Joan Gaya

Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis

It has recently been shown that repeated large-volume paracentesis associated with intravenous albumin infusion is a rapid, effective, and safe therapy of ascites in cirrhosis. To investigate whether intravenous albumin infusion is necessary in the treatment of cirrhotics with large-volume paracentesis, 105 patients with tense ascites were randomly allocated into two groups. Fifty-two patients (group 1) were treated with paracentesis (4-6 L/day until disappearance of ascites) plus intravenous albumin infusion (40 g after each tap), and 53 (group 2) with paracentesis without albumin infusion. After disappearance of ascites, patients were discharged from the hospital with diuretics. Patients developing tense ascites during follow-up were treated according to their initial schedule. Paracentesis was effective in eliminating the ascites in 50 patients from group 1 and in 48 from group 2, with the duration of the hospital stay being approximately 11 days in both groups. Paracentesis plus intravenous albumin did not induce significant changes in standard renal function tests, plasma renin activity, and plasma aldosterone. In contrast, paracentesis without albumin was associated with a significant increase in blood urea nitrogen, a marked elevation in plasma renin activity and plasma aldosterone concentration, and a significant reduction in serum sodium concentration. One patient from group 1 and 11 from group 2 developed renal impairment or severe hyponatremia after treatment, or both (chi 2 = 9.19; p less than 0.01). The development of these complications could not be predicted by clinical and laboratory data before treatment. Although the probability of survival after entry into the study was similar in patients from both groups, a multivariate analysis identified the development of hyponatremia or renal impairment, or both, following the first paracentesis treatment and the occurrence of other complications during the first hospitalization (encephalopathy, gastrointestinal bleeding, and severe infection) as being the only independent predictors of mortality. These results indicate that intravenous albumin infusion is important in avoiding renal and electrolyte complications and activation of endogenous vasoactive systems in cirrhotics with ascites who are treated with repeated large-volume paracentesis. The development of such complications may impair survival in these patients.

Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites

To identify prognostic factors in cirrhotic patients admitted to the hospital for the treatment of an episode of ascites, a survival analysis was performed in a series of 139 patients hospitalized in our Unit between 1980 and 1985. Mean follow-up was 12.8 +/- 14.2 mo (mean +/- SD). A total of 38 variables based on history, physical examination, hepatic biochemical tests, renal function tests, and endogenous vasoactive systems were analyzed for prognostic value. Eighteen of these variables had prognostic value in the univariate analysis. A multivariate analysis (Coxs regression method) disclosed that 7 of these 18 variables had independent prognostic value. Of these independent predictors of survival, mean arterial pressure and plasma norepinephrine concentration were the variables that best predicted prognosis. Two other variables that independently correlated with survival were urinary sodium excretion and glomerular filtration rate. The remaining three independent predictors of survival were nutritional status, hepatomegaly, and serum albumin concentration. Therefore, these findings indicate that, in patients with cirrhosis and ascites, parameters estimating systemic hemodynamics and renal function are better predictors of survival than those routinely used to estimate hepatic function.

Sympathetic nervous activity, renin-angiotensin system and renal excretion of prostaglandin E2 in cirrhosis. Relationship to functional renal failure and sodium and water excretion

Abstract. To investigate if functional renal failure in cirrhosis could be related to disturbances of vasoactive systems, plasma renin activity, plasma catecholamines and urinary prostaglandin E2 (PGE2) were determined in twenty‐two normal subjects and sixty‐five cirrhotics. Furthermore, in thirty‐three of these subjects, the effect of lysine‐acetylsalicylate (450 mg i.v.) on renal function was studied.

Renal function abnormalities, prostaglandins, and effects of nonsteroidal anti-inflammatory drugs in cirrhosis with ascites: An overview with emphasis on pathogenesis☆

The ability of the kidneys to excrete sodium and free water is often impaired in patients with cirrhosis. Sodium retention is a sine qua non for ascites formation. The impairment of water excretion causes hyponatremia and hypo-osmolality. In addition, these patients frequently have functional renal failure caused by intense renal vasoconstriction. The renin-angiotensin-aldosterone system and the sympathetic nervous system, which are activated in most cirrhotic patients with ascites, and a nonosmotic hypersecretion of antidiuretic hormone are important mechanisms of sodium and water retention. Angiotensin II and sympathetic nervous activity may also be involved in the pathogenesis of functional renal failure. The renal production of prostaglandins is increased in cirrhotic patients with ascites as a homeostatic response to antagonize the vascular effect of endogenous vasoconstrictors and the tubular action of antidiuretic hormone. Nonsteroidal anti-inflammatory drugs should, therefore, be administered with caution in these patients because they may induce acute renal failure and water retention. Although sulindac inhibits the renal synthesis of prostaglandins in cirrhotic patients with ascites, it appears to have less effect on renal function than do other nonsteroidal anti-inflammatory drugs administered to these patients.

Urinary excretion of 6-keto-prostaglandin F1α, thromboxane B2 and prostaglandin E2 in cirrhosis with ascites: Relationship to functional renal failure (hepatorenal syndrome)

The aim of the study was to investigate the urinary excretion of 6-keto-PGF1 alpha (a stable metabolite of PGI2), thromboxane B2 (TxB2; a stable metabolite of TxA2), and PGE2 in 18 normal subjects, 49 cirrhotics with ascites without renal failure (GFR = 90 +/- 4 ml/min, means +/- S.E.M.) and 20 cirrhotics with functional renal failure (FRF) (GFR = 36 +/- 3). The study was made after 5 days on a 50 mEq sodium diet and without diuretics. Plasma renin activity (PRA), plasma norepinephrine concentration (NE) and plasma antidiuretic hormone concentration (ADH) were also measured. Cirrhotics without FRF showed a significantly higher urinary excretion of 6-keto-PGF1 alpha, TxB2 and PGE, (15.9 +/- 1.7 ng/h, 3.0 +/- 0.3 ng/h, and 6.2 +/- 1.0 ng/h) than did normal subjects (9.2 +/- 0.9, 1.3 +/- 0.1 and 2.3 +/- 0.4). On the contrary, the urinary excretion of these prostaglandins was normal or reduced in patients with FRF (5.3 +/- 0.8, 1.3 +/- 0.2 and 1.9 +/- 0.4). PRA, NE and ADH were significantly increased in cirrhotics with FRF (15.2 +/- 3.9 ng/ml/h, 1026 +/- 149 pg/ml and 4.1 +/- 0.3 pg/ml) and in patients without FRF (8.0 +/- 1.4, 667 +/- 67 and 3.9 +/- 0.3) as compared to normal controls (1.3 +/- 0.2, 275 +/- 46 and 2.4 +/- 0.2). These results suggest that renal hemodynamics in cirrhosis depends upon a critical equilibrium between the activity of endogenous vasoconstrictor systems and the renal production of the vasodilator prostaglandins PGI2 and PGE2. In addition, they do not support FRF in cirrhosis being related to an increased renal production of the vasoconstrictor prostaglandin TxA2.

Effect of V1-vasopressin receptor blockade on arterial pressure in conscious rats with cirrhosis and ascites

Angiotensin II blockade with saralasin in human cirrhosis with ascites is associated with a significant reduction in arterial pressure, indicating that endogenous angiotensin II plays an important role in the maintenance of systemic hemodynamics in this condition. The aim of the current study was to investigate whether vasopressin also contributes to the maintenance of arterial pressure in cirrhosis with ascites. The study was performed using three groups of cirrhotic rats with ascites and three groups of control animals. The administration of d(CH2)5Tyr(Me)AVP, a selective antagonist of the vascular effect of vasopressin, to 10 cirrhotic rats induced a significant reduction in mean arterial pressure (from 94 +/- 4 to 85 +/- 4 mm Hg; P less than 0.001) and a significant increase in plasma renin activity (from 24.3 +/- 4.9 to 34.3 +/- 5.9 ng/mL.h; P less than 0.02) and plasma norepinephrine concentration (from 1474 +/- 133 to 2433 +/- 253 pg/mL; P less than 0.01). Similar results were observed following saralasin administration in a second group of 5 cirrhotic rats [mean arterial pressure decreased from 97 +/- 4 to 85 +/- 5 mm Hg (P less than 0.0001); and plasma renin activity and norepinephrine concentration increased from 18.4 +/- 5.8 to 40.3 +/- 5.7 ng/mL.h (P less than 0.02) and from 1383 +/- 70 to 2312 +/- 334 pg/mL (P less than 0.05), respectively]. The simultaneous blockade of angiotensin II and vasopressin in a third group of cirrhotic rats resulted in a significantly greater reduction of mean arterial pressure (from 97 +/- 6 to 74 +/- 6 mm Hg; P less than 0.05). No changes in arterial pressure were observed in the three groups of control rats. These findings indicate that endogenous vasopressin is as important as angiotensin II in the maintenance of arterial pressure in cirrhotic rats with ascites and support the contention that arterial hypotension is the initial event leading to the stimulation of the renin-angiotensin system and vasopressin in this animal model of cirrhosis.

Assessment of the renin-angiotensin system in cirrhotic patients : comparison between plasma renin activity and direct measurement of immunoreactive renin

The renin-angiotensin system plays an important physiological role and has prognostic significance in cirrhotics with ascites. The degree of stimulation of this system is usually estimated by measuring plasma renin activity after incubation periods of 2-3 h. Recent investigations showed that the direct measurement of immunoreactive renin also estimates the degree of activity of the system. In this study, immunoreactive renin and plasma renin activity (measured at incubation periods of 10, 20, 50 and 180 min) were determined in ten healthy subjects, five hyperreninemic non-hepatic patients and 47 cirrhotics with ascites. Cirrhotic patients showed significantly higher plasma renin activity (5.1 +/- 0.9 ng/ml per h, p less than 0.05) and immunoreactive renin (145.4 +/- 24.4 pg/ml, p less than 0.01) than healthy subjects (1.2 +/- 0.15 ng/ml per h and 25.1 +/- 1.1 pg/ml, respectively). The angiotensin I generation rate was constant during the 3-h incubation in 22 cirrhotics and a close relationship (r = 0.956, p less than 0.001) between plasma renin activity (3.5 +/- 1.6 ng/ml per h) and immunoreactive renin (71 +/- 25 pg/ml) was observed in these patients. In the remaining 25 cirrhotics the generation rate of angiotensin I declined with time and the calculated plasma renin activity at 180 min was lower than the activity calculated at 10 min by 50.7%.(ABSTRACT TRUNCATED AT 250 WORDS)

Sulindac Reduces the Urinary Excretion of Prostaglandins and Impairs Renal Function in Cirrhosis with Ascites

In 5 patients with cirrhosis and ascites the glomerular filtration rate (GFR), free water clearance (CH2O) and urinary excretion of prostaglandin E2(PGE2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were measured before and after a 3-day treatment with sulindac (400 mg/day). The administration of sulindac induced a marked fall of urinary excretion of PGE2 (from 24.2 +/- 5.5 to 3.8 +/- 1.1 ng/h; p less than 0.05), 6-keto-PGF1 alpha (from 19.9 +/- 2.9 to 5.6 +/- 1.1 ng/h; p less than 0.02) GFR (from 111 +/- 15 to 67 +/- 10 ml/min; p less than 0.01) and CH2O (from 7 +/- 1.5 to 3.7 +/- 1.3 ml/min; p less than 0.02) in all patients studied. The plasma concentration of the active metabolite sulindac sulfide in cirrhotics was 400% of that found in 6 healthy volunteers (9.6 +/- 1.7 vs. 2.4 +/- 0.6 ng/ml). Our results indicate that sulindac, at a dose of 400 mg/day, inhibits the renal synthesis of prostaglandins and impairs renal function in cirrhotics with ascites. These effects are probably related to the marked alteration of sulindac kinetics that occurs in these patients.

Aspirin (ASA) regulates 5-lipoxygenase activity and peroxisome proliferator-activated receptor α-mediated CINC-1 release in rat liver cells: novel actions of lipoxin A4 (LXA4) and ASA-triggered 15-epi-LXA4

The mechanism of action of aspirin (ASA) is related to cyclooxygenase (COX) inhibition, but additional actions cannot be excluded for their antiinflammatory properties and antithrombotic activity. In the current investigation, we examined the effects of ASA on COX and 5‐lipoxygenase (5‐LO) pathways and its impact on peroxisome proliferator‐activated receptor α (PPARα) and cytokine‐induced neutrophil chemoattractant‐1 (CINC‐1) levels in rat liver cells. In Kupffer cells, the liver resident macrophages, ASA switched eicosanoid biosynthesis from prostaglandin E2 (PGE2) to leukotriene B4 (LTB4) and 15‐epi‐lipoxin A4 (15‐epi‐LXA4) formation. In hepatocytes, ASA significantly inhibited PPARα protein expression and CINC‐1 secretion, effects that were also observed in hepatocytes exposed to the selective PPARα agonist Wy‐14643. In contrast, treatment of hepatocytes with PGE2 in association with LTB4 had no significant effect on PPARα but stimulated CINC‐1 release. Interestingly, the endogenous antiinflammatory eicosanoids LXA4 and ASA‐triggered 15‐epi‐LXA4, in addition to inhibiting macrophage 5‐LO activity to a similar extent as PGE2, significantly reduced PPARα and CINC‐1 levels in hepatocytes. Taken together and because arachidonic acid‐derived products, PPARα levels, and CINC‐1 secretion are involved in the extent and duration of an inflammatory response, these findings provide additional molecular mechanisms for the pharmacological properties of ASA.

Inhibition of 5-lipoxygenase-activating protein abrogates experimental liver injury: role of Kupffer cells

Activation of Kupffer cells is a prominent feature of necro‐inflammatory liver injury. We have recently demonstrated that 5‐lipoxygenase (5‐LO) and its accessory protein, 5‐LO‐activating protein (FLAP), are essential for the survival of Kupffer cells in culture, as their inhibition drives these liver resident macrophages to programmed cell death. In the current study, we explored whether the potent FLAP inhibitor, Bay‐X‐1005, reduces the number of Kupffer cells in vivo and whether this pharmacological intervention protects the liver from carbon tetrachloride (CCl4)‐induced damage. Rats treated with CCl4 showed an increased number of Kupffer cells, an effect that was abrogated by the administration of Bay‐X‐1005 (100 mg/Kg body weight, per oral, daily). Consistent with a role for Kupffer cells in necro‐inflammatory liver injury, partial depletion of Kupffer cells following FLAP inhibition was associated with a remarkable hepatoprotective action. Indeed, Bay‐X‐1005 significantly reduced the intense hepatocyte degeneration and large bridging necrosis induced by CCl4 treatment. Moreover, Bay‐X‐1005 induced a reduction in the gelatinolytic activity of matrix metalloproteinase‐2 (MMP‐2) and a decrease in mRNA expression of tissue inhibitor of MMP‐2. The FLAP inhibitor reduced leukotriene (LT)B4 and cysteinyl LT levels and down‐regulated 5‐LO and FLAP protein expression in the liver. It is interesting that a significant increase in the hepatic formation of lipoxin A4, an endogenous, anti‐inflammatory lipid mediator involved in the resolution of inflammation, was observed after the administration of Bay‐X‐1005. These findings support the concept that modulation of the 5‐LO pathway by FLAP inhibition may be useful in the prevention of hepatotoxin‐induced necro‐inflammatory injury.