Plasma Fibroblast Growth Factor Research Articles

Safety and efficacy of burosumab in improving phosphate metabolism, bone health, and quality of life in adolescents with X-linked hypophosphatemic rickets

Background and objectiveX-linked hypophosphatemic rickets (XLH) is due to loss-of-function mutations in the phosphate-regulating endopeptidase homologue on the X chromosome (PHEX) that lead to increased fibroblast growth factor 23 (FGF23) production. FGF23 excess causes renal phosphate wasting and insufficient 1,25-dihydroxyvitamin D (1,25(OH)2D) synthesis with reduced intestinal phosphate absorption, ultimately resulting in chronic hypophosphatemia.Children with XLH show typical skeletal lesions of rickets, deformities of the lower limbs, stunted growth with disproportionate short stature, bone pain, and physical dysfunctions.Burosumab, a fully human IgG1 monoclonal antibody that binds to FGF23 to inhibit its activity, is more effective to improve the biochemical and clinical signs of XLH than conventional treatment with phosphate supplements and vitamin D active metabolites. Data on adolescents with XLH during the transition period to young adulthood are few.In this prospective case series, we aimed to assess safety and efficacy of burosumab in adolescents with XLH who discontinued long-term conventional therapy. MethodsFive Caucasian adolescents (4 males, 1 female; mean age 15.4 ± 1.5 years) with XLH were recruited and switched from conventional treatment to burosumab (0.8–1.2 mg/kg, s. c. QW2). Burosumab was continued for 12–48 months and, once discontinued, patients were followed-up for 6–12 months. In all patients, serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 1,25(OH)2D levels, and renal tubular reabsorption of phosphate (TmP/GFR) values were assessed at entry and during burosumab. Intact FGF23 plasma levels were measured at entry. Patient-reported outcomes (PROs) were assessed at entry and every 3–6 months to evaluate the impact of low extremity pain, stiffness, and difficulties performing daily activities. ResultsAt entry, all patients showed hypophosphatemia, increased intact FGF23 levels, reduced TmP/GFR, insufficient 1,25(OH)2D levels, and in four out of five increased ALP levels. Two patients had radiological signs of rickets. During burosumab, all patients showed a significant increase in serum phosphate and 1,25(OH)2D levels, and in TmP/GFR values (P < 0.05 - P < 0.0001). Serum ALP levels significantly declined (P < 0.05) to normal values. No changes of serum calcium and PTH levels (PNS) were found during burosumab. PROs significantly improved (P < 0.02 - P < 0.0001) in all patients. Four patients discontinued burosumab when they turned 18 or 19, whereas one continued the treatment since he was still younger than 18 during the study period. Four patients who suspended burosumab showed a rapid decline in serum phosphate and 1,25(OH)2D levels and in TmP/GFR values; serum ALP levels increased, and PROs progressively worsened with a significant reduction in quality of life. These consequences were not observed in the patient who continued burosumab treatment. DiscussionOur data showed that conventional treatment improved only in part the signs and symptoms of XLH. Burosumab was well tolerated and was effective in improving phosphate metabolism, bone health, and PROs. All the benefits of burosumab were lost after its discontinuation. These results suggested that continuing burosumab is required to achieve and maintain the clinical benefits of the treatment during the transition to young adulthood in patients with XLH.

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

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

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.

The biological variation of serum 1,25-dihydroxyvitamin D and parathyroid hormone, and plasma fibroblast growth factor 23 in healthy individuals

Background and aimsMeasuring 1,25-dihydroxyvitamin D (1,25(OH)2D), parathyroid hormone 1–84 (PTH 1–84) and intact FGF23 (iFGF23) is crucial for diagnosing a variety of diseases affecting bone and mineral homeostasis. Biological variability (BV) data are important for defining analytical quality specifications (APS), the usefulness of reference intervals, and the significance of variations in serial measurements in the same subject. The aim of this study was to pioneer the provision of BV estimates for 1,25(OH)2D and to improve existing BV estimates for iFGF23 and PTH 1–84. Materials and methodsSerum and plasma-EDTA samples of sixteen healthy subjects have been collected for seven weeks and measured in duplicate by chemiluminescent immunoassay on the DiaSorin Liaison platform. After variance verification, within-subject (CVI) and between-subject (CVG) BV estimates were assessed by either standard ANOVA, or CV-ANOVA. The APSs were calculated according to the EFLM-BV-model. ResultsWe found the following CVI estimates with 95% confidence intervals:1,25(OH)2D, 22.2% (18.9–26.4); iFGF23, 16.1% (13.5–19.5); and PTH 1–84, 17.9% (14.8–21.8). The CVG were: 1,25(OH)2D, 21.2% (14.2–35.1); iFGF23, 21.1% (14.5–35.8); and PTH 1–84, 31.1% (22.1–50.8). ConclusionsWe report for the first time BV estimates for 1,25(OH)2D and enhance existing data about iFGF23-BV and PTH 1–84-BV through cutting-edge immunometric methods.

ERRγ-inducible FGF23 promotes alcoholic liver injury through enhancing CYP2E1 mediated hepatic oxidative stress

Fibroblast growth factor 23 (FGF23) is a member of endocrine FGF family, along with FGF15/19 and FGF21. Recent reports showed that under pathological conditions, liver produces FGF23, although the role of hepatic FGF23 remains nebulous. Here, we investigated the role of hepatic FGF23 in alcoholic liver disease (ALD) and delineated the underlying molecular mechanism. FGF23 expression was compared in livers from alcoholic hepatitis patients and healthy controls. The role of FGF23 was examined in hepatocyte-specific knock-out (LKO) mice of cannabinoid receptor type 1 (CB1R), estrogen related receptor γ (ERRγ), or FGF23. Animals were fed with an alcohol-containing liquid diet alone or in combination with ERRγ inverse agonist. FGF23 is mainly expressed in hepatocytes in the human liver, and it is upregulated in ALD patients. In mice, chronic alcohol feeding leads to liver damage and induced FGF23 in liver, but not in other organs. FGF23 is transcriptionally regulated by ERRγ in response to alcohol-mediated activation of the CB1R. Alcohol induced upregulation of hepatic FGF23 and plasma FGF23 levels is lost in ERRγ-LKO mice, and an inverse agonist mediated inhibition of ERRγ transactivation significantly improved alcoholic liver damage. Moreover, hepatic CYP2E1 induction in response to alcohol is FGF23 dependent. In line, FGF23-LKO mice display decreased hepatic CYP2E1 expression and improved ALD through reduced hepatocyte apoptosis and oxidative stress. We recognized CBIR-ERRγ-FGF23 axis in facilitating ALD pathology through hepatic CYP2E1 induction. Thus, we propose FGF23 as a potential therapeutic target to treat ALD.

Risk factors for hip and vertebral fractures in chronic kidney disease: the CRIC study.

Fracture risk is high in chronic kidney disease (CKD) and underlying pathophysiology and risk factors may differ from the general population. In a cohort study of 3939 participants in the chronic renal insufficiency cohort (CRIC), we used Cox regression to test associations of putative risk factors with the composite of first hip or vertebral fracture assessed using hospital discharge codes. Mean age was 58years, 45% were female, 42% were Black, and 13% were Hispanic. There were 82 hip and 24 vertebral fractures over a mean (SD) 11.1 (4.8) years (2.4 events per 1000 person-years [95% CI: 2.0, 2.9]). Measured at baseline, diabetes, lower body mass index (BMI), steroid use, proteinuria, and elevated parathyroid hormone (PTH) were each associated with fracture risk after adjusting for covariates. Lower time-updated estimated glomerular filtration rate (eGFR) was associated with fractures (HR 1.20 per 10mL/min/1.73m2 lower eGFR; 95% CI: 1.04, 1.38) as were lower time-updated serum calcium and bicarbonate concentrations. Among time-updated categories of kidney function, hazard ratios (95% CI) for incident fracture were 4.53 (1.77, 11.60) for kidney failure treated with dialysis and 2.48 (0.86, 7.14) for post-kidney transplantation, compared with eGFR ≥60. Proton pump inhibitor use, dietary calcium intake, measures of vitamin D status, serum phosphate, urine calcium and phosphate, and plasma fibroblast growth factor-23 were not associated with fracture risk. In conclusion, lower eGFR in CKD is associated with higher fracture risk, which was highest in kidney failure. Diabetes, lower BMI, steroid use, proteinuria, higher serum concentrations of PTH, and lower calcium and bicarbonate concentrations were associated with fractures and may be modifiable risk factors.

Neonatal resveratrol administration promotes skeletal muscle growth and insulin sensitivity in intrauterine growth-retarded suckling piglets associated with activation of FGF21-AMPKα pathway.

Skeletal muscle is a major insulin-sensitive tissue with a pivotal role in modulating glucose homeostasis. This study aimed to investigate the effect of resveratrol (RES) intervention during the suckling period on skeletal muscle growth and insulin sensitivity of neonates with intrauterine growth retardation (IUGR) in a pig model. Twelve pairs of normal birth weight (NBW) and IUGR neonatal male piglets were selected. The NBW and IUGR piglets were fed basal formula milk diet or identical diet supplemented with 0.1% RES from 7 to 21 days of age. Myofiber growth and differentiation, inflammation and insulin sensitivity in skeletal muscle were assessed. Early RES intervention promoted myofiber growth and maturity in IUGR piglets by ameliorating the myogenesis process and increasing thyroid hormone level. Administering RES also reduced triglyceride concentration in skeletal muscle of IUGR piglets, along with decreased inflammatory response, increased plasma fibroblast growth factor 21 (FGF21) concentration and improved insulin signaling. Meanwhile, the improvement of insulin sensitivity by RES may be partly regulated by activation of the FGF21/AMP-activated protein kinase α/sirtuin 1/peroxisome proliferator activated receptor-γ coactivator-1α pathway. Our results suggest that RES has beneficial effects in promoting myofiber growth and maturity and increasing skeletal muscle insulin sensitivity in IUGR piglets, which open a novel field of application of RES in IUGR infants for improving postnatal metabolic adaptation. © 2023 Society of Chemical Industry.

Phosphate Restriction Prevents Metabolic Acidosis and Curbs Rise in FGF23 and Mortality in Murine Folic Acid-Induced AKI.

Patients with AKI suffer a staggering mortality rate of approximately 30%. Fibroblast growth factor 23 (FGF23) and phosphate (P i ) rise rapidly after the onset of AKI and have both been independently associated with ensuing morbidity and mortality. This study demonstrates that dietary P i restriction markedly diminished the early rise in plasma FGF23 and prevented the rise in plasma P i , parathyroid hormone, and calcitriol in mice with folic acid-induced AKI (FA-AKI). Furthermore, the study provides evidence for P i -sensitive osseous Fgf23 mRNA expression and reveals that P i restriction mitigated calciprotein particles (CPPs) formation, inflammation, acidosis, cardiac electrical disturbances, and mortality in mice with FA-AKI. These findings suggest that P i restriction may have a prophylactic potential in patients at risk for AKI. In AKI, plasma FGF23 and P i rise rapidly and are independently associated with disease severity and outcome. The effects of normal (NP) and low (LP) dietary P i were investigated in mice with FA-AKI after 3, 24, and 48 hours and 14 days. After 24 hours of AKI, the LP diet curbed the rise in plasma FGF23 and prevented that of parathyroid hormone and calcitriol as well as of osseous but not splenic or thymic Fgf23 mRNA expression. The absence of Pth prevented the rise in calcitriol and reduced the elevation of FGF23 in FA-AKI with the NP diet. Furthermore, the LP diet attenuated the rise in renal and plasma IL-6 and mitigated the decline in renal α -Klotho. After 48 hours, the LP diet further dampened renal IL-6 expression and resulted in lower urinary neutrophil gelatinase-associated lipocalin. In addition, the LP diet prevented the increased formation of CPPs. Fourteen days after AKI induction, the LP diet group maintained less elevated plasma FGF23 levels and had greater survival than the NP diet group. This was associated with prevention of metabolic acidosis, hypocalcemia, hyperkalemia, and cardiac electrical disturbances. This study reveals P i -sensitive FGF23 expression in the bone but not in the thymus or spleen in FA-AKI and demonstrates that P i restriction mitigates CPP formation, inflammation, acidosis, and mortality in this model. These results suggest that dietary P i restriction could have prophylactic potential in patients at risk for AKI.

Kidney phosphate wasting predicts poor outcome in polycystic kidney disease.

Patients with ADPKD have disproportionately high levels of fibroblast growth factor-23 (FGF-23) for their CKD-stage with only a subgroup that develops kidney phosphate wasting. We assessed factors associated with phosphate wasting and hypothesize that it identifies patients with more severe disease and predicts disease progression. We included 604 patients with ADPKD from a multi-center prospective observational (DIPAK) cohort in 4 university medical centers in the Netherlands. We measured parathyroid hormone (PTH), total plasma FGF-23 levels and calculated the ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) with < 0.8 mmol/L defined as kidney phosphate wasting. We analysed the association of TmP/GFR with eGFR decline over time and the risk for a composite kidney outcome (≥ 30% eGFR decline, kidney failure or kidney replacement therapy). In our cohort (age 48 ± 12 years, 39% male, eGFR 63 ± 28 mL/min/1.73m2), 59% of patients had phosphate wasting. Male sex (coefficient -0.2, 95% confidence interval [CI] -0.2; -0.1), eGFR (0.002, 0.001-0.004), FGF-23 (0.1, 0.03-0.2), PTH(-0.2, -0.3; -0.06) and Copeptin(-0.08, -0.1; -0.08) were associated with TmP/GFR. Corrected for PTH, FGF-23 and eGFR, every 0.1 mmol/L decrease in TmP/GFR was associated with a greater eGFR decline of 0.2 ml/min/1.73m2/year (95% CI 0.01-0.3) and an increased hazard ratio of 1.09 (95% CI 1.01-1.18) of the composite kidney outcome. Our study shows that in patients with ADPKD phosphate wasting is prevalent and associated with more rapid disease progression. Phosphate wasting may be a consequence of early proximal tubular dysfunction and insufficient suppression of PTH.

Fibroblast growth factor 23 is a strong independent marker of poor outcome after an acute coronary syndrome

Abstract Our study aimed to assess the role of fibroblast growth factor 23 (FGF-23) as a prognostic marker after an acute coronary syndrome (ACS). It was a prospective and multicentric study, performed at five tertiary hospitals in our city, which included 1,190 patients with ACS. FGF-23 plasma levels and other components of mineral metabolism (calcidiol, parathormone [PTH], klotho, and phosphate), lipids, troponin, high-sensitivity C-reactive protein, and N-terminal-pro-brain natriuretic peptide were measured at discharge. The primary outcome was a combination of acute ischemic events, heart failure (HF) and death. Secondary outcomes were the separate components of the primary outcome. Median follow-up was 5.44 (3.03-7.46) years. 294 patients developed the primary outcome. Patients with FGF-23 less than median (which was settled in 110 RU/mL) were less frequently females, and were younger and had a lower load of cardiovascular risk factors. Besides, calcidiol and PTH levels were lower in patients with FGF-23 below the median. Multivariable analysis showed that FGF-23 (HR 1.18 [1.08-1.29], p&amp;lt;0.001), calcidiol (HR 0.86 [0.74-1.00], p=0.046), previous CAD or cerebrovascular accident, and hypertension were independent predictors of the primary outcome. The predictive power of FGF-23 was homogeneous across different subgroups of population. FGF-23 resulted an independent predictor of HF (HR 1.38 [1.22-1.57], p&amp;lt;0.001), and death (HR 1.21 [1.07-1.37], p=0.002), but not of acute ischemic events. According to renal function, FGF-23 was an independent predictor for the primary outcome in patients with estimated glomerular filtration rate (eGFR) above 60 ml/min/1.73m2,, showing that the potential prognostic role of FGF-23 was not exclusively related to chronic kidney disease patients. Moreover, regarding the secondary outcomes, FGF-23 resulted an independent predictor of HF and death. To sum up, FGF-23 seems to be a strong, independent, predictor of HF and death among patients with ACS. This effect is homogeneous across different subgroups of population and not limited to patients with CKD.

A Combined Biomarker That Includes Plasma Fibroblast Growth Factor 23, Erythropoietin, and Klotho Predicts Short- and Long-Term Morbimortality and Development of Chronic Kidney Disease in Critical Care Patients with Sepsis: A Prospective Cohort.

Acute Kidney Injury (AKI) is a frequent complication in intensive care unit (ICU) patients that increases mortality and chronic kidney disease (CKD) development. AKI is associated with elevated plasma fibroblast growth factor 23 (FGF23), which can be modulated by erythropoietin (EPO) and Klotho. We aimed to evaluate whether a combined biomarker that includes these molecules predicted short-/long-term outcomes. We performed a prospective cohort of ICU patients with sepsis and previously normal renal function. They were followed during their inpatient stay and for one year after admission. We measured plasma FGF23, EPO, and Klotho levels at admission and calculated a combined biomarker (FEK). A total of 164 patients were recruited. Of these, 50 (30.5%) had AKI at admission, and 55 (33.5%) developed AKI within 48 h. Patients with AKI at admission and those who developed AKI within 48 h had 12- and 5-fold higher FEK values than non-AKI patients, respectively. Additionally, patients with higher FEK values had increased 1-year mortality (41.9% vs. 18.6%, p = 0.003) and CKD progression (26.2% vs. 8.3%, p = 0.023). Our data suggest that the FEK indicator predicts the risk of AKI, short-/long-term mortality, and CKD progression in ICU patients with sepsis. This new indicator can improve clinical outcome prediction and guide early therapeutic strategies.

Fibroblast Growth Factor 23 and Risk of Heart Failure Subtype: The CRIC (Chronic Renal Insufficiency Cohort) Study

Heart failure (HF) is an important cause of morbidity and mortality among individuals with chronic kidney disease (CKD). A large body of evidence from preclinical and clinical studies implicates excess levels of fibroblast growth factor 23 (FGF23) in HF pathogenesis in CKD. It remains unclear whether the relationship between elevated FGF23 levels and HF risk among individuals with CKD varies by HF subtype. Prospective cohort study. A total of 3,502 participants were selected in the Chronic Renal Insufficiency Cohort study. Baseline plasma FGF23. Incident HF by subtype and total rate of HF hospitalization. HF was categorized as HF with preserved ejection fraction (HFpEF, ejection fraction [EF]≥ 50%), HF with reduced EF (HFrEF, EF<50%) and HF with unknown EF (HFuEF). Multivariable-adjusted cause-specific Cox proportional hazards models were used to investigate associations between FGF23 and incident hospitalizations for HF by subtype. The Lunn-McNeil method was used to compare hazard ratios across HF subtypes. Poisson regression models were used to evaluate the total rate of HF. During a median follow-up time of 10.8 years, 295 HFpEF, 242 HFrEF, and 156 HFuEF hospitalizations occurred. In multivariable-adjusted cause-specific Cox proportional hazards models, FGF23 was significantly associated with the incidence of HFpEF (HR, 1.41; 95% CI, 1.21-1.64), HFrEF (HR, 1.27; 95% CI, 1.05-1.53), and HFuEF (HR, 1.40; 95% CI, 1.13-1.73) per 1 standard deviation (SD) increase in the natural log of FGF23. The Lunn-McNeil method determined that the risk association was consistent across all subtypes. The rate ratio of total HF events increased with FGF23 quartile. In multivariable-adjusted models, compared with quartile 1, FGF23 quartile 4 had a rate ratio of 1.81 (95% CI, 1.28-2.57) for total HF events. Self-report of HF hospitalizations and possible lack of an echocardiogram at time of hospitalization. In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risks for all HF subtypes. Heart failure (HF) is a prominent cause of morbidity and mortality in individuals with chronic kidney disease (CKD). Identifying potential pathways in the development of HF is essential in developing therapies to prevent and treat HF. In a large cohort of individuals with CKD, the Chronic Renal Insufficiency Cohort (N=3,502), baseline fibroblast growth factor-23 (FGF23), a hormone that regulates phosphorous, was evaluated in relation to the development of incident and recurrent HF with reduced, preserved, and unknown ejection fraction. In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risk of all HF subtypes. These findings demonstrate the need for further research into FGF23 as a target in preventing the development of HF in individuals with CKD.

1662-P: The Bidirectional Relationship of Fibroblast Growth Factor 23 and Glucose Homeostasis

Objective: To investigate potential cross-talk between the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) and glucose homeostasis. Research Design and Methods: First, we investigated the effect of glucose loading on plasma FGF23 and its temporal relationship with changes in plasma phosphate (0-15-30-45-60-75-90-120-150-180-240-300-360-420-480 minutes) in 45 overweight (BMI 25-30) subjects using time-lag analyses. Second, we studied cross-sectional associations of plasma FGF23 with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI &amp;gt;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. Results: 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 (est. β 0.13[0.03-0.23], P=0.01), insulin (est. β 0.10[0.03-0.17], P&amp;lt;0.001), and proinsulin (est. β 0.06[0.02-0.10], P=0.01) at baseline. Upon longitudinal analyses, a higher baseline FGF23 was independently associated with the 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&amp;lt;0.001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI. Conclusions: Glucose loading has phosphate-independent effects on FGF23; vice versa, FGF23 is associated with glucose, insulin, proinsulin levels and obesity. These findings suggest deleterious cross-talk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes. Disclosure A.Van der vaart: None. C.Eelderink: None. A.Van beek: Advisory Panel; Novo Nordisk, Consultant; Novo Nordisk. S.J.Bakker: None. P.Van dijk: None. M.De borst: None.

#2971 LONG-TERM EFFECTS OF THE NEW NORDIC RENAL DIET ON PHOSPHOROUS HOMEOSTASIS IN PATIENTS WITH CHRONIC KIDNEY DISEASE STAGE 3 AND 4

Abstract Background and Aims Chronic kidney disease (CKD) causes severe disturbances in phosphate metabolism. The New Nordic Renal Diet (NNRD) is a whole food approach designed by our group, with low dietary phosphorus content (850 mg/day). In a 1-week study, NNRD had positive effects on phosphorus homeostasis in patients with CKD stage 3-4 [1]. The aim of the present study was to examine the long-term health effects of a dietary intervention with NNRD in patients with CKD stage 3-4 [2]. Method A 26-week randomized, controlled, non-blinded trial comparing the effect of NNRD vs. non-restricted habitual diet. Patients in the NNRD group received weekly home delivery of fresh food items (free of charge) and recipes for five days of the week, and on the remaining two days they were instructed to prepare meals according to the NNRD food principles. The study was designed with seven follow-up visits in the outpatient clinic where fasting blood samples and 24-hour urine collection were delivered. Linear mixed-effects models were used to assess the effects of the intervention, time, and the potential interaction between intervention and time. The primary endpoint was the difference in 24-hour urine phosphorus excretion between the two study groups. Secondary endpoints included fractional phosphorus excretion and plasma fibroblast growth factor 23 (p-FGF23). Results Sixty patients (mean age 54 years, 31 women) with mean eGFR of 34 ml/min/1.73 m2 were included. Two patients were withdrawn due to dialysis initiation. In the NNRD-group (n = 29), mean 24-hour urine phosphorus excretion during the intervention period was 651 mg (SD, 35 mg) vs. 930 mg (SD, 84 mg) in the control group (n = 29), between-group difference 279 (95% CI; -372, -91; P &amp;lt; 0.001) (Figure 1). Mean fractional phosphorus excretion was 11% (SD, 5%) in the NNRD-group and 14% (SD, 7%) in the control group, between-group difference 3% (95% CI; -6.4, -0.8; P = 0.01). Mean p-FGF23 was 162 pg/ml (SD, 130 pg/ml) in the NNRD-group and 215 pg/ml (SD, 230 pg/ml) in the control group, between-group difference 52 pg/ml (95% CI; -100, 73; P = 0.03). P-urea was 3.4 mmol/L lower in the NNRD group (95% CI; -5.3, -0.2, P = 0.03). P-albumin was 1.1 g/L higher in the NNRD group (95% CI; 0.02, 2.4; P = 0.04) and 24-h urine bicarbonate excretion was 4.1 mmol higher in the NNRD group (95% CI; 0.7, 7.5, P = 0.01). There was no difference between study groups in p-phosphorous, p-creatinine, p-potassium, p-calcium, p-lipids, or proteinuria. Conclusion NNRD intervention in the context of fresh food delivery and recipes was feasible and had a major beneficial effect on phosphorous parameters in patients with CKD 3-4.

Effect of Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist.

Cilofexor is a nonsteroidal farnesoid X receptor agonist in clinical development for treatment of nonalcoholic steatohepatitis. This work characterized the pharmacokinetics, pharmacodynamics, safety, and tolerability of cilofexor in participants with normal hepatic function or hepatic impairment (HI). Participants with stable mild, moderate, or severe HI (Child-Pugh [CP] A, B, or C, respectively, [n = 10/group]) and healthy matched controls with normal hepatic function received a single oral dose of cilofexor (30 mg for CP-A or B; 10 mg for CP-C) with a standardized meal. Overall, 56 participants received cilofexor and completed the study. Cilofexor area under the plasma concentration-time curve was 76%, 2.5-fold, and 6.3-fold higher in participants with mild, moderate, or severe HI, respectively, relative to the area under the plasma concentration-time curve in matched participants with normal hepatic function. Cilofexor unbound fraction was 38%, 2-fold, and 3.16-fold higher in participants with mild, moderate, and severe HI, respectively, relative to participants with normal hepatic function. Moderate correlations were identified between cilofexor exposure and CP score or laboratory tests components of CP score. Serum 7α-hydroxy-4-cholesten-3-one and plasma fibroblast growth factor 19 were similar in participants with mild, moderate, or severe HI and participants with normal hepatic function. Cilofexor was generally well tolerated; all cilofexor-related adverse events were mild in severity. Cilofexor can be administered to patients with mild HI without dose adjustment. Caution and dose modification are warranted when administering cilofexor to patients with moderate or severe HI.

Oncostatin M is a regulator of fibroblast growth factor 23 (FGF23) in UMR106 osteoblast-like cells

Renal phosphate and vitamin D metabolism is under the control of fibroblast growth factor 23 (FGF23), an endocrine and paracrine factor predominantly produced in bone. FGF23 formation is stimulated by active vitamin D, or parathyroid hormone (PTH), which are further regulators of phosphate homeostasis. In renal, inflammatory, and other diseases, plasma FGF23 reflects disease stage and correlates with outcome. Oncostatin M is part of the interleukin-6 (IL-6) family and regulates remodeling and PTH effects in bone as well as cardiac FGF23 production in heart failure via glycoprotein gp130. Here, we studied whether oncostatin M is a regulator of FGF23 in bone cells. Experiments were performed in UMR106 osteoblast-like cells, Fgf23 mRNA was determined by qRT-PCR, FGF23 protein by Western Blotting and ELISA, and oncostatin M receptor and leukemia inhibitory factor (LIF) receptor gene knockout accomplished by siRNA. As a result, oncostatin M dose-dependently up-regulated Fgf23 expression and protein secretion. The oncostatin M effect on FGF23 was mediated by oncostatin M receptor and gp130 and involved, at least in part, STAT3 and MEK1/2. Taken together, oncostatin M is a regulator of FGF23 through oncostatin M receptor, gp130, as well as STAT3 and MEK1/2 in UMR106 osteoblasts.

Vaginal Birth Alters Gut Transcriptome of Neonatal Pigs

Background: Women at risk of preterm birth are routinely administered prenatal doses of glucocorticoids to facilitate lung maturation and improve pulmonary outcomes in preterm infants. Additionally, preterm infants are often administered low doses of glucocorticoids postnatally for prevention of bronchopulmonary dysplasia. However, there is limited understanding about the impact of perinatal glucocorticoid exposure on the gut and liver in preterm infants. In pigs, there is a spike in plasma cortisol in newborns during parturition. We previously showed in pigs that plasma cortisol levels positively correlate with plasma fibroblast growth factor 19 (FGF19), a gut hormone that negatively regulates hepatic bile acid synthesis. FGF19 is secreted by epithelial cells predominantly in the distal ileum in response to bile acids. However, in vaginally-born pigs, FGF19 mRNA levels were higher in the proximal jejunum. This led us to hypothesize that exposure to glucocorticoids in the perinatal period has a profound impact on the transcription of genes involved in the development of gut and liver. Objective: The objective of this study was to characterize the impact of spontaneous vaginal birth and the exposure to elevated cortisol on the transcriptome in gut and liver tissue of neonatal pigs Methods: Two sows underwent a cesarean section on gestation day 114 (“Term”; term=115 day), two sows underwent a cesarean section on gestation day 105 (“Preterm”) and two additional sows were allowed to farrow at term gestational age (“Vaginal”). Small intestine tissue and plasma was collected from newborn pigs (n= 10 Preterm; n=8 Term; n=6 Vaginal). RNA-seq analysis was performed on intestinal samples mapped to the latest Sus scrofa Sscrofa11.1 reference genome (NCBI). Results: Cortisol levels were statistically highest in the vaginally-born pigs (139 ng/mL), followed by the Term (101 ng/mL) and lowest in the Preterm (61 ng/mL) pigs. Gene Ontology (GO) analysis showed significant enrichment in pathways of upregulated genes involved in response to toxic substances, stress, detoxification and inorganic substances in the jejunum of Vaginal pigs compared to Preterm and Term pigs. KEGG analysis of the proximal jejunum indicated enrichment in pathways of upregulated genes in steroid hormone biosynthesis, bile secretion, TNF signaling and IL-17 Vaginal, compared to Term and Preterm pigs. The same pattern was not the same in the distal ileum where GO analysis showed pathway enrichment of upregulated genes in oxidation-reduction processes, and transition metal ion binding in Vaginal compared to Term and Preterm pigs. KEGG analysis of the distal ileum identified pathway enrichment of upregulated genes in complement and coagulation, bile acid synthesis and secretion, fatty acid metabolism, and amino acid metabolism in Vaginal pigs. Conclusion: Genes in metabolic and cellular signaling pathways associated with cortisol are upregulated in vaginally-born pigs. This work was supported in part by federal funds from the USDA, Agricultural Research Service under Cooperative Agreement Number 3092-51000-060-01, and grants from the National Institutes of Health Grant DK-094616 (D.G.B), and the Texas Medical Center Digestive Diseases Center (NIH Grant P30 DK-56338). Caitlin Vonderohe was supported by T32 DK007664 and Greg Guthrie was supported by K01 DK129408. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Interrelation Between Hypothyroidism and Non-alcoholic Fatty Liver Disease, a Cross-sectional Study

Thyroid hormones play an important role in the regulation of diverse metabolic processes and might play a crucial role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, their association remains controversial. Therefore, our aim is to clarify whether overt or subclinical hypothyroidism was associated with NAFLD. This cross-sectional study included 60 participants with a new diagnosis of hypothyroidism and 30 age- and gender-matched healthy participants with thyroid-stimulating hormone (TSH) level <4.5mIU/L. Anthropometric measurements, laboratory parameters, plasma fibroblast growth factor 21 (FGF21), and hepatic steatosis diagnosed via controlled attenuation parameter (CAP) using transient elastography between the hypothyroid groups and control group were analyzed. Participants with hypothyroidism displayed significantly higher serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, total cholestrol, triglycerides, low-density lipoprotein cholesterol, TSH, hemoglobin A1c, fasting insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) but significantly lower serum albumin, high-density lipoprotein cholesterol, and free thyroxine levels than the control group (P=<0.001). The CAP values were significantly higher in participants with overt and subclinical hypothyroidism than the control group (P=<0.001). The only significant independent predictors of steatosis in our study were free T4, body mass index, and HOMA-IR after using multivariate logistic regression. The mean serum FGF21 levels were increased in hypothyroid participants with hepatic steatosis than those without hepatic steatosis (126.9±272.6) pg/ml vs. (106.8±138.7) pg/ml, P=0.8). Receiver operating characteristic (ROC) curve showed that FGF21 was not a significant marker for hepatic steatosis in hypothyroid participants (area under curve (AUC)=0.44, P=0.54). Individuals with subclinical or overt hypothyroidism were more likely to have NAFLD than those with normal thyroid function. Serum FGF21 levels were increased in hypothyroid individuals and its role as a marker of hepatic steatosis in hypothyroid individuals needs further assessment.

High Plasma Levels of Fibroblast Growth Factor 23 Are Associated with Increased Risk of COVID-19 in End-Stage Renal Disease Patients on Hemodialysis: Results of a Prospective Cohort.

We performed a prospective cohort of ESRD patients in hemodialysis who had measurements of plasma intact FGF23 in 2019. We determined COVID-19 infections, hospitalizations, and mortality between January 2020 and December 2021. We evaluated 243 patients. Age: 60.4 ± 10.8 years. Female: 120 (49.3%), diabetes: 110 (45.2%). During follow-up, 45 patients developed COVID-19 (18.5%), 35 patients were hospitalized, and 12 patients died (mortality rate: 26.6%). We found that patients with higher FGF23 levels (defined as equal or above median) had a higher rate of SARS-CoV-2 infection versus those with lower levels (18.8% versus 9.9%; Hazard ratio: 1.92 [1.03-3.56], p = 0.039). Multivariate analysis showed that increased plasma FGF23 was independently associated with SARS-CoV-2 infection and severe COVID-19. Our results suggest that high plasma FGF23 levels are a risk factor for developing COVID-19 in ESRD patients. These data support the potential immunosuppressive effects of high circulating FGF23 as a factor implicated in the association with worse clinical outcomes. Further data are needed to confirm this hypothesis.

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

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