Effects of Excessive Dietary Phosphorus Intake on Bone Health

PURPOSE OF REVIEW: The purpose of this review is to provide an overview of dietary phosphorus, its sources, recommended intakes, and its absorption and metabolism in health and in chronic kidney disease and to discuss recent findings in this area with a focus on the effects of inorganic phosphate additives in bone health. RECENT FINDINGS: Recent findings show that increasing dietary phosphorus through inorganic phosphate additives has detrimental effects on bone and mineral metabolism in humans and animals. There is new data supporting an educational intervention to limit phosphate additives in patients with chronic kidney disease to control serum phosphate. The average intake of phosphorus in the USA is well above the recommended dietary allowance. Inorganic phosphate additives, which are absorbed at a high rate, account for a substantial and likely underestimated portion of this excessive intake. These additives have negative effects on bone metabolism and present a prime opportunity to lower total phosphorus intake in the USA. Further evidence is needed to confirm whether lowering dietary phosphorus intake would have beneficial effects to improve fracture risk

Dietary protein intake and bone across stages of chronic kidney disease

Purpose of review: This review aims to summarize the current evidence on the effect of very-low-, low-, and high-protein diets on outcomes related to chronic kidney disease-mineral and bone disorder (CKD-MBD) and bone health in patients with CKD. Recent findings: Dietary protein restriction in the form of low- and very-low-protein diets have been used to slow down the progression of CKD. These diets can be supplemented with alpha-keto acid (KA) analogues of amino acids. Observational and randomized controlled trials have shown improvements in biochemical markers of CKD-MBD, including reductions in phosphorus, parathyroid hormone, and fibroblast growth factor-23. However, few studies have assessed changes in bone quantity and quality. Furthermore, studies assessing the effects of high-protein diets on CKD-MBD are scarce. Importantly, very-low- and low-protein diets supplemented with KA provide supplemental calcium in amounts that surpass current dietary recommendations, but to date there are no studies on calcium balance with KA. Current evidence suggests that dietary protein restriction in CKD may slow disease progression, which may subsequently benefit CKD-MBD and bone health outcomes. However, prospective randomized controlled trials assessing the effects of modulating dietary protein and supplementing with KA on all aspects of CKD-MBD and particularly bone health are needed

EOS789, a broad-spectrum inhibitor of phosphate transport, is safe with an indication of efficacy in a phase 1b randomized crossover trial in hemodialysis patients

The treatment of hyperphosphatemia remains challenging in patients receiving hemodialysis. This phase 1b study assessed safety and efficacy of EOS789, a novel pan-inhibitor of phosphate transport (NaPi-2b, PiT-1, PiT-2) on intestinal phosphate absorption in patients receiving intermittent hemodialysis therapy. Two cross-over, randomized order studies of identical design (ten patients each) compared daily EOS789 50 mg to placebo with meals and daily EOS789 100 mg vs EOS789 100 mg plus 1600 mg sevelamer with meals. Patients ate a controlled diet of 900 mg phosphate daily for two weeks and began EOS789 on day four. On day ten, a phosphate absorption testing protocol was performed during the intradialytic period. Intestinal fractional phosphate absorption was determined by kinetic modeling of serum data following oral and intravenous doses of 33Phosphate ( 33P). The results demonstrated no study drug related serious adverse events. Fractional phosphate absorption was 0.53 (95% confidence interval: 0.39,0.67) for placebo vs. 0.49 (0.35,0.63) for 50 mg EOS789; and 0.40 (0.29,0.50) for 100 mg EOS789 vs. 0.36 (0.26,0.47) for 100 mg EOS789 plus 1600 mg sevelamer (all not significantly different). The fractional phosphate absorption trended lower in six patients who completed both studies with EOS789 100 mg compared with placebo. Thus, in this phase 1b study, EOS789 was safe and well tolerated. Importantly, the use of 33P as a sensitive and direct measure of intestinal phosphate absorption allows specific testing of drug efficacy. The effectiveness of EOS789 needs to be evaluated in future phase 2 and phase 3 studies

Controlled Diet Studies of Intestinal Phosphorus Absorption in Chronic Kidney Disease

Chronic kidney disease (CKD) affects approximately 37 million American adults with many more at risk for disease development. Elevated serum phosphorus and related abnormalities in phosphorus homeostasis due to progressive loss of kidney function are primary driving forces behind cardiovascular dysfunction and mortality in CKD patients. Intestinal phosphorus absorption is an understudied aspect in phosphorus homeostasis. Despite this lack of information, current therapies focus on reducing intestinal phosphorus absorption via the use of oral phosphate binders and dietary phosphorus restriction. Abnormalities in phosphorus-regulating hormones are already present in early stages of CKD, including elevated FGF23 and decreased 1,25- dihydroxyvitamin D, which should have the effect of reduced phosphorus absorption. However, rodent studies suggest that intestinal phosphorus absorption remains at inappropriately normal levels in CKD, despite perturbations in phosphorus homeostatic hormones. In these works, we studied intestinal phosphorus absorption in patients with CKD, with a particular emphasis on controlled diet studies, and on method of intestinal phosphorus absorption assessment. In our first study, we assessed the variation and reliability of 24-hour urinary phosphorus excretion, a presumed biomarker of intestinal phosphorus absorption, in N=8 moderate-stage CKD patients. Here we found a high degree of variability in 13-consecutive measures of 24-hour urine phosphorus measures in patients consuming a controlled diet. We also found that at least two measures of 24-hour urine phosphorus is required for a reliable measure. Lastly, we found that in these moderate CKD subjects, 24-hour urine phosphorus is not related to net phosphorus absorption. However, this does not preclude the existence of a relationship in interventional studies assessing direct methods of intestinal phosphorus absorption suppression (i.e. efficacy studies of phosphorus binders) and urinary phosphorus excretion. Next, we assessed fractional intestinal phosphorus absorption in N=8 moderate-stage CKD patients compared to N=8 healthy adults matched for age, sex, and race. In this study, we administered the radioisotopic tracer, 33-Phosphorus, via oral and intravenous routes, staggered by exactly 25-hours. This mimics the gold-standard method of dual-administration of two different isotopes. In our study, the use of a single isotope is a safer method as 33-Phosphorus is lower energy compared to 32-Phosphorus, a higher energy isotope used in some previous studies of endstage kidney disease. Our results showed that fractional intestinal phosphorus absorption was similar between CKD patients and healthy adults, as we hypothesized. These findings were despite significantly lower values of serum 1,25D in CKD patients compared to healthy adults. Lastly, we considered the effect of adherence to a low-phosphorus diet on serum phosphorus area-under-the-curve during the intradialytic period in hemodialysis patients. In this secondary analysis of a placebo-arm of a drug trial that included a controlled diet, we examined the post-dialytic serum phosphorus rebound in N=13 hemodialysis patients. We found that, compared to previous reports in the literature, adhering to a low-phosphorus diet in hemodialysis patients may delay the serum phosphorus rebound in the intradialytic period. In our study, only 2 of 13 patients had returned to their pre-dialysis serum phosphorus values at 24-hours post-dialysis and 4 of 13 at 48-hours. Importantly, all patients were not using phosphate binder medications for the duration of the study. These data show a potential benefit of adherence to a low phosphorus diet for phosphorus control, even in the absence of phosphate binder medications. However, longer studies of a controlled low phosphorus diet compared with a normal phosphorus diet on serum phosphorus rebound in the intradialytic period is needed to substantiate these findings. The results from our studies are foundational in the understanding phosphorus absorption in moderate CKD. This knowledge will be critical for the development of translational interventions to limit phosphorus burden at earlier stages of the disease, thus limiting additional risk for disease progression and mortality

Intestinal Phosphorus Absorption in Chronic Kidney Disease

Chronic kidney disease (CKD) affects approximately 10% of adults worldwide. Dysregulation of phosphorus homeostasis which occurs in CKD leads to development of CKD-Mineral Bone Disorder (CKD-MBD) and contributes to increased morbidity and mortality in these patients. Phosphorus is regulated by multiple hormones (parathyroid hormone (PTH), 1,25-dihyxdroxyvitamin D (1,25D), and fibroblast growth factor 23 (FGF23)) and tissues (kidney, intestine, parathyroid glands, and bone) to maintain homeostasis. In health, the kidneys are the major site of regulation for phosphorus homeostasis. However, as kidney function declines, the ability of the kidneys to adequately excrete phosphorus is reduced. The hormonal changes that occur with CKD would suggest that the intestine should compensate for impaired renal phosphorus excretion by reducing fractional intestinal phosphorus absorption. However, limited studies in CKD animal models and patients with CKD suggest that there may be a break in this homeostatic response where the intestine fails to compensate. As many existing therapies for phosphate management in CKD are aimed at reducing absolute intestinal phosphorus absorption, better understanding of the factors that influence fractional and absolute absorption, the mechanism by which intestinal phosphate absorption occurs, and how CKD modifies these is a much-needed area of study

Post-Dialysis Serum Phosphate Equilibrium in Hemodialysis Patients on a Controlled Diet and No Binders

Background: Studies evaluating the change in serum phosphate post hemodialysis (HD) demonstrate an initial decline during dialysis but a rebound post dialysis. However, previous studies were done on usual diet and phosphate binders, with limited number of blood draws, confounding conclusions. We determined serum phosphate reduction, rebound, and equilibrium over 48 h in HD patients consuming a controlled, low phosphorus diet without binders. Methods: Serum phosphate (mg/dL) was analyzed before and after a HD treatment and frequently during the ensuing 48 h intradialytic period in the clinical research unit. Thirteen subjects were enrolled and had been off phosphate binders for 10 days and consumed a standardized low phosphate (900 mg/day) diet for 3 weeks prior to the assessments. Linear regression was used to determine relationships between the pre-HD serum phosphate, decline post-HD (post-HD drop); and a 48 h area under curve (AUC) using the trapezoidal method as a measure of overall phosphate levels from the end of dialysis to 48 h post dialysis. Repeated Measures ANOVA with Dunnett's posthoc test was used to determine rebound. Results: Five of 13 subjects returned to >90% of their pre-HD serum phosphate within the first 24 h post-HD, and serum phosphate was 94 ± 0.11% (range 63%-113%) by 48 h after the completion of HD. The 48 h AUC of serum phosphate during the interdialytic period was correlated with both pre dialysis phosphorus (r = 0.85; p = 0.0002) and the pre-post drop in serum phosphate during dialysis (r = 0.69; p = 0.0085). In contrast, the net ultrafiltration was not related to the 48 h AUC of serum phosphorus (r = 0.20; p = 0.51). Conclusions: In hemodialysis patients on standard low phosphorus diet and no phosphate binders, the interdialytic serum phosphorus level, assessed as AUC, is determined by the pre dialysis phosphorus and net-change in serum phosphorus during the dialysis treatment, but not the ultrafiltration volume [Correction added on 25 January, after first online publication: In the last sentence of the Abstract, the word "potassium" has been replaced with "phosphorus" to improve accuracy.]

Spot Urine Samples to Estimate Na and K Intake in Patients With Chronic Kidney Disease and Healthy Adults: A Secondary Analysis From a Controlled Feeding Study

Objective: The objective of this study was to assess the agreement between estimated 24-hour urinary sodium excretion (e24hUNa) and estimated 24-hour urinary potassium excretion (e24hUK), calculated from a spot urine sample using several available equations and actual sodium and potassium intake from a controlled diet in both healthy participants and those with chronic kidney disease (CKD). Design and methods: This study is a secondary analysis of a controlled feeding study in CKD patients matched to healthy controls. Participants (n = 16) consumed the controlled diet, which provided ∼2400 mg Na/day and ∼3000 mg K/day, for 8 days. On days 7 and 8, participants consumed all meals and collected all urine in an inpatient research setting, and they were discharged on day 9. The day 7 morning spot urine sample was used to calculate e24hUNa and e24hUK, which was compared with known sodium and potassium intake, respectively. Results: Average e24hUNa from the INTERSALT and Tanaka-Na equations were higher than actual sodium intake by 373 mg and 559 mg, respectively, though the differences were not significant. e24hUNa from the Nerbass-SALTED equation in CKD participants was significantly higher than actual sodium intake by ∼2000 mg (P < .001), though e24hUNa from the Nerbass-RRID equation was not different from intake. e24hUK from the Tanaka-K equation was significantly lower than actual potassium intake (P < .001). For both e24hUNa and e24hUK for all participants, agreement with actual intake was poor, and e24hUNa and e24hUK were not correlated with actual sodium or potassium intake, respectively. Conclusion: e24hUNa and e24hUK are poor indicators of true sodium and potassium intake, respectively, in both healthy and CKD participants. Findings should be confirmed in larger sample sizes with varying levels of dietary sodium and potassium

Intestinal Phosphorus Absorption in Moderate CKD and Healthy Adults Determined Using a Radioisotopic Tracer

Background: Reducing intestinal phosphorus absorption is a cornerstone in CKD-MBD management. Yet, knowledge gaps include how CKD pathophysiology affects intestinal phosphorus absorption. In vivo rodent studies suggest that intestinal phosphorus absorption remains inappropriately normal in early-moderate CKD, despite declining 1,25-dihydroxyvitamin D (1,25D). We measured intestinal phosphorus absorption in patients with moderate CKD versus healthy adults using a direct radiotracer method. Methods: Patients with CKD and healthy adults matched for age, sex, and race were enrolled in this 8-day controlled diet study: the first 6 days outpatient and the final 2 days inpatient. Oral and intravenous doses of 33P and serial blood and urine sampling determined intestinal phosphorus absorption during the final 2 days. Secondary outcomes included fasting biochemistries and 24-hour urine phosphorus (uP). Results: In total, n=8 patients with CKD (eGFR=29-55 ml/min per 1.73 m2) and n=8 matched healthy controls completed the study. On a controlled diet, no difference in fractional intestinal phosphorus absorption was detected between patients with CKD and healthy adults (0.69 versus 0.62, respectively; P=0.52), and this was similar for 24-hour uP (884 versus 935 mg/d, respectively; P=0.70). Fractional intestinal phosphorus absorption was not significantly related to 24-hour uP. Patients with CKD had higher serum intact PTH and intact FGF23 and lower 1,25D. The relationship between 1,25D and fractional intestinal phosphorus absorption was not statistically significant. Conclusions: Intestinal phosphorus absorption with typical dietary intake did not differ in patients with moderate CKD compared with controls, despite lower serum 1,25D levels. In this setting, a relationship between 24-hour uP and fractional or absolute intestinal absorption was not evident. Further investigation is needed to determine what factors influence intestinal phosphorus absorption in CKD and the apparent lack of compensation by the intestine to limit phosphorus absorption in the face of declining kidney function and reduced 1,25D. Whether this is evident across a range of dietary phosphorus intakes, as well as CKD severity, also needs to be determined

Twenty-Four-Hour Urine Phosphorus as a Biomarker of Dietary Phosphorus Intake and Absorption in CKD: A Secondary Analysis from a Controlled Diet Balance Study

BACKGROUND AND OBJECTIVES: Twenty-four-hour urine phosphorus is commonly used as a surrogate measure for phosphorus intake and absorption in research studies, but its reliability and accuracy are unproven in health or CKD. This secondary analysis sought to determine the reliability and accuracy of 24-hour urine phosphorus as a biomarker of phosphorus intake and absorption in moderate CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Eight patients with stage 3-4 CKD participated in 2-week balance studies with tightly controlled phosphorus and calcium intakes. Thirteen 24-hour urine collections per patient were analyzed for variability and reliability of 24-hour urine phosphorus and phosphorus-to-creatinine ratio. The accuracy of 24-hour urine phosphorus to predict phosphorus intake was determined using a published equation. The relationships of 24-hour urine phosphorus with phosphorus intake, net absorption, and retention were determined. RESULTS: There was wide day-to-day variation in 24-hour urine phosphorus within and among subjects (coefficient of variation of 30% and 37%, respectively). Two 24-hour urine measures were needed to achieve ≥75% reliability. Estimating dietary phosphorus intake from a single 24-hour urine resulted in underestimation up to 98% in some patients and overestimation up to 79% in others. Twenty-four-hour urine phosphorus negatively correlated with whole-body retention but was not related to net absorption. CONCLUSIONS: From a sample of eight patients with moderate CKD on a tightly controlled dietary intake, 24-hour urine phosphorus was highly variable and did not relate to dietary phosphorus intake or absorption, rather it inversely related to phosphorus retention

Pilot Study of the Effects of High-Protein Meals During Hemodialysis on Intradialytic Hypotension in Patients Undergoing Maintenance Hemodialysis

Objective Hemodialysis (HD) patients have high protein and energy requirements, and protein-energy wasting is common and associated with poor outcomes. Eating during dialysis may improve nutritional status by counteracting the catabolic effects of hemodialysis treatment; but, eating during HD may be discouraged due to concerns of postprandial hypotension. However, little data is available to support this practice. In this study, we hypothesized that high protein meals during HD does not lead to symptomatic intradialytic hypotension events. Design A 9-week, non-randomized, parallel-arm study. Setting A single in-center HD clinic. Subjects 18 HD patients from two shifts completed the study. Patients were 62±16 years-old in age with dialysis vintage 3.4±2.6 years. Intervention The intervention group (n=9) received meals of ~30g protein and ~1/3 daily recommended intakes of sodium, potassium, phosphorus, and fluid for hemodialysis patients during dialysis for 25 consecutive HD sessions. The control group (n=9) completed all aspects of the study including a visit by study personnel but were not given meals. The 25 consecutive sessions prior to the start of the intervention/control phase were used as a baseline comparison for each patient. Main Outcome Measure Symptomatic hypotension event frequency. Results In the intervention arm, there were 19 symptomatic hypotension events in 5 patients pre-study and 18 events in 6 patients during the study. In the control arm, there were 16 events in 7 patients pre-study and 13 events in 7 patients during the study. Change in the frequency of symptomatic hypotension events from pre-study to during study was not different between groups (P=0.71). There was no effect of meals on nutritional status, but patients reported positive attitudes towards receiving meals during dialysis. Conclusion High-protein meals during HD did not increase symptomatic hypotension events. Larger, longer-term studies are needed to confirm these results and evaluate whether high-protein meals on dialysis benefit nutritional status and clinical outcomes