Oxalate in Renal Stone Disease: The Terminal Metabolite That Just Won't Go Away

Susan R. Marengo; Andrea M. P. Romani

Disclosures

Nat Clin Pract Nephrol. 2008;4(7):368-377. 

In This Article

Excretion of Oxalate

In mammals, oxalate is a terminal metabolite that must be excreted or sequestered to maintain homeostasis. Oxalate is freely filterable by the glomerulus and is not appreciably bound by serum proteins.[44] Rats and humans have similar creatinine clearances (1-2.5 ml/min) and similar distribution volumes of oxalate (1.5-fold of the extracellular space).[45,46,47] Urinary oxalate excretion by normal adults ranges from 28 mg/day to 43 mg/day (311-478 µmol/day), with the average excretion being slightly higher in men than in women.[11,48] Values over 40-45 mg/day (444-500 µmol/day) are generally classified as clinical hyperoxaluria.

Following infusion into healthy volunteers of less than one day's excretion of radiolabeled oxalate, more than 90% of the infused dose was recovered in urine.[45,49,50] The movement of oxalate from blood into feces in humans has been little studied. The one such study performed to date reported negligible fecal excretion of 14C-oxalate that was administered intravenously to patients with hyperoxalemia who were on dialysis.[51] By contrast, hyperoxalemia increases fecal oxalate excretion in rats.[52] In a rat study that used subcutaneously implanted minipumps to infuse approximately 0.225 mg (2.5 µmol) of 14C-oxalate per day for 4 days, 50% of the dose was recovered in the excreta.[53] Of the excreted oxalate, 90% was in the urine and about 7% in the feces. Unfortunately, collections were not made after the treatment period. In rats, the normal daily urinary oxalate excretion is about 0.45-0.9 mg (5-10 µmol), but excretions in excess of 6.3 mg/day (70 µmol/day) are obtainable under experimental conditions.[54] Thus, it is surprising that a small load of 0.225 mg was not rapidly excreted. Other rat studies that investigated acute infusions or injections of 14C-oxalate also reported a failure to collect all of the administered dose in the excreta.[55,56] Humans and rats generally do not excrete measurable amounts of 14C-oxalate as 14C-carbon dioxide, although excretion of small amounts of 14C-carbon dioxide is occasionally detected.[51,53,57] Whether the reported differences in oxalate excretion between rats and humans are due to differing protocols, difficulties in measuring oxalate, or real differences in oxalate physiology between the two species, is unknown.

In one of our studies, 6 rats were treated for 13 days with 32.4 mg/day (360 µmol/day) of 14C-oxalate via subcutaneously implanted minipumps (SR Marengo, unpublished data). As in the other described studies,[53,55,56] a substantial proportion of oxalate was retained in the body while that which was excreted was mostly in the urine ( Table 1 ). Approximately 78% of the oxalate in the skin was directly associated with the pump pocket and the total amount of oxalate in the plasma, skeleton and skeletal muscle was less than 1% of the administered dose. Thus, most of the oxalate retained in the skin and carcass probably accumulated directly from the pump rather than being deposited via the circulation. Thus, it seems that like humans, rats excrete most of an oxalate load promptly. Rats differ from humans, however, in that they excrete a considerable portion of the load in the feces.

Unexpectedly, less than 1% of the oxalate administered in our rat study accumulated in the internal organs. Although the oxalate loads were similar among the rats, there was variation in the partitioning of oxalate for excretion and accumulation. The percentage of oxalate excreted in the urine varied by almost twofold among rats (range 16.1-30.0%; P ≤0.0001), although fecal oxalate excretion varied by much less (range 5.3-6.8%; P >0.3). The percentage of the oxalate load that was retained varied among rats by approximately twofold in the internal organs not including the kidney (range 0.03-0.06%) and skeleton (range 0.43-0.98%). By contrast, the percentage of oxalate retained in the kidneys varied by more than 50-fold among rats (range 0.7-0.01%). Correcting these values for the percentage of the administered dose of oxalate recovered for each rat did not alter this variation. Extrapolating from these observations to the clinic, it is possible that the differences in the distribution and accumulation of oxalate between individuals could have an important role in determining whether calcium oxalate nephrolithiasis or urolithiasis develops. The chemical form of nonrenal oxalate and the mechanisms regulating its distribution are unknown.

Much interest is focused on the possibility of increasing fecal oxalate excretion in order to reduce the amount of oxalate that must be excreted in the urine. In vitro studies show that the ileum of Slc26a6 knockout mice displays increased absorption of dietary oxalate, which suggests that the ileum might help protect against excess oxalate absorption, thus reducing the kidneys' oxalate burden.[24,25] Colonization by Oxalobacter sp. also increases oxalate movement from the blood into the colon in rats, possibly via 'backwards' transport by SLC26A3, although this possibility has not been formally tested.[58]Oxalobacter sp. colonization also reduces urinary oxalate excretion in humans.[59] The use of Oxalobacter sp. to reduce urinary oxalate excretion in persistently hyperoxaluric patients is under intense investigation.[59]

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