[Clinical study on growth impairment induced by oral glucocorticoids based on FGF23/Klotho homeostasis observations]. / 基于FGF23/Klothoç¨³æ€è§‚å¯Ÿå£æœç³–çš®è´¨æ¿€ç´ è‡´ç”Ÿé•¿éšœç¢çš„ä¸´åºŠç ”ç©¶.

OBJECTIVES: To observe the correlation between growth impairment induced by long-term oral glucocorticoids (GC) therapy and the ratio of FGF23/Klotho in children with primary nephrotic syndrome (PNS). METHODS: A prospective study was conducted on 56 children with GC-sensitive PNS who had discontinued GC therapy for more than 3 months and revisited the Department of Pediatrics of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine between June 2022 and December 2022. After monitoring qualitative and quantitative urine protein levels upon admission, the children with proteinuria relapse were treated with GC (GC group; n=29), while those without relapse did not receive GC treatment (non-GC group; n=27). In addition, 29 healthy children aged 3 to prepuberty were selected as the control group. Height, bone age, growth rate, and the FGF23/Klotho ratio were compared among the groups. The correlations of the FGF23/Klotho ratio with height, bone age, and growth rate were analyzed. RESULTS: The FGF23/Klotho ratio in the GC group was significantly higher than that in the non-GC group after 1 month of GC therapy (P<0.05), and the height and bone age growth rates within 6 months were lower than those in the non-GC group (P<0.05). Correlation analysis showed significant negative correlations between the FGF23/Klotho ratio after 1 month of treatment and the growth rates of height and bone age within 6 months in children with PNS (r=-0.356 and -0.436, respectively; P<0.05). CONCLUSIONS: The disturbance in FGF23/Klotho homeostasis is one of the mechanisms underlying the growth impairment caused by long-term oral GC therapy.

Fibroblast growth factor-23 and Alpha-Klotho concentrations in dogs with canine Leishmaniasis.

This study aimed to assess the concentrations of Fibroblast Growth Factor-23 (FGF-23) and α-Klotho in healthy dogs and dogs at different stages of Canine Leishmaniasis (CanL), and investigate the changes of these parameters in relation to renal function and calcium­phosphorus metabolism. A total of 74 dogs (22 healthy and 52 with CanL) of varying ages, sexes, and medium-sized breeds were included. Dogs with CanL were categorized into different stages (Stage I-IV) based on Leishvet recommendations. In addition to routine hematological parameters, plasma FGF-23, serum α-Klotho, urea, creatinine, phosphorus, calcium, parathormone, vitamin D concentrations, and urine protein/creatinine ratio were measured. Data from healthy dogs were compared to dogs with CanL overall and by stage. Dogs with CanL exhibited higher concentrations of FGF-23 (p < 0.05), α-Klotho, and parathormone (p < 0.001), as well as lower concentrations of vitamin D and calcium (p < 0.001). FGF-23 concentration was particularly elevated in Stage IV compared to other stages. However, no significant differences in α-Klotho levels were observed among the stages. FGF-23 levels showed a weak positive correlation with urea and creatinine concentrations and a moderate positive correlation with urine protein/creatinine ratio. This study demonstrated increased levels of FGF-23 and α-Klotho in dogs with CanL for the first time. The increase in FGF-23 levels was more prominent in advanced stages of the disease and correlated with higher urea and creatinine concentrations. These findings may serve as a basis for future diagnostic and therapeutic investigations, contributing to the understanding of the pathophysiology of kidney disease in CanL.

Inherited fibroblast growth factor 23 excess.

Syndromes of inherited fibroblast growth factor 23 (FGF-23) excess encompass a wide spectrum that includes X-linked hypophosphataemia (XLH), autosomal dominant and recessive forms of rickets as well as various syndromic conditions namely fibrous dysplasia/McCune Albright syndrome, osteoglophonic dysplasia, Jansen's chondrodysplasia and cutaneous skeletal hypophosphataemia syndrome. A careful attention to patient symptomatology, family history and clinical features, supported by appropriate laboratory tests will help in making a diagnosis. A genetic screen may be done to confirm the diagnosis. While phosphate supplements and calcitriol continue to be the cornerstone of treatment, in recent times burosumab, the monoclonal antibody against FGF-23 has been approved for the treatment of children and adults with XLH. While health-related outcomes may be improved by ensuring adherence and compliance to prescribed treatment with a smooth transition to adult care, bony deformities may persist in some, and this would warrant surgical correction.

In vitro regulation of fibroblast growth factor 23 by 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D synthesized by osteocyte-like MC3T3-E1 cells.

Fibroblast growth factor 23 (FGF23) is produced and secreted by osteocytes and is essential for maintaining phosphate homeostasis. One of the main regulators of FGF23, 1,25-dihydroxyvitamin D (1,25(OH)2D3), is primarily synthesized in the kidney from 25-hydroxyvitamin D (25(OH)D) by 1α-hydroxylase (encoded by CYP27B1). Hitherto, it is unclear whether osteocytes can convert 25(OH)D and thereby allow for 1,25(OH)2D3 to induce FGF23 production and secretion locally. Here, we differentiated MC3T3-E1 cells toward osteocyte-like cells expressing and secreting FGF23. Treatment with 10-6 M 25(OH)D resulted in conversion of 25(OH)D to 150 pmol/L 1,25(OH)2D3 and increased FGF23 expression and secretion, but the converted amount of 1,25(OH)2D3 was insufficient to trigger an FGF23 response, so the effect on FGF23 was most likely directly caused by 25(OH)D. Interestingly, combining phosphate with 25(OH)D resulted in a synergistic increase in FGF23 expression and secretion, likely due to activation of additional signaling pathways by phosphate. Blockage of the vitamin D receptor (VDR) only partially abolished the effects of 25(OH)D or 25(OH)D combined with phosphate on Fgf23, while completely inhibiting the upregulation of cytochrome P450 family 24 subfamily A member 1 (Cyp24a1), encoding for 24-hydroxylase. RNA sequencing and in silico analyses showed that this could potentially be mediated by the nuclear receptors Retinoic Acid Receptor ß (RARB) and Estrogen Receptor 2 (ESR2). Taken together, we demonstrate that osteocytes are able to convert 25(OH)D to 1,25(OH)2D3, but this is insufficient for FGF23 activation, implicating a direct effect of 25(OH)D in the regulation of FGF23, which occurs at least partially independent from its cognate VDR. Moreover, phosphate and 25(OH)D synergistically increase expression and secretion of FGF23, which warrants investigating consequences in patients receiving a combination of vitamin D analogues and phosphate supplements. These observations help us to further understand the complex relations between phosphate, vitamin D, and FGF23.

Progression of Vascular Calcification and Clinical Outcomes in Patients Receiving Maintenance Dialysis.

Importance: Baseline findings from the China Dialysis Calcification Study (CDCS) revealed a high prevalence of vascular calcification (VC) among patients with end-stage kidney disease; however, data on VC progression were limited. Objectives: To understand the progression of VC at different anatomical sites, identify risk factors for VC progression, and assess the association of VC progression with the risk of cardiovascular events and death among patients receiving maintenance dialysis. Design, Setting, and Participants: This cohort study was a 4-year follow-up assessment of participants in the CDCS, a nationwide multicenter prospective cohort study involving patients aged 18 to 74 years who were undergoing hemodialysis or peritoneal dialysis. Participants were recruited from 24 centers across China between May 1, 2014, and April 30, 2015, and followed up for 4 years. A total of 1489 patients receiving maintenance dialysis were included in the current analysis. Data were analyzed from September 1 to December 31, 2021. Exposures: Patient demographic characteristics and medical history; high-sensitivity C-reactive protein laboratory values; serum calcium, phosphorus, and intact parathyroid hormone (iPTH) values; and previous or concomitant use of medications. Main Outcomes and Measures: The primary outcome was progression of VC at 3 different anatomical sites (coronary artery, abdominal aorta, and cardiac valves) and identification of risk factors for VC progression. Participants received assessments of coronary artery calcification (CAC), abdominal aortic calcification (AAC), and cardiac valve calcification (CVC) at baseline, 24 months, 36 months, and 48 months. Secondary outcomes included (1) the association between VC progression and the risk of all-cause death, cardiovascular (CV)-related death, and a composite of all-cause death and nonfatal CV events and (2) the association between achievement of serum calcium, phosphorus, and iPTH target levels and the risk of VC progression. Results: Among 1489 patients, the median (IQR) age was 51.0 (41.0-60.0) years; 59.5% of patients were male. By the end of 4-year follow-up, progression of total VC was observed in 86.5% of patients; 69.6% of patients had CAC progression, 72.4% had AAC progression, and 33.4% had CVC progression. Common risk factors for VC progression at the 3 different anatomical sites were older age and higher fibroblast growth factor 23 levels. Progression of CAC was associated with a higher risk of all-cause death (model 1 [adjusted for age, sex, and body mass index]: hazard ratio [HR], 1.97 [95% CI, 1.16-3.33]; model 2 [adjusted for all factors in model 1 plus smoking status, history of diabetes, and mean arterial pressure]: HR, 1.89 [95% CI, 1.11-3.21]; model 3 [adjusted for all factors in model 2 plus calcium, phosphorus, intact parathyroid hormone, and fibroblast growth factor 23 levels and calcium-based phosphate binder use]: HR, 1.92 [95% CI, 1.11-3.31]) and the composite of all-cause death and nonfatal CV events (model 1: HR, 1.98 [95% CI, 1.19-3.31]; model 2: HR, 1.91 [95% CI, 1.14-3.21]; model 3: HR, 1.95 [95% CI, 1.14-3.33]) after adjusting for all confounding factors except the presence of baseline calcification. Among the 3 targets of calcium, phosphorus, and iPTH, patients who achieved no target levels (model 1: odds ratio [OR], 4.75 [95% CI, 2.65-8.52]; model 2: OR, 4.81 [95% CI, 2.67-8.66]; model 3 [for this analysis, adjusted for all factors in model 2 plus fibroblast growth factor 23 level and calcium-based phosphate binder use]: OR, 2.76 [95% CI, 1.48-5.16]), 1 target level (model 1: OR, 3.71 [95% CI, 2.35-5.88]; model 2: OR, 3.62 [95% CI, 2.26-5.78]; model 3: OR, 2.19 [95% CI, 1.33-3.61]), or 2 target levels (model 1: OR, 2.73 [95% CI, 1.74-4.26]; model 2: OR, 2.69 [95% CI, 1.71-4.25]; model 3: OR, 1.72 [95% CI, 1.06-2.79]) had higher odds of CAC progression compared with patients who achieved all 3 target levels. Conclusions and Relevance: In this study, VC progressed rapidly in patients undergoing dialysis, with different VC types associated with different rates of prevalence and progression. Consistent achievement of serum calcium, phosphorus, and iPTH target levels was associated with a lower risk of CAC progression. These results may be useful for increasing patient awareness and developing appropriate strategies to improve the management of chronic kidney disease-mineral and bone disorder among patients undergoing dialysis.

Effect of vitamin D supplementation on circulating fibroblast growth factor-23 concentration in adults with prediabetes.

BACKGROUND: Recent meta-analyses report that vitamin D supplementation increases blood fibroblast growth factor-23 (FGF23) level. OBJECTIVES: To determine the effect of 4000 IU/day of vitamin D3 for 12 months on circulating FGF23 levels. We also examined the association of the achieved 25-hydroxyvitamin D level [25(OH)D] with the FGF23 level at 12 months and with 12-month changes in FGF23. METHODS: An ancillary analysis among adults 70 years and older with prediabetes who participated in a trial comparing vitamin D3 4000 IU/day with placebo. Plasma intact FGF23 and serum 25(OH)D were measured at baseline and month 12 (M12). RESULTS: Characteristics of the 52 participants (vitamin D3 n = 28; placebo n = 24) did not differ significantly aside from more women than men in the vitamin D3 group. Mean ± SD age was 73.8 ± 3.7 years, BMI 31.3 ± 4.2 kg/m2, and glomerular filtration rate (GFR) 76.3 ± 11.8 mL/min/1.73m2 Baseline serum 25(OH)D level was 33.4 ± 10.8 ng/mL and increased at M12 to 54.9 ± 14.8 ng/mL in the vitamin D3 group versus 33.4 ± 14.9 in the placebo (p < 0.001). At baseline, GFR was inversely associated with FGF23 (r = - 0.349, p = 0.011). Change in FGF23 level at M12 did not differ significantly between vitamin D3 and placebo. In all participants combined, the achieved serum 25(OH)D level at M12 was not significantly associated with the M12 plasma FGF23 or the M12 change in FGF23. CONCLUSION: In obese older adults with sufficient vitamin D status and normal renal function, vitamin D3 4000 IU/day for 12 months did not significantly alter plasma intact FGF23 levels. CLINICALTRIALS: gov NCT 01,942,694, registered 9/16/2013.

Inappropriate secretion of fibroblast growth factor 23 despite hypophosphataemia with changes in bone turnover markers in a girl with systemic lupus erythematosus: Case report and review of the literature.

We report an 11-year-old girl with systemic lupus erythematosus (SLE) who showed hypophosphataemia (1.7 mg/dl, normal range: 3.9-5.8 mg/dl), a decrease in the tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) (0.77 mg/dl, normal range: 3.4-5.6 mg/dl), and an elevated serum fibroblast growth factor 23 (FGF23) (circulating phosphate-regulatory hormone) concentration (FGF23: 282 pg/ml, normal range: <52 pg/ml) at the onset. The patient was treated with intravenous pulse methylprednisolone, oral prednisolone, mycophenolate mofetil, hydroxychloroquine, and phosphorus supplement. Serum FGF23 concentrations decreased to near the reference value at 5 months after the onset of SLE, and the TmP/GFR (4.61 mg/dl) simultaneously improved. The urinary deoxypyridinoline (bone resorption marker) concentration on admission (18.9 nmol/mmol creatinine, normal range: 75.4 ± 6.8 nmol/mmol creatinine) was greatly reduced, and the bone-type alkaline phosphatase (bone formation marker) concentration (30.6 µg/l, normal range: 58.6 ± 15.3 µg/l) was also reduced during the increase in FGF23 concentrations before steroid therapy was initiated. The reason for the inappropriate secretion of FGF23, despite hypophosphataemia, remains unknown. The findings in our case suggest that changes in bone turnover markers can occur in patients with SLE and excess inappropriate secretion of FGF23, despite severe and persistent hypophosphataemia.

FGF23 Actions in CKD-MBD and other Organs During CKD.

Fibroblast growth factor 23 (FGF23) is a new endocrine product discovered in the past decade. In addition to being related to bone diseases, it has also been found to be related to kidney metabolism and parathyroid metabolism, especially as a biomarker and a key factor to be used in kidney diseases. FGF23 is upregulated as early as the second and third stages of chronic kidney disease (CKD) in response to relative phosphorus overload. The early rise of FGF23 has a protective effect on the body and is essential for maintaining phosphate balance. However, with the decline in renal function, eGFR (estimated glomerular filtration rate) declines, and the phosphorus excretion effect caused by FGF23 is weakened. It eventually leads to a variety of complications, such as bone disease (Chronic Kidney Disease-Mineral and Bone Metabolism Disorder), vascular calcification (VC), and more. Monoclonal antibodies against FGF23 are currently used to treat genetic diseases with increased FGF23. CKD is also a state of increased FGF23. This article reviews the current role of FGF23 in CKD and discusses the crosstalk between various organs under CKD conditions and FGF23. Studying the effect of hyperphosphatemia on different organs of CKD is important. The prospect of FGF23 for therapy is also discussed.

Fibroblast growth factor 23-Klotho and mineral metabolism in the first year after pediatric kidney transplantation: A single-center prospective study.

BACKGROUND: The role of fibroblast growth factor 23 (FGF23) levels in mineral metabolism before and after kidney transplantation in pediatric patients is poorly understood. METHODS: We prospectively evaluated 24 patients under 18 years of age (4.5 [3.3-9.8] years) who underwent living kidney transplantation between July 2016 and March 2018, and measured intact FGF23 and serum αKlotho levels, and other parameters of mineral metabolism before and after transplantation (Day 7, 1 and 4 months, and 1 year). Relationships between parameters were examined by linear analysis. RESULTS: FGF23 level was 440.8 [63.4-5916.3] pg/ml pre-transplant and decreased significantly to 37.1 [16.0-71.5] pg/ml at Day 7 post-transplant (-91.6%, p < .001). Thereafter, it remained at normal levels until 1 year. αKlotho level was 785 [568-1292] pg/ml pre-transplant and remained low at Day 7 and 1 month post-transplant, with an increasing trend at 4 months. Post-transplant phosphorus levels were significantly decreased compared with pre-transplant, with a lowest level of 1.7 [1.3-2.9] mg/dl, -5.7 [-6.8, -3.8] SD at Day 4, followed by gradual recovery. Phosphorus levels and the ratio of tubular maximum phosphate reabsorption were significantly and negatively associated with pre-transplant FGF23 until 4 months of post-transplant. Pre-transplant αKlotho was negatively associated with pre-transplant FGF23 but not FGF23 or other parameters after transplantation. CONCLUSION: FGF23 in pediatric kidney transplant patients decreased rapidly after transplantation and associated with post-transplant hypophosphatemia and increased phosphorus excretion. Post-transplant αKlotho was low early post-transplant but tended to increase subsequently. Post-transplant αKlotho was unaffected by pre-transplant FGF23 or other factors, suggesting pre-transplant chronic kidney disease status has no effect.

The relationship between the level of vitamin D, leptin and FGF23 in girls and young women with polycystic ovary syndrome.

Polycystic ovary syndrome is an endocrinopathy that mainly affects adolescent girls and young women of childbearing age. In girls, the presence of clinical and biochemical symptoms of hyperandrogenism should be particularly considered. The role of vitamin D deficiency in insulin resistance, inflammation, dyslipidemia, and obesity, i.e. in diseases associated with PCOS, has been investigated, which may suggest its involvement in the pathophysiology of the syndrome. Leptin has been shown to stimulate the formation of FGF23 in bones. There is a relationship between the incidence of dyslipidemia, adipose tissue mass and the concentration of fibroblast growth factor 23. The main aim of the presented research project is to assess the concentration of vitamin D, calcium, and selected hormones as well as the concentration of adipokines (leptin) in girls diagnosed with polycystic ovary syndrome. Materials and methods: The study included a population of 85 girls and young women aged 14 to 22 years. The study group included 37 girls who were diagnosed with polycystic ovary syndrome according to the modified Rotterdam's criteria. The control group consisted of 48 completely healthy girls. In the first stage of the study participants were required to answer background questions. Next, anthropometric measurements were performed. The laboratory tests assessed: leptin, FGF23, FSH, SHGB, total testosterone, DHEA-S, 25-OH-D3, PTH, calcium, androstadiene, AMH, glucose, insulin. Results: The vitamin D level in the group with polycystic ovary syndrome was lower than in the control group, but there was no statistically significant difference. The level of anti-Müllerian hormone was significantly higher in the group of girls diagnosed with PCOS compared to the control group. Statistically significant differences between both groups were also noted in the HOMA-IR value. The concentration of calcium, parathyroid hormone, FGF23 and leptin in the study and control groups showed no statistically significant difference. Conclusions: In the studied group of girls with PCOS, no correlation between the level of vitamin D and selected parameters such as: AMH leptin, HOMA-IR and FGF23 was confirmed. On this basis, it can be assumed that additional vitamin D supplementation would not reduce the symptoms of polycystic ovary syndrome.

A novel FGF23 mutation in hyperphosphatemic familial tumoral calcinosis and its deleterious effect on protein O-glycosylation.

Background: Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disease characterized by hyperphosphatemia and ectopic calcification, predominantly at periarticular locations. This study was performed to characterize the clinical profile of tumoral calcinosis and to identify gene mutations associated with HFTC and elucidated its pathogenic role. Methods: The three subjects (two male and one female) were aged 30, 25 and 15 years, respectively. The clinical features, histopathological findings, and outcomes of three subjects with HFTC were retrospectively reviewed. The three subjects were analyzed for FGF23, GALNT3 and KL mutations. Function of mutant gene was analyzed by western blotting and wheat germ agglutinin affinity chromatography. Results: All subjects had hyperphosphatemia and elevated calcium-phosphorus product. Calcinosis positions included the left shoulder, left index finger, and right hip. Bone and joint damage were present in two cases and multiple foci influenced body growth in one case. The histopathological features were firm, rubbery masses comprising multiple nodules of calcified material bordered by the proliferation of mononuclear or multinuclear macrophages, osteoclastic-like giant cells, fibroblasts, and chronic inflammatory cells. The novel mutation c.484A>G (p.N162D) in exon 3 of FGF23 was identified in one subject and his family members. Measurement of circulating FGF23 in the subject confirmed low intact FGF23 and increased C-terminal fragment. In vitro experiments showed that the mutant FGF23 proteins had defective O-glycosylation and impaired protein proteolysis protection. Conclusion: We identified a novel FGF23 missense mutation, and confirmed its damaging role in FGF23 protein O-glycosylation. Our findings expand the current spectrum of FGF23 variations that influence phosphorus metabolism.

Effect of Dietary Phosphorous Restriction on Fibroblast Growth 2 Factor-23 and sKlotho Levels in Patients with Stages 1-2 Chronic Kidney Disease.

Hyperphosphatemia has emerged as an independent risk factor for cardiovascular disease (CVD) and excess mortality in chronic kidney disease (CKD). The study evaluates the effect of dietary phosphorus (Ph) restriction (DPhR) at an early stage as a therapeutic strategy for delaying CKD progression and preventing CVD. Methods: This was a one-year interventional study conducted on 79 stage 1 and 2 CKD patients. The dietary phosphorus intake (DPhI), fibroblast growth factor-23 (FGF-23), sKlotho and serum phosphorous (SP) levels were analyzed. Patients were categorized into two groups based on their DPhI, recommended DPhI (RPhI) with <1000 mg/day of dietary phosphorous (dietary counselling) and high DPhI (HPhI) with >1000 mg/day (dietary intervention). For comparisons of differences between the two groups, independent t-test; for correlation analysis, Pearson correlation; for identifying the significant associated risk factors for CKD, binary logistic regression analysis and for comparing the means across the three visits, repeated measures ANOVA were used for statistical analysis. Results: The mean age and glomerular filtration rate (GFR) of CKD patients were 38 ± 12 years and 82.95 ± 16.93 mL/min/1.73 m2. FGF-23, SP, dietary protein and DPhI were significantly higher and sKlotho was significantly lower in HPhI group than RPhI group. In HPhI group; GFR, sKlotho, SP and FGF-23 correlated significantly with DPhI. Risk factors with a statistical bearing on the progression of CKD were animal-based diet, family history of CKD and hypertension. In HPhI group; GFR, DPhI, SP and FGF-23 levels significantly improved within the intervention period whereas a significant increase in sKlotho levels was observed in both the groups. Conclusion: Restricting DPhI emerged as a favorable therapeutic strategy for CKD patients for improving renal function and controlling hyperphosphatemia. The results of the present study may serve as the basis for future interventional studies with dietary phosphate restriction in the initial stages of CKD that would preserve renal function. Highlights: Early restriction of dietary phosphorus prevents decline in eGFR, elevation in FGF23 and increases Klotho levels.

Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia.

X-linked hypophosphataemia (XLH) is the most frequent cause of hypophosphataemia-associated rickets of genetic origin and is associated with high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). In addition to rickets and osteomalacia, patients with XLH have a heavy disease burden with enthesopathies, osteoarthritis, pseudofractures and dental complications, all of which contribute to reduced quality of life. This Consensus Statement presents the outcomes of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and provides robust clinical evidence on management in XLH, with an emphasis on patients' experiences and needs. During growth, conventional treatment with phosphate supplements and active vitamin D metabolites (such as calcitriol) improves growth, ameliorates leg deformities and dental manifestations, and reduces pain. The continuation of conventional treatment in symptom-free adults is still debated. A novel therapeutic approach is the monoclonal anti-FGF23 antibody burosumab. Although promising, further studies are required to clarify its long-term efficacy, particularly in adults. Given the diversity of symptoms and complications, an interdisciplinary approach to management is of paramount importance. The focus of treatment should be not only on the physical manifestations and challenges associated with XLH and other FGF23-mediated hypophosphataemia syndromes, but also on the major psychological and social impact of the disease.

Fibroblast growth factor-23 and parathyroid hormone suppress small intestinal magnesium absorption.

In the present study, we examined the systemic and direct effects of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) on duodenal, jejunal, and ileal Mg2+ absorption. The rats were injected with FGF-23 or PTH for 5 h before collecting the duodenum, jejunum, and ileum for Mg2+ transport analysis in Ussing chambers. The duodenum, jejunum, and ileum were directly exposed to FGF-23, PTH, or FGF-23 plus PTH with or without cell signaling inhibitors for 150 min in Ussing chambers prior to performing the Mg2+ transport study. The small intestinal tissues were also subjected to western blot analyses for FGF receptor (FGFR), PTH receptor (PTHR), Klotho, transient receptor potential melastatin 6 (TRPM6), and cyclin as well as the cystathionine ß-synthase domain divalent metal cation transport mediator 4 (CNNM4) expression. The small intestine abundantly expressed FGFR and PTHR proteins, whereas, Klotho was not expressed in rat small intestine. Systemic PTH or FGF-23 injection significantly suppressed transcellular Mg2+ transport in the duodenum and jejunum. Direct FGF-23-, PTH-, or FGF-23 plus PTH exposure also suppressed transcellular Mg2+ absorption in the duodenum and jejunum. There was no additional inhibitory effect of PTH and FGF-23 on intestinal Mg2+ absorption. The inhibitory effect of PTH, FGF-23, or FGF-23 plus PTH was abolished by Gö 6850. Systemic PTH- or FGF-23-injection significantly decreased membranous TRPM6 expression, but increased cytosolic CNNM4 expression in the duodenum, jejunum, and ileum. In the present study, we propose a novel magnesiotropic action of PTH and FGF-23 by modulating small intestinal Mg2+ absorption.

Decreased Concentration of Fibroblast Growth Factor 23 (FGF-23) as a Result of Supplementation with Selenium and Coenzyme Q10 in an Elderly Swedish Population: A Sub-Analysis.

There is a reduced intake of selenium in many countries due to low levels of selenium in the soil. This results in an increased cardiovascular risk. Fibroblast growth factor 23 (FGF-23) is active mainly in the metabolism of vitamin D and phosphorus. However, there are indications that FGF-23 may also provide information both on cardiovascular function and prognosis. The aim of the study was to evaluate the effect of supplementation with selenium and coenzyme Q10 on the FGF-23 concentration in an elderly population with low concentrations of both selenium and coenzyme Q10 and in which the supplementation improved cardiac function and mortality. In a randomised double-blind placebo-controlled trial, FGF-23 was measured in 219 individuals at the start and after 48 months. Selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 118) or placebo (n = 101) were given as a dietary supplement. The intervention time was 48 months. t-Tests, repeated measures of variance, and ANCOVA analyses were used to evaluate the differences in FGF-23 concentration. Following supplementation with selenium and coenzyme Q10, a significantly lower level of FGF-23 could be seen (p = 0.01). Applying 10 years of follow-up, those who later died a cardiovascular death had a significantly higher FGF-23 concentration after 48 months compared with those who survived (p = 0.036), and a significantly lower FGF-23 concentration could be seen in those with a normal renal function compared to those with an impaired renal function (p = 0.027). Supplementation with selenium and coenzyme Q10 to an elderly community-living population low in both substances prevented an increase of FGF-23 and also provided a reduced cardiovascular risk.

Effects of lanthanum carbonate and calcium carbonate on cardiovascular calcification in hemodialysis patients: A systematic review and meta-analysis.

OBJECTIVE: This paper was written to systematically review and meta-analyze the evidence on the efficacy of lanthanum carbonate (LC) and calcium carbonate (CC) and the risk of cardiovascular calcification on hemodialysis (HD) patients. MATERIALS AND METHODS: The Cochrane library, PubMed, Web of Science, Chinese journal full-text database (CNKI), WANGFANG DATA, and Sino Med were searched between January 1946 and December 2020. The literature with respect to the randomized controlled clinical trial comparing LC and CC in HD patients was selected. The main outcomes include coronary artery calcification score (CACS), cardiovascular events, and serum phosphorus (mmol/L). The statistical program used for meta-analysis was Stata V14.0. RESULTS: Of 388 original titles screened, data was extracted from 9 studies (625 participants). LC can significantly reduce the progression of coronary artery calcification compared to CC (standardized mean deviation (SMD) = -0.59, 95% CI: -0.94 to -0.25, p < 0.01). The LC group had lower serum phosphorus levels (SMD = -1.35, 95% CI: -2.33 to -0.36, p < 0.01), lower serum calcium levels (SMD = -1.03, 95% CI: -1.83 to -0.23, p = 0.012), and lower fibroblast growth factor 23 (FGF-23) level (SMD = -4.80, 95% CI: -7.96 to -1.64, p = 0.003) than the CC group. The Egger regression test of CACS showed no potential publication bias (p = 0.72). CONCLUSION: Compared with CC, LC can significantly delay the process of coronary artery calcification, and at the same time reduce patients' serum phosphate, serum calcium, and FGF-23. Therefore, we recommend LC as a phosphorus-lowering drug for HD patients.

The intersection of mineralocorticoid receptor activation and the FGF23-Klotho cascade: a duopoly that promotes renal and cardiovascular injury.

The nexus of chronic kidney disease (CKD) and cardiovascular disease (CVD) amplifies the morbidity and mortality of CKD, emphasizing the need for defining and establishing therapeutic initiatives to modify and abrogate the progression of CKD and concomitant CV risks. In addition to the traditional CV risk factors, disturbances of mineral metabolism are specific risk factors that contribute to the excessive CV mortality in patients with CKD. These risk factors include dysregulations of circulating factors that modulate phosphate metabolism, including fibroblast growth factor 23 (FGF23) and soluble Klotho. Reduced circulating levels and suppressed renal Klotho expression may be associated with adverse outcomes in CKD patients. While elevated circulating concentrations or locally produced FGF23 in the strained heart exert prohypertrophic mechanisms on the myocardium, Klotho attenuates tissue fibrosis, progression of CKD, cardiomyopathy, endothelial dysfunction, vascular stiffness and vascular calcification. Mineralocorticoid receptor (MR) activation in nonclassical targets, mediated by aldosterone and other ligands, amplifies CVD in CKD. In concert, we detail how the interplay of elevated FGF23, activation of the MR and concomitant reductions of circulating Klotho in CKD may potentiate each other's deleterious effects on the kidney and heart, thereby contributing to the initiation and progression of kidney and cardiac functional deterioration, acting through multipronged, albeit complementary, mechanistic pathways.

Serum Phosphorus, Parathyroid Hormone, and Serum Fibroblast Growth Factor-23 in Egyptian Patients Six Months after Undergoing Living-donor Kidney Transplantation.

End-stage renal disease is a major health problem with many complications. Previous studies emphasized the relationship of cardiovascular disease and mortality among these patients to dysregulated phosphate homeostasis. Even after successful renal transplantation, the risk is not eliminated. Several factors seem to interplay to regulate serum phosphorus levels after renal transplantation. Fibroblast growth factor-23 (FGF-23) is a hormone with the major function of inhibiting the reabsorption of phosphate by the renal tubules. Parathormone reduces the reabsorption of phosphate from the proximal tubule of the kidney. The aim of our study was to explore the changes that occurred in FGF-23 and intact parathyroid hormone (iPTH) levels in a cohort of Egyptian patients undergoing renal transplantation and to examine the effect of these factors on posttransplant serum phosphorus levels. The study was carried out prospectively on 37 candidates for live-donor renal transplantation. Serum levels of calcium, phosphorus, iPTH, and FGF-23 were measured before and 6 months after renal transplantation. Statistically significant differences were detected in serum calcium, phosphorus, FGF-23, and iPTH before and 6 months after transplantation (P < 0.001, P < 0.001, P < 0.001, and P < 0.001, respectively). The results also showed a statistically significant correlation between FGF-23 levels and phosphorus levels before transplantation. The interplay between FGF-23 and iPTH has an impact on posttransplant serum phosphorus levels.

Effectiveness of fibroblast growth factor 23 lowering modalities in chronic kidney disease: a systematic review and meta-analysis.

INTRODUCTION: The heightened fibroblast growth factor 23 (FGF23) level in patients with chronic kidney disease (CKD) is associated with increased cardiovascular disease and mortality. We performed a systematic review and meta-analysis to synthesize the available strategies to reduce FGF23 in CKD patients. METHODS: We conducted a meta-analysis by searching the databases of MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) and single-arm studies that examined the effects of dietary phosphate restriction, phosphate binders, iron supplements, calcimimetics, parathyroidectomy, dialysis techniques, and the outcome of preservation of residual renal function (RRF) on FGF23 levels in CKD patients. Random-effects model meta-analyses were used to compute changes in the outcome of interests. RESULTS: A total of 41 articles (7590 patients), comprising 36 RCTs, 5 prospective studies were included in this meta-analysis. Dietary phosphate restriction less than 800 mg per day yielded insignificant effect on FGF23 reduction. Interestingly sevelamer, lanthanum, iron-based phosphate binders, and iron supplement significantly lowered FGF23 levels. In CKD patients with secondary hyperparathyroidism, calcimimetics prescription could significantly reduce FGF23 levels, while surgical parathyroidectomy had no significant effect. In dialysis patients, preservation of RRF and hemoperfusion as well as hemodiafiltration provided a significant decrease in FGF23 levels. CONCLUSIONS: The present meta-analysis demonstrated that non-calcium-based phosphate binders including sevelamer, lanthanum, and iron-based phosphate binders, iron supplements, calcimimetics, hemoperfusion, and preservation of RRF could effectively reduce FGF23 in CKD patients.