Sodium Retention In Cirrhosis Research Articles

Pathways of hepatic and renal damage through non-classical activation of the renin-angiotensin system in chronic liver disease.

In liver cirrhosis, renin-angiotensin system (RAS) activation sustains renal sodium retention and hepatic fibrogenesis. New information has recently enlivened the traditional concept of RAS. For instance, renin and prorenin bind their ubiquitous receptors, resulting in the local production of angiotensin (Ang) II; increased serum calcium and calcimimetic agents, through stimulation of extracellular calcium-sensing receptors (CaSR), blunt renin production and lead to natriuretic effects in human and experimental cirrhosis. Alongside systemic production, there is Ang II tissue production within various organs through RAS enzymes different from angiotensin-converting enzyme (ACE), that is chymase, tissue plasminogen activator and several cathepsins. In experimental cirrhosis, inhibition of chymase leads to natriuretic and hepatic antifibrotic effects, without changes in systemic haemodynamics. In the kidney, local RAS coordinates proximal and distal tubular sodium reabsorption. However, renalase, whose plasma and tissue levels are severely altered in experimental cirrhosis, degrades systemic and renal tubule catecholamines, antagonizing the effects of renal RAS. Angiotensinogen-derived natriuretic and vasodilating peptides (Ang1-9, Ang1-7, Ang3-8) and their receptors have been described. Receptor agonists or antagonists are available to affect portal hypertension and sodium retention in cirrhosis. ACE2-dependent generation of Ang1-7 may inhibit experimental liver fibrosis. inhibition of Ang1-7 clearance by means of neprilysin blockade has portal hypotensive and natriuretic effects. Ang1-12, whose production renin does not regulate, is converted to several different angiotensin peptides via chymase. Finally, Ang II behaves as either an antinatriuretic or a natriuretic agent, based on the tissue content of AT1 R and AT2 R receptors, their ratio being prone to pharmacological modulation.

Internal dysregulation of the renin system in patients with stable liver cirrhosis

Sodium retention in cirrhosis is associated with changes in the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system (SNS), and the glomerular filtration rate (GFR). We hypothesized that in cirrhosis the acute reactions of RAAS and SNS to volume expansion are qualitatively intact, but occurring from elevated baseline levels. Acute cardiovascular, neurohumoral and renal responses to central blood volume changes were studied in cirrhotic patients and healthy controls. In patients, baseline plasma renin concentration (PRC) was elevated 5-fold compared to controls (p < .001); it increased during standing (+144%, p < .001) and remained elevated during subsequent sitting (+118%, p < .001). At baseline, plasma angiotensin II (pANGII) was not elevated significantly (14 ± 2 vs. 9 ± 2 pg/mL) in contrast to plasma aldosterone (pAldo, +160%, p < .001). During orthostatic RAAS activation, the rise in pAngII per unit increase in PRC was 0.04 pg AngII/mIU and 0.48 pg AngII/mIU in patients and controls, respectively (p < .001); similarly, the change in pAldo per unit change in pANGII was 3.6 in patients and 14.5 pg/pg in controls (p < .001). Plasma noradrenaline was elevated in the patients, but the dynamic changes were virtually identical to those of controls. During standing, abrupt decreases in renal blood flow (−63%, p < .001) and GFR (−42% p < .04) occurred only in patients. In conclusion, in stable cirrhosis, static and dynamic dysregulation exists within the RAAS; in the supine position pAngII levels are inappropriately low, and the AngII-mediated regulation of aldosterone secretion is severely impeded. In cirrhotic patients, profound reductions in renal blood flow and GFR occur during standing.

Effect of chronic administration of sildenafil on sodium retention and on the hemodynamic complications associated with liver cirrhosis in the rat

Previous studies demonstrated increased phosphodiesterase-5 (PDE5) activity and expression in the kidneys of rats with liver cirrhosis. Acute intravenous administration of PDE5 inhibitors enhanced sodium excretion in these rats. The aim of the present study was to examine the effects of chronic administration of sildenafil on renal sodium handling and hemodynamics in rats with liver cirrhosis. Male Sprague-Dawley rats underwent bile-duct ligation and excision or sham operation and were housed in metabolic cages throughout the study. Body weight, food intake, water intake and urine volume were measured daily, and plasma samples were obtained twice weekly. Fourteen days following surgery sildenafil or its vehicle (dimethylsulfoxide) were administered (20 mg/kg subcutaneously 3 times/day). Two weeks later, systemic hemodynamics were measured under general anesthesia. Sildenafil enhanced the systemic vasodilatation associated with liver cirrhosis and reduced the arterial pressure. There was no reduction in the glomerular filtration rate, however. Despite these hemodynamic changes, sildenafil prevented the decrease in sodium excretion observed in the bile-duct-ligated group receiving vehicle and markedly increased fractional sodium excretion relative to the other groups. These results suggest that chronic sildenafil administration may help prevent or ameliorate sodium retention in cirrhosis, but that hemodynamic adverse effects may ensue.

Sodium retention and ascites formation in a cholestatic mice model

Renal sodium retention in experimental liver cirrhosis originates from the distal nephron sensitive to aldosterone. The aims of this study were to (1) determine the exact site of sodium retention along the aldosterone-sensitive distal nephron, and (2) to evaluate the role of aldosterone and mineralocorticoid receptor activation in this process. Liver cirrhosis was induced by bile duct ligation in either adrenal-intact or corticosteroid-clamped mice. Corticosteroid-clamp was achieved through adrenalectomy and corticosteroid supplementation with aldosterone and dexamethasone via osmotic minipumps. 24-hours renal sodium balance was evaluated in metabolic cages. Activity and expression of sodium- and potassium-dependent adenosine triphosphatase were determined in microdissected segments of nephron. Within 4-5 weeks, cirrhosis induced sodium retention in adrenal-intact mice and formation of ascites in 50% of mice. At that time, sodium- and potassium-dependent adenosine triphosphatase activity increased specifically in cortical collecting ducts. Hyperaldosteronemia was indicated by increases in urinary aldosterone excretion and in sgk1 (serum- and glucocorticoid-regulated kinase 1) mRNA expression in collecting ducts. Corticosteroid-clamp prevented induction of sgk1 but not cirrhosis-induced sodium retention, formation of ascites and stimulation of sodium- and potassium-dependent adenosine triphosphatase activity and expression (mRNA and protein) in collecting duct. These findings demonstrate that sodium retention in cirrhosis is independent of hyperaldosteronemia and of the activation of mineralocorticoid receptor. Bile duct ligation in mice induces cirrhosis which, within 4-5 weeks, leads to the induction of sodium- and potassium-dependent adenosine triphosphatase in cortical collecting ducts, to renal sodium retention and to the formation of ascites. Sodium retention, ascites formation and induction of sodium- and potassium-dependent adenosine triphosphatase are independent of the activation of mineralocorticoid receptors by either aldosterone or glucocorticoids.

Effect of phosphodiesterase 5 inhibitor on alteration in vascular smooth muscle sensitivity and renal function in rats with liver cirrhosis

Previous studies suggested that increased activity of phosphodiesterase (PDE)5 in the kidneys of cirrhotic rats contributes to sodium retention. This study examined the role of PDE5 in the changes in vascular reactivity, hemodynamics, and sodium excretion in rats with liver cirrhosis. Four weeks after bile duct ligation (BDL) or sham operation (SO), in vitro reactivity of aortic rings to various agents and in vivo effects of a PDE5-selective inhibitor [1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)pyrazolo[3,4d]-pyrimidin-4-(5H)-one, DMPPO] were studied. The vasodilator responses to nitroglycerin and S-nitroso-N-acetyl-penicillamine (SNAP) in phenylephrine-precontracted rings without endothelium were attenuated in BDL compared with SO rats. Pretreatment with DMPPO (0.1 microM) enhanced these responses and eliminated the differences between the two groups. Vasodilation to DMPPO itself was also less in BDL rats. The responses to phenylephrine were attenuated in endothelium-rich aorta from BDL relative to SO rats, but they were similar in endothelium-denuded aorta and remained similar despite preincubation with SNAP (0.1 microM) alone or with SNAP and DMPPO. In vivo, BDL rats were vasodilated relative to SO rats; DMPPO (5 mg/kg i.v.) decreased arterial pressure and vascular resistance in both groups equally and caused significant increase in sodium excretion in BDL rats only. In conclusion, the results are in accordance with a possible increase in PDE5 activity in aorta and kidney of cirrhotic rats that results in reduced responses to NO donors and contributes to the increase in sodium retention. PDE5 inhibitors may ameliorate sodium retention in cirrhosis but may worsen vasodilation. Examining the effect of PDE5 inhibitors after chronic administration will be more revealing.

Cyclic AMP‐phosphodiesterases inhibitor improves sodium excretion in rats with cirrhosis and ascites

The mechanisms responsible for renal dysfunction and sodium retention in cirrhosis remain unclear. Cyclic AMP (cAMP) regulates sodium reabsorption in the proximal nephron. This study investigates the role of cAMP metabolism in renal dysfunction in cirrhosis. Renal function was studied by the clearance technique in anesthetized control and cirrhotic rats with or without ascites. cAMP phosphodiesterase (PDE) activity was measured in the renal cortex in vitro. Moroever, the effects on renal function of the intravenous administration of cAMP and rolipram, a powerful and specific cAMP-PDE4 inhibitor, were evaluated. In control and in non-ascitic cirrhotic rats, cAMP administration significantly increased sodium and phosphate excretions, but did not change these excretions in cirrhotic rats with ascites. cAMP-PDE activity was higher in ascitic than in control rats (P < 0.05). Rolipram infusion significantly increased sodium and phosphate excretion only in cirrhotic rats with ascites. These results suggest that increased renal cAMP-PDE activity is responsible for resistance to the natriuretic effects of cAMP in cirrhosis and plays a role in the development of ascites.

Trial for treatment of refractory ascites TIPS the scales

Trial for treatment of refractory ascites TIPS the scales

Mechanisms of water and sodium retention in cirrhosis and the pathogenesis of ascites.

Patients with advanced cirrhosis and portal hypertension often show an abnormal regulation of extracellular fluid volume, resulting in the accumulation of fluid as ascites, pleural effusion or oedema. The mechanisms responsible for ascites formation include alterations in the splanchnic circulation as well as renal functional abnormalities that favour sodium and water retention. Renal abnormalities occur in the setting of a hyperdynamic state characterized by an increase cardiac output, a reduction in total vascular resistance and an activation of neurohormonal vasoactive systems. This circulatory dysfunction, due mainly to intense arterial vasodilation in the splanchnic circulation, is considered to be a primary feature in the pathogenesis of ascites. A major factor involved in the development of splanchnic arterial vasodilation is nitric oxide (NO), a potent vasodilator that is elevated in the splanchnic circulation of patients with cirrhosis. This event decreases effective arterial blood volume and leads to fluid accumulation and renal function abnormalities which are a consequence of the homeostatic activation of vasoconstrictor and antinatriuretic factors triggered to compensate for a relative arterial underfilling. The net effect is avid retention of sodium and water as well as renal vasoconstriction. The mechanisms of sodium and water retention and ascites formation in patients with cirrhosis are discussed in this review.

Increased natriuretic efficiency of furosemide in rats with carbon tetrachloride-induced cirrhosis.

The authors examined the natriuretic efficiency of furosemide in rats with cirrhosis induced by carbon tetrachloride (CCl(4)). Rats were treated for 17 weeks with intraperitoneal injections of CCl(4) in groundnut oil twice a week throughout the study. Control rats were treated with vehicle (groundnut oil). Studies in metabolic cages showed that sodium retention was present from week 14. Renal clearance experiments were performed in chronically, instrumented conscious rats at the end of week 14 and at the termination of the study (end week 16) when ascites and hyponatremia were present. After 14 weeks, cirrhotic rats had sodium retention along with increased renal plasma flow, normal GFR, normal renal lithium handling, and a significantly increased diuretic (+41% vs. control) and natriuretic (+56% vs. control) response to a test dose furosemide (7.5 mg/kg b.w., intravenously). The natriuretic efficiency of furosemide, i.e., the natriuresis expressed relative to the furosemide excretion rate (triangle upU(Na)V/U(FUR)V) was increased by 51% versus control. After 17 weeks, ascites and hyponatremia had developed, and significant decreases in renal plasma flow (-33%), GFR (-30%), and fractional lithium excretion (-44%) were observed. At this stage urinary recovery of furosemide was significantly decreased and the diuretic (-27% vs. Control) and natriuretic (-38% vs. control) responses to furosemide were significantly impaired. However, the increased natriuretic efficiency of furosemide was still present (+34% vs. control). Together these results suggest that increased sodium reabsorption in the thick ascending limb of Henle's loop is involved in the renal sodium retention in cirrhosis in rats that eventually results in decompensation with the formation of ascites.

Sodium handling in patients with well compensated cirrhosis is dependent on the severity of liver disease and portal pressure

BACKGROUND AND AIMSTo test the contribution of portal pressure gradient (PPG) and neurohumoral factors to sodium handling in cirrhotic patients without ascites, by comparing preascitic cirrhotic patients with patients with...

Complications of cirrhosis. II. Renal and circulatory dysfunction. Lights and shadows in an important clinical problem

The pathophysiology of circulatory and renal dysfunction in cirrhosis and the treatment of ascites and related conditions (hepatorenal syndrome and spontaneous bacterial peritonitis) have been research topics of major interest during the last two decades. However, many aspects of these problem remain unclear and will constitute major areas of investigation in the next millennium. The pathogenesis of sodium retention, the most prevalent renal function abnormality of cirrhosis, is only partially known. In approximately one third of patients with ascites, sodium retention occurs despite normal activity of the renin-aldosterone and sympathetic nervous systems and increased circulating plasma levels of natriuretic peptides and activity of the so-called natriuretic hormone. These patients present an impairment in circulatory function which, although less intense, is similar to that of patients with increased activity of the renin-aldosterone and sympathetic nervous systems, suggesting that antinatriuretic factors more sensitive to changes in circulatory function that these systems may be important in the pathogenesis of sodium retention in cirrhosis. The development of drugs that inhibit the tubular effect of antidiuretic hormone and increase renal water excretion without affecting urine solute excretion has opened a field of great interest for the management of water retention and dilutional hyponatremia in cirrhosis. Two families of drugs, the V2 vasopressin receptor antagonists and the kappa-opioid agonists, have been shown to improve free water clearance and correct dilutional hyponatremia in human and experimental cirrhosis with ascites. The first type of drugs blocks the tubular effect of antidiuretic hormone and the second inhibits antidiuretic hormone secretion by the neurohypophysis. On the other hand, two new treatments have also been proved to reverse hepatorenal syndrome in cirrhosis. The most interesting one is that based on the simultaneous administration of plasma volume expansion and vasoconstrictors. The second is transjugular intrahepatic portosystemic shunt. The long-term administration (1–3 weeks) of analogs of vasopressin (ornipressin or terlipressin) or other vasoconstrictors together with plasma volume expansion with albumin is associated with a dramatic improvement in circulatory function and normalization of serum creatinine concentration in patients with severe hepatorenal syndrome. Of interest is the observation that in many of these patients, hepatorenal syndrome does not recur following discontinuation of the treatment, thus raising important questions about the mechanism by which hepatorenal syndrome follows a progressive course in most untreated cases. The pathogenesis of circulatory dysfunction in cirrhosis and the role of local mechanisms in the development of the splanchnic arteriolar vasodilation associated with portal hypertension will continue as important topics in clinical and basic research in Hepatology. Of special interest is the study of the mechanism by which circulatory function further deteriorates following complications such as severe bacterial infection or therapeutic interventions such as therapeutic paracentesis, and the adverse consequences of the impairment in circulatory function on renal and hepatic hemodynamics. Finally, although major advances have been made concerning the treatment and secondary prophylaxis of spontaneous bacterial peritonitis in cirrhosis, many aspects of the pathogenesis of this infection remain unclear. The mechanism of bacterial translocation and of the colonization of bacteria in the ascitic fluid are particularly important to design adequate measures for primary prophylaxis of this severe bacterial infection.

Role of cardiac structural and functional abnormalities in the pathogenesis of hyperdynamic circulation and renal sodium retention in cirrhosis

The aim of this study was to assess the relationship between subtle cardiovascular abnormalities and abnormal sodium handling in cirrhosis. A total of 35 biopsy-proven patients with cirrhosis with or without ascites and 14 age-matched controls underwent two-dimensional echocardiography and radionuclide angiography for assessment of cardiac volumes, structural changes and systolic and diastolic functions under strict metabolic conditions of a sodium intake of 22 mmol/day. Cardiac output, systemic vascular resistance and pressure/volume relationship (an index of cardiac contractility) were calculated. Eight controls and 14 patients with non-ascitic cirrhosis underwent repeat volume measurements and the pressure/volume relationship was re-evaluated after consuming a diet containing 200 mmol of sodium/day for 7 days. Ascitic cirrhotic patients had significant reductions in (i) cardiac pre-load (end diastolic volume 106+/-9 ml; P<0.05 compared with controls), due to relatively thicker left ventricular wall and septum (P<0.05); (ii) afterload (systemic vascular resistance 992+/-84 dyn.s.cm(-5); P<0. 05 compared with controls) due to systemic arterial vasodilatation; and (iii) reversal of the pressure/volume relationship, indicating contractility dysfunction. Increased cardiac output (6.12+/-0.45 litres/min; P<0.05 compared with controls) was due to a significantly increased heart rate. Pre-ascitic cirrhotic patients had contractile dysfunction, which was accentuated when challenged with a dietary sodium load, associated with renal sodium retention (urinary sodium excretion 162+/-12 mmol/day, compared with 197+/-12 mmol/day in controls; P<0.05). Cardiac output was maintained, since the pre-load was normal or increased, despite a mild degree of ventricular thickening, indicating some diastolic dysfunction. We conclude that: (i) contractile dysfunction is present in cirrhosis and is aggravated by a sodium load; (ii) an increased pre-load in the pre-ascitic patients compensates for the cardiac dysfunction; and (iii) in ascitic patients, a reduced afterload, manifested as systemic arterial vasodilatation, compensates for a reduced pre-load and contractile dysfunction. Cirrhotic cardiomyopathy may well play a pathogenic role in the complications of cirrhosis.

Role of cardiac structural and functional abnormalities in the pathogenesis of hyperdynamic circulation and renal sodium retention in cirrhosis

The aim of this study was to assess the relationship between subtle cardiovascular abnormalities and abnormal sodium handling in cirrhosis. A total of 35 biopsy-proven patients with cirrhosis with or without ascites and 14 age-matched controls underwent two-dimensional echocardiography and radionuclide angiography for assessment of cardiac volumes, structural changes and systolic and diastolic functions under strict metabolic conditions of a sodium intake of 22 mmol/day. Cardiac output, systemic vascular resistance and pressure/volume relationship (an index of cardiac contractility) were calculated. Eight controls and 14 patients with non-ascitic cirrhosis underwent repeat volume measurements and the pressure/volume relationship was re-evaluated after consuming a diet containing 200 mmol of sodium/day for 7 days. Ascitic cirrhotic patients had significant reductions in (i) cardiac pre-load (end diastolic volume 106±9 ml; P &lt; 0.05 compared with controls), due to relatively thicker left ventricular wall and septum (P &lt; 0.05); (ii) afterload (systemic vascular resistance 992±84 dyn·s·cm-5; P &lt; 0.05 compared with controls) due to systemic arterial vasodilatation; and (iii) reversal of the pressure/volume relationship, indicating contractility dysfunction. Increased cardiac output (6.12±0.45 litres/min; P &lt; 0.05 compared with controls) was due to a significantly increased heart rate. Pre-ascitic cirrhotic patients had contractile dysfunction, which was accentuated when challenged with a dietary sodium load, associated with renal sodium retention (urinary sodium excretion 162±12 mmol/day, compared with 197±12 mmol/day in controls; P &lt; 0.05). Cardiac output was maintained, since the pre-load was normal or increased, despite a mild degree of ventricular thickening, indicating some diastolic dysfunction. We conclude that: (i) contractile dysfunction is present in cirrhosis and is aggravated by a sodium load; (ii) an increased pre-load in the pre-ascitic patients compensates for the cardiac dysfunction; and (iii) in ascitic patients, a reduced afterload, manifested as systemic arterial vasodilatation, compensates for a reduced pre-load and contractile dysfunction. Cirrhotic cardiomyopathy may well play a pathogenic role in the complications of cirrhosis.

Effects of ursodeoxycholic acid on systemic, renal and forearm haemodynamics and sodium homoeostasis in cirrhotic patients with refractory ascites

Systemic arterial vasodilatation has been implicated in the pathogenesis of sodium retention in cirrhosis. Hydrophobic bile acids, which have vasodilatory actions, may be involved. Ursodeoxycholic acid, a hydrophilic bile acid, could potentially decrease systemic arterial vasodilatation, possibly due to its antioxidant effects, and improve sodium handling in cirrhosis. The effects of ursodeoxycholic acid on systemic, renal and forearm haemodynamics, liver function and renal sodium handling were assessed in vasodilated cirrhotic patients with refractory ascites treated with a transjugular intrahepatic porto-systemic shunt (TIPS). Eight cirrhotic patients with refractory ascites without TIPS placement served as controls for the sodium handling effects of ursodeoxycholic acid. From 1 month post TIPS, seven patients were studied before, after 1 month of treatment with ursodeoxycholic acid (15 mg.day-1.kg-1) and at 1 month follow-up. Lipid peroxidation products were used as indices of its antioxidant effects. Ursodeoxycholic acid caused a significant reduction in sodium excretion in both groups (P<0.05). This, in the post-TIPS patients (urinary sodium excretion: 35+/-8 mmol/day at 1 month versus 93+/-21 mmol/day at baseline, P<0.05), was due to a significant increase in sodium reabsorption proximal to the distal tubule (P<0.05), without any significant changes in systemic, renal or forearm haemodynamics, or in liver function. No significant change in lipid peroxidation products was observed. We conclude that: (i) in cirrhotic patients with refractory ascites, ursodeoxycholic acid causes sodium retention, (ii) the abnormality in sodium handling in the post-TIPS cirrhotic patients appears to be the result of a direct effect on the proximal nephron, suggesting that factors other than systemic vasodilatation also contribute to sodium retention in cirrhosis, (iii) caution should be exercised in administering ursodeoxycholic acid in cirrhotic patients with ascites.

The renal sympathetic and renin-angiotensin response to lower body negative pressure in well-compensated cirrhosis

Background & Aims: Certain antinatriuretic hormonal systems may be involved in the subclinical sodium handling abnormality in preascitic cirrhosis. The aims of this study were to determine the following in preascitic cirrhosis: (1) basal activity of the renal sympathetic and renin-angiotensin systems and (2) the relationship between the response of these systems to lower body negative pressure and sodium excretion. Methods: Seven preascitic cirrhotic patients and 9 age- and sex-matched controls were studied on a 150 mmol sodium per day diet. Systemic and renal hemodynamics, renal neurohormonal secretion rates, and sodium excretion were assessed before, during increasing levels of, and after lower body negative pressure, each for 30 minutes. Results: Both groups responded with a significant decrease in central venous pressure ( P < 0.01) that remained higher in the cirrhotics than in the controls throughout the study. Cirrhotics showed significant increases compared with controls in renal renin and angiotensin II secretion rates at −20 mm Hg of lower body negative pressure, which was associated with significant renal sodium retention (96 ± 17 μmol/min vs. 218 ± 21 μmol/min at baseline, P < 0.05), but there was no change in renal sympathetic activity. Conclusions: In preascitic cirrhosis, sodium retention occurs in response to lower body negative pressure, which was associated with increased renal renin-angiotensin activity. Stimulation of the intrarenal renin-angiotensin system may be the initial renal pathophysiological change causing sodium retention in cirrhosis. GASTROENTEROLOGY 1998;115:397-405

Review: the controversy over the pathophysiology of ascites formation in cirrhosis.

The pathogenesis of renal sodium retention and ascites formation in cirrhosis is a subject of much controversy. The generally accepted 'peripheral arterial vasodilatation hypothesis' seems to best explain the mechanism of sodium retention and other clinical findings, such as the hyperdynamic circulation of cirrhosis. However, recent data in pre-ascites and in early ascites do not seem to conform to the peripheral arterial vasodilatation hypothesis. Sodium handling abnormalities can be demonstrated in pre-ascitic cirrhosis when patients are challenged with a sodium load, in the absence of systemic vasodilatation or arterial underfilling. Therefore, an alternative hypothesis with a direct hepatorenal interaction, acting via sinusoidal portal hypertension and/or hepatic dysfunction as the affector mechanism, is proposed to be the initiating event in renal sodium retention in cirrhosis. The second and later process is the development of systemic arterial vasodilatation, possibly due to the presence of excess systemic vasodilators and/or decreased responsiveness of the vasculature to endogenous vasoconstrictors. This, in turn, will lead to a relatively underfilled circulation with consequent activation of neurohumoral systems, promoting further renal sodium retention as described by the peripheral arterial vasodilatation hypothesis and ultimately leading to ascites. When compensatory natriuretic mechanisms fail, refractory ascites develops and hepatorenal syndrome sets in. Thus, renal sodium retention in cirrhosis is the result of interplay of many factors, with direct hepatorenal interaction predominating in earlier stages of the cirrhotic process, while systemic vasodilatation becomes a more important pathogenetic factor as the disease progresses.

Doxazosin given into the renal arteries of patients with cirrhosis: effects on renal sodium handling, hemodynamics and hormones

Excessive sodium retention in cirrhosis is believed to be mediated mainly through sympathetic α 1-adrenergic effects of renal nerves supplying renal proximal tubules and renal vessels. Since previous studies on blockage of these nerves have been unequivocal due to confounding systemic effects and contralateral renal counterregulation, we administered doxazosin, an α 1-adrenoceptor antagonist, over 1 h into both renal arteries of four patients with decompensated cirrhosis. During the first 30 min of doxazosin infusion, when blood pressure was only slightly reduced, there was no evidence of improvement in sodium and water excretion. During the subsequent periods, blood pressure, renal plasma flow, glomerular filtration rate, and urinary output declined. The proximal tubular output of sodium, estimated on the lithium clearance, was initially unchanged, but decreased later during the infusion. Hyperreabsorption of sodium seemed to occur more markedly in the distal than in the proximal part of the nephron and was not alleviated by doxazosin. Urinary prostaglandin E 2 excretion was high but decreased in all patients after doxazosin. The study was terminated prematurely because the expected beneficial effects of doxazosin were clearly lacking, as renal function deteriorated temporarily in all the subjects studied. In conclusion, doxazosin given into the renal arteries of patients with decompensated cirrhosis did not improve the renal ability to excrete sodium. The results suggest that additional factors besides renal α 1-sympathetic activity play a major role in the renal sodium retention of patients with cirrhosis.

Dissecting the factors involved in the pathogenesis of sodium retention in cirrhosis with ascites using TIPS: [formula omitted]. Depts of Medicine∗, Radiology† & Nuclear Cardiology‡, Toronto Hospital, Toronto, Canada

Endothelin (ET), a potent endothelium-derived vasoconstrictor peptide [1] contributes to the regulation of glomerular function both through changes in hemodynamics and through changes in glomerular configuration. Three structurally and pharmacologically distinct isoforms of the peptide have been identified with a molecular weight of 2.5 kDa, each consisting of 21 amino acids. These isopeptides share a common structure with a hydrophobic C-terminal end and two disulfide bonds, thus forming a hairpin loop at the amino terminus. ET-1 differs from ET-2 by only two amino acids, and from ET-3 by six amino acids. Each ET isopeptide is encoded by separate genes at distinct chromosomal loci [2].All ETs are synthesized via proteolytical cleavage from specific prohormones (Fig. 1). Prepro ETs are long polypeptide chains consisting of ∼203 amino acids [1] which exhibit specific differences among the isopeptides. ET isopeptide precursors are proteolytically cleaved by processing endopeptidases that recognize paired basic amino acids (Arg-Arg or Lys-Arg) and thus form pro or big ET. Pro ET-1 is then converted to mature ET-1 by cleavage of the Trp21-Val22 bond via a highly specific endothelin-1-converting enzyme, which is a Phosphoramidon-sensitive, membrane bound metalloprotease (Fig. 1) [3–5]. Pro ET-3 is less susceptible to this protease, so that the presence of other types of endothelin-converting enzyme are suspected [5].ETs bind to two G-protein coupled receptors of ∼43 to ∼73 kD molecular weight [6–8], consisting of ∼415 to ∼427 amino acids and having seven transmembrane domains [6, 7]. The ETA receptor binds ET-1 with 2- to 10-fold higher affinity than ET-2 and > 100-fold higher affinity than ET-3 [6–9], whereas the ETB receptor has similar affinities to all three peptides [7, 8].Little is known about the fate of ET. ETs are either inactivated by receptor internalization or by enzymatic cleavage of the peptide prior to receptor coupling [10–13].

Effect of upright posture and physical exercise on endogenous neurohormonal systems in cirrhotic patients with sodium retention and normal supine plasma renin, aldosterone, and norepinephrine levels

It is well known that sodium retention occurs in a significant proportion of patients with cirrhosis despite normal supine plasma levels of renin, aldosterone (ALDO), and norepinephrine (NE). The current study was performed to assess whether this subset of patients also present normal activity of the renin-aldosterone and sympathetic nervous systems during upright posture in sitting position and moderate physical exercise. Nine healthy controls, 14 patients with compensated cirrhosis and 10 patients with cirrhosis, ascites, sodium retention, and normal supine plasma renin activity (PRA) and ALDO and NE concentration were sequentially studied after 60 minutes in supine rest, 30 minutes in sitting position, and 30 minutes of cycloergometric exercise (3-METs). Sitting position and exercise were associated with similar stimulation of the renin-aldosterone and sympathetic nervous systems in the three groups of subjects. Consequently, cirrhotic patients with ascites showed values of PRA and plasma concentration of ALDO and NE similar to healthy subjects and patients with compensated cirrhosis during supine rest (renin: 1.4 ± 0.3, 0.8 ± 0.2, and 0.8 ± 0.3 ng/mL.hr; aldosterone: 24.3 ± 4.7, 20.2 ± 3.9 and 21.4 ± 3.4 ng/dL; norepinephrine: 252 ± 23, 250 ± 16, and 255 ± 23 pg/mL), sitting position (renin: 2.1 ± 0.5, 1.1 ± 0.3, and 1.6 ± 0.4; aldosterone: 32.2 ± 7.3, 23.7 ± 5.3, and 26.2 ± 4.5; norepinephrine: 356 ± 38, 401 ± 63, and 420 ± 35), and exercise (renin: 2.9 ± 0.8, 1.6 ± 0.4, and 2.2 ± 0.5; aldosterone: 43 ± 6.4, 34.9 ± 8.5, and 38.2 ± 5.3; norepinephrine: 481 ± 35, 499 ± 54, and 534 ± 48). Plasma atrial natriuretic peptide concentration was significantly ( P < .05) higher in cirrhotic patients with ascites than in healthy subjects during supine rest (5.69 ± 1.1 vs. 21.0 ± 3.3 fmol/L) and exercise (9.1 ± 2.2 vs. 28.3 ± 6.6). These results indicate that sodium retention in cirrhosis may occur in the setting of a normal activity of the endogenous neurohormonal antinatriuretic systems and high plasma levels of ANP.

Enlargement of the carotid bodies in cirrhosis of the liver

The carotid bodies were dissected out at necropsy and weighed in seven subjects with cirrhosis of the liver and in seven control subjects of comparable age free of liver disease. The mean combined carotid body weight of the control group was 17 mg but in the cirrhotic patients it was 35 mg, a statistically significant difference (P < 0.005). Differential counts of the various types of glomic cell (progenitor, dark and light variants of chief cells and sustentacular cells) were carried out. The enlargement of the carotid bodies in the subjects with cirrhosis was associated with increased numbers of the dark variant of chief cell. The mean number of dark cells per unit area in the control group was 361 cells/mm2 but in the cirrhosis group it was 1024 cells/mm2, a statistically significant difference (P < 0.005). It is postulated that the prominence of dark cells may be associated with secretion of a natriuretic peptide in response to the hyperaldosteronism and sodium retention of cirrhosis of the liver. Alternatively, it may be a response to hypoxaemia resulting from porta-pulmonary shunts.