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Kidney International, Vol. 14 (/978), pp. 619-628
Age versus urinary sodium for judging renin, aldosterone, and catecholamine levels: Studies in normal subjects and patients with essential hypertension
PETER WEIDMANN, CARLO BERETTA-PICCOLI, WALTER H. ZIEGLER, GERALD KEUSCH, ZEEV GLCJCK, and FRANç0Is C. REUBI
Medizinische Poliklinik, University of Berne, Switzerland
Age versus urinary sodium for judging renin, aldosterone, and inversement correlées (P < 0,05) et PNE plasmatique ou catecholamine levels: Studies in normal subjects and patients with l'excrétion de NE en position couchée sont correlées positive- essential hypertension. The relative influence of sodium balance ment avec l'âge mais non avec UNa alors que NE plasmatique and age on plasma renin activity (PRA), aldosterone (PA), nor- est mieux correlée avec l'age qu'avec UNa.LaPA en position epinephrine (NE), and epinephrine (E) levels, and urinary NE or couchée est correlée a Ia fois avec l'age et UNa,IaPA en posi- E measured in an outpatient setting was evaluated in 90 normal tion debout seulement avec U. Sur Ia base de relations signifi- subjects and 79 patients with benign essential hypertension. catives avec soit l'âge soit UNa des intervalles de valeurs nor- Ranges of age (17 to 76 yr) and urinary sodium excretion (U5a) males avec des limites de confiance de 95% ont Pu être établis. (51to 241 mEq/24 hr) were comparable. In normal subjects, su- Les malades hypertendus ont aussi des diminutions de PRA et de pine or upright PRA and supine plasma E correlated (P <0.05) PA et une augmentation de NE en fonction de l'âge; PRA et PA inversely and supine plasma PNE or NE excretion correlated ne sont pas correlees avec UNa. La prise en consideration de positively with age, but not with UNa;theupright plasma NE l'ãge met en evidence des PRA basses ou élevées dans 10 et 7%, correlated closer with age than it did with UNa.SupinePA corre- respectivement, des situations; ces anomalies surviennent plus lated with both age and UNa; upright PA did so only with UNa. souvent dans les hypertensions modérées ou sévères (>160/ Based on significant relationships with either age or UNa, dynam- 105 mm Hg) que dans des hypertensions frustes et sont associees ic normal ranges with 95% confidence limits could be estab- a des variations parallèles de NE plasmatique ajustée en fonc- lished. Hypertensive patients exhibited also age-related de- tion de l'àge. Les valeurs de NE plasmatique sont cependant creases in PRA and PA and increases in NE; PRA and PA did not dans l'intervalle normal a l'exception de valeurs en position de- correlate with UNa. Consideration of age revealed low or high bout legèrement élevées chez 15% des malades. La PA en fonc- PRA in 10 and 7%, respectively; these abnormalities occurred tion de l'âge ou de UNa est augmentée chez 25% des malades en more commonly with moderate-severe (>160/105 mm Hg) than position couchée mais elle est habituellement normale en posi- with mild hypertension and were associated with parallel varia- tion debout. Ces constatations démontrent qu'en l'absence tions in age-adjusted plasma NE. Nevertheless, plasma NE was d'une déplétion importante de sodium l'âge peut être un facteur within the normal range, except for slightly low upright values in plus important que l'excrétion de sodium comme système de 15% of patients. PA related to age or UNa was increased in 25% of référence pour apprécier les résultats des determinations de ré- patients while supine, but it was usually normal in the upright nine et de norépinephnne. Ces deus facteurs doivent être pris en position. These findings demonstrate that without profound so- consideration pour l'interprétation de PA. Sur cette base, un dium depletion, age may be more important than sodium excre- quart des malades atteints d'hypertension essentielle ont un hy- tion as a frame of reference for judging both renin and norepi- peraldostéronisme minime quand us sont maintenus en position nephnne measurements; both factors should be considered for couchée. L'hypertension a rénine basse est beaucoup moms fré- interpretation of PA. On this basis, one fourth of patients with quente qu'il n'a été suggéré antérieurement et pourrait étre Iiée essential hypertension have mild hyperaldosteronism while a une activité adrenergique faible. maintaining the supine position. Low renin hypertension is much less common than previously suggested and may be related to low adrenergic activity. The activity of both the renin-angiotensin-al- Age ou sodium urinaire pour apprécier les concentrations de ré- dosterone system and the adrenergic nervous sys- nine, d'aldostérone et de cathéchotamine: Etude chez les sujets normaux et les malades atteints d'hypertension essentielle. tem may be influenced by the body sodium-volume L'influence relative du bilan du sodium et de l'age sur l'activité state. Thus, plasma renin, aldosterone, norepineph- refine plasmatique (PRA) et les concentrations plasrnatiques d'aldostérone (PA), de norépinéphrine (NE) et d'épinéphrine (E) et de NE ou E urinaires mesurées chez des malades externes a été évaluée chez 90 sujets normaux et 79 malades atteints Received for publication April 28, 1978; d'hypertension essentielle bénigne. Les intervalles d'âge (17 à76 and in revised form July 18, 1978. ans) et de sodium urinaire (Ua) (51 a 241 mEq/24 hr) étaient comparables. Chez les sujets normaux Ia PRA en position 0085-2538/78/0014—0619 $02.00 couchée ou debout et I'E plasmatique en position couchée sont © 1978 by the International Society of Nephrology.
619 620 Weidmann et a! rine, and epinephrine levels, and catecholamine ex- (>160/105 mm Hg). To avoid very high sodium in- cretion rates are all increased in response to sodium takes, subjects were instructed to ingest a normal depletion [1—4]. Based on this relationship, it has diet but without very salty foods or adding salt to become customary to judge blood levels of renin their food, starting at least 5 days prior to the test. and aldosterone in relation to a defined sodium in- Alter completion of a 24-hour collection for deter- take [1, 2, 5] or 24-hour sodium excretion [6]. The mination of sodium (UNa),potassium,creatinine, latter frame of reference is being used widely since norepinephrine (NE), and epinephrine (E) excre- it is applicable to an outpatient setting although tions, supine and upright (each for 1 hour) blood fixed dietary prescriptions are usually not. The rela- pressure, pulse rate, plasma sodium, potassium, tionships between sodium excretion and plasma re- creatinine, renin activity (PRA), aldosterone (PA), nm or aldosterone values are hyperbolic and diffi- NE, and E levels were obtained between 8 and 11 cult to define mathematically. Therefore, simplified A.M., according to our standard procedure [9, 13]. descriptive nomograms have been proposed [6] and Indwelling i.v. cannulas were inserted at least 30 used to stratify patients with hypertension into sub- mm before blood sampling. groups with low, normal, or high levels of these pa- Blood pressure was taken with standard cuff and rameters [6—9]. This approach, however, does not sphygmomanometer and was registered as the mean take into consideration factors other than sodium of three recordings (diastolic pressure =dis- which may also influence renin and aldosterone re- appearance of sounds). Sodium and potassium con- lease. One of these factors is the age of the patient. centrations were determined by flame photometer; In normal man, both plasma renin and aldosterone creatinine, by autoanalyzer; PRA [16] and PA [17], levels decrease progressively from the time of birth by radioimmunoassay; and NE and E in urine, by to the seventh decade of life [5, 10—13], but norepi- fluorometric [18], and in plasma, by radioenzymatic nephrine in plasma and urine increases with aging methods [19]. All endocrine measurements were [13—15]. made in duplicate, and the mean value was used. The relative importance of sodium and age as de- Mean coefficients of intraassay, interassay and con- terminants of these endocrine parameters has not trol plasma variations in 65 to 210 unselected con- been clearly delineated. Therefore, the present secutive determinations with these methods were: study was undertaken to comparatively evaluate 24- PRA, 6.5, 7.6, and 12.2%, respectively; PA, 7.5, hour sodium excretion and age as frames of refer- 15.8, and 21.2%; urinary NE, 12.4, 16.7, and 6.7%; ence for judging plasma renin, aldosterone, and nor- urinary E, 6.0, 9.1, and 7.6%; plasma NE, 4.2, 10.1, epinephrine levels, and norepinephrine excretion and 13.5%; plasma E, 4.4, 15.6, and 22.4%. In 9 rates in a population of ambulatory normal subjects. normal and 31 hypertensive subjects, repeat studies To test the clinical and pathogenic revelance of after 2 to 10 months revealed the following intra- such an analysis, a large outpatient population with subject variations: PRA, 31.3%; PA, 33.3%; urinary essential hypertension was also examined. NE and E, 27.4 and 35.2%; plasma NE and E, 24.9 and 38.9%. Methods Ninety healthy normal volunteers (43 females and Results 47 males, aged 18 to 76 yr) and 79 patients with es- Mean values in study groups and subgroups sential hypertension (34 females and 45 males, aged (Table 1). Mean values of the parameters measured 19 to 76 yr) of racially homogenious background in the present study did not differ significantly be- (white) were studied. Secondary hypertension was tween normal subjects and patients with either mild excluded by the usual tests. Hypertension was al- or moderate to severe essential hypertension, with ways benign, and no patient had congestive heart the following exceptions: plasma sodium concentra- failure or relevant renal functional impairment tion in the entire hypertensive patient population or (plasma creatinine > 1.3 mg/l00 ml). Antihyper- in the subgroup with moderate to severe hyper- tensive drugs were withdrawn at least 2 weeks be- tension was slightly but significantly lower than it fore study and replaced by placebo tablets. Based was in normal subjects, supine PRA was significant- on blood pressure values obtained during placebo ly elevated in the subgroup with moderate to severe conditions, the patients with hypertension (diastolic hypertension, and supine PA was significantly ele- >140/90 mm Hg) were divided into 44 with mild vated in all patients and both subgroups. (160/105mm Hg and/or mean pressure 123 mm Relationships in normal subjects (Table 2): With Hg) and 35 with moderate to severe hypertension sodium excretion. UNa ranged from 51 to 237 mEq/ Judging endocrine pressor factors 621
Table 1. Biochemical and endocrine parameters in normal subjects and patients with essential hypertension (mean SD)
Patients with essential hypertension
Parameters Normal subjects Mild Moderate All Age,yr 37 15 43 16 50 11 46 IS Blood pressure, mmHg 117/75 10/8 145/93 19/8 177/118 20/12 160/104 Plasma values: Sodium, mEqiliter 140 2 139 2 138 3 139 Potassium, mEqilirer 4.0 0.3 4.0 0.3 3.9 0.3 0.3 Renin activity, nglmllhr 1.9 2.7 2.1 1.5 3•3 44a 2.6 3.1 Supine 2.5 Upright 4.6 2.7 4.1 2.7 4.6 5.9 Aldosterone, ng/JOO ml 8.8 6.1c Supine 5.3 2.6 7.9 54b 10.6 6.7c Upright 15.4 9.7 14.8 11.1 16.4 10.3 15.3 10.6 Norepinephrine, ng/lOOml Supine 16.9 9.1 22.7 15.1 17.2 9.1 12.8 Upright 34.4 13.6 30.2 17.0 30.2 13.7 30.2 Epinephrine, ng/IOO ml 6.2 6.2 6.8 8.9 4.6 2.8 5.8 6.9 Supine 6.9 Upright 7.0 5.6 7.8 6.5 7.6 7.9 Urinary values: 26.6 12.6 27.3 12.0 28.8 11.2 27.5 Norepinephrine, g/g creatinine 2.9 Epinephrine, ag/g creatinine 3.2 3.5 3.4 2.9 2.7 2.9 3.1 Sodium, mEqI24 hr 136 46 133 61 143 56 137 63 Potassium, mEq/24 hr 65 22 65 27 60 63 26 Creatine clearance, ml/minlI.73m2 86 18 97 32 84 27 89 30
a P<0.025vs. normal. P<0.005vs. normal. P<0.001vs. normal.
hr. With or without inclusion of elderly subjects relationship with supine plasma E (Table 2). ( 60 yr), there were no significant correlations be- Relationships in hypertensive patients (Table 2): tween these values and supine or upright PRA, su- With urinary sodium or age. UNa ranged from 51 to pine plasma NE, NE excretion rate, or supine or 241 mEq/24 hr. UNa correlated inversely with up- upright plasma E levels. Therefore, statistical defi- right plasma NE, supine plasma E or NE excretion nition of normal ranges with 24-hour UNa as the rate, but not with PRA (Fig. 2) or other measured frame of reference could not be derived for these parameters (Table 2). In analogy to normal sub- parameters. Weak but significant inverse correla- jects, most endocrine factors in these hypertensive tions, however, were found between UNa and up- patients correlated significantly with age. right plasma NE or supine or upright PA levels Based on the mathematically defined normal (Table 2), so that normal ranges with 95% con- ranges, upright PRA related to age was low in eight fidence limits could be calculated. (10%) and high in six (7%) patients; abnormalities With age. There were significant inverse relation- were even less common for supine PRA (Fig. 3). In ships between age and supine or upright PRA (Fig. the subgroup with mild hypertension, the slope for 1) or supine PA, and positive relationships between the renin-age relationship was comparable to that in age and supine or upright plasma NE or NE excre- normal subjects; and no patient in this subgroup had tion rates (Table 2). Thus, normal ranges related to markedly high PRA levels. The subgroup with mod- age could be established. The correlation coeffi- erate to severe hypertension exhibited a steeper cients for these relationships with age were not in- slope for the renin-age relationship. Thus, five of creased with multiple regression analysis using UNa the six hyperrenemic and five of the eight patients as the second independent variable, except for the with low PRA relative to age belonged to the latter parameters upright plasma NE (r = 0.64; P < 0.001) subgroup (Fig. 3). and supine PA (r = 0.41; P < 0.005). There was no Supine PA related to either UNa (Fig. 4) or age significant correlation between age and upright PA (Fig. 5) was high in 12 (27%) patients; five of them and plasma or urinary E, except for a weak inverse belonged to the high-renin and seven to the normal 622 Weidmannet al
Table 2.Correlation matrix of the relationships between various endocrinological parameters and urinary sodium or age in normal subjects and patients with essential hypertension Essential hypertension Normal subjects Mild Moderate All Parameters N r N r N r N r
. Relationships with urinary sodium Plasmarenin Supine 99 0.03 38 —0.08 25 —0.16 63 —0.10 Upright 97 0.06 44 —0.02 35 —0.20 79 —0.14 Plasma aldosterone Supine 80 —0.29" 25 0.01 19 —0.26 44 —0.04 Upright 79 —0.35 28 —0.05 19 —0.20 47 —0.08 Plasma norepinephrine Supine 44 —0.05 21 —0.27 15 —0.31 36 —0.28 Upright 53 —0.27° 20 —0.33 14 —066" 34 —0.5P Urinary norepinephrine 58 —0.07 38 29 67 —0.40° Plasma epinephrine Supine 41 0.22 20 —0.18 14 —0.57' 34 —0.29° Upright 43 0.17 20 —0.24 14 —0.42 34 —0.26 Urinaryepinephrine 60 0.25° 38 —0.23 29 —0.06 67 —0.15 Plasma renin Relationships with age Supine 89 —0.45° 38 —0.50" 25 0.42" 63 Upright 90 —0.53° 44 35 —0.52° 79 —0.50° Plasma aldosterone Supine 70 —0.29° 26 —0.28 19 —0.31 45 —0.22 Upright 70 0.04 29 —0.31° 19 —0.35 48 —0.27° Plasma norepinephrine Supine 36 0.32a 21 056b 15 0.40 36 0.43" Upright 45 0.49° 20 0.48" 14 —0.07 34 0.28 Urinary norepinephrine 58 0.42° 38 0.51" 29 —0.09 67 0.34" Plasma epinephrine Supine 41 —0.29° 20 0.15 14 0.10 34 0.11 Upright 43 0.01 20 —0.14 14 0.01 34 —0.08 Urinary epinephrine 58 0.22 38 0.09 29 0.10 67 0.05 a P <0.05. bP<0.025. P <0.01. dP<0.005. ep <0.001. renin subgroups. Upright PA related to UNa was the 16th, between the 16th and 84th, and above the usually normal (Fig. 4). Upright plasma NE related 84th percentile (see Fig. 3); and b) adjusting NE lev- to UNa(Fig.6) and supine plasma NE (Fig. 7) or els to a reference age of 40 years by means of the urinary NE related to age were usually normal, but regression equation. Age-adjusted upright plasma upright plasma NE related to age tended to be NE values did not differ between normal subjects slightly low in 15% of patients. The norepinephrine- (37.6 [± SD] 13.0 ng/100 ml) and the hypertensive age relationships were again comparable in normal normal- or high-renin categories (30.2 14.8 and and mildly hypertensive subjects; but there was no 46.8 12.3 ng/100 ml); they were significantly de- such correlation in moderate to severe hyper- creased in the low-renin category (21.6 13.2 ng/ tension. 100 ml; P < 0.0 125) and tended to be higher in the Between renin and norepinephrine. There was no high than they were in the normal renin category significant correlation between absolute levels of (P < 0.05). Mean age-related urinary NE was also supine or upright PRA and corresponding plasma or lower in the low-renin category (18.5 6.7 Lg/g urinary NE values in either normal (r = 0.03) or creatinine) than it was in the normal- or high-renin hypertensive subjects (r = 0.17). Considering, how- categories (27.2 9.8 and 25.5 8.5 g/g creati- ever, the contrasting influence of age on these fac- nine; P < 0.005 and < 0.05, respectively) or normal tors, their relationship was explored further by a) subjects (24.3 11.1 g/g creatinine; P < 0.05), dividing the hypertensive patients into three cate- without significant differences between the three gories with age-related upright PRA levels below latter groups. Judging endocrine pressor factors 623
- ______N P 10 Tupine 1 N=89 r —0.45 Supine } fl— Normalsubjects 89 —0.45 P<0.001 . Mild OP I 44 —0.52 0.001 S. InY = .—0.18x + 1 56 20 - — Moderate OP 1 35 —0.54 0.001 00 r L.__. All OPt 79 —0.50 0.001 oooo 0 3-0 0 10 - 2- 0 0 03 00 0 0 00 5- 0%0 0 1.0 - 0 - —t 55 °° 2 0.5 - $AA 0.3— 0.2 - = 20- N90 ______L Upright r=—0.53 P< 0.001 10- 0 + 2.46 0 Normal SUt5i30O1 I- 0 00 0 0 00 — 0 00 OP t A 0 A 0 A i.:i0o000:00
I I I I " 70 20 30 40 50 60 2- I Af Age, yr Fig.1. Relationship between supine or upright plasma renin lev- els and age in normal subjects. The lines represent the regression line and the 95% confidence limits. Th> 20 30 40 50 60 70 80 20 Age, 0 A yr 0 A Fig.3. Supine and upright plasma renin levels related to age in 10 o 0 A' 0 0 •0 patients with essential hypertension (BP f).Theshaded areas 0. •c.0 0' 0 •. 0 and closed regression lines represent the ranges with 95% con- 5 0 OkA °° 0 fid'ñce limits and regression lines obtained from normal sub- .,,. 0•,-£5A •,_'oA ( .. 0 0 jects. 0A0 • o A 2- •-• £ £0 .r 0 .• A £ Between renin and aldosterone. A similar analy- • S A . • siswas also performed to compare age-adjusted su- 1.0 - S A A pine PA levels between renin-categories. Normal • A A A A 0.5 - subjects had a value of 5.5 2.6 ng/100 ml; the ______mean level was increased in each of the three renin Normal subjects 0 <60 yr categories, amounting to 8.5 4.1 (P < 0.005) in N=97,r= 0.06 0 6Oyr 0.2- low, 7.95.1 (P < 0.05) in normal, and 18.3 8.7 Hypertension . Mild ______N = 79, r = —0.14 A Moderate-severe (P < 0.001) in high-renin patients; the latter value 50 100 200 250 wasalso higher than that in the low- or normal-renin categories (P < 0.01). Urinary sodium excretion, mEq/24 hr Using the absolute levels, supine or upright PA Fig.2. Relationship between upright plasma renin activity and 24-hr urinary sodium excretion in normal subjects and patients correlated significantly with corresponding PRA with essential hypertension. levels in both normal (r =0.42,P < 0.001; r0.27, 624 Weidrnannci al
N r P N r P [Norrnal subjects 80 —0.29 <0.05 'Mild BP 25 aoi >0.1 —Normal subjects70—0.29<0.05 £ Moderate BP I 19 —0.26 >0.1 .MUd BP t 26—0.28>0.1 All BP 44 —0.04 >0.1 AModerate BP t 19—0.31 >0.1 A A B aol—
£ £
20 a) C 0 a)
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Ca A E S
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. I. 20 30 40 5Q 60 70 O Age, yr
plasma aldosterone levels related to age in pa- N p P Fig. S.Supine tientswith essential hypertension (BP 1).Theshaded area with -— Normal subjects 79 —0.35 <0.001 regression line represents the range with 95% confidence limits • Mild BP ¶ 28 —0.05 >0.1 obtained from normal subjects. £ Moderate BR 1 19 —0.20 >0.1 All BR t 47 —0.08 >0.1 lowed the policy of asking the patients to ingest a diet avoiding the very salt-rich foods and added salt. Using this instruction, our 90 normal control subjects and 79 patients with essential hypertension had comparable UNa excretions (136 vs. 137 mEq/24 hr) ranging from 51 to 241 mEq/24 hr. Spontaneous reduction of salt intake below 3 g/day may be rare. Under these conditions, age was more important than was sodium excretion as a frame of reference for judging both renin and norepinephrine measure- ments. In fact, supine and upright PRA correlated
50 100 150 200 250 Urinary sodium excretion. mEq/24 hr
Fig. 4. Supine and upright plasma aldosterone levels related to - 24-hr sodium excretion in patients with essential hypertension 50 - (BP 1).Theshaded areas with regression lines represent the ranges with 95%confidencelimits obtained from normal sub- 30- — £ • jects. ;---;-rra_zr,__ 20- S
P <0.05)and hypertensive subjects (r= 0.43and 0.53,1? <0.001). 5 Discussion — Normal subjects 53 —0.27 0.05 3 . MiICIBP t 20 —0.37 0_al The dietary conditions of this study are well ac- 2- ———a Moderate BP t 14 —0.66 0.005 cepted and used widely in the screening evaluation AIIBPt 34 —0.48 0.005 of PRA, PA, or catecholamine levels, or urinary catecholamine excretion rates in patients with hy- 50 100 150 200 250 pertension. Since admission to a hospital for all Urinary sodium excretion, mEq/24 hr such determinations would be prohibitive finan- Fig.6. Uprightplasma norepinephrine levels related to 24-hr so- cially, and since fixed dietary intakes or special ma- dium excretionin patients with essential hypertension (BP 1). Theshaded area and closedregression line representthe range neuvers such as profound sodium restriction are not with 95%confidencelimits and regression line obtained from easily applied in an outpatient setting, we have fol- normal subjects. Judging endocrine pressor factors 625 inversely and plasma or urinary NE correlated (P < minor modulating influence on PRA [6—9, 13, 20, 0.05) positively with age, but not with UNa; and the 21]. Moreover, the statistical variation of such re- positive relationship of upright plasma NE with age nin/UNa nomograms was reduced by incorporating was closer than was its inverse correlation with many paired or tripled observations for the same UNa. Plasma or urinary [131 E levels did not cone- subjects studied under several dietary conditions [6, late consistently with either frame of reference. It 91. Therefore ,thesenomograms may have underes- follows that normal ranges relative to UNa could be timated individual variation, they had no mathemat- defined mathematically only for upright plasma NE; ical basis, and they did not consider age as a factor. in contrast, such dynamic ranges relative to age The latter would appear mandatory at any level of could be established for PRA or plasma NE in both sodium balance, since stimulated PRA values that body positions as well as it could for NE excretion were measured following low sodium diet or potent rates. These findings reduce the value of subjecting diuretics [22, 23] decreased also significantly with outpatients scheduled for PRA or plasma cate- aging [5, 11, 20, 21]. cholamine determinations routinely to a 24-hr urine Mild increases in blood pressure with aging could collection for measurement of sodium, a procedure contribute to renin suppression [9, 24]. The contri- clearly more complicated than that which uses sim- bution of the latter factor itself to low renin levels in ply the patients age as reference. a normal elderly man, however, may be minimal The lack of a renin-sodium correlation in our nor- [5, 13, 21]. mal population does not militate against the exis- Compared to PRA, PA seemed to be more depen- tence of a hyperbolic relationship when values ob- dent on variations in sodium intake. Thus, PA con- tained during more profound sodium restriction are centrations in both body positions correlated in- included [6—9, 20]. The dynamic part of the arbi- versely with UNa, which allowed us to delineate trary nomograms based on this interrelation, how- mathematically defined normal ranges; but such a ever, has been limited to low sodium intakes; in relationship with age was noted only for supine PA. contrast, the effect of variations in body sodium Others noted also that a more precise relationship with UNa between 50 and 300 mEq/24 hr had only a exists between UNa and aldosterone secretion rates
L71PJ
I N r P —Normal subjects 36 0.32 <0+05 --- MUd BR t 21 0.56 <025 A ModerateBPt 15 0.40 >0.1 AIIBPt 36 0.43 <0+005
— 50 A E A A£ 30 20 . j C10 a, C50 N 15 — E Normal subjects 45 049 <0.01 - ----. Mild BP t 20 0.48 <0.025 £ModerateBP t 14 —0.07 >0.1 - All BP ¶ 34 0.28 <0.1
I 1 29 ?Q 4Q Q QQ 79 Q 20 30 40 5060 70 60 Age, yr Fig.7. Supine and upright plasma norepinephrine levels related to age in patients with essential hypertension (BP U The shaded area and closed regression lines represent the ranges with 95% confidence limits and regression lines obtained from normal subjects. 626 Weidmann et at than that which exists between UNa and serum renin PRA and six of eight with low PRA belonged to the levels [25]. The greater sensitivity of PA to dietary latter subgroup. The greater prevalence of hyper- variations may be related to a modulating influence reninemia in younger and of hyporeninemia in older of sodium on adrenocortical responsiveness to an- or more severely hypertensive patients is in accord- gioten sin or other factors [26]. The absence of a sig- ance with previous data [6, 9, 11, 21, 23, 24, 301. nificant inverse relationship between upright PA The almost complete absence of high PRA values in and age is due to marked postural aldosterone stim- our patients with mild hypertension, however, con- ulation in some elderly subjects, a finding that is trasts with some other reports [38]. Patient selec- possibly secondary to orthostatic decreases in tion and the lack of age-related normal ranges may blood pressure occurring preferentially in this age- be reasons for these differences. group and eliciting a renin-independent stimulus As a third conclusion on renin in essential hyper- [13, 271. It appears that for judging aldosterone tension, the association of age-related low PRA measurements both sodium excretion and age with low plasma or urinary NE levels in our patients should deserve consideration. supports a role for decreased adrenergic nervous Regarding PRA in essential hypertension, three activity in the pathogenesis of the low-renin state conclusions based on our observations appear justi- [9, 29, 38, 391. In contrast to previous studies [38— fied. First, considering age as a factor, we found the 40], a relationship between PRA and plasma NE, incidence of true low renin essential hypertension however, could not be delineated simply by com- to be 10%. This is substantially lower than previous paring their absolute levels (r =0.17);the lack of estimates have suggested [6, 9, 22, 23, 28—321. A di- such correlation in this and other investigations [20] rect comparison between the present data and the is expected in view of the contrasting slopes for the many higher estimates of low renin levels in which relationships between these parameters and age. age was not considered [6, 22,23,28—32] is not pos- Furthermore, even when considering age, our data sible. Some investigators found an age-related de- do not confirm significant hypercatecholamine in crease in PRA in essential hypertension, but not in high-renin essential hypertension [39, 401. It is pos- control subjects [23, 30, 33]; the number of older sible that high-renin levels may often be more de- normal subjects included, however, was small, and pendent on hypovolemia than on elevated adrener- the renin methodology in two studies differed from gic activity [91. ours since a bioassay [30] or a procedure which The significant (P < 0.005) increase in mean su- does not discriminate between active renin and in- pine PA levels in our hypertensive population, re- active renin precursor [34] was used. Moreover, gardless of severity of hypertension or renin sub- that PRA decreases with age not only in hyperten- group, complements previous observation by Genest sive but also in normotensive subjects is now well- et al [35]. Individual supine PA levels related to either documented [5, 10, 11, 13, 21, 321. There is also a urinary sodium or age were above the upper limit of tendency for low PRA in black subjects [16, 22, 23]. normal in 27% of our patients, compared to high Taking both age and race into account, the in- values in one third of Genest's cases [ii, 35]. Al- cidence of low renin essential hypertension in a ra- though age-corrected PA values were highest in our cially mixed study group was recently calculated to high-renin patients, mild hyperaldosteronism was be 9% [35]. This and the finding of a similar distribu- also commonly associated with normal PRA. On tion of PRA in 50-year-old normotensive and hyper- the other hand, PA levels measured in the upright tensive men [36] support our own low estimate in an position were comparable between our normal and entirely white population. It is suggested that pos- hypertensive subjects. This discrepancy between sible diagnostic, therapeutic, and prognostic impli- high supine and normal upright values probably re- cations of low and high renin levels in hypertension flects diminished postural aldosterone responsive- [371 should be reexamined excluding those patients ness [11,411 secondary to low PRA [41, 42] in some with physiological variations due to their age. patients with essential hypertension. Previous stud- A second conclusion on renin concerns dif- ies of 24-hour aldosterone excretion or secretion ferences related to severity of hypertension. Distri- rates [6, 25, 43, 44] may have been less sensitive in bution of individual values and slopes for the renin- detecting such mild abnormalities in circulating a!- age relationship were comparable in our normal and dosterone. Nevertheless, some authors reported in- mildly hypertensive subjects, but this slope was creased urinary aldosterone levels in essential hy- steeper in those with moderate to severe hyper- pertension [35], especially during very high sodium tension. Moreover, five of six patients with high intake [41, 45]. The mechanisms contributing to a!- Judging endocrine pressor factors 627 terated metabolism of aldosterone, and possibly al- References so other mineralocorticoids, in essential hyper- I. BROWN JJ, DAVIES DL, LEVER AF, ROBERTSON uS: Influ- tension are only partly understood and may be re- ence of sodium deprivation and loading on plasma renin in lated to decreased hepatic clearance, and possibly man. J Physiol (London) 173:408—419, 1964 2. WILLIAMS OH, CAIN JP, DLUHY RG, UNDERWOOD RH: also changes in adrenal production [35]. Studies of the control of plasma aldosterone concentration in Theexact role of the sympathetic nervous system normal man: I. Response to posture, acute and chronic vol- in essential hypertension is still unclear. Whatever ume depletion and sodium loading. J C/in Invest 51:1731— frame of reference could be used for judging plasma 1742, 1972 or urinary NE, these values were usually normal, 3. ALEXANDER RW, GILL JR JR, YAMABE H, LOVENBERGW, except for somewhat low upright circulating NE rel- KEISER HR: Effects of dietary sodium and of acute saline infusion on the interrelationship between dopamine excre- ative to age in 15% of our patients. Other studies tion and adrenergic activity in man. J Gun Invest 54:194—200, delineating a physiological age-related increase in 1974 urinary [9, 13] or plasma NE [14, 46, 47] revealed 4. ROMOFF MS. KEUSCH G, WANG M, FRIEDLER RM, Waio- also no evidence for abnormally high levels in es- MANN P, MASSRY SG: Interrelations between sodium excre- sential hypertension. 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RANDALL OS, ELLIS CN, KASHIMA in such patients [47]; using the same radioenzymatic T: Relation of renin status to neurogenic vascular resistance method [19], we have no explanation for this dis- in borderline hypertension. Am J Cardiol 36:708—7 15, 1975 8. HOLLIFIELD JW, SHERMAN K, ZWAGG RV, SHAND DO: crepancy. Although it remains difficult to in- Proposed mechanisms of propranolol's antihypertensive ef- criminate increased adrenergic activity as an impor- fect in essential hypertension. N Eng! J Med 295:68-73, 1976 tant factor, recent data from this laboratory suggest 9. WEIDMANN P, HIRSCH D, BERETTA-PICCOLI C, REUBI FC, that an exaggerated pressor sensitivity to normal ZIEGLER WH: Interrelations among blood pressure, plasma blood levels of norepinephrine may play a patho- renin activity and urinary catecholamines in benign essential hypertension. Am J Med 62:209—218, 1977 genic role in the maintenance of essential hyper- 10. HAYDUCK K, KRAUSE DK, KAUFMANN W, HUENGES R, tension [15]. 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