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

Oxalate Transport in the Kidney

The kidney tubules express three members of the SLC26A family that can transport oxalate.[20,21,60,61] SLC26A6 and SLC26A1 (also called sulfate anion transporter 1 or SAT1) are localized on the apical and basal membranes, respectively, of the proximal tubule. Perfusion studies show net absorption of oxalate in the S1 and S2 (convoluted) portions and net secretion in the S3 (straight) region of the proximal tubule.[44,62] Increasing oxalate reabsorption in the proximal tubules could be one way of reducing urinary calcium oxalate supersaturation and calcium oxalate crystallization.[34,63,64] Paradoxically, even in the absence of dietary oxalate, Slc26a6 knockout mice are hyperoxaluric and develop calcium oxalate nephrocalcinosis and nephrolithiasis.[24,25] This observation suggests that the SLC26A6 transporter normally reduces urinary oxalate excretion. Although such an action might protect the kidney from spikes in oxalate excretion, it is counterintuitive that oxalate, as a terminal metabolite, is not excreted as quickly as possible.

SLC26A7, the third oxalate transporter found in the kidney, is expressed on the basolateral membrane of a subset of principal cells and α-intercalated cells of the outer medullary collecting duct, as well as by principal cells of the distal tubule.[20,23] The physiologic role of SLC26A7 in oxalate transport is unknown, but the transporter might be involved in the deposition of calcium oxalate crystals in the lumens of the medullary collecting ducts in hyperoxaluric rats.[54] In addition, two laboratories have reported that the papilla has an oxalate transport capacity, but the transporter involved has not been yet been identified.[65,66] Oxalate transport at the papillary epithelial membrane could be involved in the deposition of calcium oxalate crystals onto Randall's plaques.[9]

The proximal tubule is the only tissue in which a physiologic function of oxalate has been identified. SLC26A6 is a broad-spectrum, electrogenic exchanger of monovalent and divalent anions that is sensitive to the inhibitor 4,4'-di-isothiocyanato-2,2'-disulfostilbene and is the prime facilitator of uphill chloride entry into the proximal tubule epithelial cells.[21,61] SLC26A6 exchanges chloride for various anions including sulfate, oxalate, formate, hydroxide, and bicarbonate,[67] and the transporter can also exchange oxalate for sulfate.[60] Interestingly, SLC26A6 has greater affinity for oxalate than for chloride, bicarbonate, sulfate, or formate.[61] The recycling of oxalate and sulfate at the apical membrane by SLC26A6 stimulates the uptake of chloride and fluid transport across the proximal tubule epithelium.[68] In addition, oxalate-chloride recycling at the apical membrane might drive sodium uptake.[61] Hassan et al.[69] recently showed that activation of protein kinase C-δ inhibits SLC26A6-mediated chloride-oxalate exchange and causes SLC26A6 to translocate from the apical plasma membrane to the cytosol. The relevance of this observation to calcium oxalate stone formation is undetermined.

SLC26A1 exchanges sulfate for oxalate or bicarbonate.[21,61,70] The transport of these ions by SLC26A1 is electrically neutral, sodium-independent, and inhibited by 4,4'-di-isothiocyanato-2,2'-disulfostilbene, phenol red, and probenecid.[61,70,71] Although oxalate and sulfate clearly inhibit one another's transport via SLC26A1, separate mechanisms regulate the transport of each anion.[61,70,71] The SLC26A1 promoter is thought to have numerous regulatory motifs, but as yet the molecular and endocrine processes that regulate the expression and activity of SLC26A1 have been little studied.[72]

Oxalate transport in the kidney is believed to be linked to the transport of several other ions (Figure 2). Thus, an anomaly in a seemingly unrelated transporter can alter oxalate transport and excretion. For example, the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel localized in the plasma membrane, shows reciprocal regulatory activity with several members of the SLC26A family, including SLC26A6.[73] These receptors interact through their PDZ domains and through binding of the SLC26A STAS domain with the R domain of the CFTR.[74] Patients with cystic fibrosis often exhibit mild hyperoxaluria and have an increased incidence of calcium oxalate nephrolithiasis.[75] The CFTR seems to be expressed in the proximal tubule, and, therefore, the defective form of the channel that is found in these patients might drive their hyperoxaluria.[75]

Figure 2.

Proposed Mechanisms of Oxalate Transport Across the Renal Epithelium in the Proximal Tubule. Transport of oxalate in the kidney is linked to that of several other ions and, thus, can be altered by an anomaly in a seemingly unrelated transporter. With kind permission from Springer Science+Business Media © Mount DB and Romero MF (2004) The SLC26 gene family of multifunctional anion exchangers. Pflugers Arch 447: 710-721; and Burckhardt BC and Burckhardt G (2003) Transport of organic anions across the basolateral membrane of proximal tubule cells. Rev Physiol Biochem Pharmacol 146: 95-158. Abbreviations: AQP-1, aquaporin-1; KCC3/4, electroneutral potassium-chloride cotransporter 3 or 4; Na+/K+-ATPase, sodium/potassium-transporting ATPase; NaSi1, solute carrier family 13 member 1; NHE3, sodium/hydrogen exchanger 3; Ox, oxalate; SLC26A1, solute carrier family 26 member 1; SLC26A6, solute carrier family 26 member 6.

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