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

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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).

FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

Fibroblast growth factor 23 (FGF23) is a phosphate-regulating (Pi-regulating) hormone produced by bone. Hereditary hypophosphatemic disorders are associated with FGF23 excess, impaired skeletal growth, and osteomalacia. Blocking FGF23 became an effective therapeutic strategy in X-linked hypophosphatemia, but testing remains limited in autosomal recessive hypophosphatemic rickets (ARHR). This study investigates the effects of Pi repletion and bone-specific deletion of Fgf23 on bone and mineral metabolism in the dentin matrix protein 1-knockout (Dmp1KO) mouse model of ARHR. At 12 weeks, Dmp1KO mice showed increased serum FGF23 and parathyroid hormone levels, hypophosphatemia, impaired growth, rickets, and osteomalacia. Six weeks of dietary Pi supplementation exacerbated FGF23 production, hyperparathyroidism, renal Pi excretion, and osteomalacia. In contrast, osteocyte-specific deletion of Fgf23 resulted in a partial correction of FGF23 excess, which was sufficient to fully restore serum Pi levels but only partially corrected the bone phenotype. In vitro, we show that FGF23 directly impaired osteoprogenitors' differentiation and that DMP1 deficiency contributed to impaired mineralization independent of FGF23 or Pi levels. In conclusion, FGF23-induced hypophosphatemia is only partially responsible for the bone defects observed in Dmp1KO mice. Our data suggest that combined DMP1 repletion and FGF23 blockade could effectively correct ARHR-associated mineral and bone disorders.

Post-ischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis.

Ischemic acute kidney injury (AKI) is common in hospitalized patients and increases the risk for chronic kidney disease (CKD). Impaired endothelial cell (EC) functions are thought to contribute in AKI to CKD transition, but the underlying mechanisms remain unclear. Here, we identify a critical role for endothelial oxygen sensing prolyl hydroxylase domain (PHD) enzymes 1-3 in regulating post-ischemic kidney repair. In renal endothelium, we observed compartment-specific differences in the expression of the three PHD isoforms in both mice and humans. We found that post-ischemic concurrent inactivation of endothelial PHD1, PHD2, and PHD3 but not PHD2 alone promoted maladaptive kidney repair characterized by exacerbated tissue injury, fibrosis, and inflammation. Single-cell RNA-seq analysis of the post-ischemic endothelial PHD1, PHD2 and PHD3 deficient (PHDTiEC) kidney revealed an endothelial glycolytic transcriptional signature, also observed in human kidneys with severe AKI. This metabolic program was coupled to upregulation of the SLC16A3 gene encoding the lactate exporter monocarboxylate transporter 4 (MCT4). Strikingly, treatment with the MCT4 inhibitor syrosingopine restored adaptive kidney repair in PHDTiEC mice. Mechanistically, MCT4 inhibition suppressed pro-inflammatory EC activation reducing monocyte-endothelial cell interaction. Our findings suggest avenues for halting AKI to CKD transition based on selectively targeting the endothelial hypoxia-driven glycolysis/MCT4 axis.

Renal osteodystrophy: something old, something new, something needed.

PURPOSE OF REVIEW: Renal osteodystrophy (ROD) is a complex disorder of bone metabolism that affects virtually all adults and children with chronic kidney disease (CKD). ROD is associated with adverse clinical outcomes including bone loss, mineralization and turnover abnormalities, skeletal deformities, fractures, cardiovascular events, and death. Despite current therapies, fracture incidence is 2-fold to 100-fold higher in adults and 2-fold to 3-fold higher in children when compared to without CKD. Limited knowledge of ROD pathogenesis, due to the lack of patient-derived large-scale multimodal datasets, impedes development of therapeutics aimed at reducing morbidity and mortality of CKD patients. The purpose of the review is to define the much needed infrastructure for the advancement of RDO treatment. RECENT FINDINGS: Recently, we created a large-scale data and tissue biorepository integrating clinical, bone quality, transcriptomic, and epigenomic data along with stored urine, blood, and bone samples. This database will provide the underpinnings for future research endeavors leading to the elucidation and characterization of the pathogenesis of ROD in CKD patients with and without dialysis. SUMMARY: The availability of an open-access NIH-funded resource that shares bone-tissue-based information obtained from patients with ROD with the broad scientific community represents a critical step in the process of discovering new information regarding unrecognized bone changes that have severe clinical complications. This will facilitate future high-impact hypothesis-driven research to redefine our understanding of ROD pathogenesis and pathophysiology and inform the development of disease-modifying and prevention strategies.

VEGF-C overexpression in kidney progenitor cells is a model of renal lymphangiectasia.

Background: Lymphangiogenesis is believed to be a protective response in the setting of multiple forms of kidney injury and mitigates the progression of interstitial fibrosis. To augment this protective response, promoting kidney lymphangiogenesis is being investigated as a potential treatment to slow the progression of kidney disease.As injury related lymphangiogenesis is driven by signaling from the receptor VEGFR-3 in response to the cognate growth factor VEGF-C released by tubular epithelial cells, this signaling pathway is a candidate for future kidney therapeutics. However, the consequences to kidney development and function to targeting this signaling pathway remains poorly defined. Methods: We generated a new mouse model expressing Vegf-C under regulation of the nephron progenitor Six2Cre driver strain (Six2Vegf-C). Mice underwent a detailed phenotypic evaluation. Whole kidneys were processed for histology and micro computed tomography 3-dimensional imaging. Results: Six2Vegf-C mice had reduced body weight and kidney function compared to littermate controls. Six2Vegf-C kidneys demonstrated large peripelvic fluid filled lesions with distortion of the pelvicalcyceal system which progressed in severity with age. 3D imaging showed a 3-fold increase in total cortical vascular density. Histology confirmed a substantial increase in LYVE1+/PDPN+/VEGFR3+ lymphatic capillaries extending alongside EMCN+ peritubular capillaries. There was no change in EMCN+ peritubular capillary density. Conclusions: Kidney lymphangiogenesis was robustly induced in the Six2Vegf-C mice. There were no changes in peritubular blood capillary density despite these endothelial cells also expressing VEGFR-3. The model resulted in a severe cystic kidney phenotype that resembled a human condition termed renal lymphangiectasia. This study defines the vascular consequences of augmenting VEGF-C signaling during kidney development and provides new insight into a mimicker of human cystic kidney disease.

Transcription factor HNF4α2 promotes osteogenesis and prevents bone abnormalities in mice with renal osteodystrophy.

Renal osteodystrophy (ROD) is a disorder of bone metabolism that affects virtually all patients with chronic kidney disease (CKD) and is associated with adverse clinical outcomes including fractures, cardiovascular events, and death. In this study, we showed that hepatocyte nuclear factor 4α (HNF4α), a transcription factor mostly expressed in the liver, is also expressed in bone, and that osseous HNF4α expression was dramatically reduced in patients and mice with ROD. Osteoblast-specific deletion of Hnf4α resulted in impaired osteogenesis in cells and mice. Using multi-omics analyses of bones and cells lacking or overexpressing Hnf4α1 and Hnf4α2, we showed that HNF4α2 is the main osseous Hnf4α isoform that regulates osteogenesis, cell metabolism, and cell death. As a result, osteoblast-specific overexpression of Hnf4α2 prevented bone loss in mice with CKD. Our results showed that HNF4α2 is a transcriptional regulator of osteogenesis, implicated in the development of ROD.

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

Inflammation 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.

FGF-23 and sclerostin in serum and bone of CKD patients.

AIMS: Renal osteodystrophy occurs in the early stages of chronic kidney disease (CKD) and progresses during loss of kidney function. Fibroblast growth factor (FGF)-23 and sclerostin, both produced by osteocytes, are increased in blood of patients with CKD. The aim of this study was to analyze the impact of decline in kidney function on FGF-23 and sclerostin protein expression in bone and to study their relationship with their serum levels and bone histomorphometry. MATERIALS AND METHODS: 108 patients aged 25 - 81 years (mean ± SD: 56 ± 13 years) underwent anterior iliac crest biopsies after double-tetracycline labeling. Eleven patients were CKD-2, 16 were CKD-3, 9 were CKD-4 - 5, and 64 CKD-5D. Patients were on hemodialysis for 49 ± 117 months. 18 age-matched patients without CKD were included as controls. Immunostaining was performed on undecalcified bone sections to quantify FGF-23 and sclerostin expression. Bone sections were also evaluated by histomorphometry for bone turnover, mineralization, and volume. RESULTS: FGF-23 expression in bone correlated positively with CKD stages (p < 0.001) increasing from 5.3- to 7.1-fold starting at CKD-2. No difference in FGF-23 expression was seen between trabecular and cortical bone. Sclerostin expression in bone correlated positively with CKD stages (p < 0.001) with an increase from 3.8- to 5.1-fold starting at CKD-2. This increase was progressive and significantly greater in cortical than cancellous bone. FGF-23 and sclerostin in blood and bone were strongly associated with bone turnover parameters. Expression of FGF-23 in cortical bone correlated positively with activation frequency (Ac.f) and bone formation rate (BFR/BS) (p < 0.05), while sclerostin correlated negatively with Ac.f, BFR/BS, and osteoblast and osteoclast numbers (p < 0.05). FGF-23 trabecular and cortical expressions correlated positively with cortical thickness (p < 0.001). Sclerostin bone expression correlated negatively with parameters of trabecular thickness and osteoid surface (p < 0.05). CONCLUSION: These data show a progressive increase in FGF-23 and sclerostin in blood and bone associated with decrease in kidney function. The observed relationships between bone turnover and sclerostin or FGF-23 should be considered when treatment modalities are developed for management of turnover abnormalities in CKD patients.

Predictive value of C-reactive protein levels for the early and later detection of postoperative complications after cytoreductive surgery and HIPEC.

Synopsis: C-reactive protein (CRP), white blood cells and procalcitonin (PCT) participate in the systemic response to inflammation and increase after postoperative infective complications. Postoperative complications after CRS and HIPEC could be predicted using the CRP cut-off value (169 mg/L at PODs 3-5 and 62 mg/L at PODs 7-10). Background: Postoperative elevation of C-reactive protein (CRP) can be used in order to predict the postoperative complications in many indications. Cytoreduction surgery (CRS) associated with hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with high morbidity. Objectives: The aim of the study was to demonstrate the CRP predictive value for the occurrence of complications. Methods: All patients who had CRS and HIPEC, regardless of the origin of peritoneal metastasis, were included in this retrospective study. Postoperative complications and CRP and white blood cell (WBC) counts were recorded from postoperative day (POD) 1 through 10. Results: Among the 127 patients included, 58 (45.7%) had no complications (NCs), 53 (41.7%) had infective complications (ICs), and 16 (12.6%) had non-infective complications (NICs). The IC group had a higher CRP value than the NC group, which was statistically significant from POD7 to POD10 (41.1 versus 107.5 p = 0.023 and 77.8 versus 140 p = 0.047, respectively). A cut-off CRP value was 169 mg/L at PODs 3-5 and 62 mg/L at PODs 7-10. The area under the curve (AUC) at POD5 was 0.56 versus 0.76 at POD7, p=0.007. The sensibility, specificity, positive and negative predictive values of these cut-offs were 55%, 83%, 74% and 67%, respectively. Moreover, 17 patients (32%) with ICs had a CRP value higher than these cut-offs before the diagnosis was made by the medical team. Conclusion: This study suggested that postoperative complications could be predicted using the CRP cut-off value on PODs 3-5 (169 mg/l) and PODs 7-10 (62 mg/l) after CRS and HIPEC.

Heparin, klotho, and FGF23: the 3-beat waltz of the discordant heart.

Excess fibroblast growth factor (FGF) 23 signaling in patients with chronic kidney disease induces left ventricular hypertrophy. In this issue, Yanucil et al. investigated the interaction of soluble klotho and heparin with FGF23 and FGF receptor isoforms. They concluded that heparin promotes the FGF23-FGF receptor isoform 4 interaction and FGF23 pathogenic effects, supporting an important role of heparin in the pathogenesis of FGF23-mediated left ventricular hypertrophy in chronic kidney disease.

Lipocalin-2: a novel link between the injured kidney and the bone.

PURPOSE OF REVIEW: Fibroblast growth factor 23 (FGF23) excess is associated with left ventricular hypertrophy (LVH) and early mortality in patients with chronic kidney disease (CKD) and in animal models. Elevated Lipocalin-2 (LCN2), produced by the injured kidneys, contributes to CKD progression and might aggravate cardiovascular outcomes. The current review aims to highlight the role of LCN2 in CKD, particularly its interactions with FGF23. RECENT FINDINGS: Inflammation, disordered iron homeostasis and altered metabolic activity are common complications of CKD, and are associated with elevated levels of kidney-produced LCN2 and bone-secreted FGF23. A recent study shows that elevated LCN2 increases FGF23 production, and contributes to cardiac injury in patients and animals with CKD, whereas LCN2 reduction in mice with CKD reduces FGF23, improves cardiovascular outcomes and prolongs lifespan. SUMMARY: In this manuscript, we discuss the potential pathophysiological functions of LCN2 as a major kidney-bone crosstalk molecule, linking the progressive decline in kidney function to excessive bone FGF23 production. We also review associations of LCN2 with kidney, cardiovascular and bone and mineral alterations. We conclude that the presented data support the design of novel therapeutic approaches to improve outcomes in CKD.

Antagonism Between PEDF and TGF-ß Contributes to Type VI Osteogenesis Imperfecta Bone and Vascular Pathogenesis.

Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder of bone and connective tissue, also known as brittle bone disease. Null mutations in SERPINF1, which encodes pigment epithelium-derived factor (PEDF), cause severe type VI OI, characterized by accumulation of unmineralized osteoid and a fish-scale pattern of bone lamellae. Although the potent anti-angiogenic activity of PEDF has been extensively studied, the disease mechanism of type VI OI is not well understood. Using Serpinf1(-/-) mice and primary osteoblasts, we demonstrate that loss of PEDF delays osteoblast maturation as well as extracellular matrix (ECM) mineralization. Barium sulfate perfusion reveals significantly increased vessel density in the tibial periosteum of Serpinf1(-/-) mouse compared with wild-type littermates. The increased bone vascularization in Serpinf1(-/-) mice correlated with increased number of CD31(+)/Endomucin(+) endothelial cells, which are involved in the coupling angiogenesis and osteogenesis. Global transcriptome analysis by RNA-Seq of Serpinf1(-/-) mouse osteoblasts reveals osteogenesis and angiogenesis as the biological processes most impacted by loss of PEDF. Intriguingly, TGF-ß signaling is activated in type VI OI cells, and Serpinf1(-/-) osteoblasts are more sensitive to TGF-ß stimulation than wild-type osteoblasts. TGF-ß stimulation and PEDF deficiency showed additive effects on transcription suppression of osteogenic markers and stimulation of pro-angiogenic factors. Furthermore, PEDF attenuated TGF-ß-induced expression of pro-angiogenic factors. These data suggest that functional antagonism between PEDF and TGF-ß pathways controls osteogenesis and bone vascularization and is implicated in type VI OI pathogenesis. This antagonism may be exploited in developing therapeutics for type VI OI utilizing PEDF and TGF-ß antibody. © 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Iron status, fibroblast growth factor 23 and cardiovascular and kidney outcomes in chronic kidney disease.

Disordered iron and mineral homeostasis are interrelated complications of chronic kidney disease that may influence cardiovascular and kidney outcomes. In a prospective analysis of 3747 participants in the Chronic Renal Insufficiency Cohort Study, we investigated risks of mortality, heart failure, end-stage kidney disease (ESKD), and atherosclerotic cardiovascular disease according to iron status, and tested for mediation by C-terminal fibroblast growth factor 23 (FGF23), hemoglobin and parathyroid hormone. Study participants were agnostically categorized based on quartiles of transferrin saturation and ferritin as "Iron Replete" (27.1% of participants; referent group for all outcomes analyses), "Iron Deficiency" (11.1%), "Functional Iron Deficiency" (7.6%), "Mixed Iron Deficiency" (iron indices between the Iron Deficiency and Functional Iron Deficiency groups; 6.3%), "High Iron" (9.2%), or "Non-Classified" (the remaining 38.8% of participants). In multivariable-adjusted Cox models, Iron Deficiency independently associated with mortality (hazard ratio 1.28, 95% confidence interval 1.04-1.58) and heart failure (1.34, 1.05- 1.72). Mixed Iron Deficiency associated with mortality (1.61, 1.27-2.04) and ESKD (1.33, 1.02-1.73). High Iron associated with mortality (1.54, 1.24-1.91), heart failure (1.58, 1.21-2.05), and ESKD (1.41, 1.13-1.77). Functional Iron Deficiency did not significantly associate with any outcome, and no iron group significantly associated with atherosclerotic cardiovascular disease. Among the candidate mediators, FGF23 most significantly mediated the risks of mortality and heart failure conferred by Iron Deficiency. Thus, alterations in iron homeostasis associated with adverse cardiovascular and kidney outcomes in patients with chronic kidney disease.

Long-Term Effects of Sglt2 Deletion on Bone and Mineral Metabolism in Mice.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve kidney and cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). However, bone fragility has emerged as a side effect in some but not in all human studies. Because use of SGLT2 inhibitors in humans affects mineral metabolism, we investigated the long-term effects of genetic loss of Sglt2 function on bone and mineral metabolism in mice. Slc5a2 nonsense mutation in Sweet Pee (SP) mice results in total loss of Sglt2 function. We collected urine, serum, and bone samples from 15-week-old and 25-week-old wild-type (WT) and SP mice fasted from food overnight. We measured parameters of renal function and mineral metabolism and we assessed bone growth, microarchitecture, and mineralization. As expected, 15-week-old and 25-week-old SP mice showed increased glucosuria, and normal kidney function compared to age-matched WT mice. At 15 weeks, SP mice did not show alterations in mineral metabolism parameters. At 25 weeks, SP mice showed reduced fasting 24-hour urinary calcium excretion and increased fractional excretion of phosphate, but normal serum calcium and phosphate, parathyroid hormone (PTH), vitamin D (1,25(OH)2D), and fibroblast growth factor (FGF23) levels. At 25 weeks, but not at 15 weeks, SP mice showed reduced body weight compared to WT. This was associated with reduced femur length at 25 weeks, suggesting impaired skeletal growth. SP mice did not show trabecular or cortical bone microarchitectural modifications but showed reduced cortical bone mineral density compared to WT mice at 25 weeks. These results suggest that loss of Sglt2 function in mice in the absence of T2DM does not alter regulatory hormones FGF23, PTH, and 1,25(OH)2D, but may contribute to bone fragility over the long term. Future studies are required to determine how loss of Sglt2 function impacts bone fragility in T2DM. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Lipocalin 2 stimulates bone fibroblast growth factor 23 production in chronic kidney disease.

Bone-produced fibroblast growth factor 23 (FGF23) increases in response to inflammation and iron deficiency and contributes to cardiovascular mortality in chronic kidney disease (CKD). Neutrophil gelatinase-associated lipocalin (NGAL or lipocalin 2; LCN2 the murine homolog) is a pro-inflammatory and iron-shuttling molecule that is secreted in response to kidney injury and may promote CKD progression. We investigated bone FGF23 regulation by circulating LCN2. At 23 weeks, Col4a3KO mice showed impaired kidney function, increased levels of kidney and serum LCN2, increased bone and serum FGF23, anemia, and left ventricular hypertrophy (LVH). Deletion of Lcn2 in CKD mice did not improve kidney function or anemia but prevented the development of LVH and improved survival in association with marked reductions in serum FGF23. Lcn2 deletion specifically prevented FGF23 elevations in response to inflammation, but not iron deficiency or phosphate, and administration of LCN2 increased serum FGF23 in healthy and CKD mice by stimulating Fgf23 transcription via activation of cAMP-mediated signaling in bone cells. These results show that kidney-produced LCN2 is an important mediator of increased FGF23 production by bone in response to inflammation and in CKD. LCN2 inhibition might represent a potential therapeutic approach to lower FGF23 and improve outcomes in CKD.

Neurotensin pathway in digestive cancers and clinical applications: an overview.

Initially, NEUROTENSIN (NTS) has been shown to play physiological and biological functions as a neuro-transmitter/modulator in the central nervous system and as an endocrine factor in the periphery, through its binding to two kinds of receptors: NTSR1 and 2 (G protein-coupled receptors) and NTSR3/sortilin (a vacuolar protein-sorting 10-domain receptor). NTS also plays oncogenic roles in many types of cancer, including digestive cancers. In tumor tissues, NTS and NTSR1 expression is higher than in healthy ones and is associated with poor prognosis. NTS and NTRS1 promote cancer progression and play key functions in metastatic processes; they modulate several signaling pathways and they contribute to changes in the tumor microenvironment. Conversely, NTRS2 involvement in digestive cancers is poorly understood. Discovered for mediating NTS biological effects, sortilin recently emerged as a promising target as its expression was found to be increased in various types of cancers. Because it can be secreted, a soluble form of sortilin (sSortilin) appears as a new serum biomarker which, on the basis of recent studies, promises to be useful in both the diagnosis and tumor progression monitoring. More precisely, it appears that soluble sortilin can be associated with other receptors like TRKB. These associations occur in exosomes and trigger the aggressiveness of cancers like glioblastoma, leading to the concept of a possible composite theranostic biomarker. This review summarizes the oncogenic roles of the NTS signaling pathways in digestive cancers and discusses their emergence as promising early diagnostic and/or prognostic biomarkers and therapeutic targets.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

5-Fluorouracil resistance mechanisms in colorectal cancer: From classical pathways to promising processes.

Colorectal cancer (CRC) is a public health problem. It is the third most common cancer in the world, with nearly 1.8 million new cases diagnosed in 2018. The only curative treatment is surgery, especially for early tumor stages. When there is locoregional or distant invasion, chemotherapy can be introduced, in particular 5-fluorouracil (5-FU). However, the disease can become tolerant to these pharmaceutical treatments: resistance emerges, leading to early tumor recurrence. Different mechanisms can explain this 5-FU resistance. Some are disease-specific, whereas others, such as drug efflux, are evolutionarily conserved. These mechanisms are numerous and complex and can occur simultaneously in cells exposed to 5-FU. In this review, we construct a global outline of different mechanisms from disruption of 5-FU-metabolic enzymes and classic cellular processes (apoptosis, autophagy, glucose metabolism, oxidative stress, respiration, and cell cycle perturbation) to drug transporters and epithelial-mesenchymal transition induction. Particular interest is directed to tumor microenvironment function as well as epigenetic alterations and miRNA dysregulation, which are the more promising processes that will be the subject of much research in the future.

Simultaneous management of disordered phosphate and iron homeostasis to correct fibroblast growth factor 23 and associated outcomes in chronic kidney disease.

PURPOSE OF REVIEW: Hyperphosphatemia, iron deficiency, and anemia are powerful stimuli of fibroblast growth factor 23 (FGF23) production and are highly prevalent complications of chronic kidney disease (CKD). In this manuscript, we put in perspective the newest insights on FGF23 regulation by iron and phosphate and their effects on CKD progression and associated outcomes. We especially focus on new studies aiming to reduce FGF23 levels, and we present new data that suggest major benefits of combined corrections of iron, phosphate, and FGF23 in CKD. RECENT FINDINGS: New studies show that simultaneously correcting iron deficiency and hyperphosphatemia in CKD reduces the magnitude of FGF23 increase. Promising therapies using iron-based phosphate binders in CKD might mitigate cardiac and renal injury and improve survival. SUMMARY: New strategies to lower FGF23 have emerged, and we discuss their benefits and risks in the context of CKD. Novel clinical and preclinical studies highlight the effects of phosphate restriction and iron repletion on FGF23 regulation.