Acta Med Scand 202: 213-219, 1977

The Adrenocortical Response to Angiotensin I1 Infusion in Anephric and Non-Nephrectomized Patients on Regular Hemodialysis K. Olgaard, S . Madsen and M. Hammer From Medical Department P o Division of Nephrology, Rigshospitalet. Copenhagen, Denmark

ABSTRACT. In the present study 8 anephric and 4 non-nephrectomized patients were stimulated with angiotensin I1 (A-11). In 5 of the anephric patients, an increased plasma aldosterone concentration (PAC) in response to ACTH stimulation bad previously been demonstrated. Aner A-I1 stimulation, all 8 anephric patients responded with a significant rise in PAC although the increase was less pronounced than in 4 non-nephrectomized patients. In both groups of patients the increase in PAC was correlated to the increase in diastolic and systolic BP and to the A-I1 dose. Furthermore, in the non-nephrectomized patients, the plasma renin activity showed a significant decline, which was inversely correlated to the increase in PAC. When all 12 patients, regardless of the difference in remaining renin-angiotensin system, were considered as one population, the variable basal levels of PAC correlated significantly to the increase in PAC during A-I1 and ACTH stimulation. It is concluded that the adrenals of anephric man respond to A-I1 with an increase in PAC and that the reason for a lower response appears to be the lack of the renin-angiotensin system.

In normal man, aldosterone secretion is regulated

mainly by ACTH, potassium, and the renin-angiotensin system (2, 15, 18, 19, 23, 28, 29, 48, 49, 59), the latter being the most important regulatory mechanism (14,51,59). The anephric patient offers an excellent opportunity for examining a direct effect on the aldosterone secretion, as the renal renin is eliminated (3, 4, 11, 43, 57) and the plasma renin activity (PRA) is very low and unresponsive to stimuli ( 1 I , 32, 56, 57). Multiple investigations on such patients have been carried out, but many of the results are contradictory (3, 10, 11, 21, 32, 33,

38.54,55,57,58,62,65,68). One would expect the

anephric patient, like normal man, to react with an increase in the plasma aldosterone concentration (PAC) after infusion of angiotensin I1 (A-11). However, this has not been confirmed, since either absent (38,58,62) or blunted responses (21 48.55) have been reported. In previous investigations we have found that anephric patients are able to increase PAC in response to ACTH and potassium stimulation (65,68, 69). The present investigation was therefore undertaken to examine whether these anephric patients, with previously proven reactivity of their adrenals. could react with an increase in PAC during A-I1 infusion. The study was performed by infusing A-I1 into 8 anephric patients and comparing the results with those in 4 non-nephrectomized patients, all on regular hemodialysis. PATIENTS The A-11 infusions were carried out in 12 patients with terminal renal failure on regular hemodialysis. In 8 of the patients (6 females, 2 males) bilateral nephrectomy had previously been performed. The mean age in the anephric group was 44.5 years (range 28-59). The mean time on regular hernodialysis was 37.6 months (range 11-84) and the mean time since bilateral nephrectomy was 28.4 months (range 4-76). The nephrological diagnoses were: chronic glomerulonephritis 3. malignant nephrosclerosis 3, polycystic kidney disease 2. The 4 non-nephrectomized patients (2 females, 2 males) had a mean age of 51.8 years (range 40-58). Their mean time on regular hernodialysis was 40.5 months (range 1744) and the nephrological diagnoses were: chronic glomerulonephritis 3, chronic interstitial nephropathy 1. All patients were hemodialysed twice a week and received a diet containing on an average 0.8 g proteidkg Ai'ta

Med Srund 202

Z 14

K . @guard et al.

Table I. Mean & S . E . M . values of 8 anephric patients during an angiotensin I I infirsion Time (min)

0 0 0 10

20 30 40 60 80 100" 120" 140b "

A-I1 dose (ng/kg min-')

Aldosterone (pg/ml)

51 6.9 55 49 97 106 125 132 148 155 178 191 132

0.0 1 .o I .o 2.0 2.0 4.0 6.0 8.0 10.0 12.0

7.3 7.6 22.1 25.1 31.8 35.6 46.1 50.6 59.1 63.6 57.9

Diastolic BP (mmHg) 82.5 83.1 81.9 87.5 90.0 90.6 91.3 94.4 %.9 95.0 97.9

4.4 3.8 5.0 5.2 5.2 5.2 4.4 5.1 6.0 6.2 6.8 %.O 5.6

Systolic BP (mmHg)

PRA (nglml h-')

138.1 5.2 138.8 5.6

0.1 1 0.07 0.1 I 0.16 0.08 0.08 0.07 0.1 I 0.04 0.11 0.07 0.08

140.6 6.1 148.1 5.5 149.4 4.8 150.6 5.8 152.5 5.4 162.5 5.0 168.8 5.4 170.7 5.7 175.0 6.5 173.0 9.7

0.04 0.02 0.04 0.04 0.02 0.05 0.05

0.03 0.02 0.03 0.02 0.02

Potassium (mmol/l)

Sodium (mmol/l)

5.7 5.7 5.8 6.0 6.1 6.1 6.2 6.2 6.1 6.3 6.1 5.9

138.0 1.3 136.6 1.8 137.5 1.3 137.3 1 . 1 137.1 1.2 136.4 1.4 136.6 1.3 l3S.9 1.4 136.1 1.4 135.4 .5 135.7 .8 133.8 .3

0.3 0.3 0.3

0.3 0.3 0.3 0.3 0.3 0.3 0.2 0.2 0.1

Conid (pgl100 ml)

11.4 1.4 10.9 1.3 10.6 1.3 10.2 1.4 9.6 1.3 8.8 1 . 1

n.2 o.x

8.1 8.2 7.8 7.9

0.9 1.1 1.0 0.9 7.6 1.0

5 patients.

7 patients.

b.wt., 50 mEq sodium, 50 mEq potassium and about 800 ml of fluid per day. All patients had a normal BP, all were in good condition and did not receive hormones or any other treatment than the dialyses, vitamins and phosphate binders. Informed consent was obtained from all patients.

'Owl 900

5

wo/

Non-ncphrectomtzcd

i-'

R 700.

METHODS

C

The reactivity ?oangiotensin II stimulation. All A-I1 infusions were carried out at 8 a.m., 3 hours before the start of the hemodialysis and 3 days after the previous dialysis. The A-I1 (Hypertensin", Ciba) was dissolved in isotonic glucose at a concentration of 166 ng/ml. All patients were in the supine position throughout the study. After 30 min rest, 3 venous blood samples were drawn and the BP was measured at 5 min intervals as

8 B

600500-

E 4 n

400300. 200-

4

I

Anaphric

120 Diastolic

t 70 10

0

mm Ha

Angiotensin Il-dose n g l k g min-'

LO 80 120 min Fig. 1. Plasma aldosterone concentration, diastolic and systolic BP in 8 anephric patients during an angiotensin I1 stimulation (meanfS.E.M.). The asterisks indicate that the infusion was terminated in one and two patients, respectively, due to an increase of more than 20 mmHg in diastolic BP. 00

Fig. 2 . Individual increase in plasma aldosterone concentration in 8 anephric and 4 non-nephrectomized patients during angiotensin 11 stimulation.

Adrenocortical response to angiotensin I1

Z I5

Table 11. MeankS.E.M. values of4 non-nephrectomized uremic patients during an angiotensin N infusion Time (min) 0 0 0 10 20 30 40

60 80" 100" 120" 140" 'I

A-I1 dose (ng/kg min-')

0.0

I .o I .o

2.o 2.0 4.0 6.0 8.0 10.0 12.0

Aldosterone (pg/ml)

Diastolic BP (mmHg)

Systolic BP (mmHg)

PRA (ng/ml h-l)

188 195 183 237 288 290 319 390 513 518 736 779

76.2 78.8 78.8 80.0 86.3 87.5 90.0 92.5 91.7 91.7 93.3 98.3

136.3 137.5 138.8 151.3 155.0 155.0 162.5 166.3 156.7 166.7 168.3 186.7

1.37 1.40 1.30 1.14 1.20 1.20 1.01 1.00 0.84 0.73 0.60 0.65

56.2 58.7 47.6 74.2 70.7 70.0 71.2 103.8 77.9 69.8 141.1 147.4

5.2 5.5 4.3 5.4 7.5 8.3 11.0 7.5 9.3 9.3 8.3 8.3

8.9 8.5 7.7 6.6 8.9 8.4 10.3 5.5 6.7 4.4 4.4 1.7

Potassium

(mmol/l) 5.3 5.3 5.4 5.5 5.6 5.6 5.5 5.7 5.5 5.5 5.4 5.4

0.23 0.18 0.40 0.25 0.17 0.20 0.11 0.07 0.05 0.13 0.02 0.04

0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.3 0.2 0.3 0.3 0.2

Sodium (mmol/l)

Cortisol (pgl100 ml)

132.3 132.0 134.5 133.0 132.3 131.0 131.3 132.3

13.4 12.3 12.3 12.0 11.2

131.0 130.3 129.3 130.3

0.9 1.1 1.9 0.9 0.6 0.9 1.3 1.5 1.5 1.5 0.9 0.9

10.1 9.4 9.1 10.1 9.3 9.5 9.4

1.7 1.3 1.4 1.4 0.9 0.8 0.9 0.9 0.8 0.9 1.0 0.8

3 patients.

control values. At time zero the A-I1 infusion was initiated in a dose of I ng/kg min - I . The dose was increased 20 min later to 2 ng/kg min - I and then with 2 ng/kg min-' every 20 min until a dose of 12 ng/kg min-'. BP was measured every 5 min and the infusion was terminated if the diastolic BP had risen more than 20 mmHg above the control level. Simultaneously. blood samples were obtained every 10 min for the first 40 min and then at intervals of 20 min just before each subsequent stepwise increase in the rate of A-I1 infusion. Plasma aldosterone, potassium, sodium, cortisol and renin activity were measured in all samples. PAC was measured by a radioimmunoassay (a), PRA according to the method of Harber et al. (22), plasma cortisol by competitive protein binding technique (67). potassium and sodium by flame photometry, and BP by a standard sphygmanometer (Tycof). Statistical significance was determined by means of Wilcoxon's test for paired data. The reactivity to ACTH stimulation was examined in 5 of the 8 anephric and in all 4 non-nephrectomized patients with a technique previously described (68). They received synthetic ACTH (Synacthen@)in three subsequent single doses of 125.0, 62.5, 62.5 ~g and the plasma concentrations of aldosterone, cortisol, sodium and potassium as well as the PRA were measured every 20 min. The aldosterone antibody was obtained from the National Institute of Arthritis and Metabolic Diseases, Bethesda, Maryland; USA.

Due to an increase of more than 20 mmHg in diastolic BP, the A-I1 infusion was terminated in one patient at an infusion rate of 6.0 ngfkg min-' (after 80 min) and in 2 patients at an infusion rate of 10 ng/kg min - I (after 120 min), while the remaining

Diastolic

BP WUI

Hg

70

-1

1000800

20 Rcnin activity n g l m l h"

-0

-

600Aldorteronr pglml

-

LOO200-

RESULTS

0

10

Anpiotmrin Il-dose

Anephric patients during angiotensin II 0 ngllcg min-' 0 0 LO 80 I20 man infusion The mean basal resting BP was 139/82 mmHg Fig. 3. Plasma aldosterone concentration, renin activity, (range 120/65-165/100) (Table I). During the A-I1 diastolic and systolic BP in 4 noa-nephrectomized uremic patients during an angiotensin I1 stimulation infusion the mean diastolic BP increased gradually (meanfS.E.M.). The asterisks indicate that the infusion (Fig. I ) to a maximum value of 98 mmHg @