Oxalate Concentrations in Human Gastrointestinal Fluid

Introduction

Calcium oxalate is the most common kidney stone composition in the United States. ¹ Urinary oxalate excretion impacts stone formation as reflected by its positive correlation with stone risk. ² Therefore, reduction of urinary oxalate is endorsed to prevent recurrent calcium oxalate stones. ³ Urinary oxalate is derived from endogenous and dietary sources with varying relative contributions. Diet has been shown to be responsible for up to 60% of urinary oxalate. ⁴ There are multiple factors that influence the bioavailability of gastrointestinal oxalate including but not limited to the intestinal microbiome, food oxalate content, conformation of oxalate, dietary calcium, intestinal cations, and transport processes. Oxalate is not only absorbed in the intestinal tract but is also secreted into it, the latter demonstrated in animal models. ⁵ There are limited studies evaluating intestinal oxalate transport processes in humans. Oxalate loading studies done in humans have demonstrated variable levels of oxalate absorption. ^6,7 However, to our knowledge, there are no investigations of the secretion of oxalate into the gastrointestinal tract of humans. Furthermore, information regarding the fate of secreted oxalate is unknown. Oxalate once secreted may remain soluble or be rendered insoluble by cations, such as calcium and magnesium. This is relevant as soluble oxalate is thought to be the form absorbed across the intestine. ⁸ In this study we sought to determine the amount of soluble and insoluble oxalate in the stomach and small intestine via ion chromatography of fasting humans subjected to gastrointestinal endoscopy and to assess any evidence of oxalate secretion.

Materials and Methods

Results

Four gastric samples and 11 small intestinal samples were collected from 11 patients (Tables 1 and 2). Of the gastric samples only one of four (25%) had detectable oxalate, a concentration of 4.9 μM soluble conformation. There was no insoluble oxalate detected in the gastric samples. In contrast, 8 of 11 (72.7%) small intestinal samples contained some amount of measurable oxalate, soluble oxalate detected ranged from 1.7 to 191 μM and insoluble oxalate detected ranged from 56 to 3243 μM. Two of the eight (25%) contained only soluble oxalate, two of the eight (25%) contained only insoluble oxalate and the remaining four (50%) contained both conformations. The ratio of quantities of total insoluble to total soluble oxalate was calculated in a subset of three small intestinal samples, which contained soluble and insoluble oxalates. In these samples insoluble oxalate was noted to be 36–52× greater than the amount of soluble oxalate. Only one subject had a reported history of calcium oxalate stone disease. The subject's gastric sample contained no detectable oxalate and the small intestinal sample showed no detectable soluble oxalate and a 76 μM concentration of insoluble oxalate.

Discussion

Oxalate is transported in the gastrointestinal tract via paracellular and transcellular processes. Paracellular transport is largely dependent on the ionized status of oxalate, membrane permeability, and electric potential gradient. ⁵ Paracellular transport of oxalate is not felt to occur in the stomach due to decreased membrane permeability as a result of tight junctions and active transport mechanisms have not been identified thus far. ¹¹ The results of prior oxalate loading studies in humans suggest that the majority of oxalate is absorbed in the colon and small intestine based on time sequences relative to known ranges of intestinal transit time. ^6,12 Though our sample size is low, the absence of detectable oxalate in the majority of stomach samples suggests that minimal oxalate secretion is occurring at this level of the gastrointestinal tract during a fasted state. However, it is possible that the acidic environment of the stomach converts any crystalline oxalate to soluble oxalate, which could be readily absorbed and thus resulting in a low luminal concentration in this segment of the gastrointestinal tract. ¹¹

In contrast to the stomach, oxalate was more prevalent and abundant in the small intestine. These findings infer that oxalate secretion may be occurring in this portion of the gastrointestinal system. The other possibility is that the oxalate present was derived from prior meals, although it is anticipated that the food-related succus should have cleared after 8 hours based on the range of reported normal oral-cecal transport time, 3–7 hours. ¹³

Intestinal samples contained greater amounts of insoluble oxalate suggesting that any secreted oxalate complexes with cations resulting in the formation of crystalline oxalate, the latter not being absorbed. Thus, the driving forces for this interaction include both the concentration of oxalate and pertinent cations, namely calcium and perhaps pH. These intraluminal crystalline events can be attenuated with low calcium intake or availability. ⁴ The consequences of the latter could result in increased oxalate absorption and subsequent urinary excretion heightening stone risk. ² This underscores the importance of maintenance of normal calcium intake for stone prevention in most patients. ¹⁴

Much research has been done in recent years regarding mechanisms of intestinal oxalate transport in animal models. The SLC26a family of ion exchangers has been identified to play an important role in oxalate transport. Knockout studies in rodents have identified specific subtypes that mediate absorption and secretion. Mice with SLC26a3 (DRA) deletions show net oxalate secretion in the colon and small intestine with resultant decreases in urinary oxalate excretion, suggesting this transporter's role in oxalate absorption. ¹⁵ Net flux of oxalate across ileal epithelium is primarily absorptive in knockout models of SLC26a6 deletions (PAT1) suggesting its role in secretion. Additionally, urinary oxalate excretion was increased by the absence of the PAT1 transporter. ¹⁶ Further studies of this model show that SLC26a6-null mice not only have increased oxalate urinary excretion, but may also develop calculous disease and these changes may be mitigated by decreased oral oxalate consumption. ¹⁷ Certain other factors may play a role in simulating intestinal secretion of oxalate including metabolic acidosis, carbonic anhydrase, oxalalobacter formigenes, and its lysate. ^{18 –20} However, since oxalalobacter formigenes is not thought to be present in the small intestine or stomach, a direct effect on gastric or small intestinal oxalate secretion is unlikely. Other compounds such as sulfate and thiosulfate may inhibit such transport. ²¹ The degree to which different parts of the intestinal tract contribute to oxalate secretion has not yet been fully characterized.

We found a wide range of oxalate concentrations in the intestine suggesting that there may be substantial inter-individual variability in intestinal oxalate transport. A wide degree of genetic variability in SLC26 transporters has been observed in recurrent calcium oxalate stone formers that may be a source for this variability. ²²

We acknowledge that this study has limitations. Samples were procured at various depths of the small intestine and the depth at which they were obtained was unknown. Thus, it is possible that the variability of oxalate concentrations in small intestine may be due to location within the intestine from where the sample was obtained and subtle differences in intestinal motility. Oxalate detected may partially have been due to residual food in the gastrointestinal tract, though the effect of this is felt to be negligible as patients were fasted and had no overt evidence of gastrointestinal motility dysfunction.

Future studies are planned to overcome some of these limitations. We plan to obtain samples after subjects are administered intravenous infusion of ¹³C-labeled oxalate, which if present in the intestinal lumen would provide definitive evidence of gastrointestinal oxalate secretion.

Conclusions

The majority of oxalate in the intestine during a fasted state is insoluble. Our results infer that gastrointestinal oxalate secretion occurs in humans in a fasted state but less likely in the stomach. Further studies are needed to prove this concept.