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Background/aims: To investigate a possible relationship between the renal production of endothelin and the presence of renal dysfunction and activation of vasoactive systems in cirrhosis, the urinary excretion and the circulating plasma levels of immunoreactive endothelin (irET) and the plasma levels of vasoactive hormones were measured in 19 healthy subjects, 12 cirrhotic patients without ascites and 39 patients with ascites and different degrees of renal dysfunction., Methods: The urinary excretion and the circulating levels of irET were assessed after 5 days on a 40 mEq sodium diet and off diuretics. Renal function parameters and the plasma levels of vasoactive hormones were also measured., Results: Patients with and without ascites had similar values of urinary irET as compared with healthy subjects (30+/-3, 31+/-3 and 29+/-2 ng/day, respectively, p>0.10). By contrast, patients with ascites had higher circulating levels of irET (15+/-1.2 pg/ml) than patients without ascites and healthy subjects (11+/-1.6 and 5+/-0.4 pg/ml, p<0.01). In patients with cirrhosis, no correlation was found between urinary irET and circulating irET. Moreover, urinary irET did not correlate with liver tests, serum and urine sodium, glomerular filtration rate or vasoactive substances. Patients with hepatorenal syndrome had similar urinary irET to patients with ascites without hepatorenal syndrome., Conclusions: Urinary excretion of irET is not increased in cirrhotic patients with ascites and does not correlate with abnormalities in renal function.

Background/aims: Circulatory abnormalities with activation of vasoconstrictor systems after large-volume paracentesis are generally considered secondary to an increased extravasation of fluid from the intravascular compartment to the extravascular space with subsequent reduction in plasma volume. To test this hypothesis, plasma volume, the transvascular escape rate of albumin, the absolute escape rate of albumin and the activity of vasoconstrictor systems were measured in 25 cirrhotic patients with ascites in baseline conditions and 2 days after total paracentesis with plasma volume expansion., Methods: Plasma volume and the transvascular escape rate of albumin, the fraction of albumin passing from the intravascular to the extravascular space per unit of time, were assessed through the plasma disappearance curve of radioiodinated human albumin. The absolute escape rate of albumin, the total flux of albumin from intravascular to extravascular space per unit of time, was also calculated., Results: Eight of the 25 patients (32%) developed marked activation of vasoconstrictor systems after paracentesis. In these patients, plasma renin activity and plasma norepinephrine concentration increased from 6.6+/-2 to 23.4+/-11 ng x ml(-1) x h(-1) and 776+/-229 to 989+/-258 pg/ml, respectively (p<0.05). No significant changes in these parameters were found in the remaining 17 patients. The activation of vasoconstrictor systems occurred in the absence of changes in plasma volume (3456+/-276 vs 3476+/-264 ml, NS), transvascular escape rate of albumin (10.4+/-1 vs 10.9+/-2%/h, NS) and absolute escape rate of albumin (9.9+/-1.9 vs 10.5+/-0.7 g/h, NS)., Conclusions: These results do not support a contraction of plasma volume as the mechanism responsible for activation of vasoconstrictor systems after paracentesis. Rather, the activation of vasoconstrictor systems in the absence of changes in plasma volume suggests that paracentesis accentuates the impairment of "effective" blood volume present in cirrhotic patients with ascites.

Background/aims: Intravenous ornipressin in cirrhotic patients with hepatorenal syndrome causes marked improvement of systemic hemodynamics and suppression of plasma renin and norepinephrine but only moderate improvement of renal function. This study was designed to investigate whether these beneficial effects could be enhanced by the simultaneous administration of dopamine. The renal effects of the i.v. infusion of norepinephrine plus prostacyclin in patients with hepatorenal syndrome were also assessed., Methods: Renal plasma flow, glomerular filtration rate, free water clearance, sodium excretion and the plasma levels of renin and norepinephrine were measured in baseline conditions and during the administration of ornipressin (6 i.u./h) and ornipressin (6 i.u./h) plus dopamine (2 micrograms/kg.min) in nine patients with hepatorenal syndrome. Five additional patients with hepatorenal syndrome were studied prior to and following the administration of norepinephrine (0.45 +/- 0.1 microgram/kg.min) and norepinephrine (0.85 +/- 0.2 microgram/kg.min) plus prostacyclin (5 ng/kg.min)., Results: Despite a significant increase in arterial pressure and marked suppression of plasma renin activity during ornipressin and ornipressin plus dopamine administration, no significant improvement in renal function was observed. Norepinephrine and norepinephrine plus prostacyclin also failed to increase renal perfusion and glomerular filtration rate., Conclusions: The combined administration of systemic vasoconstrictors (ornipressin or norepinephrine) and vasodilators (dopamine or prostacyclin), at the doses used in the current study and for a short period of time, does not improve renal function in cirrhotic patients with hepatorenal syndrome. The current study does not confirm a potential role for ornipressin in the treatment of hepatorenal syndrome.

Background/aims: Patients with cirrhosis and ascites show high plasma concentrations of endothelin. The aim of the current study was to investigate whether this feature is a compensatory response to effective hypovolemia or a consequence of systemic endotoxemia., Methods: Protocols 1 and 2 assess the effect of acute changes in effective blood volume on plasma endothelin, and protocol 3 investigates the relationship between plasma endotoxin and endothelin in patients with cirrhosis and ascites. Protocol 1 included nine healthy subjects and 26 patients with cirrhosis studied during supine rest, upright tilt (which decreases effective blood volume) and cycloergometric exercise (which activates vasoactive systems by a baroreceptor independent mechanism). Protocol 2 included six patients studied before and 1 and 3 h after the intravenous administration of a plasma expander. In protocol 3, the plasma levels of endothelin and endotoxin were measured in 17 non-infected patients with cirrhosis and also in four patients with spontaneous bacterial peritonitis at diagnosis and following resolution of infection., Results: Plasma endothelin was 3-5 times higher in patients with cirrhosis than in healthy volunteers. In healthy subjects, upright tilt and exercise were associated with a significant activation of the renin-aldosterone and sympathetic nervous systems and an increase in plasma endothelin. In patients with cirrhosis, upright tilt and exercise were associated with a significant increase and plasma volume expansion with a marked suppression of the renin-aldosterone and sympathetic nervous systems. However, in these patients none of these maneuvers affected plasma endothelin levels. In the patients with cirrhosis in protocol 3, there was no correlation between plasma endotoxin and endothelin. Resolution of peritonitis was associated with a marked fall in plasma endotoxin and no changes in plasma endothelin., Conclusions: These findings suggest that mechanisms other than effective hypovolemia or systemic endotoxemia are involved in the increased plasma endothelin of cirrhosis with ascites.

A questionnaire to assess the clinical choice of ascites treatment in cirrhosis was distributed to 1473 participants in an EASL meeting. The response rate (295, 20%) was considered satisfactory in view of the heterogeneity of the persons attending this event. Most participants (86.4%) in the survey were hepatologists and gastroenterologists. The following conclusions of the survey are noteworthy: (1) The objective of ascites therapy was to eliminate completely or almost completely the ascitic fluid for 49% of responders and to decrease ascites volume to an acceptable level of patient comfort for 48%; (2) The classical progressive therapeutic schedule of ascites is rarely used; (3) Following mobilisation of ascites, most (82%) maintain patients on diuretic therapy to avoid reaccumulation of ascites; (4) Only 5% of participants did not use paracentesis to manage ascites in cirrhosis. This was the therapeutic procedure most frequently used for patients with refractory ascites; (5) Although the most acceptable definition of refractory ascites was ascites which cannot be mobilized by maximal medical treatment, a significant proportion of participants also considered that intractable ascites due to diuretic-induced complications and recidivant ascites should be included in the definition; (6) The proportions of participants prescribing prophylactic therapy, mainly low sodium diet, to compensated patients with and without a past history of ascites were 68% and 16%, respectively.