Contr. Nephrol., vol. 3, pp. 45-51 (Karger, Basel 1976)
Measurement of Plasma Renin Concentration and Angiotensin II in Peripheral and Renal Venous Plasma in the Management of Renovascular Hypertension p.L. Padfield, 1.1. Brown, R. Fraser, A.F. Lever, 1.1. Morton, 1.1.S. Robertson and M Tree Medical Research Council, Blood Pressure Unit, Western Infirmary, Glasgow
Introduction
In the assessment of hypertension in association with renal disease a variety of diagnostic tests are available to the clinician. It has been our policy to combine results of rapid sequence urography, selective renal arteriography and divided renal function tests with the results of renin and angiotensin II measurements in deciding upon management. The purpose of this paper is to illustrate how measurement of plasma renin concentration (PRC) and angiotensin II (All) can be helpful, by reference to selected cases studied in this unit.
Blood samples for measurement of PRC (2), All (4) and aldosterone (5) are taken whenever possible during a fixed normal intake of sodium and potassium, the patients remaining supine after an overnight fast. Renal vein sampling is performed using catheters inserted via both femoral veins using a Seldinger technique. The position of the catheters is assessed by the injection of a small amount of contrast material. The right and left renal venous samples are collected simultaneously. In earlier cases blood was also obtained from a radial or brachial artery at the same sitting; more recently, however, we have adopted the procedure of sampling the low inferior vena cava since peripheral venous values for both PRC (2) and All (4) are similar to values in arterial blood. The All antagonist, saralasin (SARI -ALA 8 analogue, Norwich Pharmacal, New York, generously supplied by Dr. Harries) infusion is performed with patients supine and where possible after 3 days on a fixed normal intake of sodium and potassium. During an initial control period of 1 h 5 % dextrose in water is infused via a constant rate infusion pump into an arm vein. This is followed by saralasin in doses of 2.5, 5 and 10 J.Lg/kg/min, each infusion
Downloaded by: Université de Paris 193.51.85.197 - 1/17/2020 5:40:14 AM
Methods
46
Padfield/Brown/Fraser/Lever/Morton/Robertson/Tree
rate lasting 1 h. Blood pressure is monitored at 5-min intervals throughout using an automatic device (Elag Kiiln BRllO), checked at intervals with a clinical sphygmomanometer. If a distinct blood pressure response is seen during a given infusion rate then no further dose increase is made. Dextrose is again infused for 1 h after the final rate of saralasin infusion. Venous blood is taken from a contralateral arm at the beginning of the experiment and immediately prior to the end of each hourly rate of infusion for measurement of PRe, All and aldosterone.
Case Histories Case I A 41-year-old male presenting in the malignant phase of hypertension (220/ 160 mm Hg). Serum electrolytes suggested the presence of secondary aldosterone excess; sodium 135 mM/I, potassium 2.6 mM/1. Excretion urography and selective renal arteriography revealed a left main renal artery stenosis with post-stenotic dilatation. Divided renal function studies (table I) showed a marked reduction in urine flow from the left kidney. The concentrations of p-aminohippuric acid (PAH) and creatinine were increased on the affected side with reduced clearances, i.e. the features of renal ischaemia. Peripheral levels of PRC and All were high at 34 V/I and 185 pg/ml, respectively (normal range for PRC 4-20 V/I and for All 5-35 pg/ml), and renal vein sampling (table II) revealed a marked increase in PRC and All in the left renal vein. At operation an atheromatous plaque seen at the origin of the left renal artery was by-passed with a dacron graft (aorta to distal renal artery) which abolished a pressure gradient of 40 mm Hg across the stenosis. One year later blood pressure was near normal at 134/96 mm Hg while taking no therapy and excretion urography was normal. Peripheral venous levels of PRC (15 V/l) and All (27 pg/ml) were also normal. Case II A 7-year-old girl with severe hypertension (160/120 mm Hg) presenting with headaches and failure to thrive. Excretion urography was normal and renal arteriography revealed normal renal arteries. However, a small lucent area was noted at the lower pole of the left kidney. Divided renal function studies showed no evidence of renal ischaemia, with similar
Period 5 min
Urine flow ml/min
Na+ conc. mM/1
Creatinine conc. mg%
PAH conc. mg%
Clearance, ml/min creatinine
PAH
R, L,
8 0.1
84 40
12 108
125 1,400
98 11
350 48
R2 L2
10 0.2
82 80
8 110
105 1,250
77
344 85
22
Downloaded by: Université de Paris 193.51.85.197 - 1/17/2020 5:40:14 AM
Table I. Divided renal function study on case I showing reduced urine flow, increased concentration of PAH and creatinine with reduced clearances on the left side (indicative of left renal ischaemia)
47
Renin and Angiotensin II in Renovascular Hypertension Table II. Renal vein sampling on case I
RRV LRV Arterial
Renin, VII
All, pglml
55 220 56
78 207 207
RR V and LR V represent the mean of three samples from the right and left renal veins, respectively.
Table Ill. Renal vein sampling on case II, performed on two occasions
Renin, VII
All, pglml
First study RRV, RRV 2 tRV, LRV 2 Ive
242 222 394 270 268
108
Second study RRV LRV Ive
350 433 382
RRV
157 242
= Right renal vein; LRV = left renal vein; Ive = lower inferior vena cava.
Case III A 43-year-old male presenting with malignant hypertension and end-stage renal failure. Excretion urography and selective renal arteriography were normal and peripheral levels of PRe (238 V/!) and All (200 pglml) were high. Renal vein sampling (table IV) showed an excess of PRe and All in both renal veins with no discrepancy between left and right. Haemodialysis and various drug regimes failed to control the blood pressure and a bilateral
Downloaded by: Université de Paris 193.51.85.197 - 1/17/2020 5:40:14 AM
concentrations of PAH and creatinine in the urine from both kidneys. Peripheral venous levels of PRe (286 V/!), All (300 pg/mi) and aldosterone (104 ng%; normal range < 20 ng%) were extremely high. Renal vein sampling was performed on two occasions (table III) showing a consistent increase in PRe in the left renal vein. At subsequent operation involving a left nephrectomy a l-cm tumour was found in the lower pole of the left kidney and this was later shown to contain renin in a concentration of 9,000 Vlg as opposed to 10 Vlg in surrounding renal tissue - a renin-secreting tumour. One year postoperatively the patient is well with a normal blood pressure (116/70 mm Hg) and growing normally. Peripheral levels of PRe (7 V/!), All (10 pglml) and aldosterone (8 ng%) are normal.
Padfield/Brown /Fraser/Lever/Morton /Robertson /Tree
48
Table I V. Renal vein sampling on case III
RRV LRV
Ive
Renin, VII
All, pg/ml
77
146
71 54
173
66
Values for renal vein renin concentration represent the mean of three samples.
BP,
mmHg
::] I I I 160
120 80
PLasma renin. Ull
4001~ 200
I I
~~Hg :::~
IIIII
PLasma renin
cone (UIl)
0 800 PLasma All, 400 1 pg/mL
o
PLasma
80
aldosterone, 40
ngi100ml
o
~
-
~ Saralasin
125~g/kg/mln
Hours
1
PLasma All,
pg/mL
40~~
PLasma aLdosterone, 20 ng/l00ml
o
10~
~g/kg/mln 61L--r_,---,_,---,----, Hours
2
Fig. 1. Saralasin infusion in case Ill. Normal ranges for PRC, All and aldosterone are
indicated by the shaded areas. Fig. 2. Saralasin infusion in case IV.
Case IV A 25-year-old man with severe hypertension and clear evidence of a functional right main renal artery stenosis on the basis of an abnormal excretion urogram and renal arteriogram. The finding of a tenfold increase of plasma renin activity in the right renal vein as
Downloaded by: Université de Paris 193.51.85.197 - 1/17/2020 5:40:14 AM
nephrectomy was performed with excellent control of blood pressure without further medication. Before nephrectomy the patient underwent a saralasin infusion (fig. 1) at a rate of 2.5 IJ.g/kg/min for 1 h. This produced a striking reduction in blood pressure to normal levels within 15 min. Elevated basal levels of PRC and All were further increased with a concomitant reduction of a raised plasma aldosterone. All changes tended to revert toward basal level 1 h after stopping the infusion (fig. 1).
Renin and Angiotensin II in Renovascular Hypertension
49
opposed to the left (measured at another hospital) and the discovery of a diminished renal blood flow suggested the possibility of a good operative result. Figure 2 shows the results of a saralasin infusion at rates increasing to 10 #lg/kg/min. Although similar changes in PRe, All and aldosterone were seen, the blood pressure response was small. Despite this a dacron by-pass graft was inserted abolishing a 70-mm pressure gradient across the stenosis of the renal artery and at 3 months postoperatively, blood pressure is normal at 130/80 mm Hg.
The use of renal vein renin estimations has become an established diagnostic tool for the evaluation of renovascular hypertension and the ratio between the two sides gives good prediction as to the outcome of surgery in many, but not all, cases (1, 8, 10). The first two cases illustrate the problems in interpreting the results. The first patient with a unilateral marked reduction in renal blood flow showed a fourfold difference in renal vein PRe. This is well in excess of the generally accepted ratios for predicting surgical cure (1, 10, 12, 15). It must be emphasised, however, that this difference is accounted for mainly by the decrease in renal blood flow and not by the difference in renin secretion rate. The second patient, with normal renal blood flow, had extremely high values of PRe in peripheral and renal vein blood. The ratio of PRe in the two renal veins and the ratio between the left renal vein and peripheral blood were, however, low. In 2 of the 3 pairs the difference is less than 25 %, a figure which approaches the limits of accuracy of currently available techniques (7). The difference was consistent on repeated sampling and was obviously of diagnostic importance. We stress, therefore, the importance of repeat sampling rather than relying on a single pair of values, as in cases of unilateral renal disease where renal blood flow is normal or perhaps only minimally reduced differences observed may well be Significant, but within the limits of the error of whatever method is used for measuring renin. In both patients the sed'etion of renin from the contralateral kidney appears suppressed, there being no net secretion in the first case and a slight negative secretion in the second, l.e. the kidney has extracted renin from arterial blood. This is to be expected from work in animal models of two kidney Goldblatt hypertension (6) and is a frequent finding in man (9, 12, 15). Differences in All generally follow those of PRe, but are less marked. In both cases the uninvolved kidney also appears capable of extracting All from blood; this phenomenon also being observed in the kidney with a renin-secreting tumour. The use of saralasin in hypertension associated with renal disease may give valuable information on the pathophysiology of this group of conditions. The only known action of this compound is to competitively block the effects of All (11). Its apparent ability to lower blood pressure in patients with hypertension
Downloaded by: Université de Paris 193.51.85.197 - 1/17/2020 5:40:14 AM
Discussion
Padfield /Brow n /Fraser / Lever /Morton /Robertson /Tree
50
associated with high levels of plasma renin (3) makes it seem likely that this test might predict the subsequent response to surgery. The first patient so studied showed a hypotensive response to the low rate of infusion of saralasin and blood pressure responded well to bilateral nephrectomy, giving good evidence of AIImediated hypertension. A second patient with initially high levels of PRe and All failed to drop blood pre'ssure markedly, but still responded well to surgery. The first patient was studied while salt deplete (dialysis) and this might be expected to remove a volume factor contributing to hypertension. It is possible that the second patient might have responded if similarly studied (13). The changes in PRe, All and aldosterone across saralasin infusion were similar in each patient, a rise in renin and All being accompanied by a fall in plasma aldosterone. The changes in PRe and All are probably explained partly by an increase in renin secretion mediated by the fall of BP and partly by an interruption to the normal negative feedback of All on renin release (14). The fall in plasma aldosterone is indicative that AIl is directly concerned in the genesis of aldosterone excess in such cases of renal hypertension.
Summary Although in general, measurement of renal vein renin appears to give a good prediction as to the subsequent response to surgery, its main value lies in its ability to reflect changes in renal plasma flow; true changes in renin secretion rate being much more difficult to detect. Although it is a little early to say how much information can be derived from saralasin infusions, caution must be exercised in necessarily assuming that the test accurately reflects subsequent surgical response.
2 2
3 4
5 6
Bourgoignie, J.; Kurz, S.; Catanzaro, F.J.; Serirat, P., and Perry, H.M.: Renal venous renin in hypertension. Am. J. Med. 48: 332-342 (1970). Brown, J.J.; Davies, D.L.; Lever, A.F., and Robertson, J.1.S.: The estimation of renin in human plasma. Biochem. J. 93: 594 -600 (1964). Brunner, H.R.; Gavras, H.; Laragh, J.H., and Keenan, R.: Angiotensin II blockade in man by SARI -ALAS -angiotensin II for understanding and treatment of high blood pressure. Lancetii: 1045-1048 (1973). Dusterdieck, G. and McElwee, G.: Estimation of angiotensin II concentration in human plasma by radioimmunoassay: some applications to physiological and pathological states. Eur. J. din. Invest. 2: 32-38 (1971). Fraser, R.; Guest, s., and Young, J.: A comparison of double isotope derivative and radio immunological estimation of plasma aldosterone concentration in man. ('lin. Sci. 45: 411--415 (1973). Gross, F.; Brunner, H.R., and Ziegler, M.: Renin-angiotensin system, aldosterone and sodium balance; in Pincus Recent progress in hormone research (Academic Press, New York 1965).
Downloaded by: Université de Paris 193.51.85.197 - 1/17/2020 5:40:14 AM
References
Renin and Angiotensin II in Renovascular Hypertension
51
Dr. P.L. Padfield, Medical Research Council, Blood Pressure Unit, Western Infirmary, Glasgow G11 6NT (Scotland)
Downloaded by: Université de Paris 193.51.85.197 - 1/17/2020 5:40:14 AM
7 Hosie, K.F.; Brown, J.J.; Harper, A.M; Lever, A.F.; MacAdam, R.F.; MacGregor, J., and Robertson, J.I.S.: The release of renin into the renal circulation of the anaesthetised dog. Clin. Sci. 38: 157-174 (1970). 8 Kirkendall, W.M.; Fitz, A.E., and Lawrence, M.S.: Renal hypertension - diagnosis and surgical treatment. New Engl. J. Med. 276: 479-485 (1967). 9 Laragh, J.H.: Curable renal hypertension - renin, marker or cause. J. Am. med. Ass. 218: 733 (1971). 10 Michelakis, A.M; Foster, J.H.; Liddle, G. W.; Rhamy, R.K.; Kuchel, 0., and Gordon, R.D.: Measurement of renin in both renal veins - its use in diagnosis of renovascular hypertension. Archs intern. Med.120: 444-448 (1967). 11 Pals, D.T.; Masucci, F.D.; Stephens, R.L.; Sipos, F., and Denning, G.s.: Role of the pressor action of angiotensin II in experimental hypertension. Circulation Res. 29: 673-681 (1971). 12 Stockigt, J.R.; Noakes, CA.; Collins, R.D.; Schambelan, M, and Biglieri, E.G.: Renal vein renin in various forms of renal hypertension. Lanceti: 1194-1197 (1972). 13 Streeten, D.H.P.; Castellian, A. w.; Micalizzi, E.R.; Dalakos, T.G.; Anderson, G.H., jr.; Freiberg, J.M., and Keenan, R.E.: Saralasin (l-Sar-8-Ala-Angiotensin II): pharmacology and clinical use in angiotensin-
Measurement of Plasma Renin Concentration and Angiotensin II in Peripheral and Renal Venous Plasma in the Management of Renovascular Hypertension p.L. Padfield, 1.1. Brown, R. Fraser, A.F. Lever, 1.1. Morton, 1.1.S. Robertson and M Tree Medical Research Council, Blood Pressure Unit, Western Infirmary, Glasgow
Introduction
In the assessment of hypertension in association with renal disease a variety of diagnostic tests are available to the clinician. It has been our policy to combine results of rapid sequence urography, selective renal arteriography and divided renal function tests with the results of renin and angiotensin II measurements in deciding upon management. The purpose of this paper is to illustrate how measurement of plasma renin concentration (PRC) and angiotensin II (All) can be helpful, by reference to selected cases studied in this unit.
Blood samples for measurement of PRC (2), All (4) and aldosterone (5) are taken whenever possible during a fixed normal intake of sodium and potassium, the patients remaining supine after an overnight fast. Renal vein sampling is performed using catheters inserted via both femoral veins using a Seldinger technique. The position of the catheters is assessed by the injection of a small amount of contrast material. The right and left renal venous samples are collected simultaneously. In earlier cases blood was also obtained from a radial or brachial artery at the same sitting; more recently, however, we have adopted the procedure of sampling the low inferior vena cava since peripheral venous values for both PRC (2) and All (4) are similar to values in arterial blood. The All antagonist, saralasin (SARI -ALA 8 analogue, Norwich Pharmacal, New York, generously supplied by Dr. Harries) infusion is performed with patients supine and where possible after 3 days on a fixed normal intake of sodium and potassium. During an initial control period of 1 h 5 % dextrose in water is infused via a constant rate infusion pump into an arm vein. This is followed by saralasin in doses of 2.5, 5 and 10 J.Lg/kg/min, each infusion
Downloaded by: Université de Paris 193.51.85.197 - 1/17/2020 5:40:14 AM
Methods
46
Padfield/Brown/Fraser/Lever/Morton/Robertson/Tree
rate lasting 1 h. Blood pressure is monitored at 5-min intervals throughout using an automatic device (Elag Kiiln BRllO), checked at intervals with a clinical sphygmomanometer. If a distinct blood pressure response is seen during a given infusion rate then no further dose increase is made. Dextrose is again infused for 1 h after the final rate of saralasin infusion. Venous blood is taken from a contralateral arm at the beginning of the experiment and immediately prior to the end of each hourly rate of infusion for measurement of PRe, All and aldosterone.
Case Histories Case I A 41-year-old male presenting in the malignant phase of hypertension (220/ 160 mm Hg). Serum electrolytes suggested the presence of secondary aldosterone excess; sodium 135 mM/I, potassium 2.6 mM/1. Excretion urography and selective renal arteriography revealed a left main renal artery stenosis with post-stenotic dilatation. Divided renal function studies (table I) showed a marked reduction in urine flow from the left kidney. The concentrations of p-aminohippuric acid (PAH) and creatinine were increased on the affected side with reduced clearances, i.e. the features of renal ischaemia. Peripheral levels of PRC and All were high at 34 V/I and 185 pg/ml, respectively (normal range for PRC 4-20 V/I and for All 5-35 pg/ml), and renal vein sampling (table II) revealed a marked increase in PRC and All in the left renal vein. At operation an atheromatous plaque seen at the origin of the left renal artery was by-passed with a dacron graft (aorta to distal renal artery) which abolished a pressure gradient of 40 mm Hg across the stenosis. One year later blood pressure was near normal at 134/96 mm Hg while taking no therapy and excretion urography was normal. Peripheral venous levels of PRC (15 V/l) and All (27 pg/ml) were also normal. Case II A 7-year-old girl with severe hypertension (160/120 mm Hg) presenting with headaches and failure to thrive. Excretion urography was normal and renal arteriography revealed normal renal arteries. However, a small lucent area was noted at the lower pole of the left kidney. Divided renal function studies showed no evidence of renal ischaemia, with similar
Period 5 min
Urine flow ml/min
Na+ conc. mM/1
Creatinine conc. mg%
PAH conc. mg%
Clearance, ml/min creatinine
PAH
R, L,
8 0.1
84 40
12 108
125 1,400
98 11
350 48
R2 L2
10 0.2
82 80
8 110
105 1,250
77
344 85
22
Downloaded by: Université de Paris 193.51.85.197 - 1/17/2020 5:40:14 AM
Table I. Divided renal function study on case I showing reduced urine flow, increased concentration of PAH and creatinine with reduced clearances on the left side (indicative of left renal ischaemia)
47
Renin and Angiotensin II in Renovascular Hypertension Table II. Renal vein sampling on case I
RRV LRV Arterial
Renin, VII
All, pglml
55 220 56
78 207 207
RR V and LR V represent the mean of three samples from the right and left renal veins, respectively.
Table Ill. Renal vein sampling on case II, performed on two occasions
Renin, VII
All, pglml
First study RRV, RRV 2 tRV, LRV 2 Ive
242 222 394 270 268
108
Second study RRV LRV Ive
350 433 382
RRV
157 242
= Right renal vein; LRV = left renal vein; Ive = lower inferior vena cava.
Case III A 43-year-old male presenting with malignant hypertension and end-stage renal failure. Excretion urography and selective renal arteriography were normal and peripheral levels of PRe (238 V/!) and All (200 pglml) were high. Renal vein sampling (table IV) showed an excess of PRe and All in both renal veins with no discrepancy between left and right. Haemodialysis and various drug regimes failed to control the blood pressure and a bilateral
Downloaded by: Université de Paris 193.51.85.197 - 1/17/2020 5:40:14 AM
concentrations of PAH and creatinine in the urine from both kidneys. Peripheral venous levels of PRe (286 V/!), All (300 pg/mi) and aldosterone (104 ng%; normal range < 20 ng%) were extremely high. Renal vein sampling was performed on two occasions (table III) showing a consistent increase in PRe in the left renal vein. At subsequent operation involving a left nephrectomy a l-cm tumour was found in the lower pole of the left kidney and this was later shown to contain renin in a concentration of 9,000 Vlg as opposed to 10 Vlg in surrounding renal tissue - a renin-secreting tumour. One year postoperatively the patient is well with a normal blood pressure (116/70 mm Hg) and growing normally. Peripheral levels of PRe (7 V/!), All (10 pglml) and aldosterone (8 ng%) are normal.
Padfield/Brown /Fraser/Lever/Morton /Robertson /Tree
48
Table I V. Renal vein sampling on case III
RRV LRV
Ive
Renin, VII
All, pg/ml
77
146
71 54
173
66
Values for renal vein renin concentration represent the mean of three samples.
BP,
mmHg
::] I I I 160
120 80
PLasma renin. Ull
4001~ 200
I I
~~Hg :::~
IIIII
PLasma renin
cone (UIl)
0 800 PLasma All, 400 1 pg/mL
o
PLasma
80
aldosterone, 40
ngi100ml
o
~
-
~ Saralasin
125~g/kg/mln
Hours
1
PLasma All,
pg/mL
40~~
PLasma aLdosterone, 20 ng/l00ml
o
10~
~g/kg/mln 61L--r_,---,_,---,----, Hours
2
Fig. 1. Saralasin infusion in case Ill. Normal ranges for PRC, All and aldosterone are
indicated by the shaded areas. Fig. 2. Saralasin infusion in case IV.
Case IV A 25-year-old man with severe hypertension and clear evidence of a functional right main renal artery stenosis on the basis of an abnormal excretion urogram and renal arteriogram. The finding of a tenfold increase of plasma renin activity in the right renal vein as
Downloaded by: Université de Paris 193.51.85.197 - 1/17/2020 5:40:14 AM
nephrectomy was performed with excellent control of blood pressure without further medication. Before nephrectomy the patient underwent a saralasin infusion (fig. 1) at a rate of 2.5 IJ.g/kg/min for 1 h. This produced a striking reduction in blood pressure to normal levels within 15 min. Elevated basal levels of PRC and All were further increased with a concomitant reduction of a raised plasma aldosterone. All changes tended to revert toward basal level 1 h after stopping the infusion (fig. 1).
Renin and Angiotensin II in Renovascular Hypertension
49
opposed to the left (measured at another hospital) and the discovery of a diminished renal blood flow suggested the possibility of a good operative result. Figure 2 shows the results of a saralasin infusion at rates increasing to 10 #lg/kg/min. Although similar changes in PRe, All and aldosterone were seen, the blood pressure response was small. Despite this a dacron by-pass graft was inserted abolishing a 70-mm pressure gradient across the stenosis of the renal artery and at 3 months postoperatively, blood pressure is normal at 130/80 mm Hg.
The use of renal vein renin estimations has become an established diagnostic tool for the evaluation of renovascular hypertension and the ratio between the two sides gives good prediction as to the outcome of surgery in many, but not all, cases (1, 8, 10). The first two cases illustrate the problems in interpreting the results. The first patient with a unilateral marked reduction in renal blood flow showed a fourfold difference in renal vein PRe. This is well in excess of the generally accepted ratios for predicting surgical cure (1, 10, 12, 15). It must be emphasised, however, that this difference is accounted for mainly by the decrease in renal blood flow and not by the difference in renin secretion rate. The second patient, with normal renal blood flow, had extremely high values of PRe in peripheral and renal vein blood. The ratio of PRe in the two renal veins and the ratio between the left renal vein and peripheral blood were, however, low. In 2 of the 3 pairs the difference is less than 25 %, a figure which approaches the limits of accuracy of currently available techniques (7). The difference was consistent on repeated sampling and was obviously of diagnostic importance. We stress, therefore, the importance of repeat sampling rather than relying on a single pair of values, as in cases of unilateral renal disease where renal blood flow is normal or perhaps only minimally reduced differences observed may well be Significant, but within the limits of the error of whatever method is used for measuring renin. In both patients the sed'etion of renin from the contralateral kidney appears suppressed, there being no net secretion in the first case and a slight negative secretion in the second, l.e. the kidney has extracted renin from arterial blood. This is to be expected from work in animal models of two kidney Goldblatt hypertension (6) and is a frequent finding in man (9, 12, 15). Differences in All generally follow those of PRe, but are less marked. In both cases the uninvolved kidney also appears capable of extracting All from blood; this phenomenon also being observed in the kidney with a renin-secreting tumour. The use of saralasin in hypertension associated with renal disease may give valuable information on the pathophysiology of this group of conditions. The only known action of this compound is to competitively block the effects of All (11). Its apparent ability to lower blood pressure in patients with hypertension
Downloaded by: Université de Paris 193.51.85.197 - 1/17/2020 5:40:14 AM
Discussion
Padfield /Brow n /Fraser / Lever /Morton /Robertson /Tree
50
associated with high levels of plasma renin (3) makes it seem likely that this test might predict the subsequent response to surgery. The first patient so studied showed a hypotensive response to the low rate of infusion of saralasin and blood pressure responded well to bilateral nephrectomy, giving good evidence of AIImediated hypertension. A second patient with initially high levels of PRe and All failed to drop blood pre'ssure markedly, but still responded well to surgery. The first patient was studied while salt deplete (dialysis) and this might be expected to remove a volume factor contributing to hypertension. It is possible that the second patient might have responded if similarly studied (13). The changes in PRe, All and aldosterone across saralasin infusion were similar in each patient, a rise in renin and All being accompanied by a fall in plasma aldosterone. The changes in PRe and All are probably explained partly by an increase in renin secretion mediated by the fall of BP and partly by an interruption to the normal negative feedback of All on renin release (14). The fall in plasma aldosterone is indicative that AIl is directly concerned in the genesis of aldosterone excess in such cases of renal hypertension.
Summary Although in general, measurement of renal vein renin appears to give a good prediction as to the subsequent response to surgery, its main value lies in its ability to reflect changes in renal plasma flow; true changes in renin secretion rate being much more difficult to detect. Although it is a little early to say how much information can be derived from saralasin infusions, caution must be exercised in necessarily assuming that the test accurately reflects subsequent surgical response.
2 2
3 4
5 6
Bourgoignie, J.; Kurz, S.; Catanzaro, F.J.; Serirat, P., and Perry, H.M.: Renal venous renin in hypertension. Am. J. Med. 48: 332-342 (1970). Brown, J.J.; Davies, D.L.; Lever, A.F., and Robertson, J.1.S.: The estimation of renin in human plasma. Biochem. J. 93: 594 -600 (1964). Brunner, H.R.; Gavras, H.; Laragh, J.H., and Keenan, R.: Angiotensin II blockade in man by SARI -ALAS -angiotensin II for understanding and treatment of high blood pressure. Lancetii: 1045-1048 (1973). Dusterdieck, G. and McElwee, G.: Estimation of angiotensin II concentration in human plasma by radioimmunoassay: some applications to physiological and pathological states. Eur. J. din. Invest. 2: 32-38 (1971). Fraser, R.; Guest, s., and Young, J.: A comparison of double isotope derivative and radio immunological estimation of plasma aldosterone concentration in man. ('lin. Sci. 45: 411--415 (1973). Gross, F.; Brunner, H.R., and Ziegler, M.: Renin-angiotensin system, aldosterone and sodium balance; in Pincus Recent progress in hormone research (Academic Press, New York 1965).
Downloaded by: Université de Paris 193.51.85.197 - 1/17/2020 5:40:14 AM
References
Renin and Angiotensin II in Renovascular Hypertension
51
Dr. P.L. Padfield, Medical Research Council, Blood Pressure Unit, Western Infirmary, Glasgow G11 6NT (Scotland)
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7 Hosie, K.F.; Brown, J.J.; Harper, A.M; Lever, A.F.; MacAdam, R.F.; MacGregor, J., and Robertson, J.I.S.: The release of renin into the renal circulation of the anaesthetised dog. Clin. Sci. 38: 157-174 (1970). 8 Kirkendall, W.M.; Fitz, A.E., and Lawrence, M.S.: Renal hypertension - diagnosis and surgical treatment. New Engl. J. Med. 276: 479-485 (1967). 9 Laragh, J.H.: Curable renal hypertension - renin, marker or cause. J. Am. med. Ass. 218: 733 (1971). 10 Michelakis, A.M; Foster, J.H.; Liddle, G. W.; Rhamy, R.K.; Kuchel, 0., and Gordon, R.D.: Measurement of renin in both renal veins - its use in diagnosis of renovascular hypertension. Archs intern. Med.120: 444-448 (1967). 11 Pals, D.T.; Masucci, F.D.; Stephens, R.L.; Sipos, F., and Denning, G.s.: Role of the pressor action of angiotensin II in experimental hypertension. Circulation Res. 29: 673-681 (1971). 12 Stockigt, J.R.; Noakes, CA.; Collins, R.D.; Schambelan, M, and Biglieri, E.G.: Renal vein renin in various forms of renal hypertension. Lanceti: 1194-1197 (1972). 13 Streeten, D.H.P.; Castellian, A. w.; Micalizzi, E.R.; Dalakos, T.G.; Anderson, G.H., jr.; Freiberg, J.M., and Keenan, R.E.: Saralasin (l-Sar-8-Ala-Angiotensin II): pharmacology and clinical use in angiotensin-
