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Oxalate in renal stone disease: the terminal metabolite that just won't go away

Abstract

The incidence of calcium oxalate nephrolithiasis in the US has been increasing throughout the past three decades. Biopsy studies show that both calcium oxalate nephrolithiasis and nephrocalcinosis probably occur by different mechanisms in different subsets of patients. Before more-effective medical therapies can be developed for these conditions, we must understand the mechanisms governing the transport and excretion of oxalate and the interactions of the ion in general and renal physiology. Blood oxalate derives from diet, degradation of ascorbate, and production by the liver and erythrocytes. In mammals, oxalate is a terminal metabolite that must be excreted or sequestered. The kidneys are the primary route of excretion and the site of oxalate's only known function. Oxalate stimulates the uptake of chloride, water, and sodium by the proximal tubule through the exchange of oxalate for sulfate or chloride via the solute carrier SLC26A6. Fecal excretion of oxalate is stimulated by hyperoxalemia in rodents, but no similar phenomenon has been observed in humans. Studies in which rats were treated with 14C-oxalate have shown that less than 2% of a chronic oxalate load accumulates in the internal organs, plasma, and skeleton. These studies have also demonstrated that there is interindividual variability in the accumulation of oxalate, especially by the kidney. This Review summarizes the transport and function of oxalate in mammalian physiology and the ion's potential roles in nephrolithiasis and nephrocalcinosis.

Key Points

  • The incidence of calcium oxalate nephrolithiasis is increasing and an understanding of the mechanisms that govern the levels and actions of oxalate in the body is required to facilitate the development of treatments for this condition

  • Oxalate is obtained from diet, degradation of ascorbate, and synthesis by the liver and erythrocytes

  • Three oxalate-transporting members of the solute carrier family 26A (SLC26A7, SLC26A6 and SLC26A3) are expressed along the intestinal tract and are believed to mediate absorption of dietary oxalate

  • Oxalate is a terminal metabolite that must be excreted or sequestered; the kidneys are the primary route of excretion, and fecal excretion of oxalate has not been observed in humans

  • The kidney tubules express SLC26A6, SLC26A1 and SLC26A7, three members of the SLC26A family that transport oxalate: SLC26A6 mediates oxalate's only known function, which is to stimulate the uptake of chloride, water, and sodium by the proximal tubule

  • In addition to causing urinary calcium oxalate supersaturation, oxalate might contribute to nephrolithiasis by affecting the renal vasculature through actions on renal epithelial cells and perhaps by inducing changes in renal ion transport

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Figure 1: Sources of blood oxalate.
Figure 2: Proposed mechanisms of oxalate transport across the renal epithelium in the proximal tubule.

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Acknowledgements

This work was supported by NIH Grants DK073730 (to SR Marengo) and HL18708 (to AMP Romani) and by the American Urological Association Foundation (SR Marengo). Appreciation is expressed to SE Brown for editorial assistance.

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Marengo, S., Romani, A. Oxalate in renal stone disease: the terminal metabolite that just won't go away. Nat Rev Nephrol 4, 368–377 (2008). https://doi.org/10.1038/ncpneph0845

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