Nature Made? High Potency Magnesium 400 Mg, 60-Count
Can magnesium preparations reduce the risk of urolithiasis recurrence?
Magnesium ranks fourth among the body cations and second after potassium among intracellular cations. The total magnesium of the body is approximately 2000 meq or 25 g. Similarly, calcium contains only a small portion of magnesium (about 1%) in extracellular fluid. Approximately 60% of the total magnesium of the human body is found in bone tissue, where most of it is associated with apatite crystals. A significant amount of magnesium in bone tissue is represented as ions that can actively exchange with serum ions.
Approximately 360 mg (15 mmol) of magnesium is supplied daily with food. A significant portion of magnesium is supplied by green vegetables. The minimum intake of magnesium in an amount of 0.3 mEq / kg body weight is necessary to maintain magnesium balance in humans. Approximately one third of the total magnesium ingested with food is excreted in the urine, the rest is excreted.
Thus, when on a normal diet containing about 360 mg of magnesium, 30-40% of the magnesium ingested with food is absorbed mainly in the small intestine. A small amount of magnesium, about 40 mg (1.7 mmol) is secreted in the gastrointestinal tract in the composition of the digestive juices and about 20 mg (0.8 mmol) is absorbed back into the large intestine [1].
Absorption of dietary calcium from the gastrointestinal tract is an active process, whereas magnesium is absorbed mainly due to ionic diffusion, and also due to a simple reverse flow of water, without the participation of cellular ionic pumps and membrane transport proteins. Hypermagnesemia inhibits the production of parathyroid hormone, and acute hypomagnesemia stimulates the secretion of this hormone, which increases the absorption of magnesium from the gastrointestinal tract [1].
At the same time, clinical observations show that the majority of patients with chronic magnesium deficiency, manifested by hypomagnesemia and hypocalcemia, have normal or slightly reduced levels of parathyroid hormone, indicating an inadequately low parathormone secretion under conditions of chronic magnesium deficiency [24].
The kidneys filter approximately 2 g of magnesium per day, about 100 mg is excreted in the urine. Unlike other ions, magnesium reabsorption in the kidneys does not occur in the proximal tubules, but in the thick ascending portion of the loop of Henle, where up to 60-70% of magnesium is reabsorbed [5, 6].
Thus, most of the filtered magnesium is reabsorbed and only about 5% of it is excreted in the urine. In a state of magnesium deficiency, the kidneys are able to reduce the amount of magnesium excreted in the urine to 0.5% or less of the filtered amount. On the other hand, during the infusion of magnesium or in patients with advanced renal failure, the kidneys are capable of removing 40-70% of the filtered amount of magnesium. The concentration of magnesium in the blood plasma is the main physiological regulator of its excretion in the urine [5, 6].
Hypermagnesemia inhibits the renal reabsorption of magnesium (and calcium) in the loop of Henle, while hypomagnesemia stimulates this process, thereby preventing the loss of magnesium from the body. In turn, hypercalcemia also inhibits the reabsorption of magnesium (and calcium), leading to hypermagniuria and hypercalciuria. It is noted that metabolic alkalosis increases, and metabolic acidosis, hypokalemia and phosphate loss inhibit magnesium reabsorption in the kidneys [5].
The amount of excreted urine calcium is under the regulatory influence of a whole complex of factors. These include calciotropic hormones, the volume of extracellular fluid, the state of acid-base balance, the concentration of various ions in the urine and blood plasma [7].
Hypercalciuria, as one of the main risk factors for urolithiasis, is found quite often in patients with urolithiasis and patients with osteoporosis [8].
The concentration of magnesium ions in the urine, as well as the acidity of urine, can affect the excretion of calcium in the urine. However, the mechanisms explaining this relationship are still poorly understood.
The first description of the effect of magnesium on calciuria was made back in 1909 by Mendel and Benedict [9]. They found an increase in calcium excretion and a decrease in its concentration in the intestinal contents during the parenteral administration of magnesium to various types of experimental animals. Similar results were later obtained in the treatment of magnesium sulfate in women with preeclampsia and in healthy individuals after the administration of this drug [10, 11]. Moreover, as was shown, the calciuric effect is associated not with sulfate, but with magnesium ion [12].
Experimental studies have confirmed increased calciuria after intravenous administration of magnesium solutions in dogs with normal and impaired renal function [13]. The use of micro-puncture technique in an experiment on rats treated with infusions of magnesium chloride made it possible to establish the involvement of the loop of Henle in the development of calciuria induced by magnesium ions [14, 15].
Another important metabolic factor that can affect calcium excretion is urine pH. It is known that a large amino acid load caused by a high intake of animal protein in food decreases the urine pH and increases calcium excretion [1618]. In contrast, alkalinization of urine with potassium preparations (bicarbonate or potassium citrate) reduces urinary calcium excretion [19, 20].
There are data indicating that an increase in urinary acidity increases the excretion of calcium in the urine due to proton inhibition of the calcium channels of the renal epithelium TRPV5 and TRPV6, which are responsible for the reabsorption of calcium in the distal nephron [21, 22]. Magnesium ions are believed to act on the same links in the regulation of calcium excretion. It is noted that micromolar concentrations of magnesium are also able to inhibit the activity of calcium channels TRPV5 [23, 24].
The possibility of the clinical use of magnesium preparations in calcium urolithiasis continues to be discussed.
Some literature data indirectly indicate a possible protective effect of magnesium against calcium urolithiasis. So, it is known that magnesium is able to form complexes with oxalates in the intestinal lumen and urine [25-28], inhibit the formation of calcium oxalate crystals in vitro [25, 29, 30] and increase the excretion of citrates with urine, in the case of magnesium in the form of citrate salts [31].
This, apparently, can explain the confidence of many clinicians that magnesium is an effective means of preventing the formation of calcium urinary stones in patients with urolithiasis. For example, some authors suggest using the ratio of urinary concentrations of magnesium and calcium (Mg / Ca index) as an indicator of the risk of stone formation and stone recurrence [32-34]. In their opinion, the concentration ratio in the urine Mg / Ca below 0.7 indicates an increased risk of stone formation.
However, when examining 155 patients with non-infectious recurrent oxalate urolithiasis, no decrease in magnesium excretion in the urine was found [35]. Similar data were obtained in the study of the concentration of magnesium in the urine of healthy individuals and patients with recurrent form of calcium urolithiasis [36].
In addition, the results of a survey of 2147 patients with stones represented by pure calcium oxalate showed that only 11% of patients had reduced daily excretion of magnesium, whereas in the remaining 89% of patients this indicator was within normal values. At the same time, the frequency of recurrence of stones in the group of patients with hypomagniuria showed only a weak statistically insignificant tendency to increase compared with the group of patients with normagniuria [37]. As a result, a positive clinical effect, depending on the concentration in the urine of magnesium, was not achieved.
Thus, there is no convincing evidence that magnesium deficiency is one of the main reasons for the development of calcium oxalate urolithiasis.
Particularly noteworthy is the analysis of the results of 17 clinical trials to study the efficacy of magnesium and potassium salts using the Urolithiasis Registry Database of the Southwestern Medical Center of the University of Texas [19, 25, 26, 38-46].
Healthy volunteers and patients with urolithiasis who had no signs of magnesium deficiency, hypomagnemia, acid-base balance disorders, pathologically altered levels of potassium and blood calcium participated in the tests. In a group of 4 clinical trials (group I, average observation time 2 weeks, 47 people), patients who took magnesium oxide (MgO) or magnesium citrate (Mg 3 Citrate 2 ), high excretion of urine calcium, magnesium with a slight change the pH of urine (table 1). In a group of 8 clinical trials (group II, average observation time 2 weeks, 89 people), patients took potassium bicarbonate (KHCO 3 ) or potassium citrate (KB 3 Citrate). At the same time, the opposite dynamics was observed: pronounced alkalinization of urine, the absence of increased excretion of magnesium and a marked decrease in hypercalciuria. In a group of 5 clinical trials (group III, average follow-up time 2.6 weeks, 102 people), patients took the combined drug potassium magnesium citrate (K 4 MgCitrate 2 ). Taking the drug increased the excretion of magnesium in the urine, but less pronounced than in group I of the tests and caused alkalinization of the urine to the same extent as was observed in group II of the tests. Increased calcium excretion was not statistically significant.
These data suggest that magnesium preparations in the form of magnesium oxide (MgO) or magnesium citrate (Mg 3 Citrate 2 ) are capable of inducing hypercalcemia in patients with urolithiasis, while potassium citrates have the opposite effect. Experimental studies have shown that the calciuric effect of magnesium is associated with inhibition of calcium reabsorption in the distal convoluted nephron tubules, possibly due to inhibition of the apical calcium channels TRPV5 and not dependent on the effect of parathyroid hormone [47].
Obviously, the use of magnesium or its citrates can not be recommended as monotherapy for recurrent calcium urolithiasis.While co-administration of magnesium and potassium citrates significantly reduced the incidence of calcium-oxalate urolithiasis recurrence, as was shown in a 3-year randomized study in 64 patients [48].
Idiopathic recurrent calcium urolithiasis is a disease with unclear etiology and pathogenesis. The role of magnesium in stone formation in these patients remains poorly understood. The results of a simultaneous examination of 284 patients (cross-sectional study) with idiopathic recurrent calcium urolithiasis (IRKU) showed that increased magnesium excretion is associated with increased excretion of calcium, potassium, sodium, protein, and, to a lesser extent, citrates. At the same time, in patients with hypermagniuria, there was a higher urinary supersaturation in hydroxyapatite and a clinically more active form of recurrence of urolithiasis [49]. Thus, increased excretion of magnesium in the urine is not a protective factor in relation to the development of calcium urolithiasis.
In another work [50], it was noted that in 12 men with IRKU, serum levels of total magnesium and its fractions (free, ionized and bound to proteins) did not differ from healthy men in the control group. At the same time, in patients the level of serum albumin and magnesium in erythrocytes was lower than in the control, and the indices of excretion of magnesium in the urine corresponded to those of the control group. The ratio in the urine magnesium / creatinine in patients also did not differ from healthy individuals. However, the urine of patients had higher concentrations of protein, glucose and pH.
It should be noted that urinary supersaturation with respect to calcium oxalate in patients with IRKU was lower (1.5 vs 2.2), and with respect to hydroxyapatite it was higher (3.3 vs 1.8) than in healthy individuals. The latter deserves attention in the aspect that hydroxyapatite crystals are able to induce heterogeneous nucleation of calcium oxalate crystals [51], thereby promoting further crystal growth and stone formation. This indicates the involvement of other pathogenesis mechanisms of the IRKU, which are not directly related to the concentration of magnesium in the urine.
It is believed that with IRKU, the role of urine Mg deficiency as a risk factor for the formation of calcium stones can be questioned or completely denied. However, the noted link between intracellular Mg deficiency and tubular functional disorders, in the form of impaired glucose reabsorption, proteins and urine acidification, indicates the need for further study of this issue.
To increase the excretion of magnesium in the urine is usually used such drugs as magnesium oxide or hydroxide, potassium magnesium citrate and magnesium aspartate. Increasing the concentration of magnesium in the urine leads to a decrease in the value of the product of the ionic activity of calcium oxalate, inhibition of the growth of calcium phosphate crystals, reducing the risk of formation of brushite [52].
However, according to the latest Urolithiasis Guidelines, adopted in 2011 by the European Urological Association, there is currently no convincing evidence to recommend magnesium preparations as monotherapy to prevent the formation of calcium stones [52]. In most of the studies on the clinical use of magnesium preparations, physicochemical and biochemical changes in the urine of patients with urolithiasis were investigated [25, 29-31] without evaluating long-term results in the form of stone recurrence rate.
There are only two randomized controlled studies of the clinical effect of magnesium in urolithiasis. One study used magnesium hydroxide versus a control group that received a placebo [53]. In another study, magnesium oxide was used in comparison with a control group that did not receive any treatment [54]. None of these studies showed a statistically significant effect on the formation of urinary stones, despite the long observation period of 4 and 3 years, respectively.
The positive effect of magnesium was described in earlier studies [55, 56], but is not confirmed in controlled studies in recent years [57].
In these works, magnesium was used as an oxide or hydroxide. Obviously, the absence of a visible anti-relapse effect of these drugs suggests that magnesium itself cannot be used as a monotherapy for calcium stones. Recently, it has been increasingly used in the form of citric acid salts — magnesium citrate (K 3 Citrate) or potassium magnesium citrate (K 4 MgCitrate 2 ), given the pronounced inhibitory effect of citrate ion on calcium oxalate and calcium phosphate crystal formation [ 29-31].
Experimental laboratory tests conducted in vitro in artificial or human urine show that magnesium exhibits its inhibitory properties with respect to the formation of calcium oxalate crystals only at high concentrations significantly different from physiological values [37, 5863]. Moreover, it has been shown that the inhibitory effect of magnesium citrate on the formation of calcium oxalate crystals is due only to citrate, and not to magnesium ions [64].
CONCLUSION
The results of clinical trials indicate an increase in calciuria under the influence of magnesium preparations (magnesium oxide, magnesium hydroxide, magnesium citrate) used as monotherapy without potassium citrates. However, simultaneous alkalinization of urine can reduce the undesirable effect of hypercalciuria [46]. It can be assumed that for the prevention of recurrence of calcium stones, magnesium preparations should be used not as monotherapy, but in combination with pyridoxine, potassium alkaline citrates and / or thiazide diuretics. This should be the goal of further clinical trials.
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