High intact fibroblast growth factor 23 levels associated with low hemoglobin levels in patients on chronic hemodialysis.

Introduction: A negative association between C-terminal fibroblast growth factor 23 (cFGF23) and hemoglobin (Hb) levels has been reported in patients with predialysis chronic kidney disease. In dialysis patients, the dominant form of serum FGF23 is intact FGF23 (iFGF23); however, its association with the Hb level remains unclear. Therefore, simultaneously monitoring iFGF23 and cFGF23 levels is crucial. In this study, we investigated the associations between both forms of FGF23 (iFGF23 and cFGF23) and renal anemia in chronic hemodialysis (CHD) patients. Methods: We included 166 CHD patients from two hospitals in this cross-sectional, observational study. The primary predictors were serum iFGF23, cFGF23, and iFGF23/cFGF23 levels. The main outcome was the Hb level. Results: Among the CHD patients included, 60.8% were men with a mean age of 59.4 ± 12.7 years. In the crude analysis, iFGF23 and iFGF23/cFGF23 levels showed a significant negative association (-0.27, p = 0.004 and -0.22, p = 0.034, respectively) with the Hb level. Even after adjusting for multiple variables (a parsimonious model), every increment of natural log transformation by 1 for (ln)iFGF23 and ln(iFGF23/cFGF23) levels showed a negative correlation with the Hb level (estimate: -0.27 [95%CI: -0.44, -0.10, p = 0.001]; -0.19 [95%CI: -0.37, -0.01, p = 0.042], respectively), whereas both were positively associated with erythropoietin-stimulating agent (ESA) hyporesponsiveness (odds ratio [OR]: [95%CI: 2.30, 1.26-4.17], p = 0.006; 1.95 [95%CI: 1.08-3.50], p = 0.025). Moreover, these abovementioned associations were more dominant in patients with diabetes who used angiotensin receptor blockers. Discussion: In conclusion, a negative association between serum iFGF23 or iFGF23/cFGF23 level and the Hb level was observed in our CHD patients. Meanwhile, a higher iFGF23 or iFGF23/cFGF23 level may predispose patients to ESA hyporesponsiveness.

Serum Intact Fibroblast Growth Factor 23 Levels Are Negatively Associated with Bone Mineral Density in Chronic Hemodialysis Patients.

(1) Background: Fibroblast growth factor 23 (FGF23) is predominantly secreted from bone and plays an important role in mineral balance in chronic kidney disease. However, the relationship between FGF23 and bone mineral density (BMD) in chronic hemodialysis (CHD) patients remains unclear. (2) Methods: This was a cross-sectional observational study that involved 43 stable outpatients on CHD. A linear regression model was used to determine risk factors for BMD. Measurements included serum hemoglobin, intact FGF23 (iFGF23), C-terminal FGF23 (cFGF23), sclerostin, Dickkopf-1, α-klotho, 1,25-hydroxyvitamin D, intact parathyroid hormone levels and dialysis profiles. (3) Results: Study participants had a mean age of 59.4 ± 12.3 years, and 65% were male. In the multivariable analysis, cFGF23 levels showed no significant associations with the BMD of the lumbar spine (p = 0.387) nor that of the femoral head (p = 0.430). However, iFGF23 levels showed a significant negative association with the BMD of the lumbar spine (p = 0.015) and that of the femoral neck (p = 0.037). (4) Conclusions: Among patients on CHD, higher serum iFGF23 levels, but not serum cFGF23 levels, were associated with lower BMD values of the lumbar spine and femoral neck. However, further research is required to validate our findings.

Intact Fibroblast Growth Factor 23 Regulates Chronic Kidney Disease-Induced Myocardial Fibrosis by Activating the Sonic Hedgehog Signaling Pathway.

Background Clinically, myocardial fibrosis is one of the most common complications caused by chronic kidney disease (CKD). However, the potential mechanisms of CKD-induced myocardial fibrosis have not been clarified. Methods and Results In our in vivo study, a rat model of CKD with 5/6 nephrectomy was established. The CKD model was treated with the glioma 1 (Gli-1) inhibitor GANT-61, and myocardial fibrosis and serum intact fibroblast growth factor 23 levels were assessed 16 weeks after nephrectomy. Finally, we found that Gli-1 and Smoothened in the Sonic Hedgehog (Shh) signaling pathway were activated and that collagen-1 and collagen-3, which constitute the fibrotic index, were expressed in CKD myocardial tissue. After administering the Gli-1 inhibitor GANT-61, the degree of myocardial fibrosis was reduced, and Gli-1 expression was also inhibited. We also measured blood pressure, cardiac biomarkers, and other indicators in rats and performed hematoxylin-eosin staining of myocardial tissue. Furthermore, in vitro studies showed that intact fibroblast growth factor 23 promoted cardiac fibroblast proliferation and transdifferentiation into myofibroblasts by activating the Shh signaling pathway, thereby promoting cardiac fibrosis, as manifested by increased expression of the Shh, Patch 1, and Gli-1 mRNAs and Shh, Smoothened, and Gli-1 proteins in the Shh signaling pathway. The protein and mRNA levels of other fibrosis indicators, such as α-smooth muscle actin, which are also markers of transdifferentiation, collagen-1, and collagen-3, were increased. Conclusions On the basis of these results, intact fibroblast growth factor 23 promotes CKD-induced myocardial fibrosis by activating the Shh signaling pathway.

Tumor-Induced Osteomalacia Localized and Excised After Pregnancy.

OBJECTIVE: Tumor-induced osteomalacia (TIO) is a rare osteomalacia characterized by paraneoplastic secretion of fibroblast growth factor 23. Concomitant occurrence of TIO during pregnancy is rarer still. Our objective was to report a young patient with debilitating fractures diagnosed with TIO who became pregnant and subsequently had her tumor localized by gallium-68 (Ga-68) DOTATATE positron emission tomography/magnetic resonance imaging (PET/MRI). CASE REPORT: A 28 year-old woman with a 2-year history of stress fractures was found to have the following: (1) alkaline phosphatase level, 220 (reference range, 30-95) U/L; (2) phosphorus level, 2.1 (2.5-5.0) mg/dL; (3) 1,25-dihydroxyvitamin D3 level, <8 (18-72) pg/mL; (4) 24-hour urine phosphorus level, 0.5 (0.3-1.3) g; and (5) fibroblast growth factor 23 levels, 1241 (reference range, <180) RU/mL. The patient became pregnant, and at term, a cesarean delivery was performed. Ga-68 DOTATATE PET/MRI showed a 9-mm intracortical mass in the right fibular head and right femoral and bilateral calcaneal stress fractures. The fibular lesion was resected; pathology showed a 1.5-cm lesion with positive fibroblast growth factor receptor 1 staining. DISCUSSION: This patient with TIO had an uneventful pregnancy and delivery. TIO is typically caused by benign mesenchymal tumors. Ga-68 DOTATATE PET/computed tomography has been used for localizing tumors causing TIO, yet MRI has superior contrast resolution over computed tomography. Therefore, it is not surprising that Ga-68 PET/MRI successfully localized this patient's tumor to the intracortical space of the fibular head and distinguished it from insufficiency fractures. CONCLUSION: To our knowledge, this is the first report of phosphate treatment in a pregnant patient with TIO and the first report of a tumor-inducing TIO being localized by Ga-68 DOTATATE PET/MRI.

Clinical and Genetic Characteristics of 153 Chinese Patients With X-Linked Hypophosphatemia.

X-linked hypophosphatemia (XLH) is caused by inactivating mutations in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene, resulting in an excess of circulating intact fibroblast growth factor-23 (iFGF-23) and a waste of renal phosphate. In the present study, we retrospectively reviewed the clinical and molecular features of 153 Chinese patients, representing 87 familial and 66 sporadic cases with XLH. A total of 153 patients with XLH presented with signs or symptoms at a median age of 18.0 months (range, 9.0 months-26.0 years). Lower-limb deformity was the most frequent clinical manifestation, accounting for 79.1% (121/153). Biochemical screening showed increased serum levels of iFGF23 in patients with XLH, with a wide variation ranging from 14.39 to 730.70 pg/ml. Median values of serum iFGF23 in pediatric and adult patients were 94.87 pg/ml (interquartile range: 74.27-151.86 pg/ml) and 72.82 pg/ml (interquartile range: 39.42-136.00 pg/ml), respectively. Although no difference in circulating iFGF23 levels between these two groups was observed (P = 0.062), the proportion of patients with high levels of circulating iFGF23 (>42.2 pg/ml) was greater in the pediatric group than in the adult group (P = 0.026). Eighty-eight different mutations in 153 patients were identified, with 27 (30.7%) being novel. iFGF23 levels and severity of the disease did not correlate significantly with truncating and non-truncating mutations or N-terminal and C-terminal PHEX mutations. This study provides a comprehensive description of the clinical profiles, circulating levels of iFGF23 and gene mutation features of patients with XLH, further enriching the genotypic spectrum of the diseases. The findings show no evident correlation of circulating iFGF23 levels with the age or disease severity in patients with XLH.

Strength of Fibroblast Growth Factor 23 as a Cardiovascular Risk Predictor in Chronic Kidney Disease Weaken by ProBNP Adjustment.

BACKGROUND: Various epidemiological studies linked high fibroblast growth factor 23 (FGF23) levels with cardiovascular events in chronic kidney disease (CKD). It remains enigmatic whether high FGF23 exerts adverse cardiovascular effects, or whether it reflects detrimental effects of residual confounders. Earlier studies adjusted for CKD-mineral bone disease (CKD-MBD) regulators of FGF23 rather than for recently discovered non-CKD-MBD regulators, among which iron deficiency and heart failure are of particular importance. Moreover, they used c-terminal FGF23 (cFGF23) assays rather than more specific intact FGF23 (iFGF23) assays. METHODS: The CARE FOR HOMe study analyzed plasma ferritin, iFGF23, cFGF23 and N-terminal proBNP (NT-proBNP) along with conventional risk factors, among 575 CKD G2-G4 patients to determine the interaction between FGF23, its non-CKD-MBD regulators, and incident cardiovascular events in CKD patients. The participants were followed up for 5.1 ± 2.1 years for the occurrence of atherosclerotic events and hospitalization for acute decompensated heart failure. RESULTS: cFGF23 correlated strongly with high iFGF23 (r = 0.607), fairly with high NT-proBNP (r = 0.453) and weakly with low ferritin (r = -0.207); correlation coefficients of iFGF23 with NT-proBNP and ferritin were numerically lower. In Kaplan-Meier analyses, both endpoints were predicted by cFGF23 and iFGF23. In Cox regression models, cFGF23 remained an outcome predictor after adjustment for conventional risk factors and ferritin. This prediction was largely eliminated when further adjusting for NT-proBNP. iFGF23 was less consistently associated with adverse outcome in partly adjusted models, and failed to predict outcome in fully adjusted models. CONCLUSION: In summary, iron deficiency and heart failure affect plasma FGF23. As adjustment for NT-proBNP virtually eliminates the association between plasma FGF23 and predefined outcome, we speculate that high FGF23, rather than exerting detrimental cardiovascular effects, mirrors prevalent heart disease.

Efficacy and safety of iron isomaltoside (Monofer(®)) in the management of patients with iron deficiency anemia.

New intravenous (IV) iron preparations should ideally be capable of delivering a wide dosing range to allow iron correction in a single or low number of visits, a rapid infusion (doses up to 1,000 mg must be administered over more than 15 minutes and doses exceeding 1,000 mg must be administered over 30 minutes or more), and minimal potential side effects including low catalytic/labile iron release with minimal risk of anaphylaxis. Furthermore, they should be convenient for the patient and health-care professional, and cost effective for the health-care system. The intention behind the development of iron isomaltoside (Monofer(®)) was to fulfill these requirements. Iron isomaltoside has been shown to be effective in treating iron deficiency anemia across multiple therapeutic patient groups and compared to placebo, IV iron sucrose, and oral iron. Iron isomaltoside consists of iron and a carbohydrate moiety where the iron is tightly bound in a matrix structure. It has a low immunogenic potential, a low potential to release labile iron, and does not appear to be associated with clinically significant hypophosphatemia. Due to the structure of iron isomaltoside, it can be administered in high doses with a maximum single dosage of 20 mg/kg body weight. Clinical trials and observational studies of iron isomaltoside show that it is an effective and well-tolerated treatment of anemia across different therapeutic areas with a favorable safety profile.