Recent advances in hypertension

Combined

Staff

Recent

Clinic

Advances

in

Hypertension*

HESE are stenotyped reports of Combined Staff Clinics of the College of Physicians and Surgeons, Columbia University, and the Presbyterian Hospital, New York . The clinics, designed to integrate basic mechanisms of disease with problems of diagnosis and treatment, are conducted under the auspices of the Department of Medicine. The reports are edited by Dr . Nicholas P . Christy . DR . JOHN H . LARAGH : Since the time of Richard Bright the problem of the nature and mechanisms of high blood pressure has intrigued medical scholars, and a great body of information on this subject has been collected . In this institution interest in hypertensive vascular disease has been long and continuous . The Hypertension and Nephritis Clinic of the Vanderbilt Clinic, organized in 1923, is perhaps the oldest of its kind in this country . It has provided data for description of the long-term natural history of the untreated disease . The activities of Drs. Dana W . Atchley, Robert F . Loeb, David Seegal, George A . Perera, Marcel Goldenberg and Stanley E . Bradley and their associates have resulted over the years in a number of studies on the nature and pathogenesis of hypertension .

pathologic features . However, it certainly remains possible that within this large group there may be multiple, as yet unidentified, etiologies . Personally, I believe that the term "primary hypertension" may be misleading because it implies (1) that the elevated blood pressure in essential hypertension is the primary or initiating event and (2) that this large population, separated by exclusion, is nonetheless homogeneous . An additional problem in classification and study arises from the fact that the onset of essential hypertension is insidious . When first identified it is often accompanied by still occult cardiac, cerebral and renal complications . Therefore, it is often difficult to be sure whether an observed abnormality is an expression of the primary process or a complicating event . As indicated, the cardinal physiologic feature of essential hypertension is an increase in the total peripheral resistance, as calculated indirectly from measurements of arterial pressure and total flow (cardiac output) . The increased peripheral resistance is generally considered to be the result of generalized arteriolar constriction, which to a large extent is functional, as evidenced by its reversibility by various drugs and procedures, and by the wide spontaneous fluctuations in blood pressure and vasomotor instability so often observed in these patients . In recent years a number of investigators have reported that a significant fraction, perhaps onefourth or so, of hypertensive patients do not have increased peripheral resistance . The elevated blood pressure in this group appears to be due to an increased cardiac output . Whether the condition in this group represents an earlier stage of the same disease or a separate entity remains to be determined . Patients with early hypertensive disease do

CHARACTERISTICS OF ESSENTIAL HYPERTENSION Let us first consider some of the characteristics of what is called primary or benign essential hypertension . (Table I .) This diagnosis is always made by exclusion because as yet no pathognomonic biochemical abnormality has been identified . In making this diagnosis it is therefore incumbent on the physician first to rule out secondary hypertension. This term refers to all instances of hypertension for which a cause can be designated . The secondary group appears to account for about 10 per cent of the hypertensive population . It includes such conditions as renal or adrenal disease, nervous system disorders and coarctation of the aorta . After secondary hypertension has been excluded, there remain a large category of patients with high blood pressure, perhaps constituting about 10 per cent of the entire adult population . Essential or primary hypertension presents a number of seemingly characteristic genetic, clinical, physiologic and " Much of the work reported here was supported by Grants HE-01275 and HE-05741, from the National Institutes of Health and by the Fleitas Fund . AMERICAN JOURNAL OF MEDICINE 616



Recent Advances in Hypertension not demonstrate any clearcut abnormalities in regional blood flow, although some investigators claim to have demonstrated an increased flow in muscle and a reduced flow in skin . The earliest convincing changes appear to occur in the kidney . A reduction in renal blood flow, that is renal vasoconstriction, may be considered to be the earliest established physiologic change in the course of the disease . The renal changes will be discussed subsequently .

TABLE I SOME CHARACTERISTICS OF ESSENTIAL HYPERTENSION

1. 2.

3. 4. 5. 6. 7.

NATURAL HISTORY

Contrary to a popular notion, untreated essential hypertension has a rather long course . In the studies of Dr . George A . Perera [1] in this clinic, five hundred patients were followed, 150 from before the onset of hypertension until death, and another 350 from an uncomplicated phase until death . The results of the study indicate that in untreated patients the mean life span from the time of onset is twenty years . In this group it was observed that the height of the casually obtained blood pressure had little prognostic value . At times, patients with marked elevations in blood pressure survived for more than thirty-five years . The disease could be divided into an uncomplicated phase lasting about fifteen years, followed by a phase in which organ complications, largely arteriosclerotic and atherosclerotic, become apparent . Complications could be broken down in this way : cardiac 74 per cent, renal 42 per cent and retinal 32 per cent . More than half of the subjects died of heart disease, most often congestive heart failure, 10 to 15 per cent died of cerebral accidents, and about 10 per cent died of renal failure . Malignant hypertension occurred in less than 5 per cent . A study of this sort is important not only because it may furnish clues to etiology and pathogenesis, but also because it provides a yardstick with which to determine prognosis and the true value of a particular therapy . It indicates that until patients have been treated with the same regimen for a long time-up to twenty years-it may be difficult to evaluate the merit of a given mode of therapy . ETIOLOGIC FACTORS

Let us review briefly some of the suspected pathogenetic mechanisms and theories of causation of essential hypertension . These ideas are not necessarily presented in the order of credibility . VOL .

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1965

617

8. 9. 10 .

No known cause Diastolic pressure repeatedly > 90 mm . Hg Pulse pressure nearly always increased 'Total peripheral resistance usually increased Cardiac output most often normal-may he elevated early in the disease Cardiac work increased Normal blood flow to most regions ; diminished renal and skin blood flow and increased muscle How may occur with the passage of time Total plasma volume normal-distributional changes? Hyper-reactive to stress? Abnormal vascular reactivity? Faulty circulatory homeostasis? Altered renal physiology with accelerated natriuresis

Genetic Mechanisms . It has long been recognized that there is a strong hereditary predisposition to the development of the disease . For example, in a series studied by Platt [Z], 40 per cent of the siblings of patients with severe essential hypertension had diastolic pressures above 110 mm . Hg . However, there is a great debate about the nature of the genetic abnormality. While Platt believes that a single dominant gene determines the presence or absence of the disease, Pickering [3] holds to the rather interesting view that essential hypertension is a quantitative deviation rather than a qualitatively unique entity. Accordingly, hypertensive patients represent that fraction of the population at the upper range of a Gaussian distribution curve . Pickering believes that the inheritance of this characteristic is polygenic and that its expression also depends on environmental factors . Psychologic

and

Neurogenic

Mechanisms .

A

popular view in the Russian literature is that hypertension develops as a Pavlovian-conditioned persistent alarm reaction on the part of the vasomotor system . Brod and his associates [4], thinking along the same lines, report that hypertensive patients respond to noxious stimuli or psychic trauma with visceral and skin vasoconstriction and increased flow in muscle, a pattern resembling that of exercise . This group believes that this response is an abnormal conditioned reflex beginning in the central nervous system . Nearly all students of the disease implicate the nervous system in some way in pathogenesis . Thus the beneficial effects of tranquillizers,

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Combined Staff Clinic

anesthetics, autonomic blocking agents and of sympathectomy are well recognized . In experimental animals, Dock et al . [5] have claimed that pithing of the brain could correct Goldblatt hypertension . Heymans and associates [6], as a result of their classic studies of the carotid sinus and aortic body in blood pressure regulation, at one time proposed that increased distensibility of the carotid baroreceptors might cause hypertension . More recently, McCubbin, Green and Page [7] have suggested that there is a resetting of baroreceptor activity in hypertension . However, the human counterpart of buffer nerve hypertension has not been observed and, despite extensive investigations, the exact role of the nervous system in the human disease remains obscure . Changes in Capacity of Vessels and Increased Cardiac Output . Ledingham [8], Floyer and Wilson have collected evidence to suggest the importance of an altered relationship between blood volume and vascular tone in the production of experimental renal hypertension . The thesis is based partly on studies of the sequence of the hemodynamic changes which follow renal artery occlusion . The initial event is an increase in cardiac output, followed only later by increased peripheral resistance . A primary increase in myocardial contractility or an increase in venous tone has been suggested as mechanisms involved in the early increase in cardiac output, which is thought to set in motion a chain of events finally leading to a myogenic arteriolar response and sustained increase in peripheral resistance with return of the cardiac output to normal. These findings may have relevance to the human disease because, as already noted, hypertensive patients may exhibit an increased cardiac output early in their disease . However, in a recent study in dogs, Olmsted and Page (Circ . Res ., 16 : 134, 1965) have been unable to confirm the finding of a raised cardiac output in early experimental renal hypertension . Reaction to an Impaired Renal Capacity to Excrete Salt. Borst [9] has been able to produce sustained hypertension by protracted administration of sodium-retaining mineralocorticoids to normal subjects . He believes that the renal sodium retention, with increased central venous pressure and increased cardiac output, ultimately leads to arterial hypertension as a device for maintaining salt balance in the presence of the induced increased renal tubular reabsorption . However, such an increased sodium re-

absorption has not been clearly defined in spontaneous hypertensive disease . Excessive Dietary Sodium . Meneely and Dahl [10] believe that chronic ingestion of excessive sodium chloride is an important causative factor in human hypertension . Support for this emerges from a large body of circumstantial evidence suggesting an increased prevalence of hypertension in communities in which salt consumption is high, and from some interesting animal experiments . Dahl and his co-workers [11] have been able to breed selectively two strains of rats, one of which is resistant and the other sensitive to the development of salt-induced hypertension . There is no doubt that in the human disease sodium deprivation is, at times, quite beneficial . However, this possibly important relationship is still poorly understood . Hypertensive patients usually have normal total body sodium and potassium levels . Electrolyte Changes in the Arterioles . The arterioles of hypertensive animals and human beings have been reported to contain increased amounts of water, sodium and potassium . Because of this, Tobian [12] has proposed that waterlogging of arterioles may cause increased peripheral resistance . Much more work must be carried out to confirm and define this idea . Friedman [13] and others have presented considerable evidence that the intracellular to extracellular sodium concentration ratio of arteriolar smooth muscle is an important determinant of arteriolar tone, derangement of which may be involved in hypertensive disease . However, other investigators [ 14] have not been able to demonstrate a specific effect of the sodium ion on vascular tone . Mosaic Theory . Page [15] believes that no single factor can be held responsible for hypertension . His mosaic theory proposes that blood pressure is determined by many factors operating in constant chemical equilibrium to serve the changing requirements of the tissues for blood . Thus, while blood pressure remains stable, the mechanisms maintaining it change constantly as local vasomotor and chemical mechanisms interact with neural and hormonal factors . Resetting of baroreceptors and the interaction of angiotensin with the autonomic nervous system are examples set forth by Page's group . A Generalized Arteriolar Vasoconstriction in Which the Renal Vessels Participate . Early studies by Goldring and his associates [16,17] characterized the generalized increased arteriolar AMERICAN JOURNAL OF MEDICINE



Recent Advances in Hypertension constriction of hypertension and indicated that renal blood flow was normal early in the course of the disease . Their studies suggested that the renal ischemia which develops is a sequel to the initial hypertensive process . Pathologic studies also have indicated that no renal abnormality is demonstrable early in the disease . Because of such findings, most investigators currently hold to the view that the generalized vasoconstriction of hypertensive patients precedes and perhaps induces the vascular disease . Goldblatt [18] holds to the opposite view, that a vascular disease of the renal vessels precedes and causes the hypertension . In this regard, it should be noted that Baldwen, Gombas and Chasis (Am . J . Med., 38 : 864, 1965) have more recently presented physiologic evidence of a primary renal defect in sodium reabsorption and concentrating power in essential hypertension . Renal Causation : The Goldblatt Thesis. Although majority opinion favors an extrarenal origin for essential hypertension, the kidney continues to hold a key position in any discussion of etiology . This has been true ever since 1934 when Goldblatt and his associates reported their famous experiment . Goldblatt continues to believe [18] that in man the disease arises from a mechanism similar to that in his dogs ; he has presented some cogent arguments to support this idea . In contrast to other workers, Goldblatt does not believe that the characteristic lesion of human arteriolosclerosis can occur as a result of an elevated arterial pressure [79] . He cites his own experimental dogs in which sustained renal hypertension for up to eight years has failed to induce arteriolar lesions . ALTERED RENAL PHYSIOLOGY OF HYPERTENSION

In view of the possibly important role of the kidney in the pathogenesis of hypertension, at this point it is worth reviewing in a little more detail the renal physiologic changes which have been associated with the condition . Studies of Dr . Bradley's group [201, in which renal vein catheterization was used, indicated that the early physiologic lesion of essential hypertension is primarily vascular, presumably resulting from afferent and efferent arteriolar vasoconstriction . Blood may be diverted away from some nephrons, but the function of the parenchymal cells remains intact as indicated by normal para-aminohippurate (PAH) extraction . In contrast, in malignant hypertension there is VOL .

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619

evidence of gross parenchymal cell dysfunction together with actual hyperemia of both the surviving and nonfunctioning nephrons . In addition to these hemodynamic changes, two types of abnormalities in the renal handling of sodium chloride should be mentioned : (1) Accelerated natriuresis of hypertension : It is well recognized that patients with hypertension respond to saline solution and other types of infusions with an early, abnormally rapid natriuresis . The phenomenon is not specific for essential hypertension . It occurs in practically all hypertensive diseases and can be produced in normal subjects by raising blood pressure levels with metaraminol . Some believe that it is due to a reduced venous capacity so that the intravenous infusions cause an inordinate increase in cardiac output [21] . The abnormality can he corrected by hypotensive therapy and may be blunted somewhat by a low sodium diet . (2) The reduced sodium excretion of renal artery occlusion : The studies of White and his group [22], and others, have established the fact that even slight occlusion of a renal artery leads to reduced salt and water excretion . Howard [23] was the first to associate this phenomenon with the presence of hypertension due to unilateral renal artery stenosis . Differential clearance tests such as the Howard test have proved of value in identifying patients with Goldblatt hypertension involving only one kidney . Abnormalities are detected in these tests by evaluating the differences between the two kidneys in respect to salt and water excretion . In patients with hypertension associated with some involvement of both kidneys such a defect could be present bilaterally and would escape detection by present methods . The arterial hypertension' might act as a compensation for such a defect . ROLE OF THE ADRENAL CORTEX : AN ELECTROLYTE, KIDNEY AND ADRENAL INTERACTION

With this general background let us consider the role of the adrenal cortex in human arterial hypertension . Involvement of the adrenal cortex has long been suspected because of the effects of dietary sodium, because hypertension can be induced in animals by the administration of adrenal steroids and because Goldblatt hypertension can be corrected by adrenalectomy . Shortly after the isolation and chemical characterization of aldosterone, reports appeared in the literature suggesting that an in-



620

Combined Staff Clinic TABLE II CLINICAL FEATURES IN SIX FATAL CASES OF MALIGNANT HYPERTENSION

Hypertension Case No .

1 2 3 4 5 6

Age (yr . ) and Sex

57, M 48, M - 53, M 42, F 44, F 46, F

'

Blood (mEq ./L .)

Degree (mm . Hg)

Duration (yr .)

Sodium

Potassium

Bicarbonate

Chlo-

250/150 280/160 220/130 250/160 250/150 250/160

20 3 4 5 15 12

138 135 132 140 141 126

3 .2 3 .7 3 .6 4 .1 3 .2 3 .9

34 26 30 27 28 27

92 95 92 95 101 80

creased urinary excretion of aldosterone occurred in essential hypertension and might be involved in its pathogenesis . This view has not been supported by work in this laboratory . Aldosterone is present in such minute amounts in the body-its blood level is roughly onethousandth that of cortisol-that new methods using different approaches had to be developed to define its role not only in hypertension but also in normal man . In our own studies [24] we have employed an isotope dilution technic which precisely measures the amount of aldosterone actually secreted by the adrenal cortex . The method, which we continue to modify in technical detail, is independent of variations in the rate of hepatic inactivation or of renal clearance of the steroid . In practice, it entails the injection of a tracer amount of tritiated aldosterone intravenously, collection of the subsequent 24-hour urine specimen, and isolation in pure form of a doubly-labeled C 14 acetate of the urinary product . The specific activity of the urinary product can be determined from its H 3 to C14 ratio and from this the adrenal secretory rate is calculated . Aldosterone Secretion in Essential Hypertension.

When this method was applied to the study of patients with essential hypertension, aldosterone metabolism was found to be entirely normal . Control aldosterone secretory rates were normal, and under conditions of controlled metabolism (i .e ., balance conditions) these patients responded to sodium deprivation with the expected increase in aldosterone secretion . Furthermore, potassium administration promptly increased aldosterone secretion [25] . This latter observation confirmed the results of our earlier investigation of the effect of potassium in normal

ride

Urine Blood Urea Volume Sodium (mg . %) (ml ./ (mEq,/ day) L. day) 40 71 37 45 47 78

3,300 3,040 1,920 1,500 1,400 1,600

79 53 101 43 51 42

dogs . In a large number of studies it has not been possible to find any abnormality in aldosterone metabolism in patients with uncomplicated benign essential hypertension . Patients with intermediate forms and stages of hypertensive disease exhibited a mixed pattern ; some had normal and some had high aldosterone secretory rates . Further examination of this less homogeneous group is required because it is difficult to establish how much the various complications of the disease contributed to the results . Aldosteronism of Malignant Hypertension . In malignant hypertension the picture is quite different. Studies in this laboratory have revealed that oversecretion of aldosterone is practically always present in this condition . Parallel studies of these patients also indicated a strikingly high incidence of hypokalemic alkalosis, even though renal insufficiency was common in this group . This alkalosis may be taken as further evidence of the presence of aldosteronism in accelerated phase hypertension . (Table it .) Metabolic balance studies of patients with malignant hypertension have shown that the abnormally high secretory rates observed do not fluctuate readily with changes in the dietary salt, as they do in normal subjects . However, potassium administration remains a potent stimulus in these patients ; small dietary supplements of potassium often double the already high rates of adrenal secretion . Further study is required to clarify the meaning of this abnormal adrenal cortical behavior . In Table it the clinical features in six fatal cases of malignant hypertension are presented . The syndrome developed as a complication of long-standing hypertensive disease . The urinary AMERICAN JOURNAL OF MEDICINE



621

Recent Advances in Hypertension Increments- . .. ALDOSTERONE CORT. SEC . EXC.• SEC . mgIdey fig . /day 24 120 1200 0 0 20

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Fin. 1 . Dose-response relationship of angiotensin on aldosterone and cortisol secretion in normal subjects (semilogarithmic plot) . The findings indicate that a nearly maximal stimulation of aldosterone secretion can be produced by doses of angiotensin well below 0 .5 µg . per minute . In contrast, stimulation of cortisol secretion appeared to begin at this dosage, but at times it did not become maximal until two to four times this amount was infused . (Cort . = cortisol, sec . secretion, exc . = excretion .) From Ames, R . P ., Borkowski, A . J ., Sicinski, A . M .

and Laragh,

J . H. J. Clin. Invest., 44 : 1171, 1965 [27] .

sodium values indicate a capacity to excrete sodium freely and further argue against heart failure as a major factor . Despite the renal failure, there was a definite tendency to extracellular alkalosis. All patients exhibited marked oversecretion of aldosterone . Autopsy revealed necrotizing arteriolitis in all but one of the six . Adrenal weights were at the upper limits of normal, but there were no adrenal tumors. This suggests that adrenal hyperfunction was bilateral and was probably the result of stimulation of both adrenal glands from a source extraneous to them . Angiotensin-a Stimulus to Aldosterone Secretion.

Because of these observations, and because renal damage is the cardinal feature of malignant hypertension, it was decided to investigate the effect of the renal pressor substance, angiotensin, on aldosterone secretion [26] . This seemed a promising line of study because we had observed a few patients with malignant hypertension due to unilateral renal disease in whom removal of the offending kidney resulted in cure of the hypertensive disease [26] . At the same time, the high aldosterone secretion rates returned to normal . It was possible to demonstrate that when van . 39,

OCTOBER

1965

given as an intravenous infusion, angiotensin is a potent and selective stimulus for increasing aldosterone secretion in normal subjects [26,27] . (Fig . 1 .) A variety of other pressor agents did not produce this effect . The stimulating effect of angiotensin can be demonstrated at a lower, mildly pressor dosage, and can occur selectively, i .e., without an associated increase in cortisol secretion [27] . At about the time of our first report it was independently shown that angiotension infusion also increased urinary excretion of aldosterone in man [ .31] . Subsequently, the effect of angiotensin on aldosterone secretion was additionally characterized in animal studies employing direct adrenal perfusion . A Renal-Adrenal Hormonal interaction Which liar Become Deranged in Malignant Hypertension . These

findings led to the proposal [28] that there may be a renal-adrenal hormonal interaction for the normal control of sodium balance which is deranged in malignant hypertensive disease . By this type of feedback mechanism, renin, normally released when renal perfusion is threatened, generates angiotensin. Angiotensin stimulates increased aldosterone secretion . Aldosterone causes renal sodium and water retention,



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Combined Staff Clinic

thus compensating renal perfusion and shutting off renin release . In malignant hypertension, the severe renal damage may be supposed to cause a continual inappropriate release of renin and angiostensin, leading to sustained oversecretion of aldosterone . Coexistence of high levels of angiotensin and aldosterone in the blood might then be implicated in the production of the characteristic necrotizing vasculitis . A vicious circle could develop in which more renal damage would lead to more renin release, more aldosterone, and then more renal damage, accounting for the accelerated pace of the disorder . With this hypothesis, it is also possible to account for the benign nature of the hypertension that characterizes primary hyperaldosteronism because here, in the absence of primary renal damage, renal renin would be suppressed by the increased adrenal hormone, and no vascular damage would occur . Time does not permit full review of a body of other evidence which now supports the existence of such a renal-adrenal interaction . It should be noted, however, that animal experiments indicate that there is an inverse relationship between renal renin content and both dietary salt and mineralocorticoid activity . It has also been shown recently that sodium depletion in normal man may induce increased renin activity in the blood . The exact role of renin and angiotensin in malignant hypertension is still unsettled because of the conflicting results in measurement of these substances in various laboratories . However, the early work of Kahn et al . [29], which demonstrated angiotensinemia in malignant hypertension, would seem to support the hypothesis herein presented . Furthermore, other studies indicate that in rats the simultaneous administration of angiotensin and either desoxycorticosterone or aldosterone produces severe fatal vasculitis [30] . These agents alone do not produce these vascular changes . Present Status of Renal-Adrenal Interaction for Normal Control of Salt Balance and Arterial Pressure .

In additional studies it has been possible to show that angiotensin fulfills the characteristics of a trophic hormone for aldosterone secretion because (1) it stimulates aldosterone when given in mildly pressor dosages ; (2) the stimulation occurs selectively, without also eliciting hydrocortisone secretion ; and (3) stimulation occurs as long as the stimulus is applied, for up to

eleven days of an angiotensin infusion . Of particular importance is the observation that the pressor activity of angiotensin is directly related to sodium balance . With prolonged infusion, angiotensin-aldosterone-induced sodium retention is associated with increasing pressor sensitivity so that a smaller amount of the drug is required to maintain a pressor response . Finally, after three to five days, escape from further salt retention occurs . (Fig. 2 .) This sequence suggests an internally controlled feedback mechanism for the hormonal interaction built around the state of sodium retention and arterial pressure [27] . In this system, as sodium balance is restored and arterial pressure rises, less and less hormonal pressor activity is needed . Teleologically, too, the three potent actions of angiotensin (on blood pressure, on renal salt excretion and on aldosterone secretion) all seem designed to protect us from salt loss or arterial hypotension . As attractive as this hypothesis is, it still does not seem to explain all the facts . Thus, we still do not understand the paradoxical angiotensin natriuresis observed in cirrhosis [79] nor can we explain the potent stimulating effect of potassium on aldosterone [32] in terms of this proposed mechanism . Studies of this problem are still handicapped by the lack of specific methods for measuring renin and angiotensin in blood . Angiotensin and Aldosterone in Essential Hypertension . Since aldosterone secretion is normal

in essential hypertension, and since most studies of renin and angiotensin in this disease have yielded negative results, it seems unlikely that these hormones are involved, but this possibility is not excluded even though all measurements are normal . This possibility was suggested by studies involving the prolonged infusion of angiotensin [27] . (Fig . 2 .) As the infusion progresses, angiotensin-induced sodium retention leads to a progressive increase in pressor sensitivity, so that small and diminishing doses of angiotensin, which ultimately become insufficient to stimulate aldosterone secretion, can maintain the hypertensive state . These observations imply that sodium retention can modify the vascular sensitivity to a normal amount of angiotensin. They indicate that the state of sodium balance is a critical determinant of the activity of this hormonal system . This interaction between angiotensin and available (presumably intravascular) sodium ions to determine vascular AMERICAN JOURNAL OF MEDICINE



Recent Advances in Hypertension

Two Hypertensive States Definitely Associated with Increased Aldosterone Secretion . To summarize, at

between the two clinically . Thus, primary aldosteronism is the expression of a spontaneous increase in aldosterone secretion in an otherwise healthy subject . It is usually a benign disorder of long duration characterized by symptoms of potassium wastage and mild hypertension . All this is corrected by removing the offending



adrenal adenoma . On the other hand, malignant hypertension is characterized by severe hypertension, neurorctinopathy and evidence of advancing renal damage . Pathologically, there is necrotizing arteriolitis and adrenal tumors are characteristically absent .

While the differentiation between these two syndromes in their classic form is not difficult, a diagnostic problem can arise because occasionally a patient with primary aldosteronism may present with severe hypertension, and also because patients with renal hypertension or premalignant hypertension may exhibit signs of aldosteronism (e .g ., hypokalemic alkalosis) . In these special situations it is obviously important to determine whether the aldosteronism is the result of adrenal or of renal disease . If it is of renal origin, it must further be determined whether it results from unilateral or bilateral renal disease before appropriate surgical or medical therapy can be applied . There is no simple answer yet . Blood renin levels might be expected to he high in renal disease and low in primary adrenal oversecretion . A variety of other diagnostic tests, including angiography, may help in these cases . Some of these approaches will be amplified in the course of the discussion which follows . With this introduction to the general problem, Dr . Cannon will present in more detail some of the problems we now face experimentally, with special reference to renal mechanisms

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the present time it appears that among hypertensive patients there are two discrete syndromes in which aldosterone overseeretion participates . These are primary aldosteronism and malignant hypertension . From the foregoing data one might expect that it would not be difficult to distinguish

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FIG . 2 . Prolonged angiotensin infusion . Two normal subjects . The subject on the left had been on a low sodium diet for several weeks before the study began . The subject on the right had been on a normal sodium intake for about the same period . In both, angiotensin was given in amounts which produced slight increases in the arterial pressure, of the order of 10 to 15 mm . Hg Systolic, In the salt-depleted subject the pressor sensitivity to angiotensin did not change during the six-day period that it was given . It continued to stimulate increased aldosterone secretion during the infusion, but there were no significant changes in electrolyte balance . In contrast, in the subject receiving a normal salt diet, angiotensin produced a positive sodium balance and with this a markedly increased pressor sensitivity developed so that at the end of an eleven-day period relatively minute doses of angiotensin were required to maintain the mild pressor response . As the angiotensin dosage was reduced, the effect on aldosterone diminished, falling back almost to the control levels . "Escape" from further renal sodium retention occurred on the fifth day . These data suggest a normal homeostatic interaction between the state of salt balance and the pressor and aldosteronestimulating effects of angiotension. From Ames, R . P ., Borkowski, A . J., Sicinski, A . M . and Laragh . J . H ., J. Clin . Invest ., 44 : 1171, 1965 [27] . and other areas now under active investigation . DR . PAUL J . CANNON : * I would like to review the current status of one line of investigation into the problem of how the kidney participates in * Career Development Awardee Institutes of Health .

of the National

6 24

Combined Staff Clinic

Flu . 3 . Juxtaglomerular apparatus in a patient with curable renovascular hypertension . The section cuts longitudinally through the afferent arteriole at the glornerular mot and transversely through the macula densa . The juxtaglomerular cells are hypertrophied and hyperplastic ; the cells of the macula densa are unduly prominent . Courtesy of Dr . Sheldon Sommers .

the pathogenesis of hypertension . This line of investigation rests on the postulate that the kidney itself elaborates a pressor agent, which in some way elevates the blood pressure . Perhaps the greatest single advance in experimental hypertension in this century was the demonstration by Goldblatt [19] that a persistent elevation of blood pressure could be induced in dogs by constricting both renal arteries or by constricting one renal artery and removing the other kidney . Goldblatt and his colleagues further showed that this type of hypertension could mimic both benign and malignant human hypertension . The elevated blood pressure appeared clearly to be caused by a humor emanating from the kidney, since nephrectomy or ligation of the renal veins would quickly abolish the elevated blood pressure . The humor that was suspected was renin, a protein with pressor properties, first extracted from normal rabbit kidney by Tigerstedt and Bergman in 1898 [33] . That adrenal or electrolyte factors contributed to the hypertension

induced by renal artery clamping was suggested by the finding that the presence of the adrenal cortex or administration of adrenal cortical extract was necessary for the induction or persistence of hypertension in these dogs . Figure 3 shows a juxtaglomerular apparatus in a kidney section from a patient with renal artery stenosis, the human counterpart of Goldblatt hypertension . Within the substance of the renal cortex the distal tubule of the nephron returns to its glomerulus of origin and nestles in the angle between the afferent and efferent arterioles ; the structures in this area collectively are termed the juxtaglomerular "complex" or "apparatus ." It comprises a specialized segment of the distal tubule known as the macula densa, the mesangial cells of the glomerular root, and specialized cells in the wall of the juxtaglomerular portion of the afferent arterioles . The latter cells, called juxtaglomerular cells, contain secretory granules the number of which fluctuate with presumed secretory activity There is hypertrophy and hyperplasia of the juxtaglomerular cells and prominence of the cells comprising the macula densa in this patient (Fig . 3) in whom hypertension was cured by nephrectomy . Work by Peart et al . [35], Cook and Pickering [36], and Bing and Wiberg [37] has localized renin to the area close to but not in theglomeruli . Recently Hartroft [38] has labeled anti-renin antibodies with fluorescein and demonstrated that the antibodies were localized on the granules within the juxtaglomerular cells . TechDies have been devised by Tobian [72], Hartroft [38] and Turgeon and Sommers [39] in which the cells which comprise the juxtaglomerular apparatus are counted, and a semiquantitative index of their granularity made . This so-called juxtaglomerular cell count, or JG index, has been considered by these workers to reflect renin activity by the kidney . In 1940 Braun-Menendez [40] and Page [41] and their respective collaborators demonstrated that renin is a proteolytic enzyme which acts upon alpha s globulin substrate in plasma to produce the polypeptide, angiotensin . Rcnin, a protein, is released into renal venous blood [42,43] and to a lesser extent into renal lymph [44] . Renin substrate, sometimes called angiotensinogen, is found only in plasma in the alpha s globulin fraction . Skeggs and his group [45] have recently demonstrated the existence of AMERICAN JOURNAL OF MEDICINE



Recent Advances in Hypertension three major and two minor forms of hog-renin substrate . All are glveoproteins with molecular weights about 57,000, with similar amino acid compositions, but with minor differences in the carbohydrate portions of the molecule . The product of the renin reaction is angiotensin T, a decapeptide . In the past decade the amino acid sequence of bovine angiotensin t was determined by Elliott and Peart [46], and that of horse angiotensin i by Skeggs and co-workers [47] . These latter workers also showed that in the plasma, angiotensin i is converted to angiotensin it, an octapeptide, by a "converting" enzyme [4 ;4] . Both the decapeptide and the octapeptide have been synthesized [49,50] . Angiotensin ii, the octapeptide, is a powerful vasoconstrictor, whereas the decapeptide has much less biological activity [43,48] . The destruction of angiotensin in the body is rapidly accomplished through the action of angiotensinase [42,51,52] . Extracts that enzymatically destroy angiotensin have been prepared from plasma, erythrocytes and many tissues . In addition, several workers have published reports in which the claim is made that angiotensinase activity of plasma may vary considerably in different disease states [53,54] . During the past thirty years various functions have been proposed for the renin-angiotensin system ; even today, however, its role in homeostasis and in disease is unclear . The various functions which have been postulated for reninangiotensin will he discussed under three headings : (1) angiotensin and blood pressure control ; (2) control of renal hemodynamicsspecifically autoregulation of renal blood flow ; and (3) maintenance of salt and water homeostasis . The literature in this area is full of conflicting data, largely because of the need to use bioassay procedures to measure any of the components of the renin-angiotensin system, and also because standard methods are not employed by more than one or two groups of investigators . Angiotensin and Blood Pressure Control . A role for angiotensin in control of blood pressure might be suspected from the fact that angiotensin is by far the most powerful pressor substance known . Molecule for molecule it is many times more active than norepinephrine in raising blood pressure [55] . It acts directly on vascular smooth muscle as a powerful vasoconstrictor. It elevates blood pressure by increasing total peripheral resistance and produces no change or a decrease in cardiac output [55,56] . Thus the VOL .

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625

hemodynatic effects of angiotensin closely mimic those of primary hypertension . If excessive amounts of angiotensin could be demonstrated in the blood of patients with renal hypertension, the role of angiotensin in the pathogenesis of this disorder would be most apparent and the diagnosis would be quite easy . However, conflicting data appear in the literature . Kahn, Skeggs and their associates [29,57] claim to have found increased angiotensin concentrations in the blood of patients with malignant hypertension, twenty times those found in control subjects . Normal to slightly elevated levels were found in essential hypertension . Morris and co-workers [58] found increased angiotensin in the arterial blood of forty-six hypertensive patients with unilateral or bilateral renal ischemia, coarctation of the aorta, and acute glomerular nephritis, but they did not find the angiotensin concentrations to be increased in ninety-two other patients with essential or malignant hypertension, pyelonephritis, aldosteronism or pheochromocytoma . However, it must be stated (and herein lies the problem) that other groups, namely, those of Genest et al . [59] and Mulrow [60] have not been able to confirm these observations . Due to the conflicting data in the measurement of angiotensin, other investigators have turned to the measurement of renin in peripheral and renal venous blood in hypertensive subjects . Helmer [61], who for many years has been performing a bioassay for renin activity in blood from hypertensive patients, summarizes his findings in the graph reproduced in Figure 4 . Plasma renin activity was normal in most patients with essential hypertension and higher in patients with malignant hypertension or renal ischemia . A gross similarity between these curves for renin levels in hypertension and the curves for aldosterone secretion in hypertensive disease reported by Dr . Laragh [24] may be apparent . However, an exception occurs when hypertension is caused by an aldosterone-secreting tumor, for in this situation blood renin levels tend to be low or absent [62 J . In studies of human hypertension there has been some correlation between blood renin and aldosterone secretion ; however, there has been no direct correlation between the blood renin levels and the height of the blood pressure . Such a lack of correlation between renal or blood renin and the level of blood pressure is also apparent in experimental hypertension .



62 6

Combined Staff Clinic

BENIN IN PERIFNENAL PLASMA LU . PER

LITER

FEED BACK

lao5-op NDAM

.5) oESSNt

(076-oW MALL Nl

a

1 .1

AL MS. OEC

Peripheral venous renin concentrations in hypertensive disease . Range of renin concentration in peripheral plasma of normal subjects and of patients with arterial hypertension classified as essential, malignant and renal vascular occlusive disease . The dotted line indicates a fall in train owing to a feedback mechanism . From Helmer, 0 . M . Canad. M. A . J., 90 : 221, 1964 FIG . 4 .

]61] .

This is illustrated by data from Gross and coworkers [63] . In sodium-depleted rats both renal and blood renin levels were elevated, but blood pressure was normal. In adrenalectomized rats blood pressure was low and renin was high, whereas in rats given desoxycorticosterone and salt the blood pressure was high but renin was low . Such data have led many investigators to doubt that the direct vasoconstrictor action of angiotensin generated by circulating renin can fully explain renal hypertension . It has persuaded them to search instead for a role for renin and angiotensin in normal homeostasis, that is, in control of renal function, of aldosterone secretion, or of sodium balance [12,6365] . These investigators do not deny any role of renin-angiotensin in the pathogenesis of renal hypertension, but they imply that this role may be complex and in part mediated by hormonal and electrolyte factors . Control of Renal Hemodynamics . The intimate spatial relation between the juxtaglomerular cells and the preglomerular arterioles has led other workers to postulate a role for the renin-

angiotensin system in the control of renal hemodynamics . Infusion of angiotensin indeed affects renal hemodynamics : It produces no change or a fall in glomerular filtration rate and a striking reduction in renal blood flow [66] . Furthermore, recent studies have implicated the juxtaglomerular apparatus, renin and angiotensin in the phenomenon of autoregulation of renal blood flow . Autoregulation of renal blood flow signifies the intrinsic tendency of the kidney to maintain constant blood flow despite changes in arterial perfusion pressure [67] . Autoregulation does not appear to be mediated by nervous impulses . It depends in great measure upon the intrinsic activity of renal vascular smooth muscle cells and can he abolished by agents such as papaverine which paralyze smooth muscle function [68.69] . Guyton and co-workers [70] have carried out experiments the results of which are compatible with the idea that renal autoregulation is effected by an osmotic feedback system of the macula densa . According to this theory, a decreased osmotic pressure in renal tubular fluid would be sensed by the macula densa and would lead to constriction of the afferent arterioles in the area of the juxtaglomerular cells . Increased distal tubular osmotic pressure would then cause renal vasodilation. Thurau [69] would specifically implicate renin and angiotcnsin in the phenomenon of renal autoregulation . He states that renal autoregulation occurs only in renal cortical tissue and not in the renal medulla (where no renin has been localized), and he has observed that kidneys rich in renin "autoregulate" well, whereas kidneys poor in renin autoregulate poorly . In addition, he has noted that substances such as adenosine triphosphate (ATP), which cause slight renal vasoconstriction in kidneys low in renin, have a marked constrictor effect in renin-rich renal tissue . Thurau postulates that the composition of the intratubular fluid at the site of the macula densa regulates renin release, and thus (through the vasoconstrictor action of angiotensin released locally) affects the tone of the afferent arteriole [6 .9] . According to his theory, increased renal arterial pressure would increase filtered sodium, increase distal tubular fluid sodium, increase renal renin output and thus cause constriction of the preglomerular arterioles, with reduction in renal blood flow and reduction in glomerular filtration . To date the data in support of this AMERICAN

JOURNAL . OF MEDICINE



Recent Advances in Hypertension theory are only preliminary and suggestive . However, the hypothesis is of interest since it connects vasoconstriction in the kidney to metabolism in such a way that the renin-angiotensin system is the link between changes in metabolic activity, that is, the link between active tubular sodium reabsorption and changes in renal vascular smooth muscle tone . Sodium Balance . Phylogenetically, a role for renin and angiotensin in the control of sodium balance might be suspected from the fact that salt water fish have no juxtaglomerular cells, whereas fresh water fish and amphibia do have juxtaglomerular cells 171 ] . Since 1960 [26] much evidence has been obtained that implicates the renin-angiotensin system in the control of aldosterone secretion . Dataa also implicate this system in the control of sodium balance, not only through effects on the adrenal gland but also through direct effects on the kidney to alter the renal excretion of sodium and water [79] . Dr . Laragh has reviewed studies from this institution which indicate that angiotensin can stimulate aldosterone secretion in man . These studies imply that renal-adrenal interaction may be important in the normal control of blood pressure and sodium metabolism [28,64] . Preliminary studies of the correlation between changes in blood renin concentration and aldosterone secretion in normal subjects under conditions of varied electrolyte balance are underway in this and other laboratories . In this regard, recent work from England [72] shows that plasma renin rises in man with salt restriction and returns to normal with salt repletion, a phenomenon which parallels the changes in aldosterone secretion produced by the same maneuver . That angiotcnsin stimulates aldosterone secretion in man [26,65] has also been amply confirmed in dogs [73,74] and in sheep [75] . Davis and co-workers [76,77] have reported increased juxtaglomerular cell granulation, high levels of plasma renin, and hypersecretion of aldosterone in dogs with ascites and thoracic caval ligation, and in dogs with high-output cardiac failure secondary to a large arteriovenous fistula . Renin, angiotensin and aldosterone may be important in the normal control of sodium balance ; it is also possible that abnormal interaction between the components of this system may be important in the pathogenesis of hypertensive vascular disease . In this regard, Masson VOL . 39, ocxoBER 1965

627

and co-workers [30] found that neither renin nor aldosterone alone produced hypertensive disease in rats . However, renin, when given as an injection to rats which had been pretreated with aldosterone, caused extensive vascular damage . This group has also found that extracts of ischemic kidneys produce more vascular damage than renin injections [78]_ As Dr . Laragh has already mentioned, in patients with malignant hypertension, a condition characterized by vascular lesions and evidence of renal damage, there is marked oversecretion of aldosterone [24,25] . It has also been found that aldosterone secretion may or may not be high in patients with hypertension secondary to renal artery stenosis . In dogs with mild Goldblatt hypertension, Carpenter et al . [73] have shown that the juxtaglomerular cells, renal renin and aldosterone were minimally altered . When the Goldblatt clamps on the renal arteries of these dogs were tightened, a syndrome mimicking malignant hypertension was produced . The juxtaglomerular cells became hyperplastic, renal renin increased and aldosterone secretion was markedly increased . In addition to its effects on aldosterone, a direct intrarenal role for angiotensin in the control of sodium balance has been postulated by several workers [79,80] . Studies with angiotensin it in man reveal that pressor infusions of the polypeptide in normal subjects cause salt and water retention [66], whereas in hypertensive subjects [81] or in patients with cirrhosis and ascites [79] similar infusions induce natriuresis and diurcsis . This action of angiotensin to inhibit tubular sodium reabsorption observed in cirrhosis has also been observed in a variety of animals [82,83], in renal tissue slices [84] and in stopflow studies in dogs [851 . However, the significance of the angiotensin diuresis, as to whether it represents a physiologic or pharmacologic action of the polypeptide, is unclear . Until the past two years the signal which triggers release of renin has been presumed to be solely hemodynamic, either stretch in the afferent arteriole (86], renal artery pulse pressure [87] or mean pressure [88] . Recently more subtle hemodynamic functions have been entertained as possibilities : renal volume pulsation [89-91], tangential tension in the afferent arteriolar wall [92] and the pressure differential between the afferent arteriole and the distal tubule [ .93] . Currently the function of the

628

Combined Staff Clinic TABLE III PATHOLOGIC LESIONS

Associated with Renooascular Hypertension

Atheromatous plaques Fibromuscular hyperplasia Diffuse arteriosclerosis of renal artery Stricture of renal artery Thrombosis of renal artery Aneurysm of renal artery Renal infarction Arteriovenous fistula or malformation Lesions compressing renal artery Recorded in Homer Smith's Review of 149 "Cures" [96] Pyelonephritis 62 Hydronephrosis 23 Atrophic kidney 18 Renal arterial lesions 10 Cyst and tumor 8 macula densa [69,94,951 has also been incorporated into theories of renal renin release, and distal tubular osmolarity [94] or distal tubular sodium concentration [69,95] has been considered as a possible factor . The resolution of this question awaits both further experimentation, and also more accurate and reproducible measurements of plasma renin . DR . JOHN H . LARAGH : The remainder of the clinic will be devoted to certain clinical aspects of hypertension. Dr . Meltzer will now discuss the problem of hypertension associated with unilateral renal disease . DR . JAY I . MELTZER : As is apparent from the data already presented, the relation of abnormal renal function to hypertension is still a mystery . The experiments of Goldblatt raised the hope of surgical cure of hypertension by unilateral nephrectomy . But despite great advances in the understanding of Goldblatt hypertension, there is still no reliable test for its presence . Clinical identification is still problematic, established post hoc in each case only after successful surgery . For twenty years an empirical search for diseases to fit this concept led to only 149 cures in 575 recorded cases in which nephrectomics were performed for treatment of a wide variety of pathologic lesions associated with hypertension [96] . This small group proved the point, but the incidence was low, and virtually no technics were available for identifying the few hypertensive patients from the many normotensive patients with identical pathologic lesions . Great caution was needed to avoid harmful procedures . In the next decade, recognition of a clinical

syndrome simulating malignant hypertension, following (among other lesions) renal infarction [23,97], the development of "split" renal function tests and of aortography have called attention to diseases of the renal vasculature as causes of curable hypertension . Because of the relative ease of identification of these lesions, their frequency and the skill of vascular surgeons, the tendency has been to focus exclusively on this aspect of the general problem . The term "renovascular hypertension" is widely used and was defined recently as hypertension caused by occlusive disease of the renal arterial vasculature, which is potentially curable by surgery [98] . Accepting this definition for its clinical usefulness, one should avoid any implication that mechanisms have been defined . In Table in are listed in approximate order of frequency the pathologic lesions associated with curable renovascular disease, and the pathologic lesions recorded in the older literature as reviewed by Homer Smith in 1956 [96] . The basic clinical problem was highlighted again in a recent roentgenolgic survey which showed that every vascular lesion associated with the hypertensive group has been found in a normotensive group, but with lesser frequency [99] . One assumes that the population with essential hypertension would have more occlusive vascular disease than normotensive subjects . The clinician must differentiate vascular lesions which cause disease from those caused by it . He hopes to define a syndrome which will not only identify patients with renovascular hypertension, but also those who will be cured by surgery. In addition, he hopes to distinguish the patients who should be subjected to the complicated procedures often necessary for the diagnosis. The factors which make a statistical contribution to the probability of curable renovascular hypertension are outlined in Table tv . The initial group is a triad of history, physical examination and laboratory testing, all obtainable on an outpatient basis . The first statement under "history" calls attention to renal infarction . The second and third tend to exclude the chief diagnostic competitor, essential hypertension . The fourth calls attention to the clinical syndrome described by Perera and Haelig [100], which still seems to offer some statistical value in evaluating patients . The second part of the initial triad includes auscultation for abdominal bruits, although their specificity is a matter still to be clarified . AMERICAN IOU RN AL OF MEDICINE

629

Recent Advances in Hypertension They may occur in all the lesions of renovascular hypertension [ 101 ], but also in occlusive disease of any of the abdominal arteries . Moser and Caldwell [ 1021 found a bruit in 100 of the hypertensive patients observed at the Henry Ford Hospital. Of the fifty who had either a positive history as outlined or a positive intravenous pyclogram, thirty-three had renal arterial lesions . In Perloff's series [103], fifty-three of sixty-two selected hypertensive subjects with a bruit had renal arterial lesions . The faint highpitched systolic or continuous blow, which is the most typical, may be overlooked easily . There is no sure way to tell which side is involved . The great majority are heard near the midlinc between the xiphoid and umbilicus ; rarely is the bruit localized to the flank . A good stethoscope, a quiet room, relatively inactive peristalsis, knees flexed to relax the rectus and listening in all the likely places, on several trials, will all be rewarding . Similar bruits are present in apparently healthy normotensive subjects . In the laboratory, two tests, when the results are positive, add to the probability of renovascular hypertension . One is for the detection of hypokalernic alkalosis, reflecting secondary aldosteronism which in turn suggests activation of the renin-angiotensin mechanism . The other is the rapid sequence intravenous pyelogram which will be discussed later by Dr . Fleming. The radioactive renogram is convenient, but in our hands not very reliable . Refinements in technic and understanding are continuing and no final conclusions are now possible . Whether it will add anything to the rapid sequence intravenous pyelogram is questionable . Stewart et al . [104], reporting a survey of 500 consecutive new hypertensive subjects, found that 12 per cent had one or more of the items in the clinical triad (Table tv, class t), history, bruit and an abnormal, rapid sequence intravenous pyelogram . Of the 12 per cent, subsequent investigation led to surgery in one third . A completely negative triad excluded all but one of their patients who was cured . Most investigators do not analyze their data this way . Exception may be taken to any strong position on screening, but this type of analysis bears more study . In Stewart's report [104], app .oximately 4 per cent of the consecutive unselected hypertensive subjects were subjected to surgery . Since only 50 per cent of these were cured, it may be concluded that the incidence of certain renovascular hypertension in this series of paVOL .

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1965

TABLE. IV STEPS IN THE DIAGNOSIS OF RENOVASCIIL.A R HYPERTENSION

Class I

History (1) Acute onset following an episode of flank pain, renal injury or embolization (2) Acute onset in the young (below age twenty to thirty) especially in absence of family history (3) Acute onset in the aged, especially if blood pressure is known to be normal after age, fifty (4) Any patient with "malignant hypertension," especially de noon, with mild proteinuria, and well preserved renal function . Physical examination Abdominal bruit Laboratory data Serum electrolytes Rapid-sequence intravenous pyelograms Class II

Renal angiography Class III

Split function studies Bilateral needle renal biopsy Class IV

Measurement of gradient Bilateral wedge biopsy and frozen section

tients with hypertensive vascular disease was about 2 per cent . Claims are made that as many as two million renovascular hypertensive subjects are waiting to be discovered [981 . On the other hand, the doctor who is confronted with a negative initial "triad" must, if he persists, face a marked decrease in his chances of discovering anything of etiologic significance and a marked increase in the risk, expense and complexity of the investigation . Before proceeding diagnostically, the clinician considers his patient in terms of operative risk . Page [7051 and others have emphasized that surgery is dangerous in the presence of extensive cerebral or coronary atherosclerosis, aortic aneurysm, poor renal function, old age and inexperienced surgeons . If renovascular hypertension is suspected in a "poor-risk" patient, drug therapy may be used effectively . The possibility also exists that although successful surgery may protect the patient from the risk of stroke due to increased pressure, it may increase the risk of myocardial infarction due to ineompensable fall in perfusion pressure . If it is decided to proceed with the diagnostic study, aortography may be the single most valuable test, unique not only in specifying diagnosis, but also in determining bilaterality,

6 30

Combined Staff Clinic

TABLE V RESULTS OF SURGERY FOR RENOVASCULAR HYPERTENSION TWELVE REPORTED SERIES

Data

Number of patients subjected to surgery % normotensive after surgery . . . . % improved after surgery % failures % deathsj

Series 12

series 1-11

FMH*

297

62

42

61

60

so

30 28 8

32 7 0

18 22 10

8 12 6

PHEOt

[1141

200

* Fibromuscular hyperplasia [178] . t Pheochromocytoma [721] . t Deaths included in failures . in guiding the surgeon to nephrectomy or vascular repair, and in excluding unexpected disease . (Table iv, class n .) A positive aortogram is no guarantee of a functional or curable lesion . When associated with a positive triad (class 1), the clinician is on firm ground statistically, but more security may be required . If the aortogram is positive but the initial clinical triad is not present, it is difficult to evaluate the problem without benefit of split renal function tests . (Table rv, class in .) Of all the procedures designed to aid the clinician, this is perhaps the least innocuous, involving as it does bilateral ureteral catheterization and infusion of a hypertonic solution . In addition to a certain morbidity, even fatality [106], it is complex, expensive and of no value in determining bilateral disease or renal infarction . What relation the development of hypertension bears to the sequence of events of anatomic narrowing, functional renal change, pressure gradients and renal atrophy [107] is still uncertain . For the moment, we may consider a positive split function test as an indication of unilateral renal arterial stenosis of more than minimal proportions . If simultaneous renal clearances are performed, the value of the test is enhanced . Using the factors outlined for the selection of patients, the cumulative results of twelve large centers in the surgery of renovascular hypertension over the years 1954 to 1962 are compiled in Table v [103,105,108-117] . Of 559 patients subjected to surgery, screening data are available in 250 . When all "severe hypertensive subjects" are subjected to intensive study, only 7 per cent

are finally selected for surgery . If good clinical judgment is used in screening patients for specific study, approximately 25 per cent will ultimately be operated upon . In Table v the results of surgery are summarized . In eleven of the twelve series the findings were quite similar . They are reported in the first column. There is no uniform standard of reporting results, and there are many difficulties in interpreting the terms "cured," which usually means a sustained blood pressure of 140/90 mm . Hg or below, and "improved," which can mean anything from only systolic hypertension to lower average readings . Because it may take ten years or more to evaluate the clinical benefits of merely lowering average blood pressure, in collating these data only three categories have been used : normotensive, improved and failures, including deaths in the last group. This involved recalculating some of the published data . In only a few instances were follow-ups of more than one year made . It seemed valuable, when possible, to abstract for special attention the entity, fibromuscular hyperplasia, which appears in the second column (Table v) ; these data include three other series [103,110,718-1201 . The improved results seem to reflect a low average age of thirty-four years, and a 4 .5 to 1 female to male ratio, bespeaking the relative absence of atherosclerosis and also less confusion with secondary occlusive disease . (Table vi .) It is important to note that patients with fibromuscular hyperplasia rarely present a malignant picture, even when blood pressure levels are high, and the clinical response to surgery bears no relation to the duration of disease [118] . Over one third of these patients had bilateral disease . The important point is that many of these cures were effected by nephrectomy for unilateral disease . What if the disease recurs later on the other side? The challenge of conserving renal tissue by revascularization applies in all cases and is being met with increasing skill . That skill is nowhere more evident than in series 12, the largest in the literature [114] . (Table v.) Here the cure rates for predominantly atherosclerotic disease exceed what others have achieved in fibromuscular hyperplasia and what is reported in a review of patients with pheochromocytomas [121] . In an attempt to account for the failures, it may be said that some undoubtedly occurred as a result of inexperience in the early phases and operating on poor-risk patients with extensive atherosclerosis . Other failures clearly reflect AMERICAN JOURNAL OF MEDICINE



Recent Advances in Hypertension more basic difficulties : a phase of renovascular hypertension in which nephrectomy can no longer be of help or the possibility of underlying dffe se renal disease overlooked because of striking arteriographic findings . Preoperatively, Vertes et al . [122] proposed the use of bilateral needle renal biopsy to evaluate so-called "intrarenal obliterative vascular disease." (Table iv, class m .) They believe that surgical cure cannot be expected whenever this lesion is present . Since they found that the majority of their patients with renal arterial lesions also had bilateral intrarenal disease, they have questioned the wisdom of major vessel surgery, which at best can only increase flow to, but not through, the kidney . In a recent publication [ 123] this point was proved prospectively in seven patients . The degree of intravascular obstruction necessary to discourage surgery is a matter of judgment . Uncertain also is the question of sampling errors on needle biopsy and what weight to give to the risks of biopsy itself . Whether use of this procedure can help screen out the potential failures awaits clinical trial and further study in other hands, but it is a promising approach . During operation (a poor time to make important decisions), two procedures have been suggested to aid the surgeon . (Table iv, class iv .) Realizing that needle biopsy could never provide the 90 or so glomeruli needed to estimate the juxtaglomerular apparatus reliably, Crocker et al . [124] have proposed bilateral wedge biopsy, with examination of specimens from both kidneys by frozen section . It is certainly possible to identify some gross examples of juxtaglomerular hyperplasia by comparing one kidney to the other in this way . From quantitative data, the differences in "juxtaglomerular count" in essential hypertension and Goldblatt hypertension do not appear to be very markedan average of 242 versus 295 counts [.39] . Detection of differences of that order by frozen section seems at best difficult and of questionable reliability . In many successful operations for renal artery stenosis, renal arterial pressure gradients have been in excess of 45 turn . Hg. Ilowever . Morris' group [174], with the most generally successful results, found gradients of less than 25 mm . Hg in 25 per cent of their patients, and stated that the gradients have no relation to clinical response . It seems that disagreement on this point will persist until basic mechanisms are better understood . VOL

39, OCTOBER 1965

631 ,FABLE

VI

CLINICAL. CHARACTERISTICS OF RENAL ARTERY STFNOSIS DIIE'r0 6IBROMIISCCLAR HYPERPLASIA Summary of Five Series

Sex Mah . . . .

.

19

Female 91 Distribution Unilateral . . . . . . . . . . . . . . . . . . . . . 58 ., . Bilateral . . . . 36 Age

Range 5-55 Mean 34-38 Duration of hypertension 3 mo .-20 yr . Bruit audible 52/67 In conclusion, a group of clinical characteristics is more easily identified for the renovascular form of hypertension than for hypertension due to unilateral renal disease in general ; this fact raises some hope that a specific test for it will be developed . Dr . Cannon has summarized the current experimental attempts to implicate the renin-antiotensin system in clinical renovascular hypertension . Because of the elevations of blood renin or antiotensin in certain nonhypertensive states [12.5], the only sure way to pinpoint unilaterality is by bilateral catheterization of both renal veins for measurement of pressor substances . Preliminary reports from several laboratories are promising, but the published clinical case reports are sketchy and the follow-ups are very brief [58,61] . Suchh elaborate testing is not available to most clinicians today . It will be of special interest to evaluate these new pressor measurements in patients with hypertension and in those with unilateral renal disease which is not associated with renovascular hypertension . The clinician, working without benefit of specificity, must avoid wishful thinking and insist on good clinical evidence and a "goodrisk" patient before recommending surgery . We have tried to point out a series of factors which, if positive, increase the likelihood of the presence of curable renovascular hypertension . "Poorrisk" patients should be treated with drugs or not at all, and spared the expense and risks of tests. If the history, physical examination, and laboratory and roentgenographic studies are all negative, the great majority of patients with curable renovascular hypertension will be excluded, and will be spared the risk of a futile surgical procedure . When rigorous clinical judgment is used in selecting patients for intensive study, about 25 per cent are suitable for

Combined Staff Clinic

6 32 TABLE VII

INTRAVENOUS PYELOGRAPHIC FINDINGS SUGGESTIVE OF RENOVASCULAR HYPERTENSION

Anatomic

Unilateral small kidney Focal renal atrophy Ureteral or pelvic notching Renal artery calcification Functional

Decreased urine output Delayed calyceal and pelvic opacification Less distended collecting system Asymmetrical contrast material concentration or nephrogram effect (especially increased concentration by small kidney) operation . The results of surgery are improving, but there are still many failures and an appreciaable mortality . One final point needs emphasis . In a disease that has to be judged over a span of decades, the clinician still has no adequate controls with which to compare the results of surgery (e .g ., patients managed with long-term drug therapy or no therapy) . DR . J . H . LARAGH : It is apparent from Dr . Meltzer's analysis of the problem that at the present time we can hope to help only about 50 per cent of the patients with supposed renovascular hypertension, even when they are selected after careful clinical and laboratory study . For this reason, surgery should be undertaken with considerable circumspection . On the other hand, when it does occur, the exciting clinical event -a dramatic fall in blood pressure to normal levels when the renal artery is repaired or when the kidney is removed-will always be a stimulus for us to look for better ways of finding and treating this entity . If we understood the metabolic abnormalities within the kidney which caused the release of a pressor substance, or if we could measure the pressor substance more accurately, perhaps the testing problem could be simplified . In the meantime, however, we have to rely on the tests available . Dr . Fleming of the Department of Radiology will present data which he and Dr . Kent Ellis have collected, comparing a new type of rapid sequence pyelogram with renal arteriography . DR . RICHARD J . FLEMING : The intravenous urogram is proving to be the most rewarding screening test available for detecting the hypertensive patient with potentially curable renovascular hypertension . The urogram not only demonstrates the established gross anatomic changes but also is capable of defining some

physiologic responses of the kidney to ischemia . Within the past few years a more critical interpretation of the intravenous pyelogram has been coupled with modifications in the technic of the examination . These modifications, which will be discussed, are designed to demonstrate to better advantage two major functional abnormalities associated with renal ischemia, namely, a decrease in the urinary output and an increase in the solute concentration in the urine by the affected kidney . Atrophy of the renal parenchyma, whether generalized or localized, is the major anatomic change seen in renal ischemia [126] . If a major renal artery is involved there is a general decrease in kidney size as compared to the opposite more normal kidney . With segmental arterial disease, focal renal atrophy may be found . Of particular significance is a temporal decrease in the size of the kidney or segment of the kidney . We believe a difference of greater than 1 .5 cm in length of the two kidneys is likely to be associated with renal ischemia [127] . Differences of less than 1 .5 cm . in renal length are not regarded as significant, but of course do not rule out unilateral renovascular disease . Notching of the opacified renal pelvis and ureter caused by tortuous collateral vessels supplying the ischemic kidney, and vascular calcification in the region of the renal pedicle are uncommon but important findings . In addition to the morphologic changes just described, certain functional changes characteristic of renal ischemia can be observed on the intravenous urogram . These are (1) a decrease in urinary output and (2) hyperconcentration of contrast material, i .e ., of solutes in the urine. (Table vii .) The radiopaque, iodine-containing contrast agents in the doses currently used in intravenous pyelography are filtered by the glomerulus and are not significantly excreted or reabsorbed by renal tubular cells . These agents, therefore, resemble creatinine or inulin in their renal excretion, but in addition have the quality of being opaque when exposed to x-rays . A unilateral decrease in urinary output is manifested roentgenographically by a delay in appearance of the contrast material in one renal pelvis as compared to that of the more normal kidney. The extreme example of this is unilateral renal nonfunction in the absence of an obstructed urinary tract . A decreased volume of urine on the affected side causes the renal pelvis to be less AMERICAN

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Recent Advances in Ilypertensiun

633

F,G . 5 . fired intravenous pyelogram, 2-minute film . Note the smaller right kidney with no calyecal opacil ration evident as compared to definite op ac ilieation of the left enllertine svstem . Contrast material was apparenr on the rig fit side in the 3-minute film . h'uG . 6 . Standard intravenous pyelogram, 15-minute lilin . Note the smaller left kidney with denser npacification of the left collecting system, indicating hypcreoncentration . There is also "notching" of the opaeif[ed left ureter due to collateral ureteral arteries .

distended and consequently to appear more delicate when compared to its normal counterpart . A gross difference in the appearance time will be apparent on the standard intravenous pyelogram but more often the disparity is subtle . In order to demonstrate this change a slight modification of the standard intravenous pyelogram is necessary . This entails rapid injection of the contrast agent, using no abdominal compression (which may interfere with urinary flow from the kidney) and exposing films at 1-minute intervals up to 5 minutes, then at 10 or 15-minute intervals as desired ; the important period is the first 5 minutes . A difference in appearance time of 1 minute is considered significant . In the first minute or minute and a half after the injection of contrast material, there is a general increase in renal opacity, constituting the nephrographic phase of the urogram . This represents the material in the capillaries of the kidneys, and a fraction of a minute later in the renal tubules . Theoretically, because of the diminished perfusion, the initial nephrographic effect should be less on the side of the ischemic kidney . In contrast, after the first few minutes the nephrographic effect may become greater on the side of the ischemic kidney because of the relatively increased concentration of solutes in the tubular urine of this kidney . Unfortunately, technical factors make comparison of nephrographic effects difficult and so usually unrewarding . The pyelographic phase, which immediately vot . . 39,

OCTOBER

1965

follows the nephrographic phase, represents contrast material in the calyces and pelvis of the kidney. Discrepancies in appearance times of the radiopaque contrast material in the renal pelves can be usefully and accurately observed [128-130] . A delay in appearance time of the contrast material at the renal pelvis denotes a reduced rate of urinary output . The decrease in glomerular filtrate accompanying decreased blood flow in the ischemic kidney, coupled with normal tubular reabsorption of sodium and especially water, causes the solute, in this case the contrast agent, to become more concentrated in the urine of this ischemic kidney and manifest as a more dense pyelogram . Thus, with evidence of increased solute concentration and decreased urinary output from the ischemic kidney on an intravenous pyelogram, we have aa qualitatively positive roentgenographic split function test without the use of ureteral catheters . Hyperconcentration of contrast material in the pelvis of a smaller kidney with relatively reduced output is pathognomonic of major renal artery obstruction . Examples of this are shown in Figures 5 and 6 . Unfortunately, definite hyperconcentration is only occasionally visible on the pyelogram and may he difficult to interpret . This may well be related to the fact that these patients arc dehydrated prior to the intravenous pyelogram, thus resulting in a more concentrated urine bilaterally . In view of this, some workers advocate hydrating the patient prior to [1311 or during

63 4

Combined Staff Clinic TABLE VIII

REVIEW OF LAST ONE HUNDRED AORTOORAMS FOR HYPERTENSION PRESBYTERIAN HOSPITAL (UP TO SEPTEMBER 1964)

Pathologic Finding

Main renal artery stenosis . Bilateral main artery stenosis Segmental stenosis .

No . of Positive Cases

Positive Urogram

20

20

8

6

4

3

32

29

90%

accuracy

the intravenous pyelogram [732] . Theoretically, with hydration a greater relative density of contrast will be produced in the abnormal kidney because of greater reabsorption of water per volume of glomerular filtrate . Also, because of the decreased urinary flow from this ischemic kidney, the contrast material will clear this collecting system more slowly than that on the more normal side . These considerations are the basis of the so-called "washout intravenous pyelogram" [132-134] and hydrated intravenous pyelogram (131] . Both technics depend upon comparisons of pyelographic density and the rate of disappearance of the contrast agent from the collecting systems of each kidney . Limitations of the Intravenous Pyelogram . The intravenous urogram test is most reliable in unilateral renal artery stenosis or arterial obstruction but is occasionally positive in bilateral renal artery stenosis if the stenoses are not perfectly symmetrical . Since the pyelogram is a comparison of one kidney with the other, a fairly symmetrical bilateral stenosis can be missed . Urographic abnormalities associated with a renal artery branch or segmental stenosis may be difficult to detect, although localized morphologic and functional changes can be seen . Other pathologic processes involving the urinary tract, e .g ., unilateral obstructive uropathy, a ptotic kidney with delayed drainage, and solitary or ectopic kidneys preclude comparison of the function of the two kidneys . In these instances the intravenous pyelogram is of limited value in evaluating the hypertensive subject with potentially curable unilateral renovascular disease . Since properly timed exposures during the

first 5 minutes are so important in the rapid sequence intravenous pyelogram, a special effort should be made by the radiologist and especially the x-ray technician to see that the films taken at 1-minute intervals are timed accurately . We have seen a few instances in which exposures were allegedly made at 1-minute intervals but it was obvious from the degree of renal pelvic opacification that the timing was inaccurate . Repeat studies with more emphasis on proper timing brought out unilaterally delayed opacification . Our experience in the last 100 aortograms for study of hypertension indicates a 90 per cent accuracy of this rapid sequence intravenous pyelogram in predicting significant abnormalities . (Table viii .) DR . J . H . LARACIS : Dr. Stason will now review the problem of treatment i .e ., when and how to treat hypertension medically, and what one may and may not expect from the various forms of therapy . DR . WILLIAM B . STASON :* Attitudes toward the treatment of hypertension and its complications have undergone a rapid evolution in the past fifteen years, with the advent of better diagnostic technics and the development of effective antihypertensive agents . This presentation will attempt to review the current status of the treatment of hypertension with emphasis upon evaluation of its efficacy in prolonging life span and diminishing the incidence of complications . It will briefly outline what the group in the Nephritis-Hypertension Clinic of this hospital consider to be a reasonable clinical approach to the patient with hypertension . The cause of hypertension is unknown . It is as yet unsettled whether an elevation in blood pressure is merely a manifestation of some as yet undefined underlying process or of prime significance in and of itself. To date, treatment has been aimed empirically at correcting this measurable abnormality . To justify efforts so directed it must be shown that lowering of blood pressure lessens mortality and morbidity to an extent which more than compensates for the side effects, toxicities and inconveniences of the agents employed . A vast literature has accumulated, in which the evidence pro and con is weighed . Final answers are not available, but suggestive ones are . Proponents of treatment point to several kinds of data, including mortality statistics, * Fellow of the New York Heart Association . AMERICAN

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635

Recent Advances in Hypertension improvements in these by treatment, circumstantial and experimental evidence that hypertension leads to accelerated athcro- and arteriolosclerosis, and, finally, to studies which purport to show that effective treatment may arrest or retard progress of these processes and their resultant complications . Dr . Laragh outlined the natural history of hypertension and indicated the variable but, on the average, shortened life span of patients with essential hypertension . Figure 7, from a study by Leishman [135], shows a plot of survival in years against mortality rate for different ranges of blood pressure . A direct relationship is obvious . Actuarial tables and numerous other clinical studies support these data [736-138! . Successful treatment, either medical or surgical, is of unquestioned value in prolonging survival in malignant hypertension [139--742 and is of probable value in hypertensive encephalopathy and congestive failure associated with hypertension [142,143] . In malignant hypertension, one-year survival has been improved from less than 20 per cent to 50 to 80 per cent in several series, and five-year survival from less than 1 per cent to 20 to 50 per cent . Necropsy data have revealed healing of necrotizing arteriolitis when the blood pressure was controlled [144] . Since the advent of therapy the proportion of hypertensive patients dying of congestive heart failure has been diminished from 30 to 40 per cent to less than 10 per cent [140,142,145] . In Hamilton's series [143], left ventricular failure was managed by hypotensive therapy alone in thirty-five of fifty-five patients, and digitalis was needed only transiently in nine others, the implication being that lowering an elevated blood pressure reduces cardiac work and thereby assists in restoring cardiac compensation . Other data showing diminution in cardiac size and improvement in the electrocardiogram with effective treatment support arguments for a beneficial effect on the cardiovascular system . Evidence that treatment is of value in severe nonmalignant hypertension can be derived from several studies [135,742,146,147] . That of Leishman in 1959 [13.5], with follow-up in 1963 [146], is representative . He compared the mortality and morbidity statistics in roughly comparable groups of treated and untreated hypertensive subjects . Treated groups included only those patients in whom the agent employed was effective in lowering diastolic pressure in the VOL .

39 .

OCTOBER

1965

I

5 N 3 - 2 3

1 0,5

Malignant

2 5

10

30 50 70

% Dead

100 120 130 FDiast oP 119 -129 19

Age Na

470 49 . 5 87 45

72

a

150 •

90 95 98

Malignant

498 443 21 20

Data showing the survival rate, estimated by life tables, in patients arranged according to their diastolic pressure when first seen . The percentage dead is plotted on a probability scale, the time in years on a logarithmic scale . The age for each group is the mean age at which the patients were first seen . From Leishman, A. W . 1) . Brit . M. J., 1 : 1361, 1959, presented by Pickering, G ., Cranston, W. I . and Pears, M . A . in The Treatment of Hypertension . Springfield, III ., 1961 . Charles C Thomas. Fic . 7 .

upright position, usually to 90 or 110 mm . Hg . Figure 8 summarizes some of Leishman's findings . The figure is a plot of the probability of dying from all causes, strokes and uremia, in three grades of severity of hypertension, in three groups of patients, one untreated and the others treated with ganglionic-blocking agents or guanethedine . After the three to five years of follow-up, there was a marked diminution in mortality in all treated groups whose initial pressure was greater than 120 mm . Hg diastolic . Treatment was of questionable benefit in those with lesser elevations of blood pressure . In those with a pretreatment level greater than 130 mm . Hg diastolic, improved mortality was primarily due to the prevention of death in the first year from uremia and strokes . Leishman believes that prevention of these early deaths in patients with severe diastolic hypertension is due to arrest or reversal of the process of arteriolar fibrinoid necrosis . The fact that death occurred later, although the incidence was apparently diminished, despite good blood pressure control, he attributed to pre-existing arteriosclerosis, against which lowering of blood pressure offers little protection .



636

Combined Staff Clinic DIASTOLIC PRESSURE 150 + mm .Hg MALES

130 -149 mm .Hg

FEMALES

MALES

120-129 mm.H9 MALES

FEMALES

FEMALES

Untreated

b h 0 .5 G .B.drugs

. Guanethidine

b

.

l

"""""

OS

Y „ O

ey e 4

-

0 05 -

1

0 1

3

5 0 1

3

5

0 1

3

11

5 0 1

3

5

0 I

y~

1

3

5 0 1

3

5

8 . Probability of dying (within one year, three years and five years) from all causes, from stroke, from uremia, in three grades of hypertensive severity, in untreated patients, patients treated with ganglionic blocking agents, and patients treated with guanethidine . From Leishman, A . W . D . Lancet, 1 : 1284, 1963 . [1461 . FIG .

In treated patients with diastolic pressures of less than 130 ram . Hg, no deaths occurred within the three years of observation . The prognosis was not as good in male subjects as in female subjects in all grades of hypertension and in all treatment groups . This and other comparable studies appear to provide evidence that effective blood pressure control, at least in patients with severe hypertension, significantly diminishes mortality or, conversely, prolongs survival . Hypertension is associated with an accelerated rate of development of atherosclerosis . That hypertension per se causes this has not been established, but circumstantial evidence indicates that such a relationship is likely 1148, 149] . Necropsy studies show advanced changes in the aorta above a coarctation [148] and in pulmonary arteries in patients with chronic pulmonary hypertension [14 .9], suggesting that hydrostatic pressure itself is of critical importance . Experimental data reveal that the atherosclerosis which develops in rats on a high cholesterol diet is more severe in hypertensive than in normotensive animals [150] . The relationship to arteriolosclerosis is more controversial . Support can be derived from studies such as those by Smithwick and Castleman [151] and Heptinstall [152] reporting that

renal biopsy specimens taken at the time of sympathectomy reveal a roughly quantitativrelationship between the severity of hypertene sion and renal arteriolar changes . Experimentally, Masson et al . [153 ] have shown that arteriolar lesions in hypertensive rats can be prevented when, and roughly in proportion to the degree, blood pressure is lowered, and that they appear when blood pressure increases after discontinuing antihypertensive therapy . However, another view championed by Goldblatt maintains that the arteriolar lesions precede and are not a consequence of hypertension [19] . Lowering of blood pressure may arrest the progression of vascular degeneration in man ; this conclusion can be derived from sequential studies of renal blood flow and glomerular filtration rate [154,155] . These show that in malignant and severe nonmalignant hypertensive subjects (diastolic pressure greater than 130 mm . Hg) effective control of blood pressure arrested the deterioration in renal function which occurred uniformly in untreated patients . Results were insignificant in those with milder hypertension, perhaps because in these the deterioration in function is too slow to be detected in a five-year (maximum) follow-up period . The response of affected ocular fundi to treatAMERICAN

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Recent Advances in Hypertension ment has been studied by Kirkendall and Armstrong [156] by serial photographs of fundi . Successful control of blood pressure resulted in disappearance or diminution in hemorrhages, exudates and papilledema when present, and, in a significant proportion, in an increase in vessel caliber and relaxation of local constrictions . These workers failed, however, to note improvement in previously established arteriosclerotic changes and concluded that the angiospastic but not arteriosclerotic phenomena in the fundi of hypertensive subjects are reversed by treatment [156] . In summary, arguments for vigorous therapy include (1) a direct relationship between diastolic pressure and mortality, suggesting that the height of the blood pressure is of critical importance ; (2) marked improvement in survival of patients with malignant hypertension, encephalopathy and congestive heart failure with hypertension : (3) evidence that lowering blood pressure in patients with severe nonmalignant hypertension improves survival ; (4) the accelerated rate of athero- and arteriolosclerotic processes in hypertensive subjects ; (5) evidence that lowering blood pressure may arrest vascular degeneration, at least in renal and retinal vessels . Those who question the value of treatment, on the other hand, argue that the foregoing evidence is inadequate to establish a causal relationship between elevated blood pressure and the accelerated arteriosclerosis occurring in hypertensive subjects . Hence they question whether achievement of normal blood pressure in mild benign hypertension will prevent the emergence of vascular complications . Hypotensive therapy has been claimed to be ineffective in reversing certain pre-existing arteriolar changes in renal [154,155], retinal [156] and, suggestively, cerebral [146J vessels . Perera [157] did not find any difference in survival between treated and untreated groups of patients, all of whom had grade 3 changes in the optic fundi and myocardial damage (as indicated on the electrocardiogram) at the beginning of the observation period, despite good blood pressure control in the treated group . These data, plus the occasional precipitation of angina or cerebral ischemic attacks when treatment is instituted, certainly dampen an unqualified enthusiasm for vigorous treatment of the nonmalignant hypertensive subject with arteriosclerotic complications . VOL,

39, ocTOSrx 1965

637

Furthermore, the course of even severe hypertension is variable . Although life span is shortened on the average, some patients with high diastolic blood pressures live out a normal life span free from vascular complications [7,158] . Prognosis seems to correlate much better with evidence of end-organ damage, especially uremia and fundic changes, than with the height of diastolic blood pressure . Patients without end-organ damage enjoy a normal life span irrespective of the degree of hypertension [ 159] . Thus it can be argued that in the absence of evidence of vascular degeneration, treatment is of no value in prolonging survival . Finally, antihypertensive agents presently available are far from perfect . None specifically and solely reduces blood pressure by relieving abnormal vasoconstriction . Many do so only on orthostasis . Often they are ineffective or only transiently effective, and all have side effects or toxicity of varying severity and frequency . On balance, the evidence is substantial that treatment of malignant and severe nonmalignant hypertension, especially in the presence of vascular complications, is indicated . The question to be resolved is whether or not early vigorous treatment of mild, benign hypertension will prevent the emergence of the vascular complications which ultimately occur in the vast majority of patients who are left untreated . To this end, what is required is a well controlled, prospective, double-blind study of a large number of patients followed over a period of twenty or more years . No such study is available . The most promising report to date is that of Hamilton et al . [160] . This study comprised of sixty-one patients, all with diastolic blood pressure before treatment of consistently greater than 110 mm . Hg . The patients were chosen by a method designed to rule out clinical evidence of pre-existing arteriosclerosis, and divided alternately into treated and untreated groups . Follow-up so far has beenn for two to six years ; preliminary results indicate that, in both male and female subjects, if blood pressures are maintained at less than 110 mm . I Ig diastolic, the incidence of complications is strikingly diminished, especially strokes and left ventricular hypertrophy . Admittedly, the numbers are small and follow-up is short, but the results may be regarded as encouraging . Realizing that there are as yet many unanswered questions concerning hypertensive vascular disease, and that the arguments for vigorous early treatment are not incontroverti-

6 38

Combined Staff Clinic

ble, but needing a practical clinical approach to the patient with hypertension, the NephritisHypertension Clinic has devised the following therapeutic criteria : (1) thorough diagnostic evaluation should be carried out in every patient to discover those causes of secondary hypertension that may be remedied by specific treatment, especially adrenal tumors and renovascular hypertension ; (2) vigorous treatment of patients with malignant hypertension is obligatory ; (3) treatment of diastolic hypertension in the absence of complications or symptoms is desirable if the diastolic pressure is consistently greater than 110 mm . Hg in male and 120 mm . Hg in female subjects ; (4) treatment of diastolic hypertension of lesser degree is indicated in the presence of heart strain, progressive renal damage not attributable to other renal disease, grade 3 retinopathy, severe headaches uncontrolled by symptomatic treatment or history of cerebral vessel involvement. The goals of treatment are to lower the patient's blood pressure, to normal when erect and as much as possible when recumbent . Less than optimal control is accepted if lowering the blood pressure precipitates or exacerbates angina, results in a rising blood urea nitrogen concentration, or in transient cerebral ischemic attacks . Suboptimal control is also accepted if side effects are prohibitive at dose levels necessary to produce optimal results . In the last analysis, each case must bejudged individually, and the potential value of therapy has to be weighed against the unpleasantness, danger, and inconvenience of the agents employed . Hypotensive agents available today are many ; the most commonly used are thiazide diuretics, rauwolfia derivatives, spironolactone, hydralazinc, a-methyl-DOPA and guanethidine [161, 162] . Each may be used alone or in combination with other drugs . In mild to moderate hypertension, thiazides with or without the addition of reserpine often are sufficient . In moderate to severe hypertension, a-methyl-DOPA, hydralazine or guanethidine are employed . In acute or malignant hypertension, intramuscularly administered reserpine, intravenously administered a-methyl-DOPA, guanethidine, ganglionic blocking agents or combinations of these can be tried . In certain patients, especially in those with hypokalemic alkalosis, aldosterone antagonists may be strikingly effective . Sympathectomy is currently

reserved for patients with severe or malignantt hypertension in whom medical therapy is unsuccessful or intolerable . New agents, such as diazoxide [7631, a thiazide derivative, which produces fluid and sodium retention when given orally but has a rapid and potent antihypertensive effect when administered intravenously, have yet to be fully evaluated but look promising for the treatment of hypertensive crisis . With the drugs currently available, side effects are many and optimal blood pressure control is difficult to achieve in a large proportion of our clinic population . We await better definition of the etiology of hypertension, conclusive proof that achievement of normal blood pressure prevents degenerative vascular disease, and the development of an agent capable of achieving this end with a minimal number and severity of side effects . DR . ROBERT CANFIELD : I have a question . Do you have any understanding of the way in which angiotensin infusion causes a saluresis in patients with cirrhosis' DR . LARAGH : Clearance data indicate that angiotcnsin blocks tubular reabsorption of sodium in these patients . The effect can occur with a falling glomerular filtration rate . As much as 20 per cent of the glomerular filtrate may be diverted into the urine . The mechanism of angiotensin natriuresis in hypertensive subjects is less clearly defined ; it may be hemodynamically mediated . DR. CANFIELD : You do not think the effect is mediated through the adrenal cortex? DR . LARAGH : The effect is too immediate to involve a change in aldosterone secretion . It is true that these patients already have high aldosterone secretion but so far our data do not suggest that this is specifically involved [79] . DR . ROBERT WHITLOCK : Can potassium depletion be used to try to reduce aldosterone secretion in malignant hypertension? DR . LARAGH : Probably not . This is because the high aldosterone secretion is on another basis, i .e ., presumably because of too much circulating angiotensin . In patients with malignant hypertension, potassium administration can markedly increase the already high rates of aldosterone secretion . Dr . Cannon has shown that potassium administration can stimulate aldosterone secretion as effectively as angiotensin, but under different circumstances of electrolyte balance [32] . Also, hypertensive subjects, even those with mild hypertension, are especially AMERICAN JOURNAL OF MEDICINE

Recent Advances in Hypertension sensitive to potassium administration because they respond with marked increases in aldosterone secretion . 'I he renal handling of potassium may be intimately involved in this abnormality . Potassium depletion is not a practical approach nor does it seem to be a theoretically sound one at the present time . MR . BRUCE (k)i .DREYRR : Dr . Fleeting, when you say that your modified intravenous pyelograin is over 90 per cent accurate in detecting significant renal artery stenosis, do you mean accurate in terms of selecting patients who are ultimately cured by surgery? DR . FLEmiNC : No, I mean in terms of identifying vascular lesions which can be subsequently demonstrated by renal angiography . Surgical success, as you have heard, is a more complicated thing to evaluate . DR . HELEN M . ANDERSON : Dr . Laragh, I note that you found normal aldosterone secretion and metabolism in patients with essential hypertension . Yet others have claimed that in these patients urinary aldosterone is increased, and Conn has recently proposed that in possibly 20 per cent of patients presumed to have essential hypertension the cause of high blood pressure may really be primary aldosteronism . lie believes that these patients can be identified by an abnormally low plasma renin activity . What is your opinion on all this? DR . LARAGn : Admitting that there may be problems in specificity, there is certainly nothing wrong with using plasma renin levels to help identify patients with primary aldosteronism . Indeed, as indicated already, there is a large body of experimental evidence describing a relationship between plasma aldosterone and renin levels, and several groups have reported low plasma renin levels in patients with primary aldosteronism . We need to have more experience with such tests before they can be considered as necessary or as useful as, for example, rapid-sequence intravenous pyelography has now been shown to be in the routine evaluation of renal-adrenal function . The proposal that about 20 per cent of patients presumed to have essential hypertension actually have primary aldosteronism is based on a selection of circumstantial evidence from the literature involving, for example, the findings of adrenal adenomas in 20 per cent of the hypertensive patients who come to autopsy and of low blood renin levels in 20 per cent of these patients . If this interesting view is correct it will probably

voc . 39,

OCTOBER

196

639

take no time at all for its proponents to verify Primary aldosteronism may well be more common than some have thought but the hypothesis seems to overlook the most direct, and therefore, perhaps the most important information, namely, that aldosterone secretion, whenever measured by acceptable methods, has usually been found to be normal in uncomplicated hypertensive disease . Furthermore, of necessity, the proposal demands that aldosteronism frequently occurs with normal plasma potassium and bicarbonate levels, that is, that it occurs without changing electrolyte balance . This could happen in subjects on sodium-free diets but if salt is administered hypokalemia should be apparent . In our hands hypokalemia uniformly occurs when aldosterone is given to normal subjects for a week or more . Further work will tell the story . Meanwhile it is worth re-emphasizing the conceptual importance of defining beyond question the true role of aldosterone in the common forms of hypertensive vascualr disease . The incidence proposed by Conn is obviously not quite as difficult to reconcile with our findings as is the 72 per cent incidence of hypcraldosteronism in essential hypertension proposed by Genest and his group . We have not studied large numbers but we remain convinced that typical, uncomplicated essential hypertension occurs without any demonstrable abnormality in aldosterone secretion or metabolism . DR . NICHOLAS P . CHRISTY : In this clinic the participants have attempted to define the nature and natural history of essential hypertension, to tell what is known or thought about its etiology, to discuss in detail the mechanisms of renal and adrenal cortical dysfunction that may play a role in its pathogenesis, to present current diagnostic and therapeutic approaches to renovascular hypertension, and to evaluate medical management of the various forms of hypertensive vascular disease. The entity, essential hypertension, which may not necessarily comprise a single homogeneous group of patients, afflicts perhaps 10 per cent of the adult population . It is most important to be aware of the fact that the course of the untreated disease is on the average twenty years, and can be more than thirty-five years in duration . In over half the patients death is a result of heart disease . The etiology is unknown . The role of genetic

6 40

Combined Staff Clinic

factors is controversial . There are many hypotheses concerning etiology : the psyche and the central nervous system, increased cardiac output, changes in the capacity of the vascular compartment, abnormal reaction to impaired renal capacity to excrete salt, increased dietary sodium, electrolyte changes in arteriole walls, generalized arteriolar vasoconstriction in which renal vessels participate, renal hormones, and finally a "mosaic" of mechanisms have all been invoked as primary causes . None is accepted as primary by a majority of workers in the field . Since the famous Goldblatt experiment, one of the major questions about hypertension has been, exactly how does the ischemic kidney produce high blood pressure? In the kidney partly deprived of its blood supply the content of renin is increased in association with hyperplasia and hypertrophy of the juxtaglomerular apparatus ; there is circumstantial evidence indicating that the juxtaglomerular apparatus is the source of renin . There is no certainty about how the renin-angiotensin mechanism is related to the normal control of blood pressure or about how the juxtaglomerular structure operates in the autoregulation of renal hemodynamics . However, evidence has been reviewed indicating that this hormonal mechanism participates in the normal control of salt balance and arterial pressure . The participants tentatively propose a possible role for the renin-angiotensin mechanism in the pathogenesis of essential hypertension : it is postulated that renin may increase when renal perfusion drops ; angiotensin then increases and stimulates adrenal cortical hypersecretion of aldosterone ; salt retention follows and, by a negative feedback system, renin levels in the kidney fall . There is experimental support for individual steps in this chain of reasoning . The postulated sequence of events might account for the normal blood angiotensin levels and the normal secretory rate of aldosterone observed in essential hypertension ; it is noteworthy that under experimental conditions, as angiotensin induces sodium retention, less and less angiotensin is needed to yield a pressor effect with the passage of time . Exact data are not available but the possibility of renovascular hypertension (specifically, of hypertension associated with unilateral renal ischemia) has to be investigated seriously in about 10 to 15 per cent of all patients with high blood pressure, and will be eventually proved in about 1 to 2 per cent . One signal is the sudden

onset of severe or malignant hypertension in normotensive subjects or in patients with benign essential hypertension ; symptoms of renal infarction further raise suspicion . There may he an abdominal bruit owing to unilateral artery stenosis . Hypokalemic alkalosis may be present . A useful new roentgenographic screening technic is the "rapid sequence" intravenous pyelogram in which unilateral renal dysfunction can often be detected by taking films at 1-minute intervals . The specialized technics of angiography and of split renal function tests are useful but are more difficult to perform and carry an added risk . Angiography is necessary preoperatively . It can be used as the next step in patients who have a positive intravenous pyelogram . In various series of hypertensive patients (500 patients), 12 per cent were suspects ; 4 per cent were eventually operated on, and half of these, i .e ., 2 per cent of the total, were cured . Cure rate was better in the entity, fibromuscular hyperplasia, than in the arteriosclerotic group . Operative mortality rate (8 per cent) was significant . Atherosclerotic complications may make it unwise to recommend surgery . Further controlled studies of the long-term efficacy of both drug therapy and surgery are badly needed . But despite the variable course of benign essential hypertension and the consequent difficulty in evaluating treatment, and despite evidence from one series that control of blood pressure does not affect vascular complications, there are recent data which seem to justify attempts to lower the blood pressure by means of drugs in many patients with the disease . There is a direct relation of blood pressure to mortality rate ; survival in malignant and in very severe nonmalignant hypertension is prolonged and the death rate due to congestive heart failure is reduced when blood pressure is effectively controlled ; it may be that arterioand arteriolosclerotic complications may be delayed and necrotizing changes arrested if the blood pressure is brought down . The therapeutic approach of the Nephritis-Hypertension Clinic in this institution is (1) thorough diagnostic measures to rule out "secondary" hypertension (e .g ., renovascular, pheochromocytoma, Cushing's syndrome and primary aldosteronism) ; (2) vigorous antihypertensive treatment of all patients with malignant hypertension ; (3) treatment of asymptomatic essential hypertension if diastolic pressure is repeatedly above 110 mm. Hg in men and above 120 mm . Hg in women ; AMERICAN JOURNAL OF MEDICINE



Recent Advances in Hypertension (4) treatment

of

in the presence

lesser degrees

of

hypertension

heart "strain," progressive

renal damage, grade headache, or history

of

3 of

retinopathy, very severe cerebrovascular involve-

ment . For mild to moderate disease, thiazides arc used, with or without rauwolfia derivatives ; for more severe disease, a-methyl-DOPA, hydralazine or guanethedine are used ; for acute or malignant hypertension, the most useful drugs are

intramuscularly administered reserpine,

intravenously administered a-methyl-DOPA, ganglionic blocking agents or combinations of these . The aim is to achieve nearly normal standing blood pressure, but without precipitating an ginal attacks or small cerebrovascular accidents, or elevating the level

of

blood urea

nitrogen . It is recognized that the pharmacologic agents now available are far from perfect . Further, the value

of

antihypertensive therapy in altering of benign essential hyper-

the natural history

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39 .

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1965

82 .

83 .

84,

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90 .

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92 . 93 .

94 .

95 .

96 . 97 .

98 . 99 .

100 .

64

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