Influence of 2,3-dimercaptopropane-1-sulfonate (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) on the renal disposition of mercury in normal and uninephrectomized rats exposed to inorganic mercury.

The effects of the water-soluble chelating agents 2,3-dimercapto-1-propane sulfonate (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) on the renal disposition of inorganic mercury were studied in normal and uninephrectomized (NPX) rats injected (i.v.) with a nontoxic 0.5-mumol/kg dose of mercuric chloride (HgCl2). When a 100-mg/kg dose of either DMPS or DMSA was injected (i.p.) 24 and 30 hr after treatment with HgCl2, the renal concentration and burden of inorganic mercury decreased markedly in both normal and NPX rats during the 24 hr after the first dose of the respective chelating agent was administered. Treatment with DMPS was more effective than treatment with DMSA in reducing the renal burden of mercury in both groups of rats. The fall in the renal concentration and burden of mercury in both normal and NPX rats was due primarily to a decrease in the content of mercury in the renal cortex and outer stripe of the outer medulla. However, the decrease in the concentration of inorganic mercury in the outer stripe was significantly greater in NPX rats than in normal rats. Both chelating agents caused urinary excretion of mercury to increase significantly in normal and NPX rats. In association with the increased renal release of mercury in NPX rats, the urinary excretion of mercury per gram of kidney was significantly greater in NPX rats than in normal rats. These data indicate that the renal handling of DMPS and DMSA may be altered significantly after a substantial reduction in renal mass. Findings from the present study also show that treatment with DMPS, but not with DMSA, causes the content of mercury in the liver and cellular fraction of blood to decrease in normal and NPX rats. These findings indicate that there are significant differences in the extrarenal handling of these two chelating agents. The findings in the present study suggest that DMPS and DMSA are very effective agents in reducing the renal (and whole body) burden of inorganic mercury in normal and NPX rats.

An evaluation of Tiron (sodium 4,5-dihydroxybenzene-1,3-disulfonate) as a rescue agent for the nephropathy induced by uranyl fluoride (UO2F2) in rats.

Tiron (sodium 4,5-dihydroxybenzene-1,3-disulfonate) was tested as a potential rescue agent for the nephropathy induced by uranyl fluoride (UO2F2) in rats. When uranyl fluoride was administered (i.v.) to male Sprague-Dawley rats at a dose that delivered 250 micrograms U/kg, moderate to severe cellular necrosis occurred in pars recta segments of proximal tubules in the cortex and outer stripe of the outer medulla of the rats' kidneys within four days after treatment. The severity of renal tubular injury was not significantly diminished when rats were given a 10, 100 or 1,000 mg/kg dose of Tiron (i.p.) 30 minutes after the administration of uranyl fluoride. No obvious protection was noted even when the rats were given a 1,000 mg/kg dose of Tiron 15, 30 and 90 minutes after the administration of uranyl fluoride. Therefore, Tiron does not appear to provide rats substantial protection against a dose of uranyl fluoride that induces moderate to severe renal injury.

Nephrotoxicity of uranyl fluoride in uninephrectomized and sham-operated rats.

The aim of the present study was to determine whether the nephrotoxicity of the uranium-containing compound uranyl fluoride (UO2F2) is enhanced after unilateral nephrectomy. Unilaterally nephrectomized (NPX) and sham-operated (SO) rats were given single intravenous injections of UO2F2 at doses delivering 100 or 250 micrograms U/kg 16 days after surgery. Between the second and third day after the administration of either dose of UO2F2, the urinary excretion of the cellular enzymes lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) and the plasma solute albumin began to increase significantly in both the NPX and SO rats. The urinary excretion of the plasma solute glucose did not begin to increase significantly in the NPX and SO rats until 4 days after the administration of either dose of UO2F2. During the fifth day following the administration of either dose of UO2F2 (which was also the last day that urinary data were collected) the urinary excretion of LDH, AST, and glucose in the NPX and SO rats was greater than that during any previous day. The urinary excretion of these three compounds during this fifth day was greater in the SO rats than in the NPX rats. Also during the fifth day following the injection of either dose of UO2F2, the fractional excretion of glucose was higher in the SO rats than in the NPX rats. By the end of the fifth day, the level of histologically demonstrable cellular necrosis in the pars recta of proximal tubules in the renal cortex and outer medulla of the NPX and SO rats was statistically similar. Therefore, the nephropathy in rats induced by UO2F2 is not made more severe as a result of unilateral nephrectomy.

Nephrocalcinosis and diets containing alkali- and non-alkali-treated soy protein.

Diets containing alkali-treated soy protein have been shown to cause nephrocalcinosis in rats. In order to determine if alkali-treated soy protein is the dietary component that induces nephrocalcinosis, the effects of a purified diet containing 20% alpha-protein (an alkali-treated soy protein) were compared with the effects of the same diet containing 20% promine-D (a non-alkali-treated soy protein) on renal morphology and renal calcium and phosphorus metabolism. After a 9-week feeding trial, light and transmission electron microscopy revealed that the animals fed either the alpha-protein or promine-D diet developed nephrocalcinosis. In fact, the type of nephrocalcinosis was the same in both groups of animals. Moreover, quantitative determinations of total renal calcium and phosphorus showed that the severity of nephrocalcinosis was also the same in the two groups. No signs of nephrocalcinosis were detected in rats fed a standard commercial laboratory diet. Since nephrocalcinosis was present in the animals fed the promine-D diet, and that it was identical to that found in the animals fed the alpha-protein diet, it appears that alkali-treated soy protein is not the factor responsible for nephrocalcinosis in rats fed a diet containing the protein.

The effects of parathyroidectomy on the development of nephrocalcinosis in rats fed phosphate-supplemented and unsupplemented diets containing alpha protein.

The effects of parathyroidectomy (PTX) on the development of nephrocalcinosis in rats fed a diet containing alpha protein were investigated for the purpose of determining whether the nephrocalcinosis was phosphate-induced. PTX completely prevented the occurrence of nephrocalcinosis in rats fed a phosphate-supplemented commercial laboratory diet for 4 weeks. However, PTX did not completely prevent the occurrence of nephrocalcinosis in rats fed a phosphate-supplemented alpha protein diet. Several calciferous deposits were found in the inner medulla. The same was also found in rats that underwent sham operations and PTX rats fed the basal alpha protein diet. Total renal calcium and phosphorous levels in these three groups were also similar and were about twice as great as those in corresponding groups fed phosphate-supplemented and unsupplemented commercial laboratory diets. Therefore, we conclude that the nephrocalcinosis in rats fed a basal alpha protein diet is not induced by PTH or excess phosphate, but is induced by some other factor associated with the diet.

Phosphate and the development of nephrocalcinosis in rats fed diets containing alpha protein.

It has been suggested that nephrocalcinosis in rats fed diets containing alkali-treated soy protein may be due to a high availability of phosphate in the diet. In the present study, the development of nephrocalcinosis in rats fed a diet containing 20% alpha protein (an alkali-treated soy protein) was compared with that in rats fed the same diet supplemented with additional phosphate. Phosphate supplementation of the alpha protein diet produced a form of nephrocalcinosis that was morphologically different, at both the light- and electronmicroscopic level, from that obtained with the unsupplemented diet but was quite similar to that obtained with a phosphate-supplemented standard commercial laboratory diet. Levels of serum and urinary calcium and phosphorus and urinary cyclic AMP suggested that a phosphate-induced secondary hyperparathyroidism was present in the rats fed either of the phosphate-supplemented diets, but not in the rats fed the unsupplemented alpha protein diet. The results of this study suggest that nephrocalcinosis in rats fed a diet containing 20% alpha protein, without additional phosphate, is not typically phosphate-induced.