Curr Gastroenterol Rep (2011) 13:1725 DOI 10.

1007/s11894-010-0156-6

Management of Refractory Ascites and Hepatorenal Syndrome

Amy N. Sussman & Thomas D. Boyer

Published online: 16 November 2010 # Springer Science+Business Media, LLC 2010

Abstract One of the most common manifestations of the development of portal hypertension in the patient with cirrhosis is the appearance of ascites. Once ascites develops, the prognosis worsens and the patient becomes susceptible to complications such as bacterial peritonitis, hepatic hydrothorax, hyponatremia, and complications of diuretic therapy. As the liver disease progresses, the ascites becomes more difficult to treat and many patients develop renal failure. Most patients can be managed by diuretics which, when used correctly, will control the ascites. Spontaneous bacterial peritonitis can be treated effectively, but portends a worse prognosis. Once the ascites becomes refractory to diuretics, liver transplantation is the best option, although use of transjugular intrahepatic portosystemic shunts will control the ascites in many patients. Lastly, the development of hepatorenal syndrome indicates the patients liver disease is advanced, and transplantation again is the best option. However, use of vasoconstrictors may improve renal function in some patients, helping in their management while they await a liver transplant. Keywords Cirrhosis . Renal failure . Hepatorenal syndrome . Ascites . Hyponatremia . Refractory ascites . Hepatic hydrothorax . Terlipressin . Midodrine . Octreotide

Following the development of ascites, the patients quality of life declines significantly and survival is about 50% after 5 years of follow-up [1]. Once the ascites becomes refractory to medical therapy, the prognosis is worse, with only 4060% of patients alive after 2 years without liver transplantation [2]. With the onset of hepatorenal syndrome, the prognosis is even worse. Thus, effective management of this complication of portal hypertension is essential to improve the quality of the patients life and, if truly effective, to improve the patients prognosis. Ascites can be difficult to manage for a variety of reasons, including a lack of understanding of the physician about how to use diuretics, failure of the patient to maintain a low-sodium diet, hyponatremia, renal dysfunction, and worsening liver function (Table 1).

Pathophysiology of Refractory Ascites and Hyponatremia Ascites develops in the patient with cirrhosis as the portal hypertension worsens, and there is transudation of fluid from the liver into the peritoneal cavity. Associated with the portal hypertension is the development of the hyperdynamic circulation marked by splanchnic and peripheral vasodilatation and increased cardiac output. Blood flow to other organs such as kidney, muscle, and brain may be reduced by vasoconstriction. With worsening of splanchnic vasodilatation, renal perfusion falls and renin and aldosterone are released, leading to renal sodium retention. Levels of antidiuretic hormone also rise, leading to impaired clearance of free water and development of hyponatremia. The portal hypertension worsens and so does the splanchnic vasodilatation, leading to decreased renal perfusion and rising levels of renin and aldosterone. As a result, sodium

Introduction Ascites is a common complication of portal hypertension, and its development is a marker of decompensation.
A. N. Sussman : T. D. Boyer (*) Department of Medicine, AHSC 245035, University of Arizona College of Medicine, Tucson, AZ 85724, USA e-mail: tboyer@deptofmed.arizona.edu

18 Table 1 Causes of difficult ascites Problem Failure to use diuretics correctly Failure to maintain low-sodium diet Development of hyponatremia Approach Check spot urine Na/K Avoid dividing dose of furosemide Use adequate amounts of spironolactone Check spot urine Na/K Provide dietary instructions Avoid excessive diuresis and hypotonic fluids If severe, reflects advancing liver disease; refer for liver transplantation Echocardiography Increase diuretics If refractory, TIPS Look for overdiuresis Look for use of NSAIDs Sign of worsening liver disease; refer for liver transplantation Repeated LVP with albumin; if frequency >every 2 weeks, TIPS

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Ascites

Diagnostic paracentesis

Findings consistent with cirrhosis

Sodium restriction 2 g/d

Spironolactone 100150 mg/d

Furosemide 2040 mg/d

Development of cardiac disease Hepatic hydrothorax Worsening renal function

Fails to respond Check urine Na/K and adjust sodium intake or diuretics Develops hyponatremia Hold diuretics and fluid restriction

Refractory ascites

Persistent massive ascites despite maximum diuretic therapy or complications of therapy Weekly LVP + Albumin TIPS

LVP large-volume paracentesis; NSAIDs nonsteroidal antiinflammatory drugs; TIPS transjugular intrahepatic portosystemic shunt

Liver transplant evaluation

retention is increased, ascites is worsened, and increasing amounts of diuretics are needed to control the sodium retention. Eventually, the diuretics become ineffective either because of marked sodium retention with reduced renal function or the development of complications that limit their usefulness. The end point for these patients is the development of hepatorenal failure leading to liver transplantation or death (see section on renal failure). It is important to note that the basic pathophysiology in all patients with cirrhosis and ascites is the same, and the development of diuretic-responsive, diuretic-resistant, or intractable ascites and hepatorenal failure are simply manifestations of the worsening splanchnic and systemic vasodilatation and the renal response to underperfusion (Fig. 1) [3].

Fig. 1 Approach to progression of ascites, from responsive to resistant. large-volume paracentesis; TIPS transjugular intrahepatic portosystemic shunt

Difficult Ascites Spontaneous Bacterial Peritonitis Patients with cirrhosis are unusually susceptible to bacterial infection, including spontaneous bacterial peritonitis (SBP). Diagnosis of SBP is based on an analysis of ascitic fluid and the finding of an absolute neutrophil count greater than 250/mm3. Enteric organisms are most common and the

infection responds well to 5 days of intravenous antibiotics in combination with intravenous albumin to reduce the risk of developing hepatorenal failure [4]. The risk of SBP can be reduced by the prophylactic use of antibiotics in patients with variceal bleeding [5]. Once the patient has experienced an episode of SBP, they should receive prophylactic antibiotics to reduce the risk of recurrence. Patient at greatest risk of SBP have very-low-protein (1.0 g/dL) ascites. A recent study evaluated patients with low-protein (1.5 g/dL) ascites and advanced liver disease, but no history of SBP, who received norfloxacin or placebo. The risk of developing SBP and hepatorenal syndrome (HRS) was reduced significantly in those who received norfloxacin, and 3- and 12-month survival was improved [6]. Further studies are warranted before all patients with lowprotein ascites are placed on prophylactic antibiotics; however, this study suggests that improvement in management may influence the future risk of patients developing difficult to manage ascites (Fig. 2).

Curr Gastroenterol Rep (2011) 13:1725 Fig. 2 Proposed role of bacterial translocation on splanchnic arterial vasodilatation
Portal hypertension Increased permeability

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Portosystemic shunts

Intestinal disturbances

Intestinal bacterial overgrowth Bacterial translocation

Endotoxemia

Proinflammatory cytokines Nitric oxide

Vasodilatation

Hyponatremia Incidence and Pathogenesis Hyponatremia is seen commonly in cirrhosis, especially as the liver disease worsens. In patients with wellcompensated cirrhosis, hyponatremia is uncommon, whereas with more advanced disease, it becomes an increasingly common problem (50% with refractory ascites) [3]. The severity of hyponatremia will vary, with 22% having sodium levels less than 130 mEq/L [7]. The non-osmotic release of arginine vasopressin (AVP) is increased in cirrhotics with portal hypertension due to splanchnic vasodilatation and arterial underfilling. AVP binds to the V2 receptor on the principal cell in the kidney, which mediates water absorption via aquaporins. In the presence of AVP, aquaporins move to the plasma membrane of the collecting duct tubules, thereby increasing the permeability of the tubule to water and the development of dilutional hyponatremia [3, 8]. Diuretic therapy may also contribute to the development of hyponatremia if patients are allowed to become hypovolemic. Treatment Hyponatremia is well tolerated by cirrhotics and even with serum sodium levels less than 120 mEq/L, the patient may be alert and oriented. Because most patients with hyponatremia also have ascites, the development of the former leads to management difficulties with the latter. Diuretic therapy frequently is stopped when the serum sodium has fallen below 130 mEq/L, and is not restarted until the serum sodium has risen significantly, leading to prolonged hospitalization and/or worsening ascites. Once the hyponatremia has improved, there may be concern about using the necessary amount of diuretic

to control the ascites out of fear of causing hyponatremia. The current treatment for hyponatremia is fluid restriction, which is unpleasant for the patient and only slowly corrects the serum sodium. The Food and Drug Administration has approved an oral V2 receptor antagonist (tolvaptan) for use in hyponatremia, but there is limited published experience with its use in cirrhotics [9]. The role of these newer agents in the management of ascites awaits further trials, but their use may reduce the frequency of hyponatremia in cirrhosis and allow for better control of ascites [8]. Once the patient has developed hyponatremia, prognosis is much worse and referral to a liver transplant center is recommended [10].

Hepatic Hydrothorax Ascites may enter the thoracic cavity via small openings in the diaphragm. The fluid is preferentially drawn into the pleural space because of the difference in pressure between the thoracic and peritoneal cavities. Hepatic hydrothorax can develop in patients with minimal or massive ascites. Although the volume of ascites that enters the chest may be quite small (35 L), patients can be symptomatic because of the lack of compliance of the chest wall. The hydrothorax is most commonly on the right side, but can be on the left or bilateral. The pleural fluid is similar in composition to the ascites. Proof that the pleural fluid originates in the abdomen is based on demonstrating the movement of radiolabeled macroaggregated albumin from the peritoneal space into the thoracic space. Initial management involves thoracentesis and increase in diuretics and dietary sodium restriction, which usually controls the hydrothorax. For patients who require repeated thoracentesis, transjugular intrahepatic portosystemic shunt (TIPS) may be required [11, 12].

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Refractory Ascites Once diuretics are no longer effective in controlling the patients ascites, the ascites is said to be refractory. The ascites may be refractory because of advancing liver disease, declining renal function, development of diuretic-induced complications (eg, renal insufficiency), or patient noncompliance. Serum creatinine is a poor measure of renal function in the patient with cirrhosis, and patients with normal serum creatinine levels (<1.5 mg/dL) can still have markedly reduced glomerular filtration rates (GFRs), making them resistant to diuretic therapy [13]. Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) may reduce renal function and increase resistance to diuretic therapy. Regardless of the cause, the patient feels miserable and a different approach is required. The most direct approach is simply to remove the ascites by performing a large-volume paracentesis (LVP). Most experienced physicians will do a total paracentesis in combination with intravenous albumin [14]. The use of albumin appears to reduce the risk of post-paracentesis circulatory dysfunction and complications associated with removing large volumes of ascites. The frequency of LVP varies widely and can be as infrequent as every 6 months (for ascites that is not refractory) or as frequent as every week. The major difficulty with LVP is that the ascites tends to recur rapidly, especially in the initial post-paracentesis period. If diuretics cannot slow the rate at which the fluid reaccumulates, the frequency of paracentesis increases steadily and may become weekly, which for most patients is unacceptable. The other option for controlling ascites is the use of TIPS. Creation of a TIPS resolves the portal hypertension, and is associated with an improvement in renal function, falls in plasma levels of renin and aldosterone, and a reduction in sodium retention. The limitations of TIPS are the increased risk of hepatic encephalopathy, risk of TIPS dysfunction, risk of worsening liver function, or (in highrisk patients) early mortality [12]. Covered stents appear to reduce the risk of TIPS dysfunction [15]. LVP and TIPS have been compared in the control of refractory ascites in several controlled trials. TIPS is significantly more effective than LVP in the control of ascites, but at an increased risk of hepatic encephalopathy and with no improvement in survival [12]. A recent metaanalysis suggests improved survival in those patients who had a TIPS created as compared to LVP. Somewhat surprising was the observation that this improvement in survival was seen regardless of the patients model for endstage liver disease (MELD) score [2]. Lastly, all of these studies were done using bare stents, and it is unknown if using covered stents might improve the outcome of the TIPS patients. Pending further trials, the recommendation for patients with refractory ascites is that TIPS be limited to patients who are intolerant of LVP [12].

Renal Failure in Cirrhosis The development of acute renal failure in patients with cirrhosis is not uncommon and portends a poor prognosis. Cirrhosis complicated by acute renal failure increases the risk of death in patients who are waiting for orthotopic liver transplantation (OLT) and is associated with reduced survival following transplantation [16]. Serum creatinine prior to transplant was recently noted to be the most powerful predictor of survival post-OLT [17]. Therefore, identifying patients who are at risk for renal failure and determining the cause of kidney dysfunction in cirrhosis are of key importance in improving outcomes in these patients.

Pathophysiology of Renal Failure in Cirrhosis Disturbances in circulatory function characterized by arterial vasodilatation in the splanchnic circulation are triggered by portal hypertension [18, 19]. The mechanism underlying these hemodynamic changes is presumed due to increased production or activity of vasodilators primarily in the splanchnic circulation [20]. Nitric oxide is thought to play a key role [21]. Increased cardiac output initially compensates for a moderate decrement in systemic vascular resistance during the early stages of cirrhosis, providing normal effective arterial blood volume [19]. As portal hypertension advances, there is a progressive fall in systemic vascular resistance, at which point additional increases in cardiac output cannot compensate, leading to a global decrease in effective arterial blood volume, and leading finally to renal dysfunction through hypoperfusion via intrarenal vasoconstriction [18, 22]. Passage of bacteria from the intestinal lumen to the mesenteric lymph nodes or bacterial translocation is thought to play a central role in the generation or activation of vasodilator factors in the splanchnic area in decompensated cirrhosis [23]. Production of proinflammatory cytokines (including tumor necrosis factor- and interleukin-6) and vasodilator factors (including nitric oxide produced by the endothelium) are generated, presumably in response to bacterial products or endotoxin [23, 24]. This is supported by evidence that cirrhotic patients with increased levels of lipopolysaccharide-binding protein or circulating levels of bacterial DNA (a marker of bacterial translocation) have reduced systemic vascular resistance and increased cardiac output compared to cirrhotics who do not have these markers [25, 26]. This patient group is extremely sensitive to renal dysfunction, which is typically precipitated by events that occur frequently in advanced cirrhosis. These include hypovolemia due to either renal losses (excessive diuretics)

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or gastrointestinal losses (bleeding or excessive stool losses), in response to bacterial infections (spontaneous bacterial peritonitis), or as a consequence of exposure to nephrotoxic medications (NSAIDs due to prostaglandin inhibition, iodinated contrast, and aminoglycoside antibiotic administration).

Types of Renal Failure in Cirrhosis Identifying the specific type of renal failure or kidney injury in cirrhotic liver disease is important for prognosis and implementing appropriate therapeutic intervention. Three main categories of renal dysfunction are recognized: 1) prerenal azotemia due to renal hypoperfusion from an effective prerenal state; 2) intrinsic renal disease due to tubular injury (ischemic or toxic), glomerulonephritis (not uncommon with hepatitis C-associated disease), and interstitial nephritis; and 3) post-renal dysfunction due to obstructive uropathy (Table 2). Additionally, patients with advanced cirrhosis can develop HRS, a type of prerenal renal dysfunction that is not responsive to intravascular volume expansion and that occurs exclusively in severe liver dysfunction. It is characterized by functional renal vasoconstriction that results in significant decline in GFR decline with little to no structural alterations [27, 28].

overestimate the GFR in patients with cirrhosis and should not be used [30]. Finally, creatinine clearance overestimates GFR due to creatinine secretion and requires accurate urine collection, making this impractical in the outpatient setting. Serum creatinine greater than 1.5 mg/dL (133 mol/L) defines renal failure in cirrhosis, according to most studies and recent consensus conferences [22, 30, 31]. This arbitrary cutoff will identify only those patients with severely reduced GFR and underestimates the prevalence of renal dysfunction in this population due to low creatinine generation from reduced muscle mass. Newer serum and urinary biomarkers (eg, cystatin C) appear promising, but have not yet been validated in patients with cirrhosis. General Assessment Assessment of the cirrhotic patient with renal dysfunction should include a thorough assessment of liver function, exclusion of possible bacterial infections, and gastrointestinal bleeding in addition to assessment of renal function. Measurement of serum creatinine, serum and urinary electrolytes, formal urine analysis with microscopy, and quantification of urinary protein should be performed. Use of renal ultrasonography can define structural anatomy and identify abnormalities suggestive of chronic kidney disease or urinary tract obstruction. Finally, a renal biopsy can be performed to provide definitive diagnosis of intrinsic renal disease.

Evaluation of Patients with Renal Failure in Cirrhosis Assessment of Renal Function All patients who have advanced cirrhosis should be frequently monitored for renal dysfunction. Serum creatinine measurement remains the most established and widely accepted measure to estimate renal function in patients with cirrhosis [29]. Formulas including Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) will Diagnosis of Hepatorenal Syndrome HRS is a potentially reversible form of acute renal failure that results from functional renal vasoconstriction in the setting of minimal renal histologic abnormalities [19, 27, 28, 32]. It occurs in patients with marked splanchnic dilatation and maximal activation of the renin-angiotensin and sympathetic nervous systems, leading to pronounced renal vasoconstriction and sodium avidity. The presence of ascites is therefore a prerequisite for the diagnosis of HRS. The 1- and 5-year probabilities of developing HRS in patients with ascites are about 20% and 40%, respectively [33]. HRS is classified into two types based on clinical parameters and prognosis. Type 1 HRS is characterized by an abrupt decline in renal function that is not responsive to intravascular volume expansion. It often develops following a precipitating event (eg, spontaneous bacterial peritonitis) and is defined by a doubling of the serum creatinine (above 2.5 mg/dL or 221 mol/L) in less than 2 weeks [22, 29]. Type 2 HRS is characterized by a slowly progressive course that manifests as refractory or diuretic-resistant ascites [34]. Several diagnostic criteria that were modified recently are used to distinguish HRS, based on the

Table 2 Renal failure in cirrhosis Prerenal azotemia Intrarenal disease Hypovolemia due to gastrointestinal losses (hemorrhage, stool losses); renal losses (diuretics) Tubular injury (ischemic or toxic) Glomerulonephritis (viral hepatitis Cassociated MPGN, hepatitis Bassociated membranous nephropathy, IgA nephropathy) Interstitial nephritis (drug induced) Obstructive uropathy Effective prerenal state that is not responsive to administration of colloid in the setting of minimal histologic abnormalities

Post-renal Hepatorenal syndrome

MPGN membranoproliferative glomerulonephritis

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International Ascites Club consensus conference in 2005 (Table 3) [32].

Differential Diagnosis of Renal Failure in Cirrhosis Differentiation among the three main categories of renal failure can be difficult in patients with cirrhosis. In general, patients with prerenal azotemia manifest with hypovolemia due to either renal losses (diuretics) or gastrointestinal losses (bleeding or stool losses) resulting in volume depletion. They are markedly sodium avid (urinary sodium <20 mEq/L, fractional excretion of sodium <1% if oliguric), indicating tubular reabsorptive integrity, and respond to stopping diuretics and reexpanding intravascular volume, preferably with colloid [32]. Post-renal dysfunction due to obstructive uropathy is identified most commonly via imaging with renal ultrasonography (hydronephrosis). Intrinsic renal disease can often be identified by clinical history and urinary microscopy. Proteinuria and hematuria are hallmarks of glomerular disease. Urinary sediment should be evaluated to distinguish activity (dysmorphic red blood cells, red blood cell casts) and proteinuria quantified to identify the presence of nephrotic syndrome. Allergic interstitial nephritis can be distinguished by a temporal correlation of a new medication with sterile pyuria, and typically peripheral eosinophilia and eosinophiluria. Tubular injury is identified by urinary microscopy demonstrating pigmented granular casts, and typically does not respond to intravascular volume expansion. The urinary sodium is classically greater than 20 mEq/L and fractional excretion of sodium is greater than 1% in oliguric patients. It should be noted, however, that if patients are markedly sodium avid or have a reasonable reserve of proximal tubular function, then urinary sodium may be low. Moreover, urinary indices are not

interpretable in the presence of diuretics. Distinguishing tubular injury from HRS remains difficult because granular casts can be observed in the urinary sediment of both conditions, particularly in the setting of marked bilirubinuria [33, 35]. The presence of renal tubular epithelial cells favors a diagnosis of tubular injury. The difficulty in establishing a timely diagnosis of HRS often leads to a significant delay in the initiation of specific therapy.

Treatment of Renal Failure in Cirrhosis Early identification and treatment of the specific cause of renal failure are critical to the success of therapy. Hypovolemia should be corrected by stopping diuretics, identifying and treating the source of gastrointestinal bleeding, and volume repletion with colloid. Antiviral therapy may be effective in patients with glomerulonephritis associated with hepatitis C virus [36]. Nephrotoxins should be avoided, including discontinuation of NSAIDs and aminoglycosides; prophylactic measures should be applied if iodinated contrast is to be used. Tubular injury that manifests with volume overload, hyperkalemia, and metabolic acidosis not responsive to medical therapy should be treated with renal replacement therapy. There is no consensus on initiation, dose, or duration of dialysis in patients with cirrhosis who have tubular injury. Post-renal dysfunction should be treated with appropriate therapeutic intervention to relieve the obstruction. The treatment of HRS is outlined below.

Vasoconstrictors Administration of vasoconstrictor drugs ameliorates splanchnic and systemic vasodilatation, improves effective arterial blood volume, and mitigates renal vasoconstriction, leading to an increase in renal blood flow. In most studies, vasoconstrictors have been used in conjunction with albumin with the goal of increasing effective arterial blood volume [19]. Terlipressin, a vasopressin analogue, has been evaluated for the treatment of HRS in several smaller studies and two larger, randomized, controlled trials. Although reversal of HRS and improvement in renal function was demonstrated, overall mortality was not changed [37, 38, 39]. Continuous infusion of norepinephrine plus albumin in a small, nonrandomized, pilot study has also been shown to ameliorate renal dysfunction in HRS; however, no data exist on survival, and its use necessitates intensive-care monitoring [40]. Midodrine plus octreotide, which has the advantage of subcutaneous administration, appears to have some efficacy. However, there are no randomized clinical

Table 3 Type 1 hepatorenal syndrome diagnostic criteria Cirrhosis with ascites Serum creatinine >1.5 mg/dL (133mol/L) Doubling of the initial serum creatinine concentration to a level >2.5 mg/dL (226mol/L) in <2 weeks No improvement in serum creatinine (ie, decrease to 1.5 mg/dL or less) after at least 2 days of diuretic withdrawal and expansion of plasma volume with albumin (1 g/kg body weight/day up to a maximum of 100 g/day) Absence of shock No current or recent treatment with nephrotoxic drugs or vasodilators Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microscopic hematuria (>50 red blood cells per high power field), or abnormal renal ultrasonography

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trials and the study numbers are small. Octreotide alone is not beneficial [4143]. Although vasoconstrictor therapy appears promising, liver transplantation is still the therapy of choice for HRS. Optimal timing for initiating use of vasoconstrictors, dose and duration, failure criteria, and the influence and dose of albumin need to be determined. It is reasonable to use vasoconstrictor therapy as a bridge to liver transplantation.

excretion, no significant improvement was seen in overall survival. Moreover, TIPS is often precluded by concern for worsening hepatic encephalopathy and risk of worsening renal dysfunction due to exposure to iodinated contrast. Given the paucity of data, the efficacy of TIPS needs to be further explored in randomized clinical trials before it can be recommended as viable therapy for HRS.

Prevention Orthotopic Liver Transplantation Mortality among patients with type 1 HRS is extremely high; therefore, orthotopic liver transplantation (OLT) should be considered in all patients who have no contraindication to transplant, and should be performed early because severe renal dysfunction predicts a poorer outcome following transplantation [16, 44]. It is the only definitive therapy for HRS because it remains the only therapy that translates to improved survival. Reversal of HRS should be attempted prior to transplant because renal dysfunction has a negative impact on OLT outcome, including higher mortality and development of end-stage kidney disease [16, 45]. Treatment of HRS with the vasopressin analogue terlipressin and albumin prior to OLT demonstrated similar outcomes to those patients undergoing OLT without HRS [46]. The risk of HRS is markedly increased in patients with SBP. Therapy with intravenous albumin along with antibiotic administration administered at 1.5 g/kg of body weight at diagnosis and 1.0 g/kg at 48 h may reduce the incidence of HRS and improve in-hospital mortality and mortality at 3 months [4]. The mechanism by which albumin prevents HRS is not clear, but may be related to restoration of effective arterial blood volume and possibly antioxidant properties [19]. Long-term administration of the antibiotic norfloxacin in patients with cirrhosis and ascitic fluid total protein less than 1.5 g/dL who had either a Child-Pugh score greater than nine and serum bilirubin greater than three or renal dysfunction evidenced by a serum creatinine greater than 1.2 mg/dL, blood urea nitrogen greater than 30 mg/dL, or serum sodium less than 130 mEq/L, decreased the incidence of SBP and reduced the development of HRS, and improved survival at 3 months and 1 year [6]. The observed beneficial effects of norfloxacin are thought to be from its ability to prevent bacterial translocation, suppress proinflammatory cytokines, and improve circulatory function [52].

Renal Replacement Therapy HRS that does not respond to vasoconstrictors can be treated with renal replacement therapy [47]. This occurs most commonly in patients awaiting OLT or when there is the possibility of improvement in liver function. Initiation, dose, and modality remain to be elucidated because clinical data are lacking. Because of significant hemodynamic instability, most patients tolerate continuous renal replacement therapies or sustained low-efficiency daily dialysis best.

Conclusions Many patients with difficult-to-treat ascites will respond to more effective use of diuretics and education about a sodium-restricted diet. However, in most patients, this condition is a reflection of worsening liver disease. The difficulty may be from hyponatremia, falling GFR, or worsening sodium retention, but the underlying problem is hepatic insufficiency and the only solution is liver transplantation. The MELD score may not be high in many of these patients, but this should not be taken as a good prognostic sign. In fact, patients with refractory ascites have a 1-year survival of only 57% in the absence of liver transplantation. Use of TIPS may improve their survival somewhat, but 6-month and 1-year survivals remain poor (75% and 63%, respectively) [2]. Once patients develop HRS, their prognosis is poor and liver transplantation is the only solution. Better treatments are needed for patients with cirrhosis and responsive ascites to prevent their progression

Transjugular Intrahepatic Portosystemic Shunt TIPS has been used in the treatment of type 2 HRS (diuretic-resistant ascites). In addition to improvement in ascites, a modest improvement in renal function is evidenced by reduction in serum creatinine and a trend toward increase in GFR [48]. Fewer data exist on the use of TIPS for treatment of type 1 HRS. Three small, prospective, uncontrolled trials have assessed the role of TIPS in this patient group [4951]. Although modest improvement was reported in serum creatinine, GFR, and sodium

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Curr Gastroenterol Rep (2011) 13:1725 14. Tito L, Gines P, Arroyo V, et al.: Total paracentesis associated with intravenous albumin management of patients with cirrhosis and ascites. Gastroenterology 1990;98:14651. 15. Angermayr B, Cejna M, Koenig F, et al.: Survival in patients undergoing transjugular intrahepatic portosystemic shunt: ePTFEcovered stent grafts versus bare stents. Hepatology 2003;38:1043 50. 16. Nair S, Verma S, Thuluvath PJ: Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology 2002;117985. 17. Weismuller TJ, Prokein J, Becker T, et al.: Prediction of survival after liver transplantation by pre-transplant parameters. Scan J Gastroenterol 2008;43:736746. 18. Schrier RW, Arroyo V, Bernardi M, et al.: Peripheral arterial vasodilaton hypothesis: a proposal for the initation of renal sodium and water retention in cirrhosis. Hepatology 1988;8:11517. 19. Gins P, Schrier RW: Renal failure in cirrhosis. N Engl J Med 2009;361;13: 12791290. This excellent review discusses the pathogenesis of renal failure in patients with cirrhosis. Also, current treatments are reviewed and guidelines provided to the clinician on evaluation and management of the patient with cirrhosis and renal failure. 20. Iwakiri Y: The molecules: mechanisms of arterial vasodilatation observed in the splanchnic and systemic circulation in portal hypertension. J Clin Gastroenterol 2007;Suppl 3:S288S294. 21. Martin, PY, Gins P, Schrier RW: Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med 1998; 339:533541. 22. Arroyo V, Gins P, Gerbes AL, et al.: Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996;23:164176. 23. Wiest R, Das S, Cadelina G, et al.: Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility. J. Clin Invest 1999;104:1223 1233. 24. Wiest R, Garcia-Tsao G: Bacterial translocation (BT) in cirrhosis. Hepatology 2005;41:422433. 25. Albillos A, de la Hera A, Gonzlez M, et al.: Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. Hepatology 2003;37:208217. 26. Fraces R, Zapater P, Gonzalez M, et al.: Bacterial DNA in patients with cirrhosis and noninfected ascites mimics the soluble immune response established in patients with spontaneous bacterial peritonitis. Hepatology 2008;47:978985. 27. Bataller R, Gins P, Guevara M, Arroyo V: Hepatorenal syndrome. Semin Liver Dis 1997;17:233247. 28. Wadeo HM, Mai ML, Absan N, Gonwa TA: Hepatorenal syndrome: pathophysiology and management. Clin J Am Soc Nephrol 2006;1:1066. 29. Salerno F, Gerbes A, Gins P, et al.: Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310 1318. 30. MacAulay J, Thompson K, Kibert BA, et al.: Serum creatinine in patients with advanced liver disease is of limited value for identification of moderate renal dysfunction; are the equations for estimating renal function better? Can J Gastroenterol 2006;20:521526. 31. Moore KP, Wong F, Gins P, et al.: The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Heptatology 2003;38:258266. 32. Salerno F, Gerbes A, Gines P, et al.: Diagnosis, prevention, and treatment of the hepatorenal syndrome in cirrhosis: a consensus workshop of the International Ascites Club. Gut 2007;56:13101318. 33. Garcia-Tsao G, Parikh CR, Viola A: Acute kidney injury in cirrhosis. Hepatology 2008;48:20642077. The causes of renal failure in patients admitted with cirrhosis are defined. Most

to resistant ascites. Diagnosing the cause of liver disease and treating it effectively is the best approach. In patients who have disease for which no effective therapy exists, the prophylactic use of agents such as antibiotics may slow progression, but further studies are needed to understand why patients with liver disease progress from a diuretic responsive to unresponsive state, and subsequently to HRS.

Disclosure No potential conflict of interest relevant to this article was reported.

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