inner-city, African-American men with hypertension not on medical therapy. Most studies evaluating proteinuria use a 24-h measurement of albumin excretion. However, the ACR from a single untimed specimen correlates well with a 24-h collection 5,6 and is more practical, and less expensive than 24-h collections in the outpatient setting. There are few other studies describing associations with single void ACR. Our study is unique in that it is the first to document the association between increased urinary albumin excretion and LV mass in inner-city, young, African- American men, a group at high risk for the complications of hypertension including renal failure and congestive heart failure. This population has rarely been studied before. Previous studies of this association included primarily white populations The lack of an association in some studies 10 may have been related to racial differences in albuminuria and LVH. We also document that the sensitivity and specificity of ACR are similar to ECG criteria for LVH, and when the ACR is added to the ECG, the sensitivity is increased. There may be racial differences in the propensity toward albuminuria in hypertension. A few studies indicate that blacks are more likely than whites to have elevated urinary albumin excretion. 16,17 Urinary

4 AJH NOVEMBER 2000 VOL. 13, NO. 11 ALBUMIN CREATININE RATIO PREDICTS LVH 1171 TABLE 3. SENSITIVITY, SPECIFICITY, AND PREDICTIVE VALUES OF TESTS FOR DETECTING ECHOCARDIOGRAPHIC LVH IN OUR POPULATION OF HYPERTENSIVE YOUNG BLACK MEN ACR ECG or ACR* Threshold ECG Sensitivity Specificity PPV NPV ECG electrocardiogram (Cornell voltage-lvh); PPV positive predictive value; NPV negative predictive value; other abbreviations as in Tables 1 and 2. * ECG or ACR indicates ECG or ACR positive. albumin excretion was also higher in salt-sensitive white hypertensives than in salt-resistant hypertensives, and increases with a high dietary salt intake. 18 Blacks may be more likely to have salt-sensitive hypertension, which may explain the possible greater prevalence of microalbuminuria in blacks. We report that increased ACR is associated with increased LV mass, and that this relationship is independent of BP in the multivariate model. However, we are limited by having only two BP measurements. Both LVH and albuminuria are considered manifestations of target organ damage in hypertension and are known to be related to the severity and duration of hypertension. However, there may be a common etiologic factor other than BP, per se, that results in greater target organ damage in some individuals. It has been suggested that increased activity of the renin angiotensin system may play a role in the development of hypertension and LVH, possibly related to genetic variations. 19 Further studies are necessary to evaluate the possibility that these variations may also play a role in the parallel development of increased urinary albumin excretion and LV mass. In addition, it is well known that LVH is a potent predictor of adverse cardiovascular events. 20 Because microalbuminuria is associated with LV mass, studies evaluating the independent predictive value of microalbuminuria should consider adjusting for LV mass. Previous studies of the association between increased urinary albumin excretion and increased LV mass report conflicting results. Redon et al 7 found that LV mass was elevated in men with microalbuminuria and mild hypertension, but not in women, as compared with men with normal urinary albumin excretion. A later study by the same group found that in white hypertensive patients, LV mass was a predictor of urinary albumin excretion independent of BP. 8 In the Microalbuminuria: A Genoa Investigation on Complications study, LV mass was found to be higher in hypertensive patients with microalbuminuria, compared with hypertensive patients without microalbuminuria and normotensive controls. 9 However, LV mass was not related to urinary albumin excretion in white men and women with stage 1 hypertension in the Hypertension and Ambulatory Recording Venetia study. 10 This disparity may be explained by differences in racial factors, or in the severity of hypertension. A limitation of this study is that we included only men and not women. In addition, the ability of multiple, rather than a single untimed specimen, to limit the inherent variability in urinary albumin excretion, and thus increase the predictive power of the test, requires further investigation. In addition, because of the effects of antihypertensive medication on albumin excretion these subjects were excluded from the analysis. However, we know that a large number of African-American men have untreated hypertension, and therefore, these data may be particularly useful in this population. Increased LV mass is a strong predictor of adverse cardiovascular events, 20 but is often difficult to diagnose in an outpatient setting, without echocardiography, because of the low sensitivity of electrocardiographic criteria. 21 Because patients with target organ damage are at the greatest risk, and also potentially have the most to gain from aggressive antihypertensive therapy, JNC VI recommends a lower target BP in these patients. 4 Currently, microalbuminuria is not routinely measured. However, our study suggests that measurement of a spot ACR may be helpful in identifying young, untreated, hypertensive, African-American men with early target organ damage. If a simple ACR from an untimed specimen is further validated in future studies to predict increased LV mass, this test may become a routine part of the evaluation of hypertension in African-Americans and help to guide the aggressiveness of antihypertensive therapy in this high-risk group. ACKNOWLEDGMENT We thank Benjamin Paul for his technical assistance with this manuscript.

5 1172 POST ET AL AJH NOVEMBER 2000 VOL. 13, NO. 11 REFERENCES 1. Yudkin JS, Forrest RD, Jackson CA: Microalbuminuria is a predictor of vascular disease in non-diabetic subjects. Lancet 1988;2: Samuelsson O, Wilhelmsen L, Elmfeldt D, Pennert K, Wedel H, Wikstrand J, Berglund G: Predictors of cardiovascular morbidity in treated hypertension: results from the primary preventive trial in Gotenborg Sweden. J Hypertension 1985;3: Haffner SM: Microalbuminuria. Potential marker for increased cardiovascular risk factors in nondiabetic subjects? Arteriosclerosis 1990;10: Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure: The sixth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). NIH Publication No November Ginsberg JM, Chang BS, Matarese RA, Garella S: Use of single-voided urine samples to estimate quantitative proteinuria. N Engl J Med 1983;309: Schwab SJ, Christensen RL, Dougherty K, Klahr S: Quantification of proteinuria by the use of protein-tocreatinine ratios in single urine samples. Arch Intern Med 1987;147: Redon J, Gomez-Sanchez MA, Baldo E, Casal MC, Fernandez ML, Miralles A, Gomez-Pajuelo CG, Rodicio JL, Ruilope LM: Micro-albuminuria is correlated with left ventricular hypertrophy in male hypertensive patients. J Hypertens 1991;9(suppl 6):S148 S Redon J, Liao Y, Lozano JV, Miralles A, Baldo E, Cooper RS: Factors related to the presence of microalbuminuria in essential hypertension. Am J Hypertens 1994;7: Pontremoli R, Nicolella C, Viazzi F, Ravera M, Sofia A, Berruti V, Bezante GP, Del Sette M, Martinoli C, Sacchi G, Defarrari G: Microalbuminuria is an early marker of target organ damage in essential hypertension. Am J Hypertens 1998;11: Palatini P, Graniero GR, Mormino P, Mattarei M, Sanzuol F, Cignacco GB, Gregori S, Garavelli G, Pegoraro F, Maraglino G, Bortolazzi A, Accurso V, Dorigatti F, Graniero F, Gelisio R, Businaro R, Vriz O, Dal Follo M, Camarotto A, Pessina AC: Prevalence and clinical correlates of microalbuminuria in stage 1 hypertension. Am J Hypertens 1996;9: Giampietro O, Penno G, Clerico A, Cruschelli A, Nannipieri M, Cecere M, Rizzo L, Navalesi R: Which method for quantifying microalbuminuria in diabetics? Comparison of several immunological methods for measurement of albumin in urine. Acta Diabetologica 1992;28: Casale PN, Devereux RB, Alonso DR, Campo E, Kligfield P: Improved sex-specific criteria of left ventricular hypertrophy for clinical and computer interpretation of electrocardiograms: validation with autopsy findings. Circulation 1987;75: Reichek N, Helak J, Plappert T, Sutton MS, Weber KT: Anatomic validation of left ventricular mass estimates from clinical two-dimensional echocardiography: initial results. Circulation 1983;67: Collins HW, Kronenberg MW, Byrd BF 3d: Reproducibility of left ventricular mass measurements by twodimensional and M-mode echocardiography. J Am Coll Cardiol 1989;14: De Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, De Divitiis O, Alderman MH: Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol 1992;20: Jiang X, Srinivasan SR, Radhakrishnamurthy B, Dalferes ER, Bao W, Berenson GS: Microalbuminuria in young adults related to blood pressure in a biracial (black white) population. The Bogalusa Heart Study. Am J Hypertens 1994;7: Summerson JH, Bell RA, Konen JC: Racial differences in the prevalence of microalbuminuria in hypertension. Am J Kidney Dis 1995;26: Bigazzi R, Bianchi S, Baldari D, Sgherri G, Baldari G, Campese VM: Microalbuminuria in salt-sensitive patients. A marker for renal and cardiovascular risk factors. Hypertension 1994;23: Schunkert H, Hense HW, Holmer SR, Stender M, Perz S, Keil U, Lorell BH, Riegger GA: Association between a deletion polymorphism of the angiotensin-converting enzyme gene and left ventricular hypertrophy. N Engl J Med 1994;330: Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322: Levy D, Labib SB, Anderson KM, Christiansen JC, Kannel WB, Castelli WP: Determinants of sensitivity and specificity of electrocardiographic criteria for left ventricular hypertrophy. Circulation 1990;81:

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

AJH 2001; 14:338 344 Association Between Albumin:Creatinine Ratio and 24-Hour Ambulatory Blood Pressure in Essential Hypertension Vladimir A. Boulatov, Aud Stenehjem, and Ingrid Os Microalbuminuria (MAU)