Nitric oxide, prostaglandins, and other vasoactive substances have been hypothesized as powerful mediators of splanchnic vasodilation in cirrhosis. The consequence of this phenomenon is a decrease in the "effective" volume of blood sensed by the juxtaglomerular apparatus, leading to the secretion of renin and the activation of the renin–angiotensin system, which results in the vasoconstriction of vessels systemically and in the kidney specifically. However, the effect of this is insufficient to counteract the mediators of vasodilation in the splanchnic circulation, leading to persistent "underfilling" of the kidney circulation and worsening kidney vasoconstriction, leading to kidney failure.Studies to quantify this theory have shown that there is an overall decreased systemic vascular resistance in hepatorenal syndrome, but that the measured femoral and kidney fractions of cardiac output are respectively increased and reduced, suggesting that splanchnic vasodilation is implicated in the kidney failure. Many vasoactive chemicals have been hypothesized as being involved in mediating the systemic hemodynamic changes, including atrial natriuretic factor, prostacyclin, thromboxane A2, and endotoxin. In addition to this, it has been observed that the administration of medications to counteract splanchnic vasodilation (such as ornipressin, terlipressin, and octreotide) leads to improvement in glomerular filtration rate (which is a quantitative measure of kidney function) in patients with hepatorenal syndrome, providing further evidence that splanchnic vasodilation is a key feature of its pathogenesis.
Three independent risk factors for the development of HRS in cirrhotics have been identified: liver size, plasma renin activity, and serum sodium concentration.The prognosis of these patients is grim with untreated patients having an extremely short survival. The severity of liver disease (as evidenced by the MELD score) has been shown to be a determinant of outcome. Some patients without cirrhosis develop HRS, with an incidence of about 20% seen in one study of ill patients with alcoholic hepatitis. History
The first reports of kidney failure occurring in individuals with chronic liver diseases were from the late 19th century by Frerichs and Flint. However, the hepatorenal syndrome was first defined as acute kidney failure that occurred in the setting of biliary surgery. The syndrome was soon re-associated with advanced liver disease, and, in the 1950s, was clinically defined by Sherlock, Hecker, Papper, and Vessin as being associated with systemic hemodynamic abnormalities and high mortality. Hecker and Sherlock specifically identified that individuals with HRS had low urinary output, very low sodium in the urine, and no protein in the urine. Murray Epstein was the first to characterize splanchnic vasodilation and kidney vasoconstriction as the key alterations in hemodynamics in patients with the syndrome. The functional nature of the kidney impairment in HRS was crystallized by studies demonstrating that kidneys transplanted from patients with hepatorenal syndrome returned to function in the new host, leading to the hypothesis that hepatorenal syndrome was a systemic condition and not a kidney disease.