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Effects of terlipressin on renal function in patients with cirrhosis and ascites

Aleksander Krag  


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Accepted by: Faculty of Health Sciences University of Copenhagen
Defended on: June 26, 2008
Official opponents: Helmer Ring-Larsen , Hendrik Vilstrup , Jørgen Frøkiær
Tutors: Flemming Bendtsen , Søren Møller , Jens H Henriksen

Published in the PhD Database: July 1, 2008


English abstract
This ph.d. thesis is based on two pathophysiological studies on the effects of terlipressin on renal function in patients with cirrhosis and ascites. Ascites is a serious condition with a mortality of more than 50 % in two years, despite best current treatment. The need for better treatments is obvious. Ascites is the result of avid salt and water retention, which again is the consequence of a cascade of changes in integrative renal and vascular regulation. The generally accepted ¿arterial vasodilation hypothesis¿ states that the splanchnic arterial vasodilation is a key event behind these changes. The vasopressin analogue terlipressin, which has affinity for V1-receptors in the vascular smooth muscles, is a powerful vasoconstrictor. V1-receptors are particularly abundant in the splanchnic circulation and terlipressin can revert the splanchnic arterial vasodilation. Terlipressin is currently used in the treatment of HRS. We aimed at investigating if terlipressin could improve renal function in patients with ascites without HRS. Terlipressin was associated with increased glomerular filtration and sodium excretion as well as deactivation of renal vasoconstrictors. Thereby vasoconstriction is proved as a potential treatment of ascites. On the contrary, terlipressin, despite improved filtration, decreased free water clearance. This led to the hypothesis that terlipressin also has affinity to the V2-receptors in the collecting ducts in the kidneys and has an antidiuretic effect. In the second study we therefore investigated, the excretion of water and aquaporin-2. Aquaporin-2 is the water channel, which is regulated by the V2 receptors. Terlipressin turned out to have affinity for V2-receptors, because the terlipressin-induced antidiuresis was associated with an increase in distal fractional water reabsorption and aquaporin-2 excretion. The clinical significance of this is unclear, however this may partly explain why only 60% of patients with HRS respond to terlipressin treatment.


Danish abstract
Denne ph.d.-afhandling er baseret på to patofysiologiske studier af lægemidlet terlipressins virkning på nyrefunktionen hos patienter med cirrose og ascites. Hos patienter med cirrose er udvikling af ascites forbundet med en ringe prognose, idet mere end 50 % er døde 2 år efter udvikling af ascites på trods af behandling. Der er derfor behov for nye behandlingsformer. Ascites er udtryk for en udtalt salt og vand retention. Dette opstår som følge af en kaskade af ændringer i kredsløbets og nyrernes funktion og regulering. Den bedst dokumenterede hypotese for pathophysiologien bag disse ændringer er den ¿arterielle vasodilatations hypotese¿, som anfører den splankniske arterielle vasodilatation som nøglebegivenheden bag disse ændringer. Stoffet terlipressin er en kraftig vasokonstriktor, som har affinitet for V1 receptorerne i blodkarrenes glatte muskelceller. V1 receptorer er særligt udtalte i de splankniske kar, hvorfor terlipressin kan revertere den splankniske arterielle vasodilatation. Terlipressin anvendes til behandling af hepatorenalt syndrom. Formålet var, at undersøge om vasokonstriktion med terlipressin kunne bedre nyrefunktionen hos patienter med ascites, som ikke har udviklet hepatorenalt syndrom. Terlipressin medførte en signifikant stigning i den glomerulære filtration og i natrium udskillelsen, og vasokonstriktion kan dermed blive en potentiel behandling ved ascites. Derimod konstaterede vi, at den bedrede nyre funktion var ledsaget af et uforklaret fald i fritvandsclearance. Dette førte til en hypotese om, at terlipressin også har affinitet for V2-receptorerne i nyrernes samlerør og har en antidiuretisk effekt. Nærmere undersøgelser af udskillelse af vand og aquaporin-2, som er den vandkanal i nyrerne som reguleres via V2-receptorerne, viste at terlipressin havde affinitet for V2-receptorerne, idet den terlipressin inducerede antidiurese var ledsaget af en stigning i den fraktionelle distale vandreabsorption og en stigning i udskillelsen af aquaporin-2. Den kliniske betydning af dette fund er uafklaret, men det kan delvist forklare at kun cirka 60 % af patienter med hepatorenalt syndrom responderer på terlipressinbehandling.