Response of <i>Npt2a</i> knockout mice to dietary calcium and phosphorus

<div><p>Mutations in the renal sodium-dependent phosphate co-transporters <i>NPT2a</i> and <i>NPT2c</i> have been reported in patients with renal stone disease and nephrocalcinosis, but the relative contribution of genotype, dietary calcium and phosphate to the formation of renal mineral deposits is unclear. We previously reported that renal calcium phosphate deposits persist and/or reappear in older <i>Npt2a</i>^<i>-/-</i> mice supplemented with phosphate despite resolution of hypercalciuria while no deposits are seen in wild-type (WT) mice on the same diet. Addition of calcium to their diets further increased calcium phosphate deposits in <i>Npt2a</i>^<i>-/-</i>, but not WT mice. The response of PTH to dietary phosphate of <i>Npt2a</i>^<i>-/-</i> was blunted when compared to WT mice and the response of the urinary calcium x phosphorus product to the addition of calcium and phosphate to the diet of <i>Npt2a</i>^<i>-/-</i> was increased. These finding suggests that <i>Npt2a</i>^<i>-/-</i> mice respond differently to dietary phosphate when compared to WT mice. Further evaluation in the <i>Npt2a</i>^<i>-/-</i> cohort on different diets suggests that urinary calcium excretion, plasma phosphate and FGF23 levels appear to be positively correlated to renal mineral deposit formation while urine phosphate levels and the urine anion gap, an indirect measure of ammonia excretion, appear to be inversely correlated. Our observations in <i>Npt2a</i>^<i>-/-</i> mice, if confirmed in humans, may be relevant for the optimization of existing and the development of novel therapies to prevent nephrolithiasis and nephrocalcinosis in human carriers of <i>NPT2a</i> and <i>NPT2c</i> mutations.</p>