What Is Oxalate?
Oxalate is a chemical that comes from oxalic acid, a basic compound found in many foods and drinks. It’s a natural byproduct of metabolism in our bodies, or, can be taken in from the foods we eat. In healthy people, the level of oxalate in the bloodstream usually stays between 1 to 5 micromoles per liter. (source)
You may also like to read my blog Oxalobater Formigenes: Everything You Need To Know.
Sources Of Oxalate
Research suggests that the liver is a significant producer of oxalate in the body, contributing between 50% to 80% of the total amount. This estimate comes from studying how different levels of oxalate in our diet affect the levels of oxalate in our urine. Scientists have identified several molecules that can potentially turn into oxalate. For instance, about 15% of the oxalate found in urine comes from hydroxyproline, a compound produced when our bodies break down collagen.
Another precursor is glycolate, which is involved in a small percentage of oxalate production through a process that happens in cell structures called peroxisomes. There’s an ongoing study using a special type of glycolate to better understand its role in making oxalate in healthy individuals. (source)
Despite being found in many cells, we’re still not entirely sure what glycolate does in the body. Another compound, glyoxal, is produced when carbohydrates, lipids, or proteins undergo certain chemical reactions. Although there’s evidence that glyoxal can be turned into oxalate in laboratory studies using human cells, its importance in the body’s overall oxalate production is uncertain.
Some researchers have suggested that glyoxal might be linked to conditions like kidney stones, high oxalate levels, and diabetes, as people with diabetes tend to excrete more glyoxal and oxalate in their urine. Additionally, the amino acid glycine contributes a small amount to urinary oxalate, less than 5%, under normal conditions. Other amino acids like tryptophan, tyrosine, and phenylalanine are also thought to be potential sources of oxalate, but they likely play a minor role in its production. (source)
Oxalate And Kidney Stones
Diet And Oxalates
Although only a small portion of dietary oxalate, around 5-15%, is absorbed by the body, it still contributes significantly to our total oxalate levels, estimated to be between 20-50%. The amount of oxalate people consume varies greatly depending on their culinary preferences and regional diets. In Western diets, people typically consume between 100 to 200 milligrams of oxalate per day, with variations. This amount is generally considered safe for individuals with normal kidney function. However, there have been reported cases of acute kidney damage caused by consuming extremely high levels of oxalate-rich foods, like starfruit.
Studies suggest that most oxalate absorption occurs in the small intestine, with smaller amounts absorbed in the stomach and colon. The absorption process can be influenced by other components present in feces. Oxalate, being an ionized base, readily binds with divalent cations such as magnesium and calcium in the fecal matter. This binding reduces the absorption of oxalate in the intestines. (source)
High Oxalate Foods
| Vegetables | Spinach, rhubarb, beets, sweet potato, Chaga mushroom | |
| Beverages | Cocoa powder, coffee, some types of tea | |
| Proteins and carbohydrates | Soy, legumes, rice bran, wheatgerm, cornmeal, wholegrain flour | |
| Fruits | Starfruit, guava, watermelon, raspberries | |
| Seeds and nuts | Chia seeds, peanuts, sesame seeds, almonds, amaranth, hazelnuts, pistachios | |
| Supplements | Vitamin C (ascorbic acid) |
Gastrointestinal tract
When we eat foods containing oxalate, our body absorbs it through various parts of the digestive system, including the stomach, small intestine, and large intestine. It’s important to note that oxalate can only be absorbed if it’s in a soluble form. When oxalate binds with calcium to form insoluble complexes, absorption is blocked. The absorption process is mostly passive, meaning it occurs naturally due to differences in concentration between the inside and outside of cells, and it increases with the amount of soluble oxalate consumed. (source)
In the stomach, oxalate can cross the cell membrane through non-ionic diffusion, driven by the acidic environment. In the intestine, absorption seems to happen mainly between cells (paracellular absorption). Studies in mice have shown that a protein called SLC26A6, found in the kidneys, pancreas, and small intestine, plays a crucial role in transporting oxalate across cell membranes. Mice lacking this protein had higher levels of oxalate in their urine and were more prone to developing kidney stones, especially when their diet was rich in oxalate. Removing oxalate from their diet reduced these problems, indicating that most of the excess oxalate came from food. (source)
Furthermore, recent research suggests that certain fatty acids can help regulate oxalate levels by increasing the activity of SLC26A6. In cases of chronic kidney disease, the body may increase oxalate secretion in the intestines when kidney function is reduced. Additionally, in individuals with subclinical celiac disease, where there’s no significant fat malabsorption, a decrease in SLC26A6 expression in the small intestine is associated with higher levels of oxalate in the urine. (source)
Role Of The Gut Microbiome
The human gut is home to trillions of bacteria, which play various roles, including breaking down components from our diet. These bacteria are increasingly understood to have significant impacts on both our health and our susceptibility to diseases. Unlike some other animals, humans lack the enzymes needed to break down oxalate. Instead, we rely on certain bacteria in our gut to help break down oxalate, which can potentially decrease its absorption in the intestines.
One such bacteria, Oxalobacter formigenes, specialises in breaking down oxalate and even prompts the colon to release oxalate. Studies have shown that antibiotic use, which can disturb these oxalate-degrading bacteria, might increase the risk of kidney stones.
While many oxalate-degrading microbes have been identified in laboratory settings, their exact roles in the human body are still debated. A recent study used advanced genetic techniques to analyse gut bacteria in healthy adults and found that Oxalobacter formigenes is the primary bacteria involved in oxalate breakdown. It has the most active oxalate-degrading genes compared to other bacteria like Escherichia coli, Bifidobacterium spp., and Lactobacillus spp.
But what’s most important to acknowledge here is that Escherichia coli, Bifidobacterium spp., and Lactobacillus spp all have the capacity to breakdown oxalates.
Researchers have looked at differences in the gut microbiome between people who develop kidney stones and those who don’t. They found that individuals prone to kidney stones tend to have lower levels of Oxalobacter formigenes in their gut compared to healthy individuals. Additionally, healthy individuals seem to have a more diverse microbial community centered around Oxalobacter formigenes, suggesting a stronger potential for oxalate metabolism by gut bacteria.
Further studies have shown that the abundance of genes related to oxalate degradation in gut bacteria correlates with the amount of oxalate excreted in urine. Children with kidney stones were found to have fewer oxalate-degrading bacteria compared to healthy children, while adults with hyperoxaluria and kidney stones had higher levels of certain oxalate-metabolising bacteria than healthy controls.
However, more research, especially clinical studies, is needed to fully understand the relationship between the abundance and function of oxalate-degrading gut bacteria and urinary oxalate levels, as well as their role in kidney stone formation. (source)
Dysregulated Oxalate Balance
Problems with how our bodies handle oxalate can lead to different kinds of hyperoxaluria, where there’s too much oxalate in the urine. When urine oxalate levels exceed 40-45 milligrams per day, it’s considered hyperoxaluria, which can cause various health issues.
Primary hyperoxaluria
Primary hyperoxaluria is a genetic condition where enzymes that control oxalate production in the liver are deficient. This condition can be diagnosed through symptoms like high oxalate levels in the blood and urine, and confirmed with genetic tests. It often leads to kidney stones, kidney tissue calcification, and urinary tract infections. (source)
Secondary hyperoxaluria
Secondary hyperoxaluria, on the other hand, can be caused by factors outside of genetics. One common type is enteric hyperoxaluria, which can be triggered by surgeries like gastric bypass or conditions that affect nutrient absorption in the gut, such as pancreatic insufficiency, Crohn’s disease, or cystic fibrosis. Certain medications, like octreotide and orlistat, can also interfere with how the intestines absorb oxalate.
Dietary hyperoxaluria happens when someone consumes too much oxalate-rich food or excessive amounts of vitamin C. (source)
Metabolic Disease
Additionally, certain metabolic diseases, like obesity and diabetes, can also lead to increased oxalate levels in the urine. In obese individuals, inflammation and changes in certain liver pathways can result in higher oxalate production. Similarly, diabetes can increase urinary oxalate levels due to elevated levels of oxalate precursors.
Understanding these connections between metabolic diseases and hyperoxaluria is crucial for managing kidney health, as they can significantly increase the risk of kidney stones and kidney damage.
Regardless of the type, hyperoxaluria often leads to the formation of calcium oxalate crystals in the kidneys, which can damage kidney tissue. (source)
Cellular effects of excess oxalate
As previously mentioned, oxalate has the tendency to bind with positively charged minerals, forming complexes that can accumulate and develop into kidney stones. These stones can block the flow of urine and cause damage to the kidneys. Additionally, oxalate can directly impact the function of cells in the body.
In laboratory studies, oxalate has been shown to hinder the growth of kidney epithelial cells, prompting them to undergo harmful changes leading to fibrosis and calcification, and even causing cell death. It may also trigger a process called epithelial-to-mesenchymal transformation, which alters the characteristics of these cells. When exposed to oxalate, certain kidney cells increase the production of molecules associated with mesenchymal cells while decreasing the levels of E-cadherin, a protein important for cell adhesion.
Furthermore, oxalate activates an enzyme called nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in kidney cells, leading to the release of reactive oxygen species. These highly reactive molecules can cause oxidative stress, disrupt the balance of antioxidants like glutathione, and impair the function of mitochondria, the cell’s energy-producing organelles.
Oxalate crystals can also trigger an inflammatory response by activating immune cells like dendritic cells and macrophages. This activation leads to the release of inflammatory molecules like IL-1β through a complex called the NLRP3 inflammasome. Additionally, exposure to oxalate crystals can disrupt the function of mitochondria in human immune cells.
Researchers suspect that these cellular changes caused by oxalate may contribute to the recurrence of kidney stone formation. Another study found that macrophages treated with oxalate experienced reduced energy production, altered mitochondrial function, and decreased levels of ATP, an essential energy molecule. As a result, these cells had impaired metabolism, weakened antioxidant defences, and compromised immune responses, making them more susceptible to bacterial infections. (source)
Therapies for oxalate dysregulation
There are various conservative treatments available for mild cases of hyperoxaluria, including the type associated with kidney stone formation. These treatments focus on preventing the crystallisation of calcium oxalate in urine. Simple measures like staying well-hydrated have proven effective in preventing kidney stones. For patients with a specific type of primary hyperoxaluria (PH1), drinking plenty of fluids, at least 3 liters per day for every 1.73 square meters of body surface area, is recommended (!).
Research has also shown promise in using certain medications. Tolvaptan, for instance, has been studied in early trials and has shown potential in reducing the concentration of calcium oxalate, calcium phosphate, and uric acid in urine by increasing urine volume. Thiazide diuretics are another option because they can decrease the amount of calcium in urine while increasing magnesium levels, potentially reducing the formation of calcium oxalate kidney stones.
Administering citrate, a substance that can prevent kidney stone formation, is another approach. Studies have shown that citrate and hydroxycitrate can dissolve calcium oxalate crystals in lab settings. Even when used at lower concentrations than the crystals themselves, these substances can bind to the surfaces of oxalate crystals and dissolve them effectively. Interestingly, lemon juice has emerged as a natural alternative to pharmaceutical citrate formulations. A recent clinical trial found that lemon juice might be just as effective but with fewer gastrointestinal side effects, which are common reasons for patients discontinuing pharmaceutical treatments. (source)
Targeting oxalate absorption
In cases of enteric hyperoxaluria, treatment focuses on preventing the excessive absorption of oxalate in the intestine. As we discussed earlier, the ability of the body to absorb oxalate is affected by gut health and various components found in feces, such as cations, fats, or medications. Therefore, strategies that involve directly supplementing with calcium and limiting fat intake (which can increase the binding of oxalate to calcium in the intestine) may help reduce oxalate absorption.
One approach is using a medication called cholestyramine, which works by binding to bile acids in the intestine, preventing oxalate from being absorbed along with these acids. However, while cholestyramine has shown effectiveness in reducing oxalate absorption in animal studies, its results in human trials have been inconsistent. Nevertheless, there have been reports of success in using cholestyramine to reduce both fecal fat and urinary oxalate in patients with short bowel syndrome.
Another potential treatment involves using phosphate binders containing calcium, which could potentially form complexes with oxalate in the intestine, reducing its absorption. However, current guidelines advise caution in using calcium-based phosphate binders in patients with certain stages of chronic kidney disease due to associated risks.
In light of promising experimental findings, a phosphate binder called lanthanum carbonate, which does not contain calcium, is currently undergoing phase III trials in patients with secondary hyperoxaluria and kidney stones.
Additionally, preliminary studies have explored the use of a non-calcium phosphate binder called sevelamer hydrochloride, which showed some reduction in urinary oxalate levels in patients with enteric hyperoxaluria.
Furthermore, recent research has suggested that certain trivalent cations like iron, aluminum, or lanthanum, as well as the element neodymium, could be promising candidates for binding oxalate in the intestine. However, further preclinical testing is needed to confirm their efficacy and safety for use in treating hyperoxaluria. (source)
The impact of modifying the gut microbiome to regulate oxalate levels has been extensively studied in animals and a few human trials. Several treatments focus on using specific bacteria with oxalate-degrading abilities. For instance, in studies involving rodents with high oxalate levels, colonisation with Oxalobacter formigenes consistently led to a decrease in urinary oxalate. Besides breaking down oxalate, O. formigenes also produces a substance that triggers oxalate secretion into the gut, although the exact nature of this substance is still unknown. Despite being well-tolerated by humans, clinical trials using derivatives of O. formigenes, such as OC3 and OC5, showed mixed results in reducing urinary oxalate.
Other bacterial species like Bifidobacterium and Lactobacillus have also shown promise in reducing urinary oxalate levels in animal studies. A probiotic called Oxadrop, composed of various bacterial strains including Lactobacillus acidophilus, Lactobacillus brevis, Streptococcus thermophilus, and Bifidobacterium infantis, briefly lowered urinary oxalate levels in patients with enteric hyperoxaluria. However, it’s important to note that none of these trials assessed whether the ingested bacteria remained viable in the gut.
Several other bacterial strains are currently under investigation in early trials. Nov-001, for example, is a combination product containing an oxalate-degrading bacterium (NB1000S) and a prebiotic control molecule (NB2000P), showing promise in a phase I study and now advancing to phase II trials with patients having enteric hyperoxaluria. UBLG-36, a strain of Lactobacillus paragasseri, has demonstrated significant oxalate degradation in lab studies.
Additionally, SYNB8802, an engineered strain of Escherichia coli Nissle, reduced urinary oxalate levels in animal studies and is predicted to lower oxalate by up to 71% in patients with enteric hyperoxaluria, according to computational models based on human gut physiology. (source)
Treatments for primary hyperoxaluria
Therapeutic options for primary hyperoxaluria have traditionally been scarce and the only curative option was combined liver and kidney transplantation. Vitamin B6 supplementation reduces hepatic oxalate production by restoring AGT activity and reducing mitochondrial mis-targeting in patients with PH1 owing to specific AGXT mutations, such as G170R or F152I, in vivo and clinically.
More specifically, in vitro studies suggest that the monomer form of AGT is unstable and prone to mis-folding and aggregation, which impedes peroxisomal transport; vitamin B6 promotes dimerisation, which appears to stabilise the enzyme and may facilitate proper peroxisomal transport. (source)
Immune modulation
Immune modulation is another potential approach for treating oxalate-related diseases. For example, inhibition of NLRP3 inflammasome activation might reduce cleavage of the pro-inflammatory cytokines IL-1β and IL-18 via caspase 1 and inhibit inflammatory cell death (pyroptosis) (source)
Maintaining Balanced Oxalate Status
The balance of oxalate in the body, called oxalate homeostasis, is carefully maintained through a combination of internal production, external intake, and removal from the body. Recent research has highlighted the importance of metabolic pathways, gut bacteria, specific transporters in the cells lining organs, and proper elimination of oxalate to keep this balance in check.
However, in individuals with conditions like primary or secondary hyperoxaluria, kidney stones, acute or chronic oxalate-related kidney damage, or chronic kidney disease regardless of the cause, this balance is disrupted. This disruption can lead to inflammation in various parts of the body, worsening kidney function over time, and even cardiovascular issues such as sudden cardiac death. (source)
