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Most people have heard of oxalates because of their connection to kidney stones. Or perhaps with regards to spinach, because the calcium in spinach is bound by oxalates, and is not considered a good source of calcium. So, let’s dig a little more into oxalates, and what makes them toxic to humans.

Oxalate and oxalic acid are terms used interchangeably in nutrition and scientific circles, but they are actually distinct chemically. Oxalate is an anion (and can be reactive) whereas oxalic acid is an organic compound.

Oxalic acid can be ingested from our food, and is also produced by the liver as a byproduct from the metabolism of vitamin C, glycine, glycolate or hydroxyproline. Oxalic acid from plants or humans is a “terminal” metabolite that must be excreted or sequestered. Terminal means it does not undergo any additional changes. The kidneys are the primary route of excretion and the site of oxalate's only known function. Oxalate stimulates reabsorption of chloride, water, and sodium by the proximal tubule through the exchange of oxalate for sulfate or chloride via the solute carrier SLC26A6. (Marengo & Romani, 2008)

Oxalates have a high affinity for binding with minerals and form an oxalate salt. These salts can be water soluble (e.g. sodium oxalate and potassium oxalate) or insoluble, such as calcium oxalate (a common component of kidney stones). Water-soluble salts and unbound oxalate are readily absorbed into the blood, while insoluble salts are unable to pass through a healthy intestinal wall and are mostly excreted. Certain gut microbes will also help degrade oxalate in the gut. (See Probiotics section for details.)

When oxalate levels rise in the blood, the kidney works to excrete the excess, but if overwhelmed, it will lead to insoluble forms of oxalate that lead to kidney stones. Beyond forming kidney stones, oxalates can wreak other havoc. When calcium oxalate amounts exceed the kidney’s ability to excrete it, calcium oxalate starts to deposit in various tissues and organ systems in a process called systemic oxalosis. Calcium oxalate deposits have been reported in the myocardium, cardiac conduction system, kidneys, bones and bone marrow, leading to cardiomyopathy, heart block and other cardiac conduction defects, vascular disease, retinopathy, synovitis, oxalate osteopathy and anemia that can be resistant to treatment. (Ureckli & Atta, 2015)

The crystals aggregate as spiked crystals, sharp irregular rectangles or long fork-like needles. It is believed these crystals are a defense that plants use to protect themselves from bugs. (Doege, 2003) And oxalate plant poisonings, mainly of children from eating common houseplants Philodendron and Dieffenbachia, are the most common plant exposures reported to poison control centers. (Kearney, 2020) These needlelike crystals produce pain and edema where they contact lips, tongue, oral mucosa, conjunctiva, or skin.

Plants also use oxalates to regulate pH in association with nitrogen metabolism, metal-ion homeostasis and calcium storage. And plants contain oxalate-degrading genes, to counter the effects of oxalate secretions in fungal infections. (Kumar, Irfan & Datta, 2018) And if you’re interested in climate change, check out this one: “…calcium oxalate crystals as part of the phytomineralization process could represent a considerable carbon sink with a long residence time at the ecosystem as well as at the global level.” (Tooulakou, et al., 2016) Bad for humans, but good for plants and maybe the environment.

Unfortunately, humans and animals (both ruminant and non-ruminant) do not have oxalate-degrading genes. And anyone who has had calcium-oxalate kidney stones knows all too well what damage these crystals can cause. However, even tiny aggregations of oxalate can cause cell-membrane rupture, up-regulated intracellular reactive oxygen species (ROS), and decreased mitochondrial membrane potential. This eventually leads to necrotic cell death. (Xin-Sun, Xu & Ouyang, 2021) Elevated oxalates were also shown to cause mitochondrial dysfunction in primary monocytes from healthy subjects. (Patel, et al., 2018)

So, oxalates are not an allergy or sensitivity, but a metabolite that must be excreted or sequestered by the body to minimize its toxic effects when present in excessive amounts.

Hyperoxaluria is the name given to the increased urinary excretion of oxalic acid. There are two types, primary and secondary. Primary is a very rare, inherited metabolic problem. According to the Cleveland Clinic, there are only about 5000 patients in the U.S., and if you have it, you will know from an early age. This page will focus on secondary hyperoxaluria, and is most often linked to conditions underlying increased intestinal oxalate absorption, such as a high-oxalate diet, fat malabsorption, alterations in one’s microflora, and genetic variations of intestinal oxalate transporters.

Who Should Be Concerned

  • If you have a family history of calcium oxalate kidney stones, or have had them yourself, then this information is definitely for you. It’s estimated anywhere from 10-12% of the population will get kidney stones. Even if your doctor has given you information, do take time to read through this, because research shows that patients still have outdated information about strategies such as calcium intake. (Dion, et al., 2016)

  • If you have inflammatory bowel disease, Crohn’s or other GI conditions (e.g. leaky gut) where nutrients are not properly absorbed, hyperoxaluria might become a problem. (Hyperoxaluria, Cleveland Clinic)

  • If you have recently been on antibiotics or had several rounds of antibiotics over time, which can wipe out oxalate-degrading microbes.

  • If Paleo or Keto diet choices do not seem to help your health. Many nutrient-dense foods used in these diets are high in oxalates: spinach, nuts, sweet potatoes, plantains, chocolate and beets to name a few. For the average American, just three foods alone—spinach, potatoes, and nuts—make up 44% of their total oxalate intake. (Gul & Monga, 2014) Many of us here, in implementing dietary changes for brain health, have unwittingly started to consume larger amounts of foods high in oxalates. In addition, the loss of seasonality in our food supply exacerbates the problem, such as access to year-round spinach, that once was only available in the spring. (Norton, 2018)

  • If you have inflammation that has been hard to diagnose the root cause. “In our experiment, monocytes respond to CaOx by producing inflammatory cytokines, such as tumor necrosis factor-alpha, IL-1β, and IL-6, and chemokines, such as CCL2. These signals activate and recruit circulating monocytes and tissue macrophages to promote CaOx clearance (12). Consistent with our previous work, the supernatant from monocytes previously exposed to CaOx crystals enhanced M2 macrophage phagocytosis of CaOx (Figure 4). CaOx alone causes the monocytes to undergo differentiation into macrophages (Figures 5 and 6).” (Paul Dominguez-Gutierrez, et al., 2018)

  • Anyone concerned about Alzheimer’s disease. This paper got my attention when it stated, “In conclusion, our study suggests that entorhinal cortex COD [calcium oxalate dihydrate] and TiO2 crystals should be added to the existing list of potential AD initiators, all known to activate the NLRP3 inflammasome.” (Heller, et al., 2020)

  • If any of the other symptoms or associated diseases listed below are an issue for you, or you see unexplained cloudy urine (with no bacteria found in lab testing), then you’ll want to work with your health care provider to get a urinary test for oxalic acid to know where to go next. A list of potential diagnostic testing can be found at Cleveland Clinic Hyperoxaluria: Diagnosis and Tests page. Great Plains Lab does oxalic testing as part of their OAT panel. LabCorp and Quest offer options for single and 24-hour urinary testing. It is recommended that you refrain from taking ascorbic acid (Vitamin C) for at least 48 hours prior to the test.

Symptoms and Associated Diseases

Here are some of the symptoms and diseases that are associated with hyperoxaluria.

Kidney stones, autism, fibromyalgia or muscle pains, vulvodynia and some people might see deficiencies in calcium, magnesium, and zinc because oxalates will bind to these minerals. (Great Plains Laboratory)

Osteoporosis, arterial calcification. (Shavit, et al., 2015)

Joint pain, synovitis, tenosynovitis and bursitis. “Calcium oxalate has a tendency to crystallize in previously damaged joints, such as distal and proximal interphalangeal joints involved in osteoarthritis, thus presenting as soft tissue calcification about the degenerated joint. Inflammation may mimic the findings of erosive osteoarthritis or an atypical diuretic-related gout.” (Lorenz, et al., 2013)

Inflammation, interstitial cystitis and autoimmune problems. (Dr. Sara Gottfried)

Breast cancer. Research is sparse, but microcalcifications are present in up to 50% of all non-palpable breast cancers. Type I calcifications are composed of calcium oxalate. The mechanisms have not been established, but free oxalates have been shown to induce proliferation of breast cancer cell lines. (Castellaro, et al., 2015)

Within the Trying Low Oxalates Facebook group (a private group - you have to ask to join), the group’s founder has collated the following symptoms, both from excessive oxalate intake and dumping (more on dumping to come).

  • GI: Bloated stomach, stomach pain/nausea, sandy/light colored stool, burning stool, black specks/white crystals in stool, diarrhea / constipation / alternating diarrhea and constipation, IBD
  • Urinary: Cloudy urine, interstitial cystitis, bladder pain, kidney pain, lower back pain, gallbladder pain, vulvodynia, frequent urination, chronic UTI’s, kidney stones
  • Systemic: Insomnia, air hunger, heart palpitations, peripheral neuropathy, burning tongue/mouth, weight loss/gain, flu like symptoms
  • Eyes, ears, nose, throat: Dry cough/phlegmy cough, sore throat, sinus issues, headache, asthma, odd ear sensations (fullness)/plugged ears, vertigo and dizziness, tinnitus, fluctuations in hearing, burning/red/gritty/crusty eyes, floaters in eyes
  • Muscles, skin, joints: Burning feet/skin, joint pain, muscle twitching, frozen shoulder, back/neck pain, achy all over, rashes, psoriasis flares, cold sores
  • Mental: Irritability, fatigue, anxiety, panic, brain fog, depression, anger/sudden rage

Yep, it looks like a laundry list of every complaint out there, but individuals will typically only have some of these symptoms. The amount and location of oxalate deposition in individuals will vary, influenced by GI health, calcium and fiber intake, acid-alkaline balance, genetic variants, and gender, among other factors.


The Great Plains Lab article above summarizes that there are three primary sources of high urinary oxalic acid: 1) diet, including too many high oxalate foods; 2) fungal overgrowth in the gut, such as Aspergillum, Penicillium and possible Candida; and 3) human metabolism.

Human metabolism includes how much oxalate we normally create in the body, genetics that influence its absorption and metabolism, and gut function.

  • Several studies have found gene variants associated with kidney stones. Most research has been on kidney stones, but any problems in the pathways to either produce or neutralize oxalates can lead to an excess in other tissues. See the Genetics section below if you want to look at snps.
  • Bile salt deficiency can be an issue, because free fatty acids, which normally bind with bile salts, will instead bind with calcium to form insoluble soaps. That in turn reduces calcium’s ability to bind oxalate and clear the oxalates from the GI track and prevent absorption. In addition, GI issues, including excess permeability (ie. "leaky gut"), and a loss of microbiome diversity can lead to excess oxalate absorption.
  • The liver catabolizes hydroxyproline (a component of collagen), which creates glyoxylate and normally leads to the formation of pyruvate and glycine. However, any excess glyoxylate can be converted to oxalate. (https://www.kidney-international.org/article/S0085-2538(15)54977-6/fulltext)


1) Reduce the foods high in oxalates in your diet. Research on diet is a bit all over the place, but it seems prudent to ditch or greatly reduce high oxalate foods. An often-cited, highly controlled experimental study showed 40-50% of urinary oxalate comes from the typical diet containing 150-250 mg/day of dietary oxalate (Holmes, et al., 2001).

The reason diet is not clear is similar to the problems with any dietary interventions. Your gut health can influence how much oxalate is absorbed, along with how much calcium is in your diet, which might bind to the oxalates. And just because the food contains oxalates, that doesn’t mean that the amount listed in any food list is what you actually ingest. The total oxalate in any food depends on the soil, preparation (e.g. throwing out the water from boiled vegetables reduces the load), and what foods you eat with them, like calcium-containing dairy foods.

Because oxalate content can vary from sample-to-sample in the lab, lists tend to disagree about the actual oxalate content of many foods (e.g. some say strawberries are high, others it’s raspberries or blackberries). It is probably the most frustrating aspect of figuring out what foods to avoid. (See Oxalate content of food: a tangled web, Attalla, et al., 2014)

But, all lists do agree to avoid spinach and rhubarb.

For people with serious problems, 50-100 mg/day is considered a low oxalate diet. It’s easy to see that avoiding spinach is a good first step. According to the Trying Low Oxalates Facebook group list, ½ cup of raw baby spinach contains 159 mg of oxalates and for cooked, 327 mg per ½ cup! And if you are a juicer who includes spinach, well, just don’t go there, okay!?!?

Other commonly listed foods to avoid include potatoes (both white and sweet), beets, beet greens, Swiss chard, soy, chocolate, peanuts, tree nuts (almonds and cashews are the worst), beans (navy are the highest) and bran (except for oat and corn bran, which seem okay). Even gluten free grains can be problematic: amaranth, buckwheat, quinoa, teff, and brown rice contain high levels of oxalates.

The Trying Low Oxalates Facebook group moderates a food list derived from several groups, and their own testing. You have to join the group to peruse their list. If you start experimenting with lowering your oxalates, it is worth the effort to join this group because they have the most comprehensive list I have seen to help guide your food choices. (I am not allowed to post their food list.)

This document from the U. of Chicago contains a smaller moderated list of food oxalates, which updated the commonly referenced 2008 Harvard list. It will give you a general idea what foods to avoid or eat in moderation. But do note, that some items on this list disagree with the TLO list. See also the U. of Chicago's document How To Eat a Low Oxalate Diet for more information about oxalates and their list.

Part of the issue with diet is that oxalate amounts are additive. Is one handful of almonds going to cause a problem? Maybe not, especially if you have calcium with it and the rest of your food for the day is lower in oxalate content. But, using almond flour to bake bread or putting that handful of almonds on a spinach salad, and I’d guess you will have trouble if you don’t handle oxalates well.

Preparation might make enough of a difference for some foods. Blanching vegetables (discarding the water) and sprouting beans have been shown to reduce the amounts of oxalates. However, even reducing spinach oxalates by 40% through boiling, it still has a very high oxalate content. (Paul, et al., 2012) Of course, on the negative side, blanching reduces the polyphenol content of spinach. (Yadav & Sehgal, 2002) Arugula is a safe substitute. But, for other foods, the right preparation might decrease the oxalate content of foods enough, such as red potatoes, if they are peeled, boiled and the cooking water is discarded.

Beyond ingesting oxalates directly, if you are a smoothie maker who adds collagen peptides, hydrolysate or gelatin to your mix, or you drink a lot of bone broth, you are ingesting extra hydroxyproline on top of any animal or fish protein you might be eating. Excess hydroxyproline can also be converted into oxalates. Whey, if you can tolerate it, is a better alternative if you feel you need to add protein to your smoothie. (Taylor and Curhan, 2007 and Knight, et al., 2006)

And finally, there are several members on the Trying Low Oxalate Facebook group who swear by the Carnivore diet. Animal products typically contain the lowest amounts of oxalates.

IMPORTANT: If you want to try reducing high oxalate foods to gauge their effects, do it slowly. If you normally eat them in your diet, cut one high oxalate food in half per week at most. This is important. Over time, your body stores excess oxalates in body tissue when it cannot eliminate oxalates completely through urinary excretion.

Once the amount of ingested oxalates in your blood drops, the body starts to release oxalates from storage tissues. The problem is that release can exacerbate your symptoms (the term used by most functional doctors and bloggers is “dumping”). It’s as if you are still eating high oxalate foods all the time. Dumping is a positive thing - you need to get rid of the stored excess - but oxalates can also cause pain and inflammation, so you want to go slow to minimize the side effects.

One of you first clues you are dumping will be cloudy urine, urinary urgency, joint and/or muscle pain, muscle spasms and/or increase in your symptoms. If dumping worsens your symptoms, then add back some higher oxalate food to slow the dumping down - even a small square of chocolate can help. You might also need to forego fasts longer than one day, because fasting also can be a signal to the body to start dumping as the oxalate levels drop. (Note, my personal experience verifies dumping is a very real thing.)

The experiences of the Trying Low Oxalate group suggest this dumping process can range from several months to more than a year to clear the excess. For example, this study found it takes several days to dump excess oxalates just from the gut. (Mitchell, et al., 2018)

2) Drink lots of liquids. At least 2-2.5 liters / day. Some of that amount can be your usual beverages: coffee, tea and juices, except for tomato (too high in sodium), and carrot (high in oxalates). You’ll see black tea on many lists of foods to avoid, but it turns out the oxalate in tea is not very soluble (Liebman and Murphy, 2007). So a cup or glass a day shouldn’t be a problem, but if you find it is a problem for you, switch to herbal tea. Avoid almond milk which is extremely high in oxalates. Other nut milks should also be avoided given most nuts fall in the high to very high oxalate content category. Coconut or flax milk would be good alternatives.

3) Eat sources of calcium. Eat up to 500 mg per meal but keep it to no more than 1200 mg daily because too much calcium can lead to stones in people who are susceptible. You can eat dairy or take calcium citrate (citrate is the preferred form). According to research, it doesn’t seem to matter if it’s dairy or a pill. Calcium binds to oxalates in the gut, so they will be excreted in the stool and not absorbed. The citrate also inhibits crystal formation, growth and aggregation in the kidney while raising urine pH.

If you are uncomfortable with taking a calcium supplement, you can also use magnesium citrate (just know that you can get a Milk of Magnesia moment with too much) or potassium citrate. In fact, some doctors prescribe potassium citrate to their patients. There is one study cited below, that says in men over 60, low calcium is not significantly associated with stones, but just about everything else says, yes, get enough calcium in your diet. When supplementing with calcium, take it with a meal because you will get the greatest oxalate sequestration and but not an increased risk of hypercalciuria (leading to plaque formation and cardiovascular issues). (Dion, et al., 2016)

4) Increase citrates (also known as citric acid). As mentioned above, citrates inhibits crystal formation, growth and aggregation while raising urine pH. Just 4 ounces of lemon and lime juice per day are recommended, so it’s easy to just squeeze them into a glass of water. Orange juice (undiluted) gets lots of mentions, so if you want to drink it, get unsweetened, and drink with food to slow the sugar spike.

5) Watch your salt intake. Lowering salt intake is especially essential for stone prevention. Sodium increases stone risk by increasing urinary calcium excretion and decreasing urinary citrate. (Sorokina and Pearle, 2018) This is probably only an issue if you eat packaged foods like chips or crackers, or over-salt your food.

6) Mind your choline intake. Without choline (and it’s metabolite phosphatidylcholine), bile salts are not released properly. Without bile, fatty acids can bind with calcium, which takes it out of the available calcium-oxalate binding pool. Calculate your choline intake with a program like Cronometer and make sure to eat eggs (egg yolks are high in choline) or other good sources of choline several days a week, or liver once a week. Chris Masterjohn’s choline post will help you understand if you are getting enough choline. Scroll past the database fields to see the full background he provides.

7) Mind your gut health. This is a bit of a chicken and egg problem of where the problems started. Some argue high oxalates take a toll on some microbes that degrade oxalates, while others argue that overuse of antibiotics kill off the oxalate-degrading microbes leaving an excess of oxalates that can be absorbed. Either way, a healthy, diverse microbiome is critical to degrade oxalates in the gut. Research is mixed on using probiotics, but it does show a healthy microflora can make a difference (see Probiotics section.) Eat your favorite ferments and watch sugar and refined carb intake. Fiber is also good to help sweep out any bound oxalates, but avoid concentrated bran products, which have higher oxalates that can bind to calcium, negating calcium’s therapeutic effects. And work to fix any leaky gut issues you have.

8) Supplements have both positive and negative effects.

  • Don’t take high amounts of Vitamin C (no more than 500 mg/day). Vitamin C is a precursor of endogenously produced oxalate and taking excessive quantities may result in the precipitation of calcium oxalate. (Bhasin, et al., 2015)
  • Anti-oxidants have shown promise in rat studies. “Antioxidant therapy to urolithic rats with vitamin E, glutathione monoester, methionine, lipoic acid, or fish oil normalised the cellular antioxidant system, enzymes and scavengers, and interrupted membrane lipid and protein peroxidation reaction, ATPase inactivation, and its associated calcium accumulation. Antioxidant therapy prevented calcium oxalate precipitation in the rat kidney and reduced oxalate excretion in stone patients.” (Selvam, 2002)
  • The jury is out on B6. “Vitamin B6 might reduce oxalate excretion by reducing its production in the liver. It is a cofactor of the alanine-glyoxylate aminotransferase, which metabolizes glyoxylate into glycine. When this metabolic pathway is limited by insufficient levels of pyridoxine, more glyoxylate would be available for conversion into oxalate.” (Ferraro, et al., 2017) But, studies have been inconsistent.
  • Another unknown is Vitamin D deficiency, which is common in stone-forming populations. Although higher serum vitamin D was previously considered as a risk factor for stone formation, vitamin D deficiency may also exacerbate kidney stone formation or severity. The mechanisms behind these two outcomes are not well studied. (Tavasoli and Taheri , 2017) In the meantime, it seems prudent to avoid high-dose Vitamin D for those sensitive to oxalates.
  • Chanca Piedra is a South American herb used as a alkalizing agent, and sometimes mentioned as a replacement for prescription-strength potassium citrate. (Stern, et al., 2020)

9) Lose weight, if you are obese. "The underlying pathophysiology of stone formation in obese patients is thought to be related to insulin resistance, dietary factors, and a lithogenic urinary profile. Uric acid stones and calcium oxalate stones are observed frequently in these patients. Insulin resistance is thought to alter the renal acid-base metabolism, resulting in a lower urine pH, and increasing the risk of uric acid stone disease. Obesity is also associated with excess nutritional intake of lithogenic substances and with an increase in urinary tract infection incidence. Recent studies highlighted that renal stone disease increases the risk of myocardial infarction, progression of chronic kidney disease, and diabetes." (Carbone, et al., 2018)

10) Some people may need to reduce protein intake. Protein sources high in hydroxyproline are particularly problematic. “However, it is well established that a large proportion of urinary oxalate is derived from the endogenous metabolism of glycine, glycolate, hydroxyproline, and dietary vitamin C. A recent metabolic study compared a controlled diet with 25% of protein from gelatin (2.75 g of hydroxyproline) with the same diet except with 25% of protein from whey (containing no hydroxyproline). The diet that was high in hydroxyproline increased urinary oxalate excretion by 42%.” (Taylor and Curhan, 2007)

However, this study found that men with a body mass index < 25 would benefit from a lower protein diet, while women do not. (Ziemba and Matlaga, 2017)

And what about vegetarian diets? This study reported: “A vegetarian diet can only be recommended for calcium oxalate stone patients, if the diet (1) contains the recommended amounts of divalent cations such as calcium and its timing of ingestion to a meal rich in oxalate is considered and (2) excludes foodstuffs with a high content of nutritional factors, such as phytic acid, which are able to chelate calcium.” (Thomas, et al., 2007) Phytates take calcium out of the available oxalate binding pool and may allow for greater intestinal oxalate absorption. Yet, a different study suggested that higher phytate excretion reduces the risk of kidney stones. (Grases & Costa-Bauzá, 1999)

11) If you have problems with fat malabsorption, you will need to reduce fat intake. In this condition, oxalate absorption can increase dramatically from the normal level of 5–10% to over 30%. Enteric hyperoxaluria is associated with a diverse number of conditions that cause fat malabsorption, including inflammatory bowel disease, celiac disease, short bowel syndrome, chronic pancreatitis, biliary cirrhosis and bariatric surgery. (Lorenz, et al., 2013)

People with fat malabsorption may also benefit from the supplementation of fat-soluble vitamins A, D, E, and K. (Siener, et al., 2020)) Taurine can also help with the release of bile, improving fat digestion. Those with fat malabsorption due to pancreatic insufficiency can also benefit from pancreatic enzyme supplementation. (Lorenz, et al., 2014)

12) Try Epsom salt baths or supplement with MSM. Some people on the TLO Facebook page swear by increasing sulfates, and believe it has to do with how oxalates and sulfates compete for the same cellular transporters, mostly influenced by pH. (See Genetics section for more on SLC26A.)

Bottom line, if you are not making progress in your healing and have a seemingly healthy diet utilizing greens, nuts, chocolate, sweet potatoes, beets and other high oxalate foods, and have symptoms listed above, consider getting an oxalic acid test. And, slowly cut back your oxalate consumption while you work to find the root cause(s) of your symptoms. Eating low oxalate is not easy especially with Paleo or Keto diets, and dumping is no fun, but the improvements in health will definitely be noticeable for those with oxalate problems.


Note, most research on oxalates is in the area of kidney stones, and in primary hyperoxaluria. Doctors and practitioners are looking at both to better understand the processes and how oxalates cause problems in the rest of the body.


Primary and secondary hyperoxaluria: Understanding the enigma (Bhasin, et al., 2014)

Hyperoxaluria is characterized by an increased urinary excretion of oxalate. Primary and secondary hyperoxaluria are two distinct clinical expressions of hyperoxaluria. Primary hyperoxaluria is an inherited error of metabolism due to defective enzyme activity. In contrast, secondary hyperoxaluria is caused by increased dietary ingestion of oxalate, precursors of oxalate or alteration in intestinal microflora. The disease spectrum extends from recurrent kidney stones, nephrocalcinosis and urinary tract infections to chronic kidney disease and end stage renal disease. When calcium oxalate burden exceeds the renal excretory ability, calcium oxalate starts to deposit in various organ systems in a process called systemic oxalosis…

Oxalate rich dietary sources include rhubarb and spinach and daily intake may be in excess of 1000 mg/d[29]. Increased dietary absorption may occur in “juicing” which is being propagated as a health fad for clearing toxins from the body and also for weight loss. Previously dietary oxalate was thought to make only a minimal (10%-20%) contribution to the amount of oxalate excreted in urine but studies have shown that this is not correct. In a study by Holmes et al[10], dietary intake contributed to about 50% of the oxalate secretion proving that dietary ingestion is an important determinant in total oxalate excretion. Bioavailability of oxalate from food and, thus, urinary oxalate, is also influenced by the forms of oxalate in the food, techniques of food processing and cooking and other constituents in the meal[30]. Dietary ingestion of oxalate is reduced by concurrent ingestion of calcium or magnesium which complex with oxalate and form insoluble salts[10,31]…

Fat malabsorption increases the intestinal absorption of oxalate due to increased intestinal permeability to oxalate and formation of calcium and fatty acid complexes leading to increased amounts of soluble oxalate. An intact colon is required for increased oxalate absorption via this mechanism[32]. This form of hyperoxaluria is seen in partial gastrectomy, bariatric surgery, jejunoileal bypass, and inflammatory bowel disease[7,33]…

Ascorbic acid (Vitamin C) is a precursor of oxalate and intake of excessive quantities of vitamin C may result in precipitation of calcium oxalate[39,40]…

“Juicing” deserves a special mention as it supplies a high amount of daily oxalate. The increased amount of fluid intake in the juices increases the paracellular absorption of oxalate in the intestines. This may overwhelm the ability of the kidney to excrete the increased dietary load especially in patients with chronic kidney disease. Oxalate is ingested in the fruits and vegetables used to make the juices such as kiwi, spinach and beetroot. Low calcium intake and ingestion of excess of vitamin C is also noted which together with the oxalate intake heighten the risk of acute kidney injury[8,9]…

Calcium oxalate deposits have been reported in the myocardium, cardiac conduction system, kidneys, bones and bone marrow. This leads to cardiomyopathy, heart block and other cardiac conduction defects, vascular disease, retinopathy, synovitis, oxalate osteopathy and anemia that is noted to be resistant to treatment[52,60,61]…

In SH, stones are usually mixed (whewellite and weddellite) in contrast to PH. The excretion of urinary oxalate is increased in SH and may be > 0.7 mmol/1.73 m2 per 24 h but in some cases may exceed 1.0 mmol/1.73 m2 per 24 h[2,72,73]. Other available diagnostic tests include use of PCR in stool samples to identify oxalobacter formigenes[74,75]. Also, Increased intestinal oxalate absorption can be assessed by an absorption test using (13C2) oxalate[76]. This test can help identify hyperabsorbers who would benefit from dietary interventions focusing on lowering oxalate and increasing calcium in the diet. This diagnostic test also helps to differentiate between primary and secondary forms of hyperoxaluria[33].

Conservative measures are recommended soon after the diagnosis is made. High fluid intake is vital in preventing stone formation[77]. Patients with hyperoxaluria should be advised to increase their fluid intake to 3-4 L/d[53,60]. ..On the other hand, diet modification is a very important element in the treatment of secondary hyperoxaluria where efforts should be made to reduce oxalate intake in the diet. Calcium intake should not be restricted as it complexes with oxalate and prevents its absorption[10]. However, excessive intake of Vitamin C should be avoided…Alkalinization of the urine is well known to prevent stone formation as citrate complexes with calcium and thus decreases the amount of calcium oxalate available for precipitation. This same principle can be used in patients with hyperoxaluria. Potassium citrate can be used at a dose of 0.1-0.15 g/kg body weight[84]. Urinary pH must be maintained between 6.2 and 6.8[7].

Oxalate, inflammasome, and progression of kidney disease (Ermer, et al., 2017)

Oxalic acid is a potentially toxic dicarboxylic acid that is not further metabolized by mammals [1, 2, 3, 4, 5]. In its ionized form – oxalate – it forms highly insoluble complexes with calcium [1, 2]. When oxalate homeostasis is disturbed, oxalate accumulates in various body tissues and damages primarily the kidney, which serves as its main excretory organ. This in turn leads to further elevations of plasma oxalate levels. Recent studies have directed the focus to oxalate as an activator of inflammatory pathways. Thus, this review aims to provide an impulse to further investigate the prominent role of oxalate in inflammasome activation and the progression of kidney disease.

The liver has been identified as major site for the biosynthesis of oxalate as shown in Figure 1A. Endogenous oxalate production is thought to be fairly constant, attributing for up to 60–80% of total plasma oxalate and urinary oxalate excretion [6, 7]. Oxalate biosynthesis evolves from glyoxylate [8, 9, 10, 11] as central precursor molecule. Glyoxylate originates from the oxidation of glycolate by glycolate oxidase (GO) or from the catabolism of hydroxyproline, derived from collagen [12, 13]. Glyoxylate can be eliminated by conversion to glycine (alanine-glyoxylate aminotransferase: AGT) [10] or glycolate (glyoxylate reductase – hydroxpyruvate reductase: GRHPR) [9]. If, however, the glyoxylate supply overflows, oxalate is generated by the activity of either GO or lactate dehydrogenase (LDH). LDH is more likely to be responsible for the conversion in vivo as GO is strongly inhibited by physiological glycolate and lactate concentrations in vitro [10]. The glyoxylate cycle links various metabolic pathways for amino acids [10, 14, 15] and carbohydrates. In recent years glyoxal has been identified as another possible oxalate precursor. Glyoxal is a product of cellular peroxidation and protein glycation. Advanced glycation endproducts (AGEs) are associated with the progression of diabetic nephropathy and increased pro-inflammatory cytokines such as IL-1β, which can both be ameliorated by methylglyoxal trapping [16, 17, 18, 19]. Also, diabetics tend to excrete more oxalate than healthy individuals [20, 21, 22]. In addition, experimental glutathione depletion increases oxalate formation from glyoxal [23, 24]. These findings may suggest links between sugar metabolism, peroxidation and oxalate generation that will require further investigation.

Dietary sources of oxalate include e.g. green leafy vegetables, different seeds and roots, cocoa and tea [2, 25]. Reports from different countries average daily oxalate intake to 100–200 mg/d (1.14–2.28 mmol/d) in healthy subjects [5, 7, 26]. Following dietary oxalate loads plasma levels peak at 2–4 hours. At 6 hours post-ingestion more than 75% of the ingested oxalate is excreted. This time course implicates the small intestine as the primary location for oxalate absorption [27, 28, 29]. Additional evidence suggests a role for the stomach and large intestine in physiological oxalate absorption [30, 31, 32]. The amount of oxalate that is absorbed from a dietary load can be extrapolated from an increase in urinary oxalate excretion as indicated, for example, by a 13C–oxalate absorption test. 5–15% of the ingested oxalate load reaches the systemic circulation in healthy children and adults [27, 28, 33, 34, 35, 36]. In total, exogenous oxalate is estimated to account for approximately 20–40% of urinary oxalate as shown in Figure 1A [7, 37, 38]. However, both oxalate intake and intestinal absorption are subject to a significant intra- and inter-individual variability: in some regional and seasonal diets oxalate ingestion may be considerably higher [25, 39]. In addition, oxalate bioavailability is an important factor [40] as dietary components such as Ca2+ or Mg2+ can reduce the amount of soluble oxalate in the intestinal lumen by complex formation and precipitation, impede its intestinal absorption and thereby reduce its urinary excretion. Conversely, reduced availability of Ca2+ enhances oxalate absorption (see below). Additional factors influencing oxalate absorption such as fiber have been discussed but their relevance remains controversial [7, 29, 35, 41, 42, 43]. While oxalate absorption is largely passive and paracellular across the tight junction [44], studies using knockout mice suggest that apical transporter SLC26A3 (DRA) may also play a role in oxalate absorption [45]. Knockout mice studies suggest a pivotal role of apical transporter SLC26A6 in back-secretion of oxalate that limits its net intestinal absorption, as gene deletion of SLC26A6 results in significant hyperoxaluria [46, 47]. Likewise, knockout of the basolateral transporter SLC26A1 also results in hyperoxaluria [48]. However, the contribution of these oxalate transporters to oxalate homeostasis and risk for hyperoxaluria in humans needs to be further defined [49].

Oxalate is mainly excreted by the kidney [3, 50]. Several studies have demonstrated almost complete recovery of radiolabeled oxalate in urine following infusion into healthy subjects or given as dietary load [3, 28]. In addition to glomerular filtration, there is net tubular secretion of oxalate [51, 52, 53], mainly in the proximal tubule, although there is also evidence for oxalate transport in collecting duct and papillary cells [54, 55]. Total daily oxalate excretion by the kidney is estimated at 10–40 mg per 24 h (0.1–0.45 mmol per 24 h) in healthy children and adults, with the average excretion being slightly higher in males than in females [34, 37, 56, 57, 58]. Only a minor part is eliminated through the gastrointestinal tract [6]. Marengo et al. reported fecal oxalate excretion to account for only 5–7% of the oxalate administered in rats treated with subcutaneously implanted minipumps [37].

When oxalate homeostasis is disturbed (Figure 1B), hyperoxaluria ensues defined by a urinary excretion > 40–45 mg per 24 h (0.45–0.5 mmol per 24 h) [37, 56]. Primary hyperoxalurias (PH) are caused by mutations in the genes encoding key enzymes of hepatic oxalate biosynthesis with many of these patients presenting with end-stage renal disease (ESRD) already at time of diagnosis [59, 60, 61, 62]. Secondary or enteric hyperoxalurias are characterized by a pathological hyperabsorption of dietary oxalate that in turn increases plasma and urine oxalate (Figure 1B) [7, 63]. Secondary hyperoxalurias can have a broad range of etiologies. Fat malabsorption is a very common side effect following small bowel resection or bariatric surgery. Enteric hyperoxaluria is thought to be mediated by two mechanisms: 1) by increasing the permeability of the colonic mucosa for oxalate 2) by complexation of luminal calcium with fatty acids, increasing the amount of soluble oxalate available for absorption [64, 65, 66]. Humans are not able to degrade oxalate. In contrast, the bacterial species Oxalobacter, a gram-negative obligate anaerobic bacterium that colonizes the colon, takes up oxalate through an oxalate-formate-antiport carrier and metabolizes it to formate and CO2 for exclusive energy supply [67]. Several human and animal studies hypothesize that a lack of colonic Oxalobacter formigenes favors enteric hyperoxaluria, kidney disease and adverse cardiovascular outcomes [7, 63, 68, 69, 70, 71].

Hyperoxaluria: a gut–kidney axis? (Robijn, et al., 2011)

Oxalate is an unavoidable component of the human diet as it is a ubiquitous component of plants and plant-derived foods.29.,  30.,  31. Endogenous oxalate synthesis (see Figure 1) primarily occurs in the liver32 with glyoxylate as an immediate oxalate precursor.33,34 Glyoxylate is derived from oxidation of glycolate by glycolate oxidase or by catabolism of hydroxyproline, a component of collagen.35.,  36.,  37.,  38. Transamination of glyoxylate with alanine, by alanine/glyoxylate aminotransferase (AGT), results in the formation of pyruvate and glycine. Excess glyoxylate, however, will be converted to oxalate by glycolate oxidase or lactate dehydrogenase, of which the latter most likely catalyzes the bulk of this reaction.6,33,39 It has been suggested that increased fructose intake may increase endogenous oxalate synthesis33 and hence urinary oxalate excretion, thereby increasing the risk of incident kidney stones.40 However, conflicting results have been reported about the relationship between fructose and oxalate synthesis.41,42 Very recently, it was shown that in healthy individuals consuming controlled diets, increasing fructose concentrations had no effect on the excretion of oxalate, calcium, or uric acid…

Primary hyperoxaluria is the result of inherited (mostly) hepatic enzyme deficiencies leading to increased endogenous oxalate synthesis. Secondary hyperoxaluria results from conditions underlying increased intestinal oxalate absorption, such as (1) a high-oxalate diet, (2) fat malabsorption (enteric hyperoxaluria), (3) alterations in intestinal oxalate-degrading microorganisms, and (4) genetic variations of intestinal oxalate transporters…

Estimates of the average daily oxalate intake of the western population are highly variable, ranging between 44 and 351mg/day (0.5–4.0mmol/day).30,60,61,62 Daily intake may even exceed 1000mg/day (11.4mmol/day) when oxalate-rich foods, such as spinach or rhubarb, are consumed.60 Values of up to 2000mg (22.7mmol) have been reported in seasonal rural diets in India.63 However, the fraction of dietary oxalate that will effectively be absorbed by the intestine is highly influenced by the amount of oxalate-binding cations, such as calcium and magnesium, in the gut. In this context, several studies demonstrated that the concomitant ingestion of calcium (or magnesium) with oxalate can reduce oxaluria by forming insoluble oxalate complexes in the gut (thereby decreasing intestinal oxalate absorption),64,65,66,67,68,69 a process that is disturbed in the pathology of enteric hyperoxaluria due to fat malabsorption (see below). Among other highly variable parameters, oxalate bioavailability, amount of oxalate precursors, inherited oxalate absorption capacity, gastric emptying, intestinal transit time, and the presence of oxalate-degrading microorganisms can be named.5,60,61,62,63,64

Hyperoxaluria due to fat malabsorption refers to a condition in which intestinal oxalate absorption is increased as a result of two different mechanisms: (1) both dihydroxy bile acids and fatty acids increase the permeability of the intestinal mucosa to oxalate and (2) complexation of fatty acids with luminal calcium increases the amount of soluble oxalate that is available for absorption as insoluble CaOx complexes are no longer formed.81 It is also postulated that inhibition of intestinal oxalate-degrading bacteria in patients with bile acid malabsorption might contribute to the increased intestinal oxalate absorption, which may range from 35 to 50% of an administered oxalate dose.81 Hyperoxaluria due to fat malabsorption is typically seen in patients suffering from inflammatory bowel disorders,81 after bariatric surgery (potentially leading to kidney failure82,83,84)85,86 or after the use of gastrointestinal lipase inhibitors.87,88

Recently, it was shown that deletion of the slc26a6 oxalate transporter gene in mice, a species virtually insensitive to lithogenic agents, results in hyperoxalemia, hyperoxaluria, and CaOx urolithiasis due to a defect in intestinal oxalate secretion.96,97 It was also suggested that differences in affinity and electrogenicity of this transporter may partially explain differences in species susceptibility (mice less susceptible than humans) to nephrolithiasis.98 Furthermore, it has been reported that polymorphisms of this transporter (V185M) in the human population may explain accelerated lithogenesis in distinct subpopulations.98 Taken together, these observations suggest that alterations in intestinal oxalate transporters might be associated with reduced intestinal oxalate secretion and increased prevalence or severity of nephrocalcinosis and/or nephrolithiasis, highlighting the importance of a good understanding of oxalate transport for future treatment and/or prevention of these disorders.

Hence, it is speculated that the diet has a more important role than administration of a probiotic in reducing urinary oxalate excretion.165

The Roles and Mechanisms of Intestinal Oxalate Transport in Oxalate Homeostasis (Hatch and Freel, 2008)

In this brief overview of the role of the intestine in oxalate homeostasis we consider some of the phenomenological aspects of intestinal oxalate transport (handling) that have led to the notion that the bulk of net transcellular oxalate transport, either absorption or secretion, occurs via anion exchangers (antiporters). We then consider the emerging importance of gene families encoding these anion exchangers, especially SLC26, and how an understanding of these proteins and their segmental and cellular distribution, has led to a better understanding of intestinal oxalate exchange in health and disease. Finally, recent information on the role of oxalate degrading bacteria (Oxalobacter) in modulating intestinal oxalate handling will be considered.

Intestinal and renal handling of oxalate loads in normal individuals and stone formers (Knight, et al., 2007)

In the present study, the intestinal handling of oxalate appeared to be of two distinct types, normal and enhanced absorption. However, the small number of subjects precludes any conclusions about the influence of enhanced oxalate absorption on stone formation. Four of six SF and five of six N had similar responses to the 8 mmole oxalate load with a mean absorption of 7.7 ± 2.2%. The peak in oxalate absorption occurred 2–4 h after the oxalate load in these individuals, which is compatible with a significant amount of the absorption occurring in the small intestine. Three individuals showed enhanced absorption with the 8 mmole load, mean absorption of 23.5 ± 3.6%. The 8–24 h interval was discriminatory in these subjects, suggesting greater oxalate absorption in the large intestine. The results also suggest a dose dependent response. No subject in our study with enhanced oxalate absorption excreted more than 40 mg oxalate/day during the four 24 h urine specimens collected on self-selected diets. There are possible reasons for this including low endogenous oxalate synthesis, consumption of a low oxalate diet, an increased ratio of dietary divalent cations to oxalate limiting the absorption of oxalate, or that enhanced absorption is triggered by high doses of oxalate. All ten subjects tested for O. formigenes, including the three individuals who showed enhanced absorption, were found not to be colonized with this organism based on the PCR test utilized. This suggests enhanced absorption was not strongly linked with the absence of O. formigenes in our study. This colonization rate is low, but consistent with our recent observations in a much larger cohort from our geographic area (R. P. Holmes and H. Sidhu, unpublished observations).

Oxalate urolithiasis: significance of serum and urinary oxalate (Butz and Kohlbecker, 1980)

With a new enzymatic test using oxalate oxidase, serum and urinary oxalate can easily and quickly be determined. Serum oxalate in females was significantly higher than in males (39.5 mumol/l, 30.8 mumol/l). Increased serum levels were found only in male patients. Urinary excretion did not reveal sex-dependent differences in healthy persons. The normal range of oxalate excretion in 104 adult healthy persons was 83-365 mumol/day (95% quartile). In 130 stone formers (nonrecurrent and recurrent group) urinary oxalate excretion was found to be in the normal range. Evaluation of urinary oxalate concentration in morning samples showed increased levels in both groups of male stone formers. Oxalate concentration was unaltered in female patients.

Impacts on mitochondria and inflammation

Potentially Pathogenic Calcium Oxalate Dihydrate and Titanium Dioxide Crystals in the Alzheimer’s Disease Entorhinal Cortex (Heller, et al., 2020)

COD precipitates when the [Ca2 +][oxalate] product-defined solubility-limit is exceeded, i.e., when the Ca2 + concentration is high, when the oxalate concentration is high, or when both are higher than normal. Because exaggerated endothelial reticulum Ca2 + release, leading to elevation of neuronal cytosolic Ca2 + concentration, precedes in the mouse model aggregation of Aβ42 [35], the precipitation of inflammasome-activating COD crystals is not likely to be a result of AD, and can be one of its causes. In the absence of xylitol or ethylene glycol poisoning the oxalate precursors in the CNS is ascorbate [36]. The neuronal concentration of ascorbate is as high as 10 mM [37], twice that of glucose; and the concentration of ascorbate in stimulated macrophages is massive [38], making it likely that it is similarly massive in stimulated microglia. Excessive ascorbate concentration is a recognized cause of sterile inflammatory COD disease [39]…

In conclusion, our study suggests that entorhinal cortex COD and TiO2 crystals should be added to the existing list of potential AD initiators, all known to activate the NLRP3 inflammasome.

Oxalate induces mitochondrial dysfunction and disrupts redox homeostasis in a human monocyte derived cell line (Patel, et al., 2018)

To test whether oxalate would have any effect on human monocytes, primary monocytes from healthy subjects were exposed to low doses of CaOx crystals and NaOx. Consistent with our findings in THP-1 cells, we determined that oxalate disrupted mitochondrial function in primary monocytes within a short period of time (40 min). These results suggest that interaction of oxalate with primary monocytes may alter monocyte/macrophage function in the circulation and within the kidney. Kusmartsev et al. recently reported that human monocytes differentiated into macrophages stimulate inflammatory responses following CaOx crystal exposure and that these cells may play an important role in crystal clearance [18]. It is possible that macrophage differentiation and crystal clearance could be disrupted or cell death may occur in cases were monocytes are exposed to elevated levels of oxalate. The long term effect of some of these events could compromise the immune system over time in patients with kidney stones and/or predispose them to recurring stones. One potential source for such an event is the consumption of oxalate-rich meals. It is likely that oxalate-rich meals that induce CaOx crystalluria could cause inflammation and monocyte mitochondrial dysfunction in patients and would be accentuated in patients with hypercalciuria and/or hyperoxaluria.

Calcium Oxalate Differentiates Human Monocytes Into Inflammatory M1 Macrophages (Dominguez-Gutierrez, et al., 2018)

Both primary monocytes and THP-1 cells, a human monocytic cell line, respond strongly to CaOx crystals in a dose-dependent manner producing TNF-α, IL-1β, IL-8, and IL-10 transcripts. Exposure to CaOx followed by 1 h with LPS had an additive effect for cytokine production compared to LPS alone, however, LPS followed by CaOx led to significant decrease in cytokine production. Supernatants taken from monocytes were previously exposed to CaOx crystals enhance M2 macrophage crystal phagocytosis. CaOx, but not potassium or ZnOx, promotes monocyte differentiation into inflammatory M1-like macrophages.

Roles of Macrophage Exosomes in Immune Response to Calcium Oxalate Monohydrate Crystals (Singhto, et al., 2018)

In kidney stone disease, infiltration of macrophages in the renal interstitium can promote chronic inflammation, leading to chronic kidney disease (1–3). Macrophages secrete several types of biomolecules in response to CaOx crystals deposited in renal interstitium, including ROS, chemokines, proinflammatory cytokines, and fibrogenic factors that subsequently stimulate the inflammatory processes and provoke tubulointerstitial damage (10–12). These secretory products may also play important autocrine and/or paracrine roles in the renal interstitial milieu. In addition, interstitial CaOx crystal deposition can then activate mononuclear phagocytes (i.e., dendritic cells and macrophages) to secret IL-1β through NLRP3/ASC/caspase-1-dependent pathway, causing renal inflammation in kidney stone disease (15). These findings indicate that CaOx crystals are also involved in activation of inflammasome, the multiprotein complex that plays crucial role in innate immunity (15). Likewise, infection and cellular stress can enhance inflammasome activation in the activated macrophages as indicated by redistribution and spatial organization of ASC (apoptotic speck-like protein containing a CARD) to the cytoplasm, followed by assembly of inflammasome components, including Nod-like receptors (NLR) and caspase-1 in the perinuclear space, which is necessary for inflammasome function such as maturation of IL-1β and IL-18 for further inflammatory signaling. In contrast, primary localization of ASC and caspase-1 in the nucleus is commonly observed in the resting monocytes/macrophages (36). Consistent with the previous reports, we demonstrated herein that COM crystals could induce inflammasome activation in macrophages, leading to the increased level of IL-1β, one of the markers for inflammasome activation, in culture supernatant (Figure 4). In addition, we have demonstrated for the first time that COM crystals could induce changes in proteins expressed in exosomes isolated from macrophages and these altered exosomal proteins were involved in several immune functions (Figure 2; Tables 1 and 2).

Monocyte Mitochondrial Function in Calcium Oxalate Stone Formers (Williams, et al., 2017)

It has been previously determined that mitochondrial function is disrupted in a number of pathologies linked to inflammation and oxidative stress such as atherosclerosis, CKD, and acute kidney injury.26–28 In the present pilot study, we sought to assess whether mitochondrial function is suppressed in monocytes, lymphocytes, and platelets from CaOx stone formers compared to healthy subjects. To our knowledge, this is the first study to evaluate cellular bioenergetics in immune cells from CaOx stone formers. Cellular bioenergetics is an overall assessment of cellular metabolism that consists of pathways such as oxidative phosphorylation, glycolysis, and fatty acid oxidation. To study mitochondrial metabolism in immune cells from CaOx stone formers and healthy subjects, we utilized the mitochondrial stress test. Our data provide evidence for a significant decrease in monocyte mitochondrial function in CaOx stone formers. In particular, both maximal respiration and reserve capacity were significantly lower in monocytes from CaOx stone formers compared to healthy subjects. We also determined that the BHI is significantly depressed in CaOx stone former monocytes. In contrast, both lymphocyte and platelet mitochondrial function from CaOx stone formers was similar to those from healthy subjects.

One rationale for why monocytes from CaOx stone formers are affected rather than lymphocytes is that monocytes are a part of the innate immunity and are one of the first responders to sites of inflammation; whereas, lymphocytes are involved in adaptive immunity. Monocytes also have different mitochondrial programs compared to lymphocytes due to their physiological functions. Monocytes can differentiate into two classes of macrophages (M1 and M2) to regulate inflammation using glycolysis or oxidative phosphorylation, respectively.10 Importantly, both subtypes can convert to the other form during inflammation and this conversion could feasibly be modulated by the extent of crystal exposure. The exact reason why lymphocytes and platelets are not affected warrants further investigation.

Diet and Supplementation

Dietary oxalate and kidney stone formation (Mitchell, et al., 2019)

The contribution of dietary oxalate to stone formation has been difficult to assess accurately for reasons that include 1) the requirement to control the intake of oxalate, calcium, and other nutrients to accurately identify factors influencing oxalate excretion, 2) the difficulty of estimating oxalate intake, 3) unexplained variability in oxalate absorption and secretion, 4) variability in oxalate content of foods due to environmental/growth conditions, 5) oxalate’s interactions with dietary calcium, 6) the influence of oxalate-degrading microbes, and 7) a lack of clinical studies showing that decreasing oxalate intake lowers the frequency of stone recurrence.

The intestinal absorption of dietary oxalate is largely affected by the solubility (bioavailability) of ingested oxalate. Humans ingest on average 15–25 mmol of calcium per day compared with 1–3 mmol of oxalate, suggesting that, in the intestine, the bulk of oxalate is insoluble, crystalline CaOx. Crystalline oxalate is eliminated in the fecal stream; thus the pool of oxalate that may be absorbed is in a soluble form….In Fig. 1, the change in oxalate excretion of 12 individuals who switched from a self-selected diet (day 0) to an oxalate-free formula diet is shown (21). Notably, it takes several days for oxalate to be cleared from the gut. This was confirmed by oxalate analyses in the stool of two individuals in whom oxalate was detected on day 4 but not on day 6 (22).

Figure 2 further illustrates the relationship between dietary oxalate and urinary oxalate excretion and reveals that, over a large range of dietary oxalate intakes, 50–750 mg/day, for every 100 mg of oxalate consumed on a 1,000 mg/day calcium diet, urinary oxalate increases by 2.7 mg.

To limit calcium oxalate stone growth, we advocate that patients maintain appropriate hydration, avoid oxalate-rich foods, and consume an adequate amount of calcium.

[MY NOTE: From Table 1: Avoid Spinach, Chard, Rhubarb, Star Fruit. Limit Potato (<100 g), Chocolate, Nuts, Beets & Bran. They also say take 300-400 mg calcium with each meal.]

Role of Citrate in Pathophysiology and Medical Management of Bone Diseases (Granchi, et al., 2019)

Prezioso et al. (2015) examined the relationship between a diet rich in vegetables and urinary citrate excretion [24]. Fruits and vegetables (except for those with high oxalate content) favour citrate excretion; consequently, they decrease urinary saturation for CaOx and CaP, thus having a protective effect on the formation of kidney stones [24]. In general, fruit intake is lower in hypocitraturic than in normocitraturic subjects [131].

Several authors have studied the possible influence of the consumption of fruit juices (both citrus and noncitrus) on urinary citrate excretion. Orange juice increased the excretion of urinary oxalate, and therefore, its consumption could result in the biochemical modification of stone risk factors [132]. It should also be noted that grapefruit juice significantly increased urinary oxalate levels, but it was not associated with an increased lithogenic risk probably due to the protective effect of the high citrate content [133].

In summary, natural sources of dietary citrate should be considered as a first option for preventing kidney stone recurrence as an alternative to medical treatment [24].

Secondary hyperoxaluria due to pancreatic insufficiency (de Martines, et al., 2019)

Oxalate nephropathy is associated with exocrine pancreatic insufficiency, gastric and pancreatic surgery, and inflammatory bowel disease. Normally, dietary calcium binds oxalate to form calcium oxalate, which is excreted in the stool. In patients with pancreatic insufficiency, fatty acids bind calcium instead, allowing oxalate to be absorbed in the colon. The resulting hyperoxaluria can cause oxalate crystal formation, tubulopathy, and renal insufficiency. Treatment relies on decreasing the amount of absorbable oxalate in the intestinal lumen, as well as lowering urinary oxalate concentrations.

Medical therapy for nephrolithiasis: State of the art (Sorokin, et al., 2018)

A long-term randomized controlled trial (RCT) among recurrent idiopathic calcium oxalate stone formers demonstrated that a fluid intake of at least 2 L/day reduced the risk of stone recurrence by about 56% [27]…

If calcium supplements are indicated, they should be taken with meals, allowing the ingested calcium to complex with oxalate, thereby reducing intestinal oxalate absorption and counteracting the effect of increased urinary calcium…

Noori and colleagues [62] randomized 57 patients with hyperoxaluria and recurrent calcium oxalate stones to a low oxalate diet or to the Dietary Approaches to Stop Hypertension (DASH) diet, which is a diet high in fruits, vegetables, nuts and legumes (high oxalate content) and low in sodium and red and processed meats. Although urinary oxalate increased in the group assigned to the DASH diet and decreased in those adhering to a low oxalate (4.8 mg/day vs. −4.2 mg/day, respectively, p = 0.08), urinary saturation of calcium oxalate declined more on the DASH diet (−2.14) than on the low oxalate diet (−0.90, p = 0.08), suggesting that other dietary measures had greater impact on reducing urinary stone risk than a low oxalate diet.

[MY NOTE: the Noori study noted that urinary oxalates decreased “in association with an increase in magnesium and citrate excretion and urine pH in the DASH versus low-oxalate group.” Most people moving to DASH come from a Standard American Diet, low fruits and vegetable diet, so they were probably eating more fiber, citric acid, vitamins and minerals and less salt, all know to improve safe oxalate excretion.]…

Citrate is an important inhibitor of calcium stone formation because it directly inhibits nucleation, agglomeration and growth of calcium oxalate and/or calcium phosphate crystals and by complexing with calcium to reduce urinary saturation of calcium salts [70]. Renal citrate excretion is modulated primarily by acid–base status; acidosis increases citrate reabsorption and alkalosis enhances citrate production and excretion in the renal proximal tubule.

Fruits and vegetables increase urinary citrate because of their high alkali content, but not all fruits and juices have the same citraturic effect. Orange juice has shown the most consistent benefit because it has a high content of potassium citrate that confers an alkali load [33], [71], [72]. Lemonade, which is high in citric acid, does not affect urine pH and has less citraturic effect. While fruit juices offer a more palatable and less costly therapy than potassium citrate medication, fruit juices can be high in calories and oxalate content and this may temper their use [59], [73]. Fruits with a high malic acid (precursor to citrate) content, such as pears, may theoretically increase urinary citrate but few studies have examined this [74]. Unfortunately, no citrus fruits or juices have been tested in a randomized trial to assess their benefit in reducing stone recurrence rates…

Lowering salt intake is essential for stone prevention. Sodium increases stone risk by increasing urinary calcium excretion and decreasing urinary citrate [77], [78].

Epidemiology and economics of nephrolithiasis (Ziemba, et al., 2017)

“In men younger than 60 years of age, the RR for stone formation in the highest quintile of dietary calcium as compared with the lowest quintile was 0.69 (95% CI, 0.56–0.87) [16]. In men older than 60 years of age, there was no association [16]. Additional factors associated with the risk of kidney stones in men at longer follow-up included vitamin C intake (RR, 1.41), magnesium intake (RR, 0.71), potassium intake (RR, 0.54), fluid intake (RR, 0.71), and animal protein intake only in men with a body mass index<25 kg/m2 (RR, 1.38) [16]. Sodium, phosphorus, sucrose, phytate, vitamin B6, vitamin D, and supplemental calcium intake had no association [16].”

“Additional dietary factors associated with the risk of kidney stones in woman included increased animal protein intake (RR, 0.84), phytate intake (RR, 0.63), fluid intake (RR, 0.68), and sucrose intake (RR, 1.31) [17]. The intakes of sodium, potassium, magnesium, and phosphorus were not associated with kidney stone formation [17].”

see table 4. supplemental calcium in women is neutral risk (does not increase risk of kidney stones). Tea decreases risk.

CUA guideline on the evaluation and medical management of the kidney stone patient – 2016 update (Dion, et al., 2016)

The recommended daily intake of calcium is 1000–1200 mg separated into two doses and ideally with meals. Calcium would ideally be obtained through diet, as some studies suggest supplementation may increase cardiovascular risk.51 Where supplementation is required, calcium supplementation taken with meals is suggested, as this results in the greatest oxalate sequestration and is not associated with an increased risk of hypercalciuria.52

Dietary treatment of urinary risk factors for renal stone formation. A review of CLU Working Group (Prezioso, et al., 2015)

In older patients dietary counseling for renal stone prevention has to consider some particular aspects of aging. A restriction of sodium intake in association with a higher intake of potassium, magnesium and citrate is advisable in order to reduce urinary risk factors for stone formation but also to prevent the loss of bone mass and the incidence of hypertension, although more hemodynamic sensitivity to sodium intake and decreased renal function of the elderly have to be considered. A diet rich in calcium (1200 mg/day) is useful to maintain skeletal wellness and to prevent kidney stones although an higher supplementation could involve an increase of risk for both the formation of kidney stones and cardiovascular diseases.

Hyperoxaluria and Genitourinary Disorders in Children Ingesting Almond Milk Products (Ellis and Lieb, 2015)

Our investigation of the oxalate content of several popular plant-based milk substitutes indicates that almond milk products are a particularly rich source of dietary oxalate.

Vascular Calcification and Bone Mineral Density in Recurrent Kidney Stone Formers (Shavit, et al., 2015)

This study demonstrates that patients with calcium kidney stones suffer from significantly higher degrees of aortic calcification than age- and sex-matched non-stone formers, suggesting that VC may be an underlying mechanism explaining reported associations between nephrolithiasis and cardiovascular disease. Moreover, bone demineralization is more prominent in KSFs.

Overall, 68% of KSFs had moderate to severe AAC. In addition, 80% of KSFs had a proximal pattern of AAC distribution (located in the proximal two-thirds of the abdominal aorta).

In addition, lower BMD was clearly demonstrated in KSFs compared with the control group. However, neither VC nor osteoporosis was associated with the presence of hypercalciuria in KSFs.

Medical and Dietary Therapy for Kidney Stone Prevention (Gul and Monga, 2014)

With low fluid intake, urine output is decreased and urine flow is slower, both of which increase the risk of stone formation. Current guidelines recommend drinking enough fluids to produce at least 2.5 L of urine daily [4]. Almost all beverages, including coffee, tea, wine, beer, and fruit juices, are acceptable. The only fluids that should be avoided are tomato, grapefruit, and cranberry juice, because tomato juice is high in sodium whereas grapefruit and cranberry juices are rich in oxalate.

Soda consumption may play a role in stone formation. One study found that among patients who initially drank at least 160 mL/d of soft drinks, those who quit had a higher 3-year freedom from recurrence than did those who continued to drink soda. However, this only held true for patients who drank phosphoric acid-containing sodas, which consist primary of the colas…

Hypocitraturia is one of the most common metabolic disturbances in patients with calcium stones and affects about 60% of these patients. Patients with low urinary citrate should be encouraged to increase their consumption of foods high in citric acid, such as lemon and lime juice. Consuming just 4 oz of lemon juice per day has been shown to significantly increase urine citrate levels without increasing oxalate levels [7]. Alternatives include melon juice and orange juice, both of which are rich sources of citrate [8]…

Together, spinach, potatoes, and nuts account for 44% of oxalate intake for the average American…

Consuming 1,200 mg/d of fish oil has been associated with significant decreases in urinary calcium and oxalate concentrations and increases in urinary citrate concentration [21,22]. Cold-water fish, including salmon, tuna, mackerel, and sardines; walnuts; flax seeds; and canola oil are rich sources of EPA.

Dietary calcium from dairy and non-dairy sources and risk of symptomatic kidney stones (Taylor and Curhan, 2013)

Higher dietary calcium from either non-dairy or dairy sources is independently associated with lower kidney stone risk.

Soda and Other Beverages and the Risk of Kidney Stones (Ferraro, et al., 2013)

The analysis involved 194,095 participants; over a median follow-up of more than 8 years, 4462 incident cases occurred. There was a 23%higher risk of developing kidney stones in the highest category of consumption of sugar-sweetened cola compared with the lowest category (P for trend=0.02) and a 33% higher risk of developing kidney stones for sugar-sweetened noncola (P for trend=0.003); there was a marginally significant higher risk of developing kidney stones for artificially sweetened noncola (P for trend=0.05). Also, there was an 18% higher risk for punch (P for trend=0.04) and lower risks of 26% for caffeinated coffee (P for trend<0.001), 16% for decaffeinated coffee (P for trend=0.01), 11% for tea (P for trend=0.02), 31%–33% for wine (P for trend<0.005), 41% for beer (P for trend<0.001), and 12% for orange juice (P for trend=0.004).

Update on Oxalate Crystal Disease (Lorenz, et al, 2013)

Secondary hyperoxaluria results from increased intestinal absorption of dietary oxalate, also referred to as enteric hyperoxaluria. Foods rich in oxalate include spinach, rhubarb, sweet potatoes and peanuts. Normally, oxalate within food is complexed with calcium rendering it difficult to absorb. In states of fat malabsorption, however, free fats in the colonic lumen bind calcium (saponification), thereby increasing the amount of free oxalate available for absorption 8–10. Free fats and possibly bile acids may also increase colonic oxalate permeability 11. In patients with fat malabsorption and an intact colon, oxalate absorption can increase dramatically from the normal level of 5–10% to over 30% 12. Enteric hyperoxaluria is associated with a diverse number of conditions that cause fat malabsorption, including inflammatory bowel disease 13, celiac disease 14, short bowel syndrome, chronic pancreatitis 15, biliary cirrhosis 16 and bariatric surgery…

Oxalate deposition can also result in synovitis, tenosynovitis and bursitis 48…Calcium oxalate has a tendency to crystallize in previously damaged joints, such as distal and proximal interphalangeal joints involved in osteoarthritis, thus presenting as soft tissue calcification about the degenerated joint 47. Inflammation may mimic the findings of erosive osteoarthritis or an atypical diuretic-related gout.

Calcium oxalate crystals induce inflammation via the NLRP3-IL-1β pathway 75. In the future, IL-1β inhibitor therapies may play a therapeutic role in calcium oxalate disease.

Patients with enteric hyperoxaluria benefit from adhering to a low-fat and low-oxalate diet. Patients with fat malabsorption are often prescribed calcium supplements with meals to promote binding of dietary oxalate and decreased intestinal absorption 19. Patients with fat malabsorption secondary to pancreatic insufficiency should benefit from pancreatic enzyme supplementation 76.

Optimum nutrition for kidney stone disease (Heilberg and Goldfarb, 2013)

The therapeutic recommendations for stone prevention that result from these studies are applied where possible to stones of specific composition. Idiopathic calcium oxalate stone-formers are advised to reduce ingestion of animal protein, oxalate, and sodium while maintaining intake of 800 to 1200 mg of calcium and increasing consumption of citrate and potassium.

Oxalate nephropathy due to 'juicing': case report and review (Getting, et al., 2013)

Juicing followed by heavy consumption of oxalate-rich juices appears to be a potential cause of oxalate nephropathy and acute renal failure.

Hyperoxaluria: a gut–kidney axis? (Robijn, et al., 2011)

Patients with secondary hyperoxaluria should be recommended to avoid food with very high oxalate content (for example, spinach, rhubarb), in order to avoid disturbances of the intestinal interplay of ions resulting in increased intestinal calcium absorption. In addition, a diet high in calcium or oral administration of calcium supplements to bind oxalate in the intestine theoretically might be an efficient strategy to lower oxalate absorption; however, this should be administered with caution because of the potential risk associated with absorption of excess free calcium.

Influence of a low- and a high-oxalate vegetarian diet on intestinal oxalate absorption and urinary excretion (Thomas, et al., 2007)

Subjects and methods: Eight healthy volunteers (three men and five women, mean age 28.6+/-6.3) were studied. Each volunteer performed the [(13)C(2)]oxalate absorption test thrice on a low-oxalate mixed diet, thrice on a low-oxalate vegetarian diet and thrice on a high-oxalate vegetarian diet. For each test, the volunteers had to adhere to an identical diet and collect their 24-h urines. In the morning of the second day, a capsule containing [(13)C(2)]oxalate was ingested. Results: On the low-oxalate vegetarian diet, mean intestinal oxalate absorption and urinary oxalate excretion increased significantly to 15.8+/-2.9% (P=0.012) and 0.414+/-0.126 mmol/day (P=0.012), compared to the mixed diet. On the high-oxalate vegetarian diet, oxalate absorption (12.5+/-4.6%, P=0.161) and urinary excretion (0.340+/-0.077 mmol/day, P=0.093) did not change significantly, compared to the mixed diet. Conclusions: A vegetarian diet can only be recommended for calcium oxalate stone patients, if the diet (1) contains the recommended amounts of divalent cations such as calcium and its timing of ingestion to a meal rich in oxalate is considered and (2) excludes foodstuffs with a high content of nutritional factors, such as phytic acid, which are able to chelate calcium.

Oxalate Intake and the Risk for Nephrolithiasis (Taylor and Curhan, 2007)

Studies of dietary oxalate and stone risk also must account for the intake of other dietary factors. For example, the intake of calcium and magnesium may modulate the intestinal absorption of dietary oxalate.9

Observational data showing an inverse relation between dietary calcium and the risk for incident kidney stones13–15 suggested that dietary calcium may bind to oxalate in the gut, thereby limiting intestinal oxalate absorption (and subsequent urinary oxalate excretion). Indeed, the inhibitory effect of calcium ingestion on urinary oxalate excretion has been demonstrated in oxalate loading studies.16–18 Magnesium intake may also decrease urinary oxalate in a similar manner.19–21

In each cohort, spinach was the highest contributor to total oxalate intake. Consumption of spinach (cooked plus raw) constituted 40.4% of oxalate intake in men, 44.2% of oxalate intake in older women, and 42.3% of oxalate intake in younger women. Consumption of potatoes (not mashed or French fried) constituted 10.2% of oxalate intake in men, 11.1% of oxalate intake in older women, and 9.9% of oxalate intake in younger women. All other foods contributed <5% to oxalate intake.

In contrast, the relation between oxalate intake and stone risk did not vary by calcium intake in older or younger women.

The proportion of urinary oxalate that is derived from dietary oxalate is unclear: estimates range from 10 to 50%.12 However, it is well established that a large proportion of urinary oxalate is derived from the endogenous metabolism of glycine, glycolate, hydroxyproline, and dietary vitamin C.10,11 A recent metabolic study compared a controlled diet with 25% of protein from gelatin (2.75 g of hydroxyproline) with the same diet except with 25% of protein from whey (containing no hydroxyproline).22 The diet that was high in hydroxyproline increased urinary oxalate excretion by 42%. Another metabolic trial demonstrated that 1000 mg of supplemental vitamin C consumed twice daily increased urinary oxalate excretion by 20 to 33%.23

Oxalate absorption and endogenous oxalate synthesis from ascorbate in calcium oxalate stone formers and non-stone formers (Chai, et al., 2004)

Background: Increased rates of either oxalate absorption or endogenous oxalate synthesis can contribute to hyperoxaluria, a primary risk factor for the formation of calcium oxalate-containing kidney stones. This study involves a comparative assessment of oxalate absorption and endogenous oxalate synthesis in subpopulations of stone formers (SFs) and non-stone formers (NSFs) and an assessment of the effect of ascorbate supplementation on oxalate absorption and endogenous oxalate synthesis. Conclusion: SFs are characterized by greater rates of both oxalate absorption and endogenous oxalate synthesis, and both these factors contribute to the hyperoxaluric state. The finding that ascorbate supplementation increased urinary total and endogenous oxalate levels suggested that this practice is a risk factor for individuals predisposed to kidney stones.

Fractional magnesium absorption is significantly lower in human subjects from a meal served with an oxalate-rich vegetable, spinach, as compared with a meal served with kale, a vegetable with a low oxalate content (Bohn, et al., 2004)

The aim of the present study was to evaluate Mg absorption from a test meal served with an oxalate-rich vegetable, spinach, as compared with a test meal served with a vegetable with a low oxalate content, kale. Mg absorption was measured by a stable-isotope technique based on extrinsic labelling of the test meals and faecal monitoring of the excreted isotope labels. Nine healthy adults participated in the study. The test meals were based on 100 g phytate-free white bread, served with 300 g spinach (6.6 mmol oxalate; 0.7 mmol (25)Mg label added, 5.0 mmol total Mg) or 300 g kale (0.1 mmol oxalate; 1.2 mmol (26)Mg label added, 4.8 mmol total Mg). The test meals were served on days 1 and 3, at breakfast and lunch, using a cross-over design. The results from the present study demonstrated that apparent Mg absorption was significantly lower from the meal served with spinach (26.7 (sd 10.4) %) than the meal served with kale (36.5 (sd 11.8) %) (P=0.01). However, the lower fractional apparent Mg absorption from the test meal served with spinach can be assumed to be, at least partly, counterbalanced by the higher native Mg content of spinach as compared with kale. Although based on indirect evidence, i.e. not based on an evaluation of added (or removed) oxalic acid, the difference in Mg absorption observed in the present study is attributed to the difference in oxalic acid content between the two vegetables.

Effect of Vitamin C Supplements on Urinary Oxalate and pH in Calcium Stone-Forming Patients (Baxmann, et al., 2003)

…vitamin C supplementation may increase urinary oxalate excretion and the risk of calcium oxalate crystallization in calcium stone-forming patients. [at 1 & 2 g/day]


Absorption of oxalate from food sources typically is 3-8% of its total oxalate in non-stone-forming individuals. Recent research shows that 40-50% of urinary oxalate comes from the diet of healthy individuals consuming typical diets with 150-250 mg/d dietary oxalate. However, a subpopulation of oxalate "hyperabsorbers" is found in most studies of stoneforming patients. It is likely that all stone formers will benefit from reduction of dietary oxalate, but especially hyperoxaluric stone formers…

Oxalate binds with calcium and magnesium to form insoluble salts. In 1978, Barilla et al (53) demonstrated that adding either 2.8 mmol of calcium or magnesium to a 5 mmol sodium oxalate load containing 2.2 mmol each of calcium and magnesium reduced the 8 hr post-load oxalate excretion by 50% and 42% respectively, in eight ileal disease patients. Similar findings were seen in stone patients with 65% and 57% reductions respectively. Berg et al (54) found that adding 200 mg magnesium as the carbonate salt to meals containing 22.5 mmol oxalate (2027 mg), 14 mmol calcium and 14.4 magnesium reduced 32 hour oxalate excretion by 51% in ten healthy subjects. In a two week trial, adding 5 mmol magnesium as either the citrate or oxide to self-selected meals reduced 24 hour urinary oxalate by 16%. Increasing calcium from 1211 mg/d to 3828 mg/d by increasing dairy products and adding a calcium-rich mineral water to a high oxalate diet (2220 mg) reduced urinary oxalate 59% in healthy non-stoneforming men (55). On the lower calcium intake, all 14 subjects were hyperoxaluric, and increasing the calcium brought all urinary oxalate values to within a normal range…

Several types of bran have been tested as a dietary treatment to reduce calcium absorption and thus urinary calcium. The effectiveness of bran has been attributed mainly to its phytate content, which accounts for 70-82% of calcium binding (71). A possible explanation is that when the bran binds calcium, less calcium is available to bind to oxalate, and its absorption is increased. However, brans also contain oxalate, which may increase urinary oxalate, therefore offsetting the benefits of calcium reduction. Most studies have reported an increase in urinary oxalate after bran supplementation. Ebisuno et al (72) had stone patients consume 10 g rice bran twice daily. Urinary oxalate increased from 48.7 mg/d at baseline in 164 patients to 57.7 mg/d in the 44 remaining patients. Similar results with rice bran were reported by Jahnen et al (73). All three studies with wheat bran supplementation have found an increase in urinary oxalate (73, 74, 75). It seems prudent to restrict the amount of concentrated brans in the diet of stone formers as a precautionary measure, especially in hyperoxaluric patients…

Hyperoxaluric patients were advised to restrict dietary oxalate, and consume dairy products with the main meal. The diet group had a 13% recurrence in 3 years, while the control group had a 42 % rate. Finally Borgi et al (90) reported a benefit effect of a lower animal protein, higher calcium, lower salt diet. Although animal protein consumption only dropped 10%, dietary calcium increased and salt intake decreased by half. Comparing these changes with published effects of the amount of change of each component on urinary composition in other studies, the main effect was mediated by the change in salt.

Effect of Calcium Intake on Urinary Oxalate Excretion in Calcium Stone-Forming Patients (Nishiura, et al., 2002)

Dietary calcium lowers the risk of nephrolithiasis due to a decreased absorption of dietary oxalate that is bound by intestinal calcium. …These data suggest that a long-lasting regular calcium consumption <500 mg was not associated with high oxaluria and that a subpopulation of hypercalciuric patients who presented a higher intestinal calcium absorption (DDHC) tended to hyperabsorb oxalate as well, so that oxaluria did not change under different calcium intake.

Contribution of Dietary Oxalate to Urinary Oxalate Excretion (Holmes, et al., 2001)

When the calcium content of a diet containing 250 mg of oxalate was reduced from 1002 mg to 391 mg, urinary oxalate excretion increased by a mean of 28.2 +/- 4.8%, and the mean dietary contribution increased to 52.6 +/- 8.6%.

Transient hyperoxaluria after ingestion of chocolate as a high risk factor for calcium oxalate calculi (Balcke, et al., 1989)

In 6 male subjects the diurnal variation of urinary oxalic acid excretion was studied after ingestion of chocolate, a food stuff rich in oxalic acid. The ingestion of chocolate caused a striking but transient increase in urinary oxalic acid excretion due to its absorption in the upper gastrointestinal tract. The peak excretion rates occurred 2-4 h after the intake of the chocolate. The peak values were 235% of the fasting excretion rate in the trial with 50 g chocolate and 289% in the trial with 100 g chocolate and reached the amounts found in cases with primary hyperoxaluria. The administration of ranitidine had no influence on oxalic acid absorption. The transient hyperoxaluria observed seems to be an important factor for the formation of calcium oxalate calculi in patients on risk for stone disorders.


Because most secondary hyperoxaluria research is related to kidney stones, here’s what we know.

Genetics of kidney stone disease (Howles and Thakker, 2020)

Genetic approaches, studying both monogenic and polygenic factors in nephrolithiasis, have revealed that the following have important roles in the aetiology of kidney stones: transporters and channels; ions, protons and amino acids; the calcium-sensing receptor (a G protein-coupled receptor) signalling pathway; and the metabolic pathways for vitamin D, oxalate, cysteine, purines and uric acid. These advances, which have increased our understanding of the pathogenesis of nephrolithiasis, will hopefully facilitate the future development of targeted therapies for precision medicine approaches in patients with nephrolithiasis.

Box 2 Candidate genes from kidney stone GWAS

  • ABCG2: ATP-binding cassette subfamily G member 2
  • ALPL: alkaline phosphatase, associated with biomineralization
  • AQP1: aquaporin 1
  • BCAS3: BCAS3 microtubule-associated cell migration factor
  • BCR: BCR activator of RhoGEF and GTPase
  • CASR: calcium-sensing receptor
  • CLDN14: claudin 14
  • CYP24A1: cytochrome P450 family 24 subfamily A member 1
  • DGKD: diacylglycerol kinase-δ
  • DGKH: diacylglycerol kinase-η
  • EPB41L2: erythrocyte membrane protein band 4.1 like 2
  • FTO: FTO α-ketoglutarate-dependent dioxygenase
  • GIPC1: GIPC PDZ domain-containing family member 1
  • GCKR: glucokinase regulator
  • HIBADH: 3-hydroxyisobutyrate dehydrogenase
  • KCNK5: potassium two-pore domain channel subfamily 5 member 5
  • POU2AF1: POU class 2 homeobox-associating factor 1
  • SLC22A2: solute carrier family 22 member 2
  • SLC34A1: solute carrier family 34 member 1
  • SCNN1B: sodium channel epithelial 1 β-subunit
  • SOX9: SRY-box transcription factor 9
  • TFAP2B: transcription factor AP-2β
  • TRPV5: transient receptor potential cation channel subfamily V member 5
  • WDR72: WD repeat domain 72
  • UMOD: uromodulin

Kidney stone disease is a common problem with a complex aetiology that can occur as a result of a mono- genic disorder or as part of a polygenic trait. Studies of monogenic disorders of nephrolithiasis have increased our understanding of the transporters, channels and receptors that are involved in regulation of the compo- sition of the renal tubular fluid, and provided valuable insights into the pathways that contribute to the risk of stone formation. The prevalence of monogenic stone disease has likely been underestimated and correct diagnosis will guide management, enable screening for other disease phenotypes and also facilitate genetic coun- selling. Furthermore, with the rapid advances that are being made in genomic medicine, it is plausible that in the future, individualized drug therapies might become available based on polygenic genotype in individuals who are currently considered recurrent idiopathic stone formers. These precision medicine approaches might become a reality as genetic studies continue to increase our understanding of the pathways that underlie kidney stone formation.

Pathophysiology‐based treatment of urolithiasis (Yasui, et al., 2016)

There are many common features between urolithiasis and atherosclerosis. OPN, calcium and phosphate acid are commonly regarded as the components of calcification.48 Both diseases develop at the highest frequency in middle‐aged and elderly males, and postmenopausal females,49-52 and both involve macrophages and cytokines as inducers.53 As the incidence of urinary stones is high in developed countries, Westernized diets have been implicated as the main cause;1 however, we recently showed that administration of animal protein to rats did not cause urinary stones, although metabolic acidosis occurred and urinary calcium excretion increased. Thus, we considered that excess ingestion of cholesterol, the main cause of atherosclerosis, could be the cause of urinary stones. When rats were fed a 3% cholesterol‐loaded diet, OPN mRNA levels in renal tubular cells and kidney increased, followed by urinary stone formation.54 In addition, administration of EPA, used to treat atherosclerosis, reduced OPN levels, and inhibited stone formation in both humans and rats.55-57 The mechanism of this cholesterol load‐induced OPN increase and subsequent stone formation has not been clarified. It has been assumed that excess cholesterol ingestion causes binding of intestinal bile acid to cholesterol; this process frees oxalic acid and increases its absorption from the intestine, resulting in an increase in urinary oxalic acid excretion. An increase in oxalic acid levels is considered one of the mechanisms of excess cholesterol ingestion‐induced stone formation.54, 58, 59

Abnormal lipid metabolism has already been observed clinically in urinary stone patients.7, 15 These patients tend to have significantly elevated serum cholesterol levels. Furthermore, calcification of the aortic wall was observed by computed tomography in just 5% of young, healthy Japanese subjects, but in approximately 40% of stone patients.60 As EPA administration is effective for the prevention of hyperlipidemia and atherosclerosis, EPA might be a possible method of preventing calcium stone formation. Epidemiological study cannot show the preventive effect against urolithiasis;15 however, clinical administration of EPA has shown a preventive effect against urolithiasis.56, 57 EPA might be one such potential preventive therapy…

If a genetic predisposition to urolithiasis can be detected, prophylaxis can be achieved. Environmental factors, such as lifestyle, obesity, dietary habits and dehydration, have been implicated in urolithiasis development,7 whereas hormonal, genetic or anatomical factors might also influence its pathogenesis.8 In addition, a family history of the disease has been reported to increase the disease risk in men by 2.57‐fold,65 and the concordance rate of the disease in monozygotic twins was found to be higher than that in dizygotic twins (32.4% vs 17.3%),66 suggesting that genetic factors have a pivotal role in the etiology of urolithiasis.

Previous SNP analyses have shown that genetic polymorphisms of the genes encoding the calcium‐sensing receptor,68 vitamin D receptor,69 OPN70, 71 and matrix Gla protein72 are highly correlated with kidney stone formation (Table 1).71 These studies avoided candidate genes, which enabled identification of otherwise unpredictable loci involved in calcium nephrolithiasis. GWAS represent a fundamental advance for genetic research, but require specific bioinformatics software for data analysis and a large number of patients to maintain statistical power.73 Despite their importance, GWAS findings often explain a small proportion of the causes of complex non‐Mendelian diseases.74

Summary from Snp studies

Genes indicated by GWAS

  • SLC34A1 rs11746443 (A is risk, from snpedia.com)
  • AQP1 rs1000597 (G is risk, from snpedia.com)
  • DGKH rs142110 (unable to determine risk allele)
  • CaSR rs1801725 (unable to determine risk allele)

A whole genome SNP genotyping by DNA microarray and candidate gene association study for kidney stone disease ([
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031563/ Rungroj, et al., 2014])

PAQR6 has been reported to have progestin-binding characteristics [28]. The kidney was found to be the site of receptors for progesterone [29] and progesterone can stimulate Ca2+ reabsorption at distal part of the nephron [30]. The level of PAQR6 expression may correlate with progesterone that stimulates Ca2+ reabsorption in the kidney and it may be involved in pathogenesis of KSD. In the present study, we found that the patient group had significantly higher proportions of C allele of rs759330 than the control group, indicating that C allele was susceptible to KSD…

The patient group had significantly higher proportions of homozygous genotypes of minor alleles than that of the control group for rs2070634 and rs2070635 (P = 0.023 and 0.017), indicating that homozygous genotypes of minor alleles were susceptible to kidney stone with ORs 2.49 and 2.52, respectively…AHSG gene encodes fetuin-A or alpha-2-HS-glycoprotein, a circulating calcium-regulatory glycoprotein that inhibits extraosseous calcification. It has been reported that the patients with urolithiasis had lower urinary fetuin-A levels compared with that of healthy subjects [31]…

CD44 gene encodes CD44 molecule. This transmembrane protein is a receptor for hyaluronic acid (HA) and can also interact with osteopontin (OPN), a major component in the urinary stone matrix that inhibits nucleation, growth, and aggregation of CaOx crystals and also reduces binding of crystals to renal epithelial cells in vitro[33-36]…

HAO1 gene encodes glycolate oxidase 1. Human glycolate oxidase catalyzes flavin mononucleotide -dependent oxidation of glycolate to glyoxylate, and of glyoxylate to oxalate. The presence of glycolate oxidase 1 in liver and kidney peroxisomes and its ability to oxidize glyoxylate to oxalate, a key metabolite in the kidney stone formation, is of particular importance for individuals with primary hyperoxaluria type I, as a consequence of their inability to convert glyoxylate to glycine in the peroxisome [38-40]…

Summary from this article

  • PAQR6 rs759330 (C is risk)
  • AHSG rs2070634 (T is risk), rs2070635 (T is risk)

Calcium-sensing receptor: evidence and hypothesis for its role in nephrolithiasis (Vezzoli, et al., 2019)

Epidemiological studies observed that calcium nephrolithiasis was associated with polymorphisms of the CaSR gene regulatory region, rs6776158, located within the promoter-1, rs1501899 located in the intron 1, and rs7652589 in the 5'-untranslated region. These polymorphisms were found to reduce the transcriptional activity of promoter-1. Activating rs1042636 polymorphism located in exon 7 was associated with calcium nephrolithiasis and hypercalciuria. Genetic polymorphisms decreasing CaSR expression could predispose individuals to stones because they may impair CaSR protective effects against precipitation of calcium phosphate and oxalate. Activating polymorphisms rs1042636 could predispose to calcium stones by increasing calcium excretion.

Idiopathic stone formers carrying polymorphisms of the CaSR gene regulatory region, rs6776158, rs7652589 and rs1501899, did not show an increase of serum calcium, despite their hypothesized involvement in stone production; this suggests that these polymorphisms might be substantially ineffective in modifying CaSR function in vivo [6, 40, 41, 45]. Accordingly, CaSR polymorphisms associated with kidney stones were not associated with serum calcium in a genome-wide study [52].

To explain the lack of association with serum calcium, we have to consider that the decrease in transcriptional activity, determined by the minor allele at rs6776158, rs7652589 and rs1501899 in a luciferase reporter gene assay, was small, although significant, and could be insufficient to modify serum calcium concentrations in idiopathic stone formers [40]. Conversely, higher values of serum ionized calcium were observed in patients with primary hyperparathyroidism carrying the minor allele at these polymorphisms [48]. These patients are characterized by a low CaSR expression in the parathyroid adenoma [66] which could contribute to make overt the potential effect of these CaSR polymorphisms on serum calcium [48]. We have also to consider that the hypertonic environment of the kidney medulla has unusually high concentrations of calcium and phosphate. In this setting, CaSR activity is expected to be particularly relevant and a genetically determined decrease of CaSR expression, nominally small and not influencing serum calcium, could produce a significant effect and lead to an easier interstitial precipitation of calcium phosphate that could trigger Randall’s plaque formation.

These considerations suggest that CaSR may have a complex role in lithogenesis exerted through different pathways. Polymorphisms decreasing CaSR transcriptional activity may play a role in both normocalciuric and hypercalciuric stone formers. Activating polymorphisms could play a role in lithogenesis causing hypercalciuria. These different conditions of activity agree with the complementary litho- genetic effect of these polymorphisms observed in patients with primary hyperparathyroidism. However, the specific role of CaSR in the lithogenetic process has not been clarified and its implication in urinary calcium salt precipitation or in Randall’s plaque formation remains to be demonstrated. The potential protective effect of CaSR on stone production could be placed in a wider “anticalcification” effect that was principally evidenced in artery walls [67]. In arteries, CaSR showed an inhibitory effect on soft tissue calcification [68] and osteoblast transformation of local cells addressed to mineralize soft tissues [69]. These observations could explain the increased cardiovascular risk observed in stone formers [70, 71].

Summary from this article

  • rs6776158 (G is risk)
  • rs1501899 (A is risk)
  • rs7652589 (A is risk)
  • rs1042636 (G is risk, also associated with primary hyperparathyroidism, hypercalciuria, postmenopausal osteoporosis. )

Physiology of Intestinal Absorption and Secretion (Kiela and Ghishan, 2016)

Several SLC26 family members of anion exchangers are expressed in the gut and can utilize oxalate as a substrate. The SLC26A3 gene product known as Down Regulated in Adenoma (DRA), is expressed in the human duodenum, ileum, caecum, and distal colon, and was postulated to transport oxalate in those tissues. Other SLC26 transporters, such as SLC26A1 (SAT1), SLC26A2 (DTDST), and SLC26A7 (SUT2) also show the capacity to transport oxalate. PAT1 (SLC26A6) is responsible for cellular efflux and intestinal oxalate secretion. Intestinal oxalate absorption is regulated by a number of factors such as angiotensin II, which increases colonic oxalate secretion.

A replication study for three nephrolithiasis loci at 5q35.3, 7p14.3 and 13q14.1 in the Japanese population (Yasui, et al., 2013)

We observed a cumulative effect with these three SNPs; individuals with three or more risk alleles had a 5.9-fold higher risk for nephrolithiasis development than those with only one risk allele. Our findings elucidated the significance of genetic variation at these three loci in nephrolithiasis in the Japanese population.

Summary from this article

  • rs12654812 (T is risk)
  • rs12669187 (T is risk)
  • rs7981733 (G is risk)

Solute Carriers

There is quite a bit of research in the area of oxalate transport, most focused on solute carriers. Here is a sampling.

Cholinergic signaling inhibits oxalate transport by human intestinal T84 cells (Hassan, et al., 2012)

Anion exchanger SLC26A6 is expressed in the apical membranes of many tissues including enterocytes. Studies in Slc26a6- null mice revealed that Slc26a6 plays an essential role in transcellular intestinal oxalate transport (28, 45). These mice were found to have a critical defect in intestinal oxalate secretion, resulting in enhanced net absorption of ingested oxalate, hyperoxalemia, hyperoxaluria, and a high incidence of calcium oxalate urolithiasis (45). Thus, intestinal oxalate secretion mediated by SLC26A6 plays a major constitutive role in limiting net absorption of ingested oxalate, thereby preventing hyperoxaluria and calcium oxalate urolithiasis. Defects in the function or regulation of this key transporter are potential molecular mechanisms predisposing to calcium oxalate urolithiasis in humans…

As described above, intestinal oxalate secretion mediated by SLC26A6 plays a major constitutive role in limiting net absorption of ingested oxalate, thereby preventing hyperoxaluria and calcium oxalate urolithiasis (45). A role for cholinergic regulation of intestinal oxalate transport had not previously been recognized. Our finding that carbachol negatively regulates SLC26A6-mediated Cl-oxalate exchange activity in T84 cells suggests a potential role for cholinergic regulation of oxalate homeostasis. Most animal models of obesity and hyperinsulinemia are associated with increased parasympathetic (vagal) cholinergic activity (29, 32, 68). Increased tone of the peripheral parasympathetic nerves leads to enhanced release of acetylcholine, which triggers changes in the activity of various effector organs and tissues including the intestine. Obesity is a risk factor for kidney stones and obese stone formers often have mild hyperoxaluria (17, 49). From these observations, it is tempting to speculate that obesity-associated cholinergic activity might lead to acetylcholine-induced inhibition of SLC26A6-mediated intestinal oxalate secretion, thereby potentially contributing to the reported hyperoxaluria and high incidence of kidney stones in obese patients.

It should be emphasized, however, that net absorption of dietary oxalate depends on the balance between oxalate absorption and secretion in the intestine. The identity of the transporter(s) mediating intestinal oxalate absorption remain(s) unknown. However, preliminary studies in Slc26a3-null mice show a significant reduction in mucosal to serosal oxalate flux in the distal ileum and distal colon, which is associated with a significant decrease in urinary oxalate excretion (39), suggesting that Slc26a3 might play an important role in transcellular absorption of oxalate. Whether cholinergic signaling regulates intestinal absorption of oxalate remains to be studied.

See also, for more information on intestinal anion exchangers (Solute Carriers)

Calcium Oxalate Stone Formation in the Inner Ear as a Result of an Slc26a4 Mutation (Drop, et al., 2010)

Calcium oxalate stone formation occurs under pathological conditions and accounts for more than 80% of all types of kidney stones. In the current study, we show for the first time that calcium oxalate stones are formed in the mouse inner ear of a genetic model for hearing loss and vestibular dysfunction in humans. The vestibular system within the inner ear is dependent on extracellular tiny calcium carbonate minerals for proper function. Thousands of these biominerals, known as otoconia, are associated with the utricle and saccule sensory maculae and are vital for mechanical stimulation of the sensory hair cells. We show that a missense mutation within the Slc26a4 gene abolishes the transport activity of its encoded protein, pendrin. As a consequence, dramatic changes in mineral composition, size, and shape occur within the utricle and saccule in a differential manner. Although abnormal giant carbonate minerals reside in the utricle at all ages, in the saccule, a gradual change in mineral composition leads to a formation of calcium oxalate in adult mice. By combining imaging and spectroscopy tools, we determined the profile of mineral composition and morphology at different time points. We propose a novel mechanism for the accumulation and aggregation of oxalate crystals in the inner ear.

Role of SLC26A6-mediated Cl⁻-oxalate exchange in renal physiology and pathophysiology (Aronson, 2010)

Subsequent studies identified anion transporter SLC26A6 as responsible for proximal tubule Cl⁻-oxalate exchange activity. The most striking phenotype in Slc26a6 null mice was calcium oxalate urolithiasis due to hyperoxaluria. Hyperoxalemia and hyperoxaluria in Slc26a6 null mice were found to be caused by defective intestinal back-secretion of ingested oxalate. These findings suggested that inherited or acquired defects in SLC26A6 might lead to hyperoxaluria and increased stone risk, and have motivated studies to characterize the role of SLC26A6 in oxalate homeostasis in patients and in animal models.

Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density (Thorleifsson, et al., 2009)

Kidney stone disease is a common condition. To search for sequence variants conferring risk of kidney stones, we conducted a genome-wide association study in 3,773 cases and 42,510 controls from Iceland and The Netherlands. We discovered common, synonymous variants in the CLDN14 gene that associate with kidney stones (OR = 1.25 and P = 4.0 x 10(-12) for rs219780[C]). Approximately 62% of the general population is homozygous for rs219780[C] and is estimated to have 1.64 times greater risk of developing the disease compared to noncarriers. The CLDN14 gene is expressed in the kidney and regulates paracellular permeability at epithelial tight junctions. The same variants were also found to associate with reduced bone mineral density at the hip (P = 0.00039) and spine (P = 0.0077).

Summary from this article

  • rs219780 (C is risk) - Approximately 62% of the general population is homozygous [C]


Antibiotics can wipe out Oxalobacter formigenes and other species known to degrade oxalates but evidence is not as clear if taking probiotics can help.

The Metabolic and Ecological Interactions of Oxalate-Degrading Bacteria in the Mammalian Gut (Miller and Dearing, 2013)

There has been a concerted effort to introduce oxalate-degrading bacteria into the mammalian gut to alter ecosystem function towards more effective oxalate degradation and prevent disease [44,45,46,55,63,92]. The repeated use of certain antibiotics can result in the loss of naturally occurring oxalate-degrading bacteria [8,93,94,95,96,97]. With this loss, dietary and endogenous oxalate becomes more bioavailable both to the mammalian host and gut microbiota. Rats administered O. formigenes daily for two weeks exhibited a 39%–80% reduction in excreted urinary oxalate [46,55]. Likewise, humans administered O. formigenes for four weeks exhibited a 22%–92% reduction in excreted urinary oxalate [44]. However, in these studies, oxalate-degrading activity and the colonization of O. formigenes typically only persisted as long as there was either continuous inoculation, or maintenance of an oxalate-rich diet. In both rats and humans, activity and colonization is rapidly lost in as little as five days after returning to a low-oxalate diet [44,46,55]. Other studies used a mixed probiotic called “Oxadrop” (VSL Pharmaceuticals), which contains L. acidophilus, L. brevis, S. thermophilus, and B. infantis. Although Oxadrop taken with a normal diet did reduce oxalate excretion, when combined with a low oxalate diet, Oxadrop did not have an effect [63,92,98].

Induction of enteric oxalate secretion by Oxalobacter formigenes in mice does not require the presence of either apical oxalate transport proteins Slc26A3 or Slc26A6 (Hatch, 2020)

The results demonstrate that Oxalobacter can induce enteric oxalate excretion in the absence of either apical oxalate transporter and urinary oxalate excretion was reduced in all colonized genotypes fed a 1.5% oxalate-supplemented diet. We conclude that there are other, as yet unidentified, oxalate transporters involved in mediating the directional changes in oxalate transport across the Oxalobacter-colonized mouse large intestine.

Simultaneous use of oxalate-degrading bacteria and herbal extract to reduce the urinary oxalate in a rat model: A new strategy (Afkari, et al., 2019)

And second reason, can be due to use of two strains L. paracasei AKPL-IR (JF461540.1), L. paracasei AKKL-IR (JF461539.1), that, particularly, degrade of oxalate in vitro and in vivo, Consequently, urinary oxalate is reduced faster, which ultimately reduces the complications of the pathobiology sooner. They are submitted in NCBI site (as strains that have high power in oxalate decomposition).

Metabolomic profiling of oxalate-degrading probiotic Lactobacillus acidophilus and Lactobacillus gasseri (Chamberlain, et al., 2019)

We tested and verified the ability of L. acidophilus and L. gasseri to degrade oxalate even with availability of other carbon sources, providing supporting evidence for the need to further evaluate these Lactobacillus species as probiotic treatments for oxalate conditions. Further work is needed to fully define and characterize the L. acidophilus and L. gasseri metabolic profiles and validate their performance as oxalate-targeting probiotics.

Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project (Liu, et al., 2017)

Multivariate analysis suggested that O. formigenes abundance was associated with particular host demographic and clinical features, including age, sex, race, geographical location, BMI, and antibiotic history. Furthermore, we found that O. formigenes presence was an indicator of altered host gut microbiota structure, including higher community diversity, global network connectivity, and stronger resilience to simulated disturbances.

To summarize the outcomes, adjusted for the other covariates, we estimate that relative abundance of O. formigenes is associated with increased age, female sex, Caucasian ethnicity (compared to Asians, Pacific Islanders, Hispanics, African Americans, or for persons of other ethnicities), non-USA residence, normal BMI (compared with underweight, overweight, or obese), absence of antibiotic exposure within a year, alcohol consumption (non-drinkers have less, but rarely and 1-2 times/week do best), higher educational attainment, and normal thyroid function. In another analysis, we showed relationships of O. formigenes presence and the locality of the subject’s birth and present residence…

That O. formigenes detection is correlated with higher phylogenetic diversity in the host microbiota is consistent with comparisons of US subjects and Amerindian hunter gatherers [63]. The Amerindians had significantly higher diversity and nearly universal O. formigenes colonization at high abundance; O. formigenes was one of the most differentiating taxa between those two populations [63].

Probiotics for prevention of urinary stones (Lieske, 2017)

However, trials with probiotics designed to degrade oxalate including those containing O. formigenes, Lactobacillus, and/or Bifidobacterium spp., have been disappointing.

Dietary Hyperoxaluria Is Not Reduced by Treatment With Lactic Acid Bacteria (Siener, et al., 2013)

The results of our study clearly reveal the role of dietary oxalate as a major determinant of urinary oxalate excretion. The present data demonstrate that an oxalate-rich diet can induce persistent hyperoxaluria already in healthy subjects without disturbances of oxalate metabolism or gastrointestinal diseases. The daily consumption of an oxalate-rich diet with an oxalate content of approximately 600 mg resulted in a significant increase in urinary oxalate excretion…

However, the administration of the lactic acid bacteria preparation in this study in healthy subjects did not affect urinary oxalate excretion. At least two mechanisms are ascribed to the presence of lactic acid bacteria that use oxalate in their metabolism: decrease in intestinal oxalate concentration by degradation of oxalate and decrease in oxalate absorption. Because urinary oxalate excretion did not vary during intervention with the study preparation under the controlled oxalate-rich diet, it is unlikely that the lactic acid bacteria preparation decreased intestinal oxalate concentration and/or absorption.

Probiotics and Other Key Determinants of Dietary Oxalate Absorption (Liebman and Al-Wahsh, 2011)

Oxalate absorption appears to occur throughout the gastrointestinal tract (GIT) with both paracellular and transcellular (active and passive) uptake mechanisms (8). The timing of the peak recovery of urinary oxalate following oxalate ingestion is typically between 2 and 6 h, which suggests the small intestine is a key absorptive site. A peak recovery of urinary oxalate during this period does not preclude significant oxalate absorption in the stomach and it has been argued that a greater proportion of the food-derived oxalate would be solubilized at the normal gastric pH of 2 and thus becomes available for absorption (9). The overall contribution of colonic oxalate absorption in healthy individuals is unclear. However, it is well established that the colon is an important site for the increased oxalate absorption in individuals with enteric hyperoxaluria related to intestinal disease or intestinal surgery (10).

The term oxalate bioavailability has often been used in the literature to refer to that portion of food-derived oxalate that is absorbed from the GIT. Oxalate absorption rates from different foods have been estimated to range from ∼2 to 15% (10, 11). Oxalate bioavailability is likely dependent on a number of factors, including absorptive properties of the intestines, gut transit time, presence of divalent cations such as calcium and magnesium that can bind oxalate within the GIT, and presence of oxalate-degrading bacteria (12, 13).

Studies that have assessed the ability of probiotics that provide bacteria with oxalate-degrading capacity to reduce oxaluria, presumably by decreasing the availability of oxalate for absorption, have led to promising but generally mixed results. The current review suggests that the ability of chronic probiotic ingestion to reduce urinary oxalate excretion may be primarily confined to participants with absorptive (enteric) hyperoxaluria.

Diet, but Not Oral Probiotics, Effectively Reduces Urinary Oxalate Excretion and Calcium Oxalate Supersaturation (Lieske, et al., 2010)

Neither study preparation reduced urinary oxalate excretion nor calcium oxalate supersaturation. Fecal lactobacilli colony counts increased on both preparations, whereas enterococcal and yeast colony counts were increased on the synbiotic. Total urine volume and the excretion of oxalate and calcium were all strong independent determinants of urinary calcium oxalate supersaturation. Hence, dietary oxalate restriction reduced urinary oxalate excretion, but the tested probiotics did not influence urinary oxalate levels in patients on a restricted oxalate diet. However, this study suggests that dietary oxalate restriction is useful for kidney stone prevention.

Oxalate‐degrading Providencia rettgeri isolated from human stools (Hokama, et al., 2005)

The mechamism of oxalate degradation by P. rettgeri appears to be similar to that of Oxalobacter formigenes. This is the first report of a facultative oxalate‐degrading organism that is one of the Enterobacteriaceae.


Which Type of Water Is Recommended for Patients with Stone Disease (Hard or Soft Water, Tap or Bottled Water): Evidence from a Systematic Review over the Last 3 Decades (Sulaiman, et al., 2020)

Our review of the literature suggests that hard water and bottled mineral water might be helpful for calcium stone formers. High calcium content in them leads to hypercalciuria; however, other factors also influence stone formation and the overall impact seems to be a reduction in calcium stone formation. The mineral content varies across different water types but high magnesium and bicarbonate content in water is also recommended for kidney stone patients.

An individualized weight-based goal urine volume model significantly improves expected calcium concentrations relative to a 2-L goal urine volume (Sawyer, et al., 2013)

This study introduces the concept of predictive modeling for daily calcium excretion. Our findings indicate that body size (weight) strongly influences daily calcium excretion. We therefore suggest a weight-based goal urine volume (WGUV) model as an alternative to the prevailing recommendations for fluid intake or urine output.

One simple possibility would be to use ‘‘rule of thumb’’ step-wise recommendations based on weight ranges. For example, patients \40 kg could be advised to make 1 L of urine; 40–60 kg patients, 1.5 L; 60–80 kg patients, 2 L; 80–100 kg patients, 2.5 L; and [100 kg, at least 3 L. We also would suggest that for patients with a prior 24-h urine study, goal urine volumes can then be tailored to that individual, perhaps incorporating other risk factors such as oxalate or super-saturation values, to provide a truly individualized goal urine volume. Because our multivariate models did not demonstrate any statistical difference between genders for calcium excretion, we are not proposing different urine volume recommendations for men and women.

Low oxalate bioavailability from black tea (Liebman and Murphy, 2007)

Based on the oxalate load method, the almost identical urinary oxalate excretion levels for the tea and control treatments suggested very low bioavailability of tea-derived oxalate…At the present time, there is little overall support for the recommendation that kidney stone formers limit their intake of black tea.

Miscellaneous Topics

Alarm Photosynthesis: Calcium Oxalate Crystals as an Internal CO2 Source in Plants (Tooulakou, et al., 2016)

In combination, calcium oxalate crystals in leaves can act as a biochemical reservoir that collects nonatmospheric carbon, mainly during the night. During the day, crystal degradation provides subsidiary carbon for photosynthetic assimilation, especially under drought conditions. This new photosynthetic path, with the suggested name "alarm photosynthesis," seems to provide a number of adaptive advantages, such as water economy, limitation of carbon losses to the atmosphere, and a lower risk of photoinhibition, roles that justify its vast presence in plants.

Future investigations on the contribution of alarm photosynthesis in drought tolerance and the mechanisms controlling crystal size will lead to a better understanding of the responses of wild and cultivated plants in a warmer and water limiting planet. Additionally, a systematic quantification of calcium oxalate crystals and an evaluation of the intensity of alarm photosynthesis at the interspecific level in different climatic regions of the planet are needed. Taking into account the estimations that a large tree may produce annually up to several hundred kilograms of calcium oxalate in its aboveground tissues (Horner and Wagner, 1995; Cailleau et al., 2011; see also Garvie 2006), calcium oxalate crystals as part of the phytomineralization process could represent a considerable carbon sink with a long residence time at the ecosystem as well as at the global level. The discovery of alarm photosynthesis gives rise to the investigation of its potential role in global carbon cycle and the effect of climate change on this process.

A review of oxalate poisoning in domestic animals: tolerance and performance aspects (Rahman, et al., 2013)

Other Websites

Additional information on kidney stones and prevention: https://www.ncbi.nlm.nih.gov/books/NBK279069/