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KEY POINTS
■ The main driving force behind the development of hepatorenal syndrome (HRS) is portal hypertension, and the key event is linked to splanchnic arterial vasodilation.
■ Therapy should be geared toward increasing intravascular volume, as the underlying issue appears related to depletion of effective circulating volume depletion (third space and splanchnic vasodilation).
■ Current medical options for the treatment of either type 1 or type 2 HRS serve as a means of transition to a more definitive treatment, such as a transjugular intrahepatic portosystemic shunt (TIPS) procedure or, ideally, a liver transplant.
■ Medical management primarily involves therapies that will aid in vasoconstriction.
■ TIPS is typically used in patients who are not candidates for liver transplant or who remain on the transplant waiting list and are in need of emergent intervention.
Cirrhosis of the liver is a common clinical problem encountered by both inpatient and outpatient providers. It is the 12th leading cause of overall mortality in the United States and a marker for subsequent progression of portal hypertension complications.
1 What may be even more disconcerting to the patient than the years lost to cirrhosis is the impact this disease has on quality of life. Many complications are a result of longstanding portal hypertension brought on by the distortive, fibrotic, and regenerative changes within the liver. In the US population, these changes are most often due to alcoholic liver disease or chronic hepatitis C virus (HCV) infection.
1
Although the complications of portal hypertension are well known, one frequent complication is less noticed, more misunderstood, and underdiagnosed compared with the others. This complication is hepatorenal syndrome (HRS), which is a frequently encountered end point to portal hypertension and has an annual incidence in the range of 8% to 40% in cirrhotic patients.2 The presence of ascites increases the risk of HRS, with 20% of patients developing HRS within 1 year after the onset of ascites and 40% developing HRS by year 5.3 The frequency of this complication is further confounded by its associated high mortality.
Renal failure (RF) is common in cirrhotic patients. In part, RF can be a consequence of treatment for other entities of portal hypertension, or it can be associated with common comorbidities that lead to chronic RF (ie, hypertensive and diabetic nephropathy). HRS, however, is a different disease process. Depending on type, median survival is often cited as 1 month (type 1) and 6 months (type 2).4
Some resources also propose a type 3 and a type 4 classification. These types deal more directly with prior coexisting chronic kidney disease superimposed on HRS and acute fulminant liver failure, respectively. To date, these classifications have not been as extensively studied, and such patients have been excluded from many clinical trials because they did not meet the traditional diagnostic criteria for HRS.2 This article further identifies and defines type 1 and type 2 HRS and their management, while focusing on the basic pathophysiologic and prognostic factors that determine its outcome.
DEFINITION AND DIAGNOSIS
Renal failure in cirrhotic patients is a common finding in both inpatient and outpatient settings.The use of lactulose in hepatic encephalopathy, loop diuretics and large-volume paracentesis in ascites, and hemorrhage associated with esophageal varices portend intravascular depletion and put patients at increased risk for acute RF.3 These causes of RF are often treatable with effective volume replacement and are not to be confused with HRS, which is characterized by a separate disease process than other common causes of renal failure. Hepatorenal syndrome is a diagnosis of exclusion, and the condition should be definitively diagnosed only after treatments for the correctable causes of RF have failed.
To further complicate the early detection of HRS, renal function is often subject to misinterpretation because of alterations in creatinine and urea production. In liver disease, the decrease in muscle mass and albumin can lead to lower levels of creatinine and urea.5 This can skew significantly the calculation of glomerular filtration rate (GFR) by such measures as the Cockcroft-Gault formula.5 The recommendation in these patients is to evaluate RF based on the creatinine level, keeping in mind that a serum creatinine level of 0.6 to 0.8 mg/dL is often considered normal in advanced cirrhosis.2 Therefore, a creatinine level of 1.5 mg/dL is considered the threshold for early detection of HRS, regardless of type.
Because no laboratory study or imaging modality is considered definitive for HRS, diagnosis depends on the acumen of the clinician. This has led to misdiagnosis in as many as 60% to 70% of cases.2 Once other causes of renal failure have been eliminated, the principles for early and accurate detection of HRS revolve around five major criteria:5
1. The patient must have acute or chronic hepatic disease that includes advanced liver failure and portal hypertension.
2. The plasma creatinine level must have risen over days to weeks to a level greater than 1.5 mg/dL; that is, the creatinine cannot have been chronically elevated.
3. The patient must not have any other form of renal disease, such as that caused by shock, bacterial infection, or current or recent use of nephrotoxic drugs, and there can be no sign of GI or renal fluid loss.
4. Cessation of any diuretic medication and expansion of the plasma volume with IV albumin (1 g/kg of body weight up to a maximum of 100 g) does not lead to improved renal function (defined as a creatinine level of less than 1.5 mg/dL).
5. Urinary protein is less than 500 mg/dL in the absence of parenchymal renal disease (by urinalysis) or obstructive uropathy (by ultrasound).
These criteria apply only to persons who do not have preexisting/chronic renal disease.