C-terminal Fibroblast Growth Factor 23 Research Articles

Intact and C-Terminal Fibroblast Growth Factor 23 Assays: Do Kidney Function, Inflammation, and Iron Deficiency Influence Relationships with Clinical Outcomes?

Intact and C-Terminal Fibroblast Growth Factor 23 Assays: Do Kidney Function, Inflammation, and Iron Deficiency Influence Relationships with Clinical Outcomes?

Race and Ethnicity Predict Bone Markers and Fracture in Pediatric Patients With Chronic Kidney Disease.

Studies in healthy children have shown racial-ethnic differences in bone markers and bone outcomes including fractures. At present, limited studies have evaluated the impact of race and ethnicity on bone markers and fractures within the pediatric chronic kidney disease (CKD) population. In a cohort study of 762 children between the ages of 1.5 years and 18 years, with CKD stages 1 to 4 from the CKD in children (CKiD) cohort, the relationship between racial-ethnic group and bone markers (parathyroid hormone [PTH], 25-hydroxyvitamin D [25-OHD], 1,25-dihydroxyvitamin D [1,25(OH)2 D], and C-terminal fibroblast growth factor [FGF23]) was determined using linear mixed models. Additionally, logistic regression was used to evaluate racial-ethnic differences in prevalent fracture upon study entry. Black race was associated with 23% higher PTH levels (confidence interval [CI], 2.5% to 47.7%; p = .03), 33.1% lower 25-OHD levels (CI, -39.7% to -25.7%; p < .0001), and no difference in C-terminal FGF23 or 1,25(OH)2 D levels when compared to whites. Hispanic ethnicity was associated with 15.9% lower C-terminal FGF23 levels (CI, -28.3% to -1.5%; p = .03) and 13.8% lower 25-OHD levels (CI, -22.2% to -4.5%; p = .005) when compared to whites. Black and Hispanic children had 74% (odds ratio [OR] 0.26; CI, 0.14 to 0.49; p = .001) and 66% (OR 0.34; CI, 0.17 to 0.65; p < .0001) lower odds of any fracture than white children at study entry, respectively. Race and ethnicity are associated with differences in bone markers and despite lower 25-OHD levels, both black and Hispanic children with CKD reported a lower prevalent fracture history than white children. The current findings in the CKD population are similar to racial-ethnic differences described in healthy children. Additional studies are needed to better understand how these differences might impact the management of pediatric CKD-MBD. © 2020 American Society for Bone and Mineral Research (ASBMR).

Diagnostic accuracy of fibroblast growth factor 23 for predicting acute kidney injury in patients with acute decompensated heart failure

Elevated plasma levels of fibroblast growth factor 23 (FGF23) have emerged as a predictor for the development of acute kidney injury (AKI) in patients undergoing cardiac surgery and those with critical illnesses. However, accurate data in cases involving acute decompensated heart failure (ADHF) remains limited. Single centre cohort study was performed in patients admitted for ADHF. Plasma c-terminal FGF23 (c-FGF23) was measured at baseline and 24 hours after being diagnosed with ADHF. AKI was defined by KDIGO 2012 criteria. The study enrolled 62 patients diagnosed with ADHF. The incidence of AKI was 45% and significantly increased the risk of death. Patients developing AKI had significantly higher levels of plasma c-FGF23 at baseline in comparison with those not developing AKI [median value 1258.5 (57.2, 15 850) vs 230.2 (68.515 850) RU/mL, P = .005]. During the first 24 hours, plasma c-FGF23 levels decreased in both groups, and the levels of c-FGF23 at 24 hours were consistent with the baseline [861.8 (75.7, 15 850) vs 226.3 (56, 5450.8) RU/mL, P = .006]. Receiver operating characteristic analysis of both first time and second time for plasma c-FGF23 collection yielded an area under curve of 0.71 for the prediction of AKI incidence. With the cut-off point at 450 RU/mL, the sensitivity and specificity of plasma c-FGF23 at the baseline for predicting AKI were 71.4% and 61.8% respectively. Plasma c-FGF23 may serve as a novel biomarker for development of AKI in patients with ADHF. These results should be revalidated in larger-scale, cohort studies.

Intact and C-Terminal FGF23 Assays-Do Kidney Function, Inflammation, and Low Iron Influence Relationships With Outcomes?

Higher fibroblast growth factor-23 (FGF23) concentrations are associated with heart failure and mortality in diverse populations, but the strengths of associations differ markedly depending up on which assay is used. We sought to evaluate whether iron deficiency, inflammation, or kidney function account for differences in the strengths of associations between these 2 FGF23 assays with clinical outcomes. Case cohort study from the Cardiovascular Health Study. A total of 844 community-dwelling individuals aged 65 years or older with and without chronic kidney disease were followed for 10 years. Outcomes included death, incident heart failure (HF), and incident myocardial infarction (MI). Exposure was baseline intact and C-terminal FGF23. Using modified Cox models, adjusting sequentially we tested whether observed associations of each assay with outcomes were attenuated by iron status, inflammation, kidney function, or their combinations. FGF23 measured by either assay was associated with mortality in unadjusted analysis (intact FGF23 hazard ratio [HR] per 2-fold higher 1.45; 95% CI, 1.25-1.68; C-terminal FGF23 HR 1.38; 95% CI, 1.26-1.50). Adjustment for kidney function completely attenuated associations of intact FGF23 with mortality (HR 1.00; 95% CI, 0.85-1.17), but had much less influence on the association of C-terminal FGF23, for which results remained significant after adjustment (HR 1.15; 95% CI, 1.04-1.28). Attenuation was much less with adjustment for iron status or inflammation. Results were similar for the HF end point. Neither C-terminal or intact FGF23 was associated with MI risk. The relationship of FGF23 with clinical end points is markedly different depending on the type of FGF23 assay used. The associations of biologically active FGF23 with clinical end points may be confounded by kidney disease, and thus much weaker than previously thought.

Fibroblast growth factor 23 concentrations and modifying factors in children from age 12 to 24months.

Fibroblast growth factor 23 (FGF23) participates in phosphate, calcium and vitamin D metabolism. In children these interactions and modifying factors are largely unknown. This study evaluates temporal changes and modifiers of FGF23 concentrations from 12 to 24months, in healthy children, participating in a randomized vitamin D intervention (VIDI). Participants received vitamin D3 of 10 or 30μg/day from age 2weeks to 24months. At 12 and 24months, growth measurements and venous blood samples were obtained for analyses of intact (iFGF23) and C-terminal FGF23 (cFGF23), 25-hydroxyvitamin D (25-OHD), calcium, phosphate, parathyroid hormone, iron and ferritin. Changes in FGF23 and modifying factors were examined by linear mixed models. The study included 594 infants. Girls had higher iFGF23 than boys (p<0.001 for both 12 and 24months), cFGF23 did not differ between the sexes. Adjusted mean iFGF23 decreased from 41.4 to 38.1pg/mL in boys (p<0.001) and from 45.2 to 42.5pg/mL in girls (p=0.002). Adjusted mean cFGF23 decreased from 2.89 to 2.00pmol/L in boys (p<0.001) and from 2.92 to 1.93pmol/L in girls (p<0.001). Iron modified FGF23 in both sexes, associating positively with iFGF23 and inversely with cFGF23. In girls, 25-OHD modified iFGF23. In boys, season modified FGF23, possibly through seasonal differences in 25-OHD. Vitamin D intervention dose did not affect FGF23. FGF23 decreases from 12 to 24months. Girls have higher iFGF23 than boys, at both time points. Iron modifies FGF23 in both sexes.

Effects of ferric carboxymaltose on markers of mineral and bone metabolism: A single-center prospective observational study of women with iron deficiency.

Two weekly infusions of ferric carboxymaltose (FCM) are commonly prescribed for treatment of iron-deficiency anemia. However, administration of FCM increases intact levels of fibroblast growth factor 23 (FGF23), which causes hypophosphatemia due to renal phosphate wasting, calcitriol deficiency and secondary hyperparathyroidism. The adverse effects of FCM on mineral metabolism and bone health emerged from case reports and secondary analyses of trials. Data on these safety signals with FCM in clinical practice are limited because markers of mineral and bone metabolism are not routinely checked. To obtain real-world experience with effects of FCM on mineral and bone metabolism, we conducted a prospective observational study of 16 women who were managed at a single-center hematology clinic for iron-deficiency anemia. From October 2016 to February 2018, all participants received two weekly infusions of FCM at a hematology infusion clinic. We hypothesized that FCM would decrease phosphate, increase intact FGF23 (iFGF23), and decrease c-terminal FGF23 (cFGF23). Secondary outcomes were changes in hemoglobin, iron indices, urine fractional excretion of phosphate (FePi), parathyroid hormone (PTH), calcitriol, calcium, osteocalcin, and bone-specific alkaline phosphatase (BAP). FCM was administered at weeks zero and one, and we measured laboratory values at weeks zero, one, two, and five of the study. We used linear mixed models to analyze the significance of the changes in laboratory values over time. After two FCM infusions, nearly all (14 of 16) participants developed hypophosphatemia. iFGF23 increased, cFGF23 decreased, and phosphate decreased significantly from week zero to week two (iFGF23 increased by +134.0% [40.6, 305.8], p<0.001; cFGF23 decreased by -516.3% [-1332.7, -142.7], p=0.002; phosphate decreased by -49.8±15.4%, p<0.001). There was also a significant increase in FePi, PTH, and BAP and a significant decrease in calcitriol and calcium from week zero to week two. There was no significant change in osteocalcin during this time period. iFGF23, but not PTH, was independently associated with decreased phosphate. iFGF23 was also significantly associated with decrease in calcitriol from week zero to week two. Elevation in BAP suggests disordered bone mineralization in response to FCM therapy. In this prospective observational study of women with iron deficiency anemia, two FCM infusions significantly altered markers of bone mineralization and mineral metabolism. The results suggest that FCM should be used cautiously in the treatment of iron-deficiency anemia.

Erythropoiesis stimulating agents are associated with serum fibroblast growth factor 23 metabolism in patients on hemodialysis.

BackgroundThis study aimed to determine associations among short- and long-acting erythropoiesis stimulating agents (ESAs), changes in serum fibroblast growth factor 23 (FGF23) and biomarkers of iron metabolism.MethodsAmong 108 patients on hemodialysis (HD), 44 received every 2 weeks or monthly doses of continuous erythropoiesis receptor activator (CERA), 31 received weekly doses of darbepoetin-α, 24 received three doses per week of epoetin-β and 9 were not treated with an ESA. Intact and C-terminal FGF23 and transferrin saturation (TSAT), ferritin, erythroferrone and hepcidin 25 were measured in blood samples collected before the HD session at the end of the dialysis week (baseline, Day 0) and on Days 3, 5, 7 and 14 thereafter.ResultsLevels of ferritin, hepcidin 25 and erythroferrone as well as TSAT were significantly decreased or elevated in patients treated with CERA compared with other types of ESAs. Levels of C-terminal FGF23 increased in all groups during the observation period. Levels of intact FGF23 and ratios of intact FGF23 to C-terminal FGF23 gradually decreased between Days 3 and 7 in the CERA but not in the other groups. Multivariate models associated changes in hepcidin 25 and phosphate with those of intact FGF23.ConclusionThe long-acting ESA CERA might influence levels of intact FGF23 by increasing FGF23 cleavage in patients on HD in association with prolonged hepcidin 25 suppression.

Fibroblast Growth Factor 23 and Risk of Hospitalization with Infection in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort (CRIC) Study.

Risk of infectious disease is increased among individuals with CKD. Fibroblast growth factor 23 (FGF23) is often elevated in CKD, and may impair immune function directly or indirectly through proinflammatory and vitamin D-suppressing pathways. Whether FGF23 is associated with risk of infection has not been evaluated in a CKD population. In 3655 participants of the Chronic Renal Insufficiency Cohort study, we evaluated the association of baseline plasma levels of C-terminal FGF23 with time to first hospitalization with major infection, defined by hospital discharge with a diagnosis code for urinary tract infection, pneumonia, cellulitis/osteomyelitis, or bacteremia/septicemia. Multivariable Cox models were used to estimate hazard ratios (HRs) and adjust for confounding. During a median follow-up of 6.5 years, 1051 individuals (29%) were hospitalized with major infection. Multivariable Cox analysis indicated a graded increase in the risk of infection with higher levels of FGF23 (HR, 1.51; 95% CI, 1.23 to 1.85 with the highest quartile [≥235.9 RU/ml] versus lowest quartile [<95.3 RU/ml]; HR, 1.26; 95% CI, 1.18 to 1.35 per SD increment in log FGF23). The association was consistent across infection subtypes and demographic and clinical subgroups, and remained significant after additional adjustment for biomarkers of inflammation (IL-6, TNF-α, high-sensitivity C-reactive protein, fibrinogen, and albumin), and bone mineral metabolism (25-hydroxyvitamin D, phosphorus, calcium, and parathyroid hormone). The association was consistent across infection subtypes of urinary tract infection (482 cases), cellulitis/osteomyelitis (422 cases), pneumonia (399 cases), and bacteremia/septicemia (280 cases). Among individuals with CKD, higher FGF23 levels were independently and monotonically associated with an increased risk of hospitalization with infection.

P1304FIBROBLAST GROWTH FACTOR (FGF23) AND CARDIOVASCULAR MORTALITY IN DIALYSIS PATIENTS: A 10 YEAR PROSPECTIVE SINGLE CENTER STUDY

Abstract Background and Aims The aim of the study is to evaluate whether circulating fibroblast growth factor 23 (FGF23) predicts cardiovascular mortality in dialysis patients, independent of markers of calcium-phosphate metabolism and cardiovascular risk factors. Method A prospective observational study at Akdeniz University Medical Center including 51 peritoneal dialysis patients and 27 hemodialysis patients was undertaken from 01/2009 to 12/2019. Plasma C-terminal FGF23 concentrations in addition to other measures of mineral metabolism were performed at baseline. Patients were followed for all-cause mortality, cardiovascular mortality, non-fatal MI, non-fatal stroke, coronary revascularization, heart failure hospitalization and atrial fibrillation. Results The mean age of patients 48± 15 years. During a ten year follow up period, there were 47 deaths. The median plasma FGF23 level was 321 pg/ml (interquartile range 51-1784 pg/ml). Patients were stratified by their baseline FGF23 levels according to the tertiles. Cumulative survival analysis by tertiles of FGF23 were made with the Kaplan-Meier survival curve. Kaplan Meier analysis with log-rank did reveal a significant difference between the groups (p=0,048). Conclusion Higher FGF23 levels are associated with an increased incidence of cardiovascular mortality in dialysis patients, independent of other markers of calcium-phosphate metabolism and cardiovascular risk factors.

P0888FIBROBLAST GROWTH FACTOR 23 PRODUCES ARTERIAL STIFFNESS THROUGH CHANGES IN VASCULAR SMOOTH MUSCLE CELL PHENOTYPE

Abstract Background and Aims In patients with chronic kidney disease (CKD), high levels of c-terminal fibroblast growth factor 23 (FGF23) are associated with cardiovascular disease and mortality. Vascular smooth muscle cells (VSMC) may present two clearly differentiated functional phenotypes, contractile and synthetic. The abundance of synthetic phenotype is associated with vascular dysfunction and it is unknown whether in FGF23 may promote transition from a contractile to a synthetic phenotype in VSMC causing vascular stiffness. The present study was conducted to evaluate whether FGF23 affects VSMC phenotype and arterial stiffness. Method and Results High levels of FGF23 promoted VSMC transition from a contractile to a synthetic phenotype. These effects were mediated through FGFR1 and Ras/MAPK signaling activation. Inhibition of both pathways enhanced contractile phenotype of VSMC. The pro-contractile microRNAs, miR-221 and miR-222 were reduced by FGF23 and miR-221 transfection recovered the contractile phenotype of VSMC decreased by FGF23. In experimental rats, exogenous infusion of FGF23 produced an increase in vascular wall thickness with VSMC exhibiting synthetic phenotype and reduction of plasma levels of miR-221. Functional studies performed on aortic arterial rings revealed that passive and active forces were altered in rats treated with FGF23. In a group of CKD stage 2-3 patients with rather high levels of FGF23 it was observed an increased in pulse pressure reflecting vascular stiffness together with low plasma levels of miR-221 and miR-222. Conclusion FGF23 favors the transition of VSMC from contractile to synthetic phenotype causing vascular dysfunction and arterial stiffness; this may be a mechanism by which FGF23 contribute directly to the development of vascular disease in CKD patients.

Defective O-glycosylation of novel FGF23 mutations in a Chinese family with hyperphosphatemic familial tumoral calcinosis.

Hyperphosphatemic familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome (HFTC/HHS) is a rare disorder caused by deficiency or resistance of fibroblast growth factor 23 (FGF23). Here we reported a Chinese family with HFTC/HHS, aiming at clarifying the clinical features, bone microarchitectures and molecular mechanisms of the disease. Clinical manifestations, laboratory examinations and genetic analyses were collected from two HFTC patients. Bone microarchitectures were detected by HR-pQCT. In vitro expression and glycosylation of mutant and wild-type FGF23 proteins were analyzed by western blotting and wheat germ agglutinin affinity chromatography. Subcellular localizations of FGF23 proteins were detected by immunocytochemistry. The two brothers carried previously unreported c.413T>G, p.Leu138Arg and c.491T>A, p.Ile164Asn compound heterozygous variants in the FGF23 gene, which was "likely pathogenic" according to American College of Medical Genetics (ACMG) Standards and Guidelines. Both patients had severe hyperphosphatemia and significantly elevated C-terminal FGF23. With HHS, patient 1 presented with lower extremity pain and widespread cardiovascular calcification. HR-pQCT of his distal radius and tibia revealed decreased volume BMD and cortical thickness, which were inconsistent with hyperostosis manifestations in X-ray. He received etidronate treatment, which improved his BMD and the ectopic calcification. His brother exhibited less bone involvement but had experienced recurrent painful calcified mass from a young age and undergone several resections. In vitro experiments showed that the mutant FGF23 proteins had defective O-glycosylation and impaired secretion. However, no difference in subcellular localization was found between the wild-type and mutant FGF23 proteins. We have presented a Chinese HFTC/HHS family with novel FGF23 c.413T>G, p.Leu138Arg and c.491T>A, p.Ile164Asn variants. We clarified the bone microarchitectures of HFTC/HHS patients by HR-pQCT, and expanded the genotype-phenotype spectrum of the disease. In vivo studies suggested that O-glycosylation of FGF23 plays an important role in the pathogenesis of HFTC/HHS, providing further understanding of the disease mechanism.

FGF23 and Immune Activation are Correlated in Chronic Heart Failure and Additive Predictors of Poor Prognosis

Aims: Immune activation and disturbances of vitamin D metabolism are frequently encountered in patients with heart failure. Elevated fibroblast growth factor 23 (FGF23) levels as well as immune activation have been associated with a worse outcome in patients with heart failure. We evaluated the relationship of vitamin D metabolism and FGF23 levels with immune activation and its association with cardiac function and outcome in patients with heart failure. Methods and Results: In 149 patients with heart failure caused by nonischaemic cardiomyopathy, parameters of vitamin D metabolism (vitamin D, parathormone, phosphate, C-terminal FGF23, calcium), inflammation (hsCRP, neopterin) and cardiac function were investigated. Patients with elevated inflammatory parameters had significantly higher Ct-FGF23 levels (37.33 RU/mL vs. 17.60 RU/mL, p &lt; 0.001). The highest Ct-FGF23 and phosphate levels were found in patients with elevated neopterin and hsCRP levels as well as in in patients with progressive heart failure. Patients with high Ct-FGF23 and neopterin levels (Ct-FGF23 &gt; 22.60 RU/mL, neopterin &gt; 6.90 nmol/L) had a significantly higher risk for adverse events compared to patients with low Ct-FGF23 and neopterin levels (HR 7.386, [95%CI 2.543 – 21.447], p &lt; 0.001). Conclusions: Our study indicates a strong relationship of vitamin D metabolism, especially FGF23, with Th1 immune activation in patients with heart failure. Elevated Ct-FGF23 and neopterin levels are additive predictors for adverse cardiovascular events in patients with heart failure.

Low doses of recombinant human erythropoietin does not affect C-terminal FGF23 in healthy men.

Recombinant human erythropoietin (rhEpo) can improve human performance, but misuse remains difficult to detect. C-terminal fibroblast growth factor 23 (cFGF23) was recently demonstrated to increase following injection of a single high dose rhEpo, but the effect of more frequent low doses is unknown. Using a randomized double-blind placebo-controlled design, we investigated whether 2 weeks of subcutaneous injections three times a week of 50 IU/kg Eprex (low-dose) or 20 IU/kg Eprex (micro-dose) increase cFGF23 levels compared with saline (placebo) injections in 24 healthy males. Venous blood was sampled at day -3, 0, 1, 3, 11, 14, 18, and 25 of the treatment and analyzed for cFGF23 and erythropoietin concentration ([EPO]). The level of cFGF23 was similar at days -3, 0, 1, 3, 11, 14, 18, and 25 with the low-dose (23 ± 4, 26 ± 5, 23 ± 7, 27 ± 6, 25 ± 8, 24 ± 10, 22 ± 5, and 24 ± 7 RU/mL, respectively), micro-dose (23 ± 6, 25 ± 5, 23 ± 8, 28 ± 9, 27 ± 7, 25 ± 9, 25 ± 5, and 23 ± 6 RU/mL, respectively) and placebo (23 ± 6, 24 ± 6, 26 ± 7, 26 ± 6, 31 ± 6, 31 ± 7, 24 ± 4, and 27 ± 8 RU/mL, respectively) treatment. The correlation coefficient between plasma [EPO] and plasma cFGF23 levels was R2 = 0.01 and insignificant. The results demonstrate that cFGF23 is not sensitive to low doses of subcutaneous rhEpo injections in healthy males.

Endothelin receptor B controls the production of fibroblast growth factor 23.

Endothelin-1 (ET-1) is a member of the endothelin family of peptide hormones first discovered as endothelium-derived mediators regulating vascular tone. ET-1 also regulates the proliferation and differentiation of bone cells that synthesize fibroblast growth factor 23 (FGF23). FGF23 is a hormone controlling renal phosphate and vitamin D metabolism. Here, we studied the role of ET-1 and endothelin receptor B (ETB) for FGF23 production. Fgf23 gene expression was studied in IDG-SW3 bone cells by quantitative RT-PCR. ETB-expressing (etb+/+ ) and rescued ETB-deficient mice (etb-/- ) were studied in metabolic cages. Their serum FGF23, PTH, and 1,25(OH)2 D3 concentrations were determined by ELISA, serum and urinary phosphate and Ca2+ by photometric methods. ET-1 and ETB agonist sarafotoxin 6c suppressed Fgf23 mRNA in IDG-SW3 cells. Serum C-terminal and intact FGF23 as well as bone Fgf23 mRNA levels were significantly higher in etb-/- mice than in etb+/+ mice. Renal phosphate excretion was significantly higher in etb-/- mice despite lower phosphate levels. In addition, etb-/- animals exhibited calciuria and a significantly higher serum 1,25(OH)2 D3 concentration compared to etb+/+ mice. In conclusion, ETB-dependent ET-1 signaling is a potent suppressor of FGF23 formation. This effect is likely to be of clinical relevance given the use of endothelin receptor antagonists in various diseases.

Adverse Effects of Autoclaved Diets on the Progression of Chronic Kidney Disease and Chronic Kidney Disease-Mineral Bone Disorder in Rats

Background: Autoclaving rodent diets is common in laboratory animals, but autoclaving increases the formation of dietary advanced glycation end-products (AGE). We studied the effect of autoclaved (AC) diet alone or in combination with a diet high in bioavailable phosphorus on biochemistries of chronic kidney disease-mineral and bone disorder (CKD-MBD), intestinal gene expression, and oxidative stress. Methods: Male CKD rats (Cy/+) and normal littermates were fed 1 of 3 diets: AC 0.7% phosphorus grain-based diet for 28 weeks (AC); AC diet for 17 weeks followed by non-autoclaved (Non-AC) 0.7% phosphorus casein diet until 28 weeks (AC + Casein); or Non-AC diet for 16 weeks followed by a Non-AC purified diet until 30 weeks (Non-AC + Casein). Results: AC diets contained ~3× higher AGEs and levels varied depending on the location within the autoclave. Rats fed the AC and AC + Casein diets had higher total AGEs and oxidative stress, irrespective of kidney function. Kidney function was more severely compromised in CKD rats fed AC or AC + Casein compared to Non-AC + Casein. There was a disease-by-diet interaction for plasma phosphorus, parathyroid hormone, and c-terminal fibroblast growth factor-23, driven by high values in the CKD rats fed the AC + Casein diet. Compared to Non-AC + Casein, AC and AC + Casein-fed groups had increased expression of receptor of AGEs and intestinal NADPH oxidase dual oxidase-2, independent of kidney function. Conclusions: Autoclaving rodent diets impacts the progression of CKD and CKD-MBD, highlighting the critical importance of standardizing diets in experiments.

Limited role for fibroblast growth factor 23 in assessing prognosis in heart failure patients: data from the TIME-CHF trial.

Fibroblast growth factor 23 (FGF23) is an intensively studied biomarker at the crossroads of cardiovascular disease, heart failure (HF) and chronic kidney disease. Independent associations between increasing FGF23 levels and cardiovascular events were found in many, but not all studies. By analysing data from the TIME-CHF cohort, we sought to investigate the prognostic value of FGF23 in an elderly, multimorbid HF patient cohort. We determined differences between intact (iFGF23) and C-terminal FGF23 (cFGF23) regarding their prognostic value and their levels over time in different HF subgroups according to left ventricular ejection fraction (LVEF). In this multicentre trial of 622 patients with symptomatic HF aged ≥60 years, we determined iFGF23 and cFGF23 at baseline, 3, 6 and 12-month follow-up. In unadjusted analyses, cFGF23 significantly predicted all HF-related outcomes at all time points. The predictive value of iFGF23 was less and not statistically significant at baseline. After multivariable adjustments, the association between both cFGF23 and iFGF23 and outcome lost statistical significance apart from cFGF23 at month 3. Overall, patients with preserved and mid-range LVEF had higher levels of iFGF23 and cFGF23 than those with reduced LVEF. Levels decreased significantly during the first 3months in mid-range and reduced LVEF patients, but did not significantly change over time in those with preserved LVEF. Fibroblast growth factor 23 is of limited value regarding risk prediction in this elderly HF population. Potentially heterogeneous roles of FGF23 in different LVEF groups deserve further investigation.

Aortic Calcification and Arterial Stiffness Burden in a Chronic Kidney Disease Cohort with High Cardiovascular Risk: Baseline Characteristics of the Impact of Phosphate Reduction On Vascular End-Points in Chronic Kidney Disease Trial

Chronic kidney disease (CKD) is associated with excess cardiovascular morbidity and mortality compared to the general population. Hyperphosphataemia, associated with vascular calcification and arterial stiffness, may play a key role in the pathogenesis of cardiovascular disease (CVD) associated with CKD, although phosphate reduction strategies have not consistently proven to beneficially affect clinically relevant outcomes. The IMpact of Phosphate Reduction On Vascular End-points in CKD (IMPROVE-CKD) study is an international, multi-centre, randomized, placebo-controlled trial investigating the effect of the phosphate binder lanthanum carbonate on intermediate cardiovascular markers in patients with stage 3b–4 CKD. The primary end-point is change in carotid-femoral pulse wave velocity (PWV, SphygmoCor) after 96 weeks. Secondary outcomes include change in abdominal aortic calcification (AAC, computed tomography), serum phosphate and fibroblast growth factor 23 (FGF-23). In total, 278 participants were recruited and randomized, mean age 63 ± 13 years, 69% male, 45% diabetes, 32% CVD, 33% stage 3b CKD and 67% stage 4 CKD. Mean estimated glomerular filtration rate and serum phosphate were 26.6 ± 8.3 mL/min/1.72 m² and 1.25 ± 0.20 mmol/L, respectively. Median (interquartile range) intact and c-terminal FGF-23 levels were 133.0 (89.1–202) pg/mL and 221.1 (154.3–334.1) RU/mL, respectively. Mean PWV was 10.8 ± 3.6 m/s and 81% had AAC (median Agatston score 1,535 [63–5,744] Hounsfield units). PWV ≥10 m/s was associated with older age, diabetes, CVD, presence of AAC, higher systolic blood pressure (BP), larger waist circumference and higher alkaline phosphatase. AAC was associated with older age, male sex, diabetes, CVD, higher diastolic BP, dyslipidaemia (and use of statins), smoking, larger waist circumference and increased PWV. In conclusion, IMPROVE-CKD participants had high baseline risk for cardiovascular events, as suggested by high baseline PWV and AAC values.

Anorexia Nervosa with Markedly High Bone Turnover and Hyperphosphatemia During Refeeding Rectified by Denosumab.

We describe a unique case of hyperphosphatemia associated with a very high bone turnover rate in a 51-year-old postmenopausal woman with undiagnosed anorexia nervosa (AN) who presented with a low-trauma hip fracture. In view of her severely malnourished state, she was not fit for surgery. She was treated according to a refeeding protocol that mandated bed rest. Contrary to expectation, she developed sustained hyperphosphatemia and borderline hypercalcemia. Bone remodelling markers, both resorption and formation, were markedly elevated. Parathyroid hormone (PTH) was low-normal at 1.7pmol/L, C-terminal fibroblast growth factor 23 (FGF23) was high at 293RU/ml, but tubular maximum reabsorption of phosphate (TmPO4/GFR) was elevated at 1.93mmol/L. Denosumab 60mg was administered that was followed by: rapid normalisation of serum phosphate; normalisation of resorption markers, transient hypocalcaemia with secondary hyperparathyroidism, and normalisation of both TmPO4/GFR and C-terminal FGF23. We speculate that prolonged immobilization as part of AN management led to a high remodelling state followed by hyperphosphatemia and high-normal calcium with appropriate suppression of PTH and that marked hyperphosphatemia and high TmP/GFR despite high FGF23 indicates the necessity of PTH adequacy for excess FGF23 to lower TmP/GFR.

Biomarkers in WNT1 and PLS3 Osteoporosis: Altered Concentrations of DKK1 and FGF23.

Recent advancements in genetic research have uncovered new forms of monogenic osteoporosis, expanding our understanding of the molecular pathways regulating bone health. Despite active research, knowledge on the pathomechanisms, disease-specific biomarkers, and optimal treatment in these disorders is still limited. Mutations in WNT1, encoding a WNT/β-catenin pathway ligand WNT1, and PLS3, encoding X chromosomally inherited plastin 3 (PLS3), both result in early-onset osteoporosis with prevalent fractures and disrupted bone metabolism. However, despite marked skeletal pathology, conventional bone markers are usually normal in both diseases. Our study aimed to identify novel bone markers in PLS3 and WNT1 osteoporosis that could offer diagnostic potential and shed light on the mechanisms behind these skeletal pathologies. We measured several parameters of bone metabolism, including serum dickkopf-1 (DKK1), sclerostin, and intact and C-terminal fibroblast growth factor 23 (FGF23) concentrations in 17 WNT1 and 14 PLS3 mutation-positive subjects. Findings were compared with 34 healthy mutation-negative subjects from the same families. Results confirmed normal concentrations of conventional metabolic bone markers in both groups. DKK1 concentrations were significantly elevated in PLS3 mutation-positive subjects compared with WNT1 mutation-positive subjects (p < .001) or the mutation-negative subjects (p = .002). Similar differences were not seen in WNT1 subjects. Sclerostin concentrations did not differ between any groups. Both intact and C-terminal FGF23 were significantly elevated in WNT1 mutation-positive subjects (p = .039 and p = .027, respectively) and normal in PLS3 subjects. Our results indicate a link between PLS3 and DKK1 and WNT1 and FGF23 in bone metabolism. The normal sclerostin and DKK1 levels in patients with impaired WNT signaling suggest another parallel regulatory mechanism. These findings provide novel information on the molecular networks in bone. Extended studies are needed to investigate whether these biomarkers offer diagnostic value or potential as treatment targets in osteoporosis. © 2020 American Society for Bone and Mineral Research.

High plasma C-terminal FGF-23 levels predict poor outcomes in patients with chronic kidney disease superimposed with acute kidney injury.

Background:Elevated plasma C-terminal fibroblast growth factor-23 (cFGF-23) levels are associated with higher mortality in patients with chronic kidney disease (CKD) and acute kidney injury (AKI). Our study explored the outcome forecasting accuracy of cFGF-23 in critically ill patients with CKD superimposed with AKI (ACKD).Methods:Urine and plasma biomarkers from 149 CKD patients superimposed with AKI before dialysis were checked in this multicenter prospective observational cohort study. Endpoints were 90-day mortality and 90 days free from dialysis after hospital discharge. Associations with study endpoints were assessed using hierarchical clustering analysis, the generalized additive model, the Cox proportional hazard model, competing risk analysis, and discrimination evaluation.Results:Over a median follow up of 40 days, 67 (45.0%) patients died before the 90th day after hospital discharge and 39 (26.2%) progressed to kidney failure with replacement therapy (KFRT). Hierarchical clustering analysis demonstrated that cFGF-23 levels had better predictive ability for 90-day mortality than did other biomarkers. Higher serum cFGF-23 levels were independently associated with greater risk for 90-day mortality [hazard ratio (HR): 2.5; 95% confidence interval (CI) 1.5–4.1; p < 0.001]. Moreover, adding plasma cFGF-23 to the Demirjian AKI risk score model substantially improved risk prediction for 90-day mortality than the Demirjian model alone (integrated discrimination improvement: 0.06; p < 0.05; 95% CI 0.02–0.10). The low plasma cFGF-23 group was predicted having more weaning from dialysis in surviving patients (HR = 0.53, 95% CI, 0.29–0.95, p = 0.05).Conclusions:In patients with ACKD, plasma cFGF-23 levels are an independent risk factor to forecast 90-day mortality and 90-day progression to KFRT. In combination with the clinical risk score, plasma cFGF-23 levels could substantially improve mortality risk prediction.