Renin, angiotensin and aldosterone system in pathogenesis and management of hypertensive vascular...

Renin, Angiotensin and Aldosterone System in Pathogenesis and Management of Hypertensive Vascular Disease

JOHN H. LARAGH, M D.

LESLIE 3AER, M.D.

HANS R. BRUNNER, M.D.

FRITZ R. BUHLER, M.D.

JEAN E. SEALEY, B.S.

E. DARRACOTT VAUGHAN, Jr., M.D.

New York, New York

From the Department of Medicine, College

of Physicians and Surgeons, Columbia-

Presbyterian Medical Center, New York, New York 10032. Requests for reprints

should be addressed to Dr. John H.

Laragh.

The renin angiotensin aldosterone concatenation, via two ef-

fector components, angiotensin II and aldosterone, simultaneously regulates (1) body sodium and water content, (2) arterial

blood pressure and (3) potassium balance. Renin, secreted in response to stimuli which compromise

kidney perfusion, increases plasma angiotensin and this stimulates aldosterone secretion. Vascular tone is regulated by an interaction between angiotensin levels and available (intravas- cular) sodium ions. The two hormones thus restore sodium balance and arterial pressure, thereby turning off renin release. Potassium homeostasis is maintained by two direct but oppos- ing effects of plasma potassium levels on aldosterone and renin secretion.

Derangements of this cybernetic system are involved in the pathogenesis of malignant hypertension, primary and pseudoprimary aldosteronism, renovascular hypertension and oral contraceptive hypertension.

Subtler abnormalities in the renal adrenal axis occur in essential hypertension: Three major subgroups exhibit low (27

per cent), normal (57 per cent) or high plasma renin activity (16 per cent). When aldosterone is included, eight different hormonal profiles have been identified.

Longitudinal studies indicate that, in contrast to groups with normal and high renin activity, patients with low renin essential hypertension appear to be protected from the development of strokes and heart attacks despite similar hypertension and cardiac enlargement and a higher age.

Taken with the observations in malignant hypertension, plasma renin activity emerges as a risk factor predisposing to serious vascular injury. It thus may be a useful guide for determining etiology and prognosis.

New therapeutic strategies are also suggested. Patients with low renin activity may not require early treatment whereas it should be diligently applied in those with high renin activity. Moreover, individualized antihypertensive therapy to correct specific derangements in the renin system holds special promise.

In the past twelve years it has become apparent that the

renin-angiotensin-aldosterone system plays a vital role in the

regulation of electrolyte and blood pressure homeostasis in

man. Studies of patients with malignant hypertension in par-

ticular provided a critical clue for identification of this

Volume 52, May 1972 633

RENIN, ANGIOTENSIN AND ALDOSTERONE SYSTEM IN HYPERTENSION-LARAGH ET AL.

‘EFFECTIVE’ BLOOD VOLUME or PRESSURE-

RENAL J.G CELLS I

RENIN

I +

PLASMA SUBSTRATE - ANGIOTENSIN I I

ADRENAL CORTEX c__, ALDOSTERONE

RENAL TIJBULE- No+ RESORPTION

Figure 1. The renin-angiotensin-aldosterone system and the cybernetics of sodium and volume homeostasis.

renal-adrenal hormonal interrelationship [l-3]. It has been shown that derangements of this regula- tory system occur not only in malignant hypertension and in primary aldosteronism [l-5], but also in renal vascular hypertension [6] and in oral contraceptive hypertension [7a]. These disorders represent the more dlramatic syndromes in which abnormalities of renin and aldosterone are easily demonstrated. But, altogether they comprise only a small portion of the large hypertensive population.

In this discussion, the aberrations in the renin- angiotensin-aldosterone system characteristic of these syndromes will be considered in detail in order to elaborate the pathophysiology of the conditions and the dynamic behavior of the regula- tory system. With this information in hand, the possibility of a less apparent participation of the renal-adrenal axis in the more common forms and stages of hypertensive vascular disease will be examined. In particular, the question whether or not subtle abnormalities are involved in the large population of hypertensive subjects now subsumed under the. rubric of benign essential hypertension will be considered.

From all of this, a physiologic classification of the spectrum of hypertensive diseases in terms of apparent involvement of the renal-adrenal hormonal system can be developed. This information ‘may be useful for understanding etiology, determining prognosis and planning treatment of patients with high blood pressure.

THE SYSTEM DEFINED

The renin-angiotensin-aldosterone system appears to regulate sodium balance, fluid volume and blo’od pressure as follows: when, as the result of

such events as helmorrhage, sodium depletion, transudation or alimentary loss, effective blood volume contracts and arterial pressure falls, the kidney’s perfusion is threatened and it secretes renin into the blood stream. Renin acts enzymati- caliy on a plasma globulin to release angiotensin I. Angiotensin I is then rapidly hydrolyzed to angiotensin II by pulmonary and plasma converting enzymes. Angiotensin II, in addition to its pressor action, stimulates aldosterone secretion. Aldo- sterone acts on the kidney to cause sodium retention. This positive sodium balance leads to a secondary retention of water and expansion of the extracellular fluids. Thus angiotensin and aldosterone together act to raise the blood pressure and restore renal perfusion, thereby compensating the system and shutting off the initial signal to renal renin release (Figure 1).

Arterial blood presure is maintained by a co- ordinated interaction between plasma angiotensin and available sodium ions. The product of this interaction determines vascular tone and pressor responsiveness. This relationship has been characterized in normal human subjects receiving angiotensin infusions [14]. Angiotensin-aldosterone- induced sodium retention was associated with increased pressor sensitivity to angiotensin. Con- versely, sodium-depleted subjects exhibited a reduced pressor responsiven’ess. The low blood pressures and the markedly reduced sensitivity of patients with cirrhosis and ascites in the face of large increases in total body sodium content suggest that it is the amount of sodium retained within the vascular bed or in the effective circulation which is important in this relationship [14]. These results describe an internally controlled feedback for hormonal interaction built around the state of sodium balance. More recent studies have demonstrated that the binding affinity of angiotensin II vascular receptors is directly related to the state of sodium balance [79].

Simultaneously, the renin-angiotensin system participates in the regulation of potassium homeostasis. This activity tends to stabilize plasma potassium Ieve,ls and avoid dangerous hyperkalemia which may develop in patients with adrenal in- sufficiency after a meal of high potassium content. Increases in plasma potassium act directly on the adrenal cortex to stimulate aldosterone release. This in turn promotes kaliuresis. As the plas’ma potassium level falls, aldosterone secretion is retarded [7b,7c]. At the same time, increases in plasma potassium act directly on the kidney to inhibit renin release whereas hypoka-

634 The American Journal of Medicine

RENIN, ANGIOTENSIN AND ALDOSTERONE SYSTEM IN HYPERTENSION - LARAGH ET AL.

lemma is a potent stimulus for renin secretion.

Thus renal conservation 0’ elimination of potas-

sium ions is closeiy related to opposite changes

In both renin anti aldosterone secretion [7d,7e]. Full understanding of these interrelationships re-

quires further study. The ultimate signal indl;cing renin release has

not yet been identified, but it appears to involve

a pressure or stretch sensitive receptor in the renal afferent arterioles, a distal tubular macula densa receptor responsive to changes in sodium delivery, changes in autonomic nerve activity and

changes in potassium balance. Increases in plasma angiotensin levels may “feed back” to retard fur-

ther renin secretion. The renin-angiotensin-aldosterone system has

two effector hormones: angiotensin II and aldosterone.

Angiotensin II is an octapeptide with three striking physiologic actions: (1) in constricting the arterioles, it is by weight the most potent pressor substance known; (2) it acts directly on the kidney to cause sodium retention with lower dosages and natriuresis with larger amounts; and (3) it acts on the adrenal cortex to evoke a prompt and sustained increase in aldosterone secretion. The concentration of angiotensin II in human venous plasma normally ranges from 1 to 10 mpg/100 ml.

Aldosterone, the second effector hormone of the system, is an adrenal corticosteroid, unique because of its 18.aldehyde configuration. It acts primarily on the renal tubules to increase the re- absorption of sodium chloride and to promote the elimination of potassium ions. Like angiotensin II, aldosterone is present in relatively minute amounts. Its blood level is approximately l/lO,OOOth of that of cortisol, and in man it

ranges from 1 to 10 m,Lg/lOO ml of venous plasma. Yet, because of its great potency, aldo-

sterone undoubtedly plays a major role in sodium and potassium homeostasis.

The other components of the renin-angiotensin system do not have any known significant physiologic actions. Thus, renin is a proteolytic enzyme made and secreted primarily, if not exclusively, by the juxtaglomerular cells of the kidney. Renin acts enzymatically on a circulating plasma globulin, the renin substrate also called angiotensino- gen, to release the decapeptide angiotensin I. Angiotensin I is hydrolyzed very rapidly by converting enzymes present in the lung and more slowly by similar enzymes in plasma, which re-

move the terminal histidyl-leucine liberating into

the circulation the physiologically active octapep-

Volume 52, May 1972

tide, angiotensln II. It has not yet been possible

to measure endogenous plasma angiotensin I.

Howeve<. when converting enzymes are inhibited

in vitro! the quantitation of angiotensin I forma- tion becomes a measure of renin activity.

In this system. both the renin substrate and the converting enzymes are ordinarily present in

sufficient amount so that their concentrations are not physiologically rate-limiting for the forma- tion of angiotensin II. Therefore, a relatively small change in the concentration of renin in plasma is usually the major determinant of the final concentration of circulating angiotensin II. By

changing the plasma concentrations of the effector componen’i-s, angiotensin II and aldosterone, this hormonal interaction simultaneously regulates (1)

body sodium and water content, and thus hydro- static pressures; (2) arterial blood pressure; and (3) potassium balance.

Because the direct measurement of circulating angiotensin II requires methods of great sensitivity and because changes in plasma renin usu-

ally closely parallel induced changes in circulating angiotensin II, the measurement of plasma renin “activity” has proved to be a simpler and a most reliable indicator of changes in angiotensin generation. Moreover, since the kidney is the major source of plasma renin, measurements of plasma renin activity are ordinarily a reliable index of renal renin secretion.

For a more detailed review of the hormonal system, the reader is referred to recent mono-

graphs C&91.

STUDY APPROACHES

Patient Material. Patients at the Nephritis Hyperten-

sion Clinic or the Doctor’s Private Office Facilities of the Columbia-Presbyterian Medical Center were studied over a period of fifteen years. Although this institu-

tion accepts referrals from the greater New York area and also from more distant points, the principal catch-

ment area consists of upper parts of Manhattan and the Bronx.

Most of the patients were admitted to the metabolic unit of Presbyterian Hospital, but about 20 per cent were studied as outpatients. Prior to evaluation, all had discontinued taking antihypertensive and diuretic drugs for at least three weeks, and they were given diets con- taining unrestricted amounts of sodium. All were given a complete work-up that included intravenous pyelogra- phy and often renal arteriography.

The renin-angiotensin-aldosterone system was evaluated on the fifth day of a fixed dietary regimen of known electrolyte content. Most patients were studied in this way at two or more different levels of constant

635

RENIN. ANGIOTENSIN AND ALDOSTERONE SYSTEM IN HYPERTENSION - LARAGH ET AL.

sodium intake. Renin activity was measured from plasma samples taken at noon after the patients had been ambulatory for at l’east four hours. Matching twenty-four hour urine samples were saved for the de- termination of aldosterone and sodium excretion.

Procedures necessarily differed for the patients studied as outpatients. Such patients were instructed not to avoid sodium in their diets, and the state of their salt balance was inferred from twenty-four hour urinary sodium excretion. Among them, the rate of sodium excretion ranged from 100 to 250 mEq/day with little intraindividual variation. At these rates, the influence of any dietary inconsistency on renin and aldosterone secretion could be expected to be small. The findings among the outpatients have completely paralleled and reinforced the data obtained under controlled conditions in the metabolic unit.

Normal values were defined by submitting normal volunteers to the same dietary regimens utilized for patients. Some of the normal volunteers were studied while housed on the metabolic ward, others were not hospitalized but received a constant dietary regimen, and a third group was allowed unrestricted diets. Analytical fviettiods. Plasma renin activity was measured using a basic incubation procedure followed by either pressor bioassay or radioimmunoassay of angiotensin I. The methods are accurate and reproducible. The standard deviation of the radioimmunoassay is 11.6 per cent [lo], somewhat lower than the bioassay procedure [lo]. Interchangeability of the results is achieved when a correction factor of 2.2 is applied to bioassay results in order to account for the greater pressor activity per unit weight of angiotensin II compared with angiotensin I.

Aldosterone excretion was evaluated by measurement of the twenty-four hour urinary excretion rate of the acid-labile conjugate of the hormone. The aldosterone, which is reconstituted by acid hydrolysis, can be quantitated with a sensitive, reliable and relatively simple radioimmunoassay [ll] or, in earlier studies, a more laborious method which utilizes instead multiple chromatography, acetylation and a double isotope dilution technic [12]. Complete correlation and identity of the results of the two methods has been demonstrated over a wide range. The standard deviation of the radioimmunoassay is less than 8 per cent and is lower than that of the double isotope dilution method [ll].

It has been our view that the twenty-four hour urinary measurement is an integrated reflection of the daily adrenal secretion of aldosterone and thus provides more useful information than a plasma value which can reflect only a single point in time. Twenty- four hour urine collections are ‘essential at any rate, since the interpretation of either plasma renin or plasma aldosterone levels requires that they be related to the state of sodium balance, an evaluation of which is provided by no practical alternative to twenty-four hour urine collections.

CRITERIA FOR EVALUATION OF

HORMONAL ABNORMALITIES

Our own approaches in studying the renin-an-

giotensin-aldosterone system has been fully re-

ported elsewhere [l-4,10-12], but at least one aspect of the methods employed warrants em- phasis in this review of the state of the art for it is critically responsible for some findings we consider important. This pertains to the question of relating assay values to the state of salt balance.

It should be obvious at the outset that a system whose physiologic tasks are associated with salt

balance, and is triggered by the effects of changes in salt balance, must be evaluated relative to this feature. Whether a given level of renin, angiotensin or aldosterone can be considered normal de- pends on its physiologic assignment of the mo- ment, either to maintain a satisfa’ctory electrolyte

equilibrium or to buffer the consequences of an undesirably high or low salt level. This problem

has been given consideration by most workers in the field and generally settled by the practice of setting certain bracketed ranges of normal values for various levels of salt ~intake. Values found in

salt-controlled subjects can then be evaluated against these ranges.

The grossly abnormal levels obtained in the more acute hypertensive states can be assessed against such an index with relative ease. How- ever, when there are subtle abnormalities in the

system these may not be exposed with the use of such brackets. Thus, if the urine sodium level of the sample falls at one extreme of the bracketed range an abnormal value ,m#ight be interpreted as normal because such values would be normal for the other extreme of the bra’cket. This becomes a

problem of some consequence when the intent is to study the renin-angiotensin-aldosterone system involvement in the more indolent, chronic conditions in which deviations from normal are expectedly of smaller dimension.

Accordingly, we have taken a different approach and have attempted to construct an index of normality whose continuity would reflect t,he linear responsiveness of this system. By subjecting normal volunteers to various levels of salt balance nomograms were constructed giving normal values for renin a,ctivity and aldosterone excretion over a wide range of physiologic variation. As can be seen in Figure 2, the relationship of these values to salt balance is direct, continuous and within rather well defined limits. This index permits a more precise observation of renin-angiotensin-al-


RENIN. ANGIOTENSIN AND ALDOjTERONE SYSTEM IN HYPERlENSION LARAGH ET A_

Figure 2. Refation of both renin ac-

tivity in plasma samples obtained at

noon and of the corresponding twenty-

four hour urinary excretion of aldoste-

rone to the concurrent daily rate of SO-

dium excretion. For these normal sub-

jects, the data describe a similar dy-

namic hyperbolic relationship between

each hormone and sodium excretion.

Of note is the fact that subjects stud-

ied on random diets outside the hos-

pital exhibited similar relationships, a

finding which validates the use of this

nomogram in studying outpatients or

subjects not receivrng constant diets.

See text.

Norwol Subjects

,. RIahiDOM SAMPLf ,. L_-__. _ -. ..~

8,:

0

0 100 ZOO 300 0 100 200 URINE SODIUM mfR/QaY

dosterone system relationships in essential hypertension as will be discussed later.

It also became apparent in practice, by com- parison, that the close association between salt balance and the components of the renin-angiotensin-aldosterone system was equally well reflected whether salt balance status was determined on the basis of dfetary control (balance conditions) or on the basis of a random twenty- four hour urine collection. We found with serial daily studies that changes in the renin and aldosterone levels closely followed changes in the urinary sodium excretion rate even before equilibrium was achieved. There was often a lag of up to four days before sodium intake was reflected by urinary sodium excretion. During this period the renin and aldosterone values exhibited an appropriate relationship to sodium excretion but not to

sodium intake. Technically, too, daily sodium output is more readily tracked than either dietary intake or the more laborious and error ridden sodium balance calculations. The approach has the additional advantage of being applicable to the study elf outpatients on random diets.

Certain theoretic consrderations support the practice. The kidney is normally the major route for sodium elimination, and the rate of sodium excretion reflects the extent to which the kidney

is being directed to retain or release sodium. The hormonal activity is thus related to the target organ response rather than to changes in the homeostatic function which probably is subserved, i.e., sodium balance.

The results in Figure 2 suggest certain guidelines for classification of patients. Thus, it is ap-

parent that patients with high renin levels may not be detected if studied while adhering to a low salt diet. Also, it is difficult to identify patients with subnormal plasma renin activity when the urinary sodium excretion is above 150 mEq/day. If only one point on the curve is available for

classification of a patient, the ideal range of urinary sodium excretion would be between 40 and 100 mEq/day. In the case of plasma renin activity, occasional values appear inappropriately high in subjects not under dietary control (Figure 2). However, no subjects eating random diets exhibited inappropriately low values. Thus, patients who exhibit borderline high plasma renin activity and those whose values fall on the lower edge of the normal curve should be more definitively categorized under balance conditions.

Pathophysiology of Hypertensive Syndromes with Outstanding Abnormalities of the Renin-Angioten- sin-Aldosterone System

Malignant Hypertension Versus Primary and Pseudoprimary Aldosteronism. The syndrome of malignant hypertension is defined clinically by severe and accelerating hypertension with neuro- retinopathy and evidence of advancing renai disease, and pathologically by necrotizing arteriolitis especially involving the kidney [13]. The condition, usually a sequel to various types of benign hypertension, is nearly always fatal within a year if no treatment is applied.

An analysis of the physiologic derangements observed in this syndrome has led to an understanding of the renin-angiotensin system and its involvement in various other disorders. Thus, an

Volume 52, May 1972 637


MALIGNANT HrPERTEMSlO#

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early survey of the possible role of increased aldosterone secretion in the spectrum of hypertensive diseases revealed that aldosterone secretion was practically always increased not only in primary aldosteronism but also in malignant hypertension [l]. Indeed, the values observed in malignant hypertension were often enormously elevated to levels considerably higher than those observed in primary aldos’teronism (Figure 3). These observations raised a qu’estion: How do these two hypertensive disorders, characterized by oversecretion of aldosterone differ and what do they have in common? Actually, the two conditions are quite different. The typical clinical picture of primary aldosteronism is one of benign, often long-standing hypertension. Potassium wast- age is the cardinal physiologic defect. Pathologi- cally, there is little vascular injury. The condition is completely cured by removal of the offending adenoma. Therefore, primary aldosteronism may be viewed as a clinical expression of autonomous oversecretion of aldosterone in an otherwise healthy subject.

On the other hand, malignant hypertension is quite a different disorder both clinically and pathologically. Adrenal tumors are not the rule so tmhat

638

Figure 3. Aldosterone secretion and sodium excretion in malignant hypertension. In all but one instance, marked oversecretion was observed. At the higher levels of sodium excretion in particular, there is no overlap with the normal range. From Laragh et al. 1121.

adrenal oversecretion appears bilateral and therefore is most likely secondary to an extraneous stimulus. That is, the adrenal involvement is a secondary one. This likelihood is further supported by clinical experience indicating that the hypertensive process is not affected even by total adrenalectomy [1,2]. The renal-adrenal axis and its participation in malignant hypertension: The preceding consider- ations allowed the suspicion that the striking aldosterone discharge in malignant hypertension is a secondary response related to stimulation of the adrenals by sources external to them. In search- ing for the stimulus our group decided to study angiotensin to see whether it was the agent responsible for the hyperaldosteronism of malignant hypertension. Even though this material had become unpopular, since no role for it had been defined, we suspected that the renal pressor substance might be involved because obviously kidney ‘damage is the cardinal site of pathologic change in m,alignant hypertension. It was possible to dem- onstrate a renal-adrenal hormonal interaction because an infusion of angiotensin II into normal volunteers resulted in a ,marked increase in the adrenal secretion of aldosterone [2]. The effect was

The American Journal of Medicine


highly selective because cortisol secretion did not

increase and because the response could not be induced by any other pressor agent [14]. It there-

fore appeared that angiotensin, which is the most powerful pressor substance known, also had a second vital function-as a trophic hormone to call forth the secretion of aldosterone.

This evidence for a kidney-adrenal interaction revived interest in the renal pressor system as a regulator of blood pressure. It also allowed our hypothesis (Figure 4) concerning the mechanisms in malignant hypertension [2,3]. In malignant hy-

pertension, a critical degree of damage has developed in the kidney for initial reasons not always clear. When this critical renal damage develops, a sequence is set in motion: renin, secreted inapproprrately into the blood stream in excessive amount, interacts with the circulating renin substrate to release more angiotensin II.

Angiotensin II, in addition to raising the blood pressure by constricting the arterioles, also stimulates the secretion of aldosterone by the adrenal cortex. The aldosterone, in turn, acts on the kidney to increase sodium retention in the attempt

to elevate volume and restore renal perfusion. In normal subjects, this feedback loop is closed

by the sodium retention, and the increased renin secretion ceases. However, in those with malignant hypertension, a vicious cycle develops. The induced aldosteronism cannot turn off the secretion of renin, perhaps partly because it cannot induce appropriate sodium retention in the damaged target organ, kidney. A situation results in which there is too much angiotensin and too much aldosterone in the blood at the same time. A vicious cycle is initiated, characterized by more renin, more angiotensin and aldosterone, more hypertension and more renal damage. We believe that this vicious cycle is crucial to the pathogenesis of the malignant hypertensive syndrome.

Another way of putting it is to say that under normal circumstances the kidney, when its perfusion is threatened, triggers off a corrective and self-limiting dose of hypertension. But in malignant hypertension the kidney is behaving inappropriately, for the danger to perfusion comes from damage rather than from hypotensive phe- nomena. There is nothing to shut off the process, because the response is irrelevant to the signal. Runaway hypertension results.

There is a good deal of evidence to support this view. First, the early work of Kahn et al. [15] showed excessive angiotensin in the blood of pa-

Figure 4. The renal-adrenal axis involving renin, angio-

fensin and aldosferone in regulation of sodium and po-

tassium balance and blood pressure. The interaction is

depicted as first identified in patients with malignant

hypertension in whom, because of defective feedback, if

becomes involved in pafhogenesis. See text.

tients with malignant hypertension. Somewhat more recent animal experiments by Masson and his associates [16] indicate that in rats injections of either renin or aldosterone alone do not produce any significant pathologic changes, but when

given together, severe and rapidly fatal vasculitis follows. Furthermore, in dogs the malignant syn-

drome can be reproduced in the Goldblatt model by tightening the clamps, and this is accompanied by hyperreninemia and hyperaldosteronism not observed in dogs with the benign form of hyper-

tension [17]. This idea that an excess of renin or angiotensin causes vascular injury is additionally supported by a number of other animal studies [18-211. The contrasting pathophysiology of primary and pseudoprimary aldosteronism: In contrast to the hyperaldosteronism of malignant hypertension, primary aldosteronism (adrenal adenoma) and pseudoprimary aldosteronism (diffuse hyperplasia) are two adrenal cortical disorders characterized by seemingly autonomous oversecretion of aldosterone with suppressed plasma renin activity. Pseudoprimary aldosteronism differs in that the hormonal abnormalities are quantitatively less marked, and hypokalemia is milder or absent [22-241. Also, the hypertension in primary aldosteronism is usually cured by removing the offending adenoma whereas the hypertension of pseudoprimary aldosteronism is not improved by partial or even total adrenalectomy [22,23]. Accordingly, although these two adrenal disorders appear to differ from each other

Volume 52, May 1972 639


biologically, they have in common the clinical pre- sentation of benign hypertension with a high aldosterone level and suppressed plasma renin activity.

The benign or milder nature of these two adrenal cortical disorders as contrasted with

malignant hypertension can be attributed to the absence of renin and angiotensin [2-41. Thus,

aldosterone, secreted autonomously and in the

absence of any renal damage, would be expected to suppress renal release of renin and prevent ini- tiation of the vicious cycle which seems essentially related to the pathogenesis of malignant hypertension.

This thesis, developed from observations in these renal and adrenal disorders, relates the vascular injury of hypertension primarily to the excessive or inappropriate secretion of renin. However, it is likely that changes in sodium balance and in aldosterone secretion also can be i,m#portant in the equation. Such an association

seems likely if only from the knowledge that aldosterone operates within the system to determine sodium balance which in turn modulates both the secretion of renin [‘25,26] and the action of angiotensin [14]. Furthermore, it is known that the vasculotoxic effects of renin are best demonstrated in animals fed salt [27]. In the same way too, the experimental vascular disease produced by min- eralocorticoids such as aldosterone requires adequate dietary salt [16,28,29]. Indeed, this latter experimental state can at times become “malignant” with fibrinoid arteriolitis. Thus, from the animal experiment, it seems possible that in man too, very marked “primary” adrenal oversecretion of aldosterone might ultimately exceed the buffer capacity of the hormonal interaction and induce the vicious cycle of malignant hypertension which apparently is most often initiated by renal damage. However, in only one or two uncertain instances of primary aldosteronism has malignant hypertension been described [30,31]. Clinical Implications. The pathophysiologic ab-

errations so far described have implications for understanding normal physiology and for analyz- ing clinical problems exemplified by a whole vari- ety of milder forms of high blood pressure. A large body of evidence has now accumulated to indicate that the renal-adrenal hormonal interaction plays a major role in the day to day regulation of salt balance and blood pressure in all of us. Many studies indicate that a low sodium diet in normal subjects produices a high plasma renin level, and

the high renin level caused by the low salt diet is

probably the reason for the hyperaldosteronism and renal sodium conservation that occurs in normal subjects. Conversely, high salt diets in animals or in man will promptly arrest the secretion of renin, and then aldosterone secretion falls.

The dynamic responses of these hormones to changes in dietary salt go a long way towards explaining the magnificent constancy of our body

weight despite wide fluctuations in diet. There are also key implications of these observa-

tions for the detection and analysis of renal and adrenal abnormalities in hypertensive patients. Accordingly, if a hypertensive patient has hyperaldosteronism, the next step is to find out why. If he has hyperaldosteronism and plasma renin is increased, the aldosteronism of the patient is secondary to the release of renin and is related to some sort of renal disturbance. On the other hand, if a patient has hyperaldosteronism or clinical evidence of it (hypokalemia is a very reliable clini-

cal sign) and his plasma renin levels are low, one can then suspect that the adrenal is primarily at fault-an autonomous adenoma of diffuse hyperplasia operating to increase aldosterone secretion, induce the retention of salt and so suppress the kidney’s secretion of renin. Hypokalemia as a Clinical Sign. A most reliable clinical indicator of aldosteronism, whether it is due to a renal or an adrenal disturbance, is the presence of hypokalemia. This is to be expected, since the sodium retaining hormone aldosterone is also a kaliuretic agent. Indeed, under experimental conditions, evidence of potassium depletion is practically always associated with a physiologic excess of mineralocorticoid.

It is therefore most relevant to characterize the plasma potassium levels in all hypertensive patients with several measurements, preferably at widely spaced intervals. In so doing, two precautions should be taken: (1) the patient should not take any diuretic drugs for at least three weeks, and (2) whenever #possible, the patient should be maintained on an unrestricted or liberal sodium intake since a low sodium diet can mask the kaliuretic effect of aldosterone by reducing distal tubular sodium supply.

In our experience, the greatest degree of hypokalemia occurs in primary aldosteronism due to an adenoma. Thus, in twelve of these patients the mean plasma potassium was 2.5 mEq/L [22]. ln eleven patients with pseudoprimary aldosteronism (bilateral hyperplasia) the mean value was

640 the American Journal Of Medicine

RENIN. ANGIOTENSIN AND ALDOSTEHONE SYSTEM IN HYPERTENSION -- LARAGH ET AL.

3.6 mEqil_. jnd ;tjme vaI,.ies in this group fell

Into the lower noima: range. The lesser hypoka- iemia in the latter group can be related to an USU-

ally milder degrer: of aldosterone oversecretion. Hypokalernla after occurs in malignant hyperten- i;ion too [l], in c.ur -eport, the mean value was 3.6 mEq/L in sixft:en cases. However, il? this condition, the expression of hypokalemia is retarded because of acconepanying renal failure with aci- dosis and azotemL3

Some examples of so-called “normokalemic” primary aldosteronism have been reported [32]. However, with the approaches outlined herein we have not observed this phenomenon, and we believe it to be a rare variant of an uncommon dis-

ease. Such patients might instead represent a variant form of low renin essential hypertension, exhibiting suppressed plasma renin activity with a slightly increased aldosterone secretion [33]. Whatever the case proves to be, since some of these reportedly normokalemic patients may have mild or borderline hypertension, temporization or a program of medical management is probably a reasonable clinical alternative to exploration. Additional Work-up. The work-up of hypertensive patients suspected of having primary or pseudoprimary aldosteronism therefore involves as a first step the characterization of plasma potassium levels under the conditions described. The next step is the demonstration of inappropriately high aldosterone secretion when the urinary sodium excretion is in excess of 100 mEq/day (see nomogram, Figure 2) and of an inappropriately low plasma renin activity when the urinary sodium

excretion is somewhere below 40 mEq/day (see nomogram, Figure 2). Ideally, these measurements are best obtained under balance conditions. However, as indicated, such data can also be reliably obtained in properly instructed outpatients. The patient becomes a possible candi- date for surgery If hyperaldosteronism, hypokalemia and suppressed renin activity are unequivo- cal with the more flagrant deviations suggesting an adenoma of primary aldosteronism rather than the hyperplasia of pseudoprimary aldosteronism [22-24-j. Since the patient with the latter condition may not benefit from surgery, there is still disagreement about the value of exploration. How- ever, despite the use of various physiologic tests beyond the scope of this discussion, exploration may still be the only truly definitive approach to the differentiation of primary from pseudoprimary aldosteronism.

!X#CT 6 OFFSET OF ORaL CWWRAMPTIVE WPERTFNSION IN A SINGLE PATIENT

MAY 12fhOAY 4th MONTH 9th DAY I MONTH 4 MONTHS 1966 -- I-

Figure 5. Oral contraceptive hypertension in a thirfy- three year old woman in whom hypertension was first discovered after three years of oral contraceptive therapy with Enovid, 5 mg. Hypertension disappeared after drug withdrawal. It reappeared, as shown here, when treatment was renewed, and then disappeared again after withdrawal of the drug. The appearance and disappear- ance of hypertension was associated with concomitant increases and decreases in renin, aldosterone, renin substrate and reactivity to renin. The data illustrate that in this patient the observed increase in renin activity was largely due to an increase in renin substrate concenfmra- tion. From Newton et al. [34]

Oral Contraceptive Hypertension: A Role for Renin Substrate. Despite a number of suggestions that hypertension, the most frequent complication of pregnancy, is strongly associated with sodium and water retention and with heightened endogenous estrogen activity, not until recently was the possibility explored that administration of exogenous gonadal hormones might duplicate the association.

Following this possibility, in 1967 our group [7] reported that when oral contraceptive therapy was discontinued in eleven hypertensive women, their blood pressure levels fell, in some cases to normal. Moreover, in two patients in whom blood pressure levels returned to normal, rechallenge with another oral contraceptive reproduced the hypertensive condition.

Figure 5 illustrates the findings in a thirty-three year old woman whose blood pressure was normal prior to starting Enovid@ treatment [34]. Three years later, when she first came to our Center, it was 200/130 mm Hg. A complete work-up including renal angiography gave negative results. Contraceptive therapy was discontinued, and the blood pressure returned to normal levels in the next sel!eral months. At this point, the hormonal

Volume 52, May 1972 641


Oiiufrd Phma 140

I20

RENIN I00

SUBSTRATE 80 REACTIVITY 6.

nglmlllir 40 !

0 1000 2000 3000

RENIN SUBSTRATE q/ml

Figure 6. Effect of dilution of renin supbstrate on the rate

of generation of angiotensin compared with undiluted

samples of various concentrations. These samples were

obtained at different times in the course of oral contracep-

tive administration. Since substrate concentration is nor-

mally about 1,000 ng/ml when measured by this bioassay

method, it is apparent that increases in substrate above

the normal can markedly increase the capacity for angiotensin generatio’n. The data also #indicate that observed

changes in the substrate capacity to release angiotensin are probably related to changes in the substrate concen-

tration rather than the result of variation in concentration

of an activator or inhib,itor. From Newton et al. 1341.

components were all normal. Since there was no known association between blood pressure and contraceptive pills, the patient desired to resume therapy.

Accordingly, contraceptive therapy was re- started, this time with Orthonovum@; during this rechallenge her hormonal patterns were followed closely. Hypertension reappeared by the fourth month. The most impressive biochemical abnor- mality was a m,a.rked and persistent increase in plasma renin substrate. This was acco’mpanied by a significant increase in plasma renin activity and in aldosterone excretion. Note, however, that by the time hypertension had reappeared, plasma renin activity had dropped back to a normal control level even though ,her abnormally high renin substrate level had risen even higher.

Cessation of contraceptive therapy resulted over a four month period in a gradual return to normal of the blood pressure and of the humoral abnormalities. This patient has remained normotensive ever since.

Since this experience was reported, confirma- tion of the pressor potential of oral contraceptives has come from a number of sources, some of them involving larger samples than ours [35-421. Even reversible malignant hypertension has been reported with pill usage [43].

Fortunately, hypertension still appears as an extremely rare side effect when one considers the many millions of women who are taking these drugs on a long-term basis. It should be stated, however, that there now exist wide variations in

642

the reported incidence of contraceptive hypertension with very low incidences [40,41] being coun- terbalanced by some extremely high estimates of

18 per cent or more [36,39,42]. These high estimates result largely from the reporting of small increases in blood pressure, sometimes within the normal range. Nonetheless, they perhaps con-

stitute added testimony to the pressor potential of these drugs.

Analysis of the hormonal abnormalities in oral contraceptive hypertension: The abnormal hormonal patterns of oral contraceptive hypertension as illustrated in Figure 5 typify what has been abun- dantly documented [34,37,39,44,45-j. Plasma renin substrate is practically always markedly increased, and the plasma renin concentration esti- mated indirectly [34,46] or measured directly [44,45] usually appears suppressed. However, our findings differ from those in subsequent reports since in more than half of our hypertensive patients, plasma renin activity was not elevated but

was in the normal range at the time of study. Before assigning a causal role to these hor-

monal deviations, it must be recognized that very similar biochemical abnormalities are readily apparent in normotensive women maintained on oral contraceptives [44,45]. Indeed, it seems possible to us that normotensive women exhibit even greater and more consistent increases in plasma renin activity than have been observed in those in whom hypertension develops. Most women taking contraceptives remain normotensive despite marked and commensurate increases in both plasma renin activity and circulating angiotensin

II [44,45]. These latter values are sometimes as high as those described in malignant hypertension.

Ho’w then is the hypertension produced in these patients? An in vitro experiment has yielded possibly relevant results [34]. When a fixed amount of purified human renin was added to patient serums a progressively increasing capacity to release angiotensin was demonstrated which

could be directly related to the increased substrate

levels produced by pill therapy (Figure 6). This increased reactivity of the plasma was something of a surprise because substrate had usually been thought to be present in concentrations SuffiCient

to produce a nearly maximum rate of angiotensin production. The observation that renin substrate is normally rate limiting in man has been confirmed by another group [44], and both of these experiments extend and amplify the findings of Helmer and Judson [46]. It now seems very likely that in man a maximum reaction velocity between


RENIN, ANGIOTENSIN AND ALDOSTCRONE SYSTEM IN HYPERTENSION -- LARAGH ET AL.

enzyme and subs’rate may not be achieved until

plasma substrate !evels ar? increased by five or

more trmes the normal range.

A priori, one might expect that because of this greater substrate r-eactivity hypertension could re- suit from excessive responses to normal amounts of renin secreted in response to various physio-

logic signals. However, in vivo, with prolonged pill treatment, compensatory homeostatic adjust- ments occur with plasma renin activity tending

to return to normal (Figure 5). Several studies have suggested that this is due to a compensatory fall

in renin concentrations [34,39,44,45]. According

to this sequence of events, one mechanism for hypertension could be failure of renal renin secretion to suppress normally or adequately in

adjusting to the rising substrate concentration. As attractive as this explanation may be, it is not yet

supported by the facts since plasma renin activity was found to be normal in at least half of our hypertensive patients, and some of the values

were lower than those observed in normotensive women on the pill [7]. The hypertension induced in these patients may therefore be affecting the renal baroreceptor to reduce renin secretion. This

sequence is illustrated in Figure 5. Thus, the question still remains u’nsettled as to whether oral contraceptive hypertension is related to an inap-

propriately high renin activity or is caused by an-

other mechanism.

Other factors may be important in the equation.

One is the renal sodium retaining effect of estro-

gens, expressed clinically in the well known ten-

dency for f!urd retention and further supported by

recent studies describing an increased blood vol-

ume and cardiac output in women receiving contrlsceptive therapy [45]. In this context, oral contraceptive hypertension would involve an hy- dremrc effect perhaps similar to that induced by

an excess of mineralocorticoid hormones. Another possibilrty is a direct stimulating effect of estro-

gens on renal renin secretion, which might hamper adequate suppression in the face of hypertension. Evidence for this comes from our observations that

in some patients the increase in plasma renin ac-

tivity was greater than could be accounted for by

the increase in plasma renin substrate [34]. Diagnostic and Therapeutic Implications. It

seems from these studies that the nub of the problem is patient susceptibility. As yet, there are no clear guidelines. Even the obvious parallel be-

tween natural and “plastic” pregnancy offers no clues for we have observed oral contraceptive hypertension in a number of women who had un-

eventful pregnancies. However, as one might expect, preexisting or occult renal disease may act

to compromise the buffer capacity of the system

as occurred in two of our patients. Another sensi- tizing factor may be any preexisting tendency to

fluid retention. In the absence of more meaningful data, it is

probably safest for the clinician to administer oral contraceptives with special caution to women with

a prior history of hypertension, excessive weight

Figure 7. Essential hypertension: 219 patients. Re- lation of noon plasma renin

activity and of the corresponding daily aldosterone excretion to the concurrent daily rate of sodium excretion. Triangles = low renin,

open circles = normal renin, squares = high renin essential hypertension. From Brunner et al. [52].

n 0

l

Volume 52, May 1972 643


gain and edema during menstruation, and a familial tendency to high blood pressure and its consequences, hypertensive abnormalities or renal disease in prior pregnancies, or an edematous sensitivity to salt.

Fortunately, pill-induced edema and hyperten

sion are reversible by stopping the medication. A woman beginning to take oral contraceptives must be monitored frequently. She should be instructed

to watch her weight carefully, this being one of

the surest and earliest indicators of sodium and water retention. Her blood pressure should be taken no later than two months after starting medication, checked frequently (bimonthly) thereafter

and compared with an adequately established base line. With these simple precautions, the pill may be used as indicated by the clinical situation.

Subtle Abnormalities in the Renin-Angiotensin- Aldosterone System in Essential Hypertension.

Using the approaches and the information just described, let us next consider the problem of

benign essential hypertension. In this category, the role of the renal-adrenal axis remains to be fully clarified. Previous studies, although not altogether in agreement, have most often reported normal aldosterone excretion in these patients. However, certain abnormal features have been described such as an impaired metabolic clearance [47], a failure of normal suppression with sodium loading [48] or a failure of aldosterone to increase normally with sodium deprivation [49,50]. On the other hand, more convincing abnormalities in plasma renin activity have been reported so that

even though this measurement is normal in the majority of these patients, in significant fractions

it may be either subnormal [49-571 or abnormally increased [51,52].

Figure 7 presents a plot of 368 determinations of plasma renin activity and aldosterone excretion in 219 patients with essential hypertension. As for the normal volunteers (Figure 2) the data are related to the concurrent rate of sodium excretion, and normal limits are given by the dotted lines.

The scatter of both renin and aldosterone values is considerably wider for the hypertensive subjects than for the normal volunteers, permitting their classification into high, normal and low categories. In this series, fifty-nine patients (27 per cent) showed reduced plasma renin activity (low renin hypertension); in thirty-six patients (16 per cent) this parameter was abnormally high (high renin hypertension), and in the remaining 124 patients (57 per cent) it fell within the normal range

c521.

MEAN DIASTOLIC

BLOOD PRESSURE

mm Hg

BLOOD UREA

NITROGEN w%

CREATININE CLEARANCE

ml/min

URIC ACID mq 81.

PLASMA

[K+l mEq/L

PLASMA CHOLESTEROL

mq%

RENIN: Low Normal High I n) (59) o- (36)

8 :::.: .::: :x,x $;;;

200

100

0

Figure 8. Mean diastolic blood pressures and clinical bio-

chemical features of the three renin su’btypes of essential

hypertension.

Clinical correlates of renin subgroups: An analysis of the clinical features and natural history of these patients with essential hypertension indi- cates that the biochemical deviations have meaningful clinical correlates. The mean ages of the patients with low renin (forty-six years) and high renin (forty-three years) hypertension did not differ significantly, but those with normal renin ac-

tivity were significantly younger (37.5 years). There were, however, no differences in the known

duration of the hypertension between any of the groups.

There was a significantly greater incidence of black patients (42 per cent) with low renin activity compared with only 24 per cent with normal renin activity and 11 per cent with high renin activity. These results tend to confirm the impression that low renin hypertension is relatively more common in blacks [53,54].

Figure 8 presents relevant clinical data for the

three subgroups. Of note are the findings that both the mean diastolic pressure and blood urea nitrogen levels were significantly higher and the plasma potassium level was significantly lower in the patients with high renin activity as compared with the other two groups. No significant differences were found in any other routine indicators including plasma uric acid, plasma cholesterol and fasting blood sugar levels (not shown). There were no significant differences in diastolic hypertension, the blood urea nitrogen, plasma potas-

644 The American Journal of Medlclne

RENIN, ANGIOTENSIN AND ALDOSTE:RONE SYSTEM IN HYPERTENSION-LARAGH ET AL.

sium or plasma i holestercl levels in the groups

with normal and ow renin activity. However, per-

haps nor unexpectedly, the more severe form of hyperterlslon wittl a tendency to azotemia and hypokalemia rn the group with high renin activity was also accompanied by a greater incidence of grade 2 and 3 retlnopathy and of proteinuria. A further classification to include aldosterone:

Each of the three renin subtypes defined in essential hypertension can in turn be associated with three different patterns of aldosterone excretion as illustrated in Figure 9. Accordingly, nine theoretically possible hormonal patterns emerge in eight of which patients have been identified. The frequency of occurrence of these eight different patterns as determined from our study of 219 patients is shown in Figure 9 where low and high estimates of frequency are given for each group. The two numbers which provide a range of frequency result from the application of two different sets of criteria, strict and loose, which take into account the fact that a small fraction of the patients are either inconsistent or fall into borderline zones with respect to these traits. This analysis has been described in detail elsewhere [52]. For simplicity, mean values for frequency will form the basis of the present discussion.

The major fraction of these 219 patients (45 per cent) was found to exhibit a normal renin level with a correspondingly normal aldosterone level. Indeed, in only minor fractions of those patients with normal renin levels was there any deviation either up or down from normal aldosterone values. Especially noteworthy is the high incidence of low renin essential hypertension, with a mean of 27 per cent and a range from 19 to 31 per cent. In

high

PLASMA

RENIN normal

ACTIVITY

low normal high

ALDOSTERONE

EXCRETION

Figure 9. Frequency distributkon of various hormonal patterns observed in essential hypertension. The first value in each category is derived from application of “stringent” and the second from less stringent criteria. Whichever criteria are used, the frequency of distribution is not modified appreciably. See text. From Brunner et a/.

[521.

Volume 52, May 1972

these sI.lb]ects aldosterone secretion rates were

usually normal, although in a small and possibly

signiflcEnt portion of them they were reduced. A

rare rinding was increased aldosterone excretion in the p<esence of subnormal renin levels possibly suggest ng occult primary aldosteronism, but the few patients with this pattern had only slightly elevatec aldosterone levels and no hypokalemia.

Since we have not found tumors in similar patients, and since even total adrenalectomy does not cure their hypertension, we do not recommend

exploratory adrenal surgery for such normokalemic patients with mildly excessive aldosterone excretion [22]. Renin activity was high in 16 per cent of the group. Among these, the aldosterone excretion was either normal or correspondingly elevated. In none of the patients with high renin activity was aldosterone secretion reduced.

Returning to Figures 7 and 9, one might draw the conclusion that in patients with essential hy-

pertension renin activity is more likely to be abnormal than is aldosterone excretion. However, we cautiously venture the possibility that some of the seemingly “normal” aldosterone values may be inappropriate to the hormonal interaction. What is normal for normal subjects may not be so for hypertensive su’bjects. One example of this might be the 17 per cent (13 to 21 per cent) of patients with normal aldosterone excretion rates but low renin activity; this might in fact represent an abnormally high aldosterone value for that level of renin activity. A truly “normal” relationship between aldosterone and renin, one in which the adrenoc.ortical response is linearly appropriate to a given renin secretion, is probably the one repre- sented by the three boxes situated on the diagonal, from left lower corner to right upper corner. Amal- gamating these three groups, about 60 per cent of all of the hypertensive patients show an appropriate renal-adrenocortical relationship.

Relationship of renin and aldosterone to heart attacks and strokes in the three renin subgroups of essential hypertension: Left ventricular hy- pet-trophy as defined by electrocardiographic and roentgenographic criteria occurred with fairly equal frequency in the three renin subgroups with the incrdences ranging from 15 to 22 per cent. However, a most striking difference emerges from this analysis: Not one occurrence of heart attack or stroke was recorded among the patients with low renin essential hypertension. In contrast, these complications occurred with a frequency of 11 per cent in those with normal renin activity and of 14 per cent in those with high renin activity.

645


The complete absence of either strokes or heart attacks in low renin essential hypertension is highly significant statistically, analysis of the results indicating that the highest possible incidence of such events in a low renin hypertensive popula-

tion at large would be 4.9 per cent (5 per cent confidence limits).

These observations may go a long way towards explaining why certain hypertensive patients toler- ate remarkably high blood pressures for prolonged periods of time. Moreover, it should be pointed out that the benign nature of low renin essential hypertension is similar to the usually benign nature of primary aldosteronism [l-3], another condition in which renin is similarly suppressed

C45,W. In contrast, the high incidence of cardiovascu-

lar complications among hypertensive patients with normal or high renin activity is in keeping

with the vasculotoxic effects of renin which have already been discussed as a mechanism of the severe vasculitis in human malignant hypertension. Implications for Etiology. The various abnormal hormonal patterns observed suggest nonhomogeneity of the patients and underline the possi-

bility that multiple etiologies exist among patients heretofore classified under the umbrella of benign essential hypertension. Further study is certainly required especially in the minor categories in which very few patients have been identified. Those patients with normal renin and normal aldosterone levels may become the group for whom the term essential hypertension will survive. Diagnostic and Therapeutic Implications. These results indicating biochemical nonhomogeneity of the essential hypertensive population may have implications for patient management if they can be confirmed in larger series. First of all, because it has prognostic value, plasma renin activity may help to determine the urgency of antihypertensive therapy. Accordingly, early application of antihypertensive therapy may not be appropriate for patients with low renin activity whereas such treat-

ment should be most aggressively applied in essential hypertensive patients with high renin activity. Secondly, further understanding of drug action may permit the selected use of antihypertensive agents which can control abnormalities in renin secretion.

Hypertensive Diseases Exhibiting Inconsistent or Still Uncertain Abnormalities in Renin and Aldo- sterone

Renal Vascular Hypertension. Following the clas- sic experiment of Goldblatt et al. in 1934 [SS]

646

and the demonstration of the pressor agent renin in the renal venous blood of ischemic kidneys [59], it has often been assumed that this agent is the cause of experimental Goldblatt hypertension and its naturally occurring counterparts in man. However, numerous studies of established renovascular hypertension in animals and in man have demonstrated normal or even low plasma renin [6,17,25,60], angiotensin [61-631 and aldosterone [12] levels. In addition, active or pas- sive immunization of animals against the effects of angiotensin II has often failed to prevent or correct the hypertension [64,65].

One possible reason for these inconsistencies has perhaps been the failure to appreciate that there may be more than one mechanism for renal hypertension. Experimental renal hypertension induced by ischemia of one kidney with the contralateral one untouched differs from that in which

the opposite kidney has been removed. The former model exhibits a higher plasma renin [66] and a lower total body sodium [67] level than the latter. That these findings are pathogenetically meaningful is suggested by recent studies in which endogenous angiotensin II was blocked either by acute antibody injection [68] or by infusion of specific peptide inhibitors [68,69]. Both approaches lowered the blood pressure of the two kidney type to normal but had no effect in the one kidney model. Therefore, it appears that the renin-angiotensin system might have a causal role in the two kidney form but does not seem to be involved in one kidney renal hypertension. The results of all these animal studies suggest that two different mechanisms may be involved in the development and maintenance of experimental renal hypertension.

Such different ‘mechanisms should be considered in the analysis and evaluation of human renovascular hypertension, especially since no clear-cut evide’nce has been provided that renin is the only or the consummate,cause of this condition. Accord- ingly, although an elevated peripheral plasma renin

level supports the possibility of a Goldblatt mechanism, a normal or low plasma renin level can also occur in this condition so that this finding per se cannot rule out the diagnosis. Therefore, the measurement of peripheral plasma renin activity has been of limited usefulness as a screening procedure for curable renovascular hypertension 1701.

However, based on the evidence that circulating renin is more apt to be released from the ischemic kidney, evaluation of renin activity in the venous effluent of both kidneys has gained wide usage. A ratio in renal vein renins of 1.5 to 2.0 between the


RENIN, ANGIOTENSIN AND ALDOSTERONE SYSTEM IN HYPERTENSION - LARAGH ET AL

involved and uninvolved side is considered to pre-

dict curability [71-731. A,lthough this approach

has improved the accuracy of predicting surgical

curability, it is clear that not all patients with subsequent cure have exhibited an abnormal ratio. Once again these observations suggest that factors other than renin may be causally involved.

A factor not always taken into account in differential renal vein studies is the fact that circulating

renin is not cleared by the kidney [74,75]. Hence, even if a kidney secretes no renin at all, it contin- ues to deliver into the vein approximately that which entered it from the arterial side. Therefore, arterial input should be subtracted from the renal venous renin content so that the new contribution, i.e., the renin secretion can be evaluated. In our experience, when this correction factor was applied, patients who were subsequently proved to have curable Goldblatt hypertension exhibited a more marked disparity in renin secretion between the two kidneys. Even more important, when this approach was used to analyze patients, in those subsequently cured by surgery net renin secretion from the contralateral kidney was consistently near zero. This finding emphasizes the importance of establishing that the contralateral kidney is uninvolved befo’re advising surgery. A useful

technical refinement in performing these differential renal vein studies has been to utilize a form of renin stimulation such as sodium depletion, tilting [76,77], or controlled hypotension [78] to “un- mask” unilateralization by amplifying the rate of renin release from the involved kidney.

Notwithstanding the possible usefulness of such better differential analysis of renal renin secretion, one is still bound to explain the cause of the hypertension in that significant fraction of curable patients in whom peripheral circulating

plasma renin levels are normal preoperatively. One must search for more direct and convincing evidence for a role for renin. Possibilities worthy of research include increased pressor responsiveness to normal angiotensin levels, i.e., changes in affinity af angiotensin II vascular receptors with subtle changes in sodium balance [79] and impaired metabolism of the hormones. Alternatively, one must also face the real possibility that renin and angiotensin are not crucially involved in causing renovascular hypertension. Unilateral and Bilateral Renal Parenchymal Dis- eases. The situation with respect to unilateral intrarenal diseases and their relationship to hypertension is even less clear. An earlier review of the experience of this area by Homer Smith [80] revealed most disappointing cure rates. There has

Volume 52, May 1972

been little reason to change this impression. in

this category are included such diverse conditions

as pyelonephritis, renal atrophy, infarcts, cysts,

tumors, granulomatous diseases such as tubercu- losis, stones and hydronephrosis. The heterogene- ity of these conditions makes the development of diagnostic criteria to predict cure especially difficult. Accordingly, renal vein renin studies have all too often failed to show unilateralization. Although our understanding of these conditions remains in- complete and ill defined, it does seem that when

severe or malignant hypertension occurs, in this group too, differential renal vein renin determina-

tions may be useful for establishing the extent to which one or both sides are involved and estimat-

ing surgical potential. Further study of this heterogeneous group may identify specific intrarenal le- sions which are associated with increased renin

secretion. Similarly, there is little information about the

role of the renal-adrenal axis in bilateral renal parenchymal diseases. However, it is theoretically possible that changes in plasma renin activity could prove useful for following variations in activity of the disease processes, especially in immu- nologically based disorders associated with vascu-

litis. End Stage Kidney Diseases. In contrast to the heterogeneous group with unilateral or bilateral renal parenchymal diseases without marked renal failure, in end stage renal disease the contribution of the renal factor to the hypertensive process has been clarified by the experience with bilateral ne-

phrectomy. In a majority of hypertensive patients with chronic renal failure, regular dialysis satis- factorily controls hypertension [81]. This control is paralleled by decreases in total exchangeable sodium, extracellular fluid volume and cardiac output [82,87]. In this group, plasma renin activity

may be normal or even low [83,84]. However, in a small fraction of patients, dialysis

fails to reduce the blood pressure and it even ac- celerates the hypertension. This “uncontrollable” form of hypertension is characterized by a sometimes markedly increased plasma renin activity, angiotensin II and aldosterone [83,85-871, by a high total peripheral resistance and by small extra-

cellular volume changes causing drastic changes in blood pressure. Most of these abnormalities are corrected by bilateral nephrectomy suggesting that the kidney may be responsible for this intractable hypertension. In this particular group, demonstration of an elevated plasma renin activity has proved to be a useful guide for advising total nephrectomy.

647


TABLE I Angiotensin II Generation in Hypertensive Vascular Disease

Low Plasma Renin Activity Normal Plasma Renin Activity

A. Aldosteronism

1. Primary

2. Pseudoprimary

3. Tertiary? 1221

4. Glucocorticoid suppressible [88]

B. Mineralocorticoidism

1. ll-beta hydroxylase deficiency [89]

2. 17-alpha hydroxylase deficiency (90-921

3. Adrenal carcinoma

4. Ectopic ACTH-secreting tumors

5. Excess 18-OH DOC? [93]

C. No clearly demonstrable

adrenal-cortical disease

1. Low renin essential hypertension

2. Parenchymal renal disease*

3. Liddle’s syndrome [94]

4. Gordon’s hyperkalemic patient [95]

5. latrogenic: mineralocorticoid or

licorice ingestion

A. Normal aldosterone secretion

1. Normal renin essential

hypertension

2. Unilateral renal disease*

3. Bilateral renal vascular

or parenchymal disease*

4. Cushing’s syndrome

5. Coarctation of the aorta

6. Pheochromocytoma

High Plasma Renin Activity _~_ _.__

A. Secondary aldosteronism

1. Malignant or severe hypertension

2. Unilateral renal disease with

severe hypertension

3. Bilateral renal vascular or

parenchymal disease*

4. High renin essential hypertension

5. Renin-secreting kidney tumors [96]

6. latrogenic: oral contraceptive use

B. Without secondary aldosteronism

1. Potassium depleted patients with

above disorders

--. * Note that patients with parenchymal or renal vascular (unilateral or bilateral) disease may exhibit low, normal or high circu-

lating plasma renin activity.

A Physiologic Classification of Plasma Renin Ac-

tivity in Hypertensive Diseases. In Table I the spectrum of hypertensive disorders is summarized according to plasma renin activity, and then these conditions are subclassified depending on their associated adrenal cortical behavior. Those conditions for which references are cited have not been

discussed since they are either extremely rare or still subject to taxonomic doubts. The clinical nuances of these rare disorders can be obtained from the sources cited.

The normal interaction between renin activity

and aldosterone secretion provides a physiologic

basis for this classification. Accordingly, low plasma renin levels may be induced by antecedent adrenal overactivity and, conversely, high plasma renin levels usually lead to a secondary adrenal overactivity. However, that adrenal overactivity is probably not the only cause for suppressed plasma

TABLE II Antihypertensive Drugs-Pharmacology of Renin Stimulation and Suppression

____- Renin Inhibitors Renin Stimulators

____

Propranolol [97,105] Aldosterone antagonists [102]

Clonidine [98,99] Other diuretics [103,104]

Methyl DOPA [loo] Vasodilators:

Reserpine Nitroprusside [78]

Ganglionic blockers [loll Diazoxide [106]

Guanethidine (?) Hydralazine [107] Guancydine [lOS]

renin activity is well exemplified by the large popu-

lation of patients with low’renin essential hypertension. Another point illustrated by the tabulation is that patients with chronic kidney disease can fall into any one of the three categories. The Renal-Adrenal Axis in Therapeutic Strategy: A Look at the Future. The data here presented de-

scribe the present state of our knowledge of the renal-adrenal axis with respect to its involvement in hypertensive vascular disease, The analysis is by no means intended to exclude the possibly vital participation of other neural, humoral or local tis- sue mechanisms in the pathogenesis of these con-

ditions. However, it does appear that an understanding

of the behavior of renin and aldosterone can provide a basis for specific diagnosis at least in certain forms of renal and adrenal hypertension. The experience further suggests that biochemical pro- filing of patients with respect to the kidney and adrenal hormones may have a broad application in classifying patients with so-called essential hypertension. This information could also prove helpful in determining prognosis and planning therapy for these patients.

It is already known from scattered reports that some antihypertensive drugs increase plasma renin activity whereas others ‘markedly reduce it (Table II). It therefore seems possible that in the application of these drugs in treatment, the selec-


tion of agents that can cortect renin abnormalities

might produce a nore satisfactory blood pressure response and a Letter prognosis. This potentially

promising approai:h could cevelop criteria for more rational drug ther-apy, specifically tailored to correct a particular .3bnormal biochemical profile. In this regard! in a recent study the striking suppression of renin secretion by propranolol was used diagnostically and therapeutically to advantage in renovascular and other renin forms of high blood

pressure [105]. Thus, it might turn out to be possible pharmacologically to mimic the physiologic. naturally occurring protective response that patients with low renin levels are fortunate enough to be able to muster unaided.

It is apparent that diuretics, the mainstay of therapy, usually produce in short-term periods of

observatron_ :lety striking increases II! plasma

rerrirj actrvctj. However, there IS inadequate infor-

mat:c:n aborit the effects of their protracted admin-

istration on reni I and aldosterone secretion. Diu- retie-tnducec hyperreninemia might be undesirable in view of the possible relationship between plasma renin activity and the development of strokes and heart attacks. However, since the vasculotoxic ef-

fects of renin appear to be sodium dependent, the volume depletion associated with diuretic therapy may vitiate or eliminate this hazard. Furthermore, there is also little information about long-term ef-

fects of those antihypertensive drugs known to lower renin levels acutely, and combination drug therapy requires similar long-term studies. All these possibilities should intrigue inquiring physicians.

RENIN, ANGIOTENSIN AND ALDOSTERONE SYSTEM IN HYPERTENSION -- LAHAGH ET AL.

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2. Laragh JH, Angers M, Kelly WG, Lieberman S: Hy- potensive agents and pressor substances. The effect of epinephrine, norepinephrine, angiotensin II and others on the secretory rate of ald’osterone in man. JAMA 174: 234, 1960.

3. Laragh JH: The rol’e of aldosterone in man: evidence for regulation ‘of electrolyte balance and arterial pressure by ‘renal-adrenal system which may be involved in malignant hypertension. JAMA 174: 293, 1960.

4. Laragh JH, Cannon PJ, Ames RP: Aldosterone secretion and various forms of hypertensive vascular disease. Ann Intern Med 59: 117, 1963.

5. Conn JW: Plasma renin activity in primary aldosteronism. Importance in differential diagnosis and in research o’f essential hypertension. JAMA 190: 134, 1964.

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