Calcium oxalate crystal deposition in kidneys of hypercalciuric mice with disrupted type IIa sodium-phosphate cotransporter

Abstract

The most common theories about the pathogenesis of idiopathic kidney stones consider precipitation of calcium phosphate (CaP) within the kidneys critical for the development of the disease. We decided to test the hypothesis that a CaP substrate can promote the deposition of calcium oxalate (CaOx) in the kidneys. Experimental hyperoxaluria was induced by feeding glyoxylate to male mice with knockout (KO) of NaP(i) IIa (Npt2a), a sodium-phosphate cotransporter. Npt2a KO mice are hypercalciuric and produce CaP deposits in their renal tubules. Experimental hyperoxaluria led to CaOx crystalluria in both the hypercalciuric KO mice and the normocalciuric control B6 mice. Only the KO mice produced CaOx crystal deposits in their kidneys, but the CaOx crystals deposited separately from the CaP deposits. Perhaps CaP deposits were not available for a CaOx overgrowth. These results also validate earlier animal model observations that showed that CaP substrate is not required for renal deposition of CaOx and that other factors, such as local supersaturation, may be involved. The absence of CaOx deposition in the B6 mice despite extreme hyperoxaluria also signifies the importance of both calcium and oxalate in the development of CaOx nephrolithiasis.

Oxalate: From the Environment to Kidney Stones

“…This indicates CaP deposits are not required for the crystallisation and deposition of CaOx, as had been indicated in certain in vitro experiments (158) and in vivo monitoring of stone-forming patients (159). Although it is likely that CaOx crystals can form over CaP plaques, especially if they are formed on a suitable position along the nephron, CaP plaques are not necessary for stone formation since patients that underwent an obesity-related bypass procedure formed CaOx stones without having CaP plaques (157,159).…”

“…One of them is the sodium-phosphate cotransporter IIa (NaPi-IIa), a member of the transporter family SLC34 (SLC34A1/ Slc34a1). NaPi IIa KO mice developed hypercalciuria and deposited both CaP and CaOx crystals in their kidneys in contrast to WT mice, and these data stressed that crystallisation occured when hyperoxaluria was linked to high Ca 2+ concentrations (157). However, CaP deposits can form separately from CaOx deposits (158).…”

Clinical Consequences of Mutations in Sodium Phosphate Cotransporters

“…The presumed pathogenesis for nephrocalcinosis and nephrolithiasis in the Npt2a null mouse is stimulation of 1,25 vitamin D production by hypophosphatemia, resulting in enhanced intestinal calcium absorption and subsequent hypercalciuria. Mice lacking Npt2a function show a high incidence of intratubular calcium phosphate crystals within the first month of life that diminish with age and interstitial calcium phosphate deposits that do not disappear with aging (55)(56)(57)(58)(59). The calcium deposits in the Npt2a-deficient mice are predominantly in the cortex and outer medulla, in contrast to human nephrocalcinosis associated with stone formation that generally occurs in the medulla and papilla.…”

Unified theory on the pathogenesis of Randall’s plaques and plugs

“…They produce both intratubular and interstitial deposits of CaP crystals. [48–50] However, these interstitial deposits are not similar to the interstitial plaques seen in stone patients as they appear to start within the renal tubular lumen and eventually become relocated into the interstitium (Figure 5). [51]…”