In summary, we show here that urine PPi is increased in Npt2a-/- mice. Presence of one or two hypomorphic Enpp1asj alleles decreases urine PPi and increases renal mineral deposits in Npt2a-/- mice. Furthermore, the development of nephrocalcinosis and nephrolithiasis 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.