We here report that urine PPi levels are increased in Npt2a-/- mice when compared to WT mice, possibly to protect from renal mineralization in the setting of hyperphosphaturia. Presence of two hypomorphic Enpp1asj/asj alleles decreases urine PPi and worsens renal calcium phosphate deposit formation in Npt2a-/- mice. Conversely, development of mineral deposits in these mice can be reduced by intraperitoneal administration of sodium pyrophosphate. These studies suggest that PPi may be a thus far unrecognized factor modulating the development of renal calcifications in Npt2a-/- mice which may be, if confirmed in humans, of diagnostic and therapeutic relevance for phosphaturic disorders.