Seeing the Whole Picture: Evaluating the Contribution of Whole Grains to Phosphorus Exposure in People With Kidney Failure Undergoing Dialysis Treatment.

Excessive dietary phosphorus is a concern among patients with kidney failure undergoing dialysis treatment because it may contribute to hyperparathyroidism and hyperphosphatemia. A long-standing but untested component of the low-phosphorus diet is the promotion of refined grains over whole grains. This paper reviews the scientific premise for restricting whole grains in the dialysis population and estimates phosphorus exposure from grain products based on three grain intake patterns modeled from reported intakes in the general US population, adjusting for the presence of phosphorus additives and phosphorus bioavailability: (1) standard grain intake, (2) 100% refined grain intake, and (3) mixed (50/50 whole and refined grain) intake. Although estimated phosphorus exposure from grains was higher with the mixed grain pattern (231 mg/day) compared to the 100% refined grain pattern (127 mg/day), the amount of additional phosphorus from grains was relatively low. Given the lack of strong evidence for restricting whole grains in people with CKD, as well as the potential health benefits of whole grains, clinical trials are warranted to address the efficacy and health impact of this practice.

A U-shaped association between dietary phosphorus intake and new-onset hypertension: a nationwide cohort study in China.

BACKGROUND: The association between dietary phosphorus intake and the risk of hypertension remains uncertain. We aimed to investigate the relation of dietary phosphorus intake with new-onset hypertension among Chinese adults. METHODS: A total of 12,177 participants who were free of hypertension at baseline from the China Health and Nutrition Survey (CHNS) were included. Dietary intake was measured by 3 consecutive 24-hour dietary recalls combined with a household food inventory. New-onset hypertension was defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or diagnosed by a physician or under antihypertensive treatment during the follow-up. RESULTS: During a median follow-up of 6.1 years, 4,269 participants developed new-onset hypertension. Overall, the association between dietary phosphorus intake and new-onset hypertension followed a U-shape (P for nonlinearity<.001). Consistently, when dietary phosphorus intake was assessed as quintiles, compared with those in the 3rd to 4th quintiles (912.0-<1089.5 mg/d), a significantly higher risk of new-onset hypertension was found in participants in the 1st to 2nd quintiles (<912.0 mg/d: HR, 1.23; 95% CI, 1.14-1.33), and the fifth quintile (≥1089.5 mg/d: HR, 1.21; 95% CI, 1.10-1.33). CONCLUSION: There was a U-shaped association between dietary phosphorus intake and new-onset hypertension in general Chinese adults.

Association between dietary phosphorus intake and chronic constipation in adults: evidence from the National Health and Nutrition Examination Survey.

BACKGROUND: Several studies suggest a link between micronutrients and constipation. However, the relationship between constipation and phosphorus has rarely been examined. The main aim of this study was to investigate the association between changes in the prevalence of chronic constipation and dietary phosphorus intake among adult respondents of the National Health and Nutritional Examination Survey (NHANES). METHODS: Data were extracted from the NHANES database for the years 2005-2010. A total of 13,948 people were included in the analysis. Dietary information was collected using the respondents' 24-h dietary records. We conducted multiple logistic regression analyses to examine the correlation between phosphorus intake and poor bowel movement. The primary and secondary outcomes was constipation defined by stool consistency and stool frequency, respectively. RESULTS: Following multi-variate adjustment in model III, a significant association between chronic constipation and each additional 0.1-g intake of dietary phosphorus (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.95, 1.00; P = 0.034 for stool consistency vs. OR, 0.94; 95% CI, 0.90, 0.99; P = 0.027 for stool frequency) was observed. Following multi-variate adjustment in model III, OR values and 95% CI from the second to fourth quartiles compared to the first quartile (reference group) were 0.92 (0.66, 1.27), 0.73 (0.47, 1.13), and 0.39 (0.20, 0.76), respectively, using the stool frequency definition. CONCLUSIONS: This study revealed a negative correlation between phosphorus intake and chronic constipation. This may be due to the fact that dietary phosphorus intake is associated with softer stools and increased stool frequency. Further studies in different settings should be considered to verify these findings.

A U-shaped association between dietary phosphorus intake and new-onset diabetes: A nationwide cohort study in China.

BACKGROUND AND AIMS: The association between dietary phosphorus intake and the risk of diabetes remains uncertain. We aimed to investigate the relation of dietary phosphorus intake with new-onset diabetes among Chinese adults. METHODS AND RESULTS: A total of 16,272 participants who were free of diabetes at baseline from the China Health and Nutrition Survey were included. Dietary intake was measured by 3 consecutive 24-h dietary recalls combined with a household food inventory. Participants with self-reported physician-diagnosed diabetes, or fasting glucose ≥7.0 mmol/L or glycated hemoglobin ≥6.5% during the follow-up were defined as having new-onset diabetes. During a median follow-up of 9.0years, 1101 participants developed new-onset diabetes. Overall, the association between dietary phosphorus intake with new-onset diabetes followed a U-shape (P for nonlinearity<0.001). The risk of new-onset diabetes significantly decreased with the increment of dietary phosphorus intake (per SD increment: HR, 0.64; 95%CI, 0.48-0.84) in participants with phosphorus intake <921.6 mg/day, and increased with the increment of dietary phosphorus intake (per SD increment: HR, 1.33; 95%CI, 1.16-1.53) in participants with phosphorus intake ≥921.6 mg/day. Consistently, when dietary phosphorus intake was assessed as quintiles, compared with those in the 3rd quintile (905.0-<975.4 mg/day), significantly higher risks of new-onset diabetes were found in participants in the 1st-2nd quintiles (<905.0 mg/day: HR, 1.59; 95%CI, 1.30-1.94), and 4th-5th quintiles (≥975.4 mg/day: HR, 1.46; 95%CI, 1.19-1.78). CONCLUSIONS: There was a U-shaped association between dietary phosphorus intake and new-onset diabetes in general Chinese adults, with an inflection point at 921.6 mg/day and a minimal risk at 905.0-975.4 mg/day of dietary phosphorus intake.

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.

Towards establishing no observed adverse effect levels (NOAEL) for different sources of dietary phosphorus in feline adult diets: results from a 7-month feeding study.

High dietary phosphorus (P), particularly soluble salts, may contribute to chronic kidney disease development in cats. The aim of the present study was to assess the safety of P supplied at 1 g/1000 kcal (4184kJ) from a highly soluble P salt in P-rich dry format feline diets. Seventy-five healthy adult cats (n 25/group) were fed either a low P control (1·4 g/1000 kcal [4184kJ]; Ca:P ratio 0·97) or one of two test diets with 4 g/1000 kcal (4184 kJ); Ca:P 1·04 or 5 g/1000 kcal (4184kJ); Ca:P 1·27, both incorporating 1 g/1000 kcal (4184 kJ) sodium tripolyphosphate (STPP) - for a period of 30 weeks in a randomised parallel-group study. Health markers in blood and urine, glomerular filtration rate, renal ultrasound and bone density were assessed at baseline and at regular time points. At the end of the test period, responses following transition to a commercial diet (total P - 2·34 g/1000 kcal [4184kJ], Ca:P 1·3) for a 4-week washout period were also assessed. No adverse effects on general, kidney or bone (skeletal) function and health were observed. P and Ca balance, some serum biochemistry parameters and regulatory hormones were increased in cats fed test diets from week 2 onwards (P ≤ 0·05). Data from the washout period suggest that increased serum creatinine and urea values observed in the two test diet groups were influenced by dietary differences during the test period, and not indicative of changes in renal function. The present data suggest no observed adverse effect level for feline diets containing 1 g P/1000 kcal (4184 kJ) from STPP and total P level of up to 5 g/1000 kcal (4184 kJ) when fed for 30 weeks.

High-Phosphate Diet Induces Exercise Intolerance and Impairs Fatty Acid Metabolism in Mice.

BACKGROUND: Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in the Western diet. Physical inactivity, a common feature of Western societies, is associated with increased cardiovascular morbidity and mortality. It is unknown whether dietary Pi excess contributes to exercise intolerance and physical inactivity. METHODS: To determine an association between Pi excess and physical activity in humans, we assessed the relationship between serum Pi and actigraphy-determined physical activity level, as well as left ventricular function by cardiac magnetic resonance imaging, in DHS-2 (Dallas Heart Study phase 2) participants after adjusting for relevant variables. To determine direct effects of dietary Pi on exercise capacity, oxygen uptake, serum nonesterified fatty acid, and glucose were measured during exercise treadmill test in C57/BL6 mice fed either a high-Pi (2%) or normal-Pi (0.6%) diet for 12 weeks. To determine the direct effect of Pi on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in differentiated C2C12 myotubes were conducted after subjecting to media containing 1 to 3 mmol/L Pi (pH 7.0) to simulate in vivo phosphate conditions. RESULTS: In participants of the DHS-2 (n=1603), higher serum Pi was independently associated with reduced time spent in moderate to vigorous physical activity ( P=0.01) and increased sedentary time ( P=0.004). There was no association between serum Pi and left ventricular ejection fraction or volumes. In animal studies, compared with the control diet, consumption of high-Pi diet for 12 weeks did not alter body weight or left ventricular function but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, and fatty acid levels and led to downregulation of genes involved in fatty acid synthesis, release, and oxidation, including Fabp4, Hsl, Fasn, and Pparγ, in muscle. Similar results were recapitulated in vitro by incubating C2C12 myotubes with high-Pi media. CONCLUSIONS: Our data demonstrate a detrimental effect of dietary Pi excess on skeletal muscle fatty acid metabolism and exercise capacity that is independent of obesity and cardiac contractile function. Dietary Pi may represent a novel and modifiable target to reduce physical inactivity associated with the Western diet.

The impact of a nutritional intervention based on egg white for phosphorus control in hemodialyis patients.

BACKGROUND AND AIMS: Here we describe a dietary intervention for hyperphosphatemia in dialysis patients based on the partial replacement of meat and fish, which are one of the main sources of alimentary phosphorous, with egg white, a virtually phosphorous-free protein source. This intervention aims to reduce phosphorous intake without causing protein wasting. PATIENTS AND METHODS: As many as 23 hyperphosphatemic patients (15 male and 8 female, mean age 53.0 ± 10.0 years) on chronic standard 4 h, three times weekly, bicarbonate hemodialysis were enrolled in this open-label, randomized controlled trial. Patients in the intervention group were instructed to replace fish or meat with egg white in three meals a week for three months whereas diet was unchanged in the control group. RESULTS: Serum phosphate concentrations were significantly lower in the intervention group than in controls after three (4.9 ± 1.0 vs 6.6 ± 0.8; p < 0.001) but not after one month of treatment. Phosphate concentrations decreased more from baseline in the intervention than in the control group both after one (-1,2 ± 1,1 vs 0,5 ± 1,1; p = 0.004) and after three (-1,7 ± 1,1 vs -0,6 ± 1,1; p < 0.001) months of follow-up. No change either in body weight or in body composition assessed with bioelectrical impedance analysis or in serum albumin concentration was observed in either group. CONCLUSION: The partial replacement of meat and fish with egg white induces a significant decrease in serum phosphate without causing protein malnutrition and could represent a useful instrument to control serum phosphate levels in hemodialysis patients. CLINICALTRIALS. GOV IDENTIFIER: NCT03236701.

Cooking Legumes: A Way for Their Inclusion in the Renal Patient Diet.

OBJECTIVE: It has been observed that the consumption of legumes within a varied and Mediterranean diet has beneficial effects in prevention and control of many diseases, including chronic kidney disease (CKD). Recently, legumes have also been considered a good source of protein for CKD patients. However, despite their benefits, guidelines still recommend a limit to their consumption by these patients because of legumes' high potassium and phosphorus content, which are minerals whose intake must be controlled. The aim of this work is to analyze and compare the effect of different cooking methods in the reduction and final content of minerals in legumes to evaluate a possible increase in the frequency of their consumption by CKD patients. METHODS: Dried and canned chickpeas and lentils were cooked using different cooking techniques: (1) soaking, (2) pressure cooking, and (3) normal cooking. Initial and final potassium and phosphorus content and the percentage of humidity in each cooking technique were determined in both legumes. Mineral content was analyzed using flame photometry and nitro-vanado-molybdate colorimetry. RESULTS: The results showed potassium content reductions of up to 80% after soaking and cooking with final values under 120 mg/100 g edible portion. The initial potassium content in canned legumes was low enough, 100 mg/100 g edible portion, but with the application of a subsequent culinary treatment, it was possible to leach up to 95% of the potassium to almost negligible values. Reductions in phosphorus content were not as marked as those of potassium, but culinary treatments reach a phosphorus/protein ratio,11. CONCLUSIONS: These results show that culinary processing of legumes is a very useful tool to reduce potassium and phosphorus content to acceptable levels for their consumption by renal patients, allowing an increase in intake frequency. But, this also reveals the need to update CKD dietary guidelines.

Prevention and treatment of hyperphosphatemia in chronic kidney disease.

Hyperphosphatemia has consistently been shown to be associated with dismal outcome in a wide variety of populations, particularly in chronic kidney disease (CKD). Compelling evidence from basic and animal studies elucidated a range of mechanisms by which phosphate may exert its pathological effects and motivated interventions to treat hyperphosphatemia. These interventions consisted of dietary modifications and phosphate binders. However, the beneficial effects of these treatment methods on hard clinical outcomes have not been convincingly demonstrated in prospective clinical trials. In addition, exposure to high amounts of dietary phosphate may exert untoward actions even in the absence of overt hyperphosphatemia. Based on this concept, it has been proposed that the same interventions used in CKD patients with normal phosphate concentrations be used in the presence of hyperphosphatemia to prevent rise of phosphate concentration and as an early intervention for cardiovascular risk. This review describes conceptual models of phosphate toxicity, summarizes the evidence base for treatment and prevention of hyperphosphatemia, and identifies important knowledge gaps in the field.

Dietary Phosphorus Intake and the Kidney.

Although phosphorus is an essential nutrient required for multiple physiological functions, recent research raises concerns that high phosphorus intake could have detrimental effects on health. Phosphorus is abundant in the food supply of developed countries, occurring naturally in protein-rich foods and as an additive in processed foods. High phosphorus intake can cause vascular and renal calcification, renal tubular injury, and premature death in multiple animal models. Small studies in human suggest that high phosphorus intake may result in positive phosphorus balance and correlate with renal calcification and albuminuria. Although serum phosphorus is strongly associated with cardiovascular disease, progression of kidney disease, and death, limited data exist linking high phosphorus intake directly to adverse clinical outcomes. Further prospective studies are needed to determine whether phosphorus intake is a modifiable risk factor for kidney disease.

Role of dietary phosphate restriction in chronic kidney disease.

AIM: Patients with progressive chronic kidney disease (CKD) develop positive phosphate balance that is associated with increased cardiovascular risk and mortality. Modification of dietary phosphate is a commonly used strategy to improve outcomes but is complicated by the need for adequate dietary protein. Surprisingly, the evidence for patient-level benefits from phosphate restriction is tenuous, and the justification for using any phosphate binder for pre-dialysis patients is questionable. METHODS: The evidence for dietary phosphate modification was reviewed, along with the possible role of a smart phone application (app) that provides information on phosphate, sodium, potassium and nutrients in over 50 000 Australian foods. A pilot study of healthy participants assigned to dietetic advice and standard diet sheets, or dietetic advice, diet sheets and use of the smart phone app was performed. RESULTS: Following baseline studies, 25 participants commenced the sodium and phosphate restricted diet. After 2 weeks, both groups showed non-significant trends to reduction in urinary phosphate and sodium. App users referred to information on the app more frequently than the control group participants referred to written instructions, found referring to the app more convenient, felt they learned more new information, were more motivated to maintain the diet and were more likely to recommend their information source to family or friends (all P < 0.05). CONCLUSIONS: Maintaining phosphate balance remains an important goal of CKD management, although diets incorporating very low phosphate and protein contents may worsen patient outcomes. For selected patients, a smart phone app may improve dietary acceptance and compliance.

Intensified treatment of hyperphosphatemia associated with reduction in parathyroid hormone in patients on maintenance hemodialysis.

BACKGROUND: This study investigated the therapeutic effect of intensive phosphorus-lowering therapy on intact-parathyroid hormone (iPTH) levels in hemodialysis patients. METHODS: Ninety-five hemodialysis patients with serum phosphorus ≥1.78 mmol/L and iPTH ≥300 pg/dL were apportioned to either the treatment or control group (n = 43 and 52, respectively) based on patient commitment to treatment. The treatment group was given phosphorus-lowering therapies with phosphate binders (lanthanum, sevelamer or/and calcium reagent) combined with dietary phosphate restriction and intensified hemodialysis. The control individuals were given low doses of calcium agents, if serum calcium was <2.54 mmol/L. Percent changes in serum phosphorus and iPTH levels were compared between the two groups. In addition, based on the time required to achieve >20% decrease in serum phosphorus, the patients in the treatment group were further stratified as rapid responders (≤2 months; 27 patients) or slow responders (>2 months; 16 patients) and percent changes in iPTH were compared. RESULTS: Serum phosphorus and iPTH levels decreased from baseline in the treatment group (-24.08 ± 1.93% and -9.92 ± 3.70%, respectively) but increased in the control group (22.00 ± 3.63% and 104.21 ± 23.89%; both p < .001). In the rapid responders subgroup, the iPTH decreased (-16.93 ± 3.49%), but in the slow responders subgroup the iPTH increased slightly (0.68 ± 7.37%, p < .05). CONCLUSIONS: For these patients on maintenance hemodialysis, intensive treatment of hyperphosphatemia was associated with a decrease in iPTH levels, especially for those who had achieved substantial reduction in serum phosphorus within 2 months.

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.

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.

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.

Phosphate-a poison for humans?

Maintenance of phosphate balance is essential for life, and mammals have developed a sophisticated system to regulate phosphate homeostasis over the course of evolution. However, due to the dependence of phosphate elimination on the kidney, humans with decreased kidney function are likely to be in a positive phosphate balance. Phosphate excess has been well recognized as a critical factor in the pathogenesis of mineral and bone disorders associated with chronic kidney disease, but recent investigations have also uncovered toxic effects of phosphate on the cardiovascular system and the aging process. Compelling evidence also suggests that increased fibroblastic growth factor 23 and parathyroid hormone levels in response to a positive phosphate balance contribute to adverse clinical outcomes. These insights support the current practice of managing serum phosphate in patients with advanced chronic kidney disease, although definitive evidence of these effects is lacking. Given the potential toxicity of excess phosphate, the general population may also be viewed as a target for phosphate management. However, the widespread implementation of dietary phosphate intervention in the general population may not be warranted due to the limited impact of increased phosphate intake on mineral metabolism and clinical outcomes. Nonetheless, the increasing incidence of kidney disease or injury in our aging society emphasizes the potential importance of this issue. Further work is needed to more completely characterize phosphate toxicity and to establish the optimal therapeutic strategy for managing phosphate in patients with chronic kidney disease and in the general population.

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.

Concordance of dietary sodium intake and concomitant phosphate load: Implications for sodium interventions.

BACKGROUND AND AIMS: Both a high dietary sodium and high phosphate load are associated with an increased cardiovascular risk in patients with chronic kidney disease (CKD), and possibly also in non-CKD populations. Sodium and phosphate are abundantly present in processed food. We hypothesized that (modulation of) dietary sodium is accompanied by changes in phosphate load across populations with normal and impaired renal function. METHODS AND RESULTS: We first investigated the association between sodium and phosphate load in 24-h urine samples from healthy controls (n = 252), patients with type 2 diabetes mellitus (DM, n = 255) and renal transplant recipients (RTR, n = 705). Secondly, we assessed the effect of sodium restriction on phosphate excretion in a nondiabetic CKD cohort (ND-CKD: n = 43) and a diabetic CKD cohort (D-CKD: n = 39). Sodium excretion correlated with phosphate excretion in healthy controls (R = 0.386, P < 0.001), DM (R = 0.490, P < 0.001), and RTR (R = 0.519, P < 0.001). This correlation was also present during regular sodium intake in the intervention studies (ND-CKD: R = 0.491, P < 0.001; D-CKD: R = 0.729, P < 0.001). In multivariable regression analysis, sodium excretion remained significantly correlated with phosphate excretion after adjustment for age, gender, BMI, and eGFR in all observational cohorts. In ND-CKD and D-CKD moderate sodium restriction reduced phosphate excretion (31 ± 10 to 28 ± 10 mmol/d; P = 0.04 and 26 ± 11 to 23 ± 9 mmol/d; P = 0.02 respectively). CONCLUSIONS: Dietary exposure to sodium and phosphate are correlated across the spectrum of renal function impairment. The concomitant reduction in phosphate intake accompanying sodium restriction underlines the off-target effects on other nutritional components, which may contribute to the beneficial cardiovascular effects of sodium restriction. (f) Registration numbers: Dutch Trial Register NTR675, NTR2366.

Calciotropic and phosphaturic hormones in heart failure.

AIMS: Despite adherence to evidence-based guidelines, heart failure [HF] still results in 5-year mortality rates of 50%, indicating a need to implement additional preventive/intervention strategies. This review summarizes data on alterations in the calciotropic and phosphaturic hormones 1,25-dihydroxyvitamin D [1,25(OH)2D] and fibroblast growth factors-23 [FGF-23] in HF and discusses non-pharmacological measures for targeting these hormones. DATA SYNTHESIS: The role of 1,25(OH)2D in the regulation of calcium and phosphate homeostasis is central. 1,25(OH)2D also plays a pivotal role in cardiac function, but is downregulated by FGF-23. There is accumulating evidence from epidemiological data that HF is associated with decreased circulating 1,25(OH)2D and elevated FGF-23 levels. In patients with failing hearts, very low 1,25(OH)2D and extremely high FGF-23 levels have been reported. Experimental data support the assumption that vitamin D deficiency and high serum phosphate/FGF-23 levels increase the risk of HF. This review provides a hypothesis of how vitamin D deficiency, high calcium/phosphorus intake, physical inactivity, and age-related renal impairment may all contribute to HF by adversely affecting calcium- and phosphate-regulating hormones. Several case series in infants and a meta-analysis of randomized controlled trials in adults have already reported successful treatment of or a significant risk reduction in HF by vitamin D supplements. The association of calcium/phosphorus intake, physical activity, or renal function with calciotropic/phosphaturic hormones and HF is however less well documented. CONCLUSIONS: More attention should be paid in future to the association of circulating 1,25(OH)2D and FGF-23 levels with HF and to (non-pharmacological) measures for targeting these calciotropic/phosphaturic hormones.