RESUMEN
OBJECTIVES: Tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR) is used to evaluate renal phosphate reabsorption and it is a useful tool for the differential diagnosis of hypophosphatemic syndromes. TmP/GFR is typically calculated from fasting plasma and second morning void urine samples, obtained 2â¯h after the first void (TmP/GFR 2â¯h). The purpose of this study was to evaluate if TmP/GFR calculated from 24â¯h urine collection (TmP/GFR 24â¯h) can be used as an alternative for TmP/GFR 2â¯h in patients with urine phosphate wasting. METHODS: We enrolled adult patients with X-linked hypophosphatemia (XLH) or tumor-induced osteomalacia (TIO). All patients underwent blood and urine sample collections, to calculate TmP/GFR 24â¯h and TmP/GFR 2â¯h. RESULTS: Twenty patients (17 XLH and 3 TIO), aged 24-78 years, were included. All patients had low TmP/GFR 2â¯h (0.35â¯mmol/L, IQR 0.24-0.47â¯mmol/L) and TmP/GFR 24â¯h (0.31â¯mmol/L, IQR 0.22-0.43â¯mmol/L). The concordance correlation coefficient between TmP/GFR 2â¯h and TmP/GFR 24â¯h was 0.86 (95â¯% CI: 0.69-0.93), with a systematic bias of 0.05â¯mmol/L (95â¯% limits of agreement: -0.10 to 0.20). Furthermore, in 70â¯% (i.e., 14 patients out of 20) and 80â¯% (i.e., 16 patients out of 20) of cases the difference between TmP/GFR 2â¯h and TmP/GFR 24â¯h was within ±30â¯% and ±35â¯%, respectively. CONCLUSIONS: Despite TmP/GFR 2 and 24â¯h show a relatively suboptimal agreement, the difference between the two parameters appears to be small and not clinically significant in the setting of adult patients with FGF23-dependent urine phosphate wasting and secondary hypophosphatemia.
Asunto(s)
Factor-23 de Crecimiento de Fibroblastos , Osteomalacia , Fosfatos , Toma de Muestras de Orina , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Raquitismo Hipofosfatémico Familiar/orina , Raquitismo Hipofosfatémico Familiar/diagnóstico , Tasa de Filtración Glomerular , Hipofosfatemia/orina , Hipofosfatemia/diagnóstico , Túbulos Renales/metabolismo , Osteomalacia/orina , Osteomalacia/diagnóstico , Síndromes Paraneoplásicos/orina , Síndromes Paraneoplásicos/diagnóstico , Fosfatos/orina , Toma de Muestras de Orina/métodosRESUMEN
Dentin matrix protein-1 (DMP1) or phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) inactivation results in elevation of the phosphaturic hormone fibroblast growth factor (FGF)-23, leading to hypophosphatemia, aberrant vitamin D metabolism, and rickets/osteomalacia. Compound mutant Phex-deficient Hyp and Dmp1(ko) mice exhibit nonadditive phenotypes, suggesting that DMP1 and PHEX may have interdependent effects to regulate FGF23 and bone mineralization. To determine the relative importance of DMP1 and PHEX in regulating FGF23 and mineralization, we tested whether the transgenic expression of full-length [Dmp1(Tg(full-length))] or C-terminal Dmp1 [Dmp1(Tg(57kDa))] could rescue the phenotype of Hyp mice. We found that Dmp1(ko) and Hyp mice have similar phenotypes characterized by decreased cortical bone mineral density (-35% vs. wild type, P < 0.05) and increased serum FGF23 levels (~12-fold vs. wild type, P < 0.05). This was significantly corrected by the overexpression of either the full-length or the C-terminal transgene in Dmp1(ko) mice. However, neither of the transgenes rescued the Hyp mice phenotype. Hyp/Dmp1(Tg(full-length)) and Hyp mice were similar, but Hyp/Dmp1(Tg(57 kDa)) mice exhibited worsening of osteomalacia (-20% cortical bone mineral density) in association with increased serum FGF23 levels (+2-fold) compared with Hyp mice. Bone FGF23 mRNA expression was decreased and a 2-fold increase in the ratio of the full-length/degraded circulating FGF23 was observed, indicating that degradation of FGF23 was impaired in Hyp/Dmp1(Tg(57 kDa)) mice. The paradoxical effects of the C-terminal Dmp1 transgene were observed in Hyp/Dmp1(Tg(57 kDa)) but not in Dmp1(Tg(57 kDa)) mice expressing a functional PHEX. These findings indicate a functional interaction between PHEX and DMP1 to regulate bone mineralization and circulating FGF23 levels and for the first time demonstrate effects of the C-terminal DMP1 to regulate FGF23 degradation.
Asunto(s)
Proteínas de la Matriz Extracelular/química , Proteínas de la Matriz Extracelular/metabolismo , Raquitismo Hipofosfatémico Familiar/patología , Factores de Crecimiento de Fibroblastos/metabolismo , Fragmentos de Péptidos/metabolismo , Animales , Peso Corporal , Calcificación Fisiológica , Raquitismo Hipofosfatémico Familiar/sangre , Raquitismo Hipofosfatémico Familiar/diagnóstico por imagen , Raquitismo Hipofosfatémico Familiar/orina , Fémur/diagnóstico por imagen , Fémur/patología , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/genética , Regulación de la Expresión Génica , Ratones , Ratones Noqueados , Modelos Biológicos , Endopeptidasa Neutra Reguladora de Fosfato PHEX/metabolismo , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transcripción Genética , Microtomografía por Rayos XRESUMEN
We report a case of a male aged 50 years who consulted for renal disease recurrent lithiasis and nephrocalcinosis. The clinical examination showed external signs of rickets/osteomalacia and biochemical data as well as a severe loss of renal phosphate with hypophosphatemia, normal 25 OH vitamin D, high 1,25 OH vitamin D and hypercalciuria. Parathyroid hormone was low and renal ultrasound confirmed the existence of severe bilateral medullary nephrocalcinosis. They also found incipient chronic renal failure and incomplete renal tubular acidosis, both secondary to nephrocalcinosis and unrelated to the underlying disease. The molecular study found a change in homozygosity in intron 5 of gene SLC34A3 (NM_080877.2:c[ 448 +5G>A] + [ 448 +5G>A] ). His three children were carriers of the same variant in heterozygosis and although they were clinically asymptomatic two of them had hypercalciuria. All these data suggest that the patient had hereditary hypophosphataemic rickets with hypercalciuria (HHRH) secondary to an alteration in the sodium dependent phosphate cotransporter located in proximal tubule (NaPi-IIc). The HHRH is transmitted by autosomal recessive inheritance and is an extremely rare form of hypophosphatemic rickets. The diagnosis and treatment are essential to prevent bone sequelae of rickets and nephrocalcinosis. A correct differential diagnosis with other forms of hypophosphatemic rickets has implications on the treatment, as the management based only on phosphorus supplementation usually corrects all clinical and biochemical abnormalities, except for the loss of phosphorus in the urine. The exogenous supply of calcitriol, as advised in other hypophosphatemic rickets, may induce renal calcium deposits and nephrocalcinosis and worsens the prognosis.
Asunto(s)
Raquitismo Hipofosfatémico Familiar/orina , Hipercalciuria/etiología , Nefrocalcinosis/etiología , Nefrolitiasis/etiología , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/genética , 25-Hidroxivitamina D 2/sangre , Acidosis Tubular Renal/etiología , Calcitriol/sangre , Calcio/análisis , Membrana Celular/metabolismo , Raquitismo Hipofosfatémico Familiar/genética , Genotipo , Humanos , Intrones/genética , Riñón/química , Riñón/patología , Fallo Renal Crónico/etiología , Túbulos Renales Proximales/metabolismo , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Fósforo/metabolismo , PronósticoRESUMEN
X-linked hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D-resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 (FGF23) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti-FGF23 antibodies to inhibit endogenous FGF23 action. A single injection of the antibodies corrected the hypophosphatemia and inappropriately normal serum 1,25-dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium-phosphate cotransporter and 25-hydroxyvitamin-D-1alpha-hydroxylase and a suppressed expression of 24-hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of FGF23 underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the FGF23 antibodies for XLH.
Asunto(s)
Anticuerpos/uso terapéutico , Raquitismo Hipofosfatémico Familiar/complicaciones , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Factores de Crecimiento de Fibroblastos/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X , Osteomalacia/complicaciones , Osteomalacia/tratamiento farmacológico , Envejecimiento/efectos de los fármacos , Envejecimiento/patología , Animales , Anticuerpos/administración & dosificación , Anticuerpos/farmacología , Peso Corporal/efectos de los fármacos , Raquitismo Hipofosfatémico Familiar/sangre , Raquitismo Hipofosfatémico Familiar/orina , Femenino , Factor-23 de Crecimiento de Fibroblastos , Placa de Crecimiento/efectos de los fármacos , Placa de Crecimiento/patología , Inmunohistoquímica , Inyecciones Subcutáneas , Masculino , Ratones , Osteomalacia/sangre , Osteomalacia/orina , Tibia/efectos de los fármacos , Tibia/patología , Factores de Tiempo , Vitamina D/metabolismoRESUMEN
We recently reported the urinary prostaglandin E(2)/creatinine ratio (PGE(2)/Cr) was markedly elevated in Hyp mice, the animal model for X-linked hypophosphatemia, compared with control mice. We provided evidence for altered prostaglandin production mediating the phosphaturia and that indomethacin decreases urinary phosphate excretion in Hyp mice but not control mice. To determine the levels of urinary PGE(2)/Cr, the safety and efficacy of indomethacin on phosphate excretion in children with hypophosphatemic rickets (HPR), a prospective clinical trial was performed in 16 children with HPR and 16 age- and gender-matched healthy controls. Urinary PGE(2)/Cr excretion was determined on a 24 h timed urine collection. A randomized cross over, placebo versus indomethacin, clinical trial was performed in the 16 children with HPR. There was no difference in urinary PGE(2)/Cr excretion between controls and patients with HPR. In children with HPR, indomethacin treatment for 3 mo had no significant effect on serum phosphorus or urinary phosphate excretion. In conclusion, urinary prostaglandin excretion is similar in children with HPR compared with controls. Indomethacin had no significant effect on serum phosphorus or urinary phosphate excretion in children with HPR.