Patients with chronic kidney disease (CKD) are given calcium carbonate to bind dietary phosphorus, reduce phosphorus retention, and prevent negative calcium balance; however, data are limited on ...calcium and phosphorus balance during CKD to support this. Here, we studied eight patients with stage 3 or 4 CKD (mean estimated glomerular filtration rate 36ml/min) who received a controlled diet with or without a calcium carbonate supplement (1500mg/day calcium) during two 3-week balance periods in a randomized placebo-controlled cross-over design. All feces and urine were collected during weeks 2 and 3 of each balance period and fasting blood, and urine was collected at baseline and at the end of each week. Calcium kinetics were determined using oral and intravenous 45calcium. Patients were found to be in neutral calcium and phosphorus balance while on the placebo. Calcium carbonate supplementation produced positive calcium balance, did not affect phosphorus balance, and produced only a modest reduction in urine phosphorus excretion compared with placebo. Calcium kinetics demonstrated positive net bone balance but less than overall calcium balance, suggesting soft-tissue deposition. Fasting blood and urine biochemistries of calcium and phosphate homeostasis were unaffected by calcium carbonate. Thus, the positive calcium balance produced by calcium carbonate treatment within 3 weeks cautions against its use as a phosphate binder in patients with stage 3 or 4 CKD, if these findings can be extrapolated to long-term therapy.
Adolescence is a time for rapid growth that represents an opportunity to influence peak bone mass. Prebiotic agents, such as galacto-oligosaccharides (GOS), increase Ca absorption in animal models ...and postmenopausal women. The objectives of the present study were to investigate the dose-response relationship of GOS supplementation on Ca absorption during growth and to assess changes in colonic microbiota to better understand the mechanism by which GOS is acting. A total of thirty-one healthy adolescent girls aged 10-13 years consumed smoothie drinks twice daily with 0, 2·5 or 5 g GOS for three 3-week periods in a random order. Fractional Ca absorption was determined from urinary Ca excretion over 48 h at the end of each 3-week period using a dual stable isotope method. Faecal microbiota and bifidobacteria were assessed by PCR-denaturing gradient gel electrophoresis and quantitative PCR. Fractional Ca absorption after the 48 h treatment with control, 5 and 10 g GOS/d was 0·393 (SD 0·092), 0·444 (SD 0·086) and 0·419 (SD 0·099), respectively. Significant improvements in Ca absorption were seen with both low and high doses of GOS compared with the control (P,0·02), but itwas not a dose-response relationship. The increase in absorption was greatest in the urine collected after 24 h, which is consistent with lower gut absorption. Faecal bifidobacteria increased (control 10·89 (SD 13·86), 5 g GOS 22·80 (SD 15·74) and 10 g GOS 11·54 (SD 14·20)) with the GOS treatment (P,0·03). The results suggest that daily consumption of 5 g GOS increases Ca absorption, which may be mediated by the gut microbiota, specifically bifidobacteria.
Reducing intestinal phosphorus absorption is a cornerstone in CKD-MBD management. Yet, knowledge gaps include how CKD pathophysiology affects intestinal phosphorus absorption.
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.
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
P 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).
In total,
=8 patients with CKD (eGFR=29-55 ml/min per 1.73 m
) and
=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;
=0.52), and this was similar for 24-hour uP (884 versus 935 mg/d, respectively;
=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.
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.
Phosphorus Absorption in Healthy Adults and in Patients with Moderate Chronic Kidney Disease, NCT03108222.
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.
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Zinc deficiency limits infant growth and increases susceptibility to infections, which further compromises growth. Zinc supplementation improves the growth of zinc-deficient stunted infants, but the ...amount, frequency, and duration of zinc supplementation required to restore growth in an individual child is unknown. A dynamic model of zinc metabolism that predicts changes in weight and length of zinc-deficient, stunted infants with dietary zinc would be useful to define effective zinc supplementation regimens.
The aims of this study were to develop a dynamic model for zinc metabolism in stunted, zinc-deficient infants and to use that model to predict the growth response when those infants are given zinc supplements.
A model of zinc metabolism was developed using data on zinc kinetics, tissue zinc, and growth requirements for healthy 9-mo-old infants. The kinetic model was converted to a dynamic model by replacing the rate constants for zinc absorption and excretion with functions for these processes that change with zinc intake. Predictions of the dynamic model, parameterized for zinc-deficient, stunted infants, were compared with the results of 5 published zinc intervention trials. The model was then used to predict the results for zinc supplementation regimes that varied in the amount, frequency, and duration of zinc dosing.
Model predictions agreed with published changes in plasma zinc after zinc supplementation. Predictions of weight and length agreed with 2 studies, but overpredicted values from a third study in which other nutrient deficiencies may have been growth limiting; the model predicted that zinc absorption was impaired in that study.
The model suggests that frequent, smaller doses (5–10 mg Zn/d) are more effective for increasing growth in stunted, zinc-deficient 9-mo-old infants than are larger, less-frequent doses. The dose amount affects the duration of dosing necessary to restore and maintain plasma zinc concentration and growth.
Oleanolic acid (OA) and ursolic acid (UA) are major chemical constituents found in Fructus ligustri lucidi (FLL), a Chinese herb previously shown to increase bone properties and modulate ...calcium-vitamin D metabolism in rats. OA and UA have been reported to exert osteoprotective effects in vitro.
The present study was designed to determine whether OA or OA + UA mimicked the effects of FLL on bone and calcium homeostasis using ovariectomized rats.
Three-month-old ovariectomized Sprague-Dawley rats were stabilized for 2 mo and randomly assigned to 4 groups offered the same amount (15–17 g/d) of a control diet or experimental diets containing FLL (18.8 g/kg), OA (0.67 g/kg), or OA (0.67 g/kg) + UA (0.22 g/kg) for 6 wk. Serum was obtained for measurement of 1,25-dihydroxycholecalciferol 1,25(OH)2D3 and bones were collected for micro-CT analysis. Calcium balance was measured at weeks 1 and 6. A calcium kinetic study using 45Ca was conducted at week 6 and modeled using WinSAAM software.
Compared with the control group, rats fed the FLL-, OA-, and OA + UA-enriched diets had better bone properties and 51%, 31%, and 27% higher serum 1,25(OH)2D3 concentrations at week 6, respectively. These variables did not differ between the treatments. Calcium balance was not affected by diet at either week 1 or week 6. Kinetic modeling predicted that FLL and OA + UA diet-fed rats had 9% and 15% less endogenous excretion of calcium, respectively, compared with the control group. All 3 treatments resulted in a higher calcium mass of compartment 3 because of changes in transfer rate between compartments 2 and 3, and were positively associated with the serum 1,25(OH)2D3 concentration (R2 = 0.28; P < 0.01).
Similar to FLL, OA and OA + UA increase bone properties, serum 1,25(OH)2D3 concentration, and calcium use in ovariectomized rats, suggesting their potential role in management of osteoporosis.
Selenium (Se) is a nutritionally essential trace element and health may be improved by increased Se intake. Previous kinetic studies have shown differences in metabolism of organic
inorganic forms of ...Se e.g., higher absorption of selenomethionine (SeMet) than selenite (Sel), and more recycling of Se from SeMet than Sel. However, the effects on Se metabolism after prolonged Se supplementation are not known.
To determine how the metabolism and transport of Se changes in the whole-body in response to Se-supplementation by measuring Se kinetics before and after 2 years of Se supplementation with SeMet.
We compared Se kinetics in humans n = 31, aged 40 ± 3 y (mean ± SEM) studied twice after oral tracer administration; initially (PK1), then after supplementation for 2 y with 200 µg/d of Se as selenomethionine (SeMet) (PK2). On each occasion, we administered two stable isotope tracers of Se orally: SeMet, the predominant food form, and selenite (Na
SeO
or Sel), an inorganic form. Plasma and RBC were sampled for 4 mo; urine and feces were collected for the initial 12 d of each period. Samples were analyzed for tracers and total Se by isotope dilution GC-MS. Data were analyzed using a compartmental model, we published previously, to estimate fractional transfer between pools and pool masses in PK2.
We report that fractional absorption of SeMet or Sel do not change with SeMet supplementation and the amount of Se absorbed increased. The amount of Se excreted in urine increases but does not account for all the Se absorbed. As a result, there is a net incorporation of SeMet into various body pools. Nine of the 11 plasma pools doubled in PK2; two did not change. Differences in metabolism were observed for SeMet and Sel; RBC uptake increased 247% for SeMet, urinary excretion increased from two plasma pools for Sel and from two different pools for SeMet, and recycling to liver/tissues increased from one plasma pool for Sel and from two others for SeMet. One plasma pool increased more in males than females in PK2.
Of 11 Se pools identified kinetically in human plasma, two did not increase in size after SeMet supplementation. These pools may be regulated and important during low Se intake.
Bone loss is a current limitation for long-term space exploration. Bone markers, calcitropic hormones, and calcium kinetics of crew members on space missions of 4-6 months were evaluated. ...Spaceflight-induced bone loss was associated with increased bone resorption and decreased calcium absorption. INTRODUCTION: Bone loss is a significant concern for the health of astronauts on long-duration missions. Defining the time course and mechanism of these changes will aid in developing means to counteract these losses during space flight and will have relevance for other clinical situations that impair weight-bearing activity. MATERIALS AND METHODS: We report here results from two studies conducted during the Shuttle-Mir Science Program. Study 1 was an evaluation of bone and calcium biochemical markers of 13 subjects before and after long-duration (4-6 months) space missions. In study 2, stable calcium isotopes were used to evaluate calcium metabolism in six subjects before, during, and after flight. Relationships between measures of bone turnover, biochemical markers, and calcium kinetics were examined. RESULTS: Pre- and postflight study results confirmed that, after landing, bone resorption was increased, as indicated by increases in urinary calcium (p < 0.05) and collagen cross-links (N-telopeptide, pyridinoline, and deoxypyridinoline were all increased >55% above preflight levels, p < 0.001). Parathyroid hormone and vitamin D metabolites were unchanged at landing. Biochemical markers of bone formation were unchanged at landing, but 2-3 weeks later, both bone-specific alkaline phosphatase and osteocalcin were significantly (p < 0.01) increased above preflight levels. In studies conducted during flight, bone resorption markers were also significantly higher than before flight. The calcium kinetic data also validated that bone resorption was increased during flight compared with preflight values (668 +/- 130 versus 427 +/- 153 mg/day; p < 0.001) and clearly documented that true intestinal calcium absorption was significantly lower during flight compared with preflight values (233 +/- 87 versus 460 +/- 47 mg/day; p < 0.01). Weightlessness had a detrimental effect on the balance in bone turnover such that the daily difference in calcium retention during flight compared with preflight values approached 300 mg/day (-234 +/- 102 versus 63 +/- 75 mg/day; p < 0.01). CONCLUSIONS: These bone marker and calcium kinetic studies indicated that the bone loss that occurs during space flight is a consequence of increased bone resorption and decreased intestinal calcium absorption.
Serum calcium (Ca) is maintained in a narrow range through regulation of Ca metabolism in the intestine, kidney, and bone. Calcium is incorporated and resorbed from bone during bone remodeling via ...cellular processes as well as by exchange. Both routes contribute to calcium homeostasis. To assess the magnitude of bone turnover contribution to calcium homeostasis we labeled bone with a Ca tracer and measured Ca release following stimulation or suppression of bone resorption. Young growing male rats (n = 162) were dosed with
Ca to label skeletal Ca. After a one-month period to allow the label to incorporate into the skeleton, rats were treated with a bone resorption antagonist (OPG), a bone resorption agonist (RANKL), or vehicle control (PBS). Serum and urine
Ca and total Ca, and serum TRACP5b (a bone resorption biomarker), were monitored for 45 days following treatment. Tracer data were analyzed by a compartmental model using WinSAAM to quantify dynamic changes in Ca metabolism and identify sites of change following treatment. In RANKL treated rats, both serum
Ca and serum TRACP5b were increased by >70% due to a 25-fold increase in bone resorption. In OPG treated rats, both serum
Ca and serum TRACP5b were suppressed by >70% due to a 75% decrease in bone resorption, a 3-fold increase in bone formation, and a 50% increase in absorption. Because TRACP5b and
Ca responded similarly, we conclude that Ca release from bone into serum occurs mostly via osteoclast-mediated bone resorption. However, because serum Ca concentration did not change with altered resorption in response to either RANKL or OPG treatment, we also conclude that serum Ca concentration under normal dietary conditions in young growing male rats is maintained by processes in addition to cellular bone resorption.
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