Background
Hepatorenal syndrome (HRS) is a functional, reversible form of acute kidney injury in patients with acute or chronic severe liver disease in the absence of any other identifiable causes of renal pathology. [1] The condition is characterized by peripheral vasodilation with subsequent profound intrarenal vasoconstriction, resulting in decreased glomerular filtration. Renal vasoconstriction starts early in patients with liver disease, even before renal dysfunction is clinically evident. [2] In addition to arterial vasodilatation, progressive deterioration in cardiac function is also partly responsible for the development of HRS. [3]
Two types of HRS are described. Type 1 HRS is mainly associated with acute liver failure or alcoholic cirrhosis [4] but can also develop as a result of other forms of liver failure. It is characterized by rapid deterioration of renal function that usually occurs within 2 weeks, with an increase in serum creatinine and BUN levels and a substantial decrease in the glomerular filtration rate (GFR). Hyponatremia and other electrolyte abnormalities are common findings.
Type 2 HRS has a more insidious onset and is characterized by a steady and progressive decline in the renal function over weeks and sometimes months, as well as recurrent, diuretic-resistant ascites. It generally occurs more often in patients with hepatic dysfunction less severe than that observed in type 1. Both type 1 and type 2 HRS are associated with a poor prognosis.
Pathophysiology
The exact pathophysiologic mechanisms leading to hepatorenal syndrome (HRS) are not known; decreased renal blood flow caused by severe renal arterial and arteriolar vasoconstriction plays a major role. HRS compromises the most advanced stage of hemodynamic dysfunction that starts early in the course of severe liver disease even before ascites is clinically detectable. [3] A paradoxical interplay between local and systemic factors, which lead to both vasoconstriction and vasodilatation, appear to perpetuate severe systemic arterial hypoperfusion.
Although not directly responsible for the development of HRS, lowered mean arterial pressure is frequently observed in patients with severe liver disease; this decrease is most likely secondary to release of local hepatic vasodilatory substances. Thus, a culmination of several factors leads to the development of HRS. These include inter alia: (1) portal hypertension, (2) altered peripheral blood circulation, (3) activation of the sympathetic nervous system, and (4) the release of chemical mediators.
This release is also accompanied by enhanced dilation of the splanchnic vascular beds due to portal hypertension, resulting in the opening of portosystemic shunts and minor arteriovenous (AV) fistulae. Renal venous pressure may also be increased because of compression of the inferior vena cava by ascites.
Dilation of the splanchnic vascular bed from locally produced nitric oxide, carbon monoxide, prostacyclin, and other vasodilatory substances decreases renal perfusion pressure (mean arterial pressure - renal vein pressure) and thus decreases renal blood flow. Renal perfusion is initially maintained because of the local production of vasodilatory factors, such as prostaglandin E, prostacyclin, and nitric oxide. However, as liver disease continues to advance, splanchnic blood flow increases, and systemic perfusion reduces further.
To maintain renal homeostasis and perfusion, several vasoconstrictor systems and substances are simultaneously activated. These include the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system (SNS), and vasopressin, which lead to intense renal arterial and arteriolar vasoconstriction. As activation substantially increases, arterial and renal underfilling ensues and progresses, and HRS develops. The final result is a severely decreased GFR and renal failure in the setting of no structural or intrinsic parenchymal renal disease.
Another theory attributes renal hypoperfusion directly to the diseased liver without any pathogenetic relationship to the hemodynamic changes. Two mechanisms support this theory: (1) decreased synthesis or release of a liver-borne factor that produces renal vasodilation and (2) the presence of a hepatorenal reflex that regulates the renal function, as demonstrated in experimental animals.
The hemodynamic changes that develop in cirrhosis in the splanchnic circulation are a phenomenon that happen over time as a direct consequence of longstanding portal hypertension and are characterized by the following:
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Splanchnic vasodilatation
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Reduced effective arterial blood volume
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Hyperdynamic circulation with increased cardiac output
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Reduced systemic vascular resistance
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Vasoconstriction of various extrasplanchnic vascular beds, including the renal and cerebral circulations
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Increased activity of the renal angiotensin-aldosterone and sympathetic nervous systems and nonosmotic release of vasopressin (antidiuretic hormone)
These hemodynamic changes include tachycardia, increased cardia output, and abnormally low peripheral vascular resistance with decreased arterial blood pressure.
Cardiac dysfunction in cirrhosis is an important event. If circulatory dysfunction in cirrhosis was solely due to the progression of splanchnic arterial vasodilation and the hyperdynamic circulation, a compensatory mechanism of this disorder, cardiac output should increase as part of the homeostatic mechanism of effective arterial filling. Cardiac output is similar in patients with compensated cirrhosis, nonazotemic patients with cirrhosis and ascites, and patients with type 2 HRS despite the progressive increase in plasma levels of renin and norepinephrine during the course of cirrhosis, leading to increasing arterial vasodilation.
However, the heart rate may not increase despite the progressive stimulation of the sympathetic nervous system. This suggests that circulatory dysfunction in cirrhosis is related not only to progressive arterial vasodilation but also to an inability of the heart to increase cardiac output in response to a decrease in cardiac preload. The demonstration that type 1 HRS occurs in the setting of a significant decrease in cardiac output in nonazotemic patients with cirrhosis and spontaneous bacterial peritonitis further supports the view that cardiac dysfunction is an important event in the pathogenesis of the impairment in circulatory and renal function in decompensated cirrhosis.
Epidemiology
The prevalence of hepatorenal syndrome (HRS) has dramatically decreased in recent years, probably as a result of the improved management of cirrhotic patients and the wide use of prophylactic antibiotics for prevention of severe bacterial peritonitis. [5]
The annual incidence of HRS among adults with ascites and cirrhosis is approximately 8%. In addition, among adults with cirrhosis and portal hypertension, 20% develop HRS in the first year after diagnosis, and as many as 40% of patients develop HRS within 5 years after diagnosis. Recent data indicate a cumulative probability of developing HRS of 11.4% at 5 years. [6] These data included only patients with an initial episode of ascites with less advanced disease with the prevalence of HRS increasing with progression of liver disease. The incidence is much higher in patients with advanced liver disease awaiting liver transplantation, with a prevalence reaching as high as 48%. [7] Incidence data in children are scarce in the literature; therefore, the incidence of HRS in children is essentially unknown at this time.
Race-, sex-, and age demographics
No data suggest that any particular race group is at risk. Thus, people of all races with chronic liver disease are likely to be at risk for hepatorenal syndrome.
To date, no data support any predilection for either sex.
In most reports in adults, patients are in their fourth to eighth decades of life.
Prognosis
For adults with type 1 hepatorenal syndrome (HRS), median survival is 2 weeks, and the hospital survival rate is 10%.
For patients with type 2 HRS, median survival is 6 months.
For patients undergoing a transjugular intrahepatic portosystemic shunt (TIPS) procedure, median survival is 2-4 months after the procedure.
End-stage renal disease requiring dialysis develops in 1-7% of patients with HRS who undergo liver transplantation.
The long-term survival rate for patients with HRS is 60% at 3 years after transplantation. This is only slightly less than the survival rate for patients with liver failure and no HRS, which is 70-80% after 3 years.
Morbidity/mortality
The median survival of adults with type 1 HRS is estimated to be 2 weeks, and the hospital survival of the same patients is about 10% after 3 months. In contrast, the median survival of individuals with type 2 HRS is about 6 months. Recent data show improved survival in type 1 of (20%) and type 2 of (40%). [8] However, HRS carries the worst survival among all causes of acute kidney injury in cirrhotic patients with acute kidney injury. [9] Currently, mortality and morbidity rates in pediatric patients with HRS are unknown.
Survival and the recovery of renal function depend on the recovery of hepatic function, which is usually accomplished with liver transplantation in a minority of patients.
About 1-7% of patients with HRS develop end-stage renal disease and require dialysis despite liver transplantation and recovery of hepatic function.
Patient Education
Refer the patient and his or her family for psychosocial counseling. Patients should avoid taking nephrotoxic or hepatotoxic agents.
For patient education resources, see the Digestive Disorders Center and Infections Center, as well as Cirrhosis.
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Basic transjugular intrahepatic portosystemic shunt (TIPS) procedure. A curved catheter is placed into the right hepatic vein.
