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Kidney International, Vol. 8, (1975), p. 325—333
Effect of aging on plasma renin and aldosterone in normal man PETER WEIDMANN, SYLVIANNE DE MYTTENAERE-BURSZTEIN, MORTON H. MAXWELL and JosE DE LIMA
Nephrology and Hypertension Service, Department of Medicine, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, California
Effect ofaging on plasma renin and aldosterone in normal man. sential hypertension has been diagnosed more com- Theinfluence of aging on the renin-angiotensin-aldosterone system monly in older than young adults [1—4], and the syn- was evaluated by comparing young (20 to 30 yr) with elderly (62 to 70 yr) healthy subjects. Despite comparable body sodium-fluid drome of hyporeninemic hypoaldosteronism has been balance in the two age groups, serum renin concentration, plasma described almost exclusively in patients older than 50 renin activity and aldosterone concentrations were lower in the elderly. The age-related decreases in circulating renin and aldo- yr of age [5]. sterone concentrations were slight while subjects were supine and The possibility that aging may influence renin and receiving normal sodium intake; when upright and during sodium aldosterone metabolism has been considered pre- depletion, they were more pronounced. Inverse renin-blood pres- sure interrelations were noted during two of four study conditions viously, but the available data on the relationship be- involving normal sodium intake or mild sodium depletion (r = tween age and the function of the renin-angiotensin-al- —0.44and —0.47, respectively), but not during progressive sodium dosterone system in normotensive healthy adults are depletion. Plasma renin levels were decreased in the elderly regard- less of the presence or absence of an inverse relationship with limited and conflicting [2, 4, 6, 7]. The present study blood pressure. Aldosterone and cortisol responses to corticotropin was undertaken to further investigate this question by infusion were unaltered in the elderly. It is concluded that aging comparing plasma renin and aldosterone concentra- may cause a decrease in circulating renin, with parallel lowering of plasma aldosterone concentrations. tions under basal conditions and during stimulation with upright posture, sodium/volume depletion or Effetdu vieillissement sur les concentrations de refine et corticotropin infusion in young and elderly healthy l'aldostérone chez l'homme normal. L'influence du vieillissementsur Icsystème rCnine-angiotensine-aldostérone a été dvaluée par Ia corn- subjects. paraison de sujets normaux jeunes (20 a 30 ans) et de sujets âgés (62 a 70 ans). Malgré un bilan hydro-sodique comparable dans les deux groupes d'áges, Ia concentration sérique de refine, l'activité refine Methods du plasma et Ia concentration d'aldostérone sont inférieurs chez les sujets ages. La diminution liée a l'age de Ia refine et de l'aldostérone Twogroups of normal volunteers were studied. One circulantes est minime quand les sujets sont couches et ont un ap- group included six women and six men, ranging in age port de sodium normal; elle est plus prononcée en orthostatisme et au cours de Ia déplétion en sodium. Des relations inverses from 20 to 30 yr. The other group consisted of four rénine-pression artérielle ont été observées dans deux des quatre sit- women and three men, ranging in age from 62 to 70 yr. uations expérimentales associant un apport normal de sodium ou None of the participants had significant physical ab- une déplétion de sodium modérée (r =-0,44et r =—0,47,respec- tivement). Ces relations n'ont pas été observées au cours de Ia normalities and each was found to have a blood pres- depletion progressive en sodium. La refine est diminuee chez les su- sure of less than 140/90 mm Hg, normal concentra- jets indépendamment de Ia presence ou de l'absence d'une rela- tions of plasma creatinine and electrolytes and blood tion inverse avec Ia pression artérielle. Les reponses du cortisol et de l'aldostérone a Ia corticotrophine ne sont pas modiflées chez Ic sujet urea nitrogen, and normal urine values before entering age. II est conclu que Ic vieillissement peut entrainer une diminution the study. None were taking drugs. de Ia refine circulante avec une diminution parallèle des concentra- All studies were done while the subjects were receiv- tions d'aldosterone. ing a defined daily intake of either 120 mEq of sodium Diminished levels of circulating renin occur in sev- and 60 mEq of potassium ("normal sodium intake") eral pathologic states, but the factors responsible for or 10 mEq of sodium and 60 mEq of potassium ("re- this have not been fully elucidated. The incidence of at stricted sodium intake"). Body weight, urinary sodium least two hyporeninemic disorders appears to increase and potassium excretion, and creatinine clearance with advancing age. More specifically, low-renin es- were measured daily throughout the study. Blood pressure; serum renin concentration; plasma renin ac- Received for publication March 4, 1975; tivity; and aldosterone, sodium and potassium concen- and in revised form June 24, 1975. trations were determined in each subject in both the © 1975, by the International Society of Nephrology. supine and upright positions (each position for one
325 326 Weidmann et a! hour): a) after three days of normal sodium intake (in Haber et al using 8-hydroxyquinoline and dimercaprol the young subjects this was done twice); b) after three as protective agents [9]; each sample was measured at days of restricted sodium intake; c) after six days of two incubation conditions, i.e., at pH 7.4 and 5.7. restricted sodium intake; and d) after seven days of re- Plasma aldosterone was measured by the radio- stricted sodium intake and oral administration of fu- immunoassay method of Ito et al [10] and plasma cor- rosemide, approximately 1.2 mg/kg of body wt, at 5 tisol by competitive protein binding [11]. Plasma vol- PM on the seventh day of sodium restriction. Following ume was measured with '251-human serum albumin; three days of normal sodium intake and six and seven the radioactivity level of peripheral venous blood vol- days of sodium depletion, measurements of plasma ume was used to calculate whole blood volume by as- and blood volume were also performed. This part of suming the following: the study extended over ten days. Eight young and all whole blood volume =measuredvolume X seven elderly subjects participated in a second part, 100—hematocrit in which the response to a two-hour infusion of a 100—0.91 x hematocrit synthetic adrenocorticotropic hormone (Cortrosyn, [ Organon Inc.) at a rate of 0.1 mg/hr (approximately A paired data I test was used for statistical com- parison of measurements obtained from the young or 10 USP U of ACTH) was studied following three days elderly group before and during the various study con- of normal sodium intake: blood pressure; serum renin ditions; an unpaired data I test was applied for com- concentration and plasma renin activity; and aldoster- one, cortisol, sodium and potassium concentrations parison of the two age groups. In our previous studies, absolute plasma renin and aldosterone concentrations were measured before (8 AM) and after one and two were always found to be abnormally distributed, with hours of ACTH infusion. Blood pressure was determined with a standard an approximately normal distribution following loga- rithmic transformation of these values [12, 13]. This sphygmomanometer and pressure cuff, with the first was systematically reexamined and found to be also Korotkoff sound being recorded as systolic pressure and the fifth sound as diastolic pressure. Supine and true in the present study. Therefore, natural loga- rithms of the serum renin concentration, plasma renin upright measurements were always obtained after the activity and aldosterone values were utilized for all subjects had remained in these positions for one hour. statistical calculations involving a t test or linear re- Three values were recorded and averaged. Mean pres- sure was calculated as the sum of diastolic pressure gression analysis. and one-third of the pulse pressure. Plasma sodium Results and potassium concentrations were measured with a flame photometer (Instrumentation Laboratory). Se- Fluid and electrolyte status, and glomerularfiltra- rum renin concentration was determined by radio- lion rate (Table 1 and Fig. 1). Plasma sodium concen- immunoassay, using a modification of the method of trations measured before and during different degrees Gould, Skeggs and Kahn [8]. Plasma renin activity of sodium depletion were comparable in the young was determined by the radioimmunoassay method of and elderly subjects (Table 1).
Table I. Plasma sodiumand potassium concentrationsand plasma and blood volumes in 12 young and 7 elderly subjects during normal sodium intake and after sodium depletion (mean SD) Normal Naa Low Nabx 3 days Low Nab>< 6 days Low Nabx 7 days + FC Young Elderly Young Elderly Young Elderly Young Elderly Plasma sodium, mEq/liter Supine 140.5 2.0 139.6 1.5 139.02.4136.63.0139.42.2 139.0 1.4 139.4 1.7 139.0 1.3 Upright 140.1 0.8139.0 1.7 138.8 3.4 137.1 3.1 139.9 2.1 138.1 1.7 139.5 1.7 138.3 1.0 Plasma potassium, mEq/lizer Supine 4.150.234.120.244.04 0.304.07 0.19e4.040.294.31 0.40 3.75 0.36e 3.900.27e Upright 4.34 0.384.25 0.344.200.164.34 0.17e4.12 0.254.48 3.92 0.244.21 0.l9 Plasma volumed,ml/cm 14.4 2.5 15.3 3.3 — — 13.5 2.5 14.4 31g 13.0 l.7g 13.9 + 25g Blood volume0, mi/cm 24.44.6 25.1 5.5 — — 22.5 52g 24.0 50g22.0 3.8 23.1 50g aNormal Na =sodiumintake of 120 mEq/day. bLow Na =sodiumintake of 10 mEq/day. CF =orallyadministered furosemide, approximately 1.2 mg/kg of body wt. dEight of the 12 young subjects were studied. esignificant difference (P < 0.05) between supine and upright position. 1Significant difference (P < 0.05) between young and elderly. Significant difference (P < 0.05) vs. values during normal sodium intake. Effect of aging on renin and aldosterone 327
Norma] sodium Furosenilde the addition of orally administered furosemide. So- intake Sodium restriction dium excretion decreased progressively during low so- dium intake, with statistically similar excretion rates in the young and elderly, except for a slightly higher value in the elderly group after six days of sodium de- —; •Young pletion; the administration of furosemide led to an 160 T 0 Elderly acute increase in the sodium excretion on the last study day. Mean potassium excretion during sodium 80LI depletion tended to be slightly lower in the elderly as L IIIIi Iiii iii compared to the young subjects. Mean baseline creati- nine clearance was 108.07.9 ml/min in the young 80 and 84.1 20.4 ml in the elderly subjects (P < 0.05), and there were no consistent changes in these values during sodium depletion (Fig. 1). i iLEIIIiIJLFF Serum renin concentration, plasma renin activity 120 and plasma aldosterone concentration (Table 2, Fig. 60 2). On a normal sodium intake and with the subjects in the supine position, plasma renin and aldosterone con- 0 centrations tended to be lower in the elderly than in the young group, although these age-related differ- 4I 2 3 4 5 6 7 8 9 10 ences were significant only for serum renin concentra- J'<0.05 :P<00l Days tion and plasma renin activity measured at incubation pH 7.4 (P < 0.05). More specifically, the young and el- Fig. 1. Body weight, urinary electrolyte values and creatinine clear- derly subjects had mean renin concentrations of 17.7 ance before and during progressive sodiumI depletion in young and elderly healthy subjects. 2.5 (± SEM)and11.9 1.9 ng/ml/16 hr, respec- tively; mean renin activity levels at incubation pH 7.4 of 248 39 and 165 29 ng/100 ml/3 hr, respectively; During normal sodium intake, mean plasma potas- mean renin activity levels at pH 5.7 of 34261 and sium concentrations were also similar in the two age 238 47 ng/l00 ml/3 hr, respectively; and mean groups. However, following progressive sodium deple- aldosterone values of 4.20.5 and 3.1 0.4 ng/100 tion plasma potassium values were slightly higher in ml, respectively (Table 2). the elderly than in the young subjects (P < 0.05). Fur- Upright posture and sodium depletion caused con- thermore, the change from the supine to the upright sistent significant increases in circulating renin and al- position caused an increase in plasma potassium in the dosterone concentrations in both age groups majority of studies (53 out of 76), with significant pos- (P < 0.001). However, during each of the seven study tural increments of mean potassium concentration un- conditions in which these stimuli were used, the mean der some of the study conditions involving sodium de- values achieved were almost always significantly pletion. lower in the elderly than in the young group (P < Plasma and blood volumes were comparable in the 0.05) (Table 2, Fig. 2). two age groups. Sodium depletion caused consistent There was no correlation between postural increases significant decreases in these volumes (P < 0.05), with in circulating renin or aldosterone concentrations and a mean fall of 5 to 7% following six days of low so- associated changes in blood pressure or plasma potas- dium diet alone, and a decrease of 8 to 10% following sium values in either the young or elderly subjects. the addition of furosemide (Table 1). However, aldosterone responses to upright posture Following three days of equilibration on the initial correlated significantly with the associated increases diet containing 120 mEq of sodium and 60 mEq of po- in plasma renin (r =0.52;P < 0.01) without signifi- tassium per day, mean body weight was stable and uri- cant improvement of this correlation when the asso- nary excretion of sodium and potassium was similar in ciated changes in potassium were introduced as a sec- both groups (Fig. 1). Sodium depletion caused com- ond independent variable (r =0.53;P < 0.01). parable weight losses in the young and elderly groups, Regarding volume-renin interrelations, there was no amounting to 1.620.55 (± SD) kg (—2.5% of body correlation between the absolute values of plasma or wt) and 1.650.85 kg (—2.4% of body wt), respective- blood volumes and plasma renin activity; however, the ly, after six days of dietary sodium restriction, and increases in plasma renin following volume depletion 2.41 0.79 and 2.06 1.15 kg, respectively, following correlated (F < 0.05) with the associated decreases in 328 Weidmannet al
Table 2.Serumrenin concentrationand plasma renin activity and aldosterone concentrations in young and elderly healthy subjects during normal sodium intake and after sodium depletion (mean SCM) Renin Body Sodium intake Age N Concentration Activity (pH 7.4) Activity (pH 5.7) Aldosterone position mEq/24 hr group°" ng/ml/16 hr ng/100 ml/3 hr ng/100 ml/3 hr ng/100 ml Supine 120 x 3 days Y 32 17.7 2.5c 248 39C 342 6l 4.2 0.5 E 14 11.9 l.9c 165 238 47 3.1 0.4 10 x 3 days Y 12 35.3 4.0c 539 61c 713 92c 7.1 E 7 21.9 4.lc 347 80c 418 66c 4.8 0.4c 10 x 6 days Y 12 44.3 5.8c 695 88' 870 105e 13.8 2.7c E 7 27.4 55C 434 79C 574 95 6.40.9c lOx 7 days + Y 12 79.9 11.7 1207 196c 1664 307 18.1 2.5 furosemide E 7 47.3 l0.4c 726 152c 928 187c 8.8 Q•9C Upright120 x 3 days Y 24 41.1 4.lc 596 73C 774 92c 12.6 E 7 26.4 57C 287 65c 369 74C 5.60.8c tO x 3 days Y 12 77.6 6.8 1219 103c 1625 l53 43.8 14.5 E 7 47.4 11.0c 811+ 203e 913 235c 16.5 2.9 lOx 6days Y 12 124.3 25.6c 1548 141c 1807 206 59.7 15.O E 7 55.1 14.2c 1132 258c 1283 293 20.3 37C 10 x 7 days + Y 12 149.1 + 19.2e 2365 203c 2926 320c 65.4 12.2c furosemide E 7 89.3 25.4e 1555 330c 1690 313c 25.9 3.8c ay =young. bEelderly. C1 test using logarithms of variables showed significant difference between young and elderly subjects (P < 0.05).
blood volume in both young (r =—0.45)and elderly Relationship between circulating renin and a/dos- (r =—0.49)subjects. terone concentrations (Fig. 5). All measurements ex- Effect of corticotropin administration (Table 3). cept those obtained during corticotropin infusion were Basal concentrations of plasma aldosterone, cortisol, used for linear regression analysis. Elderly subjects sodium and potassium and renin concentration and tended to have a slightly lower plasma aldosterone activity were not significantly different in the two concentration for a given renin concentration or activ- age groups. Infusion of corticotropin caused signifi- ity, but the differences were statistically not signifi- cant increases in plasma aldosterone (P < 0.001), cor- cant. tisol (P < 0.001) and potassium (P < 0.05) concentra- Relationship between blood pressure and circulat- tions in both the young and elderly subjects. These ing renin levels (Table 4). While receiving 120 mEq of responses were similar in the two age groups; serum sodium daily, the elderly subjects showed slightly but renin concentration, plasma renin activity and sodium significantly higher supine and upright mean blood concentration showed no consistent changes. Also, pressures (95.1 8.9 and 81.3 10.7 mm Hg, respec- there was no significant correlation between the tively; P < 0.05). During progressive sodium deple- changes in plasma aldosterone and those in potassium tion, the elderly subjects showed a distinct tendency concentration. toward orthostatic decreases, and upright blood pres- Relationship between plasma renin activity meas- sures were comparable in the two age groups. ured at pH 7.4 and 5.7 (Fig. 3). There was an excellent Linear regression analysis of plasma renin concen- correlation between the plasma renin activity values trations on mean blood pressure revealed significant found following incubation at pH 7.4 and those ob- (P < 0.05) inverse correlations between these vari- tained at pH 5.7 (r =0.98;P < 0.001). Angiotensin I ables during two of the eight study conditions, e.g., generation at pH 5.7 exceeded the values at pH 7.4 during normal sodium intake and upright posture (r = by approximately 40% in the low and 20% in the high —0.44)and following three days of sodium depletion in range of measurements. the supine position (r =—0.47and —0.49, respectively) Relationship between serum renin concentration (Table 4). During the remaining six study conditions, and plasma renin activity (Fig. 4). In both age groups, significant renin-blood pressure interrelations could serum renin concentration showed an excellent corre- not be demonstrated. lation with plasma renin activity measured either at incubation pH 7.4 (r = or at pH 5.7 (r =0.93 0.94) Discussion and 0.92, respectively). There were no apparent age- related differences in the relationship between renin These data demonstrate that aging may influence concentration and activity. the functional status of the renin-angiotensin-aldoster- Effect of aging on renin and aldosterone 329
Na intake 120 x lOx 10 x 10 x concentration. These age-related differences were gen- ,nEq/24 hr 3 days 3 days 6 days 7 days + F erally slight while the subjects were supine and in- 5000 gesting a normal sodium intake, and they were more : pronounced during the stimulatory conditions of up- 3000 right posture and sodium-volume depletion. 2000 • 1 o Previous findings regarding renin and aldosterone .. ° metabolism in the aging human have been difficult to 1000 • ° interpret [2, 4, 7]. Some authors noted diminished un- .° : 9) nary aldosterone [6] or plasma renin and aldosterone 500 • •' values [7], but others reported data indicating that 300 o plasma renin concentration [2] and renin activity [4] • 8 o 200 ' § remain unchanged with aging. In the present study, circulating renin levels were evaluated with three dif- . ferent methods, namely by the determination of serum renin concentration and by measurements of plasma o renin activity at incubation pH 7.4 and 5.7. Correla- 50 tions between the results from the three methods were 30 NS P