Abstract
Mutations in the renal sodium-dependent phosphate co-transporters NPT2a and NPT2c 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 Npt2a-/- 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 Npt2a-/-, but not WT mice. The response of PTH to dietary phosphate of Npt2a-/- 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 Npt2a-/- was increased. These finding suggests that Npt2a-/- mice respond differently to dietary phosphate when compared to WT mice. Further evaluation in the Npt2a-/- 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 Npt2a-/- 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 NPT2a and NPT2c mutations.
Highlights
Mutations in the sodium phosphate co-transporters, NPT2a [1,2,3] and NPT2c [4, 5] cause hypophosphatemic rickets with hypercalciuria (HHRH) and idiopathic hypercalciuria (IH)
Our findings suggest that Npt2a-/- mice respond differently to dietary phosphate when compared to WT mice and that within the Npt2a-/- cohort the degree of renal mineralization positively correlates with plasma phosphate and fibroblast growth factor 23 (FGF23), and urinary calcium excretion, while it inversely correlates with urine phosphate and anion gap as a measure of proximal tubular bicarbonate and distal tubular ammonia excretion
Transmission electron images showed concentric calcium phosphate spheres similar to those described by others [29, 31] (Fig 1I and 1J). These findings suggest that dietary phosphate supports the formation of renal mineral deposits, at least under certain conditions, which is contrary to the current belief that oral phosphate supplementation reduces risk for renal calcification in phosphate wasting disorders by normalizing urine calcium excretion
Summary
Mutations in the sodium phosphate co-transporters, NPT2a [1,2,3] and NPT2c [4, 5] cause hypophosphatemic rickets with hypercalciuria (HHRH) and idiopathic hypercalciuria (IH). We are grateful to the Yale Mouse Metabolic Phenotyping Center NIH U24 DK-059635 and the Yale O’Brien Center Renal Physiology Core NIH P30DK079310 for help with biochemical analysis, the Yale Dept. Of Orthopaedics Histology and Histomorphometry Laboratory for help with histological and the Yale Center for Cellular and Molecular Imaging (YCCMI) for electron microscopic analysis and the Yale School of Medicine Dept. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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