Magnesium (Mg) is the second most abundant cation in the intracellular fluid (ICF) . It is involved in the majority of metabolic processes. In addition, it plays a part in DNA and protein synthesis . Magnesium is involved in the regulation of mitochondrial function, in inflammatory processes and immune defense, allergy, growth, and stress, and the control of neuronal activity, cardiac excitability, neuromuscular transmission, vasomotor tone, and blood pressure.

The intestinal absorption of dietary Mg occurs mainly in the distal small intestine and the colon. Various factors modify intestinal Mg absorption. In addition to high magnesium intake, high dietary phosphate intake is inhibitory, as is high phytate consumption. Magnesium is mainly eliminated by the kidney. Losses through intestinal secretion and sweat are negligible under normal conditions.

Magnesium deficiency is defined as a decrease in total body magnesium content. Poor dietary intake of magnesium is usually not associated with marked magnesium deficiency because of the ability of the intestine to increase Mg absorption and the kidney to conserve Mg. However, prolonged and severe dietary magnesium restriction of less than 0.5 mmol/day can produce symptomatic magnesium deficiency. Underlying causes are usually GI diseases , in particular malabsorption syndromes and massive resection of the small intestine. Hypomagnesemia can also be induced by prolonged tube feeding without magnesium supplements and excessive use of non-magnesium-containing laxatives. Renal losses mostly happened due to diuretic use (Fig. 9.1).

Hypomagnesuria (defined variably as 24-h urine Mg <60 mg) may result from hypomagnesemia. Other clinical manifestations of moderate to severe magnesium depletion include generalized weakness and neuromuscular hyperexcitability with hyperreflexia, carpopedal spasm, seizure, tremor, and rarely tetany. Cardiac findings include a prolonged QT interval and ST depression. Magnesium deficiency can also be associated with hypocalcemia (decreased parathyroid hormone (PTH) release and end-organ responsiveness) and hypokalemia (urinary loss).

Hypomagnesuric calcium nephrolithiasis is characterized by low urinary magnesium, hypocitraturia, and low urine volume. Mg acts as a competitor to calcium in oxalate binding. However, Mg oxalate (MgOx) is more soluble than calcium oxalate (CaOx), 0.07 g/100 mL versus 0.0007 g/100 mL, respectively; so MgOx does not form stones at physiological urine concentrations. Because Mg competes with Ca in binding oxalate, both in the gut and urine, the ratio of Mg/Ca in the urine has been used as an estimate of stone risk [23].

Also Mg in combination with citrate, another inhibitor, is more effective than either alone. Mg citrate slowed crystal growth rate, nucleation rate, and supersaturation [24]. Another study found Mg supplements alone had no effect, but Mg with citrate increased pH and lowered the relative saturation of brushite in urine [25]. Recently a mixture of Mg and phytate shows a synergistic effect of delaying calcium oxalate crystallization [26].

A second way Mg may reduce the CaOx stone risk is through its effect on oxalate absorption. Even though MgOx is 100 times more soluble than CaOx, it is still relatively insoluble. Because of this property, Mg binds oxalate in the gut and reduces its absorption [27, 28].

Several benefits supporting the use of oral magnesium (Mg) salts have been suggested. First, higher urinary Mg excretion may reduce the availability of oxalate to complex with calcium as Mg binds with oxalate to form a relatively soluble complex in urine. Second, higher urinary Mg concentration results in a more favorable magnesium-to-calcium ratio, a condition that offers relative protection against stone formation. Finally, Mg decreases renal tubular citrate resorption through the chelation of citrate and thus increases urinary citrate excretion [5].

Several Mg salts have been used for the treatment of stone disease. Magnesium oxide (MgOx) and magnesium hydroxide are poorly absorbed and produce only a slight decrease in urinary oxalate and a modest increase in urinary magnesium [29]. Additionally, urinary calcium levels are increased during magnesium oxide supplementation [31, 32], and thus urinary saturation of calcium oxalate is not significantly lowered with magnesium oxide. The more soluble forms of Mg are chloride, gluconate, aspartate, and citrate. Mg citrate doubled the Mg/Cr ratio 2–4 h after oral loading, while MgOx only increased the ratio by 3% [30].

A new magnesium preparation (potassium-magnesium citrate ) has been developed. It provides both magnesium and citrate in the same tablet. This formulation of potassium-magnesium citrate has been shown to provide as much bioavailable potassium as other preparations. Ettinger reported results from a randomized, double-blind trial of potassium-magnesium citrate versus placebo. In this study, 64 recurrent stone formers were randomly assigned to receive placebo or potassium-magnesium citrate (42 mEq potassium, 21 mEq magnesium, and 63 mEq citrate) daily for up to 3 years. The result was new calculi formed in 63.6% of subjects receiving placebo and in 12.9% of subjects receiving potassium-magnesium citrate [33]. When compared with placebo, the relative risk of treatment failure for potassium-magnesium citrate was 0.16. He concluded that potassium-magnesium citrate effectively prevented recurrent calcium oxalate stones and could be depended on to provide up to 85% protection over 3 years.

Several limitations of using magnesium salts to prevent nephrolithiasis are as follows:

Regardless of conflicting clinical and laboratory data regarding the benefits of Mg salts, epidemiological evidence supports the probable effectiveness of increased magnesium in preventing symptomatic kidney stones. Taylor et al. followed 45,619 men for 14 years, with dietary assessments every 4 years [40]. After multivariate adjustment, the relative risk of stone formation for subjects with the highest quintile of magnesium intake (over 450 mg/day) compared to the lowest quintile (less than 314 mg/day) was 0.71. Consequently, this decreased risk supports Mg supplementation for those with Mg deficiency.

Over 50 years ago, Fourman et al. linked potassium deficiency to a decrease in urinary citrate levels [35]. Potassium depletion results in intracellular acidosis, which in turn decreases the pH of the tubular lumen [36]. Decreasing tubular pH increases reabsorption of citrate, thereby decreasing the urinary concentration of citrate [37, 38].