Version May 2024
INTRODUCTION — Kidney stone disease (nephrolithiasis) is a common problem in primary care practice [1,2].
This topic will review the epidemiology of kidney stones and risk factors for stone formation in adults. Other aspects of kidney stones in adults are discussed separately:
●(See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis".)
●(See "Kidney stones in adults: Evaluation of the patient with established stone disease".)
●(See "Kidney stones in adults: Prevention of recurrent kidney stones".)
●(See "Kidney stones in adults: Surgical management of kidney and ureteral stones".)
EPIDEMIOLOGY
Prevalence and incidence — Kidney stones are a common problem. A study based upon the National Health and Nutrition Examination Survey (NHANES) estimated that 19 percent of males and 9 percent of females will be diagnosed with a kidney stone by the age of 70 years [1].
In a report from the third NHANES, the population prevalence increased from 3.8 percent in this period from 1976 to 1980 to 5.2 percent in the period from 1988 to 1994 [2]. The prevalence increased in males and females, and in White patients and Black patients. Although one study suggested that the incidence rates since then may have leveled off [3], the 2007 to 2010 NHANES data found a continued increase in prevalence to 8.8 percent in the United States population [1]. Factors that may be contributing to this increase in stone prevalence include the increase in obesity, rising temperatures, and improvements and higher utilization of diagnostic imaging techniques:
●Age – The prevalence of ever having had a stone increases with age. According to data from NHANES cycles 2007 to 2016, the prevalence was 5.1 percent in males age 20 to 39 years, compared with 19.7 percent in males age 80 years and older [4]. Similarly, the prevalence was 5.8 percent in females age 20 to 39 years, compared with 10.6 percent in females age 80 years and older.
Among males, the incidence (likelihood of having a first stone) is approximately 2 per 1000 per year in those under 40 years, increases to approximately 4 per 1000 per year in those 40 to 60 years, and then declines with age [5]. Among females, the incidence is approximately 2 per 1000 per year among those under 40 years and declines with age to approximately 1.5 per 1000 per year (figure 1). However, even an 80-year-old male or female may present with a first stone.
●Sex – Although the prevalence of a history of nephrolithiasis is similar among males and females below age 40 years, the overall prevalence of stone disease is approximately twice as high in males compared with females. Incidence rates are also similar in males and females below age 40 years, but above age 40 years the rates are higher in males than in females (figure 1).
●Race/ethnicity – Stone disease is most common in White patients who are not Hispanic, followed by White patients who are Hispanic, and is least common in Black patients and Asian patients.
●Geography – In the United States, there is a north-south gradient and west-east gradient, with the higher prevalence of stone disease in the southeastern United States [6]. The reason for the higher prevalence is not clear.
●Disability – In the United States, the prevalence of stone disease is higher among persons with functional disabilities than among those without disabilities (16 versus 9 percent, respectively) [7]. The reason for this higher prevalence is unclear but may be related to health care disparities in this patient population.
Stone composition — The frequency of different stone composition in adults is as follows (figure 2) [8]:
●Calcium oxalate – 70 to 80 percent
●Calcium phosphate – 15 percent (apatite is the most common type of calcium phosphate crystal; brushite is much less common)
●Uric acid – 8 percent
●Cystine – 1 to 2 percent
●Struvite – 1 percent
●Miscellaneous – <1 percent
Stone recurrence — Despite how common nephrolithiasis is, high-quality and generalizable information on stone recurrence rates is scant.
The rate of stone recurrence is 10 to 30 percent at three to five years among patients with idiopathic calcium oxalate stones [9-11]. A higher recurrence rate of approximately 15 percent at 1 year, 35 to 40 percent at 5 years, and 50 percent at 10 years was found in another study and was higher in males than females [12,13] (see "Kidney stones in adults: Evaluation of the patient with established stone disease"). This variability is due, in part, to differences in sensitivity of different types of imaging modalities and different definitions of recurrence (eg, symptomatic versus radiologic change in stone size or stone number).
The overall stone recurrence rate depends on factors such as previous stone history (including composition) and type of treatment [13].
MODIFIABLE RISK FACTORS
Urinary factors — Certain biochemical abnormalities of the urine composition have been associated with kidney stone formation. The degree to which these risk factors contribute to stone disease varies in different populations. In addition, the definitions of "abnormal" are somewhat arbitrary and may differ from study to study. Correction of these biochemical abnormalities may help to prevent recurrent stone formation. (See "Kidney stones in adults: Prevention of recurrent kidney stones".)
Calcium phosphate and calcium oxalate stones share some risk factors such as low urine volume, high urine calcium, and low urine citrate [14]. However, there are also distinct risk factors for each type of stone. As an example, higher urine oxalate is a risk factor for calcium oxalate stones, while higher urine pH is a risk factor for calcium phosphate stones. Low urine volume and lower urine pH are risk factors for uric acid stones. Because the approach to stone prevention depends upon the composition of the stone, it is essential that every attempt is made to retrieve a passed or removed stone and to send it for analysis.
One study evaluated 1270 patients in Texas over a 15-year period for recurrent stone disease and reported their frequencies of urinary abnormalities [15]. Many patients had more than one risk factor:
●Hypercalciuria – 61 percent, including some patients with primary hyperparathyroidism
●Hyperuricosuric calcium stones – 36 percent
●Hypocitraturia – 28 percent idiopathic and 3.3 percent due to distal (type 1) renal tubular acidosis or chronic diarrhea
●Hyperoxaluria – 8 percent, including enteric and primary forms and markedly increased oxalate intake
●Low urine volume (<1 L/day) – 15 percent
Another report compared the frequency of these biochemical abnormalities in first-time stone formers and in individuals who had not formed a stone, and a substantial difference was noted only for urinary calcium and citrate excretion [16]. However, as noted above, dividing patients into "normal" and "abnormal" should be discouraged, as the risk is continuous.
High urine calcium — An elevated urinary calcium excretion, with or without other risk factors, is observed in up to one-half of idiopathic calcium stone formers [17].
●Definition – Hypercalciuria has been variably defined, and each definition has limitations:
•Urinary calcium excretion greater than 250 mg/day (6.24 mmol/day) in females and greater than 300 mg/day (7.49 mmol/day) in males were the traditional definitions. However, there is no clear justification from the perspective of stone formation why a male is allowed to have more calcium in his urine than a female. The cutpoints used in published research studies and clinical laboratories vary substantially, with some using the same value for males and females, such as greater than 200 mg/day (4.99 mmol/day).
•Urinary calcium excretion greater than 4 mg/kg (0.1 mmol/kg) per day is another definition. The problem with this definition is that it allows heavier individuals to have more calcium in their urine than lighter individuals. While this may be appropriate from a calcium-balance standpoint, it does not make sense for stone formation. Since urine volume does not increase with weight gain, a "normal" urinary calcium excretion in a heavier person would result in a higher concentration of calcium in the urine (and a higher risk).
An additional problem with dichotomous definitions is that the risk of stone formation rises with increasing urinary calcium excretion above 100 mg/day (2.5 mmol/day), not at some arbitrary threshold value. This was illustrated in a cross-sectional study of 3350 males and females, of whom 2237 had a history of nephrolithiasis (figure 3) [17]. Compared with a 24-hour urinary calcium excretion below 100 mg, the relative risk of being a stone former in older females was 1.52 for a urinary calcium of 150 to 199 mg/day (3.74 to 4.97 mmol/day), 1.84 for a urinary calcium of 200 to 249 mg/day (4.99 to 6.23 mmol/day), and 1.93 for a urinary calcium of 250 to 299 mg/day (6.24 to 7.48 mmol/day). The relative risk increased further at clearly hypercalciuric levels: 2.68 and 4.94 at urinary calcium of 300 to 349 mg/day (7.49 to 8.72 mmol/day) and greater than 350 mg/day (8.73 mmol/day), respectively. Similar results were found in males and younger females. The relation to risk appears to be continuous. Thus, the use of the term "hypercalciuria" is not ideal, because there is no clear threshold below which the risk is low and above which the risk is high.
●Mechanisms – Possible reasons for higher urine calcium in calcium stone formers include primary hyperparathyroidism, chronic acidemia from distal renal tubular acidosis, and very high levels of calcium intake (typically supplemental calcium) [18,19]. However, most calcium stone formers with higher urine calcium do not have either of these disorders or have excessive calcium intake. (See "Nephrolithiasis in renal tubular acidosis".)
High urine calcium excretion without an identifiable cause is often referred to as idiopathic hypercalciuria. Conceptually, it is useful to consider three contributions to higher urinary calcium excretion [20,21]:
•Increased intestinal absorption ("absorptive hypercalciuria") in which there is an increase in intestinal calcium absorption [22,23]. However, dietary calcium intake typically should not be restricted unless it is >1000 mg/day. (See 'Calcium' below.)
•Increased bone resorption ("resorptive hypercalciuria") in which the source of the excess calcium may be bone.
•Increased renal losses ("renal hypercalciuria") in which there is a defect in renal tubular calcium reabsorption.
The clinical significance of this classification is uncertain. Most individuals with higher urine calcium exhibit more than one abnormality and may change categories over time. Thus, it is not necessary for clinical purposes to perform calcium-loading or calcium-restriction tests.
It has been suggested that idiopathic hypercalciuria is transmitted as an autosomal dominant trait. Reports have suggested certain gene defects [24,25], but others have been unsuccessful in identifying a locus. This may be due to the likely substantial heterogeneity of this disorder [26,27]. One genome-wide association study involving 6462 adults found a single-nucleotide polymorphism (SNP; rs17216707 on chromosome 20) significantly associated with 24-hour urine calcium excretion [28]. This SNP is located near CYP24A1, the gene that encodes the enzyme that inactivates 1,25-dihydroxyvitamin D.
Idiopathic hypercalciuria may be associated with a slightly higher plasma concentration of calcitriol (1,25-dihydroxyvitamin D3) [29,30], although the values are rarely above the upper limit of the reference range. Higher calcitriol levels can enhance calcium excretion both by increasing intestinal calcium absorption (absorptive hypercalciuria) and by promoting bone resorption (resorptive hypercalciuria) [31]. The latter effect has important clinical implications since lowering calcium intake may not dramatically reduce urine calcium excretion and may result in negative calcium balance, leading to calcium being removed from bone. If prolonged, the negative calcium balance can lead to osteopenia [29,32-35]. This may be particularly important since some untreated patients with hypercalciuria already have diminished bone density, due possibly to increased bone resorption [29]. However, excessive supplemental calcium does not "drive" calcium into the bones and may instead lead to higher urine calcium excretion (thereby increasing stone risk). Thus, careful consideration of the risks and benefits of supplemental calcium intake is essential.
In addition, while modest intake of supplemental vitamin D does not appear to increase the risk of stone formation in most individuals [36], excessive intake could increase the risk, particularly in combination with calcium supplements [37].
The factors responsible for the higher calcitriol levels in some patients with idiopathic hypercalciuria are not well understood. It has been proposed that a urinary phosphate leak might be the primary defect [38], leading to a mild reduction in the plasma phosphate concentration that would then stimulate the synthesis of calcitriol.
High urine oxalate — The risk of calcium oxalate stone formation increases as urine oxalate excretion increases [17]. It was believed that a small increase in oxalate excretion represented a relatively large percentage change and, therefore, was more likely to promote calcium oxalate precipitation to a greater degree than a similar absolute increase in calcium excretion [39,40], but this has been questioned. The reported frequency of hyperoxaluria varies widely depending upon the sex and number of previous stones in the population studied (table 1):
●Definition – The widely used definition of normal urinary oxalate excretion is less than 45 mg/day (0.5 mmol/day), generally less than 20 percent that of calcium [41]. However, similar limitations of the chosen "normal" cutpoint also apply to oxalate. In fact, the risk of stone formation begins to increase significantly at urinary oxalate excretion above 25 mg/day, well within the "normal" range [17]. Thus, the risk of stone formation increases with increasing urine oxalate, even if the value is within the "normal" range.
●Mechanisms – The relative contribution of endogenous and exogenous oxalate to urine oxalate excretion remains uncertain [40,42]. Although there is general agreement that increasing dietary oxalate increases urinary oxalate excretion, the amount of the increase varies substantially by the type of food (not just the oxalate content of the food); the overall impact of dietary oxalate on stone risk appears to be relatively small [40,43], but it is substantially influenced by concomitant calcium intake, with the risk being higher in those with lower calcium intake. It also varies because some individuals are more sensitive to dietary oxalate intake due to differences in oxalate absorption.
Endogenous oxalate is primarily derived from the metabolism of glycine and ascorbic acid [41]. The actual contribution of dietary oxalate to urinary oxalate excretion has been difficult to ascertain, given incomplete information on the oxalate content and bioavailability in many foods. Dietary oxalate may have a more prominent effect in individuals with idiopathic calcium oxalate nephrolithiasis; these individuals seem to have a higher rate of oxalate absorption (and urinary excretion) than control patients given the same standard diet and amount of exogenous oxalate [44]. (See "Primary hyperoxaluria".)
The importance of intestinal oxalate absorption is supported by observations regarding the effect of dietary calcium. Dietary calcium can decrease oxalate absorption in the gut by the formation of insoluble calcium oxalate salts in the intestinal lumen. When less calcium is available in the intestinal lumen to bind oxalate, oxalate absorption, and therefore urinary oxalate excretion, increases. Relatively common settings in which this occurs include:
•With a low-calcium diet, which is generally not recommended for idiopathic calcium stones [11] (see 'Calcium' below)
•With increased intestinal calcium absorption, as may be seen in individuals with higher urine calcium
•Malabsorption syndromes, as with small bowel disease (eg, Crohn disease), surgical bowel resection or diversion, including jejunoileal bypass for obesity (bariatric surgery), or cystic fibrosis [45-52]
This last situation leads to the malabsorption of fatty acids and bile salts and is called enteric hyperoxaluria. The increase in oxalate absorption and subsequent excretion is due both to binding of free calcium to fatty acids in the intestinal lumen and to increased colonic permeability to small molecules such as oxalate induced by exposure of the colon to nonabsorbed bile salts [53-56].
The rate of hyperoxaluric stone formation is higher in patients who have undergone some types of bariatric surgery. This is discussed in more detail elsewhere in this topic. (See 'Medical conditions' below.)
Alterations in gastrointestinal flora, such as may be seen with prolonged administration of antibiotics (common in disorders such as cystic fibrosis) can lead to decreased degradation of oxalate and, thus, increase the risk of hyperoxaluria [57-59]. One possibility is the loss of the bacterium Oxalobacter formigenes, or other bacteria that degrade oxalate and promote enteric oxalate secretion (thus reducing urinary oxalate excretion) [60-64].
In addition, it has been proposed that mild hyperoxaluria may be due to a genetic abnormality (with autosomal dominant inheritance) characterized by increased activity of a chloride/oxalate anion exchanger (similar to the band 3 protein, chloride/bicarbonate exchanger in the red cell). This abnormality has been demonstrated in red cells and is associated with increased fractional oxalate excretion, suggesting that it is also present in the renal tubules [39]. Another possibility suggested by an experimental model is a defect in oxalate secretion into the intestinal lumen [65].
Higher oxalate production may contribute to the risk of calcium oxalate stone formation, but the mechanisms that control endogenous oxalate production are unclear. Higher oxalate production is a likely contributor to the higher risk of stone disease in males compared with females. Dramatically increased oxalate production can occur in the setting of high-dose vitamin C therapy and primary hyperoxaluria, a rare disorder in which enzyme deficiencies lead to overproduction of oxalate from glyoxylate. (See 'Vitamin C' below and "Primary hyperoxaluria".)
Low urine citrate — A decrease in excretion of urinary inhibitors of crystal formation is another mechanism that can promote the development of kidney stones [66-70]. One substance thought to be a principal inhibitor of calcium stone formation is citrate. Low urine citrate can occur in isolation in stone formers or in combination with other urinary abnormalities including high urine calcium and high urine oxalate:
●Definition – Hypocitraturia has been defined as citrate excretion below 320 mg/day. However, as with all urinary factors, this definition is somewhat arbitrary [17], and the association with risk of stone formation is continuous [17].
●Mechanisms – Citrate acts in the tubular lumen by combining with calcium to form a nondissociable but soluble complex. As a result, there is less free calcium available to combine with oxalate. In addition, citrate also appears to inhibit the important process of crystal agglomeration, in which individual calcium oxalate crystals combine to form a stone [71].
One major factor that can limit citrate excretion by enhancing proximal reabsorption is chronic metabolic acidosis induced by chronic diarrhea, renal tubular acidosis (complete or incomplete), the administration of carbonic anhydrase inhibitors (including antiseizure medications such as topiramate and zonisamide), or ureteral diversion. (See "Nephrolithiasis in renal tubular acidosis" and 'Medications' below.)
A fall in citrate excretion can also be induced by a high animal protein diet [72], a setting in which acid generation is enhanced. High-protein diets, while still popular for weight loss, can have substantial adverse effects on urine citrate. Similarly, a diet low in fruits and vegetables may result in low urinary potassium, which is correlated with urine citrate excretion [73]. (See 'Protein' below and 'Potassium' below.)
In incomplete distal (type 1) renal tubular acidosis, a disorder that might actually represent a primary proximal tubular defect, hypocitraturia might occur in the absence of overt metabolic acidosis [74]. There are no studies establishing the frequency of incomplete distal (type 1) renal tubular acidosis in this setting. This disorder should be suspected if the urine pH is persistently above 5.3 along with low or low-normal serum total carbon dioxide; the diagnosis is confirmed by the lack of acidification of the urine after an ammonium chloride load. However, ammonium chloride loading is rarely used in the evaluation of stone formers, as patients may be treated with alkali regardless of the results of this test. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis".)
High urine uric acid — Hyperuricosuria has been traditionally, although arbitrarily, defined as a 24-hour urine uric acid excretion of more than 750 mg (4.5 mmol) in females or more than 800 mg (4.8 mmol) in males.
In the past, a higher urine uric acid had been considered to promote calcium oxalate stone formation. One proposed mechanism was that uric acid crystals formed a nidus for subsequent calcium oxalate precipitation [75]. Support for the role of hyperuricosuria came from a randomized, controlled trial in which allopurinol significantly reduced the likelihood of calcium oxalate stone recurrence in calcium stone formers with hyperuricosuria but "normal" urinary calcium excretion (0.12 versus 0.26 calculus events per year with placebo) [76].
However, the role of uric acid in calcium oxalate stone formation remains unproven. In the cross-sectional observational study of 3350 males and females (2237 with a history of nephrolithiasis), mean 24-hour uric acid excretion did not differ between stone formers and controls [17]. Multivariate adjustment for other urinary factors revealed a significant, independent, inverse association between uric acid excretion and the likelihood of being a stone former in males and marginally in younger females. By contrast, the expected associations with volume, hypercalciuria, hyperoxaluria, and hypocitraturia were found.
These observations suggest that high urine uric acid may not be a risk factor for calcium stone formation and that allopurinol may lower the risk of stone formation through a mechanism other than lowering uric acid excretion.
Higher urine uric acid is also a risk factor for uric acid stone formation, although the major risk factor for uric acid stones is a persistently lower urine pH. (See 'Urine pH' below.)
Low urine volume — Nephrolithiasis is a disease driven by the urinary concentration of lithogenic factors. Thus, higher urine volume has been consistently found to be associated with a lower risk of kidney stone formation [17]. There is no generally accepted definition of low urine volume; as with other urinary factors, the risk is continuous, but an accepted goal is at least 2.5 liters of urine daily [77].
The main determinant of urine volume is total fluid intake, and, therefore, it is not surprising that higher fluid intake has been consistently found to be one of the other strongest protective factors against kidney stone formation [78]. (See 'Fluid intake' below.)
Urine pH — The urine pH contributes to the likelihood of formation of certain types of stones. An acid urine (typical for most individuals) favors uric acid precipitation when the pH is consistently 5.5 or less. An alkaline urine (as may be seen with urinary tract infections and renal tubular acidosis but also in individuals with higher dietary alkali intake) promotes calcium phosphate stone formation, typically when the pH is 6.5 or higher. Calcium oxalate stones are not pH dependent in the physiologic range.
Dietary factors — Dietary factors can play an important role in promoting stone formation, primarily by affecting the composition of the urine. Studies over the past few decades suggest that the importance of specific dietary risk factors varies by age and sex.
A longitudinal study of three cohorts involving over 192,000 participants estimated the population attributable fraction of incident kidney stones that could be prevented by optimizing five dietary and lifestyle factors to minimize stone risk [79]. The factors were body mass index (BMI), fluid intake, Dietary Approaches to Stop Hypertension (DASH)-style diet, dietary calcium intake, and sugar-sweetened beverage intake. These five modifiable risk factors accounted for more than 50 percent of incident kidney stones. If a causal relationship exists, these findings suggest that preventive measures aimed at reducing those factors could substantially decrease the burden of kidney stones.
Fluid intake — A lower fluid intake will lead to a lower urine output, thereby promoting stone formation by increasing the concentration of lithogenic substances such as calcium and oxalate (even though the total amount of excretion of these lithogenic factors is not affected). In one report, for example, patients who had a first kidney stone had a baseline daily urine output that was 250 to 350 mL less than controls [78]. A related concern arises among individuals who work in a very hot environment (with increased insensible losses), in whom the risk of nephrolithiasis is markedly increased without adequate fluid intake [80]. (See 'Other factors' below.)
The importance of fluid intake on the risk of incident stone formation has been illustrated by data from several cohort studies [81-84]. In these reports of over 200,000 males and females, there was a 30 percent lower risk of developing symptomatic kidney stones in participants in the highest quintile of fluid intake compared with those in the lowest quintile.
In addition to lower fluid intake as a risk factor for incident stone disease, increasing fluid intake can lead to a reduction in recurrent stone formation. (See "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'Fluid intake'.)
Type of fluid — The type of fluid taken in may also be important, although data are sometimes conflicting regarding the effect on urine composition and stone risk. As examples:
●Data from three large, prospective cohort studies suggest that sugar-sweetened beverages (including both cola and non-cola beverages) are associated with an increased risk of developing kidney stones [85]. Compared with nonusers of these beverages, the relative risk was 23 percent higher among those drinking one or more sugar-sweetened colas per day and 33 percent higher among those consuming one or more sugar-sweetened non-colas per day.
●Coffee and tea have, in the past, been considered to have a high oxalate content. However, some measurements have not found these beverages to be high in oxalate. In fact, consumption of large amounts of tea appears to have a negligible impact on urinary oxalate excretion [86]. In prospective studies, higher tea and coffee (including decaffeinated coffee) consumption was associated with a lower risk of stone formation [85]. A study of twins in the United States also found that coffee and perhaps tea were relatively protective [87,88].
●Alcoholic beverages had been purported to increase the risk of stones. However, prospective studies found that beer and wine were associated with a lower risk of stone formation [85,89], possibly due to inhibition of antidiuretic hormone (ADH) release [90,91].
●Orange juice (which contains both potassium and citrate) was associated with a lower calculated risk of crystal formation (possibly due in part to increased urinary citrate excretion) [92-94], and large cohort studies found that orange juice was independently associated with a reduced likelihood of stone formation [85].
●Cranberry juice, advocated as prophylaxis against recurrent urinary tract infections, has been variably reported to increase and decrease urinary saturation of calcium oxalate and/or urine pH [95-97]. There have been no studies correlating consumption of cranberry juice to actual stone formation.
Calcium — Ingested calcium is absorbed in the intestines and later excreted in the urine; the proportion absorbed is higher in patients with hypercalciuria [98]. Although this suggests that a diet higher in calcium might promote stone disease, the opposite effect is seen, as the risk of stone formation appears to be reduced in both males and females [11,81-84]. By contrast, calcium supplements may slightly increase the propensity to form stones, at least in older females [37,84].
In the Nurses' Health Study, a higher dietary calcium intake was associated with a lower incidence of stone disease (multivariate relative risk 0.65 for highest versus lowest quintile of calcium intake) while calcium supplements were associated with a small increase in risk (relative risk 1.2 in supplement users compared with nonusers) [83]. The impact of dietary calcium may vary by age. This was suggested in a report from a cohort of males that also found an association between increased dietary calcium and decreased stone formation in males under the age of 60 years but not in older males [82].
A possible explanation for this phenomenon of contrasting risks depending upon the source of calcium (dietary versus supplements) is related to the timing of calcium intake, as follows:
●Dietary calcium sources may be ingested with foods containing oxalate, binding dietary oxalate in the gut, leading to decreased oxalate absorption and excretion. The fall in oxalate excretion exceeds the rise in calcium excretion; the net effect is a reduction in the relative supersaturation of the urine with respect to calcium oxalate [98].
●Calcium supplements are often taken in the morning or before bedtime and not with meals; thus, due to this timing, they would not be expected to effectively bind dietary oxalate. This would lead to both maintaining oxalate excretion and, by keeping calcium free in the intestinal lumen, increasing calcium absorption and urinary excretion.
It is also possible that there may be other inhibitory factors in dairy products, which are the major source of dietary calcium (though the risk was also lower with higher dietary calcium intake from nondairy sources) [99].
Some investigators have attempted to categorize individuals based upon their pattern of calcium absorption and excretion. In patients classified as having absorptive hypercalciuria, dietary calcium restriction reduced urinary calcium. However, since there would not be a concomitant change in urinary oxalate excretion, there would be a lesser reduction in the relative supersaturation of calcium oxalate, unless perhaps dietary oxalate were also restricted [100]. However, evidence is lacking that restriction of dietary calcium reduces the rate of stone formation in these patients, and there is substantial evidence that reducing dietary calcium intake could be harmful; thus, a low-calcium diet is not recommended.
An understanding of all of these factors is essential for the appropriate evaluation and treatment of patients with calcium stone disease. (See "Kidney stones in adults: Evaluation of the patient with established stone disease" and "Kidney stones in adults: Prevention of recurrent kidney stones".)
Oxalate — Oxalate is found in many foods, typically in small amounts. Oxalate is also generated from the metabolism of glycine, hydroxyproline, and vitamin C (ascorbic acid). Oxalate absorbed from dietary sources or produced from endogenous metabolism is eventually excreted in the urine. There is continued debate regarding the relative contribution of dietary and endogenously derived oxalate on urinary oxalate; it has been estimated that 10 to 50 percent of urinary oxalate is derived from dietary oxalate [40,101].
Difficulties in measuring the oxalate content of individual foods has previously led to unreliable information. Reliable assays now exist for direct determination of oxalate in foods [40,102,103]. There is currently a list of more than 200 foods analyzed with more modern methods, which can be downloaded from the following website. The lack of information on food oxalate content has previously hindered efforts to examine the impact of dietary oxalate on stone formation.
To examine the relation between stone risk and oxalate intake, a prospective study was performed based upon food frequency questionnaires of three large cohorts: the Health Professionals Follow-up Study and the Nurse's Health Studies I and II [43]. When individuals in the highest quintile for dietary oxalate intake were compared with the lowest quintile, there was a mild increase in the risk of stones for males (relative risk of 1.22, 95% CI 1.03-1.45) and for older females (relative risk of 1.21, 95% CI 1.01-1.44). This risk was higher in males with a lower dietary intake of calcium. In addition, eight or more servings of spinach per month (which accounted for >40 percent of oxalate intake) compared with fewer than one serving per month was associated with a similar increase in stone risk for males and older females. By contrast, dietary oxalate and spinach intake were not associated with an increased risk in younger females. Thus, dietary oxalate intake appears to be a modest risk factor for incident kidney stones in the general population, but this risk likely varies by individual. The urine oxalate level is a very strong predictor of stone risk. Individuals who form calcium oxalate stones may absorb a higher proportion of dietary oxalate.
Dietary intervention studies have also demonstrated that higher oxalate intake increases urinary oxalate and presumably increases the risk of stone formation [104]. However, other factors also need to be considered, such as higher intake of calcium and magnesium, which may reduce the absorption of dietary oxalate [105,106]. (See 'High urine oxalate' above.)
Nevertheless, because the risk of stone formation increases with increasing urinary oxalate, a lower intake of dietary oxalate and vitamin C seems prudent [17,101]. The challenge remains how to choose a low-oxalate diet without inappropriately restricting intake of fruits and vegetables. Aggressive restriction of dietary oxalate is not practical. Follow-up 24-hour urine oxalate measurements should be used to determine if the dietary oxalate restriction is beneficial; if not, then it should be discontinued.
Potassium — A higher dietary potassium intake was associated with a substantially reduced risk of incident stone formation in males and females [107]. One possible explanation is that higher potassium intake may reduce the risk of stone formation by reducing urinary calcium excretion [108].
Another mechanism is that higher potassium intake may increase urinary citrate excretion (since potassium-rich foods tend to have a high alkali content) thereby increasing the inhibitory properties of urine. Foods that are rich in potassium include fruits and vegetables. Although some have recommended a reduction in the intake of certain fruits and vegetables with the hope this would reduce oxalate intake and excretion, other studies found a slight protective effect of fruit ingestion [73,87]. Overall, given that dietary potassium is associated with a lower risk and fruits and vegetables are a major source of dietary potassium, it seems that there is evidence to encourage intake of fruits and vegetables (while avoiding those that are very high in oxalate such as spinach, rhubarb, and potatoes).
Sodium — A high sodium intake will enhance the excretion of calcium, a relation that has been thought to be due in part to the reabsorption of calcium passively following that of sodium and water in the proximal tubule [109]. Thus, the decrease in proximal sodium reabsorption induced by volume expansion will lead to a parallel reduction in calcium transport and increased calcium excretion [110,111]. In one study of stone formers with idiopathic hypercalciuria, for example, increasing sodium intake from 80 to 200 mEq/day led to nearly a 40 percent rise in calcium excretion (from 278 to 384 mg/day [7 to 9.5 mmol/day]) [110]. This increase in calcium excretion may result in negative calcium balance, which would promote the development of osteopenia [32,33].
A high-sodium diet may also produce an undesirable reduction in citrate excretion via an uncertain mechanism [111]. In addition, the anion accompanying sodium appears to be a determinant of the effect on calcium excretion. In particular, chloride seems to be required for the calciuresis to occur [111]. How chloride acts in this setting is not clear.
The clinical magnitude of these effects on stone formation is not clear. The Nurses' Health Study noted a relative risk of 1.30 for symptomatic stones in females in the highest quintile of sodium intake compared with those in the lowest quintile [83]. No association was seen in males or younger females [81,82,84], although the lack of an association may be due to the difficulty in accurately assessing sodium intake by questionnaires. In the study of over 3300 individuals with 24-hour urine collections, urine sodium excretion was not independently associated with likelihood of being a stone former [17], but these analyses were adjusted for calcium and citrate (the potential factors through which sodium may act). In the Women's Health Initiative, the risk of stone formation was 61 percent higher among females in the highest quintile of sodium intake compared with the lowest quintile [112].
Protein — Different types of dietary protein may have different effects on the risk of kidney stones. As an example, a high animal protein intake has been associated with a slightly higher incidence of stone disease, at least in males; by contrast, vegetable protein intake has not been associated with stone risk [81,82,107]. In addition, the risk of stones associated with animal protein intake may vary depending upon whether the source of the animal protein is dairy or nondairy. In one study, higher nondairy animal protein intake was associated with a modest but nonsignificant increase in stone risk, whereas higher dairy protein intake in young females was associated with a lower risk of stone disease [107].
Higher animal protein intake (both nondairy and dairy) is associated with higher urine calcium excretion [107,113-116]. In addition, higher nondairy, animal protein intake is associated with lower urine citrate, whereas higher dairy protein intake is associated with higher urine citrate excretion and lower urine oxalate excretion [107]. Vegetable protein has a much lesser effect on calcium, uric acid, and citrate excretion since it has a lower sulfur content and therefore generates less acid [88,115,117].
There are several factors that may explain the higher urine calcium excretion resulting from higher animal protein intake:
●Long term, a high-protein diet may lead to higher urine calcium excretion by increasing renal calcitriol production that may be mediated by an increase in kidney mass [118].
●Acid generated from higher animal protein intake (from the metabolism of sulfur-containing amino acids) is buffered in part by bone salts, resulting in the release of calcium from bone and an increase in urinary calcium excretion [113-116]. However, neutralizing the acid load associated with a high-protein diet does not ameliorate hypercalciuria. This was shown in a crossover study of 11 healthy adults fed a normal or high-protein diet in combination with either potassium citrate (an alkaline salt) or potassium chloride (a neutral salt) [119]. Although supplementation with potassium citrate both prevented the fall in urinary citrate excretion associated with the high-protein diet and completely neutralized the acid load, the high-protein diet still produced a significant increase in urinary calcium excretion.
The reduction in urine citrate excretion associated with higher nondairy, animal protein intake may be due to enhanced proximal citrate reabsorption [113,114,120]. This effect is induced at least in part by the fall in tubular fluid pH resulting from the acid load. The increased availability of hydrogen ions will convert the trivalent citrate anion into the divalent anion, which is more easily reabsorbed via the sodium-citrate cotransporter in the luminal membrane [120]. The associated fall in intracellular pH also may contribute by increasing cell citrate utilization [121]; the ensuing reduction in cell citrate levels favors passive citrate entry from the tubular lumen into the cell.
The ratio of nondairy, animal protein intake to potassium intake, which estimates dietary net acid load, may also be important to the risk of kidney stones. In one study, a higher animal protein-to-potassium ratio was associated with a higher risk of stone formation, even after adjustment for animal protein and potassium intake [107]. (See 'Potassium' above.)
Phytate — Higher amounts of dietary phytate may lower the risk of stone formation. In a study of nearly 100,000 younger female participants in the Nurses' Health Study II, the adjusted relative risk of stone formation among those in the highest quintile of phytate intake, compared with those in the lowest, was 0.63 (95% CI 0.51-0.78) [84]. Although its mechanism of action is unclear, calcium oxalate crystal formation is strongly inhibited in vitro by phytate. The principal dietary sources of phytate in this population were cold cereal, dark bread, and beans.
Sucrose — Higher sucrose intake is associated with an increased risk of stone formation in younger and older females [83,84]. Nearly 40 years ago, Lemann showed that an oral glucose load increased urine calcium excretion [122]. Although the mechanism is unknown, higher insulin levels may lead to higher urinary calcium excretion; however, some data are contradictory [123]. Fructose intake should also be minimized, as higher fructose intake is associated with a higher risk of kidney stones [124].
Vitamin C — High-dose vitamin C therapy may result in increased oxalate generation as the vitamin C (ascorbic acid) is metabolized [125,126]. A study in stone formers estimated that urinary oxalate excretion increases 6 to 13 mg/day for every 1000 mg of vitamin C ingested above 500 mg/day [125]. Subsequent metabolic studies have demonstrated that the ingestion of 2000 mg/day of vitamin C significantly increases urinary oxalate excretion in a large proportion of calcium oxalate stone formers as well as normal controls [127,128]. Two observational studies in males reported an increase in stone risk related to self-reported ingestion of larger amounts of vitamin C, but there does not appear to be an increased risk in females [129,130].
Most investigators recommend limiting the intake of vitamin C to the recommended dietary allowance (90 mg/day) among patients with a history of calcium oxalate stones [127,131].
Dietary patterns — The combination of dietary factors may also have a significant impact upon stone risk. As an example, the DASH diet is high in fruits and vegetables, moderate in low-fat dairy products, and low in animal protein. Based upon an analysis of three large cohorts, adherence to a DASH-style diet was associated with a 40 to 45 percent lower risk for incident kidney stones among males, older females, younger females, high-BMI individuals, and low-BMI individuals [132].
Another example is the Mediterranean diet, a healthy diet associated with lower risk of several conditions including cardiovascular disease and diabetes mellitus that was also found to be associated with a lower risk of kidney stones [133,134]. In the longitudinal study of three large cohorts, higher adherence to a Mediterranean dietary pattern was associated with between 13 and 41 percent lower risk of incident kidney stones independent of potential confounders [134]. Higher adherence to the Mediterranean diet was also associated with higher urinary citrate, magnesium, oxalate, phosphate, uric acid, volume, and pH, and lower urinary sodium, resulting in an overall lower supersaturation for calcium oxalate, calcium phosphate, and uric acid.
Thus, the DASH and Mediterranean diets are reasonable options in the attempt to reduce the risk of stone recurrence. One randomized trial of the DASH diet found a suggestion of a reduced risk based upon change in 24-hour urine chemistries [135], although there are no randomized trials that have examined the effectiveness on reducing risk of actual recurrent kidney stone formation.
Medications — Several drugs have been associated with an increased risk of kidney stone formation (table 2). Some drugs (eg, topiramate, acetazolamide, long-term glucocorticoids) can promote kidney stone formation by inducing metabolic abnormalities that alter the urine composition, while others (eg, triamterene) can crystallize in the urine and become the primary constituent of the kidney stone (see "Crystal-induced acute kidney injury"). As examples:
●Carbonic anhydrase inhibitors (acetazolamide, topiramate, zonisamide) increase the risk of calcium oxalate and calcium phosphate stones by reducing urinary citrate and potentially raising urine calcium due to the persistent metabolic acidosis. They can also increase the risk of calcium phosphate stones by raising the urine pH. (See "Nephrolithiasis in renal tubular acidosis", section on 'Carbonic anhydrase inhibitors'.)
●Long-term glucocorticoids can increase the risk of calcium oxalate and calcium phosphate stones by raising urine calcium.
●Laxatives may increase the risk of calcium oxalate stones by inducing a malabsorptive state and thereby increasing urine oxalate.
●Loop diuretics (eg, furosemide) may increase the risk of calcium oxalate and calcium phosphate stones by raising urine calcium.
Correction of the metabolic abnormality or discontinuation of the medication may reduce the risk of stone formation from these drugs.
NONMODIFIABLE RISK FACTORS
Family history — The relation between family history and risk of kidney stone formation was assessed in 38,000 males in the Health Professionals Follow-up Study in the United States [136]. Over an eight-year period, individuals with a positive family history had a relative risk of 2.6 of experiencing a stone as compared with those without such a history. Higher familial risk has also been noted in Italy [137].
Genetic factors — Family history data do not distinguish between genetic and environmental factors. However, there is evidence of genetic susceptibility to the development of calcium stone disease [136,138-140]. Most investigators believe that multiple genetic loci are involved, perhaps affecting calcium absorption, resorption, and excretion; oxalate absorption; and citrate absorption and excretion. Specific genes that might be involved include the calcium-sensing receptor, tight junction proteins, calcium channels in the intestine and kidney, vitamin D receptor, vitamin D 24-hydroxylase, phosphate transporters, and oxalate exchangers [27,113,141-145].
The genetic contributions of specific genes for the common forms of stone disease have not been fully identified, but a large genome-wide association study identified associations with the sodium-dependent phosphate transporter 2A (NaPi-IIa), alkaline phosphatase, claudin-14, and possibly the calcium-sensing receptor [139]. Another large study with independent confirmation found that a genome-wide polygenic risk score was associated with urinary tract stones overall and also in the absence of known clinical risk factors for kidney stone disease [140].
Further support for genetic influences undergoing nephrolithiasis was provided by a twin study from the United States [87]. Concordance rates for a history of kidney stones were compared in monozygotic and dizygotic twins among approximately 7500 male-male twin pairs. Based upon the differences in proband rates, the heritability of stone risk was calculated to be approximately 50 percent.
Much less common is Dent disease, in which an X-linked recessive defect in an outwardly rectifying chloride channel leads to hypophosphatemia and hypercalciuria. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Hypophosphatemia with hypercalciuria'.)
Medical conditions — A variety of medical conditions have been associated with an increased risk of stone formation [146-153]. These conditions and potential mechanisms for their association are discussed below:
●Primary hyperparathyroidism – Affected patients are more prone to have calcium phosphate stones, but calcium oxalate stones are also common. Secondary hyperparathyroidism does not increase the risk of stone formation. (See "Primary hyperparathyroidism: Clinical manifestations", section on 'Kidney'.)
●Hypertension – Primary (essential) hypertension has been associated with a higher risk of calcium and uric acid stone formation [146,154]. Possible mechanisms for this increased risk include lower urinary citrate excretion [155], higher urine calcium, higher urine oxalate, higher calcium oxalate supersaturation, and higher urine uric acid supersaturation.
●Gout – A history of gout has been associated with an increased risk of kidney stones in males [147,148]. This higher risk may be due to a persistently acidic urine (urine pH of 5 to 5.5) in these patients, which promotes the formation of uric acid stones.
●Diabetes mellitus – The risk in patients with diabetes may be related in part to higher urinary calcium excretion, as well as low urinary pH predisposing to uric acid nephrolithiasis [156,157].
●Obesity – Obesity and weight gain are risk factors for kidney stones [149,150,152,153]. The mechanism of increased risk due to obesity is unknown but may be related to higher uric acid excretion and lower urinary pH [158,159]. (See "Kidney stones in adults: Uric acid nephrolithiasis".)
●Medullary sponge kidney – Among calcium stone formers, it is estimated that this disorder is present in 12 to 20 percent overall and 20 to 30 percent of females or patients under age 20 years [160,161]. It is unclear whether the anatomic changes somehow cause the metabolic disturbances (eg, high urine calcium, low urine citrate) or whether their predisposition to nephrocalcinosis (and the interstitial deposition of calcium phosphate) increases the likelihood of nephrolithiasis. (See "Medullary sponge kidney", section on 'Kidney stones and nephrocalcinosis'.)
●Distal (type 1) renal tubular acidosis – The urine pH is persistently high and leads to metabolic acidosis in most patients; there is also a tendency to have medullary nephrocalcinosis. In addition to the higher urine pH, they also tend to have lower urine citrate levels, raising the risk of calcium phosphate stones. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis" and "Nephrolithiasis in renal tubular acidosis", section on 'Distal (type 1) RTA'.)
●Inflammatory bowel disease, short gut syndrome, bowel resection, or gastrointestinal bypass surgery – These conditions can significantly increase the risk of calcium oxalate stones by increasing urinary oxalate (due to increased gastrointestinal absorption), reducing urinary citrate (due to gastrointestinal loss of alkali) and urine volume (due to increased gastrointestinal loss of fluid or limiting fluid intake due to the reduction in stomach volume). (See "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults", section on 'Extraintestinal manifestations' and "Chronic complications of the short bowel syndrome in adults", section on 'Nephrolithiasis' and "Bariatric operations: Late complications with subacute presentations", section on 'Nephrolithiasis and renal failure'.)
The rate of hyperoxaluric stone formation is higher in patients who have undergone some types of bariatric surgery. In a series of 132 patients with nephrolithiasis who had undergone bariatric surgery, the average time to formation of the first stone was 3.6 years [51]. Mean oxalate excretion was 83 mg/day in these patients who underwent malabsorptive bariatric surgery (principally Roux-en-Y gastric bypass), which was significantly higher than in routine kidney stone formers or normal subjects (39 and 34 mg/day, respectively). By contrast, a study of 18 patients who underwent restrictive bariatric procedures (gastric banding or sleeve gastrectomy) and 54 patients who underwent Roux-en-Y gastric bypass showed significantly lower 24-hour urinary oxalate excretion with restrictive procedures (35 versus 61 mg), suggesting that stone risk might be lower with restrictive procedures [162]. (See "Bariatric procedures for the management of severe obesity: Descriptions".)
●Urinary tract infection – Patients with a chronic upper urinary tract infection due to a urease-producing organism such as Proteus or Klebsiella may be at higher risk for struvite stones. (See "Kidney stones in adults: Struvite (infection) stones".)
●Cystinuria – Patients with cystinuria (an autosomal recessive disorder) are at risk for developing cystine stones due to the poor solubility of the excessive amount of cystine excreted in the urine. (See "Cystinuria and cystine stones".)
Other factors — Certain environmental factors, such as warmer climate and geography [163-165], and some occupations (eg, steel workers [80], physicians that work in the operating room) have been associated with an increased risk of kidney stones. Inadequate fluid intake in these settings may be the underlying cause for stone formation.
Betel quid chewing, a common practice in Southeast Asia, has also been associated with calcium oxalate and calcium phosphate kidney stones [166].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topic (see "Patient education: Kidney stones in adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Kidney stones (nephrolithiasis) are a common problem. Approximately 19 percent of males and 9 percent of females will be diagnosed with a kidney stone by the age of 70 years. The prevalence of kidney stones varies with age, sex, race/ethnicity, and geography. (See 'Prevalence and incidence' above.)
●Stone composition – Approximately 80 percent of patients with nephrolithiasis form calcium stones, most of which are composed primarily of calcium oxalate or, less often, calcium phosphate. Other stone types include uric acid stones (8 percent), cystine stones (1 to 2 percent), struvite stones (1 percent), and miscellaneous stones (<1 percent). (See 'Stone composition' above.)
●Modifiable risk factors
•Urinary factors – Certain biochemical abnormalities of the urine composition have been associated with an increased risk for kidney stone formation, including higher urine calcium, higher urine oxalate, lower urine citrate, higher urine uric acid, and lower urine volume. The urine pH contributes to the likelihood of formation of certain types of stones; an acid urine favors uric acid precipitation, whereas an alkaline urine promotes calcium phosphate stone formation. Calcium oxalate stones are not pH dependent in the physiologic range. (See 'Urinary factors' above.)
•Dietary factors – Dietary factors can play an important role in promoting stone formation, primarily by affecting the composition of the urine. Lower intake of fluid, calcium, potassium, and phytate and higher intake of oxalate, sodium, sucrose, fructose, vitamin C, and possibly animal protein are associated with an increased risk for calcium stone formation. Higher consumption of animal protein and lower intake of fruits and vegetables increase the risk of uric acid stones by reducing urine pH and increasing generation of uric acid. Specialized diets, such as the Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets, are reasonable options in the attempt to reduce the risk of stone recurrence. (See 'Dietary factors' above.)
•Medications – Several drugs have been associated with an increased risk of kidney stone formation (table 2). Some drugs can promote kidney stone formation by inducing metabolic abnormalities that alter the urine composition, while others can crystallize in the urine and become the primary constituent of the kidney stone. (See 'Medications' above.)
●Nonmodifiable risk factors – Nonmodifiable risk factors for stone formation include a family history of stone disease, genetic susceptibility, and a variety of medical conditions. (See 'Family history' above and 'Genetic factors' above and 'Medical conditions' above.)
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