The positive association of incident kidney stones with fructose intake in 3 different cohorts suggested that the amount of fructose consumed in the diet is a risk factor for stone formation [4
]. Taylor and Curhan speculated that increasing fructose consumption may increase urinary calcium, oxalate and/or uric acid excretion, and/or reduce urinary pH. Several studies support the existence of a pathway for the formation of oxalate in the metabolism of fructose [5
]. Rofe et al. observed the conversion of small but significant amounts (~0.1%) of 14
C-labelled fructose to oxalate in incubations with isolated rat hepatocytes [16
]. These results have not as yet been confirmed in other laboratories. Conflicting results have been obtained in human studies. No increase in urinary oxalate was observed in one study with an oral load of 75 g of fructose [11
] where serum fructose reached 0.67 mM 60–90 min after the load. However, a short intravenous infusion of ~35 g of fructose did increase oxalate excretion [6
]. The serum concentration of fructose reached at 15 min with this infusion was high, 5.5 mM, suggesting that high concentrations of plasma fructose may be required to produce an increase in oxalate synthesis.
Our study was designed to test whether fructose consumption over a 4.9-fold range would affect urinary stone risk parameters. The upper limit, 21 % of calories, would be equivalent to consuming nearly 6 cans of a sweetened soda, if the soda provided all of the fructose. Our results clearly showed that oxalate excretion was not affected by fructose consumption in the individuals tested. Glycolate excretion is potentially a sensitive marker of oxalate synthesis as both oxalate and glycolate have glyoxylate as a common precursor [17
] as shown in . Because glyoxylate reductase has a higher affinity for glyoxylate than lactate dehydrogenase, in most conditions where significant glyoxylate is formed, such as when hydroxyproline is metabolized, the production of glycolate is 5–10 times higher than that of oxalate [14
]. Glycolate excretion did not change on these diets further suggesting that a pathway associated with glyoxylate production is not stimulated by fructose consumption. We also found that fructose consumption did not impact any of the other urinary parameters measured except potassium, which went up with increasing fructose consumption. The reason for the increased potassium excretion is unclear. It is possible that it is related to phosphate excretion, which also increased in this study (p = 0.086). Phosphate excretion has been reported to increase with the intravenous infusion of fructose [6
] and with increased amounts of fructose in the diet [5
Pathways for the conversion of 2 carbon precursors to glycolate and oxalate. (1)=alcohol dehydrogenase; (2) = aldehyde dehydrogenase; (3) = glycolate oxidase; (4) = glyoxylate reductase; (5) = lactate dehydrogenase; and (6) = glyoxalase.
We cannot entirely exclude an effect of fructose consumption on the absorption of dietary oxalate. A low oxalate diet (51 mg/day) was used in the studies reported here to limit the contribution of dietary oxalate to urinary oxalate excretion and to accentuate effects on endogenous oxalate synthesis. Fructose consumption has been shown to increase the balance of several ions, including calcium, magnesium, zinc, copper and iron and to decrease phosphate balance [5
]. The mechanisms associated with these changes have not been elucidated and whether oxalate absorption may be affected remains unknown.
Our studies with cultured HepG2 cells, showed that prolonged exposure of these cells to high levels of fructose produced more oxalate and glycolate compared to prolonged incubation with glucose. However, the amounts produced were only minor compared to the total levels of oxalate and glycolate produced by these cells, and the amount of oxalate produced was not significantly different from that produced by equivalent glucose levels. 13
-Fructose incubations did produce significantly more 13
-glycolate than 13
-glucose. This glycolate is potentially formed from glycolaldehyde ( ), as glycolaldehyde is formed by an aldolase-catalyzed hydrolysis of xylulose-1-phosphate [17
]. However, there is no known report of any difference in fructose and glucose metabolism that affects the synthesis or metabolism of xylulose-1-phosphate.
Incubation of glyceraldehyde and a range of potential 2 carbon precursors with HepG2 cells showed that neither glyceraldehyde nor glycolaldehyde could be metabolized to oxalate. In contrast, glyoxylate, glyoxal, and glycolate were converted to oxalate with glyoxylate > glyoxal
glycolate. Although glycolaldehyde is converted to glycolate, it appears that the intracellular concentration reached was not sufficient to stimulate oxalate synthesis. Pathways describing how these 2 and 3 carbon aldehydes and acids are converted to oxalate are shown in . The exact role of aldehyde dehydrogenase (ALDH) and which of the isoforms may be active in reducing glycolaldehyde to glycolate and glyoxal to glyoxylate are unclear. There is evidence that ALDH isolated from human liver homogenates can reduce both glyoxal and glycolaldehyde to glyoxylate and glycolate, respectively [21
]. It is of interest that glyoxal could be converted to oxalate in HepG2 cells. This dialdehyde could be expected to be converted to glycolate by the glyoxalase system after reacting with glutathione [22
]. Our results suggest that some glyoxal may escape glutathionylation and instead be converted to glyoxylate by ALDH. The formation of glyoxal, a product of cellular peroxidation [23
], may be accelerated in these cells when they are deprived of glucose as increased peroxidation is observed under these conditions [24
]. The increase in oxalate synthesis in cells incubated with 1 mM sugar may in part be due to increased glyoxal formation. The role of peroxidation and glyoxal formation in endogenous oxalate synthesis warrants further investigation.
Fructose infusions and oral fructose loads are associated with increased uric acid synthesis [7
]. An increased uric acid excretion is a risk factor for uric acid stones [10
]. This increased uric acid production is believed to be due to an accelerated adenosine diphosphate (ADP) breakdown during fructose metabolism [27
]. We observed no effect of an elevated fructose consumption for 1 week on uric acid excretion. This response is similar to that reported by Narins et al. [28
], who supplemented the diet of 8 subjects with 100 g of fructose per day for 4 days and observed no change in urinary uric acid excretion. A longer period of fructose consumption, the consumption of higher levels of fructose, or a less healthy study population may have produced different results.
The other risk factors potentially influenced by a high fructose intake are an increased calcium excretion and a lowered urinary pH. We found that both calcium excretion and urinary pH were unaffected by the amount of fructose consumed. It remains possible that dietary imbalances occur in diets where fructose or sucrose sweetened items that are energy-rich and nutrient-poor are excessively consumed. Milne and Nielsen [5
] observed a decrease in calcium balance with a high fructose, low magnesium diet, but no change in urinary calcium excretion in normal subjects.
If the risk for stone disease from fructose consumption is not associated with the urinary excretions of oxalate, calcium or uric acid, how might fructose exert its effect? One possibility is that fructose affects early lithogenic events such as the formation of Randall’s plaques [29
]. Although a magnesium deficiency has been ruled out [4
], it is possible that fructose effects manifest only in an imbalanced diet. In rats, an imbalance of either dietary phosphorus or magnesium leads to nephrocalcinosis and a lower urinary pH in animals on a fructose-enriched but not on a glucose-enriched diet [30
]. Urinary calcium excretion was unaffected.
This study has limitations in relating the results obtained with the observations of Taylor and Curhan that increased fructose consumption increases stone risk [4
]. The populations they studied were older. The sample size in our study was small because of the comprehensive controlled diets that were utilized. The possibility remains that a minor segment of the population metabolizes fructose differently from the bulk of normal individuals. Hyperoxaluric stone formers may be enriched in this group as they may not have the appropriate compensatory pathways/mechanisms to limit oxalate synthesis from fructose metabolism. A study comparing the responses of normal and stone-forming populations would be required to address this issue. The high fructose diet was consumed for only 1 week, whereas individuals in the cohorts studied by Taylor and Curhan reported on their food consumption over the preceding 12 months. Our studies with cultured HepG2 cells did show a minor increase in glycolate and oxalate synthesis, suggesting that prolonged exposure of hepatocytes to high levels of fructose may lead to increased oxalate synthesis. Furthermore, it remains possible that elevated fructose metabolism within the liver or other tissues over a long period of time produces changes that predispose individuals to the risk of incident stone formation. The mechanisms by which this occurs or whether it interacts with other factors are not understood at this time. In our study, subjects consumed a low oxalate diet to accentuate the urinary oxalate excretion associated with endogenous oxalate synthesis. It remains possible that dietary fructose modifies intestinal oxalate absorption. Lastly, the in vitro experiments with cultured hepatoma cells may not reflect the metabolism occurring in human liver tissue or other tissues of the body that contribute to endogenous oxalate production.