OVERVIEW
Kidney stones are highly prevalent, are a major cause of morbidity, and inflict a large cost on the healthcare system. Epidemiologic studies have quantified the increasing incidence and prevalence of nephrolithiasis and have delineated a wide variety of dietary, nondietary, and urinary risk factors for kidney stone formation.
At least four considerations should be kept in mind in any review of kidney stones. First, it is necessary to prioritize studies that focus on actual kidney stones as an outcome, rather than urine composition. The difficulties of using urine composition as a proxy for kidney stone risk are manifest by the wide array of well-established nonurinary kidney stone risk factors and data implicating the renal interstitium as the site of initial stone formation.1–3 Second, the importance of many kidney stone risk factors vary by individual characteristics such as age, sex, and BMI. Third, there is a relative scarcity of randomized controlled trials (RCTs) in the field of kidney stone prevention. Thus, data from well-performed observational studies can be considered in the clinical setting when devising treatment plans to reduce kidney stone recurrence. Finally, RCTs and large observational studies that help inform current understanding of kidney stone risk factors consist of participants with known calcium oxalate nephrolithiasis or populations who likely have a predominance of calcium oxalate stone disease. Thus, some conclusions from studies of calcium kidney stone disease (e.g. RCT data for water intake and stone prevention) are by necessity applied, albeit carefully and with attention to renal physiology, to less common stone types.
PREVALENCE, INCIDENCE, AND RECURRENCE
Prevalence
The prevalence of nephrolithiasis, defined as a history of stone disease, varies by age, sex, race, and geography. The prevalence in the United States increases with age and is approximately 11% for men and 7% for women: kidney stones occur in about 1 in 11 people in the United States.4 Kidney stone prevalence has increased steadily over the last 35 years for men and women, whether black, Hispanic, or white (Fig. 1.1).4,5 Although the prevalence is consistently lower in blacks and Hispanics than in whites, increases in prevalence over time have been higher for blacks and Hispanics.4 Increased detection of asymptomatic stones resulting from the increasing use and sensitivity of radiologic studies may explain in part the rise in prevalence.
Relatively few population-based studies of the prevalence of nephrolithiasis have been conducted outside of the United States. Prevalence of stone disease has increased in Japan6 and Germany.7
A study of over 1 million individuals in the United States found geographic variability with a north–south and west–east gradient; the highest prevalence of self-reported nephrolithiasis was in the southeastern United States.8
Although the prevalence of nephrolithiasis has been consistently found to be higher in men than women, a decrease in the male-to-female ratio was suggested by a study of hospital discharges.9 Data from the Nationwide Inpatient Survey between 1997 and 2002 found a 4male-to-female ratio 1.3:1. Similarly, the male-to-female prevalence ratio in the most recent NHANES data was ∼1.5, substantially lower than the commonly reported ratio of 2–3:1.
Incidence
The incidence of nephrolithiasis, defined as the first stone event, also varies by age, sex, and race. White males have the highest incidence rates. In men, the incidence begins to rise after age 20, peaks between 40 and 60 years at ∼3/1,000/y and then declines.10–12 In women, the incidence is higher in the late 20s at 2.5/1,000/y and then decreases to 1/1,000/y by age 50, remaining at this rate for the next several decades.11–14
As with prevalence, attempts to compare kidney stone incidence rates over time are complicated by trends toward more frequent imaging and concomitant diagnosis of asymptomatic kidney stones. Over a 24-year period in Iceland, the total incidence of kidney stones increased by nearly 28%.15 However, this increase was due solely to the diagnosis of asymptomatic stones; the annual incidence of symptomatic kidney stones did not increase significantly in either men or women.
A study in Rochester, Minnesota raised the possibility that incidence rates may be decreasing. Using the same methodology as a study performed 30 years earlier, the recent study reported incidence rates since 1990 may be falling in men and have leveled off in women.16 Because there were only 157 cases in men and 91 in women, additional larger studies are needed.
Fig. 1.2: Proportion of types of kidney stones in first-time stone formers (N = 11,666).Courtesy: Professor Michel Daudon is from Paris, France.
Fig. 1.3: Proportion of types of kidney stones in recurrent stone formers (N = 8,671).Courtesy: Professor Michel Daudon is from Paris, France.
Recurrence Rates
Case series suggest 30–40% of untreated individuals will form another stone within 5 years after the initial episode.12 The recurrence rates in the control arms of RCTs and an observational study from Olmstead County17 are lower. The risk of recurrence is influenced by stone type and urinary composition. Features associated with higher rates of recurrence include younger age, male sex, a family history of kidney stones, and uric acid stones.17 Fortunately, randomized trials demonstrated that interventions can reduce the likelihood of recurrence by >50%.18–21
KIDNEY STONE TYPE
Calcium containing kidney stones are the most common, accounting for >80% of incident and recurrent kidney stones (Figs. 1.2 and 1.3).22–25 The majority (>80%) of calcium stones have calcium oxalate as their major constituent; predominantly calcium phosphate stones are less common.26 Uric acid stones represent between 5% and 10% of stones, followed by cystine, struvite, and other less common stone types.22–25 Analysis of stone composition in developing countries27,28 confirms the preponderance of calcium oxalate nephrolithiasis worldwide.
Stone composition can vary by country. Although the majority of kidney stones in one Japanese series were 5calcium oxalate, the proportion of uric acid stones was 16%,29 higher than reported in many other countries. A high prevalence of struvite stones still occurs in some nonindustrialized countries: women in Sub-Saharan Africa had struvite present in 43% of kidney stones.30
Kidney stone composition also may have changed over time. For example, the proportion of struvite stones in Australia decreased from 14% in the 1970s to <7% 40 years later,31 presumably reflecting improvement in management of urinary tract infections in the Australian population. Some26 but not all32 series suggest that the proportion of calcium phosphate in calcium stones may have increased over time. The reason for a potential increase in calcium phosphate temporally is unknown; there has been speculation that preventive or therapeutic maneuvers (such as potassium citrate administration or extracorporeal shock wave lithotripsy [ESWL]) may contribute.26
Finally, kidney stone composition varies by sex, body size, and a variety of comorbidities. Women with calcium stones tend to have a greater proportion of calcium phosphate in kidney stones compared to men,22,26,32 and uric acid stones are more common in men than women.33 Independent of age and gender, higher BMI and diabetes mellitus are both associated with uric acid as compared with calcium kidney stones,33,34 a phenomena presumably due to the lower urine pH associated with insulin resistance.35
COST
The financial burden of nephrolithiasis in the United States is difficult to quantify but is in the billions of dollars. In the year 2000, estimates for the annual healthcare expenditure associated directly with kidney stones ranged between $2.1 billion36 and $4.5 billion37 (or about $5.75 billion in year 2010 dollars). Indirect annual costs of stones in 2000 (due to lost days of work) were estimated to be $775 million37 (about $995 million in 2010 dollars).
Relatively few studies outside the United States have examined the costs of kidney stone disease. In 2010, the annual budget impact for stone disease in France was estimated to be about 590 million Euros38 (about $775 million dollars using average 2010 exchange rates). If France had the same population as the United States in 2010, the cost would have been about $3.7 billion.
Costs due to stone disease in the United States appear to have increased substantially over time. In 2000, the cost of treating and diagnosing stones in the emergency department in the United States was estimated at just under $500 million.36 In a recent study, hospital emergency department charges (which are often higher than actual costs) for stone disease increased annually by 10% over a 4-year period and by 2009 totaled $5 billion39 (about $4 billon in year 2000). Reasons for these increased hospital charges are unclear, but may be due in part to higher utilization of computed tomography.
NONDIETARY RISK FACTORS
Family History
Studies of twins and populations have demonstrated that the common forms of stone disease are heritable.40 A family history of stone disease more than doubles the risk of incident kidney stone formation41 and increases the risk of stone recurrence by 60%.17 The increased risk is likely due to both genetic predisposition and similar environmental exposures. Numerous genetic causes of rare forms of nephrolithiasis (e.g. cystinuria and dent disease) have been identified, but information is still limited on genes that contribute to risk of the common forms of stone disease.
Race/Ethnicity
In a cross-sectional Canadian study, individuals of Arabic, west Indian, west Asian, and Latin American descent were more likely to be stone formers than those of European descent.42 Overall, African Americans have a lower frequency of stones.4,5
Systemic Disorders
There is substantial evidence that nephrolithiasis is a systemic disorder. Well-known conditions that lead to calcium kidney stone formation include primary hyperparathyroidism, renal tubular acidosis, and Crohn's disease. A wide variety of other common conditions including obesity, diabetes mellitus, gout, and gallstones have been linked to the development of kidney stones, and a history of kidney stones is a potential risk factor for the development of systemic diseases such as osteoporosis, chronic kidney disease, coronary heart disease, and hypertension (Table 1.1).
Increasing body size, assessed by weight, body mass index or waist circumference, increases the risk of stone formation independent of other risk factors including diet;43 for unexplained reasons, the impact is greater in women than in men.6
For example, the risk of stone formation for individuals with a BMI ≥ 30 kg/m2 compared with those with a BMI 21–23 was 30% higher among men but nearly twofold higher among women. Although individuals with higher BMI have markedly different 24-hour urine composition than those with lower BMI, including higher urine oxalate and uric acid and lower urine pH,44,45 the calculated relative supersaturation was significantly higher only for uric acid. Additional research is needed to explore further why obesity, independent of diet, may increase the risk of calcium kidney stone formation.
Diabetes mellitus has also been associated with an increased risk of stone formation, independent of diet and body size.46 Cross-sectionally, individuals with a history of diabetes were >30% more likely also to have a history of nephrolithiasis. Prospectively, a history of DM increased the risk of stone formation by 30–50% in women but not in men. In support of these findings, a study based on NHANES III data found that the risk of being a stone former increased with an increasing number of metabolic syndrome traits.47
The association between hypertension and nephrolithiasis is complex. Some prospective studies reported that individuals with hypertension were more likely to develop kidney stones,48,49 but large-scale prospective cohort studies to date have not identified hypertension as an independent risk factor for kidney stone formation.50,51 However, a history of kidney stones is clearly associated with an increased risk of developing hypertension.50–52 In large-scale prospective studies that accounted for differences in age, diet, body size, and other comorbidities, individuals with kidney stones were about 25% more likely to develop hypertension than their nonstone forming counterparts.50,51
Other common diseases such as gout and cholelithiasis are associated with higher risk of kidney stones. In a cross-sectional study, individuals with gout were 50% more likely to have a history of stones.53 When examined prospectively, individuals with a history of gout had a twofold higher risk of incident nephrolithiasis, independent of diet, weight, and medications.54 Large-scale prospective cohort studies report that participants with a history of gallstones are about 30% more likely to develop incident symptomatic kidney stones after adjusting for differences in diet, body size, and other comorbidities.55
The identification of kidney stone disease as a risk factor for other conditions provides additional evidence that nephrolithiasis is a systemic disorder. For example, a number of studies report lower bone mineral density in individuals with a history of nephrolithiasis compared with those who do not.56 The potential mechanism(s) of bone loss in stone formers is unknown, but it is possible that higher urine calcium may result in a negative calcium balance. In a study of 46 stone formers and their first-degree relatives followed for 3 years, the correlation between higher baseline 24-hour calcium excretion and subsequent decrease in femoral neck z-score was −0.37.57 This relation was independent of calcium intake and 24-hour urine markers of dietary acid load such as ammonium and sulfate. Previous reports suggest that individuals with nephrolithiasis may have higher risk of bone fracture.58,59 In a longitudinal study of 624 individuals with history of kidney stones living in Rochester, Minnesota, the risk of an incident vertebral fracture was > 4 times that expected for Rochester individuals of comparable age.59 A recent study utilizing electronic medical record data from the United Kingdom compared > 50,000 individuals with diagnostic codes for urolithiasis to over 500,000 participants without such codes matched on age and sex. The risk of incident bone fracture in individuals with a history of kidney stones was 10% higher in men and also was higher in women between the ages of 30 and 79 (the highest hazards ratio in women was 1.52 for those aged 30–39 years).60
Recent data also implicate kidney stone disease as an independent risk factor for the development of coronary heart disease. In a case-control study including over 15,000 participants with a mean follow-up of 9 years, participants with a history of kidney stones were 31% more likely to have an incident myocardial infarction after adjustment for a wide variety of comorbidities.61 In large prospective cohort studies, a history of kidney stones was associated with an increased risk of incident coronary heart disease in women (but not men) that was independent of age, body size, dietary intakes, and comorbid conditions.62 A prospective study of over 3 million individuals in Alberta, Canada, found a history of nephrolithiasis was associated with an increased risk of coronary heart disease and 7stroke; the risks were higher in women than in men and in younger than older individuals.63
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Cross-sectional data from NHANES III64 as well as case-control studies65,66 and a cohort study67 suggest that kidney stones may represent an independent risk factor for chronic kidney disease. Using the same database mentioned above, investigators performed a prospective study of nearly 2 million individuals in Alberta, Canada, and found a history of nephrolithiasis was associated with an increased risk of developing chronic kidney disease (CKD) or end-stage renal disease (ESRD); however, the absolute risks were small.
Environmental Factors
Occupations or settings with higher insensible fluid losses, such as a hot environment, increase risk of stone formation by reducing urine volume.68 The risk will also be higher when individuals have restricted access to water or bathroom facilities, leading to lower fluid intake and lower urine volume. It is possible that global warming and continued urbanization may increase the world wide burden of nephrolithiasis in the future.69
DIET AND STONE DISEASE
Because most data on the relation between diet and stone disease come from observational and physiologic studies, care must be taken when interpreting studies of diet and risk. Retrospective assessments of diet may be biased because individuals who develop stones may subsequently change their diet. Results from studies that use change in urine composition as a surrogate for actual stone formation should viewed with caution because the composition of the urine does not completely predict risk and not all the components that modify risk are included in the calculation of supersaturation (e.g. urine phytate). Thus, prospective studies that assess a variety of nutrients are best suited for examining the associations between dietary factors and risk of actual stone formation. Finally, associations between specific dietary factors and risk may vary by age, sex, and body size.
Dietary Risk Factors: Calcium Oxalate Stones
More than 80% of kidney stones contain calcium, and the majority of calcium stones consist primarily of calcium oxalate70 (see Fig. 1.2). Because calcium oxalate is most common, the majority of studies have focused on risk factors for this stone type. Dietary factors associated with increased or decreased risk are listed in Table 1.2.
Calcium
In the past, higher calcium intake was believed to increase the risk of stone formation. However, there is now substantial evidence demonstrating that a higher calcium diet is associated with a reduced risk of stone formation. One potential mechanism to explain this apparent paradox is that the higher calcium intake will bind dietary oxalate in the gut, thereby reducing oxalate absorption and urinary excretion.718
Several large prospective observational studies in men and women consistently support a reduced risk of stone formation with increasing dietary calcium intake. Compared to individuals in the lowest quintile of dietary calcium intake, those in the highest quintile had more than a 30% lower risk of forming a stone.10,13,14 These results were adjusted for multiple factors, including age, body mass index, total fluid intake, the use of thiazide diuretics, and the intake of nutrients such as animal protein, magnesium, phosphorous, sodium, and potassium. In the Women's Health Initiative Observational Study, higher dietary calcium also was associated with a lower risk of incident kidney stones.72 Calcium intake is an example of how the impact of a risk factor may vary by age: there was an inverse association between dietary calcium and stone formation in men younger than 60 years of age, but no significant association was found for men 60 years or older.73
These observational findings have been confirmed by a 5-year randomized controlled clinical trial that compared stone recurrence in 120 men with a history of calcium oxalate nephrolithiasis and idiopathic hypercalciuria assigned to a diet low in calcium (400 mg/d) or to a diet with “normal” calcium content (1,200 mg/d) and lower amounts of animal protein and sodium.18 Of note, 1,200 mg/d would represent a “high” calcium diet for many free-living individuals (in one prospective cohort study, men who subsequently developed an incident symptomatic kidney stone had mean dietary calcium of about 800 mg/d10). In addition, participants in both arms of the RCT were advised to avoid consuming a variety of specific foods high in oxalate. The risk of developing a recurrent stone on the higher calcium diet was 51% lower than for the low-calcium diet (Fig. 1.4).18
Unlike their counterparts consuming the low-calcium diet, the men in the “normal” calcium diet arm of the trial had significant decreases in 24-hour urine oxalate compared with baseline, suggesting that intestinal oxalate binding by calcium may have played a role in the study results. The “normal” calcium diet also resulted in a 49% decrease in urine calcium excretion compared to baseline, likely due to the concomitant restriction of sodium and animal protein intakes. Because dietary sodium and animal protein may influence calcium stone formation, this trial, although suggestive, did not directly address the independent role of dietary calcium in the pathogenesis of kidney stones.
It is possible that dairy products (the major source of dietary calcium) may contain as yet unidentified factors that inhibit calcium kidney stones. The men in the low-calcium diet arm in the RCT displayed in Figure 1.2 decreased calcium intake by limiting intake of milk, yogurt, and cheese. However, large-scale prospective cohort studies have reported that dietary calcium from nondairy sources (in addition to dietary calcium from dairy) also is independently associated with a reduced risk of kidney stones.74
Fig. 1.4: Comparison of low versus normal calcium diets for kidney stone prevention.18
The impact of supplemental calcium on stone risk may be different from dietary calcium. In an observational study of older women, calcium supplement users were 20% more likely to form a stone than women who did not take supplements.13 The Women's Health Initiative randomized trial also found an increased risk with calcium supplementation (1,000 mg/d), though the supplements also contained 400 IU/d of vitamin D3.75 In younger women and men, there was no association between calcium supplement use and risk of stone formation.10,14 The discrepancy between the risks from dietary calcium and calcium supplements, at least in the observational study, may be due to the timing of calcium intake. Calcium supplements are not typically taken with meals, which would diminish binding of dietary oxalate.
Because the absolute risk of forming the first kidney stone by a supplement user is only slightly increased (1.2 cases/1,000 women per year compared to 1.0/1,000 per year), supplement use is not a major contributor to stone risk. However, individuals with a history of calcium nephrolithiasis should be encouraged to obtain calcium from dietary rather than supplemental sources.9
Oxalate
Although urine oxalate is a well-established and important risk factor for calcium oxalate stone formation, the role of dietary oxalate in the pathogenesis of calcium oxalate nephrolithiasis remains unclear.76 First, the proportion of urinary oxalate derived from dietary oxalate is controversial; estimates range from 10% to 50%.76 Thus, a substantial proportion of urinary oxalate is derived from the endogenous production such as the metabolism of glycine, glycolate, and hydroxyproline. Second, other dietary factors influence urine oxalate. For example, vitamin C supplementation may be an important contributor77–79 because it can be metabolized to oxalate. Third, much of the oxalate in food may not be readily absorbed due to low bioavailability. Finally, there is variation between individuals with respect to the GI absorption of dietary oxalate. For instance, up to one-third of patients with calcium oxalate nephrolithiasis may have higher absorption of dietary oxalate.80 The reasons for the higher absorption are unclear but likely candidates include genetic predisposition and the intestinal microbiota. One study found individuals with a history of calcium oxalate nephrolithiasis were less likely to be colonized with Oxalobacter formigenes, an intestinal bacterium that degrades oxalate.81
Older reports of the oxalate content in food may be unreliable due to measurement issues, related to the quality of the assay procedure as well as the variability in oxalate content of the same food items. More recently, however, reliable assays for the direct determination of the oxalate content of food, including ion chromatography and capillary electrophoresis, have been developed. One study used these new methods to measure the oxalate content of >200 food items, measuring several different samples for each food and also performing each measure in triplicate (the values can be found at https://regepi.bwh.harvard.edu/health/Oxalate/files). Some representative foods from this list are shown in Table 1.3. Although they are sometimes grouped into “very high” or “high” oxalate categories, this distinction is arbitrary. An individual can consume large amounts of oxalate by eating individual foods that are very high in oxalate or by eating larger quantities of foods that are more moderate in oxalate content.
Large-scale prospective studies of the relation between dietary oxalate and kidney stone formation have been completed. Surprisingly, the impact of dietary oxalate, even when comparing substantial differences in intake, was modest in men and older women and not associated with stone formation in younger women.82 These population-based data should not be interpreted to mean that dietary oxalate restriction is ineffective at preventing kidney stone recurrence in selected individuals, particularly those with higher urine oxalate excretion. There is likely a subgroup of patients who have increased oxalate absorption, which would result in an increased risk of calcium oxalate stone formation.
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Sodium
Higher sodium intake results in decreased renal tubule sodium reabsorption with a subsequent reduction in calcium reabsorption. Restriction of sodium intake is a highly effective means of lowering urine calcium and therefore represents a mainstay in the dietary treatment of calcium nephrolithiasis. A RCT of dietary salt restriction in calcium oxalate stone formers with idiopathic hypercalciuria demonstrated that for every 100 mmol decrease in urine sodium, urine calcium decreased by about 100 mg/d.83
Previous prospective cohort studies found a positive, independent association between sodium consumption and new kidney stone formation in women but not men.10,13 In the Women's Health Initiative Observational Study, women in the highest compared with lowest quintile of sodium intake had a 61% increased risk of incident nephrolithiasis.72
Animal Protein
Higher animal protein intake may increase urinary calcium and decrease urinary citrate,84 thereby increasing the risk of stone formation. However, when studied prospectively, 10animal protein was associated with an increased risk in men but not women.10,13,14,72 Further, the increased risk in men was only found among men with BMI < 25 kg/m2.73
Potassium
Higher dietary potassium intake was associated with a lower risk of incident stone formation in men and older women10,13,73 possibly by reducing urine calcium excretion85 or increasing urine citrate. Recent data also shows that higher dietary potassium was associated with lower risk of incident stones in younger women.115
Sugars
Higher intake of sucrose increases urinary calcium excretion independent of calcium intake.86 In prospective studies, sucrose was associated with an increased risk in women and fructose was associated with an increased risk in men and women.13,14,87
Magnesium
Although higher magnesium intake may reduce dietary oxalate absorption, randomized trials of magnesium supplements did not find a protective effect on stone recurrence, though the dropout rates in these studies were high. In prospective observational studies, higher dietary magnesium was associated with a lower risk of stone formation in men73 but not women.13,14
Vitamin C
Vitamin C (ascorbic acid) can be metabolized to oxalate and may increase the risk of calcium kidney stone formation. Consumption of 1,000 mg of supplemental vitamin C twice daily increased mean urinary oxalate excretion by 22%, but there was notable between-person variability.78 In a prospective observational study, men who consumed 1,000 mg or more per day of vitamin C had a 40% higher risk of stone formation compared to men who consumed <90 mg/d (the recommended dietary allowance).73 In a prospective cohort study of Swedish men, supplemental vitamin C use was associated with a near doubling of the risk of incident kidney stones.88 While these data do not support the restriction of dietary vitamin C (because many foods high in vitamin C contain alkali, which could raise urine citrate and thereby inhibit calcium oxalate crystal formation), calcium oxalate stone formers should avoid high-dose vitamin C supplements.
More research is needed to elucidate the relation between vitamin C intake, oxalate metabolism, and kidney stone risk. First, it is uncertain whether vitamin C intake is associated with risk in women. Second, feeding studies of vitamin C and urine composition may be substantially complicated by ex vivo nonenzymatic conversion of urinary vitamin C to oxalate in the collection vessel during storage and/or analysis.89
Vitamin B6
Although high-dose vitamin B6 (pyridoxine) reduces oxalate production in selected patients with type 1 primary hyperoxaluria,90,91 it is unclear if there would be benefit from the use of vitamin B6 supplements to prevent common stone disease. In an observational study, higher intake of vitamin B6 was not associated with a reduced risk of kidney stone formation in men.92,93
Phytate
Phytate, found in whole grains and beans, was observed to reduce risk of stone formation in younger women,14 possibly by directly inhibiting calcium oxalate crystal formation.
Dietary Patterns
Although the examination of individual nutrients provides valuable insights, it may be easier for patients to follow certain types of dietary patterns than modifying individual nutrients. Relatively few studies have examined the impact of overall diet or dietary patterns on risk of stone formation. The Dietary Approaches to Stop Hypertension (DASH) diet, which is high in fruits and vegetables, moderate in low-fat dairy products, and low in red and processed meats, represents a novel potential means of kidney stone prevention. In a large, prospective observational study of three distinct cohorts, a higher dietary DASH score (meaning a diet more similar to the DASH diet) was associated with a 40–45% reduction in the risk of incident kidney stone formation.94 Although participants in the highest compared with lowest quintile of dietary DASH score in this study had a marked reduction in risk of kidney stones, their dietary oxalate intake was about 60% higher. The association between higher DASH score and lower stone risk was independent of age, body size, hypertension, diabetes, thiazide use, and intakes of total calories, fluid, caffeine, and alcohol.11
The potential mechanism(s) underlying the impact of a DASH diet on kidney stone risk require elucidation. Intakes of fruit and vegetables have a major effect on urine composition. In a metabolic study of 12 adults, the complete elimination of fruits and vegetables from the diet lowered urine oxalate by 31% but also decreased urine citrate and increased urine calcium.95 The net effect was an increase in urinary supersaturation with respect to calcium oxalate. In a cross-sectional study of nearly 3,500 individuals with and without nephrolithiasis, higher dietary DASH scores were associated with slightly higher 24-hour urine oxalate excretions but lower 24-hour urine citrate and higher 24-hour urine volume.96 Recently, a randomized trial compared the effects of a DASH-style diet versus a low-oxalate diet on urine composition in 57 individuals with recurrent nephrolithiasis and urine oxalate > 40 mg/d.97 Although limited by small size and a high drop-out rate, the results were provocative. The DASH diet resulted in urine citrate that was > 220 mg/d higher compared with the low-oxalate diet. Although other differences were not statistically significant compared with the low-oxalate diet, the DASH diet resulted in higher urine oxalate, higher urine volume, and lower urine supersaturation with respect to calcium oxalate.
Dietary Risk Factors for Other Stone Types
For the less common stone types, little data exist to support the role of specific dietary factors in kidney stone formation. It is possible to speculate about the impact of diet based on urine composition and our current understanding of pathophysiology, but it should be remembered that the many of the older recommendations for calcium oxalate stone prevention based on urine composition or pathophysiologic considerations were later found not to be supported by prospective studies of actual stone formation.
Uric Acid Stones
Although higher urine uric acid also contributes, the major determinant of uric acid crystal formation is low urine pH (the solubility of uric acid increases markedly as the urine pH increases from 5.0 to 6.5). Decreasing consumption of meat, chicken, and seafood will decrease purine intake and, therefore, reduce uric acid production; this may also increase urinary pH by reducing acid production. Higher intakes of fruits and vegetables raise the urine pH and should reduce the risk of uric acid crystal formation.
Given the well-documented association between greater weight and higher uric acid production and excretion and lower urine pH,44,45 it would be reasonable to encourage dietary intakes designed to maintain a healthy weight in individuals with recurrent uric acid stones.
Cystine Stones
Restricting sodium intake may reduce the urinary excretion of cystine.98 The solubility of cystine increases as urinary pH rises,99 thus higher fruit and vegetable consumption may be beneficial. There is little evidence to support the dietary restriction of proteins high in cystine, though reducing animal protein intake may be beneficial by increasing urine pH.
Calcium Phosphate Stones
Because patients with type 1 (distal) renal tubular acidosis and stone disease may benefit from alkali supplementation, they may also benefit from a diet high in fruits and vegetables. It should be noted, however, that an increase in urinary pH can increase the risk of calcium phosphate crystal formation. Dietary maneuvers directed at decreasing urinary calcium excretion (such as sodium and animal protein restriction) would also be expected to decrease calcium phosphate stone recurrence. It is unknown whether dietary phosphorus restriction would decrease calcium phosphate stone risk.
BEVERAGES AND CALCIUM STONES
Total Fluid
Nephrolithiasis is a disease driven by the urinary concentration of lithogenic factors. Thus, fluid intake, the main determinant of urine volume plays a critical role in kidney stone formation. Prospective observational data consistently demonstrate that higher fluid intake is associated with lower risk of incident kidney stones.10,13,14 In a 5-year RCT of first time calcium stone formers, higher water intake resulted in a marked reduction in kidney stone recurrence.100 In this trial, 99 participants were assigned higher water intake with a 24-hour urine volume goal of 2 L, whereas no specific intervention was employed for the 100 participants in the control arm. At baseline, 24-hour urine volume was about 1 L in both groups. Individuals in the high water intake group were instructed to measure their 12urine volume at home every 2–3 months. Participants in the high water intake group (Group 1 in Fig. 1.5) had a mean 24-hour urine volume just over 2.5 L/d at years 3, 4, and 5 of the trial and had more than a 50% reduction in stone recurrence compared to the control group (Group 2).
Fig. 1.5: Water intake and recurrent stone events in individuals with calcium nephrolithiasis. Group 1 randomized to high water intake and Group 2 without intervention.Source: Reproduced with permission from Borghi L, Meschi T, Amato F, et al. Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol. 1996;155:839-43.
Individual Beverages
While total fluid intake is most commonly discussed, the type of beverage consumed may influence risk beyond just the volume of the beverage consumed.101 The associations between specific beverages, accounting for fluid intake, with kidney stone formation are presented in Table 1.4.
Despite previous beliefs to the contrary, alcoholic beverages, coffee, and tea are not associated with an increased risk of kidney stone formation. In fact, observational studies have consistently found that coffee, tea, beer, and wine are associated with a reduced risk of stone formation.101–103 The mechanisms for these protective associations may be related to inhibition of antidiuretic hormone action in the kidney by caffeine and inhibition of antidiuretic hormone secretion by alcohol. In large-scale prospective studies, caffeine intake is independently associated with a lower risk of incident stones.104 The role of tea deserves special mention. There is a widespread belief that tea is high in oxalate and should be avoided. A cup of tea contains 14 mg of oxalate. Although this is not insignificant, the bioavailability does not appear to be high. A feeding study of tea demonstrated a negligible impact on urinary oxalate.105
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Citrus juices, such as orange and grapefruit juice, theoretically could reduce the risk of calcium stone formation by increasing urine citrate. The prospective studies found that compared with participants who consumed less than one serving per week of orange juice, participants who consumed one serving per day or more had a 12% lower risk of incident kidney stone formation.101 This association was independent of differences in age, race, body size, comorbidities, dietary intakes, and consumption of other beverages. Grapefruit juice intake was not associated with risk. One feeding study found that grapefruit consumption increased not only urine citrate but also urine oxalate.106
The relation between citrate-containing beverages and urine citrate is complex. A major determinant of urine citrate excretion is acid-base status: alkalosis decreases renal tubule reabsorption of filtered citrate and increases urinary citrate excretion.107 Thus, the effect of an orally administered citrate-containing fluid on urine citrate depends in part on fluid pH. Beverages with lower pH will have a predominance of hydrogen ion as the accompanying citrate cation, whereas beverages with higher pH have potassium as the accompanying cation. Unlike potassium citrate, intestinally absorbed citrate in the protonated form is neutral from an acid-base standpoint and would be expected (in the absence of very large quantities that overwhelm the liver's capacity to metabolize citrate to bicarbonate) to have minimal impact on urinary citrate. This principle was illustrated in a crossover metabolic study of 13 volunteers on standardized diets who consumed the same 13volume of water, lemonade, or orange juice with meals.108 Although participants consumed identical quantities of citrate in lemonade and orange juice, only orange juice resulted in higher urine citrate excretion.
An early report about the increase in urine citrate by homemade lemonade109 generated substantial enthusiasm about this beverage for preventing stone recurrence. However, subsequent studies did not consistently replicate the findings. The citrate and malate content of lemonade and several diet sodas were measured,110 with most beverages containing <8 meq of alkali per liter. Thus, it would take consumption of at least several liters per day to have an expected increase in urine citrate.
The consumption of sugar-sweetened sodas (“soft drinks”) is clearly associated with a higher risk of incident kidney stones,101–103 but the exact mechanism is uncertain. Sugar-sweetened sodas contain fructose, which has been associated with an increased the risk of kidney stones.87 Dietary patterns associated with sweetened soda consumption were found to increase the risk of stone formation.94 Intakes of other sugar-sweetened beverages, such as punch, also are associated with higher risk of kidney stones.101
URINARY FACTORS
The 24-hour urine collection provides important prognostic information and guides preventive recommendations. Like many laboratory tests, urine results have traditionally been categorized into “normal” and “abnormal.” However, this grouping is unsatisfactory. Substantial differences in kidney stone risk associated with higher or lower 24-hour urine values occur within ranges considered “normal.”77 Urine values are continuous so the dichotomization into “normal” and “abnormal” is arbitrary and potentially misleading. Thus, while terms of abnormal excretion such as “hypercalciuria,” “hyperoxaluria,” or “hypocitraturia” are often used clinically and in the scientific literature, the limitations of these terms should be acknowledged.
Urine Calcium
Hypercalciuria had traditionally been defined as urine calcium excretion > 300 mg/d in men and > 250 mg/d in women111 on a 1,000-mg/d calcium diet, but more commonly used definitions have lower thresholds and no dietary requirement. Using the traditional definitions, ~0–40% of patients with calcium stone disease will be classified as having hypercalciuria. Although possibly reasonable from a calcium balance perspective, there is insufficient justification with respect to stone formation to use different thresholds for males and females.
Fig. 1.6: Percentage of individuals without a history of nephrolithiasis who subsequently developed incident urinary stone disease (USD) by quartile of baseline urinary calcium (Ca) excretion.112 Blue bars are men; Orange bars are women.
Higher urine calcium is an established, major risk factor for calcium kidney stone formation. In a large cross-sectional study of over 2,200 stone formers and 1,100 nonstone formers, participants with 24-hour urine calcium >350 mg were between 5 and 6 times as likely to have a history of kidney stones compared with participants with 24-hour urine calcium <100 mg.77 The higher kidney stone risk associated with higher 24-hour urine calcium started well below usual cutoffs for “hypercalciuria” and was independent of age, 24-hour urine creatinine, and other urinary factors. In a 9 year prospective cohort study that included over 3,000 men and women without a history of nephrolithiasis at baseline, higher urine calcium was strongly associated with an increased risk of developing an incident kidney stone (Fig. 1.6).112 For each ~100 mg/d higher urine calcium at baseline, the risk was 20% higher for incident kidney stone formation.
Urine Oxalate
Hyperoxaluria is often defined as urinary oxalate excretion >45 mg/d, though here too a variety of thresholds are in use. Elevated urinary oxalate excretion is 3–4 times more common among men (~40%) than in women (~10%).77 Mean urinary oxalate levels are only slightly higher in kidney stone cases than in controls, but in multivariate 14models urine oxalate is clearly an important independent risk factor for stone formation.77 Depending on their age, women with 24-hour urine oxalate >40 mg were between 2.5 and 3.5 times as likely to have a history of kidney stones compared with women with 24-hour urine oxalate <20 mg.77 Men with 24-hour urine oxalate >50 mg were over 3 times as likely to have a history of kidney stones compared with men with 24-hour urine oxalate <25 mg.77 Of note, in men and women the risk begins to rise well below the 45 mg/d level.
Urine Uric Acid
The relation between uric acid excretion and calcium stone disease is unsettled. Some early cross-sectional studies reported that hyperuricosuria (typically defined as >800 mg/d in men or 750 mg/d in women) was more frequent in patients who form calcium stones than controls.113 However, in the cross-sectional study of over 2,200 stone formers and 1,100 nonstone formers, a higher urine uric acid was associated with a lower likelihood of being a stone former in men, and there was no higher risk in women.77 A double-blind trial of allopurinol successfully decreased recurrence rates of calcium stones in patients with hyperuricosuria suggesting that uric acid is important,19 but it is possible that the beneficial effect of allopurinol was through a mechanism unrelated to lowering of urine uric acid.
Urine Citrate
Hypocitraturia, often defined as 24-hour excretion < 320 mg/d, increases risk of calcium stone formation114 and is found in 5–11% of first time stone formers.77 There is suggestive evidence that increasing urinary citrate into the high-normal range could provide additional protection.77 Individuals with 24-hour urine citrate <300 mg were between 3 and 4 times as likely to have a history of kidney stones compared with those with 24-hour urine citrate >800 mg.77 As with other urinary factors, the risk varied by urine citrate level even within the “normal” range.
SUMMARY
Epidemiologic studies have greatly expanded our understanding of risk factors for stone disease. A variety of dietary, nondietary, and urinary risk factors contribute to the risk of kidney stone formation and the importance of these varies by age, sex, and BMI. There is a paucity of randomized trials in the field, and more interventional studies are needed to further our understanding of risk factors for the “hard” outcome of kidney stone formation.
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