HEPATORENAL SYNDROME

OVERVIEW

• The hepatorenal syndrome is one of many potential causes of acute kidney injury in patients with acute or chronic liver disease. Affected patients usually have portal hypertension due to cirrhosis,
severe alcoholic hepatitis, or (less often) metastatic tumors, but can also have fulminant hepatic failure from any cause.
• Arterial vasodilatation in the splanchnic circulation, which is triggered by portal hypertension, appears to play a central role in the hemodynamic changes and the decline in kidney function in the
hepatorenal syndrome. The presumed mechanism is increased production or activity of vasodilators, mainly in the splanchnic circulation, with nitric oxide thought to be most important. As the hepatic
disease becomes more severe, there is a progressive rise in cardiac output and fall in systemic vascular resistance; the latter change occurs despite local increases in renal and femoral vascular
resistance that result in part from hypotension-induced activation of the renin-angiotensin and sympathetic nervous systems.
• Renal vasoconstriction — The activation of vasoconstrictor systems tends to reduce renal blood flow [60]. Renal perfusion may initially be maintained due to vasodilators such as prostaglandins and
perhaps nitric oxide (algorithm 2). However, the natural progression of liver disease overcomes these protective mechanisms, leading to progressive renal hypoperfusion, a gradual decline in the
glomerular filtration rate, and, in some patients, the hepatorenal syndrome
  Patients with cirrhosis and ascites usually have a marked reduction in systemic vascular resistance (SVR) and in mean arterial pressure (MAP) plus an increase in cardiac output [12-14]. These
abnormalities result in a hyperdynamic circulation which can be found in patients and experimental animals with cirrhosis before the development of ascites [15-17].
 The vascular territory where the reduced SVR is most obvious is the arterial splanchnic circulation [6]. The presence of this abnormality in other vascular territories is less obvious and the subject of
controversy [16,18].

• The reduction in glomerular filtration rate in patients with liver disease is often masked clinically. Both urea and creatinine production may be substantially reduced in this setting, due to the liver
disease and to decreased muscle mass
• Patients who develop the hepatorenal syndrome usually have portal hypertension due to cirrhosis, severe alcoholic hepatitis, and, less often, metastatic tumors. However, patients with fulminant
hepatic failure from any cause may develop hepatorenal syndrome. In patients with cirrhosis and ascites, the hepatorenal syndrome occurs in approximately 20 and 40 percent at one and five years,
respectively. In patients with acute liver disease, the hepatorenal syndrome occurs in approximately 25 to 30 percent.
DIAGNOSIS OF HEPATORENAL SYNDROME
 Chronic or acute liver disease with advanced hepatic failure and portal hypertension
 Acute kidney injury
 Absence of any other cause for the AKI
 Urine red cell excretion of less than 50/HPF
 No or minimal proteinuria (less than 500 mg per day)
 A very low rate of sodium excretion (ie, urine sodium concentration less than 10 mEq/L)
 Lack of improvement in kidney function after volume expansion with intravenous albumin for at least 2 days and
withdrawal of diuretics
 Acute precipitant causes include bacterial peritonitis
TYPES OF HEPATORENAL SYNDROME

 Based upon the rapidity of the decline in kidney function, two forms of hepatorenal syndrome have been described
 Type 1 hepatorenal syndrome – twofold increase in serum creatinine (reflecting a 50 percent reduction in
creatinine clearance) to a level greater than 2.5 mg/dL (221 micromol/L) during a period of less than two weeks
 Type 2 hepatorenal syndrome –The major clinical feature in patients with type 2 hepatorenal syndrome is ascites
that is resistant to diuretics.
DIFFERENTIAL DIAGNOSIS

 Prerenal AKI- bleeding, diuretics, GI losses

 Parenchymal kidney disease
 ATN- radiocontrast, episode of sepsis with hypotension, Fe Na >2%, granular/ epithelial casts, brown casts
APPROACH TO MANAGEMENT

 The ideal therapy for hepatorenal syndrome is improvement of liver function

 Immediate goal of therapy is to raise the MAP to 10 to 15 mm Hg >82 mm Hg
 However, when improvement of liver function is not possible in the short term, medical therapy should be
instituted in an attempt to reverse the acute kidney injury associated with hepatorenal syndrome. Our suggestions
regarding the choice of medical therapy depend upon several factors, including: whether the patient is admitted to
the intensive care unit; the availability of certain drugs
APPROACH TO MANAGEMENT

 Patients admitted to ICU, norepinephrine + albumin (Grade 2B). Norepinephrine (IV, continuous infusion 0.5 to
3 mg/hr), raising the MAP by 10 mmHg + albumin (IV bolus 1g/kg per day [100 g maximum]).
 Patients not in the ICU
 Other countries: Terlipressin + albumin- (Grade 2C). Terlipressin given as IV bolus of 1-2 mg q4-6 hours, albumin as an
intravenous bolus of 1g /kg/day maximum 100 g per day for 2 days, 25-50 g/day until terlipressin therapy is discontinued
 US: Midodrine + octreotide + albumin (Grade 2C). - Midodrine given orally, (starting at 7.5 mg, up to 15 mg TID),
octreotide as continuous infusion (at 50 mcg/hr), or subcutaneously (100 to 200 mcg TID)
 Patients not responsive to therapy
 Dialysis (for those whose creatinine levels are at 1.5 mg despite medical therapy)
 TIPS
APPROACH TO MANAGEMENT

Class Drug Action Comment

Albumin Intravascular volume Complimentary component
expansion of most vasoconstrictor
therapies
Vasopressin analogs Vasopressin, ornipressin Vasopressin receptor agonist Some improvement in HRS:
serious side effects
Terlipressin V1 receptor agonist Most well-validated
vasopressin analog:
unavailable in United States
Alpha-adrenergic agonists Noradrenaline Adrenergic agonist Benefits comparable to
terlipressin: greater
availability
Midodrine Selective alpha-1 adrenergic Frequently paired with
agonist octreotide: less effective
than noradrenaline or
terlipressin
Somatostatin analog Octreotide Inhibits splanchnic blood Improves renal blood flow:
flow decreases GFR
Dopamine agonist Dopamine Improves renal blood flow:
no improvement in renal
function
STUDIES
 STUDIES

• Inclusion- adult with ascites, cirrhosis, HRS Type I, failure to improve kidney function, discontinued midodrine/ octreotide
• Exclusion criteria: serum creatinine >7, at least 1 event of large volume paracentesis, sepsis, shock, acute liver injury, any other cause of kidney
CRITERIA injury

• Terlipressin at 1 mg q6h
• Placebo at 1 mg q6h
GROUPS

• Primary endpoints- reversal of HRS

• Secondary endpoints- percentage of participants with HRS reversal within 14 days, HRS reversal without RRT by day 30, HRS reversal in patients
with SIRS, verified HRS reversal without recurrence by Day 30
ENDPOINTS Terlipressin had more side effects such as abdominal pain, nausea, vomiting, respiratory failure in 11% of the patients
•
STUDIES
PREVENTION OF HEPATORENAL SYNDROME

 •In patients with spontaneous bacterial peritonitis, we recommend the administration of intravenous albumin (1.5
g/kg) at the time of diagnosis of infection and another dose of albumin (1 g/kg) on day 3 of antibiotic treatment
 In selected patients with cirrhosis and ascites, we recommend chronic norfloxacin therapy (400 mg/day) (
Grade 1B).
 Without therapy, most patients with hepatorenal syndrome die within weeks of the onset of the kidney function
impairment