Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and current management

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1 Journal of Hepatology 38 (2003) S69 S89 Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and current management Vicente Arroyo*, Jordi Colmenero Liver Unit, Institute of Digestive Diseases, Hospital Clínic, Villarroel, 170, University of Barcelona, Barcelona, Spain 1. Introduction Ascites is the most common complication of cirrhosis [1,2]. It develops late during the course of the disease, when there is severe portal hypertension and hepatic insufficiency. Not surprisingly, it is associated with a poor survival [3] (50% mortality rate within 3 years, Fig. 1). The development of ascites is, therefore, a clear indication for liver transplantation. There are several studies indicating that parameters estimating systemic hemodynamics and renal function are better predictors of survival than those estimating hepatic function [4 6]. The prognosis of patients with dilutional hyponatremia, refractory ascites and hepatorenal syndrome (HRS) is extremely poor and liver transplantation should be indicated prior to the development of these complications [3,7]. Other parameters with prognostic value in cirrhotic patients with ascites are mean arterial pressure, plasma renin activity, plasma norepinephrine concentration, urinary sodium excretion, the renal ability to excrete free water, liver size, serum bilirubin, serum albumin concentration, and prothrombin time [8,9]. The current article is focused on the treatment of ascites and HRS in cirrhosis. To provide the reader with the rationale of the therapeutic measures used in patients with cirrhosis and ascites or HRS, the pathophysiology of these complications is briefly reviewed. The role of liver transplantation in the management of decompensated cirrhotic patients with ascites is not included in this review. * Corresponding author. Tel.: ; fax: address: arroyo@medicina.ub.es (V. Arroyo). Abbreviations: GFR, glomerular filtration rate; camp, cyclic adenosine monophosphate; ATP, adenosine triphosphate; HRS, hepatorenal syndrome; SBP, spontaneous bacterial peritonitis; ADH, antidiuretic hormone. 2. The pathophysiological basis of therapy of ascites and HRS 2.1. Ascites formation Backward and overflow theories of ascites formation From more than 40 years it has been well established that the development of ascites in cirrhosis occurs in association with several features, the most important being severe portal hypertension, a circulatory dysfunction leading to homeostatic stimulation of endogenous vasoactive systems (renin angiotensin system, sympathetic nervous system and antidiuretic hormone (ADH)) [10,11], and an impaired kidney function with renal sodium and water retention [12,13]. However, our concepts of how these abnormalities develop have been changing along the time. Initially, portal hypertension and ascites formation were considered as primary events, with circulatory dysfunction and renal impairment being secondary phenomenona (Backward Theory of Ascites Formation [14,15]). Portal hypertension and hypoalbuminemia would lead to a rupture of the Starling equilibrium within the splanchnic microcirculation resulting in increased splanchnic lymph formation. When portal hypertension is moderate, this is compensated by an increased lymph return through the thoracic duct (the thoracic duct lymph flow, which in normal persons is less than 1 l/day, may range between 5 and more than 20 l/day in patients with cirrhosis and portal hypertension [16]). However, when portal hypertension is severe, lymph formation overcomes lymph return, leading to the leakage of fluid from the interstitial space of the splanchnic organs to the abdominal cavity and this secondarily impairs circulatory and renal function. According to this hypothesis, plasma volume and cardiac output should be decreased and peripheral vascular resistance increased. The Overflow Theory of Ascites Formation was proposed when it became clear that plasma volume and cardiac output in cirrhotic patients with ascites was increased and peripheral vascular resistance was reduced [17 19]. According to /03/$30.00 q 2003 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. doi: /s (03)

2 S70 V. Arroyo, J. Colmenero / Journal of Hepatology 38 (2003) S69 S89 Fig. 1. Prognosis of patients with cirrhosis at the onset of ascites. this theory, the initial event was a primary sodium retention, primary in the sense that it was unrelated to an impairment in circulatory function [20]. The fluid retained by the kidneys would increase the plasma volume and the cardiac output, and the peripheral vascular resistance would decrease to accommodate the arterial hypervolemia [21]. A hepatorenal reflex promoted by portal hypertension was the mechanism proposed to explain sodium retention [22]. The encounter between the arterial hypervolemia and the increased portal pressure would result in an overflow ascites formation [23]. However, some major points were raised against this hypothesis. First, the evidence that arterial vasodilation in these patients is not a generalized phenomenon but rather restricted to the splanchnic circulation [24 27]. Second, the demonstration that arterial pressure and peripheral vascular resistance, which are reduced in decompensated cirrhosis with ascites, further decrease after the administration of angiotensin-ii antagonists in cirrhotic patients [28,29] and after the administration of V1 vasopressin antagonists in cirrhotic rats [30], a feature not consistent with a plasma volume expansion due to primary sodium retention. Fig. 2. Peripheral Arterial Vasodilation Hypothesis The peripheral arterial vasodilation hypothesis of renal sodium and water retention and the forward theory of ascites formation They are the most accepted mechanisms of renal dysfunction and ascites formation in cirrhosis and constitute the rationale in which modern treatments of patients with cirrhosis and ascites are based. They take into account several features observed in patients and experimental animals with cirrhosis and ascites: (1) Ascites formation develops in the setting of severe portal hypertension and the leakage of fluid is clearly due to the rupture of the Starling equilibrium within the splanchnic circulation [16]. (2) There is a chronological relationship between sodium retention, impairment in circulatory function and the formation of ascites [31 35]. (3) Circulatory dysfunction in cirrhosis is predominantly due to an arterial vasodilation in the splanchnic circulation secondary to portal hypertension [24,25,36]. Although the mechanism is not yet completely understood, evidences have been presented suggesting that this splanchnic hyperemia is due to an increased local production of vasodilators (i.e. nitric oxide) [37,38]. Vascular resistance in the remaining major vascular territories (kidneys, brain, muscle and skin) is normal or, at the latest phases of the disease, increased [39 41]. (4) The blockade of the vascular effect of angiotensin-ii, norepinephrine and ADH in advanced cirrhosis with ascites is associated with a marked hypotensive response due to a fall in vascular resistance, indicating that circulatory dysfunction would be more severe if these systems were not homeostatically stimulated to maintain arterial pressure [28 30,42]. (5) The degree of impairment in renal function (sodium retention, impairment in free water excretion and decrease in renal perfusion and glomerular filtration rate (GFR)) correlates with the degree of activity of the endogenous vasoconstrictor systems (renin angiotensin system, sympathetic nervous system and ADH) and both correlate with the severity of portal hypertension [43]. (6) Capillary permeability and lymph formation in the splanchnic organs markedly increase when both portal pressure and splanchnic arterial vasodilation develop, but not when there is only portal hypertension. In fact, splanchnic hyperemia, and not the increase in portal pressure, is the main mechanism of the increased lymph formation in portal hypertension [44]. The Peripheral Arterial Vasodilation Hypothesis (Fig. 2) considers that the primary event of renal sodium and water retention in cirrhosis is a splanchnic arterial vasodilation secondary to portal hypertension [45]. At the initial phases of the disease, when ascites is still not present, circulatory homeostasis is maintained by the development of hyperdynamic circulation (high plasma volume, cardiac index and heart rate). However, as the disease progresses and splanchnic arterial vasodilation increases this compensatory mechanism is insufficient to maintain circulatory homeostasis. Arterial pressure decreases, leading to stimulation of baroreceptors, homeostatic increase in the sympathetic nervous activity, renin angiotensin system activity and

3 V. Arroyo, J. Colmenero / Journal of Hepatology 38 (2003) S69 S89 S Ascites reabsorption Fig. 3. Forward Theory of Ascites Formation. circulating levels of ADH, and renal sodium and water retention [46 50]. Recent studies showing that blood volume in the central vascular compartment (cardiopulmonary circulation and aorta), which is the site where high and low pressure baroreceptors are located, is reduced in decompensated cirrhosis with ascites but not in patients without ascites support this hypothesis. The low central blood volume in decompensated cirrhosis with ascites is due to an extremely rapid circulation promoted by the reduced cardiac afterload [51,52]. This Peripheral Arterial Vasodilation Hypothesis is the basis of a new concept in the pathophysiology of ascites, the Forward Theory of Ascites Formation (Fig. 3). According to this theory, the accumulation of fluid within the abdominal cavity in cirrhosis is the result of the changes in the splanchnic arterial circulation promoted by portal hypertension. The arterial vasodilation in the splanchnic circulation would induce the formation of ascites by simultaneously impairing the systemic circulation, leading to sodium and water retention, and the splanchnic microcirculation, leading to the leakage of fluid into the abdominal cavity [45,53]. The volume of ascites depends not only on the amount of fluid leaking from the splanchnic microcirculation into the peritoneal cavity, but also on the rate of reabsorption of ascites back into the intravascular compartment. The lymphatics on the undersurface of the diaphragm play a major role in this latter process. These vessels and the diaphragmatic peritoneum are especially prepared for this function. A single layer of mesothelial cells covers the peritoneal surface of the diaphragm over a connective tissue matrix with a very rich plexus of terminal lymphatic vessels (lymphatic lacunae) [54,55]. The submesothelial connective tissue over the lymphatic lacunae is almost absent and wide gaps, large enough to allow the passage of erythrocytes, connect the peritoneal cavity with the lumen of the terminal lymphatics. The submesothelial lymphatic plexus drains into a deeper plexus of valved collecting vessels, which penetrate connecting tissue septa between the muscular fibers of the diaphragm and drain into parasternal trunks on the ventral thoracic wall, right lymphatic duct, and right subclavia or internal jugular veins. During inspiration, intercellular gaps close and the fluid is pumped into the systemic circulation through the combined effects of local compression, increased intra-abdominal pressure, and reduced intrathoracic pressure. During expiration, the gaps open and free communication is reestablished [56]. Reabsorption of ascites is a rate-limited process. The estimated mean rate of ascitic fluid reabsorption is 1.4 l/day, ranging from less than 0.5 l to more than 5 l [57] Renal dysfunction in cirrhosis A reduction of the renal ability to excrete sodium and free water and a decrease in renal perfusion and GFR are the three main renal function abnormalities in cirrhosis [58] (Fig. 4). Their course is usually progressive, although in some cases (mainly alcoholic cirrhosis) renal function Fig. 4. Renal function abnormalities in cirrhosis with ascites. The etched areas represent the normal range. From Ginès et al. [250]. With permission.

4 S72 V. Arroyo, J. Colmenero / Journal of Hepatology 38 (2003) S69 S89 may improve during follow-up. The main consequence of the reduced ability to excrete sodium in cirrhosis is the development of sodium retention and ascites, and this occurs when the renal sodium excretion decreases below the sodium intake [59]. This represents a marked impairment in renal sodium metabolism. The renal ability to excrete free water in healthy subjects is far in excess to that required to eliminate the water ingested in a regular diet. Free water clearance approaches 10 ml/min (14 l/ day) in healthy individuals, an amount of water that is taken only by patients with serious psychiatric conditions [60]. Dilutional hyponatremia (arbitrarily defined as a serum sodium concentration of less than 130 meq/l) is the clinical consequence of the impaired free water excretion, and this occurs when free water clearance is severely reduced (usually lower than 1 ml/min) [61]. Finally, the main consequence of the impaired renal perfusion and GFR is HRS, which has been arbitrarily defined as a GFR below 40 ml/ min (normal GFR over 120 ml/min). Sodium retention, dilutional hyponatremia and HRS appear at different times during the evolution of the disease [62]. Therefore, the clinical course of ascites in cirrhosis can be divided into phases according to the onset of each one of these complications Phase 1: impaired renal sodium metabolism in compensated cirrhosis Chronologically, the first renal function abnormality occurring in cirrhosis is an impairment in renal sodium metabolism, which can already be detected before the development of ascites, when the disease is still compensated. At this phase of the disease, patients present a normal renal perfusion, GFR and free water clearance and they are able to excrete the sodium ingested with the diet. However, they present subtle abnormalities in renal sodium excretion [63]. For example, they present a reduced natriuretic response to the acute administration of sodium chloride (i.e. after the infusion of a saline solution) and may not be able to escape from the sodium retaining effect of mineralocorticoids [64 66]. Abnormal natriuretic responses to changes in posture is another relevant feature at this phase of the disease. Urinary sodium excretion is reduced in the upright and increased in the supine posture as compared to normal subjects [67,68]. Moreover, these patients show an increased plasma volume that supports a sodium retention over normal values [46]. It is interesting that some of these abnormalities develop in those patients with higher portal pressure and lower peripheral vascular resistance, indicating a relationship with the deterioration of circulatory function [66]. The term preascitic cirrhosis has been used to define this phase of the disease, although no study has demonstrated that it represents a state of impending ascites formation. Nevertheless, it is possible that the renal ability to excrete sodium in some patients with compensated cirrhosis may be just in the limit of sodium intake. In these patients the formation of ascites might be precipitated by increasing the intake of sodium or by impairing renal sodium excretion, for example, after the administration of vasodilators such as nitrates [69,70] or prazosin [71] Phase 2: renal sodium retention without activation of the renin angiotensin aldosterone and sympathetic nervous systems As a result of the progression of the disease, in a certain moment, patients become unable to excrete their regular sodium intake. Sodium is then retained together with water and the fluid accumulates in the abdominal cavity as ascites. Urinary sodium excretion, although reduced, is usually higher than 10 meq/day and in some cases it is above meq/day. Hence, a negative sodium balance, and therefore, the loss of ascites may be achieved only by reducing the sodium content in the diet [72,73]. Renal perfusion, GFR, the renal ability to excrete free water, plasma renin activity and the plasma concentrations of ADH are normal [46,49,50]. In this setting, sodium retention is unrelated to the renin aldosterone system and the sympathetic nervous system, the two most important antinatriuretic systems identified so far [74]. The plasma levels of atrial natriuretic peptide, brain natriuretic peptide and natriuretic hormone are increased in these patients, indicating that sodium retention is not due to a reduced synthesis of endogenous natriuretic peptides [75,76]. It has been suggested that circulatory dysfunction at this phase, although greater than in compensated cirrhosis without ascites, is not intense enough to stimulate the sympathetic nervous activity and the renin angiotensin aldosterone systems. However, it would activate a still unknown, extremely sensitive, sodium-retaining mechanism (renal or extrarenal) [46,77]. Alternatively, it has been proposed that sodium retention at this phase of the disease is unrelated to the circulatory function (i.e. increased renal tubular sensitivity to aldosterone or catecholamines [46,49], decreased synthesis of a putative hepatic natriuretic factor, or existence of hepatorenal nervous reflexes promoting sodium retention [22]). However, this is unlikely since sodium retention in the absence of an impaired circulatory function would be associated with arterial hypertension, a feature not observed in patients with decompensated cirrhosis who are, in fact, hypotensive. Investigations on the intrarenal sodium handling suggest that sodium retention in these patients occurs predominantly at the distal nephron [78,79] Phase 3: stimulation of the endogenous vasoconstrictor systems with preserved renal perfusion and GFR When sodium retention is intense (urinary sodium excretion below 10 meq/day), the plasma renin activity and the plasma concentrations of aldosterone and norepinephrine are invariably increased [43,47,80,81]. Aldosterone increases sodium reabsorption in the distal and collecting tubules. In contrast, the renal sympathetic nervous activity stimulates sodium reabsorption in the proximal tubule, loop of Henle and distal tubule [82,83]. Thus, sodium retention in

5 V. Arroyo, J. Colmenero / Journal of Hepatology 38 (2003) S69 S89 S73 these patients is due to an increased sodium reabsorption in the entire nephron. The plasma volume, cardiac output and peripheral vascular resistance do not differ from the previous phase [43]. Circulatory dysfunction, however, is more intense because an increased activity of the sympathetic nervous system and renin angiotensin system is needed to maintain the circulatory homeostasis. Arterial pressure at this phase of the disease is critically dependent on the increased activity of the renin angiotensin and sympathetic nervous systems and ADH, and the administration of drugs that interfere with these systems (saralasin [28,29], losartan [84], convertingenzyme inhibitors [85], clonidine [86], V1 vasopressin antagonists [30]) may precipitate arterial hypotension and renal failure. Although angiotensin-ii, norepinephrine and ADH are powerful renal vasoconstrictors, renal perfusion and GFR in this phase is normal or only moderately reduced because their effects on the renal circulation are antagonized by intrarenal vasodilator mechanisms, particularly prostaglandins [87]. Cirrhosis is the human condition in which renal perfusion and GFR are more dependent on the renal production of prostaglandins, and severe renal failure may develop at this phase if renal prostaglandins are inhibited with nonsteroidal anti-inflammatory drugs [88 92]. Other vasodilatory systems likely involved in the maintenance of renal function at this phase of the disease are nitric oxide [93] and the natriuretic peptides [94,95]. The renal ability to excrete free water is reduced at this phase of the disease owing to the high circulating plasma levels of ADH [48]. However, only few patients have significant hyponatremia [61] because the effect of ADH is counteracted by an increased renal production of prostaglandin E2 [96] Phase 4: the development of type-2 HRS HRS is a functional renal failure secondary to an intense renal hypoperfusion. It has been classified into two types according to the intensity and form of presentation of renal failure. Type-2 HRS is characterized by a moderate and steady decrease in renal function (serum creatinine between 1.5 and 2.5 mg/dl) in the absence of other potential causes of renal failure. The International Ascites Club considers that serum creatinine should be higher than 1.5 mg/dl or GFR lower than 40 ml/min for the diagnosis of HRS [62]. However, many patients with a GFR lower than 40 ml/ min have normal serum creatinine concentration (Fig. 5). Blood urea nitrogen (BUN) is a more sensitive indicator than serum creatinine in the assessment of renal function in advanced cirrhosis [97]. Therefore, the prevalence of type-2 HRS is underestimated when only serum creatinine is used in the clinical evaluation. Type-2 HRS develops in very advanced phases of cirrhosis in the setting of an intense worsening of circulatory function. Patients with type-2 HRS present very high plasma levels of renin, aldosterone, norepinephrine and ADH, significant arterial hypotension and increased heart rate [98]. The arterial vascular resistance in these patients is increased not only in the kidneys [39,97], but also in the brain [41] and muscle [40] and skin, indicating a generalized arterial vasoconstriction to compensate for the intense splanchnic arterial vasodilation [36]. Type-2 HRS is probably due to the extreme overactivity of the endogenous vasoconstrictor systems which overcomes the intrarenal vasodilatory mechanisms [99]. There are studies suggesting that in these patients the cardiac output may not be as high as in the previous phase [100]. However, further studies are needed to confirm this feature. The degree of sodium retention is very intense in type-2 HRS. These patients exhibit a reduced filtered sodium and a markedly increased sodium reabsorption in the proximal tubule [101]. The delivery of sodium to the distal nephron, the site of action of diuretics, is therefore very low [102]. Consequently, most of these patients do not respond to diuretics and present refractory ascites [62]. Free water clearance is also markedly reduced and most patients show significant hyponatremia [61]. The prognosis of patients with type-2 HRS is very poor with a survival rate of 50% and 20% at 5 months and 1 year after the onset of the renal failure, respectively (V. Arroyo, unpublished observations) Phase 5: the development of type-1 HRS Type-1 HRS is characterized by a progressive renal failure, which has been defined as doubling of serum creatinine reaching a level greater than 2.5 mg/dl in less than 2 weeks. Although type-1 HRS may arise spontaneously, it frequently occurs in close chronological relationship with a precipitating factor such as severe bacterial infection, acute hepatitis (ischemic, alcoholic, toxic, viral) superimposed to cirrhosis, major surgical procedure or massive gastrointestinal hemorrhage [62]. Patients with type-2 HRS are especially predisposed to develop type-1 HRS [100], although it may develop also in patients with normal Fig. 5. Relationship between serum creatinine and GFR. From Ginès et al. [250]. With permission.

6 S74 V. Arroyo, J. Colmenero / Journal of Hepatology 38 (2003) S69 S89 Fig. 6. Probability of survival of patients with type-1 HRS. From Ginès et al. [7]. With permission. serum creatinine concentration. The prognosis of patients with type-1 HRS is extremely poor, with 80% of patients dying in less than 2 weeks after the onset of HRS [7] (Fig. 6). Patients die with progressive circulatory, hepatic and renal failure and hepatic encephalopathy. Type-1 HRS has been especially investigated in spontaneous bacterial peritonitis (SBP) since 30% of patients with SBP develop this type of renal failure [103]. The two most important predictors of type-1 HRS development in SBP are an increased serum creatinine prior to the infection and an intense intra-abdominal inflammatory response, as suggested by high ascitic fluid concentration of polymorphonuclears and cytokines (tumor necrosis alpha and interleukin-6) at infection diagnosis [104]. It is unknown if these features represent a more severe infection or a late diagnosis of the infection. SBP-induced HRS develops in most patients despite a rapid resolution of the infection with antibiotics [105,106]. Type-1 HRS after SBP occurs in the setting of a severe deterioration of circulatory function, as indicated by a marked increase in the plasma levels of renin and noradrenaline [7,107]. Two recent studies have assessed systemic hemodynamics and renal function in a large series of patients with SBP at infection diagnosis and 1 week later [107,108]. Resolution of the infection occurred in most cases. Patients were classified into two groups according to whether they developed HRS or not after the infection. At infection diagnosis, BUN, plasma renin activity, plasma norepinephrine concentration and the peripheral vascular resistance were higher and the cardiac output lower in patients who subsequently developed HRS. Since patients were already infected, it was unknown whether these differences reflected a distinct baseline condition prior to the infection or were related to SBP. During antibiotic treatment, a further increase in renin and norepinephrine and reduction in cardiac output were observed only in patients developing HRS. At the end of treatment mean arterial pressure and cardiac output were 10 and 30% lower, peripheral vascular resistance 32% higher, and plasma renin activity and norepinephrine concentration between five and ten times higher in patients developing HRS in comparison with those without HRS. These studies, therefore, suggest that the impairment in circulatory function in patients with HRS is far more complex than that initially considered. In addition to arterial vasodilation in the splanchnic circulation, it is evident that a decreased cardiac output also participates in the impairment of the effective arterial blood volume during severe infection. Whether this is due to a decrease in heart function, decreased venous return secondary to an increased venous compliance or both is currently unknown [100]. The demonstration that plasma volume expansion with albumin at infection diagnosis reduces by more than 60% the incidence of renal impairment and hospital mortality in patients with SBP is consistent with this latter contention [109]. The progressive nature of renal failure in type-1 HRS is related to the rapid deterioration of circulatory function observed in these patients, although changes in intrarenal vasoactive mechanisms are also probably of great importance. As previously mentioned, the kidney produces vasodilatory substances such as prostaglandins and nitric oxide that diminish the effect of the endogenous vasoconstrictor systems on renal perfusion and GFR [93,95,110]. The moderate and steady course of type-2 HRS is probably related to an increased production of these substances that antagonizes the intense overactivity of the renin angiotensin and sympathetic nervous systems and ADH. When there is an intense reduction of renal perfusion the synthesis of these vasodilatory substances may be impaired [78]. On the other hand, renal ischemia stimulates the intrarenal synthesis of vasoconstrictor substances, such as angiotensin-ii [111] and adenosine [112]. Therefore, it could be postulated that type-1 HRS is initiated by an acute deterioration of circulatory function promoted by a precipitating event in patients who already have a severely compromised circulatory function. This would lead to renal ischemia, increased intrarenal production of vasoconstrictor systems, decreased synthesis of renal vasodilators and more renal ischemia, thus creating intrarenal vicious circles that accentuate and perpetuate the deterioration of renal function (Fig. 7). Several features support this mechanism: (1) A syndrome comparable to type-1 HRS can be produced in cirrhotic patients with ascites and increased activity of the renin Fig. 7. Proposed pathogenesis of type-1 HRS.

7 V. Arroyo, J. Colmenero / Journal of Hepatology 38 (2003) S69 S89 S75 angiotensin and sympathetic nervous systems or in experimental animals with carbon tetrachloride-induced cirrhosis and ascites following inhibition of prostaglandin synthesis [87 90,92,99,113] and nitric oxide [93] or after the administration of dypiridamol, a drug that increases the circulating levels of adenosine [114]. (2) The long-term (1 2 weeks) administration of intravenous albumin and vasoconstrictor substances (ornipressin [115], noradrenalin [116]) improves circulatory function and suppresses plasma renin activity and norepinephrine concentration to normal or near-normal levels within the first 2 3 days of treatment in patients with type-1 HRS. However, an increase in GFR is not observed until 1 2 weeks. Therefore, there is a clear lag between the normalization of systemic circulatory function and the improvement in renal perfusion and GFR, which may be the period required for the deactivation of the intrarenal mechanisms. (3) Once HRS has been reverted with plasma volume expansion with albumin and vasoconstrictor agents it does not recur after stopping treatment, suggesting that the rapidly progressive renal failure is a process more related to the features associated with the precipitating event than with the liver disease itself [117]. The development of HRS in patients with SBP is not only associated with a deterioration of circulatory and renal function, but also with an impairment in hepatic function leading to hepatic encephalopathy. A recent study has shown that in these patients there is an increase in the intrahepatic vascular resistance and portal pressure that correlates closely with an increase in renin and norepinephrine [107]. Circulatory dysfunction in HRS, therefore, also affects the liver. 3. Treatment of ascites and hepatorenal syndrome in cirrhosis 3.1. Therapeutic measures for ascites and HRS Bed rest and low sodium diet The assumption of an upright posture associated with moderate physical exercise in patients with cirrhosis and ascites induces an intense stimulation of the renin aldosterone and sympathetic nervous systems [74,118]. Therefore, although there is no specific study, from a theoretical point of view bed rest may be useful in patients with poor response to diuretics. Since the natriuretic effect of furosemide starts soon after its administration and disappears in approximately 2 3 h, bed rest should be adjusted to this feature [119]. The effect of spironolactone lasts for more than 1 day, and therefore, is not important in planning bed rest. Mobilization of ascites occurs when a negative sodium balance is achieved. In 10% of patients, those with normal plasma aldosterone and norepinephrine concentration and relatively high urinary sodium excretion, this can be obtained simply by reducing the sodium intake to meq/day [73]. A greater reduction in sodium intake interferes with the nutrition and is not advisable. In the majority of cases, however, urinary sodium excretion is very low and a negative sodium balance cannot be achieved without diuretics [120]. Even in these cases, sodium restriction is important because it reduces diuretic requirements [121,122]. Nevertheless, in the face of the frequent dilemma whether to decrease sodium intake or increase diuretic dosage, it is better to increase diuretic dosage if the patients respond satisfactorily to these drugs without complications. Sodium restriction is essential in patients responding poorly to diuretics. A frequent cause of apparently refractory ascites is inadequate sodium restriction. This should be suspected when ascites does not decrease despite a good natriuretic response to diuretics [123] Diuretics Furosemide and spironolactone are the diuretics more commonly used in the treatment of ascites in cirrhosis. Furosemide inhibits chloride and sodium reabsorption in the thick ascending limb of the loop of Henle, but has no effect on the distal nephron (distal and collecting tubules) [124,125]. It is rapidly absorbed from the gut, is highly bound to plasma proteins and is actively secreted from the blood into the urine by the proximal tubular cells. Once in the luminal compartment, furosemide is carried out with the luminal fluid to the loop of Henle, where it inhibits the Na 1 2Cl 2 K 1 co-transport system located in the luminal membrane. Since between 30 and 50% of the filtered sodium is reabsorbed in the loop of Henle using this transport system, furosemide has a high natriuretic potency. At high dosage, it may increase sodium excretion up to 30% of the filtered sodium in normal subjects. Furosemide also increases the synthesis of prostaglandin E2 by the ascending limb cells, and this effect is also related to its natriuretic effect since prostaglandins inhibit sodium reabsorption in the loop of Henle and non-steroidal anti-inflammatory drugs impair the diuretic and natriuretic effect of furosemide [89,126]. The onset of the action of furosemide is very rapid (within 30 min after oral administration), with peak effect occurring within 1 2 h; the diuretic-effect ends in 3 4 h after administration. Spironolactone undergoes extensive metabolism leading to numerous biologically active compounds, the most important quantitatively being canrenone [127,128]. These aldosterone metabolites are bound to plasma proteins from which they are released slowly to the kidney and other organs. In the kidney, spironolactone acts by competitively inhibiting the tubular effect of aldosterone in the distal nephron. Aldosterone interacts with a cytosolic receptor, is translocated into the nuclei, and stimulates the synthesis of sodium channels, which are inserted into the luminal membrane, and the transporter Na-K-ATPase, which activates the extrusion of sodium from the intracellular space into the peritubular interstitial space [129]. This transporter and the activation of potassium channels in the luminal membrane are the mechanisms for the kaliuretic effect of

8 S76 V. Arroyo, J. Colmenero / Journal of Hepatology 38 (2003) S69 S89 aldosterone. Spironolactone and their metabolites enter the basolateral membrane in the collecting tubule and interact with the cytosolic receptor of aldosterone, but the complex spironolactone-receptor, contrary to that of aldosteronereceptor, is unable to interact with the DNA [ ]. The half-life of the aldosterone-induced proteins and of spironolactone metabolites are prolonged, there being a delay of 2 3 days between the onset or the discontinuation of treatment with spironolactone and the onset or the end of the natriuretic effect, respectively. The clearance of spironolactone metabolites is reduced in cirrhosis [127], so the natriuretic effect of spironolactone after discontinuation of the drug persists for a longer time in cirrhotic patients than in normal subjects. Since the amount of sodium reabsorption in the collecting tubule is relatively low (approximately 5% of the filtered sodium), the intrinsic natriuretic potency of spironolactone is lower than that of furosemide. In contrast to what occurs in healthy subjects in whom furosemide is more potent than spironolactone, in cirrhotic patients with ascites spironolactone is more effective than furosemide. This was demonstrated in a randomized controlled trial 20 years ago [133]. Cirrhotic patients with ascites and marked hyperaldosteronism (50% of the patients with ascites) do not respond to furosemide or other loop diuretics [134]. In contrast, most cirrhotic patients with ascites respond to spironolactone. Patients with normal or slightly increased plasma aldosterone concentration respond to low doses of spironolactone ( mg/day), but as much as mg/day may be required in patients with marked hyperaldosteronism. Two mechanisms account for the resistance to furosemide in patients with ascites and marked hyperaldosteronism [135] (Fig. 8). First, an increased proximal sodium reabsorption leading to a low sodium delivery to the ascending limb of the loop of Henle [136,137]. Second, most of the sodium not reabsorbed in the loop of Henle by the action of furosemide is subsequently reabsorbed in the distal nephron by the effect of aldosterone [81]. Therefore, spironolactone is the basic drug for the management of patients with cirrhosis and ascites [133]. The simultaneous administration of furosemide and spironolactone increases the natriuretic effect of Fig. 8. Mechanisms of the resistance to furosemide in cirrhosis. both agents and reduces the incidence of hypo or hyperkalemia that may be observed when these drugs are given alone. There are two different approaches to the medical treatment of ascites in cirrhosis. The stepped care approach consists of the progressive implementation of the therapeutic measures currently available, starting with sodium restriction; if ascites does not decrease spironolactone is given at increasing doses (100 mg/day as initial dose; if there is no response within 4 days, 200 mg/day; if no response, 400 mg/day). When there is no response to the highest dose of spironolactone, furosemide is added at increasing doses every 2 days ( mg/day) [73, ]. The second approach is the combined treatment, which is particularly indicated in patients with tense ascites and avid sodium retention. It begins with sodium restriction and the simultaneous administration of spironolactone 100 mg/day and furosemide 40 mg/day. If the diuretic response is insufficient after 4 days, dose of furosemide and spironolactone are increased up to 160 and 400 mg/ day, respectively [141]. There is general agreement that patients not responding to these doses will not respond to higher diuretic dosage. In cases receiving the combined treatment with an exaggerated response, diuretic adjustment should be done by reducing the dose of furosemide. The goal of diuretic treatment should be to achieve a weight loss of kg/day in patients without edema and kg/day in patients with peripheral edema [142]. Once ascites has been mobilized, diuretic treatment should be reduced. Diuretic treatment in cirrhosis is not free of complications, particularly in patients requiring high diuretic dosage. Approximately 20% of patients develop significant renal impairment (increase in blood urea and serum creatinine concentration), which is usually moderate and always reversible after diuretic withdrawal [143,144]. It is due to an imbalance between the fluid loss induced by the diuretic treatment and the reabsorption of ascites, which varies greatly from patient to patient. Patients with ascites and peripheral edema develop less frequently diuretic-induced renal failure because there is no limitation in the reabsorption of peripheral edema, and therefore, it compensates the insufficient reabsorption of ascites. Hyponatremia, secondary to a decrease in the renal ability to excrete free water, also occurs in approximately 20% of these patients [143]. It is related to a reduction in intravascular volume leading to an increased secretion of ADH and also to a reduction in the generation of free water in the loop of Henle by the effect of furosemide. Free water is formed within the kidney by the active reabsorption of sodium chloride in the water impermeable loop of Henle and this process is inhibited by the loop diuretics. The most severe complication related to diuretic treatment is hepatic encephalopathy, which occurs in approximately 25% of patients admitted to hospital with tense ascites requiring high diuretic dosage [143]. This complication is also related to an impairment in circu-

9 V. Arroyo, J. Colmenero / Journal of Hepatology 38 (2003) S69 S89 S77 lating blood volume which increases the renal production and decreases renal clearance of ammonia [145]. Other complications include hyperkalemia or metabolic acidosis in patients with hepatorenal syndrome treated with high doses of spironolactone [146], hypokalemia in patients treated with high doses of furosemide and no or low doses of spironolactone [147], gynecomastia in patients receiving spironolactone and muscle cramps. Gynecomastia is related with the antiandrogenic activity of most spironolactone metabolites [148,149]. Canrenone, which apparently has lower antiandrogenic activity than spironolactone, is available for clinical use in some countries. Muscle cramps are clearly related to a reduction in intravascular volume since they occur when there is marked activation in the renin angiotensin system and may be prevented by plasma volume expansion with albumin [150]. The oral administration of quinidine also reduces the frequency of diuretic-induced muscle cramps [151]. The term refractory ascites is used to define the ascites that cannot mobilized or the early recurrence of which (i.e. after therapeutic paracentesis) cannot be prevented due to lack of response to sodium restriction and maximal diuretic treatment (160 mg/day of furosemide and 400 mg/day of spironolactone) (diuretic-resistant ascites) or to the development of diuretic-induced complications that precludes the use of an effective diuretic dosage (diuretic-intractable ascites) [62]. Refractory ascites is an infrequent condition, occurring in less than 10% of patients admitted to hospital with tense ascites [138,140]. Most of these patients have type-2 HRS (serum creatinine concentration.1.5 mg/dl) or significant decrease of GFR (serum creatinine between 1.2 and 1.5 mg/dl). It has been estimated that a serum creatinine above 1.2 mg/dl reflects a decrease of GFR greater than 50%. Both an impaired access of diuretics to the renal tubules due to reduced renal perfusion, and a reduced delivery of sodium to the loop of Henle and distal nephron secondary to the low GFR and increased sodium reabsorption in the proximal tubule are the mechanisms of diureticresistant ascites. A deficient sodium restriction or treatment with non-steroidal anti-inflammatory drugs should be ruled out prior the diagnosis of diuretic-resistant ascites [123] Aquaretic drugs Aquaretic drugs are agents that interfere with the renal effects of ADH, inhibit water reabsorption in the collecting tubules, and produce hypotonic polyuria without affecting solute excretion. These drugs are the ideal treatment of dilutional hyponatremia in cirrhosis and in other conditions associated with increased circulating levels of ADH such as congestive heart failure and the syndrome of inappropriate ADH secretion [152]. The hydroosmotic effect of ADH is mediated by the insertion of water channels (aquaporin 2), which are stored in vesicles in the cytoplasma near the tubular lumen, in the luminal membrane of the collecting tubular epithelial cells [153]. In the unstimulated state, this membrane is impermeable to water due to the lack of water channels. In contrast, the basocellular membrane, which is very rich in aquaporin 3, is highly permeable to water. The hydroosmotic effect of ADH is initiated by the binding of the hormone to a V2 receptor on the basolateral membrane of the collecting duct epithelial cells [154]. This receptor is coupled to adenylate cyclase, the stimulation of which releases cyclic adenosine monophosphate (camp) from adenosine triphosphate (ATP) [155,156]. camp activates a protein kinase that promotes the insertion of aquaporin 2 molecules into the luminal membrane. Water is then reabsorbed passively from the hypotonic tubular lumen to the hypertonic medullary interstitium [157]. The vasoconstrictor effect of ADH [158] depends on the interaction of the hormone with a different receptor, the V1 receptor, in the vascular smooth muscle cells, which increases the cytosolic calcium concentration [152]. Many aquaretic drugs were identified prior to Demeclocycline reduces the renal effects of ADH in humans by inhibiting adenylate cyclase [159]. Kappa opioid agonists produce hypotonic polyuria in humans and experimental animals by inhibiting the release of ADH by the neurohypophysis [ ]. Finally, several selective peptide V2 antagonists were developed during the 1970s by modifying the molecule of desmopressin [164,165]. However, none of these substances could be used in cirrhosis. Demeclocycline induces renal failure in decompensated cirrhosis with ascites [166]. The kappa opiod agonists have the risk of inducing hepatic encephalopathy [167]. Finally, the peptide V2 antagonists were aquaretic in rats and dogs, but had agonistic ADH activity in humans [168]. The field of the modern aquaretic drugs started in 1991, when an orally active non-peptide V1 antagonist was discovered using functional screening strategies [169]. One year later, via a series of structural conversions of this molecule, the first selective non-peptide V2 receptor antagonist (OPC-31260) was obtained [170] and this was the basis for the synthesis of other V2 antagonists (VPA-985 [171,172], SR [173], OPC [174], YM-087 [175]). Several studies in animals with experimental cirrhosis and phase 1 and 2 studies in patients with cirrhosis and ascites have demonstrated that these agents are extremely effective in increasing free water clearance and normalizing serum sodium concentration in cirrhotic patients with ascites and dilutional hyponatremia [174, ]. The increase in urine volume is dose-dependent and when appropriate doses are given, serum sodium concentration is normalized within a few days after the onset of treatment. Many aspects concerning the aquaretic drugs in cirrhosis with ascites need to be investigated. The mode as these agents should be used in cirrhosis is an important aspect since they have clear interactions with the natriuretic agents (i.e. diuretics) given to these patients. Also, it is essential to know whether these drugs affect sodium excretion in patients with cirrhosis and ascites. Although in normal conditions aquaretic drugs increase urine volume without

10 S78 V. Arroyo, J. Colmenero / Journal of Hepatology 38 (2003) S69 S89 Fig. 9. Changes in plasma renin activity (PRA...), norepinephrine (NE ) and atrial natriuretic peptide (ANP ) in patients with HRS following treatment with vasoconstrictors and albumin. From Guevara et al. [115]. With permission. affecting sodium excretion, this has not been the case in experimental animals with cirrhosis and ascites, in which in addition to hypotonic polyuria, these agents increased the urinary sodium excretion [180]. Finally, indications of aquaretic drugs for conditions other than spontaneous dilutional hyponatremia (i.e. diuretic-induced hyponatremia, hyponatremia prior liver transplantation) should be investigated Arterial vasoconstrictors The introduction of arterial vasoconstrictors in the therapeutic armamentarium for patients with HRS is a very recent event. It is based on three pathophysiological investigations. Shapiro et al. and Nicholls et al. in 1985 and 1986, respectively [181,182], showed that the combination of a vasoconstrictor (continuous infusion of noradrenaline) and plasma volume expansion (head-out water immersion) is able to correct circulatory dysfunction (as estimated by the plasma renin activity and ADH concentration) and to improve the renal ability to excrete sodium and solute-free water in non-azotemic cirrhotic patients with ascites, an effect not observed with plasma volume expansion alone. Lenz et al. [183] showed in 1991 that the short-term (4 h) infusion of vasopressin to patients with HRS led to an improvement in circulatory function (decrease in cardiac output and increase in peripheral vascular resistance) and a marked suppression of the renin angiotensin and sympathetic nervous systems. This effect was associated with a modest, but significant, increase in renal plasma flow and GFR. The first therapeutic study on the use of vasoconstrictors in patients with HRS was performed by Guevara et al. [115]. Eight patients with HRS were treated for 3 days with the combination of plasma volume expansion with albumin and a continuous infusion of ornipressin. A normalization of the plasma levels of renin and aldosterone and a marked suppression of the plasma levels of norepinephrine was obtained in each patient (Fig. 9). However, only a slight improvement in GFR (from 15 ^ 4to24^ 4 ml/min) was observed. Based on these data, these authors treated eight additional patients with HRS with the combination of ornipressin plus albumin during 15 days. In four cases treatment had to be stopped after 4 9 days due to ischemic complications in three cases and to a bacteriemia secondary to urinary tract infection in the forth. In these patients, in whom there was a significant improvement in serum creatinine concentration during treatment, a progressive impairment of renal function was observed following treatment withdrawal. In the remaining four patients, who completed treatment, there was a significant elevation in mean arterial pressure, a normalization of plasma renin activity, a marked decrease in plasma norepinephrine concentration a marked increase in renal perfusion and GFR and a normalization in serum creatinine concentration. These four patients died 12, 60, 62 and 133 days after treatment and HRS did not recur in any of them during follow-up. Although the investigation by Guevara et al. [115] clearly indicated that the continuous infusion of ornipressin was associated with a high incidence of side effects, it rose three important points. The first and most relevant is that HRS can be reversed pharmacologically. The second is that a prolonged improvement in circulatory function is required to reverse HRS, there being a relatively long delay between the suppression of the endogenous vasoconstrictor systems and the decrease in serum creatinine concentration. Finally, the third is that once recovered from HRS, patients may maintain a relatively preserved renal function despite discontinuation of therapy. The observations of Guevara et al. [115] have been subsequently confirmed in investigations using other therapeutic regimens with no or marginal side effects [117] Therapeutic paracentesis Paracentesis is a rapid, effective and safe treatment of ascites in cirrhosis. It is currently considered the treatment of choice of tense ascites [ ]. Although paracentesis is a simple procedure, it should be performed carefully, under local anesthesia and strict sterile conditions using blunted small-sized canulas with side wholes and a suction pump. Special kits for paracentesis, including modified