The physiology of renin secretion in essential hypertension

The Physiology of Renin Secretion in Essential Hypertension

Estimation of Renin Secretion Rate and Renal Plasma Flow from

Peripheral and Renal Vein Renin Levels

JEAN E. SEALEY, B.Sc.

FRITZ R. BUHLER, M.D.*

JOHN H. LARAGH, M.D.

E. DARRACOTT VAUGHAN, Jr., M.D.

New York, New York

From the Department of Medicine, College of Physicians and Surgeons, Columbia-Pres- byterian Medical Center, New York, New York 10032. Requests for reprints should be addressed to Ms. Jean E. Sealey.

*Present address: Department of Medi- cine, University of Basel, Basel, Switzerland.

From renin measurements made in blood collected simultaneously from renal veins, aorta and vena cava, an equation was developed for estimating renin secretion rates in patients with three renin subtypes of essential hypertension. From these data a second equation was derived for estimating differential renal plasma flow in pattents with unequal kidney perfusion. The latter equation achieves maximum precision when there is no renin secretion from one side.

Plasma renin activity was identical in blood collected from the aorta or the vena cava. It was also similar, but higher, in blood collected from either right or left renal veins. The ratio of renin from the two renal veins, an expression of the variability in renal vein renin measurements in essential hypertension, was 1.5 or less in 87 per cent of patients and less than 1.83 in 95 per cent.

Renal vein renin content remained proportional to arterial renin over the range of peripheral renin levels found in essential hypertension, so that renal vein renin concentration from each kidney was consistently 124 per cent of arterial renin. The constancy of this relationship complements previous observations indicating that the metabolic clearance rate of renin is proportional to arterial renin levels. The observed equality of renin values between renal veins suggests that differential renal plasma flow is fairly equal and constant in patients with essential hypertension. Moreover, since renal plasma flow from each kidney is inversely related to the increment in renal vein renin concentration relative to arterial renin input [(V-A)/A], differential changes in (V-A)/A can be used to identify differential changes in renal plasma flow.

These derived interrelationships are relevant to an analysis of renovascular hypertension since, with this approach, reductions in renal plasma flow can be estimated using only renal vein and arterial renin measurements and adequacy of sampling can be assessed from the sum of (V-A)/A from each kidney.

There was no measurable difference in plasma renin substrate in the three renin subgroups of patients with essential hypertension so that observed differences in plasma renin activity levels appear entirely due to differences in renal renin secretion. Under conditions of this study renal renin secretion per minute was 144 times the arterial renin level.

September 1973 The American Journal of Medicine Volume 55 391

PHYSIOLOGY OF RENIN SECRETION IN ESSENTIAL HYPERTENSION-SEALEY ET AL.

Peripheral plasma renin is determined by the rate of secretion of renin and by the rate of its metabolic clearance. It has been demonstrated in man and animals that the major source for secretion of renin is the kidney [l-3], and the major site Of

clearance of renin is the liver [4-61. The clearance of renin by the fiver appears to be a proportional phenomenon [6] in that under most conditions a constant fraction of the liver blood flow is cleared. The clearance rate of renin is thus de- pendent on liver blood flow. Under steady state conditions, when liver blood flow is constant, peripheral plasma renin is directly proportional to the rate of secretion of renin by the kidneys.

pertension such as primary aldosteronism, renovascular hypertension, pheochromocytoma or Cushing’s disease. This evaluation included rapid sequence intravenous pyelography [12], renal arteriography [13], plasma electrolytes, blood urea nitrogen, creatinine clearance, serum glutamic oxaloacetic transaminase, (SGOT), lactic dehydrogenase (LDH) and alkaline phosphatase. The age of the group ranged from 16 to 69 years.

The secretion rate of renin can be calculated from the renal vein renin increment, that is renal vein renin minus the arterial input, (V-A), multi- plied by the renal plasma flow. If renal plasma flow is constant then (V-A) is directly related to renal renin secretion. Thus if renal plasma flow and hepatic blood flow are constant then (V-A) should be directly related to peripheral plasma renin.

Five additional patients with advanced or malignant hypertension were also studied. In three of these patients medication was discontinued only one day prior to study. Study Procedure. The renin-aldosterone system was evaluated on the 5th day of a fixed dietary regi- men of known electrolyte content. Renin activity was measured in plasma samples taken at noon after the patients had been ambulatory for about 4 hours. Me- tabolism ward procedures and analytical methods used have been described previously [14].

This study was designed to investigate the relationship of the renal vein renin increment (V-A) to peripheral plasma renin (A) in the three renin subgroups (low, normal or high) of patients with essential hypertension [7-lo]. Variations in the relationship could unmask differences in renal plasma flow, hepatic flow or the per cent extraction of renin by the liver in these patient groups, providing that there were no differences in plasma renin substrate. Moreover, if (V-A)/A remained constant under the conditions of the study, then changes in (V-A)/A could provide a basis for de- tecting abnormalities in renal plasma flow or liver blood flow in other studies.

To define normalcy of ambient peripheral plasma renin activity values, studies were carried out in 52 normal volunteers, utilizing the same constant dietary regimens as those used for the hypertensive patients [14]. A close relationship between plasma renin activity and urinary sodium excretion was observed in all normal subjects, and a nomogram was thus developed. Comparisons of plasma renin activity against this nomogram were used to establish three subgroups of low, normal or high renin hypertensive patients. Of the 43 patients with essential hypertension, 28 had normal plasma renin activity, 4 had high and 11 had low plasma renin activity.

In this study (V-A) was found to bear a constant relationship to arterial renin over the whole range of peripheral renin levels encountered in the three renin subgroups of essential hypertension. Thus these data can be used to discern abnormalities in renal plasma flow as they may occur in renovascular hypertension. Moreover, the observed variations in renal vein renin measurements can be a basis for judging the adequacy of sampling in patients with renovascular hypertension [ll].

Renal arteriography was carried out on a different day from the peripheral plasma renin evaluation study. The patients had been on a constant sodium intake for at least 3 days and each patient was supine for a minimum of 2 hours prior to collection of blood samples. Blood (20 ml) was collected first from each renal vein, and then from the vena cava (below the level of the kidneys) and from the aorta using the Seldinger tech- nic 1131.

Plasma renin activity and renin substrate were measured by previously described methods [lo]. In this report the units of measurement of renin are ex- pressed as nanograms angiotensin I /milliliter rather than nanograms angiotensin l/milliliter/hour to avoid possible misinterpretation of renal vein renin measurements as renin secretion rates.

METHODS

Patient Source. Forty-three patients with essential hypertension were included in the study. All had sus- tained diastolic blood pressures greater than 95 mm Hg. At least 3 weeks prior to study, administration of all antihypertensive and diuretic drugs was discontinued. Either before or on admission, all were given a complete work-up to exclude any known cause of hy-

Statistical Analysis. The relationships of arterial to venous renin, of right renal vein renin to left renal vein renin, and of renal vein renin to arterial (or venous) renin were analyzed statistically. The lines which best described the relationships were calculated by the method of least squares and the significance was evaluated using Student’s t test. To normalize the values logarithmic transformation was applied, using natural logarithms.

Comparisons of renal vein renin measurements and their relationships to the arterial level were carried out using analysis of variance (F test). Analysis of var-

392 September 1973 The American Journal of Medicine Volume 55

iance was also used to determine if the lines which best fit the data were different from the line of identity.

RESULTS

Plasma Renin Substrate Levels in the Three Renin Subgroups of Essential Hypertension. There was no statistically significant difference in plasma renin substrate in the three renin subgroups. Mean values were 1,855 f 348 (SD) ng/ml (low renin), 1,644 f 364 (normal renin) and 1,670 f 318 (high renin). Differences in plasma renin activity in the three renin subgroups therefore cannot be ascribed to differences in plasma renin substrate concentrations.

Renin substrate was also measured in plasma collected from the renal veins, aorta and vena cava of five patients. Mean values were not significantly different; 1,688 f 239 (SD) (right renal vein), 1,668 f 318 (left renal vein), 1,739 f 252 (vena cava) and 1,690 f 194 (aorta). There appears to be no measurable extraction of renin substrate by the kidney so that differences in plasma renin activity in renal vein renin samples can be ascribed to differences in renin concentration rather than to differences in renin substrate concentration. Plasma Renin Activity in Renal Vein Plasma. Renin activity, measured in plasma from the right renal vein, was compared to that of the left

loge LEFT RENAL VEIN 2.5 ng AI/ ml

2.0

I .o

-1.5 -I,0 1’ A /’ ’

/I’ +’

L q\‘/ be/’

A d>’ 4 -I .o

&’ I -1.5

/’ I

n l . ,*

,x’ m

:f l r

d . y.

. tr A /’

b=l.O/ 48

A I’. . log, 0 = -0.029 *’

I

renal vein in 43 patients with essential hypertension (Figure 1). When the difference in plasma renin activity from the right and left kidneys was tested by analysis of variance it was found to be not significant at the 1 per cent level. The slope of the line which best fit the relationship was 1.01 and the natural log of the intercept was -0.03. The line was not significantly different from the line of identity when the intercept and slope were tested simultaneously by analysis of variance. There is therefore no systematic difference in the secretion of renin from the right or left kidneys of patients with essential hypertension.

A ’ 1 I I 1

I.0 2.0 2.5 ’ loge RT RENAL VEIN RENIN

Plasma Renin Activity in Arterial and Venous Blood. Plasma renin activity was the same in blood &ollected from either the aorta or the inferi- or vena cava, below the level of the kidneys. This equal relationship is illustrated in Figure 2 for 35 paired samples. The relationship (slope = 1.038,

Patient log, intercept = -0.068) did not differ significant- Classification

/ I ly from the line of identity at the 1 per cent level.

A Low Renln

l Normal ’ Thus there appears to be no measurable clear-

l High ’ ance of renin in the capillary beds. To increase

I I the accuracy of subsequent analysis, peripheral plasma renin (A) was taken as the mean of venous and arterial determinations, whenever possible.

Figure 1. Relationship of renin in the right renal vein to that in the left renal vein in 43 patients with essential hypertension. The line expressing the relationship is not different from the line of identity, and the intercept is not significantly different from zero. Therefore, renal vein renin in the right renal vein is similar to that found in the left renal vein of patients with essential hypertension.

PHYSIOLOGY OF RENIN SECRETION IN ESSENTIAL HYPERTENSION-.~SEALEY ET AL

me ARTERIAL RENIN 2,5 - / I ng AI/ml

2,o - .,/’

/” e /‘a

,’ . ‘.

l 7’ .

I.0 - ,‘a

4x6’

_ .-,c b=/.O.38

l ‘. loge 0 = - 0.068 ,

/’ /

I I ’ I 1 , , I 1 - I.5 -1.0

2’. I.0 2.0 2.5

/’

loge VENA CAVAL RENIN ng AI/ml

/’ Y/ , I Patlent

A / -1.0 - Clossificotion

,‘,+* A Low Remn ,“b””

5’4‘ ’ - I.5 -

II

l Norm01 ”

,/,a l High ”

Figure\;. Relationship of renin activity in blood collected from the aorta to that found in vena caval blood. The two values are not different from each other in patients with essential hypertension.

Renal Vein Renin, Relative to Arterial Plasma Renin. In Figure 3, renal vein renins (V) are plotted against arterial plasma renin (A) for 43 patients (86 kidneys). Examination of this plot re-



loge RENAL VEIN RENIN 2.5 ng AI /ml

y y/g ml, ARTERIAL RENIN I .I na AI /ml

,I’ I’ 4 - I.5

Figure 3. Relationship of renal vein renin to arterial (or venous) renin in patients with essential hypertension. The slope of the line is not different from the line of identity, indicating that the relationship of renal vein renin to arterial renin ii constant at all levels of plasma renin activity found in essential hypertension. The intercept of 1.24 indicates that the renal vein renin is 124 per cent of arterial renin.

veals a consistent relationship between the two values at all renin levels. First the variability between the two kidneys of the same patient (intra- individual variability) for log V - log A, i.e., V/A, was tested by analysis of variance. The mean renin contribution to the arterial level was found to be not significantly different from each side, indicating equal bilateral renin contribution from each side. When the intra-individual variability of log V- log A was compared with the inter-individual variability no difference was found. Thus, in studies of patients with essential hypertension, the renin contribution of one kidney to the arterial level does not differ from its mate more than from any other kidney. This allows all 86 kidneys to be treated alike in further analysis.

When the slope and intercept of Figure 3 were tested by analysis of variance, the slope was found to be not significantly different from 1.0, but the intercept was significantly greater than zero (b = 1.02, log,a = 0.21). The best line describing the relationship of renal vein renin to arterial renin is thus a line parallel to the line of identity. The value for a, when converted to arithmetic value, is 1.24. This means that renal vein renin from each kidney is 24 per cent higher than arterial plasma renin and, because the slope of the line is close to unity, it means that renal vein renin is 24 per cent

higher than peripheral renin at all levels of plasma renin encountered in the study.

When the mean value for log V - log A was calculated, the anti-log of the value was again found to be 1.24, thus confirming the analysis of variance. However, when the variability of V/A was analyzed it was found to be quite considerable. Using 2 standard deviations to establish 95 per cent confidence limits, renal vein renin varied from 90 to 170 per cent of the arterial level. Renal Vein Renin, Relative to Arterial Renin in Low, Normal and High Renin Essential Hyperten- sions (Figure 4). Mean renal vein renin was 124 per cent (103 to 150 per cent, SD) of the arterial renin in 56 kidneys of the 28 patients with normal renin essential hypertension. It was 126 per cent (102 to 156 per cent) of the arterial level in 11 low renin patients and 134 per cent (113 to 159 per cent) in 4 high renin patients. When the differences between the groups were analyzed statistically, there was no significant difference in the relationship of renal vein renin to the arterial renin. However, in five additional high renin patients who had reduced renal function, as evidenced by creatinine clearance under 70 ml/min, the renal vein renin from each kidney was 150 per cent (136 to 166 per cent) of the arterial level and the difference from the patients with normal renal function was significant at the 1 per cent level.

Essential Hypertension Advonced Hypertension

. HIGH LOW NORMAL HIGH RENIN “. I, n:28 n=4 n=5

( ygd )

A I

I,()__ -__-_AM____________&_--_---_-_---_------.

i

A i

4 .

0.5 !- Figure 4. Distribution of values for renal vein renin (V) divided by arterial renin (A) in the three renin subgroups of essential hypertension. V/A was 1.26 in low renin patients, 1.24 in normal renin patients, and 1.34 in high renin patients. The differences were not statisticalli significant. However, the value of 1.50 found in high renin patients with reduced renal function was significantly higher. Thus, reductions in renal plasma flow cause increases in V/A.


PHYSIOLOGY OF RENIN SECRETION IN ESSENTIAL HYPERTENSION-SEALEY ET AL

Analysis of the Relative Concentration of Renin in the Two Renal Veins of Patients with Essential Hypertension. This analysis was carried out because a ratio of renal vein renins is often used to identify patients with renovascular hypertension who might be cured by surgery [15,16]. The higher renal vein renin was divided by the lower value so that a ratio greater than 1.0 was always achieved. The distribution of values appeared to fit a normal Gaussian curve (Figure 5). A cumulative per cent frequency distribution was derived and 95 per cent of patients had a ratio of less than 1.63. In separat- ing surgically curable patients with renovascular hypertension a ratio of 1.5 is often used as a cut- off point. However, the present analysis suggests that, using this ratio alone, 13 per cent of the patients with essential hypertension would be classi- fied as potentially curable by surgery. In the present study, no patients had a ratio of renal vein renins of greater than 2.0.

COMMENTS AND ANALYSIS

Analysis of plasma renin in blood collected from the renal veins as well as from arterial and venous blood of patients with essential hypertension has revealed in this group that renin activity in each renal vein (V) is consistently higher by 24 per cent than renin measured in blood derived from the other sources (A). This relationship is maintained over the whole range of renin values measured in the three subgroups of essential hypertension. In the following analysis it will be demonstrated that, in the absence of liver disease, peripheral plasma renin activity is a direct reflection of the rate of secretion of renin by the kidneys. In addition it will be demonstrated that, because the relationship of renal vein renin increment to the arterial renin is constant in patients with presumably normal renal blood flows, increases in (V-A)/A can in turn be used as an indicator of reductions in renal blood flow in patients with suspected renovascular disease who exhibit unequal renal perfusion. A product of these findings is the ability to calculate the secretion rate of renin from peripheral renin measurements and to estimate renal blood flow on the basis of only renal vein and peripheral renin measurements.

Renin substrate levels, measured in peripheral venous blood, were normal [lo] and similar in patients with the three subtypes of essential hypertension, despite wide differences in plasma renin activity. Thus, in the subsequent analysis, it can be assumed that changes in renin activity reflect

30 -

20 -

PERCENT _ PATIENTS

IEs) IO -

t OL

- 100 ._______.

- 80

- 60

- 40

- 20

‘0

95% (I 63

CUMULATIVE PERCENT

DISTRIBUTION

(9)

I.0 I.2 1.4 I.6 )I.7

RENAL VEIN RENIN RATIO (V, /V2)

Figure 5. Variations in renal vein renin ratios in essential hypertension. The higher value was always divided by the lower value so that a ratio greater than 1.0 was always achieved. The ratio was less than 1.63 in 95 per cent of patients and less than 1.5 in 87 per cent ofpatients.

changes in plasma renin concentration. Moreover, since no differences in renin were observed between arterial and venous blood [4,10] excepting the renal veins, for purposes of analysis, arterial and venous measuremetits can be used inter- changeably and will be represented by (A) in the calculations.

Peripheral plasma renin activity is a reflection of renal renin secretion if (1) the kidney is the only source of renin, (2) the clearance rate of renin is constant and (3) steady state conditions obtain. Renin has been found in tissues other than the kidney [17-191. However, there is no evidence that plasma renin is ordinarily derived from any of these sources. The liver has been shown to be the major site for metabolism of renin [4-6,20,21]. A fall in liver blood flow markedly reduces hepatic extraction of renin [6,20,21]. However, in none of the patients in the present study was there any evidence of liver disease. The demonstration of no difference between systemic arterial and venous renin levels in the present study supports the view that plasma renin is derived exclusively from the kidney and removed exclusively by the liver. Sam- ples were collected for plasma renin measurements from patients who had been supine for a minimum of 2 hours, after at least 3 days of constant sodium intake. Therefore, since liver function was presumably normal and steady state conditions prevailed, it is reasonable to assume that, in.this study, plasma renin activity is proportional to the rate of renal renin secretion. Increment in Renal Vein Renin = 24 Per Cent Arterial Renin. The key observation of the pres-



ent study is that the increment of renin added to the renal vein (V-A) is a constant proportion of the arterial renin at all levels of plasma renin activity found in essential hypertension. This means that the renal vein renin increment can be calculated from the arterial (or venous) renin level and vice versa if (1) the renin secretion rate is equal from both kidneys, (2) the renal plasma flow is normal and equal from both kidneys and (3) the clearance rate of renin is similar to the present study. In the present study it was shown that, in patients with essential hypertension (VR-A) = (VL-A) = 0.24 A (Table IA). Thus, the renal vein renin increment from each kidney is 24 per cent of the peripheral renin. Or, stated another way, renal vein renin is 124 per cent of peripheral plasma renin activity (Table I I, columns l-3).

TABLE I

A. Relationship of Renal Vein Renin Increment to Arterial Renin

In patients with essential hypertension who have no evidence of renal disease

(VR* - A*)/A = (VI,* - A)/A = 0.24 (1)

i.e., (VR - A) = (VL - A) = 0.24 A (2)

i.e., (VR - A)/A + (VL - A)/A = 0.48 (3)

B. Renin Secretion

Renin secretion = renal plasma flow X renal vein renin increment (4)

= RPFR(VR - A) + RPFL(VL - A) (5)

In essential hypertension VR - A = VI, - A = 0.24A (equation 2).

In essential hypertension RPFR = RPFL since VR - A =

VL - A. Assume RPF is normal in essential hypertension = 300

ml/min/kidney

Renin secretion = 300 X 0.24 A + 300 X 0.24 A = 144 A

C. Renal Plasma Flow

(6)

Renin secretion = RPF1(V1 - A) + RPF2(V2 - A) (5)

144 A = RPFl(V1 - A) + RPF2(Vz - A)

144 (Vz - A) RPFl = - RPFz---- (7)

(VI - A)/A (VI - A)

144 (Renin secretionl) RPFl =

(VI - A)/A - (8)

(VI - A)

* Vg = renal vein renin; right renal vein. * VL = renal Vein renin; left renal vein. * A = arterial or venous renin; since arterial renin = venous renin.

The data used in this analysis were derived from patients with essential hypertension. Data from studies carried out in normal man by other investigators suggest that the relationships are not different from those in essential hypertension. In a study of 13 normal subjects reported by Kaneko and co-workers [22] mean renal vein renin was 8.1 ng/ml, 27 per cent higher than the peripheral level of 6.4 ng/ml, which compares favorably to the 24 per cent found in our hypertensive popula- tion. Renin Secretion = Arterial Renin X 144. We have just shown that the renal vein renin increments can be calculated from arterial renin levels in essential hypertension. This can now be used to calculate the secretion rate of renin, since renin secretion is equal to the product of renal plasma flow and the renal vein renin increment. If renal plasma flow can be assumed to be near normal in the patients in the present study, a formula for calculation of the secretion rate of renin can be derived which utilizes only peripheral renin measurements (Table 16). Renal renin secretion was calculated to be 144 times peripheral plasma renin activity. Thus, under the conditions of this study, the kidney secretes 144 times the peripheral plasma renin level each minute. A table can be derived for the secretion rate of renin for each level of plasma renin activity (Table II, column 4). It is interesting to note that, even at low levels of plasma renin activity, the kidney still secretes

TABLE II Derivation of Renal Vein Renin Levels and Renin Secretion Rate from the Plasma Renin Activity Value

Renal Vein

Peripheral Renin Renal Vein Renin Renin Increment Renin Secretion

@g/ml) (Wml) (@ml) W/ml/ (A)* (V - A)t 0% min)§

0.4 0.10 0.50 58 0.8 0.19 0.99 115 1.6 0.38 1.98 230 3.2 0.77 3.97 460 6.4 1.54 7.94 920

12.8 3.1 15.9 1,840 25.6 6.2 31.7 3,680 51.2 12.3 63.5 7,360

* A = peripheral (arterial or venous) plasma renin activity. All other numbers in this table are derived from these which were chosen arbitrarily. t V - A = 0.24 A. $ V = A + (V - A). §.Renin secretion = 144 X A.



renin at an impressive rate, sp that when peripheral plasma renin is 0.4 ng/ml the rate of secretion of renin from the kidney is 58 ng/ml/min.

These derived data (Table II) are supported by experimental data from another study of 28 patients with essential hypertension reported by Kaneko and co-workers [23]. Mean plasma renin activity in these patients was 9.0 ng/ml and the secretion rate of renin, derived from measurements of renal vein renins and renal plasma flows, was 1,220 ng/ml/min. Using the formula just developed, calculated renin secretion would have been 1,296 ng/ml/min, a difference of only 6 per cent.

Hosie and co-workers [24] in a study in dogs noted that peripheral plasma renin was directly related to renal vein renin concentration and to the rate of renin secretion, but the relationship did not appear to be constant at all levels of plasma renin. The apparent lack of constancy of the relationship was perhaps due to the acute nature of the study. It is important to reemphasize that the interrelationship of renin secretion to peripheral plasma renin will change with changes in hepatic clearance or if there are fluctuations in the rate of renin secretion during the study. Calculation of Renal Plasma Flow. Since renin secretion rate can be calculated from arterial or peripheral venous renin values and since we have demonstrated that, in patients with essential hypertension with presumably equal and normal renal plasma flows, (V-A) from both kidneys is

equal and bears a constant relationship to arterial renin, it should be possible to appreciate differential deviations in renal plasma flow from differences in (V-A) /A from each kidney (Table IC).

Equation 7 (Table I) provides a basis for estimating renal plasma flow rates from each kidney. The kidney in question is represented by RPF,. Since there are two unknowns in this equation (RPF, and RPF2) absolute determination of renal plasma flows can only be calculated from two different sets of values perhaps derived from two different physiologic settings (e.g., after sodium depletion) so as to be able to solve simultaneous equations. Nonetheless, with one set of measurements, since the right hand side of equation 7 has negative value, it is possible to estimate a maximum value for renal plasma flow from each side (Table Ill) and also to detect gross reductions in one side as compared to the other. This has spe- cial application to analysis of Goldblatt hypertension since, when (V-A) in one kidney approaches zero (contralateral suppression), renal plasma flow from the sole renin secreting kidney can then be calculated with precision. In this situation the right hand side of equation 7 drops out. It follows that the closer (V-A) is to zero, i.e., the lower the secretion rate of renin from the uninvolved kidney, the more accurate the estimation of renal plasma flow from the suspect kidney.

It also follows from equation 7 that if (V-A)/A from either kidney is greater than 0.48 then reduction in blood flow is likely, since 144/(V1-A)/A

TABLE III The Estimation of Renal Plasma Flows from Renal Venous and Arterial Renin Levels -__

144 (Vz - A) RPF, = - RPF, X ~ Equation 7

(VI - A)/A (VI - A)

(1) (2)

Model Exam-

Renin Measurements (VI -

pie (A) (Vl) (Vz) A)

(VI - (V,- (V, - Total

A)/A A) A)/A (1) (2) RPF RPF, RPF,*

Equal and normal renal plasma flows

Renin secretion from only one kidney

Uni-nephrex subjects

Unequal kidney disease

1 1 1.24 2 4 4.96 3 8 9.92 4 16 19.8 5 8 15.7 6 8 23.4 7 8 11.84 8 8 11.0 9 8 23.4

10 100 392

1.24 4.96 9.92

19.8 8.0 8.0

. . . 19.5

148

0.24 0.24t

0.96 0.24t 1.92 0.24t 3.84 0.24t 7.68 0.96

15.36 1.92 3.84 0.48 3.0 0.375

15.36 1.92 192 1.92

0.24 0.24t

0.96 0.24t

1.92 0.24t

3.84 0.24t

0 0

0 0

. . .

. . . . . . 11.5 1.44 48 0.48

600 1 600 300 300 600 1 600 300 300 600 1 600 300 300 600 1 600 300 300 150 ? ? 150 ?$

75 ? ? 75 ?$ 300 . . . 300 300 . . . . 384 . . . 384 384 . . .

75 0.75 <175 t75 (100 75 0.25 <375 <75 <300

* Calculated by interchanging kidneys 1 and 2 in equation 7. t Since (V, - A) = (V, - A) = 0.24 A in these patients, RPF, = RPF, (see text). $ Renal plasma flow is probably normal or slightly elevated since renin secretion from that kidney was suppressed in response

to oversecretion of renin by the other kidney.


PHYSIOLOGY OF RENIN SECRETION IN ESSENTUL HYPERTENSION-SEALEY ET AL

would be less than 300, and thus RPFI must be lations are discussed fully in the subsequent paper less than 300 ml/min. by Vaughan and co-workers [l I].

Examples of normal variations in V and A and hypothetical changes in (V-A)/A are pre- sented in Table III. In the first four examples in Table I I I, (V-A) from the right renal vein is equal to that in the left renal vein and (V-A)/% from each side is 0.24. There is, therefore, no evidence of reduction in renal plasma flow in any of these examples, and the calculated total renal plasma flow is normal. Since (V-A) from both sides is equal then it is likely that renal plasma flow from each side is equal. Theoretically, it is possible that, in patients with unilateral deficiency in renin secretion, reduction in renal plasma flow might be accompanied by a proportionally similar fall in renin secretion from that kidney, resulting in an apparently normal (V-A)/A from that kidney. However, the lower level of secretion would not be able to sustain the peripheral plasma renin level. Therefore the opposite kidney would have to secrete more renin to compensate for the reduced secretion on the contralateral side in order to sustain the peripheral level. Thus, in this cir- cumstance, one would expect increased (V-A)/A from the normal kidney. If both kidneys had reduced flow and reduced renin secretion (V-A)/A would be greater than 0.24 from both sides. It therefore can be stated that if (VR-A) = (VL-A) = 0.24A then renal plasma flow is equal from both sides and is similar to that found in essential hypertension.

In patients who have only one kidney it is possible to calculate renal blood from equation 7. In example 7 (unlike 8) uninephrectomy did not result in an increase in renal blood flow as is indi- cated by the (VK-A)/A of 0.48 in the remaining kidney. The reason for the higher value of (V-A)/ A (i.e., >0.24) in subjects with only one kidney is apparent when one considers the hypothetical case of a patient with plasma renin of 16 ng/ml who undergoes uninephrectomy. Prior to nephrec- tomy, renal vein renin increments from each side would be 16 X 0.24 = 3.84 ng/ml (assuming equality of renin secretion from each side), and the secretion rate of renin would be 144 X 16 = 2,304 ng/ml/min. After uninephrectomy, renin secretion rate would fall in half to 1 ,152 ng/ml/min and this level of secretion can only sustain a peripheral plasma renin level of 8 ng/ml. However, the renal vein renin increment (V-A) in the remaining kidney would remain the same assuming no change in the rate of secretion of renin. Therefore (V-A)/A must increase to 0.48 because of the fall in A. In example 8 (Table I II), renal plasma flow has increased to compensate for the loss of kidney mass and (V-A)/A is less than 0.48 but has not returned to the normal value of 0.24.

In all circumstances when (Va-A)/A i- (VL- A)/A is greater than 0.48 there must be a reduction in renal blood flow to at least one kidney, and it is reduced to that kidney which has the proportionally higher value for (V-A)/A. However, in patients with the just postulated but never as yet documented syndrome of renin secretion deficiency from one side, the sum of (V-A)/A from both sides could be 0.48 but if the renal plasma flow from each side were not equal (V-A)/A would not be equal.

In examples 5 and 6 (Table I I I), there is no secretion of renin from the left kidney. This is the situation in classic Goldblatt hypertension in which excessive renin secretion from one kidney results in complete suppression of renin secretion from the contralateral kidney [25,26]. Under these circumstances the right hand side of equation 7 (Table I) becomes zero, and it is then possible to calculate with theoretic precision the renal blood flow to the affected kidney. However, no estimation of blood flow to the contralateral kidney is possible. The practical applications of these calcu-

For examples 9 and 10 (Table I I I) it is not possible to calculate the exact value for renal plasma flow. However, it is possible to estimate the maximum value for the total plasma flow and to identify the kidney with the greater reduction in blood flow. In order to calculate maximum value for each kidney, the kidney in question should always be 1 in the equation. From equation 8 (Table II I) it can be seen that if (VI-A)/A is greater than 0.48 then renal plasma flow must be less than 300 ml/min, how much less is depen-, dent on the relationship of the renin secretion from the contralateral kidney to the renal vein renin increment from the kidney in question. When one kidney has markedly reduced blood flow, and increased renin secretion, the presence of (V-A)/A of less than 0.24 on the contralateral side does not preclude reduced blood flow on that side. This is because (V-A) can be relatively high from that side, but because A is extremely high (V-A)/A could be less than 0.24. Therefore, in summary, (V-A)/A greater than 0.48 is always in- dicative of reduced renal blood flow, but when (V-A)/A is high from one side and less than 0.24 from the other, normal renal blood flow from the contralateral side cannot be assumed.


PHYSIOLOGY OF KNIN SECRETION IN ESSENTIAL HYPERTENSION --SEALEY ET AL

ln Practice the equation for renal blood flow is

only applicable to detection of gross changes in

renal blood flow because of the normal variability

in the values for V and A. VI and V2 differed from

each other by up to 63 per cent in 95 per cent of patients with essential hypertension. Under normal

conditions of renal blood flow V and A differ from

each other by only 24 per cent. Therefore V and A

should differ from each other by more than 63 per

cent before confidence can be placed that a

change in blood flow has occurred. Thus cal-

culated renal plasma flow must be lower than 210

ml/min before reduction in flow can be ac-

curately predicted in a patient with unilateral renin

secretion. Flow would have to be even more re-

duced in patients with bilateral renin secretion.

Hosie and co-workers [24] noted that (V-A) is

a reflection of both the secretion rate of renin and

renal plasma flow, and stressed that changes in

renal vein renin per se do not necessarily reflect

changes in the secretion rate of renin. The pres-

ent analysis has enlarged on this statement by

demonstrating that, although V-A is not a reflec-

tion of either renal renin secretion rate or renal

blood flow per se, (V-A) /A is in fact directly related

to renal blood flow and does not change with vari-

ations in renin secretion whereas on the other

hand peripheral plasma renin values are a direct

reflection of renin secretion.

(V-A)/A as an Indication of Adequate Collection Of

Renal Vein Blood. (V-A)/A can be used as a

guide to whether the renal vein catheter was cor-

rectly positioned. Thus, if the sum of (V-A)/A

from both kidneys is less than 0.48, then renal

vein blood was probably not collected since the

amount of renin secreted from the kidneys would

be insufficient to sustain the peripheral level. Al-

ternatively, if the vena caval blood was collected last, low (V-A)/A may reflect increases in renin

secretion after collection of renal vein blood.

This would result in increased (A) relative

to (V) and could lower (V-A)/A to less than 0.48.

Thus total (V-A)/A of less than 0.48 is a good in-

dication for repeat analysis. In the absence of

renal blood flow measurements, it is not possible

to pick up errors when the renal vein renin levels

are falsely high relative to the peripheral level

since this could be due to reduced renal blood

flow. Therefore, collection of blood during differ-

ential renal vein studies should be in such a se-

quence that the peripheral blood is collected last,

if all three samples cannot be collected simulta-

neously. Clearance of Renin from Plasma. In any discus- sion of the relationshio of renal vein renin concen-

tration to the arterial level consideration must be

given to the rate of clearance of renin. The pe-

ripheral level of renin is determined by both the

secretion and clearance rates and, under steady state conditions, the renin secretion rate is equal

to the metabolic clearance rate. In this study no

difference was noted in the level of renin in the

vena cava (below the level of the kidneys) and in

the aorta. Thus the clearance of renin does not

take place in the capillary bed. It has been shown

by Haecox and Vander [5] in studies of renin infu-

sions into the renal artery of dogs that there is lit-

tle, if any, clearance of renin by the kidneys. Most

available data points to the liver as the only route

of extraction of renin [4-6,20,21]. Renal vein

blood with increased renin levels increases the

concentration of renin in the vena cava so that the plasma renin level is elevated in vena caval blood

below the level of the liver. Vena caval renin is

then diluted back to peripheral levels by mixing with

hepatic vein blood in which the renin concentra-

tion is reduced by hepatic extraction. Thus, when

the secretion rate of renin is constant, the only

place in the body in which the renin concentration

is higher than the peripheral level is in the renal

veins and in the vena cava between the level of

the kidneys and liver.

Schneider and co-workers [20,21] and others

[6] have shown that, in general, the clearance of

renin by the liver is proportional to the blood flow

through the liver. Thus, reduction in blood flow

through the liver would result in decreased

extraction of renin and this would cause increased

peripheral plasma renin (A) [21]. If (V-A) from the kidney remains constant (i.e., renin secre-

tion unchanged) (V-A)/A must fall because

A has increased. Therefore reduction in liver blood flow results in a fall in (V-A)/A. In fact one

would expect renin secretion to fall to COrTIperXatt?

for the increased peripheral plasma renin, but

changes in renin secretion per se do not alter the

relationship of renal vein renin to peripheral renin. Thus in the presence of reduced clearance of

renin (V-A) /A must fall.

Plasma Renin Activity in Essential Hypertension. The data accumulated in this study indicate that

differences in plasma renin activity observed

throughout the three renin subgroups of essential

hypertension are entirely due to differences in

renal renin secretion rather than to any alterations

in metabolic clearance of renin. Thus renin secretion was proportional to peripheral plasma renin

activity and (V-A)/A was shown to be similar in the three renin subgroups. Moreover the differences in plasma renin activity cannot be attributed


PHYSIOLOGY OF RENIN SECRETION IN ESSENTIAL HYPERTENSION-SEALEY ET AL,

to any changes in renin substrate levels since renin substrate was shown to be normal and similar in the three renin subgroups of essential hypertension.

Considering the changes in (V-A)/A which can occur when renal blood flow or liver blood flow are altered, it may at first seem surprising that the relationship of renal vein to arterial renin is so constant in essential hypertensive patients over wide ranges of variation in plasma renin. One might expect that high renin patients would have slightly reduced renal blood flows [27] and this would result in a higher (V-A)/A. In fact, in high renin patients with reduced creatinine clearance this did occur (Figure 4). However, angiotensin has been shown to cause hepatic vasoconstriction and reduction in hepatic blood flow [28]. Similar directional changes in renal and hepatic blood flows due to vasoconstriction by angiotensin would have opposing influences on (‘V-A)/A. Reduction in (V-A)/A caused by diminished hepatic blood flow would be compensated for by simultaneously increased (V-A)/A resulting from decreased renal blood flow. The system is therefore designed to maintain the relationship constant. Only when renal blood flow and liver blood flow change dis- proportionately to each other does (V-A)/A change, and when it does the deviation may be used to identify the physiologic lesion.

There is no evidence that alterations in liver blood flow ordinarily exert a rate-limiting influence on plasma renin levels. However, an exception might occur under conditions of uncontrolled renin secretion in which there is no feedback to the kidney to turn off renin secretion. Such a situation does obtain in malignant hypertension in which the signal to the kidney to shut off renin is ineffec- tive. These patients often have congestive cardiac failure as a complication of the disease and this, together with the vasoconstrictor action of angiotensin II on the liver, would lead to decreased hepatic clearance of renin [21]. Thus, in malignant

hypertension, a secondary factor in pathogenesis may be decreased hepatic perfusion and thus decreased extraction of renin in conjunction with the excessive secretion of renin by the kidney. Im- provement in hepatic perfusion, due to elimination of the hepatic vasoconstrictor action of angiotensin as well as improved cardiac performance could be important factors for reversal. However, there is some evidence that the per cent extraction of renin can actually increase under conditions of hepatic congestion [21] so that clearance of renin by the liver may not be commensurately impaired under the circumstances.

A vicious circle may also develop in the hepatorenal syndrome [29] in which progressive hepatic and renal failure are associated with very high plasma renin levels. Here progressive renal vasoconstriction leads to angiotensin secretion and to hepatic vasoconstriction. The high plasma angiotensin levels apparently are incapable of turning off renin secretion in the absence of effec- tive blood volume. Measures to reverse hepatic and renal vasoconstriction might interrupt this circle.

In summary, it is important to emphasize that there is great variability in renal vein renin measurements in patients with essential hypertension. Although mean renal vein renin was consistently

24 per cent. higher than the arterial level, and mean renin from the right kidney equalled mean renin from the left, and mean arterial renin equalled mean venous renin, in individual patients these relationships were not always apparent. This variability has been defined in this study (Figures 4 and 5). In analysis of renal vein renins from patients with renovascular hypertension and other clinical situations taking this variability into ac- count should improve understanding of the limita- tions of renin measurements and the analysis herein should enable improved understanding of the physiologic basis leading to variations in renal values.

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The physiology of renin secretion in essential hypertension

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