Magnesium favorably impacts calcium oxalate stone-forming risk through multiple mechanisms. Magnesium binds oxalate in the digestive tract and inhibits the formation of calcium oxalate crystals in urine (Kohri 1988; Massey 2005). And higher magnesium consumption is significantly associated with lower risk of kidney stones (Negri 2013; Zimmermann 2005).
A study in over 45 000 US male health professionals found that those in the highest one-fifth of magnesium intake had a 29% lower risk of developing kidney stones (Taylor 2004). Another study in 311 patients with kidney stone disease evaluated magnesium levels in urine, a known marker of dietary intake of magnesium. In this population, higher urine magnesium was significantly correlated with lower urine oxalate (Eisner 2012).
The timing of magnesium supplement consumption may be important in the context of kidney stones. Magnesium must be present in the digestive tract at the same time as oxalate-containing foods in order to bind dietary oxalate and prevent it from being absorbed into general circulation, where the oxalate then has to be filtered by the kidneys, and is excreted into the urine. In a clinical study of six healthy volunteers, researchers noted administration of a magnesium supplement together with oxalate decreased oxalate absorption, whereas consumption of magnesium supplements 12 hours apart from oxalate administration did not have this effect (Zimmermann 2005).
A low-calcium diet is associated with a higher risk for calcium oxalate stones (Xu 2013). High dietary calcium, on the other hand, even when accompanied by a large increase in oxalate consumption, has been demonstrated to decrease kidney stone risk rather than increase it (Hess 1998; Sorensen, Kahn 2012; Taylor 2004). This is thought to be due to calcium’s ability to bind dietary oxalate in the intestines, which prevents oxalate absorption into the bloodstream, and eventually the kidneys and urine (Nazzal 2015). Consuming adequate calcium through diet and supplementation is associated with higher bone-mineral density (Napoli 2007). This may be another way adequate calcium intake helps prevent kidney stones. As bone mineral density decreases, urinary calcium content and stone risk increase (Arrabal-Polo, Sierra Giron-Prieto 2013). Bone resorption, or the breakdown of bone, causes calcium to leach into the blood and eventually the urine, increasing stone risk. Adequate calcium intake reduces bone resorption, conferring protection against kidney stones (Ettinger 2014; Heaney 2008; Martini 2002).
In a study in over 45 000 male health professionals without kidney stones who were followed for up to 14 years, men under the age of 60 who were in the highest one-fifth of dietary calcium consumption had a 31% lower risk of kidney stones compared with the one-fifth who consumed the least calcium (Taylor 2004). Another study in over 78 000 women without kidney stone disease found that higher dietary calcium was associated with a 5‒28% reduction in kidney stone risk, and a study in over 96 000 younger women without kidney stones found that those in the highest one-fifth of dietary calcium consumption had a 27% lower risk of kidney stones compared with those in the lowest one-fifth (Sorensen, Kahn 2012; Curhan 2004).
Calcium supplements improve urine chemistry parameters and lower kidney stone risk, even in those on a low-oxalate diet. A study in 32 healthy young men with no history of kidney stones found that calcium supplementation, combined with a low-oxalate diet, lowered urine oxalate (Stitchantrakul 2004).
It has been suggested that calcium supplements should be taken with meals in order to bind the maximal amount of dietary oxalate (Domrongkitchaiporn 2004; Heilberg 2013).
The most common types of kidney stones, calcium oxalate and uric acid, tend to form in acidic urine. Formation of the most uncommon kidney stones, cystine stones, also occurs in acidic urine (Frassetto 2011). Citrate protects against these types of stones by alkalinizing urine, binding calcium in the gut and in the urine, and inhibiting calcium oxalate crystallization (Goldberg 1989; Nicar 1987; Krieger 2015; Berg 1992). It is not surprising, then, that low urine citrate is a common finding in patients with these types of stones (Caudarella 2009). Mineral citrates, including calcium, magnesium, and potassium, are used in clinical practice and in research to increase urinary citrate, alkalinize urine, and reduce the rate of stone formation (Caudarella 2009; del Valle 2013; Sakhaee 2004; Ettinger 1997).
Magnesium, potassium, and calcium citrate. Both magnesium and citrate inhibit calcium oxalate crystal formation, though the combination of the two may be more effective than either alone (Rodgers 1999).
In a randomized controlled trial in 64 people with a history of calcium oxalate kidney stones, three years of potassium-magnesium citrate supplementation providing about 255 mg of magnesium resulted in an 85% reduction in kidney stone risk compared with placebo (Ettinger 1997). In a double-blind placebo-controlled trial in 20 participants who were put on bed rest for five weeks (in order to increase urinary calcium excretion), potassium-magnesium citrate supplementation effectively alkalinized the urine, increased citrate concentration and reduced uric acid concentration in the urine, and reduced calcium oxalate crystallization potential (Zerwekh 2007).
Studies that used several different mineral preparations of potassium and magnesium found that adding a magnesium supplement to potassium citrate therapy, or using potassium-magnesium citrate, yielded superior results for improving urine chemistry compared to treatment without magnesium (Jaipakdee 2004; Kato 2004).
Potassium citrate is used in medicine to alkalinize urine, increase urine citrate, inhibit aggregation of calcium oxalate and calcium phosphate crystals, and reduce the risk of kidney stones (Arrabal-Polo, Arrabal-Martin 2013; Xu 2013; Sakhaee, Griffith 2012).
The dosage of potassium citrate used to prevent kidney stones is generally 1200–2400 mg per day, a prescription-strength dose that frequently causes digestive upset, making it intolerable for some people (Xu 2013). Potassium citrate dietary supplements usually do not contain more than 99 mg of potassium per pill. Potassium citrate is a less concentrated source of urine-alkalinizing citrate than the magnesium or calcium forms of citrate (Higdon 2010).
A study that used a supplement containing calcium citrate and potassium citrate improved urine chemistry by reducing acidity and increasing urinary citrate in people who had undergone gastric bypass surgery. The investigators concluded that potassium-calcium citrate might be helpful for decreasing kidney stone risk in this population (Sakhaee, Griffith 2012).
The bacterial population of the gastrointestinal tract may play an important role in oxalate breakdown and metabolism, and thus in the prevention of kidney stones (Miller 2013; Murphy 2009).
Several genera of probiotic bacteria, including Lactobacillus and Bifidobacteria, appear to be capable of metabolizing oxalate, thus reducing urinary oxalate and decreasing kidney stone risk. In an uncontrolled trial, six people with calcium oxalate kidney stone disease and high urinary oxalate concentrations consumed a supplement containing Lactobacillus and Bifidobacterium strains for four weeks. Urinary oxalate concentrations dropped by nearly half at the end of the study (Campieri 2001). In a subsequent trial of 10 patients with excessive intestinal oxalate absorption (caused by several different medical conditions), the patients were administered a probiotic formula that contained Lactobacillus and Bifidobacterium strains. Average urine oxalate fell by 19% after one month on a dosage of 8.5 billion bacteria daily; during the second month, oxalate excretion was reduced by 24% at a dosage of two per day (Lieske 2005). However, later trials using the same probiotic formulation were unable to demonstrate the same beneficial effect (Lieske 2010; Goldfarb 2007).
Another preliminary trial examined the effect of a probiotic supplement containing several Bifidobacterium and Lactobacillus strainsin 11 healthy people. Oxalate absorption was reduced after four weeks of probiotic supplementation, an effect largely attributable to the marked reduction observed in individuals who were high oxalate absorbers at the beginning of the study (Okombo 2010). Another study in 14 stone-forming individuals without hyperoxaluria administered a probiotic supplementthree times per day after meals, for two weeks, along with a high-oxalate diet. Half the study subjects experienced a reduction in urinary oxalate; the greatest reduction was in the two individuals who had the greatest increase in urinary oxalate during the high-oxalate diet (Ferraz 2009). A laboratory study of different bacterial strains found that Lactobacillus species exhibited greater oxalate-degrading ability compared with Bifidobacteria (Mogna 2014).
Vitamin B6 deficiency affects as much as 24% of US adults, and may in part be induced by a high-protein diet. Inadequate vitamin B6 increases urine oxalate and kidney stone risk in laboratory animals and humans, and hyperoxaluria has been successfully reduced with vitamin B6 supplementation (Murthy 1982; Nath 1990; Kim 2014; Mitwalli 1988; Massey 2003). In a 14-year study in 85 557 women, kidney stone risk was 34% lower in women who consumed the most vitamin B6 per day from diet and supplements compared with those who consumed the least (Curhan 1999). In one study, 149 people with recurrent kidney stones were treated with 100 mg three times daily of magnesium oxide plus 10 mg once daily of vitamin B6 for 4.5‒6 years. The recurrence rate fell from an average of 1.3 per year to 0.1 per year during treatment, a 92% reduction (Prien 1974).
Some studies have found that supplementation with the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil may reduce kidney stone risk by lowering urine calcium. In one study, people with a history of kidney stones were treated with a short course (three months) and long course (18 months) of 1800 mg EPA daily. Urine calcium concentrations dropped in people who entered the study with high urinary calcium, but not in those with normal urinary calcium (Yasui 2001). In another study, 15 healthy people were given 900 mg EPA and 600 mg DHA daily for 30 days; excessive urinary oxalate excretion and calcium oxalate saturation was decreased at the end of the trial (Siener 2011). These studies suggest a possible role for fish oil in calcium oxalate kidney stone prevention.
N-acetylcysteine (NAC) is used by cells to replenish glutathione and detoxify free radicals (Zhang 2011; Rushworth 2014). A study with separate laboratory, preclinical, and clinical components found all three lines of evidence indicated potential for NAC to prevent the formation of calcium oxalate crystals and kidney stones. In the clinical phase of this trial, 17 people with calcium oxalate kidney stones were treated with 3 g per day of NAC. After one week of treatment, the number of large urinary calcium oxalate crystals was reduced by 60%, and three people experienced spontaneous passage of stones (Fan 1994). Findings from laboratory and animal studies provide additional evidence that NAC may reduce calcium oxalate crystallization and protect kidney cells from the damaging effects of calcium oxalate (Bijarnia 2008; Fishman 2013; Davalos 2010). NAC has also demonstrated activity that may help improve insulin sensitivity and protect against type 2 diabetes through multiple mechanisms (Lasram 2015). Since insulin resistance appears to be associated with kidney stone risk (Assimos 2004; Wong 2015), NAC holds promise as an integrative strategy for kidney stone prevention.
Vitamin E protects lipid molecules in cells and in the blood from oxidative damage and stress (Princen 1995; Ni 2012). In a laboratory study, vitamin E protected animal kidney cells from oxidative damage due to high oxalate conditions, suggesting it may play a role in preventing crystal deposition and stone initiation. The protective effect of vitamin E seen in this study was enhanced by the addition of the antioxidant vitamin C (Thamilselvan 2014). Animal studies have found that vitamin E inhibits stone initiation by reducing calcium oxalate crystallization, inhibiting crystal deposition in kidney tubule cells, and protecting against oxidative injury in kidney cells (Huang 2006; Thamilselvan 2005).
Green Tea and Catechins
Green tea and green tea extracts, which are rich in phytochemicals called catechins, have been shown to inhibit calcium oxalate stone formation (Jeong 2006; Itoh 2005; Graham 1992). In an animal study, the flavonoids catechin and epicatechin were evaluated for their ability to modulate kidney stone biochemical risk factors. Compared with rats given no treatment, those that received catechin or epicatechin had lower kidney calcium and fewer crystals deposited in the kidneys. The authors of the study suggested the flavonoids may have protected the interior of the kidneys from oxidative damage that could initiate stone formation (Grases 2009).
Another study, with laboratory and rodent model components, investigated the effects of catechin on calcium oxalate-mediated kidney damage. In the laboratory setting, catechin protected kidney cells from the oxidative stress ordinarily induced by calcium oxalate. In the animal component of the study, catechin appeared to protect rats from the oxidative effects of calcium oxalate (Zhai 2013).
QuercetinThe flavonoid quercetin has been studied in laboratory and preclinical models for its protective effect on kidney stone formation. One animal trial compared a mixture of quercetin and the related molecule hyperoside to potassium citrate for treating oxalate stones. The quercetin-hyperoside mixture decreased the amount of crystal deposits in kidney tissue compared with potassium citrate, and antioxidant enzyme activity was increased (Zhu 2014). In another study with both animal and lab components, quercetin protected against oxalate-induced damage in both settings, and protected against calcium oxalate crystal formation in rat kidneys (Park 2008).
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