Justine Bacchetta

The influence of glomerular filtration rate and age on fibroblast growth factor 23 serum levels in pediatric chronic kidney disease.

BACKGROUND Fibroblast growth factor 23 (FGF23) is a phosphaturic factor and a suppressor of 1alpha-hydroxylase activity in the kidney. Although its importance in chronic kidney disease (CKD) has been demonstrated in adults, there is little information in pediatric patients. OBJECTIVES The aims of this study were: 1) to determine reference values for FGF23 serum levels according to glomerular filtration rate (GFR) (measured by the reference standard, inulin clearance), gender, and age; and 2) to evaluate the effects of different etiologies and treatments on FGF23 serum levels in a prospective single-center cohort of 227 CKD children (119 boys). RESULTS Age, body weight, height, and GFR (mean +/- sd) values were: 11.3 +/- 4.1 yr, 37 +/- 16 kg, 140 +/- 20 cm, and 98 +/- 34 ml/min per 1.73 m(2), respectively. Calcium, phosphate, PTH, 25 hydroxyvitamin D, 1,25 dihydroxyvitamin D, C-terminal FGF23, and intact FGF23 (mean +/- sd) levels were: 2.43 +/- 0.11 mmol/liter, 1.41 +/- 0.22 mmol/liter, 41 +/- 23 pg/ml, 24 +/- 10 ng/ml, 152 +/- 72 pmol/liter, 76 +/- 134 relative units/ml, and 44 +/- 37 pg/ml, respectively. There was a wide range of FGF23 serum levels, but FGF23 levels increased when GFR decreased. FGF23 serum levels were not modified by gender, but they increased with age. In univariate analysis, corticosteroid therapy seemed to be associated with increased FGF23 serum levels. A multivariate linear regression analysis found a significant impact of GFR, body mass index, and solid organ transplantation on FGF23 serum levels. CONCLUSION Age, GFR, body mass index, and solid organ transplantation seem to influence FGF23 serum levels in a pediatric population. The impact of corticosteroids on FGF23 metabolism should be further investigated; further longitudinal studies will also help to better define the prognostic impact of FGF23 serum levels in pediatric CKD in terms of disease progression, cardiovascular morbidities, and bone disabilities.

Bone microarchitecture is more severely affected in patients on hemodialysis than in those receiving peritoneal dialysis.

We used high-resolution quantitative computed tomography to study the microarchitecture of bone in patients with chronic kidney disease on dialysis. We compared bone characteristics in 56 maintenance hemodialysis (21 women, 14 post-menopausal) and 23 peritoneal dialysis patients (9 women, 6 post-menopausal) to 79 healthy men and women from two cohorts matched for age, body mass index, gender, and menopausal status. All underwent dual-energy X-ray absorptiometry of the spine and hip to measure areal bone mineral density, and high-resolution peripheral quantitative computed tomography of the radius and tibia to measure volumetric bone mineral density and microarchitecture. When compared to their matched healthy controls, patients receiving hemodialysis and peritoneal dialysis had a significantly lower areal bone mineral density in the hip. Hemodialysis patients had significantly lower total, cortical, and trabecular volumetric bone mineral density at both sites. Hemodialysis patients had significantly lower trabecular volumetric bone mineral density and microarchitecture at the tibia than the peritoneal dialysis patients. Overall, peritoneal dialysis patients were less affected, their cortical thickness at the distal tibia being the only significant difference versus controls. Thus, we found more severe trabecular damage at the weight-bearing tibia in hemodialysis compared to peritoneal dialysis patients, but this latter finding needs confirmation in larger cohorts.

Bone impairment in primary hyperoxaluria: a review

Deposition of calcium oxalate crystals in the kidney and bone is a hallmark of primary hyperoxaluria (PH). Since the bone compartment can store massive amounts of oxalate, patients present with recurrent low-trauma fractures, bone deformations, severe bone pains, and specific oxalate osteopathy on X-ray. Bone biopsy from the iliac crest displays specific features such as oxalate crystals surrounded by a granulomatous reaction corresponding to an invasion of bone surface by macrophages. The objective of this manuscript is therefore to provide an overview of bone impairment in PH, by reviewing the current literature on bone and dental symptoms as well as imaging techniques used for assessing bone disease.

Biphasic Effects of Vitamin D and FGF23 on Human Osteoclast Biology

Vitamin D and FGF23 play a major role in calcium/phosphate balance. Vitamin D may control bone resorption but the potential role of FGF23 has never been evaluated. The objective of this study was therefore to compare the effects of vitamin D and FGF23 on osteoclast differentiation and activity in human monocyte-derived osteoclasts. Human monocytes, purified from blood of healthy donors, were incubated with M-CSF and RANKL to obtain mature multinucleated osteoclasts (MNC). Experiments were carried out to assess the effects of FGF23 as compared to native vitamin D (25-D) and active vitamin D (1,25-D) on osteoclast differentiation and on bone-resorbing osteoclast activity. Additional experiments with the pan fibroblast growth factor receptor inhibitor (FGFR-i) were performed. Phosphorylation Akt and Erk pathways were analyzed by Western blot analyses. Both 1,25-D and FGF23, to a lesser extent, significantly inhibited osteoclastogenesis at early stages; when adding FGFR-i, osteoclast formation was restored. Biochemical experiments showed an activation of the Akt and Erk pathways under FGF23 treatment. In contrast, in terms of activity, 1,25-D had no effect on resorption, whereas FGF23 slightly but significantly increased bone resorption; 25-D had no effects on either differentiation or on activity. These data show that 1,25-D inhibits osteoclastogenesis without regulating osteoclast-mediated bone resorption activity; FGF23 has biphasic effects on osteoclast physiology, inhibiting osteoclast formation while stimulating slightly osteoclast activity. These results may be of importance and taken into account in chronic kidney disease when therapies modulating FGF23 are available.

Hypocalcémie et déformations osseuses

Il s’agissait d’un garçon de 29 mois, né à terme, issu de parents consanguins d’origine algérienne, adressé pour prise en charge d’une hypocalcémie sévère. Il était traité depuis l’âge de 9 mois par acide valproı̈que pour des crises convulsives à répétition avec scanner cérébral normal. Il présentait par ailleurs une alopécie partielle depuis l’âge de 6 mois (fig. 1), des déformations osseuses constatées à l’âge de 8 mois et un retard de développement global. À l’examen, on observait un retard de croissance (78 cm soit – 2,5 déviation standard (DS) et un poids de

The Relationship Between Body Composition and Bone Quality Measured with HR-pQCT in Peritoneal Dialysis Patients

Background: Bone is known to be impaired in chronic kidney disease and dialysis patients. Recent studies have shown that body composition (fat mass and lean mass) may impact bone health. Some of these effects may be related to mediators that are secreted by adipose tissue. Methods: The aim of this study was to evaluate the association between body composition (dual x-ray absorptiometry [DEXA]) and adipokines (leptin, adiponectin), with bone density and microarchitecture assessed with high-resolution peripheral quantitative computed tomography (HR-pQCT) in chronic peritoneal dialysis (PD) patients in a single-center prospective study. Results: Twenty-three patients with a median age of 61 years and body mass index (BMI) of 27 kg/m2 were recruited. On univariate analysis, age was negatively associated with total volumetric bone mineral density (vBMD) (r = -0.75, p < 0.01), cortical vBMD (r = -0.85, p < 0.01), and cortical thickness (r = -0.71, p < 0.01). There was a negative association between leptin and cortical thickness (r = -0.48, p = 0.021). Fat mass (FM) was negatively correlated with cortical thickness (r = -0.52, p = 0.012). No association was found between bone parameters and dialysis duration, serum insulin, intact parathyroid hormone, osteocalcin, and adiponectin. The short dialysis vintage could in part explain the lack of correlation with bone parameters. In multivariate analysis, FM was significantly and negatively correlated with total vBMD, cortical and trabecular thickness. Conclusions: These data suggest that FM is negatively associated with bone quality in PD patients, supporting a relation between body composition and bone that is independent from other dialysis-associated complications. The relative contribution of the different fat deposits (visceral versus subcutaneous) needs to be assessed in future studies.

Combining exercise and growth hormone therapy: how can we translate from animal models to chronic kidney disease children?

Renal osteodystrophy (ROD) and growth retardation are frequent complications of paediatric chronic kidney disease (CKD) secondary to an association of abnormalities including impaired growth hormone (GH) metabolism, hypoor hyperparathyroidism, vitaminD deficiency, malnutrition, hypogonadism and drug toxicity [1]. The impact of CKD-associated bone and mineral disorders (CKD-MBDs) can be a short-term issue (abnormal mineral metabolism), but also a long-term one (ROD, fractures, impaired growth, vascular calcifications and mortality) [1]. These complications affect the quality of life because of their consequences on mental and physical wellbeing, but they also strongly impair mineral metabolism and bone quality and ultimately cause cardiovascular disease, which is the major cause of death in paediatric CKD [1]. Linear growth is specific to paediatric patients: it is a highly regulated process occurring through the modelling of new bone by skeletal accretion and longitudinal growth at the growth plate. Chondrocytes are a cornerstone of this process, along with GH [2]. One-third of the total growth occurs during infancy (i.e. the first 2 years of life), depending mainly on nutritional parameters [2]. Later childhood is marked by a constant growth velocity (but of lesser intensity than in the early stages); this phenomenon is driven by GH and thyroid hormone.When puberty occurs, testosterone and oestrogen further increase growth velocity. The epiphyseal cartilage goes through a process of progressive maturation during infancy, childhood and adolescence. When no additional epiphyseal cartilage remains to allow further growth of long bones, fusion occurs between the shaft and the epiphysis, ending the linear growth process. In children, bone formation occurs by to two different mechanisms: the first mechanism is endochondral ossification (i.e. modelling of new bone by longitudinal growth and skeletal accretion from the growth plate by chondrocytes), while the second one is similar to that observed in adults, corresponding to the skeletal remodelling of existing mineralized bone tissue by osteoblasts and osteoclasts [3]. The growth plate is an avascular tissue located between the metaphyses and epiphyses in long bones; endochondral bone formation corresponds to its progressive replacement by bone. Its regulation corresponds to a complex cascade of nutritional, cellular, paracrine and endocrine factors [4]. The growth plate consists of three different zones: resting, proliferative and hypertrophic, with each zone containing chondrocytes at different stages of differentiation, i.e. small chondrocytes with low replication rates, flat chondrocytes with high replication rates and chondrocytes at the later stage of differentiation, respectively [5]. The cellular factors involved in endochondral ossification include apoptosis, autophagy, hypoxia and trans-differentiation [5]. In terms of paracrine factors involved in the proliferation and differentiation of chondrocytes, the PTH/PTH-related proteinreceptor axis, the IndianHedgehog pathway and the Runx2 transcription factors are key components of the cascade, along with fibroblast growth factor receptor and bone morphogenetic protein signalling [5]. GH and insulin-like growth factor-1 (IGF-1) are obviously themost important endocrine factors involved, but oestrogens and androgens also play a role [5]. GH exerts at least four main actions on the growth plate: (i) increased local synthesis of IGF-1 for a paracrine effect (i.e. clonal expansion of proliferating chondrocytes), (ii) a stimulating effect on cellular differentiation to convert chondrocytes into osteogenic cells, (iii) increased cellular proliferation rate and (iv) increased synthesis and deposition of proteins by chondrocytic and osteogenic

SFRP CO-12 – Effets de la vitamine D active et du FGF23 sur l’ostéoclaste humain

Objectifs Le Fibroblast Growth Factor 23 (FGF23), hormone cle de l’axe « rein/parathyroides/os », est secrete par les osteocytes. Aucune donnee n’a ete publiee sur l’effet local du FGF23 sur les osteoclastes (OC), cellules geantes multinucleees capables de resorber la matrice osseuse. Objectif Etudier l’effet du FGF23 sur la physiologie de l’OC, en comparaison a la 1,25(OH) 2 vitamine D (1,25D). Materiels et methodes Les OC, obtenus a partir de monocytes humains purifies, ont ete exposes au FGF23 et a la 1,25D. L’osteoclastogenese a ete analysee grâce au comptage des cellules colorees (TRAP) de plus de 3 noyaux. L’activite de resorption a ete etudiee grâce a la quantification des surfaces resorbees par OC. Le FGF recepteur inhibiteur (FGFRi) et l’etude de la voie de signalisation Akt ont ete utilises pour confirmer les resultats. Resultats principaux La 1,25D et le FGF23 inhibaient l’osteoclastogenese, respectivement de 91% et de 23% (p