24-Hour Urinary Chemistries and Kidney Stone Risk.

RATIONALE & OBJECTIVE: Most previous studies of the relationship between urinary factors and kidney stone risk have either assumed a linear effect of urinary parameters on kidney stone risk or implemented arbitrary thresholds suggesting biologically implausible "all-or-nothing" effects. In addition, little is known about the hierarchy of effects of urinary factors on kidney stone risk. This study evaluated the independent associations between urine chemistries and kidney stone formation and examined their magnitude and shape. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We analyzed 9,045 24-hour urine collections from 6,217 participants of the Health Professionals Follow-Up Study and Nurses' Health Studies I and II. EXPOSURE: Urine volume and pH, and concentrations of calcium, citrate, oxalate, potassium, magnesium, uric acid, phosphorus, and sodium. OUTCOME: Incident symptomatic kidney stones. ANALYTICAL APPROACH: Multivariable logistic regression analysis incorporating restricted cubic splines to explore potentially nonlinear relationships between urinary factors and the risk of forming a kidney stone. Optimal inflection point analysis was implemented for each factor, and dominance analysis was performed to establish the relative importance of each urinary factor. RESULTS: Each urinary factor was significantly associated with stone formation except for urine pH. Higher urinary levels of calcium, oxalate, phosphorus, and sodium were associated with a higher risk of stone formation whereas higher urine volume, uric acid, citrate, potassium, and magnesium were associated with a lower risk. The relationships were substantially linear for urine calcium, uric acid, and sodium. By contrast, the magnitudes of the relationships were modestly attenuated at levels above the inflection points for urine oxalate, citrate, volume, phosphorus, potassium, and magnesium. Dominance analysis identified 3 categories of factors' relative importance: higher (calcium, volume, and citrate), intermediate (oxalate, potassium, and magnesium), and lower (uric acid, phosphorus, and sodium). LIMITATIONS: Predominantly White participants, lack of information on stone composition. CONCLUSIONS: Urine chemistries have complex relationships and differential relative associations with the risk of kidney stone formation. PLAIN-LANGUAGE SUMMARY: Kidney stones are common and likely to recur. Certain urinary factors play a role in the development of stones, but their independent roles, relative importance, and shapes of association with stone formation are not well-characterized. We analyzed 24-hour urine collections from individuals with and without kidney stones. Stones were less likely in those with higher urine volume, citrate, potassium, magnesium, and uric acid and were more likely in those with higher calcium, oxalate, phosphorus, and sodium. The acidity of the urine was not related to stones. The urinary parameters showed different degrees of relative importance, with calcium, volume, and citrate being greatest. All parameters exhibited a linear or close-to-linear shape of association with stone formation.

Associations between Net Gastrointestinal Alkali Absorption, 24-Hour Urine Lithogenic Factors, and Kidney Stones.

BACKGROUND: It is not clear whether kidney stone formers have an abnormal handling of alkali and acid precursors in the gut, which might affect urine composition and ultimately stone formation. In this study, we aimed to investigate the determinants of net gastrointestinal alkali absorption and its associations with key urinary parameters in a large group of stone formers and non-stone formers. METHODS: Data were collected from three independent cohorts with at least one 24-hour urine collection. We explored potential determinants of net gastrointestinal alkali absorption and the association between net gastrointestinal alkali absorption, urinary parameters, and stone former status. Finally, we estimated the proportion of the association between urine parameters and stone former status explained by differences in net gastrointestinal alkali absorption. RESULTS: The analysis included 6067 participants (1102 men and 4965 women; 698 and 1804 of whom were stone formers, respectively). Average net gastrointestinal alkali absorption values were consistently lower in stone formers across the three cohorts (from -15.0 to -4.9 mEq/d). Age was directly associated with net gastrointestinal alkali absorption, whereas body mass index and net endogenous acid production were inversely associated. Net gastrointestinal alkali absorption was inversely associated with supersaturation for calcium oxalate, uric acid, and renal net acid excretion and directly associated with supersaturation for calcium phosphate, urine pH, and citrate. The odds of being a stone former was 15% (13%-17%) lower per 10 mEq/24 hours higher net gastrointestinal alkali absorption. Differences in net gastrointestinal alkali absorption explained a modest amount of the differences between stone formers and non-stone formers for supersaturation for calcium oxalate (6.3%) and a sizable amount for supersaturation for uric acid (15.2%), urine pH (38.3%), citrate (26.2%), and renal net acid excretion (63.4%). CONCLUSIONS: Kidney stone formers have lower net gastrointestinal alkali absorption, and this explains differences in urine composition and the likelihood of stone formation.

Factors associated with sex differences in the risk of kidney stones.

BACKGROUND: Men are at higher risk of developing stones compared with women; however, recent data suggest a changing epidemiology, with women being relatively more affected than before. METHODS: To estimate the proportion of excess risk among men, we analysed data from large cohorts (Health Professionals Follow-up Study and Nurses' Health Study I and II). Kidney stone incidence rates were computed and hazard ratios (HRs) and 95% confidence intervals (CIs) generated with age-adjusted Cox proportional regression models. Mediation analysis estimated the excess risk for men explained by risk factors, including waist circumference, high blood pressure, diabetes, use of thiazides and dietary intake. The 24-h urine composition was also examined. RESULTS: The analysis included 268 553 participants, contributing 5 872 249 person-years of follow-up. A total of 10 302 incident stones were confirmed and the overall incidence rate was 271 and 159 per 100 000 person-years for men and women, respectively. The age-adjusted HR was 2.32 (95% CI 2.20, 2.45) and the risk of stones was consistently higher across categories of age (HRs ranging from 2.02 to 2.76) for men compared with women. The risk remained higher among men, but tended to decrease over time (48.1%), while it increased among women. Urine supersaturations for calcium oxalate and uric acid were higher among men, primarily because of higher oxalate (26.3%), uric acid (16.3%), phosphate (23.5%) and lower pH. CONCLUSIONS: The risk of kidney stones is higher among men and this difference is only partly explained by lifestyle risk factors; differences in urine chemistries explain a substantial fraction of the excess risk.

Dietary Risk Factors for Incident and Recurrent Symptomatic Kidney Stones.

OBJECTIVE: To compare dietary factors between incident symptomatic stone formers and controls, and among the incident stone formers, to determine whether dietary factors were predictive of symptomatic recurrence. PATIENTS AND METHODS: We prospectively recruited 411 local incident symptomatic kidney stone formers (medical record validated) and 384 controls who were seen at Mayo Clinic in Minnesota or Florida between January 1, 2009, and August 31, 2018. Dietary factors were based on a Viocare, Inc, food frequency questionnaire administered during a baseline in-person study visit. Logistic regression compared dietary risk factors between incident symptomatic stone formers and controls. Incident stone formers were followed up for validated symptomatic recurrence in the medical record. Cox proportional hazards models estimated risk of symptomatic recurrence with dietary factors. Analyses adjusted for fluid intake, energy intake, and nondietary risk factors. RESULTS: In fully adjusted analyses, lower dietary calcium, potassium, caffeine, phytate, and fluid intake were all associated with a higher odds of an incident symptomatic kidney stone. Among incident stone formers, 73 experienced symptomatic recurrence during a median 4.1 years of follow-up. Adjusting for body mass index, fluid intake, and energy intake, lower dietary calcium and lower potassium intake were predictive of symptomatic kidney stone recurrence. With further adjustment for nondietary risk factors, lower dietary calcium intake remained a predictor of recurrence, but lower potassium intake only remained a predictor of recurrence among those not taking thiazide diuretics or calcium supplements. CONCLUSION: Enriching diets in stone formers with foods high in calcium and potassium may help prevent recurrent symptomatic kidney stones.

Estimating 24-hour urinary excretion using spot urine measurements in kidney stone formers.

BACKGROUND: One limitation of the use of 24-hour collection is impracticality. We analysed the performance of spot urine measurements to estimate 24-hour excretion in patients with kidney stones. METHODS: A total of 74 adult patients from two centres performed a 24-hour urine collection. A sample of the last micturition was sent for spot urine analysis. Twenty patients were asked to collect two additional spot urine samples, one before dinner and the other after dinner. Urinary concentrations of creatinine, calcium, oxalate, uric acid, citrate and magnesium were measured in the 24-hour and each of the spot urine samples. Four approaches were used to estimate 24-hour urinary excretion, multiplying the ratio of the spot urinary analyte to creatinine concentration by (i) measured 24-hour urinary creatinine excretion (Prediction 1), (ii) estimated 24-hour urinary creatinine excretion (Prediction 2), (iii) assumed 1-g 24-hour urinary creatinine excretion (Prediction 3) or (iv) assumed 1.5-g 24-hour urinary creatinine excretion (Prediction 4). For each parameter we computed Lin's concordance correlation coefficients (CCCs), Bland-Altman plots and 95% limits of agreement. RESULTS: The performance of estimates obtained with Prediction 1 and Prediction 2 was similar, except for citrate and uric acid, for which Prediction 2 performed worse. Both approaches performed moderately well: citrate CCC {0.82 [95% confidence interval (CI) 0.75-0.90]}, oxalate [0.66 (95% CI 0.55-0.78)], magnesium [0.66 (95% CI 0.54-0.77)], calcium [0.63 (95% CI 0.50-0.75)] and uric acid [0.52 (95% CI 0.36-0.68)]. The performance of Predictions 3 and 4 was worse. CONCLUSIONS: Although spot urine samples may hold promise for clinical and population-based research, at present they have limited utility in clinical practice. Measuring or estimating 24-hour creatinine, rather than assuming a given creatinine excretion, will be necessary in future studies of spot urine samples.

Temporal Trends of Dietary Risk Factors after a Diagnosis of Kidney Stones.

BACKGROUND AND OBJECTIVES: Diet is an important contributor to kidney stone formation, but there are limited data regarding long-term changes in dietary factors after a kidney stone. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: We analyzed data from three longitudinal cohorts, the Health Professionals Follow-Up Study and Nurses' Health Study I and II, comparing changes in dietary factors in participants with and without kidney stones during follow-up. The daily intake of dietary calcium, supplemental calcium, animal protein, caffeine, fructose, potassium, sodium, oxalate, phytate, vitamin D, vitamin C, sugar-sweetened beverages, fluids, net endogenous acid production, and Dietary Approaches to Stop Hypertension score were assessed by repeat food frequency questionnaires and computed as absolute differences; a difference-in-differences approach was used to account for temporal changes using data from participants without kidney stones from the same calendar period. RESULTS: Included were 184,398 participants with no history of kidney stones, 7095 of whom became confirmed stone formers. Several intakes changed significantly over time in stone formers, with some showing a relative increase up to 8 years later, including caffeine (difference in differences, 8.8 mg/d; 95% confidence interval [95% CI], 3.4 to 14.1), potassium (23.4 mg/d; 95% CI, 4.6 to 42.3), phytate (12.1 mg/d; 95% CI, 2.5 to 21.7), sodium (43.1 mg/d; 95% CI, 19.8 to 66.5), and fluids (47.1 ml/d; 95% CI, 22.7 to 71.5). Other dietary factors showed a significant decrease, such as oxalate (-7.3 mg/d; 95% CI, -11.4 to -3.2), vitamin C (-34.2 mg/d; 95% CI, -48.8 to -19.6), and vitamin D (-18.0 IU/d; 95% CI, -27.9 to -8.0). A significant reduction was observed in sugar-sweetened beverages intake of -0.5 (95% CI, -0.8 to -0.3) and -1.4 (95% CI, -1.8 to -1.0) servings per week and supplemental calcium of -105.1 (95% CI, -135.4 to -74.7) and -69.4 (95% CI, -95.4 to -43.4) mg/d for women from Nurses' Health Study I and II, respectively. Animal protein, dietary calcium, fructose intake, Dietary Approaches to Stop Hypertension score, and net endogenous acid production did not change significantly over time. CONCLUSIONS: After the first episode of a kidney stone, mild and inconsistent changes were observed concerning dietary factors associated with kidney stone formation.

Urinary stone disease prevalence and associations in cystic fibrosis.

Cystic fibrosis (CF) may predispose patients to urinary stone disease (USD), but reported prevalence of USD in patients with CF in previous small studies is variable. To date, analysis of risk factors for USD within the CF population has been limited. We studied 29,396 patients in the Cystic Fibrosis Foundation Patient Registry to calculate age and sex-stratified prevalence of USD. For adult patients, we examined age and multivariable-adjusted cross-sectional associations between demographic and clinical factors, CFTR mutation class, and prevalent USD. Prevalence of USD was 0.4% (95% CI 0.3-0.5%) under age 18 years, 3.1% (2.7-3.6%) at 18-24 years, 6.4% (5.8-7.1%) at 25-34 years, 7.5% (6.5-8.5%) at 35-44 years, and 6.7% (5.8-7.8%) at 45 years and older. Prevalence for women was higher than men at younger (< 45 years) but not older ages (P value for interaction < 0.0005). Multivariable odds of prevalent USD were significantly increased for severe CFTR mutations, OR 1.53 (1.14-2.06), diabetes, OR 1.24 (1.03-1.50), hypertension, OR 1.58 (1.29-1.93), and chronic macrolide therapy, OR 1.27 (1.07-1.52). BMI was not associated with USD. USD prevalence in CF is similar to that in the general population. With the exception of BMI, known risk factors for USD in the general population also appear to be important for patients with CF. We identified several novel associations in CF patients, including greater prevalence of USD in individuals with severe CFTR mutations and among young women.

Mediterranean diet adherence and risk of incident kidney stones.

BACKGROUND: Diet plays an important role in kidney stone formation. Several individual components have been associated with the risk of kidney stone formation, but there is limited evidence regarding the role of healthful dietary patterns. OBJECTIVE: To prospectively study the association between adherence to the Mediterranean diet and the risk of incident kidney stones. METHODS: We conducted a longitudinal study using 3 different cohorts: the Health Professionals Follow-up Study (n = 42,902 men), the Nurses' Health Study I (n = 59,994 women), and the Nurses' Health Study II (n = 90,631 women). We assessed diet every 4 y using an FFQ and calculated adherence to a Mediterranean diet using the alternate Mediterranean diet score (aMED). A subgroup of 6077 participants provided ≥1 24-h urine sample, and urinary solute excretion was analyzed. We used Cox proportional hazards regression to examine the independent association between the aMED and incidence of kidney stones, adjusting for potential confounders. We used adjusted linear regression models to study the relation between aMED and urine composition. RESULTS: During 3,316,633 person-years of follow-up, 6576 cases of incident kidney stones were identified. For participants in the highest aMED score category, the risk of developing a kidney stone was between 13% and 41% lower compared with participants in the lowest score (pooled HR: 0.72, 95% CI: 0.59, 0.87; P value for trend <0.001). A higher aMED score was associated with higher urinary citrate, magnesium, oxalate, phosphate, uric acid, volume, and pH, and lower urinary sodium, resulting in lower supersaturation for calcium oxalate, calcium phosphate, and uric acid. CONCLUSION: Adherence to a Mediterranean diet is associated with a lower risk of developing a kidney stone.

Antibiotic Use and Risk of Incident Kidney Stones in Female Nurses.

RATIONALE & OBJECTIVE: The intestinal microbiome may affect urinary stone disease by modulating the amount of oxalate absorbed from the intestine and subsequently excreted in urine. This study sought to explore the association between antibiotics, which alter the intestinal microbiota, and risk for urinary stone disease. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 5,010 women in the Nurses' Health Study (NHS) I and II who had collected 24-hour urine samples. EXPOSURES: Use of antibiotics during the age range of 40 to 49 (NHS II), 40 to 59 (NHS I), and 20 to 39 years (both cohorts). OUTCOMES: Incident symptomatic urinary stone disease; urine composition. ANALYTICAL APPROACH: Cause-specific hazards regression adjusted for age, body mass index, comorbid conditions, thiazide use, and dietary factors. Follow-up was censored at the time of asymptomatic kidney stones, cancer, or death. RESULTS: Cumulative use of antibiotics for a total of 2 or more months during the age range of 40 to 49 years (NHS II) and 40 to 59 years (NHS II) was associated with significantly higher risk for developing incident stones compared with no use (pooled HR, 1.48; 95% CI, 1.12-1.96). Similar results were found for the period of 20 to 39 years (pooled HR, 1.36; 95% CI, 1.00-1.84). Results were unchanged after excluding participants who reported urinary tract infection with their stone event or as the most common reason for antibiotic use. Urine composition was generally similar across antibiotic groups except for marginally lower urine pH and citrate values among those taking antibiotics for 2 or more months. LIMITATIONS: Observational design; lack of information for type of antibiotic used; relatively large span of time between antibiotic use and urine collection. CONCLUSIONS: Use of antibiotics for more than 2 months in early adulthood and middle age is associated with higher risk for urinary stone disease in later life.

Menopause and Risk of Kidney Stones.

PURPOSE: Metabolic changes due to menopause may alter urine composition and kidney stone risk but results of prior work on this association have been mixed. We examined menopause and the risk of incident kidney stones, and changes in 24-hour urine composition in the NHS (Nurses' Health Study) II. MATERIALS AND METHODS: Using multivariate adjusted Cox proportional hazards models we prospectively analyzed 108,639 NHS II participants who provided information on menopause and kidney stones. We also analyzed 24-hour urine collections from 658 participants who performed a collection while premenopausal and a repeat collection after menopause. RESULTS: During 22 years of followup there were 3,456 incident kidney stones. The multivariate adjusted relative risk of an incident kidney stone in postmenopausal participants compared with premenopause was 1.27 (95% CI 1.08-1.46). On stratified analysis compared with premenopause the multivariate adjusted relative risk of natural and surgically induced menopause was 1.27 (95% CI 1.09-1.48) and 1.43 (95% CI 1.19-1.73), respectively. Among the 74,505 postmenopausal participants there was a total of 1,041 incident stone events. Compared with no hormone therapy neither current nor past use was significantly associated with kidney stone risk. Compared with premenopause the postmenopausal urine collections had lower mean calcium, citrate, phosphorus and uric acid, and higher mean volume. CONCLUSIONS: Postmenopausal status is associated with a higher risk of incident kidney stones. Natural menopause and surgical menopause are independently associated with higher risk. There are small but significant differences in urine composition between premenopausal and postmenopausal urine collections.

Intake of Trace Metals and the Risk of Incident Kidney Stones.

PURPOSE: The association between the intake of trace metals and the risk of incident stones has not been longitudinally investigated. MATERIALS AND METHODS: We performed a prospective analysis of 193,551 participants in the Health Professionals Follow-up Study, and the Nurses' Health Study I and II. During a followup of 3,316,580 person-years there was a total of 6,576 incident stones. We used multivariate regression models to identify associations of the intake of zinc, iron, copper and manganese with the risk of stones. In a subset of participants with 24-hour urine collections we examined the association between the intake of trace metals and urine composition. RESULTS: After multivariate adjustment total and dietary intakes of zinc and iron were not significantly associated with incident stones. A higher intake of manganese was associated with a lower risk of stones. The pooled HR of the highest quintile of total manganese intake compared with the lowest intake was 0.82 (95% CI 0.68-0.98, p = 0.02). Total but not dietary copper intake was marginally associated with a higher risk of stones (pooled HR 1.14, 95% CI 1.02-1.28, p = 0.01). There were no statistically significant associations of the total intake of manganese and copper with urinary supersaturation. CONCLUSIONS: Zinc and iron intake was not associated with a risk of stones. Copper intake may be associated with a higher risk in some individuals. Higher total manganese intake was associated with a lower risk of stones but not with traditional 24-hour urinary composite markers of stone risk. Further research is needed to elucidate the mechanisms by which manganese may reduce kidney stone formation.

Vitamin B6 intake and the risk of incident kidney stones.

Higher vitamin B6 intake might reduce urinary excretion of oxalate, one of the major determinants of risk for calcium oxalate kidney stones. Previous studies investigating the association between intake of vitamin B6 and risk of stones found conflicting results. We sought to investigate the association in three large prospective cohorts. We prospectively examined the association in the Health Professionals Follow-up Study (HPFS; n = 42,919 men), Nurses' Health Study I (NHS I; n = 60,003 older women), and Nurses' Health Study II (NHS II; n = 90,629 younger women). Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident stones across categories of total vitamin B6 intake (<3.0, 3.0-4.9, 5.0-9.9, 10.0-39.9, ≥40.0 mg/day) were generated with Cox proportional hazards regression models adjusted for potential confounders. During 3,316,846 person-years of follow-up, 6576 incident kidney stones were confirmed. In univariate and multivariate analyses, there was no association between intake of vitamin B6 and incident stones. The HR for stones in the highest category compared with the lowest was 1.05 (95% CI 0.85, 1.30; p value for trend = 0.61) for HPFS, 0.95 (95% CI 0.76, 1.18; p value for trend = 0.42) for NHS I, and 1.06 (95% CI 0.91, 1.24; p value for trend = 0.34) for NHS II. The pooled adjusted HR for the highest category compared with the lowest was 1.03 (95% CI 0.92, 1.15; p value for trend = 0.60). Intake of vitamin B6 is not associated with risk of incident kidney stones.

Body Size and the Risk of Primary Hyperparathyroidism in Women: A Cohort Study.

Greater body weight and fat mass have been associated with higher serum parathyroid hormone levels and a higher prevalence of primary hyperparathyroidism (P-HPTH) in women. However, prospective studies to evaluate whether greater body size associates with a higher incidence of developing P-HPTH have not been reported. We investigated whether greater body size was independently associated with a higher risk for developing P-HPTH in women. We conducted a prospective cohort study of 85,013 female participants in the Nurses' Health Study I followed for up to 26 years. Body size was measured via multiple metrics: weight, body mass index (BMI), and waist circumference (WC). Weight and BMI were assessed every 2 years from 1986 to 2012, and WC was assessed in 1986, 1996, and 2000. Detailed dietary and demographic exposures were quantified via validated biennial questionnaires. Incident cases of P-HPTH were confirmed by individual medical record review. Cox proportional hazards models were used to evaluate whether WC, weight, and BMI were independent risk factors for developing P-HPTH. Models were adjusted for demographic variables, comorbidities, medications, intakes of calcium and vitamin D, and exposure to ultraviolet light. We confirmed 491 incident cases of P-HPTH during 2,128,068 person-years of follow-up. The multivariable-adjusted relative risks for incident P-HPTH increased across quartiles of WC: Q1, ref; Q2, 1.34 (0.97, 1.86); Q3, 1.70 (1.24, 2.31); Q4, 2.27 (1.63, 3.18); p trend < 0.001. Similarly, the multivariable-adjusted risks for incident P-HPTH increased across quartiles of weight: Q1, ref; Q2, 1.23 (0.92, 1.65); Q3, 1.63 (1.24, 2.14); Q4, 1.65 (1.24, 2.19); p trend < 0.001. A similar but statistically non-significant trend was observed across quartiles of BMI (p trend = 0.07). In summary, body size may be an independent and modifiable risk factor for developing P-HPTH in women. © 2017 American Society for Bone and Mineral Research.

Dietary and Lifestyle Risk Factors Associated with Incident Kidney Stones in Men and Women.

PURPOSE: Several dietary and lifestyle factors are associated with a higher risk of kidney stones. We estimated the population attributable fraction and the number needed to prevent for modifiable risk factors, including body mass index, fluid intake, DASH (Dietary Approaches to Stop Hypertension) style diet, dietary calcium intake and sugar sweetened beverage intake. MATERIALS AND METHODS: We used data on the HPFS (Health Professionals Follow-Up Study) cohort and the NHS (Nurses' Health Study) I and II cohorts. Information was obtained from validated questionnaires. Poisson regression models adjusted for potential confounders were used to estimate the association of each risk factor with the development of incident kidney stones and calculate the population attributable fraction and the number needed to prevent. RESULTS: The study included 192,126 participants who contributed a total of 3,259,313 person-years of followup, during which an incident kidney stone developed in 6,449 participants. All modifiable risk factors were independently associated with incident stones in each cohort. The population attributable fraction ranged from 4.4% for a higher intake of sugar sweetened beverages to 26.0% for a lower fluid intake. The population attributable fraction for all 5 risk factors combined was 57.0% in HPFS, 55.2% in NHS I and 55.1% in NHS II. The number needed to prevent during 10 years ranged from 67 for lower fluid intake to 556 for lower dietary calcium intake. CONCLUSIONS: Five modifiable risk factors accounted for more than 50% of incident kidney stones in 3 large prospective cohorts. Assuming a causal relation, our estimates suggest that preventive measures aimed at reducing those factors could substantially decrease the burden of kidney stones in the general population.

Vitamin D Intake and the Risk of Incident Kidney Stones.

PURPOSE: Kidney stones are a common and painful condition. Longitudinal prospective studies on the association between the intake of vitamin D and the risk of incident kidney stones are lacking. MATERIALS AND METHODS: We performed a prospective analysis of 193,551 participants in the Health Professionals Follow-up Study and Nurses' Health Study I and II. Participants were divided into categories of total (less than 100, 100 to 199, 200 to 399, 400 to 599, 600 to 999, 1,000 IU per day or greater) and supplemental (none, less than 400, 400 to 599, 600 to 999, 1,000 IU per day or greater) vitamin D intake. During a followup of 3,316,846 person-years there were 6,576 incident kidney stone events. Cox proportional hazards regression models were adjusted for age, body mass index, comorbidities, use of medications and intake of other nutrients. RESULTS: After multivariate adjustment there was no statistically significant association between vitamin D intake and risk of stones in the HPFS (HR for 1,000 or greater vs less than 100 IU per day 1.08, 95% CI 0.80, 1.47, p for trend = 0.92) and the NHS I (HR 0.99, 95% CI 0.73, 1.35, p for trend = 0.70), whereas there was a suggestion of a higher risk in the NHS II (HR 1.18, 95% CI 0.94, 1.48, p for trend = 0.02). Similar results were found for supplemental vitamin D intake. CONCLUSIONS: Vitamin D intake in typical amounts was not statistically associated with risk of kidney stone formation, although higher risk with higher doses than those studied here cannot be excluded.

Dietary Protein and Potassium, Diet-Dependent Net Acid Load, and Risk of Incident Kidney Stones.

BACKGROUND AND OBJECTIVES: Protein and potassium intake and the resulting diet-dependent net acid load may affect kidney stone formation. It is not known whether protein type or net acid load is associated with risk of kidney stones. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We prospectively examined intakes of protein (dairy, nondairy animal, and vegetable), potassium, and animal protein-to-potassium ratio (an estimate of net acid load) and risk of incident kidney stones in the Health Professionals Follow-Up Study (n=42,919), the Nurses' Health Study I (n=60,128), and the Nurses' Health Study II (n=90,629). Multivariable models were adjusted for age, body mass index, diet, and other factors. We also analyzed cross-sectional associations with 24-hour urine (n=6129). RESULTS: During 3,108,264 person-years of follow-up, there were 6308 incident kidney stones. Dairy protein was associated with lower risk in the Nurses' Health Study II (hazard ratio for highest versus lowest quintile, 0.84; 95% confidence interval, 0.73 to 0.96; P value for trend <0.01). The hazard ratios for nondairy animal protein were 1.15 (95% confidence interval, 0.97 to 1.36; P value for trend =0.04) in the Health Professionals Follow-Up Study and 1.20 (95% confidence interval, 0.99 to 1.46; P value for trend =0.06) in the Nurses' Health Study I. Potassium intake was associated with lower risk in all three cohorts (hazard ratios from 0.44 [95% confidence interval, 0.36 to 0.53] to 0.67 [95% confidence interval, 0.57 to 0.78]; P values for trend <0.001). Animal protein-to-potassium ratio was associated with higher risk (P value for trend =0.004), even after adjustment for animal protein and potassium. Higher dietary potassium was associated with higher urine citrate, pH, and volume (P values for trend <0.002). CONCLUSIONS: Kidney stone risk may vary by protein type. Diets high in potassium or with a relative abundance of potassium compared with animal protein could represent a means of stone prevention.

Insights Into Nephrolithiasis From the Nurses' Health Studies.

OBJECTIVES: To review the contributions of the Nurses' Health Study (NHS) I and NHS II to understanding the role of dietary factors, beverages, body size, and urinary factors in the development of kidney stones. METHODS: We conducted a review of kidney stone-related publications of NHS I and NHS II between 1976 and 2016. RESULTS: Studies using NHS I and NHS II data have demonstrated the importance of many factors in kidney stone formation and were the first to report that higher dietary calcium was associated with a lower risk of incident kidney stones in women. Data from these cohorts were instrumental in emphasizing that nephrolithiasis is a systemic disease and suggesting that a kidney stone or shared risk factors may lead to hypertension, diabetes, and cardiovascular disease. CONCLUSIONS: Findings from the NHSs have changed the scientific understanding and the clinical practice of stone prevention and have been incorporated into widely consulted textbooks and the American Urological Association Medical Management of Kidney Stones guidelines.

Physical Activity and the Risk of Primary Hyperparathyroidism.

CONTEXT: Primary hyperparathyroidism (P-HPTH) is relatively common and predominantly affects women. Prior studies have shown that physical activity (PA) can lower PTH levels. OBJECTIVE: Our objective was to evaluate the hypothesis that lower PA is a risk factor for developing P-HPTH. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 69 621 female participants in the Nurses' Health Study I followed for 22 years. EXPOSURES: PA and other dietary and demographic exposures were quantified via detailed, and validated, biennial questionnaires. OUTCOMES: Incident P-HPTH was confirmed by medical record review after initial assessment by questionnaire. Adjusted Cox proportional hazards models were used to evaluate whether PA was an independent risk factor for developing P-HPTH. We also evaluated the risk of developing P-HPTH when combining low PA (<16 metabolic equivalent hours/week) with a previously identified independent risk factor for developing P-HPTH: low calcium intake (<800 mg/day). The relation between PA and PTH levels was evaluated in 625 participants. RESULTS: We confirmed 302 incident cases of P-HPTH during 1 474 993 person-years of follow-up. Participants in the highest quintile (Q) of PA had a 50% lower risk of developing P-HPTH: age-adjusted relative risks and 95% confidence intervals for incident P-HPTH by lowest to highest of PA were Q1 = 1.0 (reference); Q2 = 0.83 (0.60­1.15); Q3 = 0.84 (0.61­1.15); Q4 = 0.50 (0.34­0.74); Q5 = 0.50 (0.35­0.73); P for trend <.001. Extensive multivariable adjustments did not materially change these findings. The adjusted relative risk for developing P-HPTH among participants with the combination lower PA and lower calcium intake was 2.37-fold (1.60­3.51) higher than in participants with higher PA and higher calcium intake. PA was inversely correlated with serum PTH (ρ = −0.09, P = .03); the mean adjusted serum PTH in Q 2­5 of PA was lower than in Q 1 (36.3 vs 39.1 pg/mL, P = .02). CONCLUSION: Low physical activity may be a modifiable risk factor for developing P-HPTH in women.

Total, Dietary, and Supplemental Vitamin C Intake and Risk of Incident Kidney Stones.

BACKGROUND: Previous studies of vitamin C and kidney stones were conducted mostly in men and either reported disparate results for supplemental and dietary vitamin C or did not examine dietary vitamin C. STUDY DESIGN: Prospective cohort analysis. SETTING & PARTICIPANTS: 156,735 women in the Nurses' Health Study (NHS) I and II and 40,536 men in the Health Professionals Follow-up Study (HPFS). PREDICTOR: Total, dietary, and supplemental vitamin C intake, adjusted for age, body mass index, thiazide use, and dietary factors. OUTCOMES: Incident kidney stones. RESULTS: During a median follow-up of 11.3 to 11.7 years, 6,245 incident kidney stones were identified. After multivariable adjustment, total vitamin C intake (<90 [reference], 90-249, 250-499, 500-999, and ≥1,000mg/d) was not significantly associated with risk for kidney stones among women, but was among men (HRs of 1.00 [reference], 1.19 [95% CI, 0.99-1.46], 1.15 [95% CI, 0.93-1.42], 1.29 [95% CI, 1.04-1.60], and 1.43 [95% CI, 1.15-1.79], respectively; P for trend = 0.005). Median total vitamin C intake for the 500- to 999-mg/d category was ∼700mg/d. Supplemental vitamin C intake (no use [reference], <500, 500-999, and ≥1,000mg/d) was not significantly associated with risk for kidney stones among women, but was among men (HR, 1.19 [95% CI, 1.01-1.40] for ≥1,000mg/d; P for trend = 0.001). Dietary vitamin C intake was not associated with stones among men or women, although few participants had dietary intakes > 700mg/d. LIMITATIONS: Nutrient intakes derived from food-frequency questionnaires, lack of data on stone composition for all cases. CONCLUSIONS: Total and supplemental vitamin C intake was significantly associated with higher risk for incident kidney stones in men, but not in women.

Nephrolithiasis and Risk of Incident Bone Fracture.

PURPOSE: Higher urine calcium is a common feature of calcium nephrolithiasis and may be associated with lower bone mineral density in individuals with kidney stones. However previous population based studies of kidney stones and the risk of bone fracture demonstrate conflicting results. We examined independent associations between a history of kidney stones and incident fracture. MATERIALS AND METHODS: We performed prospective studies using data from the Nurses' Health Study of 107,001 women with 32 years of followup and the Health Professionals Follow-up Study of 50,982 men with 26 years of followup. We excluded premenopausal women, men younger than 45 years and individuals who reported osteoporosis at baseline. Study outcomes were incident wrist (distal radius) or incident hip (proximal femur) fracture due to low or moderate trauma. Cox proportional hazards regression was used to adjust for multiple factors, including age, race, body mass index, thiazide use, supplemental calcium and dietary intakes. RESULTS: There were 4,940 wrist and 2,391 hip fractures in women, and 862 wrist and 747 hip fractures in men. All fractures were incident. The multivariable adjusted relative risk of incident wrist fracture in participants with a history of kidney stones compared to participants without kidney stones was 1.18 (95% CI 1.04-1.34) in women and 1.21 (95% CI 1.00-1.47) in men. The pooled multivariable adjusted relative risk of wrist fracture was 1.20 (95% CI 1.08-1.33). The multivariable adjusted relative risk of incident hip fracture in participants with kidney stones was 0.96 (95% CI 0.80-1.14) in women and 0.92 (95% CI 0.74-1.14) in men. The pooled multivariable adjusted relative risk of hip fracture was 0.94 (95% CI 0.82-1.08). CONCLUSIONS: Nephrolithiasis is associated with a significantly higher risk of incident wrist but not hip fracture in women and men.