Hepatorenal syndrome (HRS) 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, severe alcoholic hepatitis, or liver failure, and usually occurs when liver function deteriorates rapidly because of a sudden insult 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 people within one year of their diagnosis, and in 39% 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 kidneys. The kidney failure of HRS is a consequence of these changes in blood flow, rather than direct damage to the kidney. 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.
Classification
Hepatorenal syndrome is a particular and common type of kidney failure that affects individuals with liver cirrhosis or, less commonly, with fulminant liver failure. The syndrome involves constriction of the blood vessels of the kidneys and dilation of blood vessels in the splanchnic circulation, which supplies the intestines. The classification of hepatorenal syndrome identifies two categories of kidney 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.
Type 1 hepatorenal syndrome Type 1 HRS is characterized by rapidly progressive kidney failure, with a doubling of serum creatinine 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 (inotropes) or other drugs to maintain blood pressure (vasopressors).Mukherjee, S. Hepatorenal syndrome. emedicine.com. Retrieved on 2 August 2009 Unlike type II, in type I hepatorenal syndrome the kidney failure improves with treatment and stabilizes. Vasoconstrictors and volume expanders are the mainstay of treatment.
In 2015, the International Club of Ascites updated their definition of HRS Type 1 in light of recent studies. Termed HRS-AKI, no minimum creatinine value is needed, that is, HRS-AKI can be diagnosed even when the serum creatinine is below 2.5mg/dl (221umol/L).
Requirement for HRS-AKI are:
Increase in serum creatinine >0.3mg/L 26umol/L within 48 hrs OR increase by >1.5 times from baseline (reading from the last 3 months) No response to withdrawal of diuretics or administration of 1g/kg of albumin 20% over the last 2 days Cirrhosis with ascites Absence of Shock state Current or recent use of nephrotoxins (e.g. NSAIDS, contrast dyes Signs of structural kidney disease proteinuria haematuria Abnormal findings on renal US
Type 2 hepatorenal syndrome In contrast, type 2 HRS is slower in onset and progression, and is not associated with an inciting event. It is defined by an increase in serum creatinine 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.
Similarly to the updated HRS-AKI, functional kidney injury in patients with cirrhosis that does not meet the criteria for HRS-AKI is termed HRS-NAKI. It can be divided into two groups, HRS-AKD, defined by eGFR <60ml/min/1.72 for less than 3 months, and HRS-CKD, defined by eGFR <60ml/min/1.72 for more than 3 months.
Signs and symptoms Both types of hepatorenal syndrome share three major components: altered liver function, abnormalities in circulation, and death. 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 jaundice, 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 kidney 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, and the exclusion of other causes.
Causes Hepatorenal syndrome usually affects individuals with cirrhosis 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 liver failure.
Certain precipitants of HRS have been identified in vulnerable individuals with cirrhosis or fulminant liver 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.
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 kidney failure in the setting of advanced liver disease. As a result, additional major and minor criteria have been developed to assist in the diagnosis of hepatorenal syndrome.
The major criteria include liver disease with portal hypertension; kidney 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 kidney function despite treatment with 1.5 litres of intravenous normal saline; the absence of proteinuria (protein in the urine); and, the absence of kidney disease or obstruction of kidney outflow as seen on ultrasound.
The minor criteria are the following: a low urine volume (less than 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 kidney failure do not have damage to the kidneys, but as in individuals with HRS, have kidney dysfunction due to decreased blood flow to the kidneys. Also, similarly to HRS, pre-renal kidney failure causes the formation of urine that has a very low sodium concentration. In contrast to HRS, however, pre-renal kidney 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 kidney 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.
Pathophysiology