Topic Editor: Grant E. Fraser, M.D., FRACGP, FACRRM, ASTEM

Review Date: 02/11/2013

Definition

Hepatorenal Syndrome (HRS) is a condition where progressive renal failure occurs in patients with advanced liver disease, generally cirrhosis, alcoholic hepatitis, or other cases of liver failure, often in the presence of portal hypertension and ascites. Renal failure in HRS is due to renal arterial vasoconstriction with the kidney itself having no intrinsic disease. Mortality is exceptionally high, with the only current highly successful treatment being liver transplant.

Description

• Hepatorenal syndrome (HRS) is a type of functional renal failure resulting from profound renal vasoconstriction occurring in patients with severe hepatic disease and impaired circulation
• Classification of HRS:
• Type 1 HRS: Rapidly progressing over 2 weeks or less, acute renal failure with at least a 100% increase from baseline serum creatinine and a value >2.5mg/dl (220 mmol/L)/. Type 1 HRS often develops in patients with advanced liver disease as a sudden event; often in response to some type of physiological insult, especially subacute bacterial peritonitis (SBP). These patients, in contrast to Type 2 HRS patients, tend to have severely diminished GFR and markedly elevated creatinine (e.g. average ~4 mg/dL and GFR often <20 mL/min). Mortality in this group is very high and often occurs in the short term
• Type 2 HRS: Gradual decline in renal function over weeks to months, generally in patients with refractory ascites who fail to respond to diuretics. Some patients with Type 2 HRS will have a precipitating event with a sudden deterioration and meet criteria for type 1 HRS
• Pathogenesis
• HRS type 1 is felt to relate to severe splanchnic arterial vasodilation, decreased cardiac output and severe renal arterial vasoconstriction possibly in response to these factors leading to a severe reduction of effective circulatory volume
• HRS type 2 is markedly less acute and severe and relates to gradual deterioration in renal function with the major issue being refractory ascites and impaired natriuresis (renal excretion of sodium)
• The changes in renal hemodynamics are thought to be triggered by a variety of causes, including diminished blood volume, augmented sympathetic activity, elevated venous pressure in the abdomen and kidneys, and altered levels of intrinsic vasoactive agents
• In patients with HRS, plasma expansion does not result in improvement of renal function
• Criteria for HRS in cirrhosis
• Cirrhosis with ascites
• Serum creatinine >1.5 mg/dL (133 mmol/L)
• No shock present
• No current or recent treatment with nephrotoxic drugs
• No Hypovolemia (defined by no sustained improvement of renal function e.g. creatinine reaching <1.5 mg/dL following at least 2 days of diuretic withdrawal if on diuretics, and volume expansion with albumin at 1 g/kg/day up to 100 g/day
• No parenchymal renal disease [ normal renal ultrasound, proteinuria <0.5 g/day and no microhematuria (<50 RBCs/hpf)]

Epidemiology

Incidence/Prevalence

• HRS develops in 20-30% of patients who develop SBP
• The likelihood of developing HRS in patients with cirrhosis and ascites is 18% at 1 year and 39% at 5 years
• Success with liver transplantation has drastically reduced the incidence of HRS

• More common after the fourth decade of life simply due to higher incidence of cirrhosis and other advanced liver disease in the older population

Gender

• More common in males than in females

Risk factors

• Factors linked with an increased risk of HRS in nonazotemic patients with cirrhosis and ascites include:
• Arterial hypotension
• Decreased free-water excretion after water load
• Dilutional hyponatremia
• Increased plasma norepinephrine concentration
• Increased plasma renin activity
• Low urinary sodium excretion
• Moderately increased renal vascular resistive index
• Poor nutritional status
• Presence of renal insufficiency (even if mild)

Etiology

• HRS can occur spontaneously in patients with end stage liver disease, cirrhosis, alcoholic hepatitis, or acute liver failure
• In patients with ascites, a common initiating event for HRS is infection, most commonly due to spontaneous bacterial peritonitis (SBP)
• HRS may also be associated with a non-alcoholic causes of cirrhosis such schistosomiasis or drug-induced cirrhosis
• HRS may develop after any major physiological stressor, including any cause of shock or decrease in blood volume (eg, diuretic use, therapeutic paracentesis, gastrointestinal [GI] hemorrhage)

History

• History for patients with suspect HRS should include:
• History of severe liver disease, generally with ascites, along with etiology of their liver disease if known
• Alcohol use history
• In some cases history may be complicated by hepatic or rarely uremic encephalopathy
• Medication history including focus on diuretics (over diuresis), nephrotoxic and hepatotoxic drug use
• Oliguria (common in Type 1 HRS)
• Symptoms of infection, such as abdominal distension and tenderness with ascites (concern for SBP), fever, chills, symptoms of pneumonia, cellulitis, urinary tract infection, meningitis or other infections
• Symptoms of upper or lower GI bleed and history of any prior such episodes and underlying diagnoses (such as esophageal varices)

Physical findings on examination

• The physical findings present in HRS relate to those present with advanced liver disease. HRS does not have specific physical findings
• Patients with advanced liver disease often have a wider pulse pressure, lower arterial blood pressure, and bounding pulses
• If a physiological stressor has precipitated HRS, findings consistent with that precipitant may be present:
• If SBP is present, abdominal tenderness with ascites, and potentially presence of fever may be present
• If GI bleed is present, hematemesis, melena or frank blood per rectum may be present
• Other cases of infection or shock may have examination findings consistent with the underlying cause
• As HRS occurs in patients with advanced cirrhosis or other advanced or severe liver disease, findings of such include:
• Ascites
• Asterixis (flapping tremor)
• Clubbing of digits
• Edema (peripheral or central)
• Fetor hepaticus (characteristic odor associated with hepatic disease)
• Gynecomastia
• Hepatic encephalopathy
• Hepatomegaly (may or may not be present)
• Jaundice
• Oliguria
• Palmar erythema
• Spider nevi
• Splenomegaly

Approach consideration

• HRS is a diagnosis of exclusion. The initial step of diagnosis is a demonstration of a reduced glomerular filtration rate (GFR)
• Criteria for HRS in cirrhosis
• Cirrhosis with ascites
• Serum creatinine >1.5 mg/dL (133 mmol/L)
• No shock present
• No current or recent treatment with nephrotoxic drugs
• No Hypovolemia (defined by no sustained improvement of renal function e.g. creatinine reaching <1.5 mg/dL following at least 2 days of diuretic withdrawal if on diuretics, and volume expansion with albumin at 1 g/kg/day up to 100 g/day
• No parenchymal renal disease [ normal renal ultrasound, proteinuria <0.5 g/day and no microhematuria (<50 RBCs/hpf)]
• Additional factors commonly present :
• Urine output <500 mL/day (especially with HRS type 1)
• Urine sodium <10 mEq/L
• Urine osmolality exceeds plasma osmolality
• Serum sodium concentration 130 mEq/L

Blood tests findings

• Complete blood count (CBC)
• CBC has limited value in detecting infection, as WBC count is neither specific nor sensitive for detecting infection in this setting. Platelet count and hemoglobin can be of value in relation to assessing blood loss (usually GI bleeding) and risk of bleeding (thrombocytopenia)
• Serum electrolytes
• Evaluation of metabolic acidosis (bicarbonate)
• Evaluation for hyponatremia and hyperkalemia
• Blood urea nitrogen (BUN)
• BUN may increase due to causes other than decreased GFR, such as pre-renal state, catabolic state, or upper GI hemorrhage
• Creatinine
• Creatinine level should be >1.5 mg/dL and in type 1 HRS creatinine level should increase to >100% above baseline and >2.5 mg/dL

Other laboratory test findings

• Urine osmolality
• Urine sodium <10 mEq/L
• Urine/ plasma creatinine >30:1
• Urinalysis
• Evidence of proteinuria or hematuria should be absent as this may indicate an organic cause other than HRS for renal failure
• Liver function test (LFT) with prothrombin time
• LFTs and INR are important in assessing Child-Pugh scores, which grade severity of hepatic dysfunction
• Culture
• Urine, blood, and ascitic fluid culture may be performed as indicated in infection is suspected

• Renal ultrasound:
• Renal ultrasound is generally indicated to rule out any structural cause of renal function deterioration, such as hydronephrosis or obstructive uropathy

Other diagnostic test findings

• Electrocardiogram (ECG):
• ECG findings may have findings consistent with hyperkalemia
• Urinary catheter placement:
• A urinary catheter may be used to document urinary output in selected cases

• Acute tubular necrosis - ischemic
• Acute tubular necrosis -nephrotoxic
• Cardiac failure
• GI fluid loss
• Glomerulonephritis
• Interstitial nephritis
• Intravascular volume depletion
• Intrinsic renal disease
• Obstructive renal nephropathy
• Prerenal azotemia
• Renal artery or vein thrombosis

General treatment items

• Supportive treatment includes careful monitoring of vital signs, regular clinical evaluation, and treatment of concomitant complications of cirrhosis
• It is essential to avoid excessive fluid use to prevent fluid overload
• Potassium-sparing diuretics are contraindicated due to the risk of severe hyperkalemia
• Bacterial infections, particularly spontaneous bacterial peritonitis, are a risk factor for hepatorenal syndrome. Prompt therapy with antibiotics and albumin infusion decreases the risk of developing HRS
• Drug therapy:
• The primary objective of pharmacological treatment is successful reversal of renal failure, thus allowing hepatic recovery
• Vasoconstrictors cause significant vasoconstriction of the splanchnic bed, thereby improving circulation to non-splanchnic organs, including the central component of the kidneys
• Several vasoconstrictors agents such as vasopressin analogues (terlipressin and ornipressin), somatostatin analogues (octreotide) and catecholamines (midodrine, norepinephrine) have shown potential for the therapy of HRS generally only in conjunction with albumin
• Combination albumin and vasoconstrictor therapy has been shown to significantly improve the glomerular filtration rate and normalize serum creatinine in approximately two-thirds of patients with HRS and cirrhosis
• A 2012 Cochrane review indicates "Terlipressin may reduce mortality and improve renal function" in Type 1 HSP. They expressed concern regarding level of evidence to support this intervention based upon available trials
• A 2012 trial of albumin plus either terlipressin or norepinephrine found these protocols to be comparable, with 39.1% vs. 43.4% of patients achieving HRS reversal respectively, with the advantage of lower cost for norepinephrine
• A 2009 trial of octreotide, midodrine, and albumin showed significant benefits over usual therapy not including these vasoactive drugs. Survival was better in both HRS type 1 and type 2 with median survival 101 days versus 18 days
• Transjugular intrahepatic portosystemic shunts (TIPS):
• TIPs procedure outcomes in HRS have not yielded consistent results. Patients who successfully survive the procedure may have positive renal outcomes, however those with a Child-Pugh scores >12 are increased risk of serious complications
• TIPS procedure has been shown to significantly improve renal function in type 1 hepatorenal syndrome. It is also known to enhance renal function and control ascites in patients with type 2 hepatorenal syndrome
• However, the applicability of TIPS in this setting is very restricted mainly due to contraindications to using TIPS in the majority of patients
• Liver transplantation:
• Liver transplantation remains the exclusive proven and permanent treatment intervention for HRS. Prioritization of transplant recipients can be done using the Model for End-Stage Liver Disease (MELD) score
• Liver transplantation is the preferred intervention for both type 1 and type 2 HRS but is limited by the availability of donors. Also, in many cases, patients may exclude themselves from candidacy due to continued alcohol abuse
• Higher risk of early mortality, postoperative morbidity and lengthy hospitalization are observed in patients with HRS undergoing transplantation as compared to other transplant patients
• A higher percentage of patients require hemodialysis postoperatively
• Renal function typically normalizes following liver transplant

Medication indicated with specific doses

Albumin human [IV]

• Adult Dosing

Midodrine

• Adult Dosing

Octreotide [Injectable]

• Adult Dosing

Dietary and activity restrictions

• To reduce swelling in patients with ascites, a low salt diet (<2 gm/day) is recommended
• Patients who are at risk of hyponatremia may require free water restriction
• Appropriate nutrition is important, since most of the patients present with malnourishment

Disposition

• Admission Criteria:
• Suspected cases of hepatorenal syndrome generally require hospitalization, hepatology and nephrology consultations
• Patients with concurrent hepatic encephalopathy, cardiopulmonary disease, or significant electrolyte abnormalities often require Intensive Care Unit admission
• Discharge Criteria:
• No specific discharge criteria

Monitoring

• Monitor hemodynamic status, urine output, hepatic and renal function, and serum electrolytes, especially potassium
• Serial renal function monitoring is required during and post therapy. If liver transplantation or hemodialysis is provided; usual monitoring for these interventions is required

Complications

• Death (extremely high 30-day mortality in type 1 HRS if liver transplant not available or appropriate)
• Dialysis dependency/end-stage renal disease in type 2 HRS
• Fluid overload with congestive heart failure (CHF) or pulmonary edema
• Hemorrhage
• Hepatic coma
• Hypotension (often severe with type 1 HRS if dialysis required)
• Metabolic acidosis
• Multiorgan failure
• Renal failure
• Secondary infections

Prevention

• Strategies which may reduce occurrence of hepatorenal syndrome include:
• Prophylaxis against bacterial infections: Bacterial infections are a significant reason for renal impairment in cirrhosis patients. Prophylactic antibiotic therapy is usually indicated in patients with a history of SBP and variceal bleeding
• Avoidance of nephrotoxic drugs: Administration of aminoglycosides in patients with cirrhosis and ascites increases susceptibility to acute tubular necrosis with renal failure occurring in ~33% of patients. Nonsteroidal anti-inflammatory (NSAID) use has also been associated with renal failure
• Regulation of diuretic use: Ascertain the lowest effective dose of diuretics, as renal impairment occurs in ~20% of patients
• Volume expansion: Plasma volume expansion using albumin is valuable for patients with SBP to help prevent circulatory and renal impairment, and death. Combining albumin therapy with antibiotic prophylaxis may reduce the incidence of HRS by 20%
• Pentoxifylline, a TNF inhibitor, has been shown effective in trials, when taken routinely by at risk patients (cirrhosis with ascites) to markedly decrease the rate HRS

Prognosis

• HRS has the worst prognosis of all cirrhotic complications. Type 1 HRS has an extremely poor prognosis, while type 2 HRS has a slightly better prognosis
• Untreated patients with type 1 HRS usually have a median survival time of less than 2 weeks with most patients dying within 8-10 weeks after onset of HRS
• Type 2 HRS patients have a longer median survival time of approximately 5-6 months
• Patients receiving liver transplantation demonstrate resolution of renal failure and have a survival rate of 70-80%

ICD-9-CM

• 572.4 Hepatorenal syndrome

ICD-10-CM

• K76.7 Hepatorenal syndrome

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