C. Viau

Kidney Disorders and Hematotoxicity From Organic-solvent Exposure

Although the kidney is the critical organ limiting occupational exposure to soluble uranium compounds, there have been no adequate studies evaluating renal tubular dysfunction in chronically exposed workers. The present investigation evaluated kidney function among 39 uranium mill workers and 36 local cement plant workers of equivalent age, sex, and race. The uranium workers showed a significantly higher excretion of beta-2-microglobulin and five amino acids than the reference group. Although the levels of tubular proteinuria were mild, a dose-effect relation existed between the clearance of beta-2-microglobulin, relative to that of creatinine, and the length of time that the uranium workers had spent in the yellowcake drying and packaging area, the work area with the highest exposures to soluble uranium. Age did not account for this relationship. Glomerular function was significantly better among the uranium workers than among the referents, though this may have been the result of differences in the physical activity of the groups during the collection period. The data presented suggest reduced renal proximal tubular reabsorbtion of amino acids and of low molecular weight proteins, consistent with uranium nephrotoxicity.

Effects of Gentamicin On the Renal Uptake of Endogenous and Exogenous Proteins in Conscious Rats

To study the effect of gentamicin on the renal uptake of proteins, Sprague-Dawley female rats were intravenously injected with solutions containing unlabeled human beta 2-microglobulin (beta 2-m), retinol-binding protein, and increasing amounts of gentamicin (from 0.063 up to 31.5 mg/kg). The concentrations of human proteins and that of endogenous beta 2-m, albumin, and IgG in the urine collected during the 2 hr following the injection were determined by immunoassays. Gentamicin transiently increased the urinary excretion of rat and human beta 2-m in a dose-dependent manner. The mean relative increase of rat beta 2-m excretion ranged from 2 at a gentamicin dose of 0.06 mg/kg up to 500 at a gentamicin dose of 31.5 mg/kg. By contrast, the urinary excretion of other proteins was only increased by a factor of 2 to 5 at the highest dose of gentamicin. The relative increase of the urinary excretion of proteins was positively correlated with the fractional reabsorption of the proteins by the rat kidney. The inhibitory effect of gentamicin on the renal uptake of protein was very similar to that observed in rats injected with polycationic proteins like lysozyme and cytochrome C. These observations, combined with the fact that gentamicin, like proteins, enters the tubular cell by adsorptive endocytosis, strongly suggest that this drug competes with proteins for common binding sites on the apical tubular membrane and for subsequent endocytosis. Furthermore, the iv injection of large amounts of gentamicin and polycationic proteins induces a lysosomal enzymuria which very likely is a manifestation of an increased exocytosis.

Renal Handling of Human Beta-2-microglobulin in Normal and Cadmium-poisoned Rats

AbstractThe renal handling of humanβ2-microglobulin (β2-m) was investigated in normal rat and in rat with cadmium-induced renal damage. Cadmium was administered either in drinking water at a concentration of 100 ppm for up to 16 months or by i. p. injection of 1 mg Cd/kg, five times a week for up to 4 months. When renal dysfunction has developed, namely after 2 and 10 months of the i. p. and oral treatment respectively, unlabelled humanβ2-m was injected intravenously and its disappearance in serum and its urinary excretion were studied by means of a sensitive immunoassay. In serum, the level ofβ2-m drops by about 90% during the 10 first min, then declines more slowly with a half life around 20 min. Serum disappearance curves ofβ2-m in normal and cadmium-treated rats did not differ markedly.The amount ofβ2-m recovered in urine during the 4 h following the injection averaged 0.03% of the injected dose in normal rats. It increased on the average to 10% in rats treated i. p. with 1 mg Cd/kg for 3 months. However, in rats given 100 ppm Cd per os for 10 months, this amount averaged only 0.14%. A similar value was observed 5 months later, although at that stage, the critical level of cadmium in kidney cortex had been reached for 6–7 months. These data which were in accordance with the disturbances of the other renal parameters measured in cadmium-treated rats indicate that: 1)humanβ2-m is reabsorbed by rat kidney at a similar rate as by human kidney;2)if the occurrence of cadmium tubulopathy is concomitant with the saturation of cadmium-binding sites in kidney, its severity depends greatly on the rate at which cadmium reaches the saturated kidneys.

Cadmium, Analgesics, and the Chronic Progressive Nephrosis in the Female Sprague-dawley Rat

Female Sprague-Dawley rats received phenacetin or aspirin at average daily doses of 135 and 27 mg/kg respectively in the diet and either demineralized water (DMW) or a 100 ppm cadmium (Cd) solution as their drinking water for 12 months. This dose of Cd produced borderline tubular toxicity, as measured by the excretion of IV-injected human β2-microglobulin. The kidney accumulation of Cd just reached the critical level of 200 ppm in all groups at the end of the study. The various treatments did not significantly affect growth, creatinine clearance, urine osmolality and the urinary excretion of β-N-acetyl-d-glucosaminidase and aminoacids. No interaction resulted from the concomitant administration of analgesics and Cd. Both aspirin subgroups (receiving DMW or Cd) showed an attenuation of the age-related decline of the renal function as revealed by a lower urinary excretion of albumin and total protein. The accentuation of the mesangial matrix seen upon aging was also partly inhibited in the aspirin rats.

Increased Urinary Excretion of Ferritin in Subjects with Moderate Proteinuria

The relationships between the urinary excretion of ferritin and that of albumin, β2-microglobulin and retinol-binding protein were studied in 60 healthy subjects and in 34 subjects exposed to a nephrotoxic agent (cadmium). The results suggest that the ferritin present in urine originates mainly from the kidney and its concentration depends on both the renal store of ferritin and the importance of tubular cell damage.

Determination of Ige Complexes and of Total Ige By Latex Immunoassay

A sensitive immunoassay based on latex particle agglutination for the measurement of circulating IgE-containing complexes is described. In this method, the anti-IgE-coated particles are incubated with diluted serum and the resulting agglutination is quantified by turbidimetry or particle counting. In the latter version, the assay is fully automated in a continuous flow system. IgE-containing complexes were detected in all tested sera. Increased concentrations were observed in about 80% of the subjects with elevated serum IgE. However, high levels of IgE-complexes may also be found in subjects with a normal or even a very low serum concentration of IgE. The same latex immunoassay can be used for the determination of total IgE, after pepsin digestion of the gamma-globulin fraction of the serum. The results obtained correlate well with those found with a sandwich radioimmunoassay (r = 0.91, n = 83). The present method, however, yields a greater number of significantly positive results than the radioimmunoassay, probably because of its ability to detect IgE entrapped in circulating complexes.