Hepatorenal syndrome

Diagnosis and management

 Definition

• HRS is defined as the development of renal failure in patients

with advanced liver failure (acute or chronic) in the absence of
any identifiable causes of renal pathology.
• Type 1 HRS is characterized by a rapid decline in renal
function, defined as a doubling of serum creatinine to a level >
2.5 mg/dL or a halving of the creatinine clearance to < 20
mL/min within 2 weeks. The clinical presentation is that of
acute renal failure.
• In type 2 HRS, renal function deteriorates more slowly, with
serum creatinine increasing to > 1.5 mg/dL or a creatinine
clearance of < 40 mL/min. The clinical presentation is that of
stable renal failure in a patient with refractory ascites.
Epidemiology

• In a large prospective study of cirrhotic patients with

ascites, 18% developed type 1 HRS at 1 year and
39% at 5 years.
• Until the recent development of effective therapies,
the median survival following the development of
type 1 HRS was 1.7 weeks, with only 10% of patients
surviving more than 10 weeks. Survival rate in type 2
HRS is 50% at 5 months and 20% at 1 year .
 Diagnosis of HRS
• The presence of renal dysfunction is often missed in patients
with cirrhosis. Because of a reduction in muscle mass in these
patients, serum creatinine may be within the normal range,
even with a very low GFR.
• The use of blood urea nitrogen (BUN) concentration as a
measure of renal function is even less reliable, because BUN
levels can be affected by the presence of gastrointestinal
bleeding or by the amount of protein in the diet.
• HRS should only be diagnosed in patients with decreased
renal function in the presence of advanced cirrhosis, chronic
liver disease with severe liver failure and portal hypertension,
or acute liver failure. Other forms of organic renal disease
must be ruled out.
Diagnosis of HRS
• Some patients with primary liver diseases are at
higher risk for developing certain forms of kidney
diseasesTable 2 .
• while some systemic processes can affect both the
liver and the kidney Table 3 .
• The International Ascites Club requires major criteria
to be fulfilled for the diagnosis of HRS Table 1 .
Despite the existence of these criteria, arriving at an
accurate diagnosis can be challenging.
Table 2. Renal Disease Associated
With Major Types of Liver Disease
Membranous glomerulonephritis (GN), essential mixed cryoglobulinemia. Hepatitis B

Membranoproliferative GN, membranous GN, cryoglobulinemia, fibrillary GN, IgA Hepatitis C

nephropathy, tubulointerstitial nephritis

IgA nephropathy Alcoholic liver disease

Prerenal azotemia/acute tubular necrosis from hypovolemia, decreased cardiac output, Obstructive jaundice
sepsis; acute tubular necrosis from toxic bile acids

Membranous GN, antineutrophil cytoplasmic autoantibody-positive vasculitis, Primary biliary

antiglomerular basement membrane disease, renal tubular acidosis, tubulointerstitial cirrhosis
nephritis
Membranous GN, membranoproliferative GN, antineutrophil cytoplasmic Primary sclerosing
autoantibody-positive vasculitis, tubulointerstitial nephritis cholangitis

Renal tubular acidosis (Type 1) secondary to copper deposition Wilson's disease

Membranoproliferative GN, antiglomerular basement membrane disease Alpha-1 antitrypsin

deficiency
Systemic Diseases Involving Both
Liver and Kidney(Table3)
• Drug toxicity -- acetaminophen, acetylsalicylic acid, carbon tetrachloride,
etc.
• Granulomatous diseases (sarcoidosis, drug-induced)
• Infectious -- malaria, leptospirosis
• Infiltrative – amyloidosis
• Inflammatory -- lupus, Sjogren's syndrome
• Nonalcoholic fatty liver disease and diabetic nephropathy
• Preeclampsia/HELLP (hemolysis, elevated liver enzymes, low platelets)
syndrome
• Polycystic kidney/liver disease (autosomal dominant/autosomal recessive
forms)
• Sickle cell disease
• Shock states (congestive heart failure, sepsis, hypovolemia
Hepatorenal Syndrome: Diagnostic
Criteria Table 1
• Major criteria (all must be present)
– Chronic or acute liver disease with advanced hepatic failure and portal
hypertension
– Low GFR as indicated by a 24-hr creatinine clearance of < 40 mL/min
or serum creatinine > 1.5 mg/dL
– Absence of shock, sepsis, volume depletion, exposure to nephrotoxins.
– No sustained improvement in renal function (to creatinine > 1.5 mg/dL
or 24-hr CrCl to > 40 mL/min) following diuretic withdrawal and
plasma volume expansion with 1.5 L of normal saline
– Proteinuria < 500 mg/dL.
– No ultrasonographic findings of obstructive uropathy or parenchymal
renal disease.
Hepatorenal Syndrome: Diagnostic
Criteria
• Additional criteria (not necessary but would
support diagnosis)
– Urine volume < 500 mL/day .
– Urine sodium < 10 mEq/L .
– Urine osmolality greater than plasma osmolality.
– Urine red blood cells < 50 per high-power field.
– Serum sodium < 130 mEq/L.
Diagnosis of HRS
• The diagnostic approach to renal failure in a patient
with cirrhosis is outlined in Table 4 and 5 Table
• Preliminary reports from an ongoing prospective
study of renal failure in patients with cirrhosis
revealed a frequency of 32% infection-induced renal
failure, 24% parenchymal renal disease, 22% prerenal
failure, 11% ATN, 8% HRS, and 3% nephrotoxic
renal failure.
 Work-up for Patients With Suspected HRS Table 4
• History
– Fluid losses -- vomiting, diarrhea, diuretic use .
– Gastrointestinal bleeding
– Infection -- fever, cough, dysuria, abdominal discomfort
– Exposure to nephrotoxins -- drugs (aminoglycosides, NSAIDs), radiocontrast agents

•
Physical exam
– Heart rate, blood pressure (including orthostatic), temperature
– Signs of infection (pulmonary, abdominal, cellulitis, etc.)
– Other causes of renal failure -- purpuric rash may suggest cryoglobulinemia
• Investigations
–
Complete blood count, electrolytes, creatinine level
– Urine sodium, osmolality
– Urinalysis for protein, cells, and casts
– Renal ultrasound
 Table 5. Differentiating HRS From Other Forms of Renal Failure in Liver Disease

Primary renal Hepatorenal Acute tubular Prerenal failure

disorder syndrome necrosis

> 30 mmol/L < 10 mmol/L > 20 mmol/L < 10 mmol/L Urine sodium

< 20 > 30 < 15 > 20 Urine creatinine/

plasma creatinine

> 500 mg/day < 500 mg/day < 500 mg/day -- Proteinuria

RBC/WBC casts None Heme-granular Bland Urine sediment

casts

Dependent on type Advanced liver Decreased effective Decreased effective Precipitants

of renal disease disease, refractory circulating volume, circulating volume
ascites, nephrotoxic agents,
gastrointestinal sepsis
bleed, SBP
Must maintain No effect No immediate Immediate Effect of volume
euvolemia effect, but must improvement in expansion
maintain euvolemia renal function
 Management of HRS -- Prevention
• Prophylaxis Against Bacterial Infections
– Prophylaxis with antibiotics is recommended in patients presenting with
gastrointestinal bleeding or those with a history of SBP
• Volume Expansion
– Postparacentesis circulatory dysfunction is not always spontaneously
reversible, it then follows that albumin should be able to prevent the
development of HRS after large-volume paracentesis. Albumin seems to be the
best plasma expander to prevent this complication.
• Judicious Use of Diuretics
– Diuretic-induced renal impairment occurs in 20% of patients with ascites
– The renal failure is nearly always reversible with cessation of the diuretics
• Avoidance of Nephrotoxic Agents
– Patients with cirrhosis and ascites are predisposed to ATN with use of
aminoglycosides
– NSAIDs should also be avoided
– Angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists
result in arterial hypotension and cause prerenal failure in cirrhotic patients
 Management of HRS -- Treatment
• Initial Management
– A diligent search should be made for precipitating factors (infection,
gastrointestinal bleeding) and treated accordingly. Likewise,
nephrotoxic drugs should be removed.
– Patients should be initially challenged with fluid to assess response and
to treat subclinical hypovolemia.
– Cirrhotic patients with an acute gastrointestinal bleed and poor liver
function and/or decreased renal function should be managed in
intensive care units to protect effective circulating blood volume and
renal perfusion
– In patients with cirrhosis and SBP, treatment with intravenous albumin
in addition to an antibiotic has been shown in one study to reduce the
incidence of renal impairment and death compared with treatment with
an antibiotic alone.
Management of HRS -- Treatment

• Pharmacologic Therapy
– The aim of pharmacologic therapy is to increase renal
blood flow. This can be accomplished either by improving
the renal perfusion pressure or by inducing renal
vasodilatation.
– Splanchnic vasoconstriction redistributes some of the
intravascular volume to the systemic circulation and
improves circulatory function and effective arterial volume,
thereby improving renal perfusion and GFR. Such agents
can be used as a bridge to liver recovery or liver
transplantation
Management of HRS -- Treatment
• Dopamine.
• Noradrenaline
• Midodrine and octreotide
• Terlipressin
– This agent is a synthetic analogue of vasopressin, with intrinsic
vasoconstrictor activity It is also a nonselective V1 vasopressin agonist
– This agent has been shown to improve systemic hemodynamics and to
improve renal function in patients with type 1 HRS
– In addition to improving renal function, this agent has been associated
with improved survival.
– One suggested protocol consists of 0.5 mg every 4 hours with a
titration upward by 0.5 mg every 3 days up to 2 mg every 4 hours.
• Endothelin antagonists
Management of HRS -- Treatment
• Renal Support
– Dialysis
• should only be offered in select cases if there is a real chance of
liver transplantation in the short term.
• Dialysis in these patients is fraught with difficulties because of
coagulopathy and hemodynamic instability, as well as risk of
sepsis.
• The effectiveness of dialysis in the treatment of HRS has not been
proven.
– Molecular adsorbent recirculating system
• It is believed that this system removes some of the vasoactive
substances that mediate the hemodynamic changes that lead to
HRS, thereby improving systemic hemodynamics and, hence, renal
perfusion.
Management of HRS -- Treatment
• Transjugular Intrahepatic Portosystemic Shunt
– Initial reports have suggested that TIPS may improve renal function in HRS
and may reduce the risk of progression from type 2 to type 1 HRS.
– The main limitation to using TIPS in HRS includes worsening encephalopathy
and liver failure from reduced liver venous perfusion, thereby causing relative
liver ischemia. However, in those patients whose main problem is one of
hemodynamic instability and renal failure rather than severe liver dysfunction,
TIPS may be a viable option, at least as a bridge to liver transplantation.

• Liver Transplantation
– The only effective and permanent treatment for end-stage cirrhosis and HRS is
liver transplantation
– patients who are transplanted with HRS have a lower probability of both graft
and patient survival after liver transplantation compared with patients without
HRS