Analysis of α-Klotho, Fibroblast Growth Factor-, Vitamin-D and Calcium-Sensing Receptor in 70 Patients with Secondary Hyperparathyroidism

Abstract

Background/Aims: 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. Methods: 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. Results: 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). Conclusions: 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.

Influence of Parathyroidectomy on Bone Metabolism and Bone Pain in Patients with Secondary Hyperparathyroidism

“…The elevated Klotho levels in our sHPT patients prior to surgery were similar to those observed by Takahashi et al [55]. However, decreased Klotho levels were reported in patients with sHPT in another trial [56]. In contrast to our results, several studies reported a decrease in Klotho after PTX [54, 55].…”

Interrelated role of Klotho and calcium-sensing receptor in parathyroid hormone synthesis and parathyroid hyperplasia

“…Previous studies showed Klotho and CaSR expression were significantly decreased in PTGs of PHTP, SHPT patients, patients after kidney transplantation, and those with end-stage renal disease (55)(56)(57). We could demonstrate a binding interaction between Klotho and CaSR that might play a synergistic effect in controlling PTH synthesis and glandular hyperplasia.…”

Expression of p53, Ki67, epidermal growth factor receptor, transforming growth-factorα, and p21 in primary and secondary hyperparathyroidism

“…These authors also found that cyclin D1 expression was greatly increased and correlated with adenoma weight, implying a potential role for CD1 in adenoma growth, and differential clinical expression of PH. According to Latus et al .,[ 18 ] CaSR, VDR, and an impaired Klotho-FGFR-axis seem to be the major players in the development of SH.…”