Plasma Fibroblast Growth Factor Research Articles

Direct regulation of fibroblast growth factor 23 by energy intake through mTOR

To test the hypothesis that fibroblast growth factor 23 (FGF23) is directly regulated by energy intake, in vivo and in vitro experiments were conducted. Three groups of rats were fed diets with high (HC), normal (NC) and low (LC) caloric content that resulted in different energy intake. In vitro, UMR106 cells were incubated in high (HG, 4.5 g/l) or low glucose (LG, 1 g/l) medium. Additional treatments included phosphorus (P), mannitol, rapamycin and everolimus. Intestinal absorption of P and plasma P concentrations were similar in the three groups of rats. As compared with NC, plasma FGF23 concentrations were increased in HC and decreased in the LC group. A significant correlation between energy intake and plasma FGF23 concentrations was observed. In vitro, mRNA FGF23 was significantly higher in UMR106 cells cultured in HG than in LG. When exposed to high P, mRNA FGF23 increased but only when cells were cultured in HG. Cells incubated with HG and mechanistic target of rapamycin (mTOR) inhibitors expressed low mRNA FGF23, similar to the values obtained in LG. In conclusion, this study shows a direct regulation of FGF23 production by energy availability and demonstrates that the mTOR signaling pathway plays a central role in this regulatory system.

The relationship between urinary kidney injury molecule-1 and blood bone metabolism markers in patients with chronic kidney disease .

The aim of this study was to evaluate the changes of urinary kidney injury molecule-1(uKIM-1) in chronic kidney disease (CKD) at different stages, and to determine the relationships between uKIM-1 and circulating bone metabolism markers. This cross-sectional study included CKD patients (n = 121) and controls (n = 65). CKD stages were assigned to each individual according to their estimated glomerular filtration rate (eGFR), which was calculated with the modification of diet in renal disease (MDRD) equation. We evaluated the relationships of bone metabolism markers (including calcium, phosphorus, intact parathyroid hormone (iPTH), 25 hydroxy vitamin D (25(OH)D), alkaline phosphatase (ALP), fibroblast growth factor 23 (FGF23), and α-Klotho), uKIM-1, and eGFR. We also compared the levels of bone metabolism markers and uKIM-1 at different CKD stages. The uKIM-1 level was standardized with urine creatinine (uCr). Compared with healthy controls, CKD patients had higher levels of uKIM-1/uCr, serum creatinine, urea, phosphorus, iPTH, and plasma FGF23, whereas they had lower levels of serum calcium, α-Klotho, and plasma 25(OH)D. In CKD patients, eGFR was positively correlated with levels of serum calcium, α-Klotho, and plasma 25(OH)D, whereas it was negatively correlated with serum phosphorus, iPTH, plasma FGF23, and uKIM-1/uCr. Serum calcium and α-Klotho were significantly decreased in patients with stage 5 CKD compared to those with stage 1 CKD. Serum phosphorus, iPTH, and plasma FGF23 were significantly elevated in patients with stage 4 CKD when compared to those with stage 1 CKD. UKIM-1/uCr was significantly elevated in patients with stage 5 CKD when compared to those with stage 1 CKD. In CKD patients, uKIM-1/uCr levels were positively correlated with levels of serum phosphorus and plasma FGF23, whereas they were negatively correlated with serum calcium and plasma 25(OH)D. UKIM-1/uCr levels are increased with the deterioration of CKD stage and are correlated with the development of CKD-mineral and bone disorder (CKD-MBD).

Association between plasma fibroblast growth factor 23 and left ventricular mass index in patients with Takayasu arteritis.

Fibroblast growth factor (FGF23) is an endocrine hormone that can be induced by inflammation and plays a role in the pathogenesis of cardiac abnormalities. Few studies have reported plasma FGF23 levels in patients with Takayasu arteritis (TAK). We hypothesized that the production of FGF23 in TAK is associated with abnormal cardiac mass. Forty-seven patients diagnosed with TAK and 52 age- and gender-matched healthy controls were included in this observational study. Plasma FGF23 was detected by human enzyme-linked immunosorbent assay. Multivariable linear regression analyses were performed to examine the association between FGF23 and left ventricular mass index (LVMI). Patients with TAK had higher plasma FGF23 than healthy controls [121.8 (84.5-168.8) vs. 86.7 (70.5-101.1) RU/ml, P < 0.001]. Patients with higher FGF23 concentrations were more likely to be females (100.0% vs. 75.0%, P = 0.01), angiographic type V (69.6% vs. 33.3%, P = 0.013), heart failure (43.5% vs. 12.5%, P = 0.018), and have higher LVMI [126.3 (81.1-177.7) vs. 85.9 (69.7-114.3) g/m2, P = 0.041]. Plasma FGF23 was significantly associated with LVMI in TAK patients [β = 0.402, 95% confidence interval (CI) 0.032-0.301, P = 0.016], after adjusting for age, gender, disease duration, angiographic type (angiographic type V vs. non-angiographic type V), the presence of cardiovascular events and hypertension, and serum N-terminal pro-B-type natriuretic peptide in the multivariate linear regression. Age (β = - 0.399, P = 0.016) and the presence of angiographic type V (β = 0.376, P = 0.018) were identified to be significant determinants of plasma FGF23 in patients with TAK. Plasma FGF23 was elevated in patients with TAK and was associated with LVMI. FGF23 may participate in the development of abnormal cardiac mass in patients with TAK.Key Points• Plasma FGF23 was elevated in patients with TAK.• FGF23 was significantly associated with LVMI in TAK.• Age and the presence of angiographic type V were determinants of plasma FGF23 in patients with TAK.

FGF21, not GCN2, influences bone morphology due to dietary protein restrictions

BackgroundDietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone. MethodsAdult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (μCT) for changes in trabecular and cortical architecture and mass. ResultsIn WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture. ConclusionsThis study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21.

Plasma fibroblast growth factor 21 levels increase with ectopic fat accumulation and its receptor levels are decreased in the visceral fat of patients with type 2 diabetes

BackgroundFibroblast growth factor 21 (FGF21) is a novel metabolic regulator that has beneficial effects on glucose and lipid metabolism. However, plasma FGF21 levels are paradoxically increased in type 2 diabetes...

Elevated FGF23 and disordered renal mineral handling with reduced bone mineralization in chronically erythropoietin over-expressing transgenic mice

Fibroblast Growth Factor 23 (FGF23) is a phosphaturic factor causing increased renal phosphate excretion as well as suppression of 1,25 (OH)2-vitamin D3. Highly elevated FGF23 can promote development of rickets and osteomalacia. We and others previously reported that acute application of erythropoietin (EPO) stimulates FGF23 production. Considering that EPO is clinically used as chronic treatment against anemia, we used here the Tg6 mouse model that constitutively overexpresses human EPO in an oxygen-independent manner, to examine the consequences of long-term EPO therapy on mineral and bone metabolism. Six to eight weeks old female Tg6 mice showed elevated intact and C-terminal fragment of FGF23 but normal plasma levels of PTH, calcitriol, calcium and phosphate. Renal function showed moderate alterations with higher urea and creatinine clearance and mild albuminuria. Renal phosphate excretion was normal whereas mild hypercalciuria was found. Renal expression of the key proteins TRPV5 and calbindin D28k involved in active calcium reabsorption was reduced in Tg6 mice. Plasma levels of the bone turnover marker osteocalcin were comparable between groups. However, urinary excretion of deoxypyridinoline (DPD) was lower in Tg6 mice. MicroCT analysis showed reduced total, cortical, and trabecular bone mineral density in femora from Tg6 mice. Our data reveal that chronic elevation of EPO is associated with high FGF23 levels and disturbed mineral homeostasis resulting in reduced bone mineral density. These observations imply the need to study the impact of therapeutically applied EPO on bone mineralization in patients, especially those suffering from chronic kidney disease.

Higher plasma fibroblast growth factor 23 levels are associated with a higher risk profile in pulmonary arterial hypertension.

Metabolic abnormalities are proposed to contribute to pulmonary arterial as well as right ventricular remodelling in pulmonary arterial hypertension. Among the proposed abnormalities are altered glucose and lipid processing, mitochondrial malfunction, oxidative stress as well as vitamin D and iron abnormalities. In the present study, we investigated 11 metabolic plasma biomarkers, with the hypothesis that metabolic proteins may mirror disease severity in pulmonary arterial hypertension. Using proximity extension assays, plasma metabolic biomarkers were measured in 48 pulmonary arterial hypertension patients at diagnosis and, in 33 of them, at an early treatment follow-up, as well as in 16 healthy controls. Among the studied metabolic biomarkers, plasma fibroblast growth factor-23 (p < 0.001), fibroblast growth factor-21 (p < 0.001), fatty acid binding protein 4 (p < 0.001) and lectin-like oxidised low-density lipoprotein receptor 1 (p < 0.001) were increased and paraoxonase-3 was decreased (p < 0.001) in pulmonary arterial hypertension at diagnosis versus controls. Fibroblast growth factor-23 showed the strongest correlations to studied clinical parameters and was therefore selected for further analyses. Fibroblast growth factor-23 correlated specifically to mean right atrial pressure (r = 0.67, p < 0.001), six-min walking distance (r = −0.66, p < 0.001), NT-proBNP (r = 0.64, p < 0.001), venous oxygen saturation (r = −0.61, p < 0.001), cardiac index (r = −0.39, p < 0.007) and pulmonary vascular resistance (r = 0.37, p < 0.01). Fibroblast growth factor-23 correlated moreover to ESC/ERS (r = 0.72, p < 0.001) and the REVEAL risk score (r = 0.61, p < 0.001). Comparing early treatment follow-up with baseline, fibroblast growth factor-23 decreased (p < 0.02), with changes in fibroblast growth factor-23 correlating to changes in six-min walking distance (r = −0.56, p < 0.003), venous oxygen saturation (r = −0.46, p < 0.01), pulmonary vascular resistance (r = 0.43, p < 0.02), mean right atrial pressure (r = 0.38, p < 0.04) and cardiac index (r = −0.39, p < 0.04). Elevated plasma fibroblast growth factor-23 levels at pulmonary arterial hypertension diagnosis were associated with worse haemodynamics and a higher risk profile, and were decreased after the administration of pulmonary arterial hypertension-specific treatment.

FGF-23 and Cardio-Renal Interactions in Heart Failure

Background Fibroblast growth factor-23 (FGF-23) is a phosphaturic hormone with a primary role in the regulation of phosphate homeostasis. Recently, FGF-23 was shown to be a strong predictor of cardiovascular outcomes, and animal models have reported multiple non-phosphaturic, or off-target, effects of FGF-23. Some of the negative cardio-renal actions reported in the literature are adverse left ventricular remodeling, induction of inflammation, renal/cardiac fibrosis, and direct effects on renal sodium retention. The aim of this current investigation was to further explore the association between FGF-23 with various parameters of cardio-renal dysfunction. Hypothesis FGF-23 will be associated with cardio-renal parameters such as inflammation, neurohormonal activation, diuretic responsiveness, and survival. Methods We analyzed plasma FGF-23 levels in 199 outpatient heart failure (HF) patients who underwent diuretic administration followed by timed urine collections. Diuretic response was defined as the sodium output per doubling of the diuretic dose. Results Higher levels of FGF-23 tended to correlate with serum phosphate (r=0.21, p=0.09) but were not correlated with serum calcium (p=0.37). There were stronger correlations between FGF-23 and several parameters of cardio-renal dysfunction including lower eGFR (r=-0.42, p 0.3 for both). Higher levels of FGF-23 predicted worse diuretic responsiveness (r=-0.47, p Conclusion In patients with HF, plasma levels of FGF-23 were associated with multiple metrics of cardio-renal dysfunction, including a strong independent association with diuretic responsiveness and mortality. Additional research is warranted to understand if FGF-23 is a marker or mediator of cardio-renal dysfunction and if interventions to lower FGF-23 levels can improve outcomes.

Impact of Tenofovir-Based Pre-exposure Prophylaxis on Biomarkers of Bone Formation, Bone Resorption, and Bone Mineral Metabolism in HIV-Negative Adults.

BackgroundPre-exposure prophylaxis (PrEP) with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) reduces the risk of HIV seroconversion but may promote bone mineral density (BMD) decline. The mechanisms of BMD decline with FTC/TDF remain unclear, and studies in HIV-positive individuals have been confounded by the effects of HIV and concomitant antiretroviral medications. We evaluated the impact of FTC/TDF on biomarkers of bone remodeling and bone mineral metabolism in HIV-negative men and women enrolled in the Partners PrEP Study.MethodsIn a random sample of HIV-negative participants randomized to FTC/TDF PrEP (n = 50) or placebo (n = 50), serum parathyroid hormone (PTH), bone biomarkers (C-telopeptide, procollagen 1 intact N-terminal propeptide, and sclerostin), and plasma fibroblast growth factor 23 were measured at baseline and month 24, and the percentage change was compared between groups. In a complementary analysis, we compared the change in biomarkers between participants with and without a 25% decline in glomerular filtration rate (GFR) on FTC/TDF.ResultsBaseline characteristics were similar between the groups (median age, 38 years; 40% women). Vitamin D insufficiency was common, but baseline GFR and PTH were in the normal range. We observed a significantly greater percent increase in serum C-telopeptide in participants randomized to FTC/TDF vs placebo (P = .03), suggesting an increase in bone remodeling. We observed no differences in the other biomarkers, or in a separate analysis comparing participants with and without a decline in GFR.ConclusionsIncreased bone remodeling may mediate the BMD decline observed with tenofovir-containing PrEP and antiretroviral therapy, independent of a TDF-mediated decrease in kidney function.

Methionine Abrogates the Reno-Protective Effect of a Low-Protein Diet Against Diabetic Kidney Disease in Obese Rats with Type 2 Diabetes

Background: Dietary interventions, including a low-protein diet (LPD) and methionine (Met) restriction, has shown longevity and metabolic health. LPD has a reno-protective effect against diabetic kidney disease (DKD) in rats with type 2 diabetes and obesity; however, it is unclear whether the beneficial effect of LPD is mediated by a low-Met intake. Methods: Rats were divided into four groups at 24 weeks of age: 1) non-diabetic Wistar lean (fa/-) rats fed a standard diet including 0.64% Met (STD) (Control); 2) Wistar fatty (fa/fa) rats with type 2 diabetes/obesity (WFRs) fed STD (0.64% Met) (Diabetes); 3) WFRs fed LPD (0.15% Met) (LPD); and 4) WFRs fed LP+Met (0.64% Met) (LP+Met). The dietary intervention was performed for 20 weeks. Findings: Accumulation of S-adenosylmethionine (SAM) in renal tubular cells of diabetic rats, associated with reduced glycine Nmethyltransferase (Gnmt) expression, led to mechanistic target of rapamycin complex1 (mTORC1) activation and impaired autophagy, resulting in the progression of DKD through mitochondrial abnormalities, oxidative stress, inflammation, tubular cell damage and tubulointerstitial fibrosis. Additionally, cystathionine γ-lyase (CGL) expression was decreased in the diabetic renal cortex. LPD reversed all of these alterations of the diabetic kidney; however, the LP+Met diet abrogated the effects of LPD in diabetic rats. Furthermore, LPD partially improved the diabetic state, while the LP+Met diet exacerbated it and was accompanied by changes in the LPD-induced expression of plasma fibroblast growth factor 21 (FGF21). Interpretation: LPD could exert a reno-protective effect through low-Met intake-mediated suppression of mTORC1 and restored autophagy, which is associated with a decrease in the accumulation of SAM due to reduced expression of Gnmt in diabetic kidneys. Funding Statement: This work was financially supported through a Grant-in-Aid for Scientific Research KAKENHI (C) (24591218), a grant for collaborative research with Kowa Hakko Kirin to MK. Declaration of Interests: Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Kyowa Hakko Kirin, Taisho Toyama Pharmaceutical Co. and Ono Pharmaceutical Co. contributed to establishing the Division of Anticipatory Molecular Food Science and Technology. The authors declare that there is no duality of interest associated with this manuscript. Ethics Approval Statement: The Research Center for Animal Life Science of Kanazawa Medical University approved all experiments, and all experiments were performed in accordance with the relevant guidelines and regulations.

Relationship between plasma fibroblast growth factor-23 and subclinical cardiovascular damages in children with primary hypertension

Objective: To examine the plasma fibroblast growth factor-23 (FGF-23) concentration in children with primary hypertension and to investigate the association between plasma FGF-23 and subclinical cardiovascular damages,and to identify its predictive value for diagnosis. Methods: With prospective study,77 patients (61 males and 16 females) who were diagnosed as primary hypertension with the average age of (11.8±2.2) years were enrolled with informed consent in Children's Hospital,Capital Institute of Pediatrics from October 2016 to December 2017. Carotid wall intima-media thickness (cIMT) measured by Doppler ultrasound and left ventricular hypertrophy (LVH) identified by echocardiography were assessed as parameters of subclinical cardiovascular damages. Patients were divided into increased cIMT group (n=18) and normal cIMT group (n=46) (64 patients with complete data of cIMT). According to left ventricular geometry,patients were divided into LVH group (n=27) and normal geometry group (n=50). Concentration of plasma FGF-23 was detected in all children by enzyme linked immunosorbent assay test. Mann-Whitney U test was used to compare plasma levels of FGF-23 between groups. Kendall's tau-b correlation coefficient was used to analyze the correlation between plasma FGF-23 and cIMT/LVH. Receiver operating characteristic (ROC) curve was used to analyze the value of plasma FGF-23 in the prediction of subclinical cardiovascular damage. Results: The concentration of plasma FGF-23 in the increased cIMT group was higher than that in the normal cIMT group (55.6 (46.2,63.5) vs. 48.6 (39.4, 57.3) ×10(3) RU/L, Z=-2.143, P=0.032) . Also, plasma FGF-23 showed positive correlation with cIMT(r=0.222, P=0.032). According to ROC curve analysis,the cutoff value of plasma FGF-23 for prediction of increased cIMT was 53.9×10(3) RU/L (55.6% sensitivity and 71.7% specificity). The concentration of plasma FGF-23 in the LVH group was significantly higher than that in normal geometry group (55.0 (46.8, 65.7) vs. 48.2 (39.5, 56.0)×10(3) RU/L, Z=-2.375, P=0.018). And,plasma FGF-23 was correlated positively with LVH (r=0.224, P=0.018). The concentration of plasma FGF-23 in patients with concentric remodeling (n=10) was significantly higher than that of the normal geometry group (56.9 (49.6, 66.3) vs. 48.2 (39.5,56.0) ×10(3) RU/L, Z=-2.093, P=0.036). According to ROC curve analysis,the cutoff value of plasma FGF-23 for prediction of LVH was 49.1×10(3) RU/L (70.4% sensitivity and 60.0% specificity). Conclusion: The concentration of plasma FGF-23 in children with primary hypertension was correlated positively with LVH and cIMT and had certain predictive value of diagnosis for subclinical cardiovascular damages.

301-LB: Effects of Amino Acid Restriction on Development of Type 2 Diabetes in NZO Mice by FGF21 Secretion

Dietary protein restriction (PR) is emerging as an alternative approach to treat obesity and glucose intolerance since it increases plasma fibroblast growth factor 21 (FGF-21) levels. Also, dietary methionine restriction (MR) is known to mimic the metabolic effects of PR by increasing FGF-21 and inducing beneficial effects. Therefore, we tested in New Zealand Obese (NZO) mice, a model of polygenic obesity and type 2 diabetes, whether a moderate PR or a MR protects against diabetes. Moreover, we investigated whether a decreased methionine intake caused by vegetarian and vegan diets modulates plasma FGF-21 in humans. NZO mice were placed on high-fat diets that provided protein at control (18 gm%), low levels (4 gm%), or on high-fat diets (protein, 18 gm%) that provided methionine at control (0.86 gm%) or low levels (0.17 gm%) for up to 9 weeks. Changes in glucose homeostasis and energy expenditure were assessed. Among humans, plasma FGF-21 levels were investigated by comparing vegetarians and vegans to omnivores, and the effect of short-term vegetarian diet on FGF-21 induction was evaluated. PR prevented the onset of hyperglycemia only when protein was substituted by fat. When protein was substituted by carbohydrates, mice developed hyperglycemia two weeks later than the control, despite elevated plasma FGF-21 levels and increased energy expenditure. MR elevated plasma FGF-21 levels and prevented the onset of hyperglycemia. Human plasma FGF-21 levels were higher in vegans and vegetarians compared to omnivores. Interestingly, already a short-term switch to a vegetarian diet increased plasma FGF-21 in omnivores. Thus, restriction of dietary protein and methionine elevates plasma FGF-21 levels, which protect from hyperglycemia, an effect compromised by high dietary carbohydrates in NZO mice. Patients at high risk of developing type 2 diabetes may benefit from dietary changes in favor of methionine restriction, via increased circulating levels of FGF-21, without protein and calorie restriction. Disclosure T. Castaño-Martinez: None. W. Jonas: None. D. Weber: None. C. Weikert: None. T. Laeger: None. Funding Deutsche Forschungsgemeinschaft

Associations of plasma fibroblast growth factor 23 and other markers of chronic kidney disease-Mineral and bone disorder with all-cause mortality in South African patients on maintenance dialysis: A 3-year prospective cohort study.

IntroductionFew studies have linked high levels of plasma C-terminal fibroblast growth factor 23 (FGF23) with poor clinical outcomes in patients on maintenance haemodialysis (MHD), while the association between intact FGF23 and mortality in this group of patients remains inconclusive.Therefore, the aim of this study was to evaluate the association between plasma levels of intact FGF23 and mortality in dialysis patients.MethodsA prospective multicenter study involving patients undergoing dialysis at three dialysis centers in Johannesburg was undertaken between 1st October 2014 and 31st December 2017.ResultsThe study comprised 165 chronic dialysis patients (111 blacks, 54 whites) with a mean age of 46.6 ±14.2 years. During a three year follow up period, there were 46 deaths (1.03 per 100 person-years). The median plasma FGF 23 level was 382 pg/ml (interquartile range [IQR], 145–2977). In adjusted multivariable analyses, there was a non-statistically significant increase in the risk of mortality with higher quartiles of FGF 23 levels: the adjusted hazard ratios (HR) for the second, third and fourth quantiles were HR 3.20 (95% CI, 0.99–10.35; P = 0.052), HR 2.43(95% CI,0.65–9.09; P = 0.19), and HR 2.09 (95% CI, 0.66–7.32; P = 0.25),respectively. Corrected serum calcium 2.38–2.5 mmol/l [HR 2.98 (95% CI, 1.07–8.29; P = 0.04] and > 2.50 mmol/l [HR 5.50 (95% CI, 1.84–16.48; P = 0.002] were independently associated with increased risk of death. Likewise, patients with intact parathyroid hormone > 600 pg/ml had a 3.46-fold higher risk of death (HR 3.46, 95% CI, 1.22–9.82 P = 0.019). These findings persisted in time -dependent analyses.ConclusionHigher levels of intact FGF 23 appear not to be independently associated with all-cause mortality in our dialysis patients, while hypercalcaemia and severe hyperparathyroidism were found to be independent predictors of mortality in this cohort of patients.

Glucocorticoids Decrease Longitudinal Bone Growth in Pediatric Kidney Transplant Recipients by Stimulating the FGF23/FGFR3 Signaling Pathway.

Renal transplantation (RTx) is an effective therapy to improve clinical outcomes in pediatric patients with terminal chronic kidney disease. However, chronic immunosuppression with glucocorticoids (GCs) reduces bone growth and BMD. The mechanisms causing GC-induced growth impairment have not been fully clarified. Fibroblast growth factor 23 (FGF23) is a peptide hormone that regulates phosphate homeostasis and bone growth. In pathological conditions, FGF23 excess or abnormal FGF receptors (FGFR) activity leads to bone growth impairment. Experimental data indicate that FGF23 expression is induced by chronic GC exposure. Therefore, we hypothesize that GCs impair bone growth by increasing FGF23 expression, which has direct effects on bone growth plate. In a post hoc analysis of a multicentric randomized clinical trial of prepubertal RTx children treated with early GC withdrawal or chronic GC treatment, we observed that GC withdrawal was associated with improvement in longitudinal growth and BMD, and lower plasma FGF23 levels as compared with a chronic GC group. In prepubertal rats, GC-induced bone growth retardation correlated with increased plasma FGF23 and bone FGF23 expression. Additionally, GC treatment decreased FGFR1 expression whereas it increased FGFR3 expression in mouse tibia explants. The GC-induced bone growth impairment in tibiae explants was prevented by blockade of FGF23 receptors using either a pan-FGFR antagonist (PD173074), a C-terminal FGF23 peptide (FGF23180-205) which blocks the binding of FGF23 to the FGFR-Klotho complex or a specific FGFR3 antagonist (P3). Finally, local administration of PD173074 into the tibia growth plate ameliorated cartilage growth impairment in GC-treated rats. These results show that GC treatment partially reduces longitudinal bone growth via upregulation of FGF23 and FGFR3 expression, thus suggesting that the FGF23/Klotho/FGFR3 axis at the growth plate could be a potential therapeutic target for the management of GC-induced growth impairment in children.

Tumor necrosis factor stimulates fibroblast growth factor 23 levels in chronic kidney disease and non-renal inflammation

Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis, and its early rise in patients with chronic kidney disease is independently associated with all-cause mortality. Since inflammation is characteristic of chronic kidney disease and associates with increased plasma FGF23 we examined whether inflammation directly stimulates FGF23. In a population-based cohort, plasma tumor necrosis factor (TNF) was the only inflammatory cytokine that independently and positively correlated with plasma FGF23. Mouse models of chronic kidney disease showed signs of renal inflammation, renal FGF23 expression and elevated systemic FGF23 levels. Renal FGF23 expression coincidedwith expression of the orphan nuclear receptor Nurr1 regulating FGF23 in other organs. Antibody-mediated neutralization of TNF normalized plasma FGF23 and suppressed ectopic renal Fgf23 expression. Conversely, TNF administration to control mice increased plasma FGF23 without altering plasma phosphate. Moreover, in Il10-deficient mice with inflammatory bowel disease and normal kidney function, plasma FGF23 was elevated and normalized upon TNF neutralization. Thus, the inflammatory cytokine TNF contributes to elevated systemic FGF23 levels and also triggers ectopic renal Fgf23 expression in animal models of chronic kidney disease.

Extraskeletal Calcifications in Hutchinson-Gilford Progeria Syndrome.

Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development. Children from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction. Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium × phosphorus product (Ca × Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p = 0.03). Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.

Metabolic Determinants of Weight Gain in Humans.

One of the fundamental challenges in obesity research is to identify subjects prone to gain weight so that obesity and its comorbidities can be promptly prevented or treated. The principles of thermodynamics as applied to human body energetics demonstrate that susceptibility to weight gain varies among individuals as a result of inter-individual differences in energy expenditure and energy intake, two factors that counterbalance one another and that together determine daily energy balance and, ultimately, bodyweight change. This review focuses on the variability among individuals in human metabolism that determines weight change. Conflicting results have been reported about the role of inter-individual differences in energy metabolism during energy balance in relation to future weight change. However, recent studies show that metabolic responses to acute, short-term dietary interventions that create energy imbalance, such as low-protein overfeeding or fasting for 24 hours, may reveal the underlying metabolic phenotype that determines the degree of resistance to diet-induced weight loss or the propensity to spontaneous weight gain over time. Metabolically “thrifty” individuals, characterized by a predilection for saving energy in settings of undernutrition and dietary protein restriction, display a minimal increase in plasma Fibroblast Growth Factor 21 (FGF21) concentrations in response to a low-protein overfeeding diet and tend to gain more weight over time as compared to metabolically “spendthrift” individuals. Similarly, inter-individual variability in the causal relationship between energy expenditure and energy intake (“energy sensing”) and in the metabolic response to cold exposure (e.g., brown adipose tissue activation) seems to some extent to be indicative of individual propensity to weight gain. Thus, an increased understanding and the clinical characterization of phenotypic differences in energy metabolism among individuals (metabolic profile) may lead to new strategies to prevent weight gain or improve weight loss interventions by targeted therapies on the basis of metabolic phenotype and susceptibility to obesity in individual persons.

Plasma Fibroblast Growth Factor 23 Is Elevated in Pediatric Primary Hypertension.

Fibroblast growth factor 23 (FGF 23), an endocrine hormone regulating the homeostasis of phosphate and vitamin D, has been shown to play a role in cardiovascular disease. Increased blood FGF 23 is found to be associated with elevated blood pressure in adults. However, measurement of FGF 23 in hypertensive children has not been documented. In this study, a total of 98 children with primary hypertension and 37 controls were recruited, and blood FGF 23 was comparatively investigated. Additionally, FGF 23 levels were compared between the subgroups of patients after hypertensive children were sub-grouped according to their cardiac geometry, hypertension stages, insulin levels, and weight. The case group had a FGF 23 level of 48.99 (16.42), expressed as the median (the interquartile range), significantly higher than the 41.72 (7.05) from the control group (p = 0.0002). While no remarkable differences were observed in FGF 23 levels between non-obese and obese hypertensive children, between patients with stage 1 and stage 2 hypertension, or between patients with normal and high insulin levels; hypertensive children with abnormal cardiac geometry had significantly higher levels of FGF 23 than patients with normal cardiac geometry (p = 0.0085). Our data revealed for the first time that hypertensive children have higher levels of FGF 23. Further studies are needed to examine if lowering FGF 23 improves the cardiac geometry in hypertensive children with higher FGF 23.

Lack of a relationship between plasma fibroblast growth factor-23 and phosphate utilization in young chicks

Fibroblast growth factor 23 (FGF-23) is proposed to be the hormone that controls phosphate (P) homeostasis in chickens. This study was initiated to investigate the effect of feeding young chicks diets that were either adequate (0.45%) or marginal (0.25%) in available P content on plasma FGF-23 levels. The dietary level of available P significantly (P ≤ 0.05) affected bone mineralization and bone length, but was without effect (P > 0.05) on growth rate and circulating FGF-23 concentrations. Substantial individual variation in bone mineralization and plasma FGF-23 levels was observed, and the correlation between these two variables was non-significant (P > 0.05). This suggested that there was no alteration in FGF-23 activity in response to suboptimal dietary P intake. The relationship of these observations to studies on the immunosuppression of FGF-23 activity is subsequentlydiscussed.

Plasma Fibroblast Growth Factor 21 Is Associated With Severity of Nonalcoholic Steatohepatitis in Patients With Obesity and Type 2 Diabetes.

The relationship between plasma fibroblast growth factor 21 (FGF21), insulin resistance, and steatohepatitis has not been systematically assessed. To determine if higher plasma FGF21 is associated with worse steatohepatitis on liver biopsy in patients with nonalcoholic fatty liver disease (NAFLD). Cross-sectional study in a university hospital. Patients with a body mass index >25 (n = 187) underwent: (i) euglycemic hyperinsulinemic clamp to assess tissue-specific insulin resistance (IR); (ii) liver magnetic resonance spectroscopy for intrahepatic triglyceride quantification, (iii) liver biopsy (if NAFLD present; n = 146); and (iv) fasting plasma FGF21 levels. Patients were divided into three groups: (i) No NAFLD (n = 41); (ii) No nonalcoholic steatohepatitis (NASH) (patients with isolated steatosis or borderline NASH; n = 52); and (iii) NASH (patients with definite NASH; n = 94). Groups were well-matched for age/sex, prevalence of type 2 diabetes mellitus, and hemoglobin A1c. During euglycemic hyperinsulinemic insulin clamp, insulin sensitivity in skeletal muscle and adipose tissue worsened from No NAFLD to NASH (both P < 0.001). Plasma FGF21 levels correlated inversely with insulin sensitivity in adipose tissue (r = -0.17, P = 0.006) and skeletal muscle (r = -0.23, P = 0.007), but not with liver insulin sensitivity. Plasma FGF21 was higher in patients with NASH (453 ± 262 pg/mL) when compared with the No NASH (341 ± 198 pg/mL, P = 0.03) or No NAFLD (325 ± 289 pg/mL, P = 0.02) groups. Plasma FGF21 increased with the severity of necroinflammation (P = 0.02), and most significantly with worse fibrosis (P < 0.001), but not with worsening steatosis (P = 0.60). Plasma FGF21 correlates with severity of steatohepatitis, in particular of fibrosis, in patients with NASH. Measurement of FGF21 may help identify patients at the highest risk of disease progression.