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Background/aims: beta-blockers effectively prevent first variceal bleeding (FVB) in cirrhotic patients. In patients with ascites, however, their use might be precluded by a high rate of contraindications and side effects. We compared the efficacy and applicability of nadolol and isosorbide-mononitrate (IsMn) in preventing FVB in a population of cirrhotic patients at high risk of variceal bleeding with ascites, who can be frequently intolerant to beta-blockers., Methods: A total of 80 consecutive cirrhotic patients with ascites and esophageal varices (25% average risk of bleeding at 1 year) were considered, 28 were excluded due to contraindications and 52 were randomly assigned to receive nadolol (n=25) or IsMn (n=27)., Results: Frequency of contraindications was greater for beta-blockers than IsMn (35 versus 0%, P=0.001). During 21.3+/-11.6 months of follow-up, side effects forced six patients taking nadolol and four taking IsMn to stop treatment. Bleeding occurred in two patients taking nadolol and ten taking IsMn. The probability of bleeding was significantly lower in the nadolol group (P<0.05), whereas overall survival was similar (seven patients on IsMn and eight on nadolol died, P=0.3)., Conclusions: In patients with ascites IsMn is tolerated but ineffective while nadolol is effective but less tolerated.

Bradykinin, a nonapeptide with vasodilatory and permeabilizing activity, is generated through the cleavage of high-M(r) ('high-molecular-weight') kininogen by kallikrein, and its generation is facilitated by plasmin. In the ascitic fluid of patients with cirrhosis, there is massive cleavage of high-M(r) kininogen and activation of fibrinolysis, but bradykinin has never been measured directly. In the ascitic fluid of 24 patients with cirrhosis, we measured bradykinin-(1-9)-nonapeptide levels by RIA after liquid-phase and subsequent HPLC extraction, and those of its catabolic product bradykininin-(1-5)-pentapeptide by ELISA after liquid-phase extraction. Cleaved high-M(r) kininogen, activated factor XII and plasmin-antiplasmin complexes were measured in ascitic fluid and plasma. Plasma renin activity (PRA) was also determined. As a control, we also analysed plasma from 24 healthy subjects matched for sex and age with the patients. In the ascitic fluid from patients with cirrhosis, the median bradykinin-(1-9) concentration was 3.3 fmol/ml (range 0.2-29.0 fmol/ml), and the median bradykinin-(1-5) concentration was 210 fmol/ml (range 58-7825 fmol/ml). The levels of bradykinin-(1-5) in ascitic fluid were higher in patients with refractory ascites [median 1091 fmol/ml (range 58-7825 fmol/ml)] than in patients with responsive ascites [134 fmol/ml (72-1084 fmol/ml)] (P=0.010). Ascitic fluid levels of bradykinin-(1-9) were not related to the severity of ascites. PRA was higher in patients with refractory ascites [23.0 ng x h(-1) x ml(-1) (7.9-80.0 ng.h(-1).ml(-1))] than in patients with responsive ascites [6.9 ng x h(-1) x ml(-1) (0.9-29.4 ng x h(-1) x ml(-1))] (P=0.002). In ascitic fluid, 48% (19-68%) of high-M(r) kininogen was cleaved, and plasmin-antiplasmin complexes were more concentrated than in plasma (P=0.0001). In conclusion, in the ascitic fluid of patients with cirrhosis, both bradykinin-(1-9) and bradykinin-(1-5) are present, with cleavage of high-M(r) kininogen and activation of fibrinolysis. The highest levels of the long-lived metabolite bradykinin-(1-5) were found in the ascitic fluid of patients with refractory ascites and high PRA. Activation of the kinin system may therefore be involved in decompensating cirrhosis, but a cause-effect relationship remains to be established.

Little is known about the regulation of high-molecular-weight-kininogen (HK) and low-molecular-weight-kininogen (LK) or the relationship of each to the degree of liver function impairment in patients with cirrhosis. In this study, we evaluated HK and LK quantitatively by a recently described particle concentration fluorescence immunoassay (PCFIA) and qualitatively by SDS PAGE and immunoblotting analyses in plasma from 33 patients with cirrhosis presenting various degrees of impairment of liver function. Thirty-three healthy subjects served as normal controls. Patients with cirrhosis had significantly lower plasma levels of HK (median 49 microg/ml [range 22-99 microg/ml]) and LK (58 microg/ml [15-100 microg/ml]) than normal subjects (HK 83 microg/ml [65-115 microg/ml]; LK 80 microg/ml [45-120 microg/ml]) (p<0.0001). The plasma concentrations of HK and LK were directly related to plasma levels of cholinesterase (P<0.0001) and albumin (P<0.0001 and P<0.001) and inversely to the Child-Pugh score (P<0.0001) and to prothrombin time ratio (P<0.0001) (reflecting the clinical and laboratory abnormalities in liver disease). Similar to normal individuals, in patients with cirrhosis, plasma HK and LK levels paralleled one another, suggesting that a coordinate regulation of those proteins persists in liver disease. SDS PAGE and immunoblotting analyses of kininogens in cirrhotic plasma showed a pattern similar to that observed in normal controls for LK (a single band at 66 kDa) with some lower molecular weight forms noted in cirrhotic plasma. A slight increase of cleavage of HK (a major band at 130 kDa and a faint but increased band at 107 kDa) was evident. The increased cleavage of HK was confirmed by the lower cleaved kininogen index (CKI), as compared to normal controls. These data suggest a defect in hepatic synthesis as well as increased destructive cleavage of both kininogens in plasma from patients with cirrhosis. The decrease of important regulatory proteins like kininogens may contribute to the imbalance in coagulation and fibrinolytic systems, which frequently occurs in cirrhotic patients.

The usefulness in cirrhotic patients of hemodynamic measurements by Doppler ultrasonography (US) is still not defined. We investigated the relationships between Doppler measurements and the severity of ascites. Portal blood flow velocity and volume, and hepatic and renal arterial resistance indexes (RI) were measured in 57 cirrhotic patients (19 without ascites, 28 with responsive ascites, and 10 with refractory ascites) and 15 healthy controls. The renal arterial RI were obtained for the main renal artery, interlobar vessels, and cortical vessels. Cirrhotic patients had decreased portal blood flow and an increased congestion index (CI). Only the CI was correlated to the severity of ascites, showing that it is also a reliable measure of the severity of portal hypertension in patients with ascites. The hepatic and renal artery RI were increased in cirrhotic patients, and the two values were correlated (r = .68; P = .00001). The RI of renal interlobar and cortical vessels were higher in patients with refractory ascites than in patients without ascites (P < .02 and P < .009), and correlated with sodium excretion rate (r = -.45; P < .003), the renin-aldosterone system, and creatinine clearance (r = -.62; P < .0002). The RI decreased from the hilum of the kidney to the outer parenchyma in healthy subjects and patients with responsive ascites, but this difference disappeared in patients with refractory ascites. This indicates that the degree of renal vasoconstriction varies in different areas according to the severity of the ascites. Cortical vessels are involved mainly in patients with refractory ascites, suggesting that the intrarenal blood flow distribution in cirrhosis tends to preserve the cortical area and that severe cortical ischemia is a feature of refractory ascites.

To evaluate the pattern of plasma cyclic adenosine 3',5'-monophosphate, cyclic guanosine 3',5'-monophosphate, atrial natriuretic factor and glucagon levels in different stages of chronic liver diseases, we measured these variables in 20 normal subjects, 25 patients with genetic hemochromatosis, associated with liver cirrhosis in 19 cases and not in six, eight patients with compensated and 15 with decompensated alcoholic or posthepatitic cirrhosis, and 12 with hepatocellular carcinoma. All variables were within the normal range in non-cirrhotic hemochromatotic patients. Cyclic adenosine 3',5'-monophosphate levels were within the normal range (9.5-15.7 nmol/l) in hemochromatotic cirrhotics and elevated in other patients. Cyclic guanosine 3',5'-monophosphate, atrial natriuretic factor and glucagon were above the normal ranges (1.92-5.91 nmol/l, 8.8-62.7 ng/l, and 39-165 ng/l, respectively) in most patients with cirrhosis both with and without hemochromatosis and in most individuals with hepatocellular carcinoma. Cyclic guanosine 3',5'-monophosphate correlated with atrial natriuretic factor in the former groups but not in the latter. These findings indicate that glucagon and atrial natriuretic factor hypersecretion is an early event in cirrhosis, regardless of its etiology. In hepatocellular carcinoma, the underlying cirrhosis may account for most hormonal and metabolic changes although cyclic guanosine 3',5'-monophosphate increases could also be due to the neoplastic process per se.

Nephrotoxicity is the main untoward effect of cyclosporine (CsA) treatment. Experimental and clinical data suggest that dietary supplementation with fish oil may lessen cyclosporine nephrotoxicity, possibly by lowering renal thromboxane (Tx) production. We have studied the renal effects of a daily supplementation for 2 months of 12 g fish oil (18% C20:5 n-3 eicosapentaenoic acid [EPA] and 12% C22:6 n-3 docosahexanoic acid [DHA]) in a placebo-controlled (12 g corn oil), prospective, randomized, double-blind study of stable CsA-treated liver transplant recipients. Thirteen patients ingested corn oil capsules and 13 fish oil. Compliance with dietary regimen was confirmed by fatty acid chromatography that showed increased plasma concentrations of EPA (from 0.4 +/- 0.02% to 4.6 +/- 0.5%, P < .0001) and DHA (from 1.8 +/- 0.2% to 3.9 +/- 0.1%, P < .0001) in the fish oil group and increased plasma concentration of linoleic acid (C18:2 n-6) in the corn oil group (from 25 +/- 2% to 28.4 +/- 2%, P < .001). At the end of the 2 months of the study, in the fish oil group the effective renal plasma flow increased by 22% (P = .012), the glomerular filtration rate increased by 33% (P = .057), the renal blood flow increased by 17% (P = .024), and the calculated total renal vascular resistances decreased by 20% (P = .034). In contrast, none of these parameters changed in the corn oil group. The renal functional reserve determined during L-arginine infusion, plasma renin activity (PRA), and plasma aldosterone (PA) remained unchanged during the study in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind crossover study versus placebo of the renal effects of the nonsteroidal anti-inflammatory drug imidazole 2-hydroxybenzoate was conducted in 10 patients with compensated liver cirrhosis. The administration of the drug (750 mg, t.i.d., for three days) did not affect renal plasma flow, glomerular filtration rate, free water clearance nor the urinary excretion of sodium or potassium. Values of plasma renin activity also did not change after drug administration. Direct tubular damage from imidazole 2-hydroxybenzoate was also excluded by normal excretion of beta-2-microglobulin and N-acetyl-beta-D-glucosaminidase. Urinary 6-keto-PGF1 alpha output were comparable during imidazole 2-hydroxybenzoate and placebo administration. These data indicate that this nonsteroidal antiinflammatory drug does not affect the renal function in patients with compensated liver cirrhosis.

The administration of atrial natriuretic factor to patients with cirrhosis, and avid sodium retention causes marked hypotension and blunted kidney responses. To evaluate whether the unresponsiveness of the kidney is caused by a fall in mean blood pressure below a critical value for the renal blood perfusion pressure (80 mm Hg), we studied nine such patients and compared the effects of synthetic atrial natriuretic factor alone (1 micrograms/kg as a bolus) with those of an atrial natriuretic factor combination with infused norepinephrine titrated to raise baseline blood pressure by 15 to 20 mm Hg (182 to 625 ng/kg/min). The administration of atrial natriuretic factor during norepinephrine infusion caused a fall in mean blood pressure to values not less than 80 mm Hg in eight of nine patients, with a slight natriuresis (greater than 5 mumol/min) in five patients but no changes in the other four. The mean urinary sodium output was markedly lower than that previously observed after atrial natriuretic factor injection into normal subjects and into cirrhotic patients without avid sodium retention. Unlike sodium excretion, urine flow rate and free water clearance (which were not affected by atrial natriuretic factor alone) were markedly improved by the coadministration of norepinephrine and atrial natriuretic factor. In four additional patients we studied the urinary electrolyte excretion during a low-dose infusion of atrial natriuretic factor (20 ng/kg/min) to which an infusion of norepinephrine titrated to maintain blood pressure over 80 mm Hg was added. In only one of these four patients urinary sodium output consistently increased during atrial natriuretic factor infusion, and the output increased even more when norepinephrine was added.(ABSTRACT TRUNCATED AT 250 WORDS)

Fifty-four cirrhotic patients with refractory ascites were treated with one-session large-volume paracentesis and randomly assigned to two groups. The first group was infused with human albumin, and the second group was infused with hemaccel at doses with comparable oncotic power. The two groups were compared for incidence of complications, recurrence of massive ascites after hospital dismissal and survival rate. The incidence of complications traditionally related to paracentesis, the probability of requiring readmission to the hospital for ascites (p = 0.48) and the probability of survival after entry into the study (p = 0.85) were the same for the two groups. A multivariate analysis of 16 parameters, including treatment modality, identified absolute unresponsiveness to diuretics as the only independent predictor of mortality. These results indicate that hemaccel infusion may safely replace albumin infusion after total paracentesis for cirrhotic patients with refractory ascites.

The plasma levels of atrial natriuretic factor in liver cirrhosis can be affected by various factors, such as ascites, renal function, use of diuretics drugs and dietary sodium intake. Moreover, the influence of high intra-abdominal pressure on cardiac atrial natriuretic factor release in patients with tense ascites has not been investigated. The aim of the present study was to evaluate the circulating levels of atrial natriuretic factor and their relationships to plasma renin activity, aldosterone concentration, and urinary sodium excretion in 45 cirrhotic patients divided into 4 groups: (a) cirrhotics without ascites; (b) nonazotemic cirrhotics with ascites; (c) cirrhotics with ascites and functional renal failure; and (d) cirrhotics with ascites taking diuretics. In some patients with tense ascites, atrial natriuretic factor was also measured after rapid abdominal relaxation by large volume paracentesis. Plasma levels of atrial natriuretic factor obtained in 13 healthy control subjects after 5 days on a 40-50 mEq sodium daily intake were 22.8 +/- 3.3 pg/ml. Mean plasma atrial natriuretic factor levels were normal in patients without ascites (35.1 +/- 11.4 pg/ml) and in those with ascites taking diuretics (27 +/- 9.2 pg/ml), but elevated in patients with ascites not taking diuretics (59.6 +/- 12 pg/ml) and in those with ascites and functional renal failure (58.5 +/- 16.6 pg/ml). These data show that plasma atrial natriuretic factor levels are elevated only in cirrhotic patients who are ascitic and not taking diuretics. In these patients atrial natriuretic factor levels were directly correlated with urinary sodium excretion, even though sodium balance was positive. This could be the consequence of the contrasting effects of antinatriuretic factors, as suggested by the inverse relationships between atrial natriuretic factor and urinary sodium on the one hand and plasma renin activity and plasma aldosterone concentration on the other. Twenty-six patients with tense ascites (12 taking diuretics and 14 not) were treated with rapid large-volume paracentesis (6500 +/- 330 ml of ascitic fluid removed in 168 +/- 16 min). At the end of the procedure, plasma atrial natriuretic factor levels had increased in all patients (from 45.5 +/- 10.1 to 100 +/- 17 pg/ml), whereas plasma renin activity and plasma aldosterone concentration had decreased (from 10.3 +/- 1.6 to 7 +/- 1.3 ng/ml/h, and 1160 +/- 197 to 781 +/- 155 pg/ml, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Paracentesis is the oldest method for treating patients with ascites, but the fear of serious side-effects and the coincident introduction of effective non-toxic diuretic drugs led to its abandonment during the fifties. In recent years, several studies have investigated whether abdominal evacuation of ascitic fluid is truly dangerous for cirrhotic patients. The results of some randomized controlled trials comparing paracentesis with a traditional diuretic therapy showed that the rate of complications after paracentesis, particularly when the procedure was combined with a sufficient plasma expansion, was equal to or lower than that of diuretic treatment. Moreover, the ability of paracentesis to resolve tense ascites, both in terms of number of successes and of time required to obtain ascites resolution, was similar or even higher. These data and the recent new interest of several investigators in employing ascitic fluid examination for diagnostic purposes have increased the use of this procedure in the clinical practice.

We investigated the renal and humoral effects of short-term administration of ibopamine, an orally active dopamine agonist, in patients with liver cirrhosis. The patients were divided into two groups on the basis of sodium excretion with a constant sodium intake of 40 mEq/d. We also compared the effects of ibopamine with those induced by intravenous infusion of dopamine hydrochloride (3 micrograms/kg per minute) in similar patients. Ibopamine caused significant increases in urine output, glomerular filtration rate, and sodium excretion throughout the 4 hours of the trial in patients with basal sodium excretion rate greater than 20 mmol/d. These renal effects were associated with a significant reduction in plasma aldosterone concentration. In contrast, only a transient increase in glomerular filtration rate and a diminution in plasma aldosterone concentration were observed after ibopamine in the patients with a basal sodium excretion rate less than 20 mmol/d. The infusion of dopamine had renal effects similar to those of ibopamine in both groups of patients. These results indicate that in cirrhotic patients with normal sodium excretion, ibopamine exerts a diuretic and natriuretic effect similar to that of dopamine infusion. However, these properties of dopaminergic agents are apparently lost in patients with avid sodium retention.

The acute effects of 50 mg of ibopamine (SB-7505), the 3,4-diisobutyryl ester of N-methyldopamine, were investigated after oral administration to 10 adult subjects without evidence of renal, hepatic or cardiovascular disease. Blood pressure and heart rate did not change while diuresis and urinary electrolyte excretion increased significantly during the 240 min of the study. Glomerular filtration rate (GFR) was also increased at 80 min after ibopamine, whereas plasma aldosterone and prolactin were slightly decreased. In contrast to dopamine, ibopamine did not stimulate plasma renin activity. These results are attributable to the ability of ibopamine to be rapidly deesterified to N-methyldopamine (epinine) which has been previously shown to exert peripheral effects similar to those of dopamine. Therefore, the increased GFR can be ascribed to an enhanced renal blood flow. On the contrary, taking into account the significant increase of the fractional excretion of sodium (FeNa) the rise in sodium excretion seems to be the consequence of a direct tubular effect of epinine, even though the slight decrease in peripheral aldosterone concentration would have been a contributing factor. Urinary flow rate might be enhanced by the high sodium delivery to the distal nephron, rather than by a postulated dopaminergic inhibition of arginine-vasopressin release.

Skeletal muscle water, Cl, Na and K were studied in 24 patients with predialysis chronic renal failure (CRF) and in 16 patients under regular dialysis treatment (RDT) for 8-16 years; 35 healthy controls were also examined. Total Cl, Na and water (Clm, Nam, TW) were high in both CRF and RDT groups (p less than 0.001); high TW in CRF was due to both extra (ECW) and intracellular (ICW) fractions, which were calculated from Cl space; in RDT only ECW was increased and ICW was normal. Muscle K was diminished in CRF, in reference to both muscle fat free dry solids and ICW, and it was slightly but significantly higher than normal in RDT. The findings demonstrate that high cell volume and low intracellular K observed in CRF are fully corrected by long-term hemodialysis, probably because these abnormalities are mainly related to cell function disturbances due to uremic state. On the contrary, the persistence of high total Cl, Na and muscle ECW seems to be an expression of expanded extracellular fluid volume.