Background
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]
Pathophysiology
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.
Etiology
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:
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Low urinary sodium excretion (< 5 mEq/L)
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Low serum sodium (dilutional hyponatremia)
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Reduced free-water excretion after water load
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Low mean arterial pressure
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High plasma renin activity
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Increased plasma norepinephrine
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Low plasma osmolality
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High urine osmolality
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High serum potassium
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Previous episodes of ascites
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Absence of hepatomegaly
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Presence of esophageal varices
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Poor nutritional status
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Moderately increased serum urea (>30 mg/dL)
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Moderately increased serum creatinine (>1.5 mg/dL)
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Moderately reduced glomerular filtration rate (GFR) (< 50 mL/min)
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Cirrhotic cardiomyopathy
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Adrenal insufficiency
Epidemiology
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.
Prognosis
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.
Patient Education
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.
