Hepatorenal syndrome refers to the development of renal failure in patients with severe liver disease. It is a life-threatening condition with poor prognosis.
The hepatorenal syndrome occurs in about 4% of patients admitted with decompensated cirrhosis. About 30% of people with spontaneous bacterial peritonitis are at risk of hepatorenal syndrome.
Most commonly, hepatorenal syndrome develops in patients with advanced cirrhosis often with complications like portal hypertension and ascites. Often, other features of the disease like jaundice, finger clubbing, palmar erythema, and spider nevi may be present.
Though Frerichs reported the presence of oliguria in patients with ascites in 1877, the term hepatorenal syndrome was first used in 1939.
Until recently, the hepatorenal syndrome was considered a rapid and fatal complication unless immediate liver transplant could be carried.
However, new pharmacological treatments can improve short-term outcomes and enhance the feasibility of performing liver transplantation.
Overall, the hepatorenal syndrome is associated with a poor prognosis.
The syndrome can be seen in most forms of severe liver disease, but the patients with primary biliary cholangitis appear relatively protected.
Frequency is equal in both sexes.
Most patients with chronic liver disease are in their fourth to eighth decades of life.
Pathophysiology of Hepatorenal Syndrome
The pathophysiology of hepatorenal syndrome is complex and not completely understood.
The hallmark of hepatorenal syndrome is renal vasoconstriction.
This is produced by the interplay of multiple processes such as
- Disturbances in systemic hemodynamics
- Activation of the vasoconstrictors
- A decrease in vasodilator activity
It is found in patients of the hepatorenal syndrome that there is increased cardiac output, low arterial pressure, and reduced systemic vascular resistance.
The extrarenal resistance is increased in patients with hepatorenal syndrome but the arterial vasodilatation in splanchnic circulation leads to decreased total systemic vascular resistance.
Renal vasoconstriction is caused by the renin-angiotensin-aldosterone system and the sympathetic nervous system which have increased activity in cirrhosis. This activity rises manifolds in hepatorenal syndrome.
There is an inverse relationship between the activity of these systems and renal plasma flow and the glomerular filtration rate.
Endothelin is a renal vasoconstrictor which is also found in increased concentration in hepatorenal syndrome, although its role is not yet known.
Adenosine is a vasodilator but acts as a vasoconstrictor in the lungs and kidneys. It might have a role in producing renal vasoconstriction by working in a synergistic way with angiotensin II [Increased levels of adenosine are found more in patients with the increased activity of the renin-angiotensin-aldosterone]
Leukotriene E4 is another powerful renal vasoconstrictor which could play a role.
Prostaglandins are local vasodilators of the kidney and antagonize the vasoconstriction. Because nonsteroidal anti-inflammatory drugs act by inhibiting prostaglandins, they can decrease renal perfusion flow.
There are two main theories that speculate the pathophysiology:
Arterial vasodilation theory
Arterial vasodilatation in the splanchnic circulation is triggered by portal hypertension; it appears to play a central role. This vasodilation leads to increased production or activity of vasodilators like nitric oxide, mainly in the splanchnic circulation. Nitric oxide is a vasodilator that is increased in people with cirrhosis and is probably the most important mediator.
This leads to the underfilling of the arteries because as the arteries dilate, it leads to a decrease in the effective arterial blood volume. This leads to reflex activation of the endogenous vasoconstrictor systems like the renin-angiotensin-aldosterone system and sympathetic nervous system.
This leads to constrictions of vessels in kidney, the brain, muscle, spleen, and extremities. But these effects are not seen in splanchnic circulation due to the production of local vasodilators such as nitric oxide.
The kidney is able to compensate in the early phases of portal hypertension and maintain renal perfusion near-normal limits by antagonizing the constriction with local vasodilator effect.
When this fails, there is an increase in the severity of the disease and uncontrolled renal vasoconstriction occurs.
It proposes that renal vasoconstriction is due to either a deficiency in the synthesis of a vasodilator or a hepatorenal reflex that leads to renal vasoconstriction.
Hepatorenal reflex is seen in experiments in dogs where a rise in intrahepatic pressure resulted in increased renal sympathoadrenal activity and a decrease in renal blood flow and GFR. Whether hepatorenal reflex is present in humans or not is debatable.
Causes, Risk Factors, and Precipitants
The hepatorenal syndrome may occur spontaneously or there could be underlying precipitating factors. These precipitants are
- Infections – spontaneous bacterial peritonitis
- Acute alcoholic hepatitis
- Large-volume paracentesis [fluid removal from peritoneum] without albumin replacement.
The following is a list of risk factors associated with the development of hepatorenal syndrome in patients with cirrhosis.
- Low excretion of sodium in urine(< 5 mEq/L)
- Moderately increased serum urea (>30 mg/dL)
- Moderately increased serum creatinine (>1.5 mg/dL)
- Moderately reduced GFR (< 50 mL/min)
- Dilutional hyponatremia or low sodium levels due to increased water content
- Reduced free-water excretion
- Low mean arterial pressure (<80)
- High plasma renin
- Increased plasma norepinephrine
- High serum potassium
- Low plasma osmolality
- High urine osmolality
- Absence of hepatomegaly
- Presence of esophageal varices
- Poor nutritional status
- Previous episodes of ascites
Types of Hepatorenal syndrome
The hepatorenal syndrome is characterized by the following in a patient of liver disease
- Increase in serum creatinine
- Normal urine sediment
- No or minimal proteins in urine (less than 500 mg per day)
- Decreased in urinary sodium excretion
- Oliguria- Decreased urine volume
However, the features are not characteristically found in all the patients.
For example, urine volumes may be high or the rise in serum creatinine may not be significant or progressive.
Or the urine sediment may show abnormalities like hematuria or granular deposits due to raised bilirubin levels.
Depending on the rapidity of the decline of kidney function, there are two types of hepatorenal syndrome described
- More serious
- A twofold increase in serum creatinine (means a 50 percent reduction in creatinine clearance) to a level greater than 2.5 mg/dL within two weeks
- Often a urine output of less than 400 to 500 mL per day
- GFR is usually below 20 mL/min
- Less severe
- Resistant to diuretics
Most of the cases have nonspecific symptoms like malaise, fatigue or distortion of taste sensation [dysgeusia].
The signs which could raise the suspicion are decreased urine output and decrease in renal function on lab studies
Other features of liver disease would be present
- Redness of palms [Palmar erythema]
- White nails [Leuconychia]
- Wasting of muscles
- Flapping tremors
- Clubbing of nails
- Spider nevi Spider-like vasodilation of vessels
- Fetor hepaticus- breath smells like a combination of rotten eggs and garlic
- Xanthelasma – sharply demarcated yellowish deposit of cholesterol underneath the skin especially around
- Gynecomastia [enlargement of breast in males]
Other signs of liver disease may be present. These include caput-medusae, ascites, paraumbilical hernia and bruits.
The diagnosis of hepatorenal syndrome is one of exclusion. It should be considered but entertained only after other potential causes of injury to kidney have been ruled out which include
- Different types of Acute or Chronic Glomerulonephritis
- Acute Tubular Necrosis
- Complete blood count with differential count
- Leucocytosis suggests the presence of infection
- Decreased hematocrit level and platelet count in tubular necrosis of kidney.
- Serum electrolytes and renal function
- Essential investigations as per criteria [see diagnostic criteria below]
- Liver function tests
- To assess the severity of the liver disease
- No bearing on kidney function
- Blood cultures
- For infection
- Cryoglobulins levels
- In hepatitis, B and/or C renal failure could be from cryoglobulinemia
- Reversible if treated early.
- Urine sodium [<5 mEq/liter is a known risk]
- Urine Creatinine
- Fractional excretion of sodium
- Calculated from sodium and creatinine values
- Helps to differentiate hepatorenal syndrome and prerenal azotemia [abnormal levels of nitrogen products] due to intrinsic renal disease
- Peritoneal fluid examination
- Fluid drained by diagnostic paracentesis
- Should be done in all cases
- Therapeutic paracentesis could cause volume depletion and aggravate kidney function though it is controversial
- If conducted albumin replacement should be done
- Abdominal ultrasonography
- To exclude hydronephrosis and intrinsic renal disease,
- With Doppler studies, renal vascular flow can be assessed
- To check heart function
The Diagnostic Criteria of Hepatorenal Syndrome
[All major criteria are required for diagnosis making]
- Chronic or acute liver disease with advanced hepatic failure and portal hypertension
- Low glomerular filtration rates
- Serum creatinine >133 μmol/L or
- 24h creatinine clearance <40 mL/min
- Absence of
- Bacterial infection
- Nephrotoxic drug treatment
- Absence of gastrointestinal or renal fluid losses
- No sustained improvement in renal function following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline
- Proteinuria <0.5 g/d and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease
[Not required for diagnosis but provide additional evidence]
- Urine volume <0.5 L/d
- Urine sodium <10 mmol/L
- Urine osmolality > plasma osmolality
- Urine red blood cells <50 high power field
- Serum sodium concentration <130 mmol/L
The best hope for reversal is an improvement in hepatic function due to complete or partial resolution of the primary disease or to successful liver transplantation.
The ideal treatment of hepatorenal is liver transplantation but because of the long waiting lists in the majority of transplant centers, most patients die before transplantation.
A precipitant should be looked for especially in type 1 syndrome. A high index of suspicion should be maintained. Most often it is bacterial peritonitis.
Patients should be evaluated for liver transplantation especially type 2 hepatorenal syndrome who have a longer survival time.
Patients with type 1 syndrome, with shorter survival time may require alternative treatment methods as a bridge to transplantation.
If patients are not candidates for liver transplantation, they have a poor prognosis and only palliative care can be given.
The treatment of hepatorenal syndrome aims at the improvement of liver function from recovery and reversal of the acute kidney injury.
In addition, drug treatment has an immediate goal to raise the mean arterial pressure.
Arterial underfilling due to extreme splanchnic vasodilatation is a hallmark of hepatorenal syndrome. Therefore vasoconstrictors have been studied and found effective. Consequently, potent vasoconstrictors capable of reversing this vasodilatation have been investigated in hepatorenal syndrome.
Norepinephrine, vasopressin and its analogs such as terlipressin and ornipressin are the vasoconstrictor drugs used.
Midodrine [a selective alpha-1 adrenergic agonist] and octreotide [a somatostatin analog, inhibits the release of endogenous vasodilator] are used when the drugs mentioned above are not available.
Patients who do not respond to one of the medical therapies listed need either transjugular intrahepatic portosystemic shunt and dialysis.
Transjugular intrahepatic portosystemic shunt
The transjugular intrahepatic portosystemic shunt is used when the patient does not respond to the drugs.
However, many of the patients of the hepatorenal syndrome are too ill to undergo this surgery. Moreover, this shunt could cause complications like hepatic encephalopathy. worsening of liver function and renal injury.
In selected patients, this shunting may provide short-term benefits.
The procedure involves a side-to-side portacaval shunt that connects the portal and hepatic veins within the hepatic parenchyma. It results in the reduction of portal pressure and returns some of the volumes of blood pooled in the splanchnic circulation.
Dialysis is most commonly done when patients are awaiting a liver transplant or when there is a scope of improvement in liver function.
Survival on dialysis is generally limited by the severity of the hepatic failure.
Haemodialysis may act as a bridge to transplantation when there is no response to drugs or TIPS procedure
A number of other drugs have been tried but are not effective. These are
- Angiotensin-converting enzyme inhibitors
It is a surgical procedure where the peritoneal fluid is shunted to the venous system. This may be considered for patients with type 2 hepatorenal syndrome who often develop refractory ascites and are not candidates for liver transplantation, and do not tolerate frequent paracentesis.
Liver transplantation is the ideal treatment but it is limited by the availability of donors.
Survival rates at 3 years are almost 60%.
Many type 1 hepatorenal syndrome patients die before the liver becomes available.
Infection in the form of spontaneous bacterial peritonitis is the main precipitant. This may be prevented by antibiotic prophylaxis with Bactrim or fluoroquinolones in patients of type 2 syndrome.
The risk of hepatorenal syndrome in cirrhosis increases over time from 10% at one year to 40% at 5 years.
Prophylactic liver transplantation could be an option but again, limited availability of donors is an issue.
Administration of albumin in bacterial peritonitis may prevent circulatory dysfunction and subsequent development of the syndrome.
The mortality of patients with liver failure worsens when the hepatorenal syndrome develops as most of the patients die within weeks.
Type 1 hepatorenal syndrome has a median survival of 2 weeks. Few patients survive more than 10 weeks. Type 2 hepatorenal syndrome has a median survival of 3-6 months.
The reversal of renal function is strongly dependent upon reversal of the liver failure whether spontaneously or with therapy or transplantation.
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