The renal circulation in hypertensive disease

The Renal Circulation in Hypertensive Disease

NORMAN K. HDLLENBERG,M.D., Ph.D. DOUGLASS F. ADAMS, M.D. Boston, Massachusetts

From the Departments of Radiologyand Meditine, Peter Bent Brigham Hospital and Harvard Medical School. Boston. Massachusetts. This study was surkorted by’ National Institutes of

Health Gmnti’ (HL 14944, GM 18674, HE 11668. and HE 05882), Clinical Research Center Grant 5-MOl-RR-31-13 and the U.S. Army R

& D Comm@ (DAMD 17 74 4023). Requests for reprintsshouldbe addressedto Dr. Norman K. Hcrilenberg.

The pivotal role of the kidney in sustaining hypertension from any

source or etiology is becoming increasingly clear. The possibility that the renal vasculature participates not only in the pathogenesis of renal vascular hypertension, but also in that of essential hypertension, has been the subject of continuing interest for 40 years. Evidence that a functional abnormallty resulting In increased renal vascular tone is present in about two-thirds of patients with uncomplicated essential hypertension is reviewed, along with more circumstantial evidence that sympathetic nervous system activity operating on the renal vasculature is responsible. Two additional groups of patients in whom a characteristic abnormality of the renal vasculature is present have also been identified. In one group there is severe hypertension which is resistant to most forms of antihypertenslve therapy but which is especially responsive to propranolol. In these patients renal blood flow and glomerular fittratlon rate are reduced, renin secretion rate is increased and the renal vessels are resistant to vasodllators, suggesting the presence of advanced organic arteriolonephrosclerosis, as a complication of long-standtng, severe hypertenston. The renal lesion, ‘in turn, contributes to the increasing severity of the process. In a .second group of patients, generally young and with uncomplicated hypertension, renal blood flow is inappropriately increased. In these patients a number of observations on their renal vasculature, renin and aldosterone responses to a volume challenge suggest an abnormality in the perception of extracellular fluid volume. A perfectly normal renal arterial tree, free of organic abnormality or an increase in tone due to active vasoconstriction, is distinctly unusual in essential hypertension. Viewed from the perspective of history, the relationship between the kidney and hypertension has an excellent pedigree. The recognition of the association of kidney disease with hypertension is usually attributed to the classic work of Richard Bright, published in 1836; however, it is quite clear that the relationship was recognized in China over 4500 years ago [ 11. The Yellow Emperor’s Classic of Internal Medicine, pointed out that “the kidneys pass on the diseases to the heart . . . When the roulse is abundant but tense and hard and full like a cord, there are dropsical swellings _ . . and an acute illness will develop which is called ‘convulsion’.” These observations were forgotten, and it remained for Bright to rediscover the relationships. His brilliant analysis related albuminurea, a full hard pulse and a number of clinical manifestations of disease

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to necropsy evidence of contracted kidneys and left ventricular hypertrophy [2]. He never mentioned hypertension, but his meaning was clearly indicated in the conclusion that renal failure “affects the minute and capillary circulation to render greater action necessary to force blood through the distant subdivisions of the vascular system.“’ This prescient statement, still one of Medicine’s great ornaments, opened 14 decades of debate. Opinion first differed on whether an elevated arterial blood pressure level was present and responsible for manifestations of the disease, and, next, whether hypertension occurred in the absence of primary renal involvement. In 1858 Ludwig Traube [2] linked the heart and kidneys through a well-defined series of processes, in an analysis which stands today. What became known as “Traube’s Theory” stated that shrunken kidneys led to high blood pressure both through a reduction in the rate of blood flow from the arterial to the venous circulation and a reduction in the volume of fluid excreted in the urine. The elevated pressure, in turn, led to left ventricular hypertrophy and dilatation. The fulcrum of the debate then shifted toward a topic which is still current. Mahomed concluded on the basis of a long and careful study at Bright’s Institution, Guys Hospital, that patients with “arterial capillary fibrosis” could suffer from hypertension in the absence of obvious primary renal involvement [ 11. The issue was clearly not closed, however. Sir William Osler summarized current thinking in 1918: “The relation between arterial and kidney lesions has been much discussed, some regarding the arterial (lesions) . . . as secondary, some as primary.” To this time the renal lesion conceptualized was apparently parenchymai, rather than vascular. Fahr [3] suggested in 1919 that renal ischemia, per se, could play an important role in the development of the hypertension which is associated with renal microvascular disease in man. The historic watershed, however, was provided by the observations of Goldblatt et al. [4] who first focused attention on the renal vasculature as a major pathogenetic factor in the development of hypertension. Within four years of Goldblatt’s report, Homer Smith and collaborators [6] described clearance technics which made it possible for the first time to assess renal perfusion and glomerular filtration directly in man. By 1943 they were able to conclude that “the evidence in man argues against the primacy of renal ischemia in the pathogenesis of essential hypertension,” and to support that conclusion with eight references from the then recent medical literature. Clearance methods did reveal many patients with essential hypertension in whom renal perfusion and function were reduced: All the studies suggested an

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abnormality of renal perfusion in most patients. Indeed, their own study revealed a diodrast clearance which was less than the average value in 57 of 60 patients with essential hypertension [6]. The critical point was that some patients were normal. The renal biopsy or necropsy may also reveal normal vessels in such patients despite severe and relatively longstanding hypertension [7,8]. Why then has debate continued about the possible contribution of generalized or regional abnormalities of renal perfusion in the pathogenesis of essential hypertension? The following review will focus on renal perfusion, renal vascular tone and reactivity in essential hypertension in an attempt to answer that question. The obviously relevant abnormalities of perfusion which occur in renal parenchymal disease and renal artery stenosis will be reviewed only when information from these sources illuminates the problem of essential hypertension. We will use information derived from studies of animal models in the same way, since the fidelity with which they mimic essential hypertension will become apparent only when essential hypertension itself is better understood. Before proceeding to those subjects, it will be useful to review the ways in which current thinking suggests that the kidney contributes to blood pressure homeostasis, and the ways in which renal perfusion can influence renal function and, ultimately, arterial blood pressure. TNE INFLUENCE OF RENAL PERFUSION ON RENAL FUNCTION AND LONG-TERM BLOOD PRESSURE CONTROL Three broad classes of mechanism by which the kidney may influence arterial blood pressure have been suggested; (1) control of sodium space and extracellular fluid volume; (2) release of one or more vasoconstrictor substances; and (3) failure to release a vasodilator substance. The renal vasculature may be involved as a pathogenetic factor in each category. (1) The potential importance of fluid volume as a determinant of arterial blood pressure was stressed by Traube over 100 years ago, but its pivotal role in sustaining an increase in blood pressure from any source or etiology has recently been brought into sharp focus by the lucid analyses of Guyton and his co-workers [ 9, lo]. Their systems analysis approach to conceptualizing cardiovascular function has led to a series of predictions which have found surprisingly strong and consistent support from a wide array of experimental observation. Perhaps the most important outcome of their analysis is the realization that whereas there are multiple short-term blood pressure regulatory mechanisms, long-term blood pressure regulation is principally a function of a single factor, fluid balance, and ultimately, therefore, is

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renal. In turn, sodium provides the skeleton which supports the extracellular fluid. Renal perfusion is potentially a determinant of sodium homeostasis through a series of interdependent mechanisms. First, glomerular filtration is plasmaflow dependent [ 1 l]. Since the rate of filtration represents the load of sodium presented to the tubules, glomerular filtration must be important in renal sodium handling. Second, there has been considerable recent interest in the potential role of nephron heterogeneity as a determinant of renal function. If different nephron populations have a different intrinsic capacity to handle filtered sodium, as has been proposed [ 12,131, then the distribution of cortical flow to different nephron populations represents a major control point. Although providing a fascinating and widely cited potential, rigorous evidence that nephron heterogeneity represents an important control point is not yet available. Third, Starling forces in the peritubular capillaries are likely to contribute to sodium reabsorption [14,15]. During each minute 120 ml of extracellular fluid are filtered and only 1 ml is excreted; 119 ml must be reabsorbed and returned to the systemic circulation. The Starling forces, capillary hydrostatic and oncotic pressure, are both unusual in the peritubular capillaries in a direction which would favor this process. Hydrostatic pressure is considerably lower than it is in systemic capillary beds because of the drop in pressure at two arteriolar levels. In addition, the ultrafiltration of fluid in the glomerulus raises the protein concentration and thus the oncotic pressure in the efferent arteriole and peritubular capillaries. Both the reduced hydrostatic and increased oncotic pressure in this capillary network promote reabsorption of fluid to a degree which can influence sodium reabsorption [ 151. Indeed, it has recently been suggested that an increase in the filtration fraction, per se, can sustain hypertension [ 161. Fourth, as we indicate herein, the renal blood supply is one of the determinants of renin release, and thus in sequence, angiotensin generation, aldosterone release and distal tubular sodium reabsorption. Even modest abnormalities of renal perfusion may exert an important influence on sodium handling by the kidney. Perhaps most important, these phenomena are not mutually exclusive: rather they might be expected to act in concert. (2) The status of the renin-angiotensin system will not be dealt with in detail here, since it is the subject of several presentations in this symposium. Specifically relevant to this analysis are the following factors: (1) Some feature of the renal vasculature, presumably pressure delivery to the juxtaglomerular apparatus, represents an important determinant of renin release [ 171. Moreover the contribution of

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renal perfusion to sodium handling by the kidney can also contribute to renin release via the second, macula densa mechanism [ 181. (2) The renal vasculature is remarkably sensitive to angiotensin II [19], and several observations suggest that angiotensin II is generated within the kidney when renin is released [18,20,21]. Thus, renin release may occur not only as a consequence of abnormal renal perfusion but also as its cause. Excessive renin release has been demonstrated in patients with essential hypertension and reduced renal perfusion [22]. Whether the renin release is a cause or a consequence of the abnormal perfusion is discussed subsequently. The application of angiotensin antagonists to clinical investigation has made it possible to address this question. (3) The possible contribution of renal vasoconstrictor substances unrelated to the renin-angiotensin system is also currently under active investigation [ 23,241. (3) The possibility of the kidney exerting an antihypertensive influence through release of vasodilator factors has also been the subject of continuing interest, a concept which has been intimately related to an interest in renal medullary function. Suggestive evidence has arisen from changes in the character of cytoplasmic granules within renal papillary interstitial cells in various models of hypertension; the ability of the transplanted renal medulla to provide an antihypertensive function and a striking influence of prostaglandins, which arise from the renal medulla, on cardiovascular function and renal sodium handling [25-291. Angiotensin is a powerful stimulator of prostaglandin release, which may represent a major determinant of the renal vascular response to angiotensin [30,31]. Immediately relevant to this analysis is a recent study by Haggitt et al. [28] in patients with hypertension. They reported a striking correlation between renal medulfary fibrosis in patients with hypertension on the one hand, and both the degree of hypertension and the intrarenal vascular abnormality on the other. The medullary fibrosis was attributed to organic vascular changes in the renal cortex and suggested that failure of medullary function could play a pathogenetic role. The physiologic counterpart of this observation was reported by Baldwin et al. [32] who found a defect in the concentrating mechanism in patients with essential hypertension, an abnormality clearly compatible with disease of the renal medulla. THE KIDNEY IN SPONTANEOUSLY HYPERTENSIVE RATS The problem of essential hypertension underlines our dependence on animal models of human disease in dissecting pathogenetic mechanisms. Our limited understanding of essential hypertension has made it

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impossible to place strong reliance on any animal model. Recently, selective inbreeding has led to a number of unrelated, genetically-determined hypertension models in rats [33]. Although it is still far from clear which, if any, of these models resembles essential hypertension in man, the availability of the inbred strains had made it possible to perform rigorous experiments on the pathogenetic role of the kidney by cross-transplantation. Some years ago Tobian and co-workers [34] demonstrated a striking antihypertensive property of kidneys when they were transplanted from the resistant strain of rats developed by Dahl to rats made hypertensive by renal artery stenosis. The kidneys from rats sensitive to salt hypertension had a much smaller antihypertensive potential. More recently, Dahl and Heine [35] have demonstrated in the same strains that hypertension follows the kidney when it is transplanted, both preventing and reversing the genetically-determined high blood pressure. Bianchi et al. [36], working with a separate strain of genetically-determined spontaneously hypertensive rats, made an identical observation. When a kidney from a rat doomed to hypertension was transplanted into a normal rat, hypertension ensued in both strains. Conversely, transplantation of the kidney from a rat in which hypertension was not anticipated prevented the development of hypertension. This is not a universal characteristic of the spontaneously hypertensive rat, however, since Coburn et al. [37] were unable to demonstrate this phenomenon in the Okamoto strain of spontaneously hypertensive rat, with an identical protocol. It may be relevant that Folkow and co-workers [38], working with the same rat strain, demonstrated a remarkably low renal vascular resistance early in their life, an observation which may also be relevant to some patients with essential hypertension, to be discussed [39-411. In a recent review, Coleman et al. [33] concluded that most lines of evidence favored an important role of the kidneys, operating uia different efferent pathways in each of the spontaneously hypertensive strains. In some a primary, inherent renal defect was demonstrable by transplantation. In others, especially the Okamoto and New Zealand strains, indirect evidence suggested that abnormalities of renal function may be provoked by the sympathetic nervous system. Many of these observations are immediately relevant to recent studies in man. MORPHOLOGY OF THE RENAL MICROVASCULATURE IN ESSENTIAL HYPERTENSION

A concensus of informed opinion today would probably hold that increased arterial pressure precedes and induces the microvascular disease in most vas-

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cular beds, including the kidney’s, in essential hypertension. Despite apparently negative information from a host of studies, Goldblatt [42,43] has continued to argue the contrary view, that organic microvascular disease involving the kidneys precedes and causes essential hypertension. This view, predicated on the conclusion that hypertension does not induce arteriolosclerosis, was based on his experience: sustained renal hypertension for periods of up to eight years in the dog apparently failed to induce arteriolar lesions [ 421. There are several reasons why debate has continued. The morphologic approach suffers from a major sampling problem. Tracy [44] has pointed out that renal arteriolonephrosclerosis is not uniformly dispersed, raising the potential for important errors when small samples are examined. The problem is accentuated by the development of similar vascular changes with increasing age in nonhypertensive subjects: Bell [7] found perfectly normal small intrarenal arteries in the absence of hypertension only in subjects under 10 years of age; only 50 per cent were perfectly normal by the age of 20 to 30 years and only 5 per cent were normal over the age of 50 years. Arteriolar abnormalities also occur in the absence of hypertension, but are present in only 10 to 20 per cent of normal subjects over 50 years of age and are rarely severe. Moritz and Oldt [45] also reported that at-teriolar changes were much less common than small artery changes in nonhypertensive persons, and none was severe. A second major sampling problem arises from the fortunate fact that chance only rarely allows examination of the renal vascular bed at necropsy in the early stages of hypertension [7,45]: it is precisely in this setting that we are least confident in the diagnosis [46,47]. In longstanding hypertension, a perfectly normal renal arterial tree is extremely rare 18,483, especially when great care is taken to insure an adequate documentation of hypertension. The observations do not answer the question posed by Goldbatt; was the renal microvascular disease present at the onset? Additional insight into the problem arose from an unexpected observation made by Tracy [ 491. A documented fall in blood pressure levels or the disappearance of hypertension occurred prior to necropsy in a number of subjects. The severity and extent of the nephrosclerotic lesion at necropsy was more consistent with the lower, more recent, pressure level than with the preceding hypertension. This observation “challenges the concept that nephrosclerosis is accumulated irreversibly at a rate governed by severity and duration of hypertension” [49]. One must invoke some form of reversibility for what ap-

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pears to be a fixed, organic lesion. This observation, should it be confirmed by an equally detailed and careful investigation, shifts the focus from organic to functional abnormalities. These observations underline another major limitation, the difficulty of identifying vasoconstriction in routine histologic sections of devitalized tissue. Friedman et al. [50] utilized rapid freezing to capture the microvascular changes in an elegant study in the rat. A pressor response induced by the infusion of norepinephrine, or in sustained metacorticoid hypertension, was associated with a reduced arteriolar lumen due to cell shortening. Vascular hypertrophy and a change in the ratio of wall thickness to lumen radius [51] is not a necessary condition of the sustained hypertensive state. A parallel study has never been attempted in patients with essential hypertension, nor is it evident how such a study could be performed. Indirect methods are required to identify active vasoconstriction [52]. RENAL BLOOD FLOW IN ESSENTIAL HYPERTENSION

The Goldblatt experiment raised the possibility that “essential” hypertension could be a form of renal hypertension, due to reduced renal perfusion [42,43,53,54]. If renal vascular anatomy and renal blood flow are often normal, why in each decade is the question of a reduction in renal perfusion as the cause of essential hypertension again raised? The answer lies in the inherent weaknesses in the methods of evaluation. The problems in histologic assessment have been reviewed. The clearance technics reviewed by Homer Smith also have limitations: There is a remarkably large normal range, which exceeds 20 per cent in normal subjects despite correction for age and sex [55]. An adequate clearance study demands a prolonged steady-state, which is difficult to achieve. Measurement of renal perfusion requires normal, active tubular transport of the indicator. Both factors must have contributed to the large coefficient of variation. Finally, over the past three decades, interest in the renal blood supply has expanded to include regional intrarenal perfusion rates, which cannot be assessed by clearance technics. For all these reasons newer methods for assessing renal perfusion have been applied as they evolved over the past 15 years. The more recent studies have been based on indicator transit through the kidney after intra-arterial injection of either a dye (with venous sampling) or a radioactive tracer (with residue detection via external counting). These methods have proved accurate and convenient for the measurement of mean renal blood flow, and the character of indicator transit has provided additional

IN HYPERTENSIVE DISEASE-HOLLENBERG.

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insight into intrarenal perfusion patterns through a number of analytic technics. Dye-dilution: The appearance of dye curves recorded from the renal vein after the injection of dye into the renal artery is complex: the down slope rapidly deviates from a monoexponential, which may be attributed to slower transit through low flow compartments within the kidney [40,56], to recirculation [57], or to inadequate mixing of a dye in the renal artery and leakage of dye into extravascular space within the kidney [58]. Because recirculation of dye occurs at a critical juncture in the evolution of the diultion curve, Logan et al. [57] devised an elegant alternative approach for the assessment of cortical perfusion. In 15 patients with essential hypertension, total renal blood flow to a kidney was measured by a constant infusion of the indicator, allowing saturation of the entire system. A bolus injection of dye was then used to assess the blood flow traversing the most rapid circulatory compartment, which was reasonably presumed to reflect flow in the renal cortex. “Cortical” blood flow and volume correlated well with total flow, whereas noncot-tical flow was independent of the total flow. These observations suggested that a reduction of renal blood flow in patients with essential hypertension occurs primarily in the cortex, with relative preservation of noncortical or medullary elements. The reduction in cortical blood flow could have reflected either parenchymal atrophy or vasoconstriction. Lowenstein and co-workers [59] applied a mathematical integral transformation which was confined to the most rapid portion of the dye curves in eight normal subjects and in 12 patients with essential hypertension, to assess the distribution of blood flow with respect to renal blood volume across the renal vasculature. They found a reduction in mean renal blood flow in essential hypertension, but the distribution of transit times was unaltered, indicating the absence of a focal reduction in renal perfusion. They attributed their findings to uniform arteriolar vasoconstriction. This provocative study, obviously relevant to all the current questions on the relationship of renal perfusion to the pathogenesis of essential hypertension, raised a fundamental question concerning the role of active vasoconstriction in pathogenesis [59]. Kioschos and co-workers [40] studied a heterogeneous group of patients with hypertension. The average renal blood flow was normal in patients with uncomplicated essential hypertension: but since an increase in the rate of renal perfusion was demonstrated in some young hypertensive patients (discussed later), flow must have been reduced in the others. An additional feature of their study, apparent

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on examination of their Tables II through V, was the frequent, striking disparity in blood flow when sequential determinations were made on a single kidney. Sequential blood flow determinations revealed an absolute difference of 29.6 f 8.0 ml/min, or about 6 per cent in five normal subjects. A threefold larger difference (88.6 f 20.5 ml/min), about 18 per cent, was present in the 15 patients with essential hypertension in whom paired determinations were made. In seven of the 15 subjects, the difference in flow on two determinations exceeded 66 ml/min, the 95 per cent confidence interval for difference in their normal subjects. Although they did not comment on this observation, such a striking degree of variability must be attributed to phasic vasoconstriction. A more detailed investigation of this phenomenon that we have performed is described herein. Residue detection of diffusible radioactive gases: The application of xenon and krypton washout to the assessment of renal blood flow and intrarenal perfusion patterns has provided information which is qualitatively and quantitatively similar to that obtained by dye dilution in patients with essential hypertension. When xenon washout reveals a reduction of renal perfusion, the dominant abnormality involves the rapid or cortical component of renal blood flow [SO-661. We classified patients with essential hypertension according to a coded analysis of their intrarenal vessels as seen by selective renal arteriography. A correlation was demonstrable between the severity of the vascular lesions and the degree of reduction in renal blood flow, cortical blood flow and renal function as assessed by creatinine clearance [60]. In general, more severe abnormalities of the arteriogram and perfusion were associated with a longer duration and more severe hypertension, as reflected in the eye grounds and the electrocardiogram. At the same time Ladefoged and Pedersen [61] found that mean renal blood flow per unit tissue mass and the rapid or cortical component was less than the mean value in normal man in all hypertensive patients and concluded that “ischemia of the kidney seems . . . to be a characteristic of all human hypertension”. It should be noted, however, that their normal subjects were six men under 30 years of age, and that a decrease in blood flow with age has been documented both in normal man [55,67] and in hypertensive subjects [61]. The abnormality of renal blood flow was correlated with evidence of severe hypertension, as indicated in assessment of cardiac status, but not with the optic fundi. Cannon and co-workers [65,66] devised an elegant analytic technic based on weighted leastsquares which avoided the subjectivity inherent in compartmental analysis. A reduced cortical component of xenon washout was demonstrable with this

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rigorous approach in patients with essential hypertension. We found increased renin secretion in hypertensive patients with the most pronounced vascular lesions [68]. The relationship between the degree of arterial abnormality demonstrated by arteriography and both a reduced renal blood flow and elevated secretion was confirmed by Grunfeld and co-workers [64]. Similarly, the correlation between .reduced cortical blood flow and renin release in essential hypertension was well-documented by Blaufox et al. [63]. All three studies showed that renin release increased as mean and cortical blood flow decreased, posing the interesting question, “Is the increased renin release a cause or a consequence of the reduced renal blood flow?” The renal vessels are normally very sensitive to angiotensin II [ 191, and this sensitivity is enhanced in essential hypertension (vide intra). Preliminary studies in our laboratory have revealed a striking potentiation of the renal blood flow increase induced by blocking of the conversion of angiotensin I to II with SQ 20881 or the vascular action of angiotensin II with 1-sar, 8-ala angiotensin in some patients with essential hypertension. Too few patients with essential hypertension have as yet been studied to draw a firm conclusion concerning the frequency of this response. Given the striking concordance between a reduction of renal flow and renin release in the three studies cited, the opposite finding reported by Schalekamp et al. [69], and subsequently extended by the same group [70], was surprising. They found a reduced plasma renin concentration in patients in whom renal blood flow was reduced. The discrepancy may vyell reflect patient selection: The three concordant studies were performed in patients who came to arteriography, who tended to be younger and who often had severe disease [60,63,64]. The patients in the latter study were much more homogeneous in their clinical status, but more heterogeneous in their age range [69,70]. Indeed, there was a significant decrease in renal blood flow with age in their study [70], and there is also a well-documented decrease in plasma renin activity with increasing age [71,72] so that the correlation may have been fortuitous-both plasma renin and renal perfusion decreasing with age, but independently. It is difficult to ignore, however, the excellent correlations they demonstrated between blood flow, filtration fraction and plasma renin concentration and their speculation that suppression of plasma renin occurs because of pressure delivery to the juxtaglomerular cells. The interesting possibility exists that the decrease that occurs in plasma renin with age reflects this phenomenon. But, it is also evident from the other studies that advance of renal microvascular disease can

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lead, ultimately, quences.

to renin secretion

RENAL VASCULAR HYPERTENSION

REACTIVITY

and its conse-

IN ESSENTIAL

Because of its obvious pathogenetic implications, vascular reactivity has been the subject of longstanding interest in patients with essential hypertension [73,74]. Because of complicating systemic effects, a host of factors influencing a pressor response, and the alinear relationship between blood pressure and blood flow in all vascular beds, the most easily interpreted index is provided by the vascular response to a vasoactive agent infused directly into the artery supplying the tissue under study. With this approach the dose administered can be sufficiently small that systemic effects are avoided [!?I,75771. An increase in vascular responsiveness to stressful stimuli and vasoactive agents in the cutaneous and skeletal muscle vascular beds is welldocumented in patients with essential hypertension [75-771. In view of the continued interest in both renal hemodynamics on the one hand, and vascular reactivity on the other, there have been surprisingly few studies on renal vascular reactivity in patients with essential hypertension. This is especially important because evidence suggests that the vascular beds of the extremity may not participate in the process in a manner parallel to that of other vascular beds [ 78,791. Moreover none of the studies on renal vascular reactivity carried out in man have utilized the optimal approach, an intra-arterial infusion, not surprising in view of the relative inaccessibility of the renal artery. Gombos and co-workers [80] reported that renal vascular responses to epinephrine and norepinephrine administered intravenously were normal in patients with essential hypertension. Peart and Brown [81] reported a reduced renal vascular response to angiotensin administered intravenously, along with the reversal of the renal functional effects of angiotensin in patients with essential hypertension. Conversely, Wolf et al. [82] and Brod and his co-workers [78,79] reported a striking increase in the renal vascular response to nonpharmacologic stimuli, emotion and exercise in patients with essential hypertension. Selective renal arteriography clinically required in both normal potential kidney donors and in patients with essential hypertension has made it possible for us to assess the renal vascular response to angiotensin infused into the renal artery in graded doses too low to induce a systemic response. All those treated were in balance on a low salt intake. A doserelated renal blood flow reduction occurred in normal subjects and in the patients with essential hypertension. The renal response in patients with essential

ADAMS

hypertension was enhanced: Both a significant reduction in the threshold dose required to initiate a vascular response and a steeper slope relating drug dose to response were present. Folkow’s [51] lucid analysis provides entre to assessing the role of geometric factors and intrinsic reactivity in enhanced vascular responses. A potentiated response could be due to one of two factors: An enhanced mechanical advantage or an increase in the intrinsic responsiveness of the vascular smooth muscle. In the former case, an increase in the ratio of vessel wall thickness to lumen radius results in a larger reduction in radius with any degree of muscle shortening. Thus, no response will occur until muscle shortening is initiated and the threshold dose to induce a response is unchanged. With increasing doses, however, progressive enhancement of the response occurs so that the slope of the relationship is increased. Conversely, in the case of intrinsic enhancement of responsiveness because of modification of vascular smooth muscle, the threshold dose required to induce a response will be reduced and a parallel shift in the dose-response is anticipated. The demonstration of both a slope and intercept change in patients with essential hypertension, as we have shown, is attributable to both factors, intrinsic enhancement and geometric factors. Before attributing the change in slope to organic abnormalities, it is worthwhile considering the possible contribution of any vasoconstriction present prior to infusing the agent. Since vasoconstriction will both reduce the lumen and increase the thickness of the arteriolar wall [50], a steeper slope will occur even in the absence of organic vascular changes. These observations provide a mechanism by which enhanced renal vascular tone may be sustained in the absence of an increased concentration of the endogenous vasoconstrictor substances, angiotensin and norepinephrine, or abnormal vasoconstrictor substances.- To the extent that either or both hormones are present in increased concentration, the trend favoring an increased renal vascular tone would be potentiated. In view of the importance of the kidney in the long-term maintenance of sustained hypertension [9,10,33] these observations provide a linking mechanism. It is now reasonable to ask an even more difficult question: “Is renal vascular tone increased in essential hypertension, or do organic vascular changes account for all the abnormalities of perfusion?” RENAL VASCULAR TONE IN ESSENTIAL HYPERTENSION

How does one assay vascular tone? We have used two approaches to assess renal vascular tone in patients with essential and secondary hypertension.

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Our working hypothesis was that an organic lesion, reflecting permanent damage which is fixed, would be associated with a fixed reduction in renal blood flow, whereas a functional abnormality might be more variable. Our second working hypothesis was that the fixed, organic lesion would be unresponsive to vasodilators: Conversely, a functional abnormality might be expected to respond to dilators with an enhanced response. Both lines of investigation have led to an identical conclusion. There is, indeed, increased vascular tone in the renal bed of most patients with essential hypertension. Baldwin and co-workers [83] some years ago reported a striking difference in renal perfusion between the two kidneys when blood flow was measured by PAH clearance and bilateral ureteral catheterization in patients with essential hypertension. The difference was attributed, not unreasonably, to asymmetrical progression of organic microvascular disease. If an equivalent difference in renal perfusion could be demonstrated in sequential measurements of blood flow in the same kidney, this difference could not be attributed to organic changes and clearly must reflect a functional abnormality. We have demonstrated such a difference in sequential studies on the same kidney in patients with essential hypertension. When paired measurements were made of renal blood flow in 18 normal subjects, an average absolute difference of 39 f 7.7 ml/100 g/min was demonstrable, slightly but significantly in excess of analytic error: Thus low grade vasomotion was demonstrable in normal man. An identical analysis in 18 patients with essential hypertension demonstrated a 2.2 fold larger difference, 86 f 15 ml/100 g/Tin. Moreover, the abnormality was attributable to the “essential” element of the hypertension rather than the hypertension per se, since sequential measurements of renal perfusion in kidneys contralateral to a significant renal artery stenosis in eight patients revealed a normal degree of variability (37 f 13.9 ml/100 g/min). This analysis finds strong confirmation in the sequential studies reported by Kioschos and co-workers [40] whose data revealed a threefold increase in the variability of renal perfusion in patients with essential hypertension. This conclusion found major support from our studies with vasodilators. The increase in blood flow induced by acetylcholine and dopamine was blunted strikingly in patients with advanced nephrosclerosis, chronic pyelonephritis and polycystic kidney disease [52], all settings in which the fixed organic lesion contributing to abnormal renal perfusion might be anticipated. Conversely, the response to both agents was potentiated in nine of 13 (69 per cent) patients with mild essential hypertension. Moreover equivalent potentiation of the response to’ acetylcholine

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was induced in normal subjects by increasing renal vascular tone pharmacologically with angiotensin. Changes in the selective renal arteriogram were in excellent accord: The potentiated response to acetylcholine and phentolamine was associated with reversal of the small vessel abnormalities visualized in the arteriogram. Conversely, the reduced blood flow response in advanced nephrosclerosis or renal parenchymal disease was associated with a reduced angiographic response to the dilator. Thus, the second line of investigation also suggests an intrinsic increase in renal vascular tone in patients with essential hypertension. This approach also provided insight into the responsible mediator. Phentolamine, the alpha-adrenergic blocker, failed to increase renal blood flow in 15 normal subjects when infused into the renal artery over a wide dose range. The same agent increased renal blood flow in six of nine (67 per cent) patients with essential hypertension over a dose range that paralleled that for alpha-adrenergic blockade. Again, the responses evident in the selective renal arieriogram were in exceltent accord: Phentolamine reversed the visualizable small vessel abnormalities. The responses to phentolamine in patients with essential hypertension are in accord with an important role of catecholamines in the increase in the renal vascular resistance. Certainly the concentration of phentolamine achieved in the renal vasculature was more than adequate to result in significant alpha blockade [84]. Moreover the nonspecific effects of this agent involve vasoconstriction so that dilatation probably reflects the reversal of an adrenergic response [ 851. A number of methodologic and conceptual advances have led to a recent resurgance of interest in the role of catecholamines in the pathogenesis and maintenance of essential hypertension [86]. The mixed evidence may reflect the fact that autonomic activation in essential hypertension is regional, rather than generalized, so that tests for generalized activation are inadequate. The physiologic basis for the possibility that sympathetic activation may involve the renal vascular bed preferentially is well-defined. Certainly the characteristics of sympathetic control of the renal circulation are different from those in other vascular beds [87-911. Although the kidney is capable of intense, neurogenically-mediated constriction [92], there is no evidence of sympathetic activity to the kidney at rest [52,93]. Regionally differentiated activation of the sympathetic nervous system, probably representing outflow from different central neuron pools has been well demonstrated in many systems, especially the renal vasculature [87-911. Thus, activation can lead to a highly selec-

80

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tive increase

in renal vascular resistance.

The renal

vasculature shows special sensitivity to some afferent stimuli, and multiple stimuli may summate to induce renal vasoconstriction whereas other vascular beds are frequently engaged with a single stimulus. It is equally possible that catecholamine release in the renal vascular bed is normal in essential hypertension, and that the increase in tone maintained by catecholamines in these patients reflects a potentiated response to a normal local concentration. As methods for measuring catecholamines in plasma improves and technics for assessing local turnover evolve, this question should become answerable. PATIENT SUBGROUPS HYPERTENSION

secretory

of a blunted renin and aldosterone

response

and higher renal blood flow de-

spite equivalent levels of cardiac output and plasma volume suggests an abnormality in volume perception. This abnormality occurs sufficiently early in the disease that it could be causal. Thus, although a reduction in renal perfusion may cause hypertension in some patients, contribute to the pathogenesis in others and potentiate the effects as a complication in yet a third group, it is evident from these observations that renal ischemia is not the initiating event in all cases. A blood flow in the normal range, especially when the normal range is wide, may be abnormally low for that person. The same logic does not apply to a supranormal blood flow.

IN ESSENTIAL

It would be naive to believe that “essential”

The combination

ADAMS

hyper-

tension represents a single, homogeneous population. We have demonstrated an increase in renal vascular tone in about two-thirds of patients. Whether this represents a homogeneous group is unclear. What is clear is at least two additional groups of patients can be defined on the basis of clinical indices and the state of their renal vasculature. (1) Increased renal blood flow in some patients with essential hypertension: Three groups working independently with three different methods for assessing renal perfusion have demonstrated a significant increase in renal blood flow in some patients with essential hypertension. Renal perfusion was assessed with the clearance of paraminohippurate [39], local indicator dilution curves [40], and xenon washout [41]. In all studies the patients were characteristically young, and the hypertension was relatively mild and of recent onset. The increase in blood flow was not attributable to an increase in perfusion pressure, per se [4 11. Although it has been suggested that the mechanism responsible for the increase in renal blood flow may be an increase in cardiac output [40], in our studies the hypertension was not labile [41] and more recent investigation has shown a normal cardiac output in this group [94]. Failure of renal blood flow and its intrarenal distribution to respond normally to sodium restriction raises the possibility of a primary disorder of volume homeostasis in this population [41]. We have confirmed and extended the observations in a more detailed study performed in 23 patients with essential hypertension under 30 years of age [94]. A fascinating association between failure of renal blood flow to decrease with sodium restriction, on one hand, and a blunted plasma renin and plasma aldosterone response to diuretic-induced volume depletion on the other was demonstrated. There was no significant difference in cardiac index, total peripheral resistance or plasma volume in the responsive and unresponsive patients.

(2) “High-renin” essential hypertension: Laragh et al. [95] described a group of patients with essential hypertension in whom plasma renin activity was pathologically high. Two clinical correlates, a mild but unequivocal increase in the blood urea nitrogen concentration and a striking blood pressure response to propranolol administration, also suggested a distinctive syndrome. We have recognized a similar distinctive patient population in whom several observations appear to define the pathogenesis. Our coded arteriographic assessment identified a group of patients in whom renal blood flow was routinely reduced, in association with a striking abhormality of the renal arteriogram. In these patients hypertension was severe, with very high arterial blood pressure which was resistant to antihypertensive therapy in association

with frequent,

marked

abnormalities

of

the eye grounds, heart size and creatinine clearance. An unequivocal increase in the rate of renin secretion was documented and plasma renin activity was approximately threefold greater than normal [60,68]. More recently, we have in a similar patient population demonstrated a gratifying therapeutic response to the administration of propranolol, despite resistance to other antihypertensive combinations. The same patients showed a blunted renal vascular response to acetylcholine and dopamine, suggesting organic, fixed abnormalities of the renal microvasculature [52]. This group represents, we believe, patients in whom nephrosclerosis has become sufficiently advanced that it becomes the major determinant of renin secretion, with its consequences, a pathogenetic sequence similar to that of accelerated nephrosclerosis, but less in degree. A continuum of renal vascular abnormalities is suggested, ranging from a mild to moderate blood flow reduction due to a functional abnormality to a more striking abnormality associated with organic vascular lesions which may ultimately become sufficiently severe that its influence dominates the clinical picture.

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