Nucleation, adhesion, and internalization of calcium-containing urinary crystals by renal cells

Renal tubular fluid in the distal nephron is supersaturated favoring nucleation of the most common crystals in renal stones, which are composed of calcium oxalate and calcium phosphate. The mechanisms whereby these newly formed crystals can be retained in the nephron and develop into calculi are not known. Calcium oxalate monohydrate and hydroxyapatite (calcium phosphate) crystals rapidly adhere to anionic sites on the surface of cultured renal epithelial cells, but this process is inhibited by specific urinary anions such as citrate, glycosaminoglycans, uropontin, or nephrocalcin, each of which can coat the crystals. Therefore, competition for the crystal surface between soluble anions in tubular fluid and anions anchored on the apical cell surface could determine whether a crystal binds to a tubular cell. Crystals of calcium oxalate dihydrate can also nucleate directly on the surface of cultured BSC-1 cells in a face-specific manner, suggesting another potential pathway for crystal deposition in the nephron. Once present on the cell surface, calcium oxalate monohydrate, calcium oxalate dihydrate, and hydroxyapatite crystals are quickly internalized by renal cells; alterations in gene expression and initiation of proliferation may then ensue. Calcium oxalate crystals can also dissolve after renal cells internalize them, but this process may require up to several weeks. Increased knowledge about cell-crystal interactions, including identification of molecules in tubular fluid and on the cell surface that modulate the process, appear critical for understanding the pathogenesis of nephrolithiasis.