RESUMO
RESUMEN El manejo de la hiperfosfatemia de los pacientes con insuficiencia renal crónica en diálisis permanece como un desafío. A pesar de utilizar un enfoque multifacético que incluye la restricción dietética, la remoción de fósforo por la diálisis y el uso de quelantes de fósforo, esta estrategia múltiple no logra reducir los niveles de fósforo en más de 2 mg/dl. El control de fósforo de los pacientes en diálisis es fundamental en razón de la relación monotónica entre los niveles séricos de fosfato y el incremento del riesgo cardiovascular. Por lo tanto, hay una necesidad de explorar nuevas estrategias para reducir los niveles séricos de fosfato a niveles normales. Recientes avances en nuestra compresión de los mecanismos que subyacen a la homeostasis del fósforo sugieren que el transporte gastrointestinal del fósforo podría ser un objetivo. Recientemente se han desarrollado inhibidores de los cotransportadores sodio fosfato del intestino y se ha revalorizado el uso de la nicotinamida, en su formulación de liberación prolongada, que también actuaria por ese mecanismo. También se han drogas como el tenapanor, que inhibiendo el intercambiador sodio/hidrogeno isoforma 3 del enterocito, disminuyen la absorción paracelular de fósforo.
ABSTRACT Management of hyperphosphatemia in patients with chronic renal failure on dialysis remains challenging. Despite using a multifaceted approach that includes dietary restriction, phosphorus removal by dialysis, and phosphate binders, these multiple strategies fail to reduce phosphorus levels by more than 2 mg/dL. Phosphorus control in dialysis patients is essential due to the monotonic relationship between serum phosphate levels and increased cardiovascular risk. Therefore, there is a need to explore new strategies to reduce serum phosphate levels to normal levels. Recent advances in understanding the mechanisms underlying phosphorus homeostasis suggest that the gastrointestinal transport of phosphorus could be a target. Inhibitors of intestinal sodium phosphate cotransporters recently developed, and using of nicotinamide, in its prolonged release formulation, which would also act by this mechanism, has been revalued. There have also been drugs such as tenapanor, which, by inhibiting the isoform three sodium/hydrogen exchanger of the enterocyte, decreases the paracellular absorption of phosphorus.
RESUMO
The serum phosphorus level is maintained through a complex interplay between intestinal absorption, exchange intracellular and bone storage pools, and renal tubular reabsorption. The kidney plays a major role in regulation of phosphorus homeostasis by renal tubular reabsorption. Type IIa and type IIc Na+/Pi transporters are important renal Na+-dependent inorganic phosphate (Pi) transporters, which are expressed in the brush border membrane of proximal tubular cells. Both are regulated by dietary Pi intake, vitamin D, fibroblast growth factor 23 (FGF23) and parathyroid hormone. The expression of type IIa Na+/Pi transporter result from hypophosphatemia quickly. However, type IIc appears to act more slowly. Physiological and pathophysiological alteration in renal Pi reabsorption are related to altered brush-border membrane expression/content of the type II Na+/Pi cotransporter. Many studies of genetic and acquired renal phosphate wasting disorders have led to the identification of novel genes. Two novel Pi regulating genes, PHEX and FGF23, play a role in the pathophysiology of genetic and acquired renal phosphate wasting disorders and studies are underway to define their mechanism on renal Pi regulation. In recent studies, sodium-hydrogen exchanger regulatory factor 1 (NHERF1) is reported as another new regulator for Pi reabsorption mechanism.
Assuntos
Fatores de Crescimento de Fibroblastos , Homeostase , Hipofosfatemia , Absorção Intestinal , Rim , Membranas , Microvilosidades , Hormônio Paratireóideo , Fosfoproteínas , Fósforo , Trocadores de Sódio-Hidrogênio , Proteínas Cotransportadoras de Sódio-Fosfato , Vitamina DRESUMO
Objective: To prepare type III sodium-phosphate cotransporter (NaPi-III) siRNA-loaded chitosan microspheres and to evaluate their physico-chemical properties and siRNA release in vitro. Methods: NaPi- III siRNA was loaded into chitosan microspheres by using the complex coacervation method. The structure of the nanoparticles was observed under scanning electron microscope and their diameter distribution was measured by a laser grain analyzer. RNase assay was used to detect the efficacy of anoparticles in prevention of siRNA from degradation. Ultraviolet spectrophotometry and HPLC technique were used to determine the entrapment efficiency, loading capacity, and siRNA releasing rate in vitro. Results: The chitosan nanoparticles loaded with NaPi-III siRNA were successfully prepared. The nanoparticles were spherical in shape and were well distributed, with an average diameter of 173 nm. After RNase treatment, D260 rose more slowly in chitosan nanoparticles-based siRNA suspension than in simple NaPi-III siRNA solution(P<0.05, t = 4.32). Loading capacity of the nanoparticles was 28.1 %, the encapsulation efficiency was 73.07 %, and the total releasing rate of NaPi-III siRNA was less than 20% within 12 hours. Conclusion: Chitosan nanoparticles loaded with NaPi-III siRNA have been prepared through a complex coacervation method. The particles have high encapsulation efficency and good stability and are homogeneous in size. They can obviously delay the release of NaPi-III siRNA in vitro and therefore prevent NaPi-III siRNA from degradation.
RESUMO
Objective:To prepare type Ⅲ sodium-phosphate cotransporter(NaPi-Ⅲ) siRNA-loaded chitosan microspheres and to evaluate their physico-chemical properties and siRNA release in vitro.Methods: NaPi-Ⅲ siRNA was loaded into chitosan microspheres by using the complex coacervation method.The structure of the nanoparticles was observed under scanning electron microscope and their diameter distribution was measured by a laser grain analyzer.RNase assay was used to detect the efficacy of anoparticles in prevention of siRNA from degradation.Ultraviolet spectrophotometry and HPLC technique were used to determine the entrapment efficiency,loading capacity,and siRNA releasing rate in vitro.Results: The chitosan nanoparticles loaded with NaPi-Ⅲ siRNA were successfully prepared.The nanoparticles were spherical in shape and were well distributed,with an average diameter of 173 nm.After RNase treatment,D_(260) rose more slowly in chitosan nanoparticles-based siRNA suspension than in simple NaPi-Ⅲ siRNA solution(P