High Dietary Phosphorus Is Associated with Increased Breast Cancer Risk in a U.S. Cohort of Middle-Aged Women.

Research has shown that high amounts of dietary phosphorus that are twice the amount of the U.S. dietary reference intake of 700 mg for adults are associated with all-cause mortality, phosphate toxicity, and tumorigenesis. The present nested case-control study measured the relative risk of self-reported breast cancer associated with dietary phosphate intake over 10 annual visits in a cohort of middle-aged U.S. women from the Study of Women's Health Across the Nation. Analyzing data from food frequency questionnaires, the highest level of daily dietary phosphorus intake, >1800 mg of phosphorus, was approximately equivalent to the dietary phosphorus levels in menus promoted by the United States Department of Agriculture. After adjusting for participants' energy intake, this level of dietary phosphorus was associated with a 2.3-fold increased risk of breast cancer incidence compared to the reference dietary phosphorus level of 800 to 1000 mg, which is based on recommendations from the U.S. National Kidney Foundation, (RR: 2.30, 95% CI: 0.94-5.61, p = 0.07). Despite the lack of statistical significance, likely due to the small sample size of the cohort, the present nested case-control study's clinically significant effect size, dose-response, temporality, specificity, biological plausibility, consistency, coherence, and analogy with other research findings meet the criteria for inferred causality in observational studies, warranting further investigations. Furthermore, these findings suggest that a low-phosphate diet should be tested on patients with breast cancer.

Modulating phosphate consumption, a novel therapeutic approach for the control of cancer cell proliferation and tumorigenesis.

Phosphorus, often in the form of inorganic phosphate (Pi), is critical to cellular function on many levels; it is required as an integral component of kinase signaling, in the formation and function of DNA and lipids, and energy metabolism in the form of ATP. Accordingly, crucial aspects of cell mitosis - such as DNA synthesis and ATP energy generation - elevate the cellular requirement for Pi, with rapidly dividing cells consuming increased levels. Mechanisms to sense, respond, acquire, accumulate, and potentially seek Pi have evolved to support highly proliferative cellular states such as injury and malignant transformation. As such, manipulating Pi availability to target rapidly dividing cells presents a novel strategy to reduce or prevent unrestrained cell growth. Currently, limited knowledge exists regarding how modulating Pi consumption by pre-cancerous cells might influence the initiation of aberrant growth during malignant transformation, and if reducing the bioavailability or suppressing Pi consumption by malignant cells could alter tumorigenesis. The concept of targeting Pi-regulated pathways and/or consumption by pre-cancerous or tumor cells represents a novel approach to cancer prevention and control, although current data remains insufficient as to rigorously assess the therapeutic value and physiological relevance of this strategy. With this review, we present a critical evaluation of the paradox of how an element critical to essential cellular functions can, when available in excess, influence and promote a cancer phenotype. Further, we conjecture how Pi manipulation could be utilized as a therapeutic intervention, either systemically or at the cell level, to ultimately suppress or treat cancer initiation and/or progression.

Adipose tissue-derived omentin-1 attenuates arterial calcification via AMPK/Akt signaling pathway.

Adipose tissue-derived adipokines mediate various kind of crosstalk between adipose tissue and other organs and thus regulate metabolism balance, inflammation state as well as disease progression. In particular, omentin-1, a newly found adipokine, has been reported to exhibit anti-calcification effects in vitro and in vivo. However, little is known about the function of endogenous adipose tissue-derived omentin-1 in arterial calcification and the detailed mechanism involved. Here, we demonstrated that global omentin-1 knockout (omentin-1-/-) resulted in more obvious arterial calcification in 5/6-nephrectomy plus high phosphate diet treated (5/6 NTP) mice while overexpression of omentin-1 attenuated attenuates osteoblastic differentiation and mineralisation of VSMCs in vitro and 5/6 NTP-induced mice arterial calcification in vivo. Moreover, we found that omentin-1 induced AMPK and Akt activation while inhibition of AMP-activated protein kinase (AMPK) and Akt signaling reversed the anti-calcification effect induced by omentin-1 both in vitro and in vivo. Our results suggest that adipose tissue-derived omentin-1 serves as a potential therapeutic target for arterial calcification and cardiovascular disease.

Pruritus in hemodialysis patients: association with phosphorus intake and serum calcium level. / Prurido no paciente em hemodiálise: associação com ingestão de fósforo e nível sérico de cálcio.

OBJECTIVE: To analyze the association between the occurrence of pruritus and adherence to the prescribed diet, biochemical indicators of renal function and the quality of hemodialysis in chronic renal patients. METHOD: A cross-sectional study performed at a dialysis clinic in the Northeast of Brazil, with 200 patients undergoing hemodialysis in the first half of 2015.To analyze the data, inferential statistics were used, using Chi-Square and Fisher's Exact tests; and Mann Whitney U test. RESULTS: The pruritus was present in 51% of the sample, being associated statistically with phosphorus consumption (P = 0.024) and elevation of serum calcium (P = 0.009). CONCLUSION: Pruritus in chronic renal patients undergoing hemodialysis is influenced by adequate nonadherence to the prescribed diet, in addition to the elevation of biochemical indicators of renal function.

Phosphate toxicity and tumorigenesis.

In this article, we briefly summarized evidence that cellular phosphate burden from phosphate toxicity is a pathophysiological determinant of cancer cell growth. Tumor cells express more phosphate cotransporters and store more inorganic phosphate than normal cells, and dysregulated phosphate homeostasis is associated with the genesis of various human tumors. High dietary phosphate consumption causes the growth of lung and skin tumors in experimental animal models. Additional studies show that excessive phosphate burden induces growth-promoting cell signaling, stimulates neovascularization, and is associated with chromosome instability and metastasis. Studies have also shown phosphate is a mitogenic factor that affects various tumor cell growth. Among epidemiological evidence linking phosphate and tumor formation, the Health Professionals Follow-Up Study found that high dietary phosphate levels were independently associated with lethal and high-grade prostate cancer. Further research is needed to determine how excessive dietary phosphate consumption influences initiation and promotion of tumorigenesis, and to elucidate prognostic benefits of reducing phosphate burden to decrease tumor cell growth and delay metastatic progression. The results of such studies could provide the basis for therapeutic modulation of phosphate metabolism for improved patient outcome.

Observation about phosphorus and protein supply in cats and dogs prior to the diagnosis of chronic kidney disease.

There is evidence that nutritional phosphorus (P) excess may be a risk factor for chronic kidney disease (CKD) in humans and pets (Advances in Nutrition: An International Review Journal (2014), 5, 104; The American Journal of Clinical Nutrition, (2013), 98, 6; Journal of Feline Medicine and Surgery, (2017); The source of phosphorus influences serum PTH, apparent digestibility and blood levels of calcium and phosphorus in dogs fed high phosphorus diets with balanced Ca/P ratio. Proc. Waltham International Nutritional Sciences Symposium, USA; Clinical aspects of natural and added phosphorus in foods, 2017, Springer Science+Business, Media). A retrospective study was conducted in order to gather data about P and protein intake in the feeding history of dogs and cats prior to the diagnosis of CKD. Cases of 75 dogs and 16 cats with CKD with comprehensive nutritional history presented to the nutrition consultation service of the Chair of Animal Nutrition and Dietetics, Ludwig-Maximilians-University Munich, between October 2009 and March 2016, were evaluated. Cases of age-matched dogs (n = 57) and cats (n = 18) without diagnosed or suspected CKD served as controls. The most frequent type of diet used in the four groups (cats CKD, cats control, dogs CKD and dogs control) was home-made. In all groups, P and protein supply was in excess (>150%) of the recommended daily allowances (RDA; Nutrient requirements of dogs and cats (2006), National Research Council, National Academy Press). Between the dog groups, no differences regarding P and protein intake existed. The P and protein intake relative to the RDA was altogether higher in cats than in dogs. Cats with CKD showed significantly higher P and protein intakes prior to diagnosis than the control cats (170 ± 36 vs. 123 ± 34 mg P/kg BW0.67 ; p < .05). These observations call for further investigations into the long-term effects of P excess.

Prurido no paciente em hemodiálise: associação com ingestão de fósforo e nível sérico de cálcio / Prurido en el paciente en hemodiálisis: asociación con ingestión de fósforo y nivel sérico de cálcio / Pruritus in hemodialysis patients: association with phosphorus intake and serum calcium level

Resumo OBJETIVO Analisar a associação entre a ocorrência do prurido e a adesão à dieta prescrita, indicadores bioquímicos da função renal e a qualidade da hemodiálise, em pacientes renais crônicos. MÉTODO Estudo transversal, realizado em uma clínica de diálise no Nordeste do Brasil, com 200 pacientes submetidos à hemodiálise, no primeiro semestre de 2015. Para análise dos dados fez-se uso da estatística inferencial, através dos testes de Qui-Quadrado e Exato de Fisher; e teste de U de Mann Whitney. RESULTADOS O prurido esteve presente em 51% da amostra, associando-se estatisticamente com o consumo de fósforo (P=0,024) e a elevação do cálcio sérico (P=0,009). CONCLUSÃO O prurido em pacientes renais crônicos submetidos à hemodiálise sofre influência da não adesão adequada à dieta prescrita, além da elevação de indicadores bioquímicos da função renal.

Resumen OBJETIVO Analizar la asociación entre la ocurrencia del prurito y la adhesión a la dieta prescrita, indicadores bioquímicos de la función renal y la calidad de la hemodiálisis, en pacientes renales crónicos. MÉTODO Estudio transversal, realizado en una clínica de diálisis en el Nordeste de Brasil, con 200 pacientes sometidos a la hemodiálisis, en el primer semestre de 2015. Para el análisis de los datos se utilizó la estadística inferencial, a través de las pruebas de Qui-Cuadrado y Exacto de Fisher; y prueba de U de Mann Whitney. RESULTADOS El prurito estuvo presente en el 51% de la muestra, asociándose estadísticamente con el consumo de fósforo (P = 0,024) y la elevación del calcio sérico (P = 0,009). CONCLUSIÓN El prurito en pacientes renales crónicos sometidos a la hemodiálisis sufre influencia de la no adhesión adecuada a la dieta prescrita, además de la elevación de indicadores bioquímicos de la función renal.

Abstract OBJECTIVE To analyze the association between the occurrence of pruritus and adherence to the prescribed diet, biochemical indicators of renal function and the quality of hemodialysis in chronic renal patients. METHOD A cross-sectional study performed at a dialysis clinic in the Northeast of Brazil, with 200 patients undergoing hemodialysis in the first half of 2015.To analyze the data, inferential statistics were used, using Chi-Square and Fisher's Exact tests; and Mann Whitney U test. RESULTS The pruritus was present in 51% of the sample, being associated statistically with phosphorus consumption (P = 0.024) and elevation of serum calcium (P = 0.009). CONCLUSION Pruritus in chronic renal patients undergoing hemodialysis is influenced by adequate nonadherence to the prescribed diet, in addition to the elevation of biochemical indicators of renal function.

Identifying early pathogenic events during vascular calcification in uremic rats.

Vascular calcification in chronic kidney disease is a very complex process traditionally explained in multifactorial terms. Here we sought to clarify relevance of the diverse agents acting on vascular calcification in uremic rats and distinguish between initiating and complicating factors. After 5/6 nephrectomy, rats were fed a 1.2% phosphorus diet and analyzed at different time points. The earliest changes observed in the aortic wall were noticed 11 weeks after nephrectomy: increased Wnt inhibitor Dkk1 mRNA expression and tissue non-specific alkaline phosphatase (TNAP) expression and activity. First deposits of aortic calcium were observed after 12 weeks in areas of TNAP expression. Increased mRNA expressions of Runx2, BMP2, Pit1, Pit2, HOXA10, PHOSPHO1, Fetuin-A, ANKH, OPN, Klotho, cathepsin S, MMP2, and ENPP1 were also found after TNAP changes. Increased plasma concentrations of activin A and FGF23 were observed already at 11 weeks post-nephrectomy, while plasma PTH and phosphorus only increased after 20 weeks. Plasma pyrophosphate decreased after 20 weeks, but aortic pyrophosphate was not modified, nor was the aortic expression of MGP, Msx2, several carbonic anhydrases, osteoprotegerin, parathyroid hormone receptor-1, annexins II and V, and CD39. Thus, increased TNAP and Dkk1 expression in the aorta precedes initial calcium deposition, and this increase is only preceded by elevations in circulating FGF23 and activin A. The expression of other agents involved in vascular calcification only changes at later stages of chronic kidney disease, in a complex branching pattern that requires further clarification.

Dietary phosphorus intake is negatively associated with bone formation among women and positively associated with some bone traits among men-a cross-sectional study in middle-aged Caucasians.

High dietary phosphorus (P) intake has acute negative effects on calcium (Ca) and bone metabolism, but long-term clinical data are contradictory. We hypothesized that high P intake is associated with impaired bone health as suggested by earlier short-term studies on bone metabolism. In this cross-sectional study, we investigated associations between dietary P intake, bone traits in the radius and tibia, and bone turnover in a population-based sample of 37- to 47-year-old Caucasian premenopausal women (n=333) and men (n=179) living in Southern Finland (60°N). We used various regression models in an "elaboration approach" to elucidate the role of P intake in bone traits and turnover. The addition of relevant covariates to the models mainly removed the significance of P intake as a determinant of bone traits. In the final regression model (P intake, weight, height, age, Ca intake, serum 25-hydroxyvitamin D, physical activity, smoking, contraceptive use in women), P intake was slightly positively associated only with bone mineral content and cross-sectional cortical bone area in the tibia of men. Among women, inclusion of Ca removed all existing significance in the crude models for any bone trait. In women P intake was negatively associated with the bone formation marker serum intact pro-collagen type I amino-terminal propeptide, whereas no association was present between P intake and bone turnover in men. In conclusion, these findings disagree with the hypothesis; P intake was not deleteriously associated with bone traits; however, P intake may negatively contribute to bone formation among women.

Plant phosphates, phytate and pathological calcifications in chronic kidney disease. / Fosfatos de origen vegetal, fitato y calcificaciones patológicas en la enfermedad renal crónica.

Phytate, or myo-inositol 1,2,3,4,5,6-hexakis dihydrogen phosphate (InsP6), is a naturally occurring phosphorus compound that is present in many foods, mainly legumes, whole grains and nuts. Patients with chronic kidney disease (CKD) have cardiovascular disease mortality up to 30times higher than the general population. Vascular calcifications (VCs) directly contribute to overall morbidity and mortality, especially in CKD. In part, this high mortality is due to elevated levels of phosphorus in the blood. Therefore, control of dietary phosphorus is essential. Dietary phosphorus can be classified according to its structure in organic phosphorus (plant and animal) and inorganic (preservatives and additives). Plant-phosphorus (legumes and nuts), mainly associated with InsP6, is less absorbable by the human gastrointestinal tract as the bioavailability of phosphorous from plant-derived foods is very low. Recent data indicate that restriction of foods containing plant phosphates may compromise the adequate supply of nutrients that have a beneficial effect in preventing cardiovascular events, such as InsP6 or fibre found in legumes and nuts. Experimental studies in animals and observational studies in humans suggest that InsP6 can prevent lithiasis and VCs and protect from osteoporosis. In conclusion, we need prospective studies to elucidate the potential benefits and risks of phytate (InsP6) through the diet and as an intravenous drug in patients on haemodialysis.

Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease.

Bone loss and increased fractures are common complications in chronic kidney disease. Because Wnt pathway activation is essential for normal bone mineralization, we assessed whether Wnt inhibition contributes to high-phosphorus-induced mineralization defects in uremic rats. By week 20 after 7/8 nephrectomy, rats fed a high-phosphorus diet had the expected high serum creatinine, phosphorus, parathyroid hormone, and fibroblast growth factor 23 (FGF23) levels and low serum calcium. There was a 15% reduction in tibial mineral density and a doubling of bone cortical porosity compared to uremic rats fed a normal-phosphorus diet. The decreases in tibial mineral density were preceded by time-dependent increments in gene expression of bone formation (Osteocalcin and Runx2) and resorption (Cathepsin K) markers, which paralleled elevations in gene expression of the Wnt inhibitors Sfrp1 and Dkk1 in bone. Similar elevations of Wnt inhibitors plus an increased phospho-ß-catenin/ß-catenin ratio occurred upon exposure of the osteoblast cell line UMR106-01 either to uremic serum or to the combination of parathyroid hormone, FGF23, and soluble Klotho, at levels present in uremic serum. Strikingly, while osteoblast exposure to parathyroid hormone suppressed the expression of Wnt inhibitors, FGF23 directly inhibited the osteoblastic Wnt pathway through a soluble Klotho/MAPK-mediated process that required Dkk1 induction. Thus, the induction of Dkk1 by FGF23/soluble Klotho in osteoblasts inactivates Wnt/ß-catenin signaling. This provides a novel autocrine/paracrine mechanism for the adverse impact of high FGF23 levels on bone in chronic kidney disease.

Additional benefit of dietitian involvement in dialysis staffs-led diet education on uncontrolled hyperphosphatemia in hemodialysis patients.

BACKGROUND: Sustained adherence to dietary phosphorus (P) restriction recommendations among hemodialysis patients is questionable. The aim of this study was to evaluate the effectiveness of additional diet education delivered by a dietitian on the control of hyperphosphatemia. METHODS: We conducted an 8-month prospective observational study in hemodialysis patients who had uncontrolled hyperphosphatemia. In the first half of the study (experimental) period, the dialysis nurses and physicians provided the routine dietetic education with the control group (n = 31), while the experimental group (n = 30) received the routine dietetic education plus an additional diet education delivered by dietitians. Both groups received the routine dietetic education in the rest of the study period to test whether the improvement of serum P level was sustained. The primary outcomes were changes in serum P level. RESULTS: At baseline, there was no significant difference in serum P levels between groups (P = 0.27). In the experimental period, monthly serum P levels decreased significantly in both groups (P < 0.001) and the magnitudes of reduction were 1.81 ± 1.46 and 0.94 ± 1.33 mg/dL in the experimental and control groups, respectively (P = 0.02), at the end. The experimental group maintained such improvement for one more month (P = 0.02), but faded out over time. CONCLUSION: Renal diet education guided either by dietitians plus dialysis staffs or dialysis staffs alone reduces serum P level and dietitian-guided diet education provides an additional benefit on controlling hyperphosphatemia in hemodialysis patients.

High Inorganic Phosphate Intake Promotes Tumorigenesis at Early Stages in a Mouse Model of Lung Cancer.

Inorganic phosphate (Pi) is required by all living organisms for the development of organs such as bone, muscle, brain, and lungs, regulating the expression of several critical genes as well as signal transduction. However, little is known about the effects of prolonged dietary Pi consumption on lung cancer progression. This study investigated the effects of a high-phosphate diet (HPD) in a mouse model of adenocarcinoma. K-rasLA1 mice were fed a normal diet (0.3% Pi) or an HPD (1% Pi) for 1, 2, or 4 months. Mice were then sacrificed and subjected to inductively coupled plasma mass/optical emission spectrometry and laser ablation inductively coupled plasma mass-spectrometry analyses, western blot analysis, histopathological, immunohistochemical, and immunocytochemical analyses to evaluate tumor formation and progression (including cell proliferation, angiogenesis, and apoptosis), changes in ion levels and metabolism, autophagy, epithelial-to-mesenchymal transition, and protein translation in the lungs. An HPD accelerated tumorigenesis, as evidenced by increased adenoma and adenocarcinoma rates as well as tumor size. However, after 4 months of the HPD, cell proliferation was arrested, and marked increases in liver and lung ion levels and in energy production via the tricarboxylic acid cycle in the liver were observed, which were accompanied by increased autophagy and decreased angiogenesis and apoptosis. These results indicate that an HPD initially promotes but later inhibits lung cancer progression because of metabolic adaptation leading to tumor cell quiescence. Moreover, the results suggest that carefully regulated Pi consumption are effective in lung cancer prevention.

[Bone and Nutrition. A novel function of phosphorus].

Phosphorus is an essential nutrient for bone formation by forming hydroxyapatite with calcium. Simultaneously, phosphorus is also a component of high energy bond of ATP, nucleic acids, and phospholipids. Recent studies have demonstrated that excess or lack of dietary phosphorus intake may cause vascular dysfunction, cardiac hypertrophy, and impaired glucose tolerance. Here, we introduce recent findings about the effects of high or low dietary phosphorus intake on several organs except for bone.

Calcium and phosphorus intake and prostate cancer risk: a 24-y follow-up study.

BACKGROUND: High calcium intake has been associated with an increased risk of advanced-stage and high-grade prostate cancer. Several studies have found a positive association between phosphorus intake and prostate cancer risk. OBJECTIVE: We investigated the joint association between calcium and phosphorus and risk of prostate cancer in the Health Professionals Follow-Up Study, with a focus on lethal and high-grade disease. DESIGN: In total, 47,885 men in the cohort reported diet data in 1986 and every 4 y thereafter. From 1986 to 2010, 5861 cases of prostate cancer were identified, including 789 lethal cancers (fatal or metastatic). We used Cox proportional hazards models to assess the association between calcium and phosphorus intake and prostate cancer, with adjustment for potential confounding. RESULTS: Calcium intakes >2000 mg/d were associated with greater risk of total prostate cancer and lethal and high-grade cancers. These associations were attenuated and no longer statistically significant when phosphorus intake was adjusted for. Phosphorus intake was associated with greater risk of total, lethal, and high-grade cancers, independent of calcium and intakes of red meat, white meat, dairy, and fish. In latency analysis, calcium and phosphorus had independent effects for different time periods between exposure and diagnosis. Calcium intake was associated with an increased risk of advanced-stage and high-grade disease 12-16 y after exposure, whereas high phosphorus was associated with increased risk of advanced-stage and high-grade disease 0-8 y after exposure. CONCLUSIONS: Phosphorus is independently associated with risk of lethal and high-grade prostate cancer. Calcium may not have a strong independent effect on prostate cancer risk except with long latency periods.

High dietary phosphorus intake is associated with all-cause mortality: results from NHANES III.

BACKGROUND: Elevated serum phosphorus is associated with all-cause mortality, but little is known about risk associated with dietary phosphorus intake. OBJECTIVE: We investigated the association between phosphorus intake and mortality in a prospective cohort of healthy US adults (NHANES III; 1998-1994). DESIGN: Study participants were 9686 nonpregnant adults aged 20-80 y without diabetes, cancer, or kidney or cardiovascular disease. Exposure to dietary phosphorus, which was assessed by using a 24-h dietary recall, was expressed as the absolute intake and phosphorus density (phosphorus intake divided by energy intake). All-cause and cardiovascular mortality was assessed through 31 December 2006. RESULTS: Median phosphorus intake was 1166 mg/d (IQR: 823-1610 mg/d); median phosphorus density was 0.58 mg/kcal (0.48-0.70 mg/kcal). Individuals who consumed more phosphorus-dense diets were older, were less often African American, and led healthier lifestyles (smoking, physical activity, and Healthy Eating Index). In analyses adjusted for demographics, cardiovascular risk factors, kidney function, and energy intake, higher phosphorus intake was associated with higher all-cause mortality in individuals who consumed >1400 mg/d [adjusted HR (95% CI): 2.23 (1.09, 4.5) per 1-unit increase in ln(phosphorus intake); P = 0.03]. At <1400 mg/d, there was no association. A similar association was seen between higher phosphorus density and all-cause mortality at a phosphorus density amount >0.35 mg/kcal [adjusted HR (95% CI): 2.27 (1.19, 4.33) per 0.1-mg/kcal increase in phosphorus density; P = 0.01]. At <0.35 mg/kcal (approximately the fifth percentile), lower phosphorus density was associated with increased mortality risk. Phosphorus density was associated with cardiovascular mortality [adjusted HR (95% CI): 3.39 (1.43, 8.02) per 0.1 mg/kcal at >0.35 mg/kcal; P = 0.01], whereas no association was shown in analyses with phosphorus intake. Results were similar by subgroups of diet quality and in analyses adjusted for sodium and saturated fat intakes. CONCLUSIONS: High phosphorus intake is associated with increased mortality in a healthy US population. Because of current patterns in phosphorus consumption in US adults, these findings may have important public health implications.

High-phosphorus/zinc-free diet aggravates hypertension and cardiac dysfunction in a rat model of the metabolic syndrome.

BACKGROUND: Cardiac dysfunction is reported in patients with the metabolic syndrome. We assessed the effects of high-phosphorus and zinc-free diet on cardiovascular system in spontaneously hypertensive rats (SHR)/NDmcr-cp (SHR/cp), a rat model of the metabolic syndrome. We also investigated the effects of N-acetyl-L-cysteine (NAC), an antioxidant, on the development of cardiac dysfunction under such conditions. METHODS: Male SHR/cp and control [Wistar Kyoto (WKY)] rats were divided into three groups and fed control diet (P 0.3% w/w, Zn 0.2% w/w) or high-phosphorus and zinc-free (P 1.2% w/w, Zn 0.0% w/w) diet. The latter group was treated with either NAC (1.5 mg/g per day) or vehicle from 6 to 18 weeks of age (n=6 or 8 for each group). RESULTS: High-phosphate and zinc-free diet increased systolic blood pressure in both WKY and SHR/cp. Echocardiography showed that high-phosphate and zinc-free diet markedly reduced left ventricular systolic and diastolic function in SHR/cp. Histopathologically, the same diet induced severe myocardial fibrosis in SHR/cp, and this effect was prevented by NAC. Whereas treatment with NAC prevented diastolic dysfunction induced by the same diet in WKY, it only improved systolic function but not diastolic function in SHR/cp. CONCLUSIONS: High-phosphate and zinc-free diet induced hypertension and cardiac dysfunction. These changes hamper the protective effects of NAC in the metabolic syndrome. SUMMARY: The present study showed that consumption of high-phosphorus and zinc-free diet increased the myocardial expression of connective tissue growth factor and reduced the expression of metallothionein, which enhanced the development of severe cardiac dysfunction in rats with the metabolic syndrome. The results suggest that the metabolic syndrome seems to aggravate cardiac dysfunction and hamper the protective effects of antioxidant, NAC.

High phosphate feeding induced arterial medial calcification in uremic rats: roles of Lanthanum carbonate on protecting vasculature.

AIMS: High cardiovascular mortality in patients with end-stage renal disease is closely associated with arterial medial calcification (AMC) caused by hyperphosphatemia, the mechanism of which associated hormones (FGF-23, klotho) and osteochondrogenic events is unclear. We examined the effect of Lanthanum carbonate on AMC via regulating the abnormalities in phosphorus metabolism of uremic rats. MAIN METHODS: 45 healthy SD rats were randomly divided into 3 groups: Normal group (n=15), CRF group (n=15), CRF diet supplemented with 2% La (n=15). AMC in great arteries were evaluated by VonKossa. Osteochondrogenic specific genes were analyzed by Immunohistochemistry and qRT-PCR. Serum FGF-23 and klotho levels were detected by ELISA kit. KEY FINDINGS: Serum phosphate was markedly increased in CRF group (6.94 ± 0.97 mmol/L) and 2%La group (5.12 ± 0.84 mmol/L) at week 4, while the latter became hypophosphatemic (2.92 ± 0.73 mmol/L vs CRF group, p<0.01) at week 10. Inhibitory effect of 2%La on development of AMC was reflected by downregulated Runx2, Osterix, BSP, Osteocalcin and collagenII and a reduction of FGF-23 at week 4(vs CRF group, p<0.01) but not week 10. SIGNIFICANCE: Beneficial effects of Lanthanum carbonate on progression of AMC in CRF could be mainly due to the decreased phosphate retention and FGF-23 in early stage and likewise a reduction of bone-associated proteins via osteochondrogenic pathway. Lanthanum carbonate has no effect on soluble klotho and serum FGF-23 in late stage of CRF.

Associations among total and food additive phosphorus intake and carotid intima-media thickness--a cross-sectional study in a middle-aged population in Southern Finland.

BACKGROUND: Dietary phosphorus (P) intake in Western countries is 2- to 3-fold higher than recommended, and phosphate is widely used as a food additive in eg. cola beverages and processed meat products. Elevated serum phosphate concentrations have been associated with cardiovascular disease (CVD) risk factors and CVD itself in several studies in patients with renal dysfunction and in a few studies in the general population. Carotid intima-media thickness (IMT) is a CVD risk factor, thus the aim of the study was to determine if an association between dietary P, especially food additive phosphate (FAP), intake, and IMT exists. METHODS: Associations among total phosphorus (TP) and FAP intake and carotid IMT were investigated in a cross-sectional study of 37- to 47-year-old females (n = 370) and males (n = 176) in Finland. Associations among TP intake, FAP intake, and IMT were tested by analysis of covariance (ANCOVA) in quintiles (TP) and sextiles (FAP) using sex, age, low-density/high-density lipoprotein cholesterol ratio, smoking status, and IMT sonographer as covariates. RESULTS: No significant associations were present between TP or FAP intake and IMT (p > 0.05, ANCOVA), but in between-group comparisons some differences were found indicating higher IMT among subjects with higher P intake. When testing for a significant linear trend with contrast analysis, a positive trend was observed between energy-adjusted TP intake and IMT among all subjects (p = 0.039), and among females a tendency for a trend existed (p = 0.067). Among all subjects, a significant positive linear trend was also present between FAP intake and IMT (p = 0.022); this trend was also seen in females (p = 0.045). In males, no significant associations or trends were noted between TP or FAP intake and IMT (p > 0.05). CONCLUSIONS: Our results indicate that a significant linear trend exists between energy-adjusted TP intake and FAP intake, and IMT among all subjects. Based on these results, high dietary P intake should be further investigated due to its potential association with adverse cardiovascular health effects in the general population.