Magnesium, citrate, magnesium citrate and magnesium-alkali citrate as modulators of calcium oxalate crystallization in urine: observations in patients with recurrent idiopathic calcium urolithiasis

Abstract

The effects of magnesium (Mg) and citrate on the metastable limit of calcium oxalate (CaOx) solubility (synonym: tolerable oxalate TO) were examined in artificial urine and in postprandial urine of male patients with idiopathic calcium urolithiasis (ICU). In artificial urine increasing pH, Mg and citrate elevate TO, decrease CaOx supersaturation only marginally, but elevate considerably free citrate; the effect of Mg alone was small in comparison with citrate alone, and the effects of both substances appeared additive. In ICU patients, matched for sex, age and CaOx supersaturation to non-stone-forming controls, TO was decreased (mean values 0.33 vs. 0.52 mM/l in controls, P < 0.05). Additional significant (P < 0.05) differences were found between ICU and controls: the former exhibited increased CaOx crystal growth, decreased crystal agglomeration time, a more acidic urinary pH, increased concentrations of free calcium and free Mg, and decreased free oxalate and free citrate. After ingestion of a urine-acidifying test meal, or this meal supplemented with either neutral Mg citrate or Mg-alkali citrate, by three groups of male ICU patients, matched for age and CaOx supersaturation, only the last-named preparation evoked an increase in TO and a decrease in crystal diameter, while the normally occurring pH decline from fasting urine was virtually abolished, and the ratios urinary Mg/citrate and calcium/citrate tended towards low values. In contrast, Mg citrate increased crystal agglomeration time, while changes in the other parameters were only insignificant. The crystals formed in urine were CaOx di- and monohydrate (by electron microscopy), and energy dispersive X-ray analysis showed calcium peaks exclusively. However, chemical analysis of crystals verified the presence not only of oxalate and calcium, but also of Mg, phosphate, citrate, and urate; moreover, these crystal constituents seemed to be influenced by Mg citrate and Mg-alkali citrate in different ways. It was concluded that (1) Mg and citrate are effectors of TO in artificial and natural urine; (2) in ICU, low TO and other disturbed CaOx crystallization parameters appear related to the prevailing low urinary pH and low free citrate; (3) Mg-alkali citrate inhibits CaOx crystallization, probably via actions of the citrate, but not the Mg. Because of the eminent role of Mg in human health and ICU, further studies on crystallization after oral intake of Mg in the form of citrate are warranted.

Mechanism of Urinary Calcium Regulation by Urinary Magnesium and pH

“…Our results suggest that high urinary magnesium can increase calciuria and potentially increase stone risk. Some have espoused the notion that magnesium is efficacious in preventing stone formation by binding or complexing oxalate in the bowel and urine, 26,27,40,41 by inhibiting calcium oxalate crystal formation, 26,42,43 and by increasing urinary citrate when given as alkali salt. 44 In vitro studies have shown that magnesium is an inhibitor of calcium oxalate crystal growth in artificial, rodent, and human urine but at supraphysiologic concentrations.…”

“…51 TRPV5 is critical in that process, and its deletion in the mouse leads to pronounced hypercalciuria. 43 TRPV5 is regulated by numerous calcitropic hormones but also by its own transported substrate. 52 As intracellular calcium concentration rises, TRPV5 open probability decreases drastically.…”

Effect of Magnesium on Calcium and Oxalate Ion Binding

“…5 All ions studied used the CHARMM27 force field. 6,7 Force field parameters determined by Yesselman and associates 8 via MATCH were used for Ox 2 -and citrate (Cit 3 -), while those for phosphate (PO 4 3 -) and dihydrogen phosphate (H 2 PO 4 -) were determined using CHARMM general force field (CGenFF) 9 in the CHARMM program. The standard TIP3P potential model was used for water.…”

“…For systems 7 and 8, citrate was inserted to evaluate its effect on aggregates. Systems 9 and 10 were generated from systems 4 and 6 by replacing their PO 4 3 -ions with H 2 PO 4 -to model an acidic urine environment. This allows us to study how pH influences Ca 2 + -Ox 2 -aggregation.…”

“…[1][2][3][4] Using molecular dynamics and theoretical chemistry modeling, we examine the role of the Mg 2 + ion in calcium and oxalate binding.…”