Intracrystalline Proteins and the Hidden Ultrastructure of Calcium Oxalate Urinary Crystals: Implications for Kidney Stone Formation

Modulation of Calcium Oxalate Dihydrate Growth by Selective Crystal-face Binding of Phosphorylated Osteopontin and Polyaspartate Peptide Showing Occlusion by Sectoral (Compositional) Zoning

“…Taken together, these results demonstrate that poly-Asp 86 -93 (and very likely other acidic peptides of OPN generated by proteolytic cleavage) binds to COD, inhibits growth normal to the {110} face, and exclusively occludes into its {110} growth sectors. These results are consistent with a variety of other in vitro studies suggesting intracrystalline OPN in urinary COD crystals (1,23,24,36).…”

“…In addition to small-molecule inhibitors like citrate, currently available in vitro and in vivo evidence suggest that urinary proteins such as OPN and trefoil factor 1 (TFF1) present in urine likewise serve as inhibitors of calcification (51, 56 -59) and, moreover, may potentially decrease crystal retention and aggregation (55,57). In addition, emerging data show that OPN may potentially direct the formation of COD and in the process incorporate (occlude) into the crystal structure (1,23,36). Interesting proposals for this occlusion include facilitating dissolution of the crystals from the inside-out by providing intracrystalline channels for fluid movement and facilitating phagocytosis of crystals by renal tubular cells for clearance of crystals from the urine (24,36,60,61).…”

“…In addition, emerging data show that OPN may potentially direct the formation of COD and in the process incorporate (occlude) into the crystal structure (1,23,36). Interesting proposals for this occlusion include facilitating dissolution of the crystals from the inside-out by providing intracrystalline channels for fluid movement and facilitating phagocytosis of crystals by renal tubular cells for clearance of crystals from the urine (24,36,60,61).…”

“…Intracrystalline organics can also be components of biominerals that dislocate the mineral structure, distorting crystal lattice (85) and modifying their thermodynamic properties (86), thus rendering them more unstable and dissolvable. In this regard, recent studies have shown that urinary proteins situated within the bulk mineral phase of calcium oxalate raise lattice strains and reduce crystallite size because of intracrystalline defects and discontinuities, which in turn allow proteolytic invasion and crystal dissolution (36,60,87).…”

“…Furthermore, OPN also contains sialic acid (26,27), which may play an indirect role in crystal binding by forming a bridge between transiently expressed crystal binding molecules and the cell surface (12). Several studies have shown that OPN has a higher affinity for COD than COM in normal urinal precipitates, with some evidence given for the incorporation of protein into calcium oxalate crystals (1,23,36).…”