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Title: Renal dysfunction in liver disease
Author: Leithead, Joanna Agnes
ISNI:       0000 0004 6425 3381
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2014
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Renal dysfunction is a major cause of morbidity and mortality in hepatology patients. In cirrhosis, portal hypertension-related renal dysfunction evolves in parallel with advancing disease, and has important prognostic implications. Similarly, in acute liver failure, acute kidney injury is associated with increased mortality and may impact on distant organ function by driving cardiac, lung, brain, as well as liver injury. Liver transplantation is the definitive treatment for portal hypertension-related renal dysfunction in cirrhosis and acute kidney injury in acute liver failure. Yet, liver transplantation itself is complicated by both acute kidney injury and chronic kidney disease. Despite the frequency of occurrence and devastating consequences of renal dysfunction in liver disease, treatment options remain limited and there is a desperate need for advancement of scientific understanding. In this thesis I have studied 3 main aspects of renal dysfunction in liver disease. Firstly, I examined the systemic haemodynamic and renal effects of acute endothelin-1 receptor antagonism in patients with advanced portal hypertensionrelated renal dysfunction. In a randomised, double-blind, placebo controlled, crossover study of patients with refractory ascites acute combined endothelin-A and endothelin-B receptor antagonism caused a fall in glomerular filtration rate despite no change in systemic haemodynamics or total renal blood flow, and a marked reduction in urinary flow rate. These findings are consistent with a reno-protective role for endothelin-1 in portal hypertension-related renal dysfunction. Secondly, I explored the hypothesis that the acute renal dysfunction that occurs in acute liver failure is distinct from the hepatorenal syndrome of cirrhosis, and instead the systemic inflammatory response may be a critical determinant. I demonstrated that the systemic inflammatory response syndrome is associated with acute kidney injury in acute liver failure patients. Importantly, this relationship was independent of the presence of infection and of severity of liver injury. Thereafter, in patients superurgently transplanted for acute liver failure I found that, in contrast to patients undergoing elective liver transplantation, pre-transplant acute kidney injury was not associated with the development of chronic kidney disease. The results support an alternative pathophysiological process underlying the renal injury that occurs in acute liver failure. Finally, I examined the long-term decline in renal function and progression to chronic kidney disease in liver transplant recipients. I observed that patients have a clinically relevant decline in glomerular filtration rate beyond the initial post-operative period, and current focus of chronic kidney disease prevention. Mulivariate modelling identified several potentially modifiable patient factors associated with a faster rate of decline. The studies presented have helped to further our knowledge of portal hypertensionrelated renal dysfunction, acute kidney injury in acute liver failure and chronic kidney disease after liver transplantation. By doing so, we have moved one step closer to improving patient morbidity and mortality as a result of renal dysfunction in liver disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available