Measurement of renal arterial blood flow velocity by Doppler ultrasonography in chronic liver disease

Hepatology Research 15 (1999) 201 – 214 www.elsevier.com/locate/ihepcom

Measurement of renal arterial blood flow velocity by Doppler ultrasonography in chronic liver disease Yuichi Kumano a,*, Makoto Ishii a, Hitoshi Nishida a, Masashi Sakamoto a, Katsumi Sasaki a, Akihiro Kawauchi b, Keiji Mitamura a a

Second Department of Internal Medicine, Showa Uni6ersity School of Medicine, 1 -5 -8 Hatanodai, Shinagwa-ku, Tokyo 142 -8666, Japan b Second Department of Surgery, Showa Uni6ersity School of Medicine 1 -5 -8 Hatanodai, Shinagawa-ku, Tokyo 142 -8666, Japan

Received 20 January 1999; received in revised form 16 February 1999; accepted 18 February 1999

Abstract Doppler ultrasonography was used to measure hepatic hemodynamics in patients with chronic liver disease. We investigated the relationships among the velocity of renal arterial blood flow by Doppler ultrasonography, neurohormonal parameters and human atrial natriuretic peptide (hANP) in chronic liver disease. These parameters were measured in 45 patients with chronic liver disease (15 patients with chronic hepatitis and 30 patients with liver cirrhosis) and 16 healthy subjects. Patients with liver cirrhosis were classified into nine patients with ascites responsive to the conventional treatment, one with refractory ascites and 20 without ascites. Renal arterial velocity was obtained from measurements in the main renal artery (RA) in the cortex. The resistive index (RI) ( =(peak systolic velocity − minimum diastolic velocity)/peak systolic velocity) in different areas of the kidney was significantly higher in patients with liver cirrhosis than in patients with chronic hepatitis and healthy subjects. Among cirrhotic patients, RI was higher in patients with ascites than in those without ascites. The RI decreased from the hilum of the kidney to the outer parenchyma in both patients with chronic liver disease and healthy subjects. Neurohormonal parameters tended to be higher but this difference was not significant in patients with liver cirrhosis, especially in those with ascites. Serum hANP levels were positively correlated with main

* Corresponding author. Tel.: +81-3-3784-8535; fax: +81-3-3784-7553. 1386-6346/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S1386-6346(98)00027-3

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renal arterial RI (r=0.728, PB 0.5), segmental arterial RI (r= 0.729, PB0.05), interlobar arterial RI (r=0.919, P=0.001) and interlobular aterial RI (r= 0.720, PB0.05) in cirrhotic patients with ascites but no correlation was found with the RI of the peripheral artery in the cortex. On the other hand, in patients without ascites, serum hANP was positively correlated with renal arterial RI, even with the RI of the cortical artery. In addition to measurement of hANP, measurement of renal arterial RI from the hilum to the cortical artery of the kidney by Doppler ultrasonography is beneficial for differentiating stage between with and without ascites in liver cirrhosis and for evaluating changes in systemic and renal hemodynamics. Neurohormonal parameters and hANP were related to the presence or absence of liver cirrhosis. The serum level of hANP is useful for estimating hyperdynamic circulation in liver cirrhosis. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Chronic liver disease; Doppler ultrasonography; Renal arterial resistive index; Human atrial natriuretic peptide

1. Introduction In liver cirrhosis, especially in the decompensated state, changes in systemic hemodynamics, which are characterized by peripheral arterial vasodilation [1], a decrease in systemic vascular resistance [2] and an increase in cardiac output [3], are well known. These changes have suggested activation of the sympathetic nervous [4,5] and renin – angiotensin – aldosterone systems [6]. In the kidney, a decrease in effective renal blood flow and the glomerular filtration rate (GFR) is caused by a decrease in cortical blood flow. Consequently, sodium and water retention increases according to the progression of liver cirrhosis [7]. Changes in renal hemodynamics in patients with liver cirrhosis and hepatorenal syndrome have been evaluated previously by angiography [8] and scintigraphy [9]. Angiography disclosed marked beading and tortuosity of the interlobular artery (ILLA) and proximal arcuate arteries, and the absence of distinct cortical nephrogram and vascular filling of the cortical vessels [8]. These findings indicated that the changes in renal hemodynamics in liver cirrhosis were linked to renal dysfunction. On the other hand, Doppler ultrasonography has been used to measure not only portal and hepatic arterial blood flow in patients with liver cirrhosis, but also effective renal blood flow in patients with renal diseases. It has been reported that changes in renal arterial blood flow velocity by Doppler ultrasonography are related to renal function in patients with chronic renal disease [10,11], acute tubular necrosis and kidney transplantation [12]. Recently, several studies have reported changes in renal arterial blood flow velocity in patients with liver cirrhosis by Doppler ultrasonography [13,14]. These studies investigated renal arterial blood flow using the RI ( =(peak systolic velocity − minimum diastolic velocity)/peak systolic velocity) as a parameter of vascular resistance [13], renal functions and neurohormonal factors. hANP, discovered in 1981, is thought to play an important role in liver cirrhosis. Epstein hypothesized that the serum level of hANP reflects hemodynamics as well as underfilling or overflow in liver cirrhosis [15]. The relationship between renal

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arterial blood flow estimated by Doppler ultrasonography and hANP is not well documented. The aim of this study was to investigate the correlations among renal arterial blood flow velocity measured by Doppler ultrasonography, the serum level of hANP, systemic hemodynamics, biochemical and neurohormonal parameters, liver function and glomerular filtration rate (GFR) in various stages of chronic liver disease.

2. Subjects and methods

2.1. Subjects Forty-five patients with chronic liver disease (28 men and 17 women, mean age 60.4 911.6 years, 15 patients with chronic hepatitis and 30 patients with liver cirrhosis) and 16 healthy subjects were examined (Table 1). Patients with liver cirrhosis were significantly older than patients with chronic hepatitis, but the male:female ratio was not significantly different among the three groups (healthy subjects, patients with chronic hepatitis and liver cirrhosis). All of the patients with chronic hepatitis were diagnosed histologically and liver cirrhosis was diagnosed histologically or clinically by means of biochemical and morphological examinations. Patients with liver cirrhosis were classified as A, B or C according to Child – Pugh’s classification and the presence of ascites. Nine patients were classified as A, 9 as B and 12 as C. A total of 20 patients did not have ascites and 10 had ascites. The etiology of chronic hepatitis was hepatitis C virus (HCV) infection in 12 patients, hepatitis B virus (HBV) infection in one and autoimmune hepatitis in two. The etiology of liver cirrhosis was HCV infection in ten patients, HBV infection in two, alcohol intake in 11, HCV infection and alcohol intake in one, HBV infection and alcohol intake in one, HBV and HCV infection in one, primary biliary cirrhosis in two and cryptogenic cirrhosis in two. The sex and age of the patients did not significantly differ according to Child–Pugh’s classification or the presence or absence of ascites. Patients with hypertension, renal or cardiac disease, or diabetes mellitus were excluded. Five cirrhotic patients with well-controlled hepatocellular carcinoma were included. Informed consent was obtained from each subject. The study protocol conformed to the 1975 Declaration of Helsinki and was approved by the ethics committee of Showa University School of Medicine.

3. Methods Doppler measurements were performed by two observers (Y.K. and M.I.) using a 3.75-MHz transducer (Sonolayer SSA-380A, Toshiba, Tokyo, Japan) after the patient had fasted for 6 h. Doppler signals were obtained three times by each

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Healthy subjects (N)

Chronic hepatitis (CH)

Liver cirrhosis (LC)

No. patients Sex (M/F) Age (years)

16 8/8 59.2 910.5

15 9/6 54.7 9 9.4*

30 19/11 63.39 11.6*

Patients with liver cirrhosisa Child–Pugh’s classification

A

B

C

Ascites (−)

Ascites (+)

9

9

12

6/3 59.4 912.5

8/4 65.39 13.1

20 12/8 61.59 10.7

10

5/4 64.6 98.6

No. patients Sex (M/F) Age (years) a

Patients with liver cirrhosis were classified to A, B and C according to Child–Pugh’s classification and presence of ascites. * PB0.05.

7/3 67.09 13.1

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Table 1 Subjects

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observer from the main RA, segmental artery (SA), interlobar artery (ILA), ILLA and peripheral artery in the cortex of the right kidney (Fig. 1), and the spectrum of blood flow was recorded. Peak systolic (Vmax) and minimum diastolic flow (Vmin) velocities were determined, and the RI was calculated as RI= (Vmax − Vmin)/Vmax, according to Sacerdoti et al. [13]. In the interlobular artery and peripheral artery in the cortex, the means of three measurements at different points were evaluated. After measuring renal arterial blood flow velocity at supine rest for 10 min, arterial pressure was recorded, and mean arterial pressure (MAP) was calculated as diastolic pressure plus one third of the pulse pressure. After the patients had fasted overnight, blood samples were taken to measure standard liver function, plasma renin activity (PRA), plasma concentrations of aldosterone, hANP, epinephrine, norepinephrine and dopamine. Diuretics and vasoactive drugs were discontinued only on the day of the examination. hANP was found in nine patients with ascites, but was not measured in one patient.

4. Statistics Results are expressed as means 9 S.D. Mann–Whitney’s test and Scheffe’s test were used to evaluate differences among the three groups. P values of less than 0.05 were considered statistically significant.

5. Results The average renal arterial blood flow velocity measured by the two observers at all of the three measurements at each point was used for the analysis. The

Fig. 1. Schematic representation of sampling locations in the kidney and definition of the RI.

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Table 2 Biochemical, neurohormonal, systemic hemodynamic parameters and renal function

MAP (mmHg) HR (beats/min) Ht (%) GFR (ml/min) Fischer’s ratio PRA (ng/ml per h) Aldosterone (ng/dl) Epinephrine (ng/ml) Norepinephrine (ng/ml) Dopamine (ng/ml) hANP (pg/ml)

N

CH

LC

Ascites (−)

Ascites (+)

929 7 69 9 7 40.19 3.5 117.6927.2 nte 2.63 92.8

92 910 68 96 43.69 4.3 111.09 24.5 nt 1.999 2.9

91 99 77 9 11*,c 34.4 96.2**,a,***,b 82.7 937.4**,c 1.66 9 0.64 7.48 910.8

93 9 8 73 9 7 36.4 9 4.6 94.7 9 29.7 1.85 90.68 3.57 95.2

89 9 11 83 9 15 30.4 97.2*,d 59.7 941.0*,d 1.31 9 0.37 12.01 9 13.7d

11.09 6.1

9.99 4.1

16.8 9 32.2

10.8 98.8

28.1 953.4

0.0259 0.022

0.0209 0.009

0.046 9 0.037

0.042 9 0.040

0.053 9 0.031

0.289 0.13

0.259 0.14

0.44 9 0.46

0.34 9 0.25

0.62 9 0.68

0.03490.036

0.04090.060

0.040 9 0.035

0.026 9 0.009

0.067 90.018

16.8 9 6.9

19.19 12.5

29.8 920.7*,a

23.7 9 18.4

39.8 921.4*,d

a

N versus LC. CH versus LC. c N and CH versus LC. d Ascites (−) versus ascites (+). e Not tested. * PB0.05. ** PB0.01. *** PB0.001. b

difference among the three measurements was less than 10%. The difference between the measurements by the two observers was also less than 10%. After renal arterial blood flow and the other parameters were measured, nine of ten cirrhotic patients with ascites responded to treatment, and the patient who did not respond was considered to have refractory ascites.

5.1. Renal arterial blood flow 6elocity in chronic li6er disease Table 2 shows biochemical, neurohormonal, and systemic hemodynamic parameters {MAP and heart rate (HR)}, GFR and the serum level of hANP in healthy subjects and patients with chronic hepatitis and liver cirrhosis. MAP was not different among the three groups, but HR was significantly higher in cirrhotic patients than in patients with chronic hepatitis and healthy subjects. Hematocrit and GFR were significantly lower in cirrhotic patients than in patients with chronic hepatitis and healthy subjects. Levels of neurohormonal parameters tended to be high in cirrhotic patients, but this difference was not statistically significant, and hANP was significantly higher in cirrhotic patients than in patients with chronic hepatitis and healthy subjects.

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Table 3 shows renal arterial blood flow velocity in patients with chronic hepatitis and liver cirrhosis and healthy subjects. RI was significantly higher and Vmin was lower in cirrhotic patients than in patients with chronic hepatitis and healthy subjects in each branch of the RA, while Vmax was not different among the three groups. Fig. 2 also shows that RI in cirrhotic patients was significantly higher than that in patients with chronic hepatitis and healthy subjects at each point. No difference in RI was found between patients with chronic hepatitis and healthy subjects. No significant correlation was found between RI and MAP, RI and GFR, or RI and neurohormonal factors in the three groups. Table 3 Renal blood flow velocity

Main RA

SA

ILA

ILLA

N

CH

LC

Vmax (m/s) Vmin (m/s)

0.799 90.131 0.27990.041

0.775 9 0.220 0.276 90.101

0.694 90.167 0.178

RI

0.646 90.039

0.650 90.052

9 0.078***,c 0.745

Vmax (m/s) Vmin (m/s)

0.501 90.067 0.17190.034

0.503 90.119 0.174 90.049

90.082***,c 0.480 90.108 0.128

RI

0.658 9 0.042

0.656 90.051

9 0.054*,c 0.734

Vmax (m/s) Vmin (m/s)

0.359 90.055 0.124 90.021

0.355 9 0.068 0.127 9 0.026

90.087**,c 0.335 90.075 0.093

RI

0.654 90.040

0.631 90.062

90.033**,c 0.726

0.231 9 0.048 0.08590.023

9 0.072**,a,***,b 0.200 90.043 0.061

0.619 90.038

9 0.019**,c 0.699

0.128 9 0.017 0.05690.012

90.059***,c 0.116 90.020 0.041

0.562 9 0.046

9 0.012**,a,***,b 0.651

Vmax (m/s) Vmin (m/s) RI

Cortical artery

Vmax (m/s) Vmin (m/s)

RI

0.208 90.035 0.079 90.016 0.616 90.046 0.126 90.012 0.054 90.009

0.569 90.030

90.077***,c a

N versus LC. CH versus LC. c N and CH versus LC. * PB0.05. ** PB0.01. *** PB0.001. b

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Fig. 2. RI of each RA in healthy subjects, chronic hepatitis and liver cirrhosis.

5.2. Renal arterial blood flow 6elocity in cirrhotic patients with and without ascites According to Child – Pugh’s classification, all of the cirrhotic patients with ascites in this study were grade C. MAP, HR, GFR, neurohormonal parameters, serum levels of hANP and renal arterial blood flow velocity estimated by RI were not significantly different between cirrhotic patients of grade A and B (data not shown). We evaluated differences in renal arterial blood flow velocity and other parameters between cirrhotic patients without (grade A: 9, B: 9, C: 2) and with ascites (grade C: 10). Age, MAP and HR were not significantly different between patients with and without ascites (Tables 1 and 2). Hematocrit and GFR were significantly lower in cirrhotic patients with ascites. Among other parameters, PRA and hANP were significantly higher in cirrhotic patients with ascites. Levels of aldosterone, epinephrine, norepinephrine and dopamine tended to be higher in cirrhotic patients with ascites, but there were no significant differences between cirrhotic patients with and without ascites (Table 2). In measurements of renal arterial blood flow velocity (Table 4), the RI values of main RA, SA, ILA and ILLA were significantly higher in cirrhotic patients with ascites than in those without ascites (Fig. 3), but the RI of the peripheral artery in the cortex was not different between patients with and without ascites. In cirrhotic patients with ascites, there was a positive correlation between hANP and the RI values of main RA (r= 0.728, PB 0.05), SA (r= 0.729, PB 0.05), ILA

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(r =0.919, P B 0.001) and ILLA (r= 0.720, PB 0.05), but there was no correlation between hANP and the RI of the peripheral artery in the cortex (r= 0.507, P= 0.17) (Fig. 4). On the other hand, in cirrhotic patients without ascites, serum hANP was positively correlated with renal arterial RI, even in the cortical area (r = 0.577, P = 0.026, data not shown). There was a negative correlation between GFR and the RI of ILA (r = −0.639, PB 0.05, data not shown). 6. Discussion The systemic hemodynamics in patients with liver cirrhosis are characterized by hyperdynamic circulation [16] accompanied by a reduction in peripheral vascular resistance, and an increase in arteriovenous anastomosis and cardiac output. Although cirrhotic patients exhibit hyperdynamic circulation, effective blood volume, or central blood volume is reduced [17], and the hyperdynamic state is exaggerated with the progression of liver cirrhosis. Changes in renal hemodynamics are observed in the early stages of cirrhosis before the decrease in creatinine clearance [8,18]. These changes are related to the activation of vasoactive systems [1]. Activation of the sympathetic nervous and renin-angiotensin systems [19] contribute to the increase in intrarenal vascular resistance in patients with liver cirrhosis. As the result of hyperdynamic circulation, serum levels of hANP increase, which reflect an increase in central blood volume not only in the decompensated state but also in the compensated state [15]. Sodium retention is initiated early in cirrhosis. Table 4 Renal blood flow velocity in cirrhotic patients with and without ascites

Main RA

SA

ILA

ILLA

Cortical artery

* PB0.05. ** PB0.01.

Ascites (−)

Ascites (+)

Vmax (m/s) Vmin (m/s) RI Vmax (m/s) Vmin (m/s) RI Vmax (m/s) Vmin (m/s) RI Vmax (m/s) Vmin (m/s)

0.684 90.158 0.192 90.080 0.726 90.074 0.476 90.084 0.139 90.053 0.707 90.085 0.339 90.069 0.101 90.034 0.708 90.076 0.213 90.044 0.068 90.020

0.715 90.191 0.150 9 0.071 0.783 9 0.088* 0.489 9 0.151 0.107 9 0.054 0.788 9 0.065* 0.328 9 0.089 0.078 9 0.027 0.764 9 0.047* 0.176 90.027* 0.048

RI Vmax (m/s) Vmin (m/s) RI

0.684 9 0.057 0.119 90.023 0.043 90.013 0.644 90.078

90.010** 0.730 9 0.053* 0.110 9 0.013 0.036 9 0.011 0.665 9 0.075

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Fig. 3. RI of each RA in cirrhotic patients with and without ascites.

The consequent increase in intravascular volume causes a rise in hANP levels. Increased hANP is sufficient to counterbalance antinatriuretic influences, such as PRA, aldosterone and neurohormonal parameters, at the early stage of liver cirrhosis, but not at a later stage [15]. On the other hand, the changes in renal arterial blood flow velocity evaluated using RI are associated with GFR in chronic renal disease [10–12]. RI is considered to be an index of vascular resistance based on studies involving the injection of Sephadex microspheres into the RA [20], and on studies of the acute rejection of renal transplantation [12]. In these studies, measurements were mainly obtained from the main RA, SA and ILA. Although it is difficult to identify peripheral vessels and the direction of blood flow since color is depicted as dots in ultrasonography, it is becoming possible to display blood flow as linear, even in the interlobular and cortical artery, due to improvements in ultrasonography. Investigation of the cortical artery is important, since hepatorenal syndrome is characterized by severe cortical ischemia [8], but only a few reports concerning cortical arterial blood flow using Doppler ultrasonography are available in cirrhotic patients [13,14,21]. For the reasons mentioned above, many factors are involved in hyperdynamic circulation and renal blood flow in liver cirrhosis. Simultaneous evaluation of renal arterial blood flow using improved Doppler ultrasonography, hANP and neurohormonal parameters are beneficial for estimating the functional state of liver cirrhosis and early events in hepatorenal syndrome.

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In this study, we investigated the relationships among renal arterial blood flow, hANP and neurohormonal parameters. We found that neurohormonal parameters and the renin-angiotensin system tended to be enhanced in liver cirrhosis, but its enhancement was not significant, while levels of PRA and hANP were significantly higher in cirrhotic patients with ascites than in those without ascites. Neurohormonal parameters did not correlate with the severity of liver cirrhosis estimated by Child – Pugh’s classification, because many counteracting vasoconstrictors and vasodilators such as NO [22], endothelin [23] and endotoxin [24] are activated in patients with cirrhosis. In comparing liver cirrhosis with and without ascites, GFR was significantly lower, and PRA and hANP were significantly higher in patients with ascites than in those without ascites. This indicates that hyperdynamic circulation with a decrease in renal cortical blood flow occurs in liver cirrhosis with ascites, and the measurement of renal arterial RI would be beneficial. In our study, renal arterial RI decreased from the main RA to the cortical artery in healthy subjects and in patients with chronic hepatitis and cirrhosis. RI was significantly higher and Vmin was significantly lower in cirrhotic patients than in patients with chronic hepatitis and healthy subjects. The changes in RI were dependent on the changes in Vmin. The increase in RI indicates an increase in renal vascular resistance. The correlation between RI and the activation of vasoconstrictive parameters was not strong. In comparing cirrhotic patients with and without ascites, although segmental arterial RI and interlobular arterial RI have been reported to increase with age [25],

Fig. 4. Relationship between RI and hANP in cirrhotic patients with ascites.

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there was no significant difference in age between the groups in our study. The etiology of liver cirrhosis also needs to be taken into consideration, since systemic hemodynamics have been reported to be different between viral cirrhosis and alcoholic cirrhosis [26]. We investigated renal arterial RI in viral cirrhosis and alcoholic cirrhosis, however, we did not find any difference. The RI values of the main renal, segmental, interlobar and interlobular arteries were significantly higher in cirrhotic patients with ascites than in those without ascites, but the RI of the cortical artery was not significantly different. On the other hand, GFR was significantly lower in cirrhotic patients with ascites. According to Sacerdoti et al. [13], RI correlates negatively with GFR in cirrhotic patients. In contrast, however, we did not find a significant correlation between the RI of the cortical artery and GFR in cirrhotic patients with ascites. Renal blood flow in cirrhotic patients with ascites seems to be different from that in those without ascites. Rivolta et al. [21] reported that RI decreased from the main RA to the cortical artery in healthy subjects and patients with responsive ascites, but this difference was not observed in patients with refractory ascites. They suggested that this finding was a feature of patients with refractory ascites, and the degree of renal vasoconstriction varied according to the severity of ascites. In this study, since only one patient showed refractory ascites as defined by Arroyo et al. [27], we could not confirm the finding reported by Rivolta et al. [21]. Moreover, the RI of the cortical artery also decreases from the main RA to the cortical artery in liver cirrhosis both with and without ascites. In our patients with ascites, very low levels of hANP were observed in two patients and a very high level of hANP was observed in one patient. All of our patients with ascites were treated with diuretics until the day before the examination. A very low level of hANP may reflect a hypovolemic state due to diuretics, whereas a high level of hANP may reflect an enhanced hyperdynamic state. The latter patient had refractory ascites and seemed to be resistant to the renal effects of hANP. Patients with hypovolemia seemed to be responsive to the renal effects of hANP, since conventional treatments were effective in decreasing ascites. On the other hand, in patients without ascites, RI correlated with hANP in each area of the RA, whereas in patients with ascites, the RI of the cortical artery did not correlate with hANP. Blood flow in the cortex seems to be a better indicator of renal function, therefore, a decrease in the correlation between RI and hANP suggests a decompensated state in liver cirrhosis. This also suggests that systemic hemodynamics in cirrhotic patients with ascites are different from that in patients without ascites. While there was a positive correlation between hANP and the RI of each branch of the RA in cirrhotic patients without ascites, the correlation between hANP and RI of cortical artery was reduced in cirrhotic patients with ascites. This result suggests that arteriovenous anastomosis developed between the interlobular artery and cortical artery, and reduced the GFR in cirrhotic patients with ascites. GFR was significantly lower in cirrhotic patients with ascites, but the RI of the cortical artery was not significantly different between those with and without ascites. This finding suggests that arteriovenous anastomosis also developed between the cortical artery and glomerulus in cirrhotic patients with ascites. In

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contrast to the finding of Rivolta et al. [21], our findings suggest that the correlation between hANP and RI in the cortical area decreased in the decompensated state before the development of refractory state. Therefore, a decrease in the correlation between renal cortical arterial RI and hANP in cirrhotic patients with ascites seems to be caused by the formation of arteriovenous anastomosis not only between interlobular and cortical artery but also between cortical artery and glomerulus. In conclusion, measurement of the renal cortical arterial RI by Doppler ultrasonography and the serum level of hANP are beneficial for differentiating cirrhotic patients between with and without ascites and for evaluating changes in systemic and renal hemodynamics. Furthermore, neurohormonal parameters and hANP are related to the presence or absence of liver cirrhosis.

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