Mechanism of furosemide resistance in analbuminemic rats and hypoalbuminemic patients

Abstract

To elucidate the mechanism of resistance of hypoalbuminemic patients to furosemide, the effect of this diuretic on urine volume of normal and analbuminemic rats (NAR) and of hypoalbuminemic patients was studied. Intravenous administration of furosemide rapidly enhanced sodium diuresis in normal rats but not in NAR. Total plasma clearance and distribution volume of furosemide were much larger in NAR than in normal rats, while no significant difference in these pharmacokinetic parameters was observed for the unbound fraction of the diuretic between the two animal groups. In contrast, urinary secretion of furosemide was significantly lower in NAR than in normal rats. Injected furosemide bound to albumin markedly promoted diuresis in NAR, while the same dose of albumin alone had no effect, indicating that binding to albumin is essential for the delivery of furosemide to the kidney, the site for its action. Injection of the complex rapidly increased the urine volume of hypoalbuminemic patients who showed a marked resistance to this diuretic. Thus, the resistance to furosemide in both NAR and hypoalbuminemic patients may be explained on the same basis.

Does Albumin Preinfusion Potentiate Diuretic Action of Furosemide in Patients with Nephrotic Syndrome?

“…Davison et al and Eadington et al reported positive results, but they did not perform a cross-over study or show any pharmacokinetic data (15,11). Inoue et al reported that effective diuresis was achieved by infusion of the albumin-furosemide complex in analbuminemic rats and hypoalbuminemic patients (2). All the patients in their experiment were hypoalbuminemic due to causes other than nephrotic syndrome.…”

“…To improve delivery of the drug, we mixed 160 mg of furosemide and 100 mL of 20% albumin solution at room temperature before administration. This method of administration was previously used by other investigators (2,16). The timing of administration of albumin and furosemide varied according to the investigators.…”

“…Intravenous infusion of albumin in combination with furosemide has been advocated as an effective method of treating edema due to the nephrotic syndrome, but its clinical efficacy is controversial (2,3,9,10). Coadministration of albumin with furosemide may improve furosemide delivery and hence diuretic effect by changing the pharmacokinetics of furosemide.…”

“…The overall response to a diuretic is determined by delivery of drug to its site of action, delivery of solute to the site of action, the dynamics of the drug with its receptor and whether or not solute is reclaimed distal to the site of action (1). Both pharmacokinetic and pharmacodynamic mechanisms have been proposed as explanations for the resistance to loop diuretics (2)(3)(4).…”

Refractory Edema with Congestive Heart Failure Stepwise Approaches Nephrology Perspectives

“…Theoretically, infusion of the furosemide-albumin complex can increase diuretic delivery to the kidney by keeping furosemide within the vascular space. 13 However, subsequent studies found that the use of mixture of loop diuretic and albumin in hypoalbuminemic patients (secondary to cirrhosis or nephrotic syndrome), with mean plasma albumin 3.0g/ dL, produced only a modest increase in sodium excretion compared with furosemide alone without an increase in the rate of furosemide excretion.…”