Obesity, Weight Gain, and the Risk of Kidney Stones FREE

Kidney stones are a major cause of morbidity. The lifetime prevalence of symptomatic nephrolithiasis is approximately 10% in men and 5% in women,^{1 - 3} and more than $2 billion is spent on treatment each year.^{4 - 5} About 80% of kidney stones contain calcium, and the majority of calcium stones consist primarily of calcium oxalate.^{6 - 7} The identification of common, modifiable risk factors for kidney stones may result in new approaches to treatment and prevention.

Obesity is associated with insulin resistance and compensatory hyperinsulinemia, metabolic derangements that may lead to the formation of calcium-containing kidney stones. A recent metabolic trial demonstrated that insulin resistance was associated with defects in renal ammonium production,⁸ and an examination of more than 4500 patients with a history of kidney stones showed that urinary pH was inversely related to body weight.⁹ A defect in renal acid excretion could lead to hypocitraturia, an important risk factor for calcium nephrolithiasis.^{6 ,10} Hyperinsulinemia may contribute to the development of calcium stones by increasing the urinary excretion of calcium.^{11 - 13}

Larger body size may also result in increased urinary excretion of uric acid and oxalate, risk factors for calcium oxalate kidney stones.^{14 - 16} In one study of nearly 6000 individuals with nephrolithiasis, men weighing more than 120 kg excreted 37% more uric acid than men who weighed less than 100 kg.¹⁷ Similar results were seen in women.¹⁷ Urinary oxalate excretion increases with increasing lean body mass, presumably reflecting changes in endogenous oxalate synthesis.¹⁸

Although larger body size may increase the urinary supersaturation of calcium salts, prospective data on the relation between body size and the risk of kidney stone formation are limited. We have previously reported on the association between higher body mass index (BMI) and an increased risk of incident nephrolithiasis in the Nurses’ Health Study (NHS) I, a large cohort of older women.¹⁹ However, we did not observe this association in the Health Professionals Follow-up Study (HPFS), a cohort of men.¹⁹ To date, no prospective study has evaluated the relation between body size and the risk of kidney stone formation in younger women, and no study has determined if weight gain influences risk. In addition, it is unknown if measures of central adiposity, such as waist circumference, are associated with risk.

To determine if weight, weight gain, BMI, and waist circumference are associated with incident kidney stone formation, we conducted a prospective study of 3 cohorts: the HPFS and the NHS I and II. Eight years of additional follow-up in the HPFS resulted in a near doubling of the number of incident kidney stones, providing a marked increase in statistical power to reevaluate the relation between BMI and stone formation in men. The inclusion of the NHS II in our analyses represents the first study of the relation between body size and kidney stone formation in younger women.

HPFS. In 1986, 51 529 male dentists, optometrists, osteopathic physicians, pharmacists, podiatrists, and veterinarians between the ages of 40 and 75 years completed and returned an initial questionnaire that provided detailed information on diet, medical history, and medications. This cohort, like those of the NHS I and NHS II, was followed by biennial mailed questionnaires that included inquiries about the incidence of newly diagnosed diseases such as kidney stones.

NHS I. In 1976, 121 700 female registered nurses between the ages of 30 and 55 years enrolled in the NHS I by completing and returning an initial questionnaire. Since we first asked NHS I participants about kidney stones in 1992, the current analysis was limited to women who answered questionnaires in 1992 or later. For this study we started follow-up in 1980, since before that date we lacked information on diet.

NHS II. In 1989, 116 671 female registered nurses between the ages of 25 and 42 years enrolled in the NHS II by completing and returning an initial questionnaire. Dietary information was first collected from this cohort in 1991.

For each cohort, information on weight and height was obtained on the baseline questionnaire. The baseline questionnaire also asked about weight in early adulthood (age 21 years in men and 18 years in women). Self-reported weight was updated every 2 years. Body mass index was calculated as the weight in kilograms divided by the square of height in meters. Self-reported weight has been validated in the HPFS and NHS I.²⁰ Self-reported weights from 123 men and 140 women in the 2 cohorts were highly correlated with values obtained by technicians who visited the participants at home (r = 0.97 for men and women).²⁰

Waist and hip circumference were reported in the HPFS in 1987 and 1996, in the NHS I in 1986 and 1996, and in the NHS II in 1993. For waist circumference, participants were instructed to measure their waist circumference at the level of the navel, and for hip circumference they were instructed to measure the largest circumference around the hips (including the buttocks). If a tape measure was not available, the questionnaire instructed participants to leave the question blank. The questionnaire also instructed the participants to perform the measurements while standing and to avoid measuring over bulky clothing. Participants reported their waist and hip circumference to the nearest quarter inch (0.64 cm). The self-reported measures of waist and hip circumference have also been validated: the correlation coefficients between self-reported waist and hip circumferences and measurements obtained by technicians sent to the homes of participants were 0.95 and 0.88, respectively, for men and 0.89 and 0.84, respectively, for women.²⁰

The semiquantitative food frequency questionnaire (first mailed to the HPFS in 1986, to the NHS I in 1980, and to the NHS II in 1991) asked about the annual average use of more than 130 foods and beverages. In addition, respondents provided information on the use of nutritional supplements, taken either alone or in multivitamin form. Subsequently, a version of this food frequency questionnaire has been mailed to study participants every 4 years. The reproducibility and validity of the food frequency questionnaires in the HPFS and NHS I have been documented.^{21 - 22}

Nutrient intake was computed from the reported frequency of consumption of each specified unit of food and from United States Department of Agriculture data on the content of the relevant nutrient in specified portions. Nutrient values were adjusted for total caloric intake to determine the nutrient composition of the diet independent of the total amount of food eaten.^{23 - 24}

The intake of supplements (such as vitamin C and calcium) in multivitamins or isolated form was determined by the brand, type, and frequency of reported use.

Information on age was obtained on the baseline questionnaire. In the HPFS and NHS II, thiazide diuretic use was updated every 2 years. In the NHS I, thiazide use was determined in 1980, 1982, and then every 6 years until 1994, when biennial updates started. In the HPFS and NHS II, a family history of kidney stones was ascertained in 1994 and 1997, respectively. Information on hypertension and diabetes mellitus was obtained at baseline and then every 2 years. The validity of these self-reported diseases has been documented.^{25 - 27}

The primary outcome was an incident kidney stone accompanied by pain or hematuria. The participants reported on the interval diagnosis of kidney stones every 2 years. Any study participant who reported a new kidney stone was sent an additional questionnaire to determine the date of occurrence and the symptoms produced by the stone. We confirmed the validity of the self-reported stones in the HPFS by obtaining medical records from a random sample of 60 men in the cohort; chart review confirmed 97% of the cases.²⁸ A similar study in the NHS I examined medical records from a random sample of 90 women who reported a kidney stone. The records confirmed the diagnosis for all but 1 participant (98%).²⁹

The study design was prospective; information on body size was collected before the diagnosis of the kidney stone. For the HPFS, person-months of follow-up were counted from the date of the return of the 1986 questionnaire to the date of a kidney stone or death or to January 31, 2002 (whichever came first). For the NHS I, person-months of follow-up were counted from the date of the return of the 1980 questionnaire to the date of a kidney stone or death or to May 31, 2000. For the NHS II, person-months of follow-up were counted from the date of the return of the 1991 questionnaire to the date of a kidney stone or death or to May 31, 2001.

Weight was updated every 2 years. We allocated person-months of follow-up according to exposure status at the start of each follow-up period. If a participant did not provide a weight for a time period, the weight from the previous time period was used. However, if weight data were missing for more than 2 consecutive time periods, no value was imputed. Instead, the participant was assigned to the missing category for that time period. Of the 4827 incident kidney stones in the study, 33 occurred in participants missing data on weight. Missing values for height, waist circumference, and hip circumference were assigned to missing categories.

Categories of body size were chosen to examine relative extremes while preserving adequate person-time in each category. Body mass index categories were selected to include World Health Organization cutoffs for overweight (BMI ≥25) and obese (BMI ≥30). Unlike men, few women (especially in the NHS II) had a waist circumference greater than 43 in (109.2 cm); therefore, different categories of waist circumference were used for men and women (though the range from highest to lowest category of waist circumference was identical).

Dietary exposures were updated every 4 years. If complete information on diet was missing at the start of a time period, the participant was excluded for that time period.

We determined the relative risk (RR) of kidney stone formation for each category of body size compared with the referent category using Cox proportional hazards regression. The Mantel extension test was used to evaluate linear trends across categories of body size.

We adjusted our analyses for age (continuous), the use of thiazide diuretics (yes or no), alcohol intake (7 categories), supplemental calcium use (4 categories), and dietary intake of fluid, animal protein, calcium, magnesium, phosphorous, phytate, potassium, sodium, sucrose, vitamin B₆, vitamin C, and vitamin D (quintile groups). To account for the fact that a given weight gain in a heavier individual represents a smaller fractional increase than the same weight gain in a lighter individual, we adjusted our weight change analyses for baseline weight. We calculated 95% confidence intervals (CIs) for all RRs. All P values are 2-tailed; P<.05 was used to determine statistical significance.

All data were analyzed using SAS version 8.2 (SAS Institute Inc, Cary, NC). The study was approved by the human research committees at the Harvard School of Public Health and Brigham and Women’s Hospital, Boston, Mass; completion of the self-administered questionnaire was considered to imply informed consent.

After excluding participants with a history of kidney stones at baseline, we studied a total of 45 988 men (HPFS), 93 758 older women (NHS I), and 101 877 younger women (NHS II).

Over a combined 2 808 334 person-years of follow-up, we documented 4827 new symptomatic kidney stones: 1609 in the HPFS, 1687 in the NHS I, and 1531 in the NHS II. The unadjusted incidence of stones was 301 per 100 000 person-years in the HPFS, 117 per 100 000 person-years in the NHS I, and 183 per 100 000 person-years in the NHS II.

Greater weight was associated with an increased risk of incident kidney stone formation in men (HPFS) and in older and younger women (NHS I and NHS II) (Table 1). The multivariable RR in men weighing more than 220 lb (100.0 kg) compared with men weighing less than 150 lb (68.2 kg) was 1.44 (95% CI, 1.11-1.86; P = .002 for trend). In older and younger women for the same weight comparisons, the multivariable RRs were 1.89 (95% CI, 1.52-2.36; P<.001 for trend) and 1.92 (95% CI, 1.59-2.31; P<.001 for trend), respectively. Since women weighed less on average than men, we also determined the risk of stone formation in women who weighed less than 130 lb (59.1 kg). No appreciable difference in risk was observed in younger or older women who weighed between 130 and 149 lb (59.1-67.7 kg) compared with those who weighed less than 130 lb.

Weight gain since early adulthood (age 21 years in men and age 18 years in women) was associated with an increased risk of incident kidney stone formation in both men and women (Table 2). The multivariable RR in men who gained more than 35 lb (15.9 kg) since early adulthood compared with those whose weight did not change was 1.39 (95% CI, 1.14-1.70; P = .001 for trend). The corresponding multivariable RRs for older and younger women were 1.70 (95% CI, 1.40-2.05; P<.001 for trend) and 1.82 (95% CI, 1.50-2.21; P<.001 for trend), respectively.

Weight loss was not associated with a reduced risk of kidney stone formation. However, only 7% of the total person-time in the study was contributed by participants who lost weight since early adulthood.

Body mass index was positively associated with the risk of kidney stone formation in both men and women (Table 3). The multivariable RR in men with a BMI of 30 or greater compared with men with a BMI of 21 to 22.9 was 1.33 (95% CI, 1.08-1.63; P<.001 for trend). In older and younger women the corresponding multivariable RRs were 1.90 (95% CI, 1.61-2.25; P<.001 for trend) and 2.09 (95% CI, 1.77-2.48; P<.001 for trend), respectively.

The multivariable RRs in older and younger women with a BMI of 35 or greater compared with women with a BMI between 21 and 23 were 2.27 (95% CI, 1.85-2.81) and 2.28 (95% CI, 1.87-2.79), respectively. There was inadequate person-time to evaluate the RR of men with a BMI of 35 or greater (only 1.5% of the total person-time in men was contributed by such individuals).

For men in the referent category of BMI (21-22.9), the annual incidence of kidney stones was 278 per 100 000 men. The population-attributable risk of developing an incident kidney stone associated with a BMI of 23 or greater was 31 per 100 000 men annually. For older and younger women in the referent category of BMI, the annual incidence of kidney stones was 84 per 100 000 women and 131 per 100 000 women, respectively. The population-attributable risk of developing an incident kidney stone associated with a BMI of 23 or greater was 28 per 100 000 older women annually and 47 per 100 000 younger women annually.

Waist circumference was positively associated with the risk of incident kidney stone formation in both men and women (Table 4 and Table 5), even after adjusting for height. On average, men had a larger waist circumference than women. The multivariable RR for men with a waist circumference greater than 43 in (109.2 cm) compared with men with a waist circumference less than 34 in (86.4 cm) was 1.48 (95% CI, 1.13-1.93; P = .002 for trend). The multivariable RRs for older and younger women with a waist circumference greater than 40 in (101.6 cm) compared with women with a waist circumference less than 31 in (78.7 cm) were 1.71 (95% CI, 1.40-2.10; P<.001 for trend) and 1.94 (95% CI, 1.49-2.52; P<.001 for trend), respectively.

Hip circumference and the ratio of waist circumference to hip circumference were also associated with an increase in risk, but the magnitudes of the RRs were smaller than that seen with waist circumference alone.

Further adjustment for family history of kidney stones, diabetes, and hypertension did not materially change the results for any measure of body size.

Our results confirm that body size is independently associated with the development of incident kidney stones. Because lean body mass is positively correlated with percent body fat³⁰ and may play an important role in stone formation,¹⁸ it is possible that greater lean body mass is at least partly responsible for the observed association between higher BMI and increased risk. However, the strong association between weight gain since early adulthood and the risk of incident stone formation suggests that adiposity plays a central role in the relation between body size and nephrolithiasis. Although lean body mass does increase somewhat as the average individual gains weight, the majority of weight gain since early adulthood is due to increases in fat rather than muscle.³¹ Furthermore, 2 distinct measures of obesity—body mass index and waist circumference adjusted for height—were associated with an increased risk of kidney stone formation.

In a prior analysis, we did not detect a statistically significant association between BMI and the risk of incident kidney stones in men.¹⁹ However, the current study of the male cohort encompasses 8 years of additional follow-up and nearly twice the number of incident kidney stones.¹⁹ Thus, the present study has a marked increase in statistical power.

The mechanism whereby obesity increases the risk of incident stone formation is uncertain. However, hyperinsulinemia is associated with obesity and has a significant effect on urine composition. More than 30 years ago, seminal work demonstrated that the ingestion of carbohydrates transiently increased the urinary excretion of calcium,³² probably by decreasing the renal reabsorption of filtered calcium.³³ Subsequent animal experiments showed that this “carbohydrate-induced calciuria” could be inhibited by pharmacologically blocking the pancreatic secretion of insulin.³⁴ Experiments in humans undergoing euglycemic hyperinsulinemic clamp demonstrate that insulin, by an as-yet unknown mechanism, increases the kidney’s fractional excretion of calcium.^{11 - 13} Clamp studies have also suggested that insulin increases the intestinal absorption of calcium.³⁵ Insulin-mediated postprandial increases in levels of urinary calcium, coupled with postprandial increases in levels of urinary oxalate, could create a urinary environment highly conducive to the formation of calcium-containing stones.

Insulin resistance, also associated with obesity, can also alter the composition of the urine. Insulin resistance may manifest in the kidney as a defect in ammonium production and the ability to excrete acid.³⁶ Recent data in humans, also using hyperinsulinemic euglycemic clamp, have confirmed that insulin resistance is associated with lower urinary pH and that urinary ammonium excretion in normal individuals increases during hyperinsulinemia.⁸ Indeed, studies of 3 large groups of individuals with nephrolithiasis have demonstrated that higher weight is associated with lower urinary pH.^{9 ,17} Although a lower urinary pH is generally associated with uric acid stones, an impaired ability to excrete acid could result in hypocitraturia, an important risk factor for calcium stones.

Urinary uric acid is a risk factor for calcium oxalate stones and is also positively associated with obesity. Higher serum uric acid levels in obese individuals may result from increased uric acid production, decreased renal excretion, or both.³⁷ Although no dietary information was available (high levels of purine intake can increase the production of uric acid), data from nearly 6000 individuals with a history of kidney stones suggests that urinary uric acid excretion is higher in heavier patients.¹⁷ Men who weighed more than 120 kg had a urinary concentration of uric acid 13% greater than that for men who weighed less than 100 kg.¹⁷ Similar changes were observed in women. A smaller study of about 500 individuals with nephrolithiasis showed a positive association between BMI and the urinary excretion of uric acid. In this study, men with a BMI of 30 or greater excreted 19% more urinary uric acid per day than men with a BMI less than 25 (similar results were seen in women).³⁸

Although BMI increased risk in all 3 cohorts, the magnitude of this effect appeared greater in women. However, women generally have a higher percent body fat than men.³⁹ Therefore, a woman with a given BMI will, on average, have more adipose tissue than a man with the same BMI. In this way, the difference we observed in the relation between BMI and risk by sex could have more to do with estimation of adiposity than with any fundamental difference in physiology.

Higher lean body mass may account for the greater incidence of kidney stone formation in men compared with women. Previously, we analyzed the 24-hour urine composition in a subset of men and women from these cohorts.⁴⁰ Although the daily urine volume was similar in men and women, the absolute amount of most excreted solutes, including calcium, was higher in men.⁴⁰ Therefore, the concentration of lithogenic factors in the urine was greater in men than women. Some authorities have postulated that estrogen reduces the urinary excretion of calcium and therefore may lower the risk of calcium-containing kidney stones.⁴¹ However, our group has found no independent association between menopause or postmenopausal hormone use and the risk of kidney stone formation.⁴²

The limitations of our study deserve mention. The measures of body size used in our study were self-reported. However, validation studies demonstrated the accuracy of these reports. In addition, any misclassification is likely to be random with respect to case status and therefore would bias the study results toward the null. Because relatively few participants lost weight over time, our study also lacked statistical power to determine if weight loss reduced the risk of kidney stone formation. Furthermore, the generalizability of our results may be limited. Only a small proportion of our study population is nonwhite, and we do not have data on stone formation in men younger than 40 years. However, no data suggest that the effect of body size on urine composition varies by age or race. Finally, we currently lack 24-hour urine collections and analyses of stone composition from most of the participants in our study. Thus, we were unable to determine if larger body size increases the risk of certain stone types but not others. We also cannot ascertain if differences in urine composition are responsible for the effect of sex on the association between body size and the risk of nephrolithiasis.

In conclusion, our results show that obesity and weight gain are associated with an increased risk of symptomatic nephrolithiasis. The positive association between body size and the risk of kidney stone formation could not be explained by differences in the intake of dietary factors that affect risk. The magnitude of the increased risk may be higher in women. Future studies should explore the effect of obesity and sex on urine composition, and weight loss should be explored as a potential treatment to prevent kidney stone formation. For now, clinicians have an additional reason to encourage weight control in their patients.