Comparison of Dietary Calcium with Supplemental Calcium and Other Nutrients as Factors Affecting the Risk for Kidney Stones in Women

Dietary factors are believed to play an important role in the formation of kidney stones [1, 2], but data on the influence of diet on stone formation in women are limited. The incidence of kidney stones in women is one third the incidence in men [3]; the reason for this marked difference is unknown. Although differences in diet may contribute, the only available data on which comparisons between men and women can be based are from casecontrol studies that included few women. No studies have provided prospective data on the relation between diet and kidney stones in women. In the past, a diet high in calcium was suspected of increasing the risk for calcium-containing kidney stones, particularly stones consisting of calcium oxalate (the most common type). This finding has often led to restriction of calcium intake in patients who have had kidney stones in an attempt to decrease the likelihood of recurrence. In a large prospective study in men, however, we recently found that high intake of dietary calcium was associated with a decreased risk for stone formation [2]. One possible explanation of this observation is that high calcium intake reduces oxalate absorption and subsequent urinary excretion of oxalate by binding oxalate in the gastrointestinal tract. Urinary oxalate may be more important than urinary calcium with respect to formation of calcium oxalate crystals [4]. Moreover, restriction of dietary calcium intake may result in negative calcium balance and decreased bone mineral density, particularly in patients with idiopathic hypercalciuria [5]. Supplemental calcium, such as calcium carbonate, is commonly used by adults in the United States. Large doses have been recommended for the prevention of various common disorders in women, such as osteoporosis and preeclampsia [6, 7]. Although some researchers are concerned that high doses of supplemental calcium may increase the risk for kidney stone formation [7], no data are available on this issue in women. Use of supplemental calcium increases urinary calcium excretion; if not taken with meals, these supplements do not decrease urinary oxalate excretion. Thus, the overall effect of supplemental calcium may actually be an increased risk for stone formation. Clearly, information on the risk for stone formation associated with intake of supplemental calcium is essential to help patients decide whether to begin or continue to use calcium supplements. Other dietary factors may also be associated with the risk for kidney stone formation [1, 2]. A diet high in sodium [8], sucrose [9], or animal protein [10] may increase the risk for stone formation, whereas a diet high in potassium [11], magnesium [12], or fluid may decrease this risk. To study the association between intake of dietary and supplemental calcium and other nutrients and the incidence of kidney stones in women, we conducted a 12-year prospective analysis among 91 731 women who were participating in the Nurses' Health Study and had no history of kidney stones at study entry. Methods Study Sample In 1976, 121 700 female registered nurses who were 30 to 55 years of age and resided in 1 of 11 U.S. states completed and returned the initial questionnaire. These women constitute the Nurses' Health Study cohort [13]. The cohort is followed by using biennial mailed questionnaires that ask about lifestyle practices and other exposures of interest, as well as the incidence of newly diagnosed disease. The sample for our analysis was limited to the 91 731 women who answered the 1992 questionnaire, which included a question on lifetime history of kidney stones, and who had completed at least one of the four dietary questionnaires since 1980 (the first year in which information on diet was collected). Assessment of Diet In 1980, 1984, 1986, and 1990, the participants were asked to complete semiquantitative food-frequency questionnaires, on which they reported the average intake of specified foods and beverages during the past year. The 1980 dietary questionnaire contained 61 items, and the subsequent questionnaires contained 131 items. Nutrient intake was computed from the reported frequency of consumption of each specified unit of food or beverage and from published data on the nutrient content of the specified portions [14]. Beginning in 1984, information was also collected on the amount of supplemental calcium (such as calcium carbonate) ingested, either as separate supplements or as part of multivitamin preparations. The reproducibility and validity of the questionnaires completed by women in this cohort have been documented elsewhere [14]. A similar questionnaire has been shown to be valid and reproducible in men [15]. Nutrient values were adjusted for total energy intake by regressing total caloric intake on absolute nutrient intake [16, 17]. Because total energy intake for a given person tends to be fixed within a narrow range, variations in nutrient intake are largely attributable to changes in composition of diet, not the total amount of food consumed. Energy-adjusted values reflect the nutrient composition of the diet independent of the total amount of food consumed. In addition, adjustment for energy reduces any variation introduced by questionnaire responses that underreported or overreported intake, thereby improving the accuracy of nutrient measurements [16, 17]. To obtain additional information on the typical pattern of the use of supplemental calcium, we mailed a questionnaire to a random sample of 100 women who reported taking supplemental calcium on the 1994 biennial questionnaire. Eighty-six of these women responded. The questionnaire asked about the specific type of calcium salt ingested and whether the supplement was taken alone or with particular meals. Follow-up and Ascertainment of Cases The 1992 questionnaire asked whether the woman had ever received a diagnosis of a kidney stone and, if so, the date of the first occurrence. If the participant reported that a kidney stone had been diagnosed in 1980 (when dietary information was first collected) or later, we mailed her a supplementary questionnaire to confirm the diagnosis and to ascertain the date of occurrence; the type of symptoms; other relevant medical conditions; and, if known, the type of stone. The rate of response to this supplementary questionnaire was 95%. To confirm the validity of the participants' reports, we obtained the medical records from a random sample of 90 of the women who reported a kidney stone. The records confirmed the diagnosis for all but 1 woman. We considered only cases of kidney stones that were diagnosed during the 12 years between the date on which the 1980 questionnaire was returned and 31 May 1992. After we excluded women for whom the date of the kidney stone either could not be confirmed or fell outside of the study period, 91 731 women with no history of kidney stones remained in the study group. Statistical Analysis The study design was prospective, and information on diet was collected before the onset of the kidney stone. For each participant, person-months of follow-up were counted from the date on which the 1980 questionnaire was returned 1) to the date on which a kidney stone developed or death occurred or 2) to 31 May 1992, whichever occurred first. Information on exposures of interest that were recorded in responses to the 1980 questionnaire was updated in 1984, 1986, and 1990. We allocated person-months of follow-up according to exposure status at the start of each follow-up period (indicated by the quintile of calcium intake and other variables). Dividing the cohort into quintiles of nutrient intake allowed us to examine a wide range of nutrient intake while maintaining enough participants in the highest and lowest categories. If complete information on diet was missing at the start of a time period, the participant was excluded for that time period. The relative risk-the incidence among women in a particular category of intake divided by the corresponding rate in the comparison category-was used as the measure of association [18]. Age-adjusted relative risks were calculated after the participants were stratified according to 5-year age categories [18]. The Mantel extension test was used to evaluate linear trends across categories of intake [19]. We used a proportional-hazards model to simultaneously adjust for several risk factors [20]. The variables considered in these models were selected on the basis of factors that published reports had indicated were related to formation of calcium stones. Variables included were age (5-year categories); alcohol consumption (eight categories); body mass index (five categories); intake of vitamin B6 (five categories); intake of vitamin C (five categories); intake of supplemental calcium (0 mg/d, 1 to 100 mg/d, 101 to 500 mg/d, and 500 mg/d); and dietary intake of calcium, animal protein, potassium, sodium, sucrose, magnesium, phosphorus, fiber, vitamin D, animal fat, total fat, and fluid (quintile groups). We calculated 95% CIs for all relative risks. All P values are two tailed. Results During the 903 849 person-years of follow-up, we documented 864 cases of new symptomatic kidney stones. Seventy-three women had systemic diseases potentially related to stone formation (Table 1). Although 13.4% of the women reported having a urinary tract infection at the time the stone developed, only 3.9% reported that they believed the stone formed as a result of this infection (Table 1). A family history of stone formation was reported by 24.2% of the women with stones. Pain was the most frequent presenting symptom, occurring in 91.1% of cases. Of the 390 women who reported information on the type of stone, 336 (86.2%) reported that the stone contained calcium. The incidence rate for the cohort was slightly less than 1 case per 1000 person-years; the rate did not vary substantially by age (Table 2). Table 1. Self-Reported Characteristics of the 864 Women with Incident Kid