Renovascular hypertension: Incidence, diagnosis, mechanism and treatment

.I Chron Dis 1973, Vol. 26, pp. 503-527. Pergamon Press. Printed in Great Britain

RENOVASCULAR HYPERTENSION : INCIDENCE, DIAGNOSIS, MECHANISM AND TREATMENT JOHN P. CAPELLI,LAURENCEG. WESSON,Jr. and EDMUNDL. HOUSEL Department of Medicine, Our Lady of Lourdes Hospital, Camden, New Jersey and the Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. (Received

21 September

1972; infinal.form

26 February

1973)

INTRODUCTION

Richard Bright [ 1J noted an association of kidney disease with elevated peripheral arterial pressure in 1827, the first clear theory of renal hypertension was that of Traube in 1856, who suggested that reductions in renal blood flow caused increased quantities of blood to enter the rest of the systemic circuit producing hypertension [2]. Excretory insufficiency leading to retention of agents causing vasoconstriction was a second theory advanced as a cause of renal hypertension [3]. A third concept and teleogical theory explained increased systemic pressure as a protective device for maintaining adequate glomerular filtration as a compensation for reductions in filtering surface area of damaged glomeruli [4]. Despite widespread belief among clinicians that the kidney was a prime factor in the genesis of hypertension, specific supporting evidence was meager. Strong evidence incriminating the kidney came with the experimental design of Goldblatt in 1928 [5]. Following Goldblatt’s experiment in dogs, occlusive renal artery techniques elicited hypertension in monkey, rat and other animals. The experimental setting was expanded by Page [6] who demonstrated that a constricting perinephritis elicited by wrapping a kidney in cellophane, silk or other material causing an inflammatory reaction could produce severe hypertension. Compression of intrarenal circulation was felt to be the factor producing the hypertension. Following these studies, Selye and Stone [7] demonstrated that aortic constriction above the left renal artery in the rat, leaving an intact circulation to the right kidney, could produce a severe, necrotizing hypertension even when the left kidney had lost its functional capacity to secrete urine. The continuation of the hypertensive process in the face of no excretory function, led Selye to coin the term ‘endocrine kidney’. The special interest engendered in the experiments was that a ‘nonfunctioning kidney’ is capable of initiating and sustaining hypertension through its persisting endocrine function. Butler applied Goldblatt’s concept to a clinical setting in 1937 and demonstrated the disappearance of hypertension following the removal of a pyelonephritic kidney in an 8 yr old boy [8]. The resulting effect upon the medical community might be termed 503 ALTHOUGH

504

JOHN P. CAPELLI, LAURENCEG. WESSON,Jr. and EDMUNDL. HOUSEL

the ‘Rape of the Nephros’, with indiscriminate application of nephrectomy for the treatment of hypertension. Fortunately, the entire subject came under critical review by Homer W. Smith in 1948. Smith proposed simple, but clearcut criteria for surgical cure of hypertension, i.e. unequivocal preexisting hypertension (blood pressure greater than 140/90 mmHg), and reduction of blood pressure levels to normal for at least 1 yr following nephrectomy [9]. Using these criteria, a cure rate of only 19 per cent (47/242) was established. In a later analysis, Smith [lo] found a cure rate of 26 per cent (149/575). Consequently, he concluded that the only indication for nephrectomy was a urological one. In the vast majority of the reported cases in Smith’s analysis pyelonephritic (atrophic) kidneys were the pathologic entities. Nevertheless, Smith cautioned against unnecessary and fruitless surgery. Fortunately, the harvesting of kidneys ceased while investigators took a closer look at the entire subject and role of the kidney in hypertension. One of the most significant contributors to clarifying renovascular hypertension was the development of aortography [ll, 121. The demonstration of stenotic lesions of the renal arterial tree permitted a more systematic approach to the study of hypertension and identification of those with potentially impaired renal blood flow. White [13] and Mueller et al [14] showed that the Goldblatt kidney in the dog excreted less urine and sodium than the contralateral kidney when filtration rate was only slightly depressed. Further studies of the effects of reduced arterial pressure on sodium excretion and urine concentration were provided by Selkurt [15] and by Berliner, Davidson and Levinsky [16-181. Clinical application of this physiologic data for demonstrating disparate kidney function in patients with suspected renovascular hypertension was made by Howard et al [19]. Lastly, the acquisition of techniques for the measurement of the separate renal venous pressor (renin) activities has gendered renewed interest in the endocrine role of the kidney in renovascular hypertension. FACTORS UNRESOLVED IN THE STUDY RENOVASCULAR HYPERTENSION

OF

(a) Incidence The incidence of renovascular hypertension has been estimated to range from 2 to 30 per cent of the hypertensive population [lo, 20-241. There have been 2 major problems in arriving at an actual estimate of this disease. The first has been the biased selection of cases for study; cases having been studied were those felt to yield the highest incidence of positive results. The second, most significant, but subtle, factor is the criteria used to establish a final diagnosis of renovascular hypertension. The presence of an arteriosclerotic plaque, or any variant of the renal vasculature, does not necessarily imply the presence of renovascular hypertension. The diagnosis of renovascular hypertension basically rests upon the demonstration of a favorable blood pressure response to surgical correction of a renal arterial stenosis. However, the demonstration of a significant functional compromise in one kidney with or without the elaboration of abnormal amounts of pressor material also provides strong evidence for this diagnosis. Poutasse, Dustan and Page [20] reported an incidence of 31 per cent in selected cases, while other groups reported an incidence of 50-90 per cent [25, 261 in similarly selected groups. Autopsy analyses have led to figures ranging from 4 to 86 per cent [27, 281. Even the report on the Cooperative Study of Renovascular Hypertension, wherein 2442 hypertensive patients were analyzed, made a

Renovascular

Hypertension:

Incidence, Diagnosis,

Mechanism and Treatment

50s

clear statement that no conclusions can be drawn from figures as to the prevalence of this disorder in the hypertensive population [29]. The requirements, therefore, to determine the incidence of this disease would be the study of an unselected population of hypertensives undergoing available diagnostic procedures together with the fulfillment of the above criteria. In the only known prospective study, Capelli, Housel, Zimskind et al [30] studied the incidence of renovascular hypertension in an unselected population of hypertensives. The final diagnosis was based upon a response to surgery and/or a positive split function study. The results revealed an incidence of renovascular hypertension in the general hypertensive population of 6 per cent. (b) Clinical features In a review of this subject by several investigators [22, 311, the seemingly uniform conclusion has been that little or no distinguishing clinical features exist between essential hypertension and renovascular hypertension. Generally, the clinical criteria suggesting further investigation for an occlusive renovascular problem have been summarized as follows: (1) onset of hypertension below the age of 30 or over the age of 50, particularly in those patients with a negative family history of hypertension; (2) the acceleration of diastolic blood pressure in any hypertensive patient previously under good control; (3) the development of hypertension following abdominal or flank trauma; (4) the development of hypertension in anyone suspected of arterial embolization; and (5) a patient with malignant hypertension. In analyzing the clinical characteristics of 175 patients with proven renovascular hypertension from the Cooperative Study, Simon et al concluded that the difference in clinical characteristics between patients with this entity and essential hypertension may more properly be considered quantitative than truly qualitative [32]. Despite the fact that patients with renovascular hypertension are more likely to be thin Caucasians, with a negative family history, these investigators concluded that there are no ‘distinctive’ features of renovascular hypertension. Abdominal bruits, which are reported to occur in 48 per cent of cases, are probably the single most valuable identifying clinical finding in renovascular hypertension [32]. Nevertheless, the diagnostic value is limited by the much greater frequency of essential hypertension in the hypertensive population. If bruits are heard in 9 per cent of the essential hypertension population, because of the size of this group, the frequency of nonrenovascular bruits may in fact exceed the entire renovascular group [32]. Consequently, the physician evaluating the hypertensive subject must decide which patient requires further study as a potential renovascular case. The special tests involved in this disorder are expensive, hazardous and time consuming for every hypertensive patient to be subjected. Therefore, the development of a clinical assessment program with relatively safe and inexpensive laboratory screening tests is necessary to select those patients who require further in-hospital study. (c) Diagnostic tests At the present time, there is no single test which is truly diagnostic of a functionally significant renal artery stenosis. As for screening studies, the intravenous urogram has been reported to indicate a disparity in approximately 80 per cent of the cases [33-371. This disparity has been represented in both renal sizes and pyelocalyceal dye concen-

506

JOHN P. CAPELLI,LAURENCEG. WESSON,Jr. and EDMUND L. HOUSEL

tration. Various manipulations of the intravenous urogram such as the timed [36, 381 or urea-washout [39, 401 urogram have been reported to increase the incidence of positive findings by 10-15 per cent. The major disadvantage with this test, however, lies in its specificity, since disparity of kidney size and/or function can occur in a variety of urologic diseases with or without hypertension. Also, assessing disparity of dye concentration can be extremely subjective. Nevertheless, the value of intravenous urography as a moderately satisfactory screening procedure was borne out by the Cooperative Study of Renovascular Hypertension [37]. In this study, the intravenous urogram was falsely abnormal in 11 per cent of the essential hypertensive population and falsely normal in 17 per cent of renovascular hypertensives. However, if the study is normal, then the likelihood of the patient having renovascular hypertension is less than 2 per cent. If the urogram is abnormal, the likelihood of renovascular hypertension is over 40 per cent [37]. The radioactive 1 1s1 sodium-0-iodohippurate (Hippuran) renogram has been suggested also as simple and safe screening procedure. This test has been reported to yield a high incidence (85 per cent) of positive results in patients with renovascular hypertension [41,42] ; however, a high incidence of false positive results has decreased the specificity of the test [43, 441. In addition to various technical problems, valid interpretation of the inscribed curve is by no means clear. The actual ‘vascular’ (renal artery) component of the curve probably represents less than 10 per cent of the initial upstroke while the remaining initial portion of the curve represents effective (total) renal blood flow, tubular uptake, concentration and secretion; the final portion of the curve represents pyelocalyceal and ureteral drainage. Since the resultant effect of significantly compromised renal blood flow must alter tubular function, changes in the second portion of the renogram curve will still be reflected; it only remains for the interpreter to realize that any one of a number of renal parenchymal diseases can similarly affect the renogram. There have been various modifications and specialization of the renogram, particularly the development of quantitative radiorenography, a technique relating fractional renal blood flow to total blood flow utilizing radioisotopic methods [45]. Another diagnostic radioisotope kidney test has been the renal scintiscan, utilizing chlormerodrin-HgzO’ and radioisotopic renal clearance tests. Nevertheless, the required technical skills and specialized equipment and the question of specificity have contributed to the lack of widespread use of radioisotopic testings. (d) Special studies 1. Arteriography. There is little doubt that the development of percutaneous arteriography utilizing the Seldinger technique has been the single most valuable study in the delineation of renal artery stenosis. With the present technique, morbidity from this procedure should be less than 1 per cent [46]. The limitations of this test are primarily those of patient sensitivity to iodides and the inability to distinguish functionally significant from functionally insignificant lesions. 2. Renal biopsy. Advocates of this test [47, 481 feel that functionally significant lesions of the renal vasculature will lead to a quantitative loss of tubular mass, i.e. ‘ischemic tubular atrophy’. Another application of this procedure has been the assessment of activity of the juxtaglomerular apparatus. This has been described in terms of

Renovascular

Hypertension:

Incidence, Diagnosis, Mechanism and Treatment

507

either total cell counts [49] or juxtaglomerular granularity [50]. The major drawback to both these histologic and histochemical techniques has been the inadequacy of tissue sampling. Ischemic tubular atrophy can be spotty in distribution; furthermore, quantitation of renal blood flow from subjective, histologic changes is not realistic. The same problem exists with histochemical techniques, since available methods are too crude to allow clinical application in a truly quantitative sense. In addition, sampling is even more difficult, since an adequate number of poilkissen must be present in the biopsy specimen. 3. Angiotensin infusion test. The infusion of angiotensin as a diagnostic test was described by Kaplan and Silah in 1964 [51 a, 61. This test is based upon the assumption that endogenous levels of angiotensin (and/or renin) are elevated in patients with true renovascular hypertension, thereby rendering them resistant to the pressor effects of infused angiotensin. Consequently, the higher the level of endogenous angiotensin, the more exogenous angiotensin will be needed to produce a given pressor effect. As the test was originally described, patients with renovascular hypertension require more than 6.5 ng/Kg/min; patients with nonmalignant forms of hypertension require a lesser dose, under 5 ng/Kg/min. However, several subsequent studies failed to confirm the original findings [52-541. The overall results revealed an overlap between renovascular and non-renovascular forms of hypertension, specifically when applied to individual cases. Further, the diminished hyporeactivity was shown to represent a nonspecific loss of reactivity since agents such as phenyllysine vasopressin produced similar results [54]. In addition, the dependence of pressor responsiveness is in part due to the state of salt and water balance, a parameter largely uncontrolled in reported studies. The lack of specificity, the ineffectiveness in surgical prognosis, the inherent risks in the test, and the availability of more specific procedures, have now caused this test to fall into disregard. 4. Plasma renin-angiotensin levels. Peripheral plasma renin assays in renal artery stenosis are generally of little value [55-571 unless accelerated hypertension exists [57]. Plasma renin levels are elevated in only lo-15 per cent of instances, so that emphasis has now been laid upon determinations of renin activity in the renal vein. The major limitation to this test has been the methodologic complexity of the assay technique. Until recently, the test was only available at research laboratories; however, it can now be obtained through many hospital and commercial laboratories. Secondly, techniques for catheterization of the renal vein may not be generally available and renal vein renin concentrations can lead to spurious conclusions. With the introduction of the radioimmunoassay, a more specific and reliable method of measurement for angiotensin activity became available. Although there are only a few scattered reports on the levels of plasma angiotensin in renovascular hypertension, the most extensive report, by Kotchen et al [58] failed to demonstrate elevated angiotensin II levels in any of the (49) patients studied. The renin-angiotensin system will be analyzed in greater depth in another part of this review. 5. Differential renal studies. Despite the inherit hazards of bilateral ureteral catheterization, the work of Howard [59] and Stamey [60], has left little doubt as to the value of this particular test in the assessment of functionally significant renal artery

508

JOHN P. CAPELLI, LAURENCEG. WESSON, Jr. and EDMUND L. HOUSEL

stenosis. This test assays the derangement in solute and water transport, based upon sound physiologic data [16], in a kidney whose renal blood flow and/or perfusion pressure is significantly compromised. The major limitations to this test are, first, that it is tedious and requires the expertise of a patient urologist; secondly, that instrumentation of the urinary tract carries a hazard, particularly in the diabetic; lastly, that interpretationof the results requires experience as well as physiologic understanding of the test. (e) Treatment Although emphasis has been on the surgical treatment of renovascular hypertension, in hopes for a cure with freedom from indefinite drug dependence, most patients can be successfully managed with available antihypertensive drug therapy [61-641. As with any form of hypertension, drug therapy must be tailored to each individual patient so that maximum benefit can be achieved with a minimum of side effects. One concern about drug treatment was the possibility that, even with good blood pressure control, the renal arterial disease would progress with eventual complete loss of renal function. Although there have been few studies in this area, Dustan, Meaney and Page [64] reported on 23 patients, 18 with atherosclerotic lesions and 5 with dysplasias of the renal artery, treated medically for l-6 yr. In 11 patients with atherosclerotic lesions, there was some progression of the lesions, but the effect upon renal function was judged to be minimal. Only 1 patient from the dysplastic group showed detectable progression, and this was slight. The control of the blood pressure in both groups was considered good. The surgical approach to treatment has been the most actively pursued once a stenotic lesion of the renal artery was demonstrated. Many surgical procedures are available, including nephrectomy, endarterectomy with or without patch graft, arterioplasty, aortorenal by-pass graft (saphenous vein or prosthesis) and splenorenal by-pass. Because of the multiple surgical approaches, the several types of lesions, the lack of uniform standards for assessing blood pressure response and the lack of follow-up reporting on the reasons for failure to respond, attempts to establish the value of surgery have had little success. In a number of postoperative follow-up studies for l-10 yr, the cure rate averages approximately 48 per cent, with an additional 40 per cent ‘improved’ [61,65-671. Operative mortality has averaged 4 per cent in one large series [66]. The patients in the improved groups are those whose blood pressure continues to require some form of drug therapy, albeit it is more easily controlled. Of the largest series of 627 treated patients [66], 32 per cent of the original group were normotensive and 69 per cent were improved at the end of 10 yr. This trend to lower cure rates in the longer follow-up periods was also seen in the earlier combined experiences of the Massachusetts General and Peter Bent Brigham Hospitals [68], but cannot as yet be clearly ascribed to the longer time interval. Fibrosing dysplastic lesions seem to have a better response to surgery than do the atherosclerotic lesions. In those series wherein the nature of the lesion is described, the overall improvement plus cure rate was 92 per cent in the dysplasias and 76 per cent in the atherosclerotic group [69-731. Thus, current evidence indicates that the initial response to surgery (i.e. cured and/or improved) should be in the range of 70-80 per cent with properly selected patients, but that within 2 yr or more, one can expect recurrence of hypertension in approximately 45 per cent of the ‘cured’ group (Table 1).

24 30 76 64 27 138 394 187 15 73 100 61

Wylie et al (1962) Stewart et al (1962) Dustan et al (1963) Kaufman et al (1964) Thompson er al (1964)

Sheps Morris etetalal(1965, (1966)1966) Before 5/l After 5/l/64/64

Fenton ef al (1966) Gifford et al (1967) Hunt et al (1969) Kjellbo et al (1969) 38 46

53 E

49 41 57

54 50 58 39 30

45

Normotensive

14 47 29 36 35

31 40 29

33 30 20 47 63

36

Improved

Blood pressure control -

*Results include all forms of surgical procedures for all types of renal arterial lesions.

Group mean

31

Patients treated and followed-ue (1220) .

33 27 16 26 19

20 19 14

13 20 22 14 7

19

Unchanged

%

5

0 8 0 7

0 47

0 6 10 5 4

18

Operative mortalitv % -

RESULTSFROMSURGICALCORRECTION OF RENALARTERYSTENOSIS IN SEVERALMEDICALCENTERS*

Perloff ef al (1961)

Reuortina Group -

TABLE1.

67 154 24 155

63 a, b 66

71 70 61 65 72

69

Reference

+

fJ

3 8 z e. 3 S z.

_E’

f’

E 6 L? P u

E. 0 .. E!

S

6 E f:

510

JOHN P. CAPELLI, LAURENCE G. WESSON,Jr. and EDMUNDL. HOUSEL

The fibrosing lesions have a much smaller operative risk as well as a better prognosis. The hypertension with both forms of stenosis can be managed satisfactorily with drug therapy in most instances in which surgery may not be considered the recommended treatment. THE RENIN-ANGIOTENSIN SYSTEM RENOVASCULAR HYPERTENSION

IN

Since the classical studies of Page and Braun-Menendez, investigators have tried to implicate the renin-angiotensin system in hypertensive states. After 20 yr, this effort remains largely unsuccessful. Gross et al [74] were unable to correlate the level of blood pressure with activity of a renin mechanism in renal artery stenosed rats. Placing a clamp on one renal artery induced an increase in renal renin content in the ischemic kidney and concomitant decrease in renin in the contralateral kidney whether or not systemic hypertension developed. With the development of systemic hypertension, removal of the nonconstricted kidney leads to a reduction of renal renin content to normal in the ischemic kidney despite persistence of hypertension. Sodium loading will also lower renin content of the ischemic kidney despite persistence of hypertension. Sodium restriction and/or adrenalectomy leads to high renal renin levels with normal to low blood pressure, while salt loading and DOCA leads to hypertension in the virtual absence of intrarenal or circulating renin. Such contradictions preclude ascribing to the renin system a preeminent role in the pathogenesis of renovascular hypertension. Koletsky et al, however, presented evidence for participation of a humoral mechanism in the early stages of the Goldblatt hypertensive rat [75, 761. During the first 2-3 weeks following suprarenal aortic constriction, blood from the renal vein of the ischemic left kidney contained high activity of a vasopressor substance with properties similar to angiotensin. Peripheral blood also contained this activity. After 3 weeks pressor activity disappeared, correlating with restoration of renal arterial pressure to the ischemic renal artery, despite persistence of the hypertension. These experiments suggested that during the early, ‘induction’ phases of renovascular hypertension, a humoral mechanism was active which was supplanted by another, unexplained, mechanism in the later, chronic stages of the hypertension. Renin and its effector substance, angiotensin, undoubtedly can lead to chronic hypertension under a variety of experimental situations. Application of unilateral renal artery clamps [773, repetitive subcutaneous injection of renin [78-803, chronic infusion of angiotensin [81-831, or the induction of intrarenal ischemia by cellophane perinephritis [6, 841, can all result in systemic hypertension. Increased levels of pressor activity appear to be the major factor during the early phases of the hypertension, while in the later stages either a reduced but still significant pressor activity is demonstrable or else normally subpressor amounts of material are sufficient to sustain the hypertension. Despite the fact that persistent elevations of renin-angiotensin activity are almost uniformly lacking in the chronic experimental renovascular hypertensive preparation unless the animal develops the malignant hypertensive syndrome, studies with the antirenin antibody suggest a continued role of this system despite ‘normal’ plasma levels [85, 861. Blood pressure elevations of dogs, hypertensive for years because of constriction of the main renal arteries, became normotensive when repeated injections of acetylated renin produced significant titers of antirenin antibody [86]. Unfortunately,

Renovascular

Hypertension : Incidence, Diagnosis,

Mechanism and Treatment

511

the significance of these renin antibody studies is marred by the impurity of the renin protein, since nonspecific depressor responses from foreign protein or peptide fragments could also account for the observed changes. Turning to studies in human renovascular hypertension, there is evidence both for and against a pathogenetic role of the renin-angiotensin system. In the following discussion, ‘renin’ will refer to ‘renin activity,’ the measurement which has been made in most studies. ‘Renin’ is measured by angiotensin generated by semipurified renin extracted from plasma or tissue. ‘Renin activity’ is measured by angiotensin generated within the plasma sample itself under partially controlled conditions including inhibitionofangiotensinase. When the difference between the assays is significant, they will be termed ‘true renin’ and ‘renin activity’, respectively. In uncomplicated essential hypertension, renin and angiotensin II values are uniformly normal or low [87-901. Although initial reports suggested that elevation of plasma renin activity might differentiate renovascular from essential hypertension [91], it is now clear that considerable overlap of plasma renin values exists among all forms of hypertension (except the malignant hypertensive syndrome) [88]. Del Greco et al [92] estimated that 42 per cent of patients with renovascular hypertension have normal peripheral renin activity levels. Confusing evaluation of published reports is that little or no mention is made of the state of sodium balance at the time of the renin determination. Early studies measuring blood angiotensin levels also failed to demonstrate consistent elevations in established renovascular hypertension [93, 943. Recent studies, however, utilizing the radioimmunoassay technique, have reported more frequent elevations of angiotensin II in renal artery stenosis [95-971, although, again, considerable overlap with essential hypertension is present [90]. Further studies are clearly needed with control of sodium balance, differential function studies, renin secretory rates and response to surgery. In recent years, investigators have reported on the inequality of renin concentrations between the 2 renal veins of patients with functionally significant lesions who responded to surgical correction [25,98,99]. Although the evidence seems clear that an elevated renal vein renin ratio (ischemic renal vein renimcontralateral renal vein renin > 1.7) is an indicator of a functionally significant lesion [99], the physiological role of renin under these circumstances still remains to be defined for several reasons. First, infusions of angiotensin acutely into both animals and man at rates sufficient to elevate blood pressure produce hemodynamic changes not seen in the hypertensive man. Systemic arterial and venous pressures rise, heart rate and cardiac output fall, moderate vasoconstriction occurs in the skin and lungs [lOO-1021, renal blood flow and excretion of water and electrolytes fall sharply [lOO]. Aside from the raised arterial blood pressure, a few of these features are seen in the hypertensive patient, although hemodynamic information is lacking in man during long-term angiotensin infusions. The changes in systemic hemodynamics are of particular interest since the patient with renovascular hypertension may behave differently from the patient with essential hypertension. Characteristically, the patient with established essential hypertension has a normal cardiac rate and cardiac output with an elevation in peripheral resistance [103, 1041. In a well-controlled study by Frohlich and coworkers [105], cardiac output was higher in all renovascular hypertensives than in their matched essential hypertensive counterparts. Ledingham and coworkers [lo&1081 have shown, experimentally, that cardiac output is depressed early in the development of renovascular hypertension,

512

JOHN P. CAPELLI,LAURENCEG. WESSON,Jr. and EDMUNDL. HOUSEL

but exceeds normal values by approximately 10 per cent at the end of the first week. This increase was attributable to equal increases in heart rate and stroke volume. Reversal of this hemodynamic state following correction of the ischemic lesion is seen to occur in about 12 hr. The initial fall in blood pressure results from a sharp drop in cardiac output, as peripheral resistance is actually increased. Within 6 hr, the peripheral resistance declines towards normal with a concomitant rise in cardiac output. Similar controlled longitudinal studies in humans with and without surgically corrected renovascular hypertension would .be valuable. Nearly all measurements of renin whether in renal tissue, renal venous blood, or peripheral plasma are referred in terms of concentration. This usually takes the form of nanograms of angiotensin I (converted to angiotensin II in a bioassay rat) produced by renin from an excess of substrate per unit volume of blood (ml, 100 ml) per unit time (min, hr). This concentration term must be distinguished from rates of synthesis, release, or removal of the enzyme, renin, since there is a tendency to ascribe changes in renin activity (angiotensin production) to changes in synthesis. An important example is a significant, unilateral renal artery stenosis associated with hypertension. The blood flow to the stenosed kidney is commonly about half that to the normal, contralateral kidney. At the same time, renal venous renin activity from the stenosed kidney is usually approximately double that from the uninvolved kidney, indicating that renin liberation into the peripheral plasma from the involved kidney may not be significantly elevated.* Because of the increased analytical needs and sometimes the technical problems, renin secretory measurements have seldom been measured. Hosie et al [109], in a careful study utilizing anesthetized dogs with simultaneous measurements of renal blood flow, renal arteriovenous differences of true renin concentration, and renal lymphatic renin, failed to demonstrate a consistent correlation of renin secretion with renal artery stenosis unless the renal vein true renin concentrations were high and the arterial concentrations were low. Negative venous-arterial differences were observed in several instances, i.e. more renin entered the kidney than emerged in the renal vein. These observations confirmed earlier studies [l 10, 1111, although the latter employed the measurement of renin activity. Changes of renin activity do not necessarily parallel changes of renin concentration [112]. In the largest single group of patients, Hollenberg and associates [113] measured renin secretory rates in essential and accelerated hypertensives utilizing the ‘33xenon wash-out technique to estimate renal blood flow.

*In a hypothetical example, let Vs, Vn and A be renin activity in units/ml from vein from stenosed kidney, vein from normal kidney and artery values of 50, 30 and 10, respectively. Let Fs and Fn be corresponding renal blood flows from stenosed and normal kidney with measured values of 500 and 250 ml/min, respectively. The amount of new renin (Q) introduced into renal venous blood equals the amount, FV, leaving in the vein after subtracting the amount, FA, entering through the artery: Q=FV-FA. The ratio of renin release by the stenosed kidney to that from the normal kidney, Qs Fs(Vs-A) _ ??.!__~. Qn Fn(Vn-A)

250(50-lo)=, .=_ 500(30-10)

o

’ ’

In the same example, the ratio of the two renal venous concentrations

is:

Renovascular

Hypertension:

Incidence, Diagnosis, Mechanism and Treatment

513

In the uncomplicated essential hypertensives, renin secretory rates were low; with progressive severity of intrarenal vascular disease and/or accelerated hypertension, plasma renin activity correlated with levels of renin secretion. In another study by Hollenberg and associates [114], renin secretory rates were measured in 4 patients with renovascular hypertension; all four patients had elevated total secretory rates (that is, combining the values for stenosed and normal kidney) when compared to uncomplicated essential hypertension. The data are difficult to interpret since all 4 patients had normal arterial renin levels, while the group of accelerated hypertensives (5 patients) with similar secretory rates, had elevated peripheral renin levels. In our studies, a patient with renal artery stenosis and who responded well to surgery had equal secretory rates from stenosed and normal kidney, although renal vein ratios indicated an increased renin activity from the ischemic kidney [30]. Bourgoignie ef al [115], reporting on renal venous renin in hypertensives with varying degrees of renal artery stenosis, measured a reduced renin secretion in the stenosed kidney as compared to the intact kidney in 3 cases and an increased secretion in 1 case. In the latter instance, the renin values were unusually highforthedegree of renal blood flow, and the state of sodium balances was not reported during the study. They note that increased renal venous renin activity may be due to decreased renal blood flow rather than to increased secretion of renin. Consequently, few if any human studies support the contention that a kidney with impaired renal blood flow is releasing more renin. The impression that neither renin nor angiotensin play a major role in established renovascular hypertension derives further support from a recent study by MacDonald and coworkers [116]. They found that animals immunized against angiotensin maintained their Goldblatt hypertension despite obliteration of pressor responses to exogenous angiotensin. Nevertheless, the lack of definitive evidence implicating the reninangiotensin system in the pathogenesis of established renovascular hypertension does not render measurements valueless; renal vein renin determinations appear capable of predicting a good response to surgery in over 90 per cent of instances [25, 98, 99, 114, 115, 117-1211 and for this reason have clinical value (Table 2). A more meaningful aspect of the role of renin in renovascular hypertension requires consideration of the vascular neuromuscular system stimulated by angiotensin. Evidence which is not yet conclusive suggests that changes in both vascular smooth muscle and the autonomic nervous system can increase their response to angiotensin so that hypertension could ensue despite normal levels of angiotensin. Sensitivity of vascular muscle to pressor agents appears to be correlated directly with its sodium, water and possibly calcium content [122-l 261. Correspondingly, increased sodium and water concentrations have been reported in experimental renovascular hypertension in rat [127], rabbit [128] and dog [129]. Not clear from these studies is the extent to which the electrolyte changes are caused by the hypertension rather than predisposed to it. Observations that angiotensin can induce sodium entry into vascular smooth muscle [122, 1301 could support either view. Although similar measurements have not been made in man, sensitivity of human forearm blood vessels to angiotensin appears to be a direct function of plasma sodium concentration [131]. Thus, irz vitro observations on vascular reactivity have been confirmed in animal studies, as well as implicated in various human observations. Imbs et al [I321 have demonstrated increasing vascular responsiveness as measured by maintenance of a set level of hypertension to continuous infusions of renin in rabbit preparations. In

16 6 8 18 9 6 8

Patient number

100 100 100 94 100 100 100

0 0 0 6 0 0 0

B.P. unchanged

%

(post-operatively)

B.P. improved

Abnormal ratio* -

15 2 7 3 3 11 4

Patient number

y0

0 0 14 33 0 36 25

criteria.

100 100 86 67 3 64 75

B.P. unchanged (post-operatively)

B.P. improved

Normal ratio -

*Renal vein renin ratios are explained in the text. Normal vs abnormal is defined on the basis of each individual investigator’s

Judson et al (1965) Kirkendall et al (1967) Fitz (1967) Michelakis et al (1967) Winer el al (1967) Amsterdam ef al (1969) Bourgoignie et al (1970)

Reporting group

117 99 98 120 121 119 115

Reference

TABLE 2. RESULTS OF RENAL VEIN RENIN RATIOS IN PREDICTING BLOOD PRESSURE RESPONSE TO SURGERY IN UNILATERAL MAIN RENAL ARTERIAL LESIONS

r

Renovascular

Hypertension:

Incidence, Diagnosis, Mechanism and Treatment

515

rabbits, the progressive pressor response to smaller doses of angiotensin could be blocked by adrenergic blockade [133], suggesting that enhancement of responsiveness was mediated reflexly through the autonomic nervous system. The authors postulated a resetting of the baroreceptors possibly in response to vasoconstriction of vessels supplying medullary vasomotor centers. Dietary sodium profoundly affects response to exogenous angiotensin. Pressor doses of angiotensin failed to sustain hypertension in subjects on low salt diets, whereas steadily decreasing quantities of angiotensin were required to sustain a constant level of hypertension in subjects on a high salt diet [83]. A positive sodium balance due perhaps in part to aldosterone stimulation appeared parallel with and possibly contributes to, the increasing sensitivity to angiotensin. Efforts to explain chronic renovascular hypertension through the renin-angiotensin system alone, with or without angiotensin-dependent ionic shifts in vascular smooth muscle, are frustrated by the observation of prompt systemic blood pressure response when the hypertension is corrected by surgery. This is not meant to exclude the system since renin may indeed play an initiating or integrating role in this condition. Rather, the conclusion emphasizes that other areas of renal humoral and metabolic functions, and systematic neural hemodynamic changes need to be considered and studied before the mechanism of renovascular hypertension is understood.

DIFFERENTIAL

RENAL

FUNCTION

STUDIES

The effects of renal artery constriction upon glomerular filtration rate and sodium and water excretion in dogs were described in 1950 and 1951 by Blake, Wegria and Ward [134], White [13] and Mueller et al [141. The most conspicuous disturbances observed by these investigators were reductions in Na and water excretions with proportionally lesser degrees of GFR depression following partial occlusion of one main renal artery. Following removal of the contralateral kidney, Na and water excretion increased in the chronically ischemic kidney to equal the amount originally excreted by both kidneys. Howard et al [19] applied the physiological findings to a patient with severe hypertension in whom the arteriogram disclosed a main renal artery stenosis and the hypertension was relieved by nephrectomy. Hulet et al [135] provided additional data on separated renal function in man. Birchall, Batson and Moore [136] then added the observation that non-reabsorbed solutes such as inulin and creatinine would be increased in concentration on the affected side. Stamey utilized these principles, namely, enhancement of the negative free water clearance together with hyperconcentration of the non-reabsorbable solutes by the ischemic kidney, to modify the technique of Howard on the premise that maneuvers enhancing renal concentrating capacity will tend to accentuate disparity of function between an ischemic and non-ischemic kidney [ 1371. He further introduced the concept of adequacy of total renal blood flow in the noninvolved kidney, i.e. freedom of small vessel disease, as a prerequisite for surgery and considered this latter factor of importance equal to changes found in the involved kidney. Howard [59] later modified his criteria to provide for the value of solute, i.e. creatinine and urine osmolality, in detecting functionally significant stenosis. Rapoport proposed a formula which would utilize concentration measurements alone, thus eliminating a major source of error in urine flow measurements [138]. Comparative excretion rates of intramuscularly E

516

JOHNP. CAPELLI,LAURENCEG. WESTON,Jr. and EDMUND L. HOUSEL

injected p-ammohippurate has proven useful in our studies [30]. This yields the ratio between the effective renal plasma flow of the two kidneys as recommended by Stamey, but it cannot give their absolute values. The sacrifice for simplicity has not proven serious since the presence of significant flow impairment of the contralateral kidney can usually be inferred from other measurements. Renal arterial narrowing modifies excretion by two mechanisms: reduction in perfusion pressure; and a decrease in total renal blood flow and/or a modification of its intrarenal distribution. When filtration rate is reduced in both kidneys simultaneously, the immediate effect is a reduced excretion of salt and water. The resulting fluid retention leads to volume expansion with reductions in renal tubular reabsorptive capacity, restoring salt and water balance to normal. When GFR is reduced in only 1 kidney, salt and water excretion from it are persistently depressed, because compensatory responses preventing indefinite volume expansion occur primarily in the contralateral, uninvolved kidney. Apparently because of intrarenal autoregulation, depressions in GFR and RPF are not seen (experimentally) until the pressure distal to the stenosis is reduced by at least 40 mmHg. Similarly, salt and water excretion do not change until GFR and RPF decrease. However, small changes in GFR, when initiated, can induce significant alterations in salt and water transport by the nephron [139]. The amount of filtered sodium is less, the fractional sodium reabsorption is increased and quantitatively less sodium is excreted. Thus, a striking feature of unilateral decreases in GFR is depression of sodiumexcretion out ofproportion to the glomerular change. As a result of enhancement of salt and water reabsorption in the proximal tubule, a reduced solute and water delivery to the distal diluting and concentrating segments of the nephrons blunt generation of solute-free water, thus leading to the characteristic negative free-water clearance and increased concentration observed in the kidneys. When salt and water reabsorption are increased then urea reabsorption will be similarly enhanced as a result of the increased urea concentration gradient throughout the nephron. Larger decreases in GFR and distal sodium delivery can lead to sufficiently extensive proximal segment reabsorption of urea that amounts of urea reaching the medulla to sustain medullary concentrating capacity are inadequate and urine osmolality is impaired, possibly to below that of the uninvolved kidney. Thus, the basis of one of Stamey’s procedures is to facilitate hyperconcentration by infusing urea during the procedure. Not only should a previously lost medullary concentration gradient in the stenosed kidney be reestablished but the urine osmotic concentration difference between the two kidneys should be widened. To analyze the predictive value of differential renal function studies several factors must be considered, foremost among which is the skill of the urologist. After this, the type of lesion as shown by arteriography must be considered, i.e. stenosis of the main renal artery, bilateral stenoses, segmental stenosis with or without main renal artery stenosis, chronic pyelonephritis, or hypertensive renal parenchymal disease. From the foregoing physiologic considerations, it is clear that unless one is dealing with occlusive disease of the main renal artery unaccompanied by parenchymal renal disease, variations of intrarenal hemodynamics in the other types of lesions are of such magnitude as to preclude reasonable predictability for successful surgery. Lastly, the methodology should be carefully identified in comparing results of one investigator with those of another. Unfortunately, a good deal of technical variation exists from one group to another, despite utilization of supposedly similar techniques of study.

Improved Negative test

: 0 0 0(55)* O(82)

38

6 1 6

33 0 33

PRESURE

50 100 78 80 100 lOO(45) 82

using a “Stamey

17 100 33

Bilateral main renal arterial lesions

8 3 9 5 4 11 11

*Value in parenthesis reflects results when split function studies were calculated UV~~/IJPHA ratio divided by value for normal kidney Uv,,t/l_Jp~~ ratio.

Perloff et al (I 961) Maxwell (1962) Dustan et al (1963)

Perloff et al (1961) Maxwell (1962) Dustan et al (1963) Stewart et al (1965) Richardson et al (1965) Fair et al (1971) Palmer (1971)

Segmental renal arterial lesions

Positive test

BLOOD

Ratio”

TO SURGICAL

140 61 59 141 142 143 145 10 10 17 0 0 0

10

(Wv,,l/Up&;

value for the affected kidney

69 140 61

145 146 18 0 :(18)

33 0 17

51. 3 % a L3 ?J c 3 E! rc

142

20 0 0 0

17 0 17

F

1::

22 0 0

Et a “G’

5’

u

ae. !? a ‘p

5 ? B u) El ij* ..

E ;rl

@

!z

P

0 0 22

:‘z 17 0 22 7

69

Reference

13

Negative test

TREATMENT

0

Positive test

% Unchanged

RESPONSES

Blood pressure response -

STUDIES IN PREDICTING

Perloff et nl(l961) Maxwell (1962) Dustan et al (1963) Howard et al (1964) Stewart et al (1965) Richardson et af (1965) Starney (1966) Palmer (1971)

FUNCTION

Unilateral main renal arterial lesions 8 15 12 10 50 30 65 10 20 61 20 61 5 23 75 25 4 78 0 23 93 0 45

OF DIFFERENTIAL RENAL

Patients studied

RESULTS

Reporting group

TABLE 3.

518

JOHN P. CAPELLI, LAURENCE G. WESSON, Jr. and EDMUND L. HOUSEL

The predictive value of differential renal function may be estimated from some representative studies (Table 3). Sixty-five per cent of 85 patients with unilateral main renal artery stenosis and subjected to the Howard test had a good response to surgery as judged by blood pressure return to normal or to previously mild hypertensive levels from 6 to 12 months after renal surgery [59,61,69,140-1421. However, 14 per cent of these cases had unequivocally negative tests, yet a good response to surgery resulted. According to results reported by Stamey [143] a good response occurred in 18 of 23 patients, or 78 per cent operated upon for unilateral main renal artery disease. In the 5 patients whose blood pressure remained unchanged post-operatively, the effective plasma flow in the contralateral kidney was considerably reduced and less than 210 ml/min/1.73 m3. However, all of 8 patients in this group with normalcontralateral renal plasma flows were cured of their hypertension. The remaining 15 patients had arteriosclerotic vascular disease and of these, 5 were considered cured while another 5 were improved. The predictive value of good contralateral renal blood flow (greater than 250 ml/min) in patients considered for renovascular surgery appears to be confirmed now by several lines of evidence. Vertes et al correlated PAH clearances with renal histology in 84 hypertensive patients [144]. They found excellent correlation between the presence of significant small-vessel disease and PAH clearances under 200 ml/min. In a more recent study, Palmer (145) measured renal plasma flows in 55 surgically treated patients with proven unilateral lesions. Of this group, 41 were cured or improved by surgery with all but 3 of these having contralateral renal blood flow greater than 260 ml/min. All of 14 patients unimproved by surgery had contralateral renal blood flows under 240 ml/min. The predictive value of differential renal function studies for surgical response to treatment of segmental arterial lesions or bilateral main renal artery lesions falls far short of that seen for main renal arterial stenosis, although Stamey has suggested criteria for segmental lesions [137]. These included at least a 2:l difference in urine flow rate and a 16 per cent or greater increase in PAH concentration from the affected kidney. Branch lesions produce proportional reductions in glomerular filtration and urine flow. However, because the area adjacent to the ischemic area may actually be hyperemic, variations in Na excretions may range from much lower to much higher in the affected kidney than in the contralateral kidney [59, 1461. The frequently minimal degree of difference between the intact kidney and the kidney with segmental stenosis has recently prompted Stamey to suggest abandonment of previously established criteria [ 1461. In those instances of bilateral main renal artery stenosis, onesideis usually more severely affected, so that urine volumes and solute excretion are disparate [59]. Nevertheless, there is too much variation to establish any predictive value of results of surgery from split function studies in these cases [59, 61, 69, 140-142, 1461. Improvement with surgery has been reported in approximately 25 per cent of cases with bilateral stenosis having a positive test, while an equal number responded despite a negative test. In branch stenosis, only 10 per cent of cases responded as predicted while 75 per cent of cases with negative tests responded to surgical correction. The problem of unilateral pyelonephritis and hypertension deserves a separate review. From the functional standpoint, the pyelonephritic kidney is entirely different from the hemodynamically impaired kidney. The major defect in the pyelonephritic kidney is tubular damage with loss of concentrating capacity and ability to retain sodium, the functional antithesis of the ischemic kidney. These characteristics set it

Renovascular

Hypertension:

Incidence, Diagnosis, Mechanism and Treatment

519

apart from the ischemic kidney where the primary defect is with largely intact nephron function and loss of blood flow and perfusion pressure. Only in lower urine volume does the pyelonephritic kidney usually differ from the normal contralateral organ. Comparative rates of sodium excretion tend to be variable, although creatinine concentrations are generally normal to low [59]. Among 22 hypertensive patients with unilateral pyelonephritis studied by Capelli et al [30], all were negative by the Howard, Stamey and Rapoport Criteria, but 9 had significant relative depression of PAH excretion. Reduction in volume flow was the major factor correlating with abnormally low excretion rates since PAH concentrations were approximately equal for each kidney despite unilateral disease. More pyelonephritic kidneys have apparently been removed without relief of the hypertension or benefit to the patient than has been the case with any other lesion [9, lo]. Two important conclusions emerge from the data on differential function measurements. First, the hemodynamically induced functional changes which exist in the kidney with compromised renal perfusion due to a single main renal artery lesion fail to explain the mechanism by which the kidney initiates the hypertensive state. Second, surgery should be reserved for those patients with renal artery stenosis whose differential function studies meet the criteria established by Howard or Stamey and further provided that the RPF in the contralateral kidney is adequate or greater than 250 ml/min. The cure or improvement rate under these conditions should approach 90 per cent. When dealing with bilateral stenosis, segmental lesions, chronic pyelonephritis and any lesions associated with impaired renal function, split function studies offer little predictability of surgical cure. CLINICAL

CONSIDERATIONS

Once a stenotic lesion of the major renal vasculature has been demonstrated by arteriography, the decision facing the clinician is whether surgery is indicated. Many factors influence this decision and they have been clarified with increasing experience. The initial factors to consider are the severity of the hypertension, its response to conventional medical management and the ability of the patient to tolerate and adhere to the drug regimen. The majority of patients with renovascular hypertension secondary to atherosclerotic lesions in the over 55 age group appear to respond well to medical management and do not show progressions of their lesions [64]. The second factor to be considered is the general condition of the patient and the extent of complicating illness such as diabetes, heart disease, cerebral vascular disease and so forth. In other words, just what is the surgical risk to the patient whose hypertension can be controlled by drug therapy. When this risk is minimal, the third factor to be considered is the available surgical skills. A nephrectomy is a rather simple procedure and within the realm of any competent urologist or general surgeon, while reconstructive vascular surgery is a procedure demanding special surgical skills. It should be evident that preservation of renal function should be always the prime objective. Nephrectomy should be limited to cases of non-functioning kidneys, extensive aneurysms of the renal artery and secondary graft failures. If the clinical situation meets these criteria, then the decision rests upon whether surgery is primarily to relieve the hypertension or to revascularize the kidney. For relief of hypertension, two specific tests are available to the clinician to aid in predicting whether surgery will relieve the hypertension, i.e. differential renal function studies and/or renal vein renin concentration ratios. This

CORRELATIONAND

8 3 2 3

Pt. no.

+(8)* f(3) +(l) +(3)

R:R ratio abn.

Group I

:i:; +(l) +(3)

Split function pos.

10* 19*

3

Pt. no.

-Indicates

test did not correlate with surgical response.

-(3)

Split function neg. 6 0 3 4

Pt. no.

SPLIT

1*

-(3) -(2) t(2)

+(6)

R:R ratio normal

+(3) -t(2) -(2)

-(6)

Split function pos.

IN

3

1

Pt. no.

FUNCTIONSTUDIES

Group III

AND

*Specific correlation undetermined in text, but results suggested strong correlation with tests and surgical response as indicated.

Number in parenthesis refers to actual number of patients studied in that particular test group.

+(3)

R:R ratio abn.

Group II

COMPARISONOF THE PREDICTIVEVALUEOF RENAL VEIN RENIN RATIOS(R:R) RENOVASCULARHYPERTENSION

*$-Indicates test showed a positive correlation with surgical response.

Kirkendallav FitzDS

Judson”’ WinerIe Kaneko15B Bourgoigniells

Group

TARLE 4.

+(3)

+(l)

R:R ratio normal

Group IV

+(3)

i-(l)

Split function normal

THE SURGICALCURE OF

Renovascular

Hypertension:

Incidence, Diagnosis,

Mechanism and Treatment

521

statement holds, true, however, only for lesions of the main renal artery. Despite recent claims of high predictability for renal vein renin concentrations, the data reveal that the predictability for these two tests is approximately equal when one is dealing with stenosis of the main renal artery (Table 4). For segmental lesions, bilateral stenoses and unilateral pyelonephritis, the split function study by any criteria does not emerge as a reliable and predictable test. Whether renal vein renin ratios will be useful in these circumstances remains to be seen since adequate data in these groups are not yet available. If the decision for surgery rests with the primary need for revascularization, then the clinician need not be concerned with predictability of response but rather with the nature and the extent of the lesion and the remaining renal function present. The renal artery dysplasias are now subdivided according to histologic types, the nature of which appears to differ one from the other [147-1491. Intimal, fibromuscular, and subadvential hyperplasia are considered progressive in their clinical behavior [149]. Consequently, thrombotic occlusion and renal infarction are to be averted by aggressive surgical revascularization. The medial fibroplasia type does not seem to show this progressive feature [149]. Correction of atherosclerotic lesions to improve blood flow should be indicated by the degree of occlusion demonstrable by arteriography, i.e. greater than 50 per cent occlusion [73]. This has proven reliable also in our experience. Thus, split function studies or renal vein renin ratios will not affect the indication for surgery in these instances where preservation of functioning renal tissue is the prime objective with improvement of hypertension, if present, a beneficial ‘sideeffect’ of the surgery. However, separated renal function studies can be useful if one is dealing with very severe renal artery stenosis and a small kidney (under 11 cm). Depressed renal function may be discovered, e.g. creatinine clearance under 5 ml/min, indicating that revascularization will offer no real hope for improving renal function or relieving hypertension. Despite a great deal of literature on this subject, very little of a definitive nature can be said on the pathogenesis of renovascular hypertension and particularly that implicating a specific renal factor. Based on information collected to date and summarized above, the pathogenetic mechanism involved in this hypertensive state, once established, may not be very different from other forms of hypertension. The major difference exists in its beginning. As inferred, from experimental and clinical investigation, the mechanism may be a series of derangements beginning with compromise of renal perfusion, leading to elaboration of a renal endocrine factor, perhaps renin-angiotensin II or another yet unidentified renal factor, which directly or indirectly induces changes in vascular smooth muscle electrolyte content, in baroreceptor sensitivity, and in cardiac functions. Endocrine induced vascular hypersensitivity to vasoactive agents could then permit hypertension to be sustained by plasma concentrations of pressor agents (i.e. catecholamines) which are normal relative to nonsensitized muscle, but are high relative to the sensitized state. The role of the neurosympathetic system in the genesis of renovascular hypertension has gained support from the recent studies of Buhler, Laragh et al [150, 1511 with the blood pressure responses observed from propranolol in this group. Actual renal pressor activity, i.e. angiotensin II production, may then fall due to overall changes in total body sodium balance, although some evidence suggests that angiotensin content of renal lymph may remain elevated [152, 1531. Other renal factors, such as ‘medullary antihypertensive principles’ (prota-

522

JOHN P. CAPELLI,LAURENCEG. WESSON,Jr. and EDMUNDL. HOUSEL

glandins E, A and ‘medullin’) may play a role, but the evidence is too fragmentary to permit meaningful speculation. Concepts of the nature of renovascular hypertension rest on some 43 yr of investigative effort. It is quite likely that over an equal number of years, one can anticipatetheir replacement by new and totally unrecognized concepts, but, hopefully closer to the basic understanding of this fascinating entity.

REFERENCES 1. Bright R: Reports of medical cases. Cases and observations illustrative of renal disease accompanied with the secretion of albumenuric urine. Guy’s Hasp Rep 1: 396-399, 1836 2. Traube L: Ueber den Zusammenhang von Herz- und Nierenkrankheiten. Berlin, A. Hirschwald I p. 1, 81 pp. 1856 3. Johnson G: On certain points in the anatomy and the pathology of Bright’s Disease of the Kidney. II. On the influence of minute blood-vessels upon the circulation. Medico-Chir Trans 51: 57-78, 1968 bei Nierenkrankheiten. Muchen Med 4. Bier A. Ueber die Ursachender Herzhypertrophic Wchnsch 47: 527-529, 1900 5. Goldblatt H, Lynch J, Hanzal RF et al: Studies on experimental hypertension; production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med 59: 347-349, 1934 6. Page IH: Production of persistent arterial hypertension by cellophane perinephritis. JAMA 113:20462048,1939 7. Selye H, Stone H: Pathogenesis of cardiovascular and renal charges which accompany malignant hypertension. J Urol 56: 399-419, 1946 8. Butler AM: Chronic pyelonephritis and arterial hypertension, J Clin Invest 16: 889-897, 1937 9. Smith HW: Hypertension and urologic disease. Am J Med 4: 724-743, 1948 10. Smith HW: Unilateral nephrectomy in hypertensive disease. J Ural 76: 685-701, 1956 11. Smith PG, Rush TW, Evans AT: Evaluation of translumbar arteriography. J Ural 65: 911-923, 1951 12. Palubinskas AJ, Wylie EJ: Roentgen diagnosis of fibromuscular hyperplasia of renal arteries. Radiology 76: 636639, 1961 13. White HL: The excretion of sodium in relation to glomerular filtration in renal function: Transactions of the second conference, p. 127. (Bradley SE, Ed) New York, 1950. The Josiah Macy Jr. Foundation. 14. Mueller CB, Surtshin A, Carlin MR er al: Glomerular and tubular influences on sodium and water excretion. Am J Physiol 165: 411-416, 1951 15. Selkurt EE: Effect of pulse pressure and mean arterial pressure modification on renal hemodynamics and electrolyte and water excretion. Circulation 4: 541-551, 1951 16. Berliner RW, Davidson DG: Production of hypertonic urine in the absence of pituitary antidiuretic hormone. J Clin Invest 36: 1416-1429, 1957 17. Levinsky NG, Berliner RW: The role of urea in the urine concentrating mechanism. J Clin Invest 38: 741-749, 1959 18. Levinsky NG, Davidson DG, Berliner RW: Effects of reduced glomerular filtration in urine concentration in the presence of anti-diuretic hormone. J Clin Invest 38: 730-740, 1959 19. Howard JE, Berthrong M, Gould BM ei al: Hypertension resulting from unilateral vascular disease and its relief by nephrectomy. Bull Johns Hopkins Hosp 94: 51-85, 1954 20. Poutasse EF, Dustan H, Page IH: Surgical treatment of hypertension due to renal vascular lesions. Med Clin NA 45: 479-486, 1961 21. Dosseter JB, Farn W, Gutelius JR et al: Differential renal function studies in the diagnosis of renal hypertension. Can Med Ass J 102: 500-504, 1970 22. Maxwell MH, Prozan GB: Renovascular hypertension. Prog Cardiovasc Dis 5: 81-117, 1962 Incidence. diagnosis, and treatment. Am J 23. Brest AN. Bower R: Renal arterial hvnertension. __ _ CardI 17: 612-616, 1966 24. Hunt JC, Strong CG, Sheps SG et al: Diagnosis and management of renovascular hypertension. Am J Cardiol23: 434-445, 1969 25. Perloff D, Sokolow M, Wylie EJ et al: Hypertension secondary to renal artery occlusive disease. Circulation 24: 1286-1304, 1961 26. Hunt JC, Fairbain JF, Tauxe NW et al: Symposium on hypertension associated with renal artery disease. Proc Staff Meet Mayo Clin 36: 679-712, 1961

Renovascular 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.

48. 49. 50. 51.

52. 53. 54. 55. 56. 57.

Hypertension:

Incidence, Diagnosis, Mechanism and Treatment

523

Blackman SS: Arteriosclerosis and partial obstruction of the main renal arteries in association with ‘essential’ hypertension in man. Bull Johns Hopkins Hasp 65: 353-375, 1939 Lisa JR, Eckstein D, Solomon D: Relationship between arteriosclerosis of the renal artery and hypertension. Am J Med Sci 205: 701-703, 1943 Maxwell MH, Bleifer KH, Franklin SS, et al: Demographic analysis of the study (Cooperative study of renovascular hypertension). JAMA 220: 1195-1204, 1972 Capelli JP, House1 El, Zimskind PD et al: Renovascular hypertension : Prospective diagnostic yield in a random access population. J Urol 1: 324-333, 1973 Peart WS: Diagnosis of renal artery stenosis. In: Antihypertensive Therapy (Gross F, Ed) pp. 468-483 New York, Springer-Verlag, 1966 Simon N, Franklin SS, Bleifer KH et al: Clinical characteristics of renovascular hypertension. JAMA 220: 1209-1218, 1972 Brown JJ, Owen K, Peart WS er al: The diagnosis and treatment of renal-artery stenosis. Brit Med J IL: 327-338, 1960 Correa RJ, Stewart BH, Boblitt DE: Intravenous pyelography as screening test in renal hypertension. Am J Roentgen 88: 1135-1141, 1962 Wilson L, Dustan HP, Page IH ef al: Diagnosis of renal arterial lesions. Arch Intern Med 112: 270-211, 1963 Maxwell MH, Gonick HC, Wiita R et al: Use of the rapid sequence intravenous pyelogram in the diagnosis of renovascular hypertension. New Engl J Med 270: 213-220, 1964 Bookstein JJ, Abrams, HL, Buenger RE ef al: Radiologic aspects of renovascular hypertension. Part 2. The role of urography in unilateral renovascular disease. JAMA 220: 1225-1230,1972 Deyton WE, Martin JF, Boyce WH et al: Differential renal function evaluation by minute sequence pyelography. J Urol90: 611-616, 1963 Stejskal RE, Staub EV, Loken MK et al: The value of the urea washout test in the assessment of curable renovascular hypertension. Am J Roentgen 92: 1397-1408,1964 Remmers AR, Schreiber MH, Smith GH ef al: The pyelogram urea washout test in the evaluation of renovascular hypertension. Am J Roentgen 107: 75@755, 1969 Winter CC: Radioisotope Renography. Baltimore. Williams and Wilkins, 1963 Sharpe AR, Magee JH, Richardson DW: Unilateral renal disease and hypertension. Arch Int Med 118: 546-552, 1966 Doig A, Lawrence JR, Philp T et al: ‘3rI-‘Hippuran’ renography in detection of unilateral renal disease in patients with hypertension. Brit Med J 1: 500-504, 1963 Sandler G, Rickards DF: The diagnostic value of 1311-Hippuran renography in hypertension. Angiology 17: 31-39, 1966 Dore EK, Taplin GV, Johnson DE et al: Quantitative radiorenography in the diagnosis of renal hypertension. J Ural 95: 670-677, 1966 Reiss MD, Bookstein JJ, Bleifer KH: Radiologic aspects of renovascular hypertension. Part 4. Arteriographic complications. JAMA 221: 374-378, 1972 Kincaid-Smith P: The diagnostic value of renal biopsy in renovascular and other forms of renal hypertension. In: Antihypertensive Therapy (Gross F, Ed) pp. 485-497. New York, SpringerVerlag, 1966 Barajas L, Lupu AN, Kaufman JJ et al: The value of renal biopsy in unilateral renovascular hypertension. Nephron 4: 231-247, 1967 Turgeon C, Sommers SC: Juxtaglomerular cell counts and human hypertension. Am J Path 38: 227-241, 1969 Cracker DW, Newton RA, Mahoney EM et al: Hypertension due to primary renal ischemia. New Engl J Med 267: 794-800, 1962 (a) Kaplan NM, Silah JG: Effect of angiotensin II on blood pressure in humans with hypertensive disease. J Clin Invest 43: 659-669, 1964 (b) Kaplan NM, Silah JE: Angiotensin-infusion test: new approach to differential diagnosis of renovascular hypertension. New Engl J Med 271: 536-541, 1964 Breckenridge A: Angiotensin infusion test. Lancet 2: 209-211, 1965 Morgan T: Angiotensin infusion. Lancet 1: 1222-1223, 1965 Nicotero JA, Moutsos SE, Perez-Stable E et al: Diagnostic and physiologic implications of angiotensin infusion test. New Engl J Med 274: 1464-1468, 1966 Peart WS: Hypertension and the kidney. II. Experimental basis of renal hypertension. Brit Med J 2: 1421-1429, 1959 Brown JJ, Davis DL, Lever AF et al: Plasma renin concentration in human hypertension. II. Renin in relation to Aetiology. Brit Med J 2: 1215-1219, 1965 Brown JJ, Davis DL, Lever AF er al: Plasma renin concentration in human hypertension. III. Renin in relation to complications of hypertension. Brit Med J 1: 505-508, 1966

524 58. 59. 60. 61. 62. 63.

64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88.

JOHN P. CAPELLI,LAURENCEG. WESSON,Jr. and EDMUNDL. HOUSEL Kotchen TA, Lytton B, Morrow LB et al: Angiotensin and aldosterone in renovascular hypertension. Arch Int Med 125: 266-272, 1970 Howard JE, Connor TR: Use of differential renal function studies in the diagnosis of renovascular hypertension. Am J Surg 107: 58-66, 1964 Stamey TA: Renovaseular Hypertension. Baltimore, Williams and Wilkins, 1963 Dustan HP, Page IH, Poutasse EF et al: An evaluation of treatment of hypertension associated with occlusive renal artery disease. Circulation 27: 1018-1022, 1963 Sheps SG, Osmundson PJ, Hunt JC et al: Hypertension and renal artery stenosis. Serial observations on 54 patients treated medically. Clin Pharmacol lher 6: 700-709, 1965 (a) Sheps SG, Bematz PE, Hunt JE: Hypertension associated with renal artery disease. Diagnosis and management. Heart Bull 14: 48-56, 1965 (b) Sheps SG, Bernatz PE, Hunt JE. Hypertension and renal artery stenosis: Medical and surgical management. Postgrad Med 40: 355-364, 1966 Dustan HP, Meaney TF, Page IH: Conservative treatment of renovascular hypertension. In: Anti-hypertensive Therapy (Gross F, Ed), pp. 544-554. Springer-Verlag, Berlin, 1966 Kaufman JJ, Maxwell MH: Surgery for renovascular hypertension. JAMA 190: 709-714, 1964 Morris GC, Jr., DeBakey ME, Zanger LCC: Renovascular hypertension. Surg. Clin N Am 46: 931-948, 1966 Fenton SSA, Lyttle JA, Pantridge JF: Diagnosis and results of surgery in renovascular hypertension. Lancet II: 118-121, 1966 Smithwick RH, Newton RC, Cracker DH et al: Surgical management of renal hypertension. Am J Surg 107: 104-120, 1964 Perloff D, Sokolow M, Wylie EJ et a/: Hypertension secondary to renal artery occlusive disease. Circulation 24: 1286-1304, 1961 Stewart BH, DeWeese MS, Conway J et al: Renal hypertension. An appraisal of diagnostic studies and of direct operative treatment. Arch Surg 85: 617-636, 1962 Wylie EJ, Perloff D, Wellington JS: Fibromuscular hyperplasia of the renal arteries. Ann Surg 156: 592-609, 1962 Thompson JE, Austin DJ, Wheeler GC: Renal Artery reconstruction for hypertension. Surgery 55: 42-54, 1964 Bookstein JJ, Abrams HL, Buenger RE et al: Radiologic aspects of renovascular hypertension. Part 3. Appraisal of arteriography. JAMA 221: 368-374, 1972 Gross F, Schaechtelin G, Brunner H et al: The role of the renin-angiotensin system in blood pressure regulation and kidney function. Can Med Assoe J 90: 258-262, 1964 Koletsky S, Jackson EB, Jr., Hess BM ef al: Role of a pressor substance in unilateral renal hypertension. Proc See Expl Biol Med 941-945, 1966 Koletsky S, Rivera-Velez, JM, Mash DG et a/: Relation of renal arterial pressure to activity of renin-angiotensin system in renal hypertension. Proe See Expl Biol Med 125: 96-100, 1967 Page IH, McCubbin JW: Renal Hypertension. pp. 122-129. Year Book Medical Publishers, 1968 Masson GMC, Plahl G, Corcoran AC et a/: Accelerated hypertensive vascular disease from saline and renin in nephrectomized dogs. Arch Path 55: 85-97, 1953 Masson GMC, Del Greco F. Corcoran AC et al: Pressor effects of subcutaneously injected renin in rats. Am J Physiol 180: 337-340, 1955 Masson GMC, Kashii C, Matsunaga M et al: Hypertensive vascular disease produced by homologous renin. Science 145: 178, 1964 Day MD, McCubbin JW, Page IH: Limited hypertensive effect of infusion of angiotensin. Am J Physiol209: 264-268, 1965 McCubbin JW, DeMoura RS, Page IH et al: Arterial hypertension elicited by subpressor amounts of angiotensin. Science 149: 1394-1395, 1965 Ames RP, Borkowski AJ, Sicinski Am et a/: Prolonged infusions of angiotensin II and norepinephrine and blood pressure, electrolyte balance, aldosterone and cortisol secretion in normal man and in cirrhosis with ascites. J Clin Invest 44: 1171-1185, 1965 Bliddal J, Masson GMC, McCubbin JW: Renin-like activity in kidneys of dogs with neurogenic and nephrogenic hypertension. Am J Physiol208: 1078-1082, 1965 Frank MH: Renin in Experimental renal hypertension in monkeys. Circ Res 12: 241-255, 1963 Deodhar SD, Haas E, Goldblatt H: Production of antirenin to homologous renin and its effect on experimental renal hypertension. J Expl Med 119: 425-432, 1964 Veyrat R, dechamplain J, Boucher R et al: Measurement of human arterial renin activity in some physiological and pathological states. Can Med Ass J 90: 215-220, 1964 Brown JJ, Davis DL, Lever AF et al: Variations in plasma renin concentration in several physiological and pathological states. Can Med Ass J 90: 201-206, 1964

Renovascular 89. 90. 91. 92. 93. 94. 95. 96. 91. 98. 99. 100. 101.

102. 103.

104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119.

Hypertension:

Incidence, Diagnosis, Mechanism and Treatment

525

Brown JJ, Lever AF, Robertson JIS: Plasma renin concentration in human hypertension Am Heart J 74: 413-418, 1967 Gocke DJ, Gerten J, Sherwood LM et al: Physiologic and pathologic variations of plasma angiotensin II in man. Clrc Res. (Supp. 1) 24: 131-147, 1969 Helmer OM, Judson WE: Quantitative determination of renin in plasma of patients with arterial hypertension. Circulation 27: 1050-1060, 1963 Del Greco F, Simon NM, Goodman S et al: Plasma renin activity in primary and secondary hypertension. Medicine 46: 475-490, 1967 Mulrow PJ, Lytton B, Stansel HC: The role of the renin-angiotensin system in the hypertension associated with renal vascular disease. In: L’Hypertension Arterielle (Milliez P and Techerdakoff P. Eds) L’Expansive Scientifiaue Francaise. Paris. 1966 Massani ZM, Finkiklman‘S, Worcel M et-al: An&otensin blood levels in hypertensive and nonhypertensive diseases. Clin Sci 30: 473483, 1966 Vallotton MB, Page LB, Haber E: Radioimmunoassay of angiotensin in human plasma. Nature, Land 215: 714-715, 1967 Catt KJ, Cain MC, Coghlan JP: Measurement of angiotensin I1 in blood. Lancet 11: 10051007, 1967 Boyd GW, Fitz AE, Adamson AR et al: Radioimmunoassay determination of plasma-renin activity. Lancet II: 213-218, 1969 Fitz A: Renal venous renin determinations in the diagnosis of surgically correctable hypertension. Circulation 36: 942-950, 1967 Kirkendall WM, Fitz AE, Lawrence MS: Renal hypertension, diagnosis, and surgical treatment. New EngI J Med 276: 479-485, 1967 DeBono E, Lee G De J, Mottram FR ef al: The action of angiotensin in man. Clin Sci 25: 123-157, 1963 Haddy FJ, Molnar JI, Borden CW et al: Comparison of direct effects of angiotensin and other vasoactive agents on small and large blood vessels in several vascular beds. Circulation 25: 239-246, 1962 Finnerty FA, Jr: Hemodynamics of angiotensin in men. Circulation 25: 255-258, 1962 Werko L, Lagerlof H: Studies on circulation of man; cardiac output and blood pressure in right auricle, right ventricle and pulmonary artery in patients with hypertensive cardiovascular disease. Acta Med Stand 133: 427-436, 1949 Freis ED : Hemodynamics of Hypertension. Physiol Rev 40 : 27-33, 1960 Frohlich ED, Ulrych M, Tarazi RC et al: A hemodynamic comparison of essential and renovascular hypertension. Circulation 35: 289-297, 1967 Ledingham JM, Cohen RD: The role of the heart in the pathogenesis of renal hypertension. Lancet 2: 979-981, 1963 Ledingham JM, Cohen RD: Changes in extracellular fluid volume and cardiac output during the development of experimental renal hypertension. Can Med Ass J 90: 292-294, 1964 Ledingham JM, Pelling D: Cardiac output and peripheral resistance in experimental renal hypertension in rats. Clrc Res Supp. II to Vols 20 and 21: 187-200, 1967 Hosie KF, Brown JJ, Harper AM et al: The release of renin into the renal circulation of the anaesthetized dog. Clin Scl38: 157-174, 1970 Vander AJ, Miller R: Control of renin secretion in the anesthetized dog. Am J Physiol 207: 537-546,1964 Wathen RL, Kingsbury WS, Staider DA et al: Effects of infusion of catccholamines and angiotensin II on renin release in anesthetized dogs. Am J Physiol 209: 1012-1024, 1965 Brown JJ, Davies DL, Lever AF et al: Renin and angiotensin; a survey of some aspects. Postgrad Med J 42: 153-176, 1966 Hollenberg NK, Epstein M, Basch RI et al: Renin secretion in essential and accelerated hypertension. Am J Med 47: 855-859, 1969 Hollenberg NK, Epstein M, Basch RI et al: Renin secretion in the patient with hypertension. Relationship to intrarenal blood flow distribution. Circ Res (Supp. 1) 24: 1-113-I-l 19, 1969 Bourgoignie J, Jurz S, Catenzaro FJ et al: Renal venous activity in hypertension. Am J Med 48: 332-342, 1970 MacDonald GJ, Louis WI, Renzini V et al: Renal-clip hypertension in rabbits immunized against angiotensin II. Circ Res 27: 197-211, 1970 Judson WE, Helmer OM: Diagnostic and prognostic values of renin activity in renal venous plasma in renovascular hypertension. Hypertension 13: 79-83, 1965 Meyer PH, Ecoiffier J, Alexandre JM et al: Prognostic value of plasma renin activity in renovascular hypertension. Circulation 36: 570-576, 1967 Amsterdam EA, Couch NP, Christlieb R et al: Renal vein renin activity in the prognosis of surgery for renovascular hypertension. Am J Med 47: 860-868, 1969

526 120. 121. 122. 123. 124. 12.5. 126.

127. 128. 129. 130. 131. 132. 133. 134. 135.

136. 137. 138. 139. 140. 141. 142. 143.

144. 145. 146. 147. 148.

JOHN P. CAPELLI,LAURENCEG. WESSON,Jr. and EDMUND L. HOUSEL

Michelakis AM, Foster JH, Liddle G et al: Measurement of renin in both renal veins. Its use in diagnosis of renovascular hypertension. Arch Int Med 120: 444-448, 1967 Winer BM, Lubbe WF, Simon M et al: Renin in the diagnosis of renovascular hypertension. JAMA 202: 121-126, 1967 Friedman SM, Friedman CL: The ionic matrix of vasoconstriction. Circ Res. (Supp. 11) 20: 147-155, 1967 Bohr DF, Uchida E: Individualities of vascular smooth muscle in response to angiotensin. Circ Res (Supp. II) 20: 135-146, 1967 Hinke JAM: Effect of Ca2+ uuon contractilitv of small arteries from DOCA-hvoertensive -. rats. Circ Res (Supp. I) 28: 23-33, 1966 Friedman SM, Wong SL, Woo G: Effects of a synthetic vasopressin on Na+, K + and H + exchanges in the rat. -fine Sot Expl Biol Med 120: 241-244, 1963 Friedman SM, Friedman CL: The emerging role of sodium and potassium in the regulation of vascular smooth muscle tension. In: Electrolytes and Cardiovascular Diseases (Bajusk E. Ed), p. 323. S. Karger, New York, 1965 Tobian L, Binnion JT: Artery wall electrolytes in renal and DCA hypertension. J Clin Invest 33: 1407-1418, 1954 Halpern B, Millie2 P, Meyer P er al: Increase in sodium content in the arterial walls during experimental hypertension. Nature, Land 201: 505-511, 1964 Jones AW, Feigl EO, Peterson LH: Water and electrolyte content of normal and hypertensive arteries in dogs. Circ Res 15: 386-392, 1964 Bohr DF: Electrolytes and smooth muscle contraction. Pharmacol Rev 16: 85-l 11, 1964 Heistad DD, Abboud FM, Ballard DR: Relationship between plasma sodium concentration and vascular reactivity in man. J. Clin Invest 50: 2022-2032, 1971 Imbs JL. Brown JJ. Davies DL et al: Plasma renin concentration in conscious rabbits during pressor infusions 0; renin. Clin Sci 32: 85-90, 1967 Dickinson CJ, Yu R: Mechanisms involved in the progressive pressor response to very small amounts of angiotensin in conscious rabbits. Circ Res (Supp. II) 20: 157-163, 1967 Blake WD, Wegria R, Ward HP: Effect of renal artery constriction on excretion of sodium and water. Am J Physiol 163: 422-435, 1950 Hulet WH, Baldwin DS, Biggs AW et al: Renal function in the separate kidneys of man. I. Hemodynamics and excretion of solute and water in normal subjects. J Clin Invest 39: 389394, 1960 Birchall R, Batson HM, Moore CB: Hypertension due to unilateral renal arterial obstruction; preliminary observations on the contributions of differential clearance studies. Am Heart J 56: 616622, 1958 Stamey TA, Nuddman IJ, Good PH et al: Functional characteristics of renovascular hypertension. Medicine 40: 347-354, 1961 Rapoport A: Modification of the Howard test for the detection of renal artery obstruction. New Engl J Med 263: 1159-1163, 1960 Wesson LG, Jr: Glomerular and tubular factors in the renal excretion of sodium chloride. Medicine 36: 281-396, 1957 Maxwell MH: Reversible renal hypertension. Clinical characteristics and predictive tests. Am J Cardiol 9: 126-135, 1962 Stewart BH, Schacht RA, Bishop RC et al: Differential function studies in renal hypertension. Indications and techniques. J Ural 94: 7-14, 1965 Richardson JR, Jr., Hagedorn CW, Hartley BJ: The function of individual kidneys in hypertension of renal vascular origin. J Lab Clin Med 65: 49-54, 1965 Stamey TA: Some observations on the filtration fraction, on the transport of sodium and water in the ischemic kidney, and on the prognostic importance of RPF in the contralateral kidney in renovascular hypertension. In : Antihypertensive Therapy (F’rinciples and Practice) (Gross F, Ed), p. 555 Springer-Verlag, Berlin, 1966. Vertes V, Geruth S, L.eb DE et al: Unilateral renal plasma flow in the assessment of correctable renovascular hypertension. New Engl J Med 273 : 855-857, 1965 Palmer JM: Prognostic value of contralateral renal plasma flow in renovascular hypertension. JAMA 217: 794-802, 1971 Fair WR, Stamey TR : Differential renal function studies in segmental renal ischemia. JAMA 217:790-793, 1971 Hunt JC, Harrison EG, Kincaid OW et al: Idiopathic fibrous and fibromuscular stenosis of the renal arteries associated with hypertension. Proc Staff Meet Mayo Clin 37: 181-184, 1962 Wellington JS: Fibromuscular hyperplasia of renal arteries in hypertension. Am J Path01 43: 955-967, 1963

Renovascular 149. 150. 151. 152. 153. 154. 155.

156.

Hypertension:

Incidence, Diagnosis,

Mechanism and Treatment

527

Stewart BH, Dustan HP, Kiser WS et al: Correlation of angiography and natural history in evaluation of patients with renovascular hypertension. J Urol 104: 231-238, 1970 Buhler FR, Laragh JH, Baer L et al: Propranolol inhibition of renin secretion. New Engl J Med 287:1209-1214,1972 Laragh JH, Baer L, Brunner HR et al: Renin, angiotensin and aldosterone system in pathogenesis and management of hypertensive vascular disease. Am J Med 52: 633-652, 1972 Lever AF, Peart WS: Renin and angiotensin-like activity in renal lymph. J Physiol 160: 548-552, 1962 Skinner SL, McCubbin JW, Page IH: Angiotensin in blood and lymph following reduction in renal arterial perfusion pressure in dogs. Clrc Res 13: 336-345, 1963 Gifford RW, Jr., Dustan HP, Stewart BH er al: Surgical treatment for atherosclerosis of the renal arteries: Results in eighty hypertensive patients. Dis Chest 51: 11 l-l 17, 1967 (a) Kjellbo H, Lund N, Bergentz SE et al: Renal artery stenosis and hypertension. II. Mortality in operated patients compared with the mortality in individually matched medically treated patients with crytogenic hypertension. Stand J Urol Nephrol 4: 43-47, 1970 (b) Zdem. Renal artery stenosis. II. Follow-up observations in operated and non-operated patients. Stand J Ural Nephrol4: 49-57, 1970 Kaneko Y, Ikeda T, Takeda T et al: Renin release during acute reduction of arterial pressure in normotensive subjects and patients with renovascular hypertension. J Clin Invest 46: 705-716, 1967