The influence of moderate hypoalbuminaemia on the renal metabolism and dynamics of furosemide in the rabbit

Abstract

1 The present study aimed to investigate the influence of hypoalbuminaemia on the pharmacokinetics and pharmacodynamics of furosemide. Hypoalbuminaemia was produced by repeated plasmapheresis, to attain plasma albumin concentrations of 21.6+0.9 g 1', compared with 33.0+0.6 g 1' in controls (P<0.001). The per cent of bound furosemide in hypoalbuminaemic rabbits (90.8+0.7%) was lower than that in control rabbits (97.4+0.5%, P<0.001). The kinetics of intravenous furosemide (2.5 mg kg-') were studied in control (n = 6) and hypoalbuminaemic rabbits (n = 6). 2 To assess the effect of hypoalbuminaemia on extrarenal clearance of furosemide, functional anephria was induced by ligating the renal pedicles of 12 rabbits, which were segregated in two groups, with and without hypoalbuminaemia. 3 In the control group, total, urinary and metabolic clearances of furosemide were 1.8 + 1.0, 5.0 + 0.4 and 6.8 + 0.6 ml min-' kg-', respectively. Compared with control rabbits, in hypoalbuminaemic rabbits, total clearance of furosemide increased by 40% (P<0.001), result of the enhancement of furosemide metabolic clearance (Clm) from 5 to 10 ml min-' kg-' (P<0.01). In hypoalbuminaemic rabbits, urinary excretion of furosemide was reduced by 26% (2451 + 115 vs 1818 + 134 pg h-', P<0.01). In anephric rabbits, furosemide total clearance was 1.77+0.12 ml min-' kg-', value not affected by hypoalbuminaemia, confirming that the increase in Clm induced by hypoalbuminaemia occurs in the kidneys. 4 Compared with controls, in hypoalbuminaemic rabbits, the rate of urinary excretion (142+9 vs 74+8 ml h-', P<0.001) and the rate of excretion of sodium (18.6+0.9 vs 9.9+0.9 mmol h-', P<0.001) were very much reduced. However, the dose-response curves were not different. 5 In conclusion, hypoalbuminaemia is associated with an increase in renal metabolic clearance of furosemide, possibly because of the increase in furosemide unbound concentration, and a decrease in the diuretic/natriuretic effect of furosemide, secondary to a reduction in furosemide tubular secretion. Thus, albumin facilitates the renal secretion of organic anions but not their metabolism.

Prophylactic furosemide infusion decreasing early major postoperative renal dysfunction in on-pump adult cardiac surgery: a randomized clinical trial

“…By blocking the luminal K/Na/2Cl co-transporter type 2 in the thick ascending limb of the loop of Henle cells, furosemide may decrease the demand in supply/demand equation. Approximately 98% of furosemide bounds to plasma proteins and the GFR of the drug is very low 18,19. Hence, for exerting this effect, it is necessary that furosemide should be actively secreted from the proximal tubule via the organic anion transporter-1 20,21.…”

Management of the Nephrotic Patient: Treatment of ECF Volume Expansion Due to Nephrotic Syndrome in Adults

“…In NS, levels of albumin and other plasma proteins are often extremely low, and the consequent increased volume of distribution decreases the amount delivered to the kidney [ 14 ]. Increasing the dose administered is the appropriate response to this; coadministration of albumin with diuretic has not been consistently demonstrated as being of additional benefi t [ 15 , 16 ].…”

Treatment of Disorders of Sodium Balance in Chronic Kidney Disease

“…Animal studies demonstrate five mechanisms that could impair the responsiveness to loop diuretics in patients with the nephrotic syndrome, including 1) decreased delivery and/or decreased tubular secretion of the diuretic, 2) increased renal diuretic metabolism, 44 3) decreased blockade of the Na-K-2Cl cotransporter by the diuretic, 45 and 4) increased NaCl reabsorption by other nephron segments. Clinical studies confirm that nephrotic patients have an impaired tubular response to loop diuretics.…”

“…Hypoalbuminemia decreases the binding of furosemide to plasma proteins and thereby increases its volume of distribution. 46 The secretion of loop diuretics by the proximal tubule is reduced by hypoalbuminemia, 44 and albumin infusion into nephrotic patients increases renal furosemide excretion in the urine. 47 Early work suggested that premixing furosemide with albumin prior to intravenous injection amplified diuresis, 48 but this was not confirmed by some others.…”