Review

Correspondence *Case Western Reserve University School of Medicine, Department of Physiology and Biophysics, 10900 Euclid Avenue, Cleveland, OH 44106-4970, USA

Email srm10@case.edu

Introduction

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 mol/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 mol/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.

Sources of oxalate

Blood oxalate derives from erythrocytes, diet, the liver, and the metabolism of ascorbate (Figure 1). The plasma oxalate level is elevated in patients with extreme hyperoxaluria but is generally normal (1–5 mol/l) in patients with idiopathic calcium oxalate nephrolithiasis.^{15, 16}

Figure 1 Sources of blood oxalate.

(A) Oxalate absorption along the intestinal tract is believed to be mediated by three oxalate-transporting members of the solute carrier family 26A (SLC26A3, SLC26A6, SLC26A7).^{16, 20, 34} Secretion into the intestinal tract might also occur.^{24, 25} Only free oxalate can be absorbed by the intestinal epithelium. The amount of free oxalate is affected both by the presence of other ions, such as calcium—which binds to oxalate—and unabsorbed lipids—which indirectly increase the amount of free oxalate by binding to calcium.^{15, 16, 28} Absorption of oxalate is also affected by the presence of gut bacteria, such as Oxalobacter formigenes, that degrade oxalate to carbon dioxide and formate.^{16, 32} (B) In the systemic circulation, erythrocytes synthesize oxalate from glyoxylate;¹⁷ in addition, oxalate enters erythrocytes via the band 3 anion transport protein (SLC4A1 or AE1).¹⁸ Ascorbate (vitamin C) in the blood can be metabolized to oxalate.⁴¹ (C) In the liver, oxalate is synthesized from glyoxylate by lactate dehydrogenase and released into the blood. The major pathways controlling the production of glyoxylate have not yet been identified, although the degradation of hydroxyproline and the oxidation of glycolate by glycolate oxidase are two sources of glyoxylate.^{35, 37} Under normal conditions, most glyoxylate is metabolized to glycine by alanine–glyoxylate aminotransferase or reduced to glycolate by D-glycerate dehydrogenase. Defects in the genes encoding these two enzymes characterize primary hyperoxaluria types I³⁸ and II,³⁹ respectively. (D) Unexcreted oxalate is stored in structural tissues and soft organs. Abbreviations: AGT, alanine–glyoxylate aminotransferase; DGDH, D-glycerate dehydrogenase; GOX, glycolate oxidase; LDH, lactate dehydrogenase; Ox, oxalate; PH-I, primary hyperoxaluria type I; PH-II, primary hyperoxaluria type II; SLC26A3, solute carrier family 26 member 3; SLC26A6, solute carrier family 26 member 6; SLC26A7, solute carrier family 26 member 7; SLC4A1, band 3 anion transport protein.

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Excretion of oxalate

In mammals, oxalate is a terminal metabolite that must be excreted or sequestered to maintain homeostasis. Oxalate is freely filterable by the glomerulus and is not appreciably bound by serum proteins.⁴⁴ Rats and humans have similar creatinine clearances (1–2.5 ml/min) and similar distribution volumes of oxalate (1.5-fold of the extracellular space).^{45, 46, 47} Urinary oxalate excretion by normal adults ranges from 28 mg/day to 43 mg/day (311–478 mol/day), with the average excretion being slightly higher in men than in women.^{11, 48} Values over 40–45 mg/day (444–500 mol/day) are generally classified as clinical hyperoxaluria.

Following infusion into healthy volunteers of less than one day's excretion of radiolabeled oxalate, more than 90% of the infused dose was recovered in urine.^{45, 49, 50} The movement of oxalate from blood into feces in humans has been little studied. The one such study performed to date reported negligible fecal excretion of ¹⁴C-oxalate that was administered intravenously to patients with hyperoxalemia who were on dialysis.⁵¹ By contrast, hyperoxalemia increases fecal oxalate excretion in rats.⁵² In a rat study that used subcutaneously implanted minipumps to infuse approximately 0.225 mg (2.5 mol) of ¹⁴C-oxalate per day for 4 days, 50% of the dose was recovered in the excreta.⁵³ Of the excreted oxalate, 90% was in the urine and about 7% in the feces. Unfortunately, collections were not made after the treatment period. In rats, the normal daily urinary oxalate excretion is about 0.45–0.9 mg (5–10 mol), but excretions in excess of 6.3 mg/day (70 mol/day) are obtainable under experimental conditions.⁵⁴ Thus, it is surprising that a small load of 0.225 mg was not rapidly excreted. Other rat studies that investigated acute infusions or injections of ¹⁴C-oxalate also reported a failure to collect all of the administered dose in the excreta.^{55, 56} Humans and rats generally do not excrete measurable amounts of ¹⁴C-oxalate as ¹⁴C-carbon dioxide, although excretion of small amounts of ¹⁴C-carbon dioxide is occasionally detected.^{51, 53, 57} Whether the reported differences in oxalate excretion between rats and humans are due to differing protocols, difficulties in measuring oxalate, or real differences in oxalate physiology between the two species, is unknown.

In one of our studies, 6 rats were treated for 13 days with 32.4 mg/day (360 mol/day) of ¹⁴C-oxalate via subcutaneously implanted minipumps (SR Marengo, unpublished data). As in the other described studies,^{53, 55, 56} a substantial proportion of oxalate was retained in the body while that which was excreted was mostly in the urine (Table 1). Approximately 78% of the oxalate in the skin was directly associated with the pump pocket and the total amount of oxalate in the plasma, skeleton and skeletal muscle was less than 1% of the administered dose. Thus, most of the oxalate retained in the skin and carcass probably accumulated directly from the pump rather than being deposited via the circulation. Thus, it seems that like humans, rats excrete most of an oxalate load promptly. Rats differ from humans, however, in that they excrete a considerable portion of the load in the feces.

Table 1 Excretory and accumulative partitioning of ¹⁴C-oxalate in rats that received a persistent oxalate challenge (SR Marengo, unpublished data).^a

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Unexpectedly, less than 1% of the oxalate administered in our rat study accumulated in the internal organs. Although the oxalate loads were similar among the rats, there was variation in the partitioning of oxalate for excretion and accumulation. The percentage of oxalate excreted in the urine varied by almost twofold among rats (range 16.1–30.0%; P 0.0001), although fecal oxalate excretion varied by much less (range 5.3–6.8%; P >0.3). The percentage of the oxalate load that was retained varied among rats by approximately twofold in the internal organs not including the kidney (range 0.03–0.06%) and skeleton (range 0.43–0.98%). By contrast, the percentage of oxalate retained in the kidneys varied by more than 50-fold among rats (range 0.7–0.01%). Correcting these values for the percentage of the administered dose of oxalate recovered for each rat did not alter this variation. Extrapolating from these observations to the clinic, it is possible that the differences in the distribution and accumulation of oxalate between individuals could have an important role in determining whether calcium oxalate nephrolithiasis or urolithiasis develops. The chemical form of nonrenal oxalate and the mechanisms regulating its distribution are unknown.

Much interest is focused on the possibility of increasing fecal oxalate excretion in order to reduce the amount of oxalate that must be excreted in the urine. In vitro studies show that the ileum of Slc26a6 knockout mice displays increased absorption of dietary oxalate, which suggests that the ileum might help protect against excess oxalate absorption, thus reducing the kidneys' oxalate burden.^{24, 25} Colonization by Oxalobacter sp. also increases oxalate movement from the blood into the colon in rats, possibly via 'backwards' transport by SLC26A3, although this possibility has not been formally tested.⁵⁸  Oxalobacter sp. colonization also reduces urinary oxalate excretion in humans.⁵⁹ The use of Oxalobacter sp. to reduce urinary oxalate excretion in persistently hyperoxaluric patients is under intense investigation.⁵⁹

Oxalate transport in the kidney

The kidney tubules express three members of the SLC26A family that can transport oxalate.^{20, 21, 60, 61} SLC26A6 and SLC26A1 (also called sulfate anion transporter 1 or SAT1) are localized on the apical and basal membranes, respectively, of the proximal tubule. Perfusion studies show net absorption of oxalate in the S1 and S2 (convoluted) portions and net secretion in the S3 (straight) region of the proximal tubule.^{44, 62} Increasing oxalate reabsorption in the proximal tubules could be one way of reducing urinary calcium oxalate supersaturation and calcium oxalate crystallization.^{34, 63, 64} Paradoxically, even in the absence of dietary oxalate, Slc26a6 knockout mice are hyperoxaluric and develop calcium oxalate nephrocalcinosis and nephrolithiasis.^{24, 25} This observation suggests that the SLC26A6 transporter normally reduces urinary oxalate excretion. Although such an action might protect the kidney from spikes in oxalate excretion, it is counterintuitive that oxalate, as a terminal metabolite, is not excreted as quickly as possible.

SLC26A7, the third oxalate transporter found in the kidney, is expressed on the basolateral membrane of a subset of principal cells and -intercalated cells of the outer medullary collecting duct, as well as by principal cells of the distal tubule.^{20, 23} The physiologic role of SLC26A7 in oxalate transport is unknown, but the transporter might be involved in the deposition of calcium oxalate crystals in the lumens of the medullary collecting ducts in hyperoxaluric rats.⁵⁴ In addition, two laboratories have reported that the papilla has an oxalate transport capacity, but the transporter involved has not been yet been identified.^{65, 66} Oxalate transport at the papillary epithelial membrane could be involved in the deposition of calcium oxalate crystals onto Randall's plaques.⁹

The proximal tubule is the only tissue in which a physiologic function of oxalate has been identified. SLC26A6 is a broad-spectrum, electrogenic exchanger of monovalent and divalent anions that is sensitive to the inhibitor 4,4'-di-isothiocyanato-2,2'-disulfostilbene and is the prime facilitator of uphill chloride entry into the proximal tubule epithelial cells.^{21, 61} SLC26A6 exchanges chloride for various anions including sulfate, oxalate, formate, hydroxide, and bicarbonate,⁶⁷ and the transporter can also exchange oxalate for sulfate.⁶⁰ Interestingly, SLC26A6 has greater affinity for oxalate than for chloride, bicarbonate, sulfate, or formate.⁶¹ The recycling of oxalate and sulfate at the apical membrane by SLC26A6 stimulates the uptake of chloride and fluid transport across the proximal tubule epithelium.⁶⁸ In addition, oxalate–chloride recycling at the apical membrane might drive sodium uptake.⁶¹ Hassan et al.⁶⁹ recently showed that activation of protein kinase C- inhibits SLC26A6-mediated chloride–oxalate exchange and causes SLC26A6 to translocate from the apical plasma membrane to the cytosol. The relevance of this observation to calcium oxalate stone formation is undetermined.

SLC26A1 exchanges sulfate for oxalate or bicarbonate.^{21, 61, 70} The transport of these ions by SLC26A1 is electrically neutral, sodium-independent, and inhibited by 4,4'-di-isothiocyanato-2,2'-disulfostilbene, phenol red, and probenecid.^{61, 70, 71} Although oxalate and sulfate clearly inhibit one another's transport via SLC26A1, separate mechanisms regulate the transport of each anion.^{61, 70, 71} The SLC26A1 promoter is thought to have numerous regulatory motifs, but as yet the molecular and endocrine processes that regulate the expression and activity of SLC26A1 have been little studied.⁷²

Oxalate transport in the kidney is believed to be linked to the transport of several other ions (Figure 2). Thus, an anomaly in a seemingly unrelated transporter can alter oxalate transport and excretion. For example, the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel localized in the plasma membrane, shows reciprocal regulatory activity with several members of the SLC26A family, including SLC26A6.⁷³ These receptors interact through their PDZ domains and through binding of the SLC26A STAS domain with the R domain of the CFTR.⁷⁴ Patients with cystic fibrosis often exhibit mild hyperoxaluria and have an increased incidence of calcium oxalate nephrolithiasis.⁷⁵ The CFTR seems to be expressed in the proximal tubule, and, therefore, the defective form of the channel that is found in these patients might drive their hyperoxaluria.⁷⁵

Figure 2 Proposed mechanisms of oxalate transport across the renal epithelium in the proximal tubule.

Transport of oxalate in the kidney is linked to that of several other ions and, thus, can be altered by an anomaly in a seemingly unrelated transporter. With kind permission from Springer Science+Business Media © Mount DB and Romero MF (2004) The SLC26 gene family of multifunctional anion exchangers. Pflugers Arch 447: 710–721; and Burckhardt BC and Burckhardt G (2003) Transport of organic anions across the basolateral membrane of proximal tubule cells. Rev Physiol Biochem Pharmacol 146: 95–158. Abbreviations: AQP-1, aquaporin-1; KCC3/4, electroneutral potassium–chloride cotransporter 3 or 4; Na⁺/K⁺-ATPase, sodium/potassium-transporting ATPase; NaSi1, solute carrier family 13 member 1; NHE3, sodium/hydrogen exchanger 3; Ox, oxalate; SLC26A1, solute carrier family 26 member 1; SLC26A6, solute carrier family 26 member 6.

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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,⁸⁴ 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.⁸⁵ 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.⁸⁶ 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.⁹² 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.¹⁰⁵ 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.¹⁰⁹ 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.¹¹³ The renal handling of phosphate and calcium has been reviewed by Berndt and Kumar,¹¹⁴ Huang and Miller,¹¹⁵ and Sayer et al.¹¹⁶

Conclusions

Traditionally, oxalate has been relegated to the status of a metabolic by-product, the role of which in stone disease is limited to the physical chemistry of crystallization. Recent investigations indicate, however, that oxalate can increase chloride, water, and sodium reabsorption in the proximal tubule and activate multiple signaling pathways in renal epithelial cells. By contrast, little is known about the partitioning of oxalate between urinary excretion, fecal excretion, and accumulation in tissues and organs. Until the factors that control this partitioning are understood, preventive medical therapies will elude patients with idiopathic hyperoxaluria, or with hyperoxaluria secondary to bariatric surgery or cystic fibrosis.

Acknowledgments

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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