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

Susan R. Marengo; Andrea M. P. Romani


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

In This Article

Summary and Introduction


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.


In the 1980s, the introduction of extracorporeal shockwave lithotripsy and percutaneous procedures revolutionized the treatment of kidney stones that were too big to pass spontaneously. Although this development greatly reduced the morbidity and mortality associated with nephrolithiasis, it did not reduce the incidence of this condition. On the contrary, the incidence of nephrolithiasis continues to increase in the US, particularly in women.[1,2] The quality of life of stone formers has not been well studied, but casual conversations reveal dissatisfaction with the status quo, and especially with the lack of effective prevention.

Evidence is accumulating that nephrolithiasis is associated with decreased renal function. Two large studies reported that stone formers have slightly, but significantly, lower glomerular filtration rates and creatinine clearances than those who are not stone formers.[3,4] Moreover, nephrolithiasis and shockwave lithotripsy might increase the risk of chronic kidney disease and hypertension.[5,6] The relative contributions of nephrolithiasis, its treatment and its underlying predispositions to these conditions are unknown.[7]

The prime factors that predispose an individual to the development of nephrolithiasis -- stone-promoting urine chemistries, Randall's plaques, and defects in the crystallization-inhibiting system -- almost certainly have variable relative importance in the pathophysiology of calcium oxalate nephrolithiasis within subsets of patients. Given the heterogeneity of the clinical presentation of calcium oxalate nephrolithiasis, it is unlikely that any one defect can explain the development of this condition in the majority of cases.

Renal biopsies and Fourier transform infrared microspectroscopy show that idiopathic stone formers with mild hyperoxaluria (40-50 mg/day [444-556 µmol/day]) have interstitial nephrocalcinosis that is localized primarily to the loops of Henle and consists of hydroxyapatite (calcium phosphate) crystals.[8] Calcium oxalate nephroliths in these individuals are often attached to Randall's plaques.[9,10] The formation or attachment of calcium oxalate crystals on these plaques is probably critical for the growth of nephroliths over extended periods, especially in stone formers whose urine is only sporadically conducive to crystal formation and attachment. Marked, persistent hyperoxaluria (60-83 mg/day [667-922 µmol/day]) is common following modern-day bariatric surgery[11,12] and is characterized by intraluminal calcium phosphate nephrocalcinosis localized to the inner medullary collecting ducts.[10] In this setting, nephroliths are typically free within the renal pelvis and are composed solely of calcium oxalate crystals.[10] Following older forms of bariatric surgery, severe hyperoxaluria (100-200 mg/day [1.1-2.2 mmol/day]) was common and renal failure and intraluminal calcium oxalate nephrocalcinosis localized to the medullary collecting ducts were occasionally reported.[13,14] These clinical observations demonstrate that different forms of hyperoxaluria promote nephrolithiasis by different mechanisms and are, thus, likely to require different interventions.

For many years, oxalate has been viewed as a metabolic waste product, a counter ion in transport studies, or an experimentally useful chelator of calcium, and it has not been considered worthy of detailed study. However, as discussed below, neither the excretion of oxalate nor the regulation of its transport are as investigators had expected, and evidence is mounting that oxalate affects normal physiology, especially in the kidney. This Review summarizes what is known of the role and transport of oxalate and also suggests mechanisms by which oxalate might promote nephrolithiasis.


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.