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.

Effect of Vitamin D on Endothelial Function: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: In nonhypertensive individuals, lower levels of 25-hydroxyvitamin D (25[OH]D) have been associated with an increased risk of hypertension, and vitamin D deficiency has been associated with endothelial dysfunction in such individuals. However, the effect of vitamin D supplementation on endothelial dysfunction in nonhypertensive individuals has not been examined in a rigorous fashion. METHODS: In this randomized, double-blind, placebo-controlled trial of nonhypertensive, nondiabetic overweight, or obese individuals with vitamin D deficiency (body mass index ≥25 and 25[OH]D ≤ 20 ng/ml), we assigned subjects to receive either ergocalciferol (50,000 units) or matching placebo, once a week for 8 weeks. Our primary outcome was endothelial-dependent vasodilation (EDV) measured by brachial artery ultrasound at baseline and 8 weeks postrandomization. RESULTS: By the end of the trial, 46 and 47 participants were allocated to receive ergocalciferol and placebo, respectively. Mean 25(OH)D levels increased from 14.9 to 30.3 in the vitamin D group and 14.4 to 17.4 in the placebo. EDV did not change significantly with either vitamin D repletion (from 6.3 ± 3.6% at baseline to 6.1 ± 4.6% at 8 weeks; P value = 0.78) or placebo (7.9 ± 4.7% to 6.8 ± 4.7%; P = 0.17). The treatment effect P value (comparing the 8-week change with ergocalciferol to the change with placebo) was 0.35. CONCLUSIONS: In this randomized, double-blind, placebo-controlled trial, there was no improvement in endothelial function (measured as EDV) after repletion of vitamin D in overweight/obese nonhypertensive individuals.

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.

The effect of vitamin D on renin-angiotensin system activation and blood pressure: a randomized control trial.

OBJECTIVE: Disruption of vitamin D signaling in rodents causes activation of the rennin-angiotensin system (RAS) and development of hypertension. Observational studies in humans found lower circulating 25-hydroxyvitamin D [25(OH)D] is associated with increased RAS activity and blood pressure (BP). We performed the first randomized control trial to investigate the effects of vitamin D supplementation on the RAS in humans. METHODS: Vitamin D deficient, [25(OH)D ≤20 ng/ml), overweight individuals without hypertension were randomized into a double-blind, placebo-controlled trial of 8-weeks treatment with ergocalciferol or placebo. Kidney-specific RAS activity, measured using renal plasma flow response to captopril in high sodium balance, was assessed at baseline and 8 weeks, as was systemic RAS activity and 24-h ambulatory BP. RESULTS: In total, 84 participants completed the study. Mean 25[OH]D levels increased from 14.7 to 30.3 ng/ml in the ergocalciferol group, P value < 0.0001, and from 14.3 to 17.4 ng/ml in the placebo group, P value = 0.3. The renal plasma flow response to captopril was 33.9 ±â€Š56.1 ml/min per 1.73 m at baseline and 35.7 ±â€Š47.7 ml/min per 1.73 m at 8 weeks in the ergocalciferol group (P value = 0.83); and was 37.3 ±â€Š46.9 ml/min per 1.73 m at baseline and 35.9 ±â€Š26.2 ml/min per 1.73 m at 8 weeks in the placebo group (P value = 0.78). Ergocalciferol had no effect on PRA, AngII, or 24-h BP measurements. CONCLUSIONS: This trial found no benefit from correcting vitamin D deficiency on RAS activity or BP after 8 weeks. These findings are not consistent with the hypothesis that vitamin D is a modifiable target for lowering BP in vitamin D deficient individuals.

Identification and Characterization of a Novel Association between Dietary Potassium and Risk of Crohn's Disease and Ulcerative Colitis.

BACKGROUND: Recent animal studies have identified that dietary salt intake may modify the risk and progression of autoimmune disorders through modulation of the IL-23/TH17 pathway, which is critical in the pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD). METHODS: We conducted a prospective study of U.S. women enrolled in the Nurses' Health Study (NHS) and NHSII who provided detailed and validated information on diet and lifestyle beginning in 1984 in NHS and 1991 in NHSII. We confirmed incident cases of UC and CD reported through 2010 in NHS and 2011 in NHSII. We used Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals. In a case-control study nested within these cohorts, we evaluated the interaction between single nucleotide polymorphisms (SNPs) in genes involved in TH17 pathway and dietary potassium on risk of CD and UC. In a cohort of healthy volunteers, we also assessed the effect of supplemental potassium on development of naïve and memory T cells, differentiated with TGFß1 or TH17 conditions. RESULTS: Among a total of 194,711 women over a follow-up of 3,220,247 person-years, we documented 273 cases of CD and 335 cases of UC. Dietary intake of potassium (Ptrend = 0.005) but not sodium (Ptrend = 0.44) was inversely associated with risk of CD. Although, both dietary potassium and sodium were not significantly associated with risk of UC, there was a suggestion of an inverse association with dietary potassium (Ptrend = 0.08). The association of potassium with risk of CD and UC appeared to be modified by loci involved in the TH17 pathway that have previously been associated with susceptibility to CD, particularly SNP rs7657746 (IL21) (Pinteraction = 0.004 and 0.01, respectively). In vitro, potassium enhanced the expression of Foxp3 in both naïve and memory CD4+ T cells via activating Smad2/3 and inhibiting Smad7 in TH17 cells. CONCLUSION: Dietary potassium is inversely associated with risk of CD with both in vitro and gene-environment interaction data suggesting a potential role for potassium in regulating immune tolerance through its effect on Tregs and TH17 pathway.

A Concept-Wide Association Study of Clinical Notes to Discover New Predictors of Kidney Failure.

BACKGROUND AND OBJECTIVES: Identifying predictors of kidney disease progression is critical toward the development of strategies to prevent kidney failure. Clinical notes provide a unique opportunity for big data approaches to identify novel risk factors for disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used natural language processing tools to extract concepts from the preceding year's clinical notes among patients newly referred to a tertiary care center's outpatient nephrology clinics and retrospectively evaluated these concepts as predictors for the subsequent development of ESRD using proportional subdistribution hazards (competing risk) regression. The primary outcome was time to ESRD, accounting for a competing risk of death. We identified predictors from univariate and multivariate (adjusting for Tangri linear predictor) models using a 5% threshold for false discovery rate (q value <0.05). We included all patients seen by an adult outpatient nephrologist between January 1, 2004 and June 18, 2014 and excluded patients seen only by transplant nephrology, with preexisting ESRD, with fewer than five clinical notes, with no follow-up, or with no baseline creatinine values. RESULTS: Among the 4013 patients selected in the final study cohort, we identified 960 concepts in the unadjusted analysis and 885 concepts in the adjusted analysis. Novel predictors identified included high-dose ascorbic acid (adjusted hazard ratio, 5.48; 95% confidence interval, 2.80 to 10.70; q<0.001) and fast food (adjusted hazard ratio, 4.34; 95% confidence interval, 2.55 to 7.40; q<0.001). CONCLUSIONS: Novel predictors of human disease may be identified using an unbiased approach to analyze text from the electronic health record.

Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement.

BACKGROUND: Recently published guidelines on the medical management of renal stone disease did not address relevant topics in the field of idiopathic calcium nephrolithiasis, which are important also for clinical research. DESIGN: A steering committee identified 27 questions, which were proposed to a faculty of 44 experts in nephrolithiasis and allied fields. A systematic review of the literature was conducted and 5216 potentially relevant articles were selected; from these, 407 articles were deemed to provide useful scientific information. The Faculty, divided into working groups, analysed the relevant literature. Preliminary statements developed by each group were exhaustively discussed in plenary sessions and approved. RESULTS: Statements were developed to inform clinicians on the identification of secondary forms of calcium nephrolithiasis and systemic complications; on the definition of idiopathic calcium nephrolithiasis; on the use of urinary tests of crystallization and of surgical observations during stone treatment in the management of these patients; on the identification of patients warranting preventive measures; on the role of fluid and nutritional measures and of drugs to prevent recurrent episodes of stones; and finally, on the cooperation between the urologist and nephrologist in the renal stone patients. CONCLUSIONS: This document has addressed idiopathic calcium nephrolithiasis from the perspective of a disease that can associate with systemic disorders, emphasizing the interplay needed between urologists and nephrologists. It is complementary to the American Urological Association and European Association of Urology guidelines. Future areas for research are identified.

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.

Carotenoids, vitamin A, vitamin C, vitamin E, and folate and risk of self-reported hearing loss in women.

BACKGROUND: Higher intake of certain vitamins may protect against cochlear damage from vascular compromise and oxidative stress, thereby reducing risk of acquired hearing loss, but data are limited. OBJECTIVE: We prospectively examined the relation between carotenoids, vitamin A, vitamin C, vitamin E, and folate intake and risk of self-reported hearing loss in women. DESIGN: This prospective cohort study followed 65,521 women in the Nurses' Health Study II from 1991 to 2009. Baseline and updated information obtained from validated biennial questionnaires was used in Cox proportional hazards regression models to examine independent associations between nutrient intake and self-reported hearing loss. RESULTS: After 1,084,598 person-years of follow-up, 12,789 cases of incident hearing loss were reported. After multivariable adjustment, we observed modest but statistically significant inverse associations between higher intake of ß-carotene and ß-cryptoxanthin and risk of hearing loss. In comparison with women in the lowest quintile of intake, the multivariable-adjusted RR of hearing loss among women in the highest quintile was 0.88 (95% CI: 0.81, 0.94; P-trend < 0.001) for ß-carotene and 0.90 (95% CI: 0.84, 0.96; P-trend < 0.001) for ß-cryptoxanthin. In comparison with women with folate intake 200-399 µg/d, very low folate intake (<200 µg/d) was associated with higher risk (RR: 1.19; 95% CI: 1.01, 1.41), and higher intake tended to be associated with lower risk (P-trend = 0.04). No significant associations were observed for intakes of other carotenoids or vitamin A. Higher vitamin C intake was associated with higher risk; in comparison with women with intake <75 mg/d, the RR among women with vitamin C intake ≥1000 mg/d (mainly supplemental) was 1.22 (95% CI: 1.06, 1.42; P-trend = 0.02). There was no significant trend between intake of vitamin E intake and risk. CONCLUSION: Higher intakes of ß-carotene, ß-cryptoxanthin, and folate, whether total or from diet, are associated with lower risk of hearing loss, whereas higher vitamin C intake is associated with higher risk.

Calcium and phosphorus regulatory hormones and risk of incident symptomatic kidney stones.

BACKGROUND AND OBJECTIVES: Calcium and phosphorus regulatory hormones may contribute to the pathogenesis of calcium nephrolithiasis. However, there has been no prospective study to date of plasma hormone levels and risk of kidney stones. This study aimed to examine independent associations between plasma levels of 1,25-dihydroxyvitamin D (1,25[OH]2D), 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, fibroblast growth factor 23 (FGF23), parathyroid hormone, calcium, phosphate, and creatinine and the subsequent risk of incident kidney stones. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study was a prospective, nested case-control study of men in the Health Professionals Follow-Up Study who were free of diagnosed nephrolithiasis at blood draw. During 12 years of follow-up, 356 men developed an incident symptomatic kidney stone. Using risk set sampling, controls were selected in a 2:1 ratio (n=712 controls) and matched for age, race, and year, month, and time of day of blood collection. RESULTS: Baseline plasma levels of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, parathyroid hormone, calcium, phosphate, and creatinine were similar in cases and controls. Mean 1,25(OH)2D and median FGF23 levels were higher in cases than controls but differences were small and statistically nonsignificant (45.7 versus 44.2 pg/ml, P=0.07 for 1,25[OH]2D; 47.6 versus 45.1 pg/ml, P=0.08 for FGF23). However, after adjusting for body mass index, diet, plasma factors, and other covariates, the odds ratios of incident symptomatic kidney stones in the highest compared with lowest quartiles were 1.73 (95% confidence interval, 1.11 to 2.71; P for trend 0.01) for 1,25(OH)2D and 1.45 (95% confidence interval, 0.96 to 2.19; P for trend 0.03) for FGF23. There were no significant associations between other plasma factors and kidney stone risk. CONCLUSIONS: Higher plasma 1,25(OH)2D, even in ranges considered normal, is independently associated with higher risk of symptomatic kidney stones. Although of borderline statistical significance, these findings also suggest that higher FGF23 may be associated with risk.

Physical activity, energy intake and the risk of incident kidney stones.

PURPOSE: Recent data suggest that higher physical activity and lower energy intake may be associated with a lower risk of kidney stones. To our knowledge whether these associations could be reproduced in other study populations after accounting for life-style and dietary factors is not known. MATERIALS AND METHODS: We analyzed data on 3 large prospective cohorts, including HPFS, and NHS I and II. Information was collected by validated biennial questionnaires. The HR of incident stones in participants in different categories of physical activity and energy intake was assessed by Cox proportion hazards regression adjusted for age, body mass index, race, comorbidity, medication, calcium supplement use, fluid and nutrient intake. RESULTS: Analysis included 215,133 participants. After up to 20 years of followup 5,355 incident cases of kidney stones occurred. On age adjusted analysis higher levels of physical activity were associated with a lower risk of incident kidney stones in women (NHS I and II) but not in men. However, after multivariate adjustment there was no significant association between physical activity and kidney stone risk in HPFS, and NHS I and II (highest vs lowest category HR 1.00, 95% CI 0.87-1.14, p for trend = 0.94, HR 1.01, 95% CI 0.85-1.19, p for trend = 0.88 and HR 1.03, 95% CI 0.90-1.18, p for trend = 0.64, respectively). Energy intake was not associated with stone risk (multivariate adjusted p for trend ≥0.49). CONCLUSIONS: In 3 large prospective cohorts there was no independent association between physical activity and energy intake, and the incidence of symptomatic kidney stones.

Fish and fatty acid consumption and the risk of hearing loss in women.

BACKGROUND: Acquired hearing loss is common and often disabling, yet limited prospective data exist on potentially modifiable risk factors. Evidence suggests that higher intake of fish and long-chain omega-3 (n-3) polyunsaturated fatty acids (PUFAs) may be associated with a lower risk of hearing loss, but prospective information on these relations is limited. OBJECTIVE: We prospectively examined the independent associations between consumption of total and specific types of fish, long-chain omega-3 PUFAs, and self-reported hearing loss in women. DESIGN: Data were from the Nurses' Health Study II, a prospective cohort study. The independent associations between consumption of fish and long-chain omega-3 PUFAs and self-reported hearing loss were examined in 65,215 women followed from 1991 to 2009. Baseline and updated information was obtained from validated biennial questionnaires. Cox proportional hazards regression models were used to estimate multivariable-adjusted RRs and 95% CIs. RESULTS: After 1,038,093 person-years of follow-up, 11,606 cases of incident hearing loss were reported. Consumption of 2 or more servings of fish per week was associated with a lower risk of hearing loss. In comparison with women who rarely consumed fish (<1 serving/mo), the multivariable-adjusted RR for hearing loss among women who consumed 2-4 servings of fish per week was 0.80 (95% CI: 0.74, 0.88) (P-trend < 0.001). When examined individually, higher consumption of each specific fish type was inversely associated with risk (P-trend ≤ 0.04). Higher intake of long-chain omega-3 PUFAs was also inversely associated with risk of hearing loss. In comparison with women in the lowest quintile of intake of long-chain omega-3 PUFAs, the multivariable-adjusted RR for hearing loss among women in the highest quintile was 0.85 (95% CI: 0.80, 0.91) and among women in the highest decile was 0.78 (95% CI: 0.72, 0.85) (P-trend < 0.001). CONCLUSION: Regular fish consumption and higher intake of long-chain omega-3 PUFAs are associated with lower risk of hearing loss in women.

Dietary calcium from dairy and nondairy sources, and risk of symptomatic kidney stones.

PURPOSE: Because of high correlations between dairy intake and total dietary calcium, previously reported associations between lower calcium intake and increased kidney stone risk represent de facto associations between milk products and risk. We examined associations between dietary calcium from nondairy and dairy sources, and symptomatic nephrolithiasis. MATERIALS AND METHODS: We performed prospective studies in the Health Professionals Follow-up Study (HPFS) in 30,762 men, and in the Nurses' Health Study (NHS) I and II in 94,164 and 101,701 women, respectively. We excluded men 60 years old or older because we previously reported inverse associations between calcium intake and risk only in men younger than 60 years. Food frequency questionnaires were used to assess calcium intake every 4 years. We used Cox proportional hazards regression to adjust for age, body mass index, supplemental calcium, diet and other factors. RESULTS: We documented 5,270 incident kidney stones during the combined 56 years of followup. In participants in the highest vs the lowest quintile of nondairy dietary calcium the multivariate relative risk of kidney stones was 0.71 (95% CI 0.56-0.92, p for trend 0.007) in HPFS, 0.82 (95% CI 0.69-0.98, p trend 0.08) in NHS I and 0.74 (95% CI 0.63-0.87, p trend 0.002) in NHS II. When comparing the highest to the lowest quintile of dairy calcium, the multivariate relative risk was 0.77 (95% CI 0.63-0.95, p trend 0.01) for HPFS, 0.83 (95% CI 0.69-0.99, p trend 0.05) for NHS I and 0.76 (95% CI 0.65-0.88, p trend 0.001) for NHS II. CONCLUSIONS: Higher dietary calcium from nondairy or dairy sources is independently associated with a lower kidney stone risk.

Altered taste perception and nutritional status among hemodialysis patients.

OBJECTIVE: The objective of this study was to examine the association between altered taste perception and nutritional status among hemodialysis patients. DESIGN: We performed a post hoc analysis of data from the Hemodialysis study (n = 1,745). Taste perception was assessed at baseline and then updated annually using an item from a quality of life survey that asked "During the past 4 weeks, to what extent were you bothered by loss of taste?" Responses were categorized as normal taste perception if subjects answered "not at all" or altered taste perception if they reported any degree of bother. Time-updated logistic regression models were used to evaluate predictors of altered taste perception. Time-updated linear regression models were used to examine the association between altered taste perception and indices of nutritional status. Multivariable proportional hazards and Poisson models were used to assess association between altered taste perception and mortality and hospitalization, respectively. RESULTS: At baseline, 34.6% reported altered taste perception, which was associated with poorer baseline nutritional status. On time-updated analysis, altered taste perception was associated with a persistently higher proportion of subjects requiring enteral nutritional supplements and lower serum albumin, serum creatinine, normalized protein catabolic rate, protein intake, sodium intake, and mid-arm muscle circumference. Altered taste perception at baseline was independently associated with increased all-cause mortality: adjusted hazard ratio (95% confidence interval) of 1.17 (1.01-1.37), although not with increased rate of hospitalization. CONCLUSION: Altered taste perception was common among prevalent hemodialysis patients and was independently associated with poorer indices of nutritional status and increased all-cause mortality.

Calcium intake and risk of primary hyperparathyroidism in women: prospective cohort study.

OBJECTIVE: To examine the association between calcium intake and risk of primary hyperparathyroidism in women. DESIGN: Prospective cohort study. SETTING: Nurses' Health Study I, which originally recruited participants from the 11 most populous states in the United States. PARTICIPANTS: 58,354 female registered nurses enrolled in the Nurses' Health Study I aged 39-66 years in 1986 and with no history of primary hyperparathyroidism. Calcium intake was assessed every four years using semiquantitative questionnaires on food frequency. MAIN OUTCOME MEASURE: Incident primary hyperparathyroidism, confirmed by medical record review. RESULTS: During 22 years of follow-up, we recorded 277 incident cases of primary hyperparathyroidism. Women were divided into five equal groups, according to intake of dietary calcium. After adjusting for age, body mass index, race, and other factors, the relative risk of primary hyperparathyroidism for women in the group with the highest intake of dietary calcium was 0.56 (95% confidence interval 0.37 to 0.86, P=0.009 for trend), compared with the group with the lowest intake. The multivariable relative risk of primary hyperparathyroidism for women taking more than 500 mg/day of calcium supplements compared with no calcium supplements was 0.41 (95% confidence interval 0.29 to 0.60, P<0.001 for trend). Analyses restricted to participants with regular physical exams did not significantly change the association between calcium intake and risk of primary hyperparathyroidism. CONCLUSION: Increased calcium intake is independently associated with a reduced risk of primary hyperparathyroidism in women.

Deficiency of the calcium-sensing receptor in the kidney causes parathyroid hormone-independent hypocalciuria.

Rare loss-of-function mutations in the calcium-sensing receptor (Casr) gene lead to decreased urinary calcium excretion in the context of parathyroid hormone (PTH)-dependent hypercalcemia, but the role of Casr in the kidney is unknown. Using animals expressing Cre recombinase driven by the Six2 promoter, we generated mice that appeared grossly normal but had undetectable levels of Casr mRNA and protein in the kidney. Baseline serum calcium, phosphorus, magnesium, and PTH levels were similar to control mice. When challenged with dietary calcium supplementation, however, these mice had significantly lower urinary calcium excretion than controls (urinary calcium to creatinine, 0.31±0.03 versus 0.63±0.14; P=0.001). Western blot analysis on whole-kidney lysates suggested an approximately four-fold increase in activated Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). In addition, experimental animals exhibited significant downregulation of Claudin14, a negative regulator of paracellular cation permeability in the thick ascending limb, and small but significant upregulation of Claudin16, a positive regulator of paracellular cation permeability. Taken together, these data suggest that renal Casr regulates calcium reabsorption in the thick ascending limb, independent of any change in PTH, by increasing the lumen-positive driving force for paracellular Ca(2+) transport.

Plasma fibroblast growth factor 23, parathyroid hormone, phosphorus, and risk of coronary heart disease.

BACKGROUND: Fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and phosphorus all have been proposed as plasma biomarkers for the development of coronary heart disease (CHD) in individuals with normal renal function. METHODS: In a nested case-control study of men in the Health Professionals Follow-up Study, free of diagnosed cardiovascular disease at blood draw, we prospectively examined associations between plasma FGF23, PTH, and phosphorus and risk of CHD. During 10 years of follow-up, 422 men developed nonfatal myocardial infarction or fatal CHD. Controls were selected in a 2:1 ratio and matched for age, date of blood collection, and smoking status. RESULTS: Mean estimated glomerular filtration rate was 86 mL/min per 1.73 m(2) in cases and controls. At baseline, there were no statistically significant differences between cases and controls in plasma levels of FGF23, PTH, or phosphorus. After adjusting for matching factors, family history of myocardial infarction, body mass index, alcohol consumption, physical activity, history of diabetes mellitus and hypertension, ethnicity, region, plasma 25-hydroxyvitamin D, and other factors, the odds ratios for incident CHD for participants in the highest, compared with lowest, quartiles were 1.03 (95% CI 0.70-1.52, P for trend 0.84) for FGF23, 1.20 (95% CI 0.82-1.76, P trend 0.99) for PTH, and 0.72 (95% CI 0.51-1.02, P trend 0.13) for phosphorus. CONCLUSIONS: Plasma FGF23, PTH, and phosphorus are not associated with the development of incident CHD in men without chronic kidney disease.

Prescribed dietary phosphate restriction and survival among hemodialysis patients.

BACKGROUND AND OBJECTIVES: Hyperphosphatemia is common among hemodialysis patients. Although prescribed dietary phosphate restriction is a recommended therapy, little is known about the long-term effects on survival. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a post hoc analysis of data from the Hemodialysis Study (n = 1751). Prescribed dietary phosphate was recorded at baseline and annually thereafter. Marginal structural proportional hazard models were fit to estimate the adjusted association between dietary phosphate restriction and mortality in the setting of time-dependent confounding. RESULTS: At baseline, prescribed daily phosphate was restricted to levels ≤ 870, 871 to 999, 1000, 1001 to 2000 mg, and not restricted in 300, 314, 307, 297, and 533 participants, respectively. More restrictive prescribed dietary phosphate was associated with poorer indices of nutritional status on baseline analyses and a persistently greater need for nutritional supplementation but not longitudinal changes in caloric or protein intake. On marginal structural analysis, there was a stepwise trend toward greater survival with more liberal phosphate prescription, which reached statistical significance among subjects prescribed 1001 to 2000 mg/d and those with no specified phosphate restriction: hazard ratios (95% CIs) 0.73 (0.54 to 0.97) and 0.71 (0.55 to 0.92), respectively. Subgroup analysis suggested a more pronounced survival benefit of liberal dietary phosphate prescription among nonblacks, participants without hyperphosphatemia, and those not receiving activated vitamin D. CONCLUSIONS: Prescribed dietary phosphate restriction is not associated with improved survival among prevalent hemodialysis patients, and increased level of restriction may be associated with greater mortality particularly in some subgroups.