| Summary: | 博士 === 國立陽明大學 === 臨床醫學研究所 === 103 === Liver cirrhosis is a common disease in Taiwan, which may lead to a severe complication of oliguric acute renal failure, so called “hepatorenal syndrome” (HRS), without effective treatment. Although a great advance in the researches of portal hypertension and liver cirrhosis has been achieved with highly reproducible animal models, the mechanisms leading to altered renal blood flow and renal dysfunction in advanced liver cirrhosis are not entirely clear yet. The critical impediment lies mainly in the paucity of an ideal animal model to correctly mimic human disease and fulfill these complex manifestations of HRS.
Usually, acute kidney injury secondary to liver dysfunction occurred in the absence of significant alterations in renal histology. The functional nature of renal dysfunction in advanced liver disease was confirmed by the successful transplantation of cadaveric kidneys from patients with HRS as well as the normalization of renal dysfunction after liver transplantation. For decades, traditional consensus defined the HRS as hypo-perfusion of the kidneys resulting from combined intense renal vasoconstriction and decreased renal blood flow in response to generalized systemic arterial vasodilatation. However, cumulative studies demonstrated that the renal vasculature of portal hypertensive and compensated cirrhotic rats had lower perfusion pressure and hypo-responsiveness to endogenous vasoconstrictors, implying renal vasodilatation. In order to illustrate the evolution of renal vascular reactivity during disease progression of liver cirrhosis, the “2-hit” hypothesis seems to be the best accepted theory. Usually, the liver dysfunction appears to be an important background factor or “first hit” when the vasodilatation related hypovolemia can be compensated by the development of hyperdynamic circulation, such as increased heart rate, avid renal sodium and water retention, and higher cardiac output. Once the auto-regulatory mechanisms are overwhelmed by the precipitating event or “second hit”, extreme effective arterial underfilling will initiate extreme intra-renal vasoconstriction and subsequent renal impairment. Such events may include the overzealous use of diuretics, large volume paracentesis, gastrointestinal bleeding, cardiomyopathy, or development of spontaneous bacterial peritonitis in ascitic patients.
Partial portal vein ligation (PVL) rat is a well-established and reproducible animal model for studies in the field of portal hypertension. For decades, the isolated perfused kidney model has been established as a valid tool for the investigations of renal physiology and pathophysiology. The combination of both mature animal models might enable us to explore the potential mechanisms of renal dysfunction in advanced liver cirrhosis. At first, the technique of isolated kidney perfusion was established and successfully demonstrated poor renal vascular responsiveness to endothelin-1 (ET-1) in the PVL rats since the 7th post-operative day. Up-regulated endothelial nitric oxide synthase (eNOS) of renal arteries may play the major role in modulating the renal vascular hypo-reactivity of PVL rats. Furthermore, endotoxemia was, a common complication of cirrhotic patients, induced by intra-peritoneal injection of lipopolysaccharide (LPS) in the PVL rats to mimic the clinical condition of “2-hit” hypothesis. There was significantly higher serum level of ET-1 developed at 5 hours following LPS injection in both SHAM and PVL rats. In contrast with vascular hypo-reactivity and down-regulated renal endothelin receptor type A (ETA) in the LPS-injected SHAM rats, LPS-injected PVL rats demonstrated significantly increased renal vascular responsiveness to ET-1 and up-regulated renal ETA expression, which might contribute to the pathogenesis of renal dysfunction in portal hypertensive patients during endotoxemia.
These findings may help improve our understanding of the pathophysiology of renal dysfunction in advanced liver cirrhosis and lead to the development of useful therapeutic strategies.
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