In Search of an Efficient Complexing Agent for Oxalates and Phosphates: A Quantum Chemical Study

Limiting gastrointestinal oxalate absorption is a promising approach to reduce urinary oxalate excretion in patients with idiopathic and enteric hyperoxaluria. Phosphate binders, that inhibit gastrointestinal absorption of dietary phosphate by the formation of easily excretable insoluble complexes, are commonly used as a treatment for hyperphosphatemia in patients with end-stage renal disease. Several of these commercially available phosphate binders also have affinity for oxalate. In this work, a series of metallic cations (Li+, Na+, Mg2+, Ca2+, Fe2+, Cu2+, Zn2+, Al3+, Fe3+ and La3+) is investigated on their binding affinity to phosphate and oxalate on one side and anionic species that could be used to administer the cationic species to the body on the other, e.g., acetate, carbonate, chloride, citrate, formate, hydroxide and sulphate. Through quantum chemical calculations, the aim is to understand the competition between the different complexes and propose possible new and more efficient phosphate and oxalate binders.

Contribution of Dietary Oxalate and Oxalate Precursors to Urinary Oxalate Excretion

Kidney stone disease is increasing in prevalence, and the most common stone composition is calcium oxalate. Dietary oxalate intake and endogenous production of oxalate are important in the pathophysiology of calcium oxalate stone disease. The impact of dietary oxalate intake on urinary oxalate excretion and kidney stone disease risk has been assessed through large cohort studies as well as smaller studies with dietary control. Net gastrointestinal oxalate absorption influences urinary oxalate excretion. Oxalate-degrading bacteria in the gut microbiome, especially Oxalobacter formigenes, may mitigate stone risk through reducing net oxalate absorption. Ascorbic acid (vitamin C) is the main dietary precursor for endogenous production of oxalate with several other compounds playing a lesser role. Renal handling of oxalate and, potentially, renal synthesis of oxalate may contribute to stone formation. In this review, we discuss dietary oxalate and precursors of oxalate, their pertinent physiology in humans, and what is known about their role in kidney stone disease.

Simple dietary advice targeting five urinary parameters reduces urinary supersaturation in idiopathic calcium oxalate stone formers

Among 208 kidney stone patients referred within 2 years, 75 patients (66 men, nine women) with truly idiopathic calcium oxalate stones (ICSF) were recruited. Dietary advice (DA) aimed at (1) urine dilution, (2) reduced crystallization promotion (lowering oxalate), and (3) increased crystallization inhibition (increasing citrate). We recommended higher intakes of fluid and calcium with meals/snacks (reducing intestinal oxalate absorption) as well as increased alkali and reduced meat protein (acid) for increasing urinary citrate. The intended effects of DA were elevations in urine volume, calcium (U-Ca) and citrate (U-Cit) as well as reductions in oxalate (U-Ox) and uric acid (U-UA). We retrospectively calculated an adherence score (AS), awarding + 1 point for parameters altered in the intended direction and − 1 point for opposite changes. Calcium oxalate supersaturation (CaOx-SS) was calculated using Tiselius’ AP(CaOx) index EQ. DA induced changes (all p < 0.0001) in urine volume (2057 ± 79 vs. 2573 ± 71 ml/day) and U-Ca (5.49 ± 0.24 vs. 7.98 ± 0.38 mmol/day) as well as in U-Ox (0.34 ± 0.01 vs. 0.26 ± 0.01 mmol/day) and U-UA (3.48 ± 0.12 vs. 3.13 ± 0.10 mmol/day). U-Cit only tendentially increased (3.07 ± 0.17 vs. 3.36 ± 0.23 mmol/day, p = 0.06). DA induced a 21.5% drop in AP(CaOx) index, from 0.93 ± 0.05 to 0.73 ± 0.05 (p = 0.0005). Decreases in CaOx-SS correlated with AS (R = 0.448, p < 0.0005), and highest AS (+ 5) always indicated lowering of CaOx-SS. Thus, simple DA can reduce CaOx-SS which may be monitored by AS.

Dietary Recommendations for Bariatric Patients to Prevent Kidney Stone Formation

Bariatric surgery (BS) is one of the most common and efficient surgical procedures for sustained weight loss but is associated with long-term complications such as nutritional deficiencies, biliary lithiasis, disturbances in bone and mineral metabolism and an increased risk of nephrolithiasis, attributed to urinary metabolic changes resultant from low urinary volume, hypocitraturia and hyperoxaluria. The underlying mechanisms responsible for hyperoxaluria, the most common among all metabolic disturbances, may comprise increased intestinal oxalate absorption consequent to decreased calcium intake or increased dietary oxalate, changes in the gut microbiota, fat malabsorption and altered intestinal oxalate transport. In the current review, the authors present a mechanistic overview of changes found after BS and propose dietary recommendations to prevent the risk of urinary stone formation, focusing on the role of dietary oxalate, calcium, citrate, potassium, protein, fat, sodium, probiotics, vitamins D, C, B6 and the consumption of fluids.

Enhanced gastrointestinal passive paracellular permeability contributes to the obesity-associated hyperoxaluria

Most kidney stones (KS) are composed of calcium oxalate and small increases in urine oxalate enhance the stone risk. Obesity is a risk factor for KS, and urinary oxalate excretion increases with increased body size. We previously established the obese ob/ob ( ob) mice as a model (3.3-fold higher urine oxalate) to define the pathogenesis of obesity-associated hyperoxaluria (OAH). The purpose of this study was to test the hypothesis that the obesity-associated enhanced small intestinal paracellular permeability contributes to OAH by increasing passive paracellular intestinal oxalate absorption. ob Mice have significantly higher jejunal (1.6-fold) and ileal (1.4-fold) paracellular oxalate absorption ex vivo and significantly higher (5-fold) urine [13C]oxalate following oral gavage with [13C]oxalate, indicating increased intestinal oxalate absorption in vivo. The observation of higher oxalate absorption in vivo compared with ex vivo suggests the possibility of increased paracellular permeability along the entire gut. Indeed, ob mice have significantly higher fractions of the administered sucrose (1.7-fold), lactulose (4.4-fold), and sucralose (3.1-fold) excreted in the urine, reflecting increased gastric, small intestinal, and colonic paracellular permeability, respectively. The ob mice have significantly reduced gastrointestinal occludin, zonula occludens-1, and claudins-1 and -3 mRNA and total protein expression. Proinflammatory cytokines and oxidative stress, which are elevated in obesity, significantly enhanced paracellular intestinal oxalate absorption in vitro and ex vivo. We conclude that obese mice have significantly higher intestinal oxalate absorption and enhanced gastrointestinal paracellular permeability in vivo, which would likely contribute to the pathogenesis of OAH, since there is a transepithelial oxalate concentration gradient to drive paracellular intestinal oxalate absorption. NEW & NOTEWORTHY This study shows that the obese ob/ob mice have significantly increased gastrointestinal paracellular oxalate absorption and remarkably enhanced paracellular permeability along the entire gut in vivo, which are likely mediated by the obesity-associated increased systemic and intestinal inflammation and oxidative stress. A transepithelial oxalate concentration gradient driving gastrointestinal paracellular oxalate absorption exists, and therefore, our novel findings likely contribute to the hyperoxaluria observed in the ob/ob mice and hence to the pathogenesis of obesity-associated hyperoxaluria.

Pathophysiology and Treatment of Hyperoxaluria

Humans cannot degrade oxalate. Thus, oxalate that is generated in the liver and/or absorbed from the intestine must be eliminated by the kidneys. Among genetic causes, primary hyperoxaluria (PH) type 1 is the most common and occurs due to deficiency of hepatic peroxisomal alanine glyoxalate aminotransferase. PH2 is caused by deficiency of lysosomal glyoxalate reductase or hydroxypyruvate reductase, whereas PH3 results from deficiency of mitochondrial 4-hydroxy-2-oxoglutarate aldolase. Enteric hyperoxaluria is caused by excessive colonic oxalate absorption due to any type of fat malabsorption. The diagnosis of hyperoxaluria is based on the history, 24-hour urine studies, and genetic testing. Early diagnosis and timely intervention are essential. To treat PH, adequate fluid intake, inhibitors of calcium oxalate crystallization (citrate or neutral phosphorus), and pyridoxine-in responsive patients are all important. Intensive dialysis and prompt kidney or combined kidney-liver transplantation are essential to minimize systemic oxalosis if renal failure occurs. Dietary modifications (low fat, low oxalate, and adequate calcium) are key for enteric hyperoxaluria. Calcium can be used as an oxalate binder. Newer modalities including oxalate degrading bacteria, oral oxalate decarboxylase preparations, and inhibitory ribonucleic acids are all under investigation. This review contains 9 figures, 6 tables, and 90 references. Key Words: bariatric surgery, calcium oxalate, dialysis, enteric hyperoxaluria, fat malabsorption, genetic testing, kidney stone, nephrolithiasis, oxalate, oxalate decarboxylase, Oxalobacter formigenes, primary hyperoxaluria, pyridoxine, transplantation, urolithiasis

HYPEROXALURIA: FORMATION MECHANISMS AND CONSEQUENCES

The work is a literature review, which demonstrates the current view on the mechanisms underlying the formation of hyperoxaluria and possible outcomes. The article includes detailed information on the biochemistry of oxalate, exogenous and endogenous resources in the human body, mechanisms of oxalate absorption in the gastrointestinal tract and renal excretion. Thefinal sectionfocuses on existing andpromising approaches to the treatment ofhyperoxaluria.

Effect of Blending and the Simultaneous Ingestion of a Probiotic Containing Oxalate-Degrading Bacteria on Oxalate Absorption

Both a high dietary oxalate intake and increased gastrointestinal absorption can lead to elevated urinary oxalate, a risk factor for kidney stone formation. Numerous studies have assessed whether daily ingestion of a probiotic containing oxalate-degrading bacteria can reduce urinary oxalate/oxalate absorption, but it appears only one previous study assessed whether the simultaneous ingestion of oxalate-degrading probiotic bacteria consumed with an oxalate load can exert this effect. This was assessed in the present study in a population of 11 healthy non-stone formers (6 males, 5 females), aged 21 – 37 y, using the probiotic VSL#3^®. A spinach-sweet potato mixture provided an oxalate dose of 534 mg and urine samples were collected for a 22 h period post-oxalate ingestion. An additional objective was to assess the effect of blending oxalate-containing foods on oxalate absorption. The overall results suggested that the spinach and sweet potato provided oxalate of low bioavailability. Changing the texture of these foods by blending did not have an effect on oxalate absorption nor was VSL#3^® effective in reducing urinary oxalate levels. VSL#3^® may have been more effective if the oxalate dose had been provided in a more bioavailable form leading to a higher initial oxalate absorption/urinary oxalate excretion.