Cell-Crystal Interactions and Kidney Stone Formation

Abstract

Background: Renal tubular fluid in the distal nephron is supersaturated with calcium and oxalate ions that nucleate to form crystals of calcium oxalate monohydrate (COM), the most common crystal in renal stones. How these nascent crystals are retained in the nephron to form calculi in certain individuals is not known. Methods: The results of experiments conducted in this and other laboratories that employ cell culture model systems to explore renal epithelial cell-urinary crystal interactions are described. Results: COM crystals rapidly adhere to anionic sites on the surface of cultured renal epithelial cells, but this process can be inhibited, if specific urinary anions such as glycosaminoglycans, uropontin, nephrocalcin, or citrate are available to coat the crystalline surface. Therefore, competition for the crystal surface between soluble anions in tubular fluid and anions on the apical cell surface could determine whether or not a crystal binds to the cell. A similar paradigm describes adhesion of calcium phosphate (hydroxyapatite) crystals, also a common constituent of human stones. Once bound, COM and hydroxyapatite crystals are quickly internalized by renal cells; reorganization of the cytoskeleton, alterations in gene expression, and initiation of proliferation may then ensue. Each of these cellular events appears to be regulated by a different set of extracellular factors. Over several weeks in culture, renal cells (BSC-1 line) dissolve internalized crystals, although once a cell binds a crystal, additional crystals are more likely to bind, possibly forming a positive feedback loop that results in kidney stone formation. Conclusions: Increased knowledge about the cell-crystal interaction, including identification of molecules in tubular fluid and on the cell surface that modulate the process, and understanding its mechanism of action appear critical for explaining the pathogenesis of nephrolithiasis.

Interaction between submicron COD crystals and renal epithelial cells

“…Third, endocytosis occurred as early as 30 minutes after exposure of the cells to the crystals. 17 During endocytosis, the formed cell-crystal complexes appeared to separate from the monolayer, and large gaps appeared at cell-cell contact regions. 18 Changes in Vero cell viability during crystal adhesion Figure 4A shows the changes in cell viability during the process of adhesion between Vero cells and submicron COD.…”

“…17 Many studies showed that cell injury could be triggered by crystal endocytosis. 17,18,34 COM crystals could be actively endocytosed individually or as aggregates by Madin-Darby canine kidney cells. 22 The crystals were intermingled with microvilli and cilia at the surface, and adjacent cells were structurally altered.…”

Epidemiology and medical management of stone disease

“…Urinary macromolecules, e.g. glycoproteins, proteins and glycosaminoglycans, adherent or bound to the crystals, counteract both crystal aggregation and crystal growth [12,20], and macromolecules are also important for the adherence of crystals to the tubular cells and for crystal-cell interaction [21,22].…”

Expression Profiling of Crystal-Induced Injury in Human Kidney Epithelial Cells

“…The adhesion of COM crystals to epithelial cells stimulates the expression of several groups of genes, including transcription factors, growth factors, and genes involved in proliferation of epithelial cells and in remodeling of the extracellular matrix [35]. Each of these cellular events may be regulated by a different set of extracellular signal transducers.…”