Ascites and hepatorenal syndrome during cirrhosis: two entities or the continuation of the same complication?

Journal of Hepatology 1999; 31: 1088-1097 Printed in Denmark . All rights reserved Munksgaard . Copenhagen

Copyright 0 European Association for the Study of the Liver I999

Journal of Hepatology

ISSN 0168-8278

Special Article

Ascites and hepatorenal syndrome during cirrhosis: two entities or the continuation of the same complication?

Paolo Gentilini, Giacomo Laffi, Giorgio La Villa, Roberto G. Romanelli and Laurence M. Blendis’

Institute of Internal Medicine. University of Florence, Italy and ‘Department of Gastroenterology, Sourasky Medical Center, Tel-Aviv, Israel

P TIENTS with cirrhosis of the liver eventually de- velop portal hypertension, often accompanied by

other complications, among which five (gastro-eso- phageal bleeding, ascites, encepalopathy, liver carci- noma and hepatic failure) are capable of influencing the survival rate of these patients and are therefore considered “major complications” (1). Portal hyperten- sion is mainly due to the increase in intrahepatic resis- tance caused by nodular regeneration, activation of he- patic stellate cells because of the increased availability of vasoconstricting agents, contraction of perisinusoid- al liver cells with collagen deposition in the Disse space, and consequent portal fibrosis (2,3). In this con- dition, most patients eventually develop sodium reten- tion, with ascites and/or peripheral edema. In a study performed in patients who were followed up to 15 years, 80% manifested this complication (1). Another study reported similar results (4). Total body water tends to increase and free water clearance, which was previously normal, is reduced, thus promoting hypona- tremia (4-6). On the other hand, spontaneous vari- ations of sodium handling during decompensated cir- rhosis have also been observed: in fact, cirrhotic pa- tients may undergo spontaneous diuresis, followed by a return to avid sodium retention (7).

In the first stage of compensated cirrhosis, subclin- ical renal functional impairment (RFI) occurs in some patients. This is characterized by a significant decrease (greater than 50% of normal) of renal plasma flow (RPF) and glomerular filtration rate (GFR) in the presence of sodium retention and hypoperfusion of the outer cortex (8). During this period, which may last for 3 months to 3 years, renal dysfunction may be un- masked by diverse precipitating factors (bleeding, di- arrhea, vomiting, diuretic abuse), leading to a rapid

Correspondence: Paolo Gentilini, Istituto di Medicina In- terna, Universid degli Studi di Firenze, Viale Morgagni 85, 50134 Firenze, Italy. Tel: 55 416 635/411 919. Fax: 55 417 123.

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decrease of blood volume. These factors, which are in- dependently capable of causing pre-renal azotemia, worsen the pre-existing renal dysfunction, leading to severe renal ischemia, the cause of the development of hepatorenal syndrome (HRS). In spite of the similarity between pre-renal azotemia and HRS, the infusion of plasma expanders leads to an evident improvement of renal function only in the former (9). In patients with decompensated cirrhosis, HRS has been found in about 18% after 1 year and in 40% after 5 years of follow-up (10).

Some patients affected by cirrhosis show structural renal damage, including glomerulonephritis, such as membrano-proliferative or membranous glomeru- lonephritis, also called “cirrhotic glomerulonephritis” which may affect the survival rate in these cases. The real incidence, severity, and significance of this organic form of renal disease are unknown. However, in pa- tients undergoing liver transplantation, 8 out of 12 showed typical signs of hepatic glomerulosclerosis (11). In another study, all six patients with hepatitis C virus (HCV)-related cirrhosis submitted to renal biopsy be- cause of proteinuria showed typical glomerulonephritis (12). We observed the organic form of renal impair- ment in 33.7% of cases. In many cases, organic renal failure is associated with circulating immunocomplex- es, high immunoglobulin levels and/or cryoglob- ulinemia. In both functional and organic renal dam- age, acute tubular necrosis (ATN) may develop follow- ing severe bacterial infection, surgical intervention or the administration of nephrotoxic drugs (13). The oc- currence of ATN can modify prognosis in cirrhotic pa- tients, thus requiring early diagnosis and accurate sur- veillance in order to avoid rapid renal deterioration.

Mechanisms of Sodium and Wter Retention To explain the positive sodium balance and consequent liquid accumulation in liver cirrhosis, Schrier et al. (14) suggested a pathogenetic theory based on “peripheral arterial vasodilation”, a revised version of the classic

Ascites and hepatorenal syndrome in cirrhosis

theory of “underhlling”. Schrier et al. considered that sodium and water retention in cirrhosis are secondary events triggered by a reduction in effective arterial blood volume (EABV). According to this theory, sinus- oidal portal hypertension leads to splanchnic vaso- dilation (15), perhaps due to the increased production of vasodilating substances such as nitric oxide (NO), glucagon, prostaglandins (PGs) and vasoactive intesti- nal peptide (VIP) (16-18), with consequent splanchnic pooling. The resulting underfilling of arterial circula- tion is sensed by arterial baroreceptors, which stimu- late the sympathetic nervous system (SNS) and the re- nin-angiotensin-aldosterone system (RAAS) and cause non-osmotic hypersecretion of arginine vasopressin (AVP), leading to renal sodium and water retention.

While there is no doubt that the above situation exists in patients with well-established ascites, the alter- native “overflow theory” postulates that the initiating event in the pathogenesis of ascites in cirrhosis is portal hypertension-induced “primary” sodium retention, i.e. not related to hemodynamic stimuli (19). The mechan- ism(s) which relates portal hypertension to sodium re- tention could be either a neurogenic hepatorenal con- nection, leading to sodium retention in response to an increase in sinusoidal portal pressure, or a hormonal pathway. According to this theory, primary sodium re- tention leads to plasma volume expansion, which in turn is responsible for adaptive circulatory changes (high cardiac output and low systemic vascular resis- tance, that is the so-called “hyperdynamic circulatory syndrome” of cirrhosis) to accommodate the excess of fluid retained by the kidney. Some data obtained in patients with compensated cirrhosis claim to support the overflow theory: first of all, the plasma levels of renin and aldosterone are not elevated, but rather de- creased in some of these patients; in addition, these patients have a decreased natriuretic response to intra- venous saline, elevated renal blood flow and glomeru- lar filtration rate, increased central volume, as assessed by radionuclide angiography, and plasma atria1 natriu- retie peptide (ANP), and sodium avidity. In fact, these patients are able to achieve sodium balance in only 48 h when given a 20 mmol/day sodium diet, compared with 5 days in control subjects, while they are unable to reach sodium balance by 7 days when challenged with a 200 mmoYday sodium diet (20,21) (Fig. 1).

Considering all the data supporting the overflow theory, as well as the data supporting the peripheral vasodilation theory, we suggest an alternative hypo- thesis, which may include the principal phenomena leading to the occurrence of ascites and eventually HRS (Fig. 2).

An impaired renal ability to excrete free water is a

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Fig. 1. Daily sodium excretion ( UNa V) in healthy subjects (circles) andpreascitic cirrhotic patients (triangles) during 7 days on a low (20 mmollday) (A) and high (200 mmoll day) (B) sodium diet. Based on data from Wong et al. (20), reproduced with permission.

frequent renal functional alteration of cirrhosis (7) and correlates with AVP plasma levels (22,23). Hyponatre- mia with ascites has been observed in about 25-30% of hospitalized cirrhotic patients (lo), while in our ex- perience the incidence is 15.4%.

The increased plasma levels of AVP in cirrhosis with ascites are due to enhanced secretion and not to im- paired metabolism (24). In turn, AVP hypersecretion is clearly mediated by non-osmotic stimuli since most patients have a degree of hyponatremia and hypoos- molality that would suppress AVP release. In the ab- sence of non-osmotic hypersecretion of anti-diuretic hormone (ADH) in cirrhosis with ascites, mild or moderate impairment of water excretion could be due

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1 CIRRHOSIS j

0 PORTAL HYPERTENSION

a 0

Na md(l;~~a$wption c-_=3 Splanchnic vasodilation

0 Increased intravascular volume

0 Decreased peripheral vascular resistance and vascdilation

(Undertilling)

a Increased heart rate and cardiac output

Fig. 2. Diagram representing the principal pathogenetic mechanisms leading to ascites and hepatorenal syndrome (HRS).

to an increase in plasma levels of a potent vasodilator agent, the substance P (25).

Hemodynamic Derangement Several neurohormonal factors are specifically aimed at regulating vessel tone and handling hemodynamics. The principal vasoactive systems are reported here:

Sympathetic nervous system (SNS) Renin-angiotensin-aldosterone system (RAAS) Vasoactive diuretic or antidiuretic hormones (AVP ANP, BNP, CNP, etc.) Autacoid systems: eicosanoids, kallikrein-kinogen- kinin system, serotonin, histamine, platelet activat- ing factor (PAF), endothelins (ETs), vasoactive in- testinal peptide (VIP), nitric oxide (NO), etc. Much of the research relating to cirrhosis is aimed

understanding the mechanisms leading to the phenomena of “hyperdynamic circulation”, i.e. in- crease in cardiac output, and splanchnic and peripheral vasodilation in the presence of preferential renal cor- tical vasoconstriction. Other investigations have fo- cused on the general tendency to hypotension with changes in central blood volume and the strong and increasing activation of major vasoactive systems (14,2628).

The derangement of systemic hemodynamics is also characterized by the opening of pre-existing or new veno-venous or arterio-venous shunts in splanchnic and other areas including the kidney. Epstein et al. (26), utilizing selective renal arteriography, demon- strated severe preferential hypoperfusion of the renal cortex and marked instability of the arcuate and inter- lobular arteries, which appeared distorted and dilated,

alterations demonstrated to be reversible after patient death. Kew et al. (28) using the washout technique with 133Xenon, and later Wilkinson et al. (29) with transit renography, demonstrated a redistribution of blood flow from the outer towards the inner cortex and the medulla in most patients affected by cirrhosis. At the same time, the opening of arterio-venous shunts, probably located between the cortex and the medulla, has been demonstrated in patients affected by chronic active liver disease and to a greater extent in patients with advanced cirrhosis by infusing 99Tc-labeled microspheres of human albumin (30 pm in diameter) directly into the renal artery of these patients (8).

In patients affected by liver cirrhosis, especially when decompensated, several authors have demon- strated increased activity of the SNS on the basis of increased norepinephrine and urine plasma catechol- amine concentration. The activation of the SNS can lead to persistent vasoconstriction of the outer renal cortex and reductions in RPF and GFR (3632). Through renal vasoconstriction and the consequent overproduction of renin, there is an increased release of angiotensin II, which contributes to renal vaso- constriction, whereas the overproduction of aldoster- one leads to increased sodium reabsorption, favoring a positive sodium balance.

An important vasoconstricting action of angiotensin II is expressed on the efferent arteriole in cirrhotic pa- tients, since it has been demonstrated that the adminis- tration of low-dose captopril (12.5 mg), which inhibits angiotensin converting enzyme (ACE) and thus angio- tensin II generation without any effect on arterial pressure, induces the reduction of GFR and filtration fraction with a significant decrease in sodium excretion

(33). In patients with decompensated cirrhosis, evidence of

a relatively decreased central blood volume in relation to the vascular capacity may independently influence so- dium and water retention (34). Epstein (7) demonstrated the natriuretic, although variable, effect of head-out water immersion, which caused central blood volume expansion in ascitic patients. Moreover, treatment with plasma expanders influences diuretic response in pa- tients with decompensated cirrhosis (35). However, the hyperdynamic circulatory syndrome was evident in cir- rhotic patients only in the supine position, when cardiac output, cardiac index and stroke volume were signifi- cantly increased, and peripheral vascular resistance (PVR) decreased when compared to both cirrhotic pa- tients in the tilting position and normal subjects (36).

The same authors observed a significantly higher left ventricular end diastolic volume in the supine position in sodium-excretor patients, suggesting that the return

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towards normal sodium balance in these patients was associated with the expansion of central volume (37) found by others in relationship to SNS activation and ANP release (38,39).

Role of Natriuretic and Other Vasoactive Substances AVP hypersecretion may be considered the principal cause of hyponatremia with a dilutional effect on circu- lating plasma volume in patients with decompensated cirrhosis, but may also characterize volume depletion due to a sodium-restricted diet, overaggressive loop di- uretic therapy, severe vomiting, diarrhea or non-com- pensated paracentesis (40). The decrease in plasma vol- ume happens rapidly and the dilution of plasma with consequent hyponatremia may be a compensating mechanism; however, pre-renal azotemia may also oc- cur (7).

AVP is one of the most potent vasoconstricting fac- tors which, through stimulation of Vl receptors, in- hibits sympathetic efferent stimuli and potentiates ba- roreflexes, while in some regions V2 receptors induce vasodilation perhaps through NO endothelial release (41). Administration of specific V2 antagonists (42) or niravoline, a rc-opioid receptor agonist that inhibits AVP release, improves water excretion in rats with ex- perimental cirrhosis, with ascites and impaired water excretion (43).

A defective production of one or more natriuretic factors has been suggested as the principal mechanism leading to sodium and water retention in liver cirrhosis. Among these factors, the principal one is atria1 natriur- eticpeptide (ANP), also known as atria1 natriuretic fac- tor (ANF). Most authors have observed a significant increase in ANP plasma levels in cirrhotic patients, especially if affected by RF1 (44). Some authors have reported increased levels of ANP parallel to the in- creased pressure in the intrasinusoidal liver bed (45) and decreased levels in patients treated with diuretics. The level of ANP is always increased by maneuvers enhancing blood volume. Headout water immersion of patients with decompensated cirrhosis provoked a rapid increase in ANP levels with an increase in natri- uresis and urinary excretion of cGMP (46). Other authors reported similar observations in patients with refractory ascites who had undergone a LeVeen shunt insertion or transjugular intrahepatic portosystemic shunts (TIPS) (47,48).

However, the continuous and significant increase in ANP secretion generally does not correspond to an in- crement in sodium and water excretion. This phenom- enon could be due to the lack of activity of ANP in cirrhosis, even if the production of cGMP from the

kidney in patients treated with exogenous ANP sug- gests that activation of renal receptors by ANP remains normal also during cirrhosis (49).

Brain natriuretic peptide (BNP) has properties simi- lar to those of ANP and it is elevated in decompen- sated cirrhosis, either with or without RF1 (50). The infusion of either ANP or BNP has a relatively limited effect on renal function and natriuresis in patients affected by decompensated cirrhosis. Infusion of low- dose BNP to patients with avid sodium retention and ascites did not elicit any natriuretic effect (51).

Recently, a third natriuretic peptide was isolated from the porcine brain, called C-type natriuretic pep- tide (CNP), which is characterized by wide distri- bution. ANP directly dilates afferent arterioles while CNP dilates them through the PG/NO pathway (52).

From an experimental point of view, the administra- tion of pharmacological doses of BNP and CNP pro- duced a natriuretic response which was blunted in cir- rhotic rats. In the same experiments, these natriuretic peptides produced a significant reduction of portal pressure (53).

In conclusion, ANP BNP and CNP seem to form a natriuretic peptide system capable of promoting local sodium and water transport and renal hemodynamics in human kidney. Moreover, they have multiple actions beyond their natriuretic effects, acting not only in the kidney but also in the liver, where the increased pres- ence of ANP and CNP, together with their respective natriuretic peptide receptors (NPRs), suggest autocrine or paracrine functions, which may counteract the consequences of portal hypertension through their vasodilatory effects (54).

Adrenomedullin (AM) is a recently isolated endo- thelium-derived related peptide (EDRP), identified as 52 aa peptide hormone, which is expressed in juxtaglo- merular structures and in distal tubular cells, where it acts as a stimulatory factor of renin production and sodium excretion, respectively, in an autocrine-para- crine fashion. The effect of AM is mediated by renal PGs at the level of the glomerulus and the distal neph- ron (55). Its potent long-lasting vasodilation involves sodium-dependent mechanisms. Together with its hypotensive action and vasodilatory effects, this hor- mone induces diuresis. Its plasma levels are elevated in liver cirrhosis, especially with RF1 (56).

,4nother natriuretic factor is called calcitonin gene- relatedpeptide (CGRP), which, together with its recep- tors, has been discovered in the kidney; it stimulates CAMP accumulation in various organs, including the kidney and together with AM contributes to regulating glomerular and distal tubular function. Experimentally

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infused high doses provoke an increase in urine flow rate, sodium and potassium excretion (57).

Urodilatin (URO), another member of the natriuret- ic peptide family discovered in human urine in 1988, is produced by renal collecting tubules (58). Unlike the other natriuretic peptides, it seems to be produced only by the kidney, especially by the distal tubules, exerting a paracrine effect with consequent natriuresis similar to that produced by ANP It seems to play an import- ant role in regulating fluid balance and sodium homeo- stasis. In patients with cirrhosis, URO has been found increased in urine, and it augments GFR and decreases RPF and distal fractional reabsorption of sodium (59).

Renal Autacoid Systems The renal autacoid systems include arachidonic acid metabolites, the kallikrein-kininogen-kinin system, platelet activating factor (PAF), endothelins (ET), NO and cytochrome P450 metabolites (60).

PGs, derived from endoperoxides under the influ- ence of PG endoperoxide synthase (PES), are present in the arteriole and arteriolar vascular endothelium, including glomerular afferent and efferent arteriole of the kidney. In patients with decompensated cirrhosis, renal excretion of PGs is increased together with TxB2, the non-enzymatic metabolite of TxA2 (61,62). The protective role played by PGs is proven by the fact that reduction in PG synthesis by NSAIDs, an inhibiting cycle-oxygenase activity, results in a rapid decrease in renal function and sodium excretion in decompensated cirrhotic patients (63).

Among the arachidonic acid metabolites, a physio- logical balance between vasodilating (PGE2 and PG12) and vasoconstricting (TxA2 and PGF-lalpha) factors has been reported. The increasing imbalance between these different products with the prevalence of the lat- ter and the release of PAF and LTs may contribute to the vasoconstriction and rapid deterioration of renal function in advanced cirrhosis with HRS (9). The over- production of TxA2 is also supported by evidence of a provisional improvement in GFR and sodium ex- cretion by the administration of a TX - synthase inhibi- tor, OKY 046, or a TX-receptor antagonist, ON0 3807 (64,65).

The kallikrein-kininogen-kinin system and other vasoactive systems are correlated with the PG system. The increased activity of the SNS and RAAS induces overproduction of PGs, which in turn increases renin release. On the other hand, bradykinin and kallidin, together with PGs, maintain vasodilation, but their va- sodilating effect can be blocked when PG release is blunted. Moreover, kinins, when acting alone, may modulate renal hemodynamics and sodium and water

excretion. The urinary excretion of kinins, an express- ion of renal kinin synthesis, is increased in patients with cirrhosis without RF1 (66). RPF and GFR are correlated with urinary kallikrein activity (66). LTs (LTC4 and LTD4) appeared to be higher than normal in patients with cirrhosis and HRS, as measured by the presence of LTE4 , which is the major metabolite of LTs (67).

PA4 a potent aggregating agent and chemotactic factor for circulating white blood cells, induces an in- creased production of LTs. It also decreases GFR and RPF, together with sodium excretion in some experi- ments. It could act as a co-factor in provoking vaso- constriction in the renal cortex of patients with HRS in the presence of enodotoxins (68).

Endothelins (ETs), especially ET-l, are considered important mediators and modulators of systemic hemodynamics and renal function on the basis of auto- crine-paracrine effect via vasocontriction. For ex- ample, post-ischemic vasoconstriction is improved by the intrarenal infusion of antibodies against endothelin or administration of antagonist to ET-l receptors. Va- soconstriction is also indirectly produced by the block of NO. ET 1 increases the production of ANP, activates the RAAS and partially blocks the water-retaining ef- fects of ADH (69). The increase of ET-1 in the systemic and renal veins is more pronounced in patients affected by decompensated cirrhosis either with or without RFI, suggesting that ET-l, may play an important role in determining renal vasoconstriction and the decrease in GFR found in cirrhotic patients with HRS (70). However the role of ET-1 in the pathogenesis of HRS remains controversial.

Nitric oxide (NO), a simple vasodilating product of endothelial cells (69), neutrophils and monocytes (71) could be considered one of the most important fac- tors in determining the decreased sensitivity of pe- ripheral receptors to catecholamines and angiotensin II, especially during the course of cirrhosis (72). Moreover, NO may play an important, direct role in the pathogenesis of peripheral vasodilation and renal vasoconstriction during cirrhosis with HRS. In fact, the administration of NO antagonists has been found to decrease peripheral vasodilation and improve splanchnic circulation in rats with experimental cir- rhosis and portal hypertension (73). Moreover, some authors recently reported increased natriuresis after the administration of local (renal) NO blocking agents in cirrhotic patients (74).

Definition of Refractory Ascites and HRS Refractory ascites can be defined as ascites accumu- lation which cannot be mobilized without serious

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consequences, despite the observation of a sodium-re- stricted diet (40 mmol/day) and treatment with high doses of diuretics (400 mg/day of spironolactone+ 160 mg/day of furosemide). According to Arroyo et al. (75), we can distinguish two different subtypes of re- fractory ascites: l Diuretic-resistant ascites: in case of markedly de-

creased or absent response to the above-mentioned treatment;

l Diuretic-intractable ascites: in case of ascites which cannot be mobilized because of the occurrence of drug-induced complications or its early recurrence. Refractory ascites is associated with greatly en-

hanced proximal sodium tubular reabsorption due to hyperactivity of the general vasoconstricting systems (SNS and RAAS), which contributes to the depressed potency of diuretics. It can be observed in about 5- 10% of cases.

The occurrence of refractory ascites generally be- comes more frequent and clinically evident after a long period of diuretic treatment, often accompanied by de- creasing values of creatinine clearance and sodium uri- nary excretion.

However, RF1 is not constantly or rapidly progress- ive, though in some instances it may progress rapidly towards olinicaliy relevant renal failure, which corre- sponds to a real HRS (75). HRS by itself is in fact characterized by an increase of serum creatinine and BUN, with a significant decrease in creatinine clear- ance, excretion of small amounts of concentrated urine, virtually free of sodium (often sodium content is less than 10 mmol/l, osmolality more than 400-500 mOsm/kg and fractional excretion of sodium below lo/o), in the absence of shock or other known causes of renal failure (75).

The distinction between functional and organic im- pairment is generally based on the presence of casts and blood cells in urinary sediment, often ac- companied by proteinuria and/or microhematuria. Moreover, histological alterations may contribute to the pathogenesis of HRS in some circumstances (76,77). The prevalent functional nature of the typical form of HRS is supported by the reversibility of this syndrome after liver transplantation, despite a poorer prognosis in some patients (78).

Pathogenetic Mechanisms Leading to HRS On the basis of the data already reported, in the natu- ral history of cirrhosis the kidneys maintain their physiological function in response to abnormal sys- temic vasodilating stimuli with the activation of the principal vasoconstricting and compensatory renal autacoid systems. From time to time, however, the ov-

erstimulus of vasoactive systems, principally the SNS and RAAS, but also TxA2, LTs etc., could lead to ac- tive renal vasoconstriction prevailing in the outer cor- tex (26), leading to relative hypoxia of the nephrons and exhausting membrane arachidonic acids and/or other essential molecules which generally lead to a cor- rect activation of the autacoid systems, thus allowing a progressive renal impairment.

During the final stage of liver disease, renal function may be conditioned by functional or organic damage to nephrons. In fact, during prolonged ischemia, which is particularly visible in the outer renal cortex, the neph- rons may be susceptible to nephrotoxic agents, such as endotoxins and some antibiotics, NSAIDs, etc. (26,79).

Predisposing and Predicting Factors of HRS Among predisposing factors, the most important seem to be related to being elderly (SO) and to suffering from spontaneous bacterial peritonitis (SBP) (8 1). Bacterial translocation from the intestine may be important in worsening endotoxemia and may have a direct effect on the kidney in patients with cirrhosis, probably me- diated by tumor necrosis factor and interleukins, as re- ported in cirrhotic patients with infections (82).

Another predisposing factor to HRS is represented by a too vigorous paracentesis not compensated by albumin or other plasma expander infusion, occurring in l&25% of patients (83). Other predisposing factors may include prolonged or intense antibiotic treatment, gastrointestinal bleeding or other causes related to plasma volume reduction, including persistent diarrhea or excessive fluid restriction, which may be per se re- sponsible for determining pre-renal azotemia or may play an additional role in HRS (77). Finally, the ad- ministration of NSAIDs, even at low doses, may deter- mine a decline in renal function in patients with de- compensated cirrhosis. In light of the alarming prog- nosis for patients with decompensated cirrhosis who have developed HRS and the very low mean survival (less than 2 weeks) (lo), the predicting factors listed below seem extremely important: 1. presence of tense ascites; 2. low sensitivity to diuretic treatment; 3. rapid recurrence of ascites after paracentesis; 4. decreasing levels of sodium concentration in urine; 5. hyponatremia; 6. elevated and progressive increase in BUN and

serum creatinine.

Differential Diagnosis of Renal Failure in Cirrhosis In clinical practice, acute renal failure is a syndrome characterized by a rapid (hours to weeks) increase in

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serum creatinine and a decrease in creatinine clearance. This situation fulfills the diagnostic criteria for

“acute renal failure” and must be distinguished from other forms of renal failure due to pre-renal, post-renal or other intrarenal causes, such as ATN, which is the most frequent cause of renal failure, especially in pa- tients with renal ischemia (13).

Pre-renal azotemia usually develops following fluid loss due to diuretic administration, severe sodium and water restriction, vomiting, diarrhea, paracentesis without infusion of plasma-expanders or gastrointesti- nal bleeding. Diuretic-induced pre-renal azotemia is a common complication of cirrhosis with ascites, rang- ing between 15 and 25% in some published series. Only these latter patients, but not those with HRS, show a favorable response to plasma expansion (9,75,77). This maneuver, therefore, should be performed in all cir- rhotic patients with azotemia and without evidence of ATN. If the patients show no improvement in renal function following expansion of plasma volume with 1.5 1 of isotonic saline, pre-renal azotemia is unlikely.

In pre-renal azotemia and during HRS, the reab- sorption capacity of tubular cells and the capability of concentrating urine are preserved, while in ATN both of these functions are compromised (13). Since pre-re- nal azotemia syndromes and ATN could be linked to each other and since tubular death may follow the ini- tial ischemic state, defining HRS may be difficult. Moreover, toxins capable of inducing ATN may pro- duce pathogenetic features similar to those observed during ischemic acute renal impairment (79).

ATN usually occurs in the setting of either shock due to gastrointestinal bleeding, severe bacterial infec- tions or the administration of nephrotoxic drugs, such as aminoglycosides or NSAIDs. Laboratory data sup- porting the diagnosis of ATN include high urinary so- dium concentration (>20 mmol/l), loss of concentrat- ing ability (U/P osmolality= l), a urine-to-plasma crea- tinine ratio lower than 20, and a pathological sediment.

Finally, in rare instances, cirrhotic patients may de- velop acute renal failure due to other causes, such as pre-existing renal diseases, pyelonephritis, urinary tract obstruction, or drug-induced interstitial nephritis.

Principles in the Treatment of Refractory Ascites and HRS Refractory ascites, often followed by HRS, is a terminal complication of advanced cirrhosis and, once estab- lished, almost invariably progresses to a fatal outcome, despite any therapeutic measure proposed so far. Prob- ably, the most useful approach to management of these patients is prevention. Any reversible factor worsening liver function should be recognized and corrected.

Paracentesis Paracentesis with intravenous albumin infusion, recog- nized as an effective and safe maneuver to remove as- cites in cirrhosis (84) has likewise been proposed in patients with HRS and tense ascites to reduce intraper- itoneal pressure, which is believed to contribute to re- nal impairment. However, any improvement in renal function after paracentesis is only transient.

Plasma expanders Infusion of plasma expanders or head-out water im- mersion were proposed as therapeutic procedures in patients with HRS (75). These maneuvers may be beneficial since they restore “fullness” of circulation, reduce the degree of activation of the vasopressor sys- tems such as RAAS and SNS, favor the release of ANP and renal PGE2 and improve diuresis and natriuresis.

The repeated administration of human albumin for prolonged periods of time delayed the recurrence of ascites and probably HRS in patients with cirrhosis and ascites of varying severity (35).

Vasoactive drugs Numerous attempts have been made to correct renal cortical ischemia by intra-renal administration of vaso- dilators, especially PGs. Systemic administration of these drugs reduced renal as well as systemic vascular resistance, thus further decreasing EABV and renal perfusion without significant improvement in renal function. Also the oral adminstration of misoprostol gave misleading results (85).

Ornipressin is a vasopressin analog which has pref- erential vasoconstricting action on the splanchnic vas- culature. Administration of this drug, in addition to increasing arterial pressure, may also induce redistri- bution of blood flow to the kidneys, thus increasing renal perfusion and improving renal function in pa- tients with HRS (86).

The administration of ornipressin and albumin to patients with HRS (87) led to a marked improvement in systemic hemodynamics and renal function and a marked increase in plasma ANF! Midodrine has been associated with significant improvement in systemic hemodynamics in nonazotemic cirrhotic patients with ascites. Further, it was sufficiently effective in inducing an improvement in systemic haemodynamics in cir- rhotic patients with HRS (88).

Le Veen shunt Despite several reports showing reversal of HRS after the insertion of a LeVeen peritoneovenous shunt, only a few controlled studies have been published on this topic.

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Portosystemic shunts TIPS, introduced for the treatment of HRS, offers the advantage of a lower mortality rate in comparison to surgical treatment. The procedure can temporarily im- prove renal function, making liver transplantation more favorable (48,89). However, any definitive con- clusion concerning its usefulness in patients with HRS awaits the results of controlled studies including a larger number of patients.

Dialysis Hemodialysis and peritoneal dialysis are ineffective or even dangerous in the management of HRS since they are associated with severe hypotension and the in- creased risk of infection and/or hemorrhage. Dialysis, however, may be of great value in selected cases awaiting liver transplantation.

Transplantation Several studies indicate that the probability of survival following liver transplantation is not satisfactory in cir- rhotic patients with renal failure. The presence of renal failure adversely affected the outcome, with a higher mortality rate. However, the survival rate at 5 years after transplantation was 60% and 68% in patients with and without HRS, respectively (78).

Conclusions RF1 should be recognized as the first, often reversible stage of compromised renal function, present in about 20% of patients with chronic liver disease. This alter- ation may precede a second, more severe renal dysfunc- tion, represented by HRS, in patients with tense, often refractory ascites.

Real HRS may be demonstrated in only a few cases admitted to hospital (about 5%), as in our experience, but the number tends to increase in patients with re- fractory ascites, who are followed for months or years (10). The prognosis for HRS is poor and treatment al- most always unsatisfactory when liver transplantation is excluded.

In conclusion, since renal dysfunction and real HRS always follow the presence of ascites, especially when tense and refractory, it is possible to conclude that re- nal impairment of various etiologies represents a con- tinuation of normal fluid accumulation during cir- rhosis.

Acknowledgement Financial support was provided by the Italian Liver Foundation, Florence, Italy.

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