C-terminal Fibroblast Growth Factor 23 Research Articles

Alterations in regulators of the renal-bone axis, inflammation and iron status in older people with early renal impairment and the effect of vitamin D supplementation.

Chronic kidney disease (CKD) leads to alterations in fibroblast growth factor 23 (FGF23) and the renal-bone axis. This may be partly driven by altered inflammation and iron status. Vitamin D supplementation may reduce inflammation. Older adults with early CKD (estimated glomerular filtration rate (eGFR) 30-60ml/min/1.73 m2; CKDG3a/b; n = 35) or normal renal function (eGFR >90ml/min/1.73 m2; CKDG1; n = 35) received 12,000, 24,000 or 48,000IU D3/month for 1year. Markers of the renal-bone axis, inflammation and iron status were investigated pre- and post-supplementation. Predictors of c-terminal and intact FGF23 (cFGF23; iFGF23) were identified by univariate and multivariate regression. Pre-supplementation, comparing CKDG3a/b to CKDG1, plasma cFGF23, iFGF23, PTH, sclerostin and TNFα were significantly higher and Klotho, 1,25-dihydroxyvitamin D and iron were lower. Post-supplementation, only cFGF23, 25(OH)D and IL6 differed between groups. The response to supplementation differed between eGFR groups. Only in the CKDG1 group, phosphate decreased, cFGF23, iFGF23 and procollagen type I N-propeptide increased. In the CKDG3a/b group, TNFα significantly decreased, and iron increased. Plasma 25(OH)D and IL10 increased, and carboxy-terminal collagen crosslinks decreased in both groups. In univariate models cFGF23 and iFGF23 were predicted by eGFR and regulators of calcium and phosphate metabolism at both time points; IL6 predicted cFGF23 (post-supplementation) and iFGF23 (pre-supplementation) in univariate models. Hepcidin predicted post-supplementation cFGF23 in multivariate models with eGFR. Alterations in regulators of the renal-bone axis, inflammation and iron status were found in early CKD. The response to vitamin D3 supplementation differed between eGFR groups. Plasma IL6 predicted both cFGF23 and iFGF23 and hepcidin predicted cFGF23.

Fibroblast growth factor 23 is pumping iron: C-terminal-fibroblast growth factor 23 cleaved peptide and its function in iron metabolism.

Iron deficiency regulates the production of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) but also its cleavage, to generate both intact (iFGF23) and C-terminal (Cter)-FGF23 peptides. Novel studies demonstrate that independently of the phosphaturic effects of iFGF23, Cter-FGF23 peptides play an important role in the regulation of systemic iron homeostasis. This review describes the complex interplay between iron metabolism and FGF23 biology. C-terminal (Cter) FGF23 peptides antagonize inflammation-induced hypoferremia to maintain a pool of bioavailable iron in the circulation. A key mechanism proposed is the down-regulation of the iron-regulating hormone hepcidin by Cter-FGF23. In this manuscript, we discuss how FGF23 is produced and cleaved in response to iron deficiency, and the principal functions of cleaved C-terminal FGF23 peptides. We also review possible implications anemia of chronic kidney disease (CKD).

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

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

Effect of ferric citrate hydrate on fibroblast growth factor 23 and platelets in non-dialysis-dependent chronic kidney disease and non-chronic kidney disease patients with iron deficiency anemia.

Iron deficiency anemia (IDA) increases levels of C-terminal fibroblast growth factor 23 (cFGF23) and platelet count (PLT), each of which is associated with cardiovascular events. Therefore, we hypothesized that iron replacement with ferric citrate hydrate (FC) would decrease cFGF23 levels and PLT in patients with IDA. In a randomized, open-label, multicenter, 24-week clinical trial, patients with non-dialysis-dependent chronic kidney disease (CKD) and non-CKD complicated by IDA (8.0 ≤ hemoglobin < 11.0g/dL; and serum ferritin < 50ng/mL [CKD]; < 12ng/mL [non-CKD]) were randomized 1:1 to FC-low (500mg:approximately 120 mg elemental iron/day) or FC-high (1000mg: approximately 240mg elemental iron/day). If sufficient iron replacement had been achieved after week 8, further treatment was discontinued. Seventy-three patients were allocated to FC-low (CKD n = 21, non-CKD n = 15) and FC-high (CKD n = 21, non-CKD n = 16). Regardless of CKD status, FC increased serum ferritin and transferrin saturation, did not change intact FGF23 or serum phosphorus, but decreased cFGF23. In FC-low group, median changes in cFGF23 from baseline to week 8 were -58.00 RU/mL in CKD and -725.00 RU/mL in non-CKD; in FC-high group, the median changes were -66.00RU/mL in CKD and -649.50 RU/mL in non-CKD. By week 8, FC treatment normalized PLT in all patients with high PLT at baseline (>35.2 × 104/µL; FC-low: 1 CKD, 8 non-CKD; FC-high: 3 CKD, 8 non-CKD). Regardless of CKD status, iron replacement with FC decreased elevated cFGF23 levels and normalized elevated PLT in patients with IDA. jRCT2080223943.

Inherited Fanconi renotubular syndromes: unveiling the intricacies of hypophosphatemic rickets/osteomalacia.

Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS. Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed. FRTS probands had mutations (eight novel) in six genes [CLCN5(n = 4), SLC2A2(n = 2), GATM, EHHADH, HNF4A,andOCRL(1 each)].Among 15 FRTS patients (11 families), rickets/osteomalaciawas the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH)2D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively. Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS.

C-terminal fragment of fibroblast growth factor 23 improves heart function in murine models of high intact fibroblast growth factor 23.

Cardiovascular disease (CVD) is the major cause of death in chronic kidney disease (CKD) and is associated with high circulating fibroblast growth factor (FGF)23 levels. It is unresolved whether high circulating FGF23 is a mere biomarker or pathogenically contributes to cardiomyopathy. It is also unknown whether the C-terminal FGF23 peptide (cFGF23), a natural FGF23 antagonist proteolyzed from intact FGF23 (iFGF23), retards CKD progression and improves cardiomyopathy. We addressed these questions in three murine models with high endogenous FGF23 and cardiomyopathy. First, we examined wild-type (WT) mice with CKD induced by unilateral ischemia-reperfusion and contralateral nephrectomy followed by a high-phosphate diet. These mice were continuously treated with intraperitoneal implanted osmotic minipumps containing either iFGF23 protein to further escalate FGF23 bioactivity, cFGF23 peptide to block FGF23 signaling, vehicle, or scrambled peptide as negative controls. Exogenous iFGF23 protein given to CKD mice exacerbated pathological cardiac remodeling and CKD progression, whereas cFGF23 treatment improved heart and kidney function, attenuated fibrosis, and increased circulating soluble Klotho. WT mice without renal insult placed on a high-phosphate diet and homozygous Klotho hypomorphic mice, both of whom develop moderate CKD and clear cardiomyopathy, were treated with cFGF23 or vehicle. Mice treated with cFGF23 in both models had improved heart and kidney function and histopathology. Taken together, these data indicate high endogenous iFGF23 is not just a mere biomarker but pathogenically deleterious in CKD and cardiomyopathy. Furthermore, attenuation of FGF23 bioactivity by cFGF23 peptide is a promising therapeutic strategy to protect the kidney and heart from high FGF23 activity.NEW & NOTEWORTHY There is a strong correlation between cardiovascular morbidity and high circulating fibroblast growth factor 23 (FGF23) levels, but causality was never proven. We used a murine chronic kidney disease (CKD) model to show that intact FGF23 (iFGF23) is pathogenic and contributes to both CKD progression and cardiomyopathy. Blockade of FGF23 signaling with a natural proteolytic product of iFGF23, C-terminal FGF23, alleviated kidney and cardiac histology, and function in three separate murine models of high endogenous FGF23.

Bilirubin Down-Regulates Oxidative Stress and Fibroblast Growth Factor 23 Expression in UMR106 Osteoblast-Like Cells.

Fibroblast growth factor 23 (FGF23) is a major regulator of phosphate and vitamin D metabolism in the kidney, and its higher levels in plasma are associated with poorer outcomes in kidney and cardiovascular diseases. It is produced by bone cells upon enhanced oxidative stress and inhibits renal phosphate reabsorption and calcitriol (active form of vitamin D) production. Bilirubin, the final product of the heme catabolic pathway in the vascular bed, has versatile biological functions, including antioxidant and anti-inflammatory effects. This study explored whether bilirubin alters FGF23 production. Experiments were performed using UMR106 osteoblast-like cells. Fgf23 transcript levels were determined by quantitative real-time polymerase chain reaction, C-terminal and intact FGF23 protein levels were determined by enzyme-linked immunosorbent assay, and cellular oxidative stress was assessed by CellROX assay. Unconjugated bilirubin down-regulated Fgf23 gene transcription and FGF23 protein abundance; these effects were paralleled by lower cellular oxidative stress levels. Also, conjugated bilirubin reduced Fgf23 mRNA abundance. Bilirubin down-regulates FGF23 production in UMR106 cells, an effect likely to be dependent on the reduction of cellular oxidative stress.

NT-proBNP Mediates the Association Between FGF23 and All-Cause Mortality in Individuals With Type 2 Diabetes.

FGF23 (fibroblast growth factor 23) is associated with a higher mortality risk in type 2 diabetes, but the mechanism is unclear. We aimed to study whether NT-proBNP (N-terminal pro-brain natriuretic peptide) mediates the association between FGF23 and mortality. We analyzed C-terminal FGF23 and NT-proBNP levels in 399 patients with type 2 diabetes. Cox regression analyses were performed, followed by mediation analyses using Structural Equation Modeling. During follow-up of 9.2 [7.6-11.3] years, 117 individuals died. FGF23 was associated with all-cause mortality, independent of potential confounders (fully adjusted hazard ratio [HR], 2.32 [95% CI, 1.21-4.43], P=0.01). The association was lost upon further adjustment for NT-proBNP (HR, 1.84; 95% CI, 0.91-3.73). NT-proBNP accounted for 26% of the mediation effect between FGF23 and all-cause mortality. These findings suggest that a higher FGF23 level is associated with increased mortality in individuals with type 2 diabetes through an effect on volume homeostasis.

Association of mineral and bone biomarkers with adverse cardiovascular outcomes and mortality in the German Chronic Kidney Disease (GCKD) cohort

Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30–60 mL·min−1 per 1.73 m2 or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters (n = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35–2.30), CV death (HR 2.18, 95% CI: 1.50–3.16), MACE (HR 1.38, 95% CI: 1.12–1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56–2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality.

Associations between anemia and FGF23 in the CKiD study

BackgroundFibroblast growth factor 23 (FGF23) is a bone-derived hormone that plays a central role in chronic kidney disease-mineral bone disorder and is associated with CKD progression and cardiovascular morbidity. Factors related to CKD-associated anemia, including iron deficiency, can increase FGF23 production. This study aimed to assess whether anemia and/or iron deficiency are associated with increased circulating concentrations of FGF23 in the large, well-characterized Chronic Kidney Disease in Children (CKiD) study cohort.MethodsHemoglobin concentrations, iron parameters, C-terminal (total) FGF23, intact FGF23, and relevant covariables were measured in cross-sectional analysis of CKiD study subjects.ResultsIn 493 pediatric patients with CKD (median [interquartile range] age 13 [9, 16] years), the median estimated glomerular filtration rate was 48 [35, 61] ml/min/1.73 m2, and 103 patients (21%) were anemic. Anemic subjects had higher total FGF23 concentrations than non-anemic subjects (204 [124, 390] vs. 109 [77, 168] RU/ml, p < 0.001). In multivariable linear regression modeling, anemia was independently associated with higher total FGF23, after adjustment for demographic, kidney-related, mineral metabolism, and inflammatory covariables (standardized β (95% confidence interval) 0.10 (0.04, 0.17), p = 0.002). In the subset of subjects with available iron parameters (n = 191), iron deficiency was not associated with significantly higher total FGF23 concentrations. In the subgroup that had measurements of both total and intact FGF23 (n = 185), in fully adjusted models, anemia was significantly associated with higher total FGF23 (standardized β (95% CI) 0.16 (0.04, 0.27), p = 0.008) but not intact FGF23 (standardized β (95% CI) 0.02 (−0.12, 0.15), p = 0.81).ConclusionsIn this cohort of pediatric patients with CKD, anemia was associated with increased total FGF23 levels but was not independently associated with elevated intact FGF23, suggesting possible effects on both FGF23 production and cleavage. Further studies are warranted to investigate non-mineral factors affecting FGF23 production and metabolism in CKD.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Relationship between bone marrow adipose tissue and kidney function in postmenopausal women

IntroductionBone marrow adipose tissue (BMAT) is associated with aging, osteoporosis, and chronic kidney disease (CKD). To date, the association between BMAT and kidney function in postmenopausal women has not been thoroughly investigated. The main purpose of this study was to determine whether a relationship exists between proton density fat fraction (PDFF) and kidney function in postmenopausal women. MethodsWe investigated the cross-sectional association between estimated glomerular filtration rate (eGFR) – calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation – and PDFF – measured at the lumbar spine and proximal femur using Water Fat Imaging (WFI) MRI – in 199 postmenopausal women from the ADIMOS cohort study. We also performed DXA scans and laboratory measurements of sclerostin and c-terminal Fibroblast Growth Factor 23 (cFGF23). ResultsParticipants' mean age was 67.5 (standard deviation, SD 10.0) years. Their median eGFR was 85.0 (interquartile range, IQR 72.2–95.0) ml/min/1.73 cm2, and their mean lumbar spine PDFF was 57.9 % (SD 9.6). When classified by eGFR-based CKD stages, 41.7 % of the cohort had an eGFR ≥ 90 (n = 83), 47.2 % had an eGFR of 60–89.9 (n = 94), and 11.1 % had an eGFR of 30–59.9 (n = 22). Participants with eGFR ≥ 90 had a lower lumbar spine PDFF than those with eGFR 60–89.9 (mean 55.8 % (9.8) vs. 58.9 % (9.0), p = 0.031) and those with eGFR 30–59.9 (55.8 % (9.8) vs. 60.8 % (9.8), p = 0.043). However, the differences did not remain significant after adjusting for predetermined confounders, including age, diabetes, Charlson comorbidity index, recent history of fragility fracture, appendicular lean mass, and lumbar spine BMD. The inclusion of sclerostin and/or cFGF23 as suspected mediators did not alter the findings. When proximal hip imaging-based PDFF was considered, no significant differences were found between the eGFR categories in the unadjusted and adjusted analyses. ConclusionNo evidence of an association between kidney function and bone marrow adiposity was found either in the lumbar spine or proximal femur in a cohort of postmenopausal women.

Blocking FGF23 signaling improves the growth plate of mice with X-linked hypophosphatemia.

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone. X-linked hypophosphatemia (XLH) is the most prevalent inherited phosphate wasting disorder due to mutations in the PHEX gene, which cause elevated circulating FGF23 levels. Clinically, it is characterized by growth impairment and defective mineralization of bones and teeth. Treatment of XLH is challenging. Since 2018, neutralizing antibodies against FGF23 have dramatically improved the therapy of XLH patients, although not all patients fully respond to the treatment, and it is very costly. C-terminal fragments of FGF23 have recently emerged as blockers of intact FGF23 signaling. Here, we analyzed the effect on growth and bone of a short 26 residues long C-terminal FGF23 (cFGF23) fragment and two N-acetylated and C-amidated cFGF23 peptides using young XLH mice (Phex C733RMhda mice). Although no major changes in blood parameters were observed after 7 days of treatment with these peptides, bone length and growth plate structure improved. The modified peptides accelerated the growth rate probably by improving growth plate structure and dynamics. The processes of chondrocyte proliferation, death, hypertrophy, and the cartilaginous composition in the growth plate were partially improved in young treated XLH mice. In conclusion, these findings contribute to understand the role of FGF23 signaling in growth plate metabolism and show that this may occur despite continuous hypophosphatemia.

#4296 EFFECTS OF FERRIC CITRATE HYDRATE ON FIBROBLAST GROWTH FACTOR 23 AND PLATELET COUNT IN CKD AND NON-CKD PATIENTS WITH IRON DEFICIENCY ANAEMIA

Abstract Background and Aims Iron deficiency increases the transcription and cleavage of the peptide hormone, fibroblast growth factor 23(FGF23). Elevated FGF23 has been associated with increased risk of cardiovascular events and mortality. Iron deficiency also increases platelet count (PLT) in part, and higher levels PLT are associated with arterial thrombosis in the brain. Ferric citrate hydrate (FC, Riona®, Torii Pharmaceutical Co., Ltd. Tokyo, Japan) is an oral iron-based phosphate binder for patients with chronic kidney disease (CKD) and also an iron preparation approved for treatment of iron deficiency anaemia (IDA) in Japan. A phase 3 study was conducted to investigate the efficacy and safety of FC in CKD and non-CKD patients with IDA. This study aimed to evaluate the effects of FC on intact FGF23 and c-terminal FGF23 levels, and the proportion of patients with high PLT (exceeding upper limit: &amp;gt;35.2 × 104/µL). Method A randomized, open-label, multicentre, uncontrolled, 24-week study was conducted at 31 centres in Japan from July 2018 to December 2019 (JapicCTI-184000) in CKD and non-CKD patients with IDA (Hb: ≥8.0 g/dL and &amp;lt;11.0 g/dL, serum ferritin &amp;lt;50 ng/mL in CKD (eGFRcre &amp;lt;60 mL/min/1.73 m2) and &amp;lt;12 ng/mL in non-CKD). CKD patients scheduled to initiate maintenance dialysis were excluded. Dynamic allocation was used to randomise subjects (CKD and non-CKD with Hb at baseline) to the FC-low group (500 mg [approximately 120 mg elemental iron]/day) or FC-high group (1000 mg [approximately 240 mg elemental iron]/day) (1:1). Notably, if investigators determined that sufficient iron replacement had been achieved from week 8 onwards, the study treatment was completed. For this reason, changes from baseline to week 8 were evaluated. Results Of 73 patients (CKD n = 42, non-CKD n = 31), 36 were allocated to the FC-low group (CKD n = 21, non-CKD n = 15) and 37 to the FC-high group (CKD n = 21, non-CKD n = 16). Baseline levels of serum ferritin, transferrin saturation (TSAT), c-terminal FGF23, intact FGF23, and PLT are shown in Table 1. Regardless of CKD status, serum ferritin and TSAT increased. After FC-low treatment, mean changes from baseline to week 8 (95% CI) in serum ferritin and TSAT were 18.8 (13.3, 24.2) ng/mL and 8.1 (4.4, 11.8) % in CKD, 17.5 (13.8, 21.3) ng/mL and 13.8 (8.7, 18.9) % in non-CKD;, they were 28.1 (13.4, 42.7) ng/mL and 8.8 (5.4, 12.1) % in CKD, 15.9 (12.1, 19.8) ng/mL and 19.9 (9.8, 30.1) % in non-CKD. After administration of FC, in both groups, intact FGF23 levels did not change, whereas c-terminal FGF23 levels decreased. Median changes (interquartile range) from baseline to week 8 of c-terminal FGF23 were -58.00 (-227.50, -12.25) RU/mL in CKD and -725.00 (-1124.00, -168.50) RU/mL in non-CKD, and -66.00 (-265.70, -27.00) RU/mL in CKD and -649.50 (-1127.00, -326.65) RU/mL in non-CKD. Serum phosphate did not change regardless of CKD status. At baseline, high PLT was observed in the FC-low group in 1 CKD case (5.0%) and 8 non-CKD cases (53.3%), and in the FC-high group in 3 CKD cases (15.8%) and 8 non-CKD cases (50.0%). In all these patients, PLT reduction to below 35.2 × 104/µL was observed until week 8. Conclusion In patients with IDA, administration of FC increased serum ferritin and TSAT, decreased c-terminal FGF23, and normalized PLT in patients with high PLT at baseline regardless of CKD status. FC may decrease the potential risk of cardiovascular events in CKD or non-CKD patients with IDA.

#6124 INTERACTIONS BETWEEN FIBROBLAST GROWTH FACTOR 23 AND SYSTEMIC INFLAMMATION IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims In patients with Chronic Kidney Disease (CKD), serum concentration of Fibroblast Growth Factor 23 (FGF23) is inversely correlated with Glomerular Filtration Rate (eGFR), as an adaptive mechanism to counterbalance the alterations of mineral metabolism. Transcription, secretion and cleavage from the intact form (iFGF23) to the c-terminal fraction (cFGF23) are regulated by several mechanisms among which inflammatory mediators seem to play a significant role. We investigated whether there was any correlation between FGF23 and several inflammatory mediators. Method In the present study we evaluated cross sectionally the correlation between FGF23 (iFGF23 and c-FGF23) and some pro-inflammatory (IL-6, TNFα, MCP-1)) and anti-inflammatory (IL-10) cytokines in a cohort of 111 prevalent CKD patients stages III-V not yet on dialysis. We excluded patients with infections or chronic inflammatory diseases in the last 3 months, neoplasia or under immunosuppressive therapy. FGF23 and cytokines were dosed by ELISA. Results Descriptive characteristics of the cohort are reported in Table 1. We found an increase in inflammation as eGFR declines: IL6 (r = -0,315, p&amp;lt;0,001), TNFa (r = -0,202, p = 0,033) and MCP1 (r = -0,278, p = 0,003). Furthermore, the ratio between C-terminal FGF23 to intact FGF23 (c/iFGF23) was directly related to eGFR, even if it did not reach statistical significance (r = 0,127, p = 0,113). The correlations between FGF23 and markers of osteo-mineral metabolism and inflammation are reported in Table 2. We found positive correlations of iFGF23 with: IL-6 (r = 0,465, p&amp;lt;0,001), TNFα (r = 0,241, p = 0,009) and IL-10 (r = 0,198, p = 0,044) Conversely, cFGF23 only correlated with MCP-1 (r = 0,264, p = 0,005). c/iFGF23 resulted inversely correlated with IL-6 (-0,326, p&amp;lt;0,001) and positively with MCP-1 (r = 0,178, p = 0,061). After the adjustment for eGFR, iFGF23 maintained his correlations only with IL-6 (r = 0,370, p &amp;lt; 0,001) and TNFα (r = 0,163, p = 0,044) while c/iFGF23 was negatively correlated with IL-6 (r -0,251, p = 0,008) and positively with MCP-1 (r = 0,204, p = 0,032). Conclusion Our data confirm that in CKD patients, as the renal function declines, there is an important increase of inflammatory cytokines and a tendency to an impaired cleavage of FGF23 from the intact to the c-terminal form. Furthermore, we observed strong correlations of iFGF23 with several inflammatory cytokines (IL-6, TNFα, IL-10) that seem to be independent of eGFR. On the contrary we did not find any correlation of cFGF23 with inflammatory mediators, except for MCP-1. Therefore, we believe that overall our results suggest that inflammatory markers are differently associated with cFGF23 and iFGF23, as if inflammation may independently influence FGF23 turnover (i.e, c/iFGF23 ratio).

Associations of FGF23 with 10-Year Change in eGFR and UACR and with Incident CKD in the CARDIA Cohort.

The relationship of fibroblast growth factor 23 (FGF23) with incident chronic kidney disease (CKD) has been examined in older but not younger populations. Linear regression models were used to examine the associations of c-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) with 10-year change (1995-96 to 2005-06) in estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR) in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Cox proportional hazards models were used to assess the association of cFGF23 with incident CKD, defined as eGFR < 60 ml/min/1.73 m2 or UACR ≥ 30 mg/g. Multivariable models adjusted for age, sex, race, education, field center, physical activity, body mass index, diabetes, smoking, and systolic blood pressure. Among 2511 participants, the mean age was 45 ± 3.6 years, mean eGFR was 96.5 ± 14.0 ml/min/1.73 m2, median UACR was 4.3 (IQR, 3.0 - 6.7) mg/g. Most (62.6%) participants were non-smokers, the prevalence of diabetes was low (6.6%), and median values for 10-year changes in eGFR and UACR were modest (-5.50 ml/min/1.73 m2 and 0.70 mg/g, respectively). No consistent associations between cFGF23 and 10-year change in eGFR and UACR were observed. During a median follow up of 9.98 years, incident CKD developed in 258 participants. There was a non-linear association of cFGF23 with incident CKD, and relative to lowest quartile of cFGF23, significant relationship detected only among participants in the highest quartile (hazard ratio 1.58, 95% confidence interval [1.09, 2.27]). Similar findings were observed for iFGF23. Among middle-aged adults in the CARDIA cohort, median eGFR and UACR changes were modest and cFGF23 and iFGF23 were not consistently associated with 10-year change in eGFR or UACR. A non-linear relationship was observed between cFGF23 and incident CKD, with individuals with highest cFGF23 levels being at risk for developing CKD.

Tumour induced osteomalacia in patients with malignancy: a meta-analysis and systematic review of case reports.

Tumour induced osteomalacia (TIO) due to FGF23 overexpression is becoming recognized in patients with malignancy. The condition may be underdiagnosed, with a scarce medical literature. To perform a meta-analysis of case reports to allow a better understanding of malignant TIO and its clinical implications. Full-texts were selected according to strict inclusion criteria. All case reports were included where patients had hypophosphatemia, malignant TIO, and FGF23 blood levels. 32/275 eligible studies (n = 34 patients) met inclusion criteria. A list of desired data was extracted and graded for methodological quality. Prostate adenocarcinoma (n = 9) were the most tumours reported. 25/34 patients had a metastatic disease and a poor clinical outcome was reported for 15/28 patients. The median levels of blood phosphate and C-terminal FGF23 (cFGF23) were 0.40 mmol/L and 788.5 RU/mL respectively. For most of patients, blood PTH was elevated or within range, and calcitriol levels were inappropriately low or normal. Alkaline phosphatase concentrations were increased for 20/22 patients. The cFGF23 values were significantly higher for patients with a poor clinical outcome when compared to other patients (1685 vs 357.5 RU/mL). In case of prostate cancer, cFGF23 levels were significantly lower (429.4 RU/mL) than for other malignancies (1007.5 RU/mL). We report for the first time a detailed description of the clinical and biological characteristics of malignant TIO. In this context, FGF23 blood measurement would be of value for the diagnostic work-up, prognostication and follow-up of patients.

Variation in the fibroblast growth factor 23 (FGF23) gene associates with serum FGF23 and bone strength in infants.

Introduction: The effects of genetic variation in fibroblast growth factor 23 (FGF23) are unclear. This study explores the associations of single-nucleotide polymorphisms (SNPs) of FGF23 with phosphate and vitamin D metabolism and bone strength in early childhood. Methods: The study is part of the vitamin D intervention in infant (VIDI) trial (2013-2016), in which healthy term infants born to mothers of Northern European origin received vitamin D3 supplementation of 10 or 30μg/day from 2 weeks to 24months of age (ClinicalTrials.gov NCT01723852). Intact and C-terminal FGF23 (cFGF23), 25-hydroxyvitamin D (25-OHD), parathyroid hormone, phosphate, and peripheral quantitative computed tomography (pQCT)-derived bone strength parameters were analyzed at 12 and 24months. The study included 622 VIDI participants with genotyping data on FGF23 SNPs rs7955866, rs11063112, and rs13312770. Results: Rs7955866 minor allele homozygotes had lowest cFGF23at both time-points (mixed model for repeated measurements, pvariant = 0.009). Minor alleles of rs11063112 were associated with a greater age-related decrease in phosphate concentration (pinteraction = 0.038) from 12 to 24months. Heterozygotes of rs13312770 had the greatest total bone mineral content (total BMC), cross-sectional area (total CSA), and polar moment of inertia (PMI) at 24months (ANOVA p = 0.005, 0.037, and 0.036, respectively). Rs13312770 minor alleles were associated with a greater increase of total BMC, but a smaller increase of total CSA and PMI, during follow-up (pinteraction <0.001, 0.043, and 0.012, respectively). Genotype of FGF23 did not modify 25-OHD. Conclusion: The study finds that genetic variation in FGF23 modifies cFGF23, phosphate, and pQCT-derived bone strength parameters from 12 to 24months of age. These findings potentially promote an understanding of the regulation of FGF23 and its role in bone metabolism and temporal changes thereof during early childhood.

Fibroblast growth factor 23, glucose homeostasis and incident diabetes: findings of two cohort studies.

The phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood. This study investigates potential cross-talk between FGF23 and glucose homeostasis. First, we investigated the effect of glucose loading on plasma C-terminal FGF23 levels and its temporal relationship with changes in plasma phosphate in 45 overweight (BMI 25-30 kg/m2) subjects using time-lag analyses. Second, we studied cross-sectional associations of plasma C-terminal FGF23 levels with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI >30 kg/m2) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI. After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag=0.04). In the population-based cohort (N=5482; mean age 52 yrs, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (b 0.13[0.03-0.23], P=0.01), insulin (b 0.10[0.03-0.17], P<0.001), and proinsulin (b 0.06[0.02-0.10], P=0.01) at baseline. Upon longitudinal analyses, a higher baseline FGF23 was independently associated with development of diabetes (199 events (4%); fully adjusted HR 1.66[95% CI 1.06-2.60], P=0.03) and development of obesity (241 events (6%); fully adjusted HR 1.84[1.34-2.50], P<0.001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI. Glucose loading has phosphate-independent effects on FGF23 and, vice versa, FGF23 is associated with glucose, insulin and proinsulin levels and obesity. These findings suggest cross-talk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.

Short-Term Effects of a Therapeutic Diet on Biochemical Parameters in Hemodialysis Patients: A Randomized Crossover Trial

Although unhealthy diets exacerbate nutritional and metabolic derangements in patients with end-stage kidney disease (ESKD), how therapeutic diets that possess a variety of different dietary strategies acutely modify diverse biochemical parameters related to cardiovascular disease remains underexplored. Thirty-three adults with end-stage kidney disease undergoing thrice-weekly hemodialysis participated in a randomized crossover trial comparing a therapeutic diet with their usual diets for 7days, separated by a 4-week washout period. The therapeutic diet was characterized by adequate calorie and protein amounts, natural food ingredients with a low phosphorus-to-protein ratio, higher portions of plant-based food, and high fiber content. The primary outcome measure was the mean difference in the change-from-baseline intact fibroblast growth factor 23 (FGF23) level between the 2 diets. The other outcomes of interest included changes in mineral parameters, uremic toxins, and high-sensitivity C-reactive protein (hs-CRP) levels. Compared with the usual diet, the therapeutic diet lowered intact FGF23 levels (P=.001), decreased serum phosphate levels (P<.001), reduced intact parathyroid hormone (PTH) levels (P=.003), lowered C-terminal FGF23 levels (P=.03), increased serum calcium levels (P=.01), and tended to lower total indoxyl sulfate levels (P=.07) but had no significant effect on hs-CRP levels. Among these changes, reduction in serum phosphate level achieved in 2days, modifications of intact PTH and calcium levels in 5days, and reductions in intact and C-terminal FGF23 levels in 7days of therapeutic diet intervention. Within the 1-week intervention period, the dialysis-specific therapeutic diet rapidly reversed mineral abnormalities and tended to decrease total indoxyl sulfate levels in patients undergoing hemodialysis but had no effect on inflammation. Future studies to assess the long-term effects of such therapeutic diets are recommended.

Bone-derived C-terminal FGF23 cleaved peptides increase iron availability in acute inflammation

AbstractInflammation leads to functional iron deficiency by increasing the expression of the hepatic iron regulatory peptide hepcidin. Inflammation also stimulates fibroblast growth factor 23 (FGF23) production by increasing both Fgf23 transcription and FGF23 cleavage, which paradoxically leads to excess in C-terminal FGF23 peptides (Cter-FGF23), rather than intact FGF23 (iFGF23) hormone. We determined that the major source of Cter-FGF23 is osteocytes and investigated whether Cter-FGF23 peptides play a direct role in the regulation of hepcidin and iron metabolism in response to acute inflammation. Mice harboring an osteocyte-specific deletion of Fgf23 showed a ∼90% reduction in Cter-FGF23 levels during acute inflammation. Reduction in Cter-FGF23 led to a further decrease in circulating iron in inflamed mice owing to excessive hepcidin production. We observed similar results in mice showing impaired FGF23 cleavage owing to osteocyte-specific deletion of Furin. We next showed that Cter-FGF23 peptides bind members of the bone morphogenetic protein (BMP) family, BMP2 and BMP9, which are established inducers of hepcidin. Coadministration of Cter-FGF23 and BMP2 or BMP9 prevented the increase in Hamp messenger RNA and circulating hepcidin levels induced by BMP2/9, resulting in normal serum iron levels. Finally, injection of Cter-FGF23 in inflamed Fgf23KO mice and genetic overexpression of Cter-Fgf23 in wild type mice also resulted in lower hepcidin and higher circulating iron levels. In conclusion, during inflammation, bone is the major source of Cter-FGF23 secretion, and independently of iFGF23, Cter-FGF23 reduces BMP-induced hepcidin secretion in the liver.