Blood Phosphate Levels Research Articles

Comparison of Hematological and Biochemical Results Derived from Arterial and Venous Blood Samples in Post-Anesthetic Dogs.

Simple SummaryIn contrast to humans, general anesthesia is required for both surgical procedures and diagnostic imaging like magnetic resonance imaging (MRI) and computed tomography (CT) in small animals. Because the post-anesthetic period is a particularly high risk time for death, serial monitoring of biochemical and hematological parameters could be required. Blood samples could be collected from an indwelling arterial catheter to avoid stress caused by venipuncture, but studies using arterial blood for hematological and biochemical testing have been limited. The aim of this study is to compare hematological and biochemical results derived from venous and arterial blood samples, and to evaluate their clinical interchangeability in post-anesthetic dogs. We found statistically significant but clinically irrelevant differences in hemoglobin, glucose, creatinine, and calcium levels, and results from venous and arterial blood samples are not clinically interchangeable for gamma-glutamyl transpeptidase and potassium levels.Collecting blood from an indwelling arterial catheter may reduce stress from repeated venipuncture in patients requiring serial monitoring, but the use of arterial blood for hematological and biochemical testing remains understudied. Here, we compared hematological and biochemical results of arterial and venous blood and evaluated their clinical interchangeability. Blood samples from dogs who had recovered from anesthesia, collected by both arterial catheterization and venipuncture, were analyzed. To assess clinical acceptance between paired samples, the limit of agreement between the values derived from the arterial and venous blood samples was compared with the allowable total error (TEa) recommended for each parameter. We found no significant differences between the arterial and venous sample results for red/white blood cell and platelet counts and hematocrit, blood urea nitrogen, phosphate, total protein, albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin, sodium, potassium, and chloride levels, whereas hemoglobin, glucose, creatinine, and calcium levels differed significantly (p < 0.05). Moreover, only gamma-glutamyl transpeptidase and potassium exceeded the recommended TEa. Hematological and biochemical results derived from venous and arterial blood samples are clinically interchangeable in post-anesthetic dogs, with the exception of gamma-glutamyl transpeptidase and potassium; thus, these values should be used with caution.

C-Terminal, but Not Intact, FGF23 and EPO Are Strongly Correlatively Elevated in Patients With Gain-of-Function Mutations in HIF2A: Clinical Evidence for EPO Regulating FGF23

Fibroblast growth factor 23 (FGF23) is a key phosphate- and vitamin D-regulating hormone. FGF23 circulates as an intact 251 amino acid protein or N- and C-terminal degradation products. Hormone activity resides in the intact molecule, but it has been suggested that high levels of the C-terminal protein can interfere with intact FGF23 (iFGF23) activity. New evidence points to involvement of the hypoxia-inducible factor (HIF)/erythropoietin (EPO)/iron pathway as important in FGF23 physiology. Exactly how this pathway regulates FGF23 is not clear. Various in vitro, in vivo, and clinical studies involving perturbations in this pathway at various points have yielded conflicting results. Many of these studies are complicated by the confounding, independent effect of renal insufficiency on FGF23. To gain insight into FGF23 physiology, we studied 8 patients with a rare paraganglioma/somatostatinoma syndrome who had elevated blood EPO levels as a result of somatic gain-of-function mutations in HIF2A (EPAS1) that stimulate tumoral EPO production. All patients had normal renal function. EPO levels varied; most were very elevated and highly correlated with C-terminal FGF23 (cFGF23) levels that were also markedly elevated. Blood phosphate and intact FGF23 levels were normal. These data from patients with normal renal function in whom HIF activation was the inciting event suggest a direct role of the HIF/EPO pathway in FGF23 transcription and translation. They also demonstrate that posttranslational regulation was finely tuned to maintain normal blood phosphate levels. Additionally, normal phosphate and intact FGF23 levels in the setting of markedly increased C-terminal FGF23 levels suggest intact FGF23 action is not attenuated by C-terminal FGF23. Published 2020. This article is a U.S. Government work and is in the public domain in the USA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Mediators of the Impact of Hourly Net Ultrafiltration Rate on Mortality in Critically Ill Patients Receiving Continuous Renal Replacement Therapy.

During continuous renal replacement therapy, a high net ultrafiltration rate has been associated with increased mortality. However, it is unknown what might mediate its putative effect on mortality. In this study, we investigated whether the relationship between early (first 48 hr) net ultrafiltration and mortality is mediated by fluid balance, hemodynamic instability, or low potassium or phosphate blood levels using mediation analysis and the primary outcome was hospital mortality. Retrospective, observational study. Mixed medical and surgical ICUs at Austin hospital, Melbourne, Australia. Critically ill patients treated with continuous renal replacement therapy within 14 days of ICU admission who survived greater than 48 hours. None. We studied 347 patients (median [interquartile range] age: 64 yr [53-71 yr] and Acute Physiology and Chronic Health Evaluation III score: 73 (54-90)]. After adjustment for confounders, compared with a net ultrafiltration less than 1.01 mL/kg/hr, a net ultrafiltration rate greater than 1.75 mL/kg/hr was associated with significantly greater mortality (adjusted odds ratio, 1.15; 95% CI, 1.03-1.29; p = 0.011). Adjusted univariable mediation analysis found no suggestion of a causal mediation pathway for this effect by blood pressure, vasopressor therapy, or potassium levels, but identified a possible mediation effect for fluid balance (average causal mediation effect, 0.95; 95% CI, 0.89-1.00; p = 0.060) and percentage of phosphate measurements with hypophosphatemia (average causal mediation effect, 0.96; 95% CI, 0.92-1.00; p = 0.055). However, on multiple mediator analyses, these two variables showed no significant effect. In contrast, a high net ultrafiltration rate had an average direct effect of 1.24 (95% CI, 1.11-1.40; p < 0.001). An early net ultrafiltration greater than 1.75 mL/kg/hr was independently associated with increased hospital mortality. Its putative effect on mortality was direct and not mediated by a causal pathway that included fluid balance, low blood pressure, vasopressor use, hypokalemia, or hypophosphatemia.

Nutrition and Micronutrient Therapy in Critical Illness Should Be Individualized.

Critically ill (intensive care unit [ICU]) patients are characterized by organ failure, intense inflammatory response, insulin resistance, and altered metabolic response. The sicker the patient, the higher the threat to nutrition and micronutrient status. In addition, many patients start the ICU stay with an altered nutrition status, which requires assessment upon admission. Nutrition needs vary among patients as well as during hospitalization, as the metabolic response changes over time. Shock and acute organ failure result in a metabolic shift toward intense catabolism: endogenous glucose production aiming at ensuring the basal adenosine triphosphate production starts immediately and occurs at the expense of the lean body mass using amino acids for neoglucogenesis. Later, the stabilization and recovery phases are characterized by higher energy and substrate needs. Indirect calorimetry is the only tool enabling determination of the metabolic level. When and how should feeding be started? Recent research shows that the route does not matter much, with equipoise between enteral and parenteral nutrition (PN) as long as overfeeding is avoided. As micronutrients are an integral part of metabolism and antioxidant defenses, their delivery must be ensured: whereas needs are well defined for healthy individuals, needs for illness remain poorly defined. PN that contains only macrosubstrates requires the daily prescription of multimicronutrient complements to qualify as total PN. Achievement of goals requires minimal monitoring, consisting of the daily verification of energy and protein goal delivery achievement and daily follow-up determining blood glucose and phosphate levels and insulin requirements.

Tumour induced osteomalacia: a diagnostic challenge and its implications in orthopaedic surgery

&lt;p class="abstract"&gt;Tumor-induced osteomalacia (TIO) is a paraneoplastic phenomenon which encompasses a wide array of clinical features ranging from musculoskeletal pain to pathological fractures. An excess of fibroblast growth factor 23 (FGF23) is produced which is a parahormone with its target receptors in proximal convoluted tubules of glomeruli. This results in decreased blood phosphate levels and decreased hydroxylation of 25-OH vitamin-D, ultimately leading to osteomalacia. Compliance with medical treatment is unsatisfactory and tedious owing to repeated dosing schedules and overwhelming side effects. Surgical excision of the lesion is the only suitable treatment.&lt;/p&gt;

Route of intestinal absorption and tissue distribution of iron contained in the novel phosphate binder ferric citrate.

Anemia of chronic kidney disease (CKD) is, in part, caused by hepcidin-mediated impaired iron absorption. However, phosphate binder, ferric citrate (FC) overcomes the CKD-induced impairment of iron absorption and increases serum iron, transferrin saturation, and iron stores and reduces erythropoietin requirements in CKD/ESRD patients. The mechanism and sites of intestinal absorption of iron contained in FC were explored here. Eight-week old rats were randomized to sham-operated or 5/6 nephrectomized (CKD) groups and fed either regular rat chow or rat chow containing 4% FC for 6 weeks. They were then euthanized, and tissues were processed for histological and biochemical analysis using Prussian blue staining, Western blot analysis to quantify intestinal epithelial tight junction proteins and real-time PCR to measure Fatty Acid receptors 2 (FFA2) and 3 (FFA3) expressions. CKD rats exhibited hypertension, anemia, azotemia, and hyperphosphatemia. FC-treated CKD rats showed significant reductions in blood pressure, serum urea, phosphate and creatinine levels and higher serum iron and blood hemoglobin levels. This was associated with marked increase in iron content of the epithelial and subepithelial wall of the descending colon and modest iron deposits in the proximal tubular epithelial cells of their remnant kidneys. No significant difference was found in hepatic tissue iron content between untreated and FC-treated CKD or control groups. Distal colon's epithelial tight Junction proteins, Occludin, JAM-1 and ZO-1 were markedly reduced in the CKD groups. The FFA2 expression in the jejunum and FFA3 expression in the distal colon were significantly reduced in the CKD rats and markedly increased with FC administration. Iron contained in the phosphate binder, FC, is absorbed by the distal colon of the CKD animals via disrupted colonic epithelial barrier and upregulation of short chain fatty acid transporters.

P1460MEDIATORS OF THE IMPACT OF HOURLY NET ULTRAFILTRATION RATE ON MORTALITY IN CRITICALLY ILL PATIENTS RECEIVING CONTINUOUS RENAL REPLACEMENT THERAPY

Abstract Background and Aims During continuous renal replacement therapy (CRRT), a high net ultrafiltration (NUF) rate is associated with increased mortality. However, it is unknown what might mediate its putative effect on mortality. This study aims to investigate whether the relationship between early (first 48h) NUF and mortality is mediated by fluid balance (FB), hemodynamic instability or low potassium or phosphate blood levels. Method We performed a retrospective, observational study in patients treated with CRRT within 14 days of ICU admission who survived &amp;gt;48 hours. The primary outcome was hospital mortality. We applied multiple mediation analysis to identify possible mediators of NUF’s putative impact on mortality. Results We studied 347 patients [median (interquartile range) age: 64 (53–71) years and Acute Physiology and Chronic Health Evaluation (APACHE) III score: 73 (54–90)]. After adjustment for confounders, compared with a NUF&amp;lt;1.01 ml/kg/h, a NUF rate &amp;gt; 1.75 mL/kg/h was associated with significantly greater mortality (adjusted odds ratio [aOR], 1.15 [95%CI, 1.03 to 1.29]; p = 0.011). Adjusted univariable mediation analysis found no suggestion of a causal mediation effect for blood pressure, vasopressor therapy, or potassium levels, but identified a possible effect for FB (average causal mediation effect (ACME), 0.95 [95%CI, 0.90 to 0.99]; p = 0.062) and percentage of phosphate measurements with hypophosphatemia (ACME, 0.96 [95%CI, 0.92 to 1.00]; p = 0.055). However, on multiple mediator analysis, such variables lost any suggestion of a significant effect. In contrast, NUF rate remained associated with mortality even in their presence (average direct effect, 1.24 [95%CI, 1.11 to 1.40]; p &amp;lt; 0.001). Conclusion An early NUF greater than 1.75 mL/kg/h was independently associated with increased hospital mortality. Its putative effect was not mediated by FB, low blood pressure, vasopressor use, hypokalemia or hypophosphatemia.

Contribution of Bone Tissue to Regulation of Calcium and Phosphate Metabolism. Role of FGF23 and Klotho Protein.

Bone tissue actively contributes to the regulation of systemic homoeostasis, and particularly the maintenance of calcium-phosphate balance. The parathyroid hormone-vitamin D feedback axis is balanced by the recently discovered bone-FGF23-kidney hormonal axis. An active complex consisting of FGF23, a receptor and Klotho protein blocks phosphate reabsorption in the proximal tubules, increasing urine phosphate levels and decreasing blood phosphate levels. Mutations of the gene mediating FGF23 transcription lead to a number of diseases, examples including autosomal dominant hypophosphataemic rickets. Klotho protein is a cofactor for FGF23 displaying cardio-, vaso- and nephroprotective activity. It increases calcium reabsorption in the kidneys and inhibits phosphate reabsorption. It also exerts antioxidative and anti-insulin effects and inhibits tissue calcification and apoptosis. As an inhibitor of bone resorption, osteoprotegerin becomes an important contributor to bone remodelling, while RANK/RANKL signalling inhibition is used in the treatment of postmenopausal osteoporosis. Osteocalcin plays an important role in energy metabolism in the human body. Sclerostin exerts a strong catabolic effect on bone tissue. Newly identified contributors to the regulation of calcium and phosphate homoeostasis suggest that bone tissue plays a complex role in the systemic metabolism.

SUN-183 DIURNAL RHYTHMS OF SERUM PHOSPHATE IN HEMODIALYSIS PATIENTS

Hyperphosphatemia is a common complication of chronic kidney disease that associates with increased risks for all-cause and cardiovascular mortality. Phosphate binder therapies are an efficacious strategy to reduce serum phosphate levels. In clinical practice, the decision on binder therapy initiation and dosage is typically determined from the pre-dialysis blood phosphate level. The healthy population exhibits diurnal rhythms in blood phosphate regulation with fluctuations of more than 1 mg/dL throughout the day (Vervloet et al. 2017). Whether such circadian rhythms persist in dialysis patients and whether the fluctuation pattern is different to that of healthy individuals is only partially understood. We profiled the diurnal rhythms of serum phosphate levels in a population of chronic hemodialysis (HD) patients. We used data from adult in-center HD patients (age ≥18 years) with HD vintage >90 days who were treated at a large dialysis organization in the United States in 2018. We computed the mean pre-dialysis blood phosphate levels at the time of the start of each HD treatment in 2-hour periods through 24 hours for the entire population, as well as stratified by phosphate binder use. Time of HD initiation was treated as time-varying exposure, allowing patients to switch time groups if they had pre-dialysis blood draws in multiple time periods of the day. The mean phosphate levels based on the time of the day with 95% confidence limits were plotted and we used a nonparametric smoothing spline model to fit data and calculate the trajectories of phosphate levels throughout the day. A total of 158,156 adult HD patients were included in the analysis. Patients were: mean age 62.8±14.3 years, 57.1% male, 58.2% white race, 15.8% Hispanic ethnicity, 41.9% with diabetes, 19.6% with congestive heart failure, and HD vintage 1509±1288 days. Mean pre-dialysis albumin was 3.8±0.4 g/dL and phosphate was 5.4±1.5 mg/dL for the population. Overall, mean phosphate levels were found to vary remarkably by 0.9 mg/dL throughout the day, with nadir levels from 0900 to 1100 hours (5.3±1.6 mg/dL), followed by a rise to a mid-day peak from 1700 to 1900 hours (5.8±1.8 mg/dL), and the highest levels had a peak time from 2300 to 0100 hours (6.2±2.1 mg/dL) (Figure 1a). Similar fluctuations and phosphate levels were observed among patients using a phosphate binder (n=143,364), however, patients not using a phosphate binder (n=14,792) exhibited absolute values of mean phosphate levels that were consistently about 1 mg/dL lower at every timepoint (Figure 1b). All patients treated with HD from 2300 through 0300 hours (n=315) were taking a phosphate binder. Our results suggest phosphate levels have a diurnal variation of about 1 mg/dL in patients on chronic hemodialysis, characterized by a nadir in the morning, a mid-day peak and a larger nocturnal peak. Further adjusted analyses are needed to confirm these results that account for patient characteristics, phosphate binder dose and duration of use.

Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney.

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls blood phosphate levels by increasing renal phosphate excretion and reducing 1,25-dihydroxyvitamin D3 [1,25(OH)2D] production. Disorders of FGF23 homeostasis are associated with significant morbidity and mortality, but a fundamental understanding of what regulates FGF23 production is lacking. Because the kidney is the major end organ of FGF23 action, we hypothesized that it releases a factor that regulates FGF23 synthesis. Using aptamer-based proteomics and liquid chromatography-mass spectrometry-based (LC-MS-based) metabolomics, we profiled more than 1600 molecules in renal venous plasma obtained from human subjects. Renal vein glycerol-3-phosphate (G-3-P) had the strongest correlation with circulating FGF23. In mice, exogenous G-3-P stimulated bone and bone marrow FGF23 production through local G-3-P acyltransferase-mediated (GPAT-mediated) lysophosphatidic acid (LPA) synthesis. Further, the stimulatory effect of G-3-P and LPA on FGF23 required LPA receptor 1 (LPAR1). Acute kidney injury (AKI), which increases FGF23 levels, rapidly increased circulating G-3-P in humans and mice, and the effect of AKI on FGF23 was abrogated by GPAT inhibition or Lpar1 deletion. Together, our findings establish a role for kidney-derived G-3-P in mineral metabolism and outline potential targets to modulate FGF23 production during kidney injury.

Bone mineral density and its correlation with serum 25-hydroxyvitamin D levels in patients with hyperthyroidism.

ObjectiveThis study aimed to determine the association between 25-hydroxyvitamin D (25(OH)D) levels and bone mineral density (BMD) in patients with hyperthyroidism after undergoing treatment.MethodsA total of 120 patients with hyperthyroidism were selected as participants. Methimazole tablets were provided to all of the participants, with an initial dose of 20 mg/day and a maintenance dose of 2.5 mg/day for 1 year. Blood calcium, phosphate, parathyroid hormone (PTH), and thyroid hormone levels were assayed using an automatic biochemical analyzer. Levels of 25(OH)D and bone alkaline phosphatase (ALP) in serum were determined by enzyme-linked immunosorbent assay. BMD was measured using dual energy X-ray absorptiometry.ResultsSerum phosphorus, PTH, and 25(OH)D levels in patients with hyperthyroidism were significantly higher, and bone ALP and 24-hour urinary calcium levels were significantly lower after treatment compared with before treatment. BMD in patients with hyperthyroidism was significantly improved after treatment. In logistic regression analysis of BMD-related risk factors, bone ALP, PTH, and 25(OH)D levels were risk factors of BMD.ConclusionTreatment for hyperthyroidism should be supplemented with vitamin D and calcium, which have important clinical significance for adjusting bone metabolism and delaying the process of osteoporosis.

Fetal Hemoglobin, Serum Total Cholesterol, Plasma Phosphate and Serum Calcium Levels in Patients with Leukemia and Lymphoma

In this study, fetal hemoglobin (HbF), blood total cholesterol, phosphate and calcium levels of leukemia and lymphoma cases in Mandalay were determined. It was a cross-sectional, comparative study. Thirty adult cases of leukemia and lymphoma and equal number of control subjects of comparable age (14 to 80 yrs) and sex were studied. Mean HbF of leukemia group (n=9), acute myeloid leukemia (AML) subgroup (n=6) and controls (n=30) were 2.72±0.47%, 3.17±0.69% and 1.39±0.25% of total Hb, respectively. The HbF levels of leukemia group and AML were significantly higher than that of controls (p&lt;0.02). Mean serum total cholesterol levels of leukemia group, AML subgroup and controls were found to be 126.5±17.38 mg%, 137.96±24.66 mg% and 177.18±7.68 mg%, respectively. Cholesterol levels of leukemia group and AML were lower than that of controls. Mean plasma phosphate levels of leukemia and lymphoma cases (n=30), leukemia group (n=9) and lymphoma group (n=21) were 1.21±0.07 mmol/l, 1.33±0.17 mmol/l and 1.15±0.06 mmol/l, respectively. Mean phosphate level of controls was 0.94 mmol/l. Plasma phosphate levels of the whole cases and individual case groups were significantly higher than that of controls (p&lt;0.001). Mean serum calcium levels of the whole cases, leukemia group and lymphoma group were 10.16±0.36 mg%, 10.03±0.75 mg% and 10.21±0.45 mg%, respectively. Mean serum calcium level of controls was 8.55±0.14 mg%. Serum calcium levels of the whole cases and individual case groups were found to be significantly higher than that of controls (p&lt;0.01). The study showed that not only raised HbF but also hypocholesterolaemia might be the diagnostic clues in leukemia cases. Recognition of blood phosphate and calcium changes leads to appropriate therapy and a reduction of morbidity.

Management of bone disease in cystinosis: Statement from an international conference.

Cystinosis is an autosomal recessive storage disease due to impaired transport of cystine out of lysosomes. Since the accumulation of intracellular cystine affects all organs and tissues, the management of cystinosis requires a specialized multidisciplinary team consisting of pediatricians, nephrologists, nutritionists, ophthalmologists, endocrinologists, neurologists' geneticists, and orthopedic surgeons. Treatment with cysteamine can delay or prevent most clinical manifestations of cystinosis, except the renal Fanconi syndrome. Virtually all individuals with classical, nephropathic cystinosis suffer from cystinosis metabolic bone disease (CMBD), related to the renal Fanconi syndrome in infancy and progressive chronic kidney disease (CKD) later in life. Manifestations of CMBD include hypophosphatemic rickets in infancy, and renal osteodystrophy associated with CKD resulting in bone deformities, osteomalacia, osteoporosis, fractures, and short stature. Assessment of CMBD involves monitoring growth, leg deformities, blood levels of phosphate, electrolytes, bicarbonate, calcium, and alkaline phosphatase, periodically obtaining bone radiographs, determining levels of critical hormones and vitamins, such as thyroid hormone, parathyroid hormone, 25(OH) vitamin D, and testosterone in males, and surveillance for nonrenal complications of cystinosis such as myopathy. Treatment includes replacement of urinary losses, cystine depletion with oral cysteamine, vitamin D, hormone replacement, physical therapy, and corrective orthopedic surgery. The recommendations in this article came from an expert meeting on CMBD that took place in Salzburg, Austria, in December 2016.

SUN-524 Burosumab Initiation In A UK XLH Cohort: Real-World Use Resonates With Research Evidence

Objectives X-linked hypophosphatemia (XLH) is a rare inherited form of osteomalacia characterised by low blood phosphate levels which lead to inadequate mineralization of bone:rickets leading in turn to a spectrum of skeletal abnormalities, physical impairment, weakness, and pain. Burosumab is an anti-FGF23 fully human monoclonal antibody, and the first treatment to target the underlying pathophysiology of XLH. Real world evidence has an important role in validating the findings of clinical research studies; more data on dose regimen and relevant biochemical outcomes outside of the clinical research study environment is required. We report these criteria following the first three months of burosumab treatment in a real-world setting. Methods An early access program (EAP) for burosumab was made available for children in the United Kingdom with XLH in 12 specialist centres. Inclusion criteria for the EAP included radiographic evidence of disease, XLH confirmed by genetic PHEX mutation, confirmed familial X-linked inheritance mutation or family history. Patients must have also had an unsatisfactory response to conventional treatment. EAP enrolment was between January and March 2018. 135 of 142 applications were approved.1 Of the 7 declined, 4 failed to meet diagnostic criteria and 3 had insufficient radiological evidence.1 132 have commenced treatment (dose in accordance with EMA marketing authorisation), of whom 41 have completed the initial 12-week burosumab titration period. Results The mean age enrolled was 7.2 years (range <1.6-16.7), 45% female, 43% male and 12% unspecified. The mean height and weight at week 0 was 110.45 cm (75-153 cm) and 25.36 kg respectively. The mean dose administered was 0.57 mg/kg at week 0 and 0.94 mg/kg at week 12 (end of the initial titration period). Mean serum phosphorus was 0.66 mmol/L (0.35-0.85 mmol/L) in week 0 rising to 1.00 mmol/L (0.57-1.58 mmol/L) at week 12 representing a 51.5% increase in serum phosphate. Mean serum ALP fell from 635.48 IU/L (269-2124 IU/L) at week 0 to 522.42 IU/L (190-1473 IU/L) at week 12, representing 18% decrease in ALP. No patients discontinued treatment due to adverse events.1Conclusions Early data from treating children and young people with XLH with burosumab in a real-world UK setting demonstrate that key biochemical responses are in line with the clinical research program findings. Ongoing monitoring and research is required to confirm the biochemical response translates to the expected subsequent impact on skeletal and non-skeletal outcomes, including linear growth and deformities.

SUN-525 Burosumab Experience In A UK Adolescent Population

Objectives X-linked hypophosphatemia (XLH) is a rare inherited form of osteomalacia characterised by low blood phosphate levels which lead to inadequate mineralization of bone:rickets leading in turn to a spectrum of skeletal abnormalities, physical impairment, weakness, and pain. Burosumab is an anti-FGF23 fully human monoclonal antibody, and the first treatment to target the underlying pathophysiology of XLH. The trials that formed the basis of regulatory approval of burosumab only included patients up to the age of 12 years old and so data are lacking on this important patient population. We report relevant biochemical data on this population for the first three months of burosumab treatment in a real-world setting. Methods An early access program (EAP) for burosumab was made available for children in the United Kingdom with XLH in 12 specialist centres. Inclusion criteria for the EAP included radiographic evidence of disease, XLH confirmed by genetic PHEX mutation, confirmed familial X-linked inheritance mutation or family history. Patients must have also had an unsatisfactory response to best available care and treatment. EAP enrolment was between January and March 2018. A total of 142 applications were received of which 135 were approved with 132 receiving treatment to date.1 Of the 7 declined, 4 failed to meet diagnostic criteria and 3 had insufficient radiological evidence.1 Treatment, including dose, was in accordance with the EMA marketing authorisation. Results Data are available on 41 patients who have completed the initial 12-week burosumab titration period. This includes 7 adolescents (13 years old or over) in whom results are available for the same period. The mean height and weight at week 0 was 147.79 cm (136.6-157.8 cm) and 48.23 kg respectively. The mean dose administered was 0.38 mg/kg at week 0 and 0.92 mg/kg at the end of the initial titration period at week 12. Mean serum phosphorus was 0.59 mmol/L (0.35-0.90 mmol/L) in week 0 rising to 0.92 mmol/L (0.57-1.13 mmol/L) at week 12 representing a 56% increase in serum phosphate levels. Mean serum ALP fell from 456 IU/L (288-554 IU/L) at week 0 to 328.9 IU/L (190-461 IU/L) at week 12, representing a 28% decrease in ALP. To date, no patients have discontinued treatment to date due to adverse events.1Conclusions Early data from treating adolescents with XLH with burosumab in a real-world UK setting demonstrate that key biochemical responses are in line with findings from the clinical study program, which included only children 12 years and younger. This provides reassurance that the improvement in key biochemical parameters is consistent across all ages within its licensed indication. Further long-term evidence is required to confirm that the biochemical response translates to the expected impact on skeletal and non-skeletal outcomes in a clinical setting.

Effectiveness and safety of switching to entecavir hepatitis B patients developing kidney dysfunction during tenofovir.

Tenofovir disoproxil fumarate (TDF) is recommended for chronic hepatitis B (CHB) treatment, but it may induce kidney dysfunction whose management is not yet known. This Italian, multicentre, retrospective study aimed to assess the efficacy and safety of switching to entecavir (ETV) patients who developed TDF-associated glomerular and/or tubular dysfunction. A total of 103 TDF-treated patients were included as follows: age 64years, 83% male, 49% cirrhotics, 98% with undetectable HBV DNA, 47% with previous lamivudine resistance (LMV-R) and 71% previously treated with adefovir. Twenty-nine (28%) were switched to ETV because estimated glomerular filtration rate (eGFRMDRD ) was <60mL/min, 37 (36%) because blood phosphate (P) levels were <2.5mg/dL and 37 (36%) for both reasons. Kidney, liver and virological parameters were recorded every 4months thereafter. During 46 (4-115)months of ETV treatment, all patients' renal parameters significantly improved as follows: creatinine from 1.30 to 1.10mg/dL (P<0.0001), eGFRMDRD from 54 to 65mL/min (P=0.002), P from 2.2 to 2.6mg/dL (P<0.0001) and maximal tubule phosphate reabsorption (TmPO4/eGFR) from 0.47 to 0.62mmol/L (P<0.0001). Thirteen patients (52%) improved their eGFRMDRD class, P levels were normalised in 13 (35%), and eight (22%) showed improvements in both parameters. Viral suppression was maintained in all but five patients (5%), all of whom had been LMV-R. The 5-year cumulative probability of ETV-R was 0% in LMV-naïve patients, and 11% in LMV-R patients (P=0.018). Entecavir is an effective and safe rescue strategy for CHB patients who develop renal dysfunction during long-term TDF treatment.

Nano-lanthanum hydroxide, a novel phosphate binder, for treating hyperphosphatemia: A preclinical study

This study is to determine the pharmacological effects of nano-lanthanum hydroxide (nano-LH) in the treatment of hyperphosphatemia, in comparison with other phosphate binders. Rat models of chronic renal failure and hyperphosphatemia were induced by adenine, which were treated with nano-LH (0.15, 0.10, and 0.05 g/Kg/d), lanthanum carbonate (0.30 g/Kg/d), and normal-size lanthanum hydroxide (0.10 g/Kg/d), respectively. To investigate the therapeutic effects, the serum levels of phosphorus, Scr, Ucr, BUN, UUN, PTH, and other hyperphosphatemia-related biochemical indicators were determined. A novel phosphorus-binding agent, nano-LH, was synthesized herein, which was rod-like particle with the length of 30–50 nm, width of 10–20 nm, and diameter of 5–10 nm. In vitro phosphorus binding experiments showed that nano-LH had better binding rate. Pharmacodynamic experiments confirmed that the therapeutic effects of lanthanum-hydroxide (0.10 g/kg/d) were superior to other existing phosphate binders in rat models of hyperphosphatemia, in lowering the blood phosphate level and improving the renal function. In the term of drug safety, our preliminary results showed that the nano-LH at appropriate dose did not cause death cases in mice, and the serum levels of alkaline phosphatase and lactate dehydrogenase were not significantly changed, indicating good oral safety. Nano-LH has high potency compared with several phosphate binders, which might be a promising therapeutic agent for the treatment of hyperphosphatemia in clinic.

Sustained Klotho delivery reduces serum phosphate in a model of diabetic nephropathy.

Diabetic nephropathy (DN) is a primary cause of end-stage renal disease and is becoming more prevalent because of the global rise in type 2 diabetes. A model of DN, the db/db uninephrectomized ( db/db-uni) mouse, is characterized by obesity, as well as compromised renal function. This model also manifests defects in mineral metabolism common in DN, including hyperphosphatemia, which leads to severe endocrine disease. The FGF23 coreceptor, α-Klotho, circulates as a soluble, cleaved form (cKL) and may directly influence phosphate handling. Our study sought to test the effects of cKL on mineral metabolism in db/db-uni mice. Mice were placed into either mild or moderate disease groups on the basis of the albumin-to-creatinine ratio (ACR). Body weights of db/db-uni mice were significantly greater across the study compared with lean controls regardless of disease severity. Adeno-associated cKL administration was associated with increased serum Klotho, intact, bioactive FGF23 (iFGF23), and COOH-terminal fragments of FGF23 ( P < 0.05). Blood urea nitrogen was improved after cKL administration, and cKL corrected hyperphosphatemia in the high- and low-ACR db/db-uni groups. Interestingly, 2 wk after cKL delivery, blood glucose levels were significantly reduced in db/db-uni mice with high ACR ( P < 0.05). Interestingly, several genes associated with stabilizing active iFGF23 were also increased in the osteoblastic UMR-106 cell line with cKL treatment. In summary, delivery of cKL to a model of DN normalized blood phosphate levels regardless of disease severity, supporting the concept that targeting cKL-affected pathways could provide future therapeutic avenues in DN. NEW & NOTEWORTHY In this work, systemic and continuous delivery of the "soluble" or "cleaved" form of the FGF23 coreceptor α-Klotho (cKL) via adeno-associated virus to a rodent model of diabetic nephropathy (DN), the db/db uninephrectomized mouse, normalized blood phosphate levels regardless of disease severity. This work supports the concept that targeting cKL-affected pathways could provide future therapeutic avenues for the severe mineral metabolism defects associated with DN.

Analisis Efektivitas Pengikat Fosfat Tablet Kalsium Karbonat yang Dikunyah Dibandingkan yang Ditelan Utuh pada Pasien Penyakit Ginjal Kronis Dengan atau Tanpa Gangguan Saluran Cerna

Chronic Kidney Disease (CKD) patient with Mineral and Bone Disorder complication have to chew calcium carbonate tablet as a phosphate binder, but infact, patient swallow it in a whole. Gastrointestinal (GI) disorders can affect the efficacy of medicine. This study aims to analyze the effectiveness comparation of chewed and whole swallowed calcium carbonate tablet in CKD patients with or without gastrointestinal disorders. This prospective quasi experimental study with non-inferiority design was conducted on May 28th to August 22nd 2012, with 22 sample (stage 3-5 CKD), 14 men, 8 women, divided into 4 groups (1st: patients with GI disorder and whole swallowed calcium carbonate, 2nd: with GI disorders and chewed tablet, 3rd: without GI disorders and whole swallowed tablet, 4th group: without GI disorders and chewed tablet, all tablet are used with meal). Before and after the 6th week research period, calcium and phosphate blood levels measurements had been taken, adherence had been measured every two weeks using the Morisky questionnaire and pill count. The results showed that there was no significant difference in the increased of calcium levels, except for group 1 compared to group 3 (p = 0.027), the decreased phosphate levels (p = 0.724; 0.089; 0.089; 0.414; 0.569; 1.000) and the value of the product calcium-phosphate (p = 1.000; 0.308; 0.186; 0.414; 0.425; 0.728). The conclusion is that the way to use the medicine and the states of gastrointestinal disorders did not significantly influence the effectiveness of calcium carbonate tablet.

Burosumab: At Long Last, an Effective Treatment for FGF23-Associated Hypophosphatemia.

Burosumab: At Long Last, an Effective Treatment for FGF23-Associated Hypophosphatemia.