Fibroblast Growth Factor 23 Excess Research Articles

Regulation of FGF23: Beyond Bone.

Fibroblast growth factor 23 (FGF23) is a bone- and bone marrow-derived hormone that is critical to maintain phosphate homeostasis. The principal actions of FGF23 are to reduce serum phosphate levels by decreasing kidney phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. FGF23 deficiency causes hyperphosphatemia and ectopic calcifications, while FGF23 excess causes hypophosphatemia and skeletal defects. Excess FGF23 also correlates with kidney disease, where it is associated with increased morbidity and mortality. Accordingly, FGF23 levels are tightly regulated, but the mechanisms remain incompletely understood. In addition to bone mineral factors, additional factors including iron, erythropoietin, inflammation, energy, and metabolism regulate FGF23. All these factors affect Fgf23 expression, while some also regulate FGF23 protein cleavage. Conversely, FGF23 may have a functional role in regulating these biologic processes. Understanding the bi-directional relationship between FGF23 and non-bone mineral factors is providing new insights into FGF23 regulation and function.

Genetic basis of hereditary hypophosphataemic rickets and phenotype presentation in children and adults.

Hypophosphataemic rickets (HR) is a genetic disorder causing defects in the renal handling of phosphorus, resulting in rickets. HR can be classified into two groups. First- those with excess fibroblast growth factor 23(FGF23) levels, which are due to gene mutations in extrarenal factors and include X-linked dominant hypophosphataemic rickets (XLHR), autosomal dominant hypophosphataemic rickets (ADHR), autosomal recessive hypophosphataemic rickets (ARHR), and hypophosphataemic rickets with hyperparathyroidism. Second- those with normal or low FGF23, which are caused by gene mutations in renal tubular phosphate transporters and include hereditary hypophosphataemic rickets with hypercalciuria (HHRH) and X-linked recessive hypophosphataemic rickets. The radiographical changes and clinical features of rickets in various types of HR are similar but not identical. Short stature, bone deformities mainly in the lower limbs, and dental problems are typical characteristics of HR. Although the initial diagnosis of HR is usually based on physical, radiological, and biochemical features, molecular genetic analysis is important to confirm the diagnosis and differentiate the type of HR. In this review, we describe clinical and biochemical features as well as genetic causes of different types of HR. The clinical and biochemical characteristics presented in this review can help in the diagnosis of different types of HR and, therefore, direct genetic analysis to look for the specific gene mutation.

The Role of DMP1 in CKD-MBD.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) has become a global health crisis with very limited therapeutic options. Dentin matrix protein 1 (DMP1) is a matrix extracellular protein secreted by osteocytes that has generated recent interest for its possible involvement in CKD-MBD pathogenesis. This is a review of DMP1 established regulation and function, and early studies implicating DMP1 in CKD-MBD. Patients and mice with CKD show perturbations of DMP1 expression in bone, associated with impaired osteocyte maturation, mineralization, and increased fibroblast growth factor 23 (FGF23) production. In humans with CKD, low circulating DMP1 levels are independently associated with increased cardiovascular events. We recently showed that DMP1 supplementation lowers circulating FGF23 levels and improves bone mineralization and cardiac outcomes in mice with CKD. Mortality rates are extremely high among patients with CKD and have only marginally improved over decades. Bone disease and FGF23 excess contribute to mortality in CKD by increasing the risk of bone fractures and cardiovascular disease, respectively. Previous studies focused on DMP1 loss-of-function mutations have established its role in the regulation of FGF23 and bone mineralization. Recent studies show that DMP1 supplementation may fill a crucial therapeutic gap by improving bone and cardiac health in CKD.

PRO56 Psychometric Validation of the Short-Form 36 (version 2) (SF-36) in Tumor-Induced Osteomalacia (TIO)

TIO is a rare condition in which benign tumors secrete excess fibroblast growth factor 23 (FGF23), resulting in phosphate wasting and hypophosphatemia, compromising muscle and bone structure and impacting function and wellbeing. A valid and reliable measure is required to evaluate the impact of treatment on health-related quality of life (HRQL). This study evaluated the item/scale properties, reliability, validity, and sensitivity to change of the SF-36 in adults with TIO and established meaningful change thresholds. Data were from two Phase 2 studies that evaluated the FGF23-blocking antibody burosumab in adults with TIO – the largest prospective dataset to date (n=27; 48% female; age 33–73 years). Item responses for the SF-36 V2 were well distributed across the scale, with slight floor and ceiling effects. Cronbach’s alpha was ≥0.70 for all eight domains. Item–total correlations were ≥0.40 except for “vigorous activity” and “tired” in the Physical Functioning domain. For stability according to the 6-minute walk test (6MWT), intraclass correlation coefficients for test–retest were ≥0.75 for four domains and ≥0.40 for the other three. Multi-trait analysis supported the relevance of the domain structure in TIO (item–scale correlations ≥0.40 for all items except vigorous activity), with good support for convergent validity with the Brief Fatigue Inventory, Brief Pain Inventory Short-Form, and 6MWT. For known groups validity, scores differed in a logical direction for the 6MWT but small samples hindered significance testing. There was some indication that the SF-36 detects change over time in TIO. The change thresholds determined were in line with thresholds provided in the SF-36 user manual. Analyses based on subgroups were exploratory because of small samples but indicated test–retest reliability, known groups validity, and responsiveness. The SF-36 is an appropriate measure to evaluate the effects of treatment on HRQL in TIO studies.

PRO64 Psychometric Validation of the Brief Fatigue Inventory (BFI) and Brief Pain Inventory Short-Form (BPI-SF) in Tumor-Induced Osteomalacia (TIO)

TIO is a rare condition in which benign tumors secrete excess fibroblast growth factor 23 (FGF23), resulting in phosphate wasting and hypophosphatemia, compromising muscle and bone structure, and causing pain and fatigue. A valid and reliable patient-reported outcome (PRO) measure is required to evaluate the impact of treatment on TIO-associated pain and fatigue. This study evaluated the item/scale properties, reliability, validity, and sensitivity to change of the BFI and BPI-SF in adults with TIO and analyzed meaningful change thresholds.

Serum Levels of Lipocalin Are Lower in Adolescents With X-Linked Hypophosphatemia

Individuals with X-linked hypophosphatemia (XLH) are at greater risk for being overweight or obese. It has generally been assumed that the primary reason for this is impaired mobility due to accelerated osteoarthritis, abnormal biomechanics of ambulation, pseudofractures and enthesopathy. These known complications limit the ability of patients with XLH to engage in regular aerobic exercise. Whether there are underlying metabolic abnormalities that also put patients with XLH at greater risk for excessive weight gain is largely unknown. A recent French study1 confirmed that patients with XLH, especially adolescents, have a predilection to obesity. Evidence suggests that elevated circulating levels of fibroblast growth factor 23 (FGF23) are associated with an increase in fat mass and dyslipidemia in elderly normal individuals. Whether the elevated levels of FGF23 in XLH play a direct pathogenic role in the risk for excessive weight gain in XLH is unclear. Lipocalin (LCN2) has recently received considerable attention as a factor regulating energy consumption and specifically is postulated to be anorexigenic and improve insulin sensitivity. We therefore measured circulating levels of LCN2, leptin and insulin in 32 patients with XLH, ages 2–60 y.o., all of whom were being treated with burosumab and 40 Cntrl subjects, matched for age, sex, and BMI or weight/height z-score for children and adolescents. Serum was obtained from excess sample from clinical 25-hydroxy vitamin D testing in our laboratory. All patients were de-identified for the study. In 7 adults with XLH 20–60 y.o. (mean age 35) and 11 Cntrls (mean age 41), mean values for BMI, LCN2, leptin and insulin levels in the two group were as follows, (XLH vs. Cntrl); BMI: 36 vs. 34 kg/m2, LCN2: 83 vs. 108 ng/mL, leptin: 26 vs. 39 ng/mL, insulin: 19 vs. 20 µIU/mL. The pediatric patients were separated into two groups: 2–10 and 11–18 y.o.. In the 2–10 y.o. group the mean values were (XLH vs. Cntrl); age: 5.5 y.o. vs. 5.8 y.o., weight/height Z-score: 0.8 vs. 1.1, LCN2: 47 vs. 60, leptin: 2.2. vs. 6.7, and insulin: 8.4 vs. 13. In the 11–18 group, mean values were (XLH vs. Cntrl); age: 14 y.o. vs. 14 y.o., weight/height Z-score: 1.0 vs. 1.2, LCN2: 65 vs. 105, leptin: 24 vs.19, and insulin: 17 vs. 48. In all age groups LCN2 was lower in the patients with XLH than Cntrls and this difference reached significance in the adolescents with XLH (p=0.04). No other parameters were significantly different among the groups. Since all patients with XLH were treated with burosumab it is unlikely that a direct effect of excess FGF23 production explains this finding. We conclude that reduced expression of lipocalin in adolescents with XLH may contribute to their risk for obesity.1Lecoq et.al. Obesity and Impaired Glucose Metabolism in Adult Patients with X-Linked Hypophosphatemia, J, Endo. Soc. 2020 https://doi.org/10.1210/jendso/bvaa046.1355

Renal Dnase1 expression is regulated by FGF23 but loss of Dnase1 does not alter renal phosphate handling

Fibroblast growth factor 23 (FGF23) is a bone-derived endocrine hormone that regulates phosphate and vitamin D metabolism. In models of FGF23 excess, renal deoxyribonuclease 1 (Dnase1) mRNA expression is downregulated. Dnase-1 is an endonuclease which binds monomeric actin. We investigated whether FGF23 suppresses renal Dnase-1 expression to facilitate endocytic retrieval of renal sodium dependent phosphate co-transporters (NaPi-IIa/c) from the brush border membrane by promoting actin polymerization. We showed that wild type mice on low phosphate diet and Fgf23−/− mice with hyperphosphatemia have increased renal Dnase1 mRNA expression while in Hyp mice with FGF23 excess and hypophosphatemia, Dnase1 mRNA expression is decreased. Administration of FGF23 in wild type and Fgf23−/− mice lowered Dnase1 expression. Taken together, our data shows that Dnase1 is regulated by FGF23. In 6-week-old Dnase1−/− mice, plasma phosphate and renal NaPi-IIa protein were significantly lower compared to wild-type mice. However, these changes were transient, normalized by 12 weeks of age and had no impact on bone morphology. Adaptation to low and high phosphate diet were similar in Dnase1−/− and Dnase1+/+ mice, and loss of Dnase1 gene expression did not rescue hyperphosphatemia in Fgf23−/− mice. We conclude that Dnase-1 does not mediate FGF23-induced inhibition of renal tubular phosphate reabsorption.

Systemic Jak1 activation provokes hepatic inflammation and imbalanced FGF23 production and cleavage.

Fibroblast growth factor 23 (FGF23) is a main regulator of mineral homeostasis. Low and high circulating FGF23 levels are associated with bone, renal, cardiovascular diseases, and increased mortality. Understanding the factors and signaling pathways affecting FGF23 levels is crucial for the management of these diseases and their complications. Here, we show that activation of the Jak1/Stat3 signaling pathway leads to inflammation in liver and to an increase in hepatic FGF23 synthesis, a key hormone in mineral metabolism. This increased synthesis leads to massive C-terminal FGF23 circulating levels, the inactive C-terminal fragment, and increased intact FGF23 levels, the active form, resulting in imbalanced production and cleavage. Liver inflammation does not lead to activation of the calcineurin-NFAT pathway, and no signs of systemic inflammation could be observed. Despite the increase of active intact FGF23, excessive C-terminal FGF23 levels block the phosphaturic activity of FGF23. Therefore, kidney function and renal αKlotho expression are normal and no activation of the MAPK pathway was detected. In addition, activation of the Jak1/Stat3 signaling pathway leads to high calcitriol levels and low parathyroid hormone production. Thus, JAK1 is a central regulator of mineral homeostasis. Moreover, this study also shows that in order to assess the impact of high FGF23 levels on disease and kidney function, the source and the balance in FGF23 production and cleavage are critical.

Excessive fibroblast growth factor 23 promotes renal fibrosis in mice with type 2 cardiorenal syndrome

Cardiorenal syndrome (CRS) has a high mortality, but its pathogenesis remains elusive. Fibroblast growth factor 23 (FGF23) is increased in both renal dysfunction and cardiac dysfunction, and FGF receptor 4 (FGFR4) has been identified as a receptor for FGF23. Deficiency of FGF23 causes growth retardation and shortens the lifespan, but it is unclear whether excess FGF23 is detrimental in CRS. This study sought to investigate whether FGF23 plays an important role in CRS-induced renal fibrosis. A mouse model of CRS was created by surgical myocardial infarction for 12 weeks. CRS mice showed a significant increase of circulatory and renal FGF23 protein levels, as well as an upregulation of p-GSK, active-β-catenin, TGF-β, collagen I and vimentin, a downregulation of renal Klotho expression and induction of cardiorenal dysfunction and cardiorenal fibrosis. These changes were enhanced by cardiac overexpression of FGF23 and attenuated by FGF receptor blocker PD173074 or β-catenin blocker IGC001. In fibroblasts (NRK-49F), expression of FGFR4 rather than Klotho was detected. Recombinant FGF23 upregulated the expression of p-GSK, active-β-catenin, TGF-β, collagen I and vimentin proteins. These changes were attenuated by FGFR4 blockade with BLU9931 or β-catenin blockade with IGC001. We concluded that FGF23 promotes CRS-induced renal fibrosis mediated by partly activating FGFR4/β-catenin signaling pathway.

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.

Fibroblast growth factor 23 and cognitive impairment: The health, aging, and body composition study.

BackgroundConcentrations of fibroblast growth factor 23 (FGF-23), a hormone that regulates phosphorus and vitamin D metabolism, increase as kidney function declines. Excess fibroblast growth factor 23 may impact brain function through promotion of vascular disease or through direct effects on neuronal tissue.MethodsIn the Healthy Aging and Body Composition Study, a longitudinal observational cohort of well-functioning older adults, intact serum FGF-23 was assayed in 2,738 individuals. Cognitive function was assessed at baseline and longitudinally at years 3, 5, and 8 by administration of the Modified Mini Mental State Examination (3MSE), a test of global cognitive function, and the Digit Symbol Substitution Test (DSST), a test primarily of executive function. The associations between FGF-23 and baseline cognitive function and incident cognitive impairment were evaluated using logistic and Poisson regression respectively, and were adjusted for demographics, baseline estimated glomerular filtration rate (eGFR), urine albumin/creatinine ratio, comorbidity, and other measures of mineral metabolism including soluble klotho.ResultsThe mean (SD) age was 74(3) years, with 51% female, and 39% black. The median (25th, 75th) FGF-23 concentration was 47 pg/mL (37, 60). Three hundred ninety-two individuals had prevalent cognitive impairment by the 3MSE and 461 by the DSST. There was no observed association between FGF-23 and baseline cognitive function for either cognitive test. There were 277 persons with incident cognitive impairment by 3MSE, and 333 persons with incident cognitive impairment by DSST. In fully adjusted models, each two-fold higher concentration of baseline FGF-23 was not associated with incident cognitive impairment by the 3MSE (IRR = 1.02[0.88, 1.19] fully adjusted model) or by the DSST (IRR = 0.98 [0.84, 1.15]. We saw no difference when analyses were stratified by eGFR greater than or less than 60 ml/min/1.73m2.ConclusionIntact FGF-23 was not associated with baseline cognitive function or incident cognitive impairment in this cohort well-functioning older adults.

Renal Phosphate Handling: Independent Effects of Circulating FGF23, PTH, and Calcium.

ABSTRACTExcess fibroblast growth factor 23 (FGF23), excess PTH, and an increase in extracellular calcium cause hypophosphatemia by lowering the maximum renal phosphate reabsorption threshold (TmP/GFR). We recently reported two cases of X‐linked hypophosphatemia (XLH) with severe tertiary hyperparathyroidism who had normalization of TmP/GFR upon being rendered hypoparathyroid following total parathyroidectomy, despite marked excess in both C‐terminal FGF23 (cFGF23) and intact FGF23 (iFGF23). We explored the effects of FGF23, PTH, and calcium on TmP/GFR in a cross‐sectional study (n = 74) across a spectrum of clinical cases with abnormalities in TmP/GFR, PTH, and FGF23. This comprised three groups: FGF23‐dependent hypophosphatemia (n = 27), hypoparathyroidism (HOPT; n = 17), and chronic kidney disease (n = 30). Measurements included TmP/GFR, cFGF23, PTH, ionized calcium, vitamin D metabolites, and bone turnover markers. The combined effect of cFGF23, PTH, and ionized calcium on TmP/GFR was modeled using hierarchical multiple regression and was probed by moderation analysis with PROCESS. Modeling analysis showed independent effects on TmP/GFR by cFGF23, PTH, and ionized calcium in conjunction with a weak but significant effect of the interaction term for PTH and FGF23; probing showed that the effect was most prominent during PTH deficiency. Teriparatide 20 μg daily was self‐administered for 28 days by one case of X‐linked hypophosphatemia with hypoparathyroidism (XLH‐HOPT) to assess the response of TmP/GFR, cFGF23, iFGF23, nephrogenous cyclic adenosine monophosphate (NcAMP), vitamin D metabolites, and bone turnover markers. After 28 days, TmP/GFR was lowered from 1.10 mmol/L to 0.48 mmol/L; this was accompanied by increases in NcAMP, ionized calcium, and bone turnover markers. In conclusion, the effect of FGF23 excess on TmP/GFR is altered by PTH such that the effect is ameliorated by hypoparathyroidism and the effect is augmented by hyperparathyroidism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Determination of FGF23 Levels for the Diagnosis of FGF23-Mediated Hypophosphatemia.

Fibroblast growth factor-23 (FGF23) measurement is a critical tool in the evaluation of patients with disordered phosphate homeostasis. Available laboratory reference ranges for blood FGF23 were developed using samples from normophosphatemic individuals. Reliance on such values can lead to misdiagnosis in patients with FGF23-mediated hypophosphatemia, such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO), in whom pathology-driving FGF23 levels can be in the "normal range." To determine FGF23 levels that are diagnostic for the identification of patients with FGF23-mediated hypophosphatemic disorders, we studied 149 patients with various disorders of FGF23-mediated and FGF23-independent hypophosphatemia and defined cut-off levels for both intact FGF23 (iFGF23) and C-terminal FGF23 (cFGF23) that can accurately distinguish between FGF23-mediated and FGF23-independent hypophosphatemia. In addition, to demonstrate the relationship between FGF23 and phosphate across the spectrum of human physiology, we assessed blood levels of FGF23 and phosphate in 434 patients with various forms of hypophosphatemia, hyperphosphatemia, and normophosphatemia. An intact FGF23 cut point of 27 pg/mL was 100% sensitive and specific in distinguishing FGF23-mediated from FGF23-independent hypophosphatemia, and a cFGF23 cut point of 90 RU/mL was 100% sensitive and specific in distinguishing specifically TIO from FGF23-independent hypophosphatemia. There was overlap in the cFGF23 range of 45-90 RU/mL between genetic forms of FGF23 excess and FGF23-independent hypophosphatemia, substantiating the superiority of iFGF23 over cFGF23 in making the diagnosis of FGF23-mediated hypophosphatemia. In this cohort, using the laboratory upper limit of normal for cFGF23 (180 RU/mL) would result in a misdiagnosis in more than half of patients with FGF23-mediated hypophosphatemia. In this, the largest study of FGF23 in chronic hypophosphatemia to date, we established iFGF23 and cFGF23 cut-off values to assist in the evaluation and diagnosis of hypophosphatemic conditions. © 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Design and development of FGF-23 antagonists: Definition of the pharmacophore and initial structure-activity relationships probed by synthetic analogues

Hereditary hypophosphatemic disorders, TIO, and CKD conditions are believed to be influenced by an excess of Fibroblast Growth Factor-23 (FGF-23) which activates a binary renal FGFRs / α-Klotho complex to regulate homeostatic metabolism of phosphate and vitamin D. Adaptive FGF-23 responses from CKD patients with excess FGF-23 frequently lead to increased mortality from cardiovascular disease. A reversibly binding small molecule therapeutic has yet to emerge from research and development in this area. Current outcomes described in this work highlight efforts related to lead identification and modification using organic synthesis of strategic analogues to probe structure-activity relationships and preliminarily define the pharmacophore of a computationally derived hit obtained from virtual high-throughput screening. Synthetic strategies for the initial hit and analogue preparation, as well as preliminary cellular in vitro assay results highlighting sub micromolar inhibition of the FGF-23 signaling sequence at a concentration well below cytotoxicity are reported herein.

Burosumab in X-linked hypophosphatemia and perspective for chronic kidney disease.

Perturbations in phosphate and vitamin D homeostasis impacts skeletal health in children and adults. Study of inherited and acquired hypophosphatemic syndromes led to the discovery of fibroblast growth factor 23 (FGF23) as a potent regulator of phosphate and vitamin D metabolism, and advanced our understanding of the pathophysiology of mineral and bone disorder in chronic kidney disease (CKD-MBD). Here, we review a recently approved therapy for patients with X-linked hypophosphatemia (XLH) using a novel anti-FGF23 antibody, burosumab, and discuss the implications of such targeted therapy in CKD. In children and adults with XLH, burosumab treatment significantly increased renal tubular phosphate reabsorption and normalized serum phosphorus concentrations. Prolonged treatment with burosumab showed a favorable safety profile, improved healing of rickets in children, and fractures and pseudofractures in adults. FGF23 excess in CKD is independently associated with left ventricular hypertrophy and cardiovascular mortality. Research strategies to lower FGF23 in animal models of CKD are rapidly advancing and a question that remains to be answered is whether FGF23 blockade will offer a new targeted intervention for disordered mineral metabolism in CKD. Findings from recently concluded clinical trials in adults and children with XLH provide evidence for improved skeletal health with burosumab therapy with normalization of phosphate and vitamin D metabolism. Targeted anti-FGF23 antibody treatment of XLH has emerged as a novel therapeutic strategy to treat an inherited disorder of FGF23 excess.

Association Between Chronic Kidney Disease–Mineral Bone Disease (CKD-MBD) and Cognition in Children: Chronic Kidney Disease in Children (CKiD) Study

Rationale & ObjectiveChronic kidney disease (CKD) in children is associated with cognitive dysfunction that affects school performance and quality of life. The relationship between CKD–mineral and bone disorder and cognitive function in children is unknown.Study DesignObservational study.Participants702 children enrolled in the Chronic Kidney Disease in Children (CKiD) Study.PredictorsPlasma fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), calcium, phosphorus, 25 hydroxyvitamin D (25[OH]D), and 1,25 dihydroxyvitamin D (1,25[OH]2D).OutcomesNeurocognitive tests of intelligence, academic achievement, and executive functions.Analytical ApproachLinear regression models to analyze the cross-sectional associations between log2FGF-23, 25(OH)D, 1,25(OH)2D, PTH, calcium, and phosphorus z scores and the cognitive test scores of interest after adjustment for demographics, blood pressure, proteinuria, and kidney function.ResultsAt baseline, median age was 12 (95% CI, 8.3, 15.2) years and estimated glomerular filtration rate was 54 (40.5, 67.8) mL/min/1.73 m2. In fully adjusted analyses, 25(OH)D, 1,25(OH)2D, PTH, calcium, and phosphorus z scores did not associate with cognitive test scores. In fully adjusted analyses, log2FGF-23 was associated with abnormal test scores for attention regulation (P < 0.05); specifically, Conners' Continuous Performance Test II Errors of Omission (β = 2.3 [1.0, 3.6]), Variability (β=1.4 [0.4, −2.4]), and Hit Reaction Time (β = 1.3 [0.2, 2.4]). Children in the highest FGF-23 tertile group had 7% and 9% greater cognitive risk for Hit Reaction Time and Errors of Omission compared with those in the lowest tertile, respectively. In fully adjusted analyses, higher FGF-23 tertile was associated with increased cognitive risk (P < 0.05) for Errors of Omission (β = 0.4 [0.1, 0.7]) and Hit Reaction Time (β = 0.4 [0.1, 0.7]).LimitationsThe study does not assess the cumulative effects of FGF-23 excess on cognitive function over time. Within-population stratified analyses were not performed due to limited sample size.ConclusionsIn children with CKD, higher plasma FGF-23 level is associated with lower performance in targeted tests of executive function, specifically attention regulation, independent of glomerular filtration rate.

McCune–Albright syndrome and type 1 diabetes mellitus: a novel presentation

McCune-Albright syndrome (MAS) is caused by postzygotic somatic activating mutations of GNAS and is classically characterized by the clinical triad of peripheral precocious puberty, café-au-lait pigmentation, and polyostotic fibrous dysplasia. It can also present with other hyperfunctioning endocrinopathies, including growth hormone excess, hyperprolactinemia, hypercortisolemia, hyperthyroidism, and renal phosphate wasting due to excess fibroblast growth factor 23. We review the clinical, biochemical, radiological, and genetic findings in a 7-year-old girl diagnosed with MAS at age 4 and then with autoimmune type 1 diabetes mellitus at age 7. While MAS is associated with hyperglycemia secondary to growth hormone excess and hypercortisolemia, an association with diabetes mellitus has not been demonstrated. We review the unique presentation of a patient with these two rare conditions.

Anorexia Nervosa with Markedly High Bone Turnover and Hyperphosphatemia During Refeeding Rectified by Denosumab.

We describe a unique case of hyperphosphatemia associated with a very high bone turnover rate in a 51-year-old postmenopausal woman with undiagnosed anorexia nervosa (AN) who presented with a low-trauma hip fracture. In view of her severely malnourished state, she was not fit for surgery. She was treated according to a refeeding protocol that mandated bed rest. Contrary to expectation, she developed sustained hyperphosphatemia and borderline hypercalcemia. Bone remodelling markers, both resorption and formation, were markedly elevated. Parathyroid hormone (PTH) was low-normal at 1.7pmol/L, C-terminal fibroblast growth factor 23 (FGF23) was high at 293RU/ml, but tubular maximum reabsorption of phosphate (TmPO4/GFR) was elevated at 1.93mmol/L. Denosumab 60mg was administered that was followed by: rapid normalisation of serum phosphate; normalisation of resorption markers, transient hypocalcaemia with secondary hyperparathyroidism, and normalisation of both TmPO4/GFR and C-terminal FGF23. We speculate that prolonged immobilization as part of AN management led to a high remodelling state followed by hyperphosphatemia and high-normal calcium with appropriate suppression of PTH and that marked hyperphosphatemia and high TmP/GFR despite high FGF23 indicates the necessity of PTH adequacy for excess FGF23 to lower TmP/GFR.

Potentielle application de l’axe fibroblast growth factor 23-Klotho dans la maladie rénale chronique

Membrane Alpha Klotho (α-klotho) is expressed in the kidney and functions as a co-receptor of FGF receptors (FGFRs) to activate specific fibroblast growth factor 23 (FGF23) signal pathway. FGF23 is produced in bones and participates in mineral homeostasis. The extracellular domain of transmembrane αklotho can be cleaved by proteases and released into the circulation as soluble α-klotho. Klotho deficiency is a pathogenic factor for chronic kidney disease progression and cardiovascular diseases. The FGF23 excess may also contribute to cardiovascular diseases where its pathogenic effect acts via the FGFR4 and independently of α-klotho. The decline in serum α-klotho followed by a rise in serum FGF23 at an early stage of chronic kidney disease can serve as a robust predictor for risk of cardiovascular diseases and mortality in both CKD patients and the general population. The first randomized trials suggest the possibility to reduce FGF23 excess in chronic kidney disease by controlling the phosphate serum using phosphate binders and reducing PTH levels with calcimimetic drug. New strategies emerge, including the administration of α-klotho recombinant and the use of epidrugs in order to correct the klotho deficiency. The FGR4 inhibitors are promising to limit the development of left ventricular hypertrophy linked to FGF23 excess. Finally, a better understanding of the molecular mechanisms of FGF23/α-klotho axis will allow us to find new strategic approaches and improve the CKD patient's management and their outcomes.

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model.

Observations in transgenic α-Klotho (Kl) mice (KlTg) defined the antiaging role of soluble Klotho (sKL130). A genetic translocation that elevates sKL levels in humans is paradoxically associated with increased circulating fibroblast growth factor 23 (FGF23) levels and the potential of both membrane KL (mKL135) and sKL130 to act as coreceptors for FGF23 activation of fibroblast growth factor receptors (FGFRs). Neither FGF23 expression nor the contributions of FGF23, mKL135, and sKL130 codependent and independent functions have been investigated in KlTg mice. In the current study, we examined the effects of Kl overexpression on FGF23 levels and functions in KlTg mice. We found that mKL135 but not sKL130 stimulated FGF23 expression in osteoblasts, leading to elevated Fgf23 bone expression and circulating levels in KlTg mice. Elevated FGF23 suppressed 1,25(OH)2D and parathyroid hormone levels but did not cause hypophosphatemic rickets in KlTg mice. KlTg mice developed low aldosterone-associated hypertension but not left ventricular hypertrophy. Mechanistically, we found that mKL135 and sKL130 are essential cofactors for FGF23-mediated ERK activation but that they inhibited FGF23 stimulation of PLC-γ and PI3K/AKT signaling. Thus, increased longevity in KlTg mice occurs in the presence of excess FGF23 that interacts with mKL and sKL to bias FGFR pathways.