The epithelial Na + channel (ENaC) resides on the apical surfaces of specific epithelia in vertebrates and plays a critical role in extracellular fluid homeostasis. Evidence that ENaC senses the external environment emerged well before the molecular identity of the channel was reported three decades ago. This article discusses progress toward elucidating the mechanisms through which specific external factors regulate ENaC function, highlighting insights gained from structural studies of ENaC and related family members. It also reviews our understanding of the role of ENaC regulation by the extracellular environment in physiology and disease. After familiarizing the reader with the channel's physiological roles and structure, we describe the central role protein allostery plays in ENaC's sensitivity to the external environment. We then discuss each of the extracellular factors that directly regulate the channel: proteases, cations and anions, shear stress, and other regulators specific to particular extracellular compartments. For each regulator, we discuss the initial observations that led to discovery, studies investigating molecular mechanism, and the physiological and pathophysiological implications of regulation. © 2024 American Physiological Society. Compr Physiol 14:5407-5447, 2024.

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Recent developments in our understanding of the pathogenesis of kidney disease in the setting of liver failure have highlighted that kidney injury, rather than occurring in isolation, is a marker of systemic disease and poor prognosis. The differential diagnosis of kidney disease associated with liver failure is broader than formerly described and new biopsy data, along with better acute kidney injury classification tools, have increased appreciation for distinct pathophysiological mechanisms. Evidence suggests that acute kidney injury contributes to worsening hepatic failure by directly injuring hepatic cells and by imposing restrictions on therapeutic strategies for portal hypertension. Furthermore, kidney injury limits the use of various therapeutic agents and increases their toxicity due to altered pharmacodynamics. A greater appreciation of CKD in this population is also overdue because management decisions are affected and increased vigilance may avoid further kidney injury. A multidisciplinary approach to kidney injury in the setting of liver failure will enable targeted therapeutic strategies that are safe and effective and serve to guide further research, while limiting clinical potential for harm. Finally, new hepatitis C antiviral therapies promise to change the landscape of liver failure, and a discussion of kidney risk factors and antiviral therapy of patients with kidney disease and hepatitis C is worthwhile.

Functional renal failure and cardiovascular dysfunction are common complications of liver cirrhosis. This study aimed to evaluate cardiac performance, systemic vascular resistance (SVR) and fluid status in patients with decompensated liver cirrhosis either with or without functional renal failure.

Sixty patients diagnosed as having decompensated liver cirrhosis were divided into two groups. Group 1 included 30 patients with decompensated liver cirrhosis with ascites and with creatinine values ≤ 1.5 mg/dl. Group 2 included 30 azotemic decompensated cirrhotic patients with diagnostic criteria of hepatorenal syndrome (HRS). Also, 20 healthy subjects, of matched age and sex to the Group 1 and Group 2 patients, were included in the study as the control group. All patients and normal controls were subjected to clinical examination, laboratory evaluation, ECG, abdominal ultrasonography and echocardiographic studies.

The echocardiographic and ECG data showed significant increase in LAD (P<0.01, P<0.01), AoD (P<0.05, P<0.01), interventricular septum thickness (IVST) (P<0.01, P<0.01), posterior wall thickness (PWT) (P<0.01, P<0.01), EDD (P<0.01, P<0.01), ESD (P<0.05, P<0.01), left ventricular (LV) mass (P<0.01, P<0.01), and Corrected QT (QTc) (P<0.01, P<0.01) interval with significant decrease in SVR (P<0.01, P<0.01). Additionally, there was significant decrease in IVC diameter in both patients groups compared to the control group (P<0.01, P<0.01).

Patients with decompensated liver cirrhosis have low SVR, and Doppler echocardiography provides an easy noninvasive tool to assess this finding. Also, these patients demonstrate small inferior vena cava (IVC) diameter with normal collapsibility, which indicates low effective plasma volume. Measuring IVC diameter and collapsibility are of value in the prediction of intravascular fluid status in liver cirrhosis. This is especially true with renal dysfunction. Early addition of oral vasoconstrictors in decompensated patients may correct the SVR and circulatory dysfunction and hinder HRS occurrence.

A considerable number of patients with advanced cirrhosis develop a hepatorenal syndrome. The pathogenesis involves liver dysfunction, splanchnic vasodilatation, and activation of vasoconstrictive systems. There are now several observations that indicate a relation between the renal failure and impaired cardiac function in patients with advanced cirrhosis. Cirrhotic cardiomyopathy has been described as a condition with impaired contractile responsiveness to stress and altered diastolic relaxation. We propose a cardiorenal interaction in patients with advanced cirrhosis and renal dysfunction that refers to a condition where cardiac dysfunction in cirrhosis is a major determinant of kidney function and survival. Thus, the relation between cardiac dysfunction and renal insufficiency should be target for future studies and development of new treatments should focus on ameliorating the cardiac dysfunction.

In recent years, acute-on-chronic liver failure has been recognized as a specific clinical form of liver failure associated with cirrhosis. The syndrome refers to an acute deterioration of liver function and subsequently of other end organs over a period of weeks following a precipitating event in a patient with previously well- or reasonably well-compensated cirrhosis. These precipitating events include either an indirect (e.g., variceal hemorrhage, sepsis) or a direct (e.g., drug-induced) hepatotoxic factor. The short-term mortality for this condition is more than 50%. At present, considerable efforts are ongoing to better characterize the syndrome, to gain further insight into its pathophysiology and to optimize therapy. This article aims to highlight the current concepts of these various aspects.

Over the past 50 years, the pathophysiology and features of the hepatorenal syndrome have been illuminated. The syndrome can be divided into 2 distinct clinical patterns: a rapidly progressive renal failure with an extremely poor prognosis (type 1) and a slow progressive renal failure that correlates with the degree of cirrhosis (type 2). Although our understanding of hepatorenal syndrome continues to grow, our current methods of treating this condition remain limited in their effectiveness. The only definitive therapy is liver transplantation. This is a review of the definition, pathophysiology, and current recommendations for management of hepatorenal syndrome with the critical care nurse in mind.

The vasoconstrictor terlipressin is widely used in the treatment of the hepatorenal syndrome and variceal bleeding. However, terlipressin may compromise cardiac function and induce ischemia.

Therefore, we aimed to assess the effects of terlipressin on cardiac function and perfusion.

Twenty-four patients with cirrhosis and ascites participated, including nine with refractory ascites. Gated myocardial perfusion imaging, mean arterial blood pressure (MAP), cardiac output (CO), ejection fraction (EF), end-diastolic volume (EDV), perfusion, and motion of the myocardium were determined before and after a bolus injection of 2 mg terlipressin.

MAP increased after terlipressin (P value of less than 0.001). EF and CO fell by -16 and -17%, respectively in the terlipressin group versus 1 and -2%, respectively in the placebo group (P value of less than 0.001 and P value of less than 0.01). In the terlipressin group, EDV increased by 18 versus -4% in the placebo group (P value of less than 0.01). Wall motion in the anterior and posterior walls fell by -18 and -22%, respectively after terlipressin treatment versus 0 and 0% in the placebo group (P value of less than 0.01). In contrast, myocardial perfusion and stroke volume were unaltered in both the groups. The change in EF during terlipressin treatment correlated significantly with the change in MAP (r=-0.60, P value <0.002). Patients with refractory ascites had a higher EF and lower EDV and ESV than the patients with nonrefractory ascites, both at baseline and after terlipressin treatment. The decrease in the left ventricular wall thickening and wall motion correlated with the Child--Pugh score, r=-0.59, P=0.005 and r=-0.48, P=0.03.

In advanced cirrhosis, the increase in afterload and EDV after terlipressin treatment result in a decrease in left ventricular wall motion, resulting in reduced CO and EF, but myocardial perfusion is preserved. Alteration in cardiac function at baseline and after terlipressin treatment relates to the stage of decompensation.

Hepatorenal syndrome (HRS) is a functional renal failure that often occurs in patients with cirrhosis and ascites. HRS develops as a consequence of a severe reduction of effective circulating volume due to both an extreme splanchnic arterial vasodilatation and a reduction of cardiac output. There are 2 different types of HRS. Type 1 HRS, which is often precipitated by a bacterial infection, especially spontaneous bacterial peritonitis, is characterized by a rapidly progressive impairment of renal function. Despite its functional origin, the prognosis of type 1 HRS is very poor. Type 2 HRS is characterized by a stable or slowly progressive renal failure so that its main clinical consequence is not acute renal failure but refractory ascites and its impact on prognosis is less negative. New treatments (vasoconstrictors plus albumin, transjugular portosystemic shunt, and molecular adsorbent recirculating system), which were introduced in the past 10 years, are effective in improving renal function in patients with HRS. Among these treatments vasoconstrictors plus albumin can also improve survival in patients with type 1 HRS. Thus, this therapeutic approach has changed the management of this severe complication in patients with advanced cirrhosis.

Cirrhosis induces extra-cellular fluid volume expansion, which when the disease is advanced can be severe and poorly responsive to therapy. Prevention and/or effective therapy for cirrhotic edema requires understanding the stimulus that initiates and maintains sodium retention. Despite much study, this stimulus remains unknown. Work over the last several years has shown that signals originating in the liver can influence a variety of systemic functions, including extra-cellular fluid volume control. We review work on the afferent mechanisms triggering sodium retention in cirrhosis and suggest that the data are most consistent with the existence of a sensor in the hepatic circulation that contributes to normal extra-cellular fluid volume control (that is, a 'volume' sensor) and that in cirrhosis, the sensor is pathologically activated by the hepatic circulatory abnormalities caused by the disease. Detailed analysis of the hepatic circulation in normal conditions and cirrhosis is needed.

Hepatorenal syndrome is a severe complication of advanced liver cirrhosis, in patients with ascites and marked circulatory dysfunction. It is clearly established that it has a functional nature, and that it is related to intense renal vasoconstriction. Despite its functional origin, the prognosis is very poor. In the present review, the most recent advances in diagnosis, pathophysiology, and treatment are discussed. Recent developments in pathophysiology are the basis of the new therapeutic strategies, which are currently under evaluation in randomised clinical trials.

Our group recently reported that elevated intra-abdominal pressure (IAP, defined as > or = 8 mm Hg) can be associated with renal dysfunction in patients with advanced decompensated heart failure (ADHF). We hypothesize that in the setting of persistently elevated IAP and progressive renal insufficiency refractory to intensive medical therapy, mechanical fluid removal can be associated with improvements in IAP and renal function.

The renal and hemodynamic profiles of 9 consecutive, volume-overloaded subjects with ADHF and elevated IAP, refractory to intensive medical therapy, were prospectively collected. All subjects experienced progressive elevation of serum creatinine and IAP in response to intravenous loop diuretics. Within 12 hours after mechanical fluid removal via paracentesis (n = 5, mean volume removed 3187 +/- 1772 mL) or ultrafiltration (n = 4, mean volume removed 1800 +/- 690 mL), there was a significant reduction in IAP (from 13 +/- 4 mm Hg to 7 +/- 2 mm Hg, P = .001), with corresponding improvement in renal function (serum creatinine from 3.4 +/- 1.4 mg/dL to 2.4 +/- 1.1 mg/dL, P = .01) without significantly altering any hemodynamic measurement.

In volume-overloaded patients admitted with ADHF refractory to intensive medical therapy, we observed a reduction of otherwise persistently elevated IAP with corresponding improvement in renal function after mechanical fluid removal.

In cirrhotic patients, portal hypertension is often associated with a hyperdynamic circulatory syndrome, with high cardiac output and reduced systemic vascular resistance and arterial pressure. The hyperdynamic circulatory syndrome is due to arterial vasodilation that mainly occurs in the splanchnic circulation, while vascular resistance in the other circulatory districts is normal or increased, accordingly with the degree of portal hypertension, liver impairment and activation of the renin-aldosterone and sympathetic nervous system. The mechanism(s) leading to splanchnic vasodilation is unclear. A favored hypothesis translocation of intestinal bacteria and/or some their products, such as endotoxin, into the interstitial space in the splanchnic organs results in the local release of vasodilating factors such as nitric oxide, carbon monoxide and others.

Advanced liver disease is characterized by decreased arterial blood pressure and peripheral vascular resistances, increased cardiac output and heart rate in the setting of a hyperdynamic circulatory pattern favoured by total blood volume expansion, circulatory overload and overactivity of the endogenous vasoactive systems. Reduced heart responses to stressful conditions such as changes in loading conditions of the heart in presence of further deterioration of liver function such as refractory ascites, hepatorenal syndrome, spontaneous bacterial peritonitis and bleeding esophageal varices have been recently identified and the knowledge of the cirrhotic cardiomyopathy syndrome has gained the dignity of a new clinical entity. Facing the availability of therapeutic interventions (paracentesis, transjugular intrahepatic portosystemic shunt, peritoneovenous shunt, orthotopic liver transplantation) currently employed to manage the life-threatening complications of the most advanced phases of cirrhotic disease, the knowledge of their impact on cardiovascular function is of paramount relevance.

Hepatorenal syndrome (HRS) is a common complication of advanced cirrhosis, characterised by renal failure and major disturbances in circulatory function. Renal failure is caused by intense vasoconstriction of the renal circulation. The syndrome is probably the final consequence of extreme underfilling of the arterial circulation secondary to arterial vasodilatation in the splanchnic vascular bed. As well as the renal circulation, most extrasplanchnic vascular beds are vasoconstricted. The diagnosis of HRS is currently based on the exclusion of other causes of renal failure. The prognosis is very poor, particularly when there is rapidly progressive renal failure (type 1). Liver transplantation is the best option in patients without contraindications to the procedure, but it is not always possible owing to the short survival expectancy. Therapies introduced during the past few years, such as vasoconstrictor drugs (vasopressin analogues, alpha-adrenergic agonists) or the transjugular intrahepatic portosystemic shunt, are effective in improving renal function. Nevertheless, liver transplantation should still be done in suitable patients even after improvement of renal function because the outcome of HRS is poor. Finally, recent findings suggest that the risk of developing HRS in the setting of spontaneous bacterial peritonitis may be reduced by the administration of albumin together with antibiotic therapy, and that of HRS occurring in severe alcoholic hepatitis can be lowered by administration of pentoxifylline. Although these findings need to be confirmed, these two strategies represent innovative approaches to lower the frequency of HRS in clinical practice.

The purpose of this study was to confirm earlier reports that low-dose vasopressin (LDVP) analogues promote urine output in patients with hepatorenal syndrome (HRS) and to check whether this mode of therapy could also be effective in renal shutdown due to nonhepatic conditions.

A prospective, open, interventional study.

An intermediate-level (step-down) medical intensive care unit within a general medical ward of a large university-affiliated hospital.

Eighteen successive hospitalized patients with HRS (mean age 65 +/- 13 years) and 11 patients with end-stage congestive heart failure (CHF) (mean age 81 +/- 5 years) who failed to restore urine output with conventional treatment (fluids, dopamine, and diuretics) given for at least 24 h.

The patients received LDVP (1 IU h-1) continuously in addition to the conventional treatment.

Urine output and creatinine clearance every 24 h.

In the HRS group, before treatment the urine output was 155 +/- 9 mL 24 -1h (mean +/- SD). After treatment with LDVP for 24, 48, and 72 h, urine output improved to 1067 +/- 87, 1020 +/- 501, and 1311 +/- 988 mL 24 -1h, respectively (P < 0.0001 for all measures; two-tailed paired t-test). In the CHF group, before treatment the urine output was 99 +/- 99 mL 24 -1h. After treatment with LDVP for 24, 48, and 72 h, this improved to 1125 +/- 994 mL 24 -1h (P = 0.0028), 1821 +/- 1300 mL 24 -1h (P = 0.004), and 2920 +/- 2423 mL 24 -1h (P = 0.0012), respectively. The improvement in urine output was not accompanied by a parallel improvement in creatinine clearance. The overall outcome did not change, and all patients except two in each group succumbed to their end-stage disease, due to nonrenal causes.

LDVP is effective in restoring urine output both in HRS and in CHF. This suggests that LDVP affects mechanisms not specifically related to liver disease. LDVP may be useful in critical patients with renal shutdown whilst awaiting liver or heart transplantation.

Hepatorenal syndrome is caused by a marked vasoconstriction of the renal circulation. It is suggested that the renal vasoconstriction is related to an overactivity of vasoconstrictor systems secondary to a vasodilation of the arterial circulation that causes a reduction in effective arterial blood volume. To test this hypothesis, 16 cirrhotic patients with hepatorenal syndrome were treated with a combination of ornipressin, a potent vasoconstrictor agent, and plasma volume expansion with albumin to improve effective arterial blood volume. The combined treatment was administered either for 3 or 15 days (8 patients each), and the effects on renal function, vasoactive systems, and systemic hemodynamics were assessed. The 3-day treatment with ornipressin and albumin was associated with a normalization of the overactivity of renin-angiotensin and sympathetic nervous systems, a marked increase in atrial-natriuretic peptide levels, and only a slight improvement in renal function. However, when ornipressin and albumin were administered for 15 days, a remarkable improvement in renal function was observed, with normalization of serum-creatinine concentration, a marked increase in renal plasma flow and glomerular filtration rate, and a persistent suppression in the activity of vasoconstrictor systems. However, 3 of 8 patients on 15-day therapy treatment had to be discontinued because of ischemic complications. In conclusion, the decrease in effective arterial blood volume and the activation of vasoconstrictor systems play a crucial role in the pathogenesis of hepatorenal syndrome. Although the prolonged administration of ornipressin combined with plasma volume expansion reverses hepatorenal syndrome, this treatment should be used with great caution in clinical practice because of the risk of ischemic complications.

This study aimed to evaluate the effect of octreotide on total effective vascular compliance, measured during rapid volume expansion, in patients with posthepatitic cirrhosis.

Twenty-nine patients with posthepatitic cirrhosis were randomly assigned to receive a 100-micrograms/h infusion of octreotide after a 100-micrograms bolus (n = 15), or a placebo (n = 14). Hemodynamic measurements were recorded before and 30 min after drug administration. Thereafter, rapid volume expansion was performed in each patient and hemodynamic measurements were repeated immediately after volume expansion.

Before volume expansion, placebo administration did not affect any of the hemodynamic values, while the hepatic blood flow was significantly decreased following octreotide administration. After volume expansion, the hemodynamic changes were similar between patients receiving octreotide and the placebo. However, the increase in right atrial pressure from the beginning to the end of volume expansion was higher and the total effective vascular compliance was lower in patients receiving octreotide (+3.5 +/- 0.3 mmHg, p = 0.05 and 1.69 +/- 0.16 ml.mmHg-1.kg-1, p < 0.05) compared to patients receiving placebo (+2.5 +/- 0.3 mmHg, 2.60 +/- 0.34 ml.mmHg-1.kg-1).

The present study suggests that octreotide decreased total effective vascular compliance in patients with posthepatitic cirrhosis. It is possible that, in patients with posthepatitic cirrhosis, venoconstriction was induced following octreotide administration.

Hepatorenal failure, a well-recognized complication of established liver disease, is characterized by early renal hemodynamic changes (vasoconstriction) before clinically recognized kidney disease. This renal vasoconstriction (increased renal vascular resistance) should be detectable noninvasively by Doppler ultrasonography. We studied whether renal Doppler ultrasonography detects abnormalities in patients with nonazotemic liver disease and its prognostic value for subsequent kidney status. We observed by renal Doppler ultrasonography 180 patients who had liver disease without azotemia. A simple parameter, resistive index, was derived for each subject on the basis of Doppler waveform analysis. Traditional parameters used to assess patients with liver disease were also recorded at the time of Doppler ultrasonography. Subsequent kidney outcomes were kidney dysfunction (doubling of initial creatinine level to 1.5 mg/dl [133 mumol/L]) or more and the presence or absence of the hepatorenal syndrome. Abnormal results of Doppler examinations (elevated resistive index) were seen in 76 (42%) of the 180 patients. Kidney dysfunction developed in 55% (42/76) of the patients with an elevated resistive index and 6% (6/104) of those with normal results of Doppler study (p < 0.00005). Hepatorenal syndrome developed in 26% (20/76) of subjects with an elevated resistive index and 1% (1/104) of those with a normal resistive index (p < 0.00005). Cox regression analysis identified resistive index as a significant independent predictor of subsequent hepatorenal syndrome (p < 0.00005) and kidney dysfunction (p < 0.00005). Renal duplex Doppler ultrasonography can noninvasively identify a subgroup of nonazotemic patients with liver disease that is at significantly higher risk for subsequent development of kidney dysfunction and the hepatorenal syndrome.

Although arterial vasodilation is a well-known feature in patients with cirrhosis, the venous system remains unexplored. To measure total effective vascular compliance, a reflection of the properties of the venous system, rapid volume expansion (300 ml of a gelatin solution in 3 min) was performed in 23 patients. Eleven patients had compensated cirrhosis (Child-Pugh grade A or B), and eight had decompensated cirrhosis (Child-Pugh grade C). Four control patients had mild chronic hepatitis, normal hepatic venous pressure and normal liver architecture. Cardiac index, hepatic venous pressures, hepatic and azygos blood flow and renal plasma flow were measured before and immediately after volume expansion. Right atrial pressure was recorded during volume expansion. This allowed the calculation of total effective vascular compliance, which was higher in patients with decompensated cirrhosis than in those with compensated cirrhosis (4.65 +/- 4.21 vs. 1.34 +/- 0.63 ml.mm Hg-1.kg-1; p less than 0.05). In response to volume expansion, renal vascular resistance decreased significantly in patients with compensated cirrhosis, but not in those with decompensated cirrhosis (-30% +/- 33% vs. +2% +/- 23%; p less than 0.05). No change was seen in glomerular filtration rate. Systemic oxygen consumption increased in patients with compensated cirrhosis, but not in those patients with decompensated cirrhosis (25% +/- 33% vs. -4% +/- 9%; p less than 0.05). Although in all patients with cirrhosis volume expansion increased central venous pressures, azygos blood flow and the hepatic venous pressure gradient did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

The pathophysiology and characteristics of decompensated alcoholic cirrhosis and functional renal failure are reviewed. The review will be restricted to alcoholic cirrhosis, because most cases of functional renal failure in the United States occur in the setting of alcoholic cirrhosis, which is also the most common cause of ascites in North America and Europe. Moreover, hepatorenal syndrome may complicate other forms of liver disease besides alcoholic cirrhosis, but the pathogenesis in such circumstances may not be the same as in the cirrhotic state.

HRS occurs frequently in patients with advanced cirrhosis of the liver and fulminant hepatitis. The pathogenesis of HRS is not clearly understood; reduced effective plasma volume and intense renal cortical vasoconstriction seem to have important roles. The HRS is a diagnosis by exclusion, and it [table: see text] is often difficult to differentiate this entity from prerenal azotemia and ATN. The HRS is characterized by its relentless progression and usually fatal outcome. The essential steps in the management of HRS are to identify and correct the precipitating factors leading to HRS and avoidance of potential hepatotoxic and nephrotoxic drugs. Patients with potentially reversible liver diseases should be treated aggressively. Volume expansion is important and should be tried first, even though hypovolemia may be not clinically evident. Dialysis may benefit patients with fluid overload and electrolyte imbalance or those awaiting liver transplantation. In selective cases, peritoneovenous shunt may be of value. Liver transplantation is the only curative therapy available at present.

We assessed the bilirubin reduction capacity of three different types of devices in vitro: a high-permeable membrane column for double-filtration plasmapheresis (DFP) (Evaflux 2A, Kuraray, Japan), and non-coated charcoal column for hemoperfusion (HP) (N-180, Asahi Medical, Japan), and ion-exchange columns for plasma adsorption (PA) (BR-350, Asahi Medical, Japan, and B-001, Kuraray, Japan). A column for DFP reduced the concentration of low-molecular proteins effectively such as plasma bilirubin and bile acids in an albumin-dependent manner. A charcoal column adsorbed low-molecular substances preferentially. But in these two columns, the loss of fibrinogen is a limiting factor for determining the processing plasma volume. Ion-exchange columns for PA adsorbed bile acids, disconjugated bilirubin, and monoconjugated bilirubin more efficiently compared with delta-bilirubin and unconjugated bilirubin. Pretreatment of the column with heparin reduced the loss of fibrinogen to less than 10%. We applied the BR-350 ion-exchange column in vivo for treatment of three patients with hyperbilirubinemia. After treatment, an alcoholic hepatitis patient with the hepatorenal syndrome (HRS) recovered from acute renal failure. However, in a patient with primary biliary cirrhosis and in a patient with fulminant hepatitis, the decrease of serum bilirubin was transient and no obvious beneficial responses were noted. The capacity and ability of the BR-350 column to adsorb plasma bilirubin was shown sufficient to treat deeply jaundiced patients, because 4 liters of the plasma of a patient with 108 mg/dl of initial total bilirubin concentration was able to be processed continuously without an obvious decrease in bilirubin adsorption capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic, femoral, and renal hemodynamics were evaluated in 7 control subjects and 20 cirrhotic patients with ascites, 14 of them without (group A) and 6 with (group B) functional renal failure. Hyperdynamic systemic circulation, increased plasma volume, and hyperreninism were present in groups A and B. These changes were more severe in group B, which showed, as compared with group A, lower total vascular resistances and mean arterial pressure together with increased cardiac index and plasma renin activity. Significant differences in regional hemodynamics were also observed between groups. In group A, femoral and renal fractions of cardiac output were respectively increased and reduced as compared with controls. By contrast, in group B, both fractions of cardiac output were reduced when compared either with controls or with group A. In the entire patient group there was a close direct correlation between femoral and renal fractions of cardiac output (r = 0.88; p less than 0.001) and both of them correlated independently with total vascular resistances (r = 0.79; p less than 0.001 in both cases). These results indicate that, in nonazotemic cirrhotics with ascites, vasodilatation in extrasplanchnic areas contributes to the genesis of the hyperdynamic circulation. The presence in group B of a reduced flow to extrasplanchnic territories, in association with an increase of the hyperdynamic circulatory status, suggests that exacerbation of splanchnic vasodilatation is involved in the development of the hepatorenal syndrome. Finally, in cirrhosis, the changes that occur in systemic hemodynamics appear to influence renal function and renal blood flow.

In patients with cirrhosis, it has been demonstrated that blood volume and degree of portal hypertension are correlated. Hence, a reduction of blood volume by furosemide could decrease portal pressure and could thereby be useful in the treatment of portal hypertension. Splanchnic and systemic haemodynamics were evaluated before and 1 h after intravenous administration of furosemide (0.75 mg/kg) in 10 patients with cirrhosis. Furosemide significantly increased haemoglobin from 12.4 to 13.0 g/dl and patients passed more than 1 l of urine within the 3 h following furosemide administration. These findings confirm that blood volume decreased after diuretic administration. Cardiac output significantly decreased from 6.6 +/- 2.3 to 5.5 +/- 2.2 l/min, while arterial pressure and heart rate did not change significantly. Furosemide significantly decreased wedged hepatic venous pressure from 31.1 +/- 6.2 to 27.7 +/- 5.2 mmHg, but not free hepatic venous pressure. Accordingly, the hepatic venous pressure gradient significantly decreased from 22.1 +/- 5.4 to 19.5 +/- 4.0 mmHg. Azygos blood flow and hepatic blood flow also significantly decreased from 0.40 +/- 0.17 to 0.31 +/- 0.13 l/min and from 1.49 +/- 0.50 to 0.82 +/- 0.30 l/min, respectively. These results show that diuretic therapy markedly influences splanchnic haemodynamics.

Ascites in patients with cirrhosis of the liver frequently is refractory to diuretic treatment. It was postulated that vasoconstriction of the renal cortex, mediated by activation of the renin-angiotensin-aldosterone-system (RAAS), may be one course of the disturbed sodium- and water-excretion in these patients. We therefore investigated in 14 cirrhotic patients with ascites under constant diuretic treatment the effects of low-dose captopril therapy on urinary sodium- and potassium-excretion, body weight, abdominal girth, serum-sodium, -potassium, creatinine-clearance, plasma-renin-activity (PRA), plasma-aldosterone (PA) and mean arterial pressure (MAP). After a control period of 4 days the patients received 2 x 6.25 mg/d captopril for 5 days and 4 x 6.25 mg/d for further 5 days. Treatment was followed by a second control period without captopril. PRA increased significantly after 2 days of captopril treatment. 2 x 6.25 mg/d captopril induced a significant increase in sodium excretion and a significant decrease of body weight. MAP decreased slightly but significantly without clinical signs of hypotension. 4 x 6.25 mg/d captopril resulted in a further reduction of body weight and a further enhancement of sodium excretion. Three days after withdrawal of captopril sodium output was significantly reduced again.

In cirrhotic patients low-dose captopril seems to be efficient in the treatment of ascites resistant to diuretics without causing major side effects.

In nine patients with decompensated alcoholic cirrhosis of the liver and impaired renal function the effect of 8-ornithin vasopressin (ornipressin) on renal function and haemodynamic parameters was studied. Ornipressin was infused at a dose of 6 IU/h over a period of four hours. During ornipressin infusion an improvement of renal function was achieved as indicated by an increase of creatinine clearance (76 (15)%; p less than 0.01), urine volume (108 (29)%; p less than 0.05) and sodium excretion (168 (30)%; p less than 0.05). The hyperdynamic circulation of hepatic failure, as characterised by increased cardiac index and heart rate as well as decreased systemic vascular resistance was reversed to a nearly normal circulatory state during ornipressin infusion. The raised noradrenaline plasma concentration (1.74 (0.31) ng/ml) and plasma renin activity (13.5 (3.9) ng/ml/h) were lowered during ornipressin infusion to 0.87 (0.21) ng/ml and 5.9 (2.1) ng/ml/h, respectively (p less than 0.01). The efficacy of a vasoconstrictor agent in reverting a hyperdynamic state and improving renal function provides evidence for the substantial role of accumulation of vasodilator substances and subsequent activation of sympathetic nervous system and renin-angiotensin-axis in the pathogenesis of renal dysfunction in hepatic failure. Values are expressed as mean (SE).

Changes in portal pressure are regulated by changes in hepatic vascular resistance, which is normally under neurohumoral control, and portal tributary blood flow. Two theories on the pathophysiology of portal hypertension have been proposed: the 'backward flow' theory, in which portal hypertension is attributable to increased resistance to portal venous flow, and the 'forward flow' theory, in which increased splanchnic blood flow maintains portal hypertension despite extreme portal-systemic shunting. The sinusoidal abnormalities caused by an accumulation of collagen in the perisinusoidal space of Disse may induce increased resistance to blood flow in various pathological conditions of the liver. Non-cirrhotic portal hypertension results from not only relatively uncommon disorders prevalent mainly in Asia and tropical countries, but also from acute and chronic phases of relatively common liver diseases. Systemic hyperdynamic circulation, characterised by an increased cardiac output and a reduced peripheral vascular resistance, and splanchnic hyperaemia may develop as consequences of portal hypertension. Although the mechanisms of these changes are not clearly understood, portal-systemic shunting as well as some vasoactive substances, including prostaglandins, may be involved. The erosive and eruptive mechanisms are the two potential explanations for variceal bleeding. In the latter, pressure should not be viewed in isolation and other additive factors such as variceal size may be involved. Several new techniques of measuring variceal pressure and blood flow may improve understanding of the actual pathophysiology of variceal bleeding. Renal haemodynamic alterations secondary to the systemic circulatory changes produced by portal hypertension may occur. The geographical pattern of prevalence in disorders associated with portal hypertension is briefly described in this paper.

Functional renal failure of cirrhosis (FRFC) is a usually fatal syndrome of acute renal failure occurring in patients with advanced liver disease. Although not conclusively proven, most evidence suggests that renal arterial and arteriolar vasoconstriction is the cause of the renal failure in these patients. However, the mediators of the vasoconstriction remain unknown. Human atrial natriuretic factor (hANF) is a hormone with potent natriuretic, diuretic, and vasorelaxant properties. A deficiency of hANF could lead to renal arterial vasoconstriction and avid renal sodium retention as seen in FRFC. This study was undertaken to determine if patients with FRFC are deficient in circulating hANF. Seven patients with advanced alcoholic liver disease and renal failure of unknown cause (FRFC) were compared with 7 patients with advanced alcoholic liver disease, ascites, and normal serum creatinine as well as with 14 healthy volunteers. Plasma hANF was measured by radioimmunoassay. Plasma hANF was 742 +/- 227 pg/ml (mean +/- SEM) in patients with FRFC compared with 360 +/- 70 pg/ml in patients with liver disease and normal serum creatinine (p greater than 0.05) and 28 +/- 5.7 pg/ml in healthy volunteers (p less than 0.005 vs. FRFC and chronic liver disease, ascites, and normal serum creatinine). Thus, FRFC is not caused by a deficiency of circulating hANF. The elevated plasma hANF levels in patients with chronic liver disease and continued sodium retention may suggest a renal insensitivity to the natriuretic effects of hANF.

Renal sodium and water retention and plasma volume expansion have been shown to precede ascites formation in experimental cirrhosis. The classical "underfilling" theory, in which ascites formation causes hypovolemia and initiates secondary renal sodium and water retention, thus seems unlikely. While the occurrence of primary renal sodium and water retention and plasma volume expansion prior to ascites formation favors the "overflow" hypothesis, the stimulation of the renin-angiotensin-aldosterone system, vasopressin release and sympathetic nervous system associated with cirrhosis is not consonant with primary volume expansion. In this present article, the "Peripheral Arterial Vasodilation Hypothesis" is proposed as the initiator of sodium and water retention in cirrhosis. Peripheral arterial vasodilation is one of the earliest observations in the cirrhotic patient and experimental animals with cirrhosis. Arterial vasodilators and arteriovenous fistula are other examples in which renal sodium and water retention occur secondary to a decreased filling of the arterial vascular tree. An increase in cardiac output and hormonal stimulation are common features of cirrhosis, arteriovenous fistula and drug-induced peripheral arterial vasodilation. However, a predilection for the retained sodium and water to transudate into the abdominal cavity occurs with cirrhosis because of the presence of portal hypertension. The Peripheral Arterial Vasodilation Hypothesis also explains the continuum from compensated to decompensated cirrhosis to the hepatorenal syndrome.

Systolic and diastolic blood pressures were recorded in 176 ambulant patients with chronic liver disease, including 36 patients with compensated cirrhosis (Group I), 119 patients with noncirrhotic chronic liver disease (Group II) and 21 patients with benign structural or functional liver disease (Group III). Group I patients had significantly lower systolic (113.0 +/- 2.2 mm Hg, mean +/- S.E.) and diastolic (65.3 +/- 1.7 mm Hg) pressures than Group II patients (125.8 +/- 3.5 and 76.6 +/- 1.5 mm Hg, respectively (p less than 0.0001) or Group III patients (125.1 +/- 3.4 and 77.5 +/- 2.4 mm Hg, respectively) (p less than 0.0001). Serum levels of GABA, a potent amino acid neurotransmitter with known vasodilatory effects in vitro, were higher in Group I patients (1.12 +/- 0.26 microM, mean +/- S.E.) than in Group II patients (0.41 +/- 0.05 microM) (p less than 0.005) or Group III patients (0.34 +/- 0.03 mM) (p less than 0.05). A constant infusion of GABA into the systemic circulation of six adult dogs, at rates required to achieve serum GABA levels within one order of magnitude of those observed in humans with cirrhosis, resulted in a 17.0 +/- 4.3 mm Hg decrease in systolic pressure (p less than 0.05) and a 10.8 +/- 3.7 mm Hg decrease in diastolic pressure (p less than 0.05). Control amino acids were not vasoactive. The results of this study suggest that, in addition to other vasoactive compounds, a GABA-mediated process might contribute to the hypotension observed in patients with compensated cirrhosis.

Acute renal failure is frequently observed in patients with ascites and alcoholic cirrhosis of the liver. In the absence of any discernible anatomic or clinical cause for the renal failure, the decrease in renal perfusion is usually associated with significant arterial hypovolemia. If there is no contraction of the effective blood volume, then the functional renal failure is entitled to be labeled "hepatorenal syndrome." This implies that there is some unique cause for intrarenal vasoconstriction independent of a contracted effective arterial blood volume. A possible cause for such vasoconstriction may be abnormal intrarenal production of prostaglandins. Therapy is ineffective, but calcium antagonists may have some therapeutic potential.

The effect of the sitting, supine, supine with legs elevated 10 degrees, and 10 degrees head-down tilt postures on renal fluid and electrolyte handling was investigated in 14 patients with hypoalbuminaemic fluid-retaining states and in 14 normal individuals. Basal (sitting) urine volume, creatinine clearance, and urinary electrolyte levels were significantly lower in patients than in controls. In patients the values of these variables increased progressively from the sitting to the supine to the legs elevated to the head-down postures. The percentage rise was higher in patients than in controls, to the extent that, in the head-low position, only creatinine clearance values remained lower in patients than in controls. The head-down posture acts as a physiological diuretic, enhancing diuresis by improving renal function in normal individuals and in patients with ascites and oedema due to hypoalbuminaemia; it also corrects the abnormal fluid and sodium retention in these patients.

Eleven patients with well-documented hepatorenal syndrome were studied by measurement of blood volume, glomerular filtration rate, renal plasma flow, plasma aldosterone concentration, renin substrate concentration, and plasma renin activity. They were then given 750 ml of stored plasma, 750 ml of fresh frozen plasma, and then an infusion of angiotensin II, in random order on successive days. Infusion of fresh frozen plasma improved function more than did stored plasma and in addition returned a very low filtration fraction toward normal. Angiotensin II infusion increased filtration fraction, but decreased glomerular filtration rate, renal plasma flow, and urine flow sharply. Patients were then given a daily infusion of 1,000 ml of fresh frozen plasma for seven to 18 days to expand the blood volume to supranormal levels as assayed by serial measurement of blood volume. Plasma aldosterone levels decreased to a normal range, glomerular filtration rate and renal plasma flow both increased, and urinary excretion of sodium and potassium both returned toward normal. The effect of intraperitoneal pressure was then studied by measuring glomerular filtration rate, renal plasma flow, pressure in the vena cava, hepatic vein free flow, and hepatic vein wedged pressure before, during, and after paracentesis to reduce the intraperitoneal pressure from 30 to 40 cm H2O to 12 to 17 cm H2O. Venous pressures moved parallel to ascitic fluid pressures, and glomerular filtration rate, renal plasma flow, and urine flow all improved sharply; then, as ascitic fluid continued to form, reducing vascular volume, urine flow, glomerular filtration rate, and renal plasma flow all decreased slowly. Six patients then underwent placement of a LeVeen shunt. Improvement in glomerular filtration rate and renal plasma flow and clinical condition was dramatic. During postoperative observation of up to two years, progressive improvement in hepatic function has occurred.

The consideration of HE and its etiology has undergone a radical turn within the past decade. At present HE is seen in the context of severe metabolic derangements, which failure of the liver, the central biochemical powerhouse of the body, must bring with it. The increased awarenesses on the biochemical mechanisms involved in the pathogenesis of HE have found, step by step, their own place in a complex but consequential mosaic of events, in which amino acid and HE are tightly linked. Clinical and experimental studies are needed to further improve the knowledge in this field, nontheless a certain number of corner-stones can be identified: A profound alteration of the central nervous system neurotransmission is responsible for most, if not all, of the symptoms characterizing HE. The plasma amino acid imbalance observed in cirrhotic patients represents a 'condicio sine qua non' HE may develop. A functional impairment of the amino acid transport systems at the level of the blood-brain barrier seems to play a crucial role in causing deleterious modifications of the synaptic neurotransmission in the central nervous system. The reduction of the brain entry of the "toxic" aromatic amino acids usually obtained by parenteral administration of especially tailored amino acid mixtures is most frequently followed by awakening from HE. In conclusion, most of the results obtained have demonstrated that HE represents a research field in which progresses in the knowledge of some of the pathogenic mechanisms have brought the investigators to new therapeutic approaches which have clearly improved the prognosis of patients suffering from this severe neuropsychiatric syndrome.

The hepatorenal syndrome (HRS) is a terminal complication of severe liver disease associated with a mortality of 80 to 90%. Although the renal functional abnormalities in the HRS suggest prerenal azotemia, volume expansion with saline, albumin or ascitic fluid rarely results in reversal of the HRS because fluid redistributes from the vascular space. Since the peritoneovenous (PV) shunt causes sustained central volume expansion, it has been advocated for the treatment of the HRS. We prospectively compared the PV shunt (N = 10) to Medical Therapy (MED) (N = 10) on renal function and mortality in 20 patients with the HRS associated with alcoholic liver disease. The HRS was diagnosed on the basis of clinical, hemodynamic, and laboratory criteria. The insertion of a PV shunt resulted in an increase in pulmonary capillary wedge pressure (4.2 +/- 1.1 vs. -1.5 +/- 1.0 mm Hg, P less than 0.01) and in cardiac index (0.8 +/- 0.3 vs. -0.2 +/- 0.3 1/min/m2, P less than 0.05). After 48 to 72 hours, weight (+3.1 +/- 1.1 kg) and serum creatinine (3.9 +/- 0.5 to 5.5 +/- 0.7 mg/dl, P less than 0.001) were increased with MED therapy and decreased (weight: -3.7 +/- 0.7 kg; serum creatinine: 3.6 +/- 0.4 to 3.0 +/- 0.5, P less than 0.05) with the PV shunt. Despite improvement in renal function, only one patient with the PV shunt had prolonged survival (210 days). In the remainder, survival was 13.8 +/- 2.2 days compared to 4.1 +/- 0.6 days with MED therapy. We conclude that the PV shunt often stabilizes renal function, but does not prolong life in patients with the HRS.

Decompensation in the cirrhotic patient is typically manifested as hepatic encephalopathy or coma. This may be precipitated by azotemia, gastrointestinal bleeding, infection, hypokalemic alkalosis, excess dietary protein, or the use of sedative, tranquilizer, or analgesic medications. The pathogenesis of hepatic encephalopathy associated with portal-systemic shunting is unknown, but theories purporting major roles for ammonia, AAAs, false neurotransmitters, and GABA have been advanced. Treatment is aimed at removing precipitating factors and eliminating nitrogenous substances from the gastrointestinal tract.