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 (14)C-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.

Analysis of the 206M polymorphic variant of the SLC26A6 gene encoding a Cl− oxalate transporter in patients with primary hyperparathyroidism

“…In the present study, the M/M genotype was extremely rare both in PHPT and healthy cohorts, namely one PHPT patient and three healthy controls, making difficult to evaluate its actual clinical impact. Secondly, as far as the renal oxalate excretions are concerned, several acquired conditions might influence urine oxalate concentrations, overcoming the effect of the genetic background (23)(24)(25)(26). In particular, high levels of 1,25-dihydroxyvitamin D 3 might induce high calcium and consequently oxalate intestinal absorption (23,24), although in the present series of PHPT patients serum 1,25-dihydroxyvitamin D 3 levels were not significantly correlated with urine oxalate concentrations.…”

Environmental factors responsible for switching on the SO42−excretory system in the kidney of seawater eels

“…In mammals, SO 4 2Ϫ filtered by the kidney easily reaches saturation and excess SO 4 2Ϫ is excreted into the urine (15,22). Therefore, apparent switching does not seem to occur in mammals, although the presence of a SO 4 2Ϫ excretory system is also suggested in mammals (16,20).…”

“…Among them, Slc13a1 and Slc26a1 play key roles in SO 4 2Ϫ reabsorption at the renal proximal tubule of mammals (5) and FW eels (23). On the other hand, Slc26a6 and Slc26a1 are suggested to be involved in renal SO 4 2Ϫ secretion in mammals (16,20). In fishes, Slc26a1 seems to be involved in renal SO 4 2Ϫ secretion in rainbow trout (14), Slc26a6a in pufferfish (13), and Slc26a6a,b,c and Slc26a1 in SW eels (35).…”

Primary and secondary hyperoxaluria: Understanding the enigma

“…Hyperoxaluria is a state of disordered metabolism characterized by an increased urinary excretion of oxalate. The normal daily oxalate excretion in healthy individuals ranges between 1040 mg per 24 h. Concentrations exceeding 4045 mg per 24 h are considered as clinical hyperoxaluria [13] . This may result from increased endogenous production of oxalate in primary hyperoxaluria (PH) or from increased intestinal absorption or increased intake of oxalate precursors in secondary hyperoxaluria (SH).…”

“…Glyoxalate is synthesized from oxidation of glycolate through enzymatic action of glycolate oxidase or from metabolism of hydroxyproline which is found in collagen or dietary sources. Increased glyoxalate is converted to oxalate by action of lactate dehydrogenase in the absence of enzymatic activity as is seen in the various types of PH [12,13] . This pathway is depicted in Figure 1.…”