Plasma levels and hepatic extraction of renin and aldosterone in alcoholic liver disease

Plasma Levels and Hepatic Extraction of Renin and Aldosterone in Alcoholic Liver Disease

WILLIAM E. MITCH, M.D.* PAUL K. WHELTON, M.D. C. ROBERT COOKE, M.D. W. GORDON WALKER, M.D. WILLIS C. MADDREY, M.D. Baltimore, Maryland

From the Departments of Medicine and Pharmacology and Experimental Therapeutics, The johns Hopkins University School of Medicine, and The johns Hopkins Hospital, Baltimore, Maryland. This work was supported in part by Research Grants AM 05655, HL 03303 and HL 15349, and Clinical Research Center Grant RR 35 from the National Institutes of Health. Requests for reprints should be addressed to Dr. William E. Mitch, Department of Pharmacology, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205. Manuscript accepted December 4, 3976. * Recipient of a Clinical Investigator Award (AM 00214) from the National Institutes of Health.

804

May 1979

Arterial plasma levels and hepatic extraction of renin and aldosterone (ALDO) were measured in 24 patients with alcoholic liver disease and in 14 normal subjects being evaluated as prospective kidney donors. Patients with liver disease had higher plasma concentrations and lower fractional hepatic extractions of both renin and ALDO than the normal subjects. The quantity of renin extracted by the liver was highly correlated with plasma renin in both normal subjects and patients. Plasma ALDO concentration was positively correlated with plasma renin (p
prednisolone or placebo administration on plasma levels and hepatic

The American Journal of Medicine

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RENIN

TABLE I

AND ALDOSTERONE

IN ALCOHOLIC

LIVER DISEASE-MITCH

ET AL.

Arterial Plasma Levels and Hepatic Extraction of Renln Activity and Aldosterone in Normal SubJects

case No.

Age (yr) and Sex

1 2 3 4 5 6 7 8 9 10 11 12 13 14

38.M 52.F 44,M 45,F 48,F 50,M 23,M 52,M 22,M 40.M 61,F 55,M 64,M 41,F

Mean f SEM

PlasmaRenb~Aclirily (ng/ml/hr) Extraction A-HV (%)

A 0.30 0.10 0.39 0 0.15 0.42 1.31 0.76 0.31 0.10 0 0.27 0.17

0.10 0 0.19 0 0.13 0.20 0.76 0.43 0.23 0.06 0 0.14 0.01

0.33 fO.10

PlasmaAkbsterone(@I) A-HV

EdUSllOIl (%)

6.6 4.1

2.6 3.5

39 85

A

33 0 49 0 87 48 58 56 74 75 0 52 6

2.8 7.8

2.8 1.7

100 22

3.3 6.3 7.3 5.9 13.9 13.6 13.5 12.4

2.5 2.2 4.1 5.1 10.1 6.2 9.5 8.8

76 54 56 88 73 45 70 71

41.4 68.6

8.1 f1.2

84.8 f6.4

NOTE: A = arterial; HV = hepatic vein.

extraction of renin and ALDO in 16 patients with alcoholic liver disease. METHODS This study was approved by The Johns Hopkins University School of Medicine Joint Committee on Clinical Investigation. The patients studied were divided into three groups: Group 1 included 14 normal subjects who were being evaluated as potential kidney donors. They were eating an unrestricted salt diet, were not receiving diuretics and had no evidence of liver, renal or hypertensive diseases. Arterial and hepatic venous blood samples were obtained simultaneously for measurement of plasma PRA and ALDO concentration prior to renal angiography. Group 2 included 24 hospitalized patients with alcoholic liver disease. A liver biopsy confirming alcoholic liver disease was performed on all patients who had satisfactory clotting ability [16]. The patients were not salt-restricted or receiving diuretics or other drugs known to affect the activity of the renin-angiotensin-aldosterone system. Hepatic extraction studies were performed within one week of hospitalization. Group 3 was comprised of 16 patients from group 2 who were studied a second time after one month of hospitalization. These patients were not receiving diuretics and were given a 1,600 mg/day sodium diet. Six received 40 mg/day of prednisolone orally in a controlled, double blind study to determine the effects of steroids on liver disease [16]. The remaining 10 patients received a placebo. After overnight recumbency, arterial and hepatic venous blood samples were withdrawn simultaneously into chilled plastic syringes containing either EDTA or heparin. Samples were centrifuged in plastic tubes at 4%, and the plasma was stored at -20” C until PRA and ALDO concentrations were determined. PRA was determined without adding excess substrate by a modification of the radioimmunoassay described by Haber et al. [17]. As reported, the sensitivity of this assay is 0.1 ng/ ml/hour angiotensin I generated [la]. Plasma ALDO concentration was measured by a radioimmunoassay

1191.Hepatic

extraction was calculated as A - HV/A X 100 (A = arterial plasma level; HV = hepatic venous plasma level]. Inferior vena cava pressure and hepatic venous wedge pressure were measured as previously described [20]. The difference between these values is the corrected hepatic venous wedge pressure, which reflects the severity of liver disease and portal venous pressure [21]. The hepatic storage capacity and transport maximum of sulfobromophthalein were measured by the infusion technic of Wheeler et al. 122,231.Plasma volume was measured as the distribution volume of injected technetium-labelled albumin (241. Serum electrolyte and albumin concentrations were measured by an autoanalyzer.

RESULTS Arterial levels and hepatic extraction of renin and ALDO in 14 normal subjects are shown in Table I. There was a significant correlation (r = 0.94, p
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805

TABLE II

Clinical Data, lntrahepatic Pressures and Liver Function Tests of Patients with Alcoholic Liver Disease Hepalic

Case No. 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

Age(vr) and Sex

CHVWP (mm ffg)

IVCP (mm Hg)

49,F 40,F 38,F 56.M 29,M 45,M 48,M 33,M 36,M 45,M 62,M 35,M 38,M 60,F 42,M 44,M 43.F 35.M 30,M 57,M 47,M 42,M 44,M 47,M

13 12 13 11 18 13 14 14 6 10 10 8 13 8 14 5 10 7 10 14 14 8 10

Mean f SEM Normal

7 11 13 12 16 7 24 11 12 15 12 16 23 19 23 15 15 23 11 16 17 15 18

11.1 f0.7 <5

56.8 62.6 39.3 34.0 81.7 47.5 34.0 64.7 66.8 58.7 53.9 61.6 44.0 67.6 58.3 55.9 87.4 61.9 54.8 63.0 71.4 42.3

15.3 Al.0 <5

NOTE: IVCP = inferior vena cava pressure; AH-C = alcoholic hepatitis-cirrhosis [ 161.

TABLE iii

(rzg)

Liver Biopsy ND ND AH-C AH-C ND AH-C ND AH-C ND AH-C ND AH-C AH-C AH-C AH-C AH-C ND AH-C ND AH-C ND AH-C ND AH-C

Ascites

Encephalopathy 0 0 t

+ 0 0 + + 0 + + 0 0 + 0 + + t 0 0

0 t 0 + 0 0 t 0 0 t 0 0 t 0

0 t

0 t

0

57.6 f2.9 42 f 5

CHVWP

= corrected

Transport (mglmin)

76.3 10.7 25.2 19.1 9.5 18.1

3.3 2.7 1.3 5.1 2.9 6.0

4.4 21.9 57.3 53.6 20.3 54.0 6.8 52.9 4.8 9.8 47.5 17.1 3.3 0.6

3.4 2.7 11.2 2.2 3.2 2.8 2.8 2.6 3.8 4.8 1.2 2.2 3.0 2.8

9.0

2.8

24.9 f4.9 61.9 f 4.3 hepatic

venous

wedge

pressure;

PV = plasma

volume;

3.3 f0.5 5.6 f 1.6

ND = not done;

Serum Albumin and Electrolytes, Arterial Plasma Levels and Hepatic Extraction of Renin Activity and Aidosterone in Patients with Alcoholic Liver Disease

Potassium _ (meqllller)

Plasma Renin Activity (nglmllhr) Extraction (%) A-HV

Case No.

Albumin (gldl)

Sodium (msqlliter)

15 16 17 18 19 20 21 22

1.7 1.7 2.5 3.0 1.4 3.3 2.7 1.9

3.8 0.8 10.4 5.0 2.7 1.5 0.5 4.0 18.9 0.1

32 0 29 0 52 66

1.3 1.7

4.4 3.8 4.1 4.1 3.7 5.0 3.1 3.4 4.6 4.3

1.2 0 3.0 0 1.4 1.0

23 24

133 132 125 127 143 138 136 131 128 133

;:2 5.30

‘3d 280

25 26 27 28 29 30 31 32 33 34 35 36 37 38

2.3 2.3 2.0 2.3 3.0 2.6 2.2 2.1 2.6

137 142 126 132 139 143 132 129 135

3.7 3.9 3.5 3.7 4.3 3.6 2.9 4.3 3.3

2.8

0

0

Li

.. 134

... .

2:5 1.9

;32 132

3:4 3.7

17:4 0.7 1.5 0.4 0.3 4.1 1.8 0.4 4.8 2.7 4.7 7.3

6:; 0 0.3 0 0 0 0 0 0.6 0.6 0.5 2.6

‘39 0 20 0 0 0 0 0 13 22 11 36

2.2

133.5

Mean f SEM Normal

Jaundice

t t t t t t t t t t t t t t t t t t t t t t t t

0 t + t

0 + + + t

Sulfobromophthaleln Storage (mglmgldl)

fO.l 3.5-5.5

NOTE: A = arterial:

A-HV

l 1.1 136-145 = arterial

hepatic

3.8 fO.l 3.5-5.0 venous

difference.

A

4.2 fl.1

17.2 f4.2

Plasma Aldosterone (ngldt)

Exlraclion

A

A-HV

(%)

24.6 6.4 35.8 16.6 9.7 10.2 3.5 11.3 b:;

7.5 5.4 0.8 12.3 1.3 8.2 3.0 3.8

31 84 0.3 74 13 80 86 34

7.8 4.6

6.8 1.7

87 37

5:; 24.5 12.0 5.5 21.3 12.1 5.2 25.4 22.5 15.0 10.9

‘d 9.5 8.7 3.8 4.8 4.8 0 8.6 14.1 0 2.2

0 39 73 69 23 40 0 34 63 0 20

. ‘d

b.

..

13.2 il.9

40.3 f6.7

RENIN AND ALDOSTERONE IN ALCOHOLIC LIVER DISEASE-MITCH

differ between those patients who had ascites and those who did not. In 13 patients with reproducible urine collections, creatinine clearance averaged 65.8 f 6.3 ml/min (SEM), and was not correlated with the serum albumin concentration, corrected hepatic venous wedge pressure, inferior vena cava pressure, sulfobromophthalein measurements, PRA or ALDO concentration. Arterial renin activity was increased in patients with liver disease compared to that in normal subjects (Tables I and III: Figure 1). Arterial plasma ALDO concentration was also increased (Tables I and III: Figure 1). The urinary sodium to creatinine ratio of 20 patients with liver disease (0.053 f 0.010meq/mg, SEM) was not significantly lower than that of normal subjects (0.079 f 0.008) suggesting that the differences in PRA and ALDO were not related to salt intake. There was a significantly lower value for hepatic venous renin activity compared to arterial renin activity (p 3 ng/mVhour were excluded from calculation of hepatic extraction in the group with liver disease, there was no significant extraction. Thus, in the presence of a low arterial renin activity, we were able to measure hepatic extraction in normal subjects but not in patients with liver disease. There was a highly significant correlation between PRA and ALDO concentrations (r = 0.70, p 15 mm Hg was considered separately. In addition, there was no correlation between hepatic extraction of either renin or ALDO and sulfobromophthalein storage or transport maximum. There was, however, a highly significant correlation between PRA and the difference between arterial and hepatic venous renin activity (r = 0.94, p
ET AL.

6

Figure 1. Arterial plasma levels of renin activity (PRA) and aldosterone in normal subjects and in patients with alcoholic liver disease. Both renin activity (p
.

2 P

I

I

I c

l I

2

4 Arterial

6

,

8

10

12

Pf?A, r&d/hf

Figure 2. Relationship between arterial plasma renin activity (PRA) and aldosterone concentration in patients with alcoholic liver disease (Y = 2.4x + 6.7. r = 0.70. o
L_

Figure 3. Hepatic extraction of renin and aldosterone in normal subjects and in patients with alcohoilc CiverdiSa8e. Hepatic extraction was lower for both rehin (p X0.02) and aldosterone (p <0.02) in patients with liver disease.

May 1976

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RENIN AND ALDOSTERONE IN ALCOHOLIC LIVER DISEASE-MITCH

7

ET AL.

placebo therapy nor was there a change in the urinary sodium to creatinine ratio (0.052 f 0.010, prednisolone; 0.060 f 0.018, placebo). Hepatic extraction of ALDO and renin were also unchanged. COMMENTS

0

10

5 Arler,aI

“RI,

15

These data demonstrate that patients with alcoholic liver disease have high plasma concentrations and low hepatic extractions of renin and ALDO when compared to normal subjects. Plasma ALDO concentration was highly correlated with PRA, suggesting that the increase in plasma ALDO may be related to the increase in plasma renin. Renin extraction by both the normal and abnormal liver was highly correlated with PRA, suggesting that hepatic capacity to extract renin in the patients with liver disease was not exceeded but may be limited by altered hepatic blood flow. Arterial renin activity in the patients with liver disease that we studied (Table III) was similar to that reported by Ayers [3] and Rosoff et al. [7], but lower than the arterial renin activity of salt-restricted cirrhotic patients [8]. The values in Tables I and III for hepatic renin extraction in man are similar to those given in previous reports [6,25]. Arterial ALDO concentrations in our patients (Table III) were similar to those reported by Saruta et al. [ll]. The average hepatic extraction of ALDO in the 14 control subjects was lower than the 97 to 98 per cent value found in three subjects by Vecsei et al. [4]. However, the

20

“~/ml/h

Figure 4. Relationship between arterial plasma renin activity (PRA) and the decrease in renin activity from artery to hepatic vein in patients with alcoholic liver disease (y = 0.33x - 0.34, r = 0.94, p
albumin concentration was significantly increased by prednisolone therapy (A = +l.l f 0.3 g/dl). There was no correlation between the changes in these two parameters. Plasma levels of ALDO and renin activity were not significantly changed by one month of prednisolone or

TABLE IV

Effects of Corticosteroid Therapy in Patients with Alcoholic Liver Disease Plasma ReninActivity

PlasmaAldosterone Hepatic Serum Albumin CHVWP IVCP Arterial Arterial Extraction (nglmllhr) (gldl) (mmHg) (mmHg) (%) (ngldl) (%) CaseNo. Treatment Conhol Change ControlChange ControlChange ControlChange ControlChange ControlChange ControlChange Hepatic Extraction

15 16 17 18 19 20

cs cs cs cs cs cs

1.7 1.7 2.5 3.0 1.4 3.3

Mean f SEM 21 22 23 24 25 26 27 28 29 30

PL PL PL PL PL PL PL PL PL PL Mean f SEM

+I.1 +2.1 +1.6 +l.O -0.3 +l.O

7 11 13 12 16 7

+1.1 f0.3 1.9 1.3 1.7 2.3 2.3 2.0 2.3 3.0 2.6

tl.8 -0.4 t1.7 -0.4 to.8 t1.6 to.5 to.2 to.6 to.7 l 0.3

+9 +2 -2 -6 +2 +7 t2.0 f2.3

24 11 12 15 12 16 23 19 23 15

-10 -2 +5 -6 +3 -7 -4 0 t8 t3

May 1979

-6 -5 -6 0 -5 -6

3.6 0.8 10.4 5.0 2.7 1.5

-4.7 fl.O 14 14 6 10 10 8 13 8 14 5

-1.0 fl.8

NOTE: CS = corticosteroid; PL = placebo;CHVWP

808

13 12 13 11 18 13

-5 -8 +4 -7 0 +1 0 +3 -4 -2

’ -3.4 +9.4 +1.3 -2.2 -1.4 -1.0

32 0 29 0 52 66

0.5 4.0 18.9

+0.6 -3.9 -7.8

30 28

2.8

-2.4

0

17.4 0.7 1.5 0.4

-14.5 to.5 -1.0 to.4

39 0 20 0

-3.5 fl.9

24.6 6.4 35.8 16.6 9.7 10.2

-7.8 f13.7

to.5 fl.9

-1.8 fl.3

-32 +39 -17 +21 -52 -6

-30 t44 0 -18 t42 t40 t50 +18.3 f12.6

-19.8 +8.4 -25.1 -9.8 -2.3 -1.1

31 84 1 74 13 80

-8.2 f5.1

-31 +1 +92 -6 +49 -10 +15.8 f18.7

3.5 11.3 0.5 7.8 4.6

-2.9 -9.2 +1.4 -1.2 -1.1

86 34 0 67 37

-8.6 -5 +5 t10 -34

5.7 24.5 12.0

t1.3 t7.4 -6.5

0 39 73

0 -8 -73

-1.4 fl.8

-14.2 f9.6

= correctedhepaticvenous wedge pressure; IVCP = inferior vena cava pressure.

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RENIN AND ALDOSTERONE IN ALCOHOLIC LIVER DISEASE-MITCH

per cent average extraction of ALDO of the 24 patients with liver disease was similar to the 38 per cent and 52 per cent extraction in two cirrhotic patients described by Vecsei et al. [4]. PRA was increased 13.5-fold. In contrast, hepatic renin extraction was decreased by only 2.4-fold. This discrepancy suggests that altered hepatic renin extraction is not the primary determinant of PRA in patients with liver disease. Since the liver is the major site of renin extraction [l2-141, these observations suggest that the major cause of high PRA and hence plasma ALDO levels is increased renin secretion. The pathophysiology of increased renin secretion in liver disease remains controversial [1,9]. Mechanisms suggested include renal hypoperfusion due to decreased splanchnic blood volume [9,10,26], hepatic release of a renal vasoconstrictor [27] and stimulation of renal nerves [28]. Renal hypoperfusion due to volume depletion alone seems unlikely, since we [Table II] and others [29,30] have found an increase in plasma volume in patients with liver disease. Renal hypoperfusion caused by inadequate delivery of blood to the kidney despite an increase in total plasma volume has been suggested by Epstein et al. [9,10].They found that immersing patients with liver disease in water and producing a redistribution of blood flow was associated with lower PRA and ALDO concentrations. They concluded that in these patients, splanchnic blood flow was insufficient causing renal hypoperfusion, secondary renin release and subsequent sodium retention. Renal hypoperfusion once initiated is apparently not maintained by the high plasma level of renin since suppression of renal renin release with betaadrenergic blocking drugs did not alter renal perfusion or intrarenal vasoconstriction in another study [15]. The stimulus for excessive aldosterone secretion in liver disease has not been clearly defined [i’,l0,11,15]. In the present study, plasma ALDO concentration was highly correlated with PRA rather than with other stimuli of ALDO secretion. Epstein et al. [9,10] also found that PRA and ALDO were correlated, and Schroeder et al. [6] have reported that infusion of saralasin lowered plasma ALDO concentration in four of five cirrhotic patients. 40

ET AL.

In contrast, Saruta et al. [ll] found that PRA was not correlated with plasma ALDO concentration in cirrhotic patients and that infusion of the angiotensin II antagonist, 1-sarcosine-8-ile angiotensin II, lowered plasma ALDO in only three of eight patients. In the same study, however, these investigators found that plasma ALDO and angiotensin II concentrations were correlated, suggesting that ALDO secretion was mediated by the renin-angiotensin system. It has also been reported that beta-adrenergic blocking agents increased urinary ALDO excretion in five of 11 cirrhotic patients despite a lowering of plasma renin [15]. Perhaps hemodynamic changes associated with beta-adrenergic blockade induced ALDO secretion since the increased ALDO excretion of these five patients could not be explained by changes in serum sodium or potassium concentrations. An alternative explanation could be that renal ALDO extraction increased by some unknown mechanism during blockade of the beta-adrenergic system. The increase in serum albumin concentration and lower inferior vena cava pressure in this small group of prednisolone-treated patients was not accompanied by lower plasma volume or a change in plasma levels or hepatic extraction of renin activity and ALDO. In a larger group of patients receiving the same regimen, Maddrey et al. [16] found that prednisolone was associated with a significant decrease in plasma volume, which suggests that diuresis occurred. From the present data, it seems unlikely that the proposed diuresis was initiated by prednisolone-induced lowering of plasma renin and ALDO. In conclusion, these findings are consistent with the speculation [9,10] that patients with alcoholic liver disease have a lower effective circulating plasma volume resulting in hypersecretion of renin and subsequent ALDO secretion. Impaired hepatic extraction also contributes to elevated plasma level, but appears to be less important in determining plasma renin and ALDO in alcoholic liver disease. ACKNOWLEDGMENT Judith Herman provided expert technical assistance.

REFERENCES 1.

Epstein M: Renal sodium handling in cirrhosis, chap. 4. The Kidney In Liver Disease (Epstein M, ed), New York, Elsevier Publishing Co., 1978. 2. Coppage WS Jr, Island DP, Cooner AE, et al.: The metabolism of aldosterone in normal subjects and in patients with hepatic cirrhosis. J Clin Invest 41: 1672. 1962. 3. Ayers CR: Plasma rerun activity and renin-substrate concentration in patients with liver disease. Circ Res 20: 594, 1967.

4. 5.

Vecsei, P. Dtisterdieck G, Jahnecke J, et al.: Secretion and turnover of aldosterone in various pathological states. Clin Sci 36:241, 1969. Schroeder ET, Rich RH, Smulyan H, et al.: Plasma renin

May 1979

levels in hepatic cirrhosis: relation to functional renal failure. Am J Med 49: 186,197o. 6. Wernze H, Seki A, Schneider KW. et al.: Hepatische Extraktion und Clearance von Renin bei Lebercirrhosen. Klin Wochenschr 50: 302.1972. 7. Rosoff L, Zia P, Reynolds T. et al.: Studies of renin and aldosterone in cirrhotic patients with ascites. Gastroenterology 69: 698, 1975.

6.

9.

Schroeder ET, Anderson GH, Goldman SH. et al.: Effect of blockade of angiotensin II on blood pressure, renin and aldosterone in cirrhosis. Kidney Int 9: 511, 1976. Epstein M, Levinson R, Sancho J, et al.: Characterization of the renin-aldosterone system in decompensated cirrhosis.

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Circ Res 41: 818,1977. 10. Epstein M, Sancho J, Haber E: Renin-aldosterone responsiveness in decompensated cirrhosis, chap. 16. The Kidney in Liver Disease [Epstein M. ed), New York, Elsevier Publishing Co., 1978. 11. Saruta T, Saito I, Nakamura R, et al.: Regulation of aldosterone in cirrhosis of the liver, chap. 19. The Kidney in Liver Disease (Epstein M, ed), New York, Elsevier Publishing Co., 1978. 12. Heacox R, Harvey AM, Vander J: Hepatic inactivation of renin. Circ Res 21:149,1967. 13. Schneider EG, Davis JO, Baumber JS, et al.: The hepatic metabolism of renin and aldosterone. A review with new observations on the heoatic clearance of renin. Circ Res I (suppl): I, 1970. 14. Taoia HR. Kuster GGR. Shorter RG. et al.: Extraction and excretion of renin by the isolated canine liver. Am J Physiol 222: 1236,1972. 15. Wilkinson SP, Bernardi M, Smith IK, et al.: Effect of beta adrenetgic blocking drugs on the renin-aldosterone system, sodium excretion, and renal hemodynamics in cirrhosis with ascites. Gastroenterology 73: 659.1977. 16. Maddrey WC, Boitnott JK, Bedine MS, et al.: Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 75: 193, 1978. 17. Haber E, Koerner T, Page LB, et al.: Application of a radioimmunoassay for AI to the physiologic management of plasma renin activity in normal subjects. J Clin Endocrinol Metab 29: 1349, 1969. 18. Walker WG, Horvath JS, Moore MA, et al.: Relation between plasma renin activity, angiotensin, and aldosterone and blood pressure in mild untreated hypertension. Circ Res __ 38: 476,1976. 19. Cooke CR, Horvath JS, Moore MA, et al.: Modulation of plasma aldosterone concentration by plasma potassium in anephric man in the absence of a change in potassium balance. J C1in Invest 52: 3028,1973.

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20. Miller FJ, Maddrey WC, Sheff RN, et al.: Hepatic venography and hemodvnamics in oatients with alcoholic hepatitis. Radiology l”l5: 313,197< 21. Reynolds TB, Ito S, Iwatsuki S: Measurement of portal pressure and its clinical application. Am J Med 49: 649, 1970.

22. Wheeler HO, Meltzer JI, Bradley SE: Biliary transport and hepatic storage of sulfobromophthalein sodium in the unanesthetized dog, in normal man, and in patients with hepatic disease. J Clin Invest 39: 1131,196O. 23. Maddrey WC, et al.: Hepatic storage and maxima1 biliary transport of sulfobromophthalein in patients with portal hypertension. Johns Hopkins Med J 124: 157,1969. 24. Maddrey WC, Thomas J, Basu AK, et al.: Plasma volume expansion in portal hypertension. Johns Hopkins Med J 125: 171,1969. 25. Christensen AR, Couch NP, Amsterdam EA. et al.: Renin extraction bv the human liver. Proc Sot Exp Biol Med 128: 821,1968. 26. Epstein M, Pins DS, Schneider N, et al.: Determinants of deranged sodium and water homeostasis in decompensated cirrhosis. J. Lab Clin Med 87: 822, 1976. 27. Levy M: Renal function in dogs with acute selective hepatic venous outflow block. Am J Physio1227: 1074,1974. 28. Anderson RJ, Cronin RE, McDonald EM, et al.: Mechanisms of portal hypertension-induced alterations in renal hemodynamics, renal water excretion, and renin secretion. J Clin Invest 58: 964,1976. 29. Lieberman FL, Ito S. Reynolds TB: Effective plasma volume in cirrhosis with ascites. Evidence that a decreased value does not account for renal sodium retention, a spontaneous reduction in glomerular filtration rate (GFR) and a fall in GFR during drug-induced diuresis. J Clin Invest 48: 975, 1969. 30. Tristani FE, Cohn J: Systemic and renal hemodynamics in oliguric hepatic failure: effect of volume expansion. J Clin Invest 46: 1894,1967.

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