(1)
Department of Urology, University of Michigan Medical Center, Ann Arbor, MI, USA
Abstract
It appears that reducing the risk of cardiovascular disease (CVD) may also be the ideal diet and lifestyle program to reduce the risk of kidney stones. Comprehensive lifestyle changes and healthy-heart parameters have synergistic impacts on reducing recurrent or incident nephrolithiasis as observed either in randomized trials from Parma, Italy, or from the observational cohort analysis when utilizing the Dietary Approaches to Stop Hypertension (DASH) program in the USA. Hypertension, dyslipidemia, weight and waist gain and accelerated large amounts of weight loss (bariatric surgery, diet, etc.), glucose intolerance/diabetes, and metabolic syndrome increase stone risk, but a higher potassium to sodium intake ratio, increased dietary magnesium, reduced animal protein, and normalizing dietary calcium and increased fluid intake could lower risk. Soluble dietary oxalates are more concerning compared to insoluble forms. A variety of dietary supplements also appear to impact risk. Arguably the best-known supplemental source of increased oxalate is from high dosages (>1,000–1,500 mg/day) of plain vitamin C (ascorbic acid), and calcium ascorbate or buffered vitamin C may cause less profound changes in oxalate. Vitamin C may lower serum uric acid and gout risk by also creating a higher urinary uric acid load in some individuals, which could also theoretically increase uric acid stone risk. Some cranberry concentrate supplements for urinary tract infection (UTI) have unusually high oxalate concentrations and need to be tested for this compound. Vitamin B6 (pyridoxine hydrochloride and potentially pyridoxal-5-phosphate) shifts oxalate metabolism toward the production of glycine at dosages of 50–100 mg per day and could be beneficial in some oxalate stone formers apart from those with primary hyperoxaluria type I. Higher dosages (300 mg or more) could also cause a sensory peripheral neuropathy. A probiotic or Oxalobacter formigenes and other intestinal bacterial may also play a role in reducing oxalate levels. Calcium supplements in excess appear to increase the risk of stone disease, especially calcium carbonate, and calcium citrate is an alternative for those with a history of oxalate stones, but supplementation also increases constipation risk with age. Vitamin D has a controversial impact on stone risk, but megadosing is never prudent. Omega-3 fatty acids supplements via anti-inflammatory effects could reduce stone risk, and omega-6 has some preliminary similar benefits, but inosine dietary supplementation is known to increase uric acid levels and stone disease. A variety of other CAM options are discussed in this chapter. What if healthcare professionals in urology could have some role in helping patients improve the quality and quantity of their life via comprehensive lifestyle recommendations for stone disease risk reduction? It appears that this is no longer a question, but a reality.
Introduction: Heart Health and Kidney Health
Is heart health tantamount to kidney health? I believe this is the case, although it does not appear to be perceived in this fashion because the research still needs to mature. For example, no previous study before the CARDIA (Coronary Adult Risk Development in Young Adults) study had examined subclinical arterial disease and stones [1]. CARDIA was a population-based observational study of 5,115 Caucasian and African-American men and women that were between the ages of 18 and 30 years at recruitment and then followed for 20 years. Researchers found there were 3.9 %, or 200, participants that reported a history of kidney stones during this time, and those with symptomatic stones were correlated with higher carotid wall thickness after 20 years, especially of the internal carotid/bulb region. A significant (p = 0.01) 1.6 times a higher risk of kidney stone participants had carotid disease, even after looking at all confounding atherosclerotic risk factors. Interestingly, the participants were an average age of 25 years when this study started, and after 20 years the majority of them went from normal weight to being overweight and obese. The average glucose and triglycerides also increased dramatically. Again, even after controlling for these risk factors, there was still a significant correlation between stones and cardiovascular disease. Perhaps physicians should inquire about the cardiovascular health of patients with a history of kidney stones. Also, it appears to be time to convince individuals to follow a heart-healthy lifestyle program to reduce the risk of kidney stones. The conclusion of this study was more profound compared to any words this author could utilize in this book: “The association between a history of kidney stones and subclinical carotid atherosclerosis in young adults adds further support to the notion that nephrolithiasis and atherosclerosis share common systemic risk factors and/or pathophysiology.”
A Mayo Clinic or Olmstead County, Minnesota, study of 4,564 stones formers matched with 10,680 controls during a mean follow of 9 years found a 38 % increased risk for myocardial infarction (MI), which was reduced to 31 % after adjusting for other comorbidities and chronic kidney disease (CKD) [2]. Kidney stones have been correlated with a higher risk of MI (OR-1.3, p < 0.05) and stroke (OR = 1.3; p < 0.05) in other studies including a cohort of 23,349 questionnaires collected from individuals 15 years or older in the IV Portuguese National Health Survey [3]. A cross-sectional study of 13,418 Japanese men 30–69 years of age found 404 stone formers on ultrasound (3 %) and 1,231 with a past history of stones. Multivariate-adjusted OR for overweight/obesity, hypertension, gout/hyperuricemia, and chronic kidney disease were significantly increased in past and current stone formers versus controls. This led the authors to suggest an association with kidney stones and traditional risk factors for heart disease [4].
It is also possible that associations of cardiovascular disease with kidney stones are not as strong when adjusting for multiple confounding variables [2], and when larger samples with stronger analytical methods are utilized, cardiovascular associations will be attenuated and at times eliminated because stone disease is complex and has multiple etiologies. For example, in the National Health and Nutrition Examination Survey III of 14,879 men and women with a reported 683 participants reporting a history of stones (median follow-up 14.9 years), the correlation between cardiovascular mortality and all-cause mortality was no longer significant in the adjusted analysis for age, gender, race, and poverty. Yet, in the unadjusted analysis, it was highly significant with hazard ratios or risk of approximately 2.0 and p < 0.0001 [5]. Therefore, the evidence suggests an association with cardiovascular health but not necessarily a consistent independent predictor or cardiovascular events. Still, if patients are made aware that reducing cardiovascular disease (CVD) risk lowers the risk of kidney stones and vice versa, the potential to reduce the burden of both conditions seems plausible and at least a “first do no harm” approach.
Comprehensive Lifestyle Changes, Stones, and Heart Health
If CVD increases the risk of kidney stones, then what would occur if multiple healthy lifestyle changes were incorporated into a clinical study to prevent kidney stones? A historic 5-year randomized trial from Parma, Italy, was published in the New England Journal of Medicine [6]. This trial demonstrated that a lower intake of animal protein and sodium and a normal intake of calcium reduced the risk for a kidney stone formation in individuals with a previous kidney stone compared to a low-calcium diet group. This was arguably one of the longest clinical trials ever published to address this issue. A total of 120 men (mean age 45 years) were included who had been diagnosed with idiopathic hypercalciuria (urinary calcium excretion >300 mg/day) on an unrestricted diet, experiencing recurrent formation of calcium oxalate stones (at least two documented events), and on no current treatments. A total of 60 men were placed on a normal-calcium diet (1,200 mg/day of calcium from food and not supplements) and low-animal protein (52 g per day or less) and low-sodium chloride (2,925 mg/day or 40 %, as sodium is equivalent to 1,170 mg/day of sodium) intervention diet. Another group of 60 men were placed in the low-calcium diet (400 mg/day) and instructed to avoid milk, yogurt, and cheese so that calcium ingestion would be reduced to just several hundred milligrams per day. Both groups were recommended to avoid large quantities of oxalate-rich foods (walnuts, spinach, chocolate, etc.) and to drink 2–3 L of water per day. The primary outcome of the study was time to a symptomatic kidney stone or the presence of an identified stone on an imaging test. Over 5 years, men that received the intervention diet (normal calcium, low protein, and salt) reduced their risk of a recurrent stone by 50 % (relapse rate of 40 vs. 20 %, p = 0.04) versus the control group (low-calcium diet). Urinary calcium was reduced significantly in both groups (−170 mg/day), but urinary oxalate excretion increased by a mean of 5.4 mg per day in the low-calcium group and was reduced in the normal-calcium group (−7.2 mg per day). This was a groundbreaking trial because it demonstrated the real importance of comprehensive lifestyle changes on kidney stone risk. The only problem was the fact that determining what had the largest impact or even an impact on kidney stone recurrence (protein, salt, and/or calcium) could not be determined.
The comprehensive DASH (Dietary Approaches to Stop Hypertension) study demonstrated an ability to dramatically lower blood pressure (−7.1 mm Hg systolic in non-hypertensive and −11.5 mm Hg systolic in hypertensive) similar to what is accomplished with medication using a comprehensive diet and lifestyle program along with reducing sodium below 1,200 mg (1/2 teaspoon) or 2,300 mg per day (1 teaspoon) compared to approximately 3,500 mg per day (1.5 teaspoons) [7, 8]. Diastolic blood pressure reductions of over 5 mm Hg in hypertensives was an average finding with some dietary changes alone.
The recommendations from DASH have been applied to other studies to determine if these comprehensive lifestyle changes could reduce the risk of kidney stones and the preliminary results are dramatic. For example, in the Health Care Professionals Follow-up Study of 45,821 men with 18 years of follow-up and the Nurses’ Health Study I and II of approximately 195,000 women with 14–18 years of follow-up each, researchers constructed a DASH diet score and evaluated incident kidney stone risk [9]. A total of 5,645 kidney stones were documented over a combined 50-year follow-up period, and those with higher DASH scores also had greater intakes of potassium, magnesium, oxalate, calcium, and vitamin C and lower sodium intake, and this group experienced a 40–45 % reduction in the risk of a kidney stone. Again, this suggests that the sum of personal lifestyle behaviors and parameters are far more powerful on cardiovascular and kidney health compared to one or just a few changes. The eight general recommendations from the original DASH diet and from this cohort were the following [7–9]:
1.
Higher intake of grains (7–8 daily servings)
2.
Higher intake of vegetables (4–5 servings a day)
3.
Higher intake of fruits (4–5 servings a day)
4.
Low-fat or no-fat dairy products (2–3 servings a day)
5.
Low to moderate intake of red and processed meat, poultry, or fish (2 or fewer servings a day) and low fats and oils (2–3 servings a day, the DASH diet had 27 % of total calories as fat, which is moderate)
6.
Higher intake of nuts, seeds, and dry beans (4–5 servings a week)
7.
Low intake of sweets (5 servings a week, also low in fat) and sweetened beverages
8.
1,500 mg or less of sodium per day or 2,400 mg a day, depending on the individual situation, and keep in mind that most sodium reduction comes from eating healthier such as reducing intake of processed foods—not from the salt shaker
Higher DASH diet scores reduced kidney stone risk even in those with reduced calcium intakes and excluding hypertensive participants did not change these results [9]. In other words, men and women of all ages appear to be able to reduce the risk of stones utilizing a comprehensive DASH diet and lifestyle program. A closer analysis into this diet in 3,426 participants with and without a history of stones found higher DASH scores (better compliance) compared to lower scores to have significantly higher urinary calcium excretion (10–12 %), higher urinary oxalate (4–18 %) and citrate (11–16 %), and urinary volume (16–32 %) [10]. Higher DASH scores were also correlated with greater urine potassium, magnesium, phosphate, and pH. The authors theorized it is the increase in citrate and urine volume along with other stone inhibitors in dairy and plants that were beneficial. The normalization of calcium and reduced animal protein and salt should have also provided some benefit. Calcium oxalate stone formers are often instructed to reduce the intake of oxalate from some foods, but these studies suggest this is not needed in some cases because it could also result in a lower intake of vegetables, fruits, and whole grains.
Hypertension
Older and preliminary observational studies have found a fairly consistent relationship between hypertension and kidney stones or vice versa [11–16]. The mechanism of action has not been elucidated, but could be due to higher urinary calcium excretion, increased urinary uric acid, and decreased urinary citrate, especially in the setting of obesity, but again this needs more attention. It appears the current strongest theory is the increase in calcium excretion, which was found to 12 % higher (25.6 mg per day more) in one well-controlled statistical retrospective series of 462 stone-forming patients [16]. Arguably one of the biggest factors for cardiovascular disease risk now has a correlation with stone risk.
Dyslipidemia, High LDL, High Triglycerides, Inflammatory Markers, and Treatment (Statins?)
High cholesterol/dyslipidemia may be an emerging risk factor for calcium oxalate and uric acid stones [17]. Yet few large observational studies have ever been conducted in this area of urology to determine if cholesterol-lowering agents via inflammation reduction or simply protecting kidney tissue from damage could cause risk reduction. Preliminary laboratory studies suggest a potential risk reduction with statins via inhibition of renal crystal retention [18]. Arguably the first human study of statin use was derived from outpatient electronic military health records from the Southwestern USA, which identified adult patients with dyslipidemia and stones [19]. The cohort consisted of 57,232 subjects with dyslipidemia and 1,904 subjects with stones. Patients on statins had a significantly lower risk of kidney stones (3.1 vs. 3.7 %; OR = 0.83, p < 0.001) on univariate analysis. Statin patients were significantly older, more likely to be female, and have comorbidities. Interestingly, multivariate analysis (adjusted for age, sex, and comorbidity) showed a stronger significant reduction (OR = 0.51, p < 0.001) in stone risk with statin use. More prospective studies are needed, but again the ability of statins to reduce inflammatory markers could be one primary mechanism of action [20]. It is of interest that not just higher LDL cholesterol but abnormally high triglycerides may increase the risk of kidney stones [17, 21]. It is also of interest that triglycerides are one of the five potential traits found in those patients with metabolic syndrome and fish oil or marine-derived omega-3 fatty acids (EPA and DHA) reduce triglycerides and may reduce some risk factors for kidney stones [22].
Obesity/Bariatric Surgery/Weight-Loss Diets and Drugs and/or Pre- and Diabetes (Glucose Intolerance)
An analysis of three large prospective cohorts involving almost a quarter of a million participants found higher body weight in men and women to be a risk factor for stones, with a RR of 1.44 in men to 1.89–1.92 in older and younger women [23]. An increased risk with increasing BMI appears to be a consistent finding from other observational series. Overall, higher BMI and waist circumference are risk factors for kidney stones [24, 25]. Whether the risk exists because of lower urinary citrate, higher uric acid, and oxalate has been well discussed. Regardless, it is known that obesity appears to cause a shift in primary kidney stone risk from a reduction in calcium oxalate stones to more prevalent uric acid stone disease [26, 27].
Diabetes is also a well-studied and consistent risk factor for a variety of stone disease [28–34]. Similar to obesity, especially for type 2 diabetics, there may be an increase in the risk of uric acid stones. Insulin resistance creates a lower urine pH via deficient ammonia production and thus an increase in risk [32]. There is also the potential for inhibitory ureteral peristalsis, which can increase the risk of stones via urinary stasis [33]. Although more oxalate excretion occurs in diabetics, the reduced urinary pH has been a consistent observation [34].
Some older obesity medications, such as orlistat, and bariatric surgery are correlated with hyperoxaluria, stone formation, and oxalate nephropathy [31]. Other weight-loss medications more recent to the marketplace such as the combination of phentermine and topiramate (Qsymia) also appear to slightly raise the risk of kidney stones at higher (92 vs. 46 mg) topiramate dosages [35]. Roux-en-Y surgery appears to cause hyperoxaluria, low urine volume, and hypocitraturia, whereas gastric binding may cause less risk due to low urine volumes and higher calcium excretion [36], but actual weight loss with banding is significantly less compared to other surgical bariatric procedures [37]. Weight gain utilizing carbohydrates and rapid weight-loss diets adhering to low-carbohydrate intake could increase the risk of calcium oxalate and uric acid stones [32, 38]. Although, whether or not one type of diet, low fat or low carbohydrate, increases the risk of stone disease more than another is controversial. For example, a 2-year comparative trial of 307 obese individuals found no impact of low-carbohydrate diets on bone density, GFR, albuminuria, or fluid and electrolytes compared to a low-fat diet [39]. Arguably, it is best to lose weight over time to improve cardiovascular health and reduce the risk of stones rather than focus specifically on the type of weight-reduction program utilized. Short-term studies of low-carbohydrate diets have suggested an increase in stone risk based on acid load [40], but again over a long-period of time, the increase in risk of stone disease is questionable compared to other popular diets [39].
Metabolic Syndrome (More Is Not Better)
After the discussion on obesity and glucose intolerance, it should not be surprising that preliminary research is beginning to demonstrate an increased risk of stone disease with an increasing number of metabolic syndrome traits, for example, from 3 % with 0 traits to almost 10 % with all five traits (abnormal glucose, blood pressure, central obesity, high triglycerides, and low HDL) [41]. Perhaps one of the strongest contributors to this risk is hypertension [42], although obesity also increases risk and metabolic syndrome patients also have an increased risk for uric acid stones [43].
Exercise and/or Water/Hydration and Fluid Types
Surprisingly few studies have addressed the impact of exercise on stone disease. Two studies have found a suggested increase risk of stone disease, but this was in the setting of reduced hydration during and after activity [44, 45]. Immobility or bed rest is associated with an increased risk [46, 47], and exercise aids in weight loss [48]. Perhaps the message to patients should be to increase physical activity in the setting of increased hydration until their urine appears clear when voiding. And exercise might operate via other pathways to reduce kidney stone risk apart from weight loss in the setting of adequate hydration; for example, inflammatory markers such as C-reactive protein (CRP) and fibrinogen appear to be consistently reduced in studies of heart disease patients [49].
Water intake is an accepted risk-reducing strategy against stone disease, especially to prevent calcium stone recurrence [50, 51]. This strategy is commonly mentioned in some guidelines, along with pharmacologic interventions such as allopurinol, citrate, and thiazides [50]. Water intake greater than 2 L per day to produce a urine output of greater than 2.5 L per day reduced stone recurrence as much as 61 % [51]. This would again suggest water intake is a conventional medical recommendation to prevent relapse and, arguably, reduce the risk of first time stone disease, but this has not been adequately addressed. Still, fruits and vegetables utilized in comprehensive lifestyle programs to reduce the risk of incident stone disease are not just high in electrolytes (potassium and magnesium) but also water content [9]. High-moisture foods such as fruits and vegetables could account for 20–25 % of human daily water intake [52].
A variety of noncaloric and some caloric fluids from water to caffeinated and decaffeinated coffee and alcoholic beverages may reduce risk, but higher sugar or soda and fruit juice beverages may increase risk [53]. Alcohol consumption can also be dehydrating, so patients should be told to drink water right before, during, and after alcohol consumption to maintain hydration and discourage increased caloric consumption from alcoholic beverages.
Citrate is a known inhibitor of calcium kidney stone formation. Lemonade from real lemons (homemade) or lemon juice has become the paradigm of a targeted ideal beverage for increased urinary citrate [54]. Increased alkali intake can increase urine pH, which could help prevent kidney stones. Multiple sodas that appear to contain a concentration of citrate equal to or greater than alkali or total alkali of lemonade used to treat low urine citrate calcium kidney stones (6.30 mEq/L citrate as alkali and 6.30 as total alkali) include Diet Sunkist Orange, Diet 7UP, Sprite Zero, Diet Canada Dry Ginger Ale, Sierra Mist Free, Diet Orange Crush, Fresca, and Diet Mountain Dew. It is also of interest that colas, including those that are caffeine free, have the lowest total alkali or less than 1.0 mEq/L [55].
Other citrate-based fruit juices (apart from lemon juice and lemonade from real lemons) such as Ruby Red grapefruit juice, orange, pineapple, cranberry, lemon/lime Gatorade, and Crystal Light lemonade sugar-free drink mix are also excellent sources of citrate [54]. Yet, in the age of a global obesity epidemic, which can raise stone risk, I am concerned about the caloric content of these products, which in many cases equals a serving of high caloric alcohol [48]. Therefore, lower caloric options such as Crystal Light or sugar-free drink mixes or reduced caloric or no-calorie citrate-based beverages are more ideal. Still, lemon and lime juice containing 1.44 and 1.38 g of citric acid per ounce and lemon and lime juice concentrates containing 1.10 and 1.06 g per ounce are still the paradigm of comparison [56]. Again, clinicians and patients need to be sensitive to the caloric content of all citrate sources, the need to dilute these sources, or simply advocate for low- or no-calorie sources in those with weight and waist issues.
Dietary Fiber
Minimal research has been conducted on the impact of higher fiber intakes with stone risk. Several small studies suggest no advantage, the potential for an increase, and even a reduction in the risk of stone disease [57–62]. The problem with many of these protocols is that water intake is controlled, and with increased fiber ingestion, fluid intake needs to be dramatically increased; compliance issues abound when attempting to increase fiber intake. It is arguable that if water intake was allowed to increase by upwards of 1 L for every 10–15 g of fiber, there would be no impact or a potential advantage of dietary fiber intake. Phytate (multiple negative charges as an ion) in fibers can also bind with calcium to form complexes and potentially reduce the risk of hypercalciuria and stones [60, 61], and may complement conventional treatment [62]. Fiber in fruits and vegetables along with nutrients (magnesium, potassium, low in sodium) and water content could reduce the risk of stones. Regardless, fiber intake is a healthy overall and cardiovascular disease risk-reducing strategy [63]. Still, it cannot be claimed that it has any definitive beneficial impact on stone risk at this time, despite the author’s belief that the benefit outweighs the risk.
Dietary Oxalate Content Controversies (Bioavailable? Soluble Versus Insoluble?)
Some educational sources provide a long and comprehensive list of high-oxalate foods and their dosages which should be avoided by some previous calcium oxalate stone formers. This tradition will not occur in this chapter perhaps due to the iconoclastic thought or purpose to instead focus more on the larger issue. Vegetarians consume and excrete more oxalate in the diet compared to those that eat meat, but vegetarians appear to have a lower risk of recurrent kidney stone risk [64, 65]. Encouraging the consumption of a predominantly plant-based diet appears to offer more of a benefit compared to counting the milligrams of oxalate from foods. For example, drinking tea usually has zero calories and helps for weight-loss programs and fluid intake that could also reduce stone risk, but can be high in dietary oxalate, but it is low in bioavailable oxalate (percentage of the total appearing in the urine) [66, 67]. A test of seven high-oxalate foods (spinach, chocolate, tea, vegetable juice, cranberry juice, pecans, and orange) found only spinach to cause hyperoxaluria in normal subjects (increase of 29.3 mg in 8 h) [67]. The real issue is the amount of soluble compared to insoluble oxalates occurring in a product [68], which impacts the bioavailability.
Plant oxalate exists in two forms: the water-soluble (absorbable) salts attached to potassium, sodium, and ammonium ions and the insoluble salts attached to calcium, magnesium, and iron that are not absorbed and become part of fecal material [68–70]. A soluble or water-soluble oxalate from plants can bind to intestinal material (e.g., calcium) and not be absorbed, or it can get absorbed and appear in the urine. Plants high in soluble oxalates are more concerning and may or may not have a greater chance of increasing urinary oxalate, especially when consumed with other food and beverage items. For example, when spices were tested, green cardamom (99 %) had the highest concentration of soluble oxalate followed by turmeric powder (91–95 %), ginger (87 %), malabathrum leaf (59 %), and black cardamom (59 %) [71, 72]. Cinnamon (6 % soluble) was the only spice that contained primarily insoluble oxalate only. Also, oxalate excretion amounts are measured as single ingested food source, but when other foods or even calcium or magnesium is ingested with dietary oxalate, it can potentially and significantly reduce absorption (magnesium as much as calcium, but have +2 charge and oxalate has a −2 charge) [73].
Additionally, there is evidence to suggest that individuals ingesting healthy food sources of oxalate might also increase the probability of housing intestinal oxalate-degrading flora such as Oxalobacter formigenes, a gram-negative and anaerobic bacterium whose primary energy source is oxalate itself [74]. The American Dietetic Association (ADA) recommends a dietary oxalate intake of 40–50 mg per day or less for those at risk of oxalate stones [75], but I do believe caution should be emphasized in cases where eliminating any food providing ample nutrients or low caloric intake as part of a weight-loss program is a primary goal. High food sources of oxalate, which are usually discouraged in high-risk oxalate stone formers, include the following [76, 77]:
Beets
Black teas
Bran concentrates and cereals
Chocolate
Legumes (beans, peanuts, soybeans)
Nuts (some tree nuts)
Rhubarb
Spinach
Still, there are nuances to these recommendations, which should be emphasized. For example, these foods are healthy and could be a part of a heart-healthy weight-loss program, or, for example, soy products are high in phytate binding calcium compounds, and tofu, for example, contains minimal soluble oxalate [77, 78]. Again, until there is more definitive proof that some of these foods incorporated into a comprehensive lifestyle program such as DASH [9] to prevent stones actually increase the risk of stone disease, there should be ample room for debate on what to restrict and not to restrict when in a kidney stone prevention program.
Another compromising option is to prevent a viable alternative to patients concerned about removing some healthy foods from diet. For example, kale is a low-calorie and low-oxalate vegetable, which has greater calcium absorbability versus spinach and could also bind intestinal oxalate [79]. This allows some patients to maintain normal calcium dietary intake and remain less concerned with high-oxalate food sources. Low-calorie teas such as green or herbal tea instead of black tea are an option [77], and some commercial chocolates contain added calcium, and these should be tested for oxalate bioavailability. This is just a short list of alternative thoughts and ideas to patients concerned about oxalate ingestion. Now, before beginning the discussion on dietary supplements and other factors and stone risk, the reader should be reminded of the various cardiovascular risk factors associated with stone disease mentioned in the first half of this chapter, and these are listed in Table 8.1.
Table 8.1
Some basic cardiovascular risk factors associated with a higher risk of kidney stonesa
Dyslipidemia (high LDL and/or triglycerides) |
Glucose intolerance/diabetes |
Hypertension |
Metabolic syndrome |
Obesity |
Physical inactivity |
Unhealthy diet |
Calcium and Vitamin D Supplements
The Women’s Health Initiative (WHI) randomized 36,282 postmenopausal women to 1,000 mg of calcium carbonate and 400 IU of vitamin D3 daily or placebo [80]. Calcium and vitamin D increased the risk of self-reported kidney stones (HR = 1.17; 95 % CI, 1.02–1.34), and the Number Needed to Harm (NNH) was 272 over 7 years. Participants were already ingesting high intakes of dietary calcium at baseline (1,150 mg/day) [80].
A total of 449 women in the calcium and vitamin D group and 381 in the placebo group reported a kidney stone during the clinical trial. Rates of kidney stones did not differ between the various demographic, dietary, and other hypothesized risk factors. Neither total calcium intake nor the use of supplements at the beginning of the study was associated with the risk of stones. Even those individuals that did not ingest their calcium supplements on a regular basis also experienced a slight increased risk of a kidney stone.
Idiopathic hypercalciuria (IH) in this population of participants might explain the potential increase in stone risk in the supplement users [48]. IH is found in 5–7 % of the adult population, and such a large randomized trial of calcium and vitamin D (arguably the largest ever done in medicine) should balance the number of IH individuals fairly equally among the two arms of the trial. What is also interesting again is that the average person in the study was again already receiving 1,150 mg of dietary calcium and 365 IU of dietary vitamin D before the study was initiated.
Although some systematic reviews suggest no overall risk of stones, it is difficult to ignore the findings of excessive amounts of calcium not providing only the potential for harm and minimal benefit [81]. A large prospective cohort of over 91,700 women with 12-year follow-up found dietary supplements of calcium associated with an increased risk of kidney stones (RR = 1.2), but dietary calcium intake was correlated with a lower risk. It is also if interest that increased sucrose and sodium also increased stone risk and increased fluid and potassium reduced stone risk [82]. There has also been some concern over clinical trials suggesting higher rates of myocardial infarction with excess calcium supplementation [83]. It would be prudent to follow the conservative and evidence-based Institute of Medicine (IOM) guidelines suggesting daily total calcium intakes of 1,000 mg per day in 19- to 50-year-old males and females, 1,000 mg per day also in 51- to 70-year-old males, and 1,200 mg in 51± year-old females and 70± year-old males [84]. Calcium citrate dietary supplements may not increase the risk of kidney stones and should be the preferred calcium supplement for those needing supplementation at a higher risk of calcium oxalate nephrolithiasis [48]. They can be utilized with and without food but are not as concentrated as lower-cost calcium carbonate supplements that need to be ingested with food. Still, calcium supplements, including calcium citrate, increase the risk of constipation, especially in the elderly.
Vitamin D is a controversial supplement because in higher dosages it has the potential to cause hypercalcemia [84]. The IOM recommendations appear to be conservative and accurate in recommending 600 IU per day for adults (men and women) up to the age of 70 years and 800 IU for 70+ individuals. Yet, there is no strong and consistent evidence to suggest higher urinary calcium levels on higher vitamin D levels right now [85, 86]. Regardless, bolus dosing should be discouraged until these questions are further answered and higher intakes have not been shown to consistently benefit individuals more than moderate dose intakes.
Cranberry and Cranberry Dietary Supplements and Oxalate
One research group noticed that an individual utilizing cranberry supplements for urinary health was diagnosed with a kidney stone soon after initiating these supplements and decided to further investigate this question, which had not been previously answered [87]. A total of five subjects utilized cranberry supplements at the recommended daily dosage on the label for 7 days, and then urinary oxalate levels increased significantly (p = 0.01) by an average of over 43 %. If over 10 % consistent increases as noted by these authors can cause calcium and oxalate to bind and crystallize or form a stone, then this is concerning. The average normal intake of oxalate from the diet is about 150 mg/day, but two cranberry tablets from this study could be expected to contain over 350 mg of oxalate per day. Another problem with many cranberry concentrate supplements is that they can contain a good amount or at least some plain vitamin C (known oxalate-increasing compound). Sodium levels also increased from this study and so did the ability of calcium and oxalate to bind together. Yet, magnesium and potassium also increased in the volunteers, which could slightly reduce risk of kidney stones. What this study showed is that most supplements do not report their potential oxalate content or ability to increase oxalate, and this needs more research. In the meantime, most individuals that have a high risk for kidney stones do not need to be on cranberry supplements unless a company can report their oxalate amount in a pill.
Cranberry juice is fraught with mixed issues and messages. Some studies reported a low bioavailability of oxalate from cranberry juice [67] and a reduction in oxalate excretion and increases in citrate in individuals with no stone risk [88]. Still, it provides an acid load and can increase urinary calcium and oxalate in other individuals [89]. It is interesting when cranberry juice (19.87 mmol/L) is analyzed for citrate content, it has been greater in some cases compared to homemade lemonade (17.42 mmol/L) [54]. In other words, cranberry concentrate supplements appear to be high in oxalate in some cases, cranberry juice is high in calories in some cases and has a mixed stone risk, and this is objective information that should be passed on to the patient. Personally, I favor the use of cranberry supplements over cranberry juice for those with UTIs, because intuitively the pills do not appear to add to the obesity epidemic in terms of caloric contribution (100–150 cal per 8 oz vs. little to no calories with pills) [48] and have worked as well thus far for the prevention of UTIs [90]. Also, the impact of cranberry juice for UTIs is being questioned, and the compliance rates of drinking cranberry juice daily for months in some trials have been poor. In children the juice may also have some efficacy, but the acidity and long-term commitment to daily use also can contribute to compliance issues [91]. If someone has a high risk for oxalate stone and UTI recurrence, then again some idea of the contribution of the amount of oxalate from the supplement would be of assistance in deciding if the benefit was worth the risk.
Inosine (Nucleoside Supplements) or d-Ribose Dietary Supplements
Inosine is not just a nucleoside produced when hypoxanthine is connected to a ribose ring (ribofuranose) via a glycosidic bond [92, 93], but it is also sold as a dietary supplement. Inosine is produced in the body, where it assists with energy production (precursor to adenosine used for the production of ATP) and increasing red blood cell concentrations of 2,3-diphosphoglycerate (2,3-DPG), which is why there was always interest in determining if supplementing with this compound could boost athletic performance. Inosine has other roles in the body; it is found in organ meats, and there is some found in brewer’s yeast, but the supplements appear to provide the largest quantities. Inosine has not been impressive as an athletic enhancement product at large dosage (up to 10,000 mg per day) [94, 95]. Also, individuals with gout or others with uric acid concerns should not take this supplement because it can significantly raise uric acid levels.
Interestingly, this supplement has and will continue to be tested in dosages of 500–3,000 mg per day in clinical trials to raise the uric acid level to anywhere from 6 to 9 mg/dL (no more or less) in neurological inflammatory disorders such as in multiple sclerosis (MS) and Parkinson’s patients to determine if there could be a clinical benefit [96–99]. Uric acid is a natural inhibitor or scavenger of certain compounds such as peroxynitrite, which could otherwise promote inflammation and axon degeneration [97]. Some MS and Parkinson’s patients have been known to harbor lower uric acid levels compared to those without MS and Parkinson’s, and those with higher uric acid appear in some cases to have a slower progression of their disease. Some preliminary 1-year testing suggests dosages of 2,000–3,000 mg per day might provide a benefit, but 4 out of 16 patients were also diagnosed with kidney stones during the study [98]. Other adverse effects did not occur; for example, inosine supplementation did not raise blood pressure, but uric acid significant increases of 4.2 at baseline to 7.1 mg per 100 mL occurred with these supplements [100]. Other somewhat related nucleoside (hypoxanthine attached to ribose = nucleoside inosine, found in tRNA) dietary supplements such as d-ribose have not been shown to increase uric acid at dosages as high as 5,000–10,000 mg per day [101, 102].
Magnesium (Dietary and Supplements)
Higher dietary magnesium intake appears to reduce the risk of hyperoxaluria in those with nephrolithiasis [103]. The conundrum of magnesium from foods is that higher sources are found in whole grains, spinach, nuts, and legumes, which have been also considered higher oxalate sources [104]. Dietary magnesium supplements many have some efficacy [103, 105], especially when combined with other kidney stone inhibitors, but dosages of magnesium are not simple to increase because of bowel toxicity (loose stools and diarrhea), which can occur [106]. Magnesium is also excreted renally, so it needs to be utilized with caution in those with renal disease. It appears dietary sources are generally healthy and more sensible at the moment for many patients and could reduce stone risk. Magnesium has a +2 charge (like calcium) as a cation and oxalate has a −2 charge, which should maintain the interest in this compound potentially lowering oxalate levels.
Omega-3 Dietary Supplements from Marine Sources (EPA and DHA) and Omega-6 Supplementation
Fish oil supplements (1,200 mg /day of the active ingredients EPA and DHA) were analyzed in a retrospective study of 29 patients (followed for a mean of 9–10 months) along with dietary changes (fluid, sodium, protein, citric juices) in patients with hypercalciuria (urinary calcium >250 mg/day in males or >200 mg/day for females) and demonstrated a significant potential to lower urinary calcium (349–247 mg/day) and oxalate (45–32 mg/day) and increase citrate (737–940 mg/day) [107]. The authors theorized that by affecting what is known as prostaglandin metabolism, which causes a reduction in compounds like PGE2 that normally can increase the risk of stones by increasing calcium in the urine, omega-3 compounds may have efficacy. Specifically, the dietary changes added to fish oil in their study included 2 L/day of urine, reduced sodium (less than 2,400 mg), protein reduction, normal calcium intake, and citric juices (4 oz concentrated lemon/lime juice per day). Overall, there was a 52 % response rate to the dietary change and fish oil supplement over an average period of 10 months, and 24 % of the patients were normocalciuric by study end, and there was an average of approximately 30 % reduction in urinary calcium after 6 months, and urine oxalate reduced in about a third of patients.
Older clinical research has suggested the ability of fish oil (e.g., EPA) to lower urinary calcium and oxalate levels in recurrent stone formers and the potential for benefit in the notable studies of Greenland Eskimos that demonstrated a lower risk of heart disease with a greater omega-3 intake from fish [22]. EPA has more research against kidney stones compared to DHA in fish oil, but both can be anti-inflammatory, which also may reduce the ability of calcium to bind to other components. Fish oil omega-3 fatty acids may impact the transport of oxalate so lower amounts are absorbed and appear in the urine. Another study of 18 months that used 1,800 mg of EPA found high baseline calcium levels in the urine were significantly reduced, but those with already normal calcium levels experienced no change [108]. This same research group followed 29 patients over a mean of 36 months on 1,800 mg of EPA preventive treatment and found reductions in stone formation during treatment, which were significant when compared to off treatment over a total observational period of 8 years [108]. Another small clinical study of 15 healthy subjects ingesting 900 mg of EPA and 600 mg of DHA over 30 days reduced significantly urinary oxalate excretion and the risk of calcium oxalate crystallization.
The problem with this exciting initial data is preliminary prospective observational research from three large cohorts (Health Professionals Follow-Up Study and Nurses’ Health Study I and II) documented 3,956 incident kidney stones over a combined 36 years of follow-up including 234,000 individuals, and no relationship was found for fatty acid intake including fish oil supplements and incident kidney stones [109]. Older women in one cohort (NHS1) actually had a significant increase in risk in the highest quintile of EPA and DHA intake with a multivariate risk of 1.28 (p = 0.04). Overall, there was no association in risk of stones and fatty acids in the other two cohorts. Another issue needs consideration before endorsing fish oil in urology, and this is the ongoing recent unimpressive data outside of urology where far more data existed initially for enthusiasm. Phase 3-like clinical trials on the recent effect of fish oil have been similar to placebo. For example, no impact of fish oil was found in a large trial on macular degeneration progression (AREDS2) [110], as well as a more definitive primary prevention cardiovascular health clinical trial in high-risk patients [111], or for prevention of postoperative atrial fibrillation [112], and from a comprehensive meta-analysis of cardiovascular events and disease [113].
Another issue is whether or not omega-3 dietary supplements function any better against kidney stone risk compared to omega-6 supplementation. For example, a significant increase in citrate and/or reduced calcium in the urine utilizing 1,000 mg of evening primrose oil (EPO) per day was found in a small preliminary study, along with decreases in oxalate [114]. EPO is a high source of the omega-6 anti-inflammatory compound known as “GLA” or “gamma-linolenic acid” and linoleic acid, which can then convert to DGLA and then PGE1, which is an anti-inflammatory compound. This needs further research; similar to omega-3 supplements, they have not received enough rigorous or placebo-controlled investigations. Still, similar anti-inflammatory effects of omega-3 and omega-6 compounds preliminarily occur outside of the field of urology (e.g., for conjunctival inflammation in patients with dry eye syndrome) [115].
Probiotic (Natural)-Oxalobacter formigenes and Lactic Acid Bacteria
Oxalobacter formigenes (O. formigenes), mentioned earlier, is a gram-negative and anaerobic bacterium whose primary metabolic energy source is oxalate itself [74, 116]. It is a natural gut probiotic, and other probiotics known as lactic acid bacteria, despite ample attention on the Internet and from other sources, have yet to prove they consistently lower oxalate levels to normal (less than 40–45 mg per day in the urine). This area of research just needs time to evolve because someone or some commercial entity should be able to offer a version of this bacterium in the future. Either O. formigenes will be offered as a probiotic or we will find a supplement or probiotics that can significantly and consistently increase the amount of this bacterium in the colon. O. formigenes utilization (solution delivered via a gastrostomy tube) twice a day for 4 weeks in select patients with primary hyperoxaluria type I (infantile oxalosis) has demonstrated the potential for plasma oxalate reduction [117]. However, a randomized trial of 43 patients observed no significant differences with placebo in urinary oxalate levels in those with primary hyperoxaluria [118]. Research may soon identify other strains of bacteria or better or more diverse deliver systems for O. formigenes and in the ideal patient populations (genetic predisposition, dietary, recurrent oxalate stone formers, etc.). Other species of bacteria may simply be isolated based on geographic location of individuals [119].
The human gut can be colonized by O. formigenes during infancy, and by age 8 almost all children test positive for it, compared to only 60–80 % of adults, and this is explained partially by the use of antibiotics [120–123] and, partially, in my opinion, unhealthy lifestyle and dietary changes and other supplements, drugs, and other scenarios that have not been fully tested against this bacterium as of yet. For example, morbidly obese patients appeared to have had a low colonization rate (8 %) with O. formigenes before bariatric surgery, which suggests that the hyperoxaluria observed after surgery is not due to the loss of colonization from this bacterium [124].
Other bacterial species (“lactic acid bacteria”) could have a role in oxalate breakdown [125], such as Lactobacillus acidophilus, and other strain combinations over 4 weeks on one older study provided a potential 40 % oxalate reduction [126], but a bacterium that can be consistently relied on commercially has not occurred. There have been dramatic reductions in the risk of calcium oxalate stone recurrence (as high as 70 %) in some studies [127] and other studies suggesting minimal benefit [118]. However, these data need to mature, because it is possible that there is just a correlation between colonization and improved lifestyle changes that simultaneously reduce kidney stone risk dramatically by themselves. In addition, just because a probiotic has the ability to reduce oxalate levels does not necessarily translate to a lower risk of recurrent stone disease, and based on cost and delivery system, it needs to show some advantage over what could be accomplished with some minimal to moderate lifestyle changes. A final issue is the intrastool and interstool variability of the amount of O. formigenes detected by certain methods such as real-time polymerase chain reaction (PCR) [128]. Thus, there is great excitement but great detail to still be investigated and elucidated.
Vitamin B6 Supplements (Pyridoxine HCL): An Effective Endogenous Oxalate Reducer in Some Conditions
Primary hyperoxaluria type 1 is the most common form of this genetic condition, which due to an enzymatic defect, and large concentrations of oxalate can be so damaging that in the advanced stages the primary effective form of treatment is kidney-liver transplantation [129]. Some treatment guidelines for this condition now recommend not only a higher fluid intake but a starting dose of 5 mg/kg per day not to exceed 20 mg/kg per day of vitamin B6 with the goal of reducing urine oxalate excretion by less than 30 %. Other special dietary interventions are not generally recommended other than those for “concurrent diseases in the absence of CKD.”
Vitamin B6 (pyridoxine) is a cofactor in the alanine-glyoxylate-transaminase (AGT, an aminotransferase) pathway and could reduce the synthesis of oxalate through the induction of enzymatic activity [129–135]. For this reason, it has been a partial success story in decreasing oxalate production in some patients with primary hyperoxaluria type 1 because it simply causes a shift in the breakdown of glyoxylic acid toward glycine as opposed to oxalic itself. In other words, more glycine is produced from glyoxylic acid because of vitamin B6, instead of oxalate, which is also an end product of glyoxylic acid. Lactate dehydrogenase (LDH) is the enzyme that normally converts glyoxylic acid into oxalate, and it competes with the B6 AGT pathway. Less glyoxylic acid (glyoxylate) becomes available as a substrate for LDH when more B6 is available. Interestingly, ethylene glycol-induced hyperoxaluria treatment in the laboratory appears beneficial when a vitamin B6 compound is utilized [133]. Ethylene glycol tastes sweet and some animals and children are attracted to it. Veterinarians deal with this issue often because some dogs and cats consume radiator fluid. Vitamin B6 involvement as a cofactor in multiple enzymatic pathways involving amino acid metabolism has drawn interest in multiple medical areas and not just for ethylene glycol poisoning but acute isoniazid overdose, certain mushroom poisonings such as Gyromitra mushroom or false morel [134].
There have been case studies of recurrent calcium oxalate stone formers taking 100 mg of vitamin B6 daily with some long-term success [132]. The general recommended daily dietary intake of B6 is approximately 1.2–1.7 mg per day in adults, but to reduce high oxalate levels, the most common dosage used thus far is 50–100 mg per day or slightly higher (up to 200 mg) of pyridoxine HCL based on oxalate levels from a 24-h urine composition test [135]. For example, a retrospective study of over 300 patients with 95 being diagnosed with idiopathic hypercalciuria also given dietary advice, and utilizing 50–100 mg a day of vitamin B6 with some eventually utilizing a maximum of 200 mg per day based on the amount of oxalate in the urine (50–60 mg oxalate per day, B6 of 50 mg, but over 60 mg oxalate per day then 100 mg B6 or higher), was published [135]. A total of 39 % of these patients normalized the amount of oxalate in their urine (55–33, p = 0.0004), but 75 % of them significantly benefitted in term of improved urinary parameters (oxalate from 58–40, p < 0.0001) with diet and vitamin B6 supplements, and researchers reported no serious side effects, such as sensory peripheral neuropathy, that can occur when ingesting too much vitamin B6. Mean follow-up was 18.4 months and mean age of 50 years.
Pyridoxine in 250- to 500-mg daily doses provided a potential benefit to 8 (no stones occurred) of 12 patients with a history of recurrent calcium oxalate stones and idiopathic hypercalciuria. It significantly reduced urinary oxalate excretion (p < 0.025) up to 18 months of treatment [136]. Another small study of two groups of stone formers, idiopathic and enteric, found it appeared effective for idiopathic but not enteric at dosages of 300 mg per day. This study suggested patients with intestinal hyperabsorption of oxalate may not benefit from B6 [137]. A study published in 1967 followed calcium oxalate kidney stone patients on 10 mg of vitamin B6 and 200 mg of magnesium oxide, and 30 of the 36 patients on this program over 5 years did not have another stone or reduced their risk [138]. Oxalate levels did not decrease but citrate levels increased significantly. Thus, there has been a long-term interest in using B6 for stone reduction, and yet no definitive trial has been published since this time.
Some companies sell a more active form or the type of B6 that is detected in the blood known as “pyridoxal-5-phosphate” (P-5-P or P5P), but it appears the majority of the past studies have utilized pyridoxine HCL or the lower cost version of B6 [139]. There is one past study of pyridoxal phosphate at 60 mg for 3 months, and it significantly reduced urinary oxalate excretion in patients with idiopathic hypercalciuria alone. These patients were also placed on a regular calcium diet. This is of enormous interest, but again the issue with vitamin B6 supplements is the lack of ample individual or comparative data against some control or placebo.
One notable large prospective epidemiologic study of over 85,500 women with no history of stones reported 1,078 incident stone cases during 14 years of follow-up [140]. A higher consumption of B6 was associated with a 34 % lower multivariate-adjusted risk in the group consuming 40 mg or more per day versus the lowest intake (less than 3 mg per day) occurred. Fish, chickpeas, chicken breast, and fortified cereals are high in vitamin B6, but can only contribute about 0.5–1 mg per serving, which is not realistic in terms of competing with clinical studies to reduce abnormally high levels of oxalate. More observational work is obviously needed.
Some companies sell tablets over the counter as high as 500 mg per tablet, but this is too high and can again increase the risk of a sensory peripheral neuropathy at dosages of 300–500 mg per day [134, 141]. Some publications refer to recommending 1–10 mg per kg based on oxalate levels, but before this can be determined in patients with stone disease, it appears that 50–200 mg of B6 usually in the form of pyridoxine hydrochloride is a cost-effective and safe dietary supplement from past studies [135]. Vitamin B6 can be ingested with and without meals, but I always recommend with meals when given a choice because it can reduce gastrointestinal side effects. It is arguably time for more rigorous testing of B6 in patients other than those with primary hyperoxaluria I to determine its overall use in stone disease.
Vitamin C Versus Buffered Vitamin C (Calcium Ascorbate or Other Sources) and the Metabolic Paradox of Increased Oxalate, but Reduced Serum Uric Acid (SUA) and Increased Urinary Uric Acid
Vitamin C has consistently been one of most utilized dietary supplements in the USA [142] and around the world [143]. The overall popularity of vitamin C supplements with the public among all age groups [142, 144, 145], and even among healthcare professionals themselves [144, 146], is notable, and it would be prudent to further elucidate the impact on stone disease. This is a controversial area because it is well known that high intakes of vitamin C supplements can increase oxalate levels [147, 148], but whether or not they significantly increase the risk of kidney stones is an area of debate. What is not controversial is the observation that increases in oxalate concentration are an abnormal metabolic consequence that should be generally discouraged and prevented. Regardless of the etiology, hyperoxaluria can contribute to kidney injury and damage [149, 150].
Past clinical trials have consistently demonstrated large increases in oxalate with increased vitamin C from dietary supplements [151–153]. This occurred in previous stone formers and in individuals with no history of kidney stones. Healthy men and women can produce large quantities of urinary oxalate, regardless of stone risk status, when ingesting larger doses of concentrated ascorbic acid from dietary supplements. For example, a previous clinical trial of calcium oxalate stone formers ingesting 1,000 (group 1) or 2,000 mg (group 2) per day of vitamin C and non-stone formers ingesting 1,000 mg (group 3) for a total of only 3 days found that all three groups experienced significant increases in oxalate excretion: 61 % increase in oxalate in group 1, 41 % in group 2, and 56 % in group [151]. Significant increases in calcium oxalate urinary supersaturation also occurred in all three groups. Urinary pH did not change after vitamin C was ingested in any of the groups. A separate crossover clinical trial (two 6-day intervals) where participants were given 1,000 mg of vitamin C and then a placebo found a significant increase in urinary oxalate occurred in stone formers (33 %) and non-stone formers (20 %) [152]. Again, no change in urinary pH occurred. A third crossover trial of 29 stone and 19 non-stone formers consuming 2,000 mg of ascorbic acid compared to no intake for 6-day intervals found similar results to the other trials [153]. A total of 40 % of both the stone and non-stone formers experienced increases in the 24-h urinary oxalate concentrations of ≥10 % and in the Tiselius index (potential measure of stone risk). No change in oxalate concentrations occurred in the other 60 %. The authors suggested caution in ingesting high doses of ascorbic acid in individuals with or without a history of stones, because an individual’s versus a population’s response to vitamin C supplements in regard to potential oxalate changes is not consistently predictable from this and previous trials. Thus, it is accepted currently that high urine levels of oxalate occur with higher doses of ascorbic acid (1,000–2,000+ mg/day), but some individuals, for an unknown intrinsic or extrinsic reason and regardless of previous stone history, do not experience a change in oxalate.
Past observational studies have found mixed results in terms of stone risk. The large (n = 45,619 males) prospective epidemiologic Health Professionals Follow-up Study (HPFS) found a 41 % increase in the 14-year incidence of stones (1,473 cases with no previous history) in men with 1,000 mg or greater of daily supplemental vitamin C intake compared to those ingesting less than 90 mg [154]. Interestingly, magnesium, potassium, and/or fluid intake all appeared to reduce risk in this study (similar to what was mentioned earlier in this chapter). An earlier report from the Nurses’ Health Study (NHS, n = 85,557) found no relationship between vitamin C and stone risk (1,078 cases, 14-year follow-up) in women even when comparing 1,500 mg or more per day versus less than 250 mg per day [140]. This was the same study observing the potential for vitamin B6 to reduce the risk of kidney stones (40 or more mg/day vs. <3 mg/day).
Perhaps one of the largest and most comprehensive studies on 24-h urinary oxalate places part of the vitamin C argument in perspective. A cross-sectional investigation of 3,348 stone and non-stone formers from the men in the HPFS, and women in the NHS, and the Nurses’ Health Study II (NHS II) was published [155]. Median urinary oxalate levels were below 40 mg, and the association between dietary and urinary oxalate levels was similar regardless of nephrolithiasis history. Individuals consuming 1,000 mg/day or more of vitamin C compared to <90 mg/day excreted significantly (p < 0.001) more (6.8 mg/day) urinary oxalate. Body mass index (BMI), total fructose intake, and 24-h urinary magnesium, potassium, and phosphorus levels were also positively correlated with urinary oxalate levels, and age and calcium intake were inversely correlated with urinary oxalate. Participants with diabetes excreted 2.0 mg/day greater urinary oxalate (p < 0.01) compared to those without diabetes. The authors concluded dietary oxalate from most foods minimally contributes to urinary oxalate, but vitamin C supplementation has a more direct correlation, and increased calcium supplementation a more inverse correlation, so both of these supplements are potentially more significant contributors to oxalate concentrations.
A more recent population-based, prospective cohort of Swedish men recruited 48,850 participants, aged 45–79 years at baseline [156]. Using a self-administered questionnaire ascorbic acid usage and 20 other supplement types were recorded. Excluded from analysis were men with previous stone disease and users of supplements other than vitamin C because of potential confounding. A total of 11 years of follow-up identified 436 first incident cases of kidney stones, and vitamin C was correlated with a dose-dependent twofold significant increased risk. Vitamin C ingestion of fewer than 7 (median) and 7 or more tablets per week demonstrated significant increased relative risk of 1.66 and 2.23 versus supplement nonusers in multivariate analysis (P for trend = 0.001). No specific dosages were recorded (just tablet number), but the authors believe the majority of patients in this study ingested 1,000 mg per day. A commentary following the article estimated 1 kidney stone per 680 high-dose vitamin C users per year if this data is accurate [157].
< div class='tao-gold-member'>
Only gold members can continue reading. Log In or Register to continue
Related posts:
Review of Lifestyle and CAM for Miscellaneous Urologic Topics (OAB and/or Incontinence, Pediatric Urology, Peyronie’s Disease, Premature Ejaculation, UTIs, Miscellaneous): Part Two
Review of Lifestyle and CAM for Miscellaneous Urologic Topics (Bladder Cancer, CP/CPPS, IC/PBS, Kidney Cancer): Part One
Lifestyle Changes, Erectile Dysfunction, and Female Sexual Dysfunction: Heart Health and Sexual Health
BPH/LUTS: Heart Healthy = Prostate Healthy
Complementary and Alternative Medicine for Erectile Dysfunction, Testosterone Replacement Therapy, and Female Sexual Dysfunction
Complementary and Alternative Medicine Interventions for BPH/LUTS
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
