FGF23 Levels Research Articles

Short-Term Effects of Escalating Doses of Cholecalciferol on FGF23 and 24,25(OH)2 Vitamin D Levels: A Preliminary Investigation

Background: There are few and controversial results on 24,25(OH)2D and FGF23 acute changes following supplementation with cholecalciferol. Methods: Twenty-seven subjects with 25(OH)D < 30 ng/mL were randomized into three groups to receive a single oral dose of 25,000 I.U. or 600,000 I.U. of cholecalciferol or placebo, respectively. We measured 25(OH)D, 1,25(OH)2D, 24,25(OH)2D, and FGF23 levels at baseline and after 72 h. The 1,25(OH)2D/25(OH)D, 1,25(OH)2D/24,25(OH)2D, and 24,25(OH)2D/25(OH)D ratios were also calculated. Results: There was an increase in 25(OH)D and 1,25 (OH)2D following both doses of cholecalciferol. In the group administered 600,000 I.U., there was a significant increase in the delta changes in 25(OH)D and 1,25(OH)2D compared to the placebo and in the delta 24,25(OH)D2 compared to the placebo and 25,000 I.U. groups (all p < 0.05). A decrease in both the 1,25(OH)2D/25(OH)D and 1,25(OH)2D/24,25(OH)2D ratio (all p < 0.05) was observed in the 600,000 I.U. group. FGF23 values significantly increased only in the group administered 600,000 I.U. Conclusions: 25(OH)D and 1,25(OH)D levels significantly increased following 600,000 IU cholecalciferol administration compared to 25,000 I.U. and placebo. Following the massive administration of cholecalciferol, the CYP24A1 enzyme is actively involved in catabolism, thus, avoiding toxic effects.

FGFR4 Is Required for Concentric Growth of Cardiac Myocytes during Physiologic Cardiac Hypertrophy.

Fibroblast growth factor (FGF) 23 is a bone-derived hormone that promotes renal phosphate excretion. Serum FGF23 is increased in chronic kidney disease (CKD) and contributes to pathologic cardiac hypertrophy by activating FGF receptor (FGFR) 4 on cardiac myocytes, which might lead to the high cardiovascular mortality in CKD patients. Increases in serum FGF23 levels have also been observed following endurance exercise and in pregnancy, which are scenarios of physiologic cardiac hypertrophy as an adaptive response of the heart to increased demand. To determine whether FGF23/FGFR4 contributes to physiologic cardiac hypertrophy, we studied FGFR4 knockout mice (FGFR4-/-) during late pregnancy. In comparison to virgin littermates, pregnant wild-type and FGFR4-/- mice showed increases in serum FGF23 levels and heart weight; however, the elevation in myocyte area observed in pregnant wild-type mice was abrogated in pregnant FGFR4-/- mice. This outcome was supported by treatments of cultured cardiac myocytes with serum from fed Burmese pythons, another model of physiologic hypertrophy, where the co-treatment with an FGFR4-specific inhibitor abrogated the serum-induced increase in cell area. Interestingly, we found that in pregnant mice, the heart, and not the bone, shows elevated FGF23 expression, and that increases in serum FGF23 are not accompanied by changes in phosphate metabolism. Our study suggests that in physiologic cardiac hypertrophy, the heart produces FGF23 that contributes to hypertrophic growth of cardiac myocytes in a paracrine and FGFR4-dependent manner, and that the kidney does not respond to heart-derived FGF23.

Changes in bone density and microarchitecture in adolescents undergoing a first kidney transplantation: a prospective study

Purpose Mineral bone disorder associated with chronic kidney disease (CKD-MBD) frequently persists after kidney transplantation (KTx), being due to pre-existing CKD-MBD, immunosuppressive therapies, and post-KTx hypophosphatemia. This study aimed to evaluate bone biomarkers and microarchitecture using high resolution peripheral quantitative computed tomography (HR-pQCT) at the time of KTx and 6 months thereafter and to compare these results with those of matched healthy controls (HC).Methods This study presented the single-center subgroup of patients aged between 10 and 18 years included in the prospective “Bone Microarchitecture in the Transplant Patient” study (TRANSOS-NCT02729142). Patients undergoing a first KTx were matched (1:2) with HC from the “Vitamin D, Bones, Nutritional and Cardiovascular Status” cohort (VITADOS) on sex, pubertal stage, and age.ResultsAt a median (interquartile range, IQR) age of 15 [13; 16] years, 19 patients (6 girls, 7 pre-emptive KTx, 7 steroid-sparing immunosuppressive strategies) underwent a first KTx, with a median [IQR] parathyroid hormone level of 1.9 [1.4; 2.9] the upper limit of normal (ULN). Higher total and trabecular bone densities, along with superior trabecular microarchitecture, were observed at KTx compared to HC. Six months post-KTx, patients had significantly impaired trabecular parameters at the radius, while results were not significantly different at the weight-bearing tibia, neither cortical parameters at both sites. Six months post-KTx, 6 (32%) patients still present with metabolic acidosis, 10 (53%) persistent hyperparathyroidism (always < 2 ULN), and 5 (26%) elevated FGF23 levels; 11 (58%) received phosphate supplementation.Conclusions: Bone density and microarchitecture at the time of KTx were superior compared to HC, but radial trabecular bone microarchitecture impairment observed 6 months post-KTx may reflect subtle albeit present post-KTx CKD-MBD.What is Known?• Mineral bone disorder associated with chronic kidney disease (CKD-MBD) frequently persists after kidney transplantation (KTx) and is associated with morbidity. However, biochemical parameters and dual X-ray absorptiometry (DXA) are poor predictors of the underlying bone disease.What is new?• The present study on 19 adolescent KTx recipients with adequate CKD-MBD control at the time of KTx reveals no significant bone disease compared to matched healthy controls. Microarchitecture impairment observes 6 months post-KTx may reflect subtle, albeit present, post-KTx CKD-MBD.

Effect of weekly high-dose vitamin D3 supplementation on the association between circulatory FGF-23 and A1c levels in people with vitamin D deficiency: A randomized controlled 10-week follow-up trial

Effect of weekly high-dose vitamin D3 supplementation on the association between circulatory FGF-23 and A1c levels in people with vitamin D deficiency: A randomized controlled 10-week follow-up trial

7999 Tumor Induced Osteomalacia Caused By Glomangiopericytoma

Abstract Disclosure: N. Kabir: None. E. Campbell: None. S. Singh: None. Introduction: Tumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused primarily by FGF-23 secreting tumors. Excessive production of FGF23 causes hypophosphatemia, decreased phosphate resorption in the gut, increased renal phosphate wasting, and decreased activation of Vitamin D. This leads to decreased bone density, bone pain, proximal muscle weakness, impaired gait, and recurrent fractures. Case Presentation: 44 year old male with a history of recurrent insufficiency fractures and weakness. At the time of evaluation, he reported fracture of tibial growth plate, sacral fracture, and metatarsal stress fracture. Other symptoms included bone pain, fatigue, muscle weakness, and intercostal muscle spasms with exertion. His pain was debilitating, requiring crutches to ambulate. Available labs at that time were significant for hypophosphatemia (1.3 mg/dL), elevated ALP (160 U/L), low 25OH-vitamin D (26 ng/mL), and normal calcium (8.7 mg/dL). Urine studies demonstrated phosphaturia (fractional excretion of phosphate, 62.4%). FGF23 level resulted at the upper limit of normal (210 RU/mL). Pending further evaluation, burosumab was started. Further work up included a 68Ga-PET-DOTATATE scan revealing a somatostatin receptor expressing soft tissue mass in the left sphenoid sinus and posterior left ethmoid sinus. The scan also demonstrated impending bilateral femur fractures, prior rib fractures, and sacral insufficiency fractures. Based on these findings, he was admitted to the hospital and underwent prophylactic, intramedullary nail fixation of his bilateral femur fractures. He underwent resection of skull base tumor with the final pathology revealing a sinonasal glomangiopericytoma. Immunohistochemical stain was positive for CD99 and cyclin D1, and focally positive for SMA, consistent with histopathologic diagnosis. Patient required prolonged inpatient rehabilitation to recover independent ambulation. Discussion: Sinonasal glomangiopericytoma (SNGP) is a mesenchymal tumor that accounts for &amp;lt;0.5% of all nasal and sinus tumors. TIO due to SNGP is extremely rare, with only a few cases reported since the 1990s. As seen with our patient, TIO from SNGP rarely presents with sinonasal symptoms, and can often be overlooked. Our patient hadb significant progression of disease and disability due to numerous delays in diagnosis and management. Definitive cure for TIO can be achieved with complete surgical resection of the tumor, but failure to diagnose in a timely manner can result in decline in quality of life. Our takeaway from this case is that providers should obtain FGF23 levels, especially in the setting of hypophosphatemia and phosphaturia, to complete the work up for osteomalacia. Presentation: 6/1/2024

8400 An Unusual Case of Brittle Bone Disease

Abstract Disclosure: S.M. Middleton: None. M. Mogri: None. Introduction: We present the case of a now 21-month-old F with prenatally suspected skeletal dysplasia; subsequent evaluation revealed concern for a form of brittle bone disease that has not been previously described. Clinical Case: The patient was delivered at 37.0 weeks gestational age via C-section. There had been prior prenatal concerns for a possible skeletal dysplasia. A skeletal survey done on day-of-life 2 noted generalized demineralization of her bones, shortening/bowing of the long bones, an acute right proximal ulnar fracture, and evidence of multiple discontinuous healed rib fractures. A repeat skeletal survey done at day-of-life 19 demonstrated worsening skeletal findings with a very poorly mineralized skull, shortening of the clavicles and extremities, progressive fractures in all extremities and further bowing of the limbs, progressive rib fractures with callus formation, and multiple vertebral bodies with stature loss concerning for compression fractures. Directed genetic testing for osteogenesis imperfecta was negative, so whole exome sequencing was pursued and identified variants of unknown significance in the KAT6B and WDR35 genes not previously described, noting that the patient was heterozygous for both. She was suspected to be a carrier for the WDR35 mutation as it is inherited in an autosomal recessive fashion, and parental genetic testing revealed that the patient’s father carried the same KAT6B mutation and was phenotypically normal. Mutations in these genes have been described in disorders associated with bone abnormalities (such as genitopatellar syndrome and cranioectodermal dysplasia 2), but with different clinical presentations. During the course of her care, she was also identified to have hypophosphatemia shortly after birth and concerns for phosphate wasting; she was noted to have a high fractional excretion of phosphate in the setting of low serum phosphorus despite enteral phosphorus supplementation. She additionally was found to have an elevated FGF23 level at the same time the suspected renal phosphate wasting was identified. Her total calcium has remained normal with normal PTH values; her 25-OH vitamin D has also been normal. She has subsequently been successfully managed on sodium phosphate and calcitriol supplementation, as well as regular zolendronate infusions, without recurrence of fractures, and is clinically doing well with improvements in her respiratory status and overall development. Conclusion: This patient illustrates a severe case of brittle bone disease that presently does not have a clear etiology, though could represent a novel genetic mutation that has not been described and could subsequently be identified with continued review of her genetic testing in the future. Reporting her case could be beneficial to other patients with similar skeletal disease in helping to identify an underlying cause. Presentation: 6/3/2024

6463 A Case of Tumour-Induced Osteomalacia Which Remitted After Treatment of Metastatic Prostate Cancer

Abstract Disclosure: J. Chua: None. M. Chuah: None. A case Tumour-induced osteomalacia (TIO) which remitted after treatment of metastatic prostate cancer. Dr Chua Jia Min, Dr Matthew Chuah Bingfeng Abstract Case report: A 69-year-old gentleman with a known history of bladder cancer presented to the emergency department with fatigue, lower back pain and bilateral lower limb weakness worsening over the past one month. MRI and bone scan revealed extensive osteoblastic bone metastases across the skeletal system. This gentleman was referred to the Endocrinology service for the evaluation of high PTH. His corrected calcium was normal at 2.17mmol/L (2.09-2.46mmol/L) and iPTH was raised at 8.74pmol/L (1.60-6.90pmol/L). He was noted to have severe hypophosphatemia 0.34mmol/L (0.94-1.50mmol/L). Bicarbonate levels were normal, there was no glycosuria or proteinuria. There was no history of IV ferrous carboxymaltose use. Further investigations were consistent with urinary phosphate loss - TRP was 0.398 and TMP-GFR was 0.199. ALP was elevated at 282ug/L (39-99ug/L). 25-hydroxyvitamin D was low at 12 ug/L, which accounted for the high PTH levels (secondary hyperparathyroidism). FGF-23 levels returned high at 1293 RU/ml (&amp;lt;180 RU/ml). BMD showed osteoporosis with T-score of -2.6 at the left femoral neck. He was subsequently diagnosed with metastatic prostate adenocarcinoma, based on histology from a bone biopsy of an affected vertebrae. PSA was markedly raised at 606ug/L. A diagnosis of TIO secondary to metastatic prostate cancer was made. The patient was started on PO sodium-phosphate solution 4ml TDS (approximately 3mmol/kg/day of elemental phosphorus), calcitriol 0.25mcg BD and vitamin D was replaced. After phosphate was replete, the patient's weakness and fatigue improved. He was subsequently started on androgen deprivation therapy with leuprorelin acetate injection once every 3 months and apalutamide daily. SC denosumab 60mg Q6monthly was also commenced in view of extensive bone metastases. Repeat imaging showed response to treatment with decrease in the size of the prostate and bone lesions. His PSA levels are now undetectable and TMP-GFR has normalised. His oral phosphate and calcitriol doses were gradually reduced and subsequently stopped. His calcium and phosphate levels remain within normal limits on no supplementation, suggesting remission of his TIO. PTH levels normalised after vitamin D repletion. Learning points TIO is a rare paraneoplastic syndrome usually associated with mesenchymal tumours, and treatment involves resection of the causative tumour. Cases of TIO secondary to prostate cancer (an epithelial cancer) are exceedingly rare. Despite metastatic disease, this patient responded exceedingly well to his cancer therapy. Suppression of the tumour cells with androgen deprivation therapy resulted in the lack of phosphotonin production and remission of his TIO. Presentation: 6/1/2024

An inducible model for medial calcification based on matrix Gla protein deficiency

Calcific deposits in the arterial media have been associated with a number of metabolic and genetic disorders including diabetes, chronic kidney disease and generalized arterial calcification of infancy. The loss of Matrix Gla protein (MGP) leads to medial elastic lamina calcification (elastocalcinosis) in both humans and animal models. While MGP-deficient (Mgp-/-) mice have been used as a reliable model to study medial elastocalcinosis, these mice are difficult to maintain because of their fragility. Also, these mice are unsuitable for long-term calcification studies in relation to age and sex as most often they die prematurely. In order to circumvent these problems we generated Mgp-/-;ApoE-FGF23 mice, which in addition to the ablation of Mgp alleles, carries a transgene expressing the phosphaturic hormone FGF23. Increased FGF23 levels in the circulation and ensuing hypophosphatemia in these mice lead to a complete prevention of medial calcification until late adulthood. Interestingly, upon feeding a high phosphorus diet for 10 days, we were able to induce medial calcification in 3-week-old Mgp-/-;ApoE-FGF23 mice. Our mineral analyses showed that the calcific deposits in these mice were Our mineral analyses showed that the Ca/P % in the calcific deposits in these mice were comparable to that of 5-week-old Mgp-/- mice although the level of crystallinity differed. The aorta explants from Mgp-/-;ApoE-FGF23 mice resulted in elastocalcinosis in the presence of 2mM phosphate in the culture medium which was completely prevented by pyrophosphate analogue alendronate. Mgp-/-;ApoE-FGF23 mice will be suitable for future in vivo or ex vivo studies examining the effects of age, sex and mineralization inhibitors on medial elastocalcinosis.

Association of FGF23 Levels and Development of Anemia in Patients with Non Dialysis Chronic Kidney Disease

Background: Anemia is one of the common complication of Chronic Kidney Disease that intensifies in grade and severity as eGFR decline which also increases the risks for cardiovascular mortality. The development of anemia and elevated fibroblast growth factor 23 levels are the earliest changes observed in chronic kidney disease. Objective: This study aims to understand the association of FGF23 levels development of anemia in chronic kidney disease patients prior to renal replacement therapy. Methods: This is an analytical type of cross sectional study carried out among 95 respondent'1ged between 18 and 75 years with CKD stage 1-5 before dialysis, divided into two groups- Group I­ comprised of 68 patients and Group 11- included 27 age and sex matched respondents not having CKD, enrolled from two te1tiary-care hospitals, namely- Sir Salimullah Medical College &amp; Mitford Hospital and National Institute of Kidney Diseases &amp; Urology (NIKDU). Socio-demographic status, disease profile and laboratory findings including serum iron, iron binding capacity, ferritin, transferrin saturation, calcium, phosphorus, intact parathormone, vitamin D, eGFR and FGF-23 levels were studied. Result: Mean age of the respondents was 50.1±10.74 (SD) years, mean estimated glomerular filtration rate was 35.92± 22.61 in group I and 91.66± 14.2 in group II. The mean FGF23 level in group I and II were 85.76± 207.54, 21.99± 12.12 pg/mL respectively, serum iron level was 81.61± 39.24 mcg/dL and 95.0± 32.38 mcg/dL in group I and II respectively, serum ferritin level was 225.59± 2 I 2.5 ng/mL and 157.85± 220.89 ng/ml. TIBC was 312.65± 95.83 mcg/dL and 418.85± 118.25 mcg/dL in group I and II respectively. In Group I and II, iron deficiency was found in 23% and 25%respectively when stratified according to serum ferritin level and 26.5% and 22.22% respectively, when stratified according to serum transferrin saturation level. This difference was significant among the group. Serum iron, ferritin, TIBC and TSAT were significantly associated with serum FGF23 levels. Conclusion: Disrupted iron metabolism and high FGF23 levels is commonly found in chronic kidney disease. Clinical laboratory findings have revealed the relation between FGF23 and anemia in no dialysis chronic kidney disease patients.

α-Klotho is associated with cardiovascular and all-cause mortality in patients with stage3band 4 chronic kidney disease(CKD): a long-term prospective cohort study.

α-Klotho deficiency may increase cardiovascular risks and worsen survival. We evaluated the association of α-Klotho with cardiovascular and all-cause mortality in pre-dialysis chronic kidney disease (CKD) patients. In this prospective study, 75 non-diabetic CKD stage 3b-4 patients werefollowed-up for a median of 8years. Primary and secondary outcomes were all-cause and cardiovascular mortality, respectively. Human soluble α-Klotho ELISA Assay (IBL-Takara 27,998-96Well), Human Fibroblast Growth Factor-23 ELISA Assay (intact FGF23, Merck Millipore MILLENZ FGF23-32K), and Human Sclerostin ELISA kits (Biomedica, Vienna, BI-20492) were used to measure serum α-Klotho, FGF23 and sclerostin levels in the certified laboratory at the Sechenov University according to the manufacturers' protocols.All patients underwent echocardiography to evaluate left ventricular mass index (LVMI), left ventricular ejection fraction by Simpson method, and cardiac (valve) calcification score by a semi-quantitative point scale. Lateral abdominal radiography by Kauppila method was used to estimate calcificationof the abdominal aorta.Cox multivariate regression and receiver-operating characteristic curve (ROC)-analysis were used to evaluate risk factors for death and their cut-off values. Primary and secondary endpoints were reached in 15 (20%) and 9 (12%) patients, respectively. Median α-Klotho levels in deceased and surviving patients were 344 and 484pg/ml, respectively (p = 0.002). In a multivariate Cox regression model, baseline α-Klotho levels (HR 0.99, 95% CI 0.98-1.00, p = 0.023), aortic calcification (HR 1.18, 95% CI 1.02-1.36, p = 0.029) and left ventricular mass index (LVMI) (HR 1.04, 95% CI 1.00-1.08, p = 0.033) were associated with the primary endpoint, whereas α-Klotho (HR 0.99, 95% CI 0.98-1.00, p = 0.029), aortic calcification (HR 1.23, 95% CI 1.07-1.42, p = 0.003) and LVMI (HR 1.04, 95% CI 1.00-1.08, p = 0.021) were associated with the secondary endpoint. α-Klotho levels had the highest area under the curve (AUC)by ROC analysis, that is, 0.766 (95% CI 0.70-0.82) for the primary endpoint and 0.842 (95% CI 0.79-0.90) for the secondary endpoint with cut-off values of 412pg/ml (HR 3.06, 95% CI 1.36-6.89, p = 0.007) and 368pg/ml (HR 4.84, 95% CI 1.59-14.73, p = 0.005), respectively. In pre-dialysis CKD patients, α-Klotho levels areassociated with all-cause and cardiovascular mortality and may be considered an early prognostic marker.

Autosomal recessive hypophosphatemic rickets type 2 due to ENPP1 deficiency (ARHR2)

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2; MIM #613312) is a very rare disorder caused by biallelic loss-of-function mutations in the ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) gene. ENPP1 deficiency encompasses a spectrum of phenotypes that includes, in addition to ARHR2, generalized arterial calcification of infancy (GACI), ossification of the posterior longitudinal ligament (OPLL), and pseudoxanthoma elasticum. ARHR2 can be found in GACI survivors, but it may also be the first manifestation of ENPP1 deficiency. Although the precise mechanisms are not fully elucidated, patients with GACI and ARHR2 have elevated serum FGF23 levels, leading to renal phosphate wasting and hypophosphatemia. As a result, the clinical and radiological phenotype of ARHR2 patients is very similar to that of patients affected with other forms of hypophosphatemic rickets, such as X-linked hypophosphatemia. Patients show signs of rickets (abnormal mineralization of growth plates in children) and osteomalacia (abnormal bone mineralization in children and adults) of varying severity. Clinical manifestations specific to ENPP1 loss-of-function mutations and common to GACI, such as ectopic calcifications (valvular, arterial, or periarticular), deafness, OPLL, and PXE, may also be found. Genetic confirmation of the disease is important so as to ensure that patients receive the appropriate treatment or have the opportunity to participate in clinical trials to evaluate the safety and efficacy of novel and promising recombinant enzyme therapies.

The Role of Daily Dialysate Calcium Exposure in Phosphaturic Hormones in Dialysis Patients.

Managing mineral bone disease (MBD) could reduce cardiovascular risk and improve the survival of dialysis patients. Our study focuses on the impact of calcium bath exposure in dialysis patients by comparing peritoneal dialysis patients (PD, intervention group) and hemodialysis patients (HD, control group). We assessed various factors, including calcium, phosphorus, magnesium, PTH, vitamin D 25-OH, C-terminal telopeptide (CTX), and FGF-23 levels, as well as the calcium bath six hours before the blood sample and the length of daily calcium exposure. We enrolled 40 PD and 31 HD patients with a mean age of 68.7 ± 13.6 years. Our cohort had median PTH and FGF-23 levels of 194 ng/L (Interquartile range [IQR] 130-316) and 1296 pg/mL (IQR 396-2698), respectively. We identified the length of exposure to a 1.25 mmol/L calcium bath, phosphate levels, and CTX as independent predictors of PTH (OR 0.279, p = 0.011; OR 0.277, p = 0.012; OR 0.11, p = 0.01, respectively). In contrast, independent predictors of FGF-23 were phosphate levels (OR 0.48, p < 0.001) and serum calcium levels (OR 0.25, p = 0.015), which were affected by the calcium bath. These findings suggest that managing dialysate calcium baths impacts phosphaturic hormones and could be a critical factor in optimizing CKD-MBD treatment in PD patients, sparking a new avenue of research and potential interventions.

MiRNAs and indicators of mineral metabolism in the population of dialysis patients

Introduction. Cardiovascular events are the leading cause of death in patients on renal replacement dialysis therapy. The vast majority of patients with CKD 5D have left ventricular hypertrophy (LVH), which is a predisposing factor to diastolic dysfunction, heart failure (HF), arrhythmias, and sudden cardiac death. In recent years, a significant role in the development of cardiovascular pathology in CKD has been attributed to disturbances in calcium and phosphorus homeostasis. Mineral bone correction may have a beneficial effect on LVH.Aim. To evaluate the associations between indices of mineral-bone metabolism and cardiac echocardiography parameters in patients on renal replacement therapy (RRT) with hemo- and peritoneal dialysis, receiving and not receiving phosphate binders.Materials and methods. The study included 75 patients, of whom 53 received treatment with program hemodialysis (HD), 22 with peritoneal dialysis (PD). The control group consisted of 28 healthy volunteers. 43 patients were treated with phosphate binders. Of all patients receiving treatment aimed at correcting hyperphosphatemia, 22 received sevelamer carbonate: 86% of patients took sevelamer carbonate at a dose of 4800 mg/day and 14% at a dose of 2400 mg/day. All biochemical parameters were determined on an automatic biochemical analyzer; FGF-23 was also determined by enzyme-linked immunosorbent assay (ELISA) and the level of intact PTH was determined by chemiluminescence immunoassay. Instrumental studies included echocardiography.Results. In patients with left ventricular hypertrophy (LVMM in the group of patients on hemodialysis 206.6 [120.0; 300.0], in the group on peritoneal dialysis 176.2 [134.0; 204.0]) the level of FGF-23 was significantly increased (p = 0.005). In the group of patients receiving sevelamer carbonate, there was a decrease in the incidence of left ventricular hypertrophy, lower levels of FGF-23 (12.4 ± 5.9), in contrast to the group that did not receive this drug (23 ± 7.3; p = 0.003 ) and PTH (110 ± 27 ng/ml, in the group that did not receive the drug – 340 ± 15; p = 0.01).Conclusions. The use of phosphate binders, in particular sevelamer carbonate, is associated with a decrease in left ventricular hypertrophy and lower levels of FGF-23.

Association between serum magnesium levels and cognitive function in patients undergoing hemodialysis.

The relationship between chronic kidney disease-mineral and bone disorder (CKD-MBD) and cognitive function remains largely unknown. This cross-sectional study aimed to explore the association between CKD-MBD and cognitive function in patients on hemodialysis. Hemodialysis patients aged ≥ 65years without diagnosed dementia were included. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). CKD-MBD markers, serum magnesium, intact parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OHD), fibroblast growth factor (FGF)-23, and soluble α-klotho were measured. Overall, 390 patients with a median age of 74 (interquartile range, 70-80) years, mean serum magnesium level of 2.4 ± 0.3mg/dL, and median MoCA and MMSE scores of 25 (22-26) and 28 (26-29), respectively, were analyzed. MoCA and MMSE scores were significantly higher (preserved cognitive function) in the high-magnesium group than in the low-magnesium group according to the unadjusted linear regression analysis (β coefficient [95% confidence interval (CI)] 1.05 [0.19, 1.92], P = 0.017 for MoCA; 1.2 [0.46, 1.94], P = 0.002 for MMSE) and adjusted multivariate analysis with risk factors for dementia (β coefficient [95% CI] 1.12 [0.22, 2.02], P = 0.015 for MoCA; 0.92 [0.19, 1.65], P = 0.014 for MMSE). Higher serum magnesium levels might be associated with preserved cognitive function in hemodialysis patients. Conversely, significant associations were not observed between cognitive function and intact PTH, 25-OHD, FGF-23, or soluble α-klotho levels.

Long-Term Follow-Up Data of Tumor-Induced Osteomalacia Managed with Surgery and/or Radiofrequency Ablation from a Single Center.

Data on radiofrequency ablation (RFA) in tumor-induced osteomalacia (TIO) are restricted to case reports (~ 11 patients) and long-term follow-up data are further scarce. We describe our experience on managing TIO from a tertiary care center in India. Retrospective study of patients with localized TIO was performed and clinical, biochemical, treatment and follow-up details were retrieved. Normalization of serum phosphorus in absence of phosphate supplementation was defined as remission. Of 33 patients (23 males), 24 patients underwent surgery as first-line treatment, and early remission, delayed remission (> 1month for phosphorus normalization) and persistence were observed 12, 3, and 9 patients at a median follow-up of 5 (4-9) years. The gender, age, tumor size, location of tumors and FGF23 levels were not statistically different in patients who were in remission after surgery versus those with persistent disease. Second/third line treatment included conventional medical treatment and/or repeat surgery (n = 3), radiotherapy (n = 3), peptide receptor radionuclide therapy (n = 1), RFA (n = 1). Two patients had transient worsening (weeks) of weakness post-surgery. 10 patients underwent RFA (first-line n = 9); at the last follow-up 5 (4-10) years, 7 are in remission. Two of three persistent disease patients had large tumors (5.6 and 3.6cm). There were no RFA-related complications except local ulcer in one. Although persistent disease was present in a few patients in both arms, there was no recurrence in either RFA or surgical cohort. RFA provide durable response similar to surgery, persistence requires multi-modality treatment.

PTH like substance secreting mesenchymal tumor causing oncogenic osteomalacia; unravelling the difficulties in localization – A report of 2 cases

BackgroundOncogenic osteomalacia is a rare paraneoplastic association of Phosphaturic mesenchymal tumor (PMT) secreting excessive levels of a PTH like substance. They usually remain undiagnosed and patients suffer for years. The rarity of this tumor and its non-specific clinical presentations poses great challenge to the treating surgeons. Its management is poorly described in literature. We report two of such rare cases without much diagnostic delay. Case reportWe had 2 cases; A 53-year-old south east Asian male with 6 months of debilitating pain over multiple sites, and another 44-year-old male patient with complaints of low back ache, and pain over both lower and upper limbs for 1.5 years. Both had low serum phosphorus and elevated FGF-23 values, but all other parameters were normal. A PMT was suspected and confirmed on a Ga68- DOTATOC scan in both cases, and on complete excision, their symptoms and the altered blood parameters got normalized. Histology was consistent with PMT. ConclusionAccurate and timely diagnosis of a PMT with non-specific features are extremely challenging, but not without solutions. Even though a tumor of rarity, with the appropriate imaging modalities like Ga68- DOTATOC scan, and estimation of FGF-23 and serum phosphorus levels, they can be diagnosed. Once identified, complete removal is often curative within a few months.

Bone marrow transplantation reduces FGF-23 levels and restores bone formation in myelodysplastic neoplasms

Bone marrow transplantation reduces FGF-23 levels and restores bone formation in myelodysplastic neoplasms

Establishing a Reference Interval for Fibroblast Growth Factor (FGF)-23 in Cats.

Fibroblast growth factor (FGF)-23 is a phosphaturic hormone. An association between increasing FGF-23 levels and progression of chronic kidney disease (CKD) was documented in cats, dogs, and humans. The information regarding reference intervals (RIs) of FGF-23 in cats is limited. We aimed to establish RIs in a large cohort of clinically healthy cats and to investigate correlations with sex and age. A total of 118 cats with unremarkable complete blood count and serum chemistry profile were included. Clinically sick cats, cats with concurrent diseases, suspicion of CKD, or receiving renal diets were excluded. FGF-23 concentrations were measured with the FGF-23 ELISA Kit. RIs were calculated using the reference interval advisor software 2.1 (Microsoft Excel). FGF-23 concentrations were correlated with sex and age. The RI for FGF-23 concentrations spanned 85.8 to 387.0 pg/mL (90% confidence interval: lower limit 40.5 to 103.9 pg/mL, upper limit: 354.6 to 425.0 pg/mL). No significant relationships (r2 = 0.044) were detected with age (p = 0.081) or sex (p = 0.191). Other studies of the same diagnostic assay calculated RIs of 56 to 700 pg/mL in 79 cats and <336 pg/mL in 108 cats, and in concordance with the present study, did not detect any correlation with sex or age.

Short-term effects of dapagliflozin on biomarkers of bone and mineral metabolism in patients with diabetic kidney disease: A prospective observational study

BackgroundThere is still a lack of information regarding the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on bone and mineral metabolism in patients with diabetes and chronic kidney disease (CKD). Therefore, we aimed to investigate the effects of SGLT2i in a cohort of patients suffering from diabetic kidney disease (DKD). MethodsIn this prospective observational study, patients with type 2 diabetes and biopsy-proven diabetic nephropathy or presumptive DKD with eGFR levels ≥20 ml/min/1.73m2 and 25-OH vitamin D levels ≥20 ng/dl were included. 41 used SGLT2i (study group) and 39 continued their current treatment regimens (control group). Serum FGF-23, sclerostin, osteoprotegerin (OPG), and hydroxyproline levels were measured at baseline, 1 month and 3 months after treatment. ResultsMean age of all patients was 67±9.3 years, and 48 (60%) were female. All patients in the study group used dapagliflozin. Taking into account the renal functions at the commencement of the study, the eGFR values for the study group and the control group were 51.2±15.6 and 44.6±16.9ml/min/1.73m2, respectively (p=0.01). After three months, these values were observed to be 47.4±16.7 and 44.3±18.8 ml/min/1.73m2 (p=0.43), respectively. At baseline, OPG levels were higher in the study group (p=0.025) but there were no differences between the groups in terms of FGF-23 and sclerostin levels (p=0.670 and p=0.467, respectively). Levels of OPG, FGF-23, and sclerostin significantly decreased throughout 3 months of treatment with dapagliflozin (p<0.001 for all). Hydroxyproline levels also declined but did not reach to statistical significance (p=0.075). Multiple linear regression models revealed that treatment with SGLT2i was associated with the change in levels of sclerostin (β=0.303, p=0.011) and OPG (β=0.210, p=0.010), but not with FGF-23 (β=0.089, p=0.150). ConclusionsFGF-23, sclerostin and OPG levels significantly declined after treatment with dapagliflozin for 3 months.

#1610 FGF23-mediated hypertension via augmented calcium entry in vascular smooth muscle cells

Abstract Background and Objectives Ongoing studies are shedding light on the potential connection between FGF23 and hypertension. In experimental settings, the administration of recombinant FGF23 in mice has been demonstrated to induce hypertension by elevating serum sodium, along with an increase in NCC receptors in the kidney. Clinical evidences further supports pro-hypertensive effects of high circulating levels of FGF23. Our group has previously demonstrated a direct influence of FGF23 on increased arterial stiffness by inducing a phenotypic transition in vascular smooth muscle cells (VSMCs) from a contractile to a synthetic phenotype. This study aimed comprehensively to evaluate, both in vivo and in vitro, whether FGF23 directly leads to hypertension through the stimulation of intracellular calcium entry in vascular cells. Methods To ascertain whether FGF23 contributes to hypertension through a direct impact on blood vessels, recombinant FGF23 (15 µg/day) was administered for 28 days via Alzet pumps. Blood pressure was meticulously measured in these animals, and we investigated alterations in vascular remodeling and calcium channels, as well as proteins associated with vascular contraction such as Orai1, STIM1, PKD1, SERCA2a, and AGTR1. In vitro experiments included the evaluation of the effect of elevated levels of recombinant FGF23 (2 ng/ml) over 9 days on intracellular calcium entry stimulated by Ang2 (100 nM) or Thapsigargin (2.5 µM). We used the FURA method to conduct these experiments. To elucidate the in vitro pro-hypertensive mechanisms of FGF23, studies were conducted with the administration of inhibitors targeting FGF Receptors 1-3 (AZD4547, 150 nM), FGF Receptor-4 (BLU9931, 10 nM), and Erk1/2 phosphorylation (PD98059, 10 μM). Additionally, changes in Orai1, STIM1, PKD1, SERCA2a, and AGTR1 were also evaluated in these VSMCs. Results After 28 days of recombinant FGF23 treatment, no significant differences were observed in serum sodium levels, yet there was a marked increase in urinary phosphorus excretion. Systolic and diastolic blood pressure values showed a progressive significant elevation in animals exposed to high levels of FGF23. The expression of AGTR1 and PKD1 levels significantly increased after FGF23 administration for 28 days (Figure). However, Orai1 and STIM1 in the thoracic aorta exhibited no significant differences following FGF23 treatment. In VSMCs, the exposure to recombinant FGF23 for 9 days resulted in increased calcium entry upon Ang2 stimulation (Figure). This effect was markedly diminished after inhibiting FGFR1-3 receptors and Erk1/2 phosphorylation (Figure). Notably, the inhibition of FGF23 receptor 4 (FGFR4) had no impact on the calcium entry induced by FGF23 (Figure). While Orai1, STIM1, IP3R, and TRPV5 in VSMCs remained unaffected by recombinant FGF23 administration, PKD1, SERCA2, and AGTR1 levels were significantly elevated compared to control cells (Figure). The addition of Thapsigargin in a Ca2+-free culture medium to VSMCs incubated with recombinant FGF23 for 9 days led to increased Ca2+ efflux from endoplasmic reticulum. Conclusion Elevated levels of FGF23 directly enhanced calcium entry in VSMCs. This effect is mediated by FGFR1-3 receptors, Erk1/2 phosphorylation, and the upregulation of related protein to cell contraction such as SERCA2a, PKD1 or AGTR1. These modifications could be responsible of FGF23-associated hypertension in the experimental model.