Citrate Modulates Calcium Oxalate Crystal Growth by Face-Specific Interactions

Abstract

Because of its ability to inhibit the growth of calcium oxalate monohydrate (COM) crystals, citrate plays an important role in preventing the formation of kidney stones. To determine the mechanism of inhibition, we studied the citrate-COM interaction using a combination of microscopic and simulation techniques. Using scanning confocal interference microscopy, we found that addition of citrate preferentially inhibits crystal growth in <100> and, to a lesser extent, <001> directions, suggesting that citrate adsorbs to the faces of COM in the order {100} > {121} > {010}. Scanning electron microscopy showed that the resulting crystals are plate shaped, with large {100} faces and rounded ends. Molecular-dynamics simulations predicted, however, that citrate interacts with the faces of COM in a different order, i.e. {100} > {010} > {121}. Our simulations showed that citrate molecules align with the rows of Ca²⁺ ions on the {010} face but do not form close contacts, presumably because of electrostatic repulsion by the carboxylate groups that project from the Ca²⁺-rich plane. We propose that this weak interaction is responsible for citrate’s limited inhibition of COM growth in <010> directions. Overall, these findings indicate that electrostatic interactions with the Ca²⁺-rich faces of COM crystals are responsible for the growth-modulating properties of citrate.

Kidney Stones in Primary Hyperoxaluria: New Lessons Learnt

“…It is well known that citrate and magnesium inhibit nucleation and growth of CaOx stones [25]–[29]. As COD is stable in pH ranges from 5 to 7.4 [30] citrate and magnesium affect crystallization by direct interaction with the crystallizing matter rather than by increasing its solubility due to the induced change in pH [30], [31]. In addition, pyridoxine (vitamin B6) the cofactor for the defective enzyme AGT (PH I), markedly reduces urinary oxalate excretion in susceptible PH I patients [18], [19] resulting in an overall effect of lowering or even eliminating CaOx stone formation in response.…”

The osteopontin-controlled switching of calcium oxalate monohydrate morphologies in artificial urine provides insights into the formation of papillary kidney stones

“…Grohe et al [37,57]). SEM analysis also show that penetration twins crystallized under the present conditions indicate no sign of {021} face development, as observed after long-term growth (≥ 180 min.)…”

Urinary citrate excretion in healthy children depends on age and gender

“…Citrate creates soluble complexes with calcium, thereby effectively reducing urinary calcium supersaturation and preventing the nucleation of both calcium oxalate and calcium phosphate [1, 2]. In addition, citrate can directly inhibit calcium oxalate crystal growth, aggregation and attachment to renal epithelial cells by adsorbing to crystal surfaces [3, 4]. Citrate enhances the inhibitory effect of Tamm–Horsfall protein on calcium oxalate aggregation and may reduce the expression of urinary osteopontin, which is a common component of the urinary stone matrix [5].…”