To evaluate the mechanism by which phosphate induces renal injury, we placed uninephrectomized, partially nephrectomized, and intact rats on dietary phosphorus intakes varying between 0.5 and 2% for 18 weeks. None of the animals on a normal phosphorus intake (0.5%) had any abnormalities. Four out of six intact animals on a 1% phosphorus diet had kidney calcium concentrations within the normal range, and only one showed any histologic changes. In contrast, all but one partial and uninephrectomized animals on a 1% phosphorus diet had increased kidney calcium content concentration, and five of the six studied had histologic changes. The degree of calcification and histologic changes in the uninephrectomized animals on a 1% phosphorus diet was similar to that found in the intact animals on a 2% phosphorus diet. Animals on a 3% phosphorus diet plus disodium ethane-1-hydroxy-1-1-diphosphonate (EHDP) had significantly less calcification and histologic changes than did animals on a similar diet without EHDP. Conclusion. As renal functional mass is reduced, the nephrotoxicity of phosporus is greatly enhanced. Phosphorus-induced renal injury is mediated through calcium phosphate deposition in the kidney. This results from intrarenal caused, because the kidney calcification can be related to phosphate excreted per functional unit rather than plasma phosphate concentrations.

The present study was undertaken to determine urinary and serum iron, transferrin and albumin levels in diabetic patients with varying amounts of proteinuria. A highly significant correlation was found between urinary albumin and transferrin excretion over a wide range of urinary albumin excretion (0.005 to 18 g/g creatinine) (r = 0.972). The urine/serum ratio of transferrin and albumin were identical, documenting a similar glomerular leak and tubule handling for these two proteins. In contrast to the above correlation between transferrin and albumin, there was no correlation between iron and either of these proteins until nephrotic range proteinuria had occurred, and even at that time the correlation was much weaker than that found between the proteins (r = 0.680). Urinary iron excretion increased early in the course of diabetic renal disease, being increased in 3 of 11 patients without proteinuria and in 8 of 10 patients with mild proteinuria. All patients with nephrotic range proteinuria had markedly increased urinary iron excretion (150 +/- 166 micrograms/g creatinine vs. 6.4 +/- 0.7 micrograms/g creatinine in controls) and decreased serum iron levels (592 +/- 189 micrograms/liter vs. 979 +/- 394 micrograms/liter in the control group). The iron/transferrin ratio in urine was consistently greater than the iron/transferrin ratio in plasma at all stages of proteinuria. In patients with both subnephrotic and nephrotic range proteinuria, approximately 35 to 40 micrograms Fe/g creatinine was present in the urine with an excess of transferrin. In conclusion, urinary iron excretion is increased early in the course of diabetic renal disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and experimental studies have shown that citrate markedly enhances the intestinal absorption of aluminum (Al), but the site and mechanism of enhanced absorption are unknown. To determine where in the gastrointestinal tract aluminum citrate (Alcitr) was absorbed. Alcitr was gavaged with D-[1-3H] glucose in male Sprague-Dawley rats. Plasma Al levels increased rapidly and simultaneously peaked with D-[1-3G] glucose, suggesting early proximal bowel absorption. In in vitro duodenal and jejunal everted gut preparations, Alcitr incubation resulted in increased tissue Al levels and markedly enhanced transmural transport of Al and citr. Unlike citr, the transmural movement of Al was independent of temperature (37 degrees C vs. 4 degrees C). On the other hand, Al lactate (al Lac) increased tissue associated Al levels but had no effect on transmural Al movement. To determine if this large flux of Al following Alcitr administration was due to paracellular movement, ruthenium red and Ussing chamber studies were used to evaluate the morphologic and functional integrity of cellular tight junctions. Alcitr, as opposed to AlCl3, markedly increased ruthenium red deposits in intercellular spaces, especially around goblet cells, and induced a prolonged significant reduction in transmural resistance. Alcitr also resulted in rapid and nearly complete (99.7%) chelation of free calcium, an event known to disrupt cellular tight junction integrity. Taken together, these data suggest that enhanced Al absorption following administration of Alcitr occurs in the proximal bowel via the paracellular pathway due to the opening of cellular tight junctions.

To evaluate the protective effect of dietary phosphorus restriction in an immunologic model of experimental renal disease, we randomized 24 Sprague-Dawley rats with established nephrotoxic serum nephritis into two groups. Group A animals (N = 13) were fed a diet with a normal phosphorus content (0.5% phosphorus), and group B animals (N = 11) received an identical diet low in phosphorus (0.04% phosphorus). Over the ensuing 133 days, group A rats developed progressive renal failure and had a mean serum creatinine concentration of 3.0 +/- 0.5 mg/dl at the time of death or completion of the study. In contrast, group B animals maintained near normal renal function and had a final mean serum creatinine concentration of 0.93 + 0.2 mg/dl (P < 0.001). Survival was markedly improved in group B animals (P < 0.001). Histologic damage was diminished greatly in group B animals by both light and electron microscopy; immunofluorescence was positive in all animals. Group A animals had increased kidney calcium concentration (30 +/- 6 mmoles/kg) when compared to group B animals (18 +/- 1 mmoles/kg) and animals with normal kidneys (13 +/- 1 nmoles/kg, P< 0.001). Conclusion. Dietary restriction of phosphorus retards functional deterioration and reduces histologic damage in experimental immunologic renal disease. The mechanism for this protective effect has not been elucidated.

To investigate the possibility of enhanced gastrointestinal absorption of aluminum in uremia, we measured the urinary aluminum excretion of rats following an oral load of 11 mg aluminum. Rats, in which uremia had been established by the remnant kidney model, excreted 1.5 to 2.2-fold higher amounts of aluminum in their urine over a collection period of five days compared with their controls. Within this period of time up to 0.17 +/- 0.08% of the oral dose of aluminum was recovered in the urine of the uremic animals. Serum concentrations of aluminum were significantly elevated five hours after ingestion of aluminum, but this increase was similar in rats with normal or reduced renal function. Uremic rats excreted significantly less aluminum during the first 24 hours after i.v. administration of 15 micrograms aluminum if the data were corrected for the higher baseline excretion rates. The excretion rate showed a negative correlation with the serum creatinine. Selective parathyroidectomy had no effect on the pattern or amount of urinary aluminum excretion after an oral load in either uremic rats or in rats with normal renal function. We conclude that the gastrointestinal absorption of aluminum is increased in uremic rats, and that parathyroid hormone has no detectable effect on the magnitude of aluminum absorption, regardless of the renal function in this model.

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A B S T R A C T Dietary phosphorus restriction (PR)prevents uremia in rats with nephrotoxic serum nephritis (NSN). One possible mechanism by which PR could be protective would be through the suppression of parathyroid hormone. To evaluate this possibility two separate protocols were designed. In the first rats were thyroparathyroidectomized (TPTX) before (n = 11) or 5 wk after (n = 7) NSN induction and compared to sham-operated parathyroid intact rats with NSN (n = 12). At the end of the 23-wk study, intact rats were azotemic, plasma creatinine 3.80±0.81 mg/100 ml vs. 0.65±0.07 for TPTX rats (P < 0.001). During the study 75% of intact rats died of uremia in contrast to none of the TPTX rats (P < 0.001). Renal histological damage was greatly diminished and calcification prevented in TPTX rats. The proteinuria of the heterologous phase was unaffected, but the protein excretion and hypertriglyceridemia (HTG) of the autologous phase were markedly decreased in the TPTX rats. The degree of HTG and proteinuria had a high positive correlation (P < 0.001). Late TPTX also produced significant decreases in proteinuria and HTG regardless of the degree of azotemia, and prevented azotemia if the plasma creatinine at the time of TPTX was -0.85 mg/ 100 ml.In additional studies selective parathyroidectomy (PTX) was performed. TPTX animals. However, selective PTX had no effect on proteinuria, histologic damage, or functional deterioration. These studies further showed that early, histologic damage and functional deterioration preceeded renal parenchymal calcification. Because animals were pair fed and both groups were given 1,25-dihydroxycholecalciferol to normalize serum Ca and P levels these studies exclude alterations in plasma Ca and P levels, dietary intake, urinary P excretion, and vitamin D administration in promoting the protective effect of TPTX on renal function.We conclude that TPTX is equally effective in preventing functional deterioration and more effective in reducing proteinuria in NSN than PR.

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