A controversy presently exists concerning the ability of albumin to inhibit the tubular reabsorption of low-molecular-weight (Mr) proteins in experimental renal diseases leading to massive proteinuria. We have examined the urinary excretion of albumin and of 2 low-Mr proteins, β2-microglobulin and cystatin C, in rats treated with toxins affecting primarily the glomerulus (puromycin aminonucleoside and Adriamycin) or the tubule (mercuric chloride and maleic acid). Above a threshold of 100 mg/24 h, albuminuria induced by puromycin aminonucleoside (50 mg/kg) and Adriamycin (5 mg/kg) was associated with a marked increase in the urinary excretion of β2-microglobulin and cystatin C peaking at more than 100-fold the baseline levels. These glomerulotoxins did not affect the urinary excretion of the tubular enzyme N-acetyl-β-D-glucosaminidase. This pattern of effects was completely different from that induced by mercuric chloride (2 mg/kg) and maleic acid (400 mg/kg) which increased the excretion of both N-acetyl-β-D-glucosaminidase and low-Mr proteins in rats with albuminuria values below 100 mg/24 h. These results strongly support the hypothesis that at high filtered loads, albumin decreases the tubular uptake of low-Mr proteins most likely by competition for a common transport mechan