New clues to the pathophysiology of hepatorenal failure.

In patients with advanced liver disease, decreases in renal blood flow, glomerular filtration rate, and urinary output are frequently observed. The deterioration in renal function is usually not due to a unique cause but is the result of the concerted action of several mechanisms operating in parallel; decreased plasma protein formation and increased intrahepatic vascular resistance lead to sequestration of blood volume, favoring hypovolemia and reduction in cardiac output. At the same time enhanced formation of nitroxide leads to peripheral vasodilation; bacterial endotoxin escaping clearance by the diseased liver stimulates the expression of a long-acting nitroxide synthase. Furthermore, vasodilating intestinal mediators such as substance P escape inactivation by the liver. In the face of peripheral vasodilation the maintenance of blood pressure requires an increase in cardiac output, which is achieved by activation of sympathetic nervous tone, renal vasoconstriction, enhanced release of renin, angiotensin, aldosterone, and antidiuretic hormone, leading to renal retention of sodium and water. Renal vasoconstriction is opposed by vasodilatatory prostaglandins, and renal failure may be triggered by inhibition of prostaglandin formation. On the other hand, vasoconstrictive eicosanoids, such as thromboxane B2 and leukotriene E2, which escape hepatic inactivation, may contribute to renal vasoconstriction. Beyond these mechanisms disturbed hepatic regulation of renal function may participate in the generation of hepatorenal syndrome. The liver regulates renal function via both a hepatorenal reflex decreasing renal blood flow and a hypothetical liver-borne diuretic factor increasing renal blood flow. Both enhanced hepatorenal reflex activity and decreased formation of the liver-borne diuretic factor could participate in the pathogenesis of hepatorenal syndrome.