RENIN-ANGIOTENSIN-ALDOSTERONE LONG-TERM BRIAN RASHAD AVERY
KEOGH,
RENAL TRANSPLANT
SYSTEM IN PATIENTS*
M.R.C.P.I.
KIRDANI,
PH.D.
A. SANDBERG,
M.D.
ARNOLD
MITTLEMAN,
M.D.
GERALD
P. MURPHY,
M.D.,
D.Sc.
From the Roswell Park Memorial Institute, New York State Department of Health, State University of New York at Buffalo, New York
ABSTRACT - Seventeen anephric patients who constituted the subjects of this study received renal allografts between the years 1969 to 1973. The renin-angiotensin-aldosterone mechanism was evaluated in relation to either a normotensive or hypertensive clinical state in these subjects. Group Z (Controls) were normotensive and on a normal diet; Group ZZwere normotensive, on sodium restriction for jive days, followed by saline infusion on the seventh day; and Group III were hypertensive, on similar sodium restriction for$ve days, followed by saline infusion on the seventh day. Glomerularjiltration rates and levels of plasma renin and aldosterone, and the secretion rate of the latter were obtained on appropriate days. These studies con.rm that an intact renin-angiotensinaldosterone relationship exists in human renal transplant patients. The presence of high aldosterone is a new but unexplainedfinding. The lack of correlation of high secretion rate without hypertension aldosterone secretion rates in our normotensive and hypertensive patients suggests that aldosterone does not play a detectable or signi$cant role in the pathogenesis of chronic or sustained transplant hypertension.
It has been established that the renin-angiotensinaldosterone system plays a role in the regulation of electrolyte and blood pressure in man. l-5 Derangement of this system results in a variety of clinical conditions, for example, primary and pseudoprimary aldosteronism, malignant hypertension, renovascular disease, and oral contraceptive hypertension. l-5 The renal element appears to be the major component in the hypertensive process of end-stage renal disease.6 This factor has been demonstrated by the response to bilateral nephrectomy in a small group of hemodialyzed patients who otherwise should have achieved a *Supported in part by the United States Public Health Service Grants RR-00262-10, AM-11754-07, and AM-0124018 from the National Institutes of Health.
normotensive state by simple ultrafiltration.6 Normotensive patients show an inverse correlation between blood pressure and plasma renin activity, whereas a similar relationship does not exist in essential hypertension. This suggests that in the latter case there is an alteration in the negative feedback mechanism in the normotensive person.7 How alterations in sodium (Na) balance affect this cybernetic system and its relationship to aldosterone secretion in patients who have had bilateral nephrectomies prior to transplantation, remains to be fully clarified. The present report deals with results of a longterm study conducted to explore the relationships of the renin-angiotensin-aldosterone system in a group of transplant patients, previously anephric, who were either’normotensive or hypertensive. In
248
UROLOGY
/ MARCH 1976
/ VOLUME
VII,
NUMBER
3
TABLE
Case Age
Group 1 (Controls). Essential clinical and biochemical parameters of normotensive transplanted patients on normal diet (1973-1974)
I.
Date of Transplant
Type of Kidney Transplanted*
FBS (mg./lOO ml.)
Serum Potassium (mEq./L.)
GFR (ml./min.ll.73M2)
PSP at 15 minutes (B)
Osmolar Clearance (mlhnin.)
1
43
May, 1973
C
107
4.3
86.50
7
2.29
2
40
June, 1969
C
114
4.2
61.36
7
2.50
3
30
Sept., 1972
LR
110
4
29
Sept., 1969
LR
94
4.0
5
32
Dec., 1969
LR
87
4.0
103.2 2 12.5
4.0 + 0.3
MEAN +
NORMAL
SD
RANGE
65-115
AT RPM1
*C = Cadaveric;
LR = living,
3.5-5.0
and Methods
Between September, 1969, and May, 1973, 17 patients with end-stage renal disease had bilateral nephrectomies one to four months prior to renal transplantation. During the intervening period these patients were maintained on hemodialysis. This policy was adopted for all patients in this study except Case 15 who did not have bilateral nephrectomy prior to transplantation. The presently recognized criteria for bilateral nephrectomy in end-stage disease did not influence this group of patients as prospective transplant recipients at the time of surgery. For the purposes of this study a total of 17 patients in three distinct renal transplant groups are reported: Group I (Controls): Five patients, all normotensive, received a normal sodium diet and standard immunosuppressive therapy, namely, azathioprine 2 mg. per kilogram per day, orally, and methyl prednisolone 32 mg. orally on alternate days. Group II: Nine patients, all normotensive, received a 10 mEq. sodium diet for five days. On the seventh day a saline infusion (1,000 ml.) was given over a three-hour period, with the patient ambulatory. Group III: Three patients with hypertensive heart disease and diastolic blood pressures
UROLOGY
/
MARCH 1976
/
Reaction
2.54
50.32
38
1.55
40
0.58
68.21 + 13.40 loo- 160
Blood Pressure -, (Mean + SD) Prone Supine
101 3.0 -k-----+-_ 69 0.4 132 _*2125 82 3.6 120 1.8 - 75 t .8 117 -‘z 74 101 -‘69
102
3.8
70
1 2.1
-k-.-82 1.4 115 8.2 14 + 8.2
5.7
118 72*34
3.2
3.0
102 -27 70
3.6
0.4
1.89 + 0.83 15-25
related.
this study sodium intake was varied under controlled conditions and a number of physiologic and biochemical indexes were monitored. Material
73.87
r
VOLUME VII, NUMBER 3
persistently greater than 95 mm. Hg received a similar 10 mEq. sodium diet daily for five days, also followed by a saline infusion (1,000 ml.) on the seventh day. In this group all diuretics were discontinued for six weeks prior to beginning the study, while hypotensive agents were discontinued for one week. All patients were on standard doses of azathioprine as outlined, and all but 2 patients (Cases 1 and 7), were on methyl prednisolone 32 mg. on alternate days. These particular patients were on prednisone 15 mg. daily. Dietary potassium intake was 50 to 70 mEq. per day in each study group. The following biochemical parameters were evaluated prior to day 1 and again on days 5 and 7: twenty-four-hour urinary electrolytes, creatinine clearance, osmolar clearance, fasting blood sugars, serum electrolytes, carbon dioxide combining power, blood urea nitrogen, and hematocrit. Liver function tests were done on all patients on day 1 only. During the control period at midday following four hours of ambulation, and on control period at midday after four hours of ambulation, and on days 5 and 7, plasma renin activity and plasma aldosterone levels were evaluated from subjects who were in the erect position. Plasma renin activity8 and plasma aldosterone concentration9 were measured by radioimmunoassay. Aldosterone secretion rates were determined over twenty-four-hour periods on days 5 and 7 after the patient had received 10 PC. 1,
249
TABLE
Aldosterone secretion and plasma renin activity II. Group I (Controls). of nwmotensive transplanted patients on normal diet (1973-1974)
GFR (ml./min./1.73M2)
Case 1
2 3 4 5 MEAN?
Plasma Aldosterone Level (ng./lOOml.)
SD
Plasma Renin Activity (ng./ml./hr.)
86.50 61.36 73.87 50.32 69.00
20.0 16.0 12.0 7.4 12.0
102.00 155.00 127.74 215.78 247.25
0.75 0.84 0.47 0.25 0.45
68.21 _’ 13.40
13.48 -+ 4.7
169.55
0.55
60?61
0;2 1.41
NORMAL VALUES AT RPM1
TABLE
Aldosterone Secretion bg./24 hr.)
lOO- 160
KEOGH,
RENAL TRANSPLANT
SYSTEM IN PATIENTS*
M.R.C.P.I.
KIRDANI,
PH.D.
A. SANDBERG,
M.D.
ARNOLD
MITTLEMAN,
M.D.
GERALD
P. MURPHY,
M.D.,
D.Sc.
From the Roswell Park Memorial Institute, New York State Department of Health, State University of New York at Buffalo, New York
ABSTRACT - Seventeen anephric patients who constituted the subjects of this study received renal allografts between the years 1969 to 1973. The renin-angiotensin-aldosterone mechanism was evaluated in relation to either a normotensive or hypertensive clinical state in these subjects. Group Z (Controls) were normotensive and on a normal diet; Group ZZwere normotensive, on sodium restriction for jive days, followed by saline infusion on the seventh day; and Group III were hypertensive, on similar sodium restriction for$ve days, followed by saline infusion on the seventh day. Glomerularjiltration rates and levels of plasma renin and aldosterone, and the secretion rate of the latter were obtained on appropriate days. These studies con.rm that an intact renin-angiotensinaldosterone relationship exists in human renal transplant patients. The presence of high aldosterone is a new but unexplainedfinding. The lack of correlation of high secretion rate without hypertension aldosterone secretion rates in our normotensive and hypertensive patients suggests that aldosterone does not play a detectable or signi$cant role in the pathogenesis of chronic or sustained transplant hypertension.
It has been established that the renin-angiotensinaldosterone system plays a role in the regulation of electrolyte and blood pressure in man. l-5 Derangement of this system results in a variety of clinical conditions, for example, primary and pseudoprimary aldosteronism, malignant hypertension, renovascular disease, and oral contraceptive hypertension. l-5 The renal element appears to be the major component in the hypertensive process of end-stage renal disease.6 This factor has been demonstrated by the response to bilateral nephrectomy in a small group of hemodialyzed patients who otherwise should have achieved a *Supported in part by the United States Public Health Service Grants RR-00262-10, AM-11754-07, and AM-0124018 from the National Institutes of Health.
normotensive state by simple ultrafiltration.6 Normotensive patients show an inverse correlation between blood pressure and plasma renin activity, whereas a similar relationship does not exist in essential hypertension. This suggests that in the latter case there is an alteration in the negative feedback mechanism in the normotensive person.7 How alterations in sodium (Na) balance affect this cybernetic system and its relationship to aldosterone secretion in patients who have had bilateral nephrectomies prior to transplantation, remains to be fully clarified. The present report deals with results of a longterm study conducted to explore the relationships of the renin-angiotensin-aldosterone system in a group of transplant patients, previously anephric, who were either’normotensive or hypertensive. In
248
UROLOGY
/ MARCH 1976
/ VOLUME
VII,
NUMBER
3
TABLE
Case Age
Group 1 (Controls). Essential clinical and biochemical parameters of normotensive transplanted patients on normal diet (1973-1974)
I.
Date of Transplant
Type of Kidney Transplanted*
FBS (mg./lOO ml.)
Serum Potassium (mEq./L.)
GFR (ml./min.ll.73M2)
PSP at 15 minutes (B)
Osmolar Clearance (mlhnin.)
1
43
May, 1973
C
107
4.3
86.50
7
2.29
2
40
June, 1969
C
114
4.2
61.36
7
2.50
3
30
Sept., 1972
LR
110
4
29
Sept., 1969
LR
94
4.0
5
32
Dec., 1969
LR
87
4.0
103.2 2 12.5
4.0 + 0.3
MEAN +
NORMAL
SD
RANGE
65-115
AT RPM1
*C = Cadaveric;
LR = living,
3.5-5.0
and Methods
Between September, 1969, and May, 1973, 17 patients with end-stage renal disease had bilateral nephrectomies one to four months prior to renal transplantation. During the intervening period these patients were maintained on hemodialysis. This policy was adopted for all patients in this study except Case 15 who did not have bilateral nephrectomy prior to transplantation. The presently recognized criteria for bilateral nephrectomy in end-stage disease did not influence this group of patients as prospective transplant recipients at the time of surgery. For the purposes of this study a total of 17 patients in three distinct renal transplant groups are reported: Group I (Controls): Five patients, all normotensive, received a normal sodium diet and standard immunosuppressive therapy, namely, azathioprine 2 mg. per kilogram per day, orally, and methyl prednisolone 32 mg. orally on alternate days. Group II: Nine patients, all normotensive, received a 10 mEq. sodium diet for five days. On the seventh day a saline infusion (1,000 ml.) was given over a three-hour period, with the patient ambulatory. Group III: Three patients with hypertensive heart disease and diastolic blood pressures
UROLOGY
/
MARCH 1976
/
Reaction
2.54
50.32
38
1.55
40
0.58
68.21 + 13.40 loo- 160
Blood Pressure -, (Mean + SD) Prone Supine
101 3.0 -k-----+-_ 69 0.4 132 _*2125 82 3.6 120 1.8 - 75 t .8 117 -‘z 74 101 -‘69
102
3.8
70
1 2.1
-k-.-82 1.4 115 8.2 14 + 8.2
5.7
118 72*34
3.2
3.0
102 -27 70
3.6
0.4
1.89 + 0.83 15-25
related.
this study sodium intake was varied under controlled conditions and a number of physiologic and biochemical indexes were monitored. Material
73.87
r
VOLUME VII, NUMBER 3
persistently greater than 95 mm. Hg received a similar 10 mEq. sodium diet daily for five days, also followed by a saline infusion (1,000 ml.) on the seventh day. In this group all diuretics were discontinued for six weeks prior to beginning the study, while hypotensive agents were discontinued for one week. All patients were on standard doses of azathioprine as outlined, and all but 2 patients (Cases 1 and 7), were on methyl prednisolone 32 mg. on alternate days. These particular patients were on prednisone 15 mg. daily. Dietary potassium intake was 50 to 70 mEq. per day in each study group. The following biochemical parameters were evaluated prior to day 1 and again on days 5 and 7: twenty-four-hour urinary electrolytes, creatinine clearance, osmolar clearance, fasting blood sugars, serum electrolytes, carbon dioxide combining power, blood urea nitrogen, and hematocrit. Liver function tests were done on all patients on day 1 only. During the control period at midday following four hours of ambulation, and on control period at midday after four hours of ambulation, and on days 5 and 7, plasma renin activity and plasma aldosterone levels were evaluated from subjects who were in the erect position. Plasma renin activity8 and plasma aldosterone concentration9 were measured by radioimmunoassay. Aldosterone secretion rates were determined over twenty-four-hour periods on days 5 and 7 after the patient had received 10 PC. 1,
249
TABLE
Aldosterone secretion and plasma renin activity II. Group I (Controls). of nwmotensive transplanted patients on normal diet (1973-1974)
GFR (ml./min./1.73M2)
Case 1
2 3 4 5 MEAN?
Plasma Aldosterone Level (ng./lOOml.)
SD
Plasma Renin Activity (ng./ml./hr.)
86.50 61.36 73.87 50.32 69.00
20.0 16.0 12.0 7.4 12.0
102.00 155.00 127.74 215.78 247.25
0.75 0.84 0.47 0.25 0.45
68.21 _’ 13.40
13.48 -+ 4.7
169.55
0.55
60?61
0;2 1.41
NORMAL VALUES AT RPM1
TABLE
Aldosterone Secretion bg./24 hr.)
lOO- 160
