Masterclass in Modern Nutrition Clinical Management of Foundational Health

Masterclass in Modern Nutrition Clinical Management of Foundational Health

EXECUTIVE SUMMARY — PART 2: SHOULD WE BE CONCERNED ABOUT ANTI-NUTRIENTS? MSE-D1113 - 09/20

FEBRUARY 2021 Masterclass in Modern Nutrition Clinical Management of Foundational Health

SHOULD WE BE CONCERNED ABOUT ANTI-NUTRIENTS?

In recent months, anti-nutrients have become a popular topic of conversation, driven by the shift in dietary fad trends such as those seen with the carnivore diet. Inevitably, common myths about anti-nutrients have also re-emerged. With this in mind, it is time to review the research and recap what the current state of play is when it comes to the top three anti-nutrients – phytates, lectins and oxalates. Do we need to be concerned about anti-nutrients? Are they really as big a problem as some suggest, and what can we do to manage them in our diet?

Phytate Phytate, also known as phytic acid or myo-inositol hexaphosphate (IP6),1 is found in cereals, whole grains, nuts, seeds and legumes.2,3 While phytate is known as an anti-nutrient because of its mineral binding capacity, there are many benefits to consuming a plant-based diet which may simultaneously have a higher phytate content. What does the research say about phytate, do we need to avoid phytate containing food, or can we simply navigate its negative impact?

What Is Phytate? To understand how to tackle phytate, let’s first identify its role in plants. Phytate is commonly found in the outer layer of cereal or within the embryo of seeds, whereby its phosphate groups strongly chelate minerals and act as a storage facility.4,5,6 Upon germination, phytic acid hydrolyses, allowing the release of both phosphate and minerals for the growth of the plant.7,8 Frustratingly, the strong chelating ability of phytate means that it can limit the bioavailability of minerals in the diet in a dose dependent manner.9 Once minerals are bound by phytate in the digestive tract, these bonds remain unaffected by digestive enzymes reducing mineral availability.10,11

Phytates Be Gone (or Just Nullified) While phytate has the potential to bind to minerals, there is no need to exclude phytate containing foods from a well-balanced, varied diet, as food preparation and cooking methods can largely influence the amount of phytate consumed.12 In fact, food preparation methods such as soaking, germinating, fermenting, and cooking is one of the easiest ways to reduce phytate content (Table 2).13,14 For example, pre-soaking and then cooking whole red lentils for one hour have been shown to reduce phytate content by up to 80%.15 Interestingly, some simple inclusions such as vitamin C and probiotics can further mitigate the effects of phytate. A dose of 50 mg of vitamin C (ascorbic acid) has been shown to counteract the phytate binding effect of iron, allowing for greater absorption.16 In addition, the administration of Lactobacillus plantarum 299v can enhance absorption of non-haem iron through several processes: the alteration of microbial metabolites; supporting enterocyte iron uptake; and reducing inflammation through immunomodulation.17 Finally, the amount of phytate to mineral ratio can help to further combat the effects of phytate.18,19,20 High Absorption Multi Mineral Powder is a convenient way to ensure adequate mineral status for those who are looking at increasing their daily mineral intake.

What Are Lectins and How Are They a Pain in the Gut? Lectins, also known as hemagglutinin, have an interesting function in the life cycle of a plant, and it’s this function that is thought to result in their undesirable gastrointestinal (GI) effects. Lectins are specific sugar-binding proteins, known as glycoproteins, commonly found in legumes, nuts, seeds, fruit and vegetables.21,22 Lectins are produced by plants as a defence mechanism against moulds, fungi and insects.23 Like phytate, lectins are unable to be broken down via digestive enzymes.24,25 If lectins are inadequately cooked, they have the ability to bind to the sugar branches of the epithelial cell proteins of the digestive tract, where they can affect barrier function and result in symptoms similar to acute gastritis in some cases.26

Are Lectins as Much of a Problem as Once Thought? Lectins have gained much attention due to their ability to disrupt GI function. As such, there are some who remove primary sources of lectins from the diet to avoid this effect. Unfortunately, they could be missing out on the benefits of lectin containing food. Furthermore, there are some populations that consume large amounts of lectins on a regular basis who do not exhibit the above-mentioned GI issues, which leads us to ask the question, are lectins as much of a problem as once thought?

What Does the Research Tell Us? Animal studies that have administered high dose, isolated lectins as a primary food source resulted in unpleasant GI side effects.27 However, in real life, lectins are not consumed as a sole food source, and when lectins have been researched as part of a combined diet their GI effects are decreased. For instance, when rats were fed raw kidney beans, known to be high in lectins, at 26% of their diet, they developed increased intestinal permeability, bacterial translocation, and bacterial overgrowth. Interestingly, these actions were reduced when sucrose was added to their diet, suggesting that it was able to inhibit the binding of these legume lectins to the epithelial cell surface.28 Masterclass in Modern Nutrition Clinical Management of Foundational Health

Taken together, research suggests that lectins shouldn’t pose a problem if lectin containing food is cooked correctly and consumed as part of a well-balanced diet. In fact, when cooked, rather than raw, legumes were added to the diet of healthy mice, they displayed improvements in short chain fatty acid levels and GI barrier function. In addition, otherwise healthy mice with induced colitis showed an anti-inflammatory GI response, whereby proinflammatory mediators, including tumour necrosis factor (TNF)-alpha were attenuated.29 Furthermore, limited studies in humans with cooked legumes have also produced an anti-inflammatory effect.30,31 Interestingly, preliminary research also indicates that lectins may even have a therapeutic benefit, with studies investigating their anti-cancer potential, suggesting their apoptotic and autophagic action may be utilised in future cancer therapy.32 How to Manage Lectin Containing Food Techniques such as boiling, soaking, germinating, fermenting, and autoclaving are ideal cooking methods for reducing lectins (Table 2).33 Given the weight of the evidence, which suggests that cooked lectin-containing foods pose minimal risk, there is no reason to restrict these foods. If GI symptoms such as bloating, pain or alternating bowel habits are a part of a patient’s case, consider if dysbiosis, food intolerance or GI insufficiency are present. After further investigations into the potential causes of GI issues have been addressed, if concern is still present, consider removing and reintroducing lectin containing foods.

Why Is There Concern Around Oxalates? Whilst initial concerns regarding oxalate intake focused on calcium-oxalate kidney stone formation, of late oxalates have been implicated in a myriad of health conditions beyond what the research indicates. Let’s take a deeper dive into research and identify if there are sub-populations who may benefit from managing dietary oxalates.

What’s the Low-Down on Oxalates? Oxalates are commonly found in varying levels in a variety of plant-based foods, assisting with calcium regulation in the plant.34,35 High levels of oxalates are found in spinach, sweet potato, rhubarb, swiss chard, amaranth, taro and sorrel.36,37 Other sources that contain smaller amounts include raw legumes, whole grains, nuts and tea.38 Oxalates can be either insoluble, passing through the digestive tract and then being excreted in faeces, or soluble. Soluble oxalates have a high affinity for chelating minerals, in particular calcium.39 Therefore the majority become bound to minerals and are subsequently excreted. However, some unbound oxalates are absorbed via the GI tract, where they are later excreted via the kidneys.40 One of the main concerns regarding the consumption of dietary oxalates is that higher consumption may result in increased urinary oxalate levels, a risk factor in the formation of calcium oxalate kidney stones.41

Are Dietary Oxalates Responsible for Kidney Stone Formation? Dietary oxalates have once thought to be the culprit of kidney stone formation. However, research shows that consuming a diet rich in plant- based, higher-oxalate containing foods doesn’t translate to an increased risk of kidney stone formation. In fact, these diets can be protective, as they elevate urinary citrate which can inhibit calcium stone formation.42 In fact, a myriad of risk factors need to be considered and investigated when addressing stone formation in patients, including hydration levels, salt and sugar intake and calcium levels in the diet, to name a few.43,44

Understanding Hyperoxaluria Hyperoxaluria is a risk factor for the development of calcium oxalate kidney stones. Hyperoxaluria, which can be classed as primary or secondary, is a term used to describe excess levels of urinary oxalate excretion. When it comes to oxalates and how oxalate levels can become elevated, it is important to clinically differentiate between the primary and secondary hyperoxaluria as they have very distinct clinical expressions, particularly when assessing research, testing and the potential for clinical management and outcomes.45 Primary hyperoxaluria is a rare inheritable genetic disorder resulting in endogenous overproduction of oxalates.46,47 Secondary hyperoxaluria results from an excess intake of dietary oxalates, or increased absorption via the GI tract. Fat malabsorption is a risk factor for secondary hyperoxaluria, which will be discussed in more depth in the information to follow.48 Excess soluble oxalates that are not bound to minerals can end up accumulating in the kidney, increasing the risk of kidney stone formation and can lead to renal damage and eventually renal failure in both presentations.49 If renal function declines, excess oxalate levels can eventually deposit in other organs, as seen in a rare form of arthritis (oxalate arthropathy).50 Primary hyperoxaluria is diagnosed through genetic testing, whereas in secondary hyperoxaluria, faecal fat determination remains the gold standard, although some pathology companies are now offering urinary oxalate testing.51 The prevalence of secondary hyperoxaluria remains poorly defined, however estimates were taken in the United States in 2019, estimating 250,000 cases recorded with associated with kidney failure and/or recurrent kidney stones.52 When you consider the total population of the US in 2019 was 328.2 million,53 this is still a relatively small number in comparison to the total population. Masterclass in Modern Nutrition Clinical Management of Foundational Health

Secondary Hyperoxaluria: The Sub-populations at Risk Research has only identified specific limited sub-populations where dietary oxalates may be an issue. Below is a review of these populations, why oxalates may pose a problem, and what can be done to manage them.

Sub-Population One: Fat Malabsorption The first subgroup to consider are those with fat malabsorption. As stated above, calcium has the ability to bind with oxalates in the GI tract which are excreted via faeces, preventing absorption. However, free fat within the colonic lumen, present in fat malabsorption, binds available calcium, allowing greater levels of unbound soluble oxalates to be absorbed.54

Sub-Population Two: Inflammatory Bowel Disease (IBD) – Crohn’s Disease The second group to consider are patients with IBD, specifically those with Crohn’s disease (CD). Nephrolithiasis (kidney stone formation) is the most common urinary complication with CD occurring in around 10% of CD patients and is directly related to the disease state in the bowel. Bowel resection is common in CD with recurrent calcium oxalate stone formation occurring more frequently after surgery (15% to 30%) compared to before surgery (4% to 5%).55 Hyperoxaluria is usually seen alongside a reduction in calcium excretion and therefore calcium supplementation and/or dietary oxalate consumption usually forms part of their management plan.56 A number of treatment strategies are available (Table 1) for those who are concerned about oxalates, and for those with Crohn’s who are at an increased risk of stone formation. One of the primary recommendations is to ensure calcium levels of 1,200 mg per day to help bind to oxalates rendering them unavailable for absorption.57,58,59,60,61

Table 1: Considerations for Those Concerned About Oxalates.62,63,64

Primary considerations: In addition, for those with IBD with kidney stones/risk of: Calcium – 1,200 mg per day If hyperoxaluria is present Other: Restrict dietary fat to 40-60 g per day Increase intake of potassium Lower oxalate intake Increase intake of magnesium Medical management Omega-3 – 1,500 mg per day Cholestyramine and/or pancreatic enzyme replacement Vitamin B6 Magnesium supplementation Surgical management

Sub-Population Three: Vulvodynia and Vulvar Vestibulitis The third group where oxalates may be of concern, are in those with vulvodynia (vulvar pain) and vulvar vestibulitis (pain, tenderness and inflammation around the opening of the vagina). While the research is very limited, it is thought that elevated urinary oxalate excretion may play a role in the presentation.65,66 In a pilot study, six out of sixteen women with vulval vestibulitis, who were placed on a low oxalate diet for two months, had improvement in symptoms. While this preliminary study suggests that managing dietary oxalate intake could be beneficial as part of their treatment plan, more research is needed.67

Manage Oxalates Although it might seem reasonable to manage dietary oxalate levels in some sub-populations as mentioned above, current data does not support the avoidance of oxalate containing foods for the general population. However, for those concerned about oxalate intake, there are measures that can be implemented to minimise their impact. Firstly, pairing with calcium containing foods can help bind oxalates, preventing their absorption. Additional guidelines for management can be found in Table 1 for those concerned. Secondly, like other anti-nutrients, traditional cooking methods can be used to reduce the oxalate content of food (Table 2), thus improving mineral bioavailability. For example, boiling can help reduce oxalates content of food by up to 87%.68 For those wanting to improve overall mineral status consider incorporating High Absorption Multi Mineral Powder into your daily routine. Masterclass in Modern Nutrition Clinical Management of Foundational Health

Table 2: Anti-Nutrients: Clinical Implication and Food Preparation (adapted from Petroski et al. 2020).69

Suggested clinical Food preparation that Food preparation that Anti-nutrient Food source implication reduces increase

Cereal grains, fruits, Autoclaving, boiling, Altered gut function; Lectins legumes, nuts, seeds, fermentation, Baking, roasting inflammation vegetables germination, soaking

Beet greens, beet root, May inhibit calcium legumes, cereal grains, Boiling, pairing with high absorption; May Baking, grilling, low- Oxalate nuts, potatoes, rhubarb, calcium foods, soaking, increase calcium kidney calcium diet, roasting sorrel, spinach, sweet steaming stone formation potatoes, Swiss chard

May inhibit absorption Cereal grains, legumes, of iron, zinc and nuts, pseudocereals Boiling, fermentation, Phytates calcium; Acts as n/a (amaranth, quinoa, germination, soaking an antioxidant; millet), seeds Antineoplastic effects

Brassica vegetables (kale, Brussels sprouts, Hypothyroidism and/ Cooking, peeling skins of Goitrogens cabbage, turnip greens, or goitre; Inhibit iodine n/a fruits and nuts Chinese cabbage, uptake High Bioavailability Magnesium Powder with Active Bs broccoli), cassava, millet Everyday magnesium supplementation Flaxseeds, fruits and High Bioavailability Magnesium (Meta Mag®) with Active B6 Endocrine disruption; vegetables (negligible Boiling, steaming, Increased risk of Phytoestrogens amounts), nuts n/a fermenting (increases Stress Meta Mag® Magnesium, Taurine and Glutamine for Stress estrogen-sensitive (negligible amounts), aglycone content) cancers MAGNESIUM soy and soy products Energy Mental and Physical Energy Powder SUPPLEMENTATION Apples, beans, berries, Meta Mag® plus supporting Inhibit iron absorption; Sleep Magnesium with Lutein and Zeaxanthin for Sleep Pattern Support cocoa, grapes, nuts, herbs and nutrients Tannins Negatively impact iron Boiling, steaming stone fruits, tea, whole stores Pain Meta Mag® Magnesium Bisglycinate, Corydalis and California Poppy for Pain grains Women Magnesium and Broccoli for Women’s Health As you can see, on balance anti-nutrients are not a problem. If there’s still concern, there are ways to limit their impact (Table 1 and 2) such as simple food preparation methods, maintaining a varied diet, and ensuring adequate mineral status. Understanding the science around anti- Cardiovascular High Potency Taurine, Glycine and Magnesium for Cardiovascular Health nutrients will help to make informed decisions about your patient’s nutrition. IRON SUPPLEMENTATION Treatment High Potency Vegetarian Iron with 5-MTHF Bioavailable iron Masterclass in Modern Nutrition Clinical Management of Foundational Health

References 1 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 2 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 3 Buades Fuster JM, Sanchís Cortés P, Perelló Bestard J, Grases Freixedas F. Plant phosphates, phytate and pathological calcifications in chronic kidney disease. Nefrologia. 2017 Jan- Feb;37(1):20-28. English, Spanish. doi: 10.1016/j.nefro.2016.07.001. 4 Bohn L, Meyer AS, Rasmussen SK. Phytate: impact on environment and human nutrition. A challenge for molecular breeding. J Zhejiang Univ Sci B. 2008 Mar;9(3):165-91. doi: 10.1631/ jzus.B0710640. 5 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 6 Gibson RS, Raboy V, King JC. Implications of phytate in plant-based foods for iron and zinc bioavailability, setting dietary requirements, and formulating programs and policies. Nutr Rev. 2018 Nov 1;76(11):793-804. doi: 10.1093/nutrit/nuy028. 7 Bohn L, Meyer AS, Rasmussen SK. Phytate: impact on environment and human nutrition. A challenge for molecular breeding. J Zhejiang Univ Sci B. 2008 Mar;9(3):165-91. doi: 10.1631/ jzus.B0710640. 8 Buades Fuster JM, Sanchís Cortés P, Perelló Bestard J, Grases Freixedas F. Plant phosphates, phytate and pathological calcifications in chronic kidney disease. Nefrologia. 2017 Jan- Feb;37(1):20-28. English, Spanish. doi: 10.1016/j.nefro.2016.07.001. 9 Fredlund K, Isaksson M, Rossander-Hulthén L, Almgren A, Sandberg AS. Absorption of zinc and retention of calcium: dose-dependent inhibition by phytate. J Trace Elem Med Biol. 2006;20(1):49-57. doi: 10.1016/j.jtemb.2006.01.003. 10 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 11 Gibson RS, Raboy V, King JC. Implications of phytate in plant-based foods for iron and zinc bioavailability, setting dietary requirements, and formulating programs and policies. Nutr Rev. 2018 Nov 1;76(11):793-804. doi: 10.1093/nutrit/nuy028. 12 Buades Fuster JM, Sanchís Cortés P, Perelló Bestard J, Grases Freixedas F. Plant phosphates, phytate and pathological calcifications in chronic kidney disease. Nefrologia. 2017 Jan- Feb;37(1):20-28. English, Spanish. doi: 10.1016/j.nefro.2016.07.001. 13 Buades Fuster JM, Sanchís Cortés P, Perelló Bestard J, Grases Freixedas F. Plant phosphates, phytate and pathological calcifications in chronic kidney disease. Nefrologia. 2017 Jan- Feb;37(1):20-28. English, Spanish. doi: 10.1016/j.nefro.2016.07.001. 14 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 15 Shi L, Arntfield SD, Nickerson M. Changes in levels of phytic acid, lectins and oxalates during soaking and cooking of Canadian pulses. Food Res Int. 2018 May;107:660-668. doi: 10.1016/j. foodres.2018.02.056. 16 Hallberg L, Brune M, Rossander L. Iron absorption in man: ascorbic acid and dose-dependent inhibition by phytate. Am J Clin Nutr. 1989 Jan;49(1):140-4. doi: 10.1093/ajcn/49.1.140. 17 Vonderheid SC, Tussing-Humphreys L, Park C, Pauls H, OjiNjideka Hemphill N, LaBomascus B, et al. A systematic review and meta-analysis on the effects of probiotic species on iron absorption and iron status. Nutrients. 2019 Dec 3;11(12):2938. doi: 10.3390/nu11122938. 18 Gibson RS, Raboy V, King JC. Implications of phytate in plant-based foods for iron and zinc bioavailability, setting dietary requirements, and formulating programs and policies. Nutr Rev. 2018 Nov 1;76(11):793-804. doi: 10.1093/nutrit/nuy028. 19 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 20 Gibson RS, Raboy V, King JC. Implications of phytate in plant-based foods for iron and zinc bioavailability, setting dietary requirements, and formulating programs and policies. Nutr Rev. 2018 Nov 1;76(11):793-804. doi: 10.1093/nutrit/nuy028. 21 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 22 Ramadass B, Dokladny K, Moseley PL, Patel YR, Lin HC. Sucrose co-administration reduces the toxic effect of lectin on gut permeability and intestinal bacterial colonization. Dig Dis Sci. 2010 Oct;55(10):2778-84. doi: 10.1007/s10620-010-1359-2. 23 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 24 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 25 Ramadass B, Dokladny K, Moseley PL, Patel YR, Lin HC. Sucrose co-administration reduces the toxic effect of lectin on gut permeability and intestinal bacterial colonization. Dig Dis Sci. 2010 Oct;55(10):2778-84. doi: 10.1007/s10620-010-1359-2. 26 Ramadass B, Dokladny K, Moseley PL, Patel YR, Lin HC. Sucrose co-administration reduces the toxic effect of lectin on gut permeability and intestinal bacterial colonization. Dig Dis Sci. 2010 Oct;55(10):2778-84. doi: 10.1007/s10620-010-1359-2. 27 Alatorre-Cruz JM, Pita-López W, López-Reyes RG, Ferriz-Martínez RA, Cervantes-Jiménez R, de Jesús Guerrero Carrillo M, et al. Effects of intragastrically-administered tepary bean lectins on digestive and immune organs: preclinical evaluation. Toxicol Rep. 2017 Dec 12;5:56-64. doi: 10.1016/j.toxrep.2017.12.008. 28 Ramadass B, Dokladny K, Moseley PL, Patel YR, Lin HC. Sucrose co-administration reduces the toxic effect of lectin on gut permeability and intestinal bacterial colonization. Dig Dis Sci. 2010 Oct;55(10):2778-84. doi: 10.1007/s10620-010-1359-2. 29 Monk JM, Zhang CP, Wu W, Zarepoor L, Lu JT, Liu R, et al. White and dark kidney beans reduce colonic mucosal damage and inflammation in response to dextran sodium sulfate. J Nutr Biochem. 2015 Jul;26(7):752-60. doi: 10.1016/j.jnutbio.2015.02.003. 30 Masters RC, Liese AD, Haffner SM, Wagenknecht LE, Hanley AJ. Whole and refined grain intakes are related to inflammatory protein concentrations in human plasma. J Nutr. 2010 Mar;140(3):587-94. doi: 10.3945/jn.109.116640. 31 Hartman TJ, Albert PS, Zhang Z, Bagshaw D, Kris-Etherton PM, Ulbrecht J, et al. Consumption of a legume-enriched, low-glycemic index diet is associated with biomarkers of insulin resistance and inflammation among men at risk for colorectal cancer. J Nutr. 2010 Jan;140(1):60-7. doi: 10.3945/jn.109.114249. 32 Bhutia SK, Panda PK, Sinha N, Praharaj PP, Bhol CS, Panigrahi DP, et al. Plant lectins in cancer therapeutics: targeting apoptosis and autophagy-dependent cell death. Pharmacol Res. 2019 Jun;144:8-18. doi: 10.1016/j.phrs.2019.04.001. 33 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 34 Chai W, Liebman M. Effect of different cooking methods on vegetable oxalate content. J Agric Food Chem. 2005 Apr 20;53(8):3027-30. doi: 10.1021/jf048128d. Masterclass in Modern Nutrition Clinical Management of Foundational Health

35 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 36 Lorenz EC, Michet CJ, Milliner DS, Lieske JC. Update on oxalate crystal disease. Curr Rheumatol Rep. 2013 Jul;15(7):340. doi: 10.1007/s11926-013-0340-4. 37 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 38 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 39 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 40 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 41 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? A narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929. 42 Taylor EN, Fung TT, Curhan GC. DASH-style diet associates with reduced risk for kidney stones. J Am Soc Nephrol. 2009 Oct;20(10):2253-9. doi: 10.1681/ASN.2009030276. 43 National Kidney Foundation. Calcium oxalate stones [Internet]. New York: National Kidney Foundation; 2019 Mar 22 [cited 2020 Dec 14]. Available from: https://www.kidney.org/atoz/ content/calcium-oxalate-stone. 44 Kidney Health Australia. Kidney stones [Internet]. South Melbourne, Victoria: Kidney Health Australia; [cited 2020 Dec 14]. Available from: https://kidney.org.au/your-kidneys/what-is- kidney-disease/types-of-kidney-disease/kidney-stones. 45 Bhasin B, Ürekli HM, Atta MG. Primary and secondary hyperoxaluria: Understanding the enigma. World J Nephrol. 2015 May 6;4(2):235-44. doi: 10.5527/wjn.v4.i2.235. 46 Bhasin B, Ürekli HM, Atta MG. Primary and secondary hyperoxaluria: Understanding the enigma. World J Nephrol. 2015 May 6;4(2):235-44. doi: 10.5527/wjn.v4.i2.235. 47 Lorenz EC, Michet CJ, Milliner DS, Lieske JC. Update on oxalate crystal disease. Curr Rheumatol Rep. 2013 Jul;15(7):340. doi: 10.1007/s11926-013-0340-4. 48 Lorenz EC, Michet CJ, Milliner DS, Lieske JC. Update on oxalate crystal disease. Curr Rheumatol Rep. 2013 Jul;15(7):340. doi: 10.1007/s11926-013-0340-4. 49 Lorenz EC, Michet CJ, Milliner DS, Lieske JC. Update on oxalate crystal disease. Curr Rheumatol Rep. 2013 Jul;15(7):340. doi: 10.1007/s11926-013-0340-4. 50 Lorenz EC, Michet CJ, Milliner DS, Lieske JC. Update on oxalate crystal disease. Curr Rheumatol Rep. 2013 Jul;15(7):340. doi: 10.1007/s11926-013-0340-4. 51 Lorenz EC, Michet CJ, Milliner DS, Lieske JC. Update on oxalate crystal disease. Curr Rheumatol Rep. 2013 Jul;15(7):340. doi: 10.1007/s11926-013-0340-4. 52 Witting C, Langman CB, Assimos D, Baum MA, Kausz A, Milliner D, et al. Pathophysiology and treatment of enteric hyperoxaluria. Clin J Am Soc Nephrol. 2020 Sep 8:CJN.08000520. doi: 10.2215/CJN.08000520. 53 Data Commons. United States [Internet]. Data Commons; 2019 [cited 2021 Jan 20]. Available from: https://datacommons.org/place/country/USA. 54 Lorenz EC, Michet CJ, Milliner DS, Lieske JC. Update on oxalate crystal disease. Curr Rheumatol Rep. 2013 Jul;15(7):340. doi: 10.1007/s11926-013-0340-4. 55 Gaspar SR, Mendonça T, Oliveira P, Oliveira T, Dias J, Lopes T. Urolithiasis and crohn’s disease. Urol Ann. 2016 Jul-Sep;8(3):297-304. doi: 10.4103/0974-7796.184879. 56 Gaspar SR, Mendonça T, Oliveira P, Oliveira T, Dias J, Lopes T. Urolithiasis and crohn’s disease. Urol Ann. 2016 Jul-Sep;8(3):297-304. doi: 10.4103/0974-7796.184879. 57 Gaspar SR, Mendonça T, Oliveira P, Oliveira T, Dias J, Lopes T. Urolithiasis and crohn’s disease. Urol Ann. 2016 Jul-Sep;8(3):297-304. doi: 10.4103/0974-7796.184879. 58 Prochaska ML, Taylor EN, Curhan GC. Insights into nephrolithiasis from the nurses’ health studies. Am J Public Health. 2016 Sep;106(9):1638-43. doi: 10.2105/AJPH.2016.303319. 59 Borghi L, Schianchi T, Meschi T, Guerra A, Allegri F, Maggiore U, Novarini A. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002 Jan 10;346(2):77-84. doi: 10.1056/NEJMoa010369 60 Gaspar SR, Mendonça T, Oliveira P, Oliveira T, Dias J, Lopes T. Urolithiasis and crohn’s disease. Urol Ann. 2016 Jul-Sep;8(3):297-304. doi: 10.4103/0974-7796.184879. 61 Prochaska ML, Taylor EN, Curhan GC. Insights into nephrolithiasis from the nurses’ health studies. Am J Public Health. 2016 Sep;106(9):1638-43. doi: 10.2105/AJPH.2016.303319. 62 Gaspar SR, Mendonça T, Oliveira P, Oliveira T, Dias J, Lopes T. Urolithiasis and crohn’s disease. Urol Ann. 2016 Jul-Sep;8(3):297-304. doi: 10.4103/0974-7796.184879. 63 Siener R, Jansen B, Watzer B, Hesse A. Effect of n-3 fatty acid supplementation on urinary risk factors for calcium oxalate stone formation. J Urol. 2011 Feb;185(2):719-24. doi: 10.1016/j. juro.2010.09.074. 64 Borghi L, Schianchi T, Meschi T, Guerra A, Allegri F, Maggiore U, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002 Jan 10;346(2):77-84. doi: 10.1056/NEJMoa010369. 65 Greenstein A, Militscher I, Chen J, Matzkin H, Lessing JB, Abramov L. Hyperoxaluria in women with vulvar vestibulitis syndrome. J Reprod Med. 2006 Jun;51(6):500-2. PMID: 16846091. 66 Baggish MS, Sze EH, Johnson R. Urinary oxalate excretion and its role in vulvar pain syndrome. Am J Obstet Gynecol. 1997 Sep;177(3):507-11. doi: 10.1016/s0002-9378(97)70137-6. 67 Poole S, Ravenhill G, Munday PE. A pilot study of the use of a low oxalate diet in the treatment of vulval vestibulitis. J Obstet Gynaecol. 1999 May;19(3):271-2. doi: 10.1080/01443619965048. 68 Chai W, Liebman M. Effect of different cooking methods on vegetable oxalate content. J Agric Food Chem. 2005 Apr 20;53(8):3027-30. doi: 10.1021/jf048128d. 69 Petroski W, Minich DM. Is there such a thing as “anti-nutrients”? a narrative review of perceived problematic plant compounds. Nutrients. 2020 Sep 24;12(10):2929. doi: 10.3390/ nu12102929.