Serum FGF23 Levels Research Articles

Assessment of fibroblast growth factor 19 as a non-invasive serum marker for hepatocellular carcinoma.

BACKGROUNDFibroblast growth factor 19 (FGF-19) is one of the founding members of the endocrine FGF subfamily. Recently, it has been the subject of much interest owing to its role in various physiological processes affecting glucose and lipid metabolism and the regulation of bile acid secretion as well as cell proliferation, differentiation, and motility. Additionally, FGF-19 secretion in an autocrine style has reportedly contributed to cancer progression in various types of malignancies including hepatocellular carcinoma (HCC). AIMTo estimate the serum FGF-19 concentrations in HCC cases and assess its diagnostic performance for the detection of HCC.METHODSWe recruited 90 adult participants and divided them into three equal groups: Healthy controls, cirrhosis patients, and HCC patients. Serum FGF-19 concentrations were measured using the Human FGF-19 ELISA kit. RESULTSWe detected a high statistically significant difference in serum FGF-19 levels among the three groups. The highest level was observed in the HCC group, followed by the cirrhosis and control groups (236.44 ± 40.94 vs 125.63 ± 31.54 vs 69.60 ± 20.90 pg/mL, respectively, P ≤ 0.001). FGF-19 was positively correlated with alpha fetoprotein (AFP; r = 0.383, P = 0.003) and international normalised ratio (r = 0.357, P = 0.005), while it was negatively correlated with albumin (r = -0.500, P ≤ 0.001). For the detection of HCC, receiver operating characteristic curve analysis showed that the best cut-off point of AFP was > 8.2 ng/mL with an area under the curve (AUC) of 0.78, sensitivity of 63.33%, specificity of 83.33%, positive predictive value (PPV) of 79.2%, negative predictive value (NPV) of 69.4%, and total accuracy of 78%. However, FGF-19 at a cut-off point > 180 pg/mL had an AUC of 0.98, sensitivity of 100%, specificity of 90.0%, PPV of 90.0%, NPV of 100%, and total accuracy of 98%.CONCLUSIONFGF-19 represents a possible novel non-invasive marker for HCC. It may improve the prognosis of HCC patients due to its utility in several aspects of HCC detection and management.

An Open-Label Exploratory Clinical Trial Evaluating the Effects of GLS (Coptidis Rhizoma-Evodiae Fructus 2 : 1) on Fibroblast Growth Factor 21 in Patients with Nonalcoholic Fatty Liver Disease.

Methods In a 12-week, open-label, exploratory clinical trial, 126 NAFLD patients were randomly divided into the GLS group (lifestyle intervention plus GLS) or the polyene phosphatidylcholine (PPC) group (lifestyle intervention plus PPC). Random numbers generated by DPS software were used in combination with opaque, sealed envelopes for allocation concealment. At baseline as well as at the end of the study, anthropometric parameters, glucose, lipids, hepatic enzymes, and FGF 21 were measured, with hepatic fat accumulation assessed by ultrasound (US) and US-based controlled attenuation parameter (CAP). Results 119 patients completed the study. Baseline parameters did not significantly differ between the two groups (P > 0.05). Compared with PPC, GLS decreased more significantly in hepatic fat accumulation, body weight index, waist circumference, waist-to-hip ratio, serum glucose, total cholesterol, triglyceride, low-density lipoprotein cholesterol, alanine transaminase, aspartate transaminase, gamma-glutamyl transferase, and FGF 21 (P < 0.05). The effects of GLS on waist circumference, waist-to-hip ratio, CAP, and gamma-glutamyl transferase (GGT) were positively correlated with serum FGF 21 (r = 0.343, 0.342, 0.315, and 0.374, respectively, P < 0.05). The GGT and FGF-21 changes were also confirmed by multiple linear regression analysis (B, 0.777; 95% CI: 0.307–1.247, P < 0.05). Conclusion GLS has a significant hepatoprotective effect on NAFLD patients, causing a decrease in FGF-21 secretion in response to the damage itself.

Serum FGF-21 levels in individuals with prediabetes and newly diagnosed type 2 diabetes mellitus

Serum FGF-21 levels in individuals with prediabetes and newly diagnosed type 2 diabetes mellitus

Relationship between Serum FGF21 and vWF Expression and Carotid Atherosclerosis in Elderly Patients with Hypertension.

Cardiovascular (CV) and cerebrovascular (CBV) diseases are common in the elderly and cause severe damage, with high morbidity, disability, and mortality. Hypertension, as a risk factor for a variety of CV and CBV diseases, also affects many elderly patients. This study aimed to investigate the relationship between serum FGF21 and vWF expression and carotid atherosclerosis (CAS) in elderly patients with hypertension. We recruited 143 elderly hypertensive patients admitted to our hospital from July 2017 to November 2019 to this study, including 75 patients with comorbid CAS (the observation group, OG) and 68 patients without CAS (the control group, CG). Enzyme-linked immunosorbent assay (ELISA) was used to test serum expression levels of FGF21 and vWF; receiver operating characteristic (ROC) curves to evaluate the value of FGF21 and vWF in diagnosing CAS and predicting the 6-month prognosis in elderly hypertensive patients; Pearson's correlation analysis to analyze the correlation of FGF21/vWF with the plaque thickness and stenosis area in hypertensive patients with CAS. The incidence of CV and CBV events was markedly higher in the high FGF21/vWF group than in the low FGF21/vWF group. Patients from OG were divided into the high FGF21/vWF group and the low FGF21/vWF group based on the median expression level of FGF21/vWF, then the incidence of cardiovascular (CV) and cerebrovascular (CBV) events was compared between the high and low expression groups. Serum levels of FGF21 and vWF were markedly higher in patients from OG than in patients from CG. Both FGF21 and vWF were in positive correlation with the plaque thickness and stenosis area in patients from OG. The area under the ROC curve (AUC) for diagnosing CAS was 0.790 by FGF21 and 0.807 by vWF; the AUC for predicting the occurrence of CV and CBV events was 0.771 by FGF21 and 0.754 by vWF. Serum levels of FGF21 and vWF are increased in elderly patients with hypertension and comorbid CAS, so they can be used for diagnosing CAS and predicting prognosis.

Association of serum fibroblast growth factor 21 with diabetic complications and insulin dose in patients with type 1 diabetes mellitus.

IntroductionFibroblast growth factor (FGF) 21 is an important regulator of glycemic control, but the association between circulating FGF21 and diabetic complications is poorly understood. Moreover, basal FGF21 secretion, especially in response to insulin dose, in patients with type 1 diabetes mellitus (T1DM), has not been well examined. Therefore, this study aimed to determine the association of circulating FGF21 levels with diabetic complications and insulin dosage in middle-aged and elderly patients with T1DM.Materials and methodsA total of 127 middle-aged and elderly patients with T1DM, including 68 patients with diabetic complications, and 106 non-diabetic individuals were analyzed in this cross-sectional study. Information on demographic characteristics and T1DM was extracted from their electronic medical records. Serum FGF21 levels were determined using ELISA.ResultsSerum FGF21 levels were significantly lower in T1DM patients (75.2 [37.4–135.1] pg/mL) than in non-diabetic participants (151.6 [92.0–224.6] pg/mL; P < 0.001). No diabetic complications were associated with serum FGF21 concentrations. Both basal and bolus insulin doses were significantly and positively correlated with serum FGF21 levels (P < 0.05). Stepwise multiple regression analysis showed that FGF21 level was associated with age and body mass index (P < 0.05), while the basal insulin dose was an independent positive predictor of serum FGF21 levels (β = 0.197, P = 0.032).ConclusionsCirculating FGF21 levels are reduced in patients with T1DM; however, they are not associated with diabetic complications. In addition, aging, obesity, and insulin dosage are positive determinants of circulating FGF21.

P202 Performance characteristics of serum FGF19 measurement compared with the Se-HCAT retention test in the diagnosis of bile acid diarrhoea in Crohn’s Disease

Abstract Background Bile acid diarrhoea (BAD) is common in patients with Crohn’s disease (CD), but its recognition is challenging since symptoms are similar to those of active inflammatory disease. The current clinical gold standard for diagnosing BAD is the Se-HCAT test, however, it is inconvenient to the patient and has limited availability. FGF19 is a hormone produced in the enterocytes of the ileum in response to absorbed BAs. Serum FGF19 levels are a direct marker of BA absorption, and they are reduced in BAD. The aim of this study was to evaluate the performance of FGF19 as a diagnostic tool for BAD in Crohn’s disease. Methods Fasting serum FGF19 levels and Se-HCAT retention were measured before bowel preparation in 63 consecutive Crohn’s disease patients referred for an ileocolonoscopy. Clinical, endoscopic and biologic data were prospectively recorded. BAD was defined as an abdominal retention &amp;lt;10% and severe BAD as &amp;lt;5% at day seven. Results BAD was present in 60% of non-resected CD (NR-CD) patients and in 93% of ileal-resected (IR-CD) patients. FGF19 levels were lower in IR-CD patients (median 23 pg/ml; IQR, 3–44) than in the NR-CD patients (61 pg/ml; IQR, 18–121) (p = 0.02). FGF19 levels were inversely related with ileal resection length in IR-CD patients (rs = -0.52, P = 0.01). FGF19 and Se-HCAT values were positively related (rs = 0.57, P &amp;lt; 0.0001), whereas FGF19 was inversely related with the number of bowel movements (rs = -0.31, P=0.01) and Bristol scale (rs = -0.27, P= 0.04). No significant relation was found between FGF19 and clinical (CDAI) nor endoscopic (SES-CD) scores. Area under the ROC curve for FGF19 to detect SeHCAT at &amp;lt;10% and &amp;lt;5% were 0.75 (95% CI 0.62–0.88) and 0.81 (95% CI 0.71–0.92) respectively. Conclusion Serum FGF19 can be used as a simple blood test to the diagnostic of BAD in CD. FGF19 measurement could be an adjunct in guiding treatments for diarrhoea in CD.

The effect of 12 weeks of training in water on serum levels of SIRT1 and FGF-21, glycemic index, and lipid profile in patients with type 2 diabetes

The effect of 12 weeks of training in water on serum levels of SIRT1 and FGF-21, glycemic index, and lipid profile in patients with type 2 diabetes

Deletion of the Pyrophosphate Generating Enzyme ENPP1 Rescues Craniofacial Abnormalities in the TNAP-/- Mouse Model of Hypophosphatasia and Reveals FGF23 as a Marker of Phenotype Severity.

Hypophosphatasia is a rare heritable metabolic disorder caused by deficient Tissue Non-specific Alkaline Phosphatase (TNAP) enzyme activity. A principal function of TNAP is to hydrolyze the tissue mineralization inhibitor pyrophosphate. ENPP1 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 1) is a primary enzymatic generator of pyrophosphate and prior results showed that elimination of ENPP1 rescued bone hypomineralization of skull, vertebral and long bones to different extents in TNAP null mice. Current TNAP enzyme replacement therapy alleviates skeletal, motor and cognitive defects but does not eliminate craniosynostosis in pediatric hypophosphatasia patients. To further understand mechanisms underlying craniosynostosis development in hypophosphatasia, here we sought to determine if craniofacial abnormalities including craniosynostosis and skull shape defects would be alleviated in TNAP null mice by genetic ablation of ENPP1. Results show that homozygous deletion of ENPP1 significantly diminishes the incidence of craniosynostosis and that skull shape abnormalities are rescued by hemi- or homozygous deletion of ENPP1 in TNAP null mice. Skull and long bone hypomineralization were also alleviated in TNAP−/−/ENPP1−/− compared to TNAP−/−/ENPP1+/+ mice, though loss of ENPP1 in combination with TNAP had different effects than loss of only TNAP on long bone trabeculae. Investigation of a relatively large cohort of mice revealed that the skeletal phenotypes of TNAP null mice were markedly variable. Because FGF23 circulating levels are known to be increased in ENPP1 null mice and because FGF23 influences bone, we measured serum intact FGF23 levels in the TNAP null mice and found that a subset of TNAP−/−/ENPP1+/+ mice exhibited markedly high serum FGF23. Serum FGF23 levels also correlated to mouse body measurements, the incidence of craniosynostosis, skull shape abnormalities and skull bone density and volume fraction. Together, our results demonstrate that balanced expression of TNAP and ENPP1 enzymes are essential for microstructure and mineralization of both skull and long bones, and for preventing craniosynostosis. The results also show that FGF23 rises in the TNAP−/− model of murine lethal hypophosphatasia. Future studies are required to determine if the rise in FGF23 is a cause, consequence, or marker of disease phenotype severity.

Oncogenic osteomalacia secondary to hemangiopericytoma: a case report

&lt;p&gt;We are going to present a case of hypo-phosphatemic rickets secondary to phosphaturic mesenchymal tumour who came with complaints of proximal muscle weakness which limited his effort tolerance and activities of daily life like standing from squatting position and rib pain. His FGF-23 levels were very high above normal levels and PET CT revealed a well-defined enhancing lesion abutting femoral neurovascular bundle. After consultation with endocrinologist, we have d done complete excision of the mass. Post-surgery all symptoms were relieved, proximal muscle strength improved gradually and serum levels of phosphorus, ALP and FGF-23 came back to normal.&lt;/p&gt;

Cardiovascular calcification in chronic kidney disease: Risk factors and effect of α-keto acid tablets

Purpose: To investigate the effect of α-keto acid tablets, and risk factors for cardiovascular calcification in patients with chronic kidney disease (CKD).Methods: A total of 128 CKD patients were enrolled in this study. They were randomly assigned to study and control groups, each with 64 patients. Control patients received symptomatic treatment, while the study group patients received α-keto acid tablets plus. Indices of cardiovascular calcification, blood lipids and mineral metabolism were determined in the 2 groups of patients and compared. Risk factors for cardiovascular calcification were also analyzed.Results: After treatment, the two groups had decreased CACS scores and reduced serum FGF-23levels, with lower values in patients in the study group. Levels of Klotho and fetuin-A were significantly elevated after treatment, with higher values observed in study group patients. The degree of cardiovascular calcification was markedly lower in study group than that in controls. There was no significant difference in blood Ca level between the control and study groups before and after treatment. Logistic multivariate analysis demonstrated that hyperlipidemia, hyperphosphatemia, hypercalcemia, hypertension and diabetes put patients at risk for cardiovascular calcification.Conclusion: Compound α-keto acid tablets delay cardiovascular calcification in patients with CKD, and alleviate symptoms of related risk factors for cardiovascular calcification.

Iron-based phosphorus chelator: Risk of iron deposition and action on bone metabolism in uremic rats.

Phosphate chelators are frequently used in patients with chronic kidney disease (CKD). New iron-based chelators remain understudied and offer a promising therapeutic option for the control of bone and mineral disorders of chronic kidney disease (BMD-CKD). We assessed the effect of the phosphorus chelator, chitosan-iron III (CH-FeCl), compared to calcium carbonate (CaCO3) in BMD-CKD and the potential iron overload in uremic rats. Thirty-two animals were divided into four groups, namely the control, CKD, CKD/CH-FeCl, and CKD/CaCO3 groups. CKD was induced by adding 0.75% (4 weeks) and 0.1% (3 weeks) adenine to the diet. The chelators were administered from week 3 through week 7. The renal function, BMD-CKD markers, and histomorphometry of the femur were assessed at week 7. The CKD group showed a significant increase in creatinine (83.9 ± 18.6 vs. 41.5 ± 22.1 µmol/L; P = 0.001), phosphate (3.5 ± 0.8 vs. 2.2 ± 0.2 mmol/L; P = 0.001), fractional excretion of phosphorus (FEP) (0.71 ± 0.2 vs. 0.2 ± 0.17; P = 0.0001), and FGF23 (81.36 ± 37.16 pg/mL vs. 7.42 ± 1.96; P = 0.011) compared to the control group. There was no accumulation of serum or bone iron after the use of CH-FeCl. The use of chelators reduced the FEP (control: 0.71 ± 0.20; CKD/CH-FeCl: 0.40 ± 0.16; CKD/CaCO3 0.34 ± 0.15; P = 0.001), without changes in the serum FGF23 and parathyroid hormone levels. Histomorphometry revealed the presence of bone disease with high remodeling in the uremic animals without changes with the use of chelators. The CH-FeCl chelator was efficient in reducing the FEP without iron accumulation, thereby paving the way for the use of this class of chelators in clinical settings in the future.

The impact of vitamin K2 and native vitamin D supplementation on vascular calcification in pediatric patients on regular hemodialysis. A randomized controlled trial.

Vascular calcification is one of the most prevalent disorders in pediatric hemodialysis patients that eventually lead to cardiovascular morbidity. Vitamin K2 was investigated in adults in previous studies and showed favorable effects on calcification markers. Our aim in this study was to evaluate the efficacy and safety of vitamin K2 and cholecalciferol on the calcification regulators in pediatric patients. A prospective, randomized and controlled trial was conducted on sixty hemodialysis pediatric patients who were divided to four groups; Group 1: administered 100 µg of vitamin K2 (MK-7); Group 2: administered 10 µg of native vitamin D; Group 3: administered 100 µg of vitamin K2 (MK-7) in addition 10 µg of native vitamin D, and Group 4: administered the standard therapy only. The duration of supplementation was 4 months. In addition to a group of healthy normal control of age and sex-matched. At the end of the study period, serum levels of FGF23, dp-uc-MGP, and uc-OC were measured. It was found that serum levels of dp-uc-MGP, uc-OC, and FGF23 were significantly higher (p < 0.05) in the hemodialysis patients as compared to the healthy normal control. After 4 months, group 3 revealed the most significant decrease in dp-uc-MGP, uc-OC as compared to the other groups. However, there was no change in FGF23. Vitamin K2 and native vitamin D showed a beneficial effect on calcification regulators in pediatric hemodialysis patients. clinical trial.gov (NCT04145492).

Serum levels of the cold stress hormones FGF21 and GDF-15 after cardiac arrest in infants and children enrolled in single center therapeutic hypothermia clinical trials

ObjectiveFibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor-15 (GDF-15) are putative neuroprotective cold stress hormones (CSHs) provoked by cold exposure that may be age-dependent. We sought to characterize serum FGF21 and GDF-15 levels in pediatric cardiac arrest (CA) patients and their association with use of therapeutic hypothermia (TH). MethodsSecondary analysis of serum samples from clinical trials. We measured FGF21 and GDF-15 levels in pediatric patients post-CA and compared levels to both pediatric intensive care (PICU) and healthy controls. Post-CA, we compared normothermia (NT) vs TH (33 °C for 72 h) treated cohorts at < 24 h, 24 h, 48 h, 72 h, and examined the change in CSHs over 72 h. We also assessed association between hospital mortality and initial levels. ResultsWe assessed 144 samples from 68 patients (27 CA [14 TH, 13 NT], 9 PICU and 32 healthy controls). Median initial FGF21 levels were higher post-CA vs. healthy controls (392 vs. 40 pg/mL, respectively, P < 0.001). Median GDF-15 levels were higher post-CA vs. healthy controls (7,089 vs. 396 pg/mL, respectively, P < 0.001). In the CA group, the median change in FGF21 from PICU day 1–3 (after 72 h of temperature control), was higher in TH vs. NT (231 vs. –20 pg/mL, respectively, P < 0.05), with no difference in GDF-15 over time. Serum GDF-15 levels were higher in CA patients that died vs. survived (19,450 vs. 5,337 pg/mL, respectively, P < 0.05), whereas serum FGF21 levels were not associated with mortality. ConclusionSerum levels of FGF21 and GDF-15 increased after pediatric CA, and FGF21 appears to be augmented by TH.

Serum FGF21 levels are altered by various factors including lifestyle behaviors in male subjects

Fibroblast growth factor (FGF) 21 has various functions, including glucose and lipid metabolism. This cross-sectional study aimed to investigate specific conditions that might influence the functions of FGF21. 398 men who underwent a health examination were enrolled in this study. Physical and biochemical parameters and information on several lifestyle behaviors were obtained from all subjects. FGF21 levels correlated with age, body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), uric acid, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), fasting plasma glucose (FPG), and HbA1c. Moreover, FGF21 levels were significantly associated with lifestyle behaviors, including smoking status and breakfast and alcohol consumption frequency. Multivariable regression analysis showed that age, ALT, γ-GTP, smoking status, and breakfast and alcohol consumption frequency were independent variables for FGF21 levels. Assessment among the non-obese and obese groups showed that FGF21 levels correlated with WC, SBP, and TC only in the non-obese group. Thus, serum FGF21 levels were affected by several factors, including lifestyle behaviors, age, and liver function. To assess the functions of FGF21 in individuals, considering these factors would be essential.

Contribution of phosphorus and PTH to the development of cardiac hypertrophy and fibrosis in an experimental model of chronic renal failure

Background and objectiveAdequate serum phosphorus levels in patients with chronic kidney disease is essential for their clinical management. However, the control of hyperphosphatemia is difficult because is normally associated with increases in serum PTH. In the present study, the effects of hyperphosphatemia, in the presence of elevated and normal PTH, on cardiac inflammation, hypertrophy and fibrosis in an experimental renal failure model were analyzed. Materials and methods4 groups of rats were formed. Two groups underwent total parathyroidectomy (PTx). Rats with Ca <7.5 mg/dL and PTH < 50 pg/mL underwent 7/8 nephrectomy (CRF) and a subcutaneous pellet was placed that releases PTH 1-34 (5 µg/kg/day). One group received a diet with normal P (NP) (CRF + PTx + rPTH + NP group) and another with a high P diet (0.9% - HP) (CRF + PTx + rPTH + HP group). Other 2 groups that only had CRF received NP (CRF + NP) and HP (CRF + HP) diet. A SHAM group for nephrectomy and parathyroidectomy was also added. After 14 weeks the rats were sacrificed. ResultsThe groups with a diet high in phosphorus (CRF + H A and CRF + PTx + rPTH + HP) had a significant reduction in creatinine clearance and also in body weight with an increase in serum phosphorus regardless of parathyroidectomy, but not serum levels of calcium, FGF23 and calcitriol that were 2–3 times higher in the group with secondary hyperparathyroidism (CRF + HP).The diameter of the cardiomyocytes was greater in the CRF + HP group, while parathyroidectomy (CRF + PTx + rPTH + HP) significantly reduced them, despite the high and similar serum phosphorus values. TNF-α, Adam17 and cardiac fibrosis at the histological and molecular level showed a similar pattern with increases in the group with severe secondary hyperparathyroidism (CRF + HP). ConclusionsHyperphosphatemia confirmed its importance in the genesis of secondary hyperparathyroidism, but also of kidney damage that was independent of PTH levels. However, inflammation, fibrosis, and cardiomyocyte growth were more closely related to PTH levels, since in the presence of similar severe hyperphosphatemia, parathyroidectomy reduced the values ​​of inflammatory parameters, cardiac hypertrophy, and fibrosis.

The phosphaturic mesenchymal tumor as a cause of oncogenic osteomalacia. Three cases and review of the literature

IntroductionThe phosphaturic mesenchymal tumour (PMT) is a very uncommon cause of oncogenic osteomalacia (OO), which is a paraneoplastic syndrome with severe clinical osteomalacia. The PMT is a neoplasia that produces the fibroblast growth factor FGF23, resulting in reduced proximal tubular phosphate reabsorption leading to hyperphosphaturia and hypophosphatemia. Our aim is to present our experience and complications in diagnosis and treatment of PMT in three patients. Material and methodsWe propose an observational, descriptive and retrospective study of three cases of OO secondary to PMT found in our database of bone and soft tissue tumours. The inclusion criteria were: symptoms related with OO, presence of hyperphosphaturic hypophosphatemia, elevated levels of FGF23 in blood and pathological diagnosis of PMT. ResultsIn all cases, the disease showed asthenia, non-specific bone pain, progressive functional weakness, and pathological fractures. The average delay time in diagnosis was 7 years. All presented with hyperphosphaturic hypophosphatemia, elevated levels of alkaline phosphatase as well as FGF23. The use of Octreoscan and PET-CT were essential to find the producing tumour and its subsequent biopsy. Treatment was surgery in two cases and one case was treated by CT-guided cryotherapy with neurophysiological control. Once the surgery was performed, the blood parameters normalized. There is no recurrence. ConclusionsPhosphaturic mesenchymal tumor is a very rare entity as part of bone and soft tissue tumors, it may occur in both tissues. The phosphate-calcium homeostasis is altered due to high serum levels of FGF23 because of PMT. Delay in diagnosis is usual, leading to renal and skeletal comorbidities. To avoid this, knowledge of this entity together with high diagnostic suspicion are critical. Surgical treatment leads to normalization of serum levels and systemic symptoms.

Effects of sevelamer carbonate versus calcium acetate on vascular calcification, inflammation, and endothelial dysfunction in chronic kidney disease.

Hyperphosphatemia is present in most patients with end‐stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium‐based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with chronic kidney disease (CKD) treated with sevelamer carbonate (SC) versus calcium acetate (CA). Fifty patients with CKD (stages 3 and 4) were enrolled and assigned to treatment with SC and CA for 12 weeks. At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. A significant increase in HDL‐cholesterol was observed with SC but not with CA in patients with CKD. Treatment with SC reduced serum phosphate, calcium phosphate, and FGF‐23 levels and there was no change with CA treatment. The inflammatory markers IL‐8, IFN‐γ, and TNFα decreased with response to both treatments. The levels of IL‐6 significantly increased with CA treatment and no change was observed in the SC treatment group. SC showed favorable effects on anti‐inflammatory and vascular calcification biomarkers compared to CA treatment in patients with CKD stages 3 and 4 with normal phosphorous values.

Serum fibroblast growth factor 21 and growth differentiation factor 15: Two sensitive biomarkers in the diagnosis of mitochondrial disorders

Mitochondrial disorders are often difficult to diagnose because of diverse clinical phenotypes. FGF-21 and GDF-15 are metabolic hormones and promising biomarkers for the diagnosis of these disorders. This study has systematically evaluated serum FGF-21 and GDF-15 levels by ELISA in a well-defined cohort of patients with definite mitochondrial disorders (n = 30), neuromuscular disease controls (n = 36) and healthy controls (n = 36) and aimed to ascertain their utility in the diagnosis of mitochondrial disorders. Both serum FGF-21 and GDF-15 were significantly elevated in patients with mitochondrial disorders, especially in those with muscle involvement. The levels were higher in patients with mitochondrial deletions (both single and multiple) and translation disorders compared to respiratory chain subunit or assembly factor defects.

Skeletal FGFR1 signaling is necessary for regulation of serum phosphate level by FGF23 and normal life span

Fibroblast growth factor (FGF) 23 produced by the bone is the principal hormone to regulate serum phosphate level. Serum FGF23 needs to be tightly regulated to maintain serum phosphate in a narrow range. Thus, we hypothesized that the bone has some phosphate-sensing mechanism to regulate the production of FGF23. Previously we showed that extracellular phosphate induces the phosphorylation of FGF receptor 1 (FGFR1) and FGFR1 signaling regulates the expression of Galnt3, whose product works to increase FGF23 production in vitro. In this study, we show the significance of FGFR1 in the regulated FGF23 production and serum phosphate level in vivo. We generated late-osteoblast/osteocyte-specific Fgfr1-knockout mice (Fgfr1fl/fl; OcnCre/+) by crossing the Ocn-Cre and the floxed Fgfr1 mouse lines. We evaluated serum phosphate and FGF23 levels, the expression of Galnt3 in the bone, the body weight and life span. A selective ablation of Fgfr1 aborted the increase of serum active full-length FGF23 and the enhanced expression of Galnt3 in the bone by a high phosphate diet. These mice showed more pronounced hyperphosphatemia compared with control mice. In addition, these mice fed with a control diet showed body weight loss after 23 weeks of age and shorter life span. These results reveal a novel significance of FGFR1 signaling in the phosphate metabolism and normal life span.

Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression.

The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.