The development of nephrocalcinosis in the rat following injections of neutral sodium phosphate.

The development of nephrocalcinosis in the rat following intraperitoneal injections of various concentrations of neutral sodium phosphate (pH 7-4) was studied using histology, histochemistry, electron microscopy and quantitative techniques. Daily injections of 0-5 M phosphate consistently produced nephrocalcinosis after 6 days or more. Calcium deposits were at first confined to the basement membranes of proximal tubules; but a longer course of injections, up to 10 days, resulted in additional basement membrane calcification in the outer cortes, and outer medulla, together with intra-luminal casts, often calcified, in the outer medulla and papilla. Calcification was not found in other organs such as liver, lung, heart or aorta. Results from quantitative estimations of total kidney calcium and phosphorus suggested that it was the calcium content which was important to the initiation of nephrocalcinosis. Ultrastructural changes, suggestive of degeneration or alteration in function, were found in mitochondria of proximal tubules in experimental animals before the onset of histologically evident nephrocalcinosis. Later changes, especially to the basal part of proximal tubular cells and their basal laminae, were thought to be consequent upon the mitochondrial changes. It is suggested that the initial renal damage was caused both directly, by a toxic effect of the phosphate load on the kidney and, indirectly, by stimulation of the parathyroid glands as a result of the hypocalcaemia and hyperphosphataemia which followed an injection of phosphate. Daily doses of 1 M phosphate for 3 days produced a type of nephrocalcinosis which was more typical of that reported by previous investigators, who used high doses of phosphate. Twice daily injections of 0-25 M phosphate for 6 days did not induce nephrocalcinosis, whereas 0-375 M phosphate given twice daily for 6 days produced only minimal calcium deposits compared with animals given 0-5 M phosphate once daily for the same period. This may have important clinical implications, since phosphate has been used to control hypercalcaemia of various etiologies.