Anand, Radhika S.;
(2003)
A Model of the Hepatorenal Syndrome.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Renal failure occurs in approximately 55% of patients with acute liver injury. Hepatorenal syndrome (HRS) is the development of renal failure secondary to liver disease in the absence of significant renal pathology. Presently there are no suitable models for the study of HRS. Recently, the rat model of galactosamine-induced acute liver failure (galn-ALF) was found to develop a hyperdynamic circulation along with a disruption in the renal haemodynamics which are characteristics of HRS. The aim of the project was to investigate the suitability of the rat model of galn-ALF as a model for HRS and to determine the role vasoactive mediators play in the pathogenesis of renal failure in this model. Characterisation of rats with galn-ALF showed that this was a suitable model for the study of HRS. The animals developed renal failure secondary to liver disease. The degree of renal impairment correlated with the degree of liver injury. The histology of the kidneys was normal and there was a reduction in the renal blood flow. A reduction in renal blood flow is indicative of renal vasoconstriction. Endothelin-1 (ET-1), a potent vasoconstrictor is elevated in patients with HRS. In the galn-ALF rat model of HRS ET-1 was found to be elevated in the plasma. In vitro autoradiography revealed that the ET-1 receptor ETA was upregulated in the renal cortex. Using the mixed receptor antagonist Bosentan in this model of HRS, renal function was improved. This suggests that elevated levels of ET-1 play a role in the pathogenesis of renal failure. Oxidant stress has also been found to play a role in renal failure. In the model there was marked lipid peroxidation. Oxidative stress was quantified by the measurement of F2- isoprostanes. These compounds are biologically active and can themselves cause renal vasoconstriction. Treatment with the anti-oxidants N-acetylcysteine and alpha-lipoic acid conferred some protection against renal impairment but was not effective in inhibiting lipid peroxidation. This suggests that a mechanism other than lipid peroxidation is involved in the renal dysfunction.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | A Model of the Hepatorenal Syndrome |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| Keywords: | Biological sciences; Liver failure |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10107327 |
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