Hepatorenal syndrome
Encyclopedia
Hepatorenal syndrome is a life-threatening medical condition that consists of rapid deterioration in kidney function
in individuals with cirrhosis
or fulminant
liver failure
. HRS is usually fatal unless a liver transplant
is performed, although various treatments, such as dialysis
, can prevent advancement of the condition.
HRS can affect individuals with cirrhosis (regardless of cause), severe alcoholic hepatitis
, or fulminant hepatic failure, and usually occurs when liver function deteriorates rapidly because of an acute injury such as an infection, bleeding in the gastrointestinal tract, or overuse of diuretic
medications. HRS is a relatively common complication of cirrhosis, occurring in 18% of cirrhotics within one year of their diagnosis, and in 39% of cirrhotics within five years of their diagnosis.
Deteriorating liver
function is believed to cause changes in the circulation that supplies the intestines, altering blood flow
and blood vessel tone in the kidney
s. The renal failure of HRS is a consequence of these changes in blood flow, rather than direct damage to the kidney; the kidneys themselves appear normal to the naked eye and tissue is normal when viewed under the microscope
, and the kidneys even function normally when placed in an otherwise healthy environment (such as if transplanted into a person with a healthy liver). The diagnosis of hepatorenal syndrome is based on laboratory tests of individuals susceptible to the condition. Two forms of hepatorenal syndrome have been defined: Type 1 HRS entails a rapidly progressive decline in kidney function, while type 2 HRS is associated with ascites
(fluid accumulation in the abdomen) that does not improve with standard diuretic
medications.
The risk of death in hepatorenal syndrome is very high; the mortality of individuals with type 1 HRS is over 50% over the short term, as determined by historical case series
. The only long-term treatment option for the condition is liver transplantation. While awaiting transplantation, people with HRS often receive other treatments that improve the abnormalities in blood vessel tone, including supportive care with medications, or the insertion of a transjugular intrahepatic portosystemic shunt
(TIPS), which is a small shunt placed to reduce blood pressure in the portal vein. Some patients may require hemodialysis
to support kidney function, or a newer technique called liver dialysis
which uses a dialysis circuit with albumin
-bound membranes to bind and remove toxins normally cleared by the liver, providing a means of extracorporeal liver support
until transplantation can be performed.
that affects individuals with liver cirrhosis
or, less commonly, with fulminant liver failure. The syndrome involves constriction of the blood vessels of the kidney
s and dilation of blood vessels in the splanchnic circulation, which supplies the intestines. The classification of hepatorenal syndrome identifies two categories of renal failure
, termed type 1 and type 2 HRS, which both occur in individuals with either cirrhosis
or fulminant liver failure. In both categories, the deterioration in kidney function is quantified either by an elevation in creatinine
level in the blood, or by decreased clearance of creatinine in the urine.
to a level greater than 221 μmol/L (2.5 mg/dL) or a halving of the creatinine clearance to less than 20 mL/min over a period of less than two weeks. The prognosis of individuals with type 1 HRS is particularly grim, with a mortality rate
exceeding 50% after one month. Patients with type 1 HRS are usually ill, may have low blood pressure
, and may require therapy with drugs to improve the strength of heart muscle contraction (inotrope
s) or other drugs to maintain blood pressure (vasopressors).
level to >133 μmol/L (1.5 mg/dL) or a creatinine clearance of less than 40 mL/min, and a urine sodium < 10 μmol/L. It also carries a poor outlook, with a median survival of approximately six months unless the affected individual undergoes liver transplantation. Type 2 HRS is thought to be part of a spectrum of illness associated with increased pressures in the portal vein circulation
, which begins with the development of fluid in the abdomen (ascites
). The spectrum continues with diuretic-resistant ascites, where the kidneys are unable to excrete sufficient sodium to clear the fluid even with the use of diuretic medications. Most individuals with type 2 HRS have diuretic-resistant ascites before they develop deterioration in kidney function.
, altered mental status
, evidence of decreased nutrition, and the presence of ascites
. Specifically, the production of ascites that is resistant to the use of diuretic
medications is characteristic of type 2 HRS. Oliguria
, which is a decrease in urine volume, may occur as a consequence of renal failure; however, some individuals with HRS continue to produce a normal amount of urine. As these signs and symptoms may not necessarily occur in HRS, they are not included in the major and minor criteria for making a diagnosis of this condition; instead HRS is diagnosed in an individual at risk for the condition on the basis of the results of laboratory tests, in the exclusion of other causes.
and elevated pressures in the portal vein system (termed portal hypertension
). While HRS may develop in any type of cirrhosis
, it is most common in individuals with alcoholic cirrhosis
, particularly if there is concomitant alcoholic hepatitis
identifiable on liver biopsies. HRS can also occur in individuals without cirrhosis, but with acute onset of liver failure, termed fulminant hepatic failure.
Certain precipitants of HRS have been identified in vulnerable individuals with cirrhosis or fulminant hepatic failure. These include bacterial infection, acute alcoholic hepatitis
, or bleeding in the upper gastrointestinal tract. Spontaneous bacterial peritonitis
, which is the infection of ascites
fluid, is the most common precipitant of HRS in cirrhotic individuals. HRS can sometimes be triggered by treatments for complications of liver disease: iatrogenic precipitants of HRS include the aggressive use of diuretic
medications or the removal of large volumes of ascitic fluid
by paracentesis
from the abdominal cavity without compensating for fluid losses by intravenous replacement.
of hepatorenal syndrome.
The major criteria include liver disease in the setting of portal hypertension
; renal failure
; the absence of shock, infection
, recent treatment with medications that affect the function of the kidney (nephrotoxins), and fluid losses; the absence of sustained improvement in renal function despite treatment with 1.5 litres of intravenous normal saline; the absence of proteinuria
, or protein
in the urine
; and, the absence of renal disease or obstruction of renal outflow as seen on ultrasound
.
The minor criteria are the following: a low urine volume
(less than 500 mL per day), low sodium
concentration in the urine, a urine osmolality
that is greater than that in the blood
, the absence of red blood cells in the urine, and a serum sodium concentration of less than 130 mmol/L.
Many other diseases of the kidney are associated with liver disease and must be excluded before making a diagnosis of hepatorenal syndrome. Individuals with pre-renal failure
do not have damage to the kidneys, but as in individuals with HRS, have renal dysfunction due to decreased blood flow to the kidneys. Also, similarly to HRS, pre-renal failure causes the formation of urine that has a very low sodium concentration. In contrast to HRS, however, pre-renal failure usually responds to treatment with intravenous fluids, resulting in reduction in serum creatinine
and increased excretion of sodium. Acute tubular necrosis
(ATN) involves damage to the tubules of the kidney, and can be a complication in individuals with cirrhosis, because of exposure to toxic medications or the development of decreased blood pressure. Because of the damage to the tubules, ATN affected kidneys usually are unable to maximally resorb sodium from the urine. As a result, ATN can be distinguished from HRS on the basis of laboratory testing, as individuals with ATN will have urine sodium measurements that are much higher than in HRS; however, this may not always be the case in cirrhotics. Individuals with ATN also may have evidence of hyaline casts or muddy-brown casts in the urine on microscopy, whereas the urine of individuals with HRS is typically devoid of cellular material, as the kidneys have not been directly injured. Some viral infections of the liver, including hepatitis B and hepatitis C
can also lead to inflammation of the glomerulus
of the kidney. Other causes of renal failure in individuals with liver disease include drug toxicity (notably the antibiotic gentamicin
) or contrast nephropathy, caused by intravenous administration of contrast
agents used for medical imaging tests.
in hepatorenal syndrome is believed to arise from abnormalities in blood vessel
tone in the kidneys. The predominant theory (termed the underfill theory) is that blood vessels in the renal circulation are constricted because of the dilation of blood vessels in the splanchnic circulation (which supplies the intestines), which is mediated by factors released by liver disease. Nitric oxide
, prostaglandins, and other vasoactive substances have been hypothesized as powerful mediators of splanchnic vasodilation in cirrhosis. The consequence of this phenomenon is a decrease in the "effective" volume of blood sensed by the juxtaglomerular apparatus
, leading to the secretion of renin
and the activation of the renin-angiotensin system, which results in the vasoconstriction of vessels systemically and in the kidney specifically. However, the effect of this is insufficient to counteract the mediators of vasodilation in the splanchnic circulation, leading to persistent "underfilling" of the renal circulation and worsening renal vasoconstriction, leading to renal failure.
Studies to quantify this theory have shown that there is an overall decreased systemic vascular resistance in hepatorenal syndrome, but that the measured femoral
and renal fractions of cardiac output
are respectively increased and reduced, suggesting that splanchnic vasodilation
is implicated in the renal failure. Many vasoactive chemicals have been hypothesized as being involved in mediating the systemic hemodynamic changes, including atrial natriuretic factor, prostacyclin
, thromboxane
A2, and endotoxin
. In addition to this, it has been observed that the administration of medications to counteract splanchnic vasodilation (such as ornipressin
, terlipressin
, and octreotide
) leads to improvement in glomerular filtration rate (which is a quantitative measure of renal function), in patients with hepatorenal syndrome, providing further evidence that splanchnic vasodilation is a key feature of its pathogenesis.
The underfill theory involves activation of the renin-angiotensin-aldosterone system, which leads to an increase in absorption of sodium from the renal tubule (termed renal sodium avidity) mediated by aldosterone
, which acts on mineralocorticoid receptor
s in the distal convoluted tubule
. This is believed to be a key step in the pathogenesis of ascites
in cirrhotics as well. It has been hypothesized that the progression from ascites to hepatorenal syndrome is a spectrum where splanchnic vasodilation defines both resistance to diuretic
medications in ascites (which is commonly seen in type 2 HRS) and the onset of renal vasoconstriction (as described above) leading to hepatorenal syndrome.
(specifically spontaneous bacterial peritonitis
) and gastrointestinal hemorrhage
are both complications in individuals with cirrhosis, and are common triggers for HRS, specific care is made in early identification and treatment of cirrhotics with these complications to prevent HRS. Some of the triggers for HRS are induced by treatment of ascites
and can be preventable. The aggressive use of diuretic
medications should be avoided. In addition, many medications that are either used to treat cirrhotic complications (such as some antibiotics) or other conditions may cause sufficient impairment in renal function in the cirrhotic to lead to HRS. Also, large volume paracentesis
—which is the removal of ascites
fluid from the abdomen using a needle or catheter in order to relieve discomfort—may cause enough alteration in hemodynamics to precipitate HRS, and should be avoided in individuals at risk. The concomitant infusion of albumin
can avert the circulatory dysfunction that occurs after large volume paracentesis, and may prevent HRS. Conversely, in individuals with very tense ascites, it has been hypothesized that removal of ascitic fluid may improve renal function if it decreases the pressure on the renal vein
s.
Individuals with ascites that has become infected spontaneously (termed spontaneous bacterial peritonitis
or SBP) are at an especially high risk for the development of HRS. In individuals with SBP, one randomized controlled trial
found that the administration of intravenous albumin on the day of admission and on the third day in hospital reduced both the rate of renal insufficiency and the mortality rate.
scores above 36) have been found to be at greatest risk of early mortality after liver transplantation. A further deterioration of renal function even after liver transplantation in individuals with HRS has been demonstrated in several studies; however, this is transient and thought to be due to the use of medications with toxicity to the kidneys, and specifically the introduction of immunosuppressant
s such as tacrolimus
and cyclosporine that are known to worsen renal function. Over the long-term, however, individuals with HRS who are the recipients of liver transplants almost universally recover kidney function, and studies show that their survival rates at three years are similar to those who have received liver transplants for reasons other than HRS.
In anticipation of liver transplantation (which may be associated with considerable in-hospital delay), several other strategies have been found to be beneficial in preserving renal function. These include the use of intravenous albumin
infusion, medications (for which the best evidence is for analogues of vasopressin
, which causes splanchnic vasoconstriction), radiological shunts to decrease pressure in the portal vein
, dialysis
, and a specialized albumin-bound membrane dialysis system termed molecular adsorbents recirculation system (MARS) or liver dialysis
.
with albumin
given intravenously. The quantity of albumin administered intravenously varies: one cited regimen is 1 gram of albumin per kilogram of body weight intravenously on the first day, followed by 20 to 40 grams daily. Notably, studies have shown that treatment with albumin alone is inferior to treatment with other medications in conjunction with albumin; most studies evaluating pre-transplant therapies for HRS involve the use of albumin in conjunction with other medical or procedural treatment.
Midodrine
is an alpha-agonist and octreotide
is an analogue of somatostatin
, a hormone involved in regulation of blood vessel tone in the gastrointestinal tract. The medications are respectively systemic vasoconstrictors and inhibitors of splanchnic vasodilation, and were not found to be useful when used individually in treatment of hepatorenal syndrome. However, one study of 13 patients with hepatorenal syndrome showed significant improvement in kidney function when the two were used together (with midodrine given orally, octreotide given subcutaneously and both dosed according to blood pressure), with three patients surviving to discharge. Another nonrandomized, observational study of individuals with HRS treated with subcutaneous octreotide and oral midodrine showed that there was increased survival at 30 days.
The vasopressin analogue ornipressin
was found in a number of studies to be useful in improvement of renal function in patients with hepatorenal syndrome, but has been limited in its use, as it can cause severe ischemia
to major organs. Terlipressin
is a vasopressin analogue that has been found in one large study to be useful for improving renal function in patients with hepatorenal syndrome with a lesser incidence of ischemia. A key criticism of all of these medical therapies has been heterogeneity in the populations investigated and the use of renal function, instead of mortality, as an outcome measure.
Other agents that have been investigated for use in treatment of HRS include pentoxifylline, acetylcysteine, and misoprostol
. The evidence for all of these therapies is based on either case series
, or in the case of pentoxifylline, extrapolated from a subset of patients treated for alcoholic hepatitis
.
(TIPS) involves the decompression of the high pressures in the portal
circulation by placing a small stent between a portal
and hepatic vein
. This is done through radiologically guided catheters which are passed into the hepatic vein either through the internal jugular vein
or the femoral vein
. Theoretically, a decrease in portal pressures is thought to reverse the hemodynamic phenomena that ultimately lead to the development of hepatorenal syndrome. TIPS has been shown to improve renal function in patients with hepatorenal syndrome. Complications of TIPS for treatment of HRS include the worsening of hepatic encephalopathy
(as the procedure involves the forced creation of a porto-systemic shunt, effectively bypassing the ability of the liver to clear toxins), inability to achieve adequate reduction in portal pressure, and bleeding.
Liver dialysis
involves extracorporeal dialysis to remove toxins from the circulation, usually through the addition of a second dialysis circuit that contains an albumin-bound membrane. The molecular adsorbents recirculation system (MARS) has shown some utility as a bridge to transplantation in patients with hepatorenal syndrome, yet the technique is still nascent.
Renal replacement therapy
may be required to bridge individuals with hepatorenal syndrome to liver transplantation, although the condition of the patient may dictate the modality used. The use of dialysis
, however, does not lead to recuperation or preservation of renal function in patients with HRS, and is essentially only used to avoid complications of renal failure until transplantation can take place. In patients who undergo hemodialysis
, there may even be an increased risk of mortality due to hypotension
in patients with HRS, although appropriate studies have yet to be performed. As a result, the role of renal replacement therapy in patients with HRS remains unclear.
, much of the epidemiological data on HRS comes from the cirrhotic population. The condition is quite common: approximately 10% of individuals admitted to hospital with ascites
have HRS. A retrospective case series of cirrhotic patients treated with terlipressin suggested that 20.0% of acute renal failure in cirrhotics was due to type 1 HRS, and 6.6% was due to type 2 HRS. It is estimated that 18% of individuals with cirrhosis
and ascites
will develop HRS within one year of their diagnosis with cirrhosis, and 39% of these individuals will develop HRS within five years of diagnosis. Three independent risk factors for the development of HRS in cirrhotics have been identified: liver size, plasma renin activity, and serum sodium concentration.
The prognosis of these patients is grim with untreated patients having an extremely short survival. The severity of liver disease (as evidenced by the MELD
score) has been shown to be a determinant of outcome. Some patients without cirrhosis develop HRS, with an incidence of about 20% seen in one study of ill patients with alcoholic hepatitis
.
, Hecker, Papper and Vessin as being associated with systemic hemodynamic abnormalities and high mortality. Hecker and Sherlock specifically identified that individuals with HRS had low urinary output, very low sodium
in the urine, and no protein in the urine. Murray Epstein was the first to characterize splanchnic vasodilation and renal vasoconstriction as the key alterations in hemodynamics in patients with the syndrome. The functional nature of the renal impairment in HRS was crystallized by studies demonstrating that kidneys transplanted from patients with hepatorenal syndrome returned to function in the new host, leading to the hypothesis that hepatorenal syndrome was a systemic condition and not a renal disease. The first systematic attempt to define hepatorenal syndrome was made in 1994 by the International Ascites Club, a group of liver specialists. The more recent history of HRS has involved elucidation of the various vasoactive mediators that cause the splanchnic and renal blood flow abnormalities of the condition.
Acute renal failure
Acute kidney injury , previously called acute renal failure , is a rapid loss of kidney function. Its causes are numerous and include low blood volume from any cause, exposure to substances harmful to the kidney, and obstruction of the urinary tract...
in individuals with cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
or fulminant
Fulminant
Fulminant is any event or process that occurs suddenly and quickly, and is intense and severe to the point of lethality, i.e., it has an explosive character. The word comes from Latin fulmināre, to strike with lightning...
liver failure
Liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
. HRS is usually fatal unless a liver transplant
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
is performed, although various treatments, such as dialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
, can prevent advancement of the condition.
HRS can affect individuals with cirrhosis (regardless of cause), severe alcoholic hepatitis
Alcoholic hepatitis
Alcoholic hepatitis is hepatitis due to excessive intake of alcohol. While distinct from cirrhosis, it is regarded as the earliest stage of alcoholic liver disease. Symptoms are jaundice, ascites , fatigue and hepatic encephalopathy...
, or fulminant hepatic failure, and usually occurs when liver function deteriorates rapidly because of an acute injury such as an infection, bleeding in the gastrointestinal tract, or overuse of diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
medications. HRS is a relatively common complication of cirrhosis, occurring in 18% of cirrhotics within one year of their diagnosis, and in 39% of cirrhotics within five years of their diagnosis.
Deteriorating liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
function is believed to cause changes in the circulation that supplies the intestines, altering blood flow
Hemodynamics
Hemodynamics, meaning literally "blood movement" is the study of blood flow or the circulation.All animal cells require oxygen for the conversion of carbohydrates, fats and proteins into carbon dioxide , water and energy in a process known as aerobic respiration...
and blood vessel tone in the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s. The renal failure of HRS is a consequence of these changes in blood flow, rather than direct damage to the kidney; the kidneys themselves appear normal to the naked eye and tissue is normal when viewed under the microscope
Microscope
A microscope is an instrument used to see objects that are too small for the naked eye. The science of investigating small objects using such an instrument is called microscopy...
, and the kidneys even function normally when placed in an otherwise healthy environment (such as if transplanted into a person with a healthy liver). The diagnosis of hepatorenal syndrome is based on laboratory tests of individuals susceptible to the condition. Two forms of hepatorenal syndrome have been defined: Type 1 HRS entails a rapidly progressive decline in kidney function, while type 2 HRS is associated with ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
(fluid accumulation in the abdomen) that does not improve with standard diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
medications.
The risk of death in hepatorenal syndrome is very high; the mortality of individuals with type 1 HRS is over 50% over the short term, as determined by historical case series
Case series
A case series is a medical research descriptive study that tracks patients with a known exposure given similar treatment or examines their medical records for exposure and outcome. It can be retrospective or prospective and usually involves a smaller number of patients than more powerful...
. The only long-term treatment option for the condition is liver transplantation. While awaiting transplantation, people with HRS often receive other treatments that improve the abnormalities in blood vessel tone, including supportive care with medications, or the insertion of a transjugular intrahepatic portosystemic shunt
Transjugular intrahepatic portosystemic shunt
A Transjugular Intrahepatic Portosystemic Shunt is an artificial channel within the liver that establishes communication between the inflow portal vein and the outflow hepatic vein...
(TIPS), which is a small shunt placed to reduce blood pressure in the portal vein. Some patients may require hemodialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
to support kidney function, or a newer technique called liver dialysis
Liver dialysis
Liver dialysis is a detoxification treatment for liver failure and has shown promise for patients with hepatorenal syndrome. It is similar to hemodialysis and based on the same principles...
which uses a dialysis circuit with albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
-bound membranes to bind and remove toxins normally cleared by the liver, providing a means of extracorporeal liver support
Artificial extracorporeal liver support
Artificial extracorporeal liver support is term that is used to describe measures that are used to carry-out liver function and are outside of the body.Devices that support liver function outside of the body are:*Liver dialysis*Bioartificial liver devices...
until transplantation can be performed.
Classification
Hepatorenal syndrome is a particular and common type of kidney failureRenal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
that affects individuals with liver cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
or, less commonly, with fulminant liver failure. The syndrome involves constriction of the blood vessels of the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s and dilation of blood vessels in the splanchnic circulation, which supplies the intestines. The classification of hepatorenal syndrome identifies two categories of renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
, termed type 1 and type 2 HRS, which both occur in individuals with either cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
or fulminant liver failure. In both categories, the deterioration in kidney function is quantified either by an elevation in creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
level in the blood, or by decreased clearance of creatinine in the urine.
Type 1 hepatorenal syndrome
Type 1 HRS is characterized by rapidly progressive renal failure, with a doubling of serum creatinineCreatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
to a level greater than 221 μmol/L (2.5 mg/dL) or a halving of the creatinine clearance to less than 20 mL/min over a period of less than two weeks. The prognosis of individuals with type 1 HRS is particularly grim, with a mortality rate
Mortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...
exceeding 50% after one month. Patients with type 1 HRS are usually ill, may have low blood pressure
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, and may require therapy with drugs to improve the strength of heart muscle contraction (inotrope
Inotrope
An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions...
s) or other drugs to maintain blood pressure (vasopressors).
Type 2 hepatorenal syndrome
In contrast, type 2 HRS is slower in onset and progression. It is defined by an increase in serum creatinineCreatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
level to >133 μmol/L (1.5 mg/dL) or a creatinine clearance of less than 40 mL/min, and a urine sodium < 10 μmol/L. It also carries a poor outlook, with a median survival of approximately six months unless the affected individual undergoes liver transplantation. Type 2 HRS is thought to be part of a spectrum of illness associated with increased pressures in the portal vein circulation
Portal hypertension
In medicine, portal hypertension is hypertension in the portal vein and its tributaries.It is often defined as a portal pressure gradient of 10 mmHg or greater.-Causes:Causes can be divided into prehepatic, intrahepatic, and posthepatic...
, which begins with the development of fluid in the abdomen (ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
). The spectrum continues with diuretic-resistant ascites, where the kidneys are unable to excrete sufficient sodium to clear the fluid even with the use of diuretic medications. Most individuals with type 2 HRS have diuretic-resistant ascites before they develop deterioration in kidney function.
Signs and symptoms
Both types of hepatorenal syndrome share three major components: altered liver function, abnormalities in circulation, and renal failure. As these phenomena may not necessarily produce symptoms until late in their course, individuals with hepatorenal syndrome are typically diagnosed with the condition on the basis of altered laboratory tests. Most people who develop HRS have cirrhosis, and may have signs and symptoms of the same, which can include jaundiceJaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
, altered mental status
Hepatic encephalopathy
Hepatic encephalopathy is the occurrence of confusion, altered level of consciousness and coma as a result of liver failure. In the advanced stages it is called hepatic coma or coma hepaticum...
, evidence of decreased nutrition, and the presence of ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
. Specifically, the production of ascites that is resistant to the use of diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
medications is characteristic of type 2 HRS. Oliguria
Oliguria
Oliguria is the low output of urine, It is clinically classified as an output below 300-500ml/day. The decreased output of urine may be a sign of dehydration, renal failure, hypovolemic shock, HHNS Hyperosmolar Hyperglycemic Nonketotic Syndrome, multiple organ dysfunction syndrome, urinary...
, which is a decrease in urine volume, may occur as a consequence of renal failure; however, some individuals with HRS continue to produce a normal amount of urine. As these signs and symptoms may not necessarily occur in HRS, they are not included in the major and minor criteria for making a diagnosis of this condition; instead HRS is diagnosed in an individual at risk for the condition on the basis of the results of laboratory tests, in the exclusion of other causes.
Causes
Hepatorenal syndrome usually affects individuals with cirrhosisCirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
and elevated pressures in the portal vein system (termed portal hypertension
Portal hypertension
In medicine, portal hypertension is hypertension in the portal vein and its tributaries.It is often defined as a portal pressure gradient of 10 mmHg or greater.-Causes:Causes can be divided into prehepatic, intrahepatic, and posthepatic...
). While HRS may develop in any type of cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, it is most common in individuals with alcoholic cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, particularly if there is concomitant alcoholic hepatitis
Alcoholic hepatitis
Alcoholic hepatitis is hepatitis due to excessive intake of alcohol. While distinct from cirrhosis, it is regarded as the earliest stage of alcoholic liver disease. Symptoms are jaundice, ascites , fatigue and hepatic encephalopathy...
identifiable on liver biopsies. HRS can also occur in individuals without cirrhosis, but with acute onset of liver failure, termed fulminant hepatic failure.
Certain precipitants of HRS have been identified in vulnerable individuals with cirrhosis or fulminant hepatic failure. These include bacterial infection, acute alcoholic hepatitis
Alcoholic hepatitis
Alcoholic hepatitis is hepatitis due to excessive intake of alcohol. While distinct from cirrhosis, it is regarded as the earliest stage of alcoholic liver disease. Symptoms are jaundice, ascites , fatigue and hepatic encephalopathy...
, or bleeding in the upper gastrointestinal tract. Spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis is the development of peritonitis despite the absence of an obvious source for the infection. It occurs almost exclusively in people with portal hypertension , usually as a result of cirrhosis of the liver...
, which is the infection of ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
fluid, is the most common precipitant of HRS in cirrhotic individuals. HRS can sometimes be triggered by treatments for complications of liver disease: iatrogenic precipitants of HRS include the aggressive use of diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
medications or the removal of large volumes of ascitic fluid
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
by paracentesis
Paracentesis
Paracentesis is a medical procedure involving needle drainage of fluid from a body cavity, most commonly the peritoneal cavity in the abdomen.A related procedure is thoracocentesis, which is needle drainage of the chest cavity...
from the abdominal cavity without compensating for fluid losses by intravenous replacement.
Diagnosis
There can be many causes of kidney failure in individuals with cirrhosis or fulminant liver failure. Consequently, it is a challenge to distinguish hepatorenal syndrome from other entities that cause renal failure in the setting of advanced liver disease. As a result, additional major and minor criteria have been developed to assist in the diagnosisDiagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...
of hepatorenal syndrome.
The major criteria include liver disease in the setting of portal hypertension
Portal hypertension
In medicine, portal hypertension is hypertension in the portal vein and its tributaries.It is often defined as a portal pressure gradient of 10 mmHg or greater.-Causes:Causes can be divided into prehepatic, intrahepatic, and posthepatic...
; renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
; the absence of shock, infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
, recent treatment with medications that affect the function of the kidney (nephrotoxins), and fluid losses; the absence of sustained improvement in renal function despite treatment with 1.5 litres of intravenous normal saline; the absence of proteinuria
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
, or protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
in the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
; and, the absence of renal disease or obstruction of renal outflow as seen on ultrasound
Ultrasound
Ultrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Ultrasound is thus not separated from "normal" sound based on differences in physical properties, only the fact that humans cannot hear it. Although this limit varies from person to person, it is...
.
The minor criteria are the following: a low urine volume
Oliguria
Oliguria is the low output of urine, It is clinically classified as an output below 300-500ml/day. The decreased output of urine may be a sign of dehydration, renal failure, hypovolemic shock, HHNS Hyperosmolar Hyperglycemic Nonketotic Syndrome, multiple organ dysfunction syndrome, urinary...
(less than 500 mL per day), low sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
concentration in the urine, a urine osmolality
Urine osmolality
Urine osmolality is a measure of urine concentration, in which large values indicate concentrated urine and small values indicate diluted urine. In healthy individuals with restricted fluid intake, urine osmolality should be greater than 800mOsm/Kg, while a 24 hour urine osmolality should average...
that is greater than that in the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, the absence of red blood cells in the urine, and a serum sodium concentration of less than 130 mmol/L.
Many other diseases of the kidney are associated with liver disease and must be excluded before making a diagnosis of hepatorenal syndrome. Individuals with pre-renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
do not have damage to the kidneys, but as in individuals with HRS, have renal dysfunction due to decreased blood flow to the kidneys. Also, similarly to HRS, pre-renal failure causes the formation of urine that has a very low sodium concentration. In contrast to HRS, however, pre-renal failure usually responds to treatment with intravenous fluids, resulting in reduction in serum creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
and increased excretion of sodium. Acute tubular necrosis
Acute tubular necrosis
Acute tubular necrosis or is a medical condition involving the death of tubular cells that form the tubule that transports urine to the ureters while reabsorbing 99% of the water . Tubular cells continually replace themselves and if the cause of ATN is removed then recovery is likely...
(ATN) involves damage to the tubules of the kidney, and can be a complication in individuals with cirrhosis, because of exposure to toxic medications or the development of decreased blood pressure. Because of the damage to the tubules, ATN affected kidneys usually are unable to maximally resorb sodium from the urine. As a result, ATN can be distinguished from HRS on the basis of laboratory testing, as individuals with ATN will have urine sodium measurements that are much higher than in HRS; however, this may not always be the case in cirrhotics. Individuals with ATN also may have evidence of hyaline casts or muddy-brown casts in the urine on microscopy, whereas the urine of individuals with HRS is typically devoid of cellular material, as the kidneys have not been directly injured. Some viral infections of the liver, including hepatitis B and hepatitis C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
can also lead to inflammation of the glomerulus
Glomerulonephritis
Glomerulonephritis, also known as glomerular nephritis, abbreviated GN, is a renal disease characterized by inflammation of the glomeruli, or small blood vessels in the kidneys...
of the kidney. Other causes of renal failure in individuals with liver disease include drug toxicity (notably the antibiotic gentamicin
Gentamicin
Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila...
) or contrast nephropathy, caused by intravenous administration of contrast
Contrast medium
A medical contrast medium is a substance used to enhance the contrast of structures or fluids within the body in medical imaging...
agents used for medical imaging tests.
Pathophysiology
The renal failureRenal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
in hepatorenal syndrome is believed to arise from abnormalities in blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
tone in the kidneys. The predominant theory (termed the underfill theory) is that blood vessels in the renal circulation are constricted because of the dilation of blood vessels in the splanchnic circulation (which supplies the intestines), which is mediated by factors released by liver disease. Nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
, prostaglandins, and other vasoactive substances have been hypothesized as powerful mediators of splanchnic vasodilation in cirrhosis. The consequence of this phenomenon is a decrease in the "effective" volume of blood sensed by the juxtaglomerular apparatus
Juxtaglomerular apparatus
The juxtaglomerular apparatus is a microscopic structure in the kidney, which regulates the function of each nephron. The juxtaglomerular apparatus is named for its proximity to the glomerulus: it is found between the vascular pole of the renal corpuscle and the returning distal convoluted tubule...
, leading to the secretion of renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
and the activation of the renin-angiotensin system, which results in the vasoconstriction of vessels systemically and in the kidney specifically. However, the effect of this is insufficient to counteract the mediators of vasodilation in the splanchnic circulation, leading to persistent "underfilling" of the renal circulation and worsening renal vasoconstriction, leading to renal failure.
Studies to quantify this theory have shown that there is an overall decreased systemic vascular resistance in hepatorenal syndrome, but that the measured femoral
Femoral artery
The femoral artery is a general term comprising a few large arteries in the thigh. They begin at the inguinal ligament and end just above the knee at adductor canal or Hunter's canal traversing the extent of the femur bone....
and renal fractions of cardiac output
Cardiac output
Cardiac output is the volume of blood being pumped by the heart, in particular by a left or right ventricle in the time interval of one minute. CO may be measured in many ways, for example dm3/min...
are respectively increased and reduced, suggesting that splanchnic vasodilation
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
is implicated in the renal failure. Many vasoactive chemicals have been hypothesized as being involved in mediating the systemic hemodynamic changes, including atrial natriuretic factor, prostacyclin
Prostacyclin
Prostacyclin is a member of the family of lipid molecules known as eicosanoids.As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably.-History:...
, thromboxane
Thromboxane
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring....
A2, and endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
. In addition to this, it has been observed that the administration of medications to counteract splanchnic vasodilation (such as ornipressin
Ornipressin
Ornipressin is a vasoconstrictor, haemostatic and renal agent....
, terlipressin
Terlipressin
Terlipressin is an analogue of vasopressin used as a vasoactive drug in the management of hypotension. It has been found to be effective when norepinephrine does not help.Indications for use include norepinephrine-resistant septic shock and hepatorenal syndrome...
, and octreotide
Octreotide
Octreotide is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone...
) leads to improvement in glomerular filtration rate (which is a quantitative measure of renal function), in patients with hepatorenal syndrome, providing further evidence that splanchnic vasodilation is a key feature of its pathogenesis.
The underfill theory involves activation of the renin-angiotensin-aldosterone system, which leads to an increase in absorption of sodium from the renal tubule (termed renal sodium avidity) mediated by aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
, which acts on mineralocorticoid receptor
Mineralocorticoid receptor
The mineralocorticoid receptor , also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, is a protein that in humans is encoded by the NR3C2 gene that is located on chromosome 4q31.1-31.2.MR is a receptor with high affinity for mineralocorticoids...
s in the distal convoluted tubule
Distal convoluted tubule
The distal convoluted tubule is a portion of kidney nephron between the loop of Henle and the collecting duct system.- Physiology :It is partly responsible for the regulation of potassium, sodium, calcium, and pH...
. This is believed to be a key step in the pathogenesis of ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
in cirrhotics as well. It has been hypothesized that the progression from ascites to hepatorenal syndrome is a spectrum where splanchnic vasodilation defines both resistance to diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
medications in ascites (which is commonly seen in type 2 HRS) and the onset of renal vasoconstriction (as described above) leading to hepatorenal syndrome.
Prevention
The risk of death in hepatorenal syndrome is very high; consequently, there is a significant emphasis on the identification of patients who are at risk for HRS, and prevention of triggers for onset of HRS. As infectionInfection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
(specifically spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis is the development of peritonitis despite the absence of an obvious source for the infection. It occurs almost exclusively in people with portal hypertension , usually as a result of cirrhosis of the liver...
) and gastrointestinal hemorrhage
Upper gastrointestinal bleeding
Upper gastrointestinal bleeding refers to hemorrhage in the upper gastrointestinal tract. The anatomic cut-off for upper GI bleeding is the ligament of Treitz, which connects the fourth portion of the duodenum to the diaphragm near the splenic flexure of the colon.Upper GI bleeds are considered...
are both complications in individuals with cirrhosis, and are common triggers for HRS, specific care is made in early identification and treatment of cirrhotics with these complications to prevent HRS. Some of the triggers for HRS are induced by treatment of ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
and can be preventable. The aggressive use of diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
medications should be avoided. In addition, many medications that are either used to treat cirrhotic complications (such as some antibiotics) or other conditions may cause sufficient impairment in renal function in the cirrhotic to lead to HRS. Also, large volume paracentesis
Paracentesis
Paracentesis is a medical procedure involving needle drainage of fluid from a body cavity, most commonly the peritoneal cavity in the abdomen.A related procedure is thoracocentesis, which is needle drainage of the chest cavity...
—which is the removal of ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
fluid from the abdomen using a needle or catheter in order to relieve discomfort—may cause enough alteration in hemodynamics to precipitate HRS, and should be avoided in individuals at risk. The concomitant infusion of albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
can avert the circulatory dysfunction that occurs after large volume paracentesis, and may prevent HRS. Conversely, in individuals with very tense ascites, it has been hypothesized that removal of ascitic fluid may improve renal function if it decreases the pressure on the renal vein
Renal vein
The renal veins are veins that drain the kidney. They connect the kidney to the inferior vena cava.It is usually singular to each kidney, except in the condition "multiple renal veins".It also divides into 2 divisions upon entering the kidney:...
s.
Individuals with ascites that has become infected spontaneously (termed spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis is the development of peritonitis despite the absence of an obvious source for the infection. It occurs almost exclusively in people with portal hypertension , usually as a result of cirrhosis of the liver...
or SBP) are at an especially high risk for the development of HRS. In individuals with SBP, one randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
found that the administration of intravenous albumin on the day of admission and on the third day in hospital reduced both the rate of renal insufficiency and the mortality rate.
Liver transplantation
The definitive treatment for hepatorenal syndrome is orthotopic liver transplantation, and all other therapies can best be described as bridges to transplantation. While liver transplantation is by far the best available management option for HRS, the mortality of individuals with HRS has been shown to be as high as 25% within the first month after transplantation. Individuals with HRS and evidence of greater hepatic dysfunction (quantified as model for end-stage liver diseaseModel for End-Stage Liver Disease
The Model for End-Stage Liver Disease, or MELD, is a scoring system for assessing the severity of chronic liver disease. It was initially developed to predict death within three months of surgery in patients who had undergone a transjugular intrahepatic portosystemic shunt procedure, and was...
scores above 36) have been found to be at greatest risk of early mortality after liver transplantation. A further deterioration of renal function even after liver transplantation in individuals with HRS has been demonstrated in several studies; however, this is transient and thought to be due to the use of medications with toxicity to the kidneys, and specifically the introduction of immunosuppressant
Immunosuppressant
An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone...
s such as tacrolimus
Tacrolimus
Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
and cyclosporine that are known to worsen renal function. Over the long-term, however, individuals with HRS who are the recipients of liver transplants almost universally recover kidney function, and studies show that their survival rates at three years are similar to those who have received liver transplants for reasons other than HRS.
In anticipation of liver transplantation (which may be associated with considerable in-hospital delay), several other strategies have been found to be beneficial in preserving renal function. These include the use of intravenous albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
infusion, medications (for which the best evidence is for analogues of vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
, which causes splanchnic vasoconstriction), radiological shunts to decrease pressure in the portal vein
Portal hypertension
In medicine, portal hypertension is hypertension in the portal vein and its tributaries.It is often defined as a portal pressure gradient of 10 mmHg or greater.-Causes:Causes can be divided into prehepatic, intrahepatic, and posthepatic...
, dialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
, and a specialized albumin-bound membrane dialysis system termed molecular adsorbents recirculation system (MARS) or liver dialysis
Liver dialysis
Liver dialysis is a detoxification treatment for liver failure and has shown promise for patients with hepatorenal syndrome. It is similar to hemodialysis and based on the same principles...
.
Medical therapy
Many major studies showing improvement in renal function in patients with hepatorenal syndrome have involved expansion of the volume of the plasmaBlood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
with albumin
Human serum albumin
Human serum albumin is the most abundant protein in human blood plasma. It is produced in the liver. Albumin constitutes about half of the blood serum protein...
given intravenously. The quantity of albumin administered intravenously varies: one cited regimen is 1 gram of albumin per kilogram of body weight intravenously on the first day, followed by 20 to 40 grams daily. Notably, studies have shown that treatment with albumin alone is inferior to treatment with other medications in conjunction with albumin; most studies evaluating pre-transplant therapies for HRS involve the use of albumin in conjunction with other medical or procedural treatment.
Midodrine
Midodrine
Midodrine is a vasopressor/antihypotensive agent. Midodrine was approved in the United States by the Food and Drug Administration in 1996 for the treatment of orthostatic hypotension...
is an alpha-agonist and octreotide
Octreotide
Octreotide is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone...
is an analogue of somatostatin
Somatostatin
Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
, a hormone involved in regulation of blood vessel tone in the gastrointestinal tract. The medications are respectively systemic vasoconstrictors and inhibitors of splanchnic vasodilation, and were not found to be useful when used individually in treatment of hepatorenal syndrome. However, one study of 13 patients with hepatorenal syndrome showed significant improvement in kidney function when the two were used together (with midodrine given orally, octreotide given subcutaneously and both dosed according to blood pressure), with three patients surviving to discharge. Another nonrandomized, observational study of individuals with HRS treated with subcutaneous octreotide and oral midodrine showed that there was increased survival at 30 days.
The vasopressin analogue ornipressin
Ornipressin
Ornipressin is a vasoconstrictor, haemostatic and renal agent....
was found in a number of studies to be useful in improvement of renal function in patients with hepatorenal syndrome, but has been limited in its use, as it can cause severe ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
to major organs. Terlipressin
Terlipressin
Terlipressin is an analogue of vasopressin used as a vasoactive drug in the management of hypotension. It has been found to be effective when norepinephrine does not help.Indications for use include norepinephrine-resistant septic shock and hepatorenal syndrome...
is a vasopressin analogue that has been found in one large study to be useful for improving renal function in patients with hepatorenal syndrome with a lesser incidence of ischemia. A key criticism of all of these medical therapies has been heterogeneity in the populations investigated and the use of renal function, instead of mortality, as an outcome measure.
Other agents that have been investigated for use in treatment of HRS include pentoxifylline, acetylcysteine, and misoprostol
Misoprostol
Misoprostol is a drug that is used for the prevention of non steroidal anti inflammatory drug induced gastric ulcers, for early abortion, to treat missed miscarriage, and to induce labor. The latter use is controversial in the United States. Misoprostol was invented and marketed by G.D...
. The evidence for all of these therapies is based on either case series
Case series
A case series is a medical research descriptive study that tracks patients with a known exposure given similar treatment or examines their medical records for exposure and outcome. It can be retrospective or prospective and usually involves a smaller number of patients than more powerful...
, or in the case of pentoxifylline, extrapolated from a subset of patients treated for alcoholic hepatitis
Alcoholic hepatitis
Alcoholic hepatitis is hepatitis due to excessive intake of alcohol. While distinct from cirrhosis, it is regarded as the earliest stage of alcoholic liver disease. Symptoms are jaundice, ascites , fatigue and hepatic encephalopathy...
.
Procedural treatments
A transjugular intrahepatic portosystemic shuntTransjugular intrahepatic portosystemic shunt
A Transjugular Intrahepatic Portosystemic Shunt is an artificial channel within the liver that establishes communication between the inflow portal vein and the outflow hepatic vein...
(TIPS) involves the decompression of the high pressures in the portal
Portal hypertension
In medicine, portal hypertension is hypertension in the portal vein and its tributaries.It is often defined as a portal pressure gradient of 10 mmHg or greater.-Causes:Causes can be divided into prehepatic, intrahepatic, and posthepatic...
circulation by placing a small stent between a portal
Hepatic portal vein
The hepatic portal vein is not a true vein, because it does not conduct blood directly to the heart. It is a vessel in the abdominal cavity that drains blood from the gastrointestinal tract and spleen to capillary beds in the liver...
and hepatic vein
Hepatic vein
In human anatomy, the hepatic veins are the blood vessels that drain de-oxygenated blood from the liver and blood cleaned by the liver into the inferior vena cava....
. This is done through radiologically guided catheters which are passed into the hepatic vein either through the internal jugular vein
Internal jugular vein
The two internal jugular veins collect the blood from the brain, the superficial parts of the face, and the neck.-Path:On both sides and at the base of the brain, the inferior petrosal sinus and the sigmoid sinus join to form the internal jugular vein...
or the femoral vein
Femoral vein
In the human body, the femoral vein is a blood vessel that accompanies the femoral artery in the femoral sheath. It begins at the adductor canal and is a continuation of the popliteal vein...
. Theoretically, a decrease in portal pressures is thought to reverse the hemodynamic phenomena that ultimately lead to the development of hepatorenal syndrome. TIPS has been shown to improve renal function in patients with hepatorenal syndrome. Complications of TIPS for treatment of HRS include the worsening of hepatic encephalopathy
Hepatic encephalopathy
Hepatic encephalopathy is the occurrence of confusion, altered level of consciousness and coma as a result of liver failure. In the advanced stages it is called hepatic coma or coma hepaticum...
(as the procedure involves the forced creation of a porto-systemic shunt, effectively bypassing the ability of the liver to clear toxins), inability to achieve adequate reduction in portal pressure, and bleeding.
Liver dialysis
Liver dialysis
Liver dialysis is a detoxification treatment for liver failure and has shown promise for patients with hepatorenal syndrome. It is similar to hemodialysis and based on the same principles...
involves extracorporeal dialysis to remove toxins from the circulation, usually through the addition of a second dialysis circuit that contains an albumin-bound membrane. The molecular adsorbents recirculation system (MARS) has shown some utility as a bridge to transplantation in patients with hepatorenal syndrome, yet the technique is still nascent.
Renal replacement therapy
Renal replacement therapy
Renal replacement therapy is a term used to encompass life-supporting treatments for renal failure.It includes:*hemodialysis,*peritoneal dialysis,*hemofiltration and*renal transplantation.These treatments will not cure chronic kidney disease...
may be required to bridge individuals with hepatorenal syndrome to liver transplantation, although the condition of the patient may dictate the modality used. The use of dialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
, however, does not lead to recuperation or preservation of renal function in patients with HRS, and is essentially only used to avoid complications of renal failure until transplantation can take place. In patients who undergo hemodialysis
Hemodialysis
In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...
, there may even be an increased risk of mortality due to hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
in patients with HRS, although appropriate studies have yet to be performed. As a result, the role of renal replacement therapy in patients with HRS remains unclear.
Epidemiology
As the majority of individuals with hepatorenal syndrome have cirrhosisCirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, much of the epidemiological data on HRS comes from the cirrhotic population. The condition is quite common: approximately 10% of individuals admitted to hospital with ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
have HRS. A retrospective case series of cirrhotic patients treated with terlipressin suggested that 20.0% of acute renal failure in cirrhotics was due to type 1 HRS, and 6.6% was due to type 2 HRS. It is estimated that 18% of individuals with cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
and ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
will develop HRS within one year of their diagnosis with cirrhosis, and 39% of these individuals will develop HRS within five years of diagnosis. Three independent risk factors for the development of HRS in cirrhotics have been identified: liver size, plasma renin activity, and serum sodium concentration.
The prognosis of these patients is grim with untreated patients having an extremely short survival. The severity of liver disease (as evidenced by the MELD
Model for End-Stage Liver Disease
The Model for End-Stage Liver Disease, or MELD, is a scoring system for assessing the severity of chronic liver disease. It was initially developed to predict death within three months of surgery in patients who had undergone a transjugular intrahepatic portosystemic shunt procedure, and was...
score) has been shown to be a determinant of outcome. Some patients without cirrhosis develop HRS, with an incidence of about 20% seen in one study of ill patients with alcoholic hepatitis
Alcoholic hepatitis
Alcoholic hepatitis is hepatitis due to excessive intake of alcohol. While distinct from cirrhosis, it is regarded as the earliest stage of alcoholic liver disease. Symptoms are jaundice, ascites , fatigue and hepatic encephalopathy...
.
History
The first reports of renal failure occurring in individuals with chronic liver diseases were from the late 19th century by Frerichs and Flint. However, the hepatorenal syndrome was first defined as acute renal failure that occurred in the setting of biliary surgery. The syndrome was soon re-associated with advanced liver disease, and, in the 1950s, was clinically defined by SherlockSheila Sherlock
Professor Dame Sheila Patricia Violet Sherlock, Mrs. James, DBE, MD, FRCP, FRCP Ed, FRS was a British physician, hepatologist and teacher.-Early life:...
, Hecker, Papper and Vessin as being associated with systemic hemodynamic abnormalities and high mortality. Hecker and Sherlock specifically identified that individuals with HRS had low urinary output, very low sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
in the urine, and no protein in the urine. Murray Epstein was the first to characterize splanchnic vasodilation and renal vasoconstriction as the key alterations in hemodynamics in patients with the syndrome. The functional nature of the renal impairment in HRS was crystallized by studies demonstrating that kidneys transplanted from patients with hepatorenal syndrome returned to function in the new host, leading to the hypothesis that hepatorenal syndrome was a systemic condition and not a renal disease. The first systematic attempt to define hepatorenal syndrome was made in 1994 by the International Ascites Club, a group of liver specialists. The more recent history of HRS has involved elucidation of the various vasoactive mediators that cause the splanchnic and renal blood flow abnormalities of the condition.