Fibroblast Growth Factor 23 Measurements Research Articles

Recent advances in fibroblast growth factor 23-related hypophosphatemic disorders.

Fibroblast growth factor 23 (FGF23) is a hormone to reduce blood phosphate concentration. Excessive actions of FGF23 induce FGF23-related hypophosphatemic disorders, such as X-linked hypophosphatemic rickets (XLH) and tumor-induced osteomalacia (TIO). We will summarize recent advances in the diagnosis and treatment of FGF23-related hypophosphatemic disorders. The measurement of blood FGF23 is useful to make a diagnosis of FGF23-related hypophosphatemic disorders. It was reported that many patients with FGF23-related hypophosphatemic disorders, especially TIO, were misdiagnosed, therefore, it is necessary to enhance the awareness of these diseases. A novel method to inhibit excessive actions of FGF23 by a human monoclonal antibody for FGF23, burosumab, has been approved in several countries. In more long-term observation than clinical trials, burosumab has also been shown to improve biochemical abnormalities and symptoms of rickets/osteomalacia. Following these advances, several registries and consensus recommendations on FGF23-related hypophosphatemic disorders, especially XLH, have been established in each country or region. Further long-term effects of burosumab and the precise mechanism of FGF23 overproduction in patients with FGF23-related hypophosphatemic disorders need to be clarified in the future studies.

Relationship between fibroblast growth factor in plasma and carotid plaque neovascularization: a pilot study.

Unstable atherosclerotic carotid plaques with intraplaque neovascularization (IPN) carry a substantial risk for ischemic stroke. Conventional ultrasound methods fall short in detecting IPN, where superb microvascular imaging (SMI) has emerged as a promising tool for both visualizing and quantification. High levels of fibroblast growth factor 23 (FGF-23) have, in observational studies, been suggested as related to cardiovascular morbidity and mortality. The association of FGF-23 to atherosclerotic carotid plaque instability remains relatively unexplored. A cohort of twenty-nine patients with ≥50% atherosclerotic carotid stenosis underwent conventional carotid ultrasound, SMI, and blood tests, including measurement of FGF-23 in plasma. Nineteen patients were characterized as symptomatic and ten as asymptomatic. Our major findings were: i) Higher FGF-23 levels were strongly correlated with increased SMI-assessed IPN. ii) Neo-vessel count recorded by quantitative SMI was positively correlated to increased FGF-23 levels, but not with basic FGF levels. (iii) In contrast, traditional risk factors for plaque instability exhibited no noteworthy associations with SMI-assessed IPN or with FGF-23 levels. This pilot study suggest the potential of FGF-23 as a valuable marker for neovascularization and atherosclerotic carotid plaque instability as a risk factor for ischemic stroke. Further research involving larger cohorts and prospective data is necessary to understand FGF-23's role in this context comprehensively.

Time-updated Fibroblast Growth Factor 23 Is Predictive for Posttransplant Diabetes Mellitus in Kidney Transplant Recipients.

This work aimed to study whether fibroblast growth factor 23 (FGF23) is predictive for incident posttransplant diabetes mellitus (PTDM) in kidney transplant recipients (KTRs). We repeatedly analyzed plasma C-terminal FGF23 concentrations in 170 KTRs enrolled in the TransplantLines Biobank and Cohort Study. Associations of time-updated plasma FGF23 with incident PTDM were studied by Cox regression. A total of 170 KTRs (46% female, aged 54.4 ± 12.4 years) with 540 FGF23 measurements were included. Plasma FGF23 concentrations at transplantation were 31.1 (0.76-2576) pmol/L. During a follow-up of 24 (12-24) months, 38 patients developed PTDM. The highest FGF23 tertile (compared to the lowest) was associated with an increased risk for PTDM (fully adjusted hazard ratio 20.9; 95% CI, 3.4-130.0; P < .001). In KTRs without diabetes at baseline, the highest tertile of FGF23, compared to the lowest, is predictive for development of PTDM.

Commentary on Severe Hypophosphatemia: The Hidden Truth.

Abnormal phosphate results are common in daily practice, but often neglected by laboratorians and clinicians. This case of severe hypophosphatemia highlights the critical implications that a delayed diagnostic workup of the underlying cause can have. Early diagnosis and treatment could have prevented years of continuous bone loss and immobility. Therefore, severe hypophosphatemia should always trigger additional investigations to find the underlying cause. Determination of the tubular maximum reabsorption of phosphate for glomerular filtration rate was pivotal for establishing renal phosphate wasting and for guiding further diagnostic measures. This rarely used parameter can easily be determined in most laboratories, but pathologists are often unaware of its diagnostic value. Consequently, many laboratories limit themselves to the measurement of timed urinary phosphate excretion, despite the fact that a wide reference interval limits its diagnostic utility. In adult patients with renal phosphate wasting, measurement of fibroblast growth factor-23 (FGF-23) helps to further narrow the spectrum of potential causes. Elevated FGF-23 concentrations are typical in tumor-induced osteomalacia, but normal values can occur when the underlying tumor secretes other phosphatonins or in the presence of interfering heterophile antibodies or human antimouse antibodies that disturb the assay (1).

Factors associated with 1-year changes in serum fibroblast growth factor 23 levels in pediatric patients with chronic kidney disease.

Fibroblast growth factor 23 (FGF23) levels increase as kidney function decreases and are associated with increased mortality in patients with chronic kidney disease (CKD). Inflammation has also been shown to increase FGF23 production in adults; however, this has not been validated in pediatric patients with CKD. Furthermore, previous studies on children involved a single measurement of FGF23 without a follow-up, and a few studies have examined changes in FGF23 levels. We measured the levels of serum intact FGF23, tumor necrosis factor-α (TNF-α), and interleukin-6 as parameters of inflammation and other variables related to bone metabolism at baseline and after 1year in 62 pediatric patients with CKD (stages 2-5D, 1-16years old). Factors related to changes in FGF23 levels were investigated. The median age of patients at the evaluation was 10.5years (interquartile range 6.0-14.0), and the estimated glomerular filtration rate (eGFR) was 59.0mL/min/1.73 m2 (45.1-69.3). Primary diseases included congenital anomalies of the kidney and urinary tract, ischemic kidney, and glomerulonephritis. The baseline value of FGF23 was 66.5pg/mL (48.3-96.4), and percent change in FGF23 levels after 1year was 8.5% (-29.9-74.7). The percent change in FGF23 levels showed a negative correlation with that in eGFR (P = 0.010), and a positive correlation with that in TNF-α levels (P = 0.035). A multivariate linear regression analysis identified TNF-α as an independent factor increasing FGF23 levels. An increase in TNF-α levels is associated with elevation of FGF23 levels in pediatric patients with CKD.

Longitude Variation of the microRNA-497/FGF-23 Axis during Treatment and Its Linkage with Neoadjuvant/Adjuvant Trastuzumab-Induced Cardiotoxicity in HER2-Positive Breast Cancer Patients.

PurposeMicroRNA-497 (miR-497) is previously reported to target fibroblast growth factor 23 (FGF-23) and regulates cardiac injury, while their value in predicting drug-induced cardiotoxicity is not reported. Thus, the current study aimed to investigate the correlation of miR-497/FGF-23 with neoadjuvant/adjuvant trastuzumab-induced cardiotoxicity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients.MethodsA total of 97 HER2-positive surgical breast cancer patients who received neoadjuvant/adjuvant trastuzumab contained regimens were enrolled; then, their peripheral blood mononuclear cells (PBMC) and serum were collected at baseline, after neoadjuvant treatment, at 3 months (M3), 6 months (M6), 9 months (M9), and 12 months (M12) after surgery. The PBMC was used for miR-497 measurements, and the serum was used for FGF-23 measurements. The cardiotoxicity events and incidence were recorded.ResultsA total of 24 (24.7%) patients occurred cardiotoxicity during the treatment period. MiR-497 decreased from baseline (median: 0.955) to M12 after surgery (median: 0.602) (p < 0.001), while FGF-23 increased from baseline (median: 0.390 ng/mL) to M12 after surgery (median: 0.566 ng/mL) (p < 0.001); besides, the miR-497/FGF-23 axis greatly reduced from baseline (median: 2.545) to M12 after surgery (median: 1.222) (p < 0.001). At most time points, miR-497 was negatively related to FGF-23 (all p < 0.05). Notably, the miR-497/FGF-23 axis at all time points (including baseline, postneoadjuvant treatment, M3, M6, M9, and M12) was related to a lower risk of cardiotoxicity (all p < 0.05). Furthermore, the miR-497/FGF-23 axis was also positively correlated with the left ventricular ejection fraction (LVEF) at all time points (all p < 0.01).ConclusionThe MiR-497/FGF-23 axis serves as a potential indicator predicting trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients.

Changes in Serum Intact Fibroblast Growth Factor 23 Concentrations From Midlife to Late Life and Their Predictors in the Community: The ARIC Study.

ObjectiveTo investigate longitudinal changes in the blood concentration of fibroblast growth factor 23 (FGF23) from midlife to late life and their major predictors in the general population.Patients and MethodsIn 14,444 participants of the Atherosclerosis Risk in Communities Study, we analyzed the association of 31,095 measurements of serum intact FGF23 with age using data from 3 visits (visit 2 [N=13,460; mean age, 57 years]; visit 3 [N=12,323; mean age, 60 years]; and visit 5 [N=6122; mean age, 76 years]) and a linear mixed-effects model. Among 5804 participants who had FGF23 measurements at both visits 3 and 5, we explored predictors of FGF23 change from midlife to late life using linear regression models. Prespecified risk factors were estimated glomerular filtration rate, body mass index, ever smoking, ever drinker, diabetes, hypertension, history of cardiovascular disease, total cholesterol, and high-density lipoprotein cholesterol.ResultsMedian FGF23 concentrations were 41.9 pg/mL (interquartile interval [IQI], 33.9 to 51.8 pg/mL) at visit 2, 38.3 pg/mL (IQI, 30.6 to 48.3 pg/mL) at visit 3, and 55.0 pg/mL (IQI, 44.4 to 70.3 pg/mL) at visit 5. A linear mixed-effects model showed that the association of FGF23 with age was nonlinear, with a slight decline or no change in age 45-60 years and a monotonic increase in age greater than or equal to 65 years (FGF23, +10 to 15 pg/mL per 10 years of age). In a multivariable linear regression model, significantly greater increases in FGF23 were noted, with midlife estimated glomerular filtration rate less than 60 mL/min per 1.73 m2 vs more than or equal to 60 mL/min per 1.73 m2 (ΔFGF23, +4.4 pg/mL [95% CI, 0.9 to 8.0]), diabetes vs no diabetes (ΔFGF23, +6.2 pg/mL [95% CI, 4.1 to 8.3]), and hypertension vs no hypertension (ΔFGF23, +4.1 pg/mL [95% CI, 2.7 to 5.4]).ConclusionFGF23 did not show any major changes in midlife but increased linearly in late life. Reduced kidney function, diabetes, and hypertension were robustly associated with a greater increase in FGF23. Further investigations are needed to understand the potential mechanisms linking these conditions to an increase in FGF23 concentrations.

Advances in understanding of phosphate homeostasis and related disorders.

Inorganic phosphate (Pi) in the mammalian body is balanced by its influx and efflux through the intestines, kidneys, bones, and soft tissues, at which several sodium/Pi co-transporters mediate its active transport. Pi homeostasis is achieved through the complex counter-regulatory feedback balance between fibroblast growth factor 23 (FGF23), 1,25-dihydroxyvitamin D (1,25(OH)2D), and parathyroid hormone. FGF23, which is mainly produced by osteocytes in bone, plays a central role in Pi homeostasis and exerts its effects by binding to the FGF receptor (FGFR) and αKlotho in distant target organs. In the kidneys, the main target, FGF23 promotes the excretion of Pi and suppresses the production of 1,25(OH)2D. Deficient and excess FGF23 result in hyperphosphatemia and hypophosphatemia, respectively. FGF23-related hypophosphatemic rickets/osteomalacia include tumor-induced osteomalacia and various genetic diseases, such as X-linked hypophosphatemic rickets. Coverage by the national health insurance system in Japan for the measurement of FGF23 and the approval of burosumab, an FGF23-neutralizing antibody, have had a significant impact on the diagnosis and treatment of FGF23-related hypophosphatemic rickets/osteomalacia. Some of the molecules responsible for genetic hypophosphatemic rickets/osteomalacia are highly expressed in osteocytes and function as local regulators of FGF23 production. A number of systemic factors also regulate FGF23 levels. Although the mechanisms responsible for Pi sensing in mammals have not yet been elucidated in detail, recent studies have suggested the involvement of FGFR1. The further clarification of the mechanisms by which osteocytes detect Pi levels and regulate FGF23 production will lead to the development of better strategies to treat hyperphosphatemic and hypophosphatemic conditions.

Challenges in the management of tumor-induced osteomalacia (TIO).

Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare acquired paraneoplastic disease, which is challenging to diagnose and treat. TIO is characterized by hypophosphatemia resulting from excess levels of tumor-secreted fibroblast growth factor 23 (FGF23), one of the key physiological regulators of phosphate metabolism. Elevated FGF23 results in renal phosphate wasting and compromised vitamin D activation, ultimately resulting in osteomalacia. Patients typically present with progressive and non-specific symptoms, including bone pain, multiple pathological fractures, and progressive muscle weakness. Diagnosis is often delayed or missed due to the non-specific nature of complaints and lack of disease awareness. Additionally, the disease-causing tumour is often difficult to detect and localize because they are often small, lack localizing symptoms and signs, and dwell in widely variable anatomical locations. Measuring serum/urine phosphate should be an inherent diagnostic component when assessing otherwise unexplained osteomalacia, fractures and weakness. In cases of hypophosphatemia with inappropriate (sustained) phosphaturia and inappropriately normal or frankly low 1,25-dihydroxy vitamin D, differentiation of the potential causes of renal phosphate wasting should include measurement of FGF23, and TIO should be considered. While patients experience severe disability without treatment, complete excision of the tumour is typically curative and results in a dramatic reversal of symptoms. Two additional key current unmet needs in optimizing TIO management are: (1 and 2) the considerable delay in diagnosis and consequent delay between the onset of symptoms and surgical resection; and (2) alternative management. These may be addressed by raising awareness of TIO, and taking into consideration the accessibility and variability of different healthcare infrastructures. By recognizing the challenges associated with the diagnosis and treatment of TIO and by applying a stepwise approach with clear clinical practice guidelines, patient care and outcomes will be improved in the future.

Clinical performance of a novel chemiluminescent enzyme immunoassay for FGF23.

Measurement of fibroblast growth factor 23 (FGF23) has been reported to be clinically useful for the differential diagnosis of chronic hypophosphatemia. However, assays for research use only are available in Japan. Thus, the objective of this study was to examine the clinical utility of a novel and automated chemiluminescent enzyme immunoassay for the measurement of FGF23. Participants were recruited from July 2015 to January 2017 at six facilities in Japan. Thirty-eight patients with X-linked hypophosphatemic rickets (XLH 15 males, 23 females, age 0-66years), five patients with tumour-induced osteomalacia (TIO 3 males, 2 females, age 60-73years), and twenty-two patients with hypophosphatemia (11 males, 11 females, age 1-75years) caused due to other factors participated in this study. With the clinical cut-off value of FGF23 at 30.0pg/mL indicated in the Diagnostic Guideline of Rickets/Osteomalacia in Japan, the sensitivity and specificity of FGF23-related hypophosphatemic rickets/osteomalacia without vitamin D deficiency (disease group-1) were 100% and 81.8%, respectively, which distinguished it from non-FGF23-related hypophosphatemia (disease group-2). Furthermore, the diagnostic sensitivity of FGF23-related hypophosphatemia with vitamin D deficiency remained at 100%. Among the four patients with FGF23 levels ≥ 30.0pg/mL in disease group-2, two patients with relatively higher FGF23 values were suspected to have genuine FGF23-related hypophosphatemia, due to the ectopic production of FGF23 in pulmonary and prostate small cell carcinomas. The novel FGF23 assay tested in this study is useful for the differential diagnosis of hypophosphatemic rickets/osteomalacia in a clinical setting.

A Case of Prostate Cancer with Multiple Bone Metastasis with High FGF23 Value Indicated by Intractable Hypocalcemia and Hypophosphatemia

A 53-year-old man was diagnosed with prostate cancer with multiple bone metastasis. Therefore androgen deprivation therapy was initiated. After treatment with denosumab injection for bone metastasis, hypocalcemia and hypophosphatemia occurred. Despite treatment for hypocalcemia with vitamin D and calcium lactate,his serum calcium and phosphate levels were refractory to treatment. The etiology of hypophosphatemia was investigated,and the level of serum fibroblast growth factor 23 (FGF23) was abnormally elevated. Three months after the first measurement of FGF23,the patient died of prostate cancer. Severe hypophosphatemia is a typical manifestation of tumor-induced hypophosphatemic osteomalacia (TIO),which is a paraneoplastic condition, mediated by FGF23 overexpression in most cases. His osteoblastic metastasis,however,did not meet the disease criteria of osteomalacia. Several reports have suggested that excessive FGF23 may mediate both severe hypophosphatemia and aggressive castrationresistant prostate cancer characteristics. Management of serum FGF23 may be a novel therapeutic strategy for castration-resistant prostate cancer with hypophosphatemia.

Early Discrimination Between Tumor-Induced Rickets/Osteomalacia and X-Linked Hypophosphatemia in Chinese Children and Adolescents: A Retrospective Case-Control Study.

In children and adolescents, distinguishing tumor-induced rickets/osteomalacia (TIR/O) from hereditary hypophosphatemic rickets/osteomalacia (HR/O) is a medical challenge. We retrospectively studied 10 Chinese children and adolescents with TIR/O who underwent surgery at a mean age of 17.4 ± 2.1 years and compared their characteristics to 24 age- and sex-matched patients with X-linked hypophosphatemia (XLH). Positive family history of HR/O and dental problems, such as enamel hypoplasia and dental abscess, were reported in 8 (33.3%) and 5 (20.8%) patients with XLX, respectively, but not in patients with TIR/O. In addition, in comparison with XLH patients, TIR/O patients had an older disease onset age (150 versus 24 months, p < 0.001), a higher height standard deviation score (SDS; -1.2 ± 1.8 versus -4.0 ± 1.4, p < 0.001), a lower Z-score of bone mineral density (BMD) at lumbar spine (LS) (-3.9 [6.0] versus +1.8 [7.0], p < 0.001), and a higher serum intact fibroblast growth factor 23 (FGF23) level (500.27 ± 87.20 versus 121.71 ± 70.94 pg/mL, p < 0.001), corresponding to a lower serum phosphate level (0.52 ± 0.07 versus 0.64 ± 0.11 mmol/L, p=0.005) and a higher serum alkaline phosphatase (ALP) level (557 [631] versus 305 [249] U/L, p=0.005). We generated receiver operating characteristic (ROC) curves and calculated the area under the ROC curve (AUC). The AUCs of onset age, FGF23, and LS Z-score were equal to 1, suggesting that these are excellent indices for the differential diagnosis between TIR/O and XLH. In summary, our study furthers our understanding of the spectrum of clinical, biochemical, and pathologic findings associated with TIR/O. For children and adolescent patients with HR/O, a comprehensive and careful clinical and laboratory evaluation is of great importance, and we recommend enquiry of the family history, onset age, and dental problems, as well as measurement of serum FGF23 and BMD. © 2021 American Society for Bone and Mineral Research (ASBMR).

Fibroblast Growth Factor 23 and Mortality Among Prevalent Hemodialysis Patients in the Japan Dialysis Outcomes and Practice Patterns Study

IntroductionElevated fibroblast growth factor 23 (FGF23) levels have been strongly associated with mortality in the predialysis and incident hemodialysis populations, but few studies have examined this relationship in a large cohort of prevalent hemodialysis patients and in particular among persons with high dialysis vintage. To address this, we analyzed data from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS).MethodsWe included 1122 prevalent hemodialysis patients from the J-DOPPS phase 5 (2012–2015) who had FGF23 measurements. We evaluated the association of FGF23 levels with all-cause mortality and cardiovascular composite outcome using Cox regression adjusted for potential confounders.ResultsAt study enrollment, median dialysis vintage was 5.8 years (interquartile range, 2.7–12.4 years) and median FGF23 level was 2113 pg/ml (interquartile range, 583–6880 pg/ml). During 3-year follow-up, 154 of the 1122 participants died. In adjusted analyses, higher FGF23 was associated with a greater hazard of death (hazard ratio per doubling of FGF23, 1.12; 95% confidence interval, 1.03–1.21); however, the association became weaker as the dialysis vintage increased and finally disappeared in the highest tertile (>9.4 years). Similar patterns of effect modification by dialysis vintage were observed for cardiovascular composite outcome and in time-dependent models.ConclusionElevated FGF23 was associated with mortality and cardiovascular events in prevalent hemodialysis patients, but the association was attenuated at longer dialysis vintages. This novel finding suggests that long-term hemodialysis patients may be less susceptible to the detrimental effects of FGF23 or correlated biological processes, and additional studies are needed to gain understanding of these possibilities.

Association of erythropoietin resistance and fibroblast growth factor 23 in dialysis patients: Results from the Japanese Dialysis Outcomes and Practice Patterns Study.

BackgroundFibroblast growth factor 23 (FGF23) plays an important role in chronic kidney disease (CKD)‐related mineral and bone disorders. High FGF23 levels are associated with increased risk of anaemia in non‐haemodialysis CKD patients. FGF23 also negatively regulates erythropoiesis in mice. We hypothesized that higher FGF23 levels are associated with increased erythropoietin hyporesponsiveness among haemodialysis patients.MethodsThe study included 1044 patients from the Japanese Dialysis Outcomes and Practice Patterns Study (J‐DOPPS) phase 5 (2012‐2015). The outcome was erythropoiesis‐stimulating agent hyporesponsiveness (ESA‐hypo), defined as mean Hgb <10 g/dL and standardized mean ESA dose >6000 u/week over 4 months following FGF23 measurement. The association between ESA‐hypo and FGF23 was estimated using multivariable‐adjusted logistic generalized estimating equation regression models.ResultsPatients with higher levels of FGF23 were younger and had higher levels of serum albumin, creatinine, albumin‐corrected calcium, phosphorus, PTH, 25(OH)‐vitamin D, and had higher percentages of intravenous (IV) iron, IV vitamin D and cinacalcet use. ESA‐hypo was present in 144 patients (13.8%). Compared with the third quintile of FGF23 levels, the odds ratio (95% CI) of ESA‐hypo was 2.14 (0.99, 4.62) and 1.74 (0.74, 4.11) for the first and fifth quintiles, respectively.ConclusionThe lowest and highest levels of FGF23 were associated with higher odds of ESA‐hypo in patients on maintenance haemodialysis, although the associations were not statistically significant. The relationship between FGF23 and anaemia, and particularly the increased risks of ESA‐hypo at low FGF23 levels which might be the result of energy saving, must be confirmed in larger clinical studies.

Evaluation of Electrolyte Concentration and Pro-Inflammatory and Oxidative Status in Dogs with Advanced Chronic Kidney Disease under Dietary Treatment.

An integrated study on the effect of renal diet on mineral metabolism, fibroblast growth factor 23 (FGF-23), total antioxidant capacity, and inflammatory markers has not been performed previously. In this study, we evaluated the effects of renal diet on mineral metabolism, oxidative stress and inflammation in dogs with stage 3 or 4 of chronic kidney disease (CKD). Body condition score (BCS), muscle condition score (MCS), serum biochemical profile, ionized calcium (i-Ca), total calcium (t-Ca), phosphorus (P), urea, creatinine, parathyroid hormone (PTH), FGF-23, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-α) and total antioxidant capacity (TAC) were measured at baseline (T0) and after 6 months of dietary treatment (T6). Serum urea, P, t-Ca, i-Ca, PTH, FGF-23, IL-6, IL-10, TNF-α and TAC measurements did not differ between T0 and T6. Serum creatinine (SCr) was increased at T6 and serum PTH concentrations were positively correlated with serum SCr and urea. i-Ca was negatively correlated with urea and serum phosphorus was positively correlated with FGF-23. Urea and creatinine were positively correlated. The combination of renal diet and support treatment over 6 months in dogs with CKD stage 3 or 4 was effective in controlling uremia, acid–base balance, blood pressure, total antioxidant capacity, and inflammatory cytokine levels and in maintaining BCS and MCS.

Serial Fibroblast Growth Factor 23 Measurements and Risk of Requirement for Kidney Replacement Therapy: The CRIC (Chronic Renal Insufficiency Cohort) Study

Studies using a single measurement of fibroblast growth factor 23 (FGF-23) suggest that elevated FGF-23 levelsare associated with increased risk for requirement for kidney replacement therapy (KRT) in patients with chronic kidney disease. However, the data do not account for changesin FGF-23 levels as kidney disease progresses. Case-cohort study. To evaluate the association between serial FGF-23 levels and risk for requiring KRT, our primary analysis included 1,597 individuals in the Chronic Renal Insufficiency Cohort Study who had up to 5 annual measurements of carboxy-terminal FGF-23. There were 1,135 randomly selected individuals, of whom 266 initiated KRT, and 462 individuals who initiated KRT outside the random subcohort. Serial FGF-23 measurements and FGF-23 trajectory group membership. Incident KRT. To handle time-dependent confounding, our primary analysis of time-updated FGF-23 levels used time-varying inverse probability weighting in a discrete time failure model. To compare our results with prior data, we used baseline and time-updated FGF-23 values in weighted Cox regression models. To examine the association of FGF-23 trajectory subgroups with risk for incident KRT, we used weighted Cox models with FGF-23 trajectory groups derived from group-based trajectory modeling as the exposure. In our primary analysis, the HR for the KRT outcome per 1 SD increase in the mean of natural log-transformed (ln)FGF-23 in the past was 1.94 (95% CI, 1.51-2.49). In weighted Cox models using baseline and time-updated values, elevated FGF-23 level was associated with increased risk for incident KRT (HRs per 1 SD ln[FGF-23] of 1.18 [95% CI, 1.02-1.37] for baseline and 1.66 [95% CI, 1.49-1.86] for time-updated). Membership in the slowly and rapidly increasing FGF-23 trajectory groups was associated with ∼3- and ∼21-fold higher risk for incident KRT compared to membership in the stable FGF-23 trajectory group. Residual confounding and lack of intact FGF-23 values. Increasing FGF-23 levels are independently associated with increased risk for incident KRT.

Prospective Evaluation of Perioperative Biochemical Tests to Predict Hypocalcemia After Total Thyroidectomy

Hypocalcemia is a common complication after total thyroidectomy. In these patients, the serum parathyroid hormone (PTH), calcium level decreases, and the phosphorus level increases. The level of fibroblast growth factor-23 (FGF-23), a phosphaturic hormone, increases in the serum to normalize the phosphorus level. In our study, we aimed to investigate the predictive value of PTH, calcium, phosphorus, 1,25-dihydroxy vitamin D (vitamin D), and FGF-23 tests in revealing patients who will develop hypocalcemia after thyroidectomy. Fifty-seven patients undergoing total thyroidectomy (fifty-two with multinodular goiter, three with Graves’ disease and two with papillary thyroid cancer) were included in this prospective study. Serum PTH, calcium, phosphorus, and vitamin D levels of the patients were measured preoperatively. Ten minutes after complete removal of the thyroid gland, intraoperative PTH (IOPTH) level was measured and the amount of decline in PTH level (PTH decline) was calculated. Postoperative PTH, calcium, phosphorus, vitamin D, and FGF-23 levels were measured 24 h after the operation. Postoperatively, hypocalcemia developed in 7 (12.3%) of the 57 patients. IOPTH, postoperative PTH, calcium, and vitamin D levels were significantly lower and PTH decline was significantly higher in patients with postoperative hypocalcemia. Postoperative FGF-23 levels were similar between the groups (p 0.952). When the IOPTH and postoperative serum calcium values were evaluated together, the highest sensitivity and positive predictive values were obtained (93.5% and 67.5%, respectively), The postoperative FGF-23 test was found to be rather unsatisfactory to reveal development of hypocalcemia (sensitivity of 14.3%). The success of detecting patients with hypocalcemia was highest when IOPTH and postoperative serum calcium levels were evaluated together. The FGF-23 measurements were found to be not sufficient in identifying hypocalcemic patients after total thyroidectomy.

MON-261 Investigation of GNAS1 Gene Mutations and Expression Patterns of Fibroblast Growth Factor 23 Protein in McCune-Albright Syndrome

McCune-Albright syndrome (MAS) is characterized by the clinical triad of polyostotic fibrous dysplasia, café-au-lait spots and gonadotropin-releasing hormone-independent precocious puberty, caused by somatic activating mutations of the GNAS1 gene in a mosaic distribution. Overproduction of FGF23 (fibroblast growth factor 23) secreted by bone lesions has been recently reported to be responsible for hypophosphatemic vitamin D-resistant rickets in this disease. This study aimed to analyze the GNAS1 gene in bone lesions of MAS and to investigate the expression patterns of FGF23 protein. Patient and methods: The patient was a 12-year-old boy with MAS. He had polyostotic fibrous dysplasia, hypophosphatemia, café-au-lait spots, and hyperthyroidism and was receiving methimazole. He underwent surgical interventions 3 times for distortions of long bones. We analyzed GNAS1 gene by using peripheral blood cells, resected bone, and muscle tissues. To evaluate FGF23 expression, we performed immunohistochemistry using the resected bone tissue and RT-PCR using the resected bone and muscle tissues along with the measurement of FGF23 in the pre- and post-operative serum. Results: Although no mutations in the GNAS1 gene were found in either peripheral blood cells or muscle tissue, a known activating mutation of p.R201H was heterozygously detected in the bone tissue. Although immunohistochemistry for FGF23 was negative in the first specimen of resected bone tissue, FGF23 mRNA was detected by RT-PCR in the second specimen, but not in muscle tissue. Changes in serum FGF23 levels after each bone resection were as follows: 100 → 54 pg/ml (1 day after first resection), 74 → 102 pg/ml (2 weeks after second resection), and 102 → 85 pg/ml (2 days after third resection). There were no changes in the serum phosphorus level, %TRP, or TmP/GFR after surgery. Discussion and conclusion: We detected GNAS1 gene mutation in only the bone lesion, reflecting its mosaic distribution. The reason why FGF23 mRNA was detected in the second resected bone tissue on RT-PCR despite the negative immunohistochemistry in the first one was attributed to differences in sensitivity between the methods or site-specific expression patterns. The serum level of FGF23 decreased through 2 days after surgery, but did not enter the normal range, and hypophosphatemia did not improve. Fibrous dysplasia was suggested to spread to the entire bone. Moreover, FGF23 increased 2 weeks after surgery probably because the production recovered in the remained lesion. Bone resection did not effectively decrease the FGF23 level.

Pre-analytical stability of FGF23 with the contemporary immunoassays

BackgroundSeveral publications have reported on the pre-analytical stability of fibroblast growth factor 23 (FGF23) and some recommend coating blood collecting tubes with protease inhibitors, in order to prevent degradation. These recommendations are based on observations for a first generation assay for the measurement of intact FGF23. However, if this also applies for the contemporary immunoassays, and at what stage of pre-analysis, is unknown. MethodsWe reviewed data from these previous reports on the issue of FGF23 stability and complemented these findings with data from novel experiments. ResultsWe concluded that the contemporary intact FGF23 assays by Immutopics, Kainos, Millipore and DiaSorin do not suffer from immediate loss of FGF23 signal and do not require blood withdrawal in protease inhibitor-coated collecting tubes. Nevertheless, FGF23 concentrations do decline when centrifugation is delayed up to 8 h and prompt centrifugation is therefore advised.

Association of Fibroblast Growth Factor-23 (FGF-23) With Incident Frailty in HIV-Infected and HIV-Uninfected Individuals.

In the Multicenter AIDS Cohort Study, we examined whether fibroblast growth factor-23 (FGF-23), a bone-derived phosphaturic hormone involved in bone metabolism, is associated with incident frailty. Furthermore, we examined whether this association differs by HIV serostatus and race. Of 715 men assessed for frailty and selected for FGF-23 measurements using stored blood samples (2007-2011), 512 men were nonfrail at/before the baseline visit. Frailty was defined by the presence of ≥3 of the following on 2 consecutive 6-month visits within 1 year: unintentional weight loss ≥10 pounds, weakness, slowness, low energy, and low physical activity. We determined the association of FGF-23 levels with incident frailty using proportional hazards models adjusting for sociodemographics, comorbidities, and kidney function. Sixty-five percent were HIV-infected; 29% were black. Median baseline FGF-23 levels were lower in HIV-infected vs. HIV-uninfected men (33.7 vs. 39.9 rU/mL, P = 0.006) but similar by race. During a median follow-up of 6.6 years, 32 men developed frailty; they had higher baseline FGF-23 levels vs. men who remained nonfrail (45 vs. 36 rU/mL, P = 0.02). FGF-23 (per doubling) was associated with a 1.63-fold risk of frailty [95% confidence interval (CI): 1.19 to 2.23]; results did not differ by HIV serostatus. Conversely, FGF-23 was associated with a 2.72-fold risk of frailty among blacks (95% CI: 1.51 to 4.91) but had minimal association among nonblacks (hazard ratio = 1.26, 95% CI: 0.77 to 2.05; p-interaction = 0.024). Among men with or at-risk of HIV infection, higher FGF-23 was associated with greater risk of frailty, particularly in blacks. The mechanisms by which FGF-23 may contribute to frailty warrant further study.