NALOXONE EFFECT ON RENAL FUNCTIONS IN LIVER CIRRHOSIS

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Renal functional abnormalities (impaired renal hemodynamics and water and electrolyte excretion) are commonly seen in patients with liver cirrhosis. Circulating levels of endogenous opioids with antidiuretic properties may be increased in liver cirrhosis, and the opioid antagonist naloxone increases creatinine clearance and water and electrolyte excretion in water-loaded patients with cirrhosis and ascites. Question 1: Are the diuretic effects of the opioid antagonist naloxone in patients with cirrhosis and ascites associated with an increase in renal hemodynamics (renal plasma flow and glomerular filtration rate) or circulating levels of hormones known to affect renal hemodynamics or tubular functions? Can a chronic infusion of naloxone result in sustained renal effects? Question 2: Can the effects of diuretics currently utilized in cirrhotic patients be enhanced by simultaneous administration of naloxone? Question 3: Are endogenous opioid systems activated in cirrhotic patients? Patients with alcoholic cirrhosis and ascites with essentially normal (creatinine clearance greater than or equal to 70 mL/min) or depressed (less than 70 mL/min) glomerular filtration rate will undergo both acute (5h) and chronic (48h) naloxone infusion studies in order to determine its effects on renal hemodynamics, water and electrolyte excretion, and hormones known to affect renal functions. Measurements will include effective renal plasma flow and glomerular filtration rate (inulin, PAH, and radioisotopic methods), water and solute excretion parameters, plasma renin, angiotensin II, aldosterone, catecholamines, vasopressin, atrial natriuretic peptide, glucagon, and insulin-like growth factor (IGF-1), urinary vasodilator prostaglandin and thromboxane metabolites. Plasma endogenous opioids (beta-endorphin, enkephalins, and dynorphin) will be determined by HPLC/RIA in order to determine which opioids are increased in cirrhotic patients and whether the circulating level correlates with basal renal functional parameters or the magnitude of the renal hemodynamic/diuretic response to naloxone. We expect that naloxone will increase glomerular filtration rate, thus resulting in diuresis; more importantly, naloxone should markedly potentiate the effect of currently-used diuretics for this condition (furosemide and spironolactone). As there are currently no therapeutic agents which predictably improve renal hemodynamics in patients with liver cirrhosis and ascites, our study findings should not only provide basic information on the role of endogenous opioids in liver disease but might prove to be clinically very useful.