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Renal arterial hypertension
Fundamentals of clinical cardiology
Renal
arterial
hypertension
Albert N. Brest, M.D. Philadelphia, Pa.
T
he association of renal disease and arterial hypertension was inferred by Bright,’ 150 years ago, when he described the morphologic relationship between left ventricular hypertrophy and renal disease. It was assumed for some years thereafter that all hypertension was of renal origin. However, the validity of this assumption was questioned subsequently as additional observations indicated that arterial hypertension was common in individuals without evidence of renal disease. A reawakening of interest in hypertension of renal origin developed with the classic experiments of Goldblatt and associates in 1934.2~3 He demonstrated that hypertension could be produced experimentally by constricting the renal artery of the dog. Subsequently, it has become apparent that renal arterial hypertension in man closely parallels the experimental hypertension produced by Goldblatt and co-workers in animals. It has become further evident during the past decade that renal arterial hypertension is the most common, potentially curable form of diastolic hypertension. Although estimates of its incidence range from 1 to 25 per cent, our own experiences suggest the incidence within the hypertensive population is about 3 per cent.“z5 Anatomy
The renal arteries usua!ly arise laterally from the aorta between the levels of the From
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lower third of the first lumbar vertebra and the upper third of the second, and slightly below the level of origin of the superior mesenteric artery.6r7 Supernumerary arteries and arteries to ectopic kidneys may arise from any level of the abdominal aorta, from the common, external, or internal iliac vessels or, rarely, from the hepatic, superior or inferior mesenteric, right colic, or lumbar arteries. Numerous studies have shown that 20 to 30 per cent of kidneys have supernumerary arteries of aortic origin or otherwise that enter the kidney either at the hilus or, as polar vessels, above or below the hilus. Usually, before each renal artery reaches the hilus of the kidney, it divides into an anterior and a posterior branch. These anterior and posterior intrahilar vessels then rebranch within the renal sinus and give rise to a variable number of interlobar arteries which spread out around the minor calyces and enter the renal columns between the renal pyramids. The interlobar arteries subsequently subdivide into branches, the arcuate arteries, which give rise in turn to interlobular arteries which reach the cortex and then give rise to the afferent arterioles of the glomeruli. Just before they enter the glomerulus, the afferent arterioles are surrounded by the myo-epithelioid tissue of the juxtaglomerular (JG) apparatus. The efferent arterioles, formed by the confluence of the glomerular Philadelphia,
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Renal
capillaries, give rise to an extensive peritubular plexus of capillaries. According to Graves,8 each renal artery gives rise to five primary branches and each of these branches supplies a separate segment of the renal parenchyma. Graves labeled these five segments as follows: apical, upper, middle, lower, and posterior. Although the segmental arteries are subject to variation in their levels of origin from the main renal artery, Graves found them usually recognizable in spite of their variations. Typically, the posterior division of the renal artery gives rise to the posterior and apical segmental arteries, while the upper, middle, and lower segmental arteries arise from the anterior division. However, numerous anatomic variations may be encountered; and some investigators feel that no single segmental classification is acceptable. g Since there are essentially no anastomoses between the various branches of the renal artery in the renal parenchyma, these vessels are functional endarteries. Although a modest collateral circulation can be provided to t.he kidney by various vessels in the adipose capsule of the kidney, and along the renal pelvis and ureter, these vessels generally do not provide sufficient blood to prevent renal ischemia following partial or complete occlusion of the artery or its branches. Pathology In all reported series, atherosclerosis and fibromuscular occlusive processes of the renal artery constitute the overwhelming majority of lesions. Occasionally, renovascular hypertension may result from uncommon lesions of the renal arterysuch as primary thrombosis, embolism, aneurysm, arteriovenous fistula, dissecting hematoma, compression by tumor or fibrous bands, and trauma. Atherosclerosis of the renal artery occurs more commonly in men. The lesion usually involves the first 2 cm. of the main renal artery; less commonly, the atheromatous process is localized to a main branch. Associated atherosclerotic disease is often present elsewhere, especially in the extracranial carotid and coronary arteries. There is also a substantial incidence of significant aneurysmal or occlusive disease,
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or both, of the abdominal aorta and of its peripheral branches. The incidence of associated abdominal aortic disease has been reported to be as high as 30 per cent. The fibromuscular occlusive processes were originally grouped together and labeled “fibromuscular llyperplasia.“10 Subsequently, these fibrous stenosing lesions have been divided into four subgroups: (1) intimal fibroplasia, which involves the intima predominantly, (2) medial fibroplasia, which involves primarily the media and often is associated with microaneurysms, (3) fibromuscular hyperplasia, a lesion of the media marked by jumbling of fibrous tissue and collagen, and (4) subadventitial fibroplasia, a disorder involving the area of the media immediately adjacent to and often including the elastica externa. Although commonly localized to the renal arteries, these disorders may at times involve other vessels, e.g., a counterpart of intimal fibroplasia may be responsible for pulseless disease in the upper extremities. Whereas atheromatous disease often is limited to the orifice and proximal half of the renal artery, these fibrous stenosing lesions often extend peripherally beyond the bifurcation of the main renal artery but infrequently involve the orifice of the vessel. Fibromuscular dysplasia occurs more commonly in young patients, especially women. The genesis of these fibromuscular occlusive processes is unknown. Pathophysiology It is generally acknowledged that the renin-angiotensin-aldosterone system is involved, at least in part, in the pathogenesis of hypertension due to renal artery stenosis.ll There is abundant experimental evidence to support this relationship. In addition, equally impressive clinical data has accumulated. Renin is a vasoinert proteolytic enzyme which is released from the JG cells in the wall of the afferent renal arteriole. The renin is discharged into the blood stream where it reacts with an or-2 globulin fraction (renin substrate) to form a decapeptide, angiotensin I. The decapeptide, which is inactive, is then converted by a rather ubiquitous converting enzyme to the vasoactive octapeptide, angiotensin II. Subse-
quently, angiotensin II is broken down enzymatically by the angiotensinases present in tissues and plasma. It is well established that angiotensin II is a potent pressor substance which can significantly elevate the arterial blood pressure.12s13 In addition, angiotensin II is the principal and most potent stimulator of aldosterone biosynthesis and secretion by the zona glomerulosa of the adrenal cortex. It appears that the sodium retention mediated by the associated (secondary) aldosteronism plays a contributory role in the pathogenesis of renal arterial hypertension. It is likely that retention of sodium in the arteriolar muscle walls enhances the vasopressor effect of the circulating angiotensinemia. The regulation of renin release is not fully understood. Two mechanisms have been implicated. The first involves a baroreceptor in the wall of the afferent renal arteriole which evokes renin release in response to a decrease in renal artery ltlood flow or alterations in pulse wave contour. The second involves a sodiumload chemoreceptor in the cells of the macula densa portion of the juxtaglomerular apparatus. Although the exact role of the reninangiotensin-aldosterone system in the pathogenesis of renal arterial hypertension is still uncertain, it would appear that this system is undoubtedly operative in many (if not most) instances of renal arterial hypertension, especially when the hypertension is moderate or severe. However, the involvement of this system does not necessarily exclude other factors that may be operative. In this regard, the kidney may play an important role in the control or release of as yet unidentified vasodePYessoY substances; and the elaboration of these latter substances could conceivably be awry in renal arterial hypertension. Clinicul
features
It is well established that renal arterial hypertension may mimic essential hypertension and, in many cases, the history does not provide any differential diagnostic clues. Furthermore, a positive or negative family history of hypertension is of no value in separating these groups. It is also noteworthy that the response, or lack of
response, to antihypertensive drugs has been of no value in differentiating renovascular from essential hypertension. On the other hand, renal arterial hypertension should be strongly suspected in the following clinical circumstances: onset of hypertension in young or elderly individuals; malignant hypertension; or sudden acceleration of previously benign hypertension.i4 Renal arterial hypertension also should be suspected when there is a history suggesting the possibility of a renovascular accident. The most helpful clinical sign leading to a diagnosis of renal arterial hypertension is an upper abdominal bruit. The murmur is often but not invariably heard best near the midline in the epigastrium with transmission to the affected (or more severely affected) llypocllondrium.15 Howthat such bruits ever, it is noteworthy are heard in no more than 50 per cent of cases. Thus, the absence of a bruit fails to differentiate renal arterial hypertension from other causes of elevated diastolic pressure. Contrariwise, the presence of an upper abdominal bruit does not necessarily signify renal artery disease, It is well established that when renal artery obstruction is severe, the increased renin release is accompanied by increased aldosterone secretion. As a result of this secondary aldosteronism, hypernatremia and hypokalemia may occur as late manifestations. Thus, several authors have suggested that renal arterial hypertension may simulate primary aldosteronism.‘“,i7 However, a full clinical and laboratory investigation will serve to differentiate primary from secondary aldosteronism. hIost important in this regard is the finding of increased circulating renin activity in renal arterial hypertension, whereas renin activity is diminished or absent in hypertension due to primary aldosteronism. Diagnosis Since the history and physical findings may be fallible, the diagnosis of renal arterial hypertension must depend ultimately on the use of appropriate laboratory procedures. Intmven.ozks $yelogram. The intravenous pyelogram is a relatively safe and inexpensive procedure which provides a com-
parative index of renal mass and kidney function bilaterally. The minute-sequence technique has been especially valuable as a screening procedure. X-rays are obtained every minute for five minutes following rapid intravenous injection of opaque medium and then every five minutes for 30 minutes. A satisfactory and equal nephrogram should be obtained within one to two minutes. The threeminute film should demonstrate equal filling of the calyces of both kidneys as nell as early filling of the renal pelvis. The four- and five-minute x-rays provide further verification of abnormalities on either or both sides. W’hitley and associatesi* found one or more of the following intravenous pyelographic alterations in renal artery stenosis: (1) disparity in renal length of 1.5 cm. or more; (2) delay in appearance of contrast medium in the calyceal system; (3) nonvisualization of an entire kidney or a portion of a kidney; (4) differences in concentration of contrast material in the affected kidney; (5) calcification of renal vessels, as seen in arteriovenous fistulas and aneurysms; and/or (6) scalloping of the ureter due to increased collateral circulation. found abnorHoward and Connor malities in 75 per cent of cases of renovascular hypertension. Correa and associateszO found abnormal pyelograms in 89 per cent of cases. Although the reported incidence of abnormal pyelographic findings varies, most authors have found one or more pyelographic alterations in at least 75 per cent of patients with renal arterial hypertension. Refinement of techniques of intravenous pyelography has been made in order to increase accuracy in the detection of renovascular hypertension. Dehydratedhydrated excretory pyelography and also the pyelogram urea washout test have found several advocates.21-23 Enhanced reabsorption of water and sodium is a characteristic physiologic sequence of renal ischemia,24 and accordingly, it has been demonstrated that the disparate reabsorption of water on the affected side (vs. the unaffected kidney) can be better identified by a water or urea diuresis. Similarly, the use of hydration and a mercurial diuretic or mannitol has been employed with the
sole purpose of accentuating subtle differences in concentration of contrast material.?l Neither Brannan and co-workerP nor Schreiber and associateP found any false negative pyelograms employing these hydrated techniques; in their investigations, the urea washout pyelograms correlated well with the split renal function studies and seemed more specific than the radioisotope renogram. Over-all, intravenous pyelography has proved to be a rewarding screening procedure in the detection of renal arterial hypertension.*j A dehydrated minute-sequence study followed by renal loading and evaluation of the response to this hydration is especially informative and possibly the method of choice. Radioisotope renogrcrm. The radioactive Ir3r renogram has been employed as a screening procedure for the detection of renovascular hypertension since its introduction in 1956.36J7 The rate of accumulation and excretion of the radioactive test agent is measured by placing external scintillation detectors over the posterior aspects of each kidney. Ii3i orthoiodohippuric acid (Hippuran) has been found more satisfactory than P idopyracet (Diodrast), mainly because of the lesser hepatic accumulation of Hippuran. Hippuran is excreted almost exclusively by the kidneys, being handled in a fashion similar to para-aminohippuric acid and thereby providing a qualitative measure of renal blood flow or tubular secretory mass. The procedure can be performed with as little as 2 or 3 microcuries of radioactive iodine but doses of 25 to 40 microcuries are usually employed.27J8 A normal tracing consists of (1) an initial spike, which has no significance other than indicating the first appearance of tracer in the kidney region, (2) a slower secondary rise which takes 2 to 5 minutes to achieve its maximum height and reflects the relative renal blood flow, and (3) a rapid exponential fall recognized as the excretory or drainage phase. The three most important features of the renal tracing are the slopes of the second and third segments and the time required to reach maximum levels. The renogram provides a qualitative assessment of &renal blood flow, kidney function, and - postrenal ex-
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cretion. Semiquantitative measurements may be obtained by calculating the time of maximum isotope uptake (T,.,) and the time of fall of the isotope curve to one half maximum uptake (TX). The advantages of radioisotope renography are ease of performance, lack of trauma and hazard to the patient, and immediate availability for interpretation. Furthermore, a repeat tracing can be obtained within 30 minutes if necessary. According to Winter,27 the renogram is 85 per cent accurate in detecting unilateral and bilateral renal disease capable of producing hypertension. It appears that reliability of the test to detect disparate kidney function is enhanced by obtaining tracings at a urine flow rate between 1.5 and 7.0 ml. per minute.28 Physiologic factors which alter renogram contour are the state of hydration, prior administration of urographic agents or drugs that depress tubular extraction of Hippuran, and emotional factors.2g Fluid restriction or the hydropenic state slows the renal turnover of tracer and produces an increase in transit time in the renogram. Renograms performed shortly after intravenous urography show flattened second and third segments due to saturation of tubular transport mechanisms; therefore renograms should not be performed for at least 24 hours following intravenous urography. Sulfonamides and other drugs known to be excreted by tubular mechanisms can alter the renogram in similar fashion. Emotional factors also can adversely affect the renogram. Although some investigators30J1 feel that the test is unreliable in detecting renovascular hypertension, it is our feeling that the renogram is a useful adjunct to intravenous pyelography for diagnostic screening purposes. In addition, it has definite value in the followup of patients with renal revascularization procedures. Split renal clearance studies. In 1953, Howard and co-workers3” introduced split renal clearance studies as a diagnostic method, following the observations that ischemic rat kidneys reabsorb increased amounts of sodium and water.24 The test involves bilateral ureteral catheterization with analysis of urine volume and content from each kidney. A 50 per cent or greater
Am. Newt 3. May, 1968
reduction in urine flow from the affected kidney plus a decrease of 15 per cent or more in sodium concentration constitute a positive Howard test. Although the method gained immediate popularity as a diagnostic procedure, subsequent investigators questioned the reliability of the test.33J4 Birchall and associates35 demonstrated that the affected kidney also excretes increased urinary concentrations of inulin and creatinine. Stamey36 reported a modification which utilizes an infusion of 8 per cent urea in saline plus antidiuretie hormone to enhance reabsorption of l&rater in the ischemic kidney. Howard and Connor subsequently modified their original technique by combining it with certain features of the Birchall and Stamey modifications. They considered a positive test to be characterized by greatly reduced urinary volume plus a reduction in sodium concentration or increased concentration of creatinine or PAH on the affected side. In our experience, a difference of 50 per cent or more in urine volume together with an increase in urine inulin (or creatinine) concentration on the involved side indicate a “dynamic” stenosis; but the urinary sodium concentration may be decreased, equal or increased on the affected side in the presence of significant lesions.38 Split renal function studies are most useful in determining whether a unilateral lesion of the renal artery is hemodynamitally significant in the etiology of the patient’s hypertension. In this regard, the test is useful in prognosticating which patients will benefit from corrective surgery. Unfortunately the technical problems and associated morbidity of these tests as well as the lack of uniformity in their interpretation have caused considerable confusion and controversy. Kennedy and associates3g believe split clearance studies are unnecessary for the routine assessment of renal artery stenosis and should be reserved for patients with equivocal renograms and intravenous pyelography. However, Stamey40 emphasizes that the decision for surgical intervention in renal artery stenosis should be based upon these tests. Renal scan and chlomerodrin accumulation iest. Since 1959, the intravenous infusion of radioactive mercury-labeled (Hglg7 or
Renal
Hg203) chlormerodrin (Neohydrin) has been used for scintillation scanning of the kidneys. Of 13 labeled mercurial compounds studied by Kessler and co-worliers,41 chlormerodrin achieved the highest concentration in the kidneys. The major portion of mercury is excreted in a few hours, but radioactivity can remain in the kidneys for several weeks or months. The long-term effect on the renal tissue is unknown. Careful mapping of the renal tissue with a photoscanner is performed. The viable renal parenchyma is outlined and nonviable tissue such as tumors, cysts, infarction, or atrophy stand out by contrast. Simple renal scanning as an isolated procedure has not proved to be a satisfactory screening method for the detection of renal arterial hypertension. However, differential measurements of the rate of accumulation of labeled chlormerodrin by each kidney during a 30 to 60 minute period followed by scintillation scanning has been found to be a more reliable screening metllod.42 The most reliable criterion by which one kidney could be compared functionally with the other was the ratio of the rate of accumulation of the right kidney relative to that of the left. In 30 out of 31 patients with unilateral renal hypertensive disease, the right/left ratios were beyond the normal range.de Sodee4j studied 270 hypertensive patients, 14 of whom were found to have unilateral renovascular hypertension. The combination of Hippuran renogram plus mercurylabeled chlormerodrin uptake and scan correlated well with arteriography and surgical findings in their experience. Renin, angiotensin, and aldosterone determinations. Increasing evidence suggests that the renin-angiotensin system plays a substantive role in the pathogenesis of renal arterial hypertension. However, the development of methods of measurement of renal pressor substances has been fraught with certain technical difficulties. Conflicting data have been found in the determination of angiotensin, probably due to the lack of standardization of the various methods. For example, Morris and associates44 in a study of 136 hypertensive patients found 46 with angiotensin concentrations greater than 5 millimicrograms
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in unilateral and bilateral renal Ischemia, coarctation of the aorta, and acute glomerulonephritis; the other 90 patients with essential or malignant hypertension, essential hypertension with pyelonephritis, primary aldosteronism, and pheochromocytoma showed angiotensin levels less than 5 millimicrograms. In contrast, Genest and co-workers4j as well as Mulrow46 have obtained dissimilar results in. patients with renovascular hypertension. More widely employed is the measurement of renin activity in peripheral or renal venous blood. As with angiotensin, several methods have been devised.47-4g Veyrat and associates50 found arterial renin activity within normal levels in patients with benign and severe essential hypertension and in about half of the patients with renal artery stenosis. However, Genest and co-workers”~“’ reported that measurement of peripheral venous renin activity is consistently useful in predicting the results of surgery for renovascular hypertension; and they consider this determination the procedure of choice in assessing the activity of the renin-angiotensin-aldosterone system. The demonstration that the renin-angiotensin system can stimulate aldosterone production has provided a further indirect method of assessing renal arterial hypertension. The finding of increased renin activity plus increased aldosterone production is consistent with renal arterial hypertension. In contrast, low or absent renin activity in the presence of increased aldosterone production suggests primary aldosteronism.17 Unfortunately, until more simple and accurate methods can be developed, the availability of these studies is limited to major research centers. Angiotensin infusion. test. Kaplan and Silah52 devised this test based on the assumption that patients with increased endogenous levels of angiotensirt will require a greater amount of exogenous angiotensin to obtain a given pressor response. An intravenous angiotensin infusion is given, in graded dosage, until a 20 mm. Hg elevation in diastolic blood pressure is obtained. Kaplan and Silahs2 found that patients with essential hypertension require less than 6.5 millimicrograms per kilogram of body weight per minute for a positive
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pressor response, whereas patients with renovascular hypertension require larger amounts to produce a similar effect. Interestingly, patients with chronic renal parenchymal disease have shown a wide variability in their response.5s Goorno and KaplanS4 reported a correlated increase in renal pressor substance obtained by direct bioassay with the angiotensin infusion test. However, other investigators have questioned the validity of the test because they were unable to correlate either significant anatomical lesions or renin levels with the angiotensin infusion test.55s56 At present, it appears that further well controlled studies are necessary to prove or disprove the validity of the angiotensin infusion test and to determine its clinical applicability. Renal biopsy. Renal biopsy has been used as a guide for detection of renal vascular disease as well as for assessment of renal parenchymal changes which might contraindicate surgical intervention. The tissue specimen obtained by percutaneous needle biopsy is small and although possibly diagnostic, it often proves to be insufficient for the study of the JG apparatus. Hence, open incisional biopsy is generally required to ensure an adequate specimen for diagnostic purposes. In man, relationships have been found between the granularity of the JG cells, serum sodium levels, and aldosterone secretion.57 Both in human and experimental hypertension, the JG cell changes are believed to correlate with an increased production and secretion of renin.j8 Use of the fluorescent antibody technique indicates that the source of renin is the JG cel1.j” Boughton and SommersGo believe that aside from its value in the diagnosis of renal ischemia, the JG cell count is a practical method of determining whether nephrectomy or arterial reconstructive may be indicated in treating surgery these patients. Vertes and associates”‘-G3 contend that bilateral renal biopsy serves as the best guide for final decision regarding surgical intervention. They believe that if the contralateral kidney is affected seriously by arteriolosclerosis, cure of the hypertension is unlikely. On the other hand, Stricklere4 described a case of malignant hypertension
Am. Hcavt J. May, 1968
secondary to bilateral renal artery obstruction with documented parenchymal small vessel disease in which surgical cure was obtained after bilateral revascularization. At present, most w-ould agree that additional correlation of biopsy findings in renal arterial hypertension is required before a final judgment concerning its exact role in diagnosis and prognosis can be finalized. Renal mgiogra~hy. The definitive diagnosis of unilateral or bilateral renal vascular disease ultimately depends upon renal angiography. This procedure may be performed via the translurnbar aortographic approach or else a catheter may be threaded into the aorta and followed by direct injection of dye at the level of the renal arteries.6s Since renal vascular insufficiency may be present despite normal pyelography, differential renal function studies or radiorenography, renal angiography is recommended whenever the clinical picture suggests the possible occurrence of this lesion. On the other hand, the angiographic demonstration of renal artery stenosis does not mean necessarily that the stenotic lesion is responsible for the patient’s hypertension; most investigators have found examples of marked renal artery stenosis in normotensive patients studied for other purposesFG Although numerous complications have been described,e7 increasing experiences have indicated that this diagnostic procedure may be consistently performed without fatal or serious complications. Other studies. Abrams and co-workersP8 lhave devised another method to detect renal vascular hypertension. They measure the renal venous washout time, which is defined as the total time elapsed from the onset of the injection of contrast medium into the renal vein to its disappearance. Cinerecording is used as a means of obtaining precise measurements of the washout time. Normal values vary between 1.25 and 3 seconds. Values above 3 seconds have been found in renal artery obstruction greater than 50 per cent, The usefulness of this test may also be extended to appraisal of the contralateral kidney, i.e., its involvement by arteriolar disease, and hence the feasibility of surgical intervention.
Renal arterial
Kiser and co-workersGg devised the phonorenogram as an indirect measurement of transmitted renal artery pulsations using a transureteral cardiac phonocatheter. The value of this procedure in detecting renovascular hypertension cannot be assessed until further analysis of these studies prove their reliability. Treatment
Renal arterial hypertension may improve with medical (antihypertensive drug) or surgical treatment. The decision as to the more appropriate therapy is generally determined by such factors as: age of the patient, severity of the hypertension, extent of accompanying cardiovascular involvement, and the degree of renal functional impairment. Medical treatment of renal arterial hypertension should be considered when the hypertension is not severe, when the patient prefers a medical regimen, and when the location of disease is such that nephrectomy is the only feasible surgical therapy.70 i\4edical management may also be indicated in those individuals, especially el.derly patients, with significant extrarenal disease, such as coronary or cerebrovascular insufficiency. In addition, the effectiveness of antihypertensive drug therapy also enters into the decision for medical versus surgical treatment. In this regard, it is noteworthy that normotension can be achieved with antihypertensive drugs in at least 50 per cent of patients with renal arterial hypertension; however, despite successful blood pressure reduction, renal function may deteriorate because of progressive ischemic renal atrophy beyond an area of renal artery stenosisS71Thus, there is an important need for close observation of renal function and size among patients treated medically, even though the blood pressure may be controlled satisfactorily. Various surgical procedures, including nephrectomy and revascularization, can be used successfully in managing renal arterial hypertension. It is generally agreed that nephrectomy should not be performed unless the kidney is irrevocably damaged or its revascularization is technically impossible. On the other hand, successful renal revascularization can provide im-
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provement or preservation of renal function as well as satisfactory blood pressure reduction. The techniques of renal revascularization are similar to those applied to OCelusive lesions elsewhere in the arterial tree. Although numerous variations in technical procedures have been used to restore normal renal arterial circulation, the two most common procedures are the bypass graft and patch graft angioplasty.72 Because of the lengthy linear involvement usually seen with fibromuscular disease, patch graft angioplasty is rarely selected for reconstruction in this condition. Arterial bypass is generally preferred in the treatment of fibromuscular disease and many arteriosclerotic lesions, particularly when aortic reconstruction is required in addition. The graft materials most commonly employed are knitted dacron and autogenous saphenous veins. The usual bypass procedures employed are the aorto-renal and the spleno-renal arterial anastomoses. Endarterectomy may be used sati.sfactorily in some instances of localized arteriosclerotic occlusion; in other cases,resection and graft replacement, or division and implantation onto the aorta may be used successfully. Endarterectomy techniques are generally not applicable to fibromuscular lesions. About 80 per cent of patients undergoing successful surgery for renal arterial hypertension obtain a significant antihypertensive response, with normotension being achieved in about one half of the group.73,74 As a result of our own surgical experiences, we have divided the postoperative results into four categories. (1) Renal artery stenosis with renal arterial hypertension; optimum improvement in blood pressure is obtained in this group. (2) Generalized arteriosclerosis with renal artery stenosis and renal arterial hypertension; the surgical results have been generally gratifying in this group, even though less satisfactory than in the former category. The less satisfactory surgical prognosis reflects the presence of extensive and often generalized vascular disease in these patients, many of whom have impaired renal function in addition to uncontrolled hypertension. (3) Essential hypertension with concomitant renal artery stenosis and renal arterial
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hypertension; blood pressure reduction following surgical treatment is never complete in these individuals since the renal arterial hypertension is merely engrafted upon an essential hypertensive process. (4) Renal artery stenosis without renal arterial hypertension; surgical treatment obviously fails to control the elevated blood pressure in these instances. It is to be anticipated that a comprehensive diagnostic workup will identify and thereby eliminate these patients from any surgical consideration. Many patients with renal arterial hypertension have significant accompanying renal functional impairment. The degree of renal deterioration depends upon (1) the duration and severity of the arterial stenosis, and whether the stenotic involvement is unilateral or bilateral, and (2) the degree and duration of hypertension, with its inevitably detrimental effect on contralateral kidney function. It is notable that renal function may deteriorate in spite of effective blood pressure control, thus emphasizing the need for close observation for progression in severity of the stenosis or deterioration of renal function among patients treated medically. Surgical experiences75,76 indicate that significant renal functional improvement may be achieved following successful renal revascularization. Therefore, renal functional status should be considered as an important indicator of the need for surgical treatment in the management of patients with renal arterial hypertension. Conclusions
Renal arterial hypertension is a potentially curable form of diastolic hypertension. Although renal angiography provides the most definitive technique available for establishing the anatomic diagnosis, other studies are required to establish whether the stenotic arterial lesion is responsible for the patient’s hypertension. Either antihypertensive drug therapy or surgery may be employed successfully in the management of renal arterial hypertension. 1.
REFERENCES Bright, R.: Reports of medical with a view of illustrating the cure of diseases by a reference
cases selected symptoms and to morbid an-
atomy,
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London, 1827, Orme, Brown, and Green. 2. Goldblatt, H., Lynch, J., Han&, R. F., and Summerville, 1%‘. W.: Studies on experimental hypertension: production of persistent elevation of systolic blood pressure by means of renal ischemia, J. Exper. Med. 59:347, 1934. 3. Goldblatt, H.: Studies on experimental hypertension. V. The pathogenesis of experimental hypertension due to renal ischemia, Ann. Int. Med. 11:69, 1937. 4. Maxwell, M. H., and Prozan, G. B.: Renovascular hypertension, Progr. Cardiovas. Dis. 5:81,1962. 5. Brest, A. N., and Bower, R.: Renal arterial hypertension. Incidence, diagnosis, and treatment, Am. J. Cardiol. 17:612, 1966. 6. Hollinshead, W. H.: Renovascular anatomv, Postgrad. Med. 40 ~241, 1966. 7, Merklin. R. 1.. and Michels. N. A.: The variant renal and suprarenal blood supply with data on the inferior phrenic, ureteral, and gonadal arteries: A statistical analysis based on 185 dissections and review of the literature, J. Internat. Coll. Surg. 29:41, 1958. 8. Graves, F. T.: The anatomy of the intrarenal arteries and its application to segmental resection of the kidney, Brit. J. Surg. 42:132, 1954. 9. Verma, Xi., Charturvedi, 1~. P., and Pathak, I<. K.: Anatomy of renal vascu!ar segments, J. L4nat. Sot. India 10:12, 1961. 10. McCormack, L. J., Dustan, H. P., Gif‘ford, li. 1V., -Jr., Meaney, T. F., Stewart, B. H., and Kiser, 15’. S.: Pathology of renal artery disease, Posterad. Med. 4.0:348. 1966. 11. Strolg, C. G., Boucher, R., and Genest, J.: Renin, angiotensin, and aldosterone in renovaecular disorders, Postgrad. Med. 40:337, 1966. 12. Genest, J.: Angiotensin, aldosterone, and human arterial hypertension, Canad. Al. A. J. 84:403,1961. 13. Peart, 1%‘. S.: The functions for renin-angiotensin, Recent Prog. Hormone Res. 22 :73, 1965. 14. Dustan, H. P., and Page, I. H.: Renal hypertensive suspect. Clinical characteristics, Am. 1. Surg. 107:%, 1964. 15. Maxwell. M. H.. Kaufman. 1. 1.. and Bleifer. K. H.: Stenosing lesions of’ &e”r&al arteries: Clinical manifestations, Postgrad. Med. 40:247, 1966. 16. I,aidlaw, J. C., Yendt, E. R., Bird, C. E., and Gornal, A. G. : Hvpertension dire to renal artery occlusion simulating primary aldosteronism, Canad. M. A. T. 90:321, 1964. 17. Conn, J. IV., dbhen, I?. ‘L., and Rovner, D. Ii. : Suppression of plasma renin activity in primary aldosteronism, J.A.M.A. 190:213, 1964. 18. ?Vhitley, J., \\?tcofski, Ii. L., Quinn, J. S., and Meschan, I.: The radiologic diagnosis of renovascular hypertension, Radiology 78:414, 1962. 19. Howard, J. E., and Connor, T. B.: Hypertension produced by unilateral renal disease, Arch. Int. Med. 109:8, 1962. 20. Correa, R. I., Jr., Stewart, B. H., and Babblitt,
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36.
D. E.: Intravenous pyelography as a screening test in renal hypertension, Am. J. Roentgenol. 88:1135, 1962. Amplatz, K.: Two radiographic tests for assessment of renovascular hypertension, Radiology 79:807, 1962. Brannan, \I’., Birchall, R., Batson, H. M., and Kittredge, W. E.: Dehydrated-hydrated urography in the diagnosis of excretory renal arterial hypertension, J. Ural. 91:26 1964. Schreiber, M. H., Sailes, H. E., Herring, M. E., and Remmers, A. R., Jr.: The pyelogramurea washout test, New England J. Med. 270:1223, 1964. White, H. L.: Excretion of sodium in relation to glomerular function in renal function, in Bradley, S. E., editor: Tr. Second Conf. Renal Function, New York, 1950, Josiah Macy, Jr., Foundation, p. 127. Martin, J. F.: Urographic diagnosis of renovascular disease, Postgrad. Med. 40:289, 1966. Taplin, G. V., Meredith, 0. M., Jr., Kode, H., and Winter, C. C.: Radioisotope renogram: external test for individual kidney function and upper urinary tract patency, J. Lab. &r Clin. Med. 48:886, 1956. Winter, C. C.: Clinical study of a new renal function test: radioactive Diodrast renogram, J. ITrol. 76:182, 1956. Wedeen, R. I’., Littman, E., Levitt, M. F., and Goldstein, M. H.: The use of 113’ Hippuran renogram in the detection of disparate kidney function in hypertensive patients, Circulation 325, 1965. -Taplin, G. V.: Radioisotope renography in renovascular hvoertension. I’ostprad. Med. 40:302, 1966. -I Moses, J. J.. Prentiss, R. J., Moose, E. V., Kiser, J. R., Bethard, W. F., Tighe, \v. J., and IVhitehead, E. L.: Evaluation of the radioactive renogram in hypertension, J. Ural. 85:679, 1961. Stokes, J. M., Friendenberg, M. J., and Sunshine, H.: Comparison of methods used to diagnose renal hypertension, Arch. Surg. 87:238, 1963. Howard, J. E., Berthrong, XI. I)., Sloan, R. D., and Yendt, E. R.: Relief of malignant hypertension by nephrectomy in four patients with unilateral renal vascular disease, Tr. A. Am. Physicians 66:164, 1953. Maxwell, M. H., Rockney, R. E., Winter, C. C., and Kleeman, C. R.: Predictive tests in unilateral renal hypertension: critical analysis of tewnty-five operated patients, Circulation 22:785, 1960. Prozan, G. B., Maxwell, M. H., Kaufman, J. J., and Kleeman, C. R.: Differential renal function in diagnosis of renovascular hypertension, Circulation 26:774, 1962. Birchall, R., Batson, H. M., aud Braunan, W.: Contribution of differential renal studies to the diagnosis of renal arterial hypertension with emphasis on the value of LT Sodium/U Creatinine, Am. J. Med. 32:164, 1962. Stamey, T. A.: Diagnosis of curabl eunilateral
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10. 41.
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-1-9.
SO.
51.
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renal hypertension by ureteral catheterization, Postgrad. Med. 29:496, 1961. Howard, J. E., and Connor, T. 8.: Hypertension produced by unilateral renal disease, -4rch. Int. Med. 209:8, 1962. Onesti, G., Kim, K., Swartz, C., and Brest, A. N.: Renal function in renal and renovascular hypertension, Postgrad. Med. 40~327, 1966. Kennedy, A. C., Luke, R. G., Briggs, J. D., and Stirling, W. B.: Detection of renovascular hypertension, Lancet 2:963, 1965. Stamep, T. A. : Renovascular hypertension, Am. J. Med. 38:829, 1965. Kessler, R. H., Lozano, R., and Pitts, R. F.: Studies on structure diuretic activity relationships of organic compounds of mercury, J. Clin. Invest. 36:656, 1957. Reba, R. C., McAfee, J. G., and Ivagner, H. N., Jr.: Radiomercury-labelled chlormerodrin for in oivo uptake studies and scintillation scanning of unilateral renal lesions associated with hypertension, Medicine 42:269, 1963. Sodee, D. B.: The screening of renal hypertension utilizing the mercury-197 chlormerodrin uptake study and scan, J. Ural. 94:313, 1965. Morris, R. E., Jr., Robinson, P. R., and Scheele, G. A.: The relationship of angiotensin to renal hypertension, Canad. M. A. J. 90:272, 1964. Genest, J., Boucher, R., de Champlain, J., Veyrat, R., Chretien, M., Biron, P., Tremblay, G., Roy, P., and Cartier, P.: Studies on reninangiotensin system in hypertensive patients, Canad. M. A. J. 90:263, 1964. Mulrow, I’.: The role of renin-angiotensin system in the hypertension associated with renal vascular disease, Canad. M. A. J. 90:277, 1964. Boucher, R., Veyrat, R., de Champlain, J., and Genest, J.: New procedures for measurements of human plasma angiotensin and renin activity levels, Canad. M. A. J. 90:194, 1964. Helmer, 0. h4.: Renin activity in blood from patients with hypertension, Canad. M. A. J. 90:221, 1964. Warzynski, R., Demirjian, Y., and Hoobler, S.: A method for the determination of renin in blood and some preliminary findings, Canad. M. A. J. 90:225,1964. Veyrat, R., de Champlain, J., Boucher, R., and Genest, J.: Measurement of human arterial renin activity in some physiological and pathological states, Canad. M. A. J. 90:215, 1964. Tremblay, G. Y., Veyrat, R., de Champlain, J., Boucher, R., Lefebvre, R., Roy, P., Cartier, P., and Genest, J.: Criteria for success of surgery in renovascular hypertension, Tr. A. Am. Physicians 77:201, 1964. Kaplan, N. M., and Silah, J. G.: The angiotensin infusion test, New England J. Med. 271:536,1964. Gentile, D. E., Marcum, S. G., and Pierce, N. F.: Angiotensin infusion test, Clin. Res. 12:26, 1965. Goorno, W. E., and Kaplan, Y. M.: Renal pressor material in various hypertensive diseases, Ann. Tnt. Med. 63:745,1965. Fitz, A. E., Valenea, M., and Kirkendall,
W. M.: Angiotensin infusion test in normal and hypertensive subjects, Clin. Res. 12:206, 1965. 56. Breckenridge, A.: hngiotensin infusion test, Lancet 2:209, 1965. 57. Pitcock. 1. A.. and Hartroft. P. R/I.: The iuxtaglomerular cells in man and their relationship to the level of plasma sodium and to the zona glomerulosa of the adrenal cortex, Am. J. Path. %:863, 1958. W. S., and Hartroft, P. M.: New ap58. Hartroft, proaches in the study of cardiovascular disease; aldosterone, renin, hypertension, and justaelomerular cells, Fed. Proc. 20:845,1961. 59. Hartroft, P. MI, Sutherland, L. E., and Hartroft, W. S.: Juxtaglomerular cells as the source of renin: further studies with the fluorescent antibody technique and the effect of passive transfer of antirenin, Canad. )‘I. A. J. 91):163, 1964. 60. Boughton, Ii. M., and Sommers, S. C.: >A new concept of renal hypertension, J. Urol. 89:133, 1963. 61. Vertes, V., and Gravel, J. A.: Observations on renal hvoertension. The role of renal hiopsv. ,_ _ _. Circulation 28:536, 1963. 62. Vertes, V., Grauel, J. A., and Goldblatt, H.: separate renal function Renal arteriography, studies and renal biopsy in human hypertension, New England J. Med. 270:656, 1964. 63. Vertes, V., Grauel, J. A., and Goldblatt, H.: Studies of patients with renal hypertension undergoing vascular surgery, New England J. Med. 272:186, 1965. 64. Strickler, W. L.: Surgical care of malignant hypertension with intrarenal arteriosclerosis, J.A.M.A. 194:233, 1965. 65. Davis, G. D.: Renal arteriography, Postgrad. Med. 40:3X0, 1966. 66. Eyler, W. R., Clark, M. D., Garman, J. E., Rian, R. L., and Meininger, D. E.: Angiography of renal areas including a comparative
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study of renal artery stenoses in patients with and without hypertension, Radiology 78:879, 1962. Crawford, E. S., Beall, A. C., Moyer, J. H., and DeBakey, M. E. : Complications of aortogSurg., Gynec., & Obst. 104:129, 1957. raphy, Abrams, H. L., Baum, S., and Stamey, T.: Renal venous washout time in renovascular hypertension, Radiology 83:597, 1962. Kiser. W. S.. Tanenbaum. H. I,.. and Holland. J. H. : The phonorenogram: transureterai phonocatheter recording of the renal artery pulse in the diagnosis of renal vascular disease, T. Urol. 92:391, 1964. Sheps, S. G., and Bernatz, P. E.: Hypertension and renal artery stenosis: medical and surgical management, Postgrad. Med. 40:355, 1966. Sheps, S. G., Osmundson, P. J., Hunt, J. C., Schirger, A., and Fairbairn, J, F.: Hypertension and renal artery stenosis. Serial observations on 54 patients treated medically, Clin. Pharmacol. & Therap. 6:700,196.5. DeBakey, M. E., Morris, G. C., Jr., Morgen, R. O., Crawford, E. S., and Cooley, D. 4.: Lesions of the renal artery: surgical technic and results, Am. J. Surg. 107:84,1964. Morris, G. C., Jr., and DeBakey, M. E.: Renal revascularization; long-term results, in Brest, A. N., and Moyer, J. H., eds.: Atherosclerotic vascular disease, 1Jew York, 1967, AppletonCentury-Crofts. Bower, R., Brest, A. N., and Wolferth, C. C., Jr.: Renovascular hypertension, Pennsylvania Med. 69:27, 1966. Morris, G. C., Jr., DeBakey, M. E., and Cooley, D. A.: Surgical treatment of renal failure of renovascular origin, J.A.M.A. 182:609, 1962. Brest, A. N., Heider, C., and Moyer, J. H.: Renal functional changes following surgery for renovascular hypertension: preoperative and long-term postoperative results, J. Ural. 90:380, 1963.
Renal
arterial
hypertension
Albert N. Brest, M.D. Philadelphia, Pa.
T
he association of renal disease and arterial hypertension was inferred by Bright,’ 150 years ago, when he described the morphologic relationship between left ventricular hypertrophy and renal disease. It was assumed for some years thereafter that all hypertension was of renal origin. However, the validity of this assumption was questioned subsequently as additional observations indicated that arterial hypertension was common in individuals without evidence of renal disease. A reawakening of interest in hypertension of renal origin developed with the classic experiments of Goldblatt and associates in 1934.2~3 He demonstrated that hypertension could be produced experimentally by constricting the renal artery of the dog. Subsequently, it has become apparent that renal arterial hypertension in man closely parallels the experimental hypertension produced by Goldblatt and co-workers in animals. It has become further evident during the past decade that renal arterial hypertension is the most common, potentially curable form of diastolic hypertension. Although estimates of its incidence range from 1 to 25 per cent, our own experiences suggest the incidence within the hypertensive population is about 3 per cent.“z5 Anatomy
The renal arteries usua!ly arise laterally from the aorta between the levels of the From
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lower third of the first lumbar vertebra and the upper third of the second, and slightly below the level of origin of the superior mesenteric artery.6r7 Supernumerary arteries and arteries to ectopic kidneys may arise from any level of the abdominal aorta, from the common, external, or internal iliac vessels or, rarely, from the hepatic, superior or inferior mesenteric, right colic, or lumbar arteries. Numerous studies have shown that 20 to 30 per cent of kidneys have supernumerary arteries of aortic origin or otherwise that enter the kidney either at the hilus or, as polar vessels, above or below the hilus. Usually, before each renal artery reaches the hilus of the kidney, it divides into an anterior and a posterior branch. These anterior and posterior intrahilar vessels then rebranch within the renal sinus and give rise to a variable number of interlobar arteries which spread out around the minor calyces and enter the renal columns between the renal pyramids. The interlobar arteries subsequently subdivide into branches, the arcuate arteries, which give rise in turn to interlobular arteries which reach the cortex and then give rise to the afferent arterioles of the glomeruli. Just before they enter the glomerulus, the afferent arterioles are surrounded by the myo-epithelioid tissue of the juxtaglomerular (JG) apparatus. The efferent arterioles, formed by the confluence of the glomerular Philadelphia,
Pa.
Renal
capillaries, give rise to an extensive peritubular plexus of capillaries. According to Graves,8 each renal artery gives rise to five primary branches and each of these branches supplies a separate segment of the renal parenchyma. Graves labeled these five segments as follows: apical, upper, middle, lower, and posterior. Although the segmental arteries are subject to variation in their levels of origin from the main renal artery, Graves found them usually recognizable in spite of their variations. Typically, the posterior division of the renal artery gives rise to the posterior and apical segmental arteries, while the upper, middle, and lower segmental arteries arise from the anterior division. However, numerous anatomic variations may be encountered; and some investigators feel that no single segmental classification is acceptable. g Since there are essentially no anastomoses between the various branches of the renal artery in the renal parenchyma, these vessels are functional endarteries. Although a modest collateral circulation can be provided to t.he kidney by various vessels in the adipose capsule of the kidney, and along the renal pelvis and ureter, these vessels generally do not provide sufficient blood to prevent renal ischemia following partial or complete occlusion of the artery or its branches. Pathology In all reported series, atherosclerosis and fibromuscular occlusive processes of the renal artery constitute the overwhelming majority of lesions. Occasionally, renovascular hypertension may result from uncommon lesions of the renal arterysuch as primary thrombosis, embolism, aneurysm, arteriovenous fistula, dissecting hematoma, compression by tumor or fibrous bands, and trauma. Atherosclerosis of the renal artery occurs more commonly in men. The lesion usually involves the first 2 cm. of the main renal artery; less commonly, the atheromatous process is localized to a main branch. Associated atherosclerotic disease is often present elsewhere, especially in the extracranial carotid and coronary arteries. There is also a substantial incidence of significant aneurysmal or occlusive disease,
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or both, of the abdominal aorta and of its peripheral branches. The incidence of associated abdominal aortic disease has been reported to be as high as 30 per cent. The fibromuscular occlusive processes were originally grouped together and labeled “fibromuscular llyperplasia.“10 Subsequently, these fibrous stenosing lesions have been divided into four subgroups: (1) intimal fibroplasia, which involves the intima predominantly, (2) medial fibroplasia, which involves primarily the media and often is associated with microaneurysms, (3) fibromuscular hyperplasia, a lesion of the media marked by jumbling of fibrous tissue and collagen, and (4) subadventitial fibroplasia, a disorder involving the area of the media immediately adjacent to and often including the elastica externa. Although commonly localized to the renal arteries, these disorders may at times involve other vessels, e.g., a counterpart of intimal fibroplasia may be responsible for pulseless disease in the upper extremities. Whereas atheromatous disease often is limited to the orifice and proximal half of the renal artery, these fibrous stenosing lesions often extend peripherally beyond the bifurcation of the main renal artery but infrequently involve the orifice of the vessel. Fibromuscular dysplasia occurs more commonly in young patients, especially women. The genesis of these fibromuscular occlusive processes is unknown. Pathophysiology It is generally acknowledged that the renin-angiotensin-aldosterone system is involved, at least in part, in the pathogenesis of hypertension due to renal artery stenosis.ll There is abundant experimental evidence to support this relationship. In addition, equally impressive clinical data has accumulated. Renin is a vasoinert proteolytic enzyme which is released from the JG cells in the wall of the afferent renal arteriole. The renin is discharged into the blood stream where it reacts with an or-2 globulin fraction (renin substrate) to form a decapeptide, angiotensin I. The decapeptide, which is inactive, is then converted by a rather ubiquitous converting enzyme to the vasoactive octapeptide, angiotensin II. Subse-
quently, angiotensin II is broken down enzymatically by the angiotensinases present in tissues and plasma. It is well established that angiotensin II is a potent pressor substance which can significantly elevate the arterial blood pressure.12s13 In addition, angiotensin II is the principal and most potent stimulator of aldosterone biosynthesis and secretion by the zona glomerulosa of the adrenal cortex. It appears that the sodium retention mediated by the associated (secondary) aldosteronism plays a contributory role in the pathogenesis of renal arterial hypertension. It is likely that retention of sodium in the arteriolar muscle walls enhances the vasopressor effect of the circulating angiotensinemia. The regulation of renin release is not fully understood. Two mechanisms have been implicated. The first involves a baroreceptor in the wall of the afferent renal arteriole which evokes renin release in response to a decrease in renal artery ltlood flow or alterations in pulse wave contour. The second involves a sodiumload chemoreceptor in the cells of the macula densa portion of the juxtaglomerular apparatus. Although the exact role of the reninangiotensin-aldosterone system in the pathogenesis of renal arterial hypertension is still uncertain, it would appear that this system is undoubtedly operative in many (if not most) instances of renal arterial hypertension, especially when the hypertension is moderate or severe. However, the involvement of this system does not necessarily exclude other factors that may be operative. In this regard, the kidney may play an important role in the control or release of as yet unidentified vasodePYessoY substances; and the elaboration of these latter substances could conceivably be awry in renal arterial hypertension. Clinicul
features
It is well established that renal arterial hypertension may mimic essential hypertension and, in many cases, the history does not provide any differential diagnostic clues. Furthermore, a positive or negative family history of hypertension is of no value in separating these groups. It is also noteworthy that the response, or lack of
response, to antihypertensive drugs has been of no value in differentiating renovascular from essential hypertension. On the other hand, renal arterial hypertension should be strongly suspected in the following clinical circumstances: onset of hypertension in young or elderly individuals; malignant hypertension; or sudden acceleration of previously benign hypertension.i4 Renal arterial hypertension also should be suspected when there is a history suggesting the possibility of a renovascular accident. The most helpful clinical sign leading to a diagnosis of renal arterial hypertension is an upper abdominal bruit. The murmur is often but not invariably heard best near the midline in the epigastrium with transmission to the affected (or more severely affected) llypocllondrium.15 Howthat such bruits ever, it is noteworthy are heard in no more than 50 per cent of cases. Thus, the absence of a bruit fails to differentiate renal arterial hypertension from other causes of elevated diastolic pressure. Contrariwise, the presence of an upper abdominal bruit does not necessarily signify renal artery disease, It is well established that when renal artery obstruction is severe, the increased renin release is accompanied by increased aldosterone secretion. As a result of this secondary aldosteronism, hypernatremia and hypokalemia may occur as late manifestations. Thus, several authors have suggested that renal arterial hypertension may simulate primary aldosteronism.‘“,i7 However, a full clinical and laboratory investigation will serve to differentiate primary from secondary aldosteronism. hIost important in this regard is the finding of increased circulating renin activity in renal arterial hypertension, whereas renin activity is diminished or absent in hypertension due to primary aldosteronism. Diagnosis Since the history and physical findings may be fallible, the diagnosis of renal arterial hypertension must depend ultimately on the use of appropriate laboratory procedures. Intmven.ozks $yelogram. The intravenous pyelogram is a relatively safe and inexpensive procedure which provides a com-
parative index of renal mass and kidney function bilaterally. The minute-sequence technique has been especially valuable as a screening procedure. X-rays are obtained every minute for five minutes following rapid intravenous injection of opaque medium and then every five minutes for 30 minutes. A satisfactory and equal nephrogram should be obtained within one to two minutes. The threeminute film should demonstrate equal filling of the calyces of both kidneys as nell as early filling of the renal pelvis. The four- and five-minute x-rays provide further verification of abnormalities on either or both sides. W’hitley and associatesi* found one or more of the following intravenous pyelographic alterations in renal artery stenosis: (1) disparity in renal length of 1.5 cm. or more; (2) delay in appearance of contrast medium in the calyceal system; (3) nonvisualization of an entire kidney or a portion of a kidney; (4) differences in concentration of contrast material in the affected kidney; (5) calcification of renal vessels, as seen in arteriovenous fistulas and aneurysms; and/or (6) scalloping of the ureter due to increased collateral circulation. found abnorHoward and Connor malities in 75 per cent of cases of renovascular hypertension. Correa and associateszO found abnormal pyelograms in 89 per cent of cases. Although the reported incidence of abnormal pyelographic findings varies, most authors have found one or more pyelographic alterations in at least 75 per cent of patients with renal arterial hypertension. Refinement of techniques of intravenous pyelography has been made in order to increase accuracy in the detection of renovascular hypertension. Dehydratedhydrated excretory pyelography and also the pyelogram urea washout test have found several advocates.21-23 Enhanced reabsorption of water and sodium is a characteristic physiologic sequence of renal ischemia,24 and accordingly, it has been demonstrated that the disparate reabsorption of water on the affected side (vs. the unaffected kidney) can be better identified by a water or urea diuresis. Similarly, the use of hydration and a mercurial diuretic or mannitol has been employed with the
sole purpose of accentuating subtle differences in concentration of contrast material.?l Neither Brannan and co-workerP nor Schreiber and associateP found any false negative pyelograms employing these hydrated techniques; in their investigations, the urea washout pyelograms correlated well with the split renal function studies and seemed more specific than the radioisotope renogram. Over-all, intravenous pyelography has proved to be a rewarding screening procedure in the detection of renal arterial hypertension.*j A dehydrated minute-sequence study followed by renal loading and evaluation of the response to this hydration is especially informative and possibly the method of choice. Radioisotope renogrcrm. The radioactive Ir3r renogram has been employed as a screening procedure for the detection of renovascular hypertension since its introduction in 1956.36J7 The rate of accumulation and excretion of the radioactive test agent is measured by placing external scintillation detectors over the posterior aspects of each kidney. Ii3i orthoiodohippuric acid (Hippuran) has been found more satisfactory than P idopyracet (Diodrast), mainly because of the lesser hepatic accumulation of Hippuran. Hippuran is excreted almost exclusively by the kidneys, being handled in a fashion similar to para-aminohippuric acid and thereby providing a qualitative measure of renal blood flow or tubular secretory mass. The procedure can be performed with as little as 2 or 3 microcuries of radioactive iodine but doses of 25 to 40 microcuries are usually employed.27J8 A normal tracing consists of (1) an initial spike, which has no significance other than indicating the first appearance of tracer in the kidney region, (2) a slower secondary rise which takes 2 to 5 minutes to achieve its maximum height and reflects the relative renal blood flow, and (3) a rapid exponential fall recognized as the excretory or drainage phase. The three most important features of the renal tracing are the slopes of the second and third segments and the time required to reach maximum levels. The renogram provides a qualitative assessment of &renal blood flow, kidney function, and - postrenal ex-
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cretion. Semiquantitative measurements may be obtained by calculating the time of maximum isotope uptake (T,.,) and the time of fall of the isotope curve to one half maximum uptake (TX). The advantages of radioisotope renography are ease of performance, lack of trauma and hazard to the patient, and immediate availability for interpretation. Furthermore, a repeat tracing can be obtained within 30 minutes if necessary. According to Winter,27 the renogram is 85 per cent accurate in detecting unilateral and bilateral renal disease capable of producing hypertension. It appears that reliability of the test to detect disparate kidney function is enhanced by obtaining tracings at a urine flow rate between 1.5 and 7.0 ml. per minute.28 Physiologic factors which alter renogram contour are the state of hydration, prior administration of urographic agents or drugs that depress tubular extraction of Hippuran, and emotional factors.2g Fluid restriction or the hydropenic state slows the renal turnover of tracer and produces an increase in transit time in the renogram. Renograms performed shortly after intravenous urography show flattened second and third segments due to saturation of tubular transport mechanisms; therefore renograms should not be performed for at least 24 hours following intravenous urography. Sulfonamides and other drugs known to be excreted by tubular mechanisms can alter the renogram in similar fashion. Emotional factors also can adversely affect the renogram. Although some investigators30J1 feel that the test is unreliable in detecting renovascular hypertension, it is our feeling that the renogram is a useful adjunct to intravenous pyelography for diagnostic screening purposes. In addition, it has definite value in the followup of patients with renal revascularization procedures. Split renal clearance studies. In 1953, Howard and co-workers3” introduced split renal clearance studies as a diagnostic method, following the observations that ischemic rat kidneys reabsorb increased amounts of sodium and water.24 The test involves bilateral ureteral catheterization with analysis of urine volume and content from each kidney. A 50 per cent or greater
Am. Newt 3. May, 1968
reduction in urine flow from the affected kidney plus a decrease of 15 per cent or more in sodium concentration constitute a positive Howard test. Although the method gained immediate popularity as a diagnostic procedure, subsequent investigators questioned the reliability of the test.33J4 Birchall and associates35 demonstrated that the affected kidney also excretes increased urinary concentrations of inulin and creatinine. Stamey36 reported a modification which utilizes an infusion of 8 per cent urea in saline plus antidiuretie hormone to enhance reabsorption of l&rater in the ischemic kidney. Howard and Connor subsequently modified their original technique by combining it with certain features of the Birchall and Stamey modifications. They considered a positive test to be characterized by greatly reduced urinary volume plus a reduction in sodium concentration or increased concentration of creatinine or PAH on the affected side. In our experience, a difference of 50 per cent or more in urine volume together with an increase in urine inulin (or creatinine) concentration on the involved side indicate a “dynamic” stenosis; but the urinary sodium concentration may be decreased, equal or increased on the affected side in the presence of significant lesions.38 Split renal function studies are most useful in determining whether a unilateral lesion of the renal artery is hemodynamitally significant in the etiology of the patient’s hypertension. In this regard, the test is useful in prognosticating which patients will benefit from corrective surgery. Unfortunately the technical problems and associated morbidity of these tests as well as the lack of uniformity in their interpretation have caused considerable confusion and controversy. Kennedy and associates3g believe split clearance studies are unnecessary for the routine assessment of renal artery stenosis and should be reserved for patients with equivocal renograms and intravenous pyelography. However, Stamey40 emphasizes that the decision for surgical intervention in renal artery stenosis should be based upon these tests. Renal scan and chlomerodrin accumulation iest. Since 1959, the intravenous infusion of radioactive mercury-labeled (Hglg7 or
Renal
Hg203) chlormerodrin (Neohydrin) has been used for scintillation scanning of the kidneys. Of 13 labeled mercurial compounds studied by Kessler and co-worliers,41 chlormerodrin achieved the highest concentration in the kidneys. The major portion of mercury is excreted in a few hours, but radioactivity can remain in the kidneys for several weeks or months. The long-term effect on the renal tissue is unknown. Careful mapping of the renal tissue with a photoscanner is performed. The viable renal parenchyma is outlined and nonviable tissue such as tumors, cysts, infarction, or atrophy stand out by contrast. Simple renal scanning as an isolated procedure has not proved to be a satisfactory screening method for the detection of renal arterial hypertension. However, differential measurements of the rate of accumulation of labeled chlormerodrin by each kidney during a 30 to 60 minute period followed by scintillation scanning has been found to be a more reliable screening metllod.42 The most reliable criterion by which one kidney could be compared functionally with the other was the ratio of the rate of accumulation of the right kidney relative to that of the left. In 30 out of 31 patients with unilateral renal hypertensive disease, the right/left ratios were beyond the normal range.de Sodee4j studied 270 hypertensive patients, 14 of whom were found to have unilateral renovascular hypertension. The combination of Hippuran renogram plus mercurylabeled chlormerodrin uptake and scan correlated well with arteriography and surgical findings in their experience. Renin, angiotensin, and aldosterone determinations. Increasing evidence suggests that the renin-angiotensin system plays a substantive role in the pathogenesis of renal arterial hypertension. However, the development of methods of measurement of renal pressor substances has been fraught with certain technical difficulties. Conflicting data have been found in the determination of angiotensin, probably due to the lack of standardization of the various methods. For example, Morris and associates44 in a study of 136 hypertensive patients found 46 with angiotensin concentrations greater than 5 millimicrograms
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in unilateral and bilateral renal Ischemia, coarctation of the aorta, and acute glomerulonephritis; the other 90 patients with essential or malignant hypertension, essential hypertension with pyelonephritis, primary aldosteronism, and pheochromocytoma showed angiotensin levels less than 5 millimicrograms. In contrast, Genest and co-workers4j as well as Mulrow46 have obtained dissimilar results in. patients with renovascular hypertension. More widely employed is the measurement of renin activity in peripheral or renal venous blood. As with angiotensin, several methods have been devised.47-4g Veyrat and associates50 found arterial renin activity within normal levels in patients with benign and severe essential hypertension and in about half of the patients with renal artery stenosis. However, Genest and co-workers”~“’ reported that measurement of peripheral venous renin activity is consistently useful in predicting the results of surgery for renovascular hypertension; and they consider this determination the procedure of choice in assessing the activity of the renin-angiotensin-aldosterone system. The demonstration that the renin-angiotensin system can stimulate aldosterone production has provided a further indirect method of assessing renal arterial hypertension. The finding of increased renin activity plus increased aldosterone production is consistent with renal arterial hypertension. In contrast, low or absent renin activity in the presence of increased aldosterone production suggests primary aldosteronism.17 Unfortunately, until more simple and accurate methods can be developed, the availability of these studies is limited to major research centers. Angiotensin infusion. test. Kaplan and Silah52 devised this test based on the assumption that patients with increased endogenous levels of angiotensirt will require a greater amount of exogenous angiotensin to obtain a given pressor response. An intravenous angiotensin infusion is given, in graded dosage, until a 20 mm. Hg elevation in diastolic blood pressure is obtained. Kaplan and Silahs2 found that patients with essential hypertension require less than 6.5 millimicrograms per kilogram of body weight per minute for a positive
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pressor response, whereas patients with renovascular hypertension require larger amounts to produce a similar effect. Interestingly, patients with chronic renal parenchymal disease have shown a wide variability in their response.5s Goorno and KaplanS4 reported a correlated increase in renal pressor substance obtained by direct bioassay with the angiotensin infusion test. However, other investigators have questioned the validity of the test because they were unable to correlate either significant anatomical lesions or renin levels with the angiotensin infusion test.55s56 At present, it appears that further well controlled studies are necessary to prove or disprove the validity of the angiotensin infusion test and to determine its clinical applicability. Renal biopsy. Renal biopsy has been used as a guide for detection of renal vascular disease as well as for assessment of renal parenchymal changes which might contraindicate surgical intervention. The tissue specimen obtained by percutaneous needle biopsy is small and although possibly diagnostic, it often proves to be insufficient for the study of the JG apparatus. Hence, open incisional biopsy is generally required to ensure an adequate specimen for diagnostic purposes. In man, relationships have been found between the granularity of the JG cells, serum sodium levels, and aldosterone secretion.57 Both in human and experimental hypertension, the JG cell changes are believed to correlate with an increased production and secretion of renin.j8 Use of the fluorescent antibody technique indicates that the source of renin is the JG cel1.j” Boughton and SommersGo believe that aside from its value in the diagnosis of renal ischemia, the JG cell count is a practical method of determining whether nephrectomy or arterial reconstructive may be indicated in treating surgery these patients. Vertes and associates”‘-G3 contend that bilateral renal biopsy serves as the best guide for final decision regarding surgical intervention. They believe that if the contralateral kidney is affected seriously by arteriolosclerosis, cure of the hypertension is unlikely. On the other hand, Stricklere4 described a case of malignant hypertension
Am. Hcavt J. May, 1968
secondary to bilateral renal artery obstruction with documented parenchymal small vessel disease in which surgical cure was obtained after bilateral revascularization. At present, most w-ould agree that additional correlation of biopsy findings in renal arterial hypertension is required before a final judgment concerning its exact role in diagnosis and prognosis can be finalized. Renal mgiogra~hy. The definitive diagnosis of unilateral or bilateral renal vascular disease ultimately depends upon renal angiography. This procedure may be performed via the translurnbar aortographic approach or else a catheter may be threaded into the aorta and followed by direct injection of dye at the level of the renal arteries.6s Since renal vascular insufficiency may be present despite normal pyelography, differential renal function studies or radiorenography, renal angiography is recommended whenever the clinical picture suggests the possible occurrence of this lesion. On the other hand, the angiographic demonstration of renal artery stenosis does not mean necessarily that the stenotic lesion is responsible for the patient’s hypertension; most investigators have found examples of marked renal artery stenosis in normotensive patients studied for other purposesFG Although numerous complications have been described,e7 increasing experiences have indicated that this diagnostic procedure may be consistently performed without fatal or serious complications. Other studies. Abrams and co-workersP8 lhave devised another method to detect renal vascular hypertension. They measure the renal venous washout time, which is defined as the total time elapsed from the onset of the injection of contrast medium into the renal vein to its disappearance. Cinerecording is used as a means of obtaining precise measurements of the washout time. Normal values vary between 1.25 and 3 seconds. Values above 3 seconds have been found in renal artery obstruction greater than 50 per cent, The usefulness of this test may also be extended to appraisal of the contralateral kidney, i.e., its involvement by arteriolar disease, and hence the feasibility of surgical intervention.
Renal arterial
Kiser and co-workersGg devised the phonorenogram as an indirect measurement of transmitted renal artery pulsations using a transureteral cardiac phonocatheter. The value of this procedure in detecting renovascular hypertension cannot be assessed until further analysis of these studies prove their reliability. Treatment
Renal arterial hypertension may improve with medical (antihypertensive drug) or surgical treatment. The decision as to the more appropriate therapy is generally determined by such factors as: age of the patient, severity of the hypertension, extent of accompanying cardiovascular involvement, and the degree of renal functional impairment. Medical treatment of renal arterial hypertension should be considered when the hypertension is not severe, when the patient prefers a medical regimen, and when the location of disease is such that nephrectomy is the only feasible surgical therapy.70 i\4edical management may also be indicated in those individuals, especially el.derly patients, with significant extrarenal disease, such as coronary or cerebrovascular insufficiency. In addition, the effectiveness of antihypertensive drug therapy also enters into the decision for medical versus surgical treatment. In this regard, it is noteworthy that normotension can be achieved with antihypertensive drugs in at least 50 per cent of patients with renal arterial hypertension; however, despite successful blood pressure reduction, renal function may deteriorate because of progressive ischemic renal atrophy beyond an area of renal artery stenosisS71Thus, there is an important need for close observation of renal function and size among patients treated medically, even though the blood pressure may be controlled satisfactorily. Various surgical procedures, including nephrectomy and revascularization, can be used successfully in managing renal arterial hypertension. It is generally agreed that nephrectomy should not be performed unless the kidney is irrevocably damaged or its revascularization is technically impossible. On the other hand, successful renal revascularization can provide im-
hypertension
703
provement or preservation of renal function as well as satisfactory blood pressure reduction. The techniques of renal revascularization are similar to those applied to OCelusive lesions elsewhere in the arterial tree. Although numerous variations in technical procedures have been used to restore normal renal arterial circulation, the two most common procedures are the bypass graft and patch graft angioplasty.72 Because of the lengthy linear involvement usually seen with fibromuscular disease, patch graft angioplasty is rarely selected for reconstruction in this condition. Arterial bypass is generally preferred in the treatment of fibromuscular disease and many arteriosclerotic lesions, particularly when aortic reconstruction is required in addition. The graft materials most commonly employed are knitted dacron and autogenous saphenous veins. The usual bypass procedures employed are the aorto-renal and the spleno-renal arterial anastomoses. Endarterectomy may be used sati.sfactorily in some instances of localized arteriosclerotic occlusion; in other cases,resection and graft replacement, or division and implantation onto the aorta may be used successfully. Endarterectomy techniques are generally not applicable to fibromuscular lesions. About 80 per cent of patients undergoing successful surgery for renal arterial hypertension obtain a significant antihypertensive response, with normotension being achieved in about one half of the group.73,74 As a result of our own surgical experiences, we have divided the postoperative results into four categories. (1) Renal artery stenosis with renal arterial hypertension; optimum improvement in blood pressure is obtained in this group. (2) Generalized arteriosclerosis with renal artery stenosis and renal arterial hypertension; the surgical results have been generally gratifying in this group, even though less satisfactory than in the former category. The less satisfactory surgical prognosis reflects the presence of extensive and often generalized vascular disease in these patients, many of whom have impaired renal function in addition to uncontrolled hypertension. (3) Essential hypertension with concomitant renal artery stenosis and renal arterial
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hypertension; blood pressure reduction following surgical treatment is never complete in these individuals since the renal arterial hypertension is merely engrafted upon an essential hypertensive process. (4) Renal artery stenosis without renal arterial hypertension; surgical treatment obviously fails to control the elevated blood pressure in these instances. It is to be anticipated that a comprehensive diagnostic workup will identify and thereby eliminate these patients from any surgical consideration. Many patients with renal arterial hypertension have significant accompanying renal functional impairment. The degree of renal deterioration depends upon (1) the duration and severity of the arterial stenosis, and whether the stenotic involvement is unilateral or bilateral, and (2) the degree and duration of hypertension, with its inevitably detrimental effect on contralateral kidney function. It is notable that renal function may deteriorate in spite of effective blood pressure control, thus emphasizing the need for close observation for progression in severity of the stenosis or deterioration of renal function among patients treated medically. Surgical experiences75,76 indicate that significant renal functional improvement may be achieved following successful renal revascularization. Therefore, renal functional status should be considered as an important indicator of the need for surgical treatment in the management of patients with renal arterial hypertension. Conclusions
Renal arterial hypertension is a potentially curable form of diastolic hypertension. Although renal angiography provides the most definitive technique available for establishing the anatomic diagnosis, other studies are required to establish whether the stenotic arterial lesion is responsible for the patient’s hypertension. Either antihypertensive drug therapy or surgery may be employed successfully in the management of renal arterial hypertension. 1.
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