AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Hepatorenal syndrome (HRS) is the development of renal failure in patients with advanced chronic liver disease, occasionally fulminant hepatitis, who have portal hypertension and ascites. Estimates indicate that at least 40% of patients with cirrhosis and ascites will develop HRS during the natural history of their disease.

During the 19th century, Frerichs and Flint made the original description of renal function disturbances in liver disease. They described oliguria in patients with chronic liver disease in the absence of proteinuria and linked the abnormalities in renal function to disturbances present in the systemic circulation. In the 1950s, the clinical description of HRS by Sherlock, Popper, and Vessin emphasized the functional nature of the syndrome, the coexistence of systemic circulatory abnormalities, and its dismal prognosis. Further studies in the following 2 decades demonstrated that renal failure occurred because of vasoconstriction of the renal circulation and intense systemic arteriolar vasodilatation resulting in reduced systemic vascular resistance and arterial hypotension.

In HRS, the histological appearance of the kidneys is normal, and the kidneys often resume normal function following liver transplantation. This makes HRS a unique pathophysiological disorder that provides possibilities for studying the interplay between vasoconstrictor and vasodilator systems on the renal circulation.

Relevant studies include those implicating the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system (SNS), and the role of renal prostaglandins (PGs).Strong associations have been reported between spontaneous bacterial peritonitis (SBP) and HRS and the use of vasopressin analogues with volume expanders in the management and prevention of HRS. Although a similar syndrome may occur in acute liver failure, HRS is usually described in the context of chronic liver disease. Despite some encouraging studies of new pharmacological therapies, the development of HRS in people with cirrhosis portends a dismal prognosis because renal failure is usually irreversible unless liver transplantation is performed.

Pathophysiology

The hallmark of HRS is renal vasoconstriction, although the pathogenesis is not fully understood. Multiple mechanisms are probably involved and include interplay between disturbances in systemic hemodynamics, activation of vasoconstrictor systems, and a reduction in activity of the vasodilator systems. The hemodynamic pattern of patients with HRS is characterized by increased cardiac output, low arterial pressure, and reduced systemic vascular resistance. Renal vasoconstriction occurs in the absence of reduced cardiac output and blood volume, which is in contrast to most clinical conditions associated with renal hypoperfusion.

Although the pattern of increased renal vascular resistance and decreased peripheral resistance is characteristic of HRS, it also occurs in other conditions, such as anaphylaxis and sepsis. Doppler studies of the brachial, middle cerebral, and femoral arteries suggest that extrarenal resistance is increased in patients with HRS, while the splanchnic circulation is responsible for arterial vasodilatation and reduced total systemic vascular resistance.

The RAAS and SNS are the predominant systems responsible for renal vasoconstriction. The activity of both systems is increased in patients with cirrhosis and ascites, and this effect is magnified in HRS. In contrast, an inverse relationship exists between the activity of these 2 systems and renal plasma flow (RPF) and the glomerular filtration rate (GFR). Endothelin is another renal vasoconstrictor present in increased concentration in HRS, although its role in the pathogenesis of this syndrome has yet to be identified. Adenosine is well known for its vasodilator properties, although it acts as a vasoconstrictor in the lungs and kidneys. Elevated levels of adenosine are more common in patients with heightened activity of the RAAS and may work synergistically with angiotensin II to produce renal vasoconstriction in HRS. This effect has also been described with the powerful renal vasoconstrictor, leukotriene E4.

The vasoconstricting effect of these various systems is antagonized by local renal vasodilatory factors, the most important of which are the PGs. Perhaps the strongest evidence supporting their role in renal perfusion is the marked decrease in RPF and the GFR when nonsteroidals, medications known to sharply reduce PG levels, are administered.

Nitric oxide (NO) is another vasodilator believed to play an important role in renal perfusion. Preliminary studies, predominantly from animal experiments, demonstrate that NO production is increased in people with cirrhosis, although NO inhibition does not result in renal vasoconstriction due to a compensatory increase in PG synthesis. However, when both NO and PG production are inhibited, marked renal vasoconstriction develops.

These findings demonstrate that renal vasodilators play a critical role in maintaining renal perfusion, particularly in the presence of overactivity of renal vasoconstrictors. However, whether vasoconstrictor activity becomes the predominant system in HRS and whether reduction in activity of the vasodilatory system contributes to this have yet to be proven.

Various theories have been proposed to explain the development of HRS in cirrhosis. The 2 main theories are the arterial vasodilation theory and the hepatorenal reflex theory. The former theory not only describes sodium and water retention in cirrhosis, but also may be the most rational hypothesis for the development of HRS. Splanchnic arteriolar vasodilatation in patients with compensated cirrhosis and portal hypertension may be mediated by several factors, the most important of which is probably NO. In the early phases of portal hypertension and compensated cirrhosis, this underfilling of the arterial bed causes a decrease in the effective arterial blood volume and results in homeostatic/reflex activation of the endogenous vasoconstrictor systems.

Activation of the RAAS and SNS occurs early with antidiuretic hormone secretion, a later event when a more marked derangement in circulatory function is present. This results in vasoconstriction not only of the renal vessels, but also in vascular beds of the brain, muscle, spleen, and extremities. The splanchnic circulation is resistant to these effects because of the continuous production of local vasodilators such as NO.

In the early phases of portal hypertension, renal perfusion is maintained within normal or near-normal limits as the vasodilatory systems antagonize the renal effects of the vasoconstrictor systems. However, as liver disease progresses in severity, a critical level of vascular underfilling is achieved. Renal vasodilatory systems are unable to counteract the maximal activation of the endogenous vasoconstrictors and/or intrarenal vasoconstrictors, which leads to uncontrolled renal vasoconstriction. Support for this hypothesis is provided by studies in which the administration of splanchnic vasoconstrictors in combination with volume expanders results in improvement in arterial pressure, RPF, and the GFR.

The alternative theory proposes that renal vasoconstriction in HRS is unrelated to systemic hemodynamics but is due to either a deficiency in the synthesis of a vasodilatory factor or a hepatorenal reflex that leads to renal vasoconstriction. Evidence points to the vasodilation theory as a more tangible explanation for the development of HRS.

Frequency

United States

HRS is common, with a reported incidence of 10% among hospitalized patients with cirrhosis and ascites. In decompensated cirrhotics, the probability of developing HRS with ascites ranges between 8-20% per year and increases to 40% at 5 years.

International

The incidence of HRS globally is similar to that in the United States.

Mortality/Morbidity

Physicians need to be aware that 2 different forms of HRS are described. Although their pathophysiology is similar, their manifestations and outcomes are different.

• Type 1 HRS is characterized by rapid and progressive renal impairment and is most commonly precipitated by SBP. Type 1 HRS occurs in approximately 25% of patients with SBP, despite rapid resolution of the infection with antibiotics. Without treatment, median survival of patients with type 1 HRS is less than 2 weeks, and virtually all patients die within 10 weeks after the onset of renal failure.
• Type 2 HRS is characterized by a moderate and stable reduction in the GFR and commonly occurs in patients with relatively preserved hepatic function. These patients are often diuretic-resistant with a median survival of 3-6 months. Although this is markedly longer than type 1 HRS, it is still shorter compared to patients with cirrhosis and ascites who do not have renal failure.

Race

People of all races who have chronic liver disease are at risk for HRS.

Sex

Frequency is equal in both sexes.

Age

Most patients with chronic liver disease are in their fourth to eighth decades of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Most individuals with cirrhosis who develop HRS have nonspecific symptoms, such as fatigue, malaise, or dysgeusia. Development of HRS is usually noticed when patients observe decreased urine output and when blood test results show a decline in renal function.

Physical

HRS has no specific signs. However, detecting stigmata of chronic liver disease is important because most patients at risk for HRS have cirrhosis. The following list of physical findings is not all-inclusive, and these findings are not present in all patients with chronic liver disease.

• Hands
• • Palmar erythema
  • Leuconychia
  • Asterixis
  • Muscle wasting
  • Clubbing
• Head, ears, nose, throat
• • Scleral icterus
  • Muscle wasting
  • Spider nevi (usually confined to the drainage area of the superior vena cava)
  • Fetor hepaticus
  • Xanthelasma
  • Chest - Gynecomastia
• Abdomen
• • Caput medusae
  • Hepatosplenomegaly
  • Ascites
  • Paraumbilical hernia
  • Bruits
• Genitalia
• • Loss of pubic hair/secondary sexual characteristics in men
  • Atrophic testes
• Extremities
• • Peripheral edema
  • Clubbing

Causes

Risk factors for developing HRS have been reported based on a large series of patients with cirrhosis and ascites and, for the most part, are related to circulatory and renal function. Three important and easily recognized risk factors are low mean arterial blood pressure (<80 mm Hg), dilutional hyponatremia, and severe urinary sodium retention (urine sodium <5 mEq/L). Interestingly, patients with advanced liver disease, defined by a high Child-Pugh score or worsening parameters of liver function, such as albumin, bilirubin, and prothrombin levels, are not at higher risk of developing HRS.

In some patients, HRS may occur spontaneously, whereas in others, it may be associated with infections (particularly SBP), acute alcoholic hepatitis, or large-volume paracentesis without albumin replacement. SBP precipitates type 1 HRS in approximately 20% of patients despite appropriate and timely diagnosis, treatment, and resolution of infection. Large-volume paracentesis without albumin replacement can precipitate type 1 HRS in up to 15% of patients. Although renal failure occurs in up to 10% of cirrhotics with gastrointestinal bleeding, this is usually in the presence of hypovolemic shock, suggesting that renal failure is related to acute tubular necrosis rather than HRS.

The following is a list of risk factors associated with the development of HRS in patients with cirrhosis who are nonazotemic. All measurements were obtained after a minimum of 5 days on a low-salt diet and without diuretics.

• Low urinary sodium excretion  (<5 mEq/L)
• Low serum sodium (dilutional hyponatremia)
• Reduced free-water excretion after water load
• Low mean arterial pressure
• High plasma renin activity
• Increased plasma norepinephrine
• Low plasma osmolality
• High urine osmolality
• High serum potassium
• Previous episodes of ascites
• Absence of hepatomegaly
• Presence of esophageal varices
• Poor nutritional status
• Moderately increased serum urea (>30 mg/dL)
• Moderately increased serum creatinine (>1.5 mg/dL)
• Moderately reduced GFR  (<50 mL/min)

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Prerenal azotemia from volume depletion
Drug-induced nephrotoxicity - Commonly implicated medications include nonsteroidals, aminoglycosides, diuretics, and iodine-containing contrast agents. Other medications that may contribute to renal dysfunction in these patients are ACE inhibitors, demeclocycline, and dipyridamole.
Postrenal azotemia from outflow obstruction
Renal vascular disease

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The diagnosis of HRS is one of exclusion and depends mainly on serum creatinine level, as no specific tests establish the diagnosis of HRS. Although serum creatinine level is a poor marker of renal function in patients with cirrhosis, no other validated and reliable noninvasive markers exist for monitoring renal function in these patients.
• Diagnosis of HRS is based on the presence of a reduced GFR in the absence of other causes of renal failure in patients with chronic liver disease. The following criteria, as proposed by the International Ascites Club in 1996, help diagnose HRS:
• • Major criteria (All major criteria are required to diagnose HRS.)
    • Low GFR, indicated by a serum creatinine level higher than 1.5 mg/dL or 24-hour creatinine clearance lower than 40 mL/min
    • Absence of shock, ongoing bacterial infection and fluid losses, and current treatment with nephrotoxic medications
    • No sustained improvement in renal function (decrease in serum creatinine to <1.5 mg/dL or increase in creatinine clearance to >40 mL/min) after diuretic withdrawal and expansion of plasma volume with 1.5 L of plasma expander
    • Proteinuria less than 500 mg/d and no ultrasonographic evidence of obstructive uropathy or intrinsic parenchymal disease
  • Additional criteria (Additional criteria are not necessary for the diagnosis but provide supportive evidence.)
    • Urine volume less than 500 mL/d
    • Urine sodium level less than 10 mEq/L
    • Urine osmolality greater than plasma osmolality
    • Urine red blood cell count of less than 50 per high-power field
    • Serum sodium concentration greater than 130 mEq/L
  • Urinary indices are not considered major criteria because a subset of patients with HRS may have high urine sodium levels and low urine osmolality (similar to acute tubular necrosis [ATN]), while other patients with cirrhosis and ATN may have low urine sodium levels and high urine osmolality.
• Complete blood cell count with differential: This may indicate the presence of underlying infection such as SBP if leukocytosis or bands are present, a condition known to present with reversible impairment in renal function. However, many patients with SBP do not have a serum leukocytosis. Because shock from gastrointestinal bleeding may cause acute tubular necrosis, checking the hematocrit level and platelet count is helpful.
• Serum electrolytes and renal function: These are essential investigations to obtain data for diagnosing HRS.
• Liver function tests with prothrombin time: Although the degree of liver failure does not correlate with the development of HRS, these investigations are necessary to assess patients' Child-Pugh scores.
• Alpha-fetoprotein: Although few studies demonstrate a relationship between hepatoma and development of HRS, this test should be performed when patients with cirrhosis decompensate.
• Blood cultures: Infections place patients at risk for decompensation, and looking for bacteremia, particularly if no precipitant is identified, is prudent. Occasionally, patients may present with culture-negative SBP (20%), and performing blood cultures is wise under these circumstances.
• Cryoglobulins: Measuring these may be helpful in patients with hepatitis B and/or C, who can develop renal failure from cryoglobulinemia. Treatment and eradication of the underlying disease, if performed early in the course of the disease process, can reverse renal failure.
• Urinalysis: Significant proteinuria or hematuria may provide a clue that an organic cause may be responsible for patients' renal failure. Similarly, urinary tract infection may be detected, and this usually is readily treatable.
• Urine electrolytes: Measuring urine sodium and creatinine levels is used as a screening test to assess the degree of sodium retention. Patients with low urine sodium excretions (<5 mEq/L) are at a greater risk of developing HRS. Urine sodium and creatinine levels are also used to calculate the fractional excretion of sodium, which is helpful in differentiating HRS and prerenal azotemia from intrinsic renal disease.

Imaging Studies

• Abdominal ultrasound: This is a useful noninvasive test to help exclude hydronephrosis and intrinsic renal disease, which may be characterized by bilateral small kidneys. When combined with Doppler studies, valuable information may be provided on renal vascular flow.
• Echocardiogram: This test may be helpful for evaluating right ventricular preload, ventricular filling pressures, and cardiac performance in response to fluid replacement.

Procedures

• Paracentesis: SBP can present with reversible impairment of renal function, and performing diagnostic paracentesis is strongly recommended in all patients. The role of therapeutic paracentesis/large-volume paracentesis (LVP) in HRS is more controversial in the absence of tense ascites. Concerns exist that further volume depletion may aggravate renal function, due to third spacing in a patient with a known underlying systemic circulatory disturbance. Albumin replacement is recommended in these patients when LVP is performed. Ten grams of albumin is administered for every liter of ascites drained, to a maximum of 50 g of albumin.
• Bladder catheterization: Catheterization may be helpful to exclude urinary retention as a potential cause of acute renal failure in these patients. However, long-term indwelling urinary catheters are not recommended (because of the risk of acquiring urinary tract infection) unless patients are incontinent and are at risk of developing skin breakdown or unless strict recording of urinary output is mandatory.
• Central line and Swan-Ganz line placement: Measurement of central venous pressure and pulmonary capillary wedge pressure may be helpful in patients who do not respond to an adequate trial of plasma expansion. Hemodynamic findings in HRS include increased cardiac output, reduced mean arterial pressure (range of 60-80 mm Hg), and reduced total systemic vascular resistance. These findings, although characteristic of patients with cirrhosis, can also be observed in other conditions, such as anaphylaxis and sepsis. Invasive hemodynamic monitoring, aside from the risk of procedure-related complications, also has limitations for assessing volume status in patients. For example, a study by Kumar showed that, in healthy volunteers, neither central venous pressure nor pulmonary artery occlusion pressure was useful for predicting ventricular preload with respect to optimizing cardiac performance.¹

Histologic Findings

Kidneys are histologically normal because HRS is a functional disorder.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The ideal treatment of HRS is liver transplantation; however, because of the long waiting lists in the majority of transplant centers, most patients die before transplantation. An urgent need exists for effective alternative therapies to increase survival chances for patients with HRS until transplantation can be performed. This is reinforced by a study that reported that patients successfully treated medically for HRS before liver transplantation had posttransplantation outcome and survival comparable to that of patients who underwent transplantation without being treated for HRS. Interventions that have shown some promise are drugs with vasoconstrictor effects in the splanchnic circulation and use of the transjugular intrahepatic portosystemic shunt (TIPS).

• Pharmacological treatment  
• • Numerous medications have been used to treat HRS with little, if any, effect. In recent years, the pharmacological approach has shifted, with greater attention focused on the role of vasoconstrictors as opposed to the initial predominant use of vasodilators. The rationale for this change is that the initial event in HRS is vasodilatation of the splanchnic circulation and use of a vasoconstrictor may thus prevent homeostatic activation of endogenous vasoconstrictors. Promising results have been reported in small studies and case reports with agonists of vasopressin V1 receptors, such as ornipressin and terlipressin, which predominantly act on the splanchnic circulation.
  • Although only a few controlled trials have been conducted in this arena, the results so far are encouraging and suggest an increasing role for medical therapy, given the current shortage of the donor pool in the face of an ever-increasing demand for organs.
• Dopamine
• • Low-dose dopamine (2-5 mcg/kg/min) is frequently prescribed to patients with renal failure in the hope that its vasodilatory properties may improve renal blood flow. Little evidence exists to support this practice; a placebo-controlled randomized trial by Bellomo and colleagues did not demonstrate any role for low-dose dopamine in early renal dysfunction.² Five studies have evaluated the role of dopamine in HRS, and none have reported significant changes in RPF, GFR, or urine output.
  • These studies are limited by small sample size and lack of a control arm. Nonetheless, they demonstrate that dopamine administration in patients with cirrhosis, with or without HRS, does not improve renal function.
• Misoprostol
• • Misoprostol is a synthetic analogue of PG E1, whose use in HRS was based on the observation that these patients had low urinary levels of vasodilatory PGs.
  • Five studies have assessed the role of either parenteral or oral misoprostol in HRS. None of these studies demonstrated an improvement in the GFR, sodium excretion, or renal function in patients with HRS. Although Fevery et al demonstrated reversal of HRS in 4 patients, these patients also received large doses of colloids.³ The likely scenario is that the massive administration of fluids played a predominant role here because Gines et al were unable to reproduce these findings with misoprostol alone.⁴
• Renal vasoconstrictor antagonists
• • Saralasin, an antagonist of angiotensin II receptors, was used first in 1979 in an attempt to reverse renal vasoconstriction. Because this drug inhibited the homeostatic response to hypotension commonly observed in patients with cirrhosis, it led to worsening hypotension and deterioration in renal function. Poor results were also observed with phentolamine, an alpha-adrenergic antagonist, highlighting the importance of the SNS in maintaining renal hemodynamics in patients with HRS.
  • A case series by Soper et al reported an improvement in the GFR in 3 patients with cirrhosis, ascites, and HRS who received an antagonist of endothelin A receptor (BQ123).⁵ All 3 patients showed a dose-response improvement in inulin and para-aminohippurate excretion, RPF, and the GFR in the absence of changes in systemic hemodynamics. These 3 patients were not candidates for liver transplantation and subsequently died. More work is needed to explore this therapeutic approach as a possible bridge to transplantation for patients with HRS.
• Systemic vasoconstrictors
• • These medications have shown the most promise for treatment of HRS in recent years and include vasopressin analogues (ornipressin, terlipressin), somatostatin analogues (octreotide), and alpha-adrenergic agonists (midodrine).
  • In 1956, Hecker and Sherlock used norepinephrine to treat patients with cirrhosis who had HRS; they were the first to describe an improvement in arterial pressure and urine output. However, no improvement was observed in biochemical parameters of renal function, and all patients subsequently died.
  • Octapressin, a synthetic vasopressin analogue, was first used in 1970 to treat type 1 HRS. RPF and the GFR improved in all patients, all of whom subsequently died from sepsis, gastrointestinal bleeding, and liver failure. Because of these discouraging results, the use of alternate vasopressin analogues, particularly ornipressin, attracted attention. Three important studies by Lenz and colleagues demonstrated that short-term use of ornipressin resulted in an improvement in circulatory function and a significant increase in RPF and the GFR.^{6, 7, 8} 
  • The combination of ornipressin and albumin was subsequently tried by Guevera in patients with HRS.^{9, 10} This was based on data suggesting that the combination of plasma volume expansion and vasoconstrictors normalized renal sodium and water handling in patients who have cirrhosis with ascites. In this important paper, 8 patients were originally to be treated for 15 days with ornipressin and albumin. Treatment had to be discontinued in 4 patients after fewer than 9 days because of complications from ornipressin use that included ischemic colitis, tongue ischemia, and glossitis. Although a marked improvement in the serum creatinine level was observed during treatment, renal function deteriorated upon treatment withdrawal. In the remaining 4 patients, the improvement in RPF and the GFR was significant and was associated with a reduction in serum creatinine levels. These patients subsequently died, but no recurrence of HRS was observed.
  • Due to the high incidence of severe adverse effects with ornipressin, the same investigators used another vasopressin analogue with fewer adverse effects, namely terlipressin. In this study, 9 patients were treated with terlipressin and albumin for 5-15 days. This was associated with a marked reduction in serum creatinine levels and improvement in mean arterial pressure. Reversal of HRS was noted in 7 of 9 patients, and HRS did not recur when treatment was discontinued. No adverse ischemic effects were reported, and, according to this study, terlipressin with albumin is a safe and effective treatment of HRS.
  • Since this early study, terlipressin has become the most studied vasopressin analogue in HRS. When used in conjunction with albumin, improvement in GFR and reduction in serum creatinine levels to below 1.5 mg/dL occur in 60-75% of patients with type 1 HRS. This may take several days, and although recurrent HRS after treatment discontinuation is uncommon (<15%), a repeat course of terlipressin with albumin is usually effective. Ischemic complications are also rare (<5%), but one limitation of terlipressin is its unavailability in many countries, including the United States. Under these circumstances, such agents as octreotide, albumin, and alpha-adrenergic agonists may be considered.
  • Angeli et al showed that long-term administration of midodrine (an alpha-adrenergic agonist) and octreotide improved renal function in 8 patients with type 1 HRS.¹¹ All patients also received albumin, and this approach was compared to dopamine at nonpressor doses. Not surprisingly, none of the patients treated with dopamine showed any improvement in renal function, but all 8 patients treated with midodrine, octreotide, and volume expansion had improvement in renal function. No adverse effects were reported in these patients. A study of 14 patients by Wong et al reported improvement in renal function in 10 patients. Three of these patients subsequently underwent liver transplantation.¹²
  • These studies demonstrate several important points. First, vasoconstrictors play an important role in the treatment of HRS, but further work is needed to identify the ideal agent and to determine if the addition of albumin is necessary. Another important conclusion of these studies is that patients may maintain relatively preserved renal function once therapy is discontinued. This suggests that if the precipitating factor, such as SBP, is not readily identified, an irreversible decline in renal function ensues.
  • N-acetylcysteine (NAC): In 1999, the Royal Free group reported their experience with NAC for the treatment of HRS. This was based on experimental models of acute cholestasis, in which administration of NAC resulted in an improvement in renal function. Twelve patients with HRS were treated with intravenous NAC, without any adverse effects, and the survival rates were 67% and 58% at 1 month and 3 months, respectively (this included 2 patients who received liver transplantation after improvement in renal function). The mechanism of action remains unknown, but this interesting study encourages further optimism for medical treatment of a condition that once carried a hopeless diagnosis in the absence of liver transplantation. Controlled studies with longer follow-up may help answer these pressing questions.

Surgical Care

• Peritoneovenous shunting  
• • Peritoneovenous shunting (PVS) seems attractive in theory because it leads to plasma volume expansion and improvement of circulatory function. However, very few studies evaluating the role of PVS in this area have been performed because PVS has been used predominantly for treating refractory ascites.
  • This may be important for patients with type 2 HRS, who often develop refractory ascites, are not candidates for orthotopic liver transplantation, and do not tolerate frequent LVPs.
  • PVS has no role in type 1 HRS.
• Surgical shunts  
• • No description on the treatment of HRS is complete without a brief review of the role of portacaval shunts, particularly with the introduction of TIPS.
  • Despite the theoretical benefit of improving portal hypertension and thus HRS with a portosystemic shunt, only a few scattered case reports have shown some benefit.
  • Currently, no indication exists for portacaval shunts in this setting.
• Liver transplantation 
• • Liver transplantation is the ideal treatment of HRS but is limited by the availability of donors.
  • Patients with HRS have a higher risk of postoperative morbidity, early mortality, and longer hospitalization. Gonwa et al reported that at least one third of patients require hemodialysis postoperatively, with a smaller percentage (5%) requiring long-term hemodialysis.¹³
  • Because renal dysfunction is common in the first few days following transplantation, avoiding nephrotoxic immunosuppressants generally is recommended until recovery of renal function. However, the GFR gradually improves and reaches an average of 40-50 mL/min by the sixth postoperative week. The systemic and neurohumoral abnormalities associated with HRS also resolve in the first postoperative month.
  • Long-term survival rates are excellent, with the survival rate at 3 years approaching approximately 60%. This is only slightly lower than the 70-80% survival rate of transplant recipients without HRS and is markedly better than the survival rate of patients with HRS not receiving transplants, which is virtually 0% at 3 years.

Consultations

• Nephrologist  
• • The importance of a nephrologist in the multidisciplinary management of patients with HRS cannot be overemphasized. Nephrologists play a critical role in assisting hepatologists and liver transplant surgeons in the management of these critically ill patients.
  • No controlled studies evaluating the role of dialysis in this setting have been performed, but most centers dialyze patients with HRS who are on a waiting list.
  • Continuous arteriovenous or venovenous hemofiltration has also been used, but the efficacy of these 2 measures has yet to be determined.
  • Variations of hemodialysis include the recently described molecular adsorbent recirculating system. This is a modified dialysis method that uses an albumin-containing dialysate that is recirculated and perfused online through charcoal- and anion-exchanger columns. A prospective, randomized, controlled trial showed improvement of type 1 HRS with this method, although long-term survival remained very poor, with survival of more than 1 month in only 1 of 8 patients in the treatment arm.
  • If transplantation is not available, hemodialysis probably will continue to be performed for patients on the waiting list.
• Interventional radiologist  
• • The use of TIPS in the treatment of HRS has yet to be established. Due to its ability to reduce portal hypertension in patients with variceal bleeding and refractory ascites, its role in HRS initially seemed logical, particularly in view of isolated reports of renal function improvement following surgical shunts in the 1970s. However, TIPS quickly fell out of favor because of high morbidity and mortality rates.
  • Small, uncontrolled studies indicate that TIPS may improve RPF and the GFR and reduce the activity of the RAAS and SNS in patients who have cirrhosis with types 1 and 2 HRS. Improvement in renal function is usually slow and occurs in approximately 60% of patients. However, the effects on renal function can be variable, and some patients fare worse. As a result, the role of TIPS in the treatment of HRS remains investigational because of the lack of prospective studies and the known risks of the procedure.

Diet

• Institute a low-salt (2 g) diet.
• Do not restrict protein intake unless patient has severe encephalopathy.

Activity

• No restrictions are necessary.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The pharmacological approach to the treatment of HRS continues to evolve, with several possible effective treatments. However, readers should be aware that none of these medications (including the addition of albumin) has been validated in randomized controlled trials. A brief review of only the most promising (but yet unproven) medications will be described because not only is this historical list extensive, but most of the trials for the medications were conducted outside the United States.

Drug Category: Vasopressin analogues

Improve circulatory dysfunction secondary to splanchnic vasodilatation. Also improve RPF, the GFR, and urine output.

Drug Name	Terlipressin
Description	Not available in United States. Nonselective V1 vasopressin agonist that has similar vasoconstrictor potency to ornipressin but a lower incidence of ischemic complications. Inactive by itself but is transformed into a biologically active form (lysine-vasopressin) by the action of tissue endopeptidases and exopeptidases. Due to its longer half-life (2-10 h) compared to ornipressin, may be administered as a bolus. Has lower incidence of adverse ischemic effects, with <5% of cases reported in a series of 1258 patients receiving it for variceal bleeding.
Adult Dose	0.5-2 mg/4h IV
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; coronary artery disease
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in cardiovascular disease, seizure disorders, nitrogen retention, asthma, or migraine; excessive doses may result in hyponatremia

Drug Category: Sympathomimetic agents

Improve renal artery perfusion.

Drug Category: Somatostatin analogs

Improvement in splanchnic circulation may improve renal hemodynamics.

Drug Category: Antioxidants

Experimental evidence demonstrates improvement of renal function in acute cholestasis and renal failure.

Drug Category: Antibiotics

Are only indicated in the treatment of HRS if renal dysfunction is precipitated by an infection. Prophylactic antibiotics may play a role in preventing SBP, which, in turn, is also a risk factor for the development of type 1 HRS in patients with type 2 HRS. The efficacy and safety of prophylactic antibiotics remains to be established because of reports of emergent resistant bacteria. May play an important role in selected patients, such as those awaiting liver transplantation, although the duration (long-term vs cyclic) remains to be determined.

Drug Name	Ciprofloxacin (Cipro)
Description	Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms, but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth.
Adult Dose	750 mg PO single dose qwk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations May increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy

Drug Name	Norfloxacin (Noroxin, Chibroxin)
Description	Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, S epidermidis, and most gram-negative organisms, but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth.
Adult Dose	400 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy

Drug Name	Sulfamethoxazole and trimethoprim (Bactrim, Bactrim DS, Septra, Septra DS)
Description	Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.
Adult Dose	1 tab (Bactrim DS) 5 d/wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; megaloblastic anemia due to folate deficiency
Interactions	May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly persons; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, give 5-15 mg/d leucovorin); caution in folate deficiency (eg, chronic alcoholism, elderly persons, those receiving anticonvulsant therapy, or those with malabsorption syndrome); hemolysis may occur in persons with G-6-PD deficiency; patients with AIDS may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation

Drug Category: Plasma volume expanders

Indicated for the correction of abnormal hemodynamic parameters.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Every attempt should be made to establish a precipitating cause of HRS. This is particularly true for type 1 HRS, which rarely occurs spontaneously and may be associated with SBP in 25% of cases. If renal function does not improve after institution of third-generation cephalosporins for SBP, a follow-up diagnostic paracentesis is recommended 48 hours later.
• Patients with HRS should be evaluated for liver transplantation. This may be more applicable for patients with type 2 HRS, who have a longer survival time, as opposed to patients with type 1 HRS, whose survival is extremely short and who may require alternative therapeutic methods (eg, TIPS, vasoconstrictors) as a bridge to transplantation.

Further Outpatient Care

• Patients with HRS need to be evaluated for liver transplantation. If they are not candidates, they have a poor prognosis and outpatient care will only be palliative in nature.

Transfer

• Patients diagnosed with HRS should be evaluated at a liver transplant center to determine if they are transplant candidates. Reasons for transferring patients include the following:
• • Assessment of candidacy for liver transplantation
  • Lack of facilities for performing dialysis at local/referring hospital
  • Entrance into study/treatment protocol for HRS at referral center

Deterrence/Prevention

• The main precipitating factor of type 1 HRS is SBP. When this develops in patients with type 2 HRS, the probability of developing type 1 HRS is very high. This may be prevented by antibiotic prophylaxis with Bactrim or fluoroquinolones in patients with a prior history of SBP. Alternatively, patients with type 2 HRS who are on the waiting list may benefit from prophylactic antibiotics, irrespective of whether they have a prior history of SBP.
• A randomized controlled trial has shown that the incidence of SBP-related renal failure is reduced if these patients are treated with antibiotics and undergo plasma volume expansion with albumin (1.5 g/kg upon diagnosis and 1 g/kg 48 h later). The incidence of HRS in patients with SBP who received albumin together with antibiotic therapy was 10% compared with an incidence of 33% in patients who did not receive albumin; in addition, hospital mortality rates were also lower in patients who received albumin expansion.
• LVP is considered another risk factor for the development of HRS, which may be prevented by the administration of albumin.
• Patients who have cirrhosis with ascites have a 10% chance of developing HRS at 1 year and a 40% chance at 5 years. One alternative to treatment aimed at preventing HRS is performing liver transplantation in these patients before HRS develops, particularly because risk factors for the development of HRS have been identified. With the current donor shortage, this does not seem to be a realistic possibility.
• In patients with acute alcoholic hepatitis, one study reported that the administration of pentoxifylline (400 mg tid for 28 d) reduced the incidence of HRS and mortality rates (8% and 24%, respectively) compared with a placebo group (35% and 46%, respectively). However, no long-term data exist on renal function or mortality rates in these patients.

Complications

• Progressive liver failure, as manifested by worsening encephalopathy, jaundice, and coagulopathy, is a preterminal condition if liver transplantation is not performed.

Prognosis

• Type 1 HRS has a median survival of 2 weeks, with few patients surviving more than 10 weeks.
• Type 2 HRS has a median survival of 3-6 months.

Patient Education

• Patients who have cirrhosis with ascites must be informed that they are at risk of developing HRS and they must be informed about the dismal prognosis this carries in the absence of liver transplantation. They should be very cautious when new medications are prescribed by physicians not familiar with their care and must avoid known nephrotoxic agents such as nonsteroidals and aminoglycosides. Any deterioration in their clinical condition should result in a prompt call to their physician to determine if they have developed HRS.
• For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles Cirrhosis and Liver Transplant.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Nephrotoxic agents should be avoided because of the risk of developing HRS. Drugs that are commonly associated with HRS in patients with cirrhosis are nonsteroidals, aspirin, aminoglycosides, and iodine-containing contrast agents.
• A diagnostic paracentesis should be considered in all patients who have cirrhosis with ascites who develop HRS, to exclude the presence of SBP. Few, if any, contraindications exist for a diagnostic paracentesis, and the use of empiric antibiotics in this situation is not justified.
• Other causes of renal failure need to be considered in the differential diagnosis, and assuming that all patients who have cirrhosis with renal impairment have HRS is wrong. A standardized approach to the evaluation of renal failure not only confirms HRS, it also identifies conditions that may be reversible.
• In patients with cirrhosis who have decompensated, evaluation of candidacy for liver transplantation should be performed before the onset of HRS. This helps physicians decide/stratify the aggressiveness of treatment when HRS develops. Liver transplant evaluation in a hospitalized patient with type 1 HRS may be too late, given the dearth of donors.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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