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Lautt WW. Hepatic Circulation: Physiology and Pathophysiology. San Rafael (CA): Morgan & Claypool Life Sciences; 2009.

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Hepatic Circulation: Physiology and Pathophysiology.

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Chapter 13Hepatorenal Syndrome

Patients who die of liver disease die in renal failure. Renal dysfunction is demonstrable at the early stages of liver disease. As liver injury progresses, functional renal failure develops, resulting in sodium and water retention, and decreased renal blood flow and glomerular filtration rate, in the absence of significant morphological changes in the kidney. Various mechanisms have been suggested for the pathogenesis of renal insufficiency secondary to acute and chronic liver injury including peripheral arterial vasodilation secondary to overproduction of vasodilator substances in the splanchnic circulation, leading to splanchnic pooling and decreased effective systemic arterial plasma volume [76,93,94,95]; overproduction of endothelin due to endotoxemia leading to renal vasoconstriction [76,93,94,95]; and activation of a hepatorenal baroreflex that stimulates renal sympathetic nerves, leading to sodium retention [69,94,153,171,182]. We have recently suggested that a hepatic blood flow-dependent hepatorenal reflex is the primary pathophysiological mechanism for renal dysfunction in liver disease. This reflex is activated by adenosine, in the space of Mall, which is regulated by hepatic blood flow [269,270,274,275].

It has long been recognized that in hepatic cirrhosis, the disturbance in hepatic portal circulation relates to the pathogenesis of sodium and water retention through the activation of a hepatorenal reflex [190]. Liver cirrhosis is characterized by increases in renal sympathetic nerve activity [69]. Selective bilateral renal denervation, produced by lumbar sympathetic anesthetic block, promotes renal water and sodium excretion in these patients [346]. Animal models of cirrhosis show an increase in renal efferent sympathetic nerve activity that contributes significantly to the pathophysiological renal retention of sodium and water resulting from activation of a hepatic afferent limb [1,168,322]. Although the efferent limb of the renal disturbance is reasonably defined, the afferent limb has, until recently, remained unclear.

A consensus appears to have arisen that the intrahepatic vascular resistance that occurs in chronic liver disease results in portal hypertension with the elevated portal pressure serving as the afferent limb of the hepatorenal reflex. However, such a reflex implies a positive feedback situation, whereby an increase in portal blood flow would cause an increase in portal pressure and activation of the hepatorenal reflex. This would result in salt and water retention and an expanded blood volume, leading to increased cardiac output and increased portal flow, with a further increase in portal pressure. Such a positive feedback would serve no useful homeostatic function. The alternate hypothesis, that portal flow is the sensed parameter regulating the hepatorenal reflex, had not been previously suggested. In fact, there had never been a suggestion of regional blood flow being monitored by sensory nerves in any organ. As with any paradigm change, anomalies in the old paradigm had increasingly appeared. A number of earlier studies had suggested that the hepatorenal reflex was unlikely to be activated in response to baroreceptors. Using anesthetized dogs, Koyoma et al. [171] observed that the partial occlusion of the portal vein resulted in activation of renal sympathetic nerves that was not related to increases in either extrahepatic portal pressure or intrahepatic sinusoidal pressure (because intrahepatic sinusoidal pressure was decreased in these studies). Levy and Wexler [238] found that sodium retention persisted in cirrhotic dogs after end-to-side portacaval anastomoses, a maneuver that normalized intrahepatic hypertension but was still associated with a dramatic decrease in intrahepatic portal blood flow. Liang [239] reported a lack of correlation of increased portal pressure with the rate of urine flow at portal pressure elevations up to 15 cm H2O; only at pressures above this level, when portal blood flow would have been reduced, did the urine flow rate begin to decrease. Most of the studies purporting to show evidence for portal pressure regulation of the hepatorenal reflex have also resulted in reduction of intrahepatic portal flow. Cirrhosis is characterized by a hyperdynamic splanchnic circulation and portal hypertension [27,94] but, because of the presence of portacaval shunts directing flow around the liver, the blood flow that directly perfuses functional sinusoidal and parenchymal hepatocytes is actually decreased [163].

The hypothesis relating intrahepatic blood flow to the hepatorenal reflex is supported by a recent series of publications and ongoing studies reported by us. The hypothesis is that reduced functional portal blood flow through the liver results in reduced washout of adenosine from the space of Mall (as described in Chapter 5 related to the hepatic arterial buffer response). Adenosine acts on sensory nerves arising in the space of Mall and activates the hepatorenal reflex. The hypothesis was tested progressively.

We established a vascular shunt connecting the portal vein and vena cava in rats to allow for control of the portal venous blood flow [275]. Partial occlusion of the portal vein, close to the hilum of the liver, decreased intrahepatic portal flow and the extra portal flow was allowed to bypass the liver through the shunt to prevent splanchnic congestion. A 50% decrease in intrahepatic portal flow through this mechanism did not cause significant changes in systemic arterial blood pressure but decreased urine flow by 38% and sodium excretion by 44%. The renal effect of reduced portal blood flow was prevented by hepatic denervation or intraportal administration of the adenosine receptor antagonist, 8-phenyltheophylline. Involvement of intrahepatic baroreceptors was eliminated because intrahepatic sinusoidal pressure was decreased after partial portal vein occlusion. These studies provided the first evidence that intrahepatic portal flow could activate a hepatorenal reflex.

Our prior studies related to the HABR indicated that adenosine in the space of Mall was regulated by intrahepatic blood flow. The observation that the hepatic perivascular region is also rich in sensory nerves [288] supported the feasibility of an adenosine-mediated afferent limb in the hepatorenal reflex. Adenosine has previously been shown to activate sensory nerves in the carotid body [367] and in the heart [359]. Stimulation of myocardial adenosine A1 receptors increased the discharge of cardiac afferent fibers and resulted in an increase in neural discharge of the renal sympathetic efferent fibers in anesthetized dogs [276,359]. To test if adenosine could activate a hepatic afferent reflex, adenosine was infused directly into the portal vein and resulted in a significant decrease in urine flow and sodium excretion. In contrast, intravenous adenosine at the same dose was without any effect on renal function, thereby indicating that the effect of the infused adenosine was through the liver and not a direct action on the kidney. Intraportal infusion of the adenosine receptor antagonist, 8-phenyltheophylline, abolished the renal response to intraportal adenosine. Furthermore, both hepatic and renal denervation abolished the renal response to adenosine, thereby proving the reflex connection (as opposed to a possible hormonal connection) [274]. Thus, these data taken together are consistent with the hypothesis that reduction in intraportal blood flow leads to an adenosine-mediated activation of hepatic afferent nerves, which results in a sympathetic reflex to the kidneys, leading to fluid retention.

This response would serve a useful function in normal physiological conditions where the reduced portal flow would cause fluid retention, thereby increasing the circulating blood volume and cardiac output. The elevated cardiac output would result in elevated portal flow, thus correcting the flow imbalance to the liver. The hypothesis also proposes that, in the diseased state, with portacaval shunts existing, the signal would be anticipated to occur as a result of the decreased intrahepatic portal flow. However, in this state, the salt and water retention would not lead to a correction of the intrahepatic flow but, rather, would lead to elevated cardiac output and elevated portal inflow (the hyperdynamic circulation), which would simply bypass the liver through the shunts and lead to a progressive, inappropriate reflex accumulation of fluid.

We have recently demonstrated that renal dysfunction is mediated through this adenosine-dependent hepatorenal reflex in both acute and chronic liver disease models in rats. Chronic administration of the hepatotoxin, thioacetamide, resulted in severe fibrosis consistent with advanced liver disease (Chapter 12, hepatic circulation and toxicology). Reduced basal urine flow and a reduced ability to excrete a saline load were demonstrated. The renal dysfunction was partially corrected by intrahepatic administration of the adenosine receptor antagonist, 8-phenyltheophylline [269]. An acute model of liver injury involved intraperitoneal injection of thioacetamide (500 mg/kg) in rats. Severe liver injury was demonstrated 24 h after the insult and was associated with reduced renal arterial blood flow and glomerular filtration rate and sodium retention. The response to a saline volume expansion challenge was inhibited. As with the other models, 8-phenylpheophylline improved urine production. To specify the adenosine receptor subtype, selective adenosine A1 and A2 receptor antagonists were compared. The selective A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine, greatly improved the impaired renal function induced by acute liver injury and this beneficial effect was blunted in rats with liver denervation. In contrast, intravenous administration of the antagonist was only effective at higher doses, thereby confirming that the adenosine receptor antagonist was acting on the liver and not directly on the kidney. The adenosine A2 agonist was without impact on the renal function [270].

Although both the chronic and acute liver disease models clearly demonstrated an adenosine-dependent hepatorenal reflex impairment of renal function, the relationship to intrahepatic portal flow in diseased livers cannot be assumed. Adenosine concentrations in the space of Mall can be elevated by reduced portal flow or intrahepatic vascular shunting, but it is equally possible that adenosine levels could be elevated independent of blood flow, secondary to hepatic inflammation [290,292,324] or by a decrease in the recycling of adenosine through the adenosine kinase pathway [26]. Regardless of the source of increased adenosine in the diseased state, the normal physiology is strongly supportive of a hepatic reflex mechanism by which the liver indirectly affects its own blood flow by adjusting major homeostatic parameters. Those adjustments are pathogenic in the presence of portacaval shunting of blood around the liver. The involvement of this reflex in liver disease suggests a therapeutic approach treating the early renal dysfunction and, perhaps, even the late-stage hepatorenal syndrome through the blockade of intrahepatic adenosine A1 receptors. Caffeine blocks the hepatic adenosine A1 but not A2 receptors (Ming and Lautt, unpublished observation) and can therefore be considered to treat fluid retention associated with reduced hepatic blood flow, including congestive heart failure. A slow release formulation should undergo clinical trial (Chapter 17). The role of the hepatorenal reflex in the homeostasis of hepatic blood flow is discussed in Chapter 16.

Copyright © 2010 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK53063


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