Left Ventricular Remodeling and Renal Function in Never- Treated Essential Hypertension

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1 J Am Soc Nephrol 14: , 2003 Left Ventricular and Renal Function in Never- Treated Essential Hypertension PIERRE FESLER, GUILHEM DU CAILAR, JEAN RIBSTEIN, and ALBERT MIMRAN Department of Internal Medicine, CHU Montpellier, France. Abstract. In the general population, renal function linearly declines with age; hypertension may accelerate this decline. Because concentric left ventricular (LV) hypertrophy is a strong marker of the severity of hypertension, the influence of LV geometry on the age-associated decline in renal function was assessed in 195 normotensive subjects and 645 patients with never-treated essential hypertension with an average duration of 30 mo. According to LV mass and relative wall thickness, hypertensive patients were divided into normal LV (NL, 48%), concentric remodeling (CR, 19%), and concentric (CH, 22%) and eccentric (EH, 11%) hypertrophy. GFR and effective renal plasma flow (ERPF) were estimated by isotopic clearance technique. GFR and ERPF were inversely correlated with age in normotensive and hypertensive subjects, and no marked influence of the BP level or the presence of LV hypertrophy was detected. However, the slope of the regression line of GFR versus age was accentuated (P 0.01) in patients with CH or CR (slope values of , ml/min per yr, respectively) when compared with patients with EH or NL (slope values of and ml/min per yr, respectively). No such results were obtained when creatinine clearance was considered. Urinary albumin excretion was higher in patients with concentric or eccentric LV hypertrophy than in patients with concentric LV remodeling or normal LV. These results demonstrate that in nevertreated essential hypertension, the age-associated decline in GFR is markedly influenced by the concentric pattern of LV response to hypertension rather than the level of BP and/or the presence of LV hypertrophy. Received November 23, Accepted January 6, Correspondence to Dr. Albert Mimran, Department of Internal Medicine, Hôpital Lapeyronie, Montpellier Cedex 5, France. Phone: ; Fax: ; a-mimran@chu-montpellier.fr / Journal of the American Society of Nephrology Copyright 2003 by the American Society of Nephrology DOI: /01.ASN F Both the heart and the kidney are major target organs of systemic hypertension. Left ventricular hypertrophy (LVH) is associated with a higher morbidity and mortality in hypertensive patients, independently of BP (1). However, the risk can be further stratified when the geometry of the left ventricle (LV) is considered. As shown by Koren et al. (2), patients with concentric LVH had a higher incidence of fatal and nonfatal cardiovascular events, whereas patients with eccentric LVH or concentric LV remodeling were at intermediate risk within a follow-up period of 10 yr. Several studies have shown that extra cardiac target organ damage could also be related to the presence of specific patterns of LVH. patients with concentric LVH have a higher incidence of hypertensive retinopathy and renal involvement (as evidenced by serum creatinine level) (3), silent cerebral white matter lesions (4), and higher degree of carotid structural change (5) when compared with hypertensive patients with other patterns of LV geometry. In a longitudinal study conducted over a period of 8 yr or more, Lindeman et al. (6) showed that mean arterial pressure was an important determinant of the rate of decrease of creatinine clearance with age. In the Multiple Risk Factor Intervention Trial (MRFIT) (7), it was observed that during an average of 16 yr of follow-up and regardless of the baseline level of arterial pressure, only 0.24% of the population proceeded to end-stage renal disease (ESRD). When patients were stratified according to baseline arterial pressure, the rate of patients proceeding to ESRD increased from 0.08% in those with optimal ( 120 mmhg) to 0.18% in those with high normal (130 to 139 mmhg) and 0.67% in patients with moderately increased (160 to 179 mmhg) systolic arterial pressure. However, in morphologic studies, renal arteriosclerosis was found in 68 to 97% of patients with hypertension (8,9). LVH is a strong marker of the severity of hypertension (2), it was hypothesized that the decline of renal function with age could be influenced by LV geometry. In the present study and using a cross-sectional design and isotopic measurements of renal hemodynamics and function, the relationship between LV geometry and age-related changes in renal function was assessed in patients with never-treated essential hypertension. Materials and Methods Study Population The study population consisted of 840 subjects (397 women and 443 men, aged 14 to 99 yr) recruited from the outpatient clinic of the department of medicine, where individuals came directly or were referred by general practitioners for detection or investigation of cardiovascular risk factors. Hypertension, defined as arterial pressure 135/85 mmhg on at least two subsequent visits, was present in 645 subjects (308 women and 337 men), and none of them had ever received antihypertensive treatment. The remaining 195 subjects were

2 882 Journal of the American Society of Nephrology J Am Soc Nephrol 14: , 2003 considered normotensive. Patients with clinical evidence of atherosclerosis (stroke, coronary, and peripheral artery disease), heart failure, renal failure (serum creatinine 130 mol/l), diabetes mellitus (fasting blood glucose 6.7 mmol/l), marked obesity (body mass index 35 kg/m 2 ), a history of alcohol abuse ( 5 drinks/d), and secondary hypertension were excluded. Doppler echocardiography was used to detect valvular lesions in all patients. BP Measurements Arterial pressure was measured every 3 min with an automatic device (Dynamap 845 XT, Critikon, France), and values are the average of at least ten measurements after a 10-min period of rest in the supine position. Determination of Renal Function Patients came to the ward with two consecutive 24-h urine collections for the determination of sodium (as an index of sodium intake), potassium, urea, creatinine, and albumin excretion (UAE, measured by RIA). GFR and effective renal plasma flow (ERPF) were estimated by urinary clearances of technetium-labeled diethylene triaminopentaacetic acid ( 99m Tc-DTPA) and 131 I-ortho iodohippurate, respectively, using the constant infusion technique, as described previously (10). Briefly, after induction of water diuresis and a 90-min equilibration period, three 20-min to 30-min urine collections were obtained by spontaneous voiding. At the end of each clearance period, patients drank a volume of water equal to the preceding urine volume. At midpoint of each clearance period, blood was drawn for the determination of plasma radioactivity and hematocrit. Blood samples were also obtained before clearance determination for the measurement of creatinine, electrolytes, total cholesterol, HDL-cholesterol, triglycerides, fasting blood glucose, glycated hemoglobin, plasma renin activity, and aldosterone concentration (RIA using the CEA Sorin kit, France). Measured creatinine clearance using 24-h urine collection (C Cr ), creatinine clearance calculated according to the Cockcroft- Gault formula (C Cr calc) (11), GFR, and ERPF were normalized for a body surface area of 1.73 m 2. Filtration fraction (FF) was calculated as GFR/ERPF and renal vascular resistance as MAP (1 hematocrit)/erpf, where MAP is mean arterial pressure. The reproducibility of day-to-day measurements of GFR and ERPF obtained in 20 subjects and expressed as coefficient of variation was 6.4 and 6.3%, respectively. Echocardiography Echocardiographic assessment of left ventricular morphology was performed by the same observer with an Acuson 128 XP10 (Acuson, Mountain View, CA) with 2.5 or 3.5 MHz transducer. M-mode studies of the left ventricle were guided by two-dimensional echocardiography using an optimal long-axis view below the tip of the mitral leaflets, and tracings were analyzed using an off-line station by two readers who had no knowledge of the patient s clinical status. Measurement points were taken at the peak of the R wave on the simultaneous electrocardiogram, on an average of three cycles per recording. Interventricular septal thickness and posterior wall thickness at end-diastole were measured according to the Penn convention. Relative wall thickness (RWT) at end-diastole was calculated as the ratio of twice the posterior wall thickness to left ventricular enddiastolic internal dimension. Fractional shortening was assessed as a measure of left ventricular performance. Left ventricular mass (LVM) was calculated by the Penn-cube method according to Devereux et al. (12) and indexed to body surface area, height, or height 2.7 (13). Left ventricular hypertrophy was defined as LV mass index greater than 110g/m 2 in female patients and 130 g/m 2 in male patients. and eccentric LVH were defined by the existence of increased ( 0.44) or normal RWT, respectively. remodeling was defined by the finding of normal LV mass associated with increased RWT. Statistical Analyses StatView version 5.0 software (SAS Institute, Cary, NC) was used for statistical analyses. Data were reported as mean SD or median and interquartile range in the presence of skewed data. Differences in continuous variables between two groups were assessed by the t test for parametric data, and differences in categorical data were assessed by the 2 analysis. Comparison among multiple groups was performed by ANOVA with the Scheffé post hoc test for continuous data and 2 analysis for categorical data. Due to skewed distribution, UAE, plasma renin activity, serum aldosterone, and the aldosterone-toplasma renin activity ratio were log-transformed before comparison of groups. Simple relationships between renal function parameters and age were examined by linear regression and calculation of the Spearman correlation coefficient. The slopes of the regression lines were reported as mean SEM, and comparison between groups was made by ANOVA (14). Two-tailed P 0.05 was considered statistically significant. Results Population Characteristics Characteristics of the study group according to the presence or absence of hypertension and the morphology of the left ventricle are summarized in Table 1. Among hypertensive subjects, 33% had LVH; and the most prevalent LV geometric pattern was normal LV geometry (48%), followed by concentric LVH (22%), concentric LV remodeling (19%), and eccentric LVH (11%). The known duration of hypertension as well as body mass index, fasting blood glucose, serum uric acid, and 24-h urinary sodium excretion were higher in patients with concentric LVH when compared with the other three hypertensive groups. Systolic, diastolic, and mean arterial pressures, as well as pulse pressure, were significantly higher in subjects with modified LV geometry than subjects with normal LV geometry; and subjects with concentric LVH had the highest level of arterial pressure among all groups. Plasma renin activity was lower in hypertensive patients with concentric and eccentric LVH when compared with patients with concentric remodeling and normal LV geometry. Plasma aldosterone concentration was similar in all groups; however, the aldosteroneto-renin ratio was increased in hypertensive patients with concentric or eccentric hypertrophy when compared with normotensive patients. Prevalence of current smoking, a possible factor of accelerated GFR decline (15), was identical in all groups. Influence of LV on Renal Function Table 2 displays renal function parameters according to the presence or absence of hypertension and LV geometry. There was no difference between groups in plasma creatinine concentration, C Cr,C Cr calc, and GFR. ERPF was slightly but significantly lower in hypertensive patients with concentric

3 J Am Soc Nephrol 14: , 2003 Renal Function in Hypertension 883 Table 1. Population characteristics according to the presence or absence of hypertension and geometry of the left ventricle a P ANOVA n (% of hypertensive population) (48%) 121 (19%) 144 (22%) 72 (11%) Male gender (%) NS Age (yr) b b bcd b Smokers (%) NS Body mass index (kg/m 2 ) b bc b Hypertension duration (mo) c bce Systolic arterial pressure (mmhg) b bc bcd bce Diastolic arterial pressure (mmhg) b bc bcd be Mean arterial pressure (mmhg) b bc bcd bce Pulse pressure (mmhg) b b bcd bc Plasma sodium (mmol/l) NS Plasma potassium (mmol/l) NS Serum uric acid (mg/dl) bc e Fasting blood glucose (mg/dl) bc e Total cholesterol (mg/dl) b b b b HDL-cholesterol (mg/dl) NS Triglycerides (mg/dl) bc Urinary sodium (mmol/24 h) bc Urinary potassium (mmol/24 h) Plasma renin activity (ng ml 1 h 1 ) 0.54 (0.34 to 1.1) 0.60 (0.28 to 1.2) 0.57 (0.30 to 1.0) 0.40 (0.21 to 0.73) c 0.42 (0.19 to 1.0) 0.02 Serum aldosterone (ng/dl) 9.0 (6.5 to 13) 11 (7.2 to 17) 10 (7.1 to 16) 10 (6.7 to 15) 10 (7.5 to 18) NS Aldosterone plasma renin activity ratio 16 (9.7 to 25) 19 (10 to 32) 22 (13 to 37) 23 (12 to 58) b 25 (15 to 51) b a Values are mean SD or median (interquartile range); NS, not significant.

4 884 Journal of the American Society of Nephrology J Am Soc Nephrol 14: , 2003 Table 2. Renal function parameters according to the presence or absence of hypertension and geometry of the left ventricle a P ANOVA Plasma creatinine (mg/dl) NS Creatinine clearance (ml/min per 1.73 m 2 ) NS Cockroft-Gault creatinine clearance (ml/min per 1.73 m 2 ) NS Glomerular filtration rate (ml/min per 1.73 m 2 ) NS Effective renal plasma flow (ml/min per 1.73 m 2 ) bd Filtration fraction (%) b b b Renal vascular resistance (mmhg ml 1 min 1000) b b bcd be a Values are mean SD; NS, not significant. LVH when compared with normotensive patients. Filtration fraction was higher in hypertensive when compared with normotensive individuals; and no difference between groups was detected within the hypertensive population. As depicted in Figure 1 and Table 3, UAE was higher in patients with concentric or eccentric LV hypertrophy than patients with concentric LV remodeling or normal LV geometry. Influence of Hypertension and LV on the Age-Related Decline in Renal Function In the whole population, measured creatinine clearance, creatinine clearance calculated according to the Cockcroft- Gault formula, GFR, and ERPF, but not filtration fraction, were inversely correlated with age. When the population was divided on the basis of the presence or absence of hypertension, no difference in the slopes of ERPF versus age was observed ( ml/min per yr for the normotensive group and for the hypertensive group, NS). However, the slope of GFR versus age was greater in the hypertensive when compared with the normotensive group ( versus ml/min per yr, P 0.053). When the hypertensive population was divided into tertiles of systolic arterial pressure, no influence of the pressure level on the slopes of GFR or ERPF versus age was detected. As shown in Table 1, LVH was present in 33% of the hypertensive population; and the slope of GFR or ERPF versus age was not modified in the presence of LVH. As shown in Table 4, when the influence of LV geometry was considered, the age-related decline in GFR was similarly enhanced in patients with concentric remodeling and concentric LVH when compared to the other groups. In contrast, in patients with normal LV geometry and eccentric LVH, the slope of GFR versus age was not modified when compared Figure 1. Urinary albumin excretion according to the presence or absence of hypertension and geometry of the left ventricle. Values are expressed as median and interquartile range. * P 0.05 versus normotensive; P 0.05 versus normal geometry; P 0.05 versus concentric remodeling; P 0.05 versus concentric hypertrophy.

5 J Am Soc Nephrol 14: , 2003 Renal Function in Hypertension 885 Table 3. Target organ damage according to the presence or absence of hypertension and geometry of the left ventricle a P ANOVA Left ventricular mass index (g/m 2 ) b bc bcd bcde Relative wall thickness (%) b bc bcd bcde Urinary albumin excretion ( g/min) 4.6 (3.1 to 7.3) 6.2 (3.9 to 10) 7.6 (4.5 to 15) b 11 (5.9 to 22) bcd 10 (5.4 to 23) bc a Values are mean SD or median (interquartile range); NS, not significant. Table 4. Slopes of linear relationships between renal function parameters and age according to the presence or absence of hypertension and geometry of the left ventricle a P ANOVA Glomerular filtration rate (ml/min per yr) bc bc e 0.01 Effective renal plasma flow (ml/min per yr) NS Measured creatinine clearance (ml/min per yr) NS Cockroft-Gault creatinine clearance (ml/min per yr) NS a Values are mean SEM; NS, not significant.

6 886 Journal of the American Society of Nephrology J Am Soc Nephrol 14: , 2003 with normotensive subjects. Although a trend for a steeper decline in ERPF with age existed in patients with abnormal LV geometry, no significant difference between slopes was detected (P 0.30). Of interest, expression of GFR and ERPF per meter of height, to mask the influence of obesity (16), yielded similar observations. Discussion In the present cross-sectional study, conducted in a large cohort of normotensive subjects and never-treated patients with essential hypertension, it was observed that LV geometry and more specifically concentric remodeling and concentric LVH tend to accentuate the slope of the inverse relationship between GFR and age. In contrast, in hypertensive patients with normal geometry or eccentric LVH, the rate of the age-related decline of GFR was similar to that of normotensive subjects. Such findings were not obtained when renal function was estimated by creatinine clearance (as measured using 24-h urine collection) or the Cockcroft-Gault formula. Of interest, the slope of the GFR versus age relationship was slightly increased as compared with normotensive subjects in hypertensive patients (as a whole); no influence of the arterial pressure level was detected in the hypertensive population when tertiles of arterial pressure were considered. In the Baltimore Longitudinal Study on Aging, the average rate of decline in 24-h creatinine clearance measured serially over a period of 8 yr or more averaged 0.75 ml/min per yr and was accentuated with the increase in baseline BP in a group of 254 normotensive and hypertensive untreated subjects (6). In a small population and within a 7-yr follow-up period, the annual fall in GFR (inulin clearance) averaged 1.4 ml/min in 17 normal subjects aged 49 yr at baseline; no difference with the fall observed in 40 treated hypertensive patients was detected (17). In cross-sectional studies, a negative relationship between age and creatinine clearance was found (18,19), and the slope of the relationship was close to values obtained in normotensive subjects included in the present study (approximately 0.7 to 0.8 ml/min per yr). As presently reported, when renal aging was assessed using a reliable marker of GFR such as 99m Tc- DTPA and the continuous infusion technique with urine collections, the magnitude of the decline in GFR averaged 0.45 ml/min per yr in 195 normal subjects. Such an observation is not surprising, because creatinine clearance may overestimate true GFR, even in subjects with fairly normal renal function (20). In the present study, only the estimate of true GFR (in contrast to creatinine clearance) allowed to demonstrate that LV geometry and specifically the concentric pattern of LV remodeling associated with never-treated hypertension is an important determinant of the age-associated decline in GFR. Several factors are susceptible to explain the effect of the concentric pattern of LV remodeling on the GFR decline with age. The age-related decrease in ERPF measured by the singleinjection clearance of para-aminohippuric acid tends to be accentuated by the existence of hypertension as shown by Schmieder et al. (21) in a rather small population. No such finding was presently observed; however, filtration fraction, which may be considered as an index of glomerular capillary pressure, tended to be higher (when compared with normotensive subjects) in all hypertensive groups and to a larger extent in patients with concentric LVH. In essential hypertension, UAE is now considered as a good predictor of cardiovascular events, independently of other known risk factors (22,23). In the present study, UAE was higher in hypertensive patients with LVH as compared with those without LVH. This is in agreement with other studies showing the positive relationship between albuminuria and LV mass (5). In fact, taken together, such findings are consistent with the fact that patients with concentric LVH are the most severe patients as evidenced by higher systolic, diastolic, and pulse pressure levels and higher UAE. Although hypertensive patients with microalbuminuria were shown to exhibit a higher decline in renal function than do patients with normal UAE within a follow-up period of 7 yr (24), it remains to be documented that UAE is a good predictor of the age-associated decline in GFR. Although subjects with diabetes (fasting blood glucose higher than 6.7 mmol/l) were excluded from this study, blood glucose was higher in the group with concentric LVH when compared with the other groups. A similar trend was observed in 475 elderly Swedish men in whom components of the insulin resistance syndrome were related to concentric remodeling (25). Unfortunately, antihypertensive treatment was used by 40% of the study population. In the present study, the oral glucose tolerance test was not performed, and thus the prevalence of impaired glucose tolerance and its eventual relationship to LV geometry could not be assessed. In a previous cross-sectional study conducted in 227 never-treated essential hypertensive patients, the slope of the decline of GFR with age was 2.5-fold steeper in patients with impaired glucose tolerance than in those with normal glucose tolerance, despite similar arterial pressure level and mean value of UAE (26). Plasma levels of atrial and brain natriuretic peptides (ANP and BNP, respectively) are higher in essential hypertensive patients as compared with normotensive subjects and positively correlated with left ventricular mass. However, it was reported that circulating BNP is higher in concentric LVH than in the other geometric patterns that were not significantly different from normotensive subjects (27). In fact, it is reasonable to assume that the increase in both peptides could result from modified LV geometry and/or an increase in sodium intake as observed in the group of patients with concentric LVH. Of interest is the recent finding that sodium intake may be an important modulator of the left ventricular response to high systemic pressure (28). Both endogenous natriuretic peptides have no sustained effect on GFR and ERPF, but result in a rise in the filtration fraction (29). In the present study, filtration fraction was higher in hypertensive than normotensive subjects, but the highest value was observed in patients with concentric LVH. It is then possible that an increase in ANP or BNP may underlie the accelerated decline of GFR with age in patients with a concentric pattern of left ventricular response to hypertension. As a consequence of the present observations, the concentric pattern of the left ventricle response to hypertension appeared

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