Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is the development of renal failure in patients with advanced chronic liver disease[1] and, 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 in the renal circulation.[2, 3]

Relevant studies include those implicating the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system (SNS), and the role of renal prostaglandins (PGs).[4] 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.[5, 6, 7, 8, 9]

Traditionally, HRS has been classified into two types: type 1 and type 2. Type 1 HRS has a more rapid onset, often precipitated by bacterial infection, gastrointestinal hemorrhage, large-volume paracentesis without albumin administration, or excessive response to diuretics, alcohol, or drugs. It can rapidly lead to decompensation, including renal and liver failure, as well as encephalopathy. Type 2 HRS is typically spontaneous and has a slower in progression, with refractory ascites as the primary clinical presentation.

In relatively recent years, the definition of HRS and the subtypes have evolved, and they largely been classified based on acute (AKI) or chronic kidney injury (CKI). Type 1 HRS has been proposed to reclassified as HRS-AKI. AKI is defined by increase in serum creatinine by 0.3 mg/dL in less than 48 hours or an increase in serum creatinine by 50% from a stable baseline reading within 3 months.[10] Stage 1 AKI would be classified as an increase in serum creatinine level by 0.3 mg/dL or a 50% increase, whereas stages 2 and 3 AKI would be a doubling and tripling, respectively, of serum creatinine levels.[10]

The hemodynamic pattern of patients with hepatorenal syndrome (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.[11, 12, 13] The pathogenesis of HRS is not fully understood, but a hallmark is renal vasoconstriction. It is likely a result of an interplay between disturbances in systemic hemodynamics, activation of the vasoconstrictor systems, and a reduction in the activity of the vasodilator systems.

The renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (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 two 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.[14] 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 prostaglandins (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 an 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.

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, whereas the splanchnic circulation is responsible for arterial vasodilatation and reduced total systemic vascular resistance.

Various theories have been proposed to explain the development of HRS in cirrhosis. The two 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 it 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 a locally acting vasodilator, nitric oxide (NO). In the early phases of portal hypertension and compensated cirrhosis, the 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. Thus, renal perfusion is maintained within normal or near-normal limits as the vasodilatory systems antagonize the renal effects of the vasoconstrictor systems. As the liver disease progresses, and stress on the portal vasculature increases, a critical level of vascular underfilling is achieved while local vasodilators remain active in the splanchnic vasculature. This, in turn, leads to a decrease in mean arterial blood pressure that subsequently leads to early activation of the RAAS and visceral sympathetic nervous system (SNS) with antidiuretic hormone (ADH) secretion. This results in vasoconstriction not only of the renal vessels but also of the vascular beds of the brain, muscle, spleen, and extremities; increases in cardiac output and heart rate as a compensatory mechanism also ensues.[15] 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 the arterial pressure, RPF, and the GFR. The splanchnic circulation remains resistant to these effects because of the continuous production of local vasodilators such as NO. Aldosterone and vasopressin stimulate both sodium and water retention.

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.

Risk factors for developing hepatorenal syndrome (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 a higher risk of developing HRS.[16]

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

A number of risk factors are 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.[16] Note the following:

• 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 glomerular filtration rate (GFR) (< 50 mL/min)

• Cirrhotic cardiomyopathy

• Adrenal insufficiency

United States statistics

Hepatorenal syndrome (HRS) is common, with a reported incidence of 10% among hospitalized patients with cirrhosis and ascites.[17] In decompensated cirrhotics, the probability of developing HRS with ascites ranges between 8%-20% per year and increases to 40% at 5 years. An estimated 35%-40% of patients with end-stage liver disease (ESLD) and ascites will develop HRS.[13]

International incidence

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

Race-, sex-, and age-related demographics

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

Frequency is equal in both sexes.

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

Hepatorenal syndrome-acute kidney injury (HRS-AKI) (previously type 1 HRS) has a median survival of 2 weeks, with few patients surviving more than 10 weeks.[18] Type 2 HRS has a median survival of 3-6 months. A retrospective cohort study in the United States found a 36.9% mortality  of patients admitted to the hospital for HRS.[19]

Morbidity/mortality

Clinicians need to be aware that two different forms of HRS are described.[20] Despite a similar pathophysiology, their manifestations and outcomes are different.

HRS-AKI is characterized by rapid and progressive renal impairment and is most commonly precipitated by spontaneous bacterial peritonitis (SBP). It occurs in approximately 25% of patients with SBP, despite rapid resolution of the infection with antibiotics. Without treatment, the median survival of patients 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 glomerular filtration rate (GFR), and it 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 HRS-AKI, it is still shorter compared to patients with cirrhosis and ascites who do not have renal failure.

Complications

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

Patients who have cirrhosis with ascites must be informed that they are at a risk of developing hepatorenal syndrome (HRS), and they must be informed about the dismal prognosis this carries in the absence of liver transplantation. These individuals should be very cautious when new medications are prescribed by physicians not familiar with their care, and they 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 patient education resources, see Infections Center and Digestive Disorders Center, as well as Cirrhosis and Liver Transplant.

Most individuals with cirrhosis who develop hepatorenal syndrome (HRS) have nonspecific symptoms, such as fatigue, malaise, or dysgeusia (altered sense of taste). Development of HRS is usually noticed when patients observe decreased urine output and when blood test results show a decline in renal function. Although type 2 HRS is typically spontaneous, type 1 (now known as HRS-acute kidney injury [AKI]) may be precipitated by infection (such as bacterial or viral hepatitis), excessive response to diuretics, use of alcohol and drugs, or large-volume paracentesis without administration of albumin.

Hepatorenal syndrome (HRS) has no specific signs. However, detecting the 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.

The hands may exhibit the following:

• Palmar erythema

• Leuconychia (white nails)

• Muscle wasting

• Asterixis (flapping tremors)

• Clubbing

Head, ears, nose, throat examination may reveal the following:

• Scleral icterus

• Spider nevi (usually confined to the drainage area of the superior vena cava)

• Fetor hepaticus (strong musty smell)

• Xanthelasma

Chest findings may include gynecomastia.

Abdominal findings may include the following:

• Caput medusae

• Hepatosplenomegaly

• Ascites

• Paraumbilical hernia

• Bruits

The genitalia may show loss of pubic hair/secondary sexual characteristics in men and/or atrophic testes.

The extremities may exhibit muscle wasting, peripheral edema, and/or clubbing.

Guidelines by the British Society of Gastroenterology (BSG), the European Association for the Study of the Liver (EASL), and the American Association for the Study of Liver Diseases (AASLD) recommend the use of abdominal ultrasonography, diagnostic paracentesis, and ascitic fluid cultures in the workup of patients with suspected hepatorenal syndrome (HRS).[21]

The diagnosis of HRS is one of exclusion[13] and depends mainly on the 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.[22]

The International Club of Ascites (ICA) proposed revised diagnostic criteria of HRS-acute kidney injury (AKI) (previously HRS type 1) in 2015, including the following[23] :

• Diagnosis of cirrhosis and ascites

• Diagnosis of AKI according to ICA-AKI criteria

• No response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin 1 g/kg body weight

• Absence of shock

• No current or recent use of nephrotoxic drugs (nonsteroidal anti-inflammatory drugs [NSAIDs], aminoglycosides, iodinated contrast media, etc)

• No macroscopic signs of structural kidney injury, as defined as an absence of proteinuria (>500 mg/day); absence of microhematuria (>50 red blood cells per high-power field [RBCs/hpf]); normal findings on renal ultrasonography

ICA-AKI criteria

• Baseline sCr is defined as a value of serum creatinine (sCr) obtained in the previous 3 months or on admission if no baseline is available.

• AKI is defined as an increase in sCr ≥ 0.3 mg/dL (≥ 26.5 µmol/L) within 48 hours or a percentage increase in sCr ≥ 50% from baseline which is known, or presumed, to have occurred within the prior 7 days.

The ICA-AKI staging of AKI is as follows:

• Stage 1: Increase in sCr ≥ 0.3 mg/dL (26.5 µmol/L) or an increase in sCr ≥ 1.5 fold to 2-fold from baseline

• Stage 2: Increase in sCr > 2 to 3-fold from baseline

• Stage 3: Increase of sCr > 3-fold from baseline or sCr ≥ 4.0 mg/dL (353.6 µmol/L) with an acute increase ≥ 0.3 mg/dL (26.5 µmol/L) or initation of renal replacement therapy

The revised diagnostic criteria divided AKI in three stages to reflect its association with severity of disease. The HRS-1 diagnostic requirement for sCr to double to a value above 2.5 mg/dL over 2 weeks was removed due to its barrier to clinicians to initiate treatment on time prior to the disease progression to higher stages of AKI. The use of decreased urine output (< 0.5 mL/kg/h for >6 h) as part of the AKI definition for patients with cirrhosis was removed due to several reasons: 1) cirrhotic patients can be and often are oliguric due to sodium retention, but they have preserved renal function, and 2) the urine output may be increased due to use of diuretics and, therefore, urine output collection may be inaccurate. It has been proposed that urine output may be used in the AKI definition only if a urinary catheter is placed for precise measurement.

Response to treatment is defined as the following:

• No response: No regression of AKI

• Partial response: Regression of AKI stage with a reduction of sCr to ≥ 0.3 mg/dL (26.5 µmol/L) above the baseline value

• Full response: Return of sCr to a value within 0.3 mg/dL (26.5 µmol/L) of the baseline value

Complete blood cell count with differential

This may indicate the presence of an underlying infection such as spontaneous bacterial peritonitis (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 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 the patients' Child-Pugh scores.[18]

Alpha-fetoprotein levels

Although few studies demonstrate a relationship between hepatoma and the development of HRS, this test should be performed when patients with cirrhosis decompensate.

Blood cultures

Infections place patients at an increased 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 and urine electrolytes

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.

Measuring urine sodium and creatinine levels is used as a screening test to assess the degree of sodium retention. Patients with low urine sodium excretion (< 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.

Abdominal ultrasonography

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.

Echocardiography

This study may be helpful for evaluating the right ventricular preload, ventricular filling pressures, and cardiac performance in response to fluid replacement.

Paracentesis

Spontaneous bacterial peritonitis (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 hepatorenal syndrome (HRS) is more controversial in the absence of tense ascites. Concerns exist that further volume depletion may aggravate the 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 the central venous pressure nor the pulmonary artery occlusion pressure were useful for predicting ventricular preload with respect to optimizing cardiac performance.[24]

Histologic findings

The kidneys are histologically normal because HRS is a functional disorder.

Every attempt should be made to establish a precipitating cause of hepatorenal syndrome (HRS). This is particularly true for HRS-acute kidney injury (AKI), which rarely occurs spontaneously and may be associated with spontaneous bacterial peritonitis (SBP) in 25% of cases. If renal function does not improve after administrattion 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— at a liver transplant center—if possible. This may be more applicable for patients with type 2 HRS, who have a longer survival time, as opposed to patients with HRS-AKI, whose survival is extremely short and who may require alternative therapeutic methods (eg, transjugular intrahepatic portosystemic shunt [TIPS], vasoconstrictors) as a bridge to transplantation.

Reasons for transferring patients to a liver transplant center 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 the referral center

If patients are not candidates for liver transplantation, they have a poor prognosis and outpatient care will only be palliative in nature.

Guidelines from the British Society of Gastroenterology (BSG), the European Association for the Study of the Liver (EASL), and the American Association for the Study of Liver Diseases (AASLD) recommend cefotaxime as the antibiotic of choice for SBP and large-volume paracentesis for the management of ascites greater than 5 L in volume.[21] For HRS, cautious diuresis, volume expansion with albumin, and the use of vasoactive drugs are recommended.

The ideal treatment of hepatorenal syndrome (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 the survival chances for patients with HRS until transplantation can be performed. This is reinforced by a study that reported patients successfully treated medically for HRS before liver transplantation had posttransplantation outcome and survival comparable to those 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, therapies aimed at volume expansion, and the use of the transjugular intrahepatic portosystemic shunt (TIPS).

Treatment overview based on acute kidney injury (AKI) stage

Stage 1 AKI

Close monitoring

Removal and minimizing risk factors:

• Withdraw diuretics
• Avoid nonsteroidal anti-inflammatory drugs (NSAIDs) and nephrotoxic drugs
• Treat infection, if present
• Consider volume expansion with albumin

Stage 2 or 3 AKI

Withdrawal of diuretics

Volume expansion with albumin

If no response to the above therapies, then proceed to vasoconstrictors and albumin

Pharmacotherapy

Numerous medications have been used to treat HRS with little, if any, effect. The pharmacologic approach has shifted, however, with greater attention now 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 the 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 terlipressin, which predominantly act on the splanchnic circulation.[25, 26, 27, 28, 29]

In a systematic review and network meta-analysis of vasoactive treatments for HRS from 26 RCTs comprising 1,736 patients, investigators found that terlipressin increased HRS reversal compared with placebo, and it may reduce mortality.[30] In addition, owing to the inaccessibility of terlipressin in many countries, initial norepinephrine administration may be more appropriate than an initial trial with midodrine+octreotide.[30]

In September 2022, the FDA approved terlipressin to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function.

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.[31] Five studies have evaluated the role of dopamine in HRS, and none have reported significant changes in renal plasma flow (RPF), the glomerular filtration rate (GFR), or urine output. These studies are limited by small sample size and the 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 four patients with HRS. Although Fevery et al demonstrated reversal of HRS in four patients, these patients also received large doses of colloids.[32] 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.[33]

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 three patients with cirrhosis, ascites, and HRS who received an antagonist of endothelin A receptor (BQ123).[34] All three patients showed a dose-response improvement in insulin and para-aminohippurate excretion, RPF, and the GFR in the absence of changes in systemic hemodynamics. These three 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 promise for the treatment of HRS; they include vasopressin analogues (terlipressin), somatostatin analogues (octreotide), and alpha-adrenergic agonists (midodrine).[35]

Terlipressin

Terlipressin is a synthetic vasopressin with twice the selectivity for V1 receptors compared to V2 receptors. V1 vasopressin receptors are abundantly expressed in the mesenteric arteries as compared with other vascular areas, whereas V2 receptors are expressed in the renal tubules. The primary actions of V1 and V2, respectively, stimulate vasoconstriction and water resorption, and thereby result in decreased portal blood inflow and reduced portal hypertension.

Approval by the FDA in September 2022 was established by the CONFIRM trial, a phase 3, randomized controlled trial that included patients with type-1 hepatorenal syndrome (HRS-1) and rapidly worsening renal function.[36] This trial accessed the percentage of patients with improved renal function via verified HRS reversal, without the need for renal replacement therapy for 10 days after treatment. Verified HRS reversal was observed in 32% of those treated with terlipressin compared with 17% in the placebo group (P = 0.0006). However, deaths due to respiratory disorders were higher in the terlipressin group compared with placebo after 90 days (11% vs 2%). Use of terlipressin is not recommended in patients with hypoxia (SpO2 < 90%), and oxygenation levels should be monitored during treatment.[36]

Early vasopressin analogue trials

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 the biochemical parameters of renal function, and all patients subsequently died.

Octapressin (not approved in the United States), a synthetic vasopressin analogue, was first used in 1970 to treat HRS-AKI. 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 (not approved in the United States), attracted attention. Three important studies by Lenz and colleagues demonstrated that short-term use of ornipressin resulted in an improvement in the circulatory function and a significant increase in RPF and the GFR.[37, 38, 39]

The combination of ornipressin and albumin was subsequently tried by Guevera in patients with HRS,[40, 41]  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 the 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 HRS-AKI. This process 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%). The overall reversal rate been described to be 40%-80%.[42] One limitation of terlipressin is it is not available in many countries. Under these circumstances, such agents as octreotide, albumin, and alpha-adrenergic agonists may be considered.[43]

Gluud et al reviewed 10 randomized studies to determine whether vasoconstrictor drugs reduce mortality in patients with HRS-AKI or type 2 HRS.[44] The trials, on a total of 376 patients, investigated outcomes of HRS treatments using terlipressin alone or with albumin, using octreotide plus albumin, or using noradrenalin plus albumin. In their analysis, Gluud and colleagues found that administration of terlipressin plus albumin may lead to short-term mortality reduction in patients with HRS-AKI, but the authors saw no such reduction in patients with the type 2 form of the disease. Trials using octreotide and noradrenaline therapies were small and indicated neither harmful nor beneficial effects from these treatments. The authors advised that the response duration from terlipressin therapy be taken into account when treatment and the timing of liver transplantation are considered for patients with HRS-AKI.

In a randomized controlled trial that compared the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in 27 patients, Cavallin and colleagues found a significantly higher rate of improvement in renal function with telipressin plus albumin compared to midodrine/octreotide plus albumin.[45]

Wong et al studied the impact of reduction in AKI stage on overall survival in patients with cirrhosis and HRS-AKI. Subjects were grouped by AKI stage and received either terlipressin with albumin (n=91) vs placebo with albumin (n=93). Reduction in AKI stage was determined by serum creatinine levels. Patients with a reduction in AKI stage had improved survival despite not having HRS-AKI reversal.[46]

Angeli et al showed that long-term administration of midodrine (an alpha-adrenergic agonist) and octreotide improved renal function in eight patients with HRS-AKI.[47] 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 eight 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.[48]

Current practice is to use terlipressin first line, if and when available, with an initial dose of 0.5-1 mg intravenous (IV) bolus every 4-6 hours. If there is less than a 25% reduction in serum creatinine (sCr) in 3 days, the dose can be increased to 2 mg IV every 4-6 hours. It should be discontinued within 14 days of there is no improvement in renal function. In countries where terlipressin is not available, octreotide (somatostatin analogue) at 100-200 micrograms subcutaneously every 8 hours with midodrine (alpha-adrenergic agonist) 7.5 -12.5 mg orally three times daily may be used. For HRS-AKI, continuous noradrenaline infusion at 0.5-3 mg/h with a titration goal of increasing mean arterial blood pressure by 10 mmHg may be used. Albumin is recommended to be used in combination with vasoconstrictor drug regimens with 2 days of IV 1 g/kg/day, followed by 20-40 g IV daily.[49]

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 two 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 prognosis in the absence of liver transplantation. Controlled studies with longer follow-up may help answer these pressing questions.

Dietary considerations

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

Peritoneovenous shunting

Peritoneovenous shunting (PVS) seems attractive in theory because it leads to plasma volume expansion and improvement of the 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 hepatorenal syndrome (HRS), who often develop refractory ascites, are not candidates for orthotopic liver transplantation, and do not tolerate frequent arge-volume paracenteses.

PVS has no role in HRS-AKI.

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  transjugular intrahepatic portosystemic shunt (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, with partial to complete recovery in 75% of the patients, but it is limited by the availability of donors.[13, 50]

In a matched-pair study by Goldaracena et al, living (LDLT) and deceased donor liver transplantation (DDLT) led to comparable long-term outcomes in patients with HRS.[51] The investigators evaluated outcomes between 30 patients with HRS who received LDLT and 90 patients with HRS who received a full-graft DDLT. They did not identify any differences in graft survival and patient survival at 1, 3, and 5 years, and the incidence of postsurgical chronic kidney disease was similar between the two groups.[51] 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.[52]

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 glomerular filtration rate (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.

Simultaneous liver-kidney transplantation is the preferred treatment in patients whose renal function is not expected to recover despite liver transplantation. Due to a lack of reliable predictive biomarkers of renal recovery post liver transplantation, there has been a dramatic increase in simultaneous liver-kidney transplantation in relatively recent years.[49] In August 2017, new guidelines for simultaneous liver-kidney transplant was published by the Organ Procurement and Transplantation Network (UNOS).[53] The patient must meet at least one of three diagnosis categories, as follows:

• A diagnosis of chronic kidney disease with a GFR of less than 60 mL/min for more than 90 consecutive days and have begun dialysis, or have a GFR of less than 30 mL/min on the day of registration on the organ waiting list;
• Has sustained acute kidney injury (AKI) with dialysis at least once every 7 days or a GFR less than 25 mL/min at least once every 7 days;
• Has metabolic disease with hyperoxaluria, or atypical hemolytic uremic syndrome from mutations in factor H or I, or familial non-neuropathic systemic amyloidosis, or methylmalonic aciduria

In a retrospective study (2009-2019) that evaluated predictors of renal recovery in recipients of liver transplant alone who met 2017 simultaneous liver-kidney transplant criteria, investigators found that an estimated glomerular filtration rate (eGFR) level above 30 mL/min within 90 days pre-liver transplantation was associated with achieving sustained relative renal recovery (RRR)—and was protective of adverse outcomes—whereas a predictor of failure to have sustained RRR was prolonged severe renal impairment pre-liver transplantation.[54]  The investigators concluded that "candidates who meet 2017 UNOS criteria for [simultaneous liver-kidney transplantation] yet undergo [liver transplant alone] can still have post-[liver transplant] renal recovery, exceeding 80% with short-term follow-up and 40% with long- term follow-up."[54]

Nephrologist

The importance of a nephrologist in the multidisciplinary management of patients with hepatorenal syndrome (HRS) cannot be overemphasized. Nephrologists play a critical role in assisting hepatologists and liver transplant surgeons in the management of these critically ill patients.

Hemodialysis (HD) has been used by most major centers on patients who are on the transplant list. Studies have generally used continuous veno-venous hemofiltration (CVVH) and intermittent HD, the modality dependent on the hemodynamic stability of the patient.

A retrospective cohort study of 472 patients with HRS or tubular necrosis who underwent intermittent HD or CVVH, with 6-month survival as the primary outcome, found 15% of nonlisted subjects were alive 6 months after initiating renal replacement therapy (RRT), of which 78% of the patients had recovered renal function and were off dialysis.[55] Of the listed patients who did not receive transplantation, 38% were alive and off dialysis by the end of 6 months. Overall, 24% of patients were alive by the end of 6 months. The study suggested a potential benefit of using of RRT as a bridging therapy to organ transplantation.[55]

An earlier study on the clinical course of four patients with HRS who underwent HD in an attempt to bridge to liver transplantation found only one of the patients received the transplant.[56] Mean survival was 236 days (range: 31 to 460 days), with 33% of the days spent hospitalized. Overall, the study reflected the high cost and burden of morbidity as well as inpatient hospitalization in such patients and cautioned for evaluation of patients on an individual basis.[56]

A study of 30 patients with HRS treated with either CVVH or HD found that 30-day survival was 27% (8 patients); none of the patients on mechanical ventilation survived. This suggested that dialysis may be a viable therapeutic option in those patients who have not decompensated to the point of mechanical ventilation.[57] An older 1995 retrospective study of 107 patients found that of the 46% of patients placed on dialysis, predictors of future hemodialysis did not include diagnosis of HRS itself but were related to thrombocytopenia, encephalopathy, and malignoma.[58]

Continuous arteriovenous or venovenous hemofiltration has also been used, but the efficacy of these two measures has yet to be determined. Variations of hemodialysis include the molecular adsorbent recirculating system.[9] 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 HRS-AKI 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.

Overall, the decision to initiate hemodialysis should be individualized to the patient. If transplantation is not available, hemodialysis probably will continue to be performed for patients on the waiting list.

Interventional radiologist

Due to its ability to reduce portal hypertension in patients with variceal bleeding and refractory ascites, the role of transjugular intrahepatic portosystemic shunt (TIPS) in HRS initially seemed logical, particularly in view of isolated reports of renal function improvement following surgical shunts in the 1970s. Small, uncontrolled studies have indicated that TIPS may improve renal plasma flow (RPF) and the glomerular filtration rate (GFR) as well as reduce the activity of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) in patients who have cirrhosis with both types HRS. Improvement in renal function is usually slow and occurs in approximately 60% of patients.

In relatively more recent years, there have been a few publications that investigated the role of TIPS in HRS. A meta-analysis of nine studies with a total of 128 patients observed post-TIPS survival to be between 47% and 64%. Overall, renal function improved in 83% of the patients. In patients with maintain stable hepatic function but experience renal decompensation, TIPS may effectively improve renal function.[59]

An observational retrospective cohort study (2005-2014) with 79,354 patients found lower inpatient mortality when comparing patients with HRS-AKI without variceal bleeding who underwent TIPS versus receiving dialysis as treatment.[60] A similar retrospective study demonstrated reduced inpatient mortality to be true in men but not women, although the drivers of this sex-disparity is unclear.[61] However, it is fairly well known that TIPS carries the risk of an increasing incidence of hepatic encephalopathy. In addition, there are many limitations of TIPS. HRS patients typically have chronic and decompensated liver failure, and they may be precluded from the procedure due to elevated bilirubin levels or cardiac dysfunction. Moreover, the contrast burden associated with TIPS has the potential of worsening renal function.[62] Although more studies now exist that evaluate the role of TIPS in the treatment of HRS, its use remains investigational because of the lack of prospective studies and the known risks of the procedure, as well as the preference of medical management as a first-line treatment.

The main precipitating factor of hepatorenal syndrome-acute kidney injury (HRS-AKI) (formerly type 1 HRS) is spontaneous bacterial peritonitis (SBP). When this condition develops in patients with type 2 HRS, the probability of developing HRS-AKI is very high. This may be prevented by antibiotic prophylaxis with sulfamethoxazole and trimethoprim (Bactrim) or fluoroquinolones in patients with a prior history of SBP. Alternatively, patients with type 2 HRS who are on the liver transplant waiting list may benefit from prophylactic antibiotics, irrespective of whether they have a prior history of SBP.

A randomized controlled trial showed 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 hours later).[63] The incidence of HRS in patients with SBP who received albumin together with antibiotic therapy was 10% compared to 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.

Large-volume paracentesis 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. Unfortunately, with the current donor shortage, this does not seem to be a realistic possibility.

Regarding patients with acute alcoholic hepatitis, a study reported that the administration of pentoxifylline (400 mg three times daily for 28 days) reduced the incidence of HRS and mortality (8% and 25%, respectively) compared with a placebo group (35% and 46%, respectively).[64] However, no long-term data exist on the renal function or mortality in these patients.

The pharmacological approach to the treatment of hepatorenal syndrome (HRS) continues to evolve, with several possible effective treatments.

Terlipressin gained FDA approval in September 2022 to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function.

However, readers should be aware that most of these medications have yet to be 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.

Class Summary

Vasopressin analogues improve circulatory dysfunction secondary to splanchnic vasodilatation. These agents also improve renal plasma flow (RPF), the glomerular filtration rate (GFR), and urine output.

Terlipressin

Terlipressin is a synthetic vasopressin analogue with twice the selectivity for vasopressin V1 receptors versus V2 receptors. This agent acts as both a prodrug of lysine-vasopressin, and it also has pharmacologic activity on its own. It is indicated to improve kidney function in adults with HRS with rapid reduction in kidney function.

Class Summary

Antibiotics are only indicated in the treatment of hepatorenal syndrome (HRS) if renal dysfunction is precipitated by an infection. Prophylactic antibiotics may play a role in preventing spontaneous bacterial peritonitis (SBP), which, in turn, is also a risk factor for the development of HRS-acute kidney injury (AKI) (formerly 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.

Cefotaxime (Claforan)

Because the most common cause of HRS-AKI is SBP, IV cefotaxime is the drug of choice (DOC).

Ciprofloxacin (Cipro)

Ciprofloxacin is a fluoroquinolone with activity against pseudomonads, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms, but it has no activity against anaerobes. It inhibits bacterial DNA synthesis and, consequently, growth.

Norfloxacin (Noroxin, Chibroxin)

Norfloxacin is a fluoroquinolone with activity against pseudomonads, streptococci, MRSA, S epidermidis, and most gram-negative organisms, but it has no activity against anaerobes. It inhibits bacterial DNA synthesis and, consequently, growth.

Sulfamethoxazole and trimethoprim (Bactrim, Bactrim DS, Septra, Septra DS)

Sulfamethoxazole and trimethoprim inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid.

Class Summary

Somatostatin analogues aid improvement in splanchnic circulation, which may improve renal hemodynamics.

Octreotide (Sandostatin)

Octreotide is a synthetic derivative of somatostatin. It is a potent physiologic inhibitor of several gastrointestinal functions, one of which is a reduction in intestinal blood flow by splanchnic vasoconstriction.

Class Summary

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

N-acetylcysteine (Mucomyst)

N-acetylcysteine is traditionally used to treat acetaminophen overdose. It replenishes low hepatic glutathione stores to prevent the synthesis of toxic epoxide intermediates. This agent does not have a role in the treatment of non–acetaminophen-related liver failure. Its exact mechanism of action in HRS remains unclear.

Class Summary

Plasma volume expanders are indicated for the correction of abnormal hemodynamic parameters.

Albumin (Albunex, Albuminar, Albumisol)

Albumin is useful for plasma volume expansion and maintenance of cardiac output.

Class Summary

Sympathomimetic agents improve renal artery perfusion.

Dopamine (Intropin)

Dopamine stimulates both adrenergic and dopaminergic receptors. Its hemodynamic effect is dependent on dose. Lower doses predominantly stimulate dopaminergic receptors, which, in turn, produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation are produced by higher doses. This agent is described for its historical interest, because it has no role in monotherapy for HRS. However, reversal of HRS has been described when dopamine was used at low doses in conjunction with ornipressin.