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Urologic Aspects of Arterial Hypertension
THE JOURNAL OF UROLOGY
Vol. 67, No. 1, January 1952 Printed in U.S.A.
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UROLOGIC ASPECTS OF ARTERIAL HYPERTENSION T . BRENT WAYMAN
AND
EUGENE B. FERRIS
li'rnm the Department of Surgery, Division of Urology, and the Department of Internal MP.dicine. University of Cincinnati, School of Medicine, and Cincinnati General Hospital, Cincinnati, 0.
Rir,hard Bright,1 in 1827-36, is credited with the first observation relating arterial hypertension to disease of the kidneys in man. Although he had no means of determining the blood pressure, he demonstrated abnormal resistance to injections offered by the renal arteries of those patients who died with enlarged and thickened hearts in whom there was no local disease of the heart to explain the hypertrophy. In 1909 Janeway 1 • a produced moderate sustained hypertension in two dogs by ligation of branches of both renal arteries. In 1932 Chanutin and Ferris1 , b produced sustained hypertension in a large series of rats by partial removal of one kidney and subsequently total removal of the other. Hypertension was sustained in some rats for as long as seven months. The classic experimental work of Goldblatt2 in producing persistent elevation of blood pressure in animals by partial constriction of the main renal artery has evoked great interest and a large series of publications. Few fail to accept the renal origin of hypertension associated with glomerulonephritis (acute and chronic), bilateral chronic pyelonephritis, bilateral polycystic disease of the kidneys, bilateral ureteral obstruction, renal amyloidosis and other conditions that involve considerable reduction of renal parenchyma. Essential hypertension by definition has been characterized as elevated blood pressure of unknown origin without recognizable disturbance of renal excretory function, in the early phase. It is in so-called essential hypertension that the primary renal origin of the elevated blood pressure is still held in doubt. Goldblatt's idea of producing hypertension by a disturbance of intrarenal hemodynamics was based primarily upon the observation that intrarenal stenosing arterial and arteriolar sclerosis is found with great frequency in both the benign and malignant phases of essential hypertension, together with the clinical and experimental evidence that hypertension can be produced by renal disturbances. There was then and there still is no known way to reproduce the intrarenal anatomic abnormality, namely, arterial and arteriolar sclerosis localized to the kidneys. His procedure of permanent constriction (not occlusion) of the main renal artery with a clamp was a compromise. It does not mean that stenosing arteriosclerosis of the main renal artery is considered to reproduce exactly the anatomical state of the kidney in hypertension. This incorrect interpretation has been made by a number of authors and investigators. Read at annual meeting, North Central Section, American Urological Association Milwaukee, Wis ., October 13, 1950. ' 1 Bright, R. : Guys Hospital Rep ., 1: 338, 1836. a, Janeway, T . C .: Proc . Soc. E xp. Biol. & Med ., 6 : 109, 1909. b, Chanutin, A. and Ferris, E . B ., Jr.: Arch. Int. Med., 49: 767 : 1932. 2 Goldblatt, H .: Am. J . Med ., 4: 100, 1948. 37
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T. BRENT WAYMAN AND EUGENE B. FERRIS
There have been three acceptable instances of the renal genesis of hypertension due to main renal artery obstruction reported by Leadbetter and Burkland,3 Prinzmetal,4 and Saphir. 6 Goldblatt found that constriction of the main renal artery of only one kidney was sufficient to induce a rise of blood pressure. In the dog, the elevated blood pressure usually lasts from four to six weeks. Removal of the one kidney, with the main renal artery constricted, results in a prompt return of blood pressure to normal. Constriction of both main renal arteries results in permanent elevation of blood pressure. The same effect is produced by constriction of one main renal artery and contralateral nephrectomy. By this means persistent hypertension has been produced in animals and the blood pressure has remained elevated in some dogs for more than six years. In these animals with persistent hypertension due to moderate constriction of both main renal arteries there was no significant alteration of renal excretory function. If both main renal arteries are greatly constricted from the start, or, if moderate constriction is practiced at first and greater constriction later, hypertension accompanied by variable degrees of impairment of renal excretory function results. The same effect can be produced by excessive constriction of one main renal artery with contralateral nephrectomy or contralateral ureteral occlusion. In those animals that develop great impairment of renal excretory function along with hypertension, fatal convulsive uremia occurs and, at autopsy, the small arteries and arterioles in many organs show pathologic changes which resemble those observed in malignant phase of essential hypertension, i.e., acute necrotizing arteriolitis. It seems clear that in the experimental animal, made hypertensive by partial occlusion of the main renal artery, that the rise in blood pressure is of humoral rather than nervous origin. Most investigators agree that a chemical agent of renal origin is the probable cause of the elevated blood pressure in experimental renal hypertension. Renin has been accepted by many investigators, as the name of the basic principle of this chemical agent. Renin has been demonstrated in the systemic blood in the acute phase of experimental benign renal hypertension, in the malignant phase of experimental renal hypertension, and in some forms of hypertension associated with renal disease in man, i.e., acute glomerulonephritis. However, it has not been demonstrated that renin in appreciable quantities exists in the systemic blood of animals in chronic benign phase of experimental renal hypertension, or in human beings in the benign or malignant phase of essential hypertension. In addition to renin, a number of other humoral mechanisms have been suggested as playing a role in essential hypertension. Perhaps the most promising lead in this regard has resulted from the work of Shorr and his associates. 6 They have detected a vasodepressor (V.D.M.) and a vaso-excitor material (V.E.M.) 3 Leadbetter, W. F. and Burkland, C. E.: J. Urol., 39: 611, 1938. • Prinzmetal, M., et al.: J.A.M .A., 118: 44, 1942. 5 Saphir, 0. and Ballinger, J.: Arch. Int. 'Med., 66: 541, 1940.
UROLOGIC ASPECTS OF ARTERIAL HYPERTENSION
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from the blood of patients in a state of shock, essential and renal hypertension suggesting that the interaction of these two substances may be of importance in setting the level of the blood pressure. In two recent books 7 , 8 on the subject of hypertension, divergent views were expressed about the mechanism of elevation of the blood pressure, indicating that the role of the kidney in essential hypertension is still unknown. Although most investigators believe that the vascular changes in the kidneys are secondary to the hypertension, the evidence for this still is inconclusive and the final answer will depend on the study of adequate kidney biopsy material in early phases of the disease. The urologist is in the unique position of being able to gather and correlate this type of information by routinely taking biopsy material during operations which require opening the parenchyma of the kidney. Since studies of experimental hypertension are inconclusive regarding the role of the kidney in human hypertension, except perhaps, in acute renal disorders such as acute glomerulonephritis, it seems worthwhile to re-evaluate the clinical evidence concerning the association of hypertension and renal disease, both unilateral and bilateral. THE INCIDENCE OF HYPERTENSION
Master,9 using a blood pressure of 150/90 as the upper limit of normal, estimated from an analysis made in 14,849 people of age 40 years and above, that one-half of the male population and 60 per cent of the female population of forty years and over are hypertensive. Braasch, 10 using a blood pressure of 150/90 as the criterion, estimated that 25 per cent of persons 30 years and older, and increasing to 60 per cent in elderly persons, have hypertension. His study was based on 975 consecutive patients taken at random from registration at the Mayo Clinic. INCIDENCE OF HYPERTENSION IN PATIENTS WITH UROLOGIC DISEASE
Goldring and Chassis, 11 in a control group of 2928 living patients, found that 26 per cent of them had hypertension, and in a group of 433 necropsy control patients, an incidence of 26.5 per cent with hypertension was found. In 585 patients with proven unilateral renal disease there were 24.2 per cent with · hypertension. Pearman12 reported that from urographic evidence the incidence of hypertension was no greater in patients with pyelonephritis than in patients with 6 Zweifach,B. W. and Shorr, E.: Proc. lst Clin. ACTH Conference, Philadelphia: Blakieton Co., 1950, p. 289. 7 Goldring,W. and Chassis, H.: Hypertension and Hypertensive Disease: New York: Commonwealth Fund, 1944. 8 Braun-Menendez, et al., Translated by L. Dexter: Renal Hypertension, Springfield, Ill., Chas. C Thomas, 1946. 9 Master, A. M., et al.: J.A.M.A., 121: 1251, 1943. 10 Braasch, W. F., Walters, W. and Hammer, H.J.: J.A.M.A., 115: 1837, 1940. 11 Goldring, W. and Chassis, H., Hypertension and Hypertensive Disease. New York: Commonwealth Fund, 1944, p. 114. 12 Pearman, R. 0. et al.: Proc. Staff. Meet., Mayo Clinic, 15: 467, 1940.
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T. BRENT WAYMAN AND EUGENE B. FERRIS
nonrenal disease. In a series of 500 patients with pyelonephritis, either unilateral or bilateral, there was a 9 per cent incidence of hypertension, in 500 patients with goiter without hyperthyroidism there was 10 per cent, and in 500 patients with gallbladder disease there was a 7 per cent incidence of hypertension. Hines13 reported among 264 patients with urologic disease, who were observed over a period averaging 15.3 years, the incidence of hypertension either prior to or subsequent to the first observation was practically identical with a control series of 790 patients without urologic disease. Braasch, Walters, and Hammer,10 and Baggenstoss and Barker14 record a high incidence of hypertension in unilateral pyelonephritic atrophy and unilateral pyonephrotic atrophy. They believe that a causal relationship is indicated by these statistics. Smith15 concluded that with the possible exception of pyelonephritis and pyronephrotic atrophy the available data did not indicate that urologic disease increased the incidence of hypertensive disease, or that it in any large number of instances was causally related to its genesis. INCIDENCE OF UROLOGIC DISEASE IN HYPERTENSION
The incidence of urologic disease as determined by pyelographic evidence in hypertensive patients varies from 45 per cent presented by Schroeder and Steele16 (24 per cent unilateral renal abnormalities) in an analysis of 250 hypertensives, to 8.9 per cent in 2,055 hypertensives as reported by Ratliff and Nesbit.17 Rath and Russek18 combined the statistics of Palmer and his coworkers, Ratliff and Conger, Braasch, Schroeder, and Steele, and others, and they noted that of a total of 6,044 hypertensive patients, 10.7 per cent exhibited evidence of urologic disease. They contrasted this figure to the 27.4 per cent incidence in normotensives reported by Wosika, Jung, and Maher and concluded that the incidence of urologic disease among hypertensives is not greater, and possibly less, than among normotensive subjects. Chassis and Redish19 in clearance studies of 21 hypertensive subjects selected at random, demonstrated that renal functional impairment proceeds to an equal degree or at a parallel rate in both kidneys. From the available data, approximately 10 per cent of hypertensive patients have demonstrable urologic abnormalities with functional impairment. Since the possibility of coincidence is very great, the only way a causal relationship can be demonstrated in any particular case is by "curing" or improving the hypertension by removing the kidney. Smith16 reviewed the literature and found 242 instances in which unilateral nephrectomy had been performed in association with hypertension. He required for a cure that the blood pressure be lowered to or below 140/90, and that it Hines, E. A., Jr. and Lander, H. H. : J.A.M.A., 116: 1050, 1941. Baggenstoss, A.H. and Barker, N. W. : Arch. Path., 32: 966, 1941. Smith, H. W.: Am. J. Med., 4: 724, 1948. 16 Schroeder, H. A. and Steele, J.M.: Arch. Int. Med., 68: 261, 1941. 17 Ratliff, R. K., Nesbit, R. M., et al.: J.A.M.A., 133: 296; 1947. 18 Rath, M. M. and Russek, H. I.: Am. Heart J., 29: 516, 1945. 19 Chassis, H. and Redish, J.: Arch. Int. Med., 70: 738, 1942. 13
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UROLOGIC ASPECTS OF ARTERIAL HYPERTENSIO:N°
remain within normal limits for at least one year. A summary of his analysis of these collected cases is shown in table 1. Smith concludes: "We are obliged, tentatively, to accept these 47 patients as 'cures', but nevertheless, it leaves a lingering doubt that the urologic disease was actually the cause of the hypertension." Of these 47 successful cases, 22 were of unilateral pyelonephritis. The age incidence of the successful cases showed 17 subjects under twenty years of age, but 24 were in their fourth or later decade of life. Ratliff and Nesbit17 reported 49 cases of severe hypertension in whom nephrectomy was performed. All but 8 of the subjects were followed 12 months or longer. Their results showed 17 cases or 34.6 per cent "cured", 6 cases, 12.4 per cent improved, and 26 cases or 53 per cent failures. Of this group there were 8 patients with pyelonephritis, 11 patients with hydronephrosis, and 7 patients with calculus pyonephrosis. Barker and Braasch20 reported a review of 61 patients who ca.me to the Mayo Clinic primarily because of hypertension. All were found to have advanced disease of one kidney and minimal, if any, evidence of disease in the other. All underwent removal of the diseased kidney. Based on a two-year follow-up on the entire series, they reported 25 cases (41 per cent) "good" results-i.e. blood TABLE
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1. Effects on blood pressure, 242 cases
NO SIGNIFICANT REDUCTION
REDUCED, BUT NOT TO NORMAL
135 (56%)
43 (18%)
REDUCED TO NORMAL; OBSERVATION LESS THAN ONE YEAR
17 (7%)
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R1£DUCED TO NORMAL FOR ONE YEAR 0~ MORE
47 (19%)
pressure 150/100 or less; 10 cases (16 per cent) "fair" results (blood pressure significantly reduced but greater than 150/100; and 26 cases (43 per cent) deaths or no lowering of blood pressure. Wilson and Byron21 and others have observed malignant arfieriolar lesions in the contralateral kidney of rats with hypertension caused by constriction of one main renal artery. Goldblatt has not been able to confirm this observation in dogs, rabbits, monkeys, sheep or goats with hypertension due -t,o constriction of one main renal artery. Goldblatt has pointed out that all the glomerular and interstitial inflammatory lesions, as well as the vascular lesio~, have been observed within an otherwise supposedly normal rat kidney. He feels that in their rat experiments they may have been dealing with bilateral reru3-l disease. There remains the possibility that the rat may differ in this respec;-t from all other animals. In spite of the experimental and statistical evidence againsfi the probability of curing hypertension by unilateral nephrectomy there are ~ ell documented cases of cures by this procedure. Subjects suitable for nephrectomy may be divided into threie categories: 1) Patients with reliable criteria of cardiovascular disease in ~ hich one kidney 20 21
Barker, N. W. and Braasch, W. F . ; Surg. Gynec. & Obst ., 84: 299',. 1947. Wilson, N. C. and Byron, F. B.; Lancet, 1: 136, 1939 .
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had insufficient functional ability to support life, and with a normal or compensated contralateral kidney (cases 1 and 2) . During childhood persistent elevation of blood pressure is uncommon and essential hypertension is rare. The majority of such cases are associated with renal disease. The probability of cure by unilateral nephrectomy when unilateral renal disease is present in children is very great. 2) Patients with associated hypertension in which nephrectomy is indicated on sound urologic principles (case 3). 3) Patients who are operated upon "in desperation." These patients should have markedly diminished function in the kidney to be removed and to have shown a continued downhill course in spite of medical and possible psychiatric therapy. These patients may have some functional disturbance in the contralateral kidney (case 4). CASE REPORTS
Case 1. J.S., a 27-year old white, married man, was admitted to Holmes Hospital on November 7, 1948 complaining of blurred vision of 3 weeks' duration. At the time of his induction into the Army in 1943, it was found that he had a systolic blood pressure of 179, which resulted in his being hospitalized for 1 week in a military hospital. There, his blood pressure was taken t.i.d., each time after 2 hours of bed rest. His blood pressure averaged 144 systolic during this period of observation, and he was accepted for military duty. He was discharged from the Army in February 1946, without further mention of hypertension. He had no urinary complaints. Two days before admission to the hospital he consulted a ophthalmologist because of failing vision. The eye grounds showed grade 4 hypertensive retinopathy, fresh hemorrhages, exudate and papilledema, and his systolic blood pressure was recorded over 200. The remainder of the physical examination was negative, except for an apical systolic murmur. Laboratory examinations showed a normal blood count. The urine was negative, except for an occasional cast and a trace of albumin. The blood urea nitrogen was 10 mg. per cent. Urine culture was sterile. He was able to concentrate the urine to 1.025 and the phenolsulfonphthalein secretion showed 35 per cent of the dye secreted in 15 minutes, with a total output of 75 per cent in 2 hours. Excretory urograms showed a normal left kidney, but no dye secreted on the right side. A right retrograde pyelogram showed a large extrarenal hydronephrosis with a small kidney shadow with very little renal parenchyma. There was obstruction at the right ureteropelvic juncture. The pyelograms were interpreted as showing a compensatory hypertrophy of the left kidney and hydronephrosis of a congenital hypoplastic right kidney due to ureteropelvic obstruction. The blood pressure response to tetraethyl ammonium chloride (TEAC) was measured on three occasions revealing very slight depressor effects of the drug. Since TEAC blocks the autonomic nervous system, the lack of depressor response
UROLOGIC ASPECTS OF ARTERIAL HYPERTENSION
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suggested that the blood pressure was maintained by humoral rather than neurogenic tone. 22 He was in the hospital 18 days before operation. Blood pressure determinations were made 4 times daily, and showed a variation from 225/170 to 160/120. On November 29, 1948 a right nephrectomy was performed. A hypoplastic kidney with a large extrarenal pelvis was removed. An aberrant artery was found obstructing the ureteropelvic juncture. There was no significant drop in blood pressure during the first 7 days following operation. During the next 5 days the blood pressure ranged between 140/100 to 120/90. Pathological report: The gross specimen consisted of a kidney measuring 10 by 6 by 3 cm. in diameter. The capsule was moderately adherent. Dissection of the vessels revealed the renal vein to appear grossly unremarkable, except that it was slightly smaller than usual. Accompanying the vein, there was one artery which was definitely smaller than the expected renal artery. This artery entered the pelvis with the vein, and appeared to nourish the superior two-thirds of the kidney. At the level of the ureteropelvic junction another small artery was present, anterior to the ureter, and seemed to be nourishing the lower third of the kidney. The pelvis when opened was seen to be extremely dilated, possessing a capacity of at the very least, 45 cc. The wall of the pelvis seemed markedly thickened and fibrotic. Microscopic sections showed a marked diminution in the number of tubules, those persisting being microcystic in type. Only an occasional identifiable glomerulus was seen. In the interstitial stroma, which was scarred, there were only occasional small infiltrations with polymorphonuclear leukocytes and lymphocytes. Rare tubules contained, clustered within their lumens, cells of acute and chronic inflammatory type. The wall of the pelvis showed a marked increase in the amount of collagenous tissue, and in the subepithelial stroma there were relatively few foci of infiltration with chronic inflammatory cells. A striking feature was a severe degree of vascular sclerosis involving vessels of all calibers to an approximate equal degree. Diagnosis: Hydronephrosis with marked atrophy of kidney; chronic pyelonephritis, slight; arterio- and arteriolar nephrosclerosis, severe. The patient has been examined every 3 months since operation. His eye grounds are normal and he is leading a normal life. His blood pressure has ranged between 112/70 to 120/78. The last examination was on September 11, 1950 at which time his blood pressure was 120/78. His urine was normal. This case is to be reported in further detail at a later date. Case 2. R.M., a 47-year old man, was admitted to Holmes Hospital on March 16, 1949 because of high blood pressure of at least 19 months' duration. Two years ago he had had a subtotal thyroidectomy. Seven months before admission he had had a cerebral accident, the results of which had not entirely disappeared. His eye grounds showed grade 4 retinopathy. The heart was tremendously enlarged. The urine contained 1 plus albumin, 1-2 white blood cells, an occasional red blood cell, and 2-3 hyalin casts. The blood urea nitrogen was
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T. BRENT WAYMAN AND EUGENE B. FERRIS
17.3 mg. per cent. Phenolsulfonphthalein 20 per cent was secreted in the first 15 minutes, with a total secretion of 55 per cent in 1½ hours. Culture of the urine was sterile. The blood pressure response to tetraethyl ammonium chloride (TEAC) was measured revealing a depressor response. The blood pressure fell from a control level of 225/150 to 150/ 110, two minutes after the injection. When the blood pressure response was tested with benzodioxane there was no significant response. Excretory urograms revealed compensatory hypertrophy of the left kidney and no dye appearing on the right side. The right ureter could be catheterized for only a distance of 1 cm. No urine was obtained from the right ureter. Contrast medium was injected up the right ureter. The right ureter was extremely narrow. The pyelogram showed an extrarenal hydronephrosis with small calyces and almost no renal parenchyma present. On April 6, 1949, a small, hypoplastic, infantile type kidney was removed. There was no aberrant artery crossing the ureteropelvic juncture. While the pelvis was large and extrarenal in type, it was entirely empty of urine at the time of nephrectomy. Pathological report: The kidney measured 9 by 8 by 2 cm. The capsule stripped with ease. The cortex was thin and almost absent in the upper pole. The pelvis and calyces were markedly dilated without demonstrable obstruction at the ureteropelvic juncture. An aberrant artery ended in the lower pole of the kidney. On microscopic examination there were seen changes typical of marked atrophy, although one segment appeared functioning. Most of the parenchyma showed profound atrophy, few intact glomeruli and tubules which were thin, dilated, and filled with colloid casts. There was an interstitial infiltration of inflammatory cells of minor degree. There had been atrophy and replacement of tubules and considerable glomerular fibrosis. Intrarenal arteries were markedly sclerotic and n arrowed. Major extrarenal vessels were less strikingly involved. Diagnoses: 1) Hydronephrosis with slight chronic pyelonephritis; 2) arterionephrosclerosis, severe; with focal cortical atrophy. There was no improvement in this patient's hypertensive vascular disease following nephrectomy. In general, he has done badly. When last examined on May 24, 1950 his blood pressure was 240/ 100 and there was a loud systolic apical murmur.
Case 3. M.B., a 43-year old white, married woman was admitted to Bethesda Hospital on August 23, 1947 because of recurring attacks of epigastric pain accompanied by nausea and vomiting. With each episode there was frequency and burning on urination, and pyuria. Two years before admission she had consulted her family physician because of severe headaches and spells of dizziness. He found that she had hypertension and had treat ed her for it during this time. Unfort unately no records were kept of the blood pressure readings. She was 11dmitted to the hospital for study regarding the episode of epigastric pain.
UROLOGIC ASPECTS OF ARTERIAL HYPERTENSION
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When first seen by us the patient had no complaints. Physical examination was essentially normal except for slight tenderness to deep palpation in the left midabdomen. Urine, blood count, and Kahn test were uormal. Cultures of the urine were sterile. Blood pressure was 160/110. Urograms revealed a normal right kidney, but the left kidney was small and there was some blunting of the calyces. A differential phenolsulfonphthalein test showed the dye to appear from both kidneys in 2½ minutes. During the next 15 minutes the right kidney secreted 30 cc urine with 30 per cent output of phenolsulfonphthalein. The left kidney secreted 7 cc urine with 7 per cent phenolsulfonphthalein. There was no leakage of urine in the bladder during the test. A left nephrectomy was performed on September 3, 1947. Pathological examination revealed a reddish brown kidney with marked granularity beneath the capsule, which stripped with difficulty. The surface was markedly pitted. The kidney measured 9.5 by 5 by 2.5 cm. The cortex was poorly demarcated from the pyramids and was estimated to be 0.5 cm. in thickness. The pelves were contracted. Microscopic sections showed the parenchyma to be in good part normal in appearance. There was mild to moderate vascular thickening and sclerosis. An occasional focus, however, showed profound atrophy with loss of glomeruli, dilatation and thinning of cast filled tubules, and marked interstitial :fibrosis. This was related to interlobular arteries which were sclerotic, occluded, and recanalized. There was little inflammatory reaction. The appearance of the lesion suggested focal ischemia with gradual infarction and atrophy. Diagnosis: Arterionephrosclerosis with focal cortical scarring. The patient's blood pressure level was recorded as 140/100 in January 1949; 136/80 in June 1949; 122/80 in August 1949; 130/70 in September 1950. Case 4, C.K., a 58-year old white man was admitted to Bethesda Hospital on June 26, 1948 for study of hypertension. Three years previously he had had a complete medical work-up and no abnormalities regarding his blood pressure or urine were present. Six months before admission he felt below par and had paroxysms of tachycardia. His blood pressure was found to be 170/110 and the urine contained 2 plus albumin. During the next 6 months his blood pressure gradually became more elevated, the albuminuria increased to 3 plus, and for several weeks he had had persistent disabling occipital headaches. General physical examination was negative. The blood pressure was 190/100. The phenolsulfonphthalein test showed 25 per cent excretion of dye in the first 30 minutes, and a total of 75 per cent in 2 hours. Concentration dilution tests showed the specific gravity of urine to vary between 1.001 and 1.026. Urine: albumin 3-4 plus; sugar negative. There was a rare red blood cell, and 2-3 white blood cells. The blood count was normal. A plain urogram showed multiple calcifications in the spleen and calcifications of blood vessels within the pelvis. X-ray of chest, complete gastro-intestinal series, and barium enema were normal. Cystoscopic examination of the bladder was normal. Urine from the right kidney contained 4 plus albumin; 8-10 red blood cells; and an occasional granu-
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T. BRENT WAYMAN AND EUGENE B. FERRIS
lar cast. Urine from the left kidney contained 3 plus albumin; a rare red blood cell; and no casts. Phenolsulfonphthalein appeared from the right kidney in 4 minutes with 10 per cent secretion in the first 15 minutes and 10 per cent in the second 15 minutes. Phenolsulfonphthalein appeared from the left kidney in 10 minutes, and there was only a trace of dye in 30 minutes. There was no leakage of phenolsulfonphthalein in the bladder. At the time of the examination the bladder urine contained 4 plus albumin, 12- 50 red blood cells, and 0- 3 granular casts per high dry field. Retrograde pyelograms were interpreted as compensatory hypertrophy of the right kidney and congenital hypoplasia of the lower two-thirds of the left kidney, with the upper third being normally developed. The eye grounds showed mild sclerotic
UROLOGIC ASPECTS OF ARTERIAL HYPERTENSION
47
taken from relatively intact renal cortex. These exhibited moderate arterionephrosclerosis with minor focal cortical scarring. There was no indication of the case of the cortical atrophy observed in the gross. The glomeruli were essentially normal. There was relatively little arterial or arteriolarsclerosis. Diagnosis: Arterio-nephrosclerosis. The patient has been under frequent and constant observation since operation. Blood pressure determinations have been made two or three times per month. The last examination was on September 15, 1950. Since January 1950, his blood pressure has averaged 157/84. The minimum blood pressure reading was 140/80, and the maximum was 170/90. His urine has contained between 1 and 2 plus albumin. There have been no red blood cells and only a very rare cast in his urine. His hemoglobin is 14 gm. He has been entirely relieved of his headaches and his only complaint has been that he "tired easily." Although it is not necessary for him to work, he works part time by choice. He looks well. DISCUSSION OF CASES
Case 1 was known to have had essential hypertension since May 1943. It is probable that a psychologic factor precipitated the malignant phase of hypertension. His only treatment consisted of nephrectomy. He was returned to the same environment and for 22 months postoperatively has had a normal blood pressure. Case 2 had almost the identical pathological changes as case 1. At the time of nephrectomy the dilated renal pelvis was empty of urine. This patient obtained no relief whatever from the hypertension. It is of interest that autonomic blockade with TEAC caused little or no fall in blood pressure in case 1, whereas there was a marked depressor response in case 2 suggesting that a humoral mechanism was predominant in the former and a neurogenic mechanism in the latter. Whether or not the blood pressure response to autonomic blockade may be helpful in predicting the effect of nephrectomy in unilateral renal disease will, of course, require further study; but this does seem to be a suggestive lead. In case 3, although the patient had been under the care of her private physician for a period of 2 years because of "high blood pressure," no records were kept of her blood pressure readings during this period. After admission to the hospital her blood pressure was recorded as 160/110. A hypertensive work-up was not done as it was thought that she had a urologic condition which required nephrectomy. Although the patient has a blood pressure of 130/70 three years after nephrectomy, proof of the presence of persistent hypertension before operation may be questioned. In case 4, the patient was known to have normal blood pressure 3 years before admission. While under the observation of a competent observer, his blood pressure became rapidly elevated. Nephrectomy was not performed as it was thought the chances of improvement from this procedure seemed remote. After two more months on medical therapy he was readmitted in hypertensive crisis
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T . BRENT WAYMAN AND EUGENE B. FERRIS
with a blood pressure of 210/120. A left nephrectomy was performed in "desperation". This patient has been observed at frequent intervals for a 2 year period following operation. Besides his clinical improvement and reduction in albumin content of the urine, the most striking result has been in the diastolic blood pressure. The maximum diastolic blood pressure recorded has been 90 mm. Hg. DISCUSSION
On the basis of the evidence presented above it is evident that the relation of hypertension to chronic bilateral kidney disease is uncertain and that the urological surgeon has little to offer therapeutically. However, despite the experimental uncertainty of the role of unilateral kidney disease in producing hypertension, it is clear that removal of the unilaterally diseased kidney has improved or cured the hypertension in certain patients, although there is no method of predicting the results to be expected. An important aspect of the problem is to develop methods of recognizing unilateral kidney disease when it occurs, and to differentiate between other "specific" types of hypertension such as pheochromocytoma. In the final analysis the recognition of unilateral kidney disease depends upon a knowledge of the function of each kidney separately because in the absence of one functional kidney, the other can function well enough to produce normal results from routine renal function studies such as phenolsulfonphthalein and concentration dilution tests. It might be wise, therefore, to take excretory urograms as a routine diagnostic procedure in all cases of hypertension in order to recognize the presence of this condition where specific therapy can be offered to the patient. Ferris and his group of investigators believe that testing the blood pressure response to TEAC is of value in recognizing those instances of hypertension where humoral factors predominate; for instance, the blood pressure in toxemia of pregnancy, in acute glomerulonephritis, and in pheochromocytoma, falls little or not at all during autonomic blockade, whereas in essential hypertension all gradations of response occur. It is of interest that the depressor response to TEAC in case 1 was very slight, which further supports the concept of a renal humoral mechanism in this case. Pheochromocytoma is another unusual form of hypertension in which the urologist may offer specific treatment, and again the early recognition of this disease is of great importance. Mention was made above of the lack of depressor response to autonomic blocking agents in the condition, in fact TEAC usually causes a pressor response. The recent development of adrenolytic drugs, such as benzodioxane and dibenamine, has given us an important and specific test for the recognition of hypertension due to circulating adrenalin. 22 • 23 22
Shapiro, A. P., Harrison, M. B., Hoffman, M. S. and Ferris, E. B.: Am. J . Med., 10:
115, 1951. 28
Goldenberg, M ., Snyder, C.H., Aranow, H.; J.A.M.A., 135: 971, 1947.
UROLOGIC ASPECTS OF ARTERIAL HYPERTENSION
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In pheochromocytoma the hypertension may be persistent, or it may occur in parnxysms. In the persistent form a consistent depressor response to benzodioxane is diagnostic of the disease. In the paroxysmal form, paroxysms of hypertension may occur spontaneously as the result of emotional stress and as the result of the administration of such agents as histamine, mecholyl, and TEAC. Since paroxysms of hypertension also occur frequently in essential hypertension it is important to test the specificity of the pressor response by abolishing it with benzodioxane. This then indicates that the pressor response was due to circulating adrenalin, and in this respect bolsters the diagnosis of pheochromocytoma.
726 Carew Tower, Cincinnati 2, Ohio
Vol. 67, No. 1, January 1952 Printed in U.S.A.
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UROLOGIC ASPECTS OF ARTERIAL HYPERTENSION T . BRENT WAYMAN
AND
EUGENE B. FERRIS
li'rnm the Department of Surgery, Division of Urology, and the Department of Internal MP.dicine. University of Cincinnati, School of Medicine, and Cincinnati General Hospital, Cincinnati, 0.
Rir,hard Bright,1 in 1827-36, is credited with the first observation relating arterial hypertension to disease of the kidneys in man. Although he had no means of determining the blood pressure, he demonstrated abnormal resistance to injections offered by the renal arteries of those patients who died with enlarged and thickened hearts in whom there was no local disease of the heart to explain the hypertrophy. In 1909 Janeway 1 • a produced moderate sustained hypertension in two dogs by ligation of branches of both renal arteries. In 1932 Chanutin and Ferris1 , b produced sustained hypertension in a large series of rats by partial removal of one kidney and subsequently total removal of the other. Hypertension was sustained in some rats for as long as seven months. The classic experimental work of Goldblatt2 in producing persistent elevation of blood pressure in animals by partial constriction of the main renal artery has evoked great interest and a large series of publications. Few fail to accept the renal origin of hypertension associated with glomerulonephritis (acute and chronic), bilateral chronic pyelonephritis, bilateral polycystic disease of the kidneys, bilateral ureteral obstruction, renal amyloidosis and other conditions that involve considerable reduction of renal parenchyma. Essential hypertension by definition has been characterized as elevated blood pressure of unknown origin without recognizable disturbance of renal excretory function, in the early phase. It is in so-called essential hypertension that the primary renal origin of the elevated blood pressure is still held in doubt. Goldblatt's idea of producing hypertension by a disturbance of intrarenal hemodynamics was based primarily upon the observation that intrarenal stenosing arterial and arteriolar sclerosis is found with great frequency in both the benign and malignant phases of essential hypertension, together with the clinical and experimental evidence that hypertension can be produced by renal disturbances. There was then and there still is no known way to reproduce the intrarenal anatomic abnormality, namely, arterial and arteriolar sclerosis localized to the kidneys. His procedure of permanent constriction (not occlusion) of the main renal artery with a clamp was a compromise. It does not mean that stenosing arteriosclerosis of the main renal artery is considered to reproduce exactly the anatomical state of the kidney in hypertension. This incorrect interpretation has been made by a number of authors and investigators. Read at annual meeting, North Central Section, American Urological Association Milwaukee, Wis ., October 13, 1950. ' 1 Bright, R. : Guys Hospital Rep ., 1: 338, 1836. a, Janeway, T . C .: Proc . Soc. E xp. Biol. & Med ., 6 : 109, 1909. b, Chanutin, A. and Ferris, E . B ., Jr.: Arch. Int. Med., 49: 767 : 1932. 2 Goldblatt, H .: Am. J . Med ., 4: 100, 1948. 37
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38
T. BRENT WAYMAN AND EUGENE B. FERRIS
There have been three acceptable instances of the renal genesis of hypertension due to main renal artery obstruction reported by Leadbetter and Burkland,3 Prinzmetal,4 and Saphir. 6 Goldblatt found that constriction of the main renal artery of only one kidney was sufficient to induce a rise of blood pressure. In the dog, the elevated blood pressure usually lasts from four to six weeks. Removal of the one kidney, with the main renal artery constricted, results in a prompt return of blood pressure to normal. Constriction of both main renal arteries results in permanent elevation of blood pressure. The same effect is produced by constriction of one main renal artery and contralateral nephrectomy. By this means persistent hypertension has been produced in animals and the blood pressure has remained elevated in some dogs for more than six years. In these animals with persistent hypertension due to moderate constriction of both main renal arteries there was no significant alteration of renal excretory function. If both main renal arteries are greatly constricted from the start, or, if moderate constriction is practiced at first and greater constriction later, hypertension accompanied by variable degrees of impairment of renal excretory function results. The same effect can be produced by excessive constriction of one main renal artery with contralateral nephrectomy or contralateral ureteral occlusion. In those animals that develop great impairment of renal excretory function along with hypertension, fatal convulsive uremia occurs and, at autopsy, the small arteries and arterioles in many organs show pathologic changes which resemble those observed in malignant phase of essential hypertension, i.e., acute necrotizing arteriolitis. It seems clear that in the experimental animal, made hypertensive by partial occlusion of the main renal artery, that the rise in blood pressure is of humoral rather than nervous origin. Most investigators agree that a chemical agent of renal origin is the probable cause of the elevated blood pressure in experimental renal hypertension. Renin has been accepted by many investigators, as the name of the basic principle of this chemical agent. Renin has been demonstrated in the systemic blood in the acute phase of experimental benign renal hypertension, in the malignant phase of experimental renal hypertension, and in some forms of hypertension associated with renal disease in man, i.e., acute glomerulonephritis. However, it has not been demonstrated that renin in appreciable quantities exists in the systemic blood of animals in chronic benign phase of experimental renal hypertension, or in human beings in the benign or malignant phase of essential hypertension. In addition to renin, a number of other humoral mechanisms have been suggested as playing a role in essential hypertension. Perhaps the most promising lead in this regard has resulted from the work of Shorr and his associates. 6 They have detected a vasodepressor (V.D.M.) and a vaso-excitor material (V.E.M.) 3 Leadbetter, W. F. and Burkland, C. E.: J. Urol., 39: 611, 1938. • Prinzmetal, M., et al.: J.A.M .A., 118: 44, 1942. 5 Saphir, 0. and Ballinger, J.: Arch. Int. 'Med., 66: 541, 1940.
UROLOGIC ASPECTS OF ARTERIAL HYPERTENSION
39
from the blood of patients in a state of shock, essential and renal hypertension suggesting that the interaction of these two substances may be of importance in setting the level of the blood pressure. In two recent books 7 , 8 on the subject of hypertension, divergent views were expressed about the mechanism of elevation of the blood pressure, indicating that the role of the kidney in essential hypertension is still unknown. Although most investigators believe that the vascular changes in the kidneys are secondary to the hypertension, the evidence for this still is inconclusive and the final answer will depend on the study of adequate kidney biopsy material in early phases of the disease. The urologist is in the unique position of being able to gather and correlate this type of information by routinely taking biopsy material during operations which require opening the parenchyma of the kidney. Since studies of experimental hypertension are inconclusive regarding the role of the kidney in human hypertension, except perhaps, in acute renal disorders such as acute glomerulonephritis, it seems worthwhile to re-evaluate the clinical evidence concerning the association of hypertension and renal disease, both unilateral and bilateral. THE INCIDENCE OF HYPERTENSION
Master,9 using a blood pressure of 150/90 as the upper limit of normal, estimated from an analysis made in 14,849 people of age 40 years and above, that one-half of the male population and 60 per cent of the female population of forty years and over are hypertensive. Braasch, 10 using a blood pressure of 150/90 as the criterion, estimated that 25 per cent of persons 30 years and older, and increasing to 60 per cent in elderly persons, have hypertension. His study was based on 975 consecutive patients taken at random from registration at the Mayo Clinic. INCIDENCE OF HYPERTENSION IN PATIENTS WITH UROLOGIC DISEASE
Goldring and Chassis, 11 in a control group of 2928 living patients, found that 26 per cent of them had hypertension, and in a group of 433 necropsy control patients, an incidence of 26.5 per cent with hypertension was found. In 585 patients with proven unilateral renal disease there were 24.2 per cent with · hypertension. Pearman12 reported that from urographic evidence the incidence of hypertension was no greater in patients with pyelonephritis than in patients with 6 Zweifach,B. W. and Shorr, E.: Proc. lst Clin. ACTH Conference, Philadelphia: Blakieton Co., 1950, p. 289. 7 Goldring,W. and Chassis, H.: Hypertension and Hypertensive Disease: New York: Commonwealth Fund, 1944. 8 Braun-Menendez, et al., Translated by L. Dexter: Renal Hypertension, Springfield, Ill., Chas. C Thomas, 1946. 9 Master, A. M., et al.: J.A.M.A., 121: 1251, 1943. 10 Braasch, W. F., Walters, W. and Hammer, H.J.: J.A.M.A., 115: 1837, 1940. 11 Goldring, W. and Chassis, H., Hypertension and Hypertensive Disease. New York: Commonwealth Fund, 1944, p. 114. 12 Pearman, R. 0. et al.: Proc. Staff. Meet., Mayo Clinic, 15: 467, 1940.
40
T. BRENT WAYMAN AND EUGENE B. FERRIS
nonrenal disease. In a series of 500 patients with pyelonephritis, either unilateral or bilateral, there was a 9 per cent incidence of hypertension, in 500 patients with goiter without hyperthyroidism there was 10 per cent, and in 500 patients with gallbladder disease there was a 7 per cent incidence of hypertension. Hines13 reported among 264 patients with urologic disease, who were observed over a period averaging 15.3 years, the incidence of hypertension either prior to or subsequent to the first observation was practically identical with a control series of 790 patients without urologic disease. Braasch, Walters, and Hammer,10 and Baggenstoss and Barker14 record a high incidence of hypertension in unilateral pyelonephritic atrophy and unilateral pyonephrotic atrophy. They believe that a causal relationship is indicated by these statistics. Smith15 concluded that with the possible exception of pyelonephritis and pyronephrotic atrophy the available data did not indicate that urologic disease increased the incidence of hypertensive disease, or that it in any large number of instances was causally related to its genesis. INCIDENCE OF UROLOGIC DISEASE IN HYPERTENSION
The incidence of urologic disease as determined by pyelographic evidence in hypertensive patients varies from 45 per cent presented by Schroeder and Steele16 (24 per cent unilateral renal abnormalities) in an analysis of 250 hypertensives, to 8.9 per cent in 2,055 hypertensives as reported by Ratliff and Nesbit.17 Rath and Russek18 combined the statistics of Palmer and his coworkers, Ratliff and Conger, Braasch, Schroeder, and Steele, and others, and they noted that of a total of 6,044 hypertensive patients, 10.7 per cent exhibited evidence of urologic disease. They contrasted this figure to the 27.4 per cent incidence in normotensives reported by Wosika, Jung, and Maher and concluded that the incidence of urologic disease among hypertensives is not greater, and possibly less, than among normotensive subjects. Chassis and Redish19 in clearance studies of 21 hypertensive subjects selected at random, demonstrated that renal functional impairment proceeds to an equal degree or at a parallel rate in both kidneys. From the available data, approximately 10 per cent of hypertensive patients have demonstrable urologic abnormalities with functional impairment. Since the possibility of coincidence is very great, the only way a causal relationship can be demonstrated in any particular case is by "curing" or improving the hypertension by removing the kidney. Smith16 reviewed the literature and found 242 instances in which unilateral nephrectomy had been performed in association with hypertension. He required for a cure that the blood pressure be lowered to or below 140/90, and that it Hines, E. A., Jr. and Lander, H. H. : J.A.M.A., 116: 1050, 1941. Baggenstoss, A.H. and Barker, N. W. : Arch. Path., 32: 966, 1941. Smith, H. W.: Am. J. Med., 4: 724, 1948. 16 Schroeder, H. A. and Steele, J.M.: Arch. Int. Med., 68: 261, 1941. 17 Ratliff, R. K., Nesbit, R. M., et al.: J.A.M.A., 133: 296; 1947. 18 Rath, M. M. and Russek, H. I.: Am. Heart J., 29: 516, 1945. 19 Chassis, H. and Redish, J.: Arch. Int. Med., 70: 738, 1942. 13
14
16
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UROLOGIC ASPECTS OF ARTERIAL HYPERTENSIO:N°
remain within normal limits for at least one year. A summary of his analysis of these collected cases is shown in table 1. Smith concludes: "We are obliged, tentatively, to accept these 47 patients as 'cures', but nevertheless, it leaves a lingering doubt that the urologic disease was actually the cause of the hypertension." Of these 47 successful cases, 22 were of unilateral pyelonephritis. The age incidence of the successful cases showed 17 subjects under twenty years of age, but 24 were in their fourth or later decade of life. Ratliff and Nesbit17 reported 49 cases of severe hypertension in whom nephrectomy was performed. All but 8 of the subjects were followed 12 months or longer. Their results showed 17 cases or 34.6 per cent "cured", 6 cases, 12.4 per cent improved, and 26 cases or 53 per cent failures. Of this group there were 8 patients with pyelonephritis, 11 patients with hydronephrosis, and 7 patients with calculus pyonephrosis. Barker and Braasch20 reported a review of 61 patients who ca.me to the Mayo Clinic primarily because of hypertension. All were found to have advanced disease of one kidney and minimal, if any, evidence of disease in the other. All underwent removal of the diseased kidney. Based on a two-year follow-up on the entire series, they reported 25 cases (41 per cent) "good" results-i.e. blood TABLE
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1. Effects on blood pressure, 242 cases
NO SIGNIFICANT REDUCTION
REDUCED, BUT NOT TO NORMAL
135 (56%)
43 (18%)
REDUCED TO NORMAL; OBSERVATION LESS THAN ONE YEAR
17 (7%)
'
R1£DUCED TO NORMAL FOR ONE YEAR 0~ MORE
47 (19%)
pressure 150/100 or less; 10 cases (16 per cent) "fair" results (blood pressure significantly reduced but greater than 150/100; and 26 cases (43 per cent) deaths or no lowering of blood pressure. Wilson and Byron21 and others have observed malignant arfieriolar lesions in the contralateral kidney of rats with hypertension caused by constriction of one main renal artery. Goldblatt has not been able to confirm this observation in dogs, rabbits, monkeys, sheep or goats with hypertension due -t,o constriction of one main renal artery. Goldblatt has pointed out that all the glomerular and interstitial inflammatory lesions, as well as the vascular lesio~, have been observed within an otherwise supposedly normal rat kidney. He feels that in their rat experiments they may have been dealing with bilateral reru3-l disease. There remains the possibility that the rat may differ in this respec;-t from all other animals. In spite of the experimental and statistical evidence againsfi the probability of curing hypertension by unilateral nephrectomy there are ~ ell documented cases of cures by this procedure. Subjects suitable for nephrectomy may be divided into threie categories: 1) Patients with reliable criteria of cardiovascular disease in ~ hich one kidney 20 21
Barker, N. W. and Braasch, W. F . ; Surg. Gynec. & Obst ., 84: 299',. 1947. Wilson, N. C. and Byron, F. B.; Lancet, 1: 136, 1939 .
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'l' . BRENT WAYMAN AND EUGENE B. FERRIS
had insufficient functional ability to support life, and with a normal or compensated contralateral kidney (cases 1 and 2) . During childhood persistent elevation of blood pressure is uncommon and essential hypertension is rare. The majority of such cases are associated with renal disease. The probability of cure by unilateral nephrectomy when unilateral renal disease is present in children is very great. 2) Patients with associated hypertension in which nephrectomy is indicated on sound urologic principles (case 3). 3) Patients who are operated upon "in desperation." These patients should have markedly diminished function in the kidney to be removed and to have shown a continued downhill course in spite of medical and possible psychiatric therapy. These patients may have some functional disturbance in the contralateral kidney (case 4). CASE REPORTS
Case 1. J.S., a 27-year old white, married man, was admitted to Holmes Hospital on November 7, 1948 complaining of blurred vision of 3 weeks' duration. At the time of his induction into the Army in 1943, it was found that he had a systolic blood pressure of 179, which resulted in his being hospitalized for 1 week in a military hospital. There, his blood pressure was taken t.i.d., each time after 2 hours of bed rest. His blood pressure averaged 144 systolic during this period of observation, and he was accepted for military duty. He was discharged from the Army in February 1946, without further mention of hypertension. He had no urinary complaints. Two days before admission to the hospital he consulted a ophthalmologist because of failing vision. The eye grounds showed grade 4 hypertensive retinopathy, fresh hemorrhages, exudate and papilledema, and his systolic blood pressure was recorded over 200. The remainder of the physical examination was negative, except for an apical systolic murmur. Laboratory examinations showed a normal blood count. The urine was negative, except for an occasional cast and a trace of albumin. The blood urea nitrogen was 10 mg. per cent. Urine culture was sterile. He was able to concentrate the urine to 1.025 and the phenolsulfonphthalein secretion showed 35 per cent of the dye secreted in 15 minutes, with a total output of 75 per cent in 2 hours. Excretory urograms showed a normal left kidney, but no dye secreted on the right side. A right retrograde pyelogram showed a large extrarenal hydronephrosis with a small kidney shadow with very little renal parenchyma. There was obstruction at the right ureteropelvic juncture. The pyelograms were interpreted as showing a compensatory hypertrophy of the left kidney and hydronephrosis of a congenital hypoplastic right kidney due to ureteropelvic obstruction. The blood pressure response to tetraethyl ammonium chloride (TEAC) was measured on three occasions revealing very slight depressor effects of the drug. Since TEAC blocks the autonomic nervous system, the lack of depressor response
UROLOGIC ASPECTS OF ARTERIAL HYPERTENSION
43
suggested that the blood pressure was maintained by humoral rather than neurogenic tone. 22 He was in the hospital 18 days before operation. Blood pressure determinations were made 4 times daily, and showed a variation from 225/170 to 160/120. On November 29, 1948 a right nephrectomy was performed. A hypoplastic kidney with a large extrarenal pelvis was removed. An aberrant artery was found obstructing the ureteropelvic juncture. There was no significant drop in blood pressure during the first 7 days following operation. During the next 5 days the blood pressure ranged between 140/100 to 120/90. Pathological report: The gross specimen consisted of a kidney measuring 10 by 6 by 3 cm. in diameter. The capsule was moderately adherent. Dissection of the vessels revealed the renal vein to appear grossly unremarkable, except that it was slightly smaller than usual. Accompanying the vein, there was one artery which was definitely smaller than the expected renal artery. This artery entered the pelvis with the vein, and appeared to nourish the superior two-thirds of the kidney. At the level of the ureteropelvic junction another small artery was present, anterior to the ureter, and seemed to be nourishing the lower third of the kidney. The pelvis when opened was seen to be extremely dilated, possessing a capacity of at the very least, 45 cc. The wall of the pelvis seemed markedly thickened and fibrotic. Microscopic sections showed a marked diminution in the number of tubules, those persisting being microcystic in type. Only an occasional identifiable glomerulus was seen. In the interstitial stroma, which was scarred, there were only occasional small infiltrations with polymorphonuclear leukocytes and lymphocytes. Rare tubules contained, clustered within their lumens, cells of acute and chronic inflammatory type. The wall of the pelvis showed a marked increase in the amount of collagenous tissue, and in the subepithelial stroma there were relatively few foci of infiltration with chronic inflammatory cells. A striking feature was a severe degree of vascular sclerosis involving vessels of all calibers to an approximate equal degree. Diagnosis: Hydronephrosis with marked atrophy of kidney; chronic pyelonephritis, slight; arterio- and arteriolar nephrosclerosis, severe. The patient has been examined every 3 months since operation. His eye grounds are normal and he is leading a normal life. His blood pressure has ranged between 112/70 to 120/78. The last examination was on September 11, 1950 at which time his blood pressure was 120/78. His urine was normal. This case is to be reported in further detail at a later date. Case 2. R.M., a 47-year old man, was admitted to Holmes Hospital on March 16, 1949 because of high blood pressure of at least 19 months' duration. Two years ago he had had a subtotal thyroidectomy. Seven months before admission he had had a cerebral accident, the results of which had not entirely disappeared. His eye grounds showed grade 4 retinopathy. The heart was tremendously enlarged. The urine contained 1 plus albumin, 1-2 white blood cells, an occasional red blood cell, and 2-3 hyalin casts. The blood urea nitrogen was
44
T. BRENT WAYMAN AND EUGENE B. FERRIS
17.3 mg. per cent. Phenolsulfonphthalein 20 per cent was secreted in the first 15 minutes, with a total secretion of 55 per cent in 1½ hours. Culture of the urine was sterile. The blood pressure response to tetraethyl ammonium chloride (TEAC) was measured revealing a depressor response. The blood pressure fell from a control level of 225/150 to 150/ 110, two minutes after the injection. When the blood pressure response was tested with benzodioxane there was no significant response. Excretory urograms revealed compensatory hypertrophy of the left kidney and no dye appearing on the right side. The right ureter could be catheterized for only a distance of 1 cm. No urine was obtained from the right ureter. Contrast medium was injected up the right ureter. The right ureter was extremely narrow. The pyelogram showed an extrarenal hydronephrosis with small calyces and almost no renal parenchyma present. On April 6, 1949, a small, hypoplastic, infantile type kidney was removed. There was no aberrant artery crossing the ureteropelvic juncture. While the pelvis was large and extrarenal in type, it was entirely empty of urine at the time of nephrectomy. Pathological report: The kidney measured 9 by 8 by 2 cm. The capsule stripped with ease. The cortex was thin and almost absent in the upper pole. The pelvis and calyces were markedly dilated without demonstrable obstruction at the ureteropelvic juncture. An aberrant artery ended in the lower pole of the kidney. On microscopic examination there were seen changes typical of marked atrophy, although one segment appeared functioning. Most of the parenchyma showed profound atrophy, few intact glomeruli and tubules which were thin, dilated, and filled with colloid casts. There was an interstitial infiltration of inflammatory cells of minor degree. There had been atrophy and replacement of tubules and considerable glomerular fibrosis. Intrarenal arteries were markedly sclerotic and n arrowed. Major extrarenal vessels were less strikingly involved. Diagnoses: 1) Hydronephrosis with slight chronic pyelonephritis; 2) arterionephrosclerosis, severe; with focal cortical atrophy. There was no improvement in this patient's hypertensive vascular disease following nephrectomy. In general, he has done badly. When last examined on May 24, 1950 his blood pressure was 240/ 100 and there was a loud systolic apical murmur.
Case 3. M.B., a 43-year old white, married woman was admitted to Bethesda Hospital on August 23, 1947 because of recurring attacks of epigastric pain accompanied by nausea and vomiting. With each episode there was frequency and burning on urination, and pyuria. Two years before admission she had consulted her family physician because of severe headaches and spells of dizziness. He found that she had hypertension and had treat ed her for it during this time. Unfort unately no records were kept of the blood pressure readings. She was 11dmitted to the hospital for study regarding the episode of epigastric pain.
UROLOGIC ASPECTS OF ARTERIAL HYPERTENSION
45
When first seen by us the patient had no complaints. Physical examination was essentially normal except for slight tenderness to deep palpation in the left midabdomen. Urine, blood count, and Kahn test were uormal. Cultures of the urine were sterile. Blood pressure was 160/110. Urograms revealed a normal right kidney, but the left kidney was small and there was some blunting of the calyces. A differential phenolsulfonphthalein test showed the dye to appear from both kidneys in 2½ minutes. During the next 15 minutes the right kidney secreted 30 cc urine with 30 per cent output of phenolsulfonphthalein. The left kidney secreted 7 cc urine with 7 per cent phenolsulfonphthalein. There was no leakage of urine in the bladder during the test. A left nephrectomy was performed on September 3, 1947. Pathological examination revealed a reddish brown kidney with marked granularity beneath the capsule, which stripped with difficulty. The surface was markedly pitted. The kidney measured 9.5 by 5 by 2.5 cm. The cortex was poorly demarcated from the pyramids and was estimated to be 0.5 cm. in thickness. The pelves were contracted. Microscopic sections showed the parenchyma to be in good part normal in appearance. There was mild to moderate vascular thickening and sclerosis. An occasional focus, however, showed profound atrophy with loss of glomeruli, dilatation and thinning of cast filled tubules, and marked interstitial :fibrosis. This was related to interlobular arteries which were sclerotic, occluded, and recanalized. There was little inflammatory reaction. The appearance of the lesion suggested focal ischemia with gradual infarction and atrophy. Diagnosis: Arterionephrosclerosis with focal cortical scarring. The patient's blood pressure level was recorded as 140/100 in January 1949; 136/80 in June 1949; 122/80 in August 1949; 130/70 in September 1950. Case 4, C.K., a 58-year old white man was admitted to Bethesda Hospital on June 26, 1948 for study of hypertension. Three years previously he had had a complete medical work-up and no abnormalities regarding his blood pressure or urine were present. Six months before admission he felt below par and had paroxysms of tachycardia. His blood pressure was found to be 170/110 and the urine contained 2 plus albumin. During the next 6 months his blood pressure gradually became more elevated, the albuminuria increased to 3 plus, and for several weeks he had had persistent disabling occipital headaches. General physical examination was negative. The blood pressure was 190/100. The phenolsulfonphthalein test showed 25 per cent excretion of dye in the first 30 minutes, and a total of 75 per cent in 2 hours. Concentration dilution tests showed the specific gravity of urine to vary between 1.001 and 1.026. Urine: albumin 3-4 plus; sugar negative. There was a rare red blood cell, and 2-3 white blood cells. The blood count was normal. A plain urogram showed multiple calcifications in the spleen and calcifications of blood vessels within the pelvis. X-ray of chest, complete gastro-intestinal series, and barium enema were normal. Cystoscopic examination of the bladder was normal. Urine from the right kidney contained 4 plus albumin; 8-10 red blood cells; and an occasional granu-
46
T. BRENT WAYMAN AND EUGENE B. FERRIS
lar cast. Urine from the left kidney contained 3 plus albumin; a rare red blood cell; and no casts. Phenolsulfonphthalein appeared from the right kidney in 4 minutes with 10 per cent secretion in the first 15 minutes and 10 per cent in the second 15 minutes. Phenolsulfonphthalein appeared from the left kidney in 10 minutes, and there was only a trace of dye in 30 minutes. There was no leakage of phenolsulfonphthalein in the bladder. At the time of the examination the bladder urine contained 4 plus albumin, 12- 50 red blood cells, and 0- 3 granular casts per high dry field. Retrograde pyelograms were interpreted as compensatory hypertrophy of the right kidney and congenital hypoplasia of the lower two-thirds of the left kidney, with the upper third being normally developed. The eye grounds showed mild sclerotic
UROLOGIC ASPECTS OF ARTERIAL HYPERTENSION
47
taken from relatively intact renal cortex. These exhibited moderate arterionephrosclerosis with minor focal cortical scarring. There was no indication of the case of the cortical atrophy observed in the gross. The glomeruli were essentially normal. There was relatively little arterial or arteriolarsclerosis. Diagnosis: Arterio-nephrosclerosis. The patient has been under frequent and constant observation since operation. Blood pressure determinations have been made two or three times per month. The last examination was on September 15, 1950. Since January 1950, his blood pressure has averaged 157/84. The minimum blood pressure reading was 140/80, and the maximum was 170/90. His urine has contained between 1 and 2 plus albumin. There have been no red blood cells and only a very rare cast in his urine. His hemoglobin is 14 gm. He has been entirely relieved of his headaches and his only complaint has been that he "tired easily." Although it is not necessary for him to work, he works part time by choice. He looks well. DISCUSSION OF CASES
Case 1 was known to have had essential hypertension since May 1943. It is probable that a psychologic factor precipitated the malignant phase of hypertension. His only treatment consisted of nephrectomy. He was returned to the same environment and for 22 months postoperatively has had a normal blood pressure. Case 2 had almost the identical pathological changes as case 1. At the time of nephrectomy the dilated renal pelvis was empty of urine. This patient obtained no relief whatever from the hypertension. It is of interest that autonomic blockade with TEAC caused little or no fall in blood pressure in case 1, whereas there was a marked depressor response in case 2 suggesting that a humoral mechanism was predominant in the former and a neurogenic mechanism in the latter. Whether or not the blood pressure response to autonomic blockade may be helpful in predicting the effect of nephrectomy in unilateral renal disease will, of course, require further study; but this does seem to be a suggestive lead. In case 3, although the patient had been under the care of her private physician for a period of 2 years because of "high blood pressure," no records were kept of her blood pressure readings during this period. After admission to the hospital her blood pressure was recorded as 160/110. A hypertensive work-up was not done as it was thought that she had a urologic condition which required nephrectomy. Although the patient has a blood pressure of 130/70 three years after nephrectomy, proof of the presence of persistent hypertension before operation may be questioned. In case 4, the patient was known to have normal blood pressure 3 years before admission. While under the observation of a competent observer, his blood pressure became rapidly elevated. Nephrectomy was not performed as it was thought the chances of improvement from this procedure seemed remote. After two more months on medical therapy he was readmitted in hypertensive crisis
'
48
T . BRENT WAYMAN AND EUGENE B. FERRIS
with a blood pressure of 210/120. A left nephrectomy was performed in "desperation". This patient has been observed at frequent intervals for a 2 year period following operation. Besides his clinical improvement and reduction in albumin content of the urine, the most striking result has been in the diastolic blood pressure. The maximum diastolic blood pressure recorded has been 90 mm. Hg. DISCUSSION
On the basis of the evidence presented above it is evident that the relation of hypertension to chronic bilateral kidney disease is uncertain and that the urological surgeon has little to offer therapeutically. However, despite the experimental uncertainty of the role of unilateral kidney disease in producing hypertension, it is clear that removal of the unilaterally diseased kidney has improved or cured the hypertension in certain patients, although there is no method of predicting the results to be expected. An important aspect of the problem is to develop methods of recognizing unilateral kidney disease when it occurs, and to differentiate between other "specific" types of hypertension such as pheochromocytoma. In the final analysis the recognition of unilateral kidney disease depends upon a knowledge of the function of each kidney separately because in the absence of one functional kidney, the other can function well enough to produce normal results from routine renal function studies such as phenolsulfonphthalein and concentration dilution tests. It might be wise, therefore, to take excretory urograms as a routine diagnostic procedure in all cases of hypertension in order to recognize the presence of this condition where specific therapy can be offered to the patient. Ferris and his group of investigators believe that testing the blood pressure response to TEAC is of value in recognizing those instances of hypertension where humoral factors predominate; for instance, the blood pressure in toxemia of pregnancy, in acute glomerulonephritis, and in pheochromocytoma, falls little or not at all during autonomic blockade, whereas in essential hypertension all gradations of response occur. It is of interest that the depressor response to TEAC in case 1 was very slight, which further supports the concept of a renal humoral mechanism in this case. Pheochromocytoma is another unusual form of hypertension in which the urologist may offer specific treatment, and again the early recognition of this disease is of great importance. Mention was made above of the lack of depressor response to autonomic blocking agents in the condition, in fact TEAC usually causes a pressor response. The recent development of adrenolytic drugs, such as benzodioxane and dibenamine, has given us an important and specific test for the recognition of hypertension due to circulating adrenalin. 22 • 23 22
Shapiro, A. P., Harrison, M. B., Hoffman, M. S. and Ferris, E. B.: Am. J . Med., 10:
115, 1951. 28
Goldenberg, M ., Snyder, C.H., Aranow, H.; J.A.M.A., 135: 971, 1947.
UROLOGIC ASPECTS OF ARTERIAL HYPERTENSION
49
In pheochromocytoma the hypertension may be persistent, or it may occur in parnxysms. In the persistent form a consistent depressor response to benzodioxane is diagnostic of the disease. In the paroxysmal form, paroxysms of hypertension may occur spontaneously as the result of emotional stress and as the result of the administration of such agents as histamine, mecholyl, and TEAC. Since paroxysms of hypertension also occur frequently in essential hypertension it is important to test the specificity of the pressor response by abolishing it with benzodioxane. This then indicates that the pressor response was due to circulating adrenalin, and in this respect bolsters the diagnosis of pheochromocytoma.
726 Carew Tower, Cincinnati 2, Ohio