Difference between revisions of "Oxalates"

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





Revision as of 13:13, 21 January 2021

Introduction

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 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 (as an anion) 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)


Unfortunately, humans and animals (both ruminant and non-ruminant) do not have oxalate-degrading genes. 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)


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 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.


Causes

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, and a loss of microbiome diversity can lead to problems.
  • 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)


Strategies

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.


See also the U. of Chicago's document How To Eat a Low Oxalate Diet for more 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 won’t be absorbed, and excreted in the stool. The citrate inhibits crystal formation, growth and aggregation 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 section on Probiotics.) 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. This mouse study showed an increase in oxalate absorption from the gut in obese mice. (Bashir, et al., 2017)


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) Yep, you read that right. Phytates. They actually help bind to oxalate so it can be excreted through the stool.


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 and chocolate, along with any of the symptoms listed above, consider getting an oxalic acid test and at minimum, 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.