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

Sources of Oxalate

Blood oxalate derives from erythrocytes, diet, the liver, and the metabolism of ascorbate (Figure 1). The plasma oxalate level is elevated in patients with extreme hyperoxaluria but is generally normal (1-5 µmol/l) in patients with idiopathic calcium oxalate nephrolithiasis.[15,16]

Figure 1.

Sources of Blood Oxalate. (A) Oxalate absorption along the intestinal tract is believed to be mediated by three oxalate-transporting members of the solute carrier family 26A (SLC26A3, SLC26A6, SLC26A7).[16,20,34] Secretion into the intestinal tract might also occur.[24,25] Only free oxalate can be absorbed by the intestinal epithelium. The amount of free oxalate is affected both by the presence of other ions, such as calcium -- which binds to oxalate -- and unabsorbed lipids -- which indirectly increase the amount of free oxalate by binding to calcium.[15,16,28] Absorption of oxalate is also affected by the presence of gut bacteria, such as Oxalobacter formigenes, that degrade oxalate to carbon dioxide and formate.[16,32] (B) In the systemic circulation, erythrocytes synthesize oxalate from glyoxylate;[17] in addition, oxalate enters erythrocytes via the band 3 anion transport protein (SLC4A1 or AE1).[18] Ascorbate (vitamin C) in the blood can be metabolized to oxalate.[41] (C) In the liver, oxalate is synthesized from glyoxylate by lactate dehydrogenase and released into the blood. The major pathways controlling the production of glyoxylate have not yet been identified, although the degradation of hydroxyproline and the oxidation of glycolate by glycolate oxidase are two sources of glyoxylate.[35,37] Under normal conditions, most glyoxylate is metabolized to glycine by alanine-glyoxylate aminotransferase or reduced to glycolate by D-glycerate dehydrogenase. Defects in the genes encoding these two enzymes characterize primary hyperoxaluria types I[38] and II,[39] respectively. (D) Unexcreted oxalate is stored in structural tissues and soft organs. Abbreviations: AGT, alanine-glyoxylate aminotransferase; DGDH, D-glycerate dehydrogenase; GOX, glycolate oxidase; LDH, lactate dehydrogenase; Ox, oxalate; PH-I, primary hyperoxaluria type I; PH-II, primary hyperoxaluria type II; SLC26A3, solute carrier family 26 member 3; SLC26A6, solute carrier family 26 member 6; SLC26A7, solute carrier family 26 member 7; SLC4A1, band 3 anion transport protein.

Erythrocytes

Erythrocytes synthesize oxalate from glyoxylate;[17] in addition, oxalate enters erythrocytes via the band 3 anion transport protein (SLC4A1 or AE1).[18] The proportion of blood oxalate that is carried by erythrocytes and the contribution of erythrocytes to oxalate synthesis are unknown.

Diet

Approximately 20-40% of blood oxalate typically derives from dietary (exogenous) sources.[15,16,19] Three oxalate-transporting members of the solute carrier family 26A are expressed along the intestinal tract and have potential roles in the absorption of oxalate, as recently reviewed.[16,20,21,22] The most recently discovered protein in this family, SLC26A7, is localized to the basolateral membrane of the stomach's parietal cells. Oxalate can be absorbed by the stomach,[23] but whether such absorption occurs transcellularly or paracellularly is not known.[16,24] The expression of SLC26A6 (also known as PAT1 or CFEX) is highest in the stomach and small intestine, where the protein is localized to the apical membrane. SLC26A3 (also known as Protein DRA) is most highly expressed on the apical membrane of the colonic epithelium.

The primary function of these three carriers is to exchange anions such as chloride, bicarbonate, hydroxide, sulfate and formate across epithelial plasma membranes. Oxalate is often included in transporter characterization studies, but the role of SLC26A transporters in the regulation of oxalate transport between the intestinal lumen and the blood is unknown. Studies of oxalate flux across the intestinal epithelium of rats under normal conditions show a small net secretion of oxalate in the small intestine and net absorption in the colon.[16,25,26] Studies of Slc26a6 knockout mice show that this carrier mediates net secretion of oxalate by the small intestine; in the carrier's absence there is net oxalate absorption.[25,26]

Absorption of 13C-oxalate from the gut of healthy volunteers ranged from 5% to 15% of oxalate intake.[27,28] Only free oxalate can be absorbed by the intestinal epithelium. The amount of free oxalate in the gut is affected by the bioavailability of the oxalate present in ingested food, the presence of other ions in the gut, and the processing of food during its preparation.[15,16,29] Excess calcium and magnesium in the gut decreases oxalate absorption by binding to oxalate directly, while unabsorbed lipids increase the free oxalate concentration by binding to calcium. Low levels of calcium and magnesium and high levels of lipids in the gut all elevate urinary oxalate excretion and the incidence of nephrolithiasis.[30,31,32] Absorption of oxalate is also affected by the presence of gut bacteria, such as Oxalobacter formigenes, which degrades oxalate into carbon dioxide and formate.[16,33] Stone formers with mild, persistent hyperoxaluria have been hypothesized to routinely absorb more dietary oxalate than do average healthy individuals that are not stone formers. Although this theory is likely to be true of a subset of stone formers, studies with ingested radiolabeled oxalate fail to consistently differentiate normal individuals from stone formers in terms of oxalate absorption.[27,34]

Liver

The liver is the primary source of endogenous oxalate, and glyoxylate is the primary immediate precursor of oxalate.[35,36] Glyoxylate is a product of several reactions in intermediary metabolism, although the relative importance of each one is not yet known. One established pathway of glyoxylate formation is the oxidation of glycolate by glycolate oxidase in the peroxisomes.[35] Another pathway is through the breakdown of hydroxyproline.[37] Thus, the consumption of large amounts of animal protein, which contains hydroxyproline, increases urinary oxalate excretion.[37] Glyoxylate concentrations in the liver are normally kept low by metabolism of glyoxylate to glycine, which is catalyzed by alanine-glyoxylate aminotransferase, a liver-specific enzyme localized in the peroxisomes that is dependent on the cofactor pyridoxine (vitamin B6) for full activity. Glycine is metabolized to serine, which is an intermediate in amino acid metabolism, the urea cycle, and gluconeogenesis.[15] Alternatively, glyoxylate can be reduced to glycolate in the cytosol via D-glycerate dehydrogenase, which is widely distributed throughout the body. The mutational inactivation or the mistargeting of alanine-glyoxylate aminotransferase (primary hyperoxaluria type I), or of D-glycerate dehydrogenase (primary hyperoxaluria type II), or the presence of a generalized peroxisomal disorder such as a Zellweger spectrum disorder, results in a buildup of glyoxylate in the liver.[38,39,40] This surfeit of glyoxylate leads to production of oxalate via lactate dehydrogenase in the cytosol of liver cells.

Ascorbate

Another source of oxalate is the catabolism of ascorbate (vitamin C) in the urine or blood.[37,41] Ascorbate can be oxidized by a variety of enzymatic and nonenzymatic pathways to dehydroascorbate, which then breaks down nonenzymatically to L-erythrulose or L-threonate, carbon dioxide, and oxalate.[41] Although some reports suggest that ascorbate increases oxalate excretion,[42] other work indicates that ascorbate decreases the risk of nephrolithiasis overall by binding to calcium and thereby reducing urinary calcium oxalate supersaturation.[43]

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....