In the previous article, Vitamin C: Superpowers, Ordinary Powers, and Common Questions, I mentioned the potential for high-doses of ascorbic acid to cause the formation of oxalate, which can cause pain, mitochondrial dysfunction, impairments in detoxification, oxidative stress, and kidney stones. This article unpacks how that happens and how to minimize oxalate formation and the potential formation of kidney stones.

By the way, if you doubt that ascorbic acid is vitamin C, read What Is The Real Vitamin C?

Conversion of Ascorbic Acid To Oxalate

The fact that ascorbic acid can convert to oxalate in humans was first reported in 1958. (1) This led to scientific interest in the possibility that oxalate derived from ascorbic acid might contribute to the formation of oxalate kidney stones. 

Does Ascorbic Acid Contribute To Calcium Oxalate Kidney Stones?

At least two observational studies found an association between increased intake of ascorbic acid intake and increased incidence of kidney stones (R, R), but association does not prove causation. The reason that association in studies like this does not establish causation is the presence of what are called "confounding variables".

For example, a likely confounding variable in studies like these would be that people who ingest more ascorbic acid would probably be more likely to do so because they have health problems, some of which might increase their risk for the formation of kidney stones (e.g. diabetes). Therefore, the study participants with higher intake of vitamin C were potentially more likely to form kidney stones because of their health condition, not because of the ascorbic acid that they consumed to help with the health condition. 

The largest observational study to date on this topic found no association between increased intake of ascorbic acid and increased incidence of kidney stones (R), concluding that "Routine restriction of vitamin C to prevent stone formation appears unwarranted." A similar study actually found a reduced incidence of kidney stones with higher ascorbic acid intake (R).

A small number of individual case studies over the decades documented people who suffered acute kidney failure as a result of oxalate nephropathy (calcium oxalate kidney stones) after a high intake of ascorbic acid orally or intravenously. (R, R, R, R, R)

However, most of these individuals, if not all of them, had kidney disease and/or other kidney-compromising conditions (e.g. amyloidosis, severe dehydration due to migraine-induced vomiting, etc) prior to, or in conjuction with, their high intake of ascorbic acid.

Thus, it appears that individuals with kidney disease, or kidney-compromising conditions, may be at risk of oxalate nephropathy if exposed to high levels of ascorbic acid. And this makes sense because their ability to excrete oxalate would be impaired by their kidney dysfunction and/or their dehydration. But these case studies are not evidence ascorbic acid causes oxalate nephropathy in people that do not have preexisting kidney disease.

In fact, the very low number of such case studies suggests that even in the extreme case of preexisting kidney failure, oxalate nephropathy induced by ascorbic acid is extremely rare. Nevertheless, it make sense to remain vigilant against the possibility and to understand how ascorbic acid converts to oxalate and how to prevent or minimize that conversion, so as to not overly elevate the amount of oxalate to be excreted by the kidneys.

Recycling Of Ascorbic Acid Via NADPH

Oxalate can be formed from ascorbic acid after it gets oxidized to dehydroascorbic acid, which can convert to oxalate. But this does not happen if oxidized ascorbic acid gets promptly recycled back to the antioxidant form of ascorbic acid by NADH, NADPH (the body's main reducing agent / electron donor), or glutathione.

NADH is produced via energy metabolism and is abundant inside cells, except perhaps during starvation.

NADPH is produced from glucose via the pentose phosphate pathway, and the efficiency of this process depends on various factors, including ...

1. Genetics affecting various enzymatic steps in the pentose phosphate pathway that produces NADPH
2. Nutrients that act as cofactors in the pentose phosphate pathway, including magnesium, riboflavin, niacin, selenium, and calcium
3. Metabolic issues that affect the availability of glucose to be used by the pentose phosphate pathway

Metabolic issues that can affect the availability of glucose to the pentose phosphate include the following:

1. Diabetes, thyroid disorders, and adrenal disorders
2. Oxidative stress
3. Deficiencies in nutrients involved in energy metabolism (e.g. B vitamins, magnesium, other electrolytes, iron, copper, and sulfur)
4. Genetic variants affecting energy metabolism (too many to name here)

Recycling of ascorbic acid using NADPH also requires a well-functioning enzyme called thioredoxin reductase to transfer electrons from NADPH to ascobyl radicals to regenerate ascorbic acid. How well thioredoxin reductase uses NADPH to recycle ascorbic acid can be affected by the genes that code for this enzyme (TXNRD1 and TXNRD2 genes). Variants in these genes can be a significant contributor to chronic illness in some people.

Glutathione's Role In Recycling Ascorbic Acid

If ascorbic acid does not get recycled by NADPH, then it falls to glutathione to recycle it via glutathione-utilizing enzymes like glutathione S-transferases (GSTs). This means that your supply of glutathione and the function of your GSTs affect your ability to recycle ascorbic acid. 

The body's supply of glutathione in its antioxidant form is affected by numerous factors such as genes involved in its synthesis (e.g. GCLM, GCLC, and GSS), genes involved in synthesizing the amino acids that form glutathione (cysteine, glycine, and glutamate), the gene for the glutathione reductase (GSR) enzyme that recycles glutathione, the availability of NADPH to be used by glutathione reductase to recycle gluthatione, and chronic infections, toxicants, and oxidative stress that deplete NADPH and glutathione.

Then when it comes to utilizing glutathione to recycle ascorbic acid, variants in glutathione S-transferase genes can affect how well your glutathione can recycle ascorbic acid.

Can Antioxidants Prevent Calcium Oxalate Kidney Stones?

Aside from glutathione, and other antioxidants control oxalate formation, and even kidney stone formation? Selvam (R) discovered that “antioxidant therapy prevented calcium oxalate precipitation in the rat kidney and reduced oxalate excretion in stone patients.” Gotz et al. showed that the antioxidant lipoic acid helped prevent calcium oxalate crystals in dogs (R). Jayanthi et al. showed that lipoic acid lowered oxalate levels in the kidneys and urine of rats (R). And vitamin E therapy prevents hyperoxaluria-induced calcium oxalate crystal deposition in the kidney by improving renal tissue antioxidant status (R). This is all good news. And it gets better.

Can Ascorbic Acid Also Prevent Calcium Oxalate Kidney Stones?

Some researchers have shown that ascorbic acid may actually reduce the likelihood of kidney stone formation in individuals who already have a history of stone formation.
Schwille et al (14) found that ascorbic acid inhibited the development of calcium oxalate crystals individuals with preexisting calcium oxalate kidney stones and did not promote the formation of kidney stones in individuals without a history of kidney stones. They concluded that “under normal conditions” ascorbic acid does not seem to contribute to the formation of oxalate kidney stones.

Grases et al (15) demonstrated that free radical-damaged cells in an experimental model using living urothelial cells (kidney epithelial cells) tended to produce a “favorable environment” for calcium oxalate crystal formation. And they found that "Antioxidants, such as ascorbic acid and mannitol, exerted the most remarkable effects in avoiding calcium oxalate crystal development."

Apparently free radical damage in the kidney is a factor in the development of kidney stones. It is therefore not so surprising that ascorbic acid and other antioxidants antioxidants can reduce kidney stone formation, even though ascorbic acid increases oxalate levels. 

However, in people with kidney disease or other kidney-compromising conditions, high doses of ascorbic acid might not be the best choice as antioxidant therapy since it has in some instances been associated with the formation of kidney stones in people with kidney disease or kidney-compromising conditions such as dehydration.

The kidneys need enough fluid to support excretion of oxalate. Therefore, high quantities of ascorbic acid should not be consumed during conditions of dehydration (e.g. during episodes of diarrhea or vomiting due to migraines or other causes).

Can Sulfate Help Prevent Oxalate Kidney Stones?

Little is known about how the kidneys excrete oxalate, but since several transporters move both oxalate and sulfate across cell membranes (e.g. the sulfate-oxalate exchanger, "sat-1", coded for by the SLC26A1 gene; and the sulfate transporter 91, coded for by the AST91 gene), it may be that these transporters are involved in excreting oxalate from the kidneys, and this process may require sufficient sulfate in order to exchange for oxalate across membranes. 

According to Susan Owens, who heads the Autism Oxalate Project at the Autism Research Institute, insufficient sulfate inside the kidney tubule cells interferes with the ability of the kidneys to remove oxalate from the blood and deliver it to the urine. This could cause higher levels of oxalate in the system.

Sulfate performs multiple essential functions in the body and is usually formed from sulfite that is generated by the metabolism of other sulfur-containing compounds. 

Can Humans Metabolize Oxalate?

It has long been assumed that humans cannot metaboilze oxalate like many bacteria can. But if you look at the biochemistry of bacterial oxalate metabolism, it is essentialy a two-step process that takes oxalate to formate and formate to carbon dioxide. 

It is well-establishd that humans can metabolize formate, and it can do so in two ways. It can metabolize format to carbon dioxide, or it can use formate in the methylation cycle as a methyl donor. 

The only real question is whether humans can convert oxalate to formate. 

And it turns out that there is quite a bit of circumstantial scientific evidence that a key enzyme in human energy metabolism can convert oxalate to formate. If that does indeed happen, then humans can in fact execute both of the all steps necessary to break down oxalate.

What is the enzyme in question? It is pyruvate decarboxylase, a biotin-dependent enzyme that converts pyruvate derived from glucose to oxaloacetate to help run the Kreb's Cycle / Citric Acid cycle that extracts electrons and protons from other pyruvate molecules that enter the cyle via acetyl coenzyme A. 

It has already been established scientifically that in a "test tube" environment pyruvate decarboxylase can run backwards and convert oxaloacetate back to pyruvate. The only reason that does not happen in humans is that the oxaloacetate concetration is too low relative to the pyruvate concentration to run the reaction backwards.

According to an intriguing analysis by Chris Masterjohn, PhD, several pieces of scientific evidence suggest that oxalate binds to pyruvate decarboxylase in the same place as oxaloacetate and that it is unlikely that the enzyme would not in fact convert oxalate to formate. 

Even more interesting is the fact that evidence suggests that this reaction proceeds at half the pace in the presence of biotin defiency, which makes sense because biotin is the cofactor for the enzyme.

In other words, biotin deficiency could cause oxalate intolerance, and biotin supplementation could support more rapid oxalate clearance.

Furthermore, anecdotal evidence described by Masterjohn could indicate that when biotin supplementation leads to symptoms like skin rashes, this could be a manifestation of "oxalate dumping" (a phenomenon familiar in the oxalate sensitivity / intolerance community) caused by biotin accelerating oxalate clearance. 

So in addition to the well-established fact that a deficiency of vitamin B6 can lead to elevations of oxalate produced via human metabolism, we now see a possibility that a deficiency of biotin could be a cause of elevated oxalates.

And what is more exciting about the biotin connection is that it relates to actual conversion of oxalate to other substances, whereas the B6 connection relates only to the prevention of oxalate formation (from glyoxalate) in human metabolism. 

If Masterjohn's hypothesis is correct, this means that humans can break down oxalate, whether it has been absorbed from food in the gastrointestinal tract or formed inside the body from ascorbic acid or glyoxalate. 

My bet is that Masterjohn is correct because I find his hypothesis biochemically compelling.

Surely something has to explain why so many people are not negatively affected by exposure to high levels of oxalates via long-term megadosing of ascorbic acid or ingesting large quantities of high-oxalate foods.

Interestingly, biotin is required for the synthesis of lipoic acid, one of the antioxidants shown to prevent the formation of oxalate kidney stones, as described in the previous section of this articlie.  

So there are two ways in which biotin deficiency could create oxalate issues and two ways in which correcting a biotin deficiency could protect against oxalate intolerance.

By the way, biotin deficiency is fairly common in people with certain health challenges, and one of the reasons for this is a genetic polymorphism in the gene for biotinase, the enzyme that recycles biotin.

People with a biotindase polymorphism generally need more biotin than people without this genetic polymorphism.

Summary

In general, oxalate formation from ascorbic acid occurs when NADPH / thioredoxin reductase and glutathione / glutathione S-transferase both fail to recycle it, but not all oxidized ascorbic acid converts to oxalate before getting excreted. You will probably not be able to entirely stop all formation of oxalate from ascorbic acid, but you should be able to minimize it by supporting the recycling of oxidized ascorbic acid.

Maintaining good NADPH and glutathione status are important when engaging in high-dose ascorbic acid therapy, except perhaps when a strongly prooxidant effect is desired (e.g. in cancer therapy) or when treatment of a dangerous condition like snake venom poisoning or polio infection requires rapid treatment that is best accomplished immediately and without delay using high-dose ascorbic acid.

In such cases, the risk of high-dose ascorbic acid therapy increasing oxidative stress or causing oxalate formation pale in comparison to the risk of death by snake venom toxicity or permanent dysfigurement by polio.

In general, oxalate formation and kidney stone formation from high-dose ascorbic acid therapy can most likely be prevented if you ....

1. Ensure high fluid intake and urine volume.
2. Avoid high-dose ascorbic acid therapy with kidney disease or dehydration.
3. Consume lipoic acid.
4. Maintain good levels of NADPH and glutathione.
5. Ensure the availability of glucose to the pentose phosphate pathway (e.g. supporting insulin sensitivity and thyroid and adrenal function, and possibly not relying on a ketogenic diet if the body is struggling to produce enough glucose).
6. Maintain sufficiency of the nutrients that are required in the relevant metabolic pathways, such as B vitamins, magnesium, other electrolytes, iron, copper, sulfur, selenium, calcium, cysteine, and glycine.
7. Potentially also employ additional measures to compensate for any genetic vulnerabilities in relevant metabolic pathways.
8. Before taking high doses of ascorbic acid, minimize other potential causes of elevated oxalate such as gut hyperpermeabilty and deficiencies of vitamin B6 and biotin.

There is still much that we do not know about what happens under various conditions in response to high-dose ascorbic acid therapy. There are reasons to employ caution, reasons to not worry excessively about it (unless you know that your body tends to form oxalate kidney stones from ascorbic acid), and also steps that can be taken to minimize problems with high-dose ascorbic acid therapy.

Bio-Individuality Of Ascorbic Acid Supplementation

When it comes to assessing your bio-individual risk for potential side effects from ascorbic acid supplementation, it can be helpful to look at variants in genes like G6PD, TXNRD1, TXNRD2, GST, etc and markers for glutathione status, and markers of enzyme cofactors like B vitamins, minerals, and electrolytes.

If you would like to chat with me about any of this and the possibility of hiring me for genetic analysis, lab test analysis, a full assessment of potential root causes of health issues, the full Bio-Individual Blueprint program, or just some biohacking advice, you can book a complimentary 15-minute chat on this page or learn more about the Bio-Individual Blueprint system here.