Dietary Phosphate Intake Research Articles

Inorganic phosphate additives in meals and adaptations to 5-days of dietary inorganic phosphate loading alter acute calcium homeostasis in two randomized cross-over studies in healthy adults.

Diets containing inorganic phosphate additives are unbalanced with respect to calcium and these diets have been linked to the development of altered bone metabolism. Using 2 randomized cross-over studies in healthy humans, we (1) characterized the hormonal and urinary response to 2 meals with the same reported phosphorus amount (562-572mg), where one was manufactured with inorganic phosphate additives and a comparatively lower Ca:P molar ratio (0.26 vs 0.48), and (2) assessed how acute homeostatic mechanisms adapt following 5-d exposure to recommended dietary phosphorus amount (~700mg P/d) compared to a diet enriched with inorganic phosphate additives (~1100mg P/d). Participants were then challenged with 500mg of oral phosphorus in the form of inorganic phosphate after an overnight fast following each diet condition. Measurements included serum calcium, phosphate, PTH, and fibroblast growth factor 23 , vitamin D metabolites, and urine calcium and phosphate excretion. Following the meal containing inorganic phosphate additives with a low Ca:P ratio, serum phosphate was higher and more phosphate was excreted in the urine compared to the low additive meal. Although the Ca:P and calcium content was lower in the high additive meal, the same amount of calcium was excreted into the urine. Subsequently, increasing only dietary phosphate through additives resulted in lower 24-h excretion of calcium. The oral phosphate challenge promoted urinary calcium excretion, despite no consumption of calcium, which was attenuated when pre-acclimated to a high phosphate diet. These data suggest that ingestion of inorganic phosphate promotes calcium excretion, but homeostatic mechanisms may exist to reduce calcium excretion that are responsive to dietary intake of phosphate. Future studies are required to evaluate potential implication of diets enriched with inorganic phosphate additives on bone health.

Spontaneous Tumor Regression and Reversion: Insights and Associations with Reduced Dietary Phosphate.

Tumors that spontaneously shrink from unknown causes in tumor regression, and that return to normal cells in tumor reversion, are phenomena with the potential to contribute new knowledge and novel therapies for cancer patient survival. Tumorigenesis is associated with dysregulated phosphate metabolism and an increased transport of phosphate into tumor cells, potentially mediated by phosphate overload from excessive dietary phosphate intake, a significant problem in Western societies. This paper proposes that reduced dietary phosphate overload and reregulated phosphate metabolism may reverse an imbalance of kinases and phosphatases in cell signaling and cellular proliferation, thereby activating autophagy in tumor regression and reversion. Dietary phosphate can also be reduced by sickness-associated anorexia, fasting-mimicking diets, and other diets low in phosphate, all of which have been associated with tumor regression. Tumor reversion has also been demonstrated by transplanting cancer cells into a healthy microenvironment, plausibly associated with normal cellular phosphate concentrations. Evidence also suggests that the sequestration and containment of excessive phosphate within encapsulated tumors is protective in cancer patients, preventing the release of potentially lethal amounts of phosphate into the general circulation. Reducing dietary phosphate overload has the potential to provide a novel, safe, and effective reversion therapy for cancer patients, and further research is warranted.

Cardiorenal Effects of Chronic High Phosphate Diet in Female Rats

Cardiorenal Syndrome Type 4 (CRS4) refers to the development of cardiovascular dysfunction as a result of chronic kidney disease. The accumulation of circulating phosphate in the later stages of chronic kidney disease (CKD) has been positively associated with cardiac hypertrophy and dysfunction. In our previous work, we found that male Sprague Dawley rats that underwent 5/6 nephrectomy (5/6Nx) to induce CKD phenotypes also developed cardiac pathology when serum phosphorus levels became elevated. Small RNA sequencing of left ventricle tissue revealed upregulated microRNA-21-5p and -3p expression in 5/6Nx rats, when compared to sham-operated controls, and suppression of miR-21-5p attenuated left ventricle pathology in male 5/6Nx rats. We hypothesize that hyperphosphatemia, independent of CKD, can impair cardiac function and that miR-21 may mediate these effects. It has been recently reported that females exhibit higher urinary phosphate excretion in response to high dietary phosphate intake than males. In this study, hyperphosphatemia was induced by placing 9-week old female wild-type (WT) Sprague Dawley and global miR-21 knockout (miR-21−/−; lacking both miR-21-5p and -3p rats) (n=4-9/group) on either high phosphate (2% Pi) or control diet (0.6% Pi) for 8 weeks. Echocardiography and renal ultrasound were performed under anesthesia to assess cardiac function and renal cross-sectional area, respectively, prior to tissue collection at endpoint. Rats of either genotype fed 2% Pi diet exhibited increased left kidney weight, left kidney/body weight, and left kidney cross-sectional area (2-way ANOVA, main effect of diet; p<0.05). In animals fed 2% Pi, miR-21−/− rats had significantly higher left ventricle fractional shortening than WT rats (57.06 ± 3.32 vs. 43.96 ± 1.34; 2-way ANOVA with Tukey multiple comparisons; p<0.05). This study allowed the cardiovascular effects of chronically elevated phosphate to be isolated from other uremic toxins elevated in CKD. We find that loss of miR-21 augments cardiac function, supporting a role for miR-21 in mediating phosphate-related pathology. Ongoing studies are focused on identifying specific molecular mechanisms driving these changes. This study was supported by T32HL007852 and R01HL128332. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Association between dietary phosphate intake and skeletal muscle energetics in adults without cardiovascular disease.

Highly bioavailable inorganic phosphate (Pi) is present in large quantities in the typical Western diet and represents a large fraction of total phosphate intake. Dietary Pi excess induces exercise intolerance and skeletal muscle mitochondrial dysfunction in normal mice. However, the relevance of this to humans remains unknown. The study was conducted on 13 individuals without a history of cardiopulmonary disease (46% female, 15% Black participants) enrolled in the pilot-phase of the Dallas Heart and Mind Study. Total dietary phosphate was estimated from 24-h dietary recall (ASA24). Muscle ATP synthesis was measured at rest, and phosphocreatinine (PCr) dynamics was measured during plantar flexion exercise using 7-T 31P magnetic resonance (MR) spectroscopy in the calf muscle. Correlation was assessed between dietary phosphate intake normalized to total caloric intake, resting ATP synthesis, and PCr depletion during exercise. Higher dietary phosphate intake was associated with lower resting ATP synthesis (r = -0.62, P = 0.03), and with higher levels of PCr depletion during plantar flexion exercise relative to the resting period (r = -0.72; P = 0.004). These associations remain significant after adjustment for age and estimated glomerular filtration rate (both P < 0.05). High dietary phosphate intake was also associated with lower serum Klotho levels, and Klotho levels are in turn associated with PCr depletion and higher ADP accumulation post exercise. Our study suggests that higher dietary phosphate is associated with reduced skeletal muscle mitochondrial function at rest and exercise in humans providing new insight into potential mechanisms linking the Western diet to impaired energy metabolism.NEW & NOTEWORTHY This is the first translational research study directly demonstrating the adverse effects of dietary phosphate on muscle energy metabolism in humans. Importantly, our data show that dietary phosphate is associated with impaired muscle ATP synthesis at rest and during exercise, independent of age and renal function. This is a new biologic paradigm with significant clinical dietary implications.

Impact of Plant and Animal Protein-Based Meals on Serum Fibroblast Growth Factor-23 Levels in Healthy Young Men: A Randomized Crossover Trial.

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone secreted by osteocytes in response to dietary phosphate intake. An increase in FGF23 level is an indicator of excess phosphate intake relative to the residual nephron number. Therefore, avoiding excessive phosphate intake and inhibiting the elevation of serum FGF23 levels are important to preserve the number of functional nephrons. This randomized crossover trial aimed to determine the potential differences in the impacts on serum FGF23 levels between plant protein and animal protein-based meals in individuals with normal renal function. Nine young men were administered plant (no animal protein) or animal protein-based meals (70% of their protein was from animal sources) with the same phosphate content. The test meals consisted of breakfast, lunch, and dinner. Blood samples were collected in the morning, after overnight fasting, and before and after eating the test meals (for two consecutive days at the same hour each day). Furthermore, a 24-h urine sample was obtained on the day the test meal was consumed. No significant interactions were found among serum phosphate, calcium, and 1,25-dihydroxyvitamin D levels. However, after eating plant protein-based meals, serum FGF23 levels decreased and serum intact parathyroid hormone levels increased (interaction, p<0.05). Additionally, urine 24-h phosphate excretion tended to be lower in individuals consuming plant protein-based meals than in those consuming animal protein-based meals (p=0.06). In individuals with normal renal function, plant protein-based meals may prevent an increase in serum FGF23 levels and kidney damage caused by phosphate loading.

Breast Cancer and Bone Mineral Density in a U.S. Cohort of Middle-Aged Women: Associations with Phosphate Toxicity.

Breast cancer is associated with phosphate toxicity, the toxic effect from dysregulated phosphate metabolism that can stimulate tumorigenesis. Phosphate toxicity and dysregulated phosphate metabolism are also associated with bone mineral abnormalities, including excessive bone mineral loss and deposition. Based on shared associations with dysregulated phosphate metabolism and phosphate toxicity, a hypothesis proposed in the present mixed methods-grounded theory study posits that middle-aged women with incidence of breast cancer had a greater magnitude of changes in bone mineral density over time compared with women who remained cancer-free. To test this hypothesis, a mixed-effects model was used to analyze the associations of breast cancer incidence with spinal bone mineral density changes in the U.S. Study of Women's Health Across the Nation. Compared with women in the cohort who remained cancer-free, women who self-reported breast cancer had higher bone mineral density at baseline, but had more rapid losses in bone mineral density during follow-up visits. These findings agree with the hypothesis that a greater magnitude of changes in bone mineral density over time is associated with breast cancer in a cohort of middle-aged women. The findings also have implications for studies investigating dysregulated phosphate metabolism and phosphate toxicity as causative factors of bone metastasis in metastatic breast cancer. Additionally, the authors previously found increased breast cancer risk associated with high dietary phosphate intake in the same cohort of middle-aged women, and more studies should investigate a low-phosphorus diet to reduce bone mineral abnormalities and tumorigenesis in breast cancer patients.

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.

Industrial Use of Phosphate Food Additives: A Mechanism Linking Ultra-Processed Food Intake to Cardiorenal Disease Risk?

The consumption of ultra-processed food (UPF) keeps rising, and at the same time, an increasing number of epidemiological studies are linking high rates of consumption of UPF with serious health outcomes, such as cardiovascular disease, in the general population. Many potential mechanisms, either in isolation or in combination, can explain the negative effects of UPF. In this review, we have addressed the potential role of inorganic phosphate additives, commonly added to a wide variety of foods, as factors contributing to the negative effects of UPF on cardiorenal disease. Inorganic phosphates are rapidly and efficiently absorbed, and elevated serum phosphate can lead to negative cardiorenal effects, either directly through tissue/vessel calcification or indirectly through the release of mineral-regulating hormones, parathyroid hormone, and fibroblast growth factor-23. An association between serum phosphate and cardiovascular and bone disease among patients with chronic kidney disease is well-accepted by nephrologists. Epidemiological studies have demonstrated an association between serum phosphate and dietary phosphate intake and mortality, even in the general American population. The magnitude of the role of inorganic phosphate additives in these associations remains to be determined, and the initial step should be to determine precise estimates of population exposure to inorganic phosphate additives in the food supply.

Exposure to Phosphates and Nitrites through Meat Products: Estimation of the Potential Risk to Pregnant Women.

Diet during pregnancy is one of the most important nutritional challenges associated with some risks for the mother and the fetus. For the first time, the study aims to estimate long-term (2018-2022) exposure to nitrate and phosphates in Serbian pregnant women, based on individual consumption data and accurate values measured in frequently consumed meat products. For this purpose, seven types of meat products, consisting of 3047 and 1943 samples, were collected from retail markets across Serbia, to analyze nitrites and phosphorus content, respectively. These data were combined with meat product consumption data from the Serbian National Food Consumption Survey to assess dietary intake of nitrites and phosphate. The results were compared with the acceptable daily intake (ADI) proposed by the European Food Safety Authority. The average dietary exposure (EDI) to phosphorus ranged from 0.733 mg/kg bw/day (liver sausage and pate) to 2.441 mg/kg bw/day (finely minced cooked sausages). Considering nitrite intake, the major sources were bacon (0.030 mg/kg bw/day) and coarsely minced cooked sausages (0.0189 mg/kg bw/day). In our study, average nitrite and phosphorus exposure in the Serbian pregnant women population are far below the EFSA recommendations (ADI 0.07 mg/kg bw/day and 40 mg/kg bw/day, respectively).

Phosphate toxicity and SERCA2a dysfunction in sudden cardiac arrest.

Almost half of the people who die from sudden cardiac arrest have no detectable heart disease. Among children and young adults, the cause of approximately one-third of deaths from sudden cardiac arrest remains unexplained after thorough examination. Sudden cardiac arrest and related sudden cardiac death are attributed to dysfunctional cardiac ion-channels. The present perspective paper proposes a pathophysiological mechanism by which phosphate toxicity from cellular accumulation of dysregulated inorganic phosphate interferes with normal calcium handling in the heart, leading to sudden cardiac arrest. During cardiac muscle relaxation following contraction, SERCA2a pumps actively transport calcium ions into the sarcoplasmic reticulum, powered by ATP hydrolysis that produces ADP and inorganic phosphate end products. Reviewed evidence supports the proposal that end-product inhibition of SERCA2a occurs as increasing levels of inorganic phosphate drive up phosphate toxicity and bring cardiac function to a sudden and unexpected halt. The paper concludes that end-product inhibition from ATP hydrolysis is the mediating factor in the association of sudden cardiac arrest with phosphate toxicity. However, current technology lacks the ability to directly measure this pathophysiological mechanism in active myocardium, and further research is needed to confirm phosphate toxicity as a risk factor in individuals with sudden cardiac arrest. Moreover, phosphate toxicity may be reduced through modification of dietary phosphate intake, with potential for employing low-phosphate dietary interventions to reduce the risk of sudden cardiac arrest.

Efficacy of Lanthanum Carbonate and Sevelamer Carbonate as Phosphate Binders in Chronic Kidney Disease—A Comparative Clinical Study

(1) Background: Hyperphosphatemia is correlated with an increased rate of mortality and morbidity due to cardiovascular diseases in chronic kidney disease (CKD) patients. It can be improved by restricting dietary intake of phosphate and oral phosphate binders, such as lanthanum carbonate and sevelamer carbonate. (2) Objective: To evaluate the clinical efficacy of sevelamer carbonate in comparison to lanthanum carbonate as phosphate binders for the treatment of hyperphosphatemia in CKD patients. (3) Methods: A randomized control comparative clinical study was conducted for one year on 150 CKD patients associated with hyperphosphatemia, divided into two groups, i.e., Group 1 (n = 75) treated with sevelamer carbonate 800 mg thrice daily and Group 2 (n = 75) treated with lanthanum carbonate 500 mg thrice daily. The patients were assessed at the time of enrollment in the study, after three months and after six months from baseline for different parameters, i.e., complete blood count, liver function tests, renal function tests, electrolytes, and serum phosphate level. (4) Results: 150 CKD patients aged 51-60 participated in the study. The mean age of patients was 54 ± 4.6 years, and males (55.71%) were more common than females (44.29%). Hypertension was the common comorbidity in both groups with chronic kidney disease. After six months of treatment, the mean serum phosphate level was significantly decreased from 8.31 ± 0.09 mg/dL to 5.11 ± 0.18 (38%) in Group 1 and from 8.79 ± 0.28 mg/dl to 4.02 ± 0.12 (54%; p < 0.05) in Group 2, respectively. In both groups, no significant difference was found in other parameters such as parathyroid hormone, calcium, uric acid, LFT, RFT, CBC, etc. (5) Conclusion: Lanthanum carbonate is more efficacious in lowering serum phosphate concentrations and effectively managing hyperphosphatemia as compared to sevelamer carbonate.

Klf4-Sirt3/Pparα-Lcad pathway contributes to high phosphate-induced lipid degradation

BackgroundPhosphorus commonly reduces lipid deposition in the vertebrates. However, the underlying mechanisms involved in the process remain unclear.MethodsYellow catfish were given three experimental diets with dietary phosphate levels of 3.22, 6.47 and 7.99 g Pi kg− 1, respectively, for 8 weeks. The contents of triglyceride, non-esterified free fatty acids, adenosine triphosphate, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide, enzymatic activities, mRNA and protein expression were determined in the intestinal tissues. Hematoxylin and eosin, Oil Red O staining, and transmission electron microscope were performed for intestinal tissues. Primary intestinal epithelial cells were isolated from yellow catfish intestine. Western blot analysis, Immunoprecipitation assays, Immunofluorescence staining, and RNA extraction and quantitative real-time PCR were decided. Luciferase reporter assays and electrophoretic mobility shift assay were used to evaluate the function of Sirt3, PPARα and Lcad promoters.ResultsHigh dietary phosphate intake activated intestinal phosphate absorption and excretion, and reduced lipid deposition through increasing lipolysis in the intestine. Moreover, phosphate incubation increased the mRNA and protein expression of krüppel like factor 4 (klf4), silent mating-type information regulation 2 homolog 3 (sirt3), peroxisome proliferator activated receptor alpha (pparα) and long chain acyl-CoA dehydrogenase (lcad) in the intestinal epithelial cells (IECs), and klf4 knockdown attenuated the phosphate-induced increase of protein levels of Sirt3, Pparα and Lcad. Further investigation found that Klf4 overexpression increased the activity of sirt3 and pparα promoters, which in turn reduced the acetylation and protein level of Lcad.ConclusionDietary Pi excess induced lipid degradation by the activation of the Klf4-Sirt3/Pparα-Lcad pathway in the intestine and primary IECs.Graphical 2J2H-vAY8k8xL15UHAsvLYVideo

Association between the intake of plant and animal proteins and the serum fibroblast growth factor-23 level in patients with chronic kidney disease analyzed by the isocaloric substitution model.

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone secreted by the bone in response to dietary phosphate intake. Since the phosphate content in the diet correlates with the protein content, both plant- and animal-based protein intake can increase the serum FGF23 level. However, a higher percentage of energy from plant protein than from animal protein is associated with a lower serum FGF23 level in patients with chronic kidney disease (CKD) in the United States. Since dietary habits differ between Asian and Western populations, we performed a cross-sectional study to determine the association between the percentages of energy from plant and animal proteins and the serum FGF23 level in Japanese CKD patients. In 107 non-dialysis CKD patients (age: 66 ± 9 years; estimated glomerular filtration rate: 56 ± 21 mL/min/1.73 m2), the percentages of energy from plant and animal proteins were assessed using a food frequency questionnaire based on food groups. Venous blood samples were used to measure the serum FGF23, phosphate, 1,25-dihydroxyvitamin D, and intact parathyroid hormone levels. The percentages of energy from plant and animal proteins showed a negative and positive association, respectively, with the serum FGF23 level. Furthermore, isocaloric substitution modeling showed that replacing animal protein with plant protein was associated with a low serum FGF23 level. Our findings suggest that encouraging diets with high plant protein level may prevent an increase in the serum FGF23 level in Japanese CKD patients.

Intensive Nutritional Counseling and Education for Management of Hyperphosphatemia in Hemodialysis Patients at Al-Khor Hospital- Hamad Medical Corporation - State of Qatar

Objectives: To assess the dietary phosphate intake of hemodialysis patients with hyperphosphatemia and the effects of a dietetic intervention focused on limiting dietary phosphate load. Design: Cross-sectional dietary phosphate intake assessment and prospective intervention study. Setting: Hospital hemodialysis units of AL-Khor hospital – Hamad Medical Corporation, Qatar. Subjects: sixteen stable adult hemodialysis patients, who had phosphorus serum levels ≥1.6 mmol/L. Intervention: Analysis of dietary composition and of the effects of individual dietetic counseling to reduce phosphorus intake while preserving the same or improving protein intake. Main outcome measures: Differences in nutrient intake between pre and post-dietary intervention among hyperphosphatemia patients, and changes in phosphorus–protein ratio, and serum phosphate, after the dietetic intervention. Results: Significant differences in nutrient intake including energy, protein, and phosphorus were detected after the intervention. After dietetic intervention in the hyperphosphatemia patients, a decrease in the dietary phosphate–protein ratio (28.9 -13.4 mg/g, P &lt;0.05) also occurred. Serum phosphate showed a trend of a significant decrease after the dietary intervention (2.2mmol/L-1.68mmol/L), P &lt; 0.05). Conclusion: Individual intensive nutritional education and counseling may be useful in reducing phosphate load and improving serum phosphorus with a positive effect on nutrient intake. A phosphate-controlled diet has a role in an integrated therapeutic approach to hyperphosphatemia and positive calcium-phosphorus balance in hemodialysis patients.

Cancer Cachexia and Dysregulated Phosphate Metabolism: Insights from Mutant p53 and Mutant Klotho Mouse Models.

The present perspective article proposes that cachexia, muscle wasting in cancer, is mediated by dysregulated phosphate metabolism and phosphate toxicity that can damage tissues in most major organ systems. A diet high in phosphorus fed to mice deficient in klotho, a cofactor that regulates phosphate metabolism, accelerates aging, sarcopenia, general organ atrophy, kyphosis, and osteoporosis. Similar effects are seen in phenotypes of mutant p53 mice that overexpress the p53 tumor suppressor gene. Although mutant p53 mice do not develop tumors compared to wild-type mice, mutant p53 mice have shorter mean lifespans. Furthermore, tumorigenesis is associated with the sequestration of excessive inorganic phosphate, and dangerous levels of phosphate are released into circulation during tumor lysis syndrome. In total, this evidence implies that tumorigenesis may be a compensatory mechanism that provides protective effects against systemic exposure to dysregulated phosphate metabolism and phosphate toxicity related to cachexia in cancer. Moreover, the hypothetical protection against phosphate toxicity afforded by tumorigenesis also provides an alternate explanation for putative tumor evasion of the immune system. Insights proposed in this perspective paper provide new directions for further research, with potential to develop novel interventions and clinical applications that modify dietary phosphate intake to reduce cachexia in cancer patients.

Sex Differences in Phosphate Homeostasis: Females Excrete More Phosphate and Calcium After an Oral Phosphate Challenge.

Dietary consumption of phosphate is increasing, and elevated serum phosphate is associated with increased cardiovascular disease (CVD) risk. Sex differences in phosphate homeostasis and response to changes in dietary phosphate intake, which are not captured by clinically measured analytes, may contribute to differences in CVD presentation and bone disease. To assess sex differences in acute phosphate homeostasis in response to a single oral phosphate challenge. Cross-sectional. General community. 78 participants (40-76 years) with measured glomerular filtration rate >60 mL/min/1.73 m2 and no clinically diagnosed CVD and 14 young healthy adults. To elucidate subtle alterations in phosphate homeostasis, we employ an acute challenge whereby the hormonal response, circulating mineral levels, and urinary excretion are assessed following an oral challenge of phosphate. Although both males and females had similar changes in circulating phosphate, calcium, and parathyroid hormone in response to the challenge, females excreted ∼1.9x more phosphate and ∼2.7x more calcium than males, despite not consuming calcium. These sex differences were recapitulated in healthy young adults. This excretion response did not correlate to age, serum phosphate, or estradiol levels. The females with greater excretion of phosphate had higher levels of bone resorption markers compared to formation markers. Taken together, these data identify sex differences in acute phosphate homeostasis, specifically that females may mobilize and excrete endogenous sources of calcium and phosphate in response to oral phosphate compared to males. While high levels of dietary phosphate negatively impact bone, our results suggest that females may incur more risk from these diets.

Long-Term Excessive Dietary Phosphate Intake Increases Arterial Blood Pressure, Activates the Renin-Angiotensin-Aldosterone System, and Stimulates Sympathetic Tone in Mice.

Increased dietary phosphate intake has been associated with severity of coronary artery disease, increased carotid intima–media thickness, left ventricular hypertrophy (LVH), and increased cardiovascular mortality and morbidity in individuals with normal renal function as well as in patients suffering from chronic kidney disease. However, the underlying mechanisms are still unclear. To further elucidate the cardiovascular sequelae of long-term elevated phosphate intake, we maintained male C57BL/6 mice on a calcium, phosphate, and lactose-enriched diet (CPD, 2% Ca, 1.25% P, 20% lactose) after weaning them for 14 months and compared them with age-matched male mice fed a normal mouse diet (ND, 1.0% Ca, 0.7% P). Notably, the CPD has a balanced calcium/phosphate ratio, allowing the effects of elevated dietary phosphate intake largely independent of changes in parathyroid hormone (PTH) to be investigated. In agreement with the rationale of this experiment, mice maintained on CPD for 14 months were characterized by unchanged serum PTH but showed elevated concentrations of circulating intact fibroblast growth factor-23 (FGF23) compared with mice on ND. Cardiovascular phenotyping did not provide evidence for LVH, as evidenced by unchanged LV chamber size, normal cardiomyocyte area, lack of fibrosis, and unchanged molecular markers of hypertrophy (Bnp) between the two groups. However, intra-arterial catheterization revealed increases in systolic pressure, mean arterial pressure, and pulse pressure in mice fed the CPD. Interestingly, chronically elevated dietary phosphate intake stimulated the renin–angiotensin–aldosterone system (RAAS) as evidenced by increased urinary aldosterone in animals fed the CPD, relative to the ND controls. Furthermore, the catecholamines epinephrine, norepinephrine, and dopamine as well as the catecholamine metabolites metanephrine. normetanephrine and methoxytyramine as measured by mass spectrometry were elevated in the urine of mice on CPD, relative to mice on the ND. These changes were partially reversed by switching 14-month-old mice on CPD back to ND for 2 weeks. In conclusion, our data suggest that excess dietary phosphate induces a rise in blood pressure independent of secondary hyperparathyroidism, and that this effect may be mediated through activation of the RAAS and stimulation of the sympathetic tone.

Phosphate Frustration: Treatment Options to Complement Current Therapies.

Hyperphosphatemia eventually develops in almost all patients with advanced chronic kidney disease and is associated with negative clinical outcomes. Thus, guidelines recommend targeting treatment to normal phosphate levels in patients with chronic kidney disease. Despite low phosphorus diets, clearance by dialysis, and phosphate binder use, many patients with chronic kidney disease on dialysis are unable to consistently achieve and maintain serum phosphate concentrations <5.5 mg/dL. A chart audit of patients on dialysis receiving phosphate binders showed that 74 to 86% were unable to consistently achieve serum phosphate ≤5.5 mg/dL over 6 months. Furthermore, although there is evidence that serum phosphate concentrations <4.5 mg/dL are associated with improved survival and cardiovascular outcomes, real-world phosphate control data suggest achieving and maintaining this goal for most patients would be extremely challenging, if not near impossible, using current therapies. As phosphate binders can only remove approximately 300 mg of the 2,500 mg or more daily dietary phosphate intake, therapeutic innovations are necessary to improve phosphate management. We present treatment options to complement current therapies including tenapanor, a novel sodium/hydrogen exchanger isoform 3 inhibitor that blocks the dominant paracellular phosphate absorption pathway and has been shown to reduce phosphate levels in several clinical trials.

Parkinson's Disease Etiology: Insights and Associations with Phosphate Toxicity.

The present paper investigated the association of Parkinson’s disease etiology with phosphate toxicity, a pathophysiological condition in which dysregulated phosphate metabolism causes excessive inorganic phosphate sequestration in body tissue that damages organ systems. Excessive phosphate is proposed to reduce Complex I function of the mitochondrial electron transport chain in Parkinson’s disease and is linked to opening of the mitochondrial permeability transition pore, resulting in increased reactive oxygen species, inflammation, DNA damage, mitochondrial membrane depolarization, and ATP depletion causing cell death. Parkinson’s disease is associated with α-synuclein and Lewy body dementia, a secondary tauopathy related to hyperphosphorylation of tau protein, and tauopathy is among several pathophysiological pathways shared between Parkinson’s disease and diabetes. Excessive phosphate is also associated with ectopic calcification, bone mineral disorders, and low levels of serum vitamin D in patients with Parkinson’s disease. Sarcopenia and cancer in Parkinson’s disease patients are also associated with phosphate toxicity. Additionally, Parkinson’s disease benefits are related to low dietary phosphate intake. More studies are needed to investigate the potential mediating role of phosphate toxicity in the etiology of Parkinson’s disease.

High phosphate-induced progressive proximal tubular injury is associated with the activation of Stat3/Kim-1 signaling pathway and macrophage recruitment.

Dietary phosphate intake in the Western population greatly exceeds the recommended dietary allowance and is linked to enhanced cardiovascular and all-cause mortality. It is unclear whether a chronic high phosphate diet (HPD) causes kidney injury in healthy individuals. Here, we show that feeding a 2% HPD in C57BL/6N mice for one up to six months resulted in hyperphosphatemia, hyperphosphaturia, increased plasma levels of fibroblast growth factor (FGF) 23, and parathyroid hormone (PTH) compared to mice on a 0.8% phosphate diet. Kidney injury was already noted after two months of HPD characterized by loss of proximal tubular (PT) cell polarity, flattened epithelia, disruption of brush border membranes, vacuolization, increased PT cell proliferation, marked interstitial mononuclear infiltration, and progressive accumulation of collagen fibers. HPD increased Stat3 activation and Kim-1 expression in PT epithelial cells and enhanced renal synthesis of chemokines recruiting monocytes and macrophages as well as macrophage related factors. Enhanced recruitment of F4/80+ macrophages around injured PT lesions was timely associated with increased Kim-1 synthesis, tubular MCP-1 expression, and degree of PT injury score. Likewise, tubulointerstitial fibrosis was associated with activation of Stat3/Kim-1 signaling pathway. The stimulation of human proximal tubular cells with high phosphate activated Stat3 signaling and induced HAVCR1 and CCL2 expression. We conclude that high phosphate results in progressive proximal tubular injury, indicating that high dietary phosphate intake may affect kidney health and therefore represents an underestimated health problem for the general population.