If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Hyperoxaluria is a major risk factor for renal stone disease and can arise from exogenous sources, such as dietary excess and enteric hyperabsorptive states, or from endogenous overproduction. In the healthy individual, most urinary oxalate arises from endogenous production and is excreted almost entirely through the kidney. In hyperoxaluric states, urine becomes supersaturated with respect to calcium oxalate, leading to crystalluria, stone formation, and/or nephrocalcinosis. When end-stage renal failure ensues, systemic oxalate deposition follows in the heart, bone, and blood vessels, leading to significant morbidity and mortality. The accompanying paper by Monico et al
in this issue of the American Journal of Kidney Diseases explores the hypothesis that hyperoxaluria may be caused by mutations in oxalate transport, in addition to better-known mutations in oxalate production.
The inherited hyperoxalurias, primary hyperoxaluria type 1 and 2 (PH1 and PH2), are rare diseases which have helped to elucidate the metabolic pathways leading to endogenous hyperoxaluria (Fig 1). Both diseases are brought about by failure to remove glyoxylate: PH1 due to deficiency of peroxisomal alanine-glyoxylate aminotransferase (AGT; encoded by the AGXT gene) and PH2 as a result of cytosolic glyoxylate reductase/hydroxypyruvate reductase (GRHPR) deficiency. In both cases, the excess glyoxylate is metabolized to oxalate by lactate dehydrogenase (LDH). These diseases are at the severe end of the spectrum for hyperoxaluria, with 50% of those presenting in childhood developing end-stage renal failure by age 15.
which has provided explanations for some of the phenotypic heterogeneity at the enzyme level. However, in spite of all this information, we are no nearer to an explanation for the wide phenotypic differences. For example, we have shown that individuals with null alleles of AGXT and GRHPR can present across a wide age range, from neonate to fifth decade,
One possible explanation for such variability may be the natural variation in each of the contributing enzymes of the metabolic pathway. We have shown in vitro that both AGT and GRHPR exert a protective effect in minimizing glyoxylate toxicity in cultured CHO (Chinese Hamster Ovary) cells transfected with all the relevant enzymes of the glyoxylate pathway.
These experiments illustrate a clear role for glycolate oxidase (GO; encoded by the HAO1 gene) in the production of glyoxylate, a key contributor to endogenous oxalate, and one could hypothesize a situation where variation in GO activity could lead to substantial interindividual variation in glyoxylate production. In addition, differences undoubtedly exist in the amount of urinary crystallization inhibitors present, the hydration status of an individual, and the presence or absence of infections as well as differences in intestinal oxalate uptake and renal oxalate handling.
Oxalate uptake and renal oxalate excretion have been given a boost by the identification of the SLC26 (solute-linked carrier) family of transporters. This family of anion exchangers includes 10 protein products with multifunctional properties and a range of substrate specificities, 3 of which, SLC26A2, A3, and A4, have disease associations.
Several have been shown to transport oxalate in exchange for either sulfate or chloride, with 2 of them, SLC26A6 and SLC26A3, showing high affinity for oxalate. SLC26A6 is expressed in the apical membrane of intestinal and renal epithelia, including the pancreatic duct cells
SLC26A6 and A3 facilitate transcellular transport of anions across the apical membrane; in some cases this exchange is electrogenic and in others electroneutral.
The Slc26a6 null mouse showed a significant increase in intestinal oxalate absorption which was insensitive to the anion exchange inhibitor DIDS (4,4′ diisothiocyanostilbene-2,2′-disulfonic acid) compared to the wildtype mouse, in which net DIDS-sensitive oxalate excretion occurred.
These results were interpreted as unopposed oxalate uptake by an as-yet unknown apical transporter, with a reduction in the apical efflux of oxalate (in exchange for chloride) and increased export across the basal membrane. In both mouse knockout models, oxalate excretion was reduced by decreasing dietary oxalate, supporting the theory that the hyperoxaluria is due to a hyperabsorptive state. It is possible that SLC26A3, which is involved in oxalate-sensitive sulfate uptake into the intestinal cells, could be the other apical membrane transporter and that one could reduce oxalate uptake by blocking this transporter. Preliminary studies with an Slc26a3 knockout mouse do indeed show a significant decrease in mucosal to serosal flux of oxalate in both the distal ileum and distal colon.
The significance of the lower affinity of human SLC26A6 for chloride may be that the enteric secretion of oxalate is less in humans than mouse, leading to a greater degree of oxalate absorption with a concomitant increased risk of renal stone formation.
An adaptive mechanism has been shown in animal studies whereby in hyperoxaluric states, eg, renal failure, increasing amounts of oxalate can be secreted into the gut,
possibly via SLC26A6. Treatment of hyperoxaluric individuals with oxalate-degrading bacteria, specifically Oxalobacter formigenes, can potentially capitalize on this response by enhancing the enteric secretion of oxalate
explore this hypothesis by analyzing the SLC26A6 gene in patients with PH1, PH2, and atypical PH. Five missense changes were found, including 2 known polymorphisms, p.Val206Met (a valine to methionine change at amino acid 206)
The p.Val206Met polymorphism, which occurred at a relatively high frequency in controls and patients, albeit mainly in the heterozygous state, reduced oxalate influx by 30% relative to the wild type transporter,
although the effect on oxalate efflux was not described. The authors were unable to show any effect of this variant on urine or plasma oxalate concentration, although it may be that subtle differences in oxalate excretion are overlooked in such gross hyperoxaluric states or that heterozygosity has no effect on transporter function. The results would therefore suggest that mutations in SLC26A6 do not account for atypical PH, at least in the cases examined here, but its role as a modifier of oxalate excretion cannot be ruled out at this stage.
Financial Disclosure: None.
Phenotypic and functional analysis of human SLC26A6 variants in patients with familial hyperoxaluria and calcium oxalate nephrolithiasis.
Urinary oxalate is a major risk factor for calcium oxalate stones. Marked hyperoxaluria arises from mutations in 2 separate loci, AGXT and GRHPR, the causes of primary hyperoxaluria (PH) types 1 (PH1) and 2 (PH2), respectively. Studies of null Slc26a6−/− mice have shown a phenotype of hyperoxaluria, hyperoxalemia, and calcium oxalate urolithiasis, leading to the hypothesis that SLC26A6 mutations may cause or modify hyperoxaluria in humans.