A correlation between decreased parathyroid α-Klotho and fibroblast growth factor receptor 1 expression with pathological category and parathyroid gland volume in dialysis patients
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In order to evaluate the effect of dietary phosphorus (P) restriction on the pathogenesis of secondary hyperparathyroidism (2°HPT) in chronic renal failure (CRF), we studied parathyroid function and parathyroid cell proliferation in 5/6 nephrectomized rats (CRF rats) fed with three different dietary P contents (0.6, 0.3 and 0.1%). Four weeks after 5/6 nephrectomy, serum immuno-reactive parathyroid hormone (PTH) concentration, PTH mRNA level in parathyroid glands and the size of parathyroid glands were increased in CRF rats compared to those of sham-operated rats when both groups of rats were fed with normal P (0.6%) diet. These changes were not accompanied by any detectable changes of serum concentrations of calcium (Ca), inorganic phosphate (Pi) or calcitriol. In contrast, such evidence of 2°HPT was obliterated in CRF rats fed with 0.3 or 0.1% P diet. In rats fed with 0.3% P diet, serum concentrations of Ca, Pi, and calcitriol were not different from those of sham-operated rats or from CRF rats fed with normal P diet. In contrast, serum Ca and calcitriol concentrations increased and serum Pi decreased in CRF rats fed with 0.1% P diet. These data suggest that 2°HPT can be completely prevented at the levels of PTH secretion, synthesis and parathyroid cell proliferation by mild dietary P restriction (0.3%) alone, and that such effects may not depend upon the changes in serum concentrations of Ca, Pi or calcitriol, but may depend on reduced dietary P content per se. Thus, mild dietary P restriction from the early stage of CRF may be clinically effective for the prevention of 2°HPT.
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Secondary hyperparathyroidism (sHPT) is known as a very common complication in patients with chronic kidney disease, and G-protein-coupled calcium-sensing receptor (CaSR), Vitamin D receptor (VDR) and Fibroblast growth factor receptor (FGFR)/Klotho complexes seem to be involved in its development.Hyperplastic parathyroid glands from 70 sHPT patients and normal parathyroid tissue from 7 patients were obtained during parathyroidectomy. Conventional morphological and immunohistochemical analysis of parathyroid glands was performed after dividing each slide in a 3x3 array.The presence of lipocytes in the normal parathyroid gland and tissue architecture (nodal in patients with sHPT) allows for discrimination between normal parathyroid glands and parathyroid glands of patients with sHPT. Protein expression of Klotho, FGFR, CaSR and VDR was higher in the normal parathyroid glands compared to the sHPT group (p<0.001, p=0.07, p =0.01 and p=0.001). The variability of each protein expression within each tissue slide was high. Therefore correlations between the different immunohistochemical variables were analyzed for each of the nine fields and than analyzed for all patients. Using this analysis, a highly significant positive correlation could be found between the expression of FGFR and VDR (p=0.0004). Interestingly, in terms of VDR we found a shift to a more mixed nuclear/cytoplasmic staining in the HPT group compared to normal parathyroid gland cells, which showed solitary nuclear staining for VDR (p>0.05).CaSR, VDR and an impaired Klotho-FGFR-axis seem to be the major players in the development of sHPT. Whether the detected correlation between FGFR and VDR and the shift to a more mixed nuclear/cytoplasmic staining of VDR will yield new insights into the pathogenesis of the disease has to be evaluated in further studies.
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Significance Secondary hyperparathyroidism (SHPT) is a severe consequence of chronic kidney disease. A better understanding of the mechanisms controlling the progression of SHPT and the regulation of parathyroid hormone (PTH) production is clinically relevant. Utilizing parathyroid gland (PTG)-specific knockout mouse models, we demonstrated calcium-sensing receptor (CaSR) and Klotho together regulate PTH synthesis and PTG growth, and that Klotho contributes to PTH suppression in the absence of CaSR. Klotho exerts an independent function in mediating PTH secretion under chronic hypocalcemia and in suppressing PTG cell proliferation. Moreover, the results revealed a previously unidentified interaction between PTG-expressed CaSR and Klotho. These findings highlight the essential and interrelated roles for CaSR and Klotho to prevent parathyroid hyperplasia, suggesting potential treatment strategies to control PTH synthesis and hyperparathyroidism.
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The parathyroid gland plays a central role in the regulation of mineral metabolism. In patients with chronic kidney disease (CKD), circulating levels of parathyroid hormone (PTH) are progressively increased as kidney function declines, as a result of phosphate retention, hypocalcemia, decreased production of 1,25-dihydroxyvitamin D [1,25(OH)2D], endogenous changes within the parathyroid gland, and skeletal resistance to the actions of PTH. In addition, the identification of fibroblast growth factor 23 (FGF23) and its cofactor Klotho offers important implications for the deeper understanding of disordered mineral metabolism in CKD. In early CKD, increased FGF23 to maintain neutral phosphate balance results in suppression of renal 1,25(OH)2D production and thereby triggers the early development of secondary hyperparathyroidism. FGF23 also acts directly on the parathyroid to decrease PTH synthesis and secretion, but this effect is blunted in advanced stages of CKD, due to decreased expression of the Klotho-FGF receptor 1 complex and increased concentrations of C-terminal FGF23 that competes with full-length FGF23 for binding to the receptor complex. Recent clinical studies also reported that high levels of FGF23 are associated with morbidity and mortality as well as treatment resistance to active vitamin D, suggesting the potential of FGF23 as a novel biomarker to guide treatment of disordered phosphate metabolism in CKD. This review will discuss the pathogenesis of secondary hyperparathyroidism, particularly focusing on the emerging role of the FGF23-Klotho axis in patients with CKD.
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Chronic kidney disease (CKD) is associated with a mineral and bone disorder (CKD-MBD) which starts early in the course of the disease and worsens with its progression. The main initial serum biochemistry abnormalities are increases in fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) and decreases in 1,25 dihydroxy vitamin D (calcitriol) and soluble α-Klotho (Klotho), allowing serum calcium and phosphate to stay normal. Subsequently, serum 25 hydroxy vitamin D (calcidiol) decreases and in late CKD stages hyperphosphatemia develops in the majority of patients. Serum calcium may stay normal, decrease, or increase. More recent reports showed that sclerostin, Dickkopf-1, and activin A also play an important role in the pathogenesis of CKD-MBD. Both the synthesis and the secretion of PTH are continuously stimulated in the course of CKD, resulting in secondary hyperparathyroidism. In addition to the above systemic disturbances, downregulation of vitamin D receptor, calcium-sensing receptor, and Klotho expression in parathyroid tissue further enhances PTH overproduction. Last but not least, miRNAs have also been shown to be involved in the hyperparathyroidism of CKD. The chronic stimulation of parathyroid secretory function is not only characterized by a progressive rise in serum PTH but also by parathyroid gland hyperplasia. It results from an increase in parathyroid cell proliferation which is not fully compensated by a concomitant increase in parathyroid cell apoptosis. Parathyroid hyperplasia is initially of the diffuse, polyclonal type. In late CKD stages it often evolves towards a nodular, monoclonal or multiclonal type of growth. Enhanced parathyroid expression of transforming growth factor-α and its receptor, the epidermal growth factor receptor, is involved in polyclonal hyperplasia. Chromosomal changes have been found to be associated with clonal outgrowth in some, but not the majority of benign parathyroid tumors removed from patients with end-stage kidney disease. In initial CKD stages skeletal resistance to the action of PTH may explain why low bone turnover predominates in a significant proportion of patients, together with other conditions inhibiting bone turnover such as reduced calcitriol levels, sex hormone deficiency, diabetes, Wnt inhibitors, and uremic toxins. High turnover bone disease (osteitis fibrosa) occurs only later on, when increased serum PTH levels are able to overcome skeletal PTH resistance. The diagnosis of secondary uremic hyperparathyroidism and osteitis fibrosa relies mainly on serum biochemistry. X-ray and other imaging methods of the skeleton provide diagnostically relevant information only in severe forms. From a therapeutic point of view, it is important to prevent the development of secondary hyperparathyroidism as early as possible in the course of CKD. A variety of prophylactic and therapeutic approaches are available, as outlined in the final part of the chapter. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG .
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