Identification of molecular subphenotypes in two cohorts of paediatric ARDS.

BACKGROUND: Two subphenotypes of acute respiratory distress syndrome (ARDS), hypoinflammatory and hyperinflammatory, have been reported in adults and in a single paediatric cohort. The relevance of these subphenotypes in paediatrics requires further investigation. We aimed to identify subphenotypes in two large observational cohorts of paediatric ARDS and assess their congruence with prior descriptions. METHODS: We performed latent class analysis (LCA) separately on two cohorts using biomarkers as inputs. Subphenotypes were compared on clinical characteristics and outcomes. Finally, we assessed overlap with adult cohorts using parsimonious classifiers. FINDINGS: In two cohorts from the Children's Hospital of Philadelphia (n=333) and from a multicentre study based at the University of California San Francisco (n=293), LCA identified two subphenotypes defined by differential elevation of biomarkers reflecting inflammation and endotheliopathy. In both cohorts, hyperinflammatory subjects had greater illness severity, more sepsis and higher mortality (41% and 28% in hyperinflammatory vs 11% and 7% in hypoinflammatory). Both cohorts demonstrated overlap with adult subphenotypes when assessed using parsimonious classifiers. INTERPRETATION: We identified hypoinflammatory and hyperinflammatory subphenotypes of paediatric ARDS from two separate cohorts with utility for prognostic and potentially predictive, enrichment. Future paediatric ARDS trials should identify and leverage biomarker-defined subphenotypes in their analysis.

Associations between anemia and FGF23 in the CKiD study.

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

Plasma FGF23 is associated with left atrial remodeling in children on hemodialysis.

BACKGROUND: FGF23 mediates cardiac fibrosis through the activation of pro-fibrotic factors in in vitro models and is markedly elevated in kidney disease. Left atrial global longitudinal strain (LA GLS) derived by echocardiographic speckle-tracking measures longitudinal shortening of the LA walls, quantifies atrial performance and may enable detection of early LA remodeling in the setting of normal ventricular function. We hypothesized that LA GLS is abnormal in children on hemodialysis (HD) compared to healthy controls of comparable age/sex distribution and that, among HD patients, greater FGF23 levels are associated with abnormal LA GLS. METHODS: Clinical and echocardiographic data from 29 children receiving HD and 13 healthy controls were collected in a cross-sectional single-center study. Plasma FGF23 concentrations were measured using ELISA. The primary outcome was LA GLS measured using 2D speckle-tracking strain analysis. Linear regression analysis was used to investigate predictors of LA GLS in HD. RESULTS: Median dialysis vintage was 1.5 (IQR 0.5-4.3) years. Median intact FGF23 levels were substantially higher in the HD vs. control group (1206 [215, 4707] vs. 51 [43, 66.5] pg/ml; P = 0.0001), and LA GLS was 39.9% SD 11.6 vs. 32.8% SD 5.7 (P = 0.04). Among HD patients, higher FGF23 was associated with lower LA GLS (ß per unit Ln-FGF23: - 2.7; 95% CI slope - 5.4, - 0.1; P = 0.04 after adjustment for age, body size, and HD vintage. FGF23 was not associated with LA phasic reservoir, conduit, or contractile strain. CONCLUSIONS: In children on HD and preserved left ventricular ejection fraction, greater FGF23 is associated with lower LA GLS (indicative of impaired atrial performance). A higher resolution version of the Graphical abstract is available as Supplementary information.

Iron Deficiency and Nephrotoxic Heavy Metals: A Dangerous Interplay?

Heavy metals are common in our environment, and all individuals are exposed to them to some extent. These toxic metals have several harmful effects on the body, including the kidney, which is a very sensitive organ. Indeed, heavy metal exposure has been linked to an increased risk of chronic kidney disease (CKD) and its progression, which may be explained by the well-established nephrotoxic effects of these metals. In this hypothesis and narrative literature review, we will shed light on the potential role that another highly common problem in patients with CKD, iron deficiency, may play in the damaging effects of heavy metal exposure in this patient group. Iron deficiency has previously been linked with an increased uptake of heavy metals in the intestine due to the upregulation of iron receptors that also take up other metals. Furthermore, recent research suggests a role of iron deficiency in the retention of heavy metals in the kidney. Therefore, we hypothesize that iron deficiency plays a crucial role in the damaging effects of heavy metal exposure in patients with CKD and that iron supplementation might be a strategy to combat these detrimental processes.

Enteral ferric citrate absorption is dependent on the iron transport protein ferroportin.

Ferric citrate is approved as an iron replacement product in patients with non-dialysis chronic kidney disease and iron deficiency anemia. Ferric citrate-delivered iron is enterally absorbed, but the specific mechanisms involved have not been evaluated, including the possibilities of conventional, transcellular ferroportin-mediated absorption and/or citrate-mediated paracellular absorption. Here, we first demonstrate the efficacy of ferric citrate in high hepcidin models, including Tmprss6 knockout mice (characterized by iron-refractory iron deficiency anemia) with and without adenine diet-induced chronic kidney disease. Next, to assess whether or not enteral ferric citrate absorption is dependent on ferroportin, we evaluated the effects of ferric citrate in a tamoxifen-inducible, enterocyte-specific ferroportin knockout murine model (Villin-Cre-ERT2, Fpnflox/flox). In this model, ferroportin deletion was efficient, as tamoxifen injection induced a 4000-fold decrease in duodenum ferroportin mRNA expression, with undetectable ferroportin protein on Western blot of duodenal enterocytes, resulting in a severe iron deficiency anemia phenotype. In ferroportin-deficient mice, three weeks of 1% ferric citrate dietary supplementation, a dose that prevented iron deficiency in control mice, did not improve iron status or rescue the iron deficiency anemia phenotype. We repeated the conditional ferroportin knockout experiment in the setting of uremia, using an adenine nephropathy model, where three weeks of 1% ferric citrate dietary supplementation again failed to improve iron status or rescue the iron deficiency anemia phenotype. Thus, our data suggest that enteral ferric citrate absorption is dependent on conventional enterocyte iron transport by ferroportin and that, in these models, significant paracellular absorption does not occur.

Beyond the Alveolar Epithelium: Plasma Soluble Receptor for Advanced Glycation End Products Is Associated With Oxygenation Impairment, Mortality, and Extrapulmonary Organ Failure in Children With Acute Respiratory Distress Syndrome.

OBJECTIVES: Soluble receptor for advanced glycation end products is a known plasma marker of alveolar epithelial injury. However, RAGE is also expressed on cell types beyond the lung, and its activation leads to up-regulation of pro-inflammatory mediators. We sought to examine the relationship between plasma soluble receptor for advanced glycation end products and primary pulmonary dysfunction, extrapulmonary organ dysfunction, and mortality in pediatric acute respiratory distress syndrome patients at two early time points following acute respiratory distress syndrome diagnosis and compare these results to plasma surfactant protein-D, a marker of pure alveolar epithelial injury. DESIGN: Prospective observational study. SETTING: Five academic PICUs. PATIENTS: Two hundred fifty-eight pediatric patients 30 days to 18 years old meeting Berlin Criteria for acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma was collected for soluble receptor for advanced glycation end products and surfactant protein-D measurements within 24 hours (day 1) and 48 to 72 hours (day 3) after acute respiratory distress syndrome diagnosis. Similar to surfactant protein-D, plasma soluble receptor for advanced glycation end products was associated with a higher oxygenation index (p < 0.01) and worse lung injury score (p < 0.001) at the time of acute respiratory distress syndrome diagnosis. However, unlike surfactant protein-D, plasma soluble receptor for advanced glycation end products was associated with worse extrapulmonary Pediatric Logistic Organ Dysfunction score during ICU stay (day 3; p < 0.01) and positively correlated with plasma levels of interleukin-6 (p < 0.01), tumor necrosis factor-α (p < 0.01), and angiopoietin-2 (p < 0.01). Among children with indirect lung injury, plasma soluble receptor for advanced glycation end products was associated with mortality independent of age, sex, race, cancer/bone marrow transplant, and Pediatric Risk of Mortality score (day 3; odds ratio, 3.14; 95% CI, 1.46-6.75; p < 0.01). CONCLUSIONS: Unlike surfactant protein-D, which is primarily localized to the alveolar epithelium plasma soluble receptor for advanced glycation end products is systemically expressed and correlates with markers of inflammation, extrapulmonary multiple organ dysfunction, and death in pediatric acute respiratory distress syndrome with indirect lung injury. This suggests that unlike surfactant protein-D, soluble receptor for advanced glycation end products is a multifaceted marker of alveolar injury and increased inflammation and that receptor for advanced glycation end products activation may contribute to the pathogenesis of multiple organ failure among children with indirect acute respiratory distress syndrome.

Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease.

Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.

A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial.

Pediatric chronic kidney disease (CKD) is characterized by many co-morbidities, including impaired growth and development, CKD-mineral and bone disorder, anemia, dysregulated iron metabolism, and cardiovascular disease. In pediatric CKD cohorts, higher circulating concentrations of fibroblast growth factor 23 (FGF23) are associated with some of these adverse clinical outcomes, including CKD progression and left ventricular hypertrophy. It is hypothesized that lowering FGF23 levels will reduce the risk of these events and improve clinical outcomes. Reducing FGF23 levels in CKD may be accomplished by targeting two key stimuli of FGF23 production-dietary phosphate absorption and iron deficiency. Ferric citrate is approved for use as an enteral phosphate binder and iron replacement product in adults with CKD. Clinical trials in adult CKD cohorts have also demonstrated that ferric citrate decreases circulating FGF23 concentrations. This review outlines the possible deleterious effects of excess FGF23 in CKD, summarizes data from the adult CKD clinical trials of ferric citrate, and presents the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) study, a randomized, placebo-controlled trial to evaluate the effects of ferric citrate on FGF23 in pediatric patients with CKD stages 3-4 (ClinicalTrials.gov Identifier NCT04741646).

Amelioration of chronic kidney disease-associated anemia by vadadustat in mice is not dependent on erythroferrone.

Vadadustat is an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor that increases endogenous erythropoietin production and has been shown to decrease hepcidin levels, ameliorate iron restriction, and increase hemoglobin concentrations in anemic patients with chronic kidney disease (CKD). In studies of physiological responses to other erythropoietic stimuli, erythropoietin induced erythroblast secretion of erythroferrone (ERFE), which acts on the liver to suppress hepcidin production and mobilize iron for erythropoiesis. We therefore investigated whether vadadustat effects on erythropoiesis and iron metabolism are dependent on ERFE. Wild type and ERFE knockout mice with and without CKD were treated with vadadustat or vehicle. In both wild type and ERFE knockout CKD models, vadadustat was similarly effective, as evidenced by normalized hemoglobin concentrations, increased expression of duodenal iron transporters, lower serum hepcidin levels, and decreased tissue iron concentrations. This is consistent with ERFE-independent increased iron mobilization. Vadadustat treatment also lowered serum urea nitrogen and creatinine concentrations and decreased expression of kidney fibrosis markers. Lastly, vadadustat affected fibroblast growth factor 23 (FGF23) profiles: in non-CKD mice, vadadustat increased plasma total FGF23 out of proportion to intact FGF23, consistent with the known effects of hypoxia-inducible factor-1α and erythropoietin on FGF23 production and metabolism. However, in the mice with CKD, vadadustat markedly decreased both total and intact FGF23, effects likely contributed to by the reduced loss of kidney function. Thus, in this CKD model, vadadustat ameliorated anemia independently of ERFE, improved kidney parameters, and decreased FGF23. How vadadustat affects CKD progression in humans warrants future studies.

Associations among erythropoietic, iron-related, and FGF23 parameters in pediatric kidney transplant recipients.

BACKGROUND: In pediatric kidney transplant recipients, anemia is common and oftentimes multifactorial. Hemoglobin concentrations may be affected by traditional factors, such as kidney function and iron status, as well as novel parameters, such as fibroblast growth factor 23 (FGF23). METHODS: Here, we evaluated associations among erythropoietic, iron-related, and FGF23 parameters in a cohort of pediatric kidney transplant recipients, hypothesizing that multiple factors are associated with hemoglobin concentrations. RESULTS: In a cross-sectional analysis of 59 pediatric kidney transplant recipients (median (interquartile range) age 16.3 (13.5, 18.6) years, median estimated glomerular filtration rate (eGFR) 67 (54, 87) ml/min/1.73 m2), the median age-related hemoglobin standard deviation score (SDS) was -2.1 (-3.3, -1.1). Hemoglobin SDS was positively associated with eGFR and calcium, and was inversely associated with erythropoietin (EPO), mycophenolate dose, and total, but not intact, FGF23. In multivariable analysis, total FGF23 remained inversely associated with hemoglobin SDS, independent of eGFR, iron parameters, EPO, and inflammatory markers, suggesting a novel FGF23-hemoglobin association in pediatric kidney transplant patients. In a subset of patients with repeat measurements, only delta hepcidin was inversely associated with delta hemoglobin SDS. Also, delta EPO positively correlated with delta erythroferrone (ERFE), and delta ERFE inversely correlated with delta hepcidin, suggesting a possible physiologic role for the EPO-ERFE-hepcidin axis in the setting of chronic kidney disease (CKD). CONCLUSION: Our study provides further insight into factors potentially associated with erythropoiesis in pediatric kidney transplant recipients. A higher resolution version of the Graphical abstract is available as Supplementary information.

Measurement of serum phosphate levels using a mobile sensor.

The measurement of serum phosphate concentration is crucial for patients with advanced chronic kidney disease (CKD) and those on maintenance dialysis, as abnormal phosphate levels may be associated with severe health risks. It is important to monitor serum phosphate levels on a regular basis in these patients; however, such measurements are generally limited to every 0.5-3 months, depending on the severity of CKD. This is due to the fact that serum phosphate measurements can only be performed at regular clinic visits, in addition to cost considerations. Here we present a portable and cost-effective point-of-care device capable of measuring serum phosphate levels using a single drop of blood (<60 µl). This is achieved by integrating a paper-based microfluidic platform with a custom-designed smartphone reader. This mobile sensor was tested on patients undergoing dialysis, where whole blood samples were acquired before starting the hemodialysis and during the three-hour treatment. This sampling during the hemodialysis, under patient consent, allowed us to test blood samples with a wide range of phosphate concentrations, and our results showed a strong correlation with the ground truth laboratory tests performed on the same patient samples (Pearson coefficient r = 0.95 and p < 0.001). Our 3D-printed smartphone attachment weighs about 400 g and costs less than 80 USD, whereas the material cost for the disposable test is <3.5 USD (under low volume manufacturing). This low-cost and easy-to-operate system can be used to measure serum phosphate levels at the point-of-care in about 45 min and can potentially be used on a daily basis by patients at home.

Ferric citrate: cardio- and renoprotective in chronic kidney disease?

Ferric citrate is a phosphate binder that may also be used to treat iron-deficiency anemia. In human studies, ferric citrate treatment in the setting of chronic kidney disease has been associated with effective phosphate control, improved iron and hematologic parameters, and decreased fibroblast growth factor 23 levels. In the present study, mice with chronic kidney disease treated with ferric citrate have similarly improved biochemical profiles, but also have improved cardiac and renal function and prolonged survival.

Effects of erythropoietin on fibroblast growth factor 23 in mice and humans.

BACKGROUND: Erythropoietin (EPO) has been reported as a novel determinant of fibroblast growth factor 23 (FGF23) production; however, it is unknown whether FGF23 is stimulated by chronic exposure to EPO or by EPO administration in nonpolycystic chronic kidney disease (CKD) models. METHODS: We analyzed the effects of chronic EPO on FGF23 in murine models with chronically high EPO levels and normal kidney function. We studied the effects of exogenous EPO on FGF23 in wild-type mice, with and without CKD, injected with EPO. Also, in four independent human CKD cohorts, we evaluated associations between FGF23 and serum EPO levels or exogenous EPO dose. RESULTS: Mice with high endogenous EPO have elevated circulating total FGF23, increased disproportionately to intact FGF23, suggesting coupling of increased FGF23 production with increased proteolytic cleavage. Similarly, in wild-type mice with and without CKD, a single exogenous EPO dose acutely increases circulating total FGF23 out of proportion to intact FGF23. In these murine models, the bone marrow is shown to be a novel source of EPO-stimulated FGF23 production. In humans, serum EPO levels and recombinant human EPO dose are positively and independently associated with total FGF23 levels across the spectrum of CKD and after kidney transplantation. In our largest cohort of 680 renal transplant recipients, serum EPO levels are associated with total FGF23, but not intact FGF23, consistent with the effects of EPO on FGF23 production and metabolism observed in our murine models. CONCLUSION: EPO affects FGF23 production and metabolism, which may have important implications for CKD patients.

Clinical experience with the use of ferric citrate as a phosphate binder in pediatric dialysis patients.

BACKGROUND: Ferric citrate, an iron-based phosphate binder, has been shown to improve both hyperphosphatemia and iron deficiency in adult chronic kidney disease patients, but its use in the pediatric dialysis population has not been described. METHODS: This is a retrospective analysis of 11 unselected pediatric dialysis patients who received ferric citrate as a phosphate binder between 2015 and 2017. Time-averaged laboratory values were compared pre- and post-ferric citrate initiation using the Wilcoxon signed-rank test. RESULTS: The median age of this cohort was 13 years old (range 4-17 years old). Five patients were on hemodialysis, and six patients were on peritoneal dialysis. The median duration of ferric citrate therapy was 214 days (range 39-654 days), with a median time-averaged ferric citrate dose of 3.5 tablets per day (range 1.5-8.4 tablets per day). Compared to the pre-ferric citrate period, ferric citrate treatment was associated with decreased serum phosphate (6.5 to 5.2 mg/dl, p = 0.014), decreased phosphate age-related standard deviation score (SDS) (2.3 to 0.9, p = 0.019), increased transferrin saturation (26 to 34%, p = 0.049), increased ferritin (107 to 230 ng/ml, p = 0.074), and maintenance of hematocrit. CONCLUSIONS: In pediatric dialysis patients, ferric citrate may be able to concurrently lower phosphate levels and treat iron deficiency. However, larger studies are needed to further evaluate safety and efficacy in the pediatric chronic kidney disease population.

Non-renal-Related Mechanisms of FGF23 Pathophysiology.

PURPOSE OF REVIEW: We will review non-renal-related mechanisms of fibroblast growth factor 23 (FGF23) pathophysiology. RECENT FINDINGS: FGF23 production and metabolism may be affected by many bone, mineral, and kidney factors. However, it has recently been demonstrated that other factors, such as iron status, erythropoietin, and inflammation, also affect FGF23 production and metabolism. As these non-mineral factors are especially relevant in the setting of chronic kidney disease (CKD), they may represent emerging determinants of CKD-associated elevated FGF23 levels. Moreover, FGF23 itself may promote anemia and inflammation, thus contributing to the multifactorial etiologies of these CKD-associated comorbidities. CKD-relevant, non-mineral-related, bidirectional relationships exist between FGF23 and anemia, and between FGF23 and inflammation. Iron deficiency, anemia, and inflammation affect FGF23 production and metabolism, and FGF23 itself may contribute to anemia and inflammation, highlighting complex interactions that may affect aspects of CKD pathogenesis and treatment.

Fractures and Osteomalacia in a Patient Treated With Frequent Home Hemodialysis.

Bone deformities and fractures are common consequences of renal osteodystrophy in the dialysis population. Persistent hypophosphatemia may be observed with more frequent home hemodialysis regimens, but the specific effects on the skeleton are unknown. We present a patient with end-stage renal disease treated with frequent home hemodialysis who developed severe bone pain and multiple fractures, including a hip fracture and a tibia-fibula fracture complicated by nonunion, rendering her nonambulatory and wheelchair bound for more than a year. A bone biopsy revealed severe osteomalacia, likely secondary to chronic hypophosphatemia and hypocalcemia. Treatment changes included the addition of phosphate to the dialysate, a higher dialysate calcium concentration, and increased calcitriol dose. Several months later, the patient no longer required a wheelchair and was able to ambulate without pain. Repeat bone biopsy revealed marked improvements in bone mineralization and turnover parameters. Also, with increased dialysate phosphate and calcium concentrations, as well as increased calcitriol, circulating fibroblast growth factor 23 levels increased.

Treatment of Pediatric Chronic Kidney Disease-Mineral and Bone Disorder.

PURPOSE OF REVIEW: In this paper, we review the pathogenesis and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD), especially as it relates to pediatric CKD patients. RECENT FINDINGS: Disordered regulation of bone and mineral metabolism in CKD may result in fractures, skeletal deformities, and poor growth, which is especially relevant for pediatric CKD patients. Moreover, CKD-MBD may result in extra-skeletal calcification and cardiovascular morbidity. Early increases in fibroblast growth factor 23 (FGF23) levels play a key, primary role in CKD-MBD pathogenesis. Therapeutic approaches in pediatric CKD-MBD aim to minimize complications to the growing skeleton and prevent extra-skeletal calcifications, mainly by addressing hyperphosphatemia and secondary hyperparathyroidism. Ongoing clinical trials are focused on assessing the benefit of FGF23 reduction in CKD. CKD-MBD is a systemic disorder that has significant clinical implications. Treatment of CKD-MBD in children requires special consideration in order to maximize growth, optimize skeletal health, and prevent cardiovascular disease.

Effects of dietary iron intake and chronic kidney disease on fibroblast growth factor 23 metabolism in wild-type and hepcidin knockout mice.

In the setting of normal kidney function, iron deficiency is associated with increased FGF23 production and cleavage, altering circulating FGF23 levels. Our objective was to determine how chronic kidney disease (CKD) and dietary iron intake affect FGF23 production and metabolism in wild-type (WT) and hepcidin knockout (HKO) mice. For 8 wk, the mice were fed diets that contained adenine (to induce CKD) or no adenine (control group), with either low-iron (4 ppm) or standard-iron (335 ppm) concentrations. The low-iron diet induced iron deficiency anemia in both the WT and HKO mice. Among the WT mice, in both the control and CKD groups, a low-iron compared with a standard-iron diet increased bone Fgf23 mRNA expression, C-terminal FGF23 (cFGF23) levels, and FGF23 cleavage as manifested by a lower percentage intact FGF23 (iFGF23). Independent of iron status, CKD was associated with inhibition of FGF23 cleavage. Similar results were observed in the HKO control and CKD groups. Dietary iron content was more influential on FGF23 parameters than the presence or absence of hepcidin. In the CKD mice (WT and HKO, total n = 42), independent of the effects of serum phosphate, iron deficiency was associated with increased FGF23 production but also greater cleavage, whereas worse kidney function was associated with increased FGF23 production but decreased cleavage. Therefore, in both the WT and HKO mouse models, dietary iron content and CKD affected FGF23 production and metabolism.