Tubular resistance to furosemide contributes to the attenuated diuretic response in nephrotic rats

Abstract

A blunted response to loop diuretics frequently occurs in nephrotic syndrome (NS). Observations that nephrotic humans have reduced sodium excretion at normal rates of diuretic excretion have suggested that tubular resistance to the drug may contribute to diuretic resistance. To determine if tubular resistance to furosemide exists in NS, late proximal and early distal tubular micropuncture was performed in rats with puromycin aminonucleoside-induced NS and in control rats after an i.v. bolus dose of furosemide of 1 mg/kg body wt. Absolute and fractional urinary sodium excretions were less (P< 0.05) in NS rats than in control rats after furosemide. Inulin clearance and total urinary furosemide excretion, however, were not different between groups. Thus, similar to reports in humans, the urinary sodium-to-furosemide excretion ratio was less (P < 0.05) in NS than in control rats. Single-nephron GFR and chloride delivery to late proximal sites were not different between groups after furosemide. In contrast, absolute and fractional chloride deliveries to early distal sites were less (P < 0.05) in NS rats after furosemide. Calculated loop chloride reabsorption after furosemide was greater (P < 0.05) in NS than in control rats when expressed either as percentage of filtered load (39.4 ± 3.1 versus 28.2 ± 2.0%) or delivered load (67.9 ± 4.7 versus 48.3 ±3.0%). Loop fluid reabsorption was not different between groups. Thus, loop chloride reabsorption is inhibited to a lesser extent by i.v. furosemide in NS than in normal rats. Furthermore, as total urinary furosemide excretion is equivalent in both groups, the decrease in loop chloride reabsorption appears to result from resistance by that segment to the diuretic.