Pathogenesis of sodium retention in cirrhosis.
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Ascites↗
Biomedical subjects
V Arroyo
Publications and source records attributed to V Arroyo.
Paracentesis in the management of cirrhotic ascites.
During the last few years, several studies including six randomised, controlled trials reevaluating therapeutic paracentesis in the management of cirrhotic patients with tense ascites have been reported. The main findings of these investigations are: (i) Repeated large-volume paracentesis (evacuation of 4-6 l/day until complete mobilization of ascites) or total paracentesis (complete mobilization of ascites in only one tap) associated with i.v. albumin infusion (6-8 g/l of ascitic fluid removed) are more effective in eliminating the intra-abdominal fluid than conventional diuretic therapy, are associated with a lower incidence of complications and considerably reduce the duration of hospital stay and the cost of treatment; (ii) The mobilization of ascites by paracentesis without albumin infusion is associated with an impairment in effective circulating blood volume, as indicated by a decrease in cardiac output, central venous pressure, pulmonary capillary wedge pressure and plasma concentration of atrial natriuretic peptide and a marked elevation of plasma renin activity and aldosterone concentration. In 20% of patients this circulatory disturbance is accompanied by the development of renal impairment and/or dilutional hyponatraemia. These changes can be detected within the first 24 h following complete mobilization of ascites and do not occur when plasma volume is expanded with albumin; (iii) Hemaccel and dextran 70 appear to be as effective as albumin in preventing renal and electrolyte complications after paracentesis; (iv) Therapeutic paracentesis is an alternative treatment to peritoneovenous shunting in cirrhotic patients with refractory ascites.
Ascites↗
Mechanism of sodium retention and ascites formation in cirrhosis.
Renal sodium and water retention and ascites associated with cirrhosis develop in the setting of severe sinusoidal portal hypertension, hyperdynamic circulation (characterized by arterial hypotension, hypervolaemia, high cardiac output and low peripheral vascular resistance), homeostatic activation of the renin-angiotensin-aldosterone system, sympathetic nervous system and antidiuretic hormone production (i.e. mechanisms designed to maintain arterial pressure within normal limits) and marked increase in hepatic and splanchnic lymph production that overcomes the transport capacity of the lymphatic vessels to the general circulation, leading to leakage of fluid within the peritoneal cavity. Splanchnic arteriolar vasodilation and the increased splanchnic blood flow that characterize portal hypertensive states could be a major factor in the pathogenesis of cirrhotic ascites because it may account for the hyperdynamic circulation, the activation of endogenous neurohormonal systems that cause sodium and water retention and, also, by altering of splanchnic capillary haemodynamics and permeability, the excessive production of lymph in this vascular territory.
Ascites↗
Impaired responsiveness to angiotensin II in experimental cirrhosis: role of nitric oxide.
Impaired vascular responsiveness to angiotensin II is a common feature in human cirrhosis with ascites. The aim of this study was to investigate whether vascular reactivity to angiotensin II is also decreased in rats with carbon tetrachloride-induced cirrhosis and ascites and to assess the role of endogenous nitric oxide in this abnormality. Increasing doses of angiotensin II (from 31 to 500 ng.kg-1.min-1) induced significantly smaller increases in total peripheral resistance in conscious cirrhotic rats with ascites (n = 8) than in control animals (n = 9) at each dose tested. A reduced response to angiotensin II was also observed in vitro in aortic rings of rats with cirrhosis and ascites compared with that in control aortic rings (maximal response: 104 +/- 16 mg vs. 204 +/- 18 mg; p < 0.001). This in vitro hyporesponsiveness to angiotensin II in aortic rings of cirrhotic rats with ascites was reversed on endothelium denudation or nitric oxide synthesis inhibition with N omega-nitro-L-arginine but was not influenced by cyclooxygenase inhibition with indomethacin. In conclusion, this study shows reduced vascular reactivity to angiotensin II in carbon tetrachloride-induced cirrhosis with ascites and indicates that this abnormality is mediated by nitric oxide.
Angiotensin II↗
Effect of dipyridamole on kidney function in cirrhosis.
Adenosine is a potent endogenous renal vasoconstrictor. To investigate the sensitivity of the renal circulation to adenosine in cirrhosis, we evaluated kidney function and vasoactive hormones in 20 patients with cirrhosis before and after administration of dipyridamole (0.4 mg/kg, intravenously), a drug that increases extracellular levels of adenosine. In patients with ascites and increased plasma renin activity (6.9 +/- 4.0 ng/ml.hr [mean +/- S.D.]) (n = 7), dipyridamole induced marked reductions in renal plasma flow (from 623 +/- 294 to 374 +/- 188 ml/min, p = 0.03), glomerular filtration rate (from 89 +/- 22 to 48 +/- 16 ml/min, p = 0.009), urine volume (from 7.1 +/- 2.1 to 1.5 +/- 1.1 ml/min, p = 0.0001), free water clearance (from 4.0 +/- 1.7 to 0.4 +/- 0.6 ml/min, p = 0.001) and sodium excretion (from 28 +/- 36 to 7 +/- 15 mu Eq/min, p = 0.05) in the absence of changes in arterial pressure, plasma renin activity and levels of aldosterone, norepinephrine and antidiuretic hormone. In patients without ascites (n = 5) and in patients with ascites and normal plasma renin activity (0.9 +/- 0.5 ng/ml.hr) (n = 8), renal plasma flow and glomerular filtration rate did not change significantly after dipyridamole administration, whereas excretion of sodium and free water was reduced. These results indicate that in cirrhotic patients with ascites and overactivity of the renin-angiotensin system, dipyridamole induces renal vasoconstriction in the absence of changes in systemic hemodynamics, suggesting that these patients are particularly sensitive to the renal vasoconstrictor effect of endogenous adenosine.
Ascites↗
Spontaneous bacterial peritonitis in cirrhosis: predictive factors of infection resolution and survival in patients treated with cefotaxime.
Cefotaxime is the most commonly used antibiotic for initial therapy of spontaneous bacterial peritonitis in cirrhosis. However, since the introduction of cefotaxime no study has been performed to investigate factors influencing prognosis in cirrhotic patients with this type of infection. In this study, predictive factors for infection resolution and patient survival were investigated in 213 consecutive episodes of spontaneous bacterial peritonitis in 185 cirrhotic patients. All patients were initially treated with cefotaxime. One hundred sixty-five episodes (77%) resolved with cefotaxime alone, and two more episodes (1%), initially unresponsive to cefotaxime, were cured after modification of antibiotic therapy. In a multivariate analysis (stepwise logistic regression), only 4 of 51 clinical and laboratory variables obtained at the time of diagnosis of infection were identified as independent predictors of infection resolution: band neutrophils in white blood cell count, community-acquired vs. hospital-acquired peritonitis, blood urea nitrogen level and serum aspartate aminotransferase level. No patient experienced serious adverse effects related to cefotaxime. Eighty-two patients died during hospitalization (38% mortality rate in relation to the 213 episodes of peritonitis). In the multivariate analysis, six variables were independently correlated with survival: blood urea nitrogen level, serum aspartate aminotransferase level, community-acquired vs. hospital-acquired peritonitis, age, Child-Pugh score and ileus. No microbiological data had predictive value for infection resolution or survival.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Renal failure in cirrhosis and liver transplantation.
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Ascites↗
Brachial and femoral artery blood flow in cirrhosis: relationship to kidney dysfunction.
Brachial artery and common femoral artery blood flows and cardiac output were measured with duplex-Doppler ultrasonography in 12 normal subjects, 12 patients with compensated cirrhosis and 35 patients with cirrhosis and ascites (8 with functional kidney failure). The aim of this study was to investigate whether arteriolar vasodilation in these vascular territories contributes to hyperdynamic circulation in cirrhosis. Cardiac output was significantly increased and systemic vascular resistance significantly reduced in the three groups of cirrhotic patients. We found no significant differences between normal subjects and compensated cirrhotic patients in brachial artery (55 +/- 7 vs. 57 +/- 7 ml/min) and femoral artery (353 +/- 20 vs. 310 +/- 25 ml/min) blood flow. Nonazotemic cirrhotic patients with ascites showed significantly lower (p < 0.05) brachial artery blood flow (40 +/- 3 ml/min) than healthy subjects and compensated patients. Femoral artery blood flow (327 +/- 25 ml/min), however, was not significantly different. Brachial artery (25 +/- 3 ml/min) and femoral artery (213 +/- 22 ml/min) blood flows were markedly reduced in the patients with kidney failure (p < 0.05 with respect to the other three groups). Glomerular filtration rate correlated directly with brachial (r = 0.74, p = 0.0001) and femoral (r = 0.52, p = 0.03) artery blood flow in the cirrhotic patients. These results indicate that the arteriolar vasodilation causing hyperdynamic circulation in cirrhosis does not take place in the brachial and femoral vascular territories.
Aged↗
Renal effects of acute isosorbide-5-mononitrate administration in cirrhosis.
The aim of this study was to assess the effects of an oral dose (20 mg) of isosorbide-5-mononitrate on systemic hemodynamics, kidney function, plasma renin activity and plasma aldosterone and atrial natriuretic peptide concentrations in 16 nonazotemic cirrhotic patients. Isosorbide-5-mononitrate significantly reduced cardiopulmonary pressures, cardiac output, peripheral vascular resistance, mean arterial pressure, renal plasma flow, glomerular filtration rate, free water clearance, sodium excretion and atrial natriuretic peptide concentration and significantly increased renin and aldosterone values. Cardiopulmonary pressures, atrial natriuretic peptide, cardiac output and mean arterial pressure decreased to a similar extent in patients with (n = 9) and without ascites (n = 7). In patients with ascites we noted marked increases in plasma renin activity (3.7 +/- 1.1 ng/ml/hr to 6.4 +/- 1.8 ng/ml/hr; p = 0.01) and aldosterone level (61.1 +/- 17.5 ng/dl to 108.4 +/- 36.1 ng/dl; p = 0.01). In contrast, in patients without ascites the elevation of plasma renin activity (0.5 +/- 0.16 ng/ml/hr to 0.95 +/- 0.27 ng/ml/hr; p = 0.02) and aldosterone level (5.9 +/- 1.3 ng/dl to 12.3 +/- 3.8 ng/dl; p = 0.02) was mild, and in no case did these parameters increase over the upper normal limit. Isosorbide-5-mononitrate produced a significantly greater reduction of glomerular filtration rate (-21.4% +/- 3.3% vs. -8.9% +/- 4.2%; p = 0.03) and free water clearance (-82.4% +/- 16.1% vs. -34.5% +/- 12.3%; p = 0.03) in patients with ascites than in those without.(ABSTRACT TRUNCATED AT 250 WORDS)
Aldosterone↗
Pathogenesis of arterial hypotension in cirrhotic rats with ascites: role of endogenous nitric oxide.
Nitric oxide is a vasodilator tonically secreted by endothelial cells that is involved in the regulation of arteriolar tone. This study, which includes two protocols, was performed to investigate whether nitric oxide plays a role in the pathogenesis of arterial hypotension in cirrhosis with ascites. In protocol 1, the administration of increasing doses (25, 50, 250, 500 and 1,000 micrograms.kg-1.min-1) of the nitric oxide biosynthesis inhibitor N omega-nitro-L-arginine to 18 conscious rats with cirrhosis and ascites produced, at each dose tested, a significantly greater increase in arterial pressure than in 17 conscious control rats. At the lowest dose of N omega-nitro-L-arginine, arterial pressure significantly rose in cirrhotic rats but not in controls. In protocol 2, arterial pressure, estimated renal plasma flow, glomerular filtration rate and sodium excretion were measured in 12 cirrhotic rats with ascites and 10 control rats before and during the sequential infusion of previously selected doses of N omega-nitro-L-arginine (25, 50 and 250 micrograms.kg-1.min-1). Changes in arterial pressure reproduced those observed in protocol 1. In control rats, N omega-nitro-L-arginine caused a decrease in estimated renal plasma flow without affecting glomerular filtration rate or sodium excretion. In contrast, N omega-nitro-L-arginine administration to cirrhotic animals did not produce any appreciable renal vasoconstrictor effect, and it increased glomerular filtration rate and sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration.
To investigate the long-term probability of the appearance of the first episode of spontaneous bacterial peritonitis in cirrhosis with ascites and to identify predictors of this complication, we closely followed throughout their illness 127 patients consecutively admitted to our unit for the treatment of an episode of ascites without prior spontaneous bacterial peritonitis (follow-up period: 21 +/- 22 mo). Thirteen patients (10%) had the first spontaneous bacterial peritonitis episode during follow-up. The appearance probability of this complication is 11% at 1 yr and 15% at 3 yr. Thirty-three variables obtained at admission (including clinical data, standard liver and kidney function test results, ascitic fluid protein concentrations and hemodynamic parameters) were analyzed in relation to their value in predicting spontaneous bacterial peritonitis development. In univariate analysis (Kaplan-Meier curves) five variables reached statistical significance (p less than 0.05) as predictive factors for the development of the first spontaneous bacterial peritonitis episode. These five variables were poor nutritional status, increased serum bilirubin levels, increased serum AST levels, decreased prothrombin activity and reduced total protein concentration in ascitic fluid. When these five variables were introduced in a multivariate analysis, only the ascitic fluid protein concentration was found to correlate independently with spontaneous bacterial peritonitis development (p = 0.002). The probability of first spontaneous bacterial peritonitis after 3 yr of follow-up was 24% and 4% in patients with ascitic fluid protein content lower than 1 gm/dl and greater than or equal to 1 gm/dl, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Arteriolar vasodilation and the pathogenesis of the hyperdynamic circulation and renal sodium and water retention in cirrhosis.
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Dilatation, Pathologic↗
Mineralocorticoid escape in patients with compensated cirrhosis and portal hypertension.
Failure to escape from mineralocorticoids in compensated cirrhosis is considered a major argument supporting the overflow theory of ascites. To assess the frequency and mechanism of mineralocorticoid escape in cirrhosis, 9-alpha-fluorohydrocortisone (0.6 mg/day) was administered to 19 patients with compensated cirrhosis, portal hypertension, and no history of ascites who were able to maintain sodium balance on a 250 mmol Na+ diet. Fifteen patients (78.9%) escaped from mineralocorticoids, while 4 patients (21.1%) did not escape and developed ascites. Patients who did not escape had significantly higher cardiac index (4.97 +/- 0.42 vs 3.46 +/- 0.21 L.min-1.m-2) and lower peripheral vascular resistance (485.9 +/- 37.5 vs. 665.8 +/- 32.9 dyne.s.cm-5/m2) than those who escaped. Hepatic venous pressure gradient was not significantly different. The escape phenomenon was associated with a significant increase in mean arterial pressure, creatinine clearance, and atrial natriuretic factor and suppression of plasma renin activity. All of these parameters showed minimal or no changes in patients who did not escape. These results indicate that failure to escape from mineralocorticoids is uncommon in patients with compensated cirrhosis, is related to an inadequate expansion of effective plasma volume due to the accumulation of ascites, and occurs in patients with marked peripheral arteriolar vasodilation.
Adult↗
Effects of somatostatin on renal function in cirrhosis.
To investigate the renal effects of somatostatin in cirrhosis, renal function and plasma and urinary levels of endogenous neurohumoral vasoactive substances were measured in conditions of intravenous water overload (20 mL/kg body wt with 5% glucose) before and during the intravenous infusion of somatostatin (250-500 micrograms/h) in 6 cirrhotic patients without ascites and 17 nonazotemic cirrhotic patients with ascites. Somatostatin induced a significant reduction of renal plasma flow, glomerular filtration rate, and free water clearance in both groups of patients. In patients with ascites, somatostatin also reduced urinary sodium excretion. Changes in renal function were significantly more marked in patients with ascites than in those without ascites and occurred in the absence of changes in mean arterial pressure and plasma levels of renin, aldosterone, norepinephrine, antidiuretic hormone, and atrial natriuretic peptide. Somatostatin induced a significant reduction in the plasma concentration of glucagon and urinary excretion of prostaglandin E2 that was not related to changes in renal function. These findings indicate that somatostatin administration induces renal vasoconstriction and impairs glomerular filtration rate, free water clearance, and sodium excretion in cirrhosis by a mechanism unrelated to systemic hemodynamics and endogenous neurohumoral vasoactive systems.
Dinoprostone↗
Renal insensitivity to atrial natriuretic peptide in patients with cirrhosis and ascites. Effect of increasing systemic arterial pressure.
The IV infusion of pharmacological doses (0.05 microgram.kg-1.min-1) of atrial natriuretic peptide to 16 patients with cirrhosis and ascites induced a significant increase in sodium excretion (65 +/- 23 to 517 +/- 231 mu Eq/min), urine volume (10.7 +/- 2.3 to 15.7 +/- 3.7 mL/min), and glomerular filtration rate (89 +/- 4 to 110 +/- 4 mL/min) in only 5 patients (responders). No significant changes in these parameters (15 +/- 6 to 11 +/- 4 mu Eq/min, 5.5 +/- 1.0 to 4.2 +/- 1.1 mL/min, and 81 +/- 5 to 79 +/- 6 mL/min, respectively) were observed in the remaining patients (nonresponders). Compared with responders, nonresponders had significantly lower baseline sodium excretion (P less than 0.02), urine flow (P less than 0.05), free water clearance (2.5 +/- 0.9 vs. 6.9 +/- 2.1 mL/min; P less than 0.05), and mean arterial pressure (82 +/- 3 vs. 96 +/- 2 mm Hg; P less than 0.01) and significantly higher plasma renin activity (16.3 +/- 4.9 vs. 1.8 +/- 0.2 ng.mL-1.h-1; P less than 0.05) and aldosterone level (99 +/- 24 vs. 13 +/- 2 ng/dL; P less than 0.05). Atrial natriuretic peptide produced a similar reduction of arterial pressure in both groups. To investigate whether the blunted natriuretic response to atrial natriuretic peptide in nonresponders was caused by their lower arterial pressure, atrial natriuretic peptide was infused in 7 of these patients after increasing their arterial pressure to the levels of responders with nonrepinephrine. The increase in arterial pressure (from 81 +/- 5 to 95 +/- 5 mm Hg), which was not associated with significant changes in plasma renin activity and aldosterone concentration, did not reverse the blunted renal response to atrial natriuretic peptide in any of these patients. These results indicate that cirrhotic patients with blunted renal response to atrial natriuretic peptide are characterized by low arterial pressure, marked overactivity of the renin-aldosterone system, and severe sodium and water retention. Correction of hypotension without increasing effective blood volume does not restore renal insensitivity to atrial natriuretic peptide.
Atrial Natriuretic Factor↗
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)
Humans↗
Selective intestinal decontamination in the prevention of bacterial infection in patients with acute liver failure.
To investigate whether selective intestinal decontamination from oral administration of poorly absorbable antibiotics is effective in preventing bacterial infection in patients with acute liver failure, the incidence of nosocomial infection in 34 patients consecutively admitted to hospital between 1985-1990 and treated with either neomycin + colistin + nystatin or norfloxacin + nystatin (group I) was compared to the incidence of infection in 57 patients who did not receive oral, poorly absorbable antibiotics and who were consecutively admitted between 1972-1984 (group II). Patients from groups I and II had similar clinical and laboratory data at hospital admission. Twelve patients from group I and 33 from group II developed bacterial infection during the study period. The probability of infection was significantly different (p = 0.0083) in the two groups: 19% vs. 39% at the 3rd day of admission, 33% vs. 74% at the 7th day, and 48% vs. 78% at the 14th day, respectively. This difference was due to a different rate of infection from enterobacteria. Enterobacteria caused one infectious episode in group I and 24 in group II (p less than 0.001). The incidence of infections caused by other organisms, however, was similar in both groups (15 and 19 episodes, respectively). These results suggest that selective intestinal decontamination is useful in reducing the risk of infection from enterobacteria in patients with acute liver failure.
Adult↗
[Liver cirrhosis: pathogenesis of ascites and disturbance of renal function].
The accumulation of ascites in cirrhosis has been classically attributed to the transudation of fluid from the splanchnic vascular bed to the peritoneal cavity due to the presence of portal hypertension. This transudation of fluid would induce hypovolemia responsible for the renal abnormalities frequently observed in these patients. Recent studies, however, indicate that the pathophysiology of ascites in cirrhosis is far more complex. Cirrhotic patients with ascites usually have profound disturbances in systemic hemodynamics and renal function and an activation of the endogenous vasoactive systems that contribute to the formation of ascites. In the present article the pathogenesis of these disturbances and their possible contribution to the formation of ascites are discussed.
Ascites↗