Potential Roles of Oxalate in Nephrolithiasis
The role of urinary oxalate in nephrolithiasis is nothing if not controversial.[34,76,77,78] Given the heterogeneity of nephrolithiases, it is almost certain that the roles of calcium and/or oxalate in some subsets of stone formers are limited to simply forming calcium oxalate crystals when present in sufficient quantities. For example, hypercalciuria is frequently reported to be the most common urinary defect in idiopathic stone formers.[76,77] Yet, populations with persistent mild hyperoxaluria, a low incidence of hypercalciuria and an increased incidence of calcium oxalate nephrolithiasis have been documented (e.g. patients with cystic fibrosis,[79,80] individuals who have undergone gastric bypass surgery,[12,81] and people from the Arabian Peninsula and Pakistan).[82,83]
Oxalate can affect stone formation and growth in ways other than contributing to urinary calcium oxalate supersaturation and crystallization, for example via regulation of its retention and excretion. Transgenic mouse data indicate that SLC26A6 seems to reduce oxalate absorption from the gut and increase absorption by the proximal tubules, thus reducing urinary oxalate excretion.[24,25] The ability to gradually excrete an oxalate load in the urine might reduce an individual's risk of crystal formation and growth.
Oxalate might also affect the renal vasculature, a theory originated in the mid-twentieth century by Carr, who believed that improper papillary drainage promotes crystal formation and deposition. Later work shows that vascular endothelial cells take up oxalate and that prolonged oxalate exposure inhibits proliferation of these cells while increasing their concentration of cytoplasmic and nuclear calcium. Little is known of oxalate's effect on renal blood flow, but one study in rats found that acute infusions of oxalate into the renal artery reduced blood flow and cortical microcirculation. More support for a role of vascular defects in the promotion of stone formation comes from the clinical association of hypertension with nephrolithiasis and from reports that vasodilators such as enalapril and losartan reduce calcium oxalate nephrolithiasis in ethylene-glycol-treated rats.[87,88,89]
Observations that nephrotoxicity increases calcium oxalate nephrocalcinosis in rats and that oxalate induces both apoptosis and proliferation of renal epithelial cells have given rise to the hypothesis that oxalate promotes nephrolithiasis via interactions with the renal epithelium.[90,91] If this hypothesis is true, variable susceptibility or adaptability to oxalate-mediated effects could explain why stone formers and those who are not stone formers can have identical levels of hyperoxaluria. The exposure of renal epithelial cells to oxalate causes oxidative damage, mitochondrial damage, activation of second messenger pathways (such as those mediated by p38 MAP kinase and phospholipase A), inflammatory response signaling, changes in the expression of putative modulators of crystallization (such as osteopontin, bikunin and Tamm-Horsfall protein), and changes in the glycocalyx.[93,94,95,96,97,98,99,100,101,102,103,104]
The effects of oxalate on renal epithelial cells have been extensively discussed by Jonassen et al. Although some of these effects are directly due to oxalate, others are secondary to oxalate-induced oxidative damage or inflammatory responses.[96,106] The changes effected by oxalate could promote nephrolithiasis by providing debris for crystal nucleation, making the apical plasma membrane more adhesive to crystals, or altering the availability of crystallization-inhibiting proteins. Such changes would presumably promote nephrolithiasis by giving crystals time to grow so they would be large enough to aggregate or attach to a growing nephrolith or to Randall's plaques upon reaching the renal pelvis.
To complicate the study of the effects of oxalate on renal epithelial cells, these cells internalize both free oxalate and calcium oxalate crystals.[91,107] Moreover, it is hard to avoid crystallization of calcium oxalate in in vitro preparations, and calcium oxalate crystalluria exists at even modest levels of hyperoxaluria in vivo. Thus, whether the effects of calcium oxalate on the renal epithelium are attributable to its soluble or to its crystalline form is still under debate.[93,94,108]
Oxalate-induced changes in renal ion transport are obvious mechanisms by which oxalate could promote nephrolithiasis, but these potential mechanisms have received almost no attention from investigators. Extratubular calciferous crystalline deposits, mostly comprising calcium phosphate, have been documented frequently since Randall's 1940 study. As discussed above, patients with mild or marked hyperoxaluria develop interstitial or intraluminal calcium phosphate nephrocalcinosis, respectively.[8,10] These findings suggest that there are pre-existing defects in phosphate or calcium transport caused by oxalate or another, as yet unknown, factor. Spontaneous calcium phosphate nephrocalcinosis is present in the interstitium of Tamm-Horsfall protein-osteopontin double knockout mice, in renal type IIa sodium-phosphate cotransporter knockout mice (localization undetermined), and in genetically hypercalciuric rats, but not in hyperoxaluric rats or mice.[110,111,112] Furthermore, elevated phosphate excretion characterizes rodents with calcium phosphate nephrocalcinosis. These results suggest that the calcium phosphate nephrocalcinosis typical of calcium oxalate stone formers might have multiple origins. Surprisingly, despite the flurry of interest in the pyrophosphate transporter ANK, which is expressed in the joints and kidney, no renal calcifications have been found in mice with aberrant ANK function. The renal handling of phosphate and calcium has been reviewed by Berndt and Kumar, Huang and Miller, and Sayer et al.
Nat Clin Pract Nephrol. 2008;4(7):368-377. © 2008
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Cite this: Oxalate in Renal Stone Disease: The Terminal Metabolite That Just Won't Go Away - Medscape - Jul 01, 2008.