Animal models of pediatric chronic kidney disease. Is adenine intake an appropriate model?

AbstractPediatric chronic kidney disease (CKD) has peculiar features. In particular, growth impairment is a major clinical manifestation of CKD that debuts in pediatric age because it presents in a large proportion of infants and children with CKD and has a profound impact on the self-esteem and social integration of the stunted patients. Several factors associated with CKD may lead to growth retardation by interfering with the normal physiology of growth plate, the organ where longitudinal growth rate takes place. The study of growth plate is hardly possible in humans and justifies the use of animal models. Young rats made uremic by 5/6 nephrectomy have been widely used as a model to investigate growth retardation in CKD. This article examines the characteristics of this model and analyzes the utilization of CKD induced by high adenine diet as an alternative research protocol

X-linked hypophosphatemia and growth

X-Linked hypophosphatemia (XLH) is the most common form of hereditary rickets caused by loss-of function mutations in the PHEX gene. XLH is characterized by hypophosphatemia secondary to renal phosphate wasting, inappropriately low concentrations of 1,25 dihydroxyvitamin D and high circulating levels of fibroblast growth factor 23 (FGF23). Short stature and rachitic osseous lesions are characteristic phenotypic findings of XLH although the severity of these manifestations is highly variable among patients. The degree of growth impairment is not dependent on the magnitude of hypophosphatemia or the extent of legs´ bowing and height is not normalized by chronic administration of phosphate supplements and 1α hydroxyvitamin D derivatives. Treatment with growth hormone accelerates longitudinal growth rate but there is still controversy regarding the potential risk of increasing bone deformities and body disproportion. Treatments aimed at blocking FGF23 action are promising, but information is lacking on the consequences of counteracting FGF23 during the growing period. This review summarizes current knowledge on phosphorus metabolism in XLH, presents updated information on XLH and growth, including the effects of FGF23 on epiphyseal growth plate of the Hyp mouse, an animal model of the disease, and discusses growth hormone and novel FGF23 related therapies

Raquitismo hipofosfatémico ligado al cromosoma X: estudio clínico-experimental sobre factores de riesgo cardiovascular relacionados con el factor de crecimiento fibroblástico 23

El raquitismo hipofosfatémico ligado al X (XLH) es la hipofosfatemia hereditaria más frecuente. Ocurre a consecuencia de mutaciones que implican pérdida de función del gen PHEX, y sus síntomas engloban defectos de crecimiento, deformidades óseas, dentales y auditivas. Bioquímicamente se caracteriza por la presencia de hipofosfatemia con hiperfosfaturia, concentraciones séricas de 1,25-dihidroxi vitamina D [1,25 (OH) 2D] bajas, así como niveles elevados del factor de crecimiento fibroblástico 23 (FGF23). Esta hormona ha sido relacionada en numerosos estudios con la aparición de eventos de enfermedad cardiovascular, como hipertensión arterial (HT), hipertrofia de ventrículo izquierdo (HVI) o ateroesclerosis, e incluso muerte prematura. En el presente trabajo, se diseñó un estudio de doble vertiente: experimental, utilizando al ratón Hyp como modelo de la enfermedad; y clínico, reclutando pacientes con XLH tratados con suplementos de fosfato y derivados de la vitamina D para analizar posible relación entre XLH y enfermedad cardiovascular. Tras el análisis de los resultados obtenidos se ha podido concluir que: 1) El ratón Hyp tiene valores de presión sanguínea compatibles con HT y hallazgos histológicos indicativos de HVI. 2) No existe asociación directa demostrada entre los niveles de FGF23 y la HVI o la HT. 3) No se evidencia mayor prevalencia de HT en niños y adolescentes con XLH. 4) En pacientes pediátricos con XLH existen datos ecocardiográficos sugerentes de HVI aunque los resultados no permiten confirmar o rechazar el mayor riesgo cardiovascular en estos enfermos. 5) El presente estudio tampoco demuestra que la existencia de signos clínicos ecográficos de HVI se asocie con concentraciones circulantes más alta de FGF23. 6) No se han encontrado signos de afectación cardiovascular en pacientes adultos con XLH, pero el pequeño tamaño muestral impide obtener una conclusión firme al respecto

Cardiovascular manifestations in x-linked hypophosphatemia

Annual Scientific Meeting of the European Society for Paedriatic Nephrology (51st, 2018, Antalya, Turkey

Marked alterations in the structure, dynamics and maturation of growth plate likely explain growth retardation and bone deformities of young Hyp mice

Mechanisms underlying growth impairment and bone deformities in X-linked hypophosphatemia are not fully understood. We here describe marked alterations in the structure, dynamics and maturation of growth plate in growth-retarded young Hyp mice, in comparison with wild type mice. Hyp mice exhibited reduced proliferation and apoptosis rates of chondrocytes as well as severe disturbance in the process of chondrocyte hypertrophy disclosed by abnormal expression of proteins likely involved in cell enlargement, irregular chondro-osseous junction and disordered bone trabecular pattern and vascular invasion in the primary spongiosa. (Hyp mice had elevated circulating FGF23 levels and over activation of ERK in the growth plate.) All these findings provide a basis to explain growth impairment and metaphyseal deformities in XLH. Hyp mice were compared with wild type mice serum parameters, nutritional status and growth impairment by evaluation of growth cartilage and bone structures. Hyp mice presented hyphosphatemia with high FGF23 levels. Weight gain and longitudinal growth resulted reduced in them with numerous skeletal abnormalities at cortical bone. It was also observed aberrant trabecular organization at primary spongiosa and atypical growth plate organization with abnormal proliferation and hypertrophy of chondrocytes and diminished apoptosis and vascular invasion processes. The present results show for the first time the abnormalities present in the growth plate of young Hyp mice and suggest that both cartilage and bone alterations may be involved in the growth impairment and the long bone deformities of XLH

MAPK inhibition and growth hormone: a promising therapy in XLH

X-linked hypophosphatemia (XLH) leads to growth retardation and bone deformities, which are not fully avoided by conventional treatment with phosphate and vitamin D analogs. Pediatric patients have been treated with growth hormone (GH), and recent findings suggest that blocking fibroblast growth factor 23 actions may be the most effective therapy, but its effects on growth are not known. We here report the effect of MAPK inhibition alone or associated with GH on growth and growth plate and bone structure of young Hyp (the XLH animal model) mice. Untreated Hyp mice were severely growth retarded and had marked alterations in both growth plate structure and dynamics as well as defective bone mineralization. GH accelerated growth and improved mineralization and the cortical bone, but it failed in normalizing growth plate and trabecular bone structures. MAPK inhibition improved growth and rickets and, notably, almost normalized the growth plate organization. The administration of a MAPK pathway inhibitor plus GH was the most beneficial treatment because of the positive synergistic effect on growth plate and bone structures. Thus, the growth-promoting effect of GH is likely linked to increased risk of bone deformities, whereas the association of GH and MAPK inhibition emerges as a promising new therapy for children with XLH.-Fuente, R., Gil-Peña, H., Claramunt-Taberner, D., Hernández-Frías, O., Fernández-Iglesias, Á., Alonso-Durán, L., Rodríguez-Rubio, E., Hermida-Prado, F., Anes-González, G., Rubio-Aliaga, I., Wagner, C., Santos, F. MAPK inhibition and growth hormone: a promising therapy in XLH