The renal failure in hepatorenal syndrome is believed to arise from abnormalities in blood vessel tone in the kidneys.The predominant theory (termed the underfill theory) is that blood vessels in the renal circulation are constricted because of the dilation of blood vessels in the splanchnic circulation (which supplies the intestines), which is mediated by factors released by liver disease. 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 renal circulation and worsening renal vasoconstriction, leading to renal 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 renal fractions of cardiac output are respectively increased and reduced, suggesting that splanchnic vasodilation is implicated in the renal 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 renal function), in patients with hepatorenal syndrome, providing further evidence that splanchnic vasodilation is a key feature of its pathogenesis.
The underfill theory involves activation of the renin-angiotensin-aldosterone system, which leads to an increase in absorption of sodium from the renal tubule (termed renal sodium avidity) mediated by aldosterone, which acts on mineralocorticoid receptors in the distal convoluted tubule. This is believed to be a key step in the pathogenesis of ascites in cirrhotics as well. It has been hypothesized that the progression from ascites to hepatorenal syndrome is a spectrum where splanchnic vasodilation defines both resistance to diuretic medications in ascites (which is commonly seen in type 2 HRS) and the onset of renal vasoconstriction (as described above) leading to hepatorenal syndrome.