Increased Serum Phosphate Levels Research Articles

Correlation between serum phosphate and all-cause mortality in critically ill patients with coronary heart disease accompanied by chronic kidney disease: a retrospective study using the MIMIC-IV database.

The adverse clinical endpoints of cardiovascular and kidney diseases are correlated with increased serum phosphate levels. However, in critically ill patients with coronary heart disease (CHD) accompanied by chronic kidney disease (CKD), the prognostic value of serum phosphate remains unclear. Patients' medical records from the Medical Information Mart for Intensive Care IV database who had concomitant CKD and CHD were classified into four distinct groups in this large retrospective observational cohort study based on the quartiles of serum phosphate levels. Vital status and the duration of hospital and ICU stays within the short-term follow-up periods of 30 and 90 days constituted the primary outcomes. All-cause mortality in the intensive care unit (ICU) and hospital constituted the secondary outcomes. Further, the Cox proportional hazard and restricted cubic spline (RCS) regression models were employed to ascertain how serum phosphate levels correlated with the primary outcomes. In addition, the occurrence rate of the secondary outcomes across the four quartiles was determined utilizing the Kaplan-Meier method. Among the total 3,557 patients (67.6% male) included, the hospital and ICU all-cause mortality rates were 14.6% and 10%, separately. Higher quartiles of serum phosphate concentrations were associated with shorter short-term survival rates, as shown by the Kaplan-Meier curves. Additionally, the Cox proportional hazards analysis illustrated that serum phosphate was independently linked to a higher death risk in the hospital [HR, 1.10 (95% CI: 1.03-1.18), P = 0.007] and ICU [HR, 1.14 (95% CI: 1.07-1.22), P < 0.001]. Lastly, the RCS regression models suggested a robust non-linear correlation between serum phosphate concentrations and death risk in the ICU and hospital (both P for non-linearity <0.001). The prognostic value of serum phosphate is significant in critically ill patients with CHD accompanied by CKD. Furthermore, serum phosphate is potentially valuable for identifying patients with this concomitant condition.

Effects of intravenous sodium thiosulfate on vascular calcification in dialysis patients with end-stage renal disease: a systematic review and meta-analysis.

In dialysis patients, vascular calcification is a common complication and is closely related to the morbidity and mortality of cardiovascular disease. We performed a systematic review to determine the efficacy and safety of sodium thiosulfate (STS) in the progression of vascular calcification in dialysis patients with end-stage renal disease. The PubMed, Web of Science, Embase, Cochrane Library, Wanfang, CNKI, China Biology Medicine disc and Weipu databases were searched up to 9 March 2022 for clinical trials to synthesise findings on the efficacy and safety of STS in the progression of vascular calcification in dialysis patients. The primary outcome was coronary artery calcification scores (CACS) or abdominal aortic calcification scores (AACS) or Kauppila index. The secondary outcome was pulse-wave velocity (PWV). Laboratory data were shown in safety data. A random-effect model was used to provide the summary measures of effect [standardised mean difference (SMD) and 95% confidence interval (CI)]. Seven randomised, controlled trials and one nonrandomised, controlled trial involving 370 patients were included. Six studies reported that the progression of CACS or AACS was slower in the intravenous STS group compared with the control group (SMD -3.24, 95% CI: -5.29, -1.18, p = 0.002). Two studies showed the increase in PWV was less in the STS group compared with the control group (SMD -0.52, 95% CI: -0.92, -0.13, p = 0.009). During the trial period, a lower high-sensitivity C-reactive protein level (SMD 1.61, 95% CI: 0.19, 3.04, p = 0.03), a decrease in serum bicarbonate level (SMD 0.67, 95% CI: 0.22, 1.11, p = 0.003) and an increase in serum phosphate level (SMD -0.32, 95% CI: -0.62, -0.03, p = 0.03) were noted in the intravenous STS group compared with the control group. However, serum calcium and parathyroid hormone levels showed no difference between the two groups after the trials. The most common adverse events were temporary nausea and vomiting, which occurred in 12.5 to 75% of patients. Intravenous STS may slow down the progression of vascular calcification and ameliorate arterial stiffness in dialysis patients. Reliably defining the efficacy and safety of intravenous STS in attenuating the progression of vascular calcification requires a high-quality trial with a large sample size.

TRLS-08. EXPERIENCE WITH THE SELECTIVE FIBROBLAST GROWTH FACTOR INHIBITOR ERDAFITINIB IN THREE PEDIATRIC PATIENTS WITH CNS TUMORS

Abstract Activation of FGF signaling has been described for at least 3% of pediatric solid tumors including pediatric gliomas. Therapeutic actionability of FGF signaling activations, however, remains challenging. Here, we report on three patients with FGFR activation treated with erdafitinib, originally approved for the treatment of FGFR3 or FGFR2 mutated urothelial carcinoma. Our patients were treated for posterior fossa group A ependymoma (patient (Pat) 1&amp;2) and glioma NOS °II-III (Pat3). Dose of erdafitinib at initiation of therapy was 5,2mg/kg/d; 3,8mg/kg/d and 2,8mg/kg/d for Pat1-3 respectively. Rationale for treatment with erdafitinib was increased FGFR3 expression in tumor tissue (TT) of Pat1, increased FGFR1 expression in TT of Pat2, and in Pat3 an activating FGFR1 internal tandem duplication (ITD). Both ependymoma patients received erdafitinib as a fourth line treatment and progressed rapidly under therapy. Treatment was discontinued after 2 weeks (Pat2) and 3 months (Pat1) due to progressive disease. Pat3, with the FGFR1 ITD, responded very well to therapy with a decrease in tumor size and reduced contrast-enhancement after 3&amp;6 months. Therapy was discontinued after six months due to dystrophic nail changes. During treatment, our patients reported on diarrhea, abdominal pain, pain in the lower extremities, dysgeusia, hypersensitivity of the oral mucosa, dry skin and dystrophic nail changes. Additionally, we observed a distinct increase in longitudinal growth (Pat1&amp;3), increased serum phosphate levels, LFPs, alpha-amylase, cholinesterase, alkaline phosphatase and LDH. Summing up, treatment with erdafitinib has high potential for a selected cohort of pediatric CNS tumor patients, as demonstrated by the treatment response of Pat3 with the FGFR1 IDT. However, further defining the exact molecular alterations that predict the individual patient’s response as well as side effects in the pediatric population are imperative to elucidate the further role of erdafitinib in treatment of pediatric CNS tumors.

Clinical Evidence and Selecting Patients for Treatment with Erdafitinib in Advanced Urothelial Carcinoma.

Erdafitinib received accelerated approval on April 12, 2019, for patients with metastatic or locally advanced urothelial carcinoma with susceptible fibroblast growth factor receptor (FGFR) 3 or FGFR2 genetic alterations and who have progressed during or following at least one platinum-based chemotherapy. It thus became the first-ever targeted therapy to receive accelerated FDA approval for metastatic bladder cancer. In the BLC2001 trial, erdafitinib demonstrated an overall response rate of 40% in patients with urothelial carcinoma. Common adverse events include hyperphosphatemia and retinopathy and require regular monitoring. While the increase in serum phosphate levels has been determined to be a pharmacodynamic marker of response, further interrogation of other clinical, genomic, and transcriptomic biomarkers is warranted. Results of the ongoing Phase III trial, THOR, which is comparing erdafitinib to the standard of care (chemotherapy or immunotherapy), are expected to confer full approval. Establishing guidelines for optimal erdafitinib sequencing with immunotherapy and other approved targeted therapies (enfortumab vedotin and sacituzumab govitecan) remains an unmet need.

A case report to assess the safety and efficacy of Burosumab, an investigational antibody to FGF23, in a single pediatric patient with Epidermal Nevus Syndrome and associated hypophosphatemic rickets

Epidermal Nevus Syndrome (ENS), also known as Cutaneous Skeletal Hypophosphatemia Syndrome or Linear Sebaceous Nevus Syndrome, is caused by a mosaic somatic mutation of RAS (Rat Sarcoma genes) which leads to abnormally elevated levels of fibroblast growth factor 23 (FGF23). FGF23 is a major regulator in phosphate homeostasis. There are multiple disorders, along with Epidermal Nevus Syndrome (ENS), that result in unusually high circulating levels of FGF23. This increase ultimately leads to renal phosphate wasting and reduced levels of 1,25-dihydroxy vitamin D. Across these disorders, the clinical symptoms are similar and often include osteomalacia (hypophosphatemic rickets in children), muscle weakness, fatigue, joint deformities, bone pain, and fractures. Burosumab (KRN23), is an IgG1 monoclonal antibody that binds to the FGF23 receptor and inhibits the activity of FGF23. This leads to an increase in serum phosphate levels. Burosumab emerged as a potential therapy in FGF23 overactivity disorders. Burosumab was successful in the treatment of X-linked hypophosphatemia (XLH) and is now FDA-approved for its treatment. Studies have indicated that Burosumab therapy in subjects with XLH consistently increases and sustains serum phosphorus levels and tubular reabsorption of phosphate without a major impact on urine calcium levels or vitamin D metabolism. We studied the effect of Burosumab treatment in a single pediatric patient with Epidermal Nevus Syndrome. Serum phosphorus rose gradually as we titrated the dose of Burosumab upwards. During treatment, a persistent elevation of parathyroid hormone levels was noted along with a persistent elevation of serum calcium. We presumed the patient had tertiary hyperparathyroidism. However, after the removal of three parathyroid glands, the pathology came back with a single enlarged parathyroid adenoma. Subsequently, his calcium and PTH, and phosphorus levels stabilized while taking only Burosumab.ClinicalTrials.gov NCT04320316.

Association of circulating calciprotein particle levels with skeletal muscle mass and strength in middle-aged and older adults.

Calciprotein particles (CPPs) are tiny mineral-protein aggregates consisting of calcium-phosphate and fetuin-A. Recent studies have suggested that CPPs may contribute to the pathogenesis of chronic inflammation and arteriosclerosis. Reduced skeletal muscle mass and strength reportedly contribute independently to increased serum phosphate levels. This finding suggests that reduced skeletal muscle mass and strength can endogenously induce an increase in circulating CPP levels. Therefore, we investigated the potential association between circulating CPP levels and skeletal muscle mass and strength in middle-aged and older adults. One hundred eighty-two middle-aged and older adults (age, 46-83 years) were included in this cross-sectional study (UMIN000034741). Circulating CPP levels were measured using the gel filtration method. Appendicular skeletal muscle mass was assessed using multifrequency bioelectrical impedance analysis with a tetrapolar eight-point tactile electrode system. The skeletal muscle mass index was calculated from appendicular skeletal muscle mass and height. Handgrip and knee extension strengths were used as measures of skeletal muscle strength. The skeletal muscle mass index was negatively correlated with circulating CPP levels (r = -0.31; P < 0.05). This association remained significant after adjustment for potential covariates (β = -0.34; P < 0.05). In contrast, skeletal muscle strength, represented by handgrip strength and knee extension strength, was not significantly associated with circulating CPP levels. In middle-aged and older adults, a lower skeletal muscle mass index was independently associated with higher circulating CPP levels. The present results suggest that maintaining skeletal muscle mass may prevent an increase in circulating CPP levels.

Serum phosphate level and its kinetic as an early marker of acute kidney injury in tumor lysis syndrome.

Acute kidney injury (AKI) is a major cause of mortality in tumor lysis syndrome. The biochemical parameters and kinetics of tumor lysis syndrome remain poorly described. Particularly, whether blood serum phosphate variations may help in the identification and management of patients who will eventually develop AKI remains to be studied. In this retrospective study, we included patients with tumor lysis syndrome episodes without AKI at diagnosis, and analyzed serum phosphate kinetic, clinical and tumor lysis syndrome biochemical variables to identify factors associated with AKI onset, and determine threshold values of phosphatemia associated with AKI development. One hundred thirty tumor lysis syndrome episodes occurred in 120 patients during an 11-year period at the University Hospital of Angers. AKI developed in 56 tumor lysis syndrome episodes. In multivariable analysis, among the analyzed factors, only an increase in serum phosphate levels (before AKI diagnosis), exposure to platinum salts and an increase in LDH levels were associated with AKI development. Before AKI onset, a serum phosphate cut-off of 2.1mmol/L was not effective in predicting AKI development (sensitivity 48%, specificity 84%, area under the receiver operating characteristic curve (AUC) 0.63 [0.52-0.74]). No other biochemical parameters were effective to better predict AKI occurrence. This work suggests that increases in serum phosphate and LDH appear to be early and reliable biomarkers of AKI in tumor lysis syndrome. No valuable threshold value of serum phosphate was found to effectively predict AKI. This work is the basis for further prospective controlled studies on phosphate monitoring and phosphate lowering therapies to prevent AKI during tumor lysis syndrome.

Association of serum levels of calcium, phosphate, and vitamin D with risk of developing aortic stenosis: the UK Biobank cohort.

This study was aimed to investigate the associations of serum calcium, phosphate, and vitamin D levels with the risk of developing aortic stenosis (AS). We included 296 415 participants who were free of prior diagnosis of any valvular heart disease from the UK Biobank. Serum levels of phosphate, calcium, and vitamin D were measured. Incidental AS was determined by the records of hospital data. Cox regression was used to examine the association of serum mineral levels with incidental AS after adjustment for potential confounders. The mean age was 56.4 years (SD 8.14) and 53.3% of participants were women. During an average follow-up of 8.1 years, 1232 individuals developed AS. After adjustment, each 0.5-unit increase in serum phosphate level was associated with a 50% increase of AS risk (hazard ratio 1.50, 95% confidence interval 1.26-1.80). We observed no association of serum calcium and vitamin D levels with AS. Increased serum phosphate level, but not calcium or vitamin D, was associated with a higher risk of incident AS, this association did not differed substantially between patients with and without decreased kidney function. This finding implied that phosphate may be a potential interventional target for AS.

Fibroblast Growth Factor-23-Klotho Axis in Cardiorenal Syndrome: Mediators and Potential Therapeutic Targets.

Cardiorenal syndrome (CRS) is a complex disorder that refers to the category of acute or chronic kidney diseases that induce cardiovascular disease, and inversely, acute or chronic heart diseases that provoke kidney dysfunction. There is a close relationship between renal and cardiovascular disease, possibly due to the presence of common risk factors for both diseases. Thus, it is well known that renal diseases are associated with increased risk of developing cardiovascular disease, suffering cardiac events and even mortality, which is aggravated in those patients with end-stage renal disease or who are undergoing dialysis. Recent works have proposed mineral bone disorders (MBD) as the possible link between kidney dysfunction and the development of cardiovascular outcomes. Traditionally, increased serum phosphate levels have been proposed as one of the main factors responsible for cardiovascular damage in kidney patients. However, recent studies have focused on other MBD components such as the elevation of fibroblast growth factor (FGF)-23, a phosphaturic bone-derived hormone, and the decreased expression of the anti-aging factor Klotho in renal patients. It has been shown that increased FGF-23 levels induce cardiac hypertrophy and dysfunction and are associated with increased cardiovascular mortality in renal patients. Decreased Klotho expression occurs as renal function declines. Despite its expression being absent in myocardial tissue, several studies have demonstrated that this antiaging factor plays a cardioprotective role, especially under elevated FGF-23 levels. The present review aims to collect the recent knowledge about the FGF-23-Klotho axis in the connection between kidney and heart, focusing on their specific role as new therapeutic targets in CRS.

MO802DOES ETELCALCETIDE REVERSE MYELOFIBROTIC BONE CHANGES DUE TO HYPERPARATHYROIDISM? A CASE REPORT

Abstract Background and Aims A 21 year old boy with a diagnosis of Autosomal Recessive Polycystic Kidney Disease and Caroli disease reached a final stage of chronic kidney disease (CKD) and started haemodialysis. Method After 3 years in haemodialysis he underwent a kidney transplant from a cadaveric donor. His transplanted kidney worked fairly well until the patients was 31 year old when he developed graft dysfunction (serum creatinine from 2.7 to 5 mg/dL in a very short period). There was a concomitant increase in serum phosphate levels (8.3 mg/dl) and iPTH that progressively increased to 1032 pg/ml despite a traditional therapy. Results At age 32, the patient returned to haemodialysis treatment thrice weekly with a concomitant a progressive worsening of hyperparathyroidism with bone pain . Cinacalcet at a dosage of 30 mg daily treatment was initiated, then it was increased to 120 mg daily without any benefit. Two years later, being the clinical situation without any improvement and being the patient scarcely compliant to the therapy and because a further enlargement of parathyroid glands was observed, a Parathyroidectomy (PTX) was advised. Nevertheless, PTX was not performed because of patient’s refusal. Furthermore, despite Erythropoietic Stimulating Agent (ESA) therapy, he developed severe anemia that required regular and frequent blood transfusions. iPTH increased to 4500 pg/ml [Fig.1] with a parallel rise in alkaline phosphatase &amp;gt;600 UI/L [Fig.2]. A Computed Tomography scan showed multiple bone-thickening lesions. He thus initiated Etelcalcetide 5 mg e.v. 3 times a week, after the HD session but without any benefit. The dosage was then increased to 7.5 mg but the patient gradually became frail and developed pancytopenia and low-grade fever. Hematological evaluation with bone marrow biopsy was performed in December 2019. Bone marrow histology showed severe fibrosis [Myelofibrosis (MF) grade 3] with normal bone marrow cytogenetics. Blood samples for mutations in JAK-2, CALR, and MPL and BCR-ABL rearrangement were negative. There was no evidence for a myeloproliferative neoplasm (MPN) or metastatic lesions. During the following months, while on a 7,5 mg dose of etalcalcetide, there was a gradual reduction in iPTH [Fig.1] and serum alkaline phosphatase [Fig.2], up to 500 pg/dl and 200 IU/L respectively. The patient developed asymptomatic, often severe, hypocalcemia which was managed with therapy. The patient’s clinical conditions gradually improved, anemia responded to lower doses of ESAs. A bone marrow biopsy was repeated after one year (December 2020) and it showed a reduction in fibrosis (MF grade varying from 1-2). Then etelcalcetide dosage was reduced while serum calcium and phosphate levels were in the normal limit. Conclusion Myelofibrosis secondary to renal osteodystrophy is an uncommon complication. It has been rarely reported and usually is associated with primary hyperparathyroidism. Marrow fibrosis and pancytopenia is related to the excessive iPTH that upregulates production of cytokines and paracrine factors in the bone marrow (IL-1a, IL-6, FNF-a, TGF–b, and platelet-derived growth factor) and it has an important stimulatory effect on fibroblast proliferation. It is known that surgical parathyroidectomy is associated with a reduction of bone marrow fibrosis in primary hyperparathyroidism. To our knowledge, this is probably the first case of tertiary hyperparathyroidism in which the effect of etelcalcetide is comparable to parathyroidectomy as far as on calcium-phosphate balance, and a significant improvement in bone marrow fibrosis and hemoglobin. In conclusion, etelcalcetide at least in this patient seems as effective as PTX on bone balance, bone marrow and anemia.

Effects of Active Vitamin D or FGF23 Antibody on Hyp Mice Dentoalveolar Tissues

Mutations in the PHEX gene lead to X-linked hypophosphatemia (XLH), a form of inherited rickets featuring elevated fibroblast growth factor 23 (FGF23), reduced 1,25-dihydroxyvitamin D (1,25D), and hypophosphatemia. Hyp mutant mice replicate the XLH phenotype, including dentin, alveolar bone, and cementum defects. We aimed to compare effects of 1,25D versus FGF23-neutralizing antibody (FGF23Ab) monotherapies on Hyp mouse dentoalveolar mineralization. Male Hyp mice, either injected subcutaneously with daily 1,25D or thrice weekly with FGF23 blocking antibody from 2 to 35 d postnatal, were compared to wild-type (WT) controls and untreated Hyp mice. Mandibles were analyzed by high-resolution micro–computed tomography (micro-CT), histology, and immunohistochemistry. Both interventions maintained normocalcemia, increased serum phosphate levels, and improved dentoalveolar mineralization in treated versus untreated Hyp mice. 1,25D increased crown dentin volume and thickness and root dentin/cementum volume, whereas FGF23Ab effects were limited to crown dentin volume. 1,25D increased bone volume fraction, bone mineral density, and tissue mineral density in Hyp mice, whereas FGF23Ab failed to significantly affect these alveolar bone parameters. Neither treatment fully attenuated dentin and bone defects to WT levels, and pulp volumes remained elevated regardless of treatment. Both treatments reduced predentin thickness and improved periodontal ligament organization, while 1,25D promoted a more profound improvement in acellular cementum thickness. Altered cell densities and lacunocanalicular properties of alveolar and mandibular bone osteocytes and cementocytes in Hyp mice were partially corrected by either treatment. Neither treatment normalized the altered distributions of bone sialoprotein and osteopontin in Hyp mouse alveolar bone. Moderate improvements from both 1,25D and FGF23Ab treatment regimens support further studies and collection of oral health data from subjects receiving a newly approved anti-FGF23 therapy. The inability of either treatment to fully correct Hyp mouse dentin and bone prompts further experiments into underlying pathological mechanisms to identify new therapeutic approaches.

Sclerostin antibody treatment increases bone mass and normalizes circulating phosphate levels in growing Hyp mice

X-linked hypophosphatemia (XLH), caused by a loss-of-function mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX), is the most common form of vitamin D-resistant rickets. Loss of functional PHEX results in elevated fibroblast growth factor 23 (FGF23) levels, impaired phosphate reabsorption, and inhibited skeletal mineralization. Sclerostin, a protein produced primarily in osteocytes, suppresses bone formation by antagonizing Wnt signaling and is reported to be elevated in XLH patients. This study used the Hyp mouse model to investigate sclerostin's role in the pathophysiology of XLH by evaluating the use of a monoclonal antibody to sclerostin in a mouse model of XLH, the Hyp mouse. Male and female wild-type and Hyp littermates were injected with 25 mg/kg of vehicle or sclerostin antibody (Scl-Ab) twice weekly, beginning at 4 weeks of age and euthanized at 8 weeks of age. Scl-Ab treatment increased serum phosphate levels and suppressed circulating levels of intact FGF23 in treated wild-type and Hyp mice of both sexes. Cortical area, trabecular bone volume fraction (BV/TV), metaphyseal apparent density, and the peak load increased with Scl-Ab treatment in both sexes. This short-term treatment study suggests that Scl-Ab treatment can effectively improve some of the pathologies associated with XLH, including normalization of phosphate, and that sclerostin may play a role in regulating FGF23 and phosphate metabolism in XLH. © 2019 American Society for Bone and Mineral Research.

Iron deficiency plays essential roles in the trigger, treatment, and prognosis of autosomal dominant hypophosphatemic rickets.

Autosomal dominant hypophosphatemic rickets (ADHR) is unique for its incomplete penetrance, variety of disease onsets, and waxing and waning phenotypes. Iron deficiency is a trigger of ADHR. This study aimed to clarify the role of iron deficiency in ADHR. Data of clinical manifestations and laboratory examinations were collected from patients among eight kindreds with ADHR. Multiple regression and Pearson's correlation tests were performed to test the relationships of serum phosphate levels and other laboratory variables during the patients' follow-ups. Among 23 ADHR patients with fibroblast growth factor 23 (FGF23) mutations, 14 patients presented with obvious symptoms. Ten patients had iron deficiency at the onset of ADHR, coinciding with menarche, menorrhagia, pregnancy, and chronic gastrointestinal bleeding. Two patients who did not have their iron status tested presented with symptoms after abortion and pregnancy in one patient each, which suggested that they also had iron deficiency at onset. Patients were treated with ferrous succinate tablets, vitamin C, and neutral phosphate and calcitriol. With correction of the iron status, the patients' symptoms showed notable improvement, with increased serum phosphate levels. Two patients' FGF23 levels also declined to the normal range. There were strong correlations between serum phosphate and serum iron levels (r = 0.7689, p < 0.0001), serum ferritin levels (r = 0.5312, p = 0.002), iron saturation (r = 0.7907, p < 0.0001), and transferrin saturation (r = 0.7875, p < 0.001). We also examined the relationships between serum phosphate levels and hemoglobin-related indices, which were significant (hemoglobin: r = 0.71, p < 0.0001; MCV: r = 0.7589, p < 0.0001; MCH: r = 0.8218, p < 0.0001; and MCHC: r = 0.7751, p < 0.0001). Longitudinal data of six patients' follow-up also showed synchronous changes in serum phosphate with serum iron levels. Iron deficiency plays an important role in triggering ADHR. Monitoring and correcting the iron status are helpful for diagnosing and treating ADHR. Iron metabolism parameters and hemoglobin-related parameters are positively correlated with serum phosphate levels in patients with ADHR and iron deficiency, and these might serve as good indicators of prognosis of ADHR.

Sclerostin Antibody Treatment Increases Bone Mass and Normalizes Circulating Phosphate Levels in Growing Hyp Mice.

X-linked hypophosphatemia (XLH), caused by a loss-of-function mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX), is the most common form of vitamin D-resistant rickets. Loss of functional PHEX results in elevated fibroblast growth factor 23 (FGF23) levels, impaired phosphate reabsorption, and inhibited skeletal mineralization. Sclerostin, a protein produced primarily in osteocytes, suppresses bone formation by antagonizing Wnt signaling and is reported to be elevated in XLH patients. This study used the Hyp mouse model to investigate sclerostin's role in the pathophysiology of XLH by evaluating the use of a monoclonal antibody to sclerostin in a mouse model of XLH, the Hyp mouse. Male and female wild-type and Hyp littermates were injected with 25 mg/kg of vehicle or sclerostin antibody (Scl-Ab) twice weekly, beginning at 4 weeks of age and euthanized at 8 weeks of age. Scl-Ab treatment increased serum phosphate levels and suppressed circulating levels of intact FGF23 in treated wild-type and Hyp mice of both sexes. Cortical area, trabecular bone volume fraction (BV/TV), metaphyseal apparent density, and the peak load increased with Scl-Ab treatment in both sexes. This short-term treatment study suggests that Scl-Ab treatment can effectively improve some of the pathologies associated with XLH, including normalization of phosphate, and that sclerostin may play a role in regulating FGF23 and phosphate metabolism in XLH. © 2019 American Society for Bone and Mineral Research.

Chronic kidney disease and aging differentially diminish bone material and microarchitecture in C57Bl/6 mice.

Chronic kidney disease (CKD) is a common disease of aging and increases fracture risk over advanced age alone. Aging and CKD differently impair bone turnover and mineralization. We thus hypothesize that the loss of bone quality would be greatest with the combination of advanced age and CKD. We evaluated bone from young adult (6 mo.), middle-age (18 mo.), and old (24 mo.) male C57Bl/6 mice three months following either 5/6th nephrectomy, to induce CKD, or Sham procedures. CKD exacerbated losses of cortical and trabecular microarchitecture associated with aging. Aging and CKD each resulted in thinner, more porous cortices and fewer and thinner trabeculae. Bone material quality was also reduced with CKD, and these changes to bone material were distinct from those due to age. Aging reduced whole-bone flexural strength and modulus, micrometer-scale nanoindentation modulus, and nanometer-scale tissue and collagen strain (small-angle x-ray scattering [SAXS]. By contrast, CKD reduced work to fracture and variation in bone tissue modulus and composition (Raman spectroscopy), and increased percent collagen strain. The increased collagen strain burden was associated with loss of toughness in CKD. In addition, osteocyte lacunae became smaller, sparser, and more disordered with age for Sham mice, yet these age-related changes were not clearly observed in CKD. However, for CKD, larger lacunae positively correlated with increased serum phosphate levels, suggesting that osteocytes play a role in systemic mineral homeostasis. This work demonstrates that CKD reduces bone quality, including microarchitecture and bone material properties, and that loss of bone quality with age is compounded by CKD. These findings may help reconcile why bone mass does not consistently predict fracture in the CKD population, as well as why older individuals with CKD are at high risk of fragility.

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.

Low magnesium diet aggravates phosphate-induced kidney injury.

Magnesium is known to protect against phosphate-induced tubular cell injuries in vitro. We investigated in vivo effects of magnesium on kidney injuries and phosphate metabolism in mice exposed to a high phosphate diet. Heminephrectomized mice were maintained on a high phosphate/normal magnesium diet or a high phosphate/low magnesium diet for 6 weeks. We compared renal histology, phosphaturic hormones and renal α-Klotho expression between the two diet groups. High phosphate diet-induced tubular injuries and interstitial fibrosis were remarkably aggravated by the low-magnesium diet. At 1 week after high phosphate feeding when serum creatinine levels were similar between the two groups, the low magnesium diet suppressed not only fecal phosphate excretion but also urinary phosphate excretion, resulting in increased serum phosphate levels. Parathyroid hormone (PTH) levels were not appropriately elevated in the low magnesium diet group despite lower 1,25-dihydroxyvitamin D and serum calcium levels compared with the normal magnesium diet group. Although fibroblast growth factor 23 (FGF23) levels were lower in the low magnesium diet group, calcitriol-induced upregulation of FGF23 could not restore the impaired urinary phosphate excretion. The low magnesium diet markedly downregulated α-Klotho expression in the kidney. This downregulation of α-Klotho occurred even when mice were fed the low phosphate diet. A low magnesium diet aggravated high phosphate diet-induced kidney injuries. Impaired PTH secretion and downregulation of renal α-Klotho were likely to be involved in the blunted urinary phosphate excretion by the low magnesium diet. Increasing dietary magnesium may be useful to attenuate phosphate-induced kidney injury.

Abstract 2100: Selective inhibition of FGFR4 by INCB062079 is efficacious in models of FGF19- and FGFR4-dependent cancers

Abstract Aberrant signaling through Fibroblast Growth Factor Receptors (FGFR) has been reported in multiple types of human cancers. FGFR4 signaling contributes to the development and progression of subsets of cancer: in approximately 10 percent of hepatocellular carcinoma (HCC), genetic amplification of FGF19, encoding an endocrine FGF ligand that activates FGFR4-KLB receptors, has been reported. In models with this alteration, FGF19-FGFR4 signaling is oncogenic and antagonism of the FGF19-FGFR4 axis has been shown to be efficacious suggesting that selective targeting of FGFR4 may be an effective strategy for malignancies with FGFR4 activation. We describe the preclinical characterization of INCB062079 a potent and selective inhibitor of the FGFR4 kinase. In biochemical assays INCB062079 inhibited FGFR4 with low nM potency and exhibited at least 250-fold selectivity against other FGFR kinases and greater than 800-fold selectivity against a large kinase panel. This selectivity derives from the ability of INCB062079 to bind irreversibly to Cys552, a residue within the active site of FGFR4 that is non-conserved among other FGFR receptors. Covalent binding of INCB062079 to Cys552 was demonstrated using a LC/MS/MS-based proteomic analysis that confirmed specificity for the target Cys. In assays using HCC cells with autocrine production of FGF19, INCB062079 inhibited the autophosphorylation of FGFR4 and blocked signal transduction by FGFR4 to downstream markers of pathway activation. Cancer cell lines that have amplification and expression of FGF19 are uniquely sensitive to growth inhibition by INCB062079 (EC50 less than 200 nM) compared with HCC cell lines or normal cells without FGF19-FGFR4 dependence (EC50 &amp;gt; 5000 nM) confirming selectivity for FGFR4. In vivo, oral administration of INCB062079 inhibited the growth and induced significant regressions of subcutaneous xenograft tumors dependent upon FGFR4 activity at doses that were well-tolerated (10-30 mg/kg BID) and did not result in a significant increase in serum phosphate levels which is observed with FGFR1/2/3 inhibition. Suppression of tumor growth correlated with pharmacodynamic inhibition of FGFR4 signaling. Collectively, these preclinical studies demonstrate that INCB062079 potently and selectively inhibits models of FGF19-FGFR4-dependent cancers in vitro and in vivo, supporting clinical evaluation in patients harboring oncogenic FGFR4 activation. Citation Format: Phillip C.C. Liu, Liang Lu, Kevin Bowman, Matthew C. Stubbs, Liangxing Wu, Darlise DiMatteo, Sindy Condon, Ronald Klabe, Ding-Quan Qian, Xiaoming Wen, Paul Collier, Karen Gallagher, Michael Hansbury, Xin He, Bruce Ruggeri, Yan-ou Yang, Maryanne Covington, Timothy C. Burn, Sharon Diamond-Fosbenner, Richard Wynn, Reid Huber, Wenqing Yao, Swamy Yeleswaram, Peggy Scherle, Gregory Hollis. Selective inhibition of FGFR4 by INCB062079 is efficacious in models of FGF19- and FGFR4-dependent cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2100. doi:10.1158/1538-7445.AM2017-2100

Stratégies visant à réduire la phosphatémie dans la maladie rénale chronique

Chronic kidney disease is known to be associated with phosphate retention. The mechanisms are complex and the early increase in serum phosphate levels in chronic kidney disease is not strictly related to the dietary phosphate load or to the degree of phosphate retention. It also implicates the activity of intestinal sodium–phosphate cotransporters, the degree of bone turnover and the retention and/or phosphate release from the skeleton, and the feedback mechanisms regulating the phosphaturia. Indeed, the increase in serum phosphate levels is only a reflection of underlying complex mechanisms, and many important factors play a role including parathyroid hormone, vitamin D, fibroblast growth factor 23 (FGF23), and others. Hyperphosphatemia increases the risk of cardiovascular morbidity and mortality in chronic kidney disease as well as in subjects with normal renal function. Oral phosphate binders are prescribed in patients with chronic kidney disease and in those treated by dialysis, to prevent intestinal absorption of dietary phosphate and reduce serum phosphate. In prospective observational studies, they have been shown to decrease all-cause and cardiovascular mortality risk. However, different problems have been associated with currently available phosphate binders including the induction of a positive calcium balance and impaired outcomes with calcium-based phosphate binders or increased costs with non-calcium-based phosphate binders. Iron-based phosphate binders represent a new class of phosphate binders. The aim of this article is to provide an update review of the pathophysiological mechanisms leading and maintaining elevated serum phosphate levels in patients with chronic kidney disease and patients in dialysis, and the educational, nutritional, and therapeutic strategies that can be undertaken to control the hyperphosphatemia.

Effectiveness of educational or behavioral interventions on adherence to phosphate control in adults receiving hemodialysis: a systematic review.

People with end-stage kidney disease (ESKD) develop impaired excretion of phosphate. Hyperphosphatemia develops in ESKD as a result of the kidney's reduced ability to excrete ingested phosphate load and is characterized by high bone turnover and increased musculoskeletal morbidity including bone pain and muscle weakness. Increased serum phosphate levels are also associated with cardiovascular disease and associated mortality. These effects are significant considering that cardiovascular disease is the leading cause of death in ESKD, making phosphate control a crucial treatment goal. To determine the effectiveness of education or behavioral interventions on adherence to phosphate control in adults with ESKD receiving hemodialysis (HD). Adults aged over 18 years with ESKD undergoing HD, attending dialysis facilities regardless of frequency and duration of treatment sessions per week. Studies with participants receiving hemodiafiltration were excluded. All types of educational and behavioral interventions aimed at improving adherence to dietary phosphate restriction, phosphate binder medication and HD. Randomized controlled trials (RCTs), non-RCTs, before and after and cohort studies. Outcome measures included serum phosphate levels, patient knowledge and adherence to phosphate control methods, chronic kidney disease (CKD) self-management behavior and perceived self-efficacy for CKD related to phosphate control. A search was conducted in CINAHL, MEDLINE, The Cochrane Library, Embase, Web of Science, PsycINFO and ProQuest Dissertations and Theses Global to find published studies between January 2005 and December 2015. Risk of bias was assessed by three reviewers prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI). Data were extracted using the standardized data extraction tool from JBI-MAStARI. Data were pooled using JBI software. Mean differences (95% confidence interval [CI]) and effect size estimates were calculated for continuous outcomes. Meta-analysis using a random-effects model was performed for serum phosphate levels, and where the findings could not be pooled using meta-analysis, results have been presented in a narrative form. Standard GRADE (Grading of Recommendations Assessment, Development and Evaluation) evidence assessment of outcomes has been reported. A total of 18 studies were included in the review: seven studies focused on dietary phosphate, four studies focused on medications (phosphate binders) and six studies focused on dietary phosphate and medications. Only one study taught patients about diet, medications and HD to control phosphate. Sixteen studies showed significant improvements in phosphate levels. Meta-analysis of eight RCTs favored educational or behavioral interventions over standard care for serum phosphate control, with a weighted mean reduction of -0.23 mmol/l (95% CI -0.37, -0.08) in treatment groups. Overall, educational or behavioral interventions increase adherence to phosphate control. Studies in this systematic review revealed improved outcomes on serum phosphate levels, patient knowledge and adherence to phosphate control methods, CKD self-management behavior and perceived self-efficacy for CKD related to phosphate control. However, there is a lack of sufficient data on how some of the studies implemented their interventions, suggesting that further research is required. Successful strategies that improve and optimize long-term adherence to phosphate control still need to be formulated.