Oxalates, Kidney Stones, & Joint Pain: Genetic Reasons to Avoid Oxalates

Key takeaways:
~ Many healthy foods contain oxalates, but dietary intake must be balanced with the metabolism and excretion of oxalates.
~ Genetic variants can disrupt the balance of oxalates, leading to the formation of kidney stones or oxalate crystals.
~ Genes also impact the biosynthesis of oxalates in the body.
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Oxalates, Kidney Stones, Joint Pain

Oxalates are organic compounds found in many of the foods we eat.  We can also produce oxalates in the body through certain pathways. Oxalates can bind with calcium and be excreted through the intestines, or they can enter the bloodstream and eventually be excreted through the kidneys.

Oxalate levels in the body need to be balanced with the metabolism and excretion, matching the production and intake. When this is out of balance, problems can arise with oxalate crystal formation, which can cause kidney stones, joint pain, or other problems.

Where do oxalates come from?

We get oxalates from our diet, especially from high-oxalate foods such as spinach, rhubarb, chocolate, beets, and nuts. In general, oxalates are found in fruits and vegetables – some fruits and vegetables contain high levels of oxalates, while others contain only a tiny amount. When we eat plants high in oxalates, the gut microbiome takes care of eliminating some of the oxalates, and then our intestines absorb some of the oxalates we have eaten. Oxalates are absorbed as free oxalate. If calcium is available in the intestines (e.g. from consuming dairy products), it easily binds to oxalates and prevents absorption.[ref]

We can also synthesize oxalates in our bodies through the metabolism of different substances. The biosynthesis of oxalates in the liver accounts for 50-80% of the body’s oxalate pool. Dietary intake accounts for the remainder.[ref]

Precursors of oxalates produced in the body include amino acids and carbohydrate sources. Hydroxyproline, from collagen breakdown, and glycine are amino acid sources that can be metabolized to form oxalates. Glycolate, glyoxylate, and glyoxal are derived from carbohydrates and can form oxalates in the body through their catabolic pathway.[ref]

How are oxalates eliminated?

When you eat foods that contain oxalates, your gut microbiome plays a big role in how much of the oxalates you will absorb. The bacteria Oxalobacter formigenes uses oxalates as a primary energy source, so the presence of this bacterium can protect against oxalate absorption. One study found that people who had Oxalobacter formigenes in their gut microbiome had lower urinary oxalate levels. The same study found that the absence of Oxalobacter formigenes correlated with higher plasma oxalate levels.[ref]

The kidneys play a key role in maintaining the balance of oxalates in the body. Free oxalates are excreted by the kidneys, or they can combine with calcium ions in the kidneys to form calcium oxalate crystals. If the calcium oxalate crystals infiltrate the vessel walls in the kidneys, this can lead to the formation of kidney stones or even kidney disease.[ref]

High oxalate levels: Kidney stones, crystals, joint pain, and oxidative stress

Oxalate levels in the body are carefully regulated through a balance of dietary absorption, liver production, kidney filtration, intestinal secretion, and reabsorption.

When any part of this system is disrupted—whether by changes in the gut microbiome, excessive absorption in the intestines, impaired kidney function, or genetic variants that increase oxalate production—oxalate levels can rise abnormally high.

Kidney stone:
High levels of oxalate in the kidneys can lead to the formation of calcium oxalate kidney stones.[ref] Approximately 80% of kidney stones are composed of oxalate bound to calcium. According to a 2005 study, “5% of American women and 12% of men will develop a kidney stone at some time in their life, and prevalence has been rising in both sexes.”[ref]

Urinary nanocrystals:
Urinary crystals can form in urine that contains calcium and oxalates. These may be the precursors to kidney stones in people with certain changes in their kidney morphology. A study in healthy adults showed that a low-oxalate diet decreased urinary oxalate nanocrystals, and a high-oxalate diet significantly increased urinary oxalate nanocrystals.  [ref]

Beyond the kidneys: Joint pain, eye problems, skin deposition

In addition to forming kidney stones, oxalate crystals can sometimes be deposited in the joints, skin, and retina. These crystals can deposit in synovial fluid, cartilage, tendons, and bones, triggering an inflammatory response within the joint. Similar to gout, the inflammation causes joint pain, swelling, and stiffness. [ref][ref]

Oxalate-induced arthritis, or joint inflammation due to oxalates, is caused by the deposition of sharp calcium oxalate crystals in the synovial fluid that surrounds a joint. Often, this type of arthritis is seen in people with genetic mutations that cause high oxalate levels.[ref][ref]

Tissue remodeling and fibrosis are seen in animal models of hyperoxaluria. This may add to the joint and skin problems seen in people with high oxalate levels.[ref]

Animal models of high oxalate levels show that there is an increase in mitochondrial reactive oxygen species (ROS) that can lead to oxidative stress if glutathione is inadequate. Mitochondrial dysfunction is found in some people with hyperoxaluria.[ref]

What causes high oxalate levels?

High oxalate levels can be due to absorbing excess dietary oxalate, forming excess oxalates in the liver, or not excreting oxalates at the right level through the kidneys.

1) Oxalate in foods:

Foods high in oxalate include spinach, rhubarb, wheat bran, nuts, and chocolate. (See the Lifehacks section for a more complete list.) In addition, hydroxyproline is an amino acid found in many protein-rich foods that can be metabolized into oxalates. Gelatin and collagen supplements are particularly high in hydroxyproline.[ref]

2) Excess absorption of oxalate:

Enteric hyperoxaluria is a metabolic disorder that is primarily due to increased absorption of dietary oxalates. Typically, this is due to a malabsorption problem from Crohn’s disease, short bowel syndrome, or bariatric surgery. Pancreatic enzyme insufficiency can also play a role. Essentially, fatty acids aren’t reabsorbed properly in the small intestine and instead bind to dietary calcium. The absorption of oxalates is regulated in the intestines by being bound to calcium, limiting their absorption, so anything that disrupts calcium in the intestines can affect oxalate levels.[ref]

3) Endogenous oxalate formation

There are two main sources of oxalate created in the body as a metabolite.[ref]

1. Vitamin C (ascorbic acid) is broken down into oxalate without needing enzymes. This means that taking excess vitamin C can increase oxalate levels.
2. Glyoxylate is readily converted into oxalate. Glyoxylate is made from glycolate and from the amino acids glycine, serine, and hydroxyproline.
   1. Glycine can be converted to glyoxylate, but it is usually a minor contributor to oxalate levels.
   2. Serine can be converted to glycine or it can also be converted to hydroxypyruvate, which can then be converted to glyoxylate with the help of the GRHPR enzyme.
   3. Hydroxyproline comes from collagen breakdown (or from dietary collagen consumption). It can also be converted to glyoxylate or to glycine.

Let’s dive into hydroxyproline a little more in-depth:
In the kidneys and liver, the amino acid hydroxyproline is metabolized in the mitochondria to form pyruvate (used for ATP production) and glyoxylate. Hydroxyproline can be catabolized from collagen, such as that found in your connective tissue. The normal daily turnover of collagen in the body is estimated to be 2-3 g/day. [ref] The AGXT gene encodes the enzyme responsible for breaking down glyoxylate into glycine so that it doesn’t get converted into oxalates.

Genetics and Oxalates:

Genetic variants in genes related to oxalate formation, transport, and excretion are associated with altered oxalate levels in the body.

Many of the studies on oxalates focus on kidney stone formation, and these studies provide a clear picture of the interaction between oxalate homeostasis, kidney function, and calcium levels. Variants in the CaSR (calcium-sensing receptor) gene increase the risk of kidney stones due to the association between calcium binding to oxalate to form stones.

Primary hyperoxaluria (PH) is caused by genetic mutations that result in high levels of oxalate in the body. People with primary hyperoxaluria are likely to develop kidney stones at a young age.

There are three types of primary hyperoxaluria: [ref]

• Primary hyperoxaluria type 1 is caused by a mutation in the AGXT gene, which causes a deficiency in the body’s ability to metabolize glyoxylate into other compounds.
• Primary hyperoxaluria type 2 is caused by mutations in the GRHPR gene, which is also involved in glyoxylate metabolism.
• Primary hyperoxaluria type 3 is caused by mutations in the HOGA1 gene, which is involved in the breakdown of hydroxyproline in the mitochondria for use as pyruvate or glyoxalate.

Lifehacks: Solutions for Oxalate Problems

Please be sure to consult with your healthcare provider if you have any questions on diet, supplements, or your genetic variants.

Testing your oxalate levels:

An organic acids test, which you can order on your own or through a functional medicine doctor, will show you whether you currently have high levels of oxalate metabolites. Oxalate metabolites include glyceric acid, glycolic acid, and oxalic acid. Glyceric and glycolic acids are elevated in hyperoxaluria.[ref]. Here’s a guide to understanding organic acids test results for oxalates.

Dietary interventions:

Reducing dietary oxalates or pairing foods containing oxalates with foods that block absorption may help to reduce oxalate crystal formation in the body.

Low Oxalate Diet:

If you carry one of the pathogenic hyperoxaluria genetic variants, talk with your doctor and consider whether it would be appropriate to adopt a diet lower in oxalates.

High oxalate foods include:[ref][ref][ref]

• Leafy greens: Spinach, chard, Swiss chard, sorrel, kale, collards
• Rhubarb
• Chocolate
• Amaranth
• Starfruit
• Okra
• Soybeans (raw, boiled), soy milk
• Sweet potato
• Almonds
• Beets
• Rice and Wheat Bran
• Licorice root
• Coffee, black tea

Here is a more detailed list: Foods that contain oxalates

Reducing absorption of oxalates from foods: