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We report a new low-affinity hemoglobinopathy (Hemoglobin Oviedo) in a family with isolated low oxygen saturation (89-92%) caused by a previously undescribed variant (NM_000518.5: c.115A > G;p.Thr39Ala) in the hemoglobin subunit ß encoding gene (HBB gene) located on chromosome 11.
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Vascular calcification has a global health impact that is closely linked to bone loss. The Receptor Activator of Nuclear Factor Kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, fundamental for bone metabolism, also plays an important role in vascular calcification. The Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a novel receptor for RANKL, regulates bone remodeling, and it appears to be involved in vascular calcification. Besides RANKL, LGR4 interacts with R-spondins (RSPOs), which are known for their roles in bone but are less understood in vascular calcification. Studies were conducted in rats with chronic renal failure fed normal or high phosphorus diets for 18 weeks, with and without control of circulating parathormone (PTH) levels, resulting in different degrees of aortic calcification. Additionally, vascular smooth muscle cells (VSMCs) were cultured under non-calcifying (1 mM phosphate) and calcifying (3 mM phosphate) media with different concentrations of PTH. To explore the role of RANKL in VSMC calcification, increasing concentrations of soluble RANKL were added to non-calcifying and calcifying media. The effects mediated by RANKL binding to its receptor LGR4 were investigated by silencing the LGR4 receptor in VSMCs. Furthermore, the gene expression of the RANK/RANKL/OPG system and the ligands of LGR4 was assessed in human epigastric arteries obtained from kidney transplant recipients with calcification scores (Kauppila Index). Increased aortic calcium in rats coincided with elevated systolic blood pressure, upregulated Lgr4 and Rankl gene expression, downregulated Opg gene expression, and higher serum RANKL/OPG ratio without changes in Rspos gene expression. Elevated phosphate in vitro increased calcium content and expression of Rankl and Lgr4 while reducing Opg. Elevated PTH in the presence of high phosphate exacerbated the increase in calcium content. No changes in Rspos were observed under the conditions employed. The addition of soluble RANKL to VSMCs induced genotypic differentiation and calcification, partly prevented by LGR4 silencing. In the epigastric arteries of individuals presenting vascular calcification, the gene expression of RANKL was higher. While RSPOs show minimal impact on VSMC calcification, RANKL, interacting with LGR4, drives osteogenic differentiation in VSMCs, unveiling a novel mechanism beyond RANKL-RANK binding.
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Músculo Liso Vascular , Ligando RANK , Receptores Acoplados a Proteínas G , Calcificación Vascular , Ligando RANK/metabolismo , Ligando RANK/genética , Animales , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Calcificación Vascular/metabolismo , Calcificación Vascular/patología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Ratas , Humanos , Masculino , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Osteoprotegerina/metabolismo , Osteoprotegerina/genética , Hormona Paratiroidea/metabolismo , Células Cultivadas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a severe disease, termed coronavirus disease 2019 (COVID-19), with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms and their modulation has shown a mortality benefit. METHODS: In a cohort of 56 critically ill COVID-19 patients, peripheral blood transcriptomes were obtained at admission to an intensive care unit (ICU) and clustered using an unsupervised algorithm. Differences in gene expression, circulating microRNAs (c-miRNAs) and clinical data between clusters were assessed, and circulating cell populations estimated from sequencing data. A transcriptomic signature was defined and applied to an external cohort to validate the findings. RESULTS: We identified two transcriptomic clusters characterised by expression of either interferon-related or immune checkpoint genes, respectively. Steroids have cluster-specific effects, decreasing lymphocyte activation in the former but promoting B-cell activation in the latter. These profiles have different ICU outcomes, despite no major clinical differences at ICU admission. A transcriptomic signature was used to identify these clusters in two external validation cohorts (with 50 and 60 patients), yielding similar results. CONCLUSIONS: These results reveal different underlying pathogenetic mechanisms and illustrate the potential of transcriptomics to identify patient endotypes in severe COVID-19 with the aim to ultimately personalise their therapies.
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COVID-19 , Humanos , COVID-19/genética , SARS-CoV-2 , Transcriptoma , Enfermedad Crítica , Unidades de Cuidados IntensivosRESUMEN
The clinical manifestations of primary distal renal tubular acidosis usually begin in childhood, but the disease is caused by a genetic defect that persists throughout life. This review focuses on the complications of distal tubular acidosis that occur or remain long-term such as nephrocalcinosis and urolithiasis, growth impairment, bone mineralization, severe hypokalemia, kidney cysts, and progressive kidney failure, as well as other persistent manifestations that occur independent of acidosis but are associated with some inherited forms of the disease. The pathogenic factors responsible for kidney failure are discussed in particular because it is a complication to which different publications have recently drawn attention and which affects a high percentage of adults with primary distal renal tubular acidosis. The need to maintain optimal metabolic control of the disease and scheduled clinical follow-up throughout life and the importance of organizing protocols for the transition of patients to adult nephrology services are emphasized.
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Acidosis Tubular Renal , Acidosis , Hipopotasemia , Nefrocalcinosis , Insuficiencia Renal , Adulto , Humanos , Acidosis Tubular Renal/complicaciones , Acidosis Tubular Renal/diagnóstico , Acidosis Tubular Renal/genética , Hipopotasemia/etiología , Nefrocalcinosis/terapia , Nefrocalcinosis/complicaciones , Insuficiencia Renal/complicacionesRESUMEN
IgG3 would play an important role in the immune adaptive response against SARS-CoV-2, and low plasma levels might increase the risk of COVID-19 severity and mortality. The IgG3 hinge sequence has a variable repeat of a 15 amino acid exon with common 4-repeats (M) and 3-repeats (S). This length IGHG3 polymorphism might affect the IgG3 effector functions. The short hinge length would reduce the IgG3 flexibility and impairs the neutralization and phagocytosis compared to larger length-isoforms. We genotyped the IGHG3 length polymorphism in patients with critical COVID-19 (N = 516; 107 death) and 152 moderate-severe but no-critical cases. Carriers of the S allele had an increased risk of critical ICU and mortality (p < 0.001, OR = 2.79, 95% CI = 1.66-4.65). This adverse effect might be explained by a less flexibility and reduced ability to induce phagocytosis or viral neutralization for the short length allele. We concluded that the IgG3 hinge length polymorphism could be a predictor of critical COVID-19 and the risk of death. This study was based on a limited number of patients from a single population, and requires validation in larger cohorts.
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COVID-19 , Aminoácidos , COVID-19/genética , Exones , Humanos , Inmunoglobulina G/genética , SARS-CoV-2RESUMEN
A previously healthy 12-year-old boy had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related multisystem inflammatory syndrome (MIS-C) that was rapidly fatal. Autopsy revealed the presence of a large intracardiac thrombus. SARS-CoV-2 spike protein was detected in intestinal cells, supporting the hypothesis that viral presence in the gut may be related to the immunologic response of MIS-C.
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COVID-19 , Intestinos , Glicoproteína de la Espiga del Coronavirus , COVID-19/complicaciones , COVID-19/patología , Niño , Resultado Fatal , Humanos , Intestinos/virología , Masculino , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria SistémicaRESUMEN
Mineral homeostasis is regulated by a complex network involving endocrine actions by calcitriol, parathyroid hormone (PTH), and FGF23 on several organs including kidney, intestine, and bone. Alterations of mineral homeostasis are found in chronic kidney disease and other systemic disorders. The interplay between the immune system and the skeletal system is not fully understood, but cytokines play a major role in modulating calcitriol production and function. One of the main cellular signaling pathways mediating cytokine function is the Janus kinase (JAK)--signal transducer and activator of transcription (STAT) pathway. Here, we used a mouse model (Jak1S645P+/- ) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans, and shows altered mineral metabolism, with higher fibroblast growth factor 23 (FGF23) levels, lower PTH levels, and higher calcitriol levels. The higher calcitriol levels are probably due to extrarenal calcitriol production. Furthermore, systemic Jak1/Stat3 activation led to growth impairment and skeletal alterations. The growth plate in long bones showed decreased chondrocyte proliferation rates and reduced height of terminal chondrocytes. Furthermore, we demonstrate that Jak1 is also involved in bone remodeling early in life. Jak1S645P+/- animals have decreased bone and cortical volume, imbalanced bone remodeling, reduced MAP kinase signaling, and local inflammation. In conclusion, Jak1 plays a major role in bone health probably both, directly and systemically by regulating mineral homeostasis. Understanding the role of this signaling pathway will contribute to a better knowledge in bone growth and in mineral physiology, and to the development of selective Jak inhibitors as osteoprotective agents.
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Huesos/metabolismo , Huesos/fisiología , Calcitriol/metabolismo , Trastornos del Crecimiento/metabolismo , Janus Quinasa 1/metabolismo , Transducción de Señal/fisiología , Animales , Remodelación Ósea/fisiología , Proliferación Celular/fisiología , Condrocitos/metabolismo , Condrocitos/fisiología , Citocinas/metabolismo , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos , Placa de Crecimiento/metabolismo , Placa de Crecimiento/fisiología , Homeostasis/fisiología , Humanos , Inflamación/metabolismo , Riñón/metabolismo , Riñón/fisiología , Masculino , Ratones , Ratones Endogámicos C3H , Mutación/genética , Hormona Paratiroidea/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
X-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets, is caused by inactivating mutations of the phosphate-regulating endopeptidase gene (PHEX). XLH is mainly characterized by short stature, bone deformities and rickets, while in hypophosphatemia, normal or low vitamin D levels and low renal phosphate reabsorption are the principal biochemical aspects. The cause of growth impairment in patients with XLH is not completely understood yet, thus making the study of the growth plate (GP) alterations necessary. New treatment strategies targeting FGF23 have shown promising results in normalizing the growth velocity and improving the skeletal effects of XLH patients. However, further studies are necessary to evaluate how this treatment affects the GP as well as its long-term effects and the impact on adult height.
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Raquitismo Hipofosfatémico Familiar/patología , Factor-23 de Crecimiento de Fibroblastos/metabolismo , Placa de Crecimiento/patología , Endopeptidasa Neutra Reguladora de Fosfato PHEX/genética , Animales , Anticuerpos Neutralizantes/farmacología , Anticuerpos Neutralizantes/uso terapéutico , Calcitriol/farmacología , Calcitriol/uso terapéutico , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Raquitismo Hipofosfatémico Familiar/genética , Factor-23 de Crecimiento de Fibroblastos/efectos de los fármacos , Hormona del Crecimiento/farmacología , Hormona del Crecimiento/uso terapéutico , Placa de Crecimiento/efectos de los fármacos , Placa de Crecimiento/crecimiento & desarrollo , Humanos , Regulación hacia ArribaRESUMEN
BACKGROUND AND AIMS: The interferon-induced transmembrane proteins play an important antiviral role by preventing viruses from traversing the cellular lipid bilayer. IFITM3 gene variants have been associated with the clinical response to influenza and other viruses. Our aim was to determine whether the IFITM3 rs12252 polymorphism was associated with the risk of developing severe symptoms of COVID-19 in our population. METHODS: A total of 288 COVID-19 patients who required hospitalization (81 in the intensive care unit) and 440 age matched controls were genotyped with a Taqman assay. Linear regression models were used to compare allele and genotype frequencies between the groups, correcting for age and sex. RESULTS: Carriers of the minor allele frequency (rs12252 C) were significantly more frequent in the patients compared to controls after correcting by age and sex (p = 0.01, OR = 2.02, 95%CI = 1.19-3.42). This genotype was non-significantly more common among patients who required ICU. CONCLUSIONS: The IFITM3 rs12252 C allele was a risk factor for COVID-19 hospitalization in our Caucasian population. The extent of the association was lower than the reported among Chinese, a population with a much higher frequency of the risk allele.
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Pueblo Asiatico/genética , COVID-19/genética , Proteínas de la Membrana/genética , Proteínas de Unión al ARN/genética , Población Blanca/genética , Anciano , COVID-19/sangre , COVID-19/epidemiología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Modelos Lineales , Masculino , Proteínas de la Membrana/sangre , Persona de Mediana Edad , Polimorfismo Genético , Proteínas de Unión al ARN/sangre , Factores de RiesgoRESUMEN
BACKGROUND: Recent reports indicate that chronic reduction of glomerular filtration rate (GFR) is common in patients with distal renal tubular acidosis (DRTA). Factors responsible for decreased GFR need clarification. METHODS: We reviewed records of 25 patients with genetically confirmed DRTA included in the RenalTube database. Patients < 18 years at diagnosis and having at least one annual follow-up were selected and classified in two groups according to GFR ≥ 90 (normal GFR) or < 90 mL/min/1.73 m2 (low GFR) after median follow-up of 8.8 years. RESULTS: Eighteen and seven patients had normal and low GFR (X ± SEM, 121.16 ± 28.87 and 71.80 ± 10.60 mL/min/1.73 m2, respectively, p < 0.01). At diagnosis, these 2 subgroups did not differ in sex, age, underlying mutated gene, GFR, height SDS, or percentage of ultrasound nephrocalcinosis. Serum creatinine (SCr) was different but likely due to median ages of presentation being 0.6 and 4.0 in normal and low GFR patients, respectively. On the last recorded visit, no differences between both groups were found in serum bicarbonate, serum potassium, or alkali dosage. Height SDS of patients with normal GFR was - 0.15 ± 0.47 whereas it was - 1.06 ± 0.60 in the low GFR group (p = 0.27). Interestingly, 23% of the whole group had low birth weight (LBW; < 2500 g), equating to 20% and 29% in the normal and low GFR patients, respectively (p = 0.65). CONCLUSIONS: Our findings confirm the risk of kidney function reduction in patients with DRTA of pediatric age onset, suggesting that low GFR is related with less favorable growth outcome and discloses the high frequency of LBW in primary DRTA, a hitherto unrecognized feature.
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Acidosis Tubular Renal , Nefrocalcinosis , Acidosis Tubular Renal/diagnóstico , Acidosis Tubular Renal/genética , Niño , Creatinina , Tasa de Filtración Glomerular , Humanos , Riñón/diagnóstico por imagen , Nefrocalcinosis/genéticaRESUMEN
The formation of the epiphyseal bone plate, the flat bony structure that provides strength and firmness to the growth plate cartilage, was studied in the present study by using light, confocal, and scanning electron microscopy. Results obtained evidenced that this bone tissue is generated by the replacement of the lower portion of the epiphyseal cartilage. However, this process differs considerably from the usual bone tissue formation through endochondral ossification. Osteoblasts deposit bone matrix on remnants of mineralized cartilage matrix that serve as a scaffold, but also on non-mineralized cartilage surfaces and as well as within the perivascular space. These processes occur simultaneously at sites located close to each other, so that, a core of the sheet of bone is established very quickly. Subsequently, thickening and reshaping occurs by appositional growth to generate a dense parallel-fibered bone structurally intermediate between woven and lamellar bone. All these processes occur in close relationship with a cartilage but most of the bone tissue is generated in a manner that may be considered as intramembranous-like. Overall, the findings here reported provide for the first time an accurate description of the tissues and events involved in the formation of the epiphyseal bone plate and gives insight into the complex cellular events underlying bone formation at different sites on the skeleton.
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Desarrollo Óseo/fisiología , Calcificación Fisiológica , Placa de Crecimiento/crecimiento & desarrollo , Osteogénesis/fisiología , Animales , Placas Óseas , Huesos/fisiología , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Condrocitos , Placa de Crecimiento/fisiología , Humanos , Osteoblastos/fisiologíaRESUMEN
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.
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Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Hormona del Crecimiento/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/genética , Raquitismo Hipofosfatémico Familiar/genética , Raquitismo Hipofosfatémico Familiar/metabolismo , Raquitismo Hipofosfatémico Familiar/patología , Factor-23 de Crecimiento de Fibroblastos , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones NoqueadosRESUMEN
AIM: To describe incomplete distal renal tubular acidosis (iDRTA) in paediatric patients, a term used for the diagnosis of patients who do not develop spontaneous overt metabolic acidosis but are unable to acidify the urine in response to an ammonium chloride load. METHODS: Tests used to explore urinary acidification were revised. In addition, publications in English extracted from 161 entries yielded by a PubMed database search, using 'incomplete distal renal tubular acidosis' as keyword, were reviewed. RESULTS: Incomplete distal renal tubular acidosis has mostly been identified in adults with autoimmune diseases, nephrolithiasis, nephrocalcinosis and/or osteopenia. iDRTA has been reported in few paediatric patients with rickets, congenital abnormalities of kidney and urological tract and/or growth failure. The pathophysiological mechanisms potentially responsible for the defect of urinary acidification are discussed as well as the clinical and biochemical findings of iDRTA described in children. CONCLUSION: The presentation of iDRTA in children differs from adults. The clinical and biochemical features of iDRTA are not well characterised in paediatric patients. The detection of iDRTA in groups of population such as heterozygous carriers of primary DRTA gene mutations and children with hypocitraturia or hypercalciuria might be of clinical interest to better know the pathophysiology and natural history of iDRTA.
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Acidosis Tubular Renal , Cálculos Renales , Raquitismo , Acidosis Tubular Renal/diagnóstico , Adulto , Niño , Heterocigoto , Humanos , Hipercalciuria/diagnósticoRESUMEN
Chronic kidney disease (CKD) alters the morphology and function of the growth plate (GP) of long bones by disturbing chondrocyte maturation. GP chondrocytes were analyzed in growth-retarded young rats with CKD induced by adenine intake (AD), control rats fed ad libitum (C) or pair-fed with the AD group (PF), and CKD rats treated with growth hormone (ADGH). In order to study the alterations in the process of GP maturation, we applied a procedure recently described by our group to obtain high-quality three-dimensional images of whole chondrocytes that can be used to analyze quantitative parameters like cytoplasm density, cell volume, and shape. The final chondrocyte volume was found to be decreased in AD rats, but GH treatment was able to normalize it. The pattern of variation in the cell cytoplasm density suggests that uremia could be causing a delay to the beginning of the chondrocyte hypertrophy process. Growth hormone treatment appears to be able to compensate for this disturbance by triggering an early chondrocyte enlargement that may be mediated by Nkcc1 action, an important membrane cotransporter in the GP chondrocyte enlargement.
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Condrocitos/metabolismo , Hormona del Crecimiento/metabolismo , Placa de Crecimiento/metabolismo , Animales , Ciclo Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Condrocitos/fisiología , Condrogénesis/efectos de los fármacos , Femenino , Hormona del Crecimiento/farmacología , Placa de Crecimiento/efectos de los fármacos , Hormona de Crecimiento Humana/metabolismo , Hipertrofia/tratamiento farmacológico , Hipertrofia/metabolismo , Ratas , Ratas Sprague-Dawley , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/fisiopatología , Uremia/metabolismoRESUMEN
BACKGROUND: Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome. METHODS: We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form. RESULTS: Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (±1.16). There was an increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate. CONCLUSION: Long-term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients.
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Acidosis Tubular Renal/terapia , Pérdida Auditiva Sensorineural/terapia , Acidosis Tubular Renal/complicaciones , Acidosis Tubular Renal/genética , Adolescente , Adulto , Anciano , Bicarbonatos/sangre , Calcio/orina , Niño , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Sordera/complicaciones , Sordera/genética , Sordera/terapia , Femenino , Estudios de Asociación Genética , Tasa de Filtración Glomerular , Pérdida Auditiva Sensorineural/complicaciones , Pérdida Auditiva Sensorineural/genética , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Mutación , Nefrocalcinosis/complicaciones , Nefrocalcinosis/genética , Nefrocalcinosis/terapia , Enfermedades Raras/complicaciones , ATPasas de Translocación de Protón Vacuolares/genética , Adulto JovenRESUMEN
OBJECTIVE: To find out if cardiovascular alterations are present in pediatric patients with X-linked hypophosphatemia (XLH). STUDY DESIGN: Multicentre prospective clinical study on pediatric patients included in the RenalTube database ( www.renaltube.com ) with genetically confirmed diagnosis of XLH by mutations in the PHEX gene. The study's protocol consisted of biochemical work-up, 24-h ambulatory blood pressure monitoring (ABPM), carotid ultrasonography, and echocardiogram. All patients were on chronic treatment with phosphate supplements and 1-hydroxy vitamin D metabolites. RESULTS: Twenty-four patients (17 females, from 1 to 17 years of age) were studied. Serum concentrations (X ± SD) of phosphate and intact parathyroid hormone were 2.66 ± 0.60 mg/dl and 58.3 ± 26.8 pg/ml, respectively. Serum fibroblast growth factor 23 (FGF23) concentration was 278.18 ± 294.45 pg/ml (normal < 60 pg/ml). Abnormally high carotid intima media thickness was found in one patient, who was obese and hypertensive as revealed by ABPM, which disclosed arterial hypertension in two other patients. Z scores for echocardiographic interventricular septum end diastole and left ventricular posterior wall end diastole were + 0.77 ± 0.77 and + 0.94 ± 0.86, respectively. Left ventricular mass index (LVMI) was 44.93 ± 19.18 g/m2.7, and four patients, in addition to the obese one, had values greater than 51 g/m2.7, indicative of left ventricular hypertrophy. There was no correlation between these echocardiographic parameters and serum FGF23 concentrations. CONCLUSIONS: XLH pediatric patients receiving conventional treatment have echocardiographic measurements of ventricular mass within normal reference values, but above the mean, and 18% have LVMI suggestive of left ventricular hypertrophy without correlation with serum FGF23 concentrations. This might indicate an increased risk of cardiovascular involvement in XLH.
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Enfermedades Cardiovasculares/etiología , Raquitismo Hipofosfatémico Familiar/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Adolescente , Niño , Preescolar , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Lactante , MasculinoRESUMEN
This corrects the article DOI: 10.1038/pr.2015.243.
RESUMEN
BACKGROUND: To evaluate whether there are differences in the phenotype of primary distal renal tubular acidosis (dRTA) patients according to the causal defective gene. METHODS: Twenty-seven non-oriental patients with genetically confirmed dRTA were grouped according to the identified underlying mutations in either ATP6V1B1 (n = 10), ATP6V0A4 (n = 12), or SLC4A1 (n = 5) gene. Demographic features, growth impairment, biochemical variables and presence of deafness, nephrocalcinosis, and urolithiasis at diagnosis were compared among the three groups. RESULTS: Patients with SLC4A1 mutations presented later than those with ATP6V1B1 or ATP6V0A4 defects (120 vs. 7 and 3 months, respectively). Hearing loss at diagnosis was present in the majority of patients with ATP6V1B1 mutations, in two patients with ATP6V0A4 mutations, and in none of cases harboring SLC4A1 mutations. Serum potassium concentration (X ± SD) was higher in SLC4A1 group (3.66 ± 0.44 mEq/L) than in ATP6V0A4 group (2.96 ± 0.63 mEq/L) (p = 0.046). There were no differences in the other clinical or biochemical variables analyzed in the three groups. CONCLUSIONS: This study indicates that non-oriental patients with dRTA caused by mutations in the SLC4A1 gene present later and have normokalemia or milder hypokalemia. Hypoacusia at diagnosis is characteristically associated with ATP6V1B1 gene mutations although it may also be present in infants with ATP6V0A4 defects. Other phenotypical manifestations do not allow predicting the involved gene.
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Acidosis Tubular Renal/genética , Pérdida Auditiva/genética , Hipopotasemia/genética , Acidosis Tubular Renal/sangre , Acidosis Tubular Renal/complicaciones , Acidosis Tubular Renal/diagnóstico , Adolescente , Edad de Inicio , Proteína 1 de Intercambio de Anión de Eritrocito/genética , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Pérdida Auditiva/diagnóstico , Humanos , Hipopotasemia/sangre , Hipopotasemia/diagnóstico , Lactante , Masculino , Mutación , Fenotipo , Potasio/sangre , Índice de Severidad de la Enfermedad , ATPasas de Translocación de Protón Vacuolares/genéticaRESUMEN
BackgroundIn a model of growth retardation secondary to chronic kidney disease (CKD) induced by adenine, this study explores the effects of growth hormone (GH) therapy on growth plate and mineral metabolism.MethodsWeaning female rats receiving a 0.5% adenine diet during 21 days, untreated (AD) or treated with GH (ADGH) for 1 week, were compared with control rats receiving normal diet, either ad libitum or pair-fed with AD animals. AD and ADGH rats had similarly elevated serum concentrations of urea nitrogen, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23).ResultsUremia induced by adenine caused growth retardation and disturbed growth cartilage chondrocyte hypertrophy. We demonstrated marked expression of aquaporin 1 in the growth plate, but its immunohistochemical signal and the expression levels of other proteins potentially related with chondrocyte enlargement, such as Na-K-2Cl cotransporter, insulin-like growth factor 1 (IGF-1), and IGF-1 receptor, were not different among the four groups of rats. The distribution pattern of vascular endothelial growth factor was also similar. AD rats developed femur bone structure abnormalities analyzed by micro-computerized tomography.ConclusionGH treatment accelerated longitudinal growth velocity, stimulated the proliferation and enlargement of chondrocytes, and did not modify the elevated serum PTH or FGF23 concentrations or the abnormal bone structure.
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Hormona del Crecimiento/farmacología , Placa de Crecimiento/efectos de los fármacos , Minerales/metabolismo , Uremia/metabolismo , Adenina , Animales , Nitrógeno de la Urea Sanguínea , Condrocitos/metabolismo , Femenino , Factores de Crecimiento de Fibroblastos/sangre , Inflamación , Hormona Paratiroidea/sangre , Ratas , Ratas Sprague-Dawley , Uremia/inducido químicamente , Factor A de Crecimiento Endotelial Vascular/metabolismo , Microtomografía por Rayos XRESUMEN
This corrects the article DOI: 10.1038/pr.2017.95.