Abstract
Mutations in the proximal tubular sodium-dependent phosphate co-transporters NPT2a and NPT2c have been reported in patients with renal stone disease and nephrocalcinosis, however the relative contribution of genotype, dietary calcium and phosphate, and modifiers of mineralization such as pyrophosphate (PPi) to the formation of renal mineral deposits is unclear. In the present study, we used Npt2a-/- mice to model the renal calcifications observed in these disorders. We observed elevated urinary excretion of PPi in Npt2a-/- mice when compared to WT mice. Presence of two hypomorphic Extracellular nucleotide pyrophosphatase phosphodiesterase 1 (Enpp1asj/asj) alleles decreased urine PPi and worsened renal calcifications in Npt2a-/- mice. These studies suggest that PPi is a thus far unrecognized factor protecting Npt2a-/- mice from the development of renal mineral deposits. Consistent with this conclusion, we next showed that renal calcifications in these mice can be reduced by intraperitoneal administration of sodium pyrophosphate. If confirmed in humans, urine PPi could therefore be of interest for developing new strategies to prevent the nephrocalcinosis and nephrolithiasis seen in phosphaturic disorders.
Highlights
Mutations in the sodium phosphate co-transporters NPT2a [1,2,3] and NPT2c [4, 5] have been associated with intraluminal stones and mineral deposits in the renal parenchyma in patients with familial forms of hypophosphatemia
There is concern that oral phosphate therapy might contribute to the formation of renal mineralization despite reduced 1,25(OH)2D levels and reduced urinary calcium excretion under certain conditions, for example in patients with X-linked hypophosphatemia (XLH) treated with oral phosphate supplements given multiple times throughout the day [44, 45] and in otherwise healthy individuals following treatment with phosphate enema [46]
We recently reported that reduced urine levels of osteopontin (Opn), an extracellular matrix factor affecting binding of phosphate to hydroxyapatite crystals, contribute to the development of nephrocalcinosis in Npt2a-/- mice [12]
Summary
Mutations in the sodium phosphate co-transporters NPT2a [1,2,3] and NPT2c [4, 5] have been associated with intraluminal stones (nephrolithiasis) and mineral deposits in the renal parenchyma (nephrocalcinosis) in patients with familial forms of hypophosphatemia. NPT2a has been associated with nephrolithiasis [6] and altered renal function [7, 8]. With both genetic abnormalities affected individuals show renal phosphate-wasting, high circulating levels of 1,25(OH)2D, and absorptive hypercalciuria as a result of increased intestinal uptake of calcium [4, 5, 9, 10], and oral phosphate supplements are currently thought to reduce the risk for renal mineralization by lowering circulating levels of 1,25 (OH)2D and absorptive hypercalciuria [11]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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