Mechanisms of Diuretic Resistance and Tolerance

Oh, Yoon Kyu; Na, Ki Young; Kim, Gheun Ho; Kim, So Young; Han, Jin Suk

Abstract

Diuretics are natriuretic agents which inhibit sodium reabsorption at their major site of action on the renal tubules and increase the excretion of sodium and combined anions. Increment of urine volume is the secondary to the natriuretic effects. Diuretic resistance occurs that threshold dose of diuretics is higher than that of other patients. It is frequently manifested among the edematous patients such as those with the nephrotic syndrome. Prolonged use of diuretics decreases the natriuretic effect of diuretics, which is called diuretic tolerance. This is important adaptations of distal nephron segment. To elucidate the mechanism of diuretic resistance, 1 mg of bumetanide was given to the nephrotic syndrome(NS) patients group and control group, respectively. The peak plasma concentration was delayed in NS patients. The proportion of urine free bumetanide for 24 hours was 73% in NS patients but 100% in control group. The ratio of urine volume and amount of Na+ and Cl - for 24 hours to the total and free urine bumetanide was decreased in NS patients. The study suggests that pharmacokinetic and pharmacodynamic changes of the diuretics induce the diuretic resistance. To determine the additive diuretic effect of albumin to the action of the furosemide, 160 mg of furosemide was administered intravenously with albumin in NS patients. Simultaneous infusion of albumin and furosemide did not enhance the diuretic effect of furosemide pharmacodynamically and pharmacokinetically. Albumin preinfusion 30 minutes before furosemide administration potentiates the diuresis, but natiuresis and pharmacokinetics were not changed. Semiquantitative immunoblotting of rat kidneys was carried out to investigate whether chronic diuretics adminstration induces changes in the abundance of Na+ transporters in distal nephron. Furosemide infusion increased cortical and outer medullary abundances of Na+-Cl- cotransporter(TSC) and all 3 subunits of the epithelial sodium channel(ENaC). Hydrochlorothiazide infusion increased abundances of some kinds of subunits of ENaC. These increases in the abundances of Na+ transporters may account for the generation of diuretic tolerance.These data suggest that to overcome the diuretic resistance or tolerance, diuretic dose increment over the threshold level and more frequent administration of the diuretics are recommended. Diuretic combinations are also proposed. Addition of albumin to augment the diuretics effect ought to be considered cautiously.