Normal Renin Secretion in Hypertensive Patients with Primarily Unilateral Chronic Hydronephrosis

Vol. 112, Printed in

THE JOURNAL OF UROLOGY

Copyright © 1974 by The Williams & Wilkins Co.

NORMAL RENIN SECRETION IN HYPERTENSIVE PATIENTS WITH PRIMARILY UNILATERAL CHRONIC HYDRONEPHROSIS E. D. VAUGHAN, JR.,* F. R. BUHLERt

AND

J. H. LARAGH

From the Department of Medicine, College of Physicians and Surgeons, Columbia University and the Presbyterian. Hospital, New York, New York

In clinical practice acute and chronic hydronephrosis, either unilateral 1 or bilateral, 2 is frequently accompanied by a significant elevation in blood pressure. The hypertension could be simply coincidental or could be caused by the hydronephrotic renal damage, through either impaired sodium excretion or abnormal renin release. In cases of bilateral hydronephrosis the demonstration of increased exchangeable sodium 3 and the usual prompt reversal of the hypertension after catheter drainage and diuresis 2 would suggest that the hypertensive state is primarily maintained by the abnormal retention of salt and water subsequent to urinary tract obstruction. Thus, these patients would appear to have a volume-dependent form of hypertension. 4 In addition, Palmer and associates have reported normal peripheral and renal vein renins in a hypertensive patient with a hydronephrotic solitary kidney. 5 After a corrective operation reversal of the hypertension was associated with an osmotic diuresis and negative water balance, again suggesting volume dependency. In contrast, Belman and associates have reported a case of abdominal pregnancy in which there was hypertension, unilateral ureteral obstruction and elevated renal vein renin from the hydronephrotic kidney. 6 After a corrective operation the hypertension abated and the renin value returned to normal. Animal studies have demonstrated renm Accepted for publication December 14, 1973. * Requests for reprints: Department of Urology, University of Virginia School of Medicine, Charlottesville, Virginia 22901. t Current address: Department of Medicine, University of Basel, 4002 Basel, Switzerland. 1 Schwartz, D. T.: Unilateral upper urinary tract obstruction and arterial hypertension. N. Y. State J. Med., 69: 668, 1969. 'Vaughan, E. D., Jr. and Gillenwater, J. Y.: Diagnosis, characterization and management of post-obstructive diuresis. J. Urol., 109: 286, 1973. 'Muldowney, F. P., Duffy, G. J., Kelly, D. G., Duff, F. A., Harrington, C. and Freaney, R.: Sodium diuresis after relief of obstructive uropathy. New Engl. J. Med., 274: 1294, 1966. 'Laragh, J. H.: Vasoconstriction-volume analysis for understanding and treating of hypertension: the use of renin and aldosterone profiles. Amer. J. Med., 55: 261, 1973. 5 Palmer, J.M., Zweiman, F. G. and Assaykeen, T. A.: Renal hypertension due to hydronephrosis with normal plasma renin activity. New Engl. J. Med., 283: 1032, 1970. 'Belman, A. B., Kropp, K. A. and Simon, N. M.: Renal-pressor hypertension secondary to unilateral hydronephrosis. New Engl. J. Med., 278: 1133, 1968.

release following acute ureteral occlusion. 7 • 8 Ir, dogs acute unilateral ureteral occlusion is associated with an increase in blood pressure and a rise in ipsilateral renal vein renin despite a concurrent rise in renal blood flow. 8 A causal relationship between the renin release and the increase in blood pressure is suggested by the fact that pretreatment with desoxycorticosterone acetate and salt abolished the rise in renin and blood pressure. 8 In contrast, chronic animal studies have shown that the renin release is not sustained and that the peripheral renin is normal with prolonged unilateral ureteral occlusion. 9 A recent study of patients with essential hypertension has shown that in the absence of hepatic disease the peripheral plasma renin reflects the rate of renin secretion. 10 Thus, abnormally high peripheral renin levels in relation to the 24-hour urine sodium excretion indicate abnormal renin secretion. 11 Our study was done to determine whether there was evidence of abnormal renin secretion, as indicated by the peripheral renin activity value, in 13 hypertensive patients with chronic hydronephrosis. The data show that the peripheral renin in chronic hydronephrosis is usually normal or low, suggesting that this disease in its established state is not a cause of increased renin secretion. There· fore, indications for surgical intervention in obstructive uropathy should be primarily directed toward preservation of renal function. Any subsequent amelioration of coexisting hypertension that occurs would appear to be a consequence of im-· proved renal excretory function rather than correction of abnormal endocrine function associ' Vander, A. J. and Miller, R.: Control of renin secretion in the anesthetized dog. Amer. J. Physiol., 2117: 537, 1964. 'Vaughan, E. D., Jr., Shenasky, J. H., II and Gillenwater, J. Y.: Mechanisms of acute hemodynamic response to ureteral occlusion. Invest. Urol., 9: 109, 1971. 'Vaughan, E. D., Jr., Sweet, R. C. and Gillenwater. J. Y.: Peripheral renin and blood pressure changes following complete unilateral ureteral occlusion. J. Urol., 104: 89, 1970. '"Sealey, J. E., Buhler, F. R., Laragh, J. H. and Vaughan, E. D., Jr.: The physiology ofrenin secretion in essential hypertension. Estimation of renin secretion rate and renal plasma flow from peripheral and renal vein renin levels. Amer. J. Med., 55: 391, 1973. 11 Laragh, J. H., Baer, L., Brunner, H. R., Buhler, F. R., Sealey, J. E. and Vaughan, E. D., Jr.: angiotensin and aldosterone system in pathogenesis management of hypertensive vascular disease. Amer. J. Med., 52: 633, 1972.

153

154

VAUGHAN, BUHLER AND LARAGH TABLE

1. Clinical data and peripheral plasma renin activity in patients with chronic hydronephrosis

Pt.-Age-Race-Sex

Syst. Diast. (mm.Hg)

(mg.%)

Ccr. (ml./ min.)

BUN

EH 65

B

F

200

llO

21

45

,JG 30

w

F

165

120

14

100

GO'B 47

w

F

200

120

16

100

SA 45

MK 50 KS 40

w w w

F F

M

150 240 126

ll2 120 100

12 ll 20

AT 51

w

M

150

102

18

RG 48

w

M

100

120

17

HZ

65

w

M

190

llO

25

42

GB 37

F

M

EB 58

w w w

F

150 230 190

100 130 108

12 17 50

65 88 27

RC 34

w

M

200

135

13

113

MW 53

UnaV (mEq.)

PRA (ng./ ml./hr.)

31 85 85

1.0 1.4 0.79

Aldo. (µg./24 hrs.) 5.6 8.9 6.6

100

8.4 38 115 91 174

12 4.6 2.2 4.0 1.0

56

41

3.3

82

3.5

4.8

21 67 59 140 55

3.9 2.4 2.0 1.9 2.8

11 5.4 8.9 14 5.3

45 68

11.7 10.0

ated with renin release. MATERIAL AND METHODS

The subjects were 13 patients in whom antihypertensive and diuretic therapy had been withheld for at least 1 month before study. All patients had sustained diastolic blood pressures greater than 100 mm. Hg off antihypertensive medication. Evidence of unilateral or bilateral hydronephrosis was seen in all patients by excretory urography. Evaluation of the renin-aldosterone system. Peripheral plasma renin activity was measured from samples collected at noon, after 3 to 4 hours of ambulation. Concurrent 24-hour urine specimens were collected for the determination of aldosterone and sodium excretion. Similar outpatient procedures were used, as reported elsewhere, 12 in which the measurements of plasma renin activity and aldosterone excretion rates have been shown to parallel those found under rigid balance ward conditions. 11 With the use of nomograms derived from normal subjects patients were then classified into renin subcategories: 1) high, 2) normal and 3) low. 13 In selected cases, under steady state conditions, differential renal vein and inferior vena cava renin samples were collected and analyzed as reported in patients with essential hypertension 10 and renal 12 Buhler, F. R., Laragh, J. H., Baer, L., Vaughan, E. D., Jr. and Brunner, H. R.: Propranolol inhibition of renin secretion: a specific approach to diagnosis and treatment of renin-dependent hypertensive diseases. New Engl. J. Med., 287: 1209, 1972. 13 Brunner, H. R., Laragh, J. H., Baer, L., Newton, M. A., Goodwin, F. T., Krakoff, L. R., Bard, R. H. and Buhler, F. R.: Essential hypertension: renin and aldosterone, heart attack and stroke. New Engl. J. Med., 286: 441, 1972.

95 6 22.5 8.7 7.0 19

40 40

Diagnosis Rt. ureteropelvic junction obstruction. grade 4 hydronephrosis Spina bifida, bilat. hydronephrosis L > R, grade 2 to 3 Rt. ureteropelvic junction obstruction, grade 2 Lt. hydronephrosis, grade 2 Lt. hydronephrosis, 2° calculus, grade 3 Lt. ureterope1vic junction obstruction, grade 2 Lt. grade 2 hydronephrosis, 2° to tuberculous stricture Lt. hydronephrosis. grade :i, 2° to lymphoma Lt. renal artery stenosis, rt. ureteropelvic junction obstruction, grade 3 Lt. ureteropelvic obstruction, grade 2 Lt. ureteral stricture with non-function Lt. ureteropelvic junction, grade 3 of solitary kidney Lt. ureteropelvic junction obstruction with grade 2 hydronephrosis and pelvic calculus

arterial disease. 14 Analytical methods. Plasma renin activity was determined by a method recently described, using a radioimmunoassay to quantitate generated angiotensin I. 15 The 24-hour excretion of aldosterone was also measured by radioimmunoassay. 16 RESULTS

Etiology of hydronephrosis. As shown in table 1, 12 patients had unilateral hydronephrosis and, of those, 8 had unilateral ureteropelvic junction obstruction as the etiology of the hydronephrosis. In 1 patient this process involved a solitary kidney. Two patients had ureteral strictures, 1 of tuberculous origin. One additional patient had severe unilateral ureteral obstruction from a retroperitoneal lymphosarcoma, while the cause of unilateral hydronephrosis was unknown in 1. One patient with spina bifida and a neurogenic bladder had bilateral hydronephrosis with more severe involvement on the left side and without evidence of ureterovesical reflux on cystography. Classification of patients according to plasma renin activity. The figure and table 1 show the relation of plasma renin activity to the concurrent rate of daily sodium excretion in the 13 patients. 1 'Vaughan, E. D., Jr., Buhler, F. R., Laragh, J. H., Sealey, J. E., Baer, L. and Bard, R. H.: Renovascular hypertension: renin measurements to indicate hypersecretion and contralateral suppression, estimate renal plasma flow, and score for surgical curability. Amer. J. Med., 55: 402, 1973. 15 Sealey, J. E., Gerten-Banes, J. and Laragh, J. H.: The renin system: variations in man measured by radioimmunoassay or bioassay. Kidney Int., 1: 240, 1972. "Sealey, J.E., Buhler, F. R., Laragh, J. H., Manning, E. L. and Brunner, H. R.: Aldosterone excretion: physiological variations in man measured by radioimmunoassay or double-isotope dilution. Circ. Res., 31: 367, 1972.

155

NORMAL RENIN SECRETION IN HYPERTENSIVE PATIENTS

The dotted lines in the figure describe the dynamic hyperbolic relation between sodium excretion and plasma renin activity as found in normal volunteers. 13 Of the 17 determinations obtained in these 13 patients, 12 were in the normal range, falling within the dotted lines. Moreover, these normal values usually fell into the low normal range. One patient had an elevated renin value on 2 occasions and 2 patients were classified as low renin hypertensives. Thus, of the 13 patients only 1 showed evidence of abnormally high renin secretion. However, it is of some interest that this patient (R. C.) had the highest blood pressure. Relationship of renal venous to arterial renin activity. The results of the differential renin vein and inferior vena cava renin sampling in 5 patients is shown in table 2. The results in all cases fall within the range found in patients with essential hypertension. In that study we found that in order to maintain peripheral renin constant, renal vein renin (V) from each kidney must be at least 24 per cent higher (V-A/A) than the peripheral arterial renin (A) or 48 per cent higher from one kidney if the contralateral kidney is not secreting any renin. 10 In a companion study of patients with renal arterial disease we found that complete suppression of renin secretion from the contralateral uninvolved kidney (V-A/A = 0) and an

PLASMA RENIN ACTIVITY IN RELATION TO 24 HOUR SODIUM EXCRETION 1111 13 PATIENTS WITH CHRONIC HYORONEPHROSIS

\

II

10 9

8

7

PLASMA RENIN ACTIVITY ng/ml/hr

6

TABLE

2. Renal vein renin analysis in patients with chronic hydronephrosis

Renal vein renin (ng./ml./hr.): Affected Contralateral Arterial (V-A)/A: Affected Contralateral

RC

GO"B

SA

MK

HZ

7.3 7.7 6.0

1.6 1.7 1.1

5.3 5.0 4.0

4.8 .S.7

7.0 5.s

4.7

4.9

0.22 0.28

0.45 0.54

0.33 0.25

0.02 0.21

(l.]()

OA3

abnormally increased renal vein renin relative to the arterial renin from the stenotic kidney greater than 48 per cent), together with a peripheral renin value indicating increased renin secretion, were reliable indicators when used together for identifying renovascular hypertension and predicting its curability. 14 It can be seen that none of these patients fulfilled these criteria, demonstrating that there was a bilateral renin contribution without lateralization to the phrotic kidney. This observation is of partict:iai interest in patient R. C. who demonstrated an increased peripheral renin level for the sodium excretion. Thus, here too the renin secretion was from both kidneys and not solely from the one which was hydronephrotic. Results of corrective therapy. Two patients C. and E. B.) underwent pyeloplasty while l (A. T .) had ureteral dilatation. In these patients the hypertension has persisted following reversal of the hydronephrotic state. In 1 patient (E. B.) there has been a rise in creatinine clearance from 27 to 55 ml per minute and the associated hypertension, although still present, is more easily manageable with antihypertensive medications. Although lim ited, these results suggest that the hypertension in these patients was associated with but not caused solely by the hydronephrotic kidney or alternatively that the degree of renal damage with attendant impairment of salt and water balance was such that these derangements were not corrected by an operation. DISCUSSION

5

4

3

2

o~----~----~----~ 0

URINARY

100 SODIUM

200

300

EXCRETION mEq/24hr

Noon plasma renin activity in relation to concurrent rate of sodium excretion in 13 hypertensive patients with chronic hydronephrosis. One patient (11!!1) shows high plasma renin activity, 10 normal (fj) plasma renin activity and 2 low (A) plasma renin activity.

The findings of normal (10) and even of low (2) peripheral plasma renin values as related to the concurrent 24-hour sodium excretion in 12 of 13 patients would suggest that renin secretion is not abnormally high in chronic dronephrosis. Moreover in 5 patients, including the 1 patient with a high peripheral renin, there were symmetrical increments of renal vein renin above arterial renin, indicating bilateral renin contribution as seen in patients with essential hypertension. 10 Thus, the 3 indicators which, when taken together in a combined scoring system, have been proved to be reliable in predicting curability in unilateral renovascular hypertension: 1) a peripheral plasma renin activity in relation to sodium excretion, 2) complete suppression of renin

156

VAUGHAN, BOHLER AND LARAGH

secretion from the contralateral uninvolved kidney volvement. A corrective operation might cure or and 3) an abnormally increased renal vein renin ameliorate the hypertension when nephron repair relative to arterial renin from the stenotic kidney, is adequate to improve the capacity for sodium, are all absent in chronic hydronephrosis. 14 excretion and thus reduce the volume component The lack of a stimulus for renin release in in this renin-volume interaction, However, in anichronic hydronephrosis is perhaps explained by the mals the degree of repair that occurs is dependent pattern of nephron damage that occurs with uni- on the duration of obstruction, 20 among other lateral ureteral obstruction. Thus, with acute par- factors, and is usually not total. 21 Incomplete tial unilateral ureteral obstruction, Suki and associ- repair possibly explains the persistence of hyperates have demonstrated nephron under perfusion tension in the operated cases in our series. Thus, surgical intervention in patients with with decreased urinary sodium and increased urinary osmolality from the obstructed kidney. 17 This chronic hydronephrosis should be directed toward same pattern of sodium and water excretion is potential improvement of renal function. When usually associated with a positive Howard test in there is a functioning hydronephrotic kidney but patients with renovascular hypertension. 18 More- surgical correction is impossible, nephrectomy over it is only with acute ureteral occlusion in might be contraindicated in that further impairanimals that increased renin secretion has been ment of sodium excretion could accentuate the demonstrated. 7 ' 8 In contrast, the pattern of neph- hypertensive state. ron under-perfusion does not obtain in chronic SUMMARY unilateral hydronephrosis when peripheral renin levels have been shown to be normal. 9 In patients Peripheral plasma renin activity was normal studied following the surgical correction of unilat- (10) or occasionally low (2) in 12 of 13 patients with eral ureteropelvic obstruction it has been shown primarily unilateral chronic hydronephrosis, all of that there are proportional reductions in glomeru- whom exhibited sustained arterial hypertension. In lar filtration rate and tubular function. 19 Thus, in addition, differential renal vein renin studies in 5 chronic hydronephrosis, proportional and progres- patients, including the 1 patient with a high sive renal damage would not serve as a stimulus for peripheral renin value, failed to demonstrate laterrenin release and might be associated with an alization of the renal vein renin increment necesactual reduction in renin secretion. sary to maintain the peripheral renin level to the Taken altogether, the data suggest that elevated hydronephrotic kidney nor any contralateral supblood pressure observed in patients with chronic pression of renal renin secretion. Thus, established hydronephrosis is not primarily renin dependent• hydronephrosis does not appear to be a stimulus in the sense that there is not abnormal renin for abnormal renin secretion, Since renin does not secretion from the hydronephrotic kidney. How- seem to be involved these observations perhaps ever, recent observations suggest that in a segment point to abnormal sodium retention as the basis for of hypertensive patients there are subtle increases the hypertension associated with hydronephrosis, in volume relative to the plasma renin and these 2 even when unilateral. This thesis would also sugfactors interact to maintain high blood pressure. 4 gest that there is subtle bilateral disease with the In the present setting, hydronephrotic atrophy contralateral kidney not having a normal capacity with loss of nephron function may be the cause of to excrete sodium. subtle volume changes. Inability of the contralatHence, a reconstructive operation should be eral kidney to compensate for the sodium retention directed toward the potential improvement of also suggests the presence of bilateral renal in- renal function which possibly might ameliorate the hypertensive state through an improvement of 1' Suki, W., Eknoyan, G., Rector, F. C., Jr. and Seldin, D. W.: Patterns of nephron perfusion in acute and sodium excretion rather than by combating abnormal renin secretion. chronic hydronephrosis. J. Clin. Invest., 45: 122, 1966. 18 Connor, T. B., Thomas, W. C., Jr., Haddock, L. and Howard, J. E.: Unilateral renal disease as a cause of hypertension: its detection by ureteral catheterization studies. Ann. Intern. Med., 52: 544, 1960. 1 ' Gillenwater, J. Y., Westervelt, F. B., Vaughan, E. D., Jr. and Carter, C. B.: Impaired renal function in unilateral hydronephrosis. In: Fourth International Congress of Nephrology Abstracts. Stockholm, Sweden, 1969.

'°Vaughan, E. D., Jr. and Gillenwater, J. Y.: Recovery following complete chronic ureteral occlusion: functional, radiographic and pathologic alterations. J. Urol., 106: 27, 1971. 21 Vaughan, E. D., Jr., Sweet, R. E. and Gillenwater, J. Y.: Unilateral ureteral occlusion: pattern of nephron repair and compensatory response. J. Urol., 109: 979, 1973.